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NEJM Readers’ Choice Clinical Care Collection

A COLLECTION OF THE MOST POPULAR CLINICAL CARE ARTICLES OF 2013

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PERSPECTIVE

Dead Man Walking

ORIGINAL ARTICLE

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

ORIGINAL ARTICLE

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

REVIEW ARTICLE

Critical Care Medicine: Severe Sepsis and Septic Shock

CLINICAL PRACTICE

Vitamin B12 Deficiency

CLINICAL PRACTICE

Infective Endocarditis

CLINICAL PRACTICE

Herpes Zoster

CLINICAL PRACTICE

Carotid Stenosis

CLINICAL PROBLEM-SOLVING

A Patient with Syncope

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 23-2013: A 54-Year-Old Woman with Abdominal Pain, Vomiting, and Confusion

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november 14, 2013Perspective

“Shocked” wouldn’t be accurate, since we were accus

tomed to our uninsured patients’ receiving inadequate medical care. “Saddened” wasn’t right, either, only pecking at the edge of our response. And “disheartened” just smacked of victimhood. After hearing this story, we were neither shocked nor saddened nor disheartened. We were simply appalled.

We met Tommy Davis in our hospital’s clinic for indigent persons in March 2013 (the name and date have been changed to protect the patient’s privacy). He and his wife had been chronically uninsured despite working fulltime jobs and were now facing disastrous consequences.

The week before this appointment, Mr. Davis had come to our emergency department with abdominal pain and obstipation. His examination, laboratory tests, and CT scan had cost him $10,000 (his entire life savings), and at evening’s end he’d been sent home with a diagnosis of metastatic colon cancer.

The year before, he’d had similar symptoms and visited a pri

mary care physician, who had taken a cursory history, told Mr. Davis he’d need insurance to be adequately evaluated, and billed him $200 for the appointment. Since Mr. Davis was poor and ineligible for Kentucky Medicaid, however, he’d simply used enemas until he was unable to defecate. By the time of his emergency department evaluation, he had a fully obstructed colon and widespread disease and chose to forgo treatment.

Mr. Davis had had an inkling that something was awry, but he’d been unable to pay for an evaluation. As his wife sobbed next to him in our examination room, he recounted his months of weight loss, the unbearable pain of his bowel movements, and his gnawing suspicion that he had cancer. “If we’d found it sooner,” he contended, “it would have made a difference. But now I’m just a dead man walking.”

For many of our patients, poverty alone limits access to care. We recently saw a man with AIDS and a fullbody rash who couldn’t afford bus fare to a dermatology appointment. We sometimes pay

for our patients’ medications because they are unable to cover even a $4 copayment. But a fair number of our patients — the medical “havenots” — are denied basic services simply because they lack insurance, and our country’s response to this problem has, at times, seemed toothless.

In our clinic, uninsured patients frequently find necessary care unobtainable. An obese 60yearold woman with symptoms and signs of congestive heart failure was recently evaluated in the clinic. She couldn’t afford the echocardiogram and evaluation for ischemic heart disease that most internists would have ordered, so furosemide treatment was initiated and adjusted to relieve her symptoms. This past spring, our colleagues saw a woman with a newly discovered lung nodule that was highly suspicious for cancer. She was referred to a thoracic surgeon, but he insisted that she first have a PET scan — a test for which she couldn’t possibly pay.

However unconscionable we may find the story of Mr. Davis, a U.S. citizen who will die because

Dead Man WalkingMichael Stillman, M.D., and Monalisa Tailor, M.D.

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he was uninsured, the literature suggests that it’s a common tale. A 2009 study revealed a direct correlation between lack of insurance and increased mortality and suggested that nearly 45,000 American adults die each year because they have no medical coverage.1 And although we can’t confidently argue that Mr. Davis would have survived had he been insured, research suggests that possibility; formerly uninsured adults given access to Oregon Medicaid were more likely than those who remained uninsured to have a usual place of care and a personal physician, to attend outpatient medical visits, and to receive recommended preventive care.2 Had Mr. Davis been insured, he might well have been offered timely and appropriate screening for colorectal cancer, and his abdominal pain and obstipation would surely have been urgently evaluated.

Elected officials bear a great deal of blame for the appalling vulnerability of the 22% of American adults who currently lack insurance. The Affordable Care Act (ACA) — the only legitimate legislative attempt to provide nearuniversal health coverage — remains under attack from some members of Congress, and our own two senators argue that enhancing marketplace competition and enacting tort reform will provide security enough for our nation’s poor.

In discussing (and grieving over) what has happened to Mr. Davis and our many clinic patients whose health suffers for lack of insurance, we have considered our own obligations. As some congresspeople attempt to defund Obamacare, and as some states’ governors and attorneys general deliberate over whether to implement health insurance exchanges

and expand Medicaid eligibility, how can we as physicians ensure that the needs of patients like Mr. Davis are met?

First, we can honor our fundamental professional duty to help. Some have argued that the onus for providing access to health care rests on society at large rather than on individual physicians,3 yet the Hippocratic Oath compels us to treat the sick according to our ability and judgment and to keep them from harm and injustice. Even as we continue to hope for and work toward a future in which all Americans have health insurance, we believe it’s our individual professional responsibility to treat people in need.

Second, we can familiarize ourselves with legislative details and educate our patients about proposed health care reforms. During our appointment with Mr. Davis, he worried aloud that under the ACA, “the government would tax him for not having insurance.” He was unaware (as many of our poor and uninsured patients may be) that under that law’s final rule, he and his family would meet the eligibility criteria for Medicaid and hence have access to comprehensive and affordable care.

Finally, we can pressure our professional organizations to demand health care for all. The American College of Physicians, the American Medical Association, and the Society of General Internal Medicine have endorsed the principle of universal health care coverage yet have generally remained silent during years of political debate. Lack of insurance can be lethal, and we believe our professional community should treat inaccessible coverage as a public health catastrophe and stand behind people who are at risk.

Seventy percent of our clinic

patients have no health insurance, and they are all frighteningly vulnerable; their care is erratic, they are disqualified from receiving certain preventive and screening measures, and their lack of resources prevents them from participating in the medical system. And this is not a community or statespecific problem. A recent study showed that underinsured patients have higher mortality rates after myocardial infarction,4 and it is well documented that our country’s uninsured present with laterstage cancers and more poorly controlled chronic diseases than do patients with insurance.5 We find it terribly and tragically inhumane that Mr. Davis and tens of thousands of other citizens of this wealthy country will die this year for lack of insurance.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

From the Department of Medicine, University of Louisville School of Medicine, Louisville, KY.

This article was published on October 23, 2013, at NEJM.org.

1. Wilper AP, Woolhandler S, Lasser KE, McCormick D, Bor DH, Himmelstein DU. Health insurance and mortality in US adults. Am J Public Health 2009;99:228995.2. Finkelstein A, Taubman S, Wright B, et al. The Oregon health insurance experiment: evidence from the first year. Q J Econ 2012; 127:1057106.3. Huddle TS, Centor RM. Retainer medicine: an ethically legitimate form of practice that can improve primary care. Ann Intern Med 2011;155:6335.4. Ng DK, Brotman DJ, Lau B, Young JH. Insurance status, not race, is associated with mortality after an acute cardiovascular event in Maryland. J Gen Intern Med 2012;27:136876.5. Institute of Medicine. America’s uninsured crisis: consequences for health and health care. Consensus report. Washington, DC: National Academies Press, February 23, 2009 (http://www.iom.edu/Reports/2009/AmericasUninsuredCrisisConsequences forHealthandHealthCare.aspx).DOI: 10.1056/NEJMp1312793Copyright © 2013 Massachusetts Medical Society.

Dead Man Walking

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A bs tr ac t

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Estruch at the Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain, or at [email protected], or to Dr. Martínez-González at the Department of Preventive Medi-cine and Public Health, Facultad de Me-dicina–Clínica Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain, or at [email protected].

* The PREDIMED (Prevención con Dieta Mediterránea) study investigators are listed in the Supplementary Appendix, available at NEJM.org.

Drs. Estruch and Martínez-González con-tributed equally to this article.

This article was published on February 25, 2013, at NEJM.org.

N Engl J Med 2013;368:1279-90.DOI: 10.1056/NEJMoa1200303Copyright © 2013 Massachusetts Medical Society.

Background

Observational cohort studies and a secondary prevention trial have shown an in-verse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary preven-tion of cardiovascular events.

Methods

In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Medi-terranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational ses-sions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.

Results

A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, ac-cording to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, ver-sus the control group (109 events). No diet-related adverse effects were reported.

Conclusions

Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government’s Instituto de Salud Carlos III and oth-ers; Controlled-Trials.com number, ISRCTN35739639.)

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

Ramón Estruch, M.D., Ph.D., Emilio Ros, M.D., Ph.D., Jordi Salas-Salvadó, M.D., Ph.D., Maria-Isabel Covas, D.Pharm., Ph.D., Dolores Corella, D.Pharm., Ph.D., Fernando Arós, M.D., Ph.D.,

Enrique Gómez-Gracia, M.D., Ph.D., Valentina Ruiz-Gutiérrez, Ph.D., Miquel Fiol, M.D., Ph.D., José Lapetra, M.D., Ph.D., Rosa Maria Lamuela-Raventos, D.Pharm., Ph.D., Lluís Serra-Majem, M.D., Ph.D., Xavier Pintó, M.D., Ph.D., Josep Basora, M.D., Ph.D., Miguel Angel Muñoz, M.D., Ph.D., José V. Sorlí, M.D., Ph.D.,

José Alfredo Martínez, D.Pharm, M.D., Ph.D., and Miguel Angel Martínez-González, M.D., Ph.D., for the PREDIMED Study Investigators*

Mediterr anean Diet and Cardiovascular Events

ORIGINAL ARTICLE

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

The traditional Mediterranean diet is characterized by a high intake of olive oil, fruit, nuts, vegetables, and cereals; a

moderate intake of fish and poultry; a low intake of dairy products, red meat, processed meats, and sweets; and wine in moderation, consumed with meals.1 In observational cohort studies2,3 and a secondary prevention trial (the Lyon Diet Heart Study),4 increasing adherence to the Medi-terranean diet has been consistently beneficial with respect to cardiovascular risk.2-4 A system-atic review ranked the Mediterranean diet as the most likely dietary model to provide protection against coronary heart disease.5 Small clinical trials have uncovered plausible biologic mecha-nisms to explain the salutary effects of this food pattern.6-9 We designed a randomized trial to test the efficacy of two Mediterranean diets (one supplemented with extra-virgin olive oil and an-other with nuts), as compared with a control diet (advice on a low-fat diet), on primary cardiovas-cular prevention.

Me thods

Study design

The PREDIMED trial (Prevención con Dieta Med-iterránea) was a parallel-group, multicenter, ran-domized trial. Details of the trial design are pro-vided elsewhere.10-12 The trial was designed and conducted by the authors, and the protocol was approved by the institutional review boards at all study locations. The authors vouch for the accu-racy and completeness of the data and all analy-ses and for the fidelity of this report to the pro-tocol, which is available with the full text of this article at NEJM.org.

Supplemental foods were donated, including extra-virgin olive oil (by Hojiblanca and Patrimo-nio Comunal Olivarero, both in Spain), walnuts (by the California Walnut Commission), al-monds (by Borges, in Spain), and hazelnuts (by La Morella Nuts, in Spain). None of the sponsors had any role in the trial design, data analysis, or reporting of the results.

Participant Selection and Randomization

Eligible participants were men (55 to 80 years of age) and women (60 to 80 years of age) with no cardiovascular disease at enrollment, who had either type 2 diabetes mellitus or at least three of the following major risk factors: smoking, hypertension, elevated low-density lipoprotein

cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart dis-ease. Detailed enrollment criteria are provided in the Supplementary Appendix, available at NEJM .org. All participants provided written informed consent.

Beginning on October 1, 2003, participants were randomly assigned, in a 1:1:1 ratio, to one of three dietary intervention groups: a Mediter-ranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Randomization was per-formed centrally by means of a computer-gener-ated random-number sequence.

Interventions and Measurements

The dietary intervention8,10-13 is detailed in the Supplementary Appendix. The specific recom-mended diets are summarized in Table 1. Par-ticipants in the two Mediterranean-diet groups received either extra-virgin olive oil (approxi-mately 1 liter per week) or 30 g of mixed nuts per day (15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds) at no cost, and those in the control group received small nonfood gifts. No total calorie restriction was advised, nor was physical activity promoted.

For participants in the two Mediterranean-diet groups, dietitians ran individual and group dietary-training sessions at the baseline visit and quarterly thereafter. In each session, a 14-item dietary screener was used to assess adherence to the Mediterranean diet8,14 (Table S1 in the Sup-plementary Appendix) so that personalized ad-vice could be provided to the study participants in these groups.

Participants in the control group also re-ceived dietary training at the baseline visit and completed the 14-item dietary screener used to assess baseline adherence to the Mediterranean diet. Thereafter, during the first 3 years of the trial, they received a leaflet explaining the low-fat diet (Table S2 in the Supplementary Appen-dix) on a yearly basis. However, the realization that the more infrequent visit schedule and less intense support for the control group might be limitations of the trial prompted us to amend the protocol in October 2006. Thereafter, par-ticipants assigned to the control diet received personalized advice and were invited to group sessions with the same frequency and intensity as those in the Mediterranean-diet groups, with

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the use of a separate 9-item dietary screener (Table S3 in the Supplementary Appendix).

A general medical questionnaire, a 137-item validated food-frequency questionnaire,15 and the Minnesota Leisure-Time Physical Activity Questionnaire were administered on a yearly basis.10 Information from the food-frequency questionnaire was used to calculate intake of energy and nutrients. Weight, height, and waist circumference were directly measured.16 Bio-markers of compliance, including urinary hy-droxytyrosol levels (to confirm compliance in the group receiving extra-virgin olive oil) and plasma alpha-linolenic acid levels (to confirm compliance in the group receiving mixed nuts), were measured in random subsamples of par-ticipants at 1, 3, and 5 years (see the Supplemen-tary Appendix).

End Points

The primary end point was a composite of myo-cardial infarction, stroke, and death from cardio-vascular causes. Secondary end points were stroke, myocardial infarction, death from cardio-vascular causes, and death from any cause. We used four sources of information to identify end points: repeated contacts with participants, con-tacts with family physicians, a yearly review of medical records, and consultation of the Nation-al Death Index. All medical records related to end points were examined by the end-point adju-dication committee, whose members were un-aware of the study-group assignments. Only end points that were confirmed by the adjudication committee and that occurred between October 1, 2003, and December 1, 2010, were included in the analyses. The criteria for adjudicating pri-mary and secondary end points are detailed in the Supplementary Appendix.

Statistical Analysis

We initially estimated that a sample of 9000 par-ticipants would be required to provide statistical power of 80% to detect a relative risk reduction of 20% in each Mediterranean-diet group versus the control-diet group during a 4-year follow-up period, assuming an event rate of 12% in the control group.10,17 In April 2008, on the advice of the data and safety monitoring board and on the basis of lower-than-expected rates of end-point events, the sample size was recalculated as 7400 participants, with the assumption of a 6-year follow-up period and underlying event rates of

Table 1. Summary of Dietary Recommendations to Participants in the Mediterranean-Diet Groups and the Control-Diet Group.

Food Goal

Mediterranean diet

Recommended

Olive oil* ≥4 tbsp/day

Tree nuts and peanuts† ≥3 servings/wk

Fresh fruits ≥3 servings/day

Vegetables ≥2 servings/day

Fish (especially fatty fish), seafood ≥3 servings/wk

Legumes ≥3 servings/wk

Sofrito‡ ≥2 servings/wk

White meat Instead of red meat

Wine with meals (optionally, only for habitual drinkers)

≥7 glasses/wk

Discouraged

Soda drinks <1 drink/day

Commercial bakery goods, sweets, and pastries§ <3 servings/wk

Spread fats <1 serving/day

Red and processed meats <1 serving/day

Low-fat diet (control)

Recommended

Low-fat dairy products ≥3 servings/day

Bread, potatoes, pasta, rice ≥3 servings/day

Fresh fruits ≥3 servings/day

Vegetables ≥2 servings/wk

Lean fish and seafood ≥3 servings/wk

Discouraged

Vegetable oils (including olive oil) ≤2 tbsp/day

Commercial bakery goods, sweets, and pastries§ ≤1 serving/wk

Nuts and fried snacks ≤1 serving /wk

Red and processed fatty meats ≤1 serving/wk

Visible fat in meats and soups¶ Always remove

Fatty fish, seafood canned in oil ≤1 serving/wk

Spread fats ≤1 serving/wk

Sofrito‡ ≤2 servings/wk

* The amount of olive oil includes oil used for cooking and salads and oil con-sumed in meals eaten outside the home. In the group assigned to the Medi-terranean diet with extra-virgin olive oil, the goal was to consume 50 g (ap-proximately 4 tbsp) or more per day of the polyphenol-rich olive oil supplied, instead of the ordinary refined variety, which is low in polyphenols.

† For participants assigned to the Mediterranean diet with nuts, the recommend-ed consumption was one daily serving (30 g, composed of 15 g of walnuts, 7.5 g of almonds, and 7.5 g of hazelnuts).

‡ Sofrito is a sauce made with tomato and onion, often including garlic and aro-matic herbs, and slowly simmered with olive oil.

§ Commercial bakery goods, sweets, and pastries (not homemade) included cakes, cookies, biscuits, and custard.

¶ Participants were advised to remove the visible fat (or the skin) of chicken, duck, pork, lamb, or veal before cooking and the fat of soups, broths, and cooked meat dishes before consumption.


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8.8% and 6.6% in the control and intervention groups, respectively. Power curves under several assumptions can be found in Figure S1 in the Supplementary Appendix.

Yearly interim analyses began after a median of 2 years of follow-up. With the use of O’Brien–Fleming stopping boundaries, the P values for stopping the trial at each yearly interim analysis were 5×10−6, 0.001, 0.009, and 0.02 for benefit and 9×10−5, 0.005, 0.02, and 0.05 for adverse ef-fects.18 The stopping boundary for the benefit of the Mediterranean diets with respect to the pri-mary end point was crossed at the fourth inter-im evaluation; on July 22, 2011, the data and safety monitoring board recommended stopping the trial on the basis of end points documented through December 1, 2010.

All primary analyses were performed on an intention-to-treat basis by two independent ana-lysts. Time-to-event data were analyzed with the use of Cox models with two dummy variables (one for the Mediterranean diet with extra-virgin olive oil and another for the Mediterranean diet

with nuts) to obtain two hazard ratios for the comparison with the control group. To account for small imbalances in risk factors at baseline among the groups, Cox regression models were used to adjust for sex, age, and baseline risk fac-tors. We tested the proportionality of hazards with the use of time-varying covariates. All analyses were stratified according to center. Pre-specified subgroup analyses were conducted ac-cording to sex, age, body-mass index (BMI), cardiovascular-risk-factor status, and baseline adherence to the Mediterranean diet. Sensitivity analyses were conducted under several assump-tions, including imputation of data for missing values and participants who dropped out (see the Supplementary Appendix).

R esult s

Baseline Characteristics of the Study Participants

From October 2003 through June 2009, a total of 8713 candidates were screened for eligibility, and

Table 2. Baseline Characteristics of the Participants According to Study Group.*

Characteristic

Mediterranean Diet with EVOO

(N = 2543)

Mediterranean Diet with Nuts

(N = 2454)Control Diet(N = 2450)

Female sex — no. (%)† 1493 (58.7) 1326 (54.0) 1463 (59.7)

Age — yr† 67.0±6.2 66.7±6.1 67.3±6.3

Race or ethnic group — no. (%)

White, from Europe 2470 (97.1) 2390 (97.4) 2375 (96.9)

Hispanic, from Central or South America 35 (1.4) 29 (1.2) 38 (1.6)

Other 38 (1.5) 35 (1.4) 37 (1.5)

Smoking status — no. (%)

Never smoked 1572 (61.8) 1465 (59.7) 1527 (62.3)

Former smoker 618 (24.3) 634 (25.8) 584 (23.8)

Current smoker 353 (13.9) 355 (14.5) 339 (13.8)

Body-mass index†‡

Mean 29.9±3.7 29.7±3.8 30.2±4.0

<25 — no. (%) 195 (7.7) 204 (8.3) 164 (6.7)

25–30 — no. (%) 1153 (45.3) 1163 (47.4) 1085 (44.3)

>30 — no. (%) 1195 (47.0) 1087 (44.3) 1201 (49.0)

Waist circumference — cm 100±10 100±11 101±11

Waist-to-height ratio†§ 0.63±0.06 0.63±0.06 0.63±0.07

Hypertension — no. (%)¶ 2088 (82.1) 2024 (82.5) 2050 (83.7)

Type 2 diabetes — no. (%)†‖ 1282 (50.4) 1143 (46.6) 1189 (48.5)

Dyslipidemia — no. (%)** 1821 (71.6) 1799 (73.3) 1763 (72.0)

Family history of premature CHD — no. (%)†† 576 (22.7) 532 (21.7) 560 (22.9)

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7447 were randomly assigned to one of the three study groups (Fig. S2 in the Supplementary Ap-pendix). Their baseline characteristics according to study group are shown in Table 2. Drug-treat-ment regimens were similar for participants in the three groups, and they continued to be bal-anced during the follow-up period (Table S4 in the Supplementary Appendix).

Participants were followed for a median of 4.8 years (interquartile range, 2.8 to 5.8). After the initial assessment, 209 participants (2.8%) chose not to attend subsequent visits, and their follow-up was based on reviews of medical re-cords. By December 2010, a total of 523 partici-pants (7.0%) had been lost to follow-up for 2 or more years. Dropout rates were higher in the con-trol group (11.3%) than in the Mediterranean-diet groups (4.9%) (Fig. S2 in the Supplementary Appendix). As compared with participants who remained in the trial, those who dropped out

were younger (by 1.4 years), had a higher BMI (the weight in kilograms divided by the square of the height in meters; by 0.4), a higher waist-to-height ratio (by 0.01), and a lower score for ad-herence to the Mediterranean diet (by 1.0 points on the 14-item dietary screener) (P<0.05 for all comparisons).

Compliance with the Dietary Intervention

Participants in the three groups reported similar adherence to the Mediterranean diet at baseline (Table 2, and Fig. S3 in the Supplementary Ap-pendix) and similar food and nutrient intakes. During follow-up, scores on the 14-item Medi-terranean-diet screener increased for the par-ticipants in the two Mediterranean-diet groups (Fig. S3 in the Supplementary Appendix). There were significant differences between these groups and the control group in 12 of the 14 items at 3 years (Table S5 in the Supplementary Appen-

Table 2. (Continued.)

Characteristic


(N = 2543)


(N = 2454)Control Diet(N = 2450)

Medication use — no. (%)

ACE inhibitors 1236 (48.6) 1223 (49.8) 1216 (49.6)

Diuretics† 534 (21.0) 477 (19.4) 562 (22.9)

Other antihypertensive agents 725 (28.5) 710 (28.9) 758 (30.9)

Statins 1039 (40.9) 964 (39.3) 983 (40.1)

Other lipid-lowering agents 121 (4.8) 145 (5.9) 126 (5.1)

Insulin 124 (4.9) 126 (5.1) 134 (5.5)

Oral hypoglycemic agents† 768 (30.2) 680 (27.7) 757 (30.9)

Antiplatelet therapy 475 (18.7) 490 (20.0) 513 (20.9)

Hormone-replacement therapy‡‡ 42 (2.8) 35 (2.6) 39 (2.7)

Score for adherence to Med diet§§ 8.7±2.0 8.7±2.0 8.4±2.1

* Plus–minus values are means ±SD. ACE denotes angiotensin-converting enzyme, and EVOO extra-virgin olive oil.† P<0.05 for comparisons between groups.‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.§ The waist-to-height ratio (an index of central obesity) is the waist circumference divided by height.¶ Hypertension was defined as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of

90 mm Hg or higher, or the use of antihypertensive therapy.‖ Diabetes was defined as a fasting blood glucose level of 126 mg per deciliter (7.0 mmol per liter) or higher on two

occasions, a 2-hour plasma glucose level of 200 mg per deciliter (11 mmol per liter) or higher during a 75-g oral glu-cose-tolerance test, or the use of antidiabetic medication.

** Dyslipidemia was defined as a low-density lipoprotein cholesterol level higher than 160 mg per deciliter (4.1 mmol per liter), a high-density lipoprotein cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or lower in men or 50 mg per deciliter (1.3 mmol per liter) or lower in women, or the use of lipid-lowering therapy.

†† A family history of premature coronary heart disease (CHD) was defined as a diagnosis of the disease in a male first-degree relative younger than 55 years of age or in a female first-degree relative younger than 65 years of age.

‡‡ The values for hormone-replacement therapy are for women only.§§ The score for adherence to the Mediterranean diet is based on the 14-item dietary screener shown in Table S1 in the

Supplementary Appendix (a score of 0 indicates minimum adherence, and a score of 14 indicates maximum adherence).




dix). Changes in objective biomarkers also indi-cated good compliance with the dietary assign-ments (Fig. S4 and S5 in the Supplementary Appendix).

Participants in the two Mediterranean-diet groups significantly increased weekly servings of fish (by 0.3 servings) and legumes (by 0.4 serv-ings) in comparison with those in the control group (Table S6 in the Supplementary Appendix). In addition, participants assigned to a Mediter-ranean diet with extra-virgin olive oil and those assigned to a Mediterranean diet with nuts sig-

nificantly increased their consumption of extra-virgin olive oil (to 50 and 32 g per day, respec-tively) and nuts (to 0.9 and 6 servings per week, respectively). The main nutrient changes in the Mediterranean-diet groups reflected the fat con-tent and composition of the supplemental foods (Tables S7 and S8 in the Supplementary Appen-dix). No relevant diet-related adverse effects were reported (see the Supplementary Appen-dix). We did not find any significant difference in changes in physical activity among the three groups.

Table 3. Outcomes According to Study Group.*

End Point


(N = 2543)


(N = 2454)Control Diet(N = 2450) P Value†

Mediterranean Diet with EVOO vs. Control Diet

Mediterranean Diet with Nuts vs. Control Diet

Person-yr of follow-up 11,852 10,365 9763

Primary end point‡

No. of events 96 83 109

Crude rate/1000 person-yr (95% CI) 8.1 (6.6–9.9) 8.0 (6.4–9.9) 11.2 (9.2–13.5) 0.009 0.02

Secondary end points

Stroke



Myocardial infarction



Death from cardiovascular causes



Death from any cause



Hazard ratio for each Mediterranean diet vs. control (95% CI)

Primary end point

Unadjusted 0.70 (0.53–0.91) 0.70 (0.53–0.94) 1.00 (ref) 0.009 0.02

Multivariable-adjusted 1§ 0.69 (0.53–0.91) 0.72 (0.54–0.97) 1.00 (ref) 0.008 0.03

Multivariable-adjusted 2¶ 0.70 (0.54–0.92) 0.72 (0.54–0.96) 1.00 (ref) 0.01 0.03

Secondary end points‖

Stroke 0.67 (0.46–0.98) 0.54 (0.35–0.84) 1.00 (ref) 0.04 0.006

Myocardial infarction 0.80 (0.51–1.26) 0.74 (0.46–1.19) 1.00 (ref) 0.34 0.22

Death from cardiovascular causes 0.69 (0.41–1.16) 1.01 (0.61–1.66) 1.00 (ref) 0.17 0.98

Death from any cause 0.82 (0.64–1.07) 0.97 (0.74–1.26) 1.00 (ref) 0.15 0.82

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End Points

The median follow-up period was 4.8 years. A total of 288 primary-outcome events occurred: 96 in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). Tak-ing into account the small differences in the ac-crual of person-years among the three groups, the respective rates of the primary end point were 8.1, 8.0, and 11.2 per 1000 person-years (Table 3). The unadjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.70 (95% CI, 0.53 to 0.94) for a Mediterranean diet with nuts (Fig. 1) as compared with the con-trol diet (P = 0.015, by the likelihood ratio test, for the overall effect of the intervention).

The results of multivariate analyses showed a similar protective effect of the two Mediterra-nean diets versus the control diet with respect to

the primary end point (Table 3). Regarding com-ponents of the primary end point, only the com-parisons of stroke risk reached statistical signifi-cance (Table 3, and Fig. S6 in the Supplementary Appendix). The Kaplan–Meier curves for the primary end point diverged soon after the trial started, but no effect on all-cause mortality was apparent (Fig. 1). The results of several sensitiv-ity analyses were also consistent with the find-ings of the primary analysis (Table S9 in the Supplementary Appendix).

Subgroup Analyses

Reductions in disease risk in the two Mediterra-nean-diet groups as compared with the control group were similar across the prespecified sub-groups (Fig. 2, and Table S10 in the Supplemen-tary Appendix). In addition, to account for the protocol change in October 2006 whereby the intensity of dietary intervention in the control group was increased, we compared hazard ratios


End Point


(N = 2543)


(N = 2454)Control Diet(N = 2450) P Value†

Mediterranean Diet with EVOO vs. Control Diet

Mediterranean Diet with Nuts vs. Control Diet

Hazard ratio for Mediterranean diets combined vs. control (95% CI)

Primary end point

Unadjusted 0.70 (0.55–0.89) 1 (ref) 0.003

Multivariable-adjusted 1§ 0.71 (0.56–0.90) 1 (ref) 0.004

Multivariable-adjusted 2¶ 0.71 (0.56–0.90) 1 (ref) 0.005

Secondary end points‖

Stroke 0.61 (0.44–0.86) 1 (ref) 0.005

Myocardial infarction 0.77 (0.52–1.15) 1 (ref) 0.20

Death from cardiovascular causes 0.83 (0.54–1.29) 1 (ref) 0.41

Death from any cause 0.89 (0.71–1.12) 1 (ref) 0.32

* CI denotes confidence interval, and ref reference.† All P values were calculated with the use of Cox proportional-hazards models with robust variance estimators and stratification according to

recruiting center.‡ The primary end point was a composite of myocardial infarction, stroke, and death from cardiovascular causes.§ The primary end point was stratified according to recruiting center and adjusted for sex, age (continuous variable), family history of pre-

mature coronary heart disease (yes or no), and smoking status (never smoked, former smoker, or current smoker).¶ The primary end point was additionally adjusted for body-mass index (continuous variable), waist-to-height ratio (continuous variable),

hypertension at baseline (yes or no), dyslipidemia at baseline (yes or no), and diabetes at baseline (yes or no).‖ The secondary end points were stratified according to recruiting center and adjusted for sex, age (continuous variable), family history of

premature coronary heart disease (yes or no), smoking status (never smoked, former smoker, or current smoker), body-mass index (con-tinuous variable), waist-to-height ratio (continuous variable), hypertension at baseline (yes or no), dyslipidemia at baseline (yes or no), and diabetes at baseline (yes or no).




for the Mediterranean-diet groups (both groups merged vs. the control group) before and after this date. Adjusted hazard ratios were 0.77 (95% CI, 0.59 to 1.00) for participants recruited before October 2006 and 0.49 (95% CI, 0.26 to 0.92) for those recruited thereafter (P = 0.21 for interaction).

Discussion

In this trial, an energy-unrestricted Mediterra-nean diet supplemented with either extra-virgin olive oil or nuts resulted in an absolute risk re-duction of approximately 3 major cardiovascular

Inci

denc

e of

Com

posi

te C

ardi

ovas

cula

rEn

d Po

int

1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5

Years

0.06

0.04

0.02

0.00

0.05

0.03

0.01

0 1 2 3 4 5

B Total Mortality

A Primary End Point (acute myocardial infarction, stroke, or death from cardiovascular causes)

Med diet, EVOO: hazard ratio, 0.70 (95% CI, 0.53–0.91); P=0.009

Med diet, nuts: hazard ratio, 0.70 (95% CI, 0.53–0.94); P=0.02

No. at RiskControl dietMed diet, EVOOMed diet, nuts

245025432454

226824862343

202023202093

158319871657

126816871389

94613101031

Tota

l Mor

talit

y

1.0

0.8

0.6

0.4

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Years

0.06

0.04

0.02

0.00

0.05

0.07

0.03

0.01

0 1 2 3 4 5

Med diet, EVOO: hazard ratio, 0.81 (95% CI, 0.63–1.05); P=0.11

Med diet, nuts: hazard ratio, 0.95 (95% CI, 0.73–1.23); P=0.68

No. at RiskControl dietMed diet, EVOOMed diet, nuts

245025432454

226824852345

202623222097

158519881662

127216901395

94813081037

Control diet

Control diet

Med diet, nuts

Med diet, nuts

Med diet, EVOO

Med diet, EVOO

Figure 1. Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population.

Panel A shows the incidence of the primary end point (a composite of acute myocardial infarction, stroke, and death from cardiovascular causes), and Panel B shows total mortality. Hazard ratios were stratified according to center (Cox model with robust variance estimators). CI denotes confidence interval, EVOO extra-virgin olive oil, and Med Mediterranean.

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events per 1000 person-years, for a relative risk reduction of approximately 30%, among high-risk persons who were initially free of cardiovas-cular disease. These results support the benefits of the Mediterranean diet for cardiovascular risk

reduction. They are particularly relevant given the challenges of achieving and maintaining weight loss. The secondary prevention Lyon Diet Heart Study also showed a large reduction in rates of coronary heart disease events with a modified

1.0 2.0

Control Diet BetterMediterranean Diets Better

Sex

Male

Female

Age

<70 yr

≥70 yr

Diabetes

No

Yes

Hypertension

No

Yes

Dyslipidemia

No

Yes

Smoking

Never

Ever

Family history of premature CHD

No

Yes

BMI

<25

25–30

>30

Waist

<Median

≥Median

Waist-to-height ratio

<Median

≥Median

Baseline score for adherence to Mediterranean diet

<9 (low)

≥9 (high)

End-point components

Stroke

Myocardial infarction

Death from cardiovascular causes

CombinedMediterranean Diets Hazard Ratio (95% CI)

ControlDietSubgroup

0.5

P Value forInteraction

0.62

0.84

0.63

0.06

0.06

0.75

0.97

0.05

0.72

0.82

0.44

no. of participants with primary end-pointevent/total no. of participants

64/987107/2178 0.69 (0.51–0.94)

45/146372/2819 0.73 (0.50–1.07)

47/150486/3272 0.73 (0.52–1.05)

62/94693/1725 0.71 (0.51–0.98)

40/126158/2572 0.67 (0.45–1.01)

69/1189121/2425 0.71 (0.53–0.96)

11/40040/885 1.25 (0.64–2.45)98/2050139/4112 0.65 (0.50–0.84)

36/68777/1377 0.95 (0.64–1.42)

73/1763102/3620 0.60 (0.44–0.80)

54/152780/3037 0.67 (0.47–0.94)

55/92399/1960 0.75 (0.54–1.03)

87/1890144/3889 0.72 (0.55–0.94)

22/56035/1108 0.75 (0.43–1.29)

7/16418/399 0.69 (0.29–1.67)

37/108588/2316 1.04 (0.71–1.54)

65/120173/2282 0.51 (0.37–0.71)

48/117787/2561 0.76 (0.53–1.08)

61/127392/2436 0.67 (0.48–0.93)

47/118281/2549 0.74 (0.52–1.06)

62/126898/2448 0.68 (0.50–0.94)

61/125693/2178 0.81 (0.58–1.12)

48/119486/2819 0.64 (0.45–0.92)

58/245081/4997 0.61 (0.44–0.86)

38/245068/4997 0.77 (0.52–1.15)

30/245057/4997 0.83 (0.54–1.29)

Figure 2. Results of Subgroup Analyses.

Shown are adjusted hazard ratios for the primary end point within specific subgroups. Squares denote hazard ratios; horizontal lines represent 95% confidence intervals. Hazard ratios indicate the relative risk in both intervention groups merged together (vs. the control group) within each stratum. Hazard ratios were stratified according to recruiting center and were adjusted for sex, age (continuous vari-able), family history of premature coronary heart disease (CHD) (yes or no), smoking (never smoked, former smoker, or current smok-er), body-mass index (BMI) (continuous variable), waist-to-height ratio (continuous variable), hypertension at baseline (yes or no), dys-lipidemia at baseline (yes or no), and diabetes at baseline (yes or no). Scores for adherence to the Mediterranean diet range from 0 to 14, with higher scores indicating greater adherence.




Mediterranean diet enriched with alpha-linolenic acid (a key constituent of walnuts). That result, however, was based on only a few major events.4,19,20

There were small between-group differences in some baseline characteristics in our trial, which were not clinically meaningful but were statisti-cally significant, and we therefore adjusted for these variables. In fully adjusted analyses, we found significant results for the combined cardiovas-cular end point and for stroke, but not for myo-cardial infarction alone. This could be due to stronger effects on specific risk factors for stroke but also to a lower statistical power to identify effects on myocardial infarction. Our findings are consistent with those of prior observational studies of the cardiovascular protective effects of the Mediterranean diet,2,5 olive oil,21-23 and nuts24,25; smaller trials assessing effects on tra-ditional cardiovascular risk factors6-9 and novel risk factors, such as markers of oxidation, in-flammation, and endothelial dysfunction6,8,26-28; and studies of conditions associated with high cardiovascular risk — namely, the metabolic syndrome6,16,29 and diabetes.30-32 Thus, a causal role of the Mediterranean diet in cardiovascular prevention has high biologic plausibility. The results of our trial might explain, in part, the lower cardiovascular mortality in Mediterranean countries than in northern European countries or the United States.33

The risk of stroke was reduced significantly in the two Mediterranean-diet groups. This is consistent with epidemiologic studies that showed an inverse association between the Mediterra-nean diet2,34 or olive-oil consumption22 and in-cident stroke.

Our results compare favorably with those of the Women’s Health Initiative Dietary Modifica-tion Trial, wherein a low-fat dietary approach resulted in no cardiovascular benefit.35 Salient components of the Mediterranean diet report-edly associated with better survival include mod-erate consumption of ethanol (mostly from wine), low consumption of meat and meat products, and high consumption of vegetables, fruits, nuts, legumes, fish, and olive oil.36,37 Perhaps there is a synergy among the nutrient-rich foods includ-ed in the Mediterranean diet that fosters favor-able changes in intermediate pathways of car-diometabolic risk, such as blood lipids, insulin sensitivity, resistance to oxidation, inflammation, and vasoreactivity.38

Our study has several limitations. First, the protocol for the control group was changed half-way through the trial. The lower intensity of dietary intervention for the control group during the first few years might have caused a bias to-ward a benefit in the two Mediterranean-diet groups, since the participants in these two groups received a more intensive intervention during that time. However, we found no significant in-teraction between the period of trial enrollment (before vs. after the protocol change) and the benefit in the Mediterranean-diet groups. Sec-ond, we had losses to follow-up, predominantly in the control group, but the participants who dropped out had a worse cardiovascular risk pro-file at baseline than those who remained in the study, suggesting a bias toward a benefit in the control group. Third, the generalizability of our findings is limited because all the study partici-pants lived in a Mediterranean country and were at high cardiovascular risk; whether the results can be generalized to persons at lower risk or to other settings requires further research.

As with many clinical trials, the observed rates of cardiovascular events were lower than antici-pated, with reduced statistical power to sepa-rately assess components of the primary end point. However, favorable trends were seen for both stroke and myocardial infarction. We ac-knowledge that, even though participants in the control group received advice to reduce fat in-take, changes in total fat were small and the largest differences at the end of the trial were in the distribution of fat subtypes. The interventions were intended to improve the overall dietary pat-tern, but the major between-group differences involved the supplemental items. Thus, extra-virgin olive oil and nuts were probably respon-sible for most of the observed benefits of the Mediterranean diets. Differences were also ob-served for fish and legumes but not for other food groups. The small between-group differ-ences in the diets during the trial are probably due to the facts that for most trial participants the baseline diet was similar to the trial Mediter-ranean diet and that the control group was given recommendations for a healthy diet, suggesting a potentially greater benefit of the Mediterra-nean diet as compared with Western diets.

In conclusion, in this primary prevention trial, we observed that an energy-unrestricted Medi-terranean diet, supplemented with extra-virgin

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olive oil or nuts, resulted in a substantial reduc-tion in the risk of major cardiovascular events among high-risk persons. The results support the benefits of the Mediterranean diet for the primary prevention of cardiovascular disease.

Supported by the official funding agency for biomedical re-search of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifi-cally developed for the trial (RTIC G03/140, to Dr. Estruch; RTIC RD 06/0045, to Dr. Martínez-González and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesi-dad y Nutrición [CIBERobn]), and by grants from Centro Nacio-nal de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Re-gional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, and P11/02505), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Pub-lic Health Division of the Department of Health of the Auto-nomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Na-varra (P27/2011).

Dr. Estruch reports serving on the board of and receiving lecture fees from the Research Foundation on Wine and Nutri-tion (FIVIN); serving on the boards of the Beer and Health Foundation and the European Foundation for Alcohol Research (ERAB); receiving lecture fees from Cerveceros de España and Sanofi-Aventis; and receiving grant support through his institu-tion from Novartis. Dr. Ros reports serving on the board of and receiving travel support, as well as grant support through his institution, from the California Walnut Commission; serving on the board of the Flora Foundation (Unilever); serving on the board of and receiving lecture fees from Roche; serving on the board of and receiving grant support through his institution from Amgen; receiving consulting fees from Damm and Abbott

Laboratories; receiving consulting fees and lecture fees, as well as grant support through his institution, from Merck; receiving lecture fees from Danone, Pace, AstraZeneca, and Rottapharm; receiving lecture fees and payment for the development of edu-cational presentations, as well as grant support through his in-stitution, from Ferrer; receiving payment for the development of educational presentations from Recordati; and receiving grant support through his institution from Sanofi-Aventis, Takeda, Daiichi Sankyo, Nutrexpa, Feiraco, Unilever, and Karo Bio. Dr. Salas-Salvadó reports serving on the board of and receiving grant support through his institution from the International Nut and Dried Fruit Council; receiving consulting fees from Danone; and receiving grant support through his institution from Eroski and Nestlé. Dr. Arós reports receiving payment for the develop-ment of educational presentations from Menarini and AstraZeneca. Dr. Lamuela-Raventos reports serving on the board of and re-ceiving lecture fees from FIVIN; receiving lecture fees from Cerveceros de España; and receiving lecture fees and travel sup-port from PepsiCo. Dr. Serra-Majem reports serving on the boards of the Mediterranean Diet Foundation and the Beer and Health Foundation. Dr. Pintó reports serving on the board of and receiving grant support through his institution from the Residual Risk Reduction Initiative (R3i) Foundation; serving on the board of Omegafort; serving on the board of and receiving payment for the development of educational presentations, as well as grant support through his institution, from Ferrer; re-ceiving consulting fees from Abbott Laboratories; receiving lec-ture fees, as well as grant support through his institution, from Merck and Roche; receiving lecture fees from Danone and Esteve; receiving payment for the development of educational presenta-tions from Menarini; and receiving grant support through his institution from Sanofi-Aventis, Kowa, Unilever, Boehringer Ingelheim, and Karo Bio. No other potential conflict of interest relevant to this article was reported.


We thank the participants in the trial for their enthusiastic and sustained collaboration and Joan Vila from Institut Munici-pal d’Investigació Mèdica, Barcelona, for expert assessment in the statistical analyses.

appendixThe author’s affiliations are as follows: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (R.E., E.R., J.S.-S., M.-I.C., D.C., M.F., J.L., R.M.L.-R., J.B., J.V.S., J.A.M.) and the PREDIMED (Prevención con Dieta Mediterránea) Network (RD 06/0045) (R.E., J.S.-S., F.A., E.G.-G., V.R.-G., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M., M.A.M.-G.), Instituto de Salud Carlos III, Madrid; the Department of Internal Medicine (R.E.) and Lipid Clinic, Department of Endocrinology and Nutrition (E.R.), Institut d’Investigacions Biomèdiques August Pi I Sunyer, Hospital Clinic, University of Barcelona, Barcelona; Human Nutrition Department, Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus (J.S.-S.); Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona (M.-I.C.); the Department of Preventive Medicine, Uni-versity of Valencia, Valencia (D.C.); the Department of Cardiology, University Hospital of Alava, Vitoria (F.A.); the Department of Preven-tive Medicine, University of Malaga, Malaga (E.G.-G.); Instituto de la Grasa, Consejo Superior de Investigaciones Cientificas, Seville (V.R.-G.); Institute of Health Sciences (IUNICS), University of Balearic Islands, and Hospital Son Espases, Palma de Mallorca (M.F.); the Department of Family Medicine, Primary Care Division of Seville, San Pablo Health Center, Seville (J.L.); the Department of Nutrition and Food Science, School of Pharmacy, Xarxa de Referència en Tecnologia dels Aliments, Instituto de Investigación en Nutrición y Se-guridad Alimentaria, University of Barcelona, Barcelona (R.M.L.-R.); the Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas (L.S.-M.); Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona (X.P.); Primary Care Division, Catalan Institute of Health, Institut d’Investigació en Atenció Primària Jordi Gol, Tarragona-Reus (J.B.) and Barcelona (M.A.M.); Primary Care Division, Valencia Institute of Health, Valencia (J.V.S.); and the Depart-ments of Nutrition and Food Sciences, Physiology and Toxicology (J.A.M.) and Preventive Medicine and Public Health (M.A.M.-G.), University of Navarra, Pamplona — all in Spain.

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Monjaud I, Delaye J, Mamelle N. Mediter-ranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779-85.5. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evi-dence supporting a causal link between dietary factors and coronary heart dis-ease. Arch Intern Med 2009;169:659-69.6. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on en-dothelial dysfunction and markers of vas-cular inflammation in the metabolic syn-drome: a randomized trial. JAMA 2004; 292:1440-6.7. Vincent-Baudry S, Defoort C, Gerber M, et al. The Medi-RIVAGE study: reduc-tion of cardiovascular disease risk factors after a 3-mo intervention with a Mediter-ranean-type diet or a low-fat diet. Am J Clin Nutr 2005;82:964-71.8. Estruch R, Martínez-González MA, Corella D, et al. Effects of a Mediterra-nean-style diet on cardiovascular risk fac-tors: a randomized trial. Ann Intern Med 2006;145:1-11.9. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low-carbohydrate, Med-iterranean, or low-fat diet. N Engl J Med 2008;359:229-41. [Erratum, N Engl J Med 2009;361:2681.]10. Martínez-González MA, Corella D, Salas-Salvadó J, et al. Cohort profile: de-sign and methods of the PREDIMED study. Int J Epidemiol 2012;41:377-85.11. The PREDIMED Study (http://www .predimed.org).12. The PREDIMED network (http://www .predimed.es).13. Zazpe I, Sanchez-Tainta A, Estruch R, et al. A large randomized individual and group intervention conducted by registered dieticians increased the adherence to Mediterranean-type diets: the PREDIMED study. J Am Diet Assoc 2008;108:1134-44.14. Schröder H, Fitó M, Estruch R, et al. A short screener is valid for assessing Mediterranean diet adherence among old-er Spanish men and women. J Nutr 2011; 141:1140-5.15. Fernández-Ballart JD, Piñol JL, Zazpe I, et al. Relative validity of a semi-quantita-tive food-frequency questionnaire in an elderly Mediterranean population of Spain. Br J Nutr 2010;103:1808-16.16. Salas-Salvadó J, Fernández-Ballart J,

Ros E, et al. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med 2008;168:2449-58.17. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hy-percholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007.18. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Bio-metrics 1979;35:549-56.19. Kris-Etherton P, Eckel RH, Howard BV, St Jeor S, Bazzarre TL. Lyon Diet Heart Study: benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association step I dietary pattern on cardiovascular disease. Circu-lation 2001;103:1823-5.20. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coro-nary heart disease. Lancet 1994;343:1454-9. [Erratum, Lancet 1995;345:738.]21. Bendinelli B, Masala G, Saieva C, et al. Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study. Am J Clin Nutr 2011; 93:275-83.22. Samieri C, Féart C, Proust-Lima C, et al. Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study. Neurology 2011;77:418-25.23. Buckland G, Travier N, Barricarte A, et al. Olive oil intake and CHD in the Euro-pean Prospective Investigation into Can-cer and Nutrition Spanish cohort. Br J Nutr 2012;108:2075-82.24. Kris-Etherton PM, Hu FB, Ros E, Sa-baté J. The role of tree nuts and peanuts in the prevention of coronary heart disease: multiple potential mechanisms. J Nutr 2008;138:1746S-1751S.25. Ros E, Tapsell LC, Sabaté J. Nuts and berries for heart health. Curr Atheroscler Rep 2010;12:397-406.26. Fitó M, Guxens M, Corella D, et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial. Arch Intern Med 2007; 167:1195-203.27. Mena MP, Sacanella E, Vázquez-Agell M, et al. Inhibition of circulating immune cell activation: a molecular antiinflam-

matory effect of the Mediterranean diet. Am J Clin Nutr 2009;89:248-56.28. Fuentes F, López-Miranda J, Sánchez E, et al. Mediterranean and low-fat diets improve endothelial function in hyper-cholesterolemic men. Ann Intern Med 2001;134:1115-9.29. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagio-takos DB. The effect of Mediterranean diet on metabolic syndrome and its com-ponents: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Car-diol 2011;57:1299-313.30. Esposito K, Maiorino MI, Ceriello A, Giugliano D. Prevention and control of type 2 diabetes by Mediterranean diet: a systematic review. Diabetes Res Clin Pract 2010;89:97-102.31. Salas-Salvadó J, Bulló M, Babio N, et al. Reduction in the incidence of type 2 dia-betes with the Mediterranean diet: results of the PREDIMED-Reus nutrition inter-vention randomized trial. Diabetes Care 2011;34:14-9.32. Martínez-González MA, de la Fuente-Arrillaga C, Nuñez-Córdoba JM, et al. Ad-herence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ 2008;336:1348-51.33. Müller-Nordhorn J, Binting S, Roll S, Willich SN. An update on regional varia-tion in cardiovascular mortality within Europe. Eur Heart J 2008;29:1316-26.34. Kastorini CM, Milionis HJ, Ioannidi A, et al. Adherence to the Mediterranean diet in relation to acute coronary syndrome or stroke nonfatal events: a comparative analysis of a case/case-control study. Am Heart J 2011;162:717-24.35. Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardio-vascular disease: the Women’s Health Ini-tiative Randomized Controlled Dietary Modification Trial. JAMA 2006;295:655-66.36. Trichopoulou A, Bamia C, Trichopou-los D. Anatomy of health effects of Medi-terranean diet: Greek EPIC prospective cohort study. BMJ 2009;338:b2337.37. Buckland G, Mayén AL, Agudo A, et al. Olive oil intake and mortality within the Spanish population (EPIC-Spain). Am J Clin Nutr 2012;96:142-9.38. Jacobs DR Jr, Gross MD, Tapsell LC. Food synergy: an operational concept for understanding nutrition. Am J Clin Nutr 2009;89:1543S-1548S.Copyright © 2013 Massachusetts Medical Society.

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A bs tr ac t

From the Departments of Internal Medi-cine (E.N., A.V., M.N., P.S.), Microbiology (C.E.V.), Gastroenterology (J.F.W.M.B., J.J.K.), and Cardiology (J.G.P.T.) and the Clinical Research Unit (M.G.W.D.), Aca-demic Medical Center, University of Am-sterdam, Amsterdam; the Laboratory of Microbiology, Wageningen University, Wageningen (S.F., E.G.Z., W.M.V.); the Department of Experimental and Medical Microbiology, Leiden University Medical Center, Leiden (E.J.K.); and the Department of Gastroenterology, Hagaziekenhuis, The Hague (J.J.K.) — all in the Netherlands; and the Department of Bacteriology and Immunology, Medical Faculty, University of Helsinki, Helsinki (W.M.V.). Address reprint requests to Dr. Keller at the Aca-demic Medical Center, Department of Gastroenterology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, or at [email protected].

This article was published on January 16, 2013, at NEJM.org.

N Engl J Med 2013;368:407-15.DOI: 10.1056/NEJMoa1205037Copyright © 2013 Massachusetts Medical Society.

Background

Recurrent Clostridium difficile infection is difficult to treat, and failure rates for anti-biotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection.

Methods

We randomly assigned patients to receive one of three therapies: an initial vanco-mycin regimen (500 mg orally four times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a nasoduode-nal tube; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage. The primary end point was the resolution of diarrhea associated with C. difficile infection without relapse after 10 weeks.

Results

The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile–associated diarrhea after the first infu-sion. The 3 remaining patients received a second infusion with feces from a differ-ent donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P<0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the in-fusion group on the infusion day. After donor-feces infusion, patients showed in-creased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species.

Conclusions

The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. (Funded by the Nether-lands Organization for Health Research and Development and the Netherlands Organization for Scientific Research; Netherlands Trial Register number, NTR1177.)

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile

Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., Susana Fuentes, Ph.D., Erwin G. Zoetendal, Ph.D., Willem M. de Vos, Ph.D., Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D.,

Joep F.W.M. Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D., Marcel G.W. Dijkgraaf, Ph.D., and Josbert J. Keller, M.D., Ph.D.

Donor-Feces Infusion for Recurrent C. difficile

ORIGINAL ARTICLE

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n engl j med 368;5 nejm.org january 31, 2013408

Antibiotic treatment for an initial Clostridium difficile infection typically does not induce a durable response in approxi-

mately 15 to 26% of patients.1-3 An effective treatment against recurrent C. difficile infection is not available. Generally, repeated and extended courses of vancomycin are prescribed.4 The esti-mated efficacy of antibiotic therapy for a first recurrence is 60%, a proportion that further de-clines in patients with multiple recurrences.2,5-7 Mechanisms that have been proposed for recur-rence include persistence of spores of C. difficile, diminished antibody response to clostridium tox-ins, and persistent disturbance with a reduced di-versity of intestinal microbiota.8-12

Infusion of feces from healthy donors has been reported as an effective treatment for recur-rent C. difficile infection in more than 300 pa-tients.13-18 However, experience with this proce-dure is limited by a lack of randomized trials supporting its efficacy and the unappealing na-ture of the treatment. In this study, donor feces were infused in patients with recurrent C. difficile infection and compared with conventional 14-day vancomycin treatment, with and without bowel lavage.

Me thods

Study Design

The complete methods are included in the Sup-plementary Appendix, which along with the re-search protocol is available with the full text of this article at NEJM.org.

In this open-label, randomized, controlled trial, we compared three treatment regimens: the in-fusion of donor feces preceded by an abbreviated regimen of vancomycin and bowel lavage, a stan-dard vancomycin regimen, and a standard van-comycin regimen with bowel lavage.

The study was conducted at the Academic Medical Center in Amsterdam. Patients who had been admitted to referring hospitals were visited by the study physicians, who performed the ran-domization. All participants provided written in-formed consent. A data and safety monitoring board monitored the trial on an ongoing basis. The research protocol was approved by the ethics committee at the Academic Medical Center. The first and last two authors vouch for the accuracy and completeness of the reported data and for the fidelity of the report to the study protocol.

Study Population

Included in the study were patients who were at least 18 years of age and who had a life expectancy of at least 3 months and a relapse of C. difficile in-fection after at least one course of adequate antibi-otic therapy (≥10 days of vancomycin at a dose of ≥125 mg four times per day or ≥10 days of metro-nidazole at a dose of 500 mg three times per day). C. difficile infection was defined as diarrhea (≥3 loose or watery stools per day for at least 2 con-secutive days or ≥8 loose stools in 48 hours) and a positive stool test for C. difficile toxin. Available isolates were characterized by polymerase-chain-reaction (PCR) ribotyping.19

Exclusion criteria were prolonged compromised immunity because of recent chemotherapy, the presence of human immunodeficiency virus (HIV) infection with a CD4 count of less than 240, or prolonged use of prednisolone at a dose of at least 60 mg per day; pregnancy; use of antibiot-ics other than for treatment of C. difficile infection at baseline; admission to an intensive care unit; or need for vasopressor medication.

Treatments

Patients received an abbreviated regimen of van-comycin (500 mg orally four times per day for 4 or 5 days), followed by bowel lavage with 4 liters of macrogol solution (Klean-Prep) on the last day of antibiotic treatment and the infusion of a suspen-sion of donor feces through a nasoduodenal tube the next day; a standard vancomycin regimen (500 mg orally four times per day for 14 days); or a standard vancomycin regimen with bowel lavage on day 4 or 5. Patients in whom recurrent C. difficile infection developed after the first donor-feces in-fusion were given a second infusion with feces from a different donor. Patients in whom antibi-otic therapy failed were offered treatment with donor feces off protocol.

Infusion of Donor Feces

Donors (<60 years of age) were volunteers who were initially screened using a questionnaire ad-dressing risk factors for potentially transmissible diseases. Donor feces were screened for parasites (including Blastocystis hominis and Dientamoeba fra-gilis), C. difficile, and enteropathogenic bacteria. Blood was screened for antibodies to HIV; human T-cell lymphotropic virus types 1 and 2; hepatitis A, B, and C; cytomegalovirus; Epstein–Barr virus; Treponema pallidum; Strongyloides stercoralis; and Ent-

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Donor-Feces Infusion for Recurrent C. difficile

amoeba histolytica. A donor pool was created, and screening was repeated every 4 months. Before donation, another questionnaire was used to screen for recent illnesses.

Feces were collected by the donor on the day of infusion and immediately transported to the hospital. Feces were diluted with 500 ml of ster-ile saline (0.9%). This solution was stirred, and the supernatant strained and poured in a sterile bottle. Within 6 hours after collection of feces by the donor, the solution was infused through a nasoduodenal tube (2 to 3 minutes per 50 ml). The tube was removed 30 minutes after the infu-sion, and patients were monitored for 2 hours. For patients who had been admitted at referring hospitals, the donor-feces solution was produced at the study center and immediately transported and infused by a study physician.

Outcomes

The primary end point was cure without relapse within 10 weeks after the initiation of therapy. For patients in the infusion group who required a second infusion of donor feces, follow-up was extended to 10 weeks after the second infusion. The secondary end point was cure without relapse after 5 weeks. Cure was defined as an absence of diarrhea or persistent diarrhea that could be ex-plained by other causes with three consecutive negative stool tests for C. difficile toxin. Relapse was defined as diarrhea with a positive stool test for C. difficile toxin. An adjudication committee whose members were unaware of study-group assignments decided which patients were cured.

Patients kept a stool diary and were ques-tioned about stool frequency and consistency, medication use, and adverse effects on days 7, 14, 21, 35, and 70 after the initiation of vanco-mycin. Stool tests for C. difficile toxin were per-formed in a central laboratory (Premier Toxins A&B, Meridian Bioscience) on days 14, 21, 35, and 70 and whenever diarrhea occurred.

Analysis of Fecal Microbiota

We analyzed the fecal microbiota for bacterial diversity by extracting DNA from samples from patients before and after donor-feces infusion and from the respective donor samples.20 We then characterized 16S ribosomal RNA gene am-plicons using the Human Intestinal Tract Chip (HITChip), a phylogenetic microarray, as described previously.21 We estimated the diversity of the

bacterial communities before and after donor-feces infusion using Simpson’s Reciprocal Index of diversity,22 on a scale ranging from 1 to 250, with higher values indicating greater diversity.

Statistical Analysis

The objective was to determine the superiority of donor-feces infusion, as compared with vanco-mycin, both without and with bowel lavage. A cure rate of 90% for donor-feces infusion13,14 and of 60% for antibiotic therapy2,6 was assumed. Per group, 38 patients were needed to achieve a pow-er of 80% to detect a difference between groups with a one-sided level of significance of 0.025. To account for dropouts, we planned to enroll 40 pa-tients per group. All analyses were performed on a modified intention-to-treat basis with the ex-clusion of one patient who required high-dose prednisolone treatment after randomization but before the study treatment was initiated. Differ-ences in cure rates were assessed with Fisher’s exact probability test. Since the trial was termi-nated early according to the Haybittle–Peto rule (i.e., P<0.001 for the primary end point), rate ra-tios for the primary end point (overall cure) were calculated with their exact 99.9% confidence in-terval.

On the basis of Simpson’s Reciprocal Index of diversity,22 the statistical significance of a change in microbiota diversity was assessed with the use of a paired-samples Student t-test. A principal component analysis was performed on profiles derived from the HITChip phylogenetic microar-ray.21 Wilcoxon signed-rank tests were performed with the application of the Benjamini–Hochberg approach to determine microbial groups that were significantly different in matched pairs of fecal samples obtained from patients before and after infusion.23

R esult s

Patients and Termination of the Trial

From January 2008 through April 2010, a total of 43 patients were randomly assigned to receive donor-feces infusion (17 patients), vancomycin (13), or vancomycin and bowel lavage (13). Ini-tially, the inclusion of 40 patients per study group was planned. Because most patients in both con-trol groups had a relapse, the data and safety monitoring board performed the interim efficacy analysis and advised termination of the trial, as




described in the Supplementary Appendix. At that time, 43 patients were included, with one of them subsequently excluded from further analysis (Ta-ble 1 and Fig. 1). In 39 patients, a positive toxin test before inclusion was confirmed by a positive C. difficile culture. PCR ribotyping was performed on strains obtained from 34 patients (see the Supplementary Appendix).

Forty-one patients completed the study proto-col. One patient in the vancomycin-only group was discharged home from the hospital after the initiation of vancomycin. At home, the patient decided to discontinue all medication because of

severe heart failure and chronic obstructive pul-monary disease and died 13 days after random-ization, without providing data on response. In the intention-to-treat analysis, vancomycin ther-apy was considered to have failed in this patient. Another patient in the infusion group required high-dose prednisolone because of a rapid de-crease in renal-graft function. The patient had received a renal transplant from an unrelated do-nor 11 months before study enrollment, and graft dysfunction was noted immediately after ran-domization but before the study treatment was initiated. At that time, the nephrologist objected

Table 1. Baseline Demographic and Clinical Characteristics of the Patients.*

Characteristic

Donor-Feces Infusion(N = 16)

Vancomycin Only(N = 13)

Vancomycin and Bowel Lavage

(N = 13) P Value†

Age — yr 73±13 66±14 69±16 0.39

Body-mass index‡ 22±3 22±4 24±4 0.41

Female sex — no. (%) 8 (50) 7 (54) 3 (23) 0.22

Karnofsky performance status§ 50±18 50±17 56±21 0.62

Median Charlson comorbidity index (range) — score¶ 3 (0–4) 1 (0–8) 1 (0–6) 0.53

Median recurrences of CDI (range) — no. 3 (1–5) 3 (1–4) 2 (1–9) 0.69

Previous failure of tapered vancomycin therapy — no. (%) 10 (62) 8 (62) 6 (46) 0.63

Reported antibiotic use before CDI — no. (%) 16 (100) 12 (92) 13 (100) 0.62

Hospital-acquired CDI infection — no. (%) 10 (62) 6 (46) 10 (77) 0.27

Admitted to a hospital at study inclusion — no. (%) 5 (31) 4 (31) 4 (31) 1.00

Days of antibiotic use for CDI since first diagnosis — no.‖ 63±41 51±27 49±38 0.56

Use of proton-pump inhibitor — no. (%) 13 (81) 10 (77) 11 (85) 0.88

ICU admission in preceding month — no. (%) 1 (6) 0 1 (8) 1.00

Feeding tube present — no. (%) 3 (19) 2 (15) 2 (15) 0.96

Median stool frequency per 24 hr (range) — no. 5 (3–20) 5 (3–12) 5 (3–10) 0.72

Leukocyte count — per mm3**

Median 8000 8100 6500 0.39

Range 4000–15,000 4000–23,000 3000–14,000

Albumin — g/dl** 3.7±0.7 3.8±0.7 3.9±0.8 0.66

Median creatinine (range) — mg/dl** 1.3 (0.6–10.3) 1.0 (0.5–1.8) 0.9 (0.6–5.2) 0.26

Ribotype 027 in first sample — no. (%)†† 3 (23) 1 (11) 0 0.28

* Plus–minus values are means ±SD. To convert the values for creatinine to micromoles per liter, multiply by 88.4. CDI denotes Clostridium difficile infection, and ICU intensive care unit.

† P values are for the overall comparison among the three groups.‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.§ The Karnofsky performance status ranges from 0 to 100, with higher scores indicating improved functional status.¶ Scores on the Charlson comorbidity index range from 0 to 6 for each of 17 indicators, with higher scores indicating greater severity of illness.‖ Data were missing for one patient in the infusion group and one in the vancomycin-only group.** Data were missing for one patient in the vancomycin-only group.†† Data for ribotype 027 (a more virulent strain of C. difficile) were missing for three patients in the infusion group, four in the vancomycin-

only group, and two in the group receiving vancomycin with bowel lavage.

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22 nejm readers’ choice clinical care collectionDonor-Feces Infusion for Recurrent C. difficile


to treatment with donor feces. The patient was treated with vancomycin for 45 days, had a re-currence 41 days after cessation of vancomycin, and was subsequently cured by donor-feces infu-sion. This patient was excluded from the analysis because of a clinically driven protocol deviation, which meant that the patient’s response to treat-ment could not be evaluated.

Donors

Of 77 candidates, 25 donors were approved (see the Supplementary Appendix for results of donor screening). Feces from 15 donors were used for 43 infusions in the infusion group and for pa-tients who had a relapse after vancomycin treat-ment. A mean (±SD) of 141±71 g of feces was in-fused. The mean time from defecation to infusion was 3.1±1.9 hours.

Study Outcomes

Of 16 patients in the infusion group, 13 (81%) were cured after the first infusion of donor feces. The 3 remaining patients received a second infu-sion with feces from a different donor at 14, 50, and 53 days after randomization; of these pa-tients, 2 were subsequently cured. Overall, donor feces cured 15 of 16 patients (94%). Resolution of infection occurred in 4 of 13 patients (31%) in the vancomycin-alone group and in 3 of 13 pa-tients (23%) in the group receiving vancomycin with bowel lavage. Donor-feces infusion was sta-tistically superior to both vancomycin regimens (P<0.01 for both comparisons after the first infu-sion and P<0.001 for overall cure rates) (Fig. 2). The overall cure rate ratio of donor-feces infusion was 3.05 as compared with vancomycin alone (99.9% confidence interval [CI], 1.08 to 290.05)

43 Underwent randomization

102 Patients were assessed for eligibilityor their treating physicians contacted

the study center

49 Were excluded2 Were pregnant2 Were admitted to the intensive care unit2 Had life expectancy <3 mo3 Were immunocompromised8 Were not able to give informed consent1 Was allergic to vancomycin

31 Did not meet criteria of both diarrhea andpositive stool toxin for Clostridium difficile

10 Declined to participate

17 Were assigned to receivedonor-feces infusion

13 Were assigned to receivevancomycin and bowel lavage

1 Was excluded 1 Died

16 Completed evaluation 13 Completed evaluation

13 Were assigned to receivevancomycin

12 Completed evaluation

Figure 1. Enrollment and Outcomes.

After randomization, one patient in the infusion group required high-dose prednisolone because of a rapid decrease in renal-graft function that was noted immediately after randomization but before the study treatment was initiated. This patient was excluded from the analysis. One patient in the vancomycin-only group died before the first stool sample could be tested for the presence of Clostridium diff icile toxin.




and 4.05 as compared with vancomycin with bowel lavage (99.9% CI, 1.21 to 290.12).

The median time to recurrence was 23 days (range, 13 to 43) after the initiation of vancomy-cin alone and 25 days (range, 18 to 70) after the initiation of vancomycin with bowel lavage. Five weeks after the initiation of therapy, there was a recurrence of infection in 1 of 16 patients (6%) in the infusion group, 8 of 13 (62%) in the van-comycin-alone group, and 7 of 13 (54%) in the group receiving vancomycin with bowel lavage.

Fourteen patients who were cured reported having diarrhea during follow-up; these episodes were short and self-limited in 10 patients. Three patients had a preexistent defecation frequency of at least three stools per day, a frequency that was markedly increased during episodes with C. dif-ficile infection and returned to normal after donor-feces infusion. In these patients, toxin tests were repeatedly negative, and there was no clinical suspicion of recurrence. One patient in the van-comycin-only group had persistent diarrhea, with repeatedly negative toxin tests; this patient was considered to have had a response, although there was clinical suspicion of recurrence.

Eighteen patients who had a relapse after ini-tial antibiotic treatment received off-protocol do-nor-feces infusions; of these patients, 15 (83%) were cured. Eleven patients were cured after one donor-feces infusion, and 4 patients were cured after a second infusion.

Adverse Events

A complete description of adverse events is includ-ed in the Supplementary Appendix. Immediately after donor-feces infusion, most patients (94%) had diarrhea. In addition, cramping (31%) and belching (19%) were reported (Table 2). In all pa-tients, these symptoms resolved within 3 hours. During follow-up, three patients who were treat-ed with donor feces (19%) had constipation. No other adverse events related to study treatment were reported. The death of one patient from se-vere heart failure and chronic obstructive pulmo-nary disease in the vancomycin-only group was considered to be unrelated to the study drug.

81.3

93.8

30.823.1

Perc

enta

ge C

ured

with

out R

elap

se

100

80

90

70

60

40

30

10

50

20

0First Infusion

of Donor Feces(N=16)

Infusion of DonorFeces Overall

(N=16)

Vancomycin(N=13)

Vancomycin withBowel Lavage

(N=13)

P<0.001

P=0.008

P=0.003

P<0.001

Figure 2. Rates of Cure without Relapse for Recurrent Clostridium difficile Infection.

Shown are the proportions of patients who were cured by the infusion of donor feces (first infusion and overall results), by standard vancomycin therapy, and by standard vancomycin therapy plus bowel lavage.

Table 2. Adverse Events in 16 Patients in the Infusion Group.*

Adverse EventOn Day of Infusion

of Donor FecesDuring

Follow-up

no. of events

Belching 3 0

Nausea 1 0

Vomiting 0 0

Abdominal cramps 5 0

Diarrhea 15 0

Constipation 0 3

Abdominal pain 2 (associated with cramping)

0

Infection 0 2†

Hospital admission NA 1‡

Death 0 0

Other adverse event 1§ 1‡

* Adverse events that were reported on the day of donor- feces infusion and those that were reported during follow-up are listed separately. NA denotes not applicable.

† During follow-up, one patient with recurrent urinary tract infections had a urinary tract infection for which antibiotics were prescribed. Another patient had fever during hemo-dialysis for which antibiotics were prescribed; cultures remained negative.

‡ On day 56, one patient was hospitalized for symptomatic choledocholithiasis, for which endoscopic retrograde cholangiopancreatography and stone extraction were per-formed.

§ One patient with autonomic dysfunction had dizziness combined with diarrhea after donor-feces infusion.

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Fecal Microbiota

The Simpson’s Reciprocal Index of diversity of fe-cal microbiota obtained from nine patients who were evaluated before the donor-feces infusion was consistently low (mean, 57±26) and increased within 2 weeks after infusion to 179±42 (P<0.001), becoming undistinguishable from the fecal mi-crobiota diversity level of the donors (mean, 172±54) (Fig. 3). In eight patients for whom sam-ples were available, the diversity of fecal micro-biota remained undistinguishable from that of the donor during follow-up.

In addition, a principal component analysis was performed on the phylogenetic microarray profiles of each sample. This unsupervised anal-ysis showed that nearly 50% of the variation in the data was explained by the first two principal components, indicating a major shift in the pa-tients’ microbiota after donor-feces infusion to-ward that of the donors (Fig. S2 in the Supple-mentary Appendix).

After donor-feces infusion, we observed quantitative changes in relevant groups of intes-tinal bacteria (P<0.05) (Table S2 in the Supple-mentary Appendix). These changes included in-creased numbers of Bacteroidetes species and of clostridium clusters IV and XIVa (by a factor of 2 to 4 for both groups) and decreased numbers of Proteobacteria (by a factor of up to 100).

Discussion

In this small, open-label, randomized, controlled trial, we found that the infusion of donor feces is a potential therapeutic strategy against recurrent C. difficile infection. Our study population of mainly elderly patients reflects the population in whom C. difficile infection develops in daily prac-tice. However, we excluded three groups of pa-tients at risk for recurrent C. difficile infection. Patients with prolonged immunodeficiency were excluded to prevent the potential translocation of infused intestinal bacteria. Infectious complica-tions were not observed after donor infusion in our study and have not been reported in the lit-erature.15 Also, critically ill patients who were admitted to an intensive care unit (ICU) were ex-cluded. However, C. difficile infection in the ICU is associated with high death rates,24 and anecdotal reports have shown promising results of donor-feces infusion in critically ill patients.25,26 The third excluded group comprised patients requir-

ing additional antibiotics to treat infections oth-er than C. difficile because it seems reasonable to postpone donor-feces infusion until antibiotics can be stopped, enabling colonization of the bowel with healthy donor feces.

Although our study was designed for patients with any recurrence of C. difficile infection, only 8 of 43 patients were included after a first re-lapse, reflecting the reluctance of patients and physicians to choose donor-feces infusion at an early stage. The efficacy of antibiotic therapy de-creases with subsequent recurrences, and it seems reasonable to initiate treatment with donor-feces infusion after the second or third relapse. It has yet to be established whether other promising treatment strategies, such as fidaxomycin or infu-sion of antibodies against clostridium toxins,3,27 are effective against recurrent C. difficile infection.

The power calculation of our study was based on the efficacy of vancomycin for a first recur-rence of C. difficile infection. Because most pa-tients had several relapses before inclusion in the study (typically, after a failure of vancomycin therapy), the efficacy of vancomycin in our study was considerably lower than expected, which prob-

Sim

pson

’s R

ecip

roca

l Ind

ex

250

150

200

100

50

0Donors Patients before

InfusionPatients after

Infusion

Figure 3. Microbiota Diversity in Patients before and after Infusion of Donor Feces, as Compared with Diversity in Healthy Donors.

Microbiota diversity is expressed as Simpson’s Recip-rocal Index of diversity in fecal samples obtained from nine patients before and 14 days after the first infusion of donor feces, as compared with their donors. The in-dex ranges from 1 to 250, with higher values indicating more diversity. The box-and-whisker plots indicate in-terquartile ranges (boxes), medians (dark horizontal lines in the boxes), and highest and lowest values (whiskers above and below the boxes).




ably contributed to the findings of a difference between study groups. At study termination, 16 patients had been treated with donor-feces infu-sion. The success rate of donor-feces infusion was extended off protocol in another 18 patients who had initially been assigned to receive antibiotic therapy. A prolonged tapering schedule of vanco-mycin may be prescribed for recurrent C. difficile infection and was not incorporated into the trial for practical reasons. This may be a limitation of our study, although 56% of the patients were un-successfully treated with prolonged and tapering vancomycin schedules before inclusion.

Several questions remain unanswered. The op-timal protocol for donor-feces infusion is un-known. We pretreated patients with vancomycin and bowel lavage, following a protocol that was effective in previously published case series.15,28 Bowel lavage was incorporated to reduce the pathogenic bowel content, facilitating coloniza-tion of healthy donor microbiota. Whether bowel lavage indeed contributes to the efficacy of do-nor-feces infusion is not known.29 However, the possibility that bowel lavage itself cures C. diffi-cile is unlikely, since no benefit was seen in the second control group, in whom vancomycin was combined with bowel lavage. Furthermore, the amount of feces required and the importance of varying potential routes of infusion (nasoduode-nal tube, enema, or colonoscopy) are unknown since the literature reports many different treat-ment protocols.15,18,30 In our study, infusion of a relatively large amount of feces through a naso-duodenal tube had an acceptable adverse-event profile and was logistically manageable.

The mechanism underlying the efficacy of donor-feces infusion is probably the reestablish-ment of the normal microbiota as a host defense

against C. difficile.31 Changes in the gut bacterial phyla Firmicutes and Bacteroidetes were associ-ated with C. difficile infection.31,32 We found that the fecal microbiota in patients with C. difficile infection had a reduced bacterial diversity, as com-pared with healthy persons, extending previous observations.12 Infusion of donor feces resulted in improvement in the microbial diversity, which persisted over time. Also, there was an increase in Bacteroidetes species and clostridium clusters IV and XIVa (Firmicutes), whereas Proteobacteria species decreased.

In conclusion, in patients with recurrent C. dif-ficile infection, the infusion of donor feces, as compared with vancomycin therapy, resulted in better treatment outcomes. In particular, patients with multiple relapses of C. difficile infection ben-efited from this unconventional approach.

Supported by grants from the Netherlands Organization for Health Research and Development (ZonMW, 170881001; VENI grant, MN: 016096044) and a Spinoza Award (to Dr. de Vos) from the Netherlands Organization for Scientific Research.

Dr. van Nood reports receiving lecture fees from Astellas; Drs. Kuijper, Speelman, and Keller, serving on an advisory board for and receiving consulting fees from Astellas; and Drs. Kuijper and Keller, serving on an advisory board for and receiv-ing consulting fees from Microbex. No other potential conflict of interest relevant to this article was reported.


We thank Hans Zaaijer and Tom van Gool for their contribu-tion to the donor screening; the European Study Group of Clos-tridium difficile for their support; Jeroen Jansen, Martijn Bauer, Jeanin van Hooft, Hanke Wattel, Wim Meijer, Jan Veenstra, An-nekatrien Depla, Ser Peters, Gitte van Twillert, Marcel Spanier, Michiel van Agtmael, Reindert Vermeijden, Gerard van Asselt, Oanh Thang, and all other participating doctors in the referring hospitals; Paul Fockens, Jan van der Meer, Harry Buller, Zinzi Hegeman, Rob Weijts, Isaie Reuling, Iuke Douwes Dekker, Men-no Vergeer, Wim Nicolaas, and Vanessa Harris for their contri-bution to the study; Philippe Puylaert and Wilma Akkermans-van Vliet for their assistance in the microbiota analysis; and Frank Giardiello, Johan Offerhaus, and Marcel Levi for review-ing a previous draft of the manuscript.

References

1. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with met-ronidazole. Clin Infect Dis 2005;40:1586-90.2. Pépin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006;42:758-64.3. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-31.4. Bartlett JG. The case for vancomycin

as the preferred drug for treatment of Clostridium difficile infection. Clin Infect Dis 2008;46:1489-92.5. Kelly CP, LaMont JT. Clostridium difficile — more difficult than ever. N Engl J Med 2008;359:1932-40.6. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strate-gies for 163 cases of recurrent Clostridi-um difficile disease. Am J Gastroenterol 2002;97:1769-75.7. McFarland LV, Surawicz CM, Green-berg RN, et al. A randomized placebo-controlled trial of Saccharomyces boular-dii in combination with standard

antibiotics for Clostridium difficile dis-ease. JAMA 1994;271:1913-8. [Erratum, JAMA 1994;272:518.]8. Walters BA, Roberts R, Stafford R, Seneviratne E. Relapse of antibiotic asso-ciated colitis: endogenous persistence of Clostridium difficile during vancomycin therapy. Gut 1983;24:206-12.9. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recur-rent Clostridium difficile diarrhoea. Lan-cet 2001;357:189-93.10. Idem. Asymptomatic carriage of Clos-tridium difficile and serum levels of IgG

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antibody against toxin A. N Engl J Med 2000;342:390-7.11. Leav BA, Blair B, Leney M, et al. Se-rum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI). Vaccine 2010; 28:965-9.12. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal mi-crobiome in recurrent Clostridium diffi-cile-associated diarrhea. J Infect Dis 2008; 197:435-8.13. Aas J, Gessert CE, Bakken JS. Recur-rent Clostridium difficile colitis: case se-ries involving 18 patients treated with donor stool administered via a nasogas-tric tube. Clin Infect Dis 2003;36:580-5.14. Borody TJ. “Flora power” — fecal bac-teria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028-9.15. van Nood E, Speelman P, Kuijper EJ, Keller JJ. Struggling with recurrent Clos-tridium difficile infections: is donor fae-ces the solution? Euro Surveill 2009; 14(34):pii:19316.16. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010;44:567-70.17. Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results of faecal donor instillation therapy for recurrent Clos-tridium difficile-associated diarrhoea. Scand J Infect Dis 2010;42:857-61.18. Gough E, Shaikh H, Manges AR. Sys-tematic review of intestinal microbiota

transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53:994-1002.19. Paltansing S, van den Berg RJ, Gu-seinova RA, Visser CE, van der Vorm ER, Kuijper EJ. Characteristics and incidence of Clostridium difficile-associated dis-ease in the Netherlands, 2005. Clin Mi-crobiol Infect 2007;13:1058-64.20. Salonen A, Nikkilä J, Jalanka-Tuovin-en J, et al. Comparative analysis of fecal DNA extraction methods with phyloge-netic microarray: effective recovery of bacterial and archaeal DNA using me-chanical cell lysis. J Microbiol Methods 2010;81:127-34.21. Rajilić-Stojanović M, Heilig HG, Mo-lenaar D, et al. Development and applica-tion of the human intestinal tract chip, a phylogenetic microarray: analysis of uni-versally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol 2009;11:1736-51.22. Zhou J, Xia B, Treves DS, et al. Spatial and resource factors influencing high mi-crobial diversity in soil. Appl Environ Mi-crobiol 2002;68:326-34.23. Benjamini YHY. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995;57:289-300.24. Kenneally C, Rosini JM, Skrupky LP, et al. Analysis of 30-day mortality for Clostridium difficile-associated disease in the ICU setting. Chest 2007;132:418-24.25. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in

the treatment of pseudomembranous en-terocolitis. Surgery 1958;44:854-9.26. You DM, Franzos MA, Holman RP. Successful treatment of fulminant Clos-tridium difficile infection with fecal bac-teriotherapy. Ann Intern Med 2008;148: 632-3.27. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010;362:197-205.28. Nieuwdorp M, van Nood E, Speelman P, et al. Treatment of recurrent Clostridi-um difficile-associated diarrhoea with a suspension of donor faeces. Ned Tijdschr Geneeskd 2008;152:1927-32. (In Dutch.)29. Liacouras CA, Piccoli DA. Whole-bowel irrigation as an adjunct to the treat-ment of chronic, relapsing Clostridium difficile colitis. J Clin Gastroenterol 1996; 22:186-9.30. Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009;15:285-9.31. Khoruts A, Dicksved J, Jansson JK, Sa-dowsky MJ. Changes in the composition of the human fecal microbiome after bac-teriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gas-troenterol 2010;44:354-60.32. Manges AR, Labbe A, Loo VG, et al. Comparative metagenomic study of alter-ations to the intestinal microbiota and risk of nosocomial Clostridium difficile-associated disease. J Infect Dis 2010;202: 1877-84.Copyright © 2013 Massachusetts Medical Society.

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n engl j med 369;9 nejm.org august 29, 2013840

Critical Care MedicineSimon R. Finfer, M.D., and Jean-Louis Vincent, M.D., Ph.D., Editors

Severe Sepsis and Septic ShockDerek C. Angus, M.D., M.P.H., and Tom van der Poll, M.D., Ph.D.

From the CRISMA (Clinical Research, Inves-tigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh (D.C.A.); and the Center for Experimental and Mo-lecular Medicine, Division of Infectious Diseases, and Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Am-sterdam (T.P.). Address reprint requests to Dr. Angus at the Department of Criti-cal Care Medicine, University of Pitts-burgh, 614 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261, or at [email protected]; or to Dr. van der Poll at the Division of Infectious Diseases, Academ-ic Medical Center, Meibergdreef 9, Rm. G2-130, 1105 AZ Amsterdam, the Nether-lands, or at [email protected].

This article was updated on November 21, 2013, at NEJM.org.

N Engl J Med 2013;369:840-51.DOI: 10.1056/NEJMra1208623Copyright © 2013 Massachusetts Medical Society.

Sepsis is one of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis (σηψις) was the process by which flesh rots, swamps generate foul airs, and wounds fester.1 Galen later considered sepsis

a laudable event, necessary for wound healing.2 With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infec-tion, often described as “blood poisoning,” and assumed to be the result of the host’s invasion by pathogenic organisms that then spread in the bloodstream. However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of sepsis: many patients with sepsis died despite successful erad-ication of the inciting pathogen. Thus, researchers suggested that it was the host, not the germ, that drove the pathogenesis of sepsis.3

In 1992, an international consensus panel defined sepsis as a systemic inflam-matory response to infection, noting that sepsis could arise in response to mul-tiple infectious causes and that septicemia was neither a necessary condition nor a helpful term.4 Instead, the panel proposed the term “severe sepsis” to describe instances in which sepsis is complicated by acute organ dysfunction, and they codified “septic shock” as sepsis complicated by either hypotension that is refrac-tory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus panel endorsed most of these concepts, with the caveat that signs of a systemic inflammatory response, such as tachycardia or an elevated white-cell count, occur in many infectious and noninfectious conditions and therefore are not helpful in distinguishing sepsis from other conditions.5 Thus, “severe sepsis” and “sepsis” are sometimes used interchangeably to describe the syndrome of infection com-plicated by acute organ dysfunction.

Incidence a nd C auses

The incidence of severe sepsis depends on how acute organ dysfunction is defined and on whether that dysfunction is attributed to an underlying infection. Organ dysfunction is often defined by the provision of supportive therapy (e.g., mechani-cal ventilation), and epidemiologic studies thus count the “treated incidence” rath-er than the actual incidence. In the United States, severe sepsis is recorded in 2% of patients admitted to the hospital. Of these patients, half are treated in the intensive care unit (ICU), representing 10% of all ICU admissions.6,7 The number of cases in the United States exceeds 750,000 per year7 and was recently reported to be rising.8 However, several factors — new International Classification of Diseases, 9th Revision (ICD-9) coding rules, confusion over the distinction between septicemia and severe sepsis, the increasing capacity to provide intensive care, and increased awareness and surveillance — confound the interpretation of temporal trends.

Studies from other high-income countries show similar rates of sepsis in the ICU.9 The incidence of severe sepsis outside modern ICUs, especially in parts of

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28 nejm readers’ choice clinical care collectioncritical care medicine

n engl j med 369;9 nejm.org august 29, 2013 841

the world in which ICU care is scarce, is largely unknown. Extrapolating from treated incidence rates in the United States, Adhikari et al. estimated up to 19 million cases worldwide per year.10 The true incidence is presumably far higher.

Severe sepsis occurs as a result of both com-munity-acquired and health care–associated in-fections. Pneumonia is the most common cause, accounting for about half of all cases, followed by intraabdominal and urinary tract infections.7,8,11,12 Blood cultures are typically positive in only one third of cases, and in up to a third of cases, cultures from all sites are negative.7,11,13,14 Staphy-lococcus aureus and Streptococcus pneumoniae are the most common gram-positive isolates, whereas Escherichia coli, klebsiella species, and Pseudomonas aeruginosa predominate among gram-negative iso-lates.11,14 An epidemiologic study of sepsis showed that during the period from 1979 to 2000, gram-positive infections overtook gram-negative infections.15 However, in a more recent study involving 14,000 ICU patients in 75 coun-tries, gram-negative bacteria were isolated in 62% of patients with severe sepsis who had positive cultures, gram-positive bacteria in 47%, and fungi in 19%.12

Risk factors for severe sepsis are related both to a patient’s predisposition for infection and to the likelihood of acute organ dysfunction if in-fection develops. There are many well-known risk factors for the infections that most commonly precipitate severe sepsis and septic shock, includ-ing chronic diseases (e.g., the acquired immuno-deficiency syndrome, chronic obstructive pul-monary disease, and many cancers) and the use of immunosuppressive agents.7 Among patients with such infections, however, the risk factors for organ dysfunction are less well studied but probably include the causative organism and the patient’s genetic composition, underlying health status, and preexisting organ function, along with the timeliness of therapeutic intervention.16 Age, sex, and race or ethnic group all influence the incidence of severe sepsis, which is higher in infants and elderly persons than in other age groups, higher in males than in females, and higher in blacks than in whites.7,17

There is considerable interest in the contribu-tion of host genetic characteristics to the inci-dence and outcome of sepsis, in part because of strong evidence of inherited risk factors.18 Many studies have focused on polymorphisms in genes

encoding proteins implicated in the pathogene-sis of sepsis, including cytokines and other me-diators involved in innate immunity, coagula-tion, and fibrinolysis. However, findings are often inconsistent, owing at least in part to the heterogeneity of the patient populations stud-ied.19,20 Although a recent genomewide associa-tion study21 explored drug responsiveness in sepsis, no such large-scale studies of susceptibil-ity to or outcome of sepsis have been performed.

Clinic a l Fe at ur es

The clinical manifestations of sepsis are highly variable, depending on the initial site of infec-tion, the causative organism, the pattern of acute organ dysfunction, the underlying health status of the patient, and the interval before initiation of treatment. The signs of both infection and or-gan dysfunction may be subtle, and thus the most recent international consensus guidelines provide a long list of warning signs of incipient sepsis (Table 1).5 Acute organ dysfunction most commonly affects the respiratory and cardiovas-cular systems. Respiratory compromise is classi-cally manifested as the acute respiratory distress syndrome (ARDS), which is defined as hypox-emia with bilateral infiltrates of noncardiac ori-gin.22 Cardiovascular compromise is manifested primarily as hypotension or an elevated serum lactate level. After adequate volume expansion, hypotension frequently persists, requiring the use of vasopressors, and myocardial dysfunction may occur.23

The brain and kidneys are also often affected. Central nervous system dysfunction is typically manifested as obtundation or delirium. Imaging studies generally show no focal lesions, and findings on electroencephalography are usually consistent with nonfocal encephalopathy. Criti-cal illness polyneuropathy and myopathy are also common, especially in patients with a pro-longed ICU stay.24 Acute kidney injury is mani-fested as decreasing urine output and an in-creasing serum creatinine level and frequently requires treatment with renal-replacement ther-apy. Paralytic ileus, elevated aminotransferase levels, altered glycemic control, thrombocytope-nia and disseminated intravascular coagulation, adrenal dysfunction, and the euthyroid sick syn-drome are all common in patients with severe sepsis.5




Ou t come

Before the introduction of modern intensive care with the ability to provide vital-organ support, severe sepsis and septic shock were typically le-thal. Even with intensive care, rates of in-hospital

death from septic shock were often in excess of 80% as recently as 30 years ago.25 However, with advances in training, better surveillance and monitoring, and prompt initiation of therapy to treat the underlying infection and support failing organs, mortality is now closer to 20 to 30% in

Table 1. Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.*

Sepsis (documented or suspected infection plus ≥1 of the following)†

General variables

Fever (core temperature, >38.3°C)

Hypothermia (core temperature, <36°C)

Elevated heart rate (>90 beats per min or >2 SD above the upper limit of the normal range for age)

Tachypnea

Altered mental status

Substantial edema or positive fluid balance (>20 ml/kg of body weight over a 24-hr period)

Hyperglycemia (plasma glucose, >120 mg/dl [6.7 mmol/liter]) in the absence of diabetes

Inflammatory variables

Leukocytosis (white-cell count, >12,000/mm3)

Leukopenia (white-cell count, <4000/mm3)

Normal white-cell count with >10% immature forms

Elevated plasma C-reactive protein (>2 SD above the upper limit of the normal range)

Elevated plasma procalcitonin (>2 SD above the upper limit of the normal range)

Hemodynamic variables

Arterial hypotension (systolic pressure, <90 mm Hg; mean arterial pressure, <70 mm Hg; or decrease in systolic pressure of >40 mm Hg in adults or to >2 SD below the lower limit of the normal range for age)

Elevated mixed venous oxygen saturation (>70%)‡

Elevated cardiac index (>3.5 liters/min/square meter of body-surface area)§

Organ-dysfunction variables

Arterial hypoxemia (ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, <300)

Acute oliguria (urine output, <0.5 ml/kg/hr or 45 ml/hr for at least 2 hr)

Increase in creatinine level of >0.5 mg/dl (>44 μmol/liter)

Coagulation abnormalities (international normalized ratio, >1.5; or activated partial-thromboplastin time, >60 sec)

Paralytic ileus (absence of bowel sounds)

Thrombocytopenia (platelet count, <100,000/mm3)

Hyperbilirubinemia (plasma total bilirubin, >4 mg/dl [68 μmol/liter])

Tissue-perfusion variables

Hyperlactatemia (lactate, >1 mmol/liter)

Decreased capillary refill or mottling

Severe sepsis (sepsis plus organ dysfunction)

Septic shock (sepsis plus either hypotension [refractory to intravenous fluids] or hyperlactatemia)¶

* Data are adapted from Levy et al.5

† In children, diagnostic criteria for sepsis are signs and symptoms of inflammation plus infection with hyperthermia or hypothermia (rectal temperature, >38.5°C or <35°C, respectively), tachycardia (may be absent with hypothermia), and at least one of the following indications of altered organ function: altered mental status, hypoxemia, increased serum lac-tate level, or bounding pulses.

‡ A mixed venous oxygen saturation level of more than 70% is normal in newborns and children (pediatric range, 75 to 80%).§ A cardiac index ranging from 3.5 to 5.5 liters per minute per square meter is normal in children.¶ Refractory hypotension is defined as either persistent hypotension or a requirement for vasopressors after the adminis-

tration of an intravenous fluid bolus.

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many series.7,26 With decreasing death rates, at-tention has focused on the trajectory of recovery among survivors. Numerous studies have sug-gested that patients who survive to hospital dis-charge after sepsis remain at increased risk for death in the following months and years. Those who survive often have impaired physical or neu-rocognitive functioning, mood disorders, and a low quality of life.27 In most studies, determining the causal role of sepsis in such subsequent disor-ders has been difficult. However, a recent analy-sis of the Health and Retirement Study, involving a large, longitudinal cohort of aging Americans, suggested that severe sepsis significantly acceler-ated physical and neurocognitive decline.28

Pathoph ysiol o gy

Host Response

As the concept of the host theory emerged, it was first assumed that the clinical features of sepsis were the result of overly exuberant inflamma-tion. Later, Bone et al.29 advanced the idea that the initial inflammatory response gave way to a subsequent “compensatory antiinflammatory re-sponse syndrome.” However, it has become ap-parent that infection triggers a much more com-plex, variable, and prolonged host response, in which both proinflammatory and antiinflamma-tory mechanisms can contribute to clearance of infection and tissue recovery on the one hand and organ injury and secondary infections on the other.30 The specific response in any patient de-pends on the causative pathogen (load and viru-lence) and the host (genetic characteristics and coexisting illnesses), with differential responses at local, regional, and systemic levels (Fig. 1). The composition and direction of the host response probably change over time in parallel with the clinical course. In general, proinflammatory reac-tions (directed at eliminating invading pathogens) are thought to be responsible for collateral tissue damage in severe sepsis, whereas antiinflamma-tory responses (important for limiting local and systemic tissue injury) are implicated in the en-hanced susceptibility to secondary infections.

Innate Immunity

Knowledge of pathogen recognition has in-creased tremendously in the past decade. Patho-gens activate immune cells through an interac-tion with pattern-recognition receptors, of which

four main classes — toll-like receptors, C-type lectin receptors, retinoic acid inducible gene 1–like receptors, and nucleotide-binding oligomerization domain–like receptors — have been identified, with the last group partially acting in protein complexes called inflammasomes (Fig. 1).31 These receptors recognize structures that are conserved among microbial species, so-called pathogen-associated molecular patterns, result-ing in the up-regulation of inflammatory gene transcription and initiation of innate immunity. The same receptors also sense endogenous mol-ecules released from injured cells, so-called damage-associated molecular patterns, or alarm-ins, such as high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and his-tones.32 Alarmins are also released during sterile injury such as trauma, giving rise to the concept that the pathogenesis of multiple organ failure in sepsis is not fundamentally different from that in noninfectious critical illness.32

Coagulation Abnormalities

Severe sepsis is almost invariably associated with altered coagulation, frequently leading to dis-seminated intravascular coagulation.33 Excess fibrin deposition is driven by coagulation through the action of tissue factor, a transmem-brane glycoprotein expressed by various cell types; by impaired anticoagulant mechanisms, including the protein C system and antithrom-bin; and by compromised fibrin removal owing to depression of the fibrinolytic system (Fig. 2).33 Protease-activated receptors (PARs) form the mo-lecular link between coagulation and inflamma-tion. Among the four subtypes that have been identified, PAR1 in particular is implicated in sepsis.33 PAR1 exerts cytoprotective effects when stimulated by activated protein C or low-dose thrombin but exerts disruptive effects on endo-thelial-cell barrier function when activated by high-dose thrombin.34 The protective effect of activated protein C in animal models of sepsis is dependent on its capacity to activate PAR1 and not on its anticoagulant properties.34

Antiinflammatory Mechanisms and Immunosuppression

The immune system harbors humoral, cellular, and neural mechanisms that attenuate the poten-tially harmful effects of the proinflammatory response (Fig. 1).30 Phagocytes can switch to an




antiinflammatory phenotype that promotes tis-sue repair, and regulatory T cells and myeloid-derived suppressor cells further reduce inflam-mation. In addition, neural mechanisms can inhibit inflammation.35 In the so-called neuroin-flammatory reflex, sensory input is relayed through the afferent vagus nerve to the brain stem, from which the efferent vagus nerve acti-vates the splenic nerve in the celiac plexus, re-sulting in norepinephrine release in the spleen and acetylcholine secretion by a subset of CD4+

T cells. The acetylcholine release targets α7 cho-linergic receptors on macrophages, suppressing the release of proinflammatory cytokines.36 In animal models of sepsis,35 disruption of this neural-based system by vagotomy increases sus-ceptibility to endotoxin shock, whereas stimula-tion of the efferent vagus nerve or α7 cholinergic receptors attenuates systemic inflammation.

Patients who survive early sepsis but remain dependent on intensive care have evidence of im-munosuppression, in part reflected by reduced

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nProinflammatory response Excessive inflammation causing collateral damage (tissue injury)

Antiinflammatory response

Pathogen factors

Host factors

EnvironmentGeneticsAgeOther illnessesMedications

Load VirulencePathogen-associated molecular patterns

Immunosuppression with enhanced susceptibility to secondary infections

CytokinesProteasesReactive oxygen species Complement products

Perpetuation of inflammation

Coagulation proteases

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Neuroendocrine regulationImpaired functionof immune cells

Inhibition of proinflammatory gene transcription

Complement activation Coagulation activation Necrotic cell death

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Vagus nerve

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Antiinflammatory cytokinesSoluble cytokine receptorsNegative regulators of TLR signalingEpigenetic regulation

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adrenal axis

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Host cell

Figure 1. The Host Response in Severe Sepsis.

The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosup-pressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined by both host factors (e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial load and virulence). In-flammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern-recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in part by acting on the same pattern-recognition receptors that are triggered by pathogens.

http://nejm.org




expression of HLA-DR on myeloid cells.37 These patients frequently have ongoing infectious foci, despite antimicrobial therapy, or reactivation of latent viral infection.38,39 Multiple studies have documented reduced responsiveness of blood leukocytes to pathogens in patients with sep-sis,30 findings that were recently corroborated by postmortem studies revealing strong functional impairments of splenocytes obtained from pa-

tients who had died of sepsis in the ICU.37 Be-sides the spleen, the lungs also showed evidence of immunosuppression; both organs had en-hanced expression of ligands for T-cell inhibi-tory receptors on parenchymal cells.37 Enhanced apoptosis, especially of B cells, CD4+ T cells, and follicular dendritic cells, has been implicat-ed in sepsis-associated immunosuppression and death.40,41 Epigenetic regulation of gene expres-

2

Drazen

8/29/13

7/24/13



Author

Fig #

Title

ME

DEArtist

Issue date

COLOR FIGURE

Draft 6Angus

Knoper

Mic

roci

rcul

atio

nTi

ssue

Release of mitochondrial

contents

Mitochondrialdysfunction

Increased coagulation Decreased anticoagulation

Monocyte

Neutrophil

NETs with trapped

platelets

Tissuefactor

↓ Antithrombin

Endothelial cell↓Tissue

factor pathway inhibitor ↓ TM ↓ Endothelial

protein C receptor

↓ Protein C

↓ Activatedprotein C

↓ Activated protein Cand ↑ thrombin

↓Fibrinolysis↑ PAI-1

Thrombosis

Tissue hypoperfusionLoss of

barrier function

↓Tissue oxygenation

Organ failure

↑PAR1

S1P3 S1P1

↑ S1P3 and ↓ S1P1

↑ Angiopoietin 2

↓ VE cadherin and↓Tight junctions

Cell shrinkageand cell death

Capillary leak and interstitial

edema

Vasodilatation

↓ Blood pressure

↓ Red-cell deformability

Thrombus

Tissue hypoperfusion Loss of barrier function

Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.

Sepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor) and im-pairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathways (mediated by acti-vated protein C, antithrombin, and tissue factor pathway inhibitor), plus impaired fibrinolysis owing to enhanced release of plasminogen activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced expression of two endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neu-trophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion, which is aggra-vated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired by the loss of barrier function of the endothelium owing to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial cell-to-cell tight junctions, high levels of angiopoietin 2, and a disturbed balance between sphingosine-1 phosphate receptor 1 (S1P1) and S1P3 within the vascular wall, which is at least in part due to preferential induction of S1P3 through protease activated receptor 1 (PAR1) as a result of a reduced ratio of activated protein C to thrombin. Oxygen use is impaired at the subcellular level because of damage to mitochondria from oxidative stress.




Tabl

e 2.

Gui

delin

es fo

r th

e Tr

eatm

ent o

f Sev

ere

Seps

is a

nd S

eptic

Sho

ck fr

om th

e Su

rviv

ing

Seps

is C

ampa

ign.

*

Elem

ent

of C

are

Gra

de†

Res

usci

tatio

n

Beg

in g

oal-d

irec

ted

resu

scita

tion

duri

ng fi

rst 6

hr

afte

r re

cogn

ition

1C

Beg

in in

itial

flui

d re

susc

itatio

n w

ith c

ryst

allo

id a

nd c

onsi

der

the

addi

tion

of a

lbum

in1B

Con

side

r th

e ad

ditio

n of

alb

umin

whe

n su

bsta

ntia

l am

ount

s of

cry

stal

loid

are

req

uire

d to

mai

ntai

n ad

equa

te a

rter

ial p

ress

ure

2C

Avo

id h

etas

tarc

h fo

rmul

atio

ns1C

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in in

itial

flui

d ch

alle

nge

in p

atie

nts

with

tiss

ue h

ypop

erfu

sion

and

sus

pect

ed h

ypov

olem

ia, t

o ac

hiev

e ≥3

0 m

l of c

ryst

allo

ids

per

kilo

gram

of b

ody

wei

ght‡

1C

Con

tinue

flui

d-ch

alle

nge

tech

niqu

e as

long

as

ther

e is

hem

odyn

amic

impr

ovem

ent

UG

Use

nor

epin

ephr

ine

as th

e fir

st-c

hoic

e va

sopr

esso

r to

mai

ntai

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mea

n ar

teri

al p

ress

ure

of ≥

65 m

m H

g1B

Use

epi

neph

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whe

n an

add

ition

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gent

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eede

d to

mai

ntai

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equa

te b

lood

pre

ssur

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vas

opre

ssin

(at

a d

ose

of 0

.03

units

/min

) w

ith w

eani

ng o

f nor

epin

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if to

lera

ted

UG

Avo

id th

e us

e of

dop

amin

e ex

cept

in c

aref

ully

sel

ecte

d pa

tient

s (e

.g.,

patie

nts

with

a lo

w r

isk

of a

rrhy

thm

ias

and

eith

er k

now

n m

arke

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ft v

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w h

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se d

obut

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add

it to

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card

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elev

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avas

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lum

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id th

e us

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intr

aven

ous

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ocor

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adeq

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d va

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r th

erap

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stor

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mod

ynam

ic s

tabi

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if h

ydro

cort

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e is

use

d, a

d-m

inis

ter

at a

dos

e of

200

mg/

day

2C

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et a

hem

oglo

bin

leve

l of 7

to 9

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patie

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with

out h

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, cri

tical

cor

onar

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tery

dis

ease

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myo

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, or

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ctio

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ain

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lture

s be

fore

ant

ibio

tic th

erap

y is

adm

inis

tere

d1C

Perf

orm

imag

ing

stud

ies

prom

ptly

to c

onfir

m s

ourc

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inis

ter

broa

d-sp

ectr

um a

ntib

iotic

ther

apy

with

in 1

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afte

r di

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sis

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ither

sev

ere

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r se

ptic

sho

ck1B

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Rea

sses

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tibio

tic th

erap

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ily fo

r de

-esc

alat

ion

whe

n ap

prop

riat

e1B

Perf

orm

sou

rce

cont

rol w

ith a

tten

tion

to r

isks

and

ben

efits

of t

he c

hose

n m

etho

d w

ithin

12

hr a

fter

dia

gnos

is1C

Res

pira

tory

sup

port

Use

a lo

w ti

dal v

olum

e an

d lim

itatio

n of

insp

irat

ory-

plat

eau-

pres

sure

str

ateg

y fo

r A

RD

S1A

/1B

App

ly a

min

imal

am

ount

of p

ositi

ve e

nd-e

xpir

ator

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essu

re in

AR

DS

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inis

ter

high

er r

athe

r th

an lo

wer

pos

itive

end

-exp

irat

ory

pres

sure

for

patie

nts

with

sep

sis-

indu

ced

AR

DS

2C

Use

rec

ruitm

ent m

aneu

vers

in p

atie

nts

with

sev

ere

refr

acto

ry h

ypox

emia

due

to A

RD

S2C

Use

pro

ne p

ositi

onin

g in

pat

ient

s w

ith s

epsi

s-in

duce

d A

RD

S an

d a

ratio

of t

he p

artia

l pre

ssur

e of

art

eria

l oxy

gen

(mm

Hg)

to th

e fr

actio

n of

insp

ired

oxy

gen

of

<100

, in

faci

litie

s th

at h

ave

expe

rien

ce w

ith s

uch

prac

tice

2C

Elev

ate

the

head

of t

he b

ed in

pat

ient

s un

derg

oing

mec

hani

cal v

entil

atio

n, u

nles

s co

ntra

indi

cate

d1B

Use

a c

onse

rvat

ive

fluid

str

ateg

y fo

r es

tabl

ishe

d ac

ute

lung

inju

ry o

r A

RD

S w

ith n

o ev

iden

ce o

f tis

sue

hypo

perf

usio

n1C

Use

wea

ning

pro

toco

ls1A

http://nejm.org




sion may also contribute to sepsis-associated immunosuppression.42

Organ Dysfunction

Although the mechanisms that underlie organ failure in sepsis have been only partially eluci-dated, impaired tissue oxygenation plays a key role (Fig. 2). Several factors — including hypo-tension, reduced red-cell deformability, and microvascular thrombosis — contribute to dimin-ished oxygen delivery in septic shock. Inflamma-tion can cause dysfunction of the vascular endo-thelium, accompanied by cell death and loss of barrier integrity, giving rise to subcutaneous and body-cavity edema.43 In addition, mitochondrial damage caused by oxidative stress and other mech-anisms impairs cellular oxygen use.44 Moreover, injured mitochondria release alarmins into the extracellular environment, including mitochon-drial DNA and formyl peptides, which can acti-vate neutrophils and cause further tissue injury.45

Tr e atmen t

The Surviving Sepsis Campaign, an international consortium of professional societies involved in critical care, treatment of infectious diseases, and emergency medicine, recently issued the third iteration of clinical guidelines for the manage-ment of severe sepsis and septic shock (Table 2).23 The most important elements of the guidelines are organized into two “bundles” of care: an ini-tial management bundle to be accomplished with-in 6 hours after the patient’s presentation and a management bundle to be accomplished in the ICU.23 Implementation of the bundles is associ-ated with an improved outcome.46,47

The principles of the initial management bundle are to provide cardiorespiratory resusci-tation and mitigate the immediate threats of uncontrolled infection. Resuscitation requires the use of intravenous fluids and vasopressors, with oxygen therapy and mechanical ventilation pro-vided as necessary. The exact components re-quired to optimize resuscitation, such as the choice and amount of fluids, appropriate type and intensity of hemodynamic monitoring, and role of adjunctive vasoactive agents, all remain the subject of ongoing debate and clinical trials; many of these issues will be covered in this se-ries.23 Nonetheless, some form of resuscitation is considered essential, and a standardized approach C

entr

al n

ervo

us s

yste

m s

uppo

rt

Use

sed

atio

n pr

otoc

ols,

targ

etin

g sp

ecifi

c do

se-e

scal

atio

n en

d po

ints

1B

Avo

id n

euro

mus

cula

r bl

ocke

rs if

pos

sibl

e in

pat

ient

s w

ithou

t AR

DS

1C

Adm

inis

ter

a sh

ort c

ours

e of

a n

euro

mus

cula

r bl

ocke

r (<

48 h

r) fo

r pa

tient

s w

ith e

arly

, sev

ere

AR

DS

2C

Gen

eral

sup

port

ive

care

Use

a p

roto

col-s

peci

fied

appr

oach

to b

lood

glu

cose

man

agem

ent,

with

the

initi

atio

n of

insu

lin a

fter

two

cons

ecut

ive

bloo

d gl

ucos

e le

vels

of >

180

mg/

dl (

10 m

mol

/lit

er),

targ

etin

g a

bloo

d gl

ucos

e le

vel o

f <18

0 m

g/dl

1A

Use

the

equi

vale

nt o

f con

tinuo

us v

enov

enou

s he

mof

iltra

tion

or in

term

itten

t hem

odia

lysi

s as

nee

ded

for

rena

l fai

lure

or

fluid

ove

rloa

d2B

Adm

inis

ter

prop

hyla

xis

for

deep

-vei

n th

rom

bosi

s1B

Adm

inis

ter

stre

ss-u

lcer

pro

phyl

axis

to p

reve

nt u

pper

gas

troi

ntes

tinal

ble

edin

g1B

Adm

inis

ter

oral

or

ente

ral f

eedi

ngs,

as

tole

rate

d, r

athe

r th

an e

ither

com

plet

e fa

stin

g or

pro

visi

on o

f onl

y in

trav

enou

s gl

ucos

e w

ithin

the

first

48

hr a

fter

a d

iagn

osis

of

sev

ere

seps

is o

r se

ptic

sho

ck2C

Add

ress

goa

ls o

f car

e, in

clud

ing

trea

tmen

t pla

ns a

nd e

nd-o

f-life

pla

nnin

g as

app

ropr

iate

1B

* D

ata

are

adap

ted

from

Del

linge

r et

al.23

AR

DS

deno

tes

acut

e re

spir

ator

y di

stre

ss s

yndr

ome,

and

IC

U in

tens

ive

care

uni

t.†

For

all

grad

es, t

he n

umbe

r in

dica

tes

the

stre

ngth

of t

he r

ecom

men

datio

n (1

, rec

omm

ende

d; 2

, sug

gest

ed),

and

the

lett

er in

dica

tes

the

leve

l of e

vide

nce,

from

hig

h (A

) to

low

(D

), w

ith

UG

indi

catin

g un

grad

ed. R

ecom

men

datio

ns t

hat

are

spec

ific

to p

edia

tric

sev

ere

seps

is in

clud

e th

erap

y w

ith fa

ce-m

ask

oxyg

en, h

igh-

flow

nas

al c

annu

la o

xyge

n, o

r na

soph

aryn

geal

con

-tin

uous

pos

itive

end

-exp

irat

ory

pres

sure

in t

he p

rese

nce

of r

espi

rato

ry d

istr

ess

and

hypo

xem

ia (

2C);

use

of p

hysi

cal e

xam

inat

ion

ther

apeu

tic e

nd p

oint

s, s

uch

as c

apill

ary

refil

l (2C

); a

d-m

inis

trat

ion

of a

bol

us o

f 20

ml o

f cry

stal

loid

s (o

r al

bum

in e

quiv

alen

t) p

er k

ilogr

am o

f bod

y w

eigh

t du

ring

a p

erio

d of

5 t

o 10

min

utes

for

hypo

vole

mia

(2C

); in

crea

sed

use

of in

otro

pes

and

vaso

dila

tors

in s

eptic

sho

ck w

ith lo

w c

ardi

ac o

utpu

t as

soci

ated

with

ele

vate

d sy

stem

ic v

ascu

lar

resi

stan

ce (

2C);

and

use

of h

ydro

cort

ison

e on

ly in

chi

ldre

n w

ith s

uspe

cted

or

prov

-en

abs

olut

e ad

rena

l ins

uffic

ienc

y (2

C).

‡ T

he g

uide

lines

rec

omm

end

com

plet

ing

the

initi

al fl

uid

resu

scita

tion

with

in 3

hou

rs (

UG

).




has been advocated to ensure prompt, effective management.23 The initial management of in-fection requires forming a probable diagnosis, obtaining cultures, and initiating appropriate and timely empirical antimicrobial therapy and source control (i.e., draining pus, if appropriate).

The choice of empirical therapy depends on the suspected site of infection, the setting in which the infection developed (i.e., home, nurs-ing home, or hospital), medical history, and lo-cal microbial-susceptibility patterns. Inappropri-ate or delayed antibiotic treatment is associated with increased mortality.48,49 Thus, intravenous antibiotic therapy should be started as early as possible and should cover all likely pathogens. It has not been determined whether combination antimicrobial therapy produces better outcomes than adequate single-agent antibiotic therapy in patients with severe sepsis.50-53 Current guide-lines recommend combination antimicrobial therapy only for neutropenic sepsis and sepsis caused by pseudomonas species. Empirical anti-fungal therapy should be used only in patients at high risk for invasive candidiasis.50

The patient should also be moved to an ap-propriate setting, such as an ICU, for ongoing care. After the first 6 hours, attention focuses on monitoring and support of organ function, avoidance of complications, and de-escalation of care when possible. De-escalation of initial broad-spectrum therapy may prevent the emergence of resistant organisms, minimize the risk of drug toxicity, and reduce costs, and evidence from observational studies indicates that such an ap-proach is safe.54 The only immunomodulatory therapy that is currently advocated is a short course of hydrocortisone (200 to 300 mg per day for up to 7 days or until vasopressor support is no longer required) for patients with refractory septic shock.23 This recommendation is support-ed by a meta-analysis,55 but the two largest stud-ies had conflicting results,56,57 and other clinical trials are ongoing.58,59

se a rch for ne w ther a pies

Recent Failures

One of the great disappointments during the past 30 years has been the failure to convert advances in our understanding of the underlying biologic features of sepsis into effective new therapies.60 Researchers have tested both highly specific

agents and agents exerting more pleiotropic ef-fects. The specific agents can be divided into those designed to interrupt the initial cytokine cascade (e.g., antilipopolysaccharide or anti–pro-inflammatory cytokine strategies) and those de-signed to interfere with dysregulated coagulation (e.g., antithrombin or activated protein C).61 The only new agent that gained regulatory approval was activated protein C.62 However, postapproval concern about the safety and efficacy of activated protein C prompted a repeat study, which did not show a benefit and led the manufacturer, Eli Lilly, to withdraw the drug from the market.11 All other strategies thus far have not shown efficacy. With the recent decision to stop further clinical devel-opment of CytoFab, a polyclonal anti–tumor ne-crosis factor antibody (ClinicalTrials.gov number, NCT01145560), there are no current large-scale trials of anticytokine strategies in the treatment of sepsis.

Among the agents with broader immunomod-ulatory effects, glucocorticoids have received the most attention. Intravenous immune globulin is also associated with a potential benefit,63 but important questions remain, and its use is not part of routine practice.23 Despite a large num-ber of observational studies suggesting that the use of statins reduces the incidence or improves the outcome of sepsis and severe infection,64 such findings have not been confirmed in ran-domized, controlled trials, so the use of statins is not part of routine sepsis care.23

PROBLEMS WITH therapeutic development

Faced with these disappointing results, many ob-servers question the current approach to the de-velopment of sepsis drugs. Preclinical studies commonly test drugs in young, healthy mice or rats exposed to a septic challenge (e.g., bacteria or bacterial toxins) with limited or no ancillary treat-ment. In contrast, patients with sepsis are often elderly or have serious coexisting illnesses, which may affect the host response and increase the risk of acute organ dysfunction. Furthermore, death in the clinical setting often occurs despite the use of antibiotics, resuscitation, and intensive life sup-port, and the disease mechanisms in such cases are probably very different from those underlying the early deterioration that typically occurs in ani-mal models in the absence of supportive care. There are also large between-species genetic dif-ferences in the inflammatory host response.65

http://nejm.org




In clinical studies, the enrollment criteria are typically very broad, the agent is administered on the basis of a standard formula for only a short period, there is little information on how the agent changes the host response and host–pathogen interactions, and the primary end point is death from any cause. Such a research strategy is prob-ably overly simplistic in that it does not select pa-tients who are most likely to benefit, cannot adjust therapy on the basis of the evolving host response and clinical course, and does not capture poten-tially important effects on nonfatal outcomes.

NEW STRATEGIES

Consequently, hope is pinned on newer so-called precision-medicine strategies with better preclin-ical models, more targeted drug development, and clinical trials that incorporate better patient selection, drug delivery, and outcome measure-ment. For example, options to enrich the pre-clinical portfolio include the study of animals that are more genetically diverse, are older, or have preexisting disease. Longer experiments with more advanced supportive care would allow better mimicry of the later stages of sepsis and multiorgan failure, permitting the testing of drugs in a more realistic setting and perhaps fa-cilitating the measurement of outcomes such as cognitive and physical functioning. In addition, preclinical studies could be used to screen for potential biomarkers of a therapeutic response for which there are human homologues.

Activated protein C mutants that lack antico-agulant properties are examples of more target-ed drug development and were shown to provide protection from sepsis-induced death in animals, without an increased risk of bleeding.66 Bio-markers such as whole-genome expression pat-terns in peripheral-blood leukocytes may aid in stratifying patients into more homogeneous sub-groups or in developing more targeted therapeu-tic interventions.67 The insight that severe sepsis can cause immunosuppression raises the possi-bility of using immune-stimulatory therapy (e.g., interleukin-7, granulocyte–macrophage colony-stimulating factor,68 or interferon-γ 69), but ide-ally, such therapy would be used only in patients in whom immunosuppression is identified or predicted. Thus, such therapies could be deployed on the basis of laboratory measures, such as monocyte HLA-DR expression. In addition, con-cern about accelerated neurocognitive decline in

survivors of sepsis opens up avenues to explore agents currently being tested in patients with dementia and related conditions.

The designs of trials could be modified to more easily incorporate these ideas. For exam-ple, the considerable uncertainty at the begin-ning of a trial with regard to the appropriate selection of patients and drug-administration strategy and the possibility of treatment inter-actions may be better handled with the use of a Bayesian design. A trial could commence with multiple study groups that reflect the various un-certainties to be tested but then automatically nar-row assignments to the best-performing groups on the basis of predefined-response adaptive randomization rules. Such designs could be par-ticularly helpful when testing combination ther-apy or incorporating potential biomarkers of drug responsiveness.

Conclusions

Severe sepsis and septic shock represent one of the oldest and most pressing problems in medi-cine. With advances in intensive care, increased awareness, and dissemination of evidence-based guidelines, clinicians have taken large strides in reducing the risk of imminent death associated with sepsis. However, as more patients survive sepsis, concern mounts over the lingering se-quelae of what was previously a lethal event. Strategies are also needed to reach the many mil-lions of patients with sepsis who are far from modern intensive care. At the same time, advanc-es in molecular biology have provided keen in-sight into the complexity of pathogen and alarm recognition by the human host and important clues to a host response that has gone awry. However, harnessing that information to provide effective new therapies has proved to be difficult. To further improve the outcome of patients with sepsis through the development of new therapeu-tic agents, newer, smarter approaches to clinical-trial design and execution are essential.

Dr. Angus reports receiving grant support through his insti-tution from Eisai, consulting fees from Idaho Technology, Pfizer, Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli Lilly for serving as a member of a clinical-trial data and safety monitoring board. Dr. van der Poll reports receiving grant sup-port through his institution from Sirtris Pharmaceuticals and consulting fees from Eisai. No other potential conflict of inter-est relevant to this article was reported.





References

1. Majno G. The ancient riddle of sigma eta psi iota sigma (sepsis). J Infect Dis 1991;163:937-45.2. Funk DJ, Parrillo JE, Kumar A. Sepsis and septic shock: a history. Crit Care Clin 2009;25:83-101.3. Cerra FB. The systemic septic response: multiple systems organ failure. Crit Care Clin 1985;1:591-607.4. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM Consensus Conference on sepsis and organ failure. Chest 1992;101: 1481-3.5. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS Inter-national Sepsis Definitions Conference. Crit Care Med 2003;31:1250-6.6. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflamma-tory response syndrome (SIRS): a prospec-tive study. JAMA 1995;273:117-23.7. Angus DC, Linde-Zwirble WT, Lidick-er J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the Unit-ed States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10.8. Lagu T, Rothberg MB, Shieh MS, Pe-kow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012;40:754-6. [Erra-tum, Crit Care Med 2012;40:2932.]9. Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care 2004;8:222-6.10. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet 2010;376:1339-46.11. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055-64.12. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9.13. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombi-nant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003;290:238-47.14. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (ac-tivated). Clin Infect Dis 2003;37:50-8.15. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.16. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29: Suppl:S109-S116.17. Mayr FB, Yende S, Linde-Zwirble WT,

et al. Infection rate and acute organ dys-function risk as explanations for racial differences in severe sepsis. JAMA 2010; 303:2495-503.18. Sørensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environ-mental influences on premature death in adult adoptees. N Engl J Med 1988;318:727-32.19. Chung LP, Waterer GW. Genetic pre-disposition to respiratory infection and sepsis. Crit Rev Clin Lab Sci 2011;48:250-68.20. Namath A, Patterson AJ. Genetic polymorphisms in sepsis. Crit Care Nurs Clin North Am 2011;23:181-202.21. Man M, Close SL, Shaw AD, et al. Be-yond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacoge-nomics J 2012 February 7 (Epub ahead of print).22. Ranieri VM, Rubenfeld GD, Thomp-son BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33.23. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: interna-tional guidelines for management of se-vere sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637.24. De Jonghe B, Sharshar T, Lefaucheur J, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859-67.25. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time? Crit Care Med 1998;26:2078-86.26. Kumar G, Kumar N, Taneja A, et al. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest 2011;140: 1223-31.27. Angus DC, Carlet J. Surviving inten-sive care: a report from the 2002 Brussels Roundtable. Intensive Care Med 2003;29: 368-77.28. Iwashyna TJ, Ely EW, Smith DM, Lan-ga KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010;304:1787-94.29. Bone RC, Grodzin CJ, Balk RA. Sep-sis: a new hypothesis for pathogenesis of the disease process. Chest 1997;112:235-43.30. van der Poll T, Opal SM. Host-patho-gen interactions in sepsis. Lancet Infect Dis 2008;8:32-43.31. Takeuchi O, Akira S. Pattern recogni-tion receptors and inf lammation. Cell 2010;140:805-20.32. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest 2012;122:2711-9.33. Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010;38: Suppl:S26-S34.

34. Ruf W. New players in the sepsis-pro-tective activated protein C pathway. J Clin Invest 2010;120:3084-7.35. Andersson U, Tracey KJ. Reflex prin-ciples of immunological homeostasis. Annu Rev Immunol 2012;30:313-35.36. Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve cir-cuit. Science 2011;334:98-101.37. Boomer JS, To K, Chang KC, et al. Im-munosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306:2594-605.38. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008;300:413-22.39. Torgersen C, Moser P, Luckner G, et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg 2009;108:1841-7.40. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002;168:2493-500.41. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immu-nol 2001;166:6952-63.42. Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of im-mune cell functions during post-septic immunosuppression. Epigenetics 2011;6: 273-83.43. Goldenberg NM, Steinberg BE, Slutsky AS, Lee WL. Broken barriers: a new take on sepsis pathogenesis. Sci Transl Med 2011;3:88ps25.44. Galley HF. Oxidative stress and mito-chondrial dysfunction in sepsis. Br J An-aesth 2011;107:57-64.45. Zhang Q, Raoof M, Chen Y, et al. Cir-culating mitochondrial DAMPs cause in-flammatory responses to injury. Nature 2010;464:104-7.46. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and out-come after a multicenter severe sepsis edu-cational program in Spain. JAMA 2008; 299:2294-303.47. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010;38:367-74.48. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic re-view and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother 2010;54:4851-63.49. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the

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critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-96.50. Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for pa-tients with severe sepsis and septic shock: an evidence-based review. Crit Care Med 2004;32:S495-S512.51. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacte-raemia? A meta-analysis. Lancet Infect Dis 2004;4:519-27.52. Brunkhorst FM, Oppert M, Marx G, et al. Effect of empirical treatment with moxifloxacin and meropenem vs merope-nem on sepsis-related organ dysfunction in patients with severe sepsis: a random-ized trial. JAMA 2012;307:2390-9.53. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam mono-therapy versus beta lactam-aminoglyco-side combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004;328:668. [Erratum, BMJ 2004;328:884.]54. Heenen S, Jacobs F, Vincent JL. Anti-biotic strategies in severe nosocomial sepsis: why do we not de-escalate more often? Crit Care Med 2012;40:1404-9.55. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of

severe sepsis and septic shock in adults: a systematic review. JAMA 2009;301:2362-75.56. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71.57. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.58. ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock (ADRENAL). ClinicalTrials.gov, 2013 (http://clinicaltrials.gov/ct2/show/NCT01448109).59. Hydrocortisone for Prevention of Sep-tic Shock (HYPRESS). ClinicalTrials.gov, 2013 (http://www.clinicaltrials.gov/ct2/show/NCT00670254).60. Angus DC. The search for effective therapy for sepsis: back to the drawing board? JAMA 2011;306:2614-5.61. Webster NR, Galley HF. Immuno-modulation in the critically ill. Br J An-aesth 2009;103:70-81.62. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant hu-man activated protein C for severe sepsis. N Engl J Med 2001;344:699-709.63. Laupland KB, Kirkpatrick AW, Delaney A. Polyclonal intravenous immunoglobu-lin for the treatment of severe sepsis and

septic shock in critically ill adults: a sys-tematic review and meta-analysis. Crit Care Med 2007;35:2686-92.64. Yende S, Milbrandt EB, Kellum JA, et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med 2011;39:1871-8.65. Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory dis-eases. Proc Natl Acad Sci U S A 2013;110: 3507-12.66. Kerschen EJ, Fernandez JA, Cooley BC, et al. Endotoxemia and sepsis mortal-ity reduction by non-anticoagulant acti-vated protein C. J Exp Med 2007;204:2439-48.67. Wong HR. Clinical review: sepsis and septic shock — the potential of gene ar-rays. Crit Care 2012;16:204.68. Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stim-ulating factor to reverse sepsis-associated immunosuppression: a double-blind, ran-domized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009; 180:640-8.69. Döcke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997;3:678-81.Copyright © 2013 Massachusetts Medical Society.

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nejm.org 39

clinical practice



This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the author’s clinical recommendations.

An audio version of this article is available at NEJM.org

Vitamin B12 DeficiencySally P. Stabler, M.D.

From the University of Colorado School of Medicine, Aurora. Address reprint re-quests to Dr. Stabler at the Division of Hematology, University of Colorado, Aurora, CO 80045, or at [email protected].

N Engl J Med 2013;368:149-60. DOI: 10.1056/NEJMcp1113996Copyright © 2013 Massachusetts Medical Society.

A 57-year-old woman reports increasing symptoms of painful paresthesias in both legs for the past 18 months. Physical examination reveals impaired position sense and vibration sense. The serum vitamin B12 level is 205 pg per milliliter (151.2 pmol per liter), which is above the lower end of the laboratory reference range. The hemato-crit is 42%, with a mean corpuscular volume of 96 fl. The serum methylmalonic acid level is 3600 nmol per liter (normal level, <400), and the serum homocysteine level 49.1 μmol per liter (normal level, <14). How should this patient be further evaluated and treated?

The Clinic a l Problem

The recognition and treatment of vitamin B12 deficiency is critical since it is a re-versible cause of bone marrow failure and demyelinating nervous system disease. Vitamin B12 (cobalamin) is synthesized by microorganisms and detected in trace amounts mostly in foods of animal origin.1 Uptake in the gastrointestinal tract depends on intrinsic factor, which is synthesized by the gastric parietal cells, and on the “cubam receptor” in the distal ileum.2 The most frequent cause of severe vitamin B12 deficiency is a loss of intrinsic factor due to autoimmune atrophic gas-tritis,3 historically called “pernicious anemia,” even though many patients present with mainly neurologic manifestations.4,5

Pathophysiology of Vitamin B12 Deficiency

Vitamin B12 is a cofactor for only two enzymes: methionine synthase and l-methyl-malonyl–coenzyme A mutase6,7 (see Fig. 1 in the Supplementary Appendix, avail-able with the full text of this article at NEJM.org). The interaction between folate and B12 is responsible for the megaloblastic anemia seen in both vitamin deficien-cies. Dyssynchrony between the maturation of cytoplasm and that of nuclei leads to macrocytosis, immature nuclei, and hypersegmentation in granulocytes6 in the peripheral blood (Fig. 1A). The hypercellular and dysplastic bone marrow can be mistaken for signs of acute leukemia (Fig. 1B).10 The ineffective erythropoiesis re-sults in intramedullary hemolysis and release of lactate dehydrogenase, features that are similar to those of microangiopathic hemolytic anemia.8 Clinical and labo-ratory findings of megaloblastic anemia in the peripheral blood and bone marrow are shown in Figure 2.

Vitamin B12 is necessary for the development and initial myelination of the central nervous system as well as for the maintenance of its normal function. Demyelination of the cervical and thoracic dorsal and lateral columns of the spinal cord, occasional demyelination of cranial and peripheral nerves, and demyelin-ation of white matter in the brain5 (i.e., “combined-systems disease” or “subacute combined degeneration”) can occur with vitamin B12 deficiency (Fig. 2). Pathologi-

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40 nejm readers’ choice clinical care collectionT h e n e w e ngl a nd j o u r na l o f m e dic i n e


cal analysis reveals a “spongy degeneration” due to the loss of and swelling of myelin sheaths; this degeneration is visible on magnetic reso-nance imaging.11 For unclear reasons, the sever-ity of megaloblastic anemia is inversely corre-lated with the degree of neurologic dysfunction.4,5

Less common conditions associated with vi-tamin B12 deficiency include glossitis, malab-sorption, infertility, and thrombosis (including thrombosis at unusual sites such as cerebral ve-nous sinus thrombosis).12,13 Thrombosis has been attributed to the marked hyperhomocysteinemia seen in severe cases of vitamin B12 deficiency. Patients occasionally have hyperpigmentation, which clears with treatment.6

Causes of Vitamin B12 Deficiency

Table 1 and Figure 3 list causes of vitamin B12 deficiency and recommended management. Per-nicious anemia is discussed below, since this is the most common cause of severe vitamin B12 deficiency worldwide.

Dietary vitamin B12 deficiency in infants and children is also discussed because of the in-creasing recognition of severe abnormalities in exclusively breast-fed infants of mothers with vitamin B12 deficiency.

Pernicious AnemiaPernicious anemia1 is an autoimmune gastritis resulting from the destruction of gastric parietal cells and the associated lack of intrinsic factor to bind ingested vitamin B12. The immune response is directed against the gastric H/K–ATPase, which accounts for associated achlorhydria.2,3 Other autoimmune disorders, especially thyroid disease, type 1 diabetes mellitus, and vitiligo, are

also commonly associated with pernicious ane-mia. Whether the stomach pathogen Helicobacter pylori plays a causative role in pernicious anemia is unclear.19 Autoimmune gastritis may cause malabsorption of iron, with clinical iron deficien-cy developing early in life and eventually progress-ing to malabsorption of vitamin B12.20 The preva-lence of pernicious anemia ranges from 50 to 4000 cases per 100,000 persons, depending on the diagnostic criteria.1 All age groups are af-fected, but the median age range in large series is 70 to 80 years.21,22 Pernicious anemia is more common in persons of African or European an-cestry (4.3% and 4.0% prevalence among older adults, respectively) than in those of Asian ances-try.1,21 Milder forms of atrophic gastritis with hypochlorhydria and an inability to release di-etary protein-bound vitamin B12 affect up to 20% of older adults.19,23,24

Dietary Deficiency in Infancy and ChildhoodThe infant of a mother with vitamin B12 defi-ciency may be born with the deficiency or it may occur if he or she is exclusively breast-fed,15,16 usually between 4 and 6 months of age. Typical manifestations of vitamin B12 deficiency in chil-dren include failure of brain development and overall growth and development, developmental regression, hypotonia, feeding difficulties, leth-argy, tremors, hyperirritability, and coma (Fig. 2).15,16 Brain imaging may reveal atrophy and delayed myelination. Anemia may be present. Vitamin B12 replacement results in rapid im-provement in responsiveness, and many infants recover fully. However, the longer the period of deficiency, the more likely that there will be permanent disabilities. Mothers of infants with

key Clinical points

vitamin b12 deficiency

• Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating neurologic disease, or both.

• Autoimmune gastritis (pernicious anemia) is the most common cause of severe deficiency.

• Methodologic problems may compromise the sensitivity and specificity of current vitamin B12 assays.

• Measurement of methylmalonic acid, homocysteine, or both is used to confirm vitamin B12 deficiency in untreated patients; an elevated level of methylmalonic acid is more sensitive and specific for the diagnosis.

• For patients with pernicious anemia or malabsorption, lifelong vitamin B12 therapy is indicated.

• High-dose oral vitamin B12 tablets (1000 to 2000 µg) taken daily are as effective as intramuscular monthly injections in correcting blood and neurologic abnormalities.


nejm.org 41clinical pr actice


vitamin B12 deficiency often have unrecognized pernicious anemia, but alternatively, they may have a history of gastric bypass surgery, the short-gut syndrome, or a long-term vegetarian or vegan diet.16 Tandem mass spectrometry, used in neonatal screening programs in all 50 states, may detect nutritional B12 deficiency owing to an increase in propionyl carnitine, but direct measurement of methylmalonic acid has higher sensitivity.25 Other causes of B12 deficiency in children, such as ileal resections, the Imerslund–Gräsbeck syndrome, inflammatory bowel disease, and pernicious anemia, are listed in Table 1.18

S tr ategies a nd E v idence

Evaluation

Both the clinical recognition of vitamin B12 defi-ciency and confirmation of the diagnosis by means of testing can be difficult. An approach to testing is shown in Table 2.

The patient’s history may include symptoms of anemia, underlying disorders causing malab-sorption, and neurologic symptoms. The most common neurologic symptoms are symmetric paresthesias or numbness and gait problems.4,5 The physical examination may reveal pallor, ede-ma, pigmentary changes in the skin, jaundice, or neurologic defects such as impaired vibration sense, impaired position and cutaneous sensa-tion, ataxia, and weakness (Fig. 2).

Bone marrow biopsy and aspiration are not necessary for the diagnosis of megaloblastic anemia and may be misleading in cases of severe pancytopenia with hypercellularity, increased erythroblasts, and even cytogenetic abnormali-ties, confusing the diagnosis with acute leuke-mia.8-10 Imaging of the spinal cord is not indi-cated in patients with recognized vitamin B12 deficiency, but in cases of severe myelopathy that are not initially recognized as the result of vita-min B12 deficiency, there is characteristic hyper-intensity on T2-weighted imaging, described as an inverted V-shaped pattern in the cervical and thoracic spinal cord.11

Vitamin B12 AssayThe first test performed to confirm the diagnosis of vitamin B12 deficiency is generally measure-ment of the serum vitamin B12 level. Although an extremely low level (<100 pg per milliliter [<73.8 pmol per liter]) is usually associated with clinical deficiency, such low levels are infre-

quently observed. Both false negative and false positive values are common (occurring in up to 50% of tests) with the use of the laboratory- reported lower limit of the normal range as a cutoff point for deficiency.4,24,26 The high rate of false negative and false positive results may be

A

B

Figure 1. Peripheral-Blood Cells and Bone Marrow Specimen Obtained from a Patient with Vitamin B12 Deficiency.

In Panel A, a peripheral-blood smear shows oval macro-cytes as well as fragmented, misshapen cells and an immature megaloblastic nucleated red cell (arrow). The variation in red-cell size and shape could lead to a misdiagnosis of microangiopathic hemolytic anemia instead of megaloblastic anemia.8,9 The mean corpuscu-lar volume was in the normal range, but an extremely high red-cell distribution width suggested macrocytosis combined with microcytic fragmented cells. In Panel B, a bone marrow aspirate shows megaloblastic features. Large erythroblasts and other red-cell precursors are characterized by an open, immature nuclear chromatin pattern. There is dyssynchrony between the maturation of cytoplasm and that of nuclei in later red-cell and granulocyte precursors. A “giant” band is present. Sev-eral red-cell precursors have dysplastic nuclei (arrows), with nuclear fragments (arrowhead) that are compati-ble with cellular apoptosis and resulting intramedullary hemolysis. (Photographs courtesy of John W. Ryder, M.D., Department of Pathology, University of Colorado School of Medicine.)

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BrainAltered mental statusCognitive defects“Megaloblastic madness”: depression, mania, irritability, paranoia, delusions, lability

Optic atrophy, anosmia, loss of taste, glossitis

Infertility

Bone marrowHypercellular, increased erythroid precursorsOpen, immature nuclear chromatinDyssynchrony between maturation of cytoplasm and nucleiGiant bands, metamyelocytesKaryorrhexis, dysplasiaAbnormal results on flow cytometry and cytogenetic analysis

Spinal cordMyelopathySpongy degeneration

ParesthesiasLoss of proprioception: vibration, position, ataxic gait, limb weakness; spasticity (hyperreflexia); positive Romberg sign; Lhermitte’s sign; segmental cutaneous sensory level

Autonomic nervous systemPostural hypotensionIncontinenceImpotence

Peripheral nervous systemCutaneous sensory lossHyporeflexiaSymmetric weaknessParesthesias

Abnormalities in infants and childrenDevelopmental delay or regression, permanent disabilityDoes not smileFeeding difficultiesHypotonia, lethargy, comaHyperirritability, convulsions, tremors, myoclonusMicrocephalyChoreoathetoid movements

Peripheral bloodMacrocytic red cells, macroovalocytesAnisocytosis, fragmented formsHypersegmented neutrophils, 1% with six lobes or 5% with 5 lobesLeukopenia, possible immature white cellsThrombocytopeniaPancytopeniaElevated lactate dehydrogenase level (extremes possible)Elevated indirect bilirubin and aspartate aminotransferase levelsDecreased haptoglobin levelElevated levels of methylmalonic acid, homocysteine, or both




due to the fact that only 20% of the total mea-sured vitamin B12 is on the cellular delivery pro-tein, transcobalamin; the remainder is bound to haptocorrin, a protein of unknown function.27 Most laboratories now perform automated assays of vitamin B12 on platforms used for many other analytes. There is often poor agreement when samples are assayed by different laboratories or with the use of different methods.31-34 Because intrinsic factor is used as the assay-binding pro-tein, anti–intrinsic factor antibodies (which are common in pernicious anemia) must be removed chemically from the sample, which has proved to be problematic in the automated assays.33,34 Re-cent studies show normal values34 or falsely high values33 of vitamin B12 in many patients with per-nicious anemia. New assays of holotranscobala-min (to measure the vitamin B12 saturation of transcobalamin) provide a modest improvement in specificity over that provided by assays of total serum vitamin B12, but they have not been clini-cally validated27-29 and are not yet available com-mercially in the United States.

Given the limitations of available assays, cli-nicians should not use a laboratory’s reported lower limit of the normal range to rule out the diagnosis of vitamin B12 deficiency in patients with compatible clinical abnormalities. Clinicians should also recognize that vitamin B12 values are frequently low in patients without other meta-bolic or clinical evidence of vitamin B12 deficiency (i.e., megaloblastic anemia or myelopathy).

Measurement of Serum Methylmalonic Acid and Total HomocysteineMeasurement of methylmalonic acid, total ho-mocysteine, or both is useful in making the diag-nosis of vitamin B12 deficiency in patients who have not received treatment.4,22,24,26,33,35,36 The levels of both methylmalonic acid and total ho-

mocysteine are markedly elevated in the vast ma-jority (>98%) of patients with clinical B12 defi-ciency (Fig. 4),7,22 including those who have only neurologic manifestations of deficiency (i.e., no anemia).4,22

Elevated levels of methylmalonic acid and total homocysteine decrease immediately after treat-ment, and the levels can be remeasured to docu-ment adequate vitamin B12 replacement. Levels of these metabolites are normal in up to 50% of patients with low vitamin B12 levels who have no hematologic or neurologic response to replacement therapy, indicating that the low values are false positive results.26 Given the limitations of vitamin B12 assays in confirming the diagnosis of B12 deficiency,31,34 it may be prudent to measure meth-ylmalonic acid, total homocysteine, or both in pa-tients with compatible clinical findings or pro-vide empirical treatment with the use of defined end points to document a clinical response.

An elevated level of methylmalonic acid is rea-sonably specific for vitamin B12 deficiency, and the level always decreases with vitamin B12 thera-py.24,36 Modest increases (to 300 to 700 nmol per liter) occur with renal failure.36,37 However, nearly all patients with megaloblastic anemia or myelopathy have levels of methylmalonic acid that are higher than 500 nmol per liter, and 86% have levels that are higher than 1000 nmol per liter (Fig. 3). The level of serum total homocys-teine is less specific, since it is also elevated in folate deficiency,22,35 classic homocystinuria, and renal failure.

Tests to Determine the Cause of Vitamin B12 Deficiency

If the patient consumes sufficient amounts of vi-tamin B12 and has clinically confirmed B12 defi-ciency, then malabsorption must be present. Testing for pernicious anemia is described in Table 2. A positive test for anti–intrinsic factor or anti–parietal-cell antibodies is indicative of per-nicious anemia; surveillance for autoimmune thyroid disease is reasonable in patients with positive antibody tests. Chronic atrophic gastritis can be diagnosed on the basis of an elevated fast-ing serum gastrin level and a low level of serum pepsinogen I.3,19 Some experts recommend en-doscopy to confirm gastritis and rule out gastric carcinoid and other gastric cancers, since pa-tients with pernicious anemia are at increased risk for such cancers.3

The Schilling test of radioactive vitamin B12

Figure 2 (facing page). Clinical and Laboratory Findings in Vitamin B12 Deficiency.

The spectrum of disease associated with vitamin B12 deficiency is wide, from asymptomatic to life-threatening pancytopenia or myelopathy. An increase in the mean red-cell volume or distribution width or a mean volume that is higher than expected for the patient’s age, pre-sumed iron status (either high or low iron levels), and the presence of thalassemia are important determinants of macrocytosis, rather than an absolute value above the reference range. Cerebral symptoms are usually accom-panied by paresthesias and signs of myelopathy or neuropathy.5

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en m

onth

ly fo

r life

, or o

ral c

yano

coba

la-

min

at a

dai

ly d

ose

of 1

000

to 2

000

µg fo

r lif

e*

Adm

inis

ter

iron

and

fola

te r

epla

cem

ent a

s ne

eded

for

full

hem

o-gl

obin

res

pons

e, e

spec

ially

in p

atie

nts

with

inte

stin

al d

is-

ease

; per

form

sur

veill

ance

for

othe

r au

toim

mun

e co

ndi-

tions

, esp

ecia

lly th

yroi

d di

seas

e in

pat

ient

s w

ith p

erni

ciou

s an

emia

; per

form

upp

er e

ndos

copy

in p

atie

nts

with

sym

p-to

ms

of g

astr

ic c

ance

r† o

r ir

on d

efic

ienc

y

Tota

l or

part

ial g

astr

ecto

my

Sam

e as

for

pern

icio

us a

nem

iaSa

me

as fo

r pe

rnic

ious

ane

mia

Gas

tric

byp

ass

or o

ther

bar

iatr

ic s

urge

rySa

me

as fo

r pe

rnic

ious

ane

mia

Sam

e as

for

pern

icio

us a

nem

ia

Ileal

res

ectio

n or

org

an r

econ

stru

ctiv

e su

rger

y (i

leal

con

duit

dive

rsio

n an

d ile

ocys

to-

plas

ty)

Sam

e as

for

pern

icio

us a

nem

iaSa

me

as fo

r pe

rnic

ious

ane

mia

Infla

mm

ator

y bo

wel

dis

ease

, tro

pica

l spr

ueSa

me

as fo

r pe

rnic

ious

ane

mia

Sam

e as

for

pern

icio

us a

nem

ia

Imer

slun

d–G

räsb

eck

and

othe

r sy

ndro

mes

‡Sa

me

as fo

r pe

rnic

ious

ane

mia

Gen

etic

cou

nsel

ing

to d

etec

t vita

min

B12

def

icie

ncy

in fa

mily

m

embe

rs

Mild

mal

abso

rptio

n

Prot

ein-

boun

d vi

tam

in B

12 m

alab

sorp

tion

Ora

l cya

noco

bala

min

at a

dos

e of

500

to 1

000

µg d

aily

or

intr

a-m

uscu

lar

cyan

ocob

alam

in a

t a d

ose

of 1

000

µg d

aily

or

ever

y ot

her

day

for

1 w

k, th

en w

eekl

y fo

r 4

to 8

wk,

and

then

m

onth

ly fo

r lif

e

Perf

orm

test

s fo

r ir

on d

efic

ienc

y, a

nem

ia o

f chr

onic

kid

ney

dis-

ease

, and

ane

mia

of c

hron

ic in

flam

mat

ion;

thes

e co

nditi

ons

coex

ist f

requ

ently

in o

lder

adu

lts, m

ay li

mit

the

resp

onse

to

trea

tmen

t, an

d m

ay r

equi

re fu

rthe

r tr

eatm

ent

Mild

atr

ophi

c ga

stri

tisSa

me

as fo

r pr

otei

n-bo

und

vita

min

B12

mal

abso

rptio

nSa

me

as fo

r pr

otei

n-bo

und

vita

min

B12

mal

abso

rptio

n

Use

of m

etfo

rmin

14Sa

me

as fo

r pr

otei

n-bo

und

vita

min

B12

mal

abso

rptio

nSa

me

as fo

r pr

otei

n-bo

und

vita

min

B12

mal

abso

rptio

n

Use

of d

rugs

that

blo

ck s

tom

ach

acid

Sam

e as

for

prot

ein-

boun

d vi

tam

in B

12 m

alab

sorp

tion

Sam

e as

for

prot

ein-

boun

d vi

tam

in B

12 m

alab

sorp

tion

Die

tary

def

icie

ncy

Adu

lts Veg

an o

r ve

geta

rian

die

t, or

die

t low

in m

eat

and

dair

y pr

oduc

tsSu

pple

men

ts c

onta

inin

g >2

µg

of v

itam

in B

12 o

r fo

ods

fort

ified

w

ith v

itam

in B

12

Perf

orm

test

s fo

r ir

on d

efic

ienc

y, w

hich

is v

ery

com

mon

Infa

nts

Bre

ast-

feed

ing

in in

fant

s w

ith v

itam

in B

12–

defic

ient

mot

hers

15,1

6In

tram

uscu

lar

cyan

ocob

alam

in a

t a d

ose

of 2

50 to

100

0 µg

dai

ly,

then

wee

kly

until

pat

ient

rec

over

s; tr

eatm

ent o

f mot

her

to

enri

ch b

reas

t milk

; ora

l sup

plem

enta

tion

with

1 to

2 µ

g of

vi

tam

in B

12 d

aily

or

vita

min

B12

–enr

iche

d fo

rmul

a or

food

Con

firm

met

abol

ic r

espo

nse

in in

fant

s or

ref

er p

aren

ts to

gen

et-

ics

spec

ialis

t for

eva

luat

ion;

pro

vide

nut

ritio

nal c

ouns

elin

g fo

r m

othe

rs




absorption is no longer available. A potential replacement absorption test is under develop-ment wherein the increase in vitamin B12 satura-tion of holotranscobalamin is measured after several days of oral B12 loading,39 but this re-quires further study.

Treatment of Vitamin B12 Deficiency

The daily requirement of vitamin B12 has been set at 2.4 μg,40,41 but higher amounts — 4 to 7 μg per day — which are common in persons who eat meat or take a daily multivitamin, are associated with lower methylmalonic acid values.42 Healthy older adults should consider taking supplemental crystalline vitamin B12 as recommended by the Food and Nutrition Board.41 However, most pa-tients with clinical vitamin B12 deficiency have malabsorption and will require parenteral or high-dose oral replacement. Adequate supplementa-tion results in resolution of megaloblastic anemia and resolution of or improvement in myelopathy.

Injected Vitamin B12 There are many recommended schedules for in-jections of vitamin B12 (called cyanocobalamin in the United States and hydroxocobalamin in Eu-rope).6,23 About 10% of the injected dose (100 of 1000 μg) is retained. Patients with severe abnor-malities should receive injections of 1000 μg at least several times per week for 1 to 2 weeks, then weekly until clear improvement is shown, followed by monthly injections. Hematologic re-sponse is rapid, with an increase in the reticulo-cyte count in 1 week and correction of megalo-blastic anemia in 6 to 8 weeks. Patients with severe anemia and cardiac symptoms should be treated with transfusion and diuretic agents, and electrolytes should be monitored. Neurologic symptoms may worsen transiently and then sub-side over weeks to months.5 The severity and du-ration of the neurologic abnormalities before treatment influence the eventual degree of recov-ery.4,5 Treatment of pernicious anemia is lifelong. In patients in whom vitamin B12 supplementa-tion is discontinued after clinical recovery, neu-rologic symptoms recur within as short a period as 6 months, and megaloblastic anemia recurs in several years.6

High-Dose Oral TreatmentHigh-dose oral treatment is effective and is increas-ingly popular. A study performed 45 years ago

Chi

ldre

n

Dis

ease

s si

mila

r to

thos

e ca

usin

g m

alab

-so

rptio

n in

adu

lts10

0 µg

of i

ntra

mus

cula

r vi

tam

in B

12 m

onth

ly o

r hi

gh-d

ose

oral

vi

tam

in B

12 d

aily

in y

oung

er c

hild

ren;

trea

tmen

t as

per

adul

ts in

old

er c

hild

ren

Con

firm

per

nici

ous

anem

ia o

r co

ngen

ital m

alab

sorp

tion

Rec

reat

iona

l or

occu

patio

nal a

buse

of n

itrou

s ox

ide§

Intr

amus

cula

r cy

anoc

obal

amin

at a

dos

e of

100

0 µg

adm

inis

-te

red

on th

e sa

me

sche

dule

as

that

for

pern

icio

us a

nem

ia

abov

e an

d fo

r lif

e if

unde

rlyi

ng p

erni

ciou

s an

emia

is p

rese

nt

Eval

uate

for

vita

min

B12

mal

abso

rptio

n; p

rovi

de a

ddic

tion

coun

-se

ling

Nitr

ous

oxid

e an

esth

esia

in o

ccul

t per

nici

ous

anem

ia17

* In

tram

uscu

lar

hydr

oxoc

obal

amin

can

be

subs

titut

ed fo

r in

tram

uscu

lar

cyan

ocob

alam

in, b

ut d

ocum

ent

the

long

-ter

m r

espo

nse

if it

is a

dmin

iste

red

at 3

-mon

th in

terv

als.

† E

xper

ts a

re n

ot in

agr

eem

ent

abou

t th

e ne

cess

ity o

r fr

eque

ncy

of r

outin

e up

per

endo

scop

y in

pat

ient

s w

ith p

erni

ciou

s an

emia

. How

ever

, sym

ptom

s su

gges

tive

of g

astr

ic c

arci

nom

a, u

n-ex

plai

ned

iron

def

icie

ncy,

and

pro

ven

gast

roin

test

inal

blo

od lo

ss s

houl

d pr

ompt

a fu

ll in

vest

igat

ion.

‡ C

onge

nita

l mal

abso

rptio

n of

vita

min

B12

res

ults

from

mut

atio

ns o

f the

ilea

l cub

am r

ecep

tor,

cub

ilin,

or

amni

onle

ss (

as in

the

Im

ersl

und–

Grä

sbec

k sy

ndro

me)

and

from

mut

atio

ns in

ga

stri

c in

trin

sic

fact

or. T

hese

syn

drom

es a

re u

sual

ly m

anife

sted

in in

fanc

y an

d ea

rly

child

hood

, alth

ough

stu

dies

hav

e sh

own

a de

lay

in o

nset

eve

n in

to a

dole

scen

ce.18

§ N

itrou

s ox

ide

inac

tivat

es t

he v

itam

in B

12–d

epen

dent

enz

yme

met

hion

ine

synt

hase

and

cau

ses

form

atio

n of

vita

min

B12

ana

logu

es a

nd g

radu

al t

issu

e de

plet

ion

of v

itam

in B

12.

http://nejm.org




Figure 3. The Normal Mechanisms and Defects of Absorption of Vitamin B12.

The vitamin B12 (Cbl) released from food protein by peptic action is bound to haptocorrin (HC) in the stomach and travels to the duodenum, where pancreatic proteases digest the HC, releasing Cbl to bind to intrinsic factor (IF). The IF-Cbl complex binds to a specific receptor in the distal ileum (the cubam receptor) and is internalized, eventu-ally released from lysosomes, and transported into the blood. Both HC and transcobalamin (TC) bind Cbl in the cir-culation, although the latter is the cellular delivery protein. Adapted from Stabler.6




Tabl

e 2.

Lab

orat

ory

Test

ing

in V

itam

in B

12 D

efic

ienc

y.*

Test

Sens

itivi

tySp

ecifi

city

Com

men

ts

Mea

sure

men

t to

dete

ct d

efic

ienc

y

Seru

m v

itam

in B

12 <

200

pg/m

l or

labo

-ra

tory

cut

off l

evel

65–9

5% fo

r pr

oven

clin

ical

def

icie

ncy†

; 50%

fo

r de

tect

ing

elev

ated

leve

l of m

ethy

lma-

loni

c ac

id

50–6

0% fo

r cl

inic

al r

espo

nse†

; 80%

for

de-

tect

ing

elev

ated

leve

l of m

ethy

lmal

onic

ac

id

Cur

rent

vita

min

B12

ass

ays

are

espe

cial

ly

prob

lem

atic

in p

atie

nts

with

ant

i–in

trin

sic

fact

or a

ntib

odie

s

Seru

m v

itam

in B

12 <

350

pg/m

l90

%25

% fo

r de

tect

ing

elev

ated

leve

l of m

ethy

l-m

alon

ic a

cid

Hol

otra

nsco

bala

min

<20

to 4

5 pm

ol/

liter

‡In

suffi

cien

t dat

a on

sen

sitiv

ity fo

r cl

inic

al d

e-fic

ienc

y; 4

6–89

% fo

r de

tect

ing

elev

ated

le

vel o

f met

hylm

alon

ic a

cid

Insu

ffici

ent d

ata

on s

peci

ficity

for

clin

ical

de-

ficie

ncy;

28–

96%

for

dete

ctin

g el

evat

ed

leve

l of m

ethy

lmal

onic

aci

d

Leve

ls o

f hol

otra

nsco

bala

min

incr

ease

in r

e-na

l fai

lure

; sup

erio

r to

mea

sure

men

t of

tota

l vita

min

B12

in p

regn

ancy

, whe

n th

e to

tal l

evel

dec

reas

es

Seru

m m

ethy

lmal

onic

aci

d >4

00 n

mol

/lit

er§

98%

for

clin

ical

def

icie

ncy

Poor

spe

cific

ity fo

r clin

ical

resp

onse

in p

atie

nts

with

mod

est e

leva

tion

of le

vel o

f met

hyl-

mal

onic

aci

d (3

00–1

000

nmol

/lite

r)¶

Ren

al fa

ilure

and

vol

ume

depl

etio

n m

ay in

-cr

ease

leve

l of s

erum

met

hylm

alon

ic

acid

, but

rar

ely

to >

1000

nm

ol/l

iter

Seru

m o

r pl

asm

a to

tal h

omoc

yste

ine

>21

µmol

/lite

r96

% fo

r cl

inic

al d

efic

ienc

yH

omoc

yste

ine

leve

l als

o in

crea

sed

in c

linic

al

fola

te d

efic

ienc

y an

d re

nal i

nsuf

ficie

ncy

Test

to d

eter

min

e ca

use

of d

efic

ienc

y‖

Pern

icio

us a

nem

ia

Ant

i–in

trin

sic

fact

or a

ntib

odie

s50

%10

0%M

ust b

e te

sted

>7

days

aft

er v

itam

in B

12 in

-je

ctio

n to

pre

vent

fals

e po

sitiv

e re

sult

Ant

i–pa

riet

al-c

ell a

ntib

odie

s80

%50

–100

%

Atr

ophi

c bo

dy g

astr

itis

(ant

ral s

parin

g)**

Fast

ing

high

ser

um g

astr

in le

vel

(>10

0 pm

ol/l

iter)

85%

Low

leve

l of s

erum

pep

sino

gen

I (<

30 µ

g/lit

er)

90%

Endo

scop

y w

ith p

enta

gast

rin-

fast

hy

poch

lorh

ydri

a10

0%R

arel

y pe

rfor

med

Mal

abso

rptio

n of

vita

min

B12

††

Vita

min

B12

abs

orpt

ion

test

Schi

lling

test

no

long

er a

vaila

ble

Incr

ease

in s

erum

hol

otra

nsco

bala

min

le

vel a

fter

ora

l loa

ding

Unk

now

nU

nkno

wn

Prom

isin

g pr

eclin

ical

dat

a, b

ut s

till e

xper

i-m

enta

l

*

To c

onve

rt t

he v

alue

s fo

r vi

tam

in B

12 t

o pi

com

oles

per

lite

r, m

ultip

ly b

y 0.

7378

.†

A

vaila

ble

assa

ys a

re la

rgel

y ch

emilu

min

esce

nt m

icro

part

icle

imm

unoa

ssay

s pe

rfor

med

with

the

use

of a

utom

ated

ana

lyze

rs t

hat

in g

ener

al s

how

hig

her

valu

es t

han

the

radi

odilu

tion

and

mic

robi

olog

ic a

ssay

s us

ed in

pas

t st

udie

s of

clin

ical

ly c

onfir

med

def

icie

ncy.

4,22

,24,

26 Th

us, t

hese

tes

ts a

re li

kely

to

have

low

er s

ensi

tiviti

es a

nd s

peci

ficiti

es t

han

the

olde

r as

says

.‡

Th

e ho

lotr

ansc

obal

amin

ass

ay h

as b

een

stud

ied

wid

ely

in E

urop

e27-3

0 but

is n

ot y

et c

omm

erci

ally

ava

ilabl

e in

the

Uni

ted

Stat

es. T

he a

ppro

pria

te lo

wer

end

of t

he r

efer

ence

ran

ge is

st

ill u

nder

deb

ate.

33 T

he v

alue

s fo

r se

nsiti

vity

and

spe

cific

ity a

re r

evie

wed

in H

eil e

t al

.29

§

Uri

nary

met

hylm

alon

ic a

cid

has

not

been

ext

ensi

vely

stu

died

, but

val

ues

grea

ter

than

2.5

µm

ol p

er m

illim

ole

of c

reat

inin

e su

gges

t de

ficie

ncy.

¶

Elev

ated

leve

ls o

f met

hylm

alon

ic a

cid

fall

with

vita

min

B12

ther

apy,

but

an

asso

ciat

ed c

linic

al r

espo

nse

is h

ighl

y va

riabl

e, d

epen

ding

larg

ely

on th

e pr

esen

ce o

f vita

min

B12

–rel

ated

dis

ease

.‖

Ev

iden

ce o

f a c

ausa

l pat

holo

gic

proc

ess

does

not

con

firm

coe

xist

ing

B12

def

icie

ncy,

sin

ce u

nder

lyin

g ga

stro

inte

stin

al d

isea

se m

ay p

reda

te t

he d

efic

ienc

y by

man

y ye

ars.

** T

he r

elat

ions

hip

betw

een

atro

phic

bod

y ga

stri

tis (

auto

imm

une

gast

ritis

) an

d in

fect

ion

with

Hel

icob

acte

r py

lori

is v

aria

ble.

Ant

ral s

pari

ng is

a t

ype

of a

trop

hic

body

gas

triti

s in

whi

ch

the

cells

in t

he a

ntru

m c

an p

rodu

ce h

igh

leve

ls o

f gas

trin

.†

† T

here

is m

alab

sorp

tion

if cl

inic

ally

pro

ven

vita

min

B12

def

icie

ncy

is p

rese

nt in

a p

atie

nt w

ho e

ats

mea

t, re

ceiv

es m

ultiv

itam

in t

hera

py, o

r bo

th.

http://nejm.org




showed that 0.5 to 4% of radioactively labeled oral vitamin B12 can be absorbed by passive dif-fusion in both normal controls and patients with pernicious anemia.43 Thus, oral doses of 1000 μg deliver 5 to 40 μg, even if taken with food.

A randomized trial that compared an oral dose of 2000 μg daily with parenteral therapy (seven injections of 1000 μg of cyanocobalamin over a period of 1 month, followed by monthly injections) in patients with pernicious anemia, atrophic gastritis, or a history of ileal resection showed similar reductions in the mean corpus-cular volume and increases in the hematocrit at 4 months in both groups.38 All participants (four in each group) with paresthesias, ataxia, or memory loss had resolution or improved with treatment. However, levels of methylmalonic acid after treatment were significantly lower

with daily oral treatment (169 nmol per liter, vs. 265 nmol per liter with parenteral treatment) and vitamin B12 levels were significantly higher (1005 pg per milliliter vs. 325 pg per milliliter [741.5 vs. 239.8 pmol per liter]). A more recent trial with a similar design involving a proprie-tary oral vitamin B12 preparation also revealed significantly lower levels of methylmalonic acid in the oral-treatment group at the 3-month follow-up.30 In a randomized trial comparing oral with intramuscular vitamin B12 (1000-μg doses, daily for 10 days, then weekly for 4 weeks, and month-ly thereafter), the two groups had similar im-provements in hematologic abnormalities and vitamin B12 levels at 90 days.44 Case series of patients treated with oral vitamin B12 have yielded variable results; elevated levels of meth-ylmalonic acid, homocysteine, or both were re-ported in about half of patients with malabsorp-tion who were treated with twice-weekly oral doses of 1000 μg,45 whereas normal homocyste-ine levels were reported in patients treated with 1500 μg daily after gastrectomy.46 Data are lack-ing from long-term studies to assess whether oral treatment is effective when doses are ad-ministered less frequently than daily. Studies involving older adults, many of whom had chronic atrophic gastritis, showed that 60% re-quired large oral doses (>500 μg daily) to correct elevated levels of methylmalonic acid.47,48

Proponents of parenteral therapy state that compliance and monitoring are better in patients who receive this form of therapy because they have frequent contact with health care providers, whereas proponents of oral therapy maintain that compliance will be improved in patients who receive oral therapy because of convenience, comfort, and decreased expense. High-dose vita-min B12 tablets (500 to 1500 μg) are available in the United States without a prescription. Self-administered injections are also easily taught, economical, and in my experience, effective. Pa-tients should be informed of the pros and cons of oral versus parenteral therapy, and regardless of the form of treatment, those with pernicious anemia or malabsorption should be reminded of the need for lifelong replacement.

A r e a s of Uncerta in t y

Vitamin B12 deficiency is the major cause of hy-perhomocysteinemia in countries with folate- fortified food, such as the United States and

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Figure 4. Serum Methylmalonic Acid and Total Homocysteine Concentrations in 491 Episodes of Vitamin B12 Deficiency.

The data shown have been combined from studies performed over a period of 25 years.4,6,22,24,26,35,37,38 Most of the patients with clinically confirmed vitamin B12 deficiency had documented pernicious anemia and a proven re-sponse to vitamin B12 therapy. Open circles indicate episodes in patients with a hematocrit lower than 38%, and solid circles indicate episodes in those with a hematocrit of 38% or higher. Patients without anemia had neurologic manifestations of vitamin B12 deficiency and similar values of methylmalonic acid and total homocysteine. The axis for serum methylmalo-nic acid is plotted on a log scale. The dashed lines indicate values that are 3 SD above the mean for healthy blood donors: 376 nmol per liter for meth-ylmalonic acid and 21.3 µmol per liter for total homocysteine. The level of methylmalonic acid was greater than 500 nmol per liter in 98% of the pa-tients and greater than 1000 nmol per liter in 86%. Adapted from Stabler.7




Canada. Epidemiologic studies show significant associations between elevated homocysteine lev-els and vascular disease and thrombosis. How-ever, large randomized trials of combined high-dose vitamin B therapy in patients with vascular disease have shown no reduction in vascular events.49 Vitamin B12 status should be evaluated in patients with hyperhomocysteinemia before folic acid treatment is initiated.

The potential role of mild vitamin B12 defi-ciency in cognitive decline with aging remains uncertain. Epidemiologic studies indicate an in-verse association between vitamin B12 supplemen-tation and neurodegenerative disease, but results of randomized trials have been largely negative.50

Besides oral tablets, vitamin B is available in sublingual preparations, oral sprays, nasal gels or sprays, and transdermal patches. Data on the absorption and efficacy of these alternative prep-arations are lacking.

Guidelines

Nutritional guidelines for vitamin B12 intake are published by the Food and Nutrition Board,41 and nutritional guidelines for vegetarians are published by the American Dietetic Association.40 There are no recommendations from the Ameri-can Society of Hematology for the diagnosis and treatment of vitamin B12 deficiency. The Ameri-can Academy of Neurology recommends mea-surements of vitamin B12, methylmalonic acid, and homocysteine in patients with symmetric polyneuropathy.51 The American Society for Gas-trointestinal Endoscopy recommends a single

endoscopic evaluation at the diagnosis of perni-cious anemia.52

Conclusions a nd R ecommendations

The patient in the vignette has neurologic abnor-malities that are consistent with vitamin B12 de-ficiency. Since vitamin B12 levels may be above the lower end of the laboratory reference range even in patients with clinical deficiency, methyl-malonic acid, total homocysteine, or both should be measured to document vitamin B12 deficiency before treatment is initiated; the elevated levels in this patient confirm the diagnosis. In the ab-sence of dietary restriction or a known cause of malabsorption, further evaluation is warranted — in particular, testing for pernicious anemia (anti–intrinsic factor antibodies). Either paren-teral vitamin B12 treatment (8 to 10 loading injec-tions of 1000 μg each, followed by monthly 1000-μg injections), or high-dose oral vitamin B12 treatment (1000 to 2000 μg daily) is an effec-tive therapy. I would review both options (includ-ing the possibility of self-injection at home) with the patient. Effective vitamin replacement will correct blood counts in 2 months and correct or improve neurologic signs and symptoms within 6 months.

Dr. Stabler reports holding patents (assigned to the University of Colorado and Competitive Technologies) on the use of homo-cysteine, methylmalonic acid, and other metabolites in the diag-nosis of vitamin B12 and folate deficiency, but no longer receiv-ing royalties for these patents. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References

1. Stabler SP, Allen RH. Vitamin B12 de-ficiency as a worldwide problem. Annu Rev Nutr 2004;24:299-326.2. Nielsen MJ, Rasmussen MR, Andersen CB, Nexø E, Moestrup SK. Vitamin B(12) transport from food to the body’s cells-a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 2012;9:345-54.3. Toh BH, Chan J, Kyaw T, Alderuccio F. Cutting edge issues in autoimmune gas-tritis. Clin Rev Allergy Immunol 2012; 42:269-78.4. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the ab-sence of anemia or macrocytosis. N Engl J Med 1988;318:1720-8.5. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic as-pects of cobalamin deficiency. Medicine 1991;70:229-45.

6. Stabler SP. Megaloblastic anemias: pernicious anemia and folate deficiency. In: Young NS, Gerson SL, High KA, eds. Clinical hematology. Philadelphia: Mos-by, 2006:242-51.7. Stabler SP. Vitamin B12. In: Erdman JW Jr, MacDonald IA, Zeisel SH, eds. Pres-ent knowledge in nutrition. 10th ed. New York: Wiley-Blackwell, 2012:343-58.8. Dalsania CJ, Khemka V, Shum M, De-vereux L, Lachant NA. A sheep in wolf’s clothing. Am J Med 2008;121:107-9.9. Andrès E, Affenberger S, Zimmer J, et al. Current hematological findings in co-balamin deficiency: a study of 201 con-secutive patients with documented co-balamin deficiency. Clin Lab Haematol 2006;28:50-6.10. Parmentier S, Meinel J, Oelschlaegel U, et al. Severe pernicious anemia with dis-tinct cytogenetic and flow cytometric ab-

errations mimicking myelodysplastic syn-drome. Ann Hematol 2012;91:1979-81.11. Pittock SJ, Payne TA, Harper CM. Re-versible myelopathy in a 34-year-old man with vitamin B12 deficiency. Mayo Clin Proc 2002;77:291-4.12. Remacha AF, Souto JC, Piñana JL, et al. Vitamin B12 deficiency, hyperhomo-cysteinemia and thrombosis: a case and control study. Int J Hematol 2011;93: 458-64.13. Limal N, Scheuermaier K, Tazi Z, Sene D, Piette JC, Cacoub P. Hyperhomocyste-inaemia, thrombosis and pernicious anae-mia. Thromb Haemost 2006;96:233-5.14. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in pa-tients with type 2 diabetes and risk of vi-tamin B-12 deficiency: randomised pla-cebo controlled trial. BMJ 2010;340:c2181.15. Dror DK, Allen LH. Effect of vitamin

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B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev 2008;66:250-5.16. Honzik T, Adamovicova M, Smolka V, Magner M, Hruba E, Zeman J. Clinical pre-sentation and metabolic consequences in 40 breastfed infants with nutritional vita-min B12 deficiency — what have we learned? Eur J Paediatr Neurol 2010;14: 488-95.17. Singer MA, Lazaridis C, Nations SP, Wolfe GI. Reversible nitrous oxide-induced myeloneuropathy with pernicious ane-mia: case report and literature review. Muscle Nerve 2008;37:125-9.18. Tanner SM, Sturm AC, Baack EC, Li-yanarachchi S, de la Chapelle A. Inherited cobalamin malabsorption: mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis 2012;7:56.19. Lewerin C, Jacobsson S, Lindstedt G, Nilsson-Ehle H. Serum biomarkers for atrophic gastritis and antibodies against Helicobacter pylori in the elderly: implica-tions for vitamin B12, folic acid and iron status and response to oral vitamin thera-py. Scand J Gastroenterol 2008;43:1050-6.20. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hema-tologic presentation of autoimmune gas-tritis: age-related progression from iron deficiency to cobalamin depletion. Blood 2006;107:1673-9.21. Wun Chan JC, Yu Liu HS, Sang Kho BC, et al. Pernicious anemia in Chinese: a study of 181 patients in a Hong Kong hospital. Medicine (Baltimore) 2006;85:129-38.22. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylma-lonic acid and total homocysteine determi-nations for diagnosing cobalamin and fo-late deficiencies. Am J Med 1994;96:239-46.23. Carmel R. How I treat cobalamin (vi-tamin B12) deficiency. Blood 2008;112: 2214-21.24. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin defi-ciency in elderly outpatients. J Am Geriatr Soc 1992;40:1197-204.25. Sarafoglou K, Rodgers J, Hietala A, Matern D, Bentler K. Expanded newborn screening for detection of vitamin B12 de-ficiency. JAMA 2011;305:1198-200.26. Stabler SP, Allen RH, Savage DG, Lin-denbaum J. Clinical spectrum and diag-nosis of cobalamin deficiency. Blood 1990;76:871-81.27. Nexo E, Hoffmann-Lücke E. Holo-transcobalamin, a marker of vitamin B-12 status: analytical aspects and clinical util-ity. Am J Clin Nutr 2011;94:359S-365S.28. Schrempf W, Eulitz M, Neumeister V, et al. Utility of measuring vitamin B12 and its active fraction, holotranscobalamin, in neurological vitamin B12 deficiency syn-dromes. J Neurol 2011;258:393-401.29. Heil SG, de Jonge R, de Rotte MC, et

al. Screening for metabolic vitamin B12 deficiency by holotranscobalamin in pa-tients suspected of vitamin B12 deficien-cy: a multicentre study. Ann Clin Biochem 2012;49:184-9.30. Castelli MC, Friedman K, Sherry J, et al. Comparing the efficacy and tolerabili-ty of a new daily oral vitamin B12 formu-lation and intermittent intramuscular vi-tamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther 2011;33(3):358.e2-371.e2.31. Carmel R, Brar S, Agrawal A, Penha PD. Failure of assay to identify low co-balamin concentrations. Clin Chem 2000;46:2017-8.32. Galloway M, Hamilton M. Macrocyto-sis: pitfalls in testing and summary of guidance. BMJ 2007;335:884-6.33. Yang DT, Cook RJ. Spurious eleva-tions of vitamin B12 with pernicious ane-mia. N Engl J Med 2012;366:1742-3.34. Carmel R, Agrawal YP. Failures of co-balamin assays in pernicious anemia. N Engl J Med 2012;367:385-6. [Erratum, N Engl J Med 2012;367:976.]35. Stabler SP, Marcell PD, Podell ER, et al. Elevation of total homocysteine in the serum of patients with cobalamin or fo-late deficiency detected by capillary gas chromatography–mass spectrometry. J Clin Invest 1988;81:466-74.36. Stabler SP, Marcell PD, Podell ER, Al-len RH, Lindenbaum J. Assay of methyl-malonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography–mass spectrometry. J Clin Invest 1986;77:1606-12.37. Rasmussen K, Vyberg B, Pedersen KO, Brøchner-Mortensen J. Methylmalonic acid in renal insufficiency: evidence of ac-cumulation and implications for diagno-sis of cobalamin deficiency. Clin Chem 1990;36:1523-4.38. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191-8.39. Greibe E, Nexo E. Vitamin B12 ab-sorption judged by measurement of holo-transcobalamin, active vitamin B12: eval-uation of a commercially available EIA kit. Clin Chem Lab Med 2011;49:1883-5.40. American Dietetic Association, Dieti-tians of Canada. Position of the American Dietetic Association and Dietitians of Canada: vegetarian diets. J Am Diet Assoc 2003;103:748-65.41. Institute of Medicine Food and Nutri-tion Board. Dietary reference intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, bio-tin and choline. Washington, DC: Nation-al Academies Press, 1998.42. Bor MV, von Castel-Roberts KM, Kauwell GP, et al. Daily intake of 4 to 7 μg

dietary vitamin B-12 is associated with steady concentrations of vitamin B-12–related biomarkers in a healthy young population. Am J Clin Nutr 2010;91:571-7.43. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968;184:247-58.44. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Baructa S, Senturk T. Oral versus intramuscular cobalamin treat-ment in megaloblastic anemia: a single-center, prospective, randomized open-label study. Clin Ther 2003;25:3124-34.45. Bor MV, Cetin M, Aytaç S, Altay C, Ueland PM, Nexo E. Long term biweekly 1 mg oral vitamin B12 ensures normal hematological parameters, but does not correct all other markers of vitamin B12 deficiency: a study in patients with inher-ited vitamin B12 deficiency. Haematolog-ica 2008;93:1755-8.46. Kim HI, Hyung WJ, Song KJ, Choi SH, Kim CB, Noh SH. Oral vitamin B12 re-placement: an effective treatment for vita-min B12 deficiency after total gastrecto-my in gastric cancer patients. Ann Surg Oncol 2011;18:3711-7.47. Rajan S, Wallace JI, Brodkin KI, Beresford SA, Allen RH, Stabler SP. Re-sponse of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. J Am Geriatr Soc 2002;50: 1789-95.48. Eussen SJ, de Groot LC, Clarke R, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficien-cy: a dose-finding trial. Arch Intern Med 2005;165:1167-72.49. Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supple-mentation in cardiovascular disease pre-vention: an updated meta-analysis of ran-domized controlled trials. Eur J Intern Med 2012;23:745-54.50. Nachum-Biala Y, Troen AM. B-vita-mins for neuroprotection: narrowing the evidence gap. Biofactors 2012;38:145-50.51. England JD, Gronseth GS, Franklin G, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review) — report of the American Academy of Neu-rology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM&R 2009;1:14-22.52. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of endos-copy in the surveillance of premalignant conditions of the upper GI tract. Gastro-intest Endosc 2006;63:570-80.Copyright © 2013 Massachusetts Medical Society.


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when they exist. The article ends with the authors’ clinical recommendations.


Infective EndocarditisBruno Hoen, M.D., Ph.D., and Xavier Duval, M.D., Ph.D.

From Service de Maladies Infectieuses et Tropicales, Centre Hospitalier Régional Universitaire, and Unité Mixte de Recher-che 6249 Chrono-environnement, Centre National de la Recherche Scientifique, Université de Franche-Comté, Besançon (B.H.); Association pour l’Etude et la Prévention de l’Endocardite Infectieuse, Paris (B.H., X.D.); and INSERM Centre d’Investigation Clinique 007, Assistance Publique–Hôpitaux de Paris, Hôpital Universitaire Bichat, and INSERM Unité 738, Université Paris Diderot, Paris 7, Unité de Formation et de Recherche de Médecine–Bichat, Bichat (X.D.) — all in France. Address reprint requests to Dr. Hoen at Service de Maladies Infectieuses et Tropicales, CHRU de Besançon, 25030 Besançon CEDEX, France, or at bruno [email protected].

Drs. Hoen and Duval contributed equally to this article.

This article was updated on June 27, 2013, at NEJM.org.

N Engl J Med 2013;368:1425-33.DOI: 10.1056/NEJMcp1206782Copyright © 2013 Massachusetts Medical Society.

A 55-year-old man with a history of mitral regurgitation seeks care after an episode of transient weakness in his right arm and speech difficulties. He underwent dental scaling 1 month earlier. He notes recent intermittent fevers and weight loss. On cardiac examination, his regurgitation murmur appears to be unchanged. A transthoracic echocardiogram shows a mobile, 12-mm mitral-valve vegetation and grade 2 (mild) regurgitation. Magnetic resonance imaging of the brain reveals recent ischemic le-sions. How should the patient be further evaluated and treated?

THE CLINIC A L PROBLEM

Infective endocarditis has an estimated annual incidence of 3 to 9 cases per 100,000 persons in industrialized countries.1-7 The male:female case ratio is more than 2:1. The highest rates are observed among patients with prosthetic valves, intracardiac devices, unrepaired cyanotic congenital heart diseases, or a history of infective endo-carditis, although 50% of cases of infective endocarditis develop in patients with no known history of valve disease. Other risk factors include chronic rheumatic heart disease (which now accounts for <10% of cases in industrialized countries), age-related degenerative valvular lesions,1,2,5 hemodialysis, and coexisting conditions such as diabetes, human immunodeficiency virus infection, and intravenous drug use. More than one third of the cases of infective endocarditis in the United States in recent years were reported to be health care–associated (nosocomial or non-nosocomial).8 The clustering of several of these predisposing factors with age probably explains the increased incidence of infective endocarditis among persons 65 years of age or older (Fig. 1).7

MICROBIOLOGY

Streptococci and staphylococci account for 80% of cases of infective endocarditis, with proportions varying according to valve (native vs. prosthetic), source of infection, patient age, and coexisting conditions. Staphylococci are now the most frequently identified microorganisms in several types of infective endocarditis (Fig. 1; and Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org),2,7,9 which results from the increased proportion of health care–associated cases of infective endocarditis. In parallel, the incidence of cases attributable to oral streptococci has decreased in industrialized countries.2

Cases of infective endocarditis in which a blood culture is negative (10% of cases) may reflect one of two situations: infective endocarditis in patients exposed to antibiotic agents before the diagnosis of infective endocarditis or infective endocar-ditis caused by fastidious microorganisms. In the latter case, serologic testing, valve or blood polymerase-chain-reaction (PCR) assay, and highly specialized microbio-logic techniques lead to the identification of the pathogen in 60% of cases,10 with the most frequent microorganisms being bartonella species, brucella species,

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Coxiella burnetii (the agent causing Q fever), bacte-ria in the HACEK group (haemophilus species, Aggregatibacter [formerly Actinobacillus] actinomy-cetemcomitans, Cardiobacterium hominis, Eikenella cor-rodens, and Kingella kingae), and Tropheryma whip-plei.6,10,11

PATHOGENESIS

Normal valvular endothelium is naturally resistant to colonization by bacteria. In the conventional model of native-valve infectious endocarditis, in-fection results from the colonization of damaged valvular endothelium by circulating bacteria with specific adherence properties. Endothelial dam-age may result from so-called jet lesions due to turbulent blood flow or may be provoked by elec-trodes or catheters or by repeated intravenous in-jections of solid particles in intravenous-drug users. Chronic inflammation, as in chronic rheumatic heart disease and degenerative valvular lesions,12 may also promote infective endocarditis. How-ever, the conventional model may not accurately explain the pathogenesis of infective endocardi-tis due to intracellular microorganisms, such as C. burnetii, bartonella species, or T. whippelii, in which the exposure and immune response of the host may play a prominent role.13

CLASSIFICATION

Whereas infective endocarditis was previously clas-sified according to its mode of presentation (acute, subacute, or chronic), it is now categorized accord-ing to underlying cardiac conditions, location, the presence of intracardiac devices, or the mode of acquisition. These classifications overlap, with some cases of infective endocarditis belonging to

more than one group. Table 1 in the Supplemen-tary Appendix shows the distribution of cases among these categories and the corresponding microorganisms.

OUTCOMES

In contemporary population-based studies of in-fective endocarditis in industrialized countries, in-hospital mortality ranges from 15 to 22%,5,7 and 5-year mortality is approximately 40%.14 How-ever, rates vary widely across subgroups of pa-tients. For instance, in-hospital mortality is less than 10% among patients with right-sided lesions or oral streptococcal, left-sided, native-valve le-sions, whereas it is 40% or more among patients with prosthetic-valve infective endocarditis due to Staphylococcus aureus. In a multivariate analysis assessing risk factors for death among patients with infective endocarditis, independent predic-tors included higher age, S. aureus infection, heart failure, cerebrovascular and embolic events, and health care–associated infective endocarditis.5,7

S TR ATEGIES A ND E V IDENCE

PRESENTATION AND DIAGNOSIS

The diagnosis of infective endocarditis is generally based on clinical, microbiologic, and echocar-diographic findings. The Duke criteria (Table 1) have sensitivity and specificity of more than 80% and are the reference criteria for diagnosis.15 However, they should not replace clinical judg-ment for diagnosis in the individual patient, es-pecially in the first stage of care.

Fever is common, occurring in 80% of cases.6,7 In large, contemporary case series, recognition of

key Clinical points

infective endocarditis

• Staphylococci and streptococci account for 80% of cases of infective endocarditis, with staphylococci currently the most common pathogens.

• Cerebral complications are the most frequent and most severe extracardiac complications. Vegetations that are large, mo-bile, or in the mitral position and infective endocarditis due to Staphylococcus aureus are associated with an increased risk of symptomatic embolism.

• Identifying the causative microorganism is central to diagnosis and appropriate treatment; two or three blood cultures should routinely be drawn before antibiotic therapy is initiated.

• When infective endocarditis is suspected, echocardiography should be performed as soon as possible.• Indications for surgery include heart failure, uncontrolled infection, and prevention of embolic events.• Treatment should involve a multidisciplinary team with expertise in cardiology, cardiac surgery, and infectious disease.• Indications for antibiotic prophylaxis have been restricted to invasive dental procedures in patients with a prosthetic valve,

a history of infective endocarditis, or unrepaired cyanotic congenital heart disease.




a new murmur and worsening of a known murmur are reported in 48% and 20% of cases, respectively. Other signs are less common: hematuria in 25% of cases, splenomegaly in 11%, splinter hemor-rhages in 8%, Janeway’s lesions in 5%, Roth’s spots in 5%, and conjunctival hemorrhage in 5%. Sepsis, meningitis, unexplained heart failure, sep-tic pulmonary emboli, stroke, acute peripheral arterial occlusion, and renal failure may also be presenting manifestations.16 Elevated inflamma-tory markers (erythrocyte sedimentation rate and C-reactive protein level) are observed in two thirds of cases, and leukocytosis and anemia in about half the cases.6,17

Cerebral complications are the most severe ex-tracardiac complications of infective endocarditis, as well as the most frequent (occurring in 15 to 20% of patients).18,19 They include ischemic and hemorrhagic stroke (preceding the diagnosis of infective endocarditis in 60% of patients20,21), transient ischemic attack, silent cerebral embolism, mycotic aneurysm, brain abscess, and meningitis. Specific characteristics of vegetations (those that are large, mobile, and located in the mitral valve)21 and S. aureus infection21,22 have been associated with an increased risk of symptomatic embolic events. Systematic magnetic resonance imaging (MRI) of the brain may reveal cerebral abnormali-ties in up to 80% of patients, including embolic events (mostly asymptomatic) in 50%.23

Mycotic aneurysms result from septic arterial embolism to the intraluminal space or vasa vaso-rum and spread of infection through the vessel wall. These aneurysms were reported in 5% of cases in older case series,24 but they are now detected more frequently because of the wider use of imaging. Magnetic resonance angiography is the best confirmation test.25

MICROBIOLOGIC DIAGNOSIS

Identifying the causative microorganism is cen-tral to making the diagnosis of infective endocar-ditis and guiding antimicrobial treatment. Blood cultures should be performed routinely before the administration of antibiotics. When three sets of blood cultures are performed, the pathogen is identified in about 90% of cases. Serologic tests for bartonella, C. burnetii, and brucella should be performed in patients with negative blood cultures who have risk factors for these infections. If the causative pathogen has not been identified by means of blood cultures and the patient requires valve surgery, gene amplification in cardiac-valve specimens, as well as immunostaining tech-niques, if available, may yield a microbiologic diagnosis.10,26,27

DIAGNOSIS OF VALVULAR LESIONS

Transthoracic echocardiography is performed first and is better than transesophageal echocardiog-

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Figure 1. Incidence of Definite Infective Endocarditis, According to Age and Microorganism.

Streptococci and staphylococci account for 80% of cases of infective endocarditis, with proportions varying according to valve (native vs. prosthetic), source of infection, patient age, and coexisting conditions. The clustering of various predisposing factors with age probably explains the higher incidence of infective endocarditis in persons 65 years of age or older. Adapted from Selton-Suty et al.7

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raphy for detecting abscesses in the anterior aortic valve in a patient with a prosthetic valve and for assessing the hemodynamic consequences of val-vular dysfunction. Transesophageal echocardiog-raphy has higher sensitivity and specificity overall and is recommended when the results of trans-thoracic echocardiography are negative and there is a high clinical suspicion, poor imaging quality, and the presence of prosthetic valves or an intra-cardiac device, as well as in cases in which the transthoracic echocardiographic findings are sug-gestive of infective endocarditis but not definitive.

Combined transthoracic and transesophageal echocardiography shows vegetations (Fig. 2) in 90% of cases, valve regurgitation in 60%, para-valvular abscess in 20%,6,7 and infrequently, de-hiscence of the prosthesis, pseudoaneurysms, and fistulas. In cases with initially negative findings on echocardiography, repeat examination should be performed if infective endocarditis continues to be suspected. Repeat transthoracic or trans-esophageal echocardiography is recommended if a new complication is suspected and when ther-apy has been completed.

Table 1. Duke Criteria for the Diagnosis of Infective Endocarditis.*

Definite diagnosis

Pathological criteria: microorganisms identified by culture or histologic examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen; or active endocarditis confirmed by histologic examina-tion of vegetation or intracardiac abscess

Clinical criteria: two major, one major and three minor, or five minor criteria

Major clinical criteria

Blood culture positive for infective endocarditis

Microorganisms typically associated with infective endocarditis identified from two separate blood cultures: viridans streptococci, Streptococcus bovis, bacteria in the HACEK group, or Staphylococcus aureus; or community-acquired enterococci in the absence of a primary focus

Microorganisms consistent with infective endocarditis identified from persistently positive blood cultures: at least two positive cultures of blood samples drawn >12 hr apart, or positive results of all of three or a majority of four or more separate blood cultures (with first and last samples drawn at least 1 hr apart)

Single positive blood culture for Coxiella burnetii or IgG antibody titer for Q fever phase 1 antigen >1:800

Evidence of endocardial involvement

Echocardiogram positive for infective endocarditis: pendulum-like intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative ana-tomical explanation; abscess; or new partial dehiscence of prosthetic valve†

New valvular regurgitation (worsening or changing of preexisting murmur not a sufficient criterion)

Minor clinical criteria

Predisposition to infective endocarditis, such as a predisposing heart condition, or intravenous drug use

Fever, defined as a temperature >38°C

Vascular phenomena, such as major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, and Janeway’s lesions

Immunologic phenomena, such as glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor

Microbiologic evidence: positive blood culture but with no major clinical criterion met or serologic evidence of active infection with an organism consistent with infective endocarditis

Possible diagnosis

Clinical criteria (see above): one major criterion and one minor criterion or three minor criteria

Rejected diagnosis

Firmly established alternative diagnosis; resolution of infective endocarditis–like syndrome with antibiotic therapy for ≤4 days; no pathological evidence of infective endocarditis at surgery or autopsy, with antibiotic therapy for ≤4 days; or criteria for possible infective endocarditis not met

* Adapted from Li et al.15 HACEK denotes haemophilus species, Aggregatibacter (formerly Actinobacillus) actinomycetem-comitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.

† Transesophageal echocardiography is recommended in patients with prosthetic valves and possible infective endocarditis according to clinical criteria or infective endocarditis complicated by paravalvular abscess; transthoracic echocardiography is recommended as the first test in other patients.




TREATMENT

The treatment of patients with suspected or con-firmed infective endocarditis should be provided by a multidisciplinary team with expertise in car-diology, cardiac surgery, and infectious disease.28 Successful treatment is dependent on eradication of the causative agent, which requires prolonged bactericidal antibiotic treatment. Surgery may con-tribute to this goal by removing infected material and draining abscesses.

Antibiotic TreatmentGuidelines for appropriate antibiotic treatment of infective endocarditis are published by profession-al societies and updated regularly.29-31 Table 2 in the Supplementary Appendix is adapted from the European Society of Cardiology guidelines and reviews antibiotic regimens recommended be-fore an organism is identified and for most com-mon causative bacteria.30

For native-valve infective endocarditis due to common microorganisms, the duration of anti-biotic treatment ranges from 2 weeks (for un-complicated infective endocarditis due to fully penicillin-susceptible streptococci treated with a beta-lactam antibiotic combined with an amino-glycoside) to 6 weeks (for enterococcal infective endocarditis). For infective endocarditis involving a prosthetic valve, the duration of antibiotic thera-py is usually 6 weeks, and regimens are basi-cally the same as those for native-valve infective endocarditis, with the notable exception of staphy-lococcal prosthetic-valve infective endocarditis, for which the regimen should include both rif-ampin, whenever the strain is susceptible to this antibiotic, and gentamicin.

When valve replacement is performed during antibiotic treatment of native-valve infective endo-carditis, the duration of antibiotic therapy should remain the same as the duration recommended for native-valve infective endocarditis and should not be switched to that recommended for pros-thetic-valve infective endocarditis. In both na-tive-valve and prosthetic-valve infective endocar-ditis, the duration of treatment should be calculated from the first day of appropriate anti-biotic therapy, not from the day of surgery. After surgery, a new full course of treatment should be started only if valve cultures are positive.32

Among aminoglycosides, only gentamicin has been fully evaluated for the treatment of infec-tive endocarditis and should be used when the disease is caused by gram-positive cocci. Clinical

trials have shown that a 14-day course of genta-micin, given once daily instead of twice daily, in combination with ceftriaxone is effective for the treatment of uncomplicated cases of streptococcal infective endocarditis involving a native valve.33,34 Combination therapy with a beta-lactam antibi-otic and an aminoglycoside should be used for prosthetic-valve infective endocarditis (Table 2 in the Supplementary Appendix).

In cases of enterococcal infective endocarditis, whenever the strain does not exhibit high-level resistance to gentamicin, that drug should be used in combination with an antibiotic agent that is active against the bacterial cell wall. Gentamicin is generally given for the full 6-week course of antibiotic treatment; however, in an observational study, the cure rate of enterococcal infective endo-carditis was as high as 81%, with a median dura-tion of aminoglycoside administration of 15 days. This suggests that shorter courses of aminogly-cosides (2 to 3 weeks), which minimize the risk of renal toxicity, may be effective.35 The question of whether gentamicin should be administered in divided daily doses continues to be debated; clinical data are lacking, and experimental data are conflicting. The combination of ampicillin (at a dose of 12 g per 24 hours) with ceftriaxone (at a dose of 2 g twice daily) may be effective in infective endocarditis due to Enterococcus faecalis, regardless of whether the strain is highly resis-tant to gentamicin36 or not highly resistant.37

Gentamicin is no longer recommended for staphylococcal infective endocarditis involving a native valve, because there is no documented clinical benefit and there is a risk of nephrotox-

LA

LV

Figure 2. Transesophageal Echocardiogram Showing a Large Vegetation on a Native Mitral Valve.

A large vegetation (white arrow) can be seen near the mitral valve (black arrow). LA denotes left atrium, and LV left ventricle.

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icity.38 In cases involving a prosthetic valve, how-ever, a regimen that includes gentamicin for the first 2 weeks is recommended, especially in cases of methicillin-resistant S. aureus (MRSA) infection, to mitigate the risk of selection of rifampin-resistant escape mutants.

Daptomycin (at a dose of 6 mg per kilogram of body weight per day, given once daily) was approved by the Food and Drug Administration for adults with S. aureus bacteremia and right-sided infective endocarditis, on the basis of a randomized trial showing its noninferiority to standard therapy (vancomycin or an antistaphy-lococcal penicillin).39 Observational studies have also shown the efficacy of daptomycin in pa-tients with left-sided infective endocarditis40 and in patients with infective endocarditis in-volving an implanted intracardiac device (with daptomycin used at a dose of 8 to 10 mg per kilogram per day).41 Daptomycin has been recom-mended as an alternative to vancomycin for the treatment of adults with infective endocarditis due to MRSA.42

Surgical TreatmentThe rate of early valve replacement or repair (i.e., surgery performed during the course of antibi-otic treatment for infective endocarditis) has in-creased over the past three decades to approxi-mately 50%.6,7 The main indications for early valve surgery are heart failure, uncontrolled in-fection, and prevention of embolic events (Table 2).30 Observational studies assessing associations between the timing of surgery and outcomes have yielded inconsistent results.14

In a recent randomized trial involving 76 pa-tients with severe left-sided infective endocardi-tis and a large vegetation but no indications for emergency surgery at the time of randomization, the incidence of the composite end point of in-hospital death or embolic events within the first 6 weeks after randomization was significantly lower among patients assigned to surgery within 48 hours after randomization than among those assigned to usual care (3% vs. 23%); the benefit was driven by the reduction in embolic events.43 However, it is unclear whether these results should be generalized to support the routine use of early valve surgery, because the patients enrolled in this study were young (mean age, 47 years), with a low frequency of coexisting conditions and very low mortality (<5%).

After a cerebral embolic event, most patients

still have an indication for valve surgery. The decision to proceed with surgery must take into account the risk of further embolism and the risks associated with surgery. The incidence of stroke among patients receiving appropriate an-timicrobial therapy decreases from 4.8 cases per 1000 patient-days in the first week of therapy to 1.7 per 1000 patient-days in the second week, with further decreases thereafter.20 A history of em-bolic stroke or transient ischemic attack is not in itself a contraindication to surgery. Postoperative neurologic deterioration is infrequent after a silent cerebral embolism or a transient ischemic attack. After an ischemic stroke, the risk associated with surgery depends on the neurologic condition of the patient19; generally, surgery is performed if the patient does not have severe neurologic dam-age, as long as cerebral hemorrhage has been ruled out by means of cerebral imaging.30

Anticoagulant and Antiplatelet TherapiesObservational data have suggested an increased risk of death from cerebral hemorrhage, with no reduction in the risk of embolic events, in pa-tients with prosthetic-valve infective endocarditis due to S. aureus who were receiving treatment with oral anticoagulant agents.44 European Society of Cardiology guidelines currently recommend that in patients already receiving oral anticoagulant therapy in whom infective endocarditis develops and is complicated by ischemic and nonhemor-rhagic stroke, the oral anticoagulant agent be replaced with heparin for 2 weeks; however, the guidelines acknowledge the low level of evidence supporting this recommendation.30

Antiplatelet agents are not recommended for patients with infective endocarditis. In a double-blind, placebo-controlled trial, patients with in-fective endocarditis who were randomly assigned to receive aspirin at a dose of 325 mg per day for 4 weeks had no significant decrease in the inci-dence of embolic events and had a nonsignifi-cant increase in the rate of cerebral bleeding episodes.45 Observational studies have yielded conflicting findings with respect to the associa-tions of aspirin use before infective endocarditis with risks of death and embolic events.46-49 In the absence of bleeding, aspirin taken for other indications may not need to be discontinued.

ProphylaxisIn the past decade, on the basis of expert opinion, indications for antibiotic prophylaxis against infec-




tive endocarditis have been restricted to patients who have a prosthetic valve, a history of infective endocarditis, or unrepaired cyanotic congenital heart disease and who are planning to undergo an invasive dental procedure; the recommended regi-mens are summarized in Table 3 in the Supple-mentary Appendix.30,50 In the United Kingdom, antibiotic prophylaxis against infective endocarditis is no longer recommended in any circumstances.51 To date, reports indicate no appreciable increase in the incidence of infective endocarditis due to viri-dans group streptococci since the guidelines were revised to recommend a restricted use of antibi-otic prophylaxis.52,53 Good oral, dental, and skin hygiene are recommended to reduce risks.

A R E A S OF UNCERTA IN T Y

The appropriate duration of antibiotic therapy, es-pecially aminoglycosides, remains uncertain. Al-though a combination of oral ciprofloxacin and

rifampin was reported to be effective for S. aureus infective endocarditis in a study of intravenous-drug users,54 oral therapy cannot currently be rec-ommended for infective endocarditis.

Despite the recent randomized trial suggesting a benefit of early surgery,43 the appropriate tim-ing of surgery remains controversial. When sur-gery is performed within the first week of anti-biotic treatment, there may be increased risks of relapse and prosthetic-valve dysfunction.55

The usefulness of systematic brain imaging and the preferred treatment of patients with infective endocarditis and cerebral mycotic aneurysms are also uncertain. Because unruptured aneurysms may resolve with antibiotic therapy alone,24 such patients should receive antibiotics, with serial an-giography performed to document the resolution of the aneurysm. Endovascular treatment should be pursued only if the aneurysm is very large (e.g., >10 mm) or if it is not resolving or is en-larging despite treatment with antibiotics.25

Table 2. Indications for and Timing of Surgery in Patients with Left-Sided, Native-Valve Infective Endocarditis.*

Indication Timing of Surgery†

Heart failure

Aortic or mitral-valve infective endocarditis with severe acute regurgitation or obstruction caus-ing refractory pulmonary edema or cardiogenic shock

Emergency

Aortic or mitral-valve infective endocarditis with fistula into a cardiac chamber or pericardium causing refractory pulmonary edema or cardiogenic shock

Emergency

Aortic or mitral-valve infective endocarditis with severe acute regurgitation or obstruction and persistent heart failure or signs of poor hemodynamic tolerance (early mitral-valve closure or pulmonary hypertension)

Urgent

Aortic or mitral-valve infective endocarditis with severe regurgitation and heart failure easily con-trolled with medical treatment

Elective

Uncontrolled infection

Locally uncontrolled infection (abscess, false aneurysm, fistula, enlarging vegetation, or dehis-cence of prosthetic valve)

Urgent

Persistent fever and positive blood cultures for >5–7 days Urgent

Infection caused by fungi or multidrug-resistant organisms, such as Pseudomonas aeruginosa and other gram-negative bacilli

Elective

Prevention of embolism

Aortic or mitral-valve infective endocarditis with large vegetations (>10 mm in length) after one or more embolic episodes, despite appropriate antibiotic therapy, especially during the first 2 weeks of therapy

Urgent

Aortic or mitral-valve infective endocarditis with large vegetations (>10 mm) and other predictors of complicated course (heart failure, persistent infection, or abscess)

Urgent

Isolated, very large vegetations (>15 mm); surgery may be preferred if a procedure preserving the native valve is feasible

Urgent

* Adapted from Habib et al.30

† Emergency surgery was defined as surgery performed within 24 hours after the condition was identified, urgent surgery as that performed within a few days after the condition was identified, and elective surgery as that performed after at least 1 or 2 weeks of antibiotic therapy.

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GUIDELINES

Guidelines addressing the prophylaxis and man-agement of infective endocarditis have been pub-lished by professional societies in the United States and Europe.29-31 The recommendations presented here are largely consistent with these guidelines.

CONCLUSIONS A ND R ECOMMENDATIONS

The patient in the vignette has evidence of native mitral-valve infective endocarditis complicated by cerebral emboli. Antibiotic treatment should be started immediately after two to three blood cul-tures have been drawn. Pending culture results, an aminopenicillin with beta-lactam inhibitor (either ampicillin with sulbactam or amoxicillin with clavulanate potassium)29,30 should be given in combination with gentamicin. The recent cere-bral embolic events and the large, mobile mitral-

valve vegetation seen on the echocardiogram are indications for urgent mitral-valve surgery, in the absence of contraindications. If blood cultures are still negative at the time of surgery, a sample of valve tissue should be obtained for culture, and a broad-range PCR assay should be performed to help identify the causative microorganism, with adaptation of the antibiotic regimen to the iden-tified microorganism. The patient should be coun-seled concerning the prevention of recurrent in-fective endocarditis (oral and overall hygiene and appropriate use of antibiotic prophylaxis, given that he will now have both a history of infective endo-carditis and a prosthetic valve).

Dr. Duval reports receiving grant support through his institu-tion from Pfizer and travel expenses from Roche. No other po-tential conflict of interest relevant to this article was reported.


We thank Dr. L. Kritharides and Dr. R.W. Sy for sharing data from the Australian population-based study on infective endo-carditis.

REFERENCES

1. Correa de Sa DD, Tleyjeh IM, Anave-kar NS, et al. Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc 2010;85:422-6. [Erratum, Mayo Clin Proc 2010;85:772.]2. Duval X, Delahaye F, Alla F, et al. Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive popula-tion-based surveys. J Am Coll Cardiol 2012;59:1968-76.3. Fedeli U, Schievano E, Buonfrate D, Pellizzer G, Spolaore P. Increasing inci-dence and mortality of infective endocar-ditis: a population-based study through a record-linkage system. BMC Infect Dis 2011;11:48.4. Federspiel JJ, Stearns SC, Peppercorn AF, Chu VH, Fowler VG Jr. Increasing US rates of endocarditis with Staphylococcus aureus: 1999-2008. Arch Intern Med 2012; 172:363-5.5. Sy RW, Kritharides L. Health care ex-posure and age in infective endocarditis: results of a contemporary population-based profile of 1536 patients in Australia. Eur Heart J 2010;31:1890-7.6. Murdoch DR, Corey GR, Hoen B, et al. Clinical presentation, etiology, and out-come of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med 2009;169:463-73.7. Selton-Suty C, Célard M, Le Moing V, et al. Preeminence of Staphylococcus au-reus in infective endocarditis: a 1-year

population-based survey. Clin Infect Dis 2012;54:1230-9.8. Benito N, Miró JM, de Lazzari E, et al. Health care-associated native valve endo-carditis: importance of non-nosocomial acquisition. Ann Intern Med 2009;150: 586-94.9. Tleyjeh IM, Abdel-Latif A, Rahbi H, et al. A systematic review of population-based studies of infective endocarditis. Chest 2007;132:1025-35.10. Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis 2010;51:131-40.11. Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference center: etiologic diagnosis of 348 cases. Medicine (Baltimore) 2005;84:162-73.12. Stehbens WE, Delahunt B, Zuccollo JM. The histopathology of endocardial sclero-sis. Cardiovasc Pathol 2000;9:161-73.13. Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Mi-crobiol Rev 2001;14:177-207.14. Bannay A, Hoen B, Duval X, et al. The impact of valve surgery on short- and long-term mortality in left-sided infective endo-carditis: do differences in methodological approaches explain previous conflicting results? Eur Heart J 2011;32:2003-15.15. Li JS, Sexton DJ, Mick N, et al. Pro-posed modifications to the Duke criteria for the diagnosis of infective endocardi-tis. Clin Infect Dis 2000;30:633-8.16. Richet H, Casalta JP, Thuny F, et al.

Development and assessment of a new early scoring system using non-specific clinical signs and biological results to identify children and adult patients with a high probability of infective endocarditis on admission. J Antimicrob Chemother 2008;62:1434-40.17. Crawford MH, Durack DT. Clinical presentation of infective endocarditis. Cardiol Clin 2003;21:159-66.18. Thuny F, Avierinos JF, Tribouilloy C, et al. Impact of cerebrovascular complica-tions on mortality and neurologic out-come during infective endocarditis: a pro-spective multicentre study. Eur Heart J 2007;28:1155-61.19. Sonneville R, Mirabel M, Hajage D, et al. Neurologic complications and out-comes of infective endocarditis in criti-cally ill patients: the ENDOcardite en REAnimation prospective multicenter study. Crit Care Med 2011;39:1474-81.20. Dickerman SA, Abrutyn E, Barsic B, et al. The relationship between the initiation of antimicrobial therapy and the inci-dence of stroke in infective endocarditis: an analysis from the ICE Prospective Co-hort Study (ICE-PCS). Am Heart J 2007;154:1086-94.21. Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echo-cardiography: a prospective multicenter study. Circulation 2005;112:69-75. [Erra-tum, Circulation 2005;112(9):e125.]22. Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events

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in infective endocarditis. J Am Coll Car-diol 2001;37:1069-76.23. Duval X, Iung B, Klein I, et al. Effect of early cerebral magnetic resonance im-aging on clinical decisions in infective endocarditis: a prospective study. Ann In-tern Med 2010;152:497-504.24. Corr P, Wright M, Handler LC. Endo-carditis-related cerebral aneurysms: radio-logic changes with treatment. AJNR Am J Neuroradiol 1995;16:745-8.25. Peters PJ, Harrison T, Lennox JL. A dangerous dilemma: management of infectious intracranial aneurysms com-plicating endocarditis. Lancet Infect Dis 2006;6:742-8.26. Greub G, Lepidi H, Rovery C, et al. Diagnosis of infectious endocarditis in patients undergoing valve surgery. Am J Med 2005;118:230-8.27. Lepidi H, Coulibaly B, Casalta JP, Raoult D. Autoimmunohistochemistry: a new method for the histologic diagnosis of infective endocarditis. J Infect Dis 2006;193:1711-7.28. Botelho-Nevers E, Thuny F, Casalta JP, et al. Dramatic reduction in infective en-docarditis-related mortality with a man-agement-based approach. Arch Intern Med 2009;169:1290-8.29. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for health-care professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovas-cular Disease in the Young, and the Coun-cils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111(23):e394-e434. [Errata, Circulation 2005;112:2373, 2007;115(15):e408, 116(21):e547, 2008; 118(12):e497.]30. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC): endorsed by the European Society of Clinical Microbi-ology and Infectious Diseases (ESCMID) and the International Society of Chemo-therapy (ISC) for Infection and Cancer. Eur Heart J 2009;30:2369-413.31. Gould FK, Denning DW, Elliott TS, et al. Guidelines for the diagnosis and anti-biotic treatment of endocarditis in adults: a report of the Working Party of the Brit-ish Society for Antimicrobial Chemother-apy. J Antimicrob Chemother 2012;67:269-89. [Erratum, J Antimicrob Chemother 2012;67:1304.]32. Morris AJ, Drinković D, Pottumarthy S, MacCulloch D, Kerr AR, West T. Bacte-

riological outcome after valve surgery for active infective endocarditis: implications for duration of treatment after surgery. Clin Infect Dis 2005;41:187-94.33. Francioli P, Ruch W, Stamboulian D. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone and netilmicin for 14 days: a prospective mul-ticenter study. Clin Infect Dis 1995;21: 1406-10.34. Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicil-lin-susceptible streptococci. Clin Infect Dis 1998;27:1470-4.35. Olaison L, Schadewitz K. Enterococ-cal endocarditis in Sweden, 1995-1999: can shorter therapy with aminoglycosides be used? Clin Infect Dis 2002;34:159-66.36. Gavaldà J, Len O, Miró JM, et al. Treat-ment of Enterococcus faecalis endocardi-tis with ampicillin plus ceftriaxone. Ann Intern Med 2007;146:574-9.37. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al. Ampicillin plus ceftriax-one is as effective as ampicillin plus gen-tamicin for treating Enterococcus faecalis infective endocarditis. Clin Infect Dis 2013 February 25 (Epub ahead of print).38. Cosgrove SE, Vigliani GA, Fowler VG Jr, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 2009;48:713-21.39. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653-65.40. Das I, Saluja T, Steeds R. Use of dap-tomycin in complicated cases of infective endocarditis. Eur J Clin Microbiol Infect Dis 2011;30:807-12.41. Durante-Mangoni E, Casillo R, Ber-nardo M, et al. High-dose daptomycin for cardiac implantable electronic device- related infective endocarditis. Clin Infect Dis 2012;54:347-54.42. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infec-tious Diseases Society of America for the treatment of methicillin-resistant Staphy-lococcus aureus infections in adults and children: executive summary. Clin Infect Dis 2011;52:285-92.43. Kang D-H, Kim Y-J, Kim S-H, et al. Early surgery versus conventional treat-ment for infective endocarditis. N Engl J Med 2012;366:2466-73.44. Tornos P, Almirante B, Mirabet S, Per-manyer G, Pahissa A, Soler-Soler J. Infec-tive endocarditis due to Staphylococcus aureus: deleterious effect of anticoagu-lant therapy. Arch Intern Med 1999;159: 473-5.45. Chan KL, Dumesnil JG, Cujec B, et al.

A randomized trial of aspirin on the risk of embolic events in patients with infec-tive endocarditis. J Am Coll Cardiol 2003;42:775-80.46. Chan KL, Tam J, Dumesnil JG, et al. Effect of long-term aspirin use on embol-ic events in infective endocarditis. Clin Infect Dis 2008;46:37-41.47. Pepin J, Tremblay V, Bechard D, et al. Chronic antiplatelet therapy and mortali-ty among patients with infective endocar-ditis. Clin Microbiol Infect 2009;15:193-9.48. Snygg-Martin U, Rasmussen RV, Has-sager C, Bruun NE, Andersson R, Olaison L. The relationship between cerebrovas-cular complications and previously estab-lished use of antiplatelet therapy in left-sided infective endocarditis. Scand J Infect Dis 2011;43:899-904.49. Anavekar NS, Tleyjeh IM, Anavekar NS, et al. Impact of prior antiplatelet ther-apy on risk of embolism in infective endo-carditis. Clin Infect Dis 2007;44:1180-6. [Erratum, Clin Infect Dis 2007;44:1398.]50. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart As-sociation: a guideline from the American Heart Association Rheumatic Fever, En-docarditis, and Kawasaki Disease Com-mittee, Council on Cardiovascular Dis-ease in the Young, and the Council on Clinical Cardiology, Council on Cardio-vascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circu-lation 2007;116:1736-54. [Erratum, Circu-lation 2007;116(15):e376-e377.]51. Richey R, Wray D, Stokes T. Prophy-laxis against infective endocarditis: sum-mary of NICE guidance. BMJ 2008;336: 770-1.52. Thornhill MH, Dayer MJ, Forde JM, et al. Impact of the NICE guideline recom-mending cessation of antibiotic prophy-laxis for prevention of infective endocar-ditis: before and after study. BMJ 2011; 342:d2392.53. Desimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endo-carditis caused by viridans group strepto-cocci before and after publication of the 2007 American Heart Association’s endo-carditis prevention guidelines. Circula-tion 2012;126:60-4.54. Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized com-parison with parenteral therapy. Am J Med 1996;101:68-76.55. Thuny F, Beurtheret S, Mancini J, et al. The timing of surgery influences mortal-ity and morbidity in adults with severe complicated infective endocarditis: a pro-pensity analysis. Eur Heart J 2011;32:2027-33.Copyright © 2013Massachusetts Medical Society.

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clinical practice


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Caren G. Solomon, M.D., M.P.H., Editor




Herpes ZosterJeffrey I. Cohen, M.D.

From the Medical Virology Section, Lab-oratory of Infectious Diseases, National Institutes of Health, Bethesda, MD. Ad-dress reprint requests to Dr. Cohen at the Laboratory of Infectious Diseases, Nation-al Institutes of Health, Bldg. 50, Rm. 6134, 50 South Dr., MSC1807, Bethesda, MD 20892-1807, or at [email protected].


A 65-year-old man presents with a rash of 2 days’ duration over the right forehead with vesicles and pustules, a few lesions on the right side and tip of the nose, and slight blurring of vision in the right eye. The rash was preceded by tingling in the area and is now associated with aching pain. How should this patient be evaluated and treated?


Primary infection with varicella–zoster virus (VZV) results in chickenpox, charac-terized by viremia with a diffuse rash and seeding of multiple sensory ganglia, where the virus establishes lifelong latency. Herpes zoster is caused by reactivation of latent VZV in cranial-nerve or dorsal-root ganglia, with spread of the virus along the sensory nerve to the dermatome. There are more than 1 million cases of herpes zoster in the United States each year, with an annual rate of 3 to 4 cases per 1000 persons. Studies suggest that the incidence of herpes zoster is increasing.1 Unvac-cinated persons who live to 85 years of age have a 50% risk of herpes zoster. Up to 3% of patients with the disease require hospitalization.

The major risk factor for herpes zoster is increasing age. With increasing time after varicella infection, there is a reduction in the level of T-cell immunity to VZV,2 which, unlike levels of virus-specific antibodies, correlates with protection against herpes zoster. The risk is higher for women than for men, for whites than for blacks, and for persons with a family history of herpes zoster than for those without such a background.3 Chickenpox that occurs in utero or early in infancy, at a time when the cellular immune system is not fully mature, is associated with herpes zoster in childhood. Immunocompromised persons with impaired T-cell immunity, includ-ing recipients of organ or hematopoietic stem-cell transplants, those receiving im-munosuppressive therapy, and those with lymphoma, leukemia, or human immu-nodeficiency virus (HIV) infection, are at increased risk for herpes zoster and for severe disease.

Postherpetic neuralgia, or pain persisting after the rash has resolved (often de-fined specifically as pain persisting for 90 days or more after the onset of the rash), is a feared complication of herpes zoster. The pain may persist for many months or even years; it may be severe and interfere with sleep and activities of daily living, resulting in anorexia, weight loss, fatigue, depression, withdrawal from social ac-tivities and employment, and loss of independent living. Depending on age and the definition used, postherpetic neuralgia develops in 10 to 50% of persons with herpes zoster. The risk increases with age (particularly after 50 years of age) and is also increased among persons with severe pain at the onset of herpes zoster or with a severe rash and a large number of lesions.

Various neurologic complications have been reported to occur with herpes zos-





n engl j med 369;3 nejm.org july 18, 2013256

ter, including Bell’s palsy, the Ramsay Hunt syn-drome, transverse myelitis, transient ischemic attacks, and stroke.4 In addition, ophthalmologic complications of herpes zoster occurring in the V1 distribution of the trigeminal nerve can include keratitis, scleritis, uveitis, and acute retinal ne-crosis (Table 1). Immunocompromised persons can have additional complications, including dis-seminated skin disease, acute or progressive outer retinal necrosis, chronic herpes zoster with verru-cous skin lesions, and development of acyclovir-resistant VZV. In these patients, the disease can involve multiple organs (e.g., lung, liver, brain, and gastrointestinal tract), and patients may present with hepatitis or pancreatitis several days before the rash appears.5


Symptoms

The rash of herpes zoster is dermatomal and does not cross the midline, a feature that is consistent with reactivation from a single dorsal-root or cranial-nerve ganglion. The thoracic, trigeminal (Fig. 1A), lumbar, and cervical dermatomes are the most frequent sites of rash, although any area of the skin can be involved. In nonimmunocom-promised persons, a few scattered lesions outside the affected dermatome are not unexpected. The rash is often preceded by tingling, itching, or pain (or a combination of these) for 2 to 3 days, and these symptoms can be continuous or episodic.

Depending on the location and severity, this pro-dromal pain may lead to misdiagnosis and costly testing. The rash begins as macules and papules, which evolve into vesicles and then pustules (Fig. 1B). New lesions appear over a period of 3 to 5 days, often with filling in of the dermatome despite antiviral treatment. The rash usually dries with crusting in 7 to 10 days. Some persons have pain in the absence of a rash, termed zoster sine herpete, which is difficult to diagnose and may lead to numerous unnecessary tests or procedures. Im-munocompromised patients may have dissemi-nated rashes with viremia and new lesions occur-ring for up to 2 weeks. The characteristics of pain associated with herpes zoster vary. Patients may have paresthesias (e.g., burning and tingling), dysesthesia (altered or painful sensitivity to touch), allodynia (pain associated with nonpainful stim-uli), or hyperesthesia (exaggerated or prolonged response to pain). Pruritus is also commonly as-sociated with herpes zoster.

Diagnosis

Most cases of herpes zoster can be diagnosed clinically, although atypical rashes may require a direct immunofluorescence assay for VZV antigen or a polymerase-chain-reaction (PCR) assay for VZV DNA in cells from the base of lesions after they are unroofed. In a study comparing PCR with other diagnostic methods, the sensitivity and specificity of PCR for detecting VZV DNA were 95% and 100%, respectively, whereas the values

key Clinical points

herpes zoster

• In the absence of the herpes zoster vaccine, persons who live to 85 years of age have a 50% risk of her-pes zoster.

• The persons most likely to benefit from antiviral therapy for herpes zoster are those who have or are at risk for complications of herpes zoster, including immunocompromised persons, those 50 years of age or older, and those with severe pain or severe rash.

• Antiviral agents hasten the resolution of herpes zoster lesions and decrease the severity of acute pain but have not been shown to reduce the risk of postherpetic neuralgia.

• Valacyclovir or famciclovir is preferable to acyclovir because of ease of dosing and higher levels of anti-viral drug activity.

• Patients with herpes zoster and new visual symptoms should be evaluated by an ophthalmologist to determine whether eye-specific therapy is needed.

• The herpes zoster vaccine is recommended by the Advisory Committee on Immunization Practices for persons 60 years of age or older and is used in those with or without a history of herpes zoster.

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62 nejm readers’ choice clinical care collectionclinical pr actice


for immunofluorescence testing for VZV antigen were 82% and 76%.6 The condition that is most commonly mistaken for herpes zoster is herpes simplex virus infection, which can recur in a der-matomal distribution; accordingly, when patients present with “recurrent zoster” or atypical lesions or are immunocompromised with disseminated skin lesions, specific testing for both VZV and herpes simplex virus is often useful. VZV has been detected in the saliva of persons with herpes zos-ter,7 although such testing does not currently have a demonstrated role in clinical practice.

A PCR assay of the cerebrospinal fluid (CSF) has been used for the diagnosis of central nervous system (CNS) vasculopathy; evidence of an increase in the ratio of the anti-VZV antibody level in the CSF to that in the blood is more sensitive.4 A PCR assay of the blood may be helpful for the diag-nosis of visceral herpes zoster in immunocom-promised persons who present with hepatitis or pancreatitis in the absence of a rash.5 A PCR as-say for VZV in the blood or CSF has been used for the diagnosis of zoster sine herpete.

Treatment and PreventionAntiviral TherapyAntiviral therapy is recommended for herpes zos-ter in certain nonimmunocompromised patients and all immunocompromised patients (Table 2).

Other persons might also benefit from antiviral therapy, although they have a lower risk of com-plications from herpes zoster. Three guanosine analogues — acyclovir, valacyclovir, and famci-clovir — have been approved by the Food and Drug Administration (FDA) for the treatment of herpes zoster (Table 3). The oral bioavailability and levels of antiviral drug activity in the blood are higher and more consistent in patients receiv-ing thrice-daily valacyclovir or famciclovir than in those receiving acyclovir five times daily. This is important because VZV is less sensitive than herpes simplex virus to acyclovir, valacyclovir, and famciclovir.

These antiviral agents hasten the resolution of lesions, reduce the formation of new lesions, reduce viral shedding, and decrease the severity of acute pain (Table 3). For example, in the largest randomized, double-blind trial of acyclovir for herpes zoster, oral acyclovir given within 47 hours after the onset of rash shortened the mean time to the last day of new-lesion formation, the loss of vesicles, and full crusting by 0.5 days, 1.8 days, and 2.2 days, respectively, as compared with placebo.10 In another large trial, acyclovir re-duced the duration of viral shedding by 0.8 days as compared with placebo.11 In a meta-analysis of several randomized, controlled trials, antiviral agents did not significantly reduce the incidence

Table 1. Selected Complications of Herpes Zoster in Nonimmunocompromised Persons.*

Complication Manifestations Site of VZV Reactivation

Aseptic meningitis Headache, meningismus Cranial nerve V

Bacterial superinfection Streptococcus, staphylococcus cellulitis Any sensory ganglia

Bell’s palsy Unilateral facial paralysis Cranial nerve VII

Eye involvement (herpes zoster ophthalmicus)

Keratitis, episcleritis, iritis, conjunctivi-tis, uveitis, acute retinal necrosis, optic neuritis, acute glaucoma

Cranial nerve II, III, or V (ophthalmic [V1] branch)

Hearing impairment Deafness Cranial nerve VIII

Motor neuropathy Weakness, diaphragmatic paralysis, neurogenic bladder

Any sensory ganglia

Postherpetic neuralgia Pain persisting after the rash has resolved Any sensory ganglia

Ramsay Hunt syndrome Ear pain and vesicles in the canal, numbness of anterior tongue, facial paralysis

Cranial nerve VII geniculate ganglia, with spread to cranial nerve VIII

Transverse myelitis Paraparesis, sensory loss, sphincter impairment

Vertebral ganglia

Vasculopathy (encephalitis) Vasculitis of cerebral arteries, confu-sion, seizures, TIAs, stroke

Cranial nerve V

* TIA denotes transient ischemic attack, and VZV varicella–zoster virus.




of postherpetic neuralgia,20 and they are not ap-proved for the prevention of the condition by the FDA. In some studies, treatment with either va-lacyclovir or famciclovir has been shown to be superior to treatment with acyclovir for reducing pain associated with herpes zoster.14,15 Valacy-clovir is similar to famciclovir in terms of effi-cacy in reducing acute pain and accelerating healing.21 As compared with acyclovir, valacyclo-vir and famciclovir require fewer daily doses but are more expensive.

In controlled trials, treatment has been initi-

ated within 72 hours after the onset of the rash, and it is recommended that treatment start as early as possible within this interval. However, many experts recommend that if new skin lesions are still appearing or complications of herpes zoster are present, treatment should be initiated even if the rash began more than 3 days earlier. Treatment is usually given for 7 days in the ab-sence of complications of herpes zoster. Intrave-nous acyclovir is recommended for immunocom-promised persons who require hospitalization and for persons with severe neurologic complications. Foscarnet is used for immunocompromised pa-tients with acyclovir-resistant VZV.

GlucocorticoidsThe use of glucocorticoids with antiviral therapy for uncomplicated herpes zoster remains contro-versial. Randomized, controlled trials have shown benefits of a tapering course of predisone22 or prednisolone,12 including a reduction in acute pain,12,22 improved performance of activities of daily living,22 accelerated early healing,12 and in one study22 but not another,12 a reduction in the time to complete healing. The addition of gluco-corticoids to antiviral therapy has not been shown to reduce the incidence of postherpetic neuralgia. Owing to their immunosuppressive properties, glucocorticoids should not be administered for herpes zoster without concomitant antiviral ther-apy. Glucocorticoids should be avoided in patients with hypertension, diabetes mellitus, peptic ulcer disease, or osteoporosis; particular caution is war-ranted in the case of elderly patients, who are at increased risk for serious adverse events. Predni-sone is used for the treatment of certain CNS com-

Table 2. Indications for Antiviral Treatment in Patients with Herpes Zoster.*

Age ≥50 yr

Moderate or severe pain

Severe rash

Involvement of the face or eye

Other complications of herpes zoster

Immunocompromised state

* Although antiviral agents may benefit other patients with herpes zoster, they are primarily recommended by experts for patients with these indications who either have com-plications or are at increased risk for complications from herpes zoster.8,9

A

B

Figure 1. Clinical Features of Herpes Zoster.

Panel A shows herpes zoster in the ophthalmic (V1) branch of the trigeminal ganglia. Photograph courtesy of Michael Oxman, M.D. Panel B shows vesicles and pustules in a patient with herpes zoster. These are representative photographs and are not from the case presented.

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plications of herpes zoster, such as vasculopathy or Bell’s palsy in nonimmunocompromised patients.

Acute Pain Associated with Herpes ZosterSeveral medications have been used for the treat-ment of acute pain associated with herpes zoster (Table 4). Nonsteroidal antiinflammatory drugs or acetaminophen can be administered in patients with mild pain. Opioids, such as oxycodone, are used for more severe pain associated with herpes zoster. Opioids were more effective than gaba pen-tin for herpes zoster–related pain in a random-ized, placebo-controlled trial.23 In one controlled trial24 but not another,23 gabapentin reduced pain associated with herpes zoster. Lidocaine patches reduced pain associated with herpes zoster in a placebo-controlled trial; they should be applied to intact skin only, not to the area of the rash.25 Although tricyclic antidepressants have not been

shown to be effective in randomized, controlled clinical trials for acute pain associated with her-pes zoster, they have been used when opioids were insufficient for pain.

Eye Disease Associated with Herpes ZosterPatients with herpes zoster in the V1 distribution of the trigeminal nerve (including lesions on the forehead and the upper eyelid) and either lesions on the tip or side of the nose or new visual symp-toms should be evaluated by an ophthalmologist. Other treatment may be needed in addition to antiviral therapy, including mydriatic eyedrops to dilate the pupil and reduce the risk of scarring (synechiae); topical glucocorticoids for keratitis, episcleritis, or iritis; medications to reduce intra-ocular pressure for the treatment of glaucoma; and intravitreal antiviral therapy for immuno-compromised patients with retinal necrosis.

Table 3. Antiviral Therapy for Herpes Zoster.

Medication Dose Effects Observed in Controlled Trials Side Effects

Nonimmunocompromised persons

Acyclovir (e.g., Zovirax) 800 mg orally five times daily for 7–10 days

Reduced time to last new-lesion formation, loss of vesicles, full crusting, cessation of viral shedding, reduced severity of acute pain10-12

Malaise

Famciclovir (e.g., Famvir) 500 mg orally three times daily for 7 days

Reduced time to last new-lesion formation, loss of vesicles, full crusting, cessation of viral shedding, cessation of pain13,14

Headache, nausea

Valacyclovir (e.g., Valtrex) 1 g orally three times daily for 7 days

Reduced time to last new-lesion formation, loss of vesicles, full crusting, cessation of pain15,16

Headache, nausea

Brivudin (e.g., Zostex, Helpin)*

125 mg orally once daily for 7 days

Reduced time to last new-lesion formation, full crusting, cessation of pain17

Headache, nausea; contraindi-cated in persons receiving fluorouracil or other fluoro-pyrimidines

Immunocompromised persons requiring hospitalization or persons with severe neurologic complications

Acyclovir (e.g., Zovirax) 10 mg/kg intravenously every 8 hr for 7–10 days

Reduced time to last new-lesion formation, full crusting, cessation of viral shedding, cessation of pain, reduced cutaneous dissemination, reduced visceral herpes zoster18,19

Renal insufficiency

Foscarnet (e.g., Foscavir) for acyclovir-resistant VZV†

40 mg/kg intravenously every 8 hr until lesions

are healed

Not reported Renal insufficiency, hypokale-mia, hypocalcemia, hypo-magnesemia, hypophospha-temia, nausea, diarrhea, vomiting, anemia, granulocy-topenia, headache

* Brivudin is not available in the United States and has not been approved by the Food and Drug Administration (FDA).† Foscarnet is not approved for this use by the FDA.




Tabl

e 4.

Med

icat

ions

Com

mon

ly U

sed

for

Trea

tmen

t of A

cute

Pai

n A

ssoc

iate

d w

ith H

erpe

s Z

oste

r.*

Med

icat

ion

Dos

eD

ose

Adj

ustm

ent

Max

imum

Dos

eSi

de E

ffec

ts

Opi

oid

and

nono

pioi

d an

alge

sics

Oxy

codo

ne5

mg

ever

y 4

hr a

s ne

eded

Incr

ease

by

5 m

g fo

ur ti

mes

dai

ly e

very

2

days

as

tole

rate

dN

one

spec

ified

, but

sho

uld

not e

xcee

d 12

0 m

g da

ily e

xcep

t in

cons

ulta

tion

with

a p

ain

spec

ialis

t

Dro

wsi

ness

, diz

zine

ss, c

on-

stip

atio

n, n

ause

a, v

om-

iting

Tram

adol

50 m

g on

ce o

r tw

ice

daily

Incr

ease

by

50–1

00 m

g da

ily in

div

ided

do

ses

ever

y 2

days

as

tole

rate

d40

0 m

g da

ily; 3

00 m

g da

ily if

pat

ient

is

>75

year

s of

age

Dro

wsi

ness

, diz

zine

ss, c

on-

stip

atio

n, n

ause

a, v

om-

iting

Glu

coco

rtic

oids

†

Pred

niso

ne60

mg

daily

for

7 da

ys, t

hen

decr

ease

to

30

mg

daily

for

7 da

ys, t

hen

de-

crea

se to

15

mg

daily

for

7 da

ys

Non

e60

mg

daily

Gas

troi

ntes

tinal

dis

tres

s,

naus

ea, v

omiti

ng, m

ood

chan

ges,

ede

ma,

glu

-co

se in

tole

ranc

e, in

-cr

ease

d bl

ood

pres

sure

Ant

icon

vuls

ants

Gab

apen

tin30

0 m

g at

bed

time

or 1

00–3

00 m

g th

ree

times

dai

lyIn

crea

se b

y 10

0–30

0 m

g th

ree

times

da

ily e

very

2 d

ays

as to

lera

ted

3600

mg

daily

Dro

wsi

ness

, diz

zine

ss, a

tax-

ia, p

erip

hera

l ede

ma

Preg

abal

in75

mg

at b

edtim

e or

75

mg

twic

e da

ilyIn

crea

se b

y 75

mg

twic

e da

ily e

very

3

days

as

tole

rate

d60

0 m

g da

ilyD

row

sine

ss, d

izzi

ness

, ata

x-ia

, per

iphe

ral e

dem

a

Tric

yclic

ant

idep

ress

ants

Nor

trip

tylin

e25

mg

at b

edtim

eIn

crea

se b

y 25

mg

daily

eve

ry 2

–3 d

ays

as to

lera

ted

150

mg

daily

Dro

wsi

ness

, dry

mou

th,

blur

red

visi

on, w

eigh

t ga

in, u

rina

ry r

eten

tion

Topi

cal t

hera

py

Lido

cain

e pa

tch

(5%

)O

ne p

atch

, app

lied

to in

tact

ski

n on

ly,

for

up to

12

hr p

er d

ayN

one

One

pat

ch fo

r up

to 1

2 hr

per

day

Loca

l irr

itatio

n; if

sys

tem

ic,

abso

rptio

n ca

n ca

use

drow

sine

ss, d

izzi

ness

* Th

is t

able

pro

vide

s ex

ampl

es a

nd is

not

mea

nt t

o be

com

preh

ensi

ve. M

odifi

ed fr

om D

wor

kin

et a

l.8 by

per

mis

sion

of O

xfor

d U

nive

rsity

Pre

ss.

† T

he u

se o

f glu

coco

rtic

oids

is c

ontr

over

sial

bec

ause

the

y ar

e of

ten

asso

ciat

ed w

ith a

dver

se e

vent

s in

old

er p

atie

nts.

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Postherpetic NeuralgiaPain associated with postherpetic neuralgia is often challenging to treat. A detailed discussion of the management of postherpetic neuralgia is beyond the scope of this article. In brief, medica-tions shown in randomized trials to reduce pain associated with postherpetic neuralgia include topical lidocaine,26 anticonvulsant agents (e.g., gabapentin27 and pregabalin28), opioids,29 tricyclic antidepressants (e.g., nortriptyline30), and capsa-icin.31 Combination therapy, such as gabapentin and nortriptyline32 or an opiate and gabapentin,33 have been more effective for postherpetic neural-gia than single-agent therapy but also confer a greater risk of side effects. Even with treatment, many patients do not have adequate relief of pain, and for such patients, referral to a pain specialist can be helpful.

Prevention of Herpes ZosterA live attenuated herpes zoster vaccine is recom-mended by the Advisory Committee on Immuni-zation Practices for persons 60 years of age or older to prevent herpes zoster and its complica-tions, including postherpetic neuralgia.9,34 On the basis of the results of a recent clinical trial, the vaccine is now approved by the FDA to prevent herpes zoster in persons 50 years of age or old-er.35 The efficacy of the vaccine in preventing herpes zoster is 70% for persons 50 to 59 years of age, 64% for persons 60 to 69 years of age, and 38% for persons 70 years of age or older.34-36 However, vaccine efficacy in preventing posther-petic neuralgia is 66% for persons 60 to 69 years of age and is undiminished at 67% for persons 70 years of age or older.34,36 Although the effec-tiveness of the vaccine to prevent herpes zoster is reduced in persons 70 years of age or older, the increased risk of severe disease and the persisting efficacy of the vaccine in preventing postherpetic neuralgia in these older persons strongly favor vaccinating them. A follow-up study showed that the reduction in the risk of herpes zoster remained significant for at least 5 years after vaccination, though the effectiveness declined over time.37 In vaccinated (as compared with unvaccinated) per-sons in whom herpes zoster developed, pain was significantly shorter in duration and less severe.34

The vaccine can be given to persons with a his-tory of herpes zoster. In a recent study, rates of adverse events associated with vaccination were similar among persons who had had herpes zos-

ter (at a mean of 3.6 years before vaccination) and among those with no history of the disease.38

The optimal timing of vaccination after an episode of herpes zoster is uncertain. Because the risk of recurrent herpes zoster after a recent epi-sode of the disease is relatively low39 and because the cellular immune response to VZV during the first 3 years after vaccination is similar to that after an episode of herpes zoster,40 one might delay vaccination for 3 years in immunocompetent persons with a recent history of herpes zoster, provided that the diagnosis of herpes zoster has been well documented by a health care provider. The vaccine is contraindicated in persons with hematologic cancers whose disease is not in re-mission or who have received cytotoxic chemo-therapy within 3 months, in persons with T-cell immunodeficiency (e.g., HIV infection with a CD4 cell count of ≤200 per cubic millimeter or <15% of total lymphocytes), and in those receiving high-dose immunosuppressive therapy (e.g., ≥20 mg of prednisone daily for ≥2 weeks or anti–tumor necrosis factor therapy).

Infection ControlAlthough herpes zoster is less contagious than varicella, patients with herpes zoster can trans-mit VZV to susceptible persons, in whom vari-cella may develop. For nonimmunocompromised persons with dermatomal herpes zoster, contact precautions should be used, and lesions should be covered if possible.41 Despite these measures, viral transmission has occasionally been reported in such patients.42 For persons with disseminat-ed lesions and for immunocompromised persons with herpes zoster, airborne and contact precau-tions are required until all lesions have crusted.


Improved therapies are needed for pain associ-ated with herpes zoster and postherpetic neural-gia and to prevent the development of postherpetic neuralgia. In addition, studies are needed to deter-mine which patients are at highest risk for posther-petic neuralgia so that more aggressive therapy can be given. There is uncertainty regarding the safety and effectiveness of the vaccine in persons with immunocompromising conditions that are currently considered contraindications to vacci-nation, the duration of immunity induced by the vaccine, and the need for booster doses.




Guidelines

Recommendations have been developed for the management of herpes zoster by a group of ex-perts8 and for the prevention of herpes zoster by the Advisory Committee on Immunization Prac-tices.9 The present review is generally concordant with these recommendations.


Whereas herpes zoster is often mild in healthy young persons, older persons are at increased risk for pain and complications, including postherpetic neuralgia, ocular disease, motor neuropathy, and CNS disease. In the vast major-ity of cases, the diagnosis can be made clinically. Antiviral therapy is most beneficial for persons who have complications of herpes zoster or who are at increased risk for complications, such as older persons and immunocompromised per-sons, and should be initiated as soon as possible, generally within 72 hours after the onset of the

rash. Valacyclovir or famciclovir is preferred over acyclovir owing to the reduced frequency of dos-ing and higher levels of antiviral drug activity. The patient described in the vignette should re-ceive oral antiviral therapy, medication for pain (e.g., an opioid, with the addition of gabapentin if needed), and prompt referral to an ophthal-mologist. He should also be advised to avoid con-tact with persons who have not had varicella or have not received the varicella vaccine until his lesions have completely crusted. I would recom-mend herpes zoster vaccination to reduce the risk of recurrence, but in an immunocompetent patient such as this one, I would defer vaccina-tion for approximately 3 years, since the current episode of herpes zoster should boost his cellular immune response to VZV for that period of time.

The views expressed here are those of the author and not necessarily those of the U.S. government.

No potential conflict of interest relevant to this article was reported.


I thank Drs. Adriana Marques and Michael Oxman for their comments on an earlier version of the manuscript.

References

1. Rimland D, Moanna A. Increasing in-cidence of herpes zoster among veterans. Clin Infect Dis 2010;50:1000-5.2. Hayward AR, Herberger M. Lympho-cyte responses to varicella zoster virus in the elderly. J Clin Immunol 1987;7:174-8.3. Hicks LD, Cook-Norris RH, Mendoza N, Madkan V, Arora A, Tyring SK. Family history as a risk factor for herpes zoster: a case-control study. Arch Dermatol 2008; 144:603-8.4. Gilden D, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus vascu-lopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol 2009;8:731-40.5. de Jong MD, Weel JF, van Oers MH, Boom R, Wertheim-van Dillen PM. Mo-lecular diagnosis of visceral herpes zos-ter. Lancet 2001;357:2101-2.6. Sauerbrei A, Eichhorn U, Schacke M, Wutzler PJ. Laboratory diagnosis of her-pes zoster. J Clin Virol 1999;14:31-6.7. Mehta SK, Tyring SK, Gilden DH, et al. Varicella-zoster virus in the saliva of patients with herpes zoster. J Infect Dis 2008;197:654-7.8. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the manage-ment of herpes zoster. Clin Infect Dis 2007;44:Suppl 1:S1-S26.9. Harpaz R, Ortega-Sanchez IR, Seward

JF. Prevention of herpes zoster: recom-mendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-5):1-30.10. McKendrick MW, McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. Br Med J (Clin Res Ed) 1986; 293:1529-32.11. Huff JC, Bean B, Balfour HH Jr, et al. Therapy of herpes zoster with oral acyclo-vir. Am J Med 1988;85:84-9.12. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J. A ran-domized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994;330:896-900.13. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia — a random-ized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:89-96.14. Degreef H. Famciclovir, a new oral antiherpes drug: results of the first con-trolled clinical study demonstrating its efficacy and safety in the treatment of un-complicated herpes zoster in immuno-competent patients. Int J Antimicrob Agents 1994;4:241-6.15. Beutner KR, Friedman DJ, Forszpan-iak C, Andersen PL, Wood MJ. Valaciclovir

compared with acyclovir for improved therapy for herpes zoster in immunocom-petent adults. Antimicrob Agents Che-mother 1995;39:1546-53.16. Lin WR, Lin HH, Lee SS, et al. Com-parative study of the efficacy and safety of valaciclovir versus acyclovir in the treat-ment of herpes zoster. J Microbiol Immu-nol Infect 2001;34:138-42.17. Wassilew SW, Wutzler P. Oral brivudin in comparison with acyclovir for improved therapy of herpes zoster in immunocom-petent patients: results of a randomized, double-blind, multicentered study. Antivi-ral Res 2003;59:49-56.18. Balfour HH Jr, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med 1983;308:1448-53.19. Shepp DH, Dandliker PS, Meyers JD. Treatment of varicella–zoster virus infec-tion in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine. N Engl J Med 1986;314:208-12.20. Li Q, Chen N, Yang J, et al. Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst Rev 2009;2:CD006866.21. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral thera-py for herpes zoster: randomized, con-

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trolled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 2000;9:863-9.22. Whitley RJ, Weiss H, Gnann JW Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a ran-domized, placebo-controlled trial. Ann Intern Med 1996;125:376-83.23. Dworkin RH, Barbano RL, Tyring SK, et al. A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster. Pain 2009; 142:209-17.24. Berry JD, Petersen KL. A single dose of gabapentin reduces acute pain and al-lodynia in patients with herpes zoster. Neurology 2005;65:444-7.25. Lin PL, Fan SZ, Huang CH, et al. An-algesic effect of lidocaine patch 5% in the treatment of acute herpes zoster: a dou-ble-blind and vehicle-controlled study. Reg Anesth Pain Med 2008;33:320-5.26. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch re-lieves postherpetic neuralgia more effec-tively than a vehicle topical patch: results of an enriched enrollment study. Pain 1999;80:533-8.27. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain 2001;94:215-24.28. Stacey BR, Barrett JA, Whalen E, Phil-lips KF, Rowbotham MC. Pregabalin for postherpetic neuralgia: placebo-con-trolled trial of fixed and flexible dosing

regimens on allodynia and time to onset of pain relief. J Pain 2008;9:1006-17.29. Watson CP, Babul N. Efficacy of oxy-codone in neuropathic pain: a random-ized trial in postherpetic neuralgia. Neu-rology 1998;50:1837-41.30. Raja SN, Haythornthwaite JA, Pappa-gallo M, et al. Opioids versus antidepres-sants in postherpetic neuralgia: a random-ized, placebo-controlled trial. Neurology 2002;59:1015-21.31. Irving GA, Backonja MM, Dunteman E, et al. A multicenter, randomized, dou-ble-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med 2011;12:99-109.32. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combina-tion for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009;374:1252-61.33. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gaba-pentin, or their combination for neuro-pathic pain. N Engl J Med 2005;352:1324-34.34. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84.35. Schmader KE, Levin MJ, Gnann JW Jr, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis 2012;54:922-8.36. Oxman MN, Levin MJ. Vaccination

against herpes zoster and postherpetic neuralgia. J Infect Dis 2008;197:Suppl 2:S228-S236.37. Schmader KE, Oxman MN, Levin MJ, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis 2012;55:1320-8.38. Morrison VA, Oxman MN, Levin MJ, et al. Safety of zoster vaccine in elderly adults following documented herpes zos-ter. J Infect Dis 2013 May 31 (Epub ahead of print).39. Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zos-ter in an immunocompetent elderly popu-lation. J Infect Dis 2012;206:190-6.40. Weinberg A, Zhang JH, Oxman MN, et al. Varicella-zoster virus-specific im-mune responses to herpes zoster in el-derly participants in a trial of a clinically effective zoster vaccine. J Infect Dis 2009;200:1068-77.41. Siegel JD, Rhinehart E, Jackson M, Chiarello L. 2007 Guideline for isolation precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control 2007;35:Suppl 2:S65-S164.42. Lopez AS, Burnett-Hartman A, Nam-biar R, et al. Transmission of a newly characterized strain of varicella-zoster vi-rus from a patient with herpes zoster in a long-term-care facility, West Virginia, 2004. J Infect Dis 2008;197:646-53.Copyright © 2013 Massachusetts Medical Society.

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clinical practice


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Carotid StenosisJames C. Grotta, M.D.

From the University of Texas Medical School at Houston. Address reprint re-quests to Dr. Grotta at the Department of Neurology, University of Texas Medical School at Houston, 6431 Fannin St., 7.044, Houston, TX 77030, or at [email protected].


A 53-year-old woman who smoked and had hypertension had brief numbness of the right side of her body. Six months later, aphasia and right hemiparesis suddenly devel-oped, and they resolved after 48 hours. Computed tomographic angiography (CTA) showed left internal-carotid-artery stenosis of 70% just distal to the bifurcation. Mag-netic resonance imaging (MRI) confirmed a left frontotemporal infarct without hem-orrhagic transformation or cerebral edema. Cardiac evaluation was normal. What is the appropriate management of this patient’s carotid stenosis?


Carotid artery disease causes approximately 10 to 20% of strokes, and appropriate intervention is important for secondary and possibly primary stroke prevention. The degree of carotid stenosis is the strongest determinant of stroke risk.

Atherosclerosis

Atherosclerosis, the most common disease affecting the carotid artery, occurs most frequently at its bifurcation (Fig. 1A and 1B). Atherosclerotic plaques cause symp-toms most often through distal embolism to branches of the retinal or cerebral arteries; hemodynamically significant luminal stenosis may also result in critical reduction of perfusion.

Most emboli result from activation of platelets on the plaque surface; less fre-quently, they result from cholesterol particles. An “unstable plaque” with rupture of the cap may cause emboli.1 Emboli in retinal arterioles lead to transient mon-ocular blindness (amaurosis fugax).2 Emboli in the cerebral circulation most often lodge in the middle cerebral-artery branches, but they can also end up in anterior or posterior cerebral-artery branches, depending on the anatomy of the circle of Willis. If patients who have had a stroke attributed to carotid disease are ques-tioned closely, at least 50% report symptoms preceding the stroke that are consis-tent with a transient ischemic attack (TIA).3 Stroke syndromes related to carotid disease involve some combination of motor or sensory symptoms (involving the contralateral face, arm, or leg) or speech, language, or visual symptoms.

Reduction of flow due to high-grade stenosis causes symptoms referable to brain regions at the border zones between the anterior, middle, and posterior cere-bral arteries, where perfusion pressure is the lowest and most vulnerable to further reduction by proximal stenosis.4 Such lesions often cause repetitive TIAs that are brief (<1 minute), sometimes with limb shaking, as compared with embolic TIAs, which tend to be longer (5 to 30 minutes).5 Border-zone (“watershed”) infarcts can be distinguished from embolic infarcts on brain imaging (see Fig. S1a and S1b in the Supplementary Appendix, available with the full text of this article at NEJM.org).

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n engl j med 369;12 nejm.org september 19, 20131144

The prognosis for patients with carotid disease is most closely linked to the degree of stenosis, with a 2-mm residual luminal diameter or a 60 to 70% reduction in diameter associated with a marked increase in the risk of stroke.6 Plaque ulcerations are common, but they do not strongly correlate with subsequent ipsilateral ischemic stroke.7

Whereas total occlusion of the carotid in some patients results in a devastating stroke, it can be asymptomatic in patients with adequate collateral flow to the intracranial arteries.8 The contralateral carotid provides collateral flow through the an-terior communicating artery (Fig. S2 in the Sup-plementary Appendix). Consequently, contralat-eral carotid stenosis or occlusion is an important determinant of risk that should be considered in planning treatment. Carotid siphon atherosclero-sis can also cause TIAs and strokes.9

Dissection and Fibromuscular Dysplasia

Dissection of the carotid artery is a common cause of stroke in patients younger than 45 years of age, and it is frequently detected by means of noninvasive vascular imaging.10,11 Carotid dissec-tion usually occurs about 2 cm distal to the bifur-cation (Fig. S3a in the Supplementary Appendix), and it may be related to trauma to the artery by the transverse processes of the C2 and C3 verte-brae or the styloid process. Dissection, which can occur spontaneously, is due to a hematoma in the tunica media that ruptures through the intima and compromises the arterial lumen. If the dissection extends toward the adventitia, a dissecting aneu-

rysm (often erroneously called a pseudoaneurysm) can develop, but these aneurysms rarely bleed un-less the dissection extends intracranially. Consid-erable ipsilateral neck, facial, or head pain occurs in more than 60% of dissections, and if such pain is present after trauma or in association with a TIA or stroke, dissection should be suspected. Horner’s syndrome may also be present as a result of in-jured sympathetic nerves in the arterial wall, and lower cranial nerves may be compressed. Genetic collagen abnormalities such as the Ehlers–Danlos syndrome (type IV) should be considered in pa-tients with spontaneous dissection.

Fibromuscular dysplasia is twice as common in women as in men,11 and it is marked by fibrotic thickening of the arterial wall, most often the me-dia (Fig. S3b in the Supplementary Appendix). Fibromuscular dysplasia is associated with intra-cranial aneurysms and carotid dissection. Both dissection and fibromuscular dysplasia can cause strokes due to embolization or hemodynamically significant narrowing of the luminal diameter.

Other, less common arterial diseases are be-yond the scope of this review. Coiling, looping, and kinking of the extracranial carotids are com-mon but rarely of pathologic significance.12


Diagnosis

A carotid bruit may signal the presence of clini-cally significant internal carotid artery disease; this finding is present in 70 to 89% of patients with a

key Clinical points

CAROTID STENOSIS

• Carotid artery disease is a common cause of stroke and should be assessed by means of one of several readily available noninvasive tests in all patients who have had a transient ischemic attack (TIA) or stroke in the carotid-artery distribution.

• Control of smoking, hypertension, and hyperlipidemia and the use of an antiplatelet agent are in-dicated to reduce the risk of stroke among persons with carotid artery disease.

• In patients with an ischemic stroke or a TIA in the carotid-artery distribution, carotid endarterectomy should be considered within 2 weeks if there is stenosis of more than 70% of the diameter of the ipsi-lateral carotid artery (measured according to the method used in the North American Symptomatic Carotid Endarterectomy Trial) due to atherosclerosis. There is less benefit in patients with stenosis of 50 to 69% and in asymptomatic patients, and there is no benefit in patients with stenosis of less than 50%.

• Carotid stenting is an alternative to carotid endarterectomy, particularly in patients at high surgical risk and in younger patients (<70 years of age).




2-mm luminal narrowing. However, a bruit is a nonspecific finding, since it is heard in 5% of pa-tients who are 45 to 80 years of age in the absence of clinically significant internal carotid disease.13

The various tests for evaluating carotid disease are listed in Table 1. The most common screening test is duplex Doppler ultrasonography (Fig. 2). Ultrasonography is highly accurate in identifying calcification of carotid-artery plaque and intra-plaque hemorrhage and measuring the degree of stenosis,14 and it is indicated in patients who have had ischemic symptoms in the carotid-artery dis-tribution or who have a carotid bruit and would be candidates for intervention. A peak systolic ve-locity in excess of 200 cm per second usually in-dicates stenosis of 50% or more.15

CTA (Fig. 3) and magnetic resonance angiog-raphy (MRA) are widely used to evaluate the ca-rotid artery.16,17 Carotid Doppler ultrasonography with either CTA or MRA may be sufficient for making clinical decisions about the management of carotid disease. However, in some cases, ce-rebral angiography may be necessary to provide additional anatomical detail18 (Fig. 1A and 1B).

The most important information gained from each of these tests is the percentage of stenosis. The measurement method used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET)19 is used most widely (Fig. 1C). The diameter of the smallest residual lumen is compared with the diameter of the normal artery distal to the carotid bifurcation, according to the following formula: the percentage of stenosis = [1 − (minimal diameter ÷ distal diameter)] × 100. Imaging also identifies the location of the bifur-cation in relation to the angle of the jaw, the extent of plaque, distal arterial tortuosity or ste-nosis, and the status of contralateral carotid and

A

B

C

Figure 1. Atherosclerosis at the Bifurcation of the Ca-rotid Artery in the Patient in the Case Vignette.

Panel A shows a cerebral arteriogram indicating ste-notic plaque (arrow) before stenting. Panel B shows a three-dimensional reconstruction of the angiogram. Panel C shows calculation of the percentage of steno-sis with the use of the North American Symptomatic Carotid Endarterectomy Trial criteria. The minimal di-ameter (X3) is 0.89 mm, and the distal diameter (X2) is 3.30 mm. The percentage of stenosis is calculated as [1 − (X3 ÷ X2)] × 100, which in this case is 73%. Imag-es courtesy of Peng Chen, M.D.

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collateral flow, and it can usually be used to dis-tinguish atherosclerosis from other conditions (Fig. S3a and S3b in the Supplementary Appendix).

Other techniques to assess carotid atheroscle-rosis have been described; these include high-reso-lution MRI of the arterial wall to examine the morphologic characteristics of the plaque,1 ultra-sonographic assessment of the carotid intima–media thickness,20 detection of microemboli by means of ultrasonography,21 and imaging of ad-hesion molecules on the surface of the plaque or inflamed area.22 However, data are lacking to de-termine the role of these techniques, if any, in clinical practice.

Medical Management

Aggressive treatment of modifiable risk factors for carotid atherosclerosis — especially hyperten-sion and hyperlipidemia — and cessation of smok-ing are central to stroke prevention. Measures to reduce stroke risk have been reviewed in a previ-ous Clinical Practice article23 and in guidelines for primary and secondary stroke prevention.24,25

Some aspects of risk-factor management par-ticular to patients with severe carotid-artery ste-nosis warrant mention. In patients with hyper-tension, treatment goals must take into account the risk of reduced cerebral perfusion with overly aggressive treatment, pending correction of steno-sis. Treated patients should be followed carefully for clinical deterioration, and relative hypotension should be immediately corrected. Furthermore, special attention to blood-pressure control is re-

quired to avoid hypoperfusion during carotid endarterectomy or stenting and the hyperperfu-sion syndrome immediately afterward.26

Statin drugs are effective for both primary and secondary stroke prevention, and they may lead to stabilization and even regression of intima–media thickness of the carotid-artery wall.27

Antiplatelet drugs logically would be of par-ticular benefit in patients with carotid plaques that cause platelet activation. Patients undergoing carotid endarterectomy have a reduced risk of perioperative stroke if they receive aspirin preop-eratively.28 For long-term secondary prevention of stroke, current guidelines recommend aspirin, clopidogrel, or the combination of aspirin and dipyridamole.24 The combination of aspirin and clopidogrel is not recommended because of an increased risk of bleeding, but data from studies of coronary stenting suggest that this combina-tion should be routinely used for a short period (e.g., 1 to 3 months) after carotid-artery stenting.29

Current guidelines suggest that anticoagula-tion therapy with heparin followed by warfarin can be used for 3 to 6 months in patients with acute extracranial dissection.24 Newer oral anti-coagulants have not been studied in these patients. Patients with extensive trauma, intracranial dis-section, or dissection that is discovered weeks after it occurred probably should not receive anticoagu-lation therapy. Treatment with antiplatelet agents is a reasonable alternative; a study comparing warfarin with aspirin in patients with a carotid dissection is ongoing.30 Patients with fibromus-

Table 1. Tests to Detect Carotid Stenosis.

Test Feasibility Accuracy Risks

Ultrasonography Widely available, rapidly performed

Detects bifurcation only None

Magnetic resonance angiography

Requires patient to be immobile for duration of test; not feasible in patients with metallic implants or in severely obese patients

Cannot discriminate subtotal from total occlusion

Gadolinium usually not needed; when used, it carries risk of nephrogenic systemic fibrosis; gadolinium contraindicated in patients with renal insufficiency

Computed tomographic angiography

Widely available, rapidly performed

Provides good resolution of entire vascular tree

Iodinated contrast material carries risk of nephrotoxic effects; computed tomographic angi-ography should be avoided in patients with renal insufficiency

Catheter angiography Requires angiography team Excellent 0.5–1.0% Risk of stroke, myocar-dial infarction, arterial injury, retroperitoneal bleeding




cular dysplasia usually receive aspirin for stroke prevention.

Carotid Endarterectomy

Symptomatic Carotid StenosisIn several randomized trials involving patients who had a TIA or stroke associated with ipsilateral carotid stenosis (symptomatic stenosis), carotid endarterectomy reduced the subsequent risk of stroke.31-34 In the NASCET,31,32 among patients with stenosis of 70% or more, the 2-year risk of ipsilateral stroke was 9% in the group of patients randomly assigned to carotid endarterectomy (plus medical therapy) versus 26% in the group assigned to medical therapy alone (P<0.001). The 5-year risks were 15.7% in the endarterectomy group versus 22.2% in the medical-therapy group (P = 0.04) among patients with stenosis of 50 to 69%. There was no benefit of carotid endarterectomy in pa-tients with stenosis of less than 50%. Among all patients who were randomly assigned to carotid endarterectomy, perioperative strokes occurred in 5.5% (nondisabling in 3.7% and disabling in 1.8%), death in 1.1%, and wound hematoma in 5.5%. The European Carotid Surgery Trial,33 an-other randomized trial comparing carotid endar-terectomy plus medical management with medical management alone, yielded similar results, with a significant benefit of surgery in patients with stenosis of at least 70%.

A meta-analysis of the major trials of carotid endarterectomy showed that the benefit from this procedure was greatest when it was performed within 2 weeks after a TIA or stroke, rather than later.35

Asymptomatic Carotid StenosisCarotid stenosis that is not associated with ipsi-lateral symptoms (asymptomatic stenosis) is typ-ically detected on screening ultrasonographic ex-amination or as part of the investigation of a symptomatic contralateral artery. The most ap-propriate management of asymptomatic stenosis is less clear than that for symptomatic disease, despite several randomized trials addressing this question.36-41 The Asymptomatic Carotid Athero-sclerosis Surgery study,39 which involved patients with stenosis of more than 60% who were random-ly assigned to carotid endarterectomy with medical management or medical management alone, was discontinued after a mean follow-up of 2.7 years. The combined risk of perioperative stroke or death

was 1.5%. The risk of ipsilateral stroke projected over 5 years was 5.1% with carotid endarterecto-my versus 11.0% without carotid endarterectomy (P = 0.004). A similar study in Europe, the Asymp-tomatic Carotid Surgery Trial,40 showed a similar projected reduction in the risk of stroke with ca-rotid endarterectomy but a higher rate of periop-erative stroke or death (3.1%). In both studies, the absolute risk reduction for stroke associated with carotid endarterectomy was only 1 percent-age point per year; this finding indicates that a substantial benefit is likely only in patients with a prolonged life expectancy. The absolute risk re-duction was 11.0 percentage points among men but only 2.8 percentage points among women. In post hoc analyses, besides female sex, factors as-sociated with increased surgical risk included a long plaque dimension and contralateral carotid stenosis or occlusion.41 Surgical expertise and surgical technique are critically important for minimizing the risk of perioperative complica-tions and realizing the small benefit of carotid endarterectomy. Since these trials were carried out more than two decades ago, before the use of statins and other aggressive approaches to the management of risk factors, it is possible that a benefit of carotid endarterectomy in asymptom-atic patients would no longer be observed if both groups received current medical treatment.

Carotid Stenting

Carotid-artery angioplasty with stenting has emerged as an alternative to carotid endarterec-tomy in patients at high risk for complications

Figure 2. Duplex Ultrasonography of the Carotid Artery Showing Severe Carotid Stenosis.

On the left, the arrowheads outline the internal carotid artery. The plaque is visible in the lumen. On the right, the spectral Doppler waveform shows elevated peak systolic and end diastolic velocities (486 and 164 cm per second, respectively) that are consistent with ste-nosis of more than 70%. The ultrasonographic device (CX50, Philips Healthcare) had a linear 3-to-12-MHz transducer. Images courtesy of Andrew Barreto, M.D.

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from endarterectomy such as contralateral occlu-sion or severe coronary artery disease. The Stent-ing and Angioplasty with Protection in Patients at High Risk for Endarterectomy study42 showed that stenting (with an emboli-protection device) was not inferior to endarterectomy with respect to the rate of a composite outcome of stroke, myocardial infarction, or death at 30 days (4.8% vs. 9.8%) and the rate of ipsilateral stroke or death between 31 days and 1 year. Other trials, however, were discontinued because of high rates of periprocedural neurologic events with

carotid stenting.43-46 More recently, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)47 and the International Carotid Stenting Study (ICSS)48 have provided additional informative results. In CREST, symptomatic and asymptomatic patients with stenosis of 50% on angiography or 70% or more on ultrasonography or CTA were randomly assigned to the study treatments; this study required training of inter-ventionists and used distal protection devices. CREST showed no significant difference between the stenting and endarterectomy groups overall in the rates of a composite outcome that included major periprocedural complications (stroke, myo-cardial infarction, or death) and ipsilateral stroke over a 4-year follow-up period (7.2% vs. 6.8%). Whereas the presence or absence of symptoms did not significantly affect the findings, there was a significant interaction of treatment with age: pa-tients younger than 70 years of age had a slightly better outcome after carotid stenting, whereas older patients benefited more from carotid end-arterectomy. The endarterectomy group, as com-pared with the stenting group, had a higher fre-quency of periprocedural myocardial infarction (2.3% vs. 1.1%) but a lower frequency of peripro-cedural stroke (2.3% vs. 4.1%). At 2 years of fol-low-up, the rate of carotid restenosis (a predictor of subsequent stroke) was relatively low (approxi-mately 6%) in both groups.49 Among patients in the ICSS, only short-term follow-up has been re-ported, but for those randomly assigned to ca-rotid stenting there was a significantly increased risk of stroke, death, or myocardial infarction at 120 days. In both studies, medical management was at the discretion of the treating physician.

In aggregate, the available data provide sup-port for carotid endarterectomy or carotid stent-ing in most patients with symptomatic stenosis of more than 70% (number needed to treat to pre-vent one stroke at 24 months, 6),31 in selected patients with symptomatic stenosis of 50 to 69% (number needed to treat to prevent one stroke at 5 years, 15),32 and in a selected subgroup of asymp tomatic patients with a low risk of peri-procedural complications (e.g., no clinically sig-nificant cardiopulmonary or other coexisting conditions and an age younger than 70 years) (number needed to treat to prevent one stroke at 5 years, 17).39 Carotid endarterectomy is currently considered the preferable intervention in most patients, although selected patients (e.g., those

A

B

Figure 3. Computed Tomographic (CT) Arteriography in the Patient in the Case Vignette.

In Panel A, a CT arteriogram shows left carotid-artery stenosis (arrow). In Panel B, embolic occlusion (arrow) of the left middle cerebral-artery branch is shown.




younger than 70 years of age with favorable ana-tomical features or symptomatic patients with severe stenosis who have coexisting conditions conferring a high surgical risk) may benefit more from carotid stenting.


The benefits of carotid endarterectomy or carotid stenting in addition to current medical therapy, as compared with current medical therapy alone, are uncertain in patients with asymptomatic ca-rotid stenosis, especially women. The most ap-propriate timing and choice of carotid interven-tion after stroke also remain uncertain, as do the timing and choice of procedure in patients with carotid stenosis who require other major surgery, especially coronary-artery bypass grafting. It is not known whether improvements in techniques of carotid stenting will result in reduced rates of complications. Data are lacking on the benefits and risks of carotid stenting in patients with dis-section or fibromuscular dysplasia; these patients are at high risk for complications from interven-tion, and dissections often heal with medical man-agement.11 The most appropriate duration of dual antiplatelet therapy after carotid stenting is also uncertain.

Guidelines

Guidelines for the treatment of patients with ca-rotid stenosis have been published previous-ly.24,25,29,50 The recommendations in this article are generally consistent with these guidelines.


The patient described in the vignette had a TIA, and 6 months later she had a stroke due to em-bolization from a stenotic atherosclerotic plaque in the left internal carotid artery. She is at high risk for subsequent stroke, and the carotid steno-sis should be treated. On the basis of a meta-anal-ysis of randomized trials and current guidelines, I would recommend treatment within 2 weeks after her stroke.29,35,50 Either carotid endarterectomy or stenting is an option for management. Where-as carotid endarterectomy is preferred in many cases, given this patient’s relatively young age as well as her recent stroke, which increases the risks associated with surgery and general anes-thesia, I would consider her to be a good candi-date for carotid stenting as long as the lesion could be treated with this approach. Advice and treatment are needed to help her quit smoking. Her hypertension should be well controlled; she should receive statin therapy. Although the most appropriate duration of combined therapy with aspirin and clopidogrel after stent placement re-mains unclear, I would provide treatment with aspirin and clopidogrel for 1 month and then as-pirin indefinitely.

Dr. Grotta reports receiving consulting fees from Merck, Hae-monetics, Genentech, Janssen, Pfizer, Lundbeck, and Ferrer; lecture fees from IPG and Vindico; a grant to his institution from Haemonetics; and royalties from patents regarding a method for treating cerebral ischemia. No other potential con-flict of interest relevant to this article was reported.


References

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6. Brice JG, Dowsett DJ, Lowe RD. Hae-modynamic effects of carotid artery ste-nosis. Br Med J 1964;2:1363-6.7. Lennihan L, Kupsky WJ, Mohr JP, Hauser WA, Correll JW, Quest DO. Lack of association between carotid plaque hema-toma and ischemic cerebral symptoms. Stroke 1987;18:879-81.8. Pessin MS, Hinton RC, Davis KR, et al. Mechanisms of acute carotid stroke. Ann Neurol 1979;6:245-52.9. Marzewski DJ, Furlan AJ, St Louis P, Little JR, Modic MT, Williams G. Intracra-nial internal carotid artery stenosis: long-term prognosis. Stroke 1982;13:821-4.10. Bogousslavsky J, Pierre P. Ischemic stroke in patients under age 45. Neurol Clin 1992;10:113-24.11. Zweifler RM, Silverboard G. Arterial dissections and fibromuscular dysplasia.

In: Mohr JP, Wolf PA, Grotta JC, Moskow-itz MA, Mayberg MR, von Kummer R, eds. Stroke: pathophysiology, diagnosis, and management. 5th ed. Philadelphia: Else-vier, 2011:661-86.12. Mohr JP, Mast H. Carotid artery dis-ease. In: Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kum-mer R, eds. Stroke: pathophysiology, di-agnosis, and management. 5th ed. Phila-delphia: Elsevier, 2011:334-61.13. Ratchford EV, Jin Z, Di Tullio MR, et al. Carotid bruit for detection of hemody-namically significant carotid stenosis: the Northern Manhattan Study. Neurol Res 2009;31:748-52.14. Meairs S, Hennerici M, Mohr JP. Ul-trasonography. In: Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, eds. Stroke: pathophysi-

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ology, diagnosis, and management. 5th ed. Philadelphia: Elsevier, 2011:831-69.15. de Bray JM, Glatt B. Quantification of atheromatous stenosis in the extracranial internal carotid artery. Cerebrovasc Dis 1995;5:414-26.16. Dzialowski I, Puetz V, von Kummer R. Computed tomography–based evaluation of cerebrovascular disease. In: Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, May-berg MR, von Kummer R, eds. Stroke: pathophysiology, diagnosis, and manage-ment. 5th ed. Philadelphia: Elsevier, 2011:870-81.17. Warach S, Baird AE, Dani KA, Winter-mark M, Kidwell CS. Magnetic resonance imaging of cerebrovascular diseases. In: Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, eds. Stroke: pathophysiology, diagnosis, and management. 5th ed. Philadelphia: Else-vier, 2011:882-909.18. Sattenberg RJ, Saver JL, Gobin YP, Liebeskind DS. Cerebral angiography. In: Mohr JP, Wolf PA, Grotta JC, Moskowitz MA, Mayberg MR, von Kummer R, eds. Stroke: pathophysiology, diagnosis, and management. 5th ed. Philadelphia: Else-vier, 2011:910-28.19. Gagne PJ, Matchett J, MacFarland D, et al. Can the NASCET technique for measur-ing carotid stenosis be reliably applied out-side the trial? J Vasc Surg 1996;24:449-56.20. Lorenz MW, Markus HS, Bots ML, Ros-vall M, Sitzer M. Prediction of clinical car-diovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459-67.21. Markus HS, MacKinnon A. Asymp-tomatic embolization detected by Doppler ultrasound predicts stroke risk in symp-tomatic carotid artery stenosis. Stroke 2005;36:971-5.22. Goes E, Janssens W, Maillet B, Freson M, Steyaert L, Osteaux M. Tissue charac-terization of atheromatous plaques: cor-relation between ultrasound image and histological findings. J Clin Ultrasound 1990;18:611-7.23. Davis SM, Donnan GA. Secondary prevention after ischemic stroke or tran-sient ischemic attack. N Engl J Med 2012; 366:1914-22.24. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare profes-sionals from the American Heart Associa-tion/American Stroke Association. Stroke 2011;42:227-76.25. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary pre-vention of stroke: a guideline for health-care professionals from the American Heart Association/American Stroke Asso-ciation. Stroke 2011;42:517-84. [Erratum, Stroke 2011;42(2):e26.]

26. Henderson RD, Phan TG, Piepgras DG, Wijdicks EF. Mechanisms of intrace-rebral hemorrhage after carotid endarter-ectomy. J Neurosurg 2001;95:964-9.27. Furberg CD, Adams HP Jr, Applegate WB, et al. Effect of lovastatin on early ca-rotid atherosclerosis and cardiovascular events. Circulation 1994;90:1679-87.28. Taylor DW, Barnett JHM, Haynes RB, et al. Low-dose and high-dose acetylsali-cylic acid for patients undergoing carotid endarterectomy: a randomised clinical trial. Lancet 1999;353:2179-84.29. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guide-line for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947.30. Cervical Artery Dissection in Stroke Study Trial Investigators. Antiplatelet therapy vs. anticoagulation in cervical ar-tery dissection: rationale and design of the Cervical Artery Dissection in Stroke Study (CADISS). Int J Stroke 2007;2:292-6.31. North American Symptomatic Carot-id Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325: 445-53.32. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339: 1415-25.33. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carot-id Surgery Trial (ECST). Lancet 1998;351: 1379-87.34. Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy and preven-tion of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991;266:3289-94.35. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Endarterecto-my for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004;363:915-24.36. The CASANOVA Study Group. Carotid surgery versus medical therapy in asymp-tomatic carotid stenosis. Stroke 1991;22: 1229-35.37. Mayo Asymptomatic Carotid Endar-terectomy Study Group. Results of a ran-domized controlled trial of carotid endar-terectomy for asymptomatic carotid stenosis. Mayo Clin Proc 1992;67:513-8.38. Hobson RW II, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 1993;328:221-7.39. Executive Committee for the Asymp-tomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid

artery stenosis. JAMA 1995;273:1421-8.40. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterec-tomy in patients without recent neuro-logical symptoms: randomised controlled trial. Lancet 2004;363:1491-502. [Erratum, Lancet 2004;364:416.]41. Young B, Moore WS, Robertson JT, et al. An analysis of perioperative surgical mortality and morbidity in the Asymptom-atic Carotid Atherosclerosis Study. Stroke 1996;27:2216-24.42. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting ver-sus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-501.43. CAVATAS Investigators. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Verte-bral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001;357:1729-37.44. CaRESS Steering Committee. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial: 1-year results. J Vasc Surg 2005;42:213-9.45. Ringleb PA, Allenberg J, Brückmann H, et al. 30 Day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006;368:1239-47. [Erratum, Lancet 2006;368:1238.]46. Mas J-L, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in pa-tients with symptomatic severe carotid stenosis. N Engl J Med 2006;355:1660-71.47. Brott TG, Hobson RW II, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11-23. [Errata, N Engl J Med 2010;363:198, 498.]48. Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (Interna-tional Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010;375:985-97. [Erratum, Lancet 2010;376:90.]49. Lal BK, Beach KW, Roubin GS, et al. Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial. Lancet Neurol 2012;11:755-63.50. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. Cath-eter Cardiovasc Interv 2013;81(1):E76-E123.Copyright © 2013 Massachusetts Medical Society.


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In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with

the reader (regular type). The authors’ commentary follows.


From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School — both in Boston. Address reprint requests to Dr. Miller at the Department of Internal Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at almiller@ partners.org.

N Engl J Med 2013;369:966-72.DOI: 10.1056/NEJMcps1300093Copyright © 2013 Massachusetts Medical Society.

A 35-year-old man presented to the emergency department after having an episode of syncope while playing soccer. Loss of consciousness lasted only seconds and was pre-ceded by a brief period of light-headedness. When he regained consciousness, he had no nausea, diaphoresis, chest pain, or dyspnea. He was not injured and had no bowel or bladder incontinence. Witnesses reported no tonic–clonic movements. The patient had no history of fainting or light-headedness.

In the evaluation of syncope, the history of the episode is critical; particular atten-tion should be paid to any symptoms that occurred before loss of consciousness, the context within which syncope occurred, and any consequences (e.g., injury or postictal confusion). Neurally mediated, or vasovagal, syncope is typically associ-ated with a prodrome of nausea, diaphoresis, and tunnel vision. In the absence of a prodrome, a diagnosis of cardiac syncope is more likely, although the presence of a prodrome does not rule out cardiac syncope. Cardiac syncope is generally related to inadequate cardiac output, which may be a consequence of an outflow-tract obstruction, tachycardia, or bradycardia. The occurrence of an injury with syncope is also suggestive of — though not specific for — cardiac syncope. How-ever, the absence of injury does not rule out cardiac syncope.

Vasovagal syncope is often situational, occurring in association with specific activities (e.g., coughing or micturition) or with pain, and it generally occurs when the patient is standing. It is atypical for vasovagal syncope to occur when a person is seated or reclining and even more atypical during exercise, which further sup-ports a diagnosis of cardiac syncope in this patient. The patient’s normal mental status on recovery of consciousness and the absence of bowel or bladder inconti-nence argue against seizure. The patient did not have tonic–clonic jerks, but their presence is in any case not specific for seizure as the underlying cause. A more detailed history should be obtained to identify any risk factors for cardiac disease, including a family history of heart disease or sudden death.

The patient did not take medications, did not use tobacco or illicit drugs, and drank alcohol only occasionally. He was born in Mexico, immigrated to the United States as a teenager, and lived with his wife in western Massachusetts, where he worked as a dairy farmer. He did not recall any major childhood illnesses. His maternal grand-mother and a maternal uncle had both died suddenly at 65 years of age without known antecedent cardiovascular disease. He had five siblings and three children, all of whom were well.

The fact that the patient took no medications eliminates one point of concern, since some medications, particularly beta-blockers, calcium-channel blockers, anti-hypertensive agents, and QT-prolonging medications, can cause syncope. The ab-


A Patient with SyncopeMichelle C. Fox, M.D., Neal Lakdawala, M.D., Amy Leigh Miller, M.D., Ph.D.,

and Joseph Loscalzo, M.D., Ph.D.

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sence of risk factors for coronary disease argues against myocardial ischemia, and a seemingly healthy childhood lowers the index of suspicion for undiagnosed congenital heart disease. Al-though the patient had two relatives who died suddenly, neither death occurred at a young age.

At initial presentation, the patient had normal vi-tal signs, and the physical examination was un-remarkable. An electrocardiogram (ECG) was normal. Echocardiography showed a structurally normal heart. The patient was discharged with an event monitor, and 2 weeks later he had an episode of monomorphic wide-complex tachycardia, with a heart rate of almost 300 beats per minute, while playing soccer. At the time, he noted mild dyspnea and neck discomfort but reported no chest pain, palpitations, or light-headedness. He was admit-ted for further evaluation and management of his condition.

Monomorphic wide-complex tachycardias include supraventricular tachycardia with aberrant con-duction, supraventricular tachycardia with pre-excitation, and ventricular tachycardia. Although ventricular tachycardia is the most common cause of wide-complex tachycardia, in a young healthy patient, supraventricular tachycardias remain a distinct possibility. In general, however, patients should be presumed to have ventricular tachy-cardia until proved otherwise. A history of coro-nary artery disease increases the likelihood of ventricular tachycardia, whereas structural cardiac abnormalities can be associated with an increased likelihood of preexcitation, ventricular tachycar-dia, or both. Accordingly, evaluation for both ischemia and structural heart disease is warrant-ed in patients presenting with wide-complex tachycardia.

In a patient with sustained, hemodynamically stable wide-complex tachycardia, physical find-ings suggestive of atrioventricular dissociation can be diagnostic. In most cases, however, the diagnosis is made on the basis of ECG or inva-sive testing. A finding of atrioventricular disso-ciation on ECG is diagnostic of ventricular tachycardia; other features, such as the QRS axis, width, and morphologic characteristics, are informative but not definitive. Unfortunately, recordings obtained by means of ambulatory monitoring rarely provide diagnostic informa-tion. In such cases, programmed stimulation (an electrophysiological study) can often induce the

tachycardia, allowing for definitive diagnosis and appropriate treatment.

This patient’s clinical course underscores the risk of discharging a patient with possible car-diac syncope with a plan for ambulatory moni-toring. The intensity of the initial evaluation of syncope depends on clinical risk stratification. In a patient presenting with exercise-associated syncope, an exercise stress test should be per-formed as part of the initial evaluation; in this patient, a stress test might have reproduced the arrhythmia in a controlled environment.

The results of coronary angiography were normal. An invasive electrophysiological study showed a ventricular tachycardia originating from an endo-cardial, inferolateral focus in the left ventricle; an endocardial voltage map did not reveal significant scarring. After radiofrequency endocardial abla-tion, ventricular tachycardia could no longer be induced.

In assessing monomorphic ventricular tachycar-dia, the first consideration is the presence or ab-sence of structural heart disease. In this young, healthy patient whose echocardiogram showed a structurally normal heart, the leading diagnosis is idiopathic ventricular tachycardia, which fre-quently occurs with exercise or emotional stress and is most often explained by an automatic focus, although reentrant circuits involving the Purkinje fibers can also produce idiopathic ven-tricular tachycardia. It tends to be paroxysmal and spontaneously terminating and is often as-sociated with premature ventricular beats from the same automatic focus. Syncope is not typical of idiopathic ventricular tachycardia but can be associated with it. Although the most common site of origin is the right ventricular outflow tract, resulting in a pattern of left bundle-branch block with an inferior axis, inferolateral idio-pathic ventricular tachycardias can be observed. There are no findings suggestive of a more sinister cause of arrhythmia, such as multiple ventricular tachycardia involving different cir-cuits (which would suggest processes such as sarcoidosis), an electroanatomical map sugges-tive of marked scarring (which would be mani-fested as reduced voltage level), or concomitant conduction abnormalities.

Given that the patient spent his childhood in Mexico, Chagas’ disease is an important consid-eration. In Chagas’ disease, conduction abnor-




malities (right bundle-branch block or left ante-rior hemiblock, high-grade atrioventricular nodal block, sinus-node dysfunction, or a com-bination of these conduction abnormalities) of-ten precede other abnormalities. In the absence of conduction abnormalities, idiopathic ventric-ular tachycardia remains the most likely diagno-sis, but it must be considered a diagnosis of ex-clusion. Cardiac magnetic resonance imaging (MRI), which has greater sensitivity for detect-ing subtle abnormalities than echocardiography, should be considered to rule out structural heart disease. Although ischemia is associated with polymorphic ventricular tachycardia and ven-tricular fibrillation rather than monomorphic ventricular arrhythmias, given its high preva-lence and the ready availability of treatments, ischemia should be ruled out in patients with new ventricular arrhythmias. As in this case, cardiac catheterization is often performed in patients with wide-complex tachycardia, since it can be used to rule out obstructive coronary ar-tery disease or anomalies.

A cardiac MRI scan showed no abnormalities oth-er than the lesions created by radiofrequency abla-tion. On follow-up exercise stress testing, the pa-tient achieved 17.8 metabolic equivalents; he had frequent premature ventricular contractions with the same morphologic features as his ventricular tachycardia, but there was no sustained arrhyth-mia. Given continued ectopy, which was consis-tent with his clinical arrhythmia, and given the hemodynamically significant nature of that ar-rhythmia, the decision was made to place an im-plantable cardioverter–defibrillator (ICD) before discharge.

Whereas ICDs are clearly indicated for the sec-ondary prevention of cardiac events related to structural heart disease, idiopathic ventricular tachycardia is rarely an indication for ICD place-ment, since these arrhythmias are generally nonlethal and can in most cases be eliminated by means of catheter ablation. However, alterna-tive approaches to the management of care should be considered when there is concern that the arrhythmia will recur after an initial attempt at ablation; options include a second attempt at ablation, particularly if there is a substantial ec-topic burden, or long-term pharmacologic ther-apy. The choice of pharmacologic agent for the

suppression of ventricular arrhythmias depends in part on the proposed mechanism of ventricu-lar tachycardia. Beta-blockers may prevent exer-cise-induced ventricular tachycardia by suppress-ing reentry, reducing automaticity, or reducing myocardial oxygen demand. Some idiopathic left ventricular tachycardias are exquisitely sensitive to verapamil; these “verapamil-sensitive ventric-ular tachycardias” are typically induced by exer-cise and in classic cases are characterized by a pattern of right bundle-branch block with a su-perior axis. Antiarrhythmic agents (e.g., amio-darone or sotalol) may be considered, since they can both reduce the burden of the arrhythmia and slow its rate. Some patients are reluctant to undergo long-term treatment with medication. In considering treatment options, the risks asso-ciated with the medications and with ICD place-ment must be discussed, the latter including inappropriate shocks and post-traumatic stress disorder.

A year later, during sexual intercourse, the pa-tient had an episode of monomorphic ventricular tachycardia, which was terminated by a single shock from his ICD.

Given the recurrence of ventricular arrhythmias, another catheter ablation should be strongly considered. Although antiarrhythmic therapy could be contemplated, catheter ablation is pref-erable as the next therapeutic intervention, given the patient’s young age. A repeat echocardio-gram should be obtained to reassess the patient for structural heart disease, since the recurrent arrhythmia raises the question of whether the initial diagnosis of idiopathic ventricular tachy-cardia was incorrect or (although much less likely) whether a different, unrelated arrhythmia may have developed. Unfortunately, the presence of an ICD precludes repeat cardiac MRI, but volt-age mapping in the electrophysiology laboratory can be very informative with respect to the bur-den of scarring.

On admission, the patient was afebrile, with a heart rate of 92 beats per minute, blood pressure of 125/66 mm Hg, and oxygen saturation of 99% while he was breathing ambient air. Notable find-ings on physical examination included a nondis-placed precordial impulse and a widely split sec-ond heart sound without a murmur or a gallop. An

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ECG revealed a new right bundle-branch block (Fig. 1). An echocardiogram showed normal left ventricular size and thickness, with minimally re-duced systolic function (ejection fraction, approx-imately 50 to 55%); it was otherwise normal. An electrophysiological study showed a large endo-cardial and epicardial scar in the lateral wall of the left ventricle that was consistent with myocardial fibrosis (Fig. 2). After endocardial and epicardial ablation along the scar, ventricular tachycardia was no longer inducible.

The development of a new structural abnormal-ity, a clinically significant scar, suggests a pro-gressive cardiomyopathy. Although ventricular tachycardia can lead to a transient depression in global systolic function, the abnormalities ob-served on electroanatomical mapping cannot be attributed to the arrhythmia or to the earlier ablation. In the absence of coronary heart dis-ease, these findings are suggestive of certain cardiomyopathies, including cardiac sarcoidosis, giant-cell myocarditis, genetic cardiomyopa-thies, and Chagas’ disease.

The cause of Chagas’ disease is the protozoal parasite Trypanosoma cruzi, which is endemic in Central and South America. Infection with T. cruzi should be suspected in persons who have emi-grated from these areas, including this patient, who was born in Mexico. Although acute infec-

tion often goes unrecognized, chronic disease will develop in up to 30% of patients with acute infection. A hallmark of chronic disease is car-diomyopathy. Conduction abnormalities, such as the right bundle-branch block observed in this patient, are characteristic of Chagas’ disease, and involvement of the posterolateral wall of the left ventricle is very common.

Cardiac sarcoidosis can also cause conduc-tion abnormalities and ventricular arrhythmias, but it is typically a patchy process that is less likely than Chagas’ disease to produce a single large region of fibrosis. Nonetheless, sarcoidosis must be considered in patients with unexplained, recurrent ventricular arrhythmias. When sarcoid-osis is a possibility, cardiac MRI (which is con-traindicated in this patient because of his ICD) or combined positron-emission tomography and computed tomography (PET-CT) should be per-formed. Other, less likely possibilities include giant-cell myocarditis, an autoimmune disease that results in severe heart failure and refractory ventricular arrhythmias characterized by a much more accelerated course than that observed in this patient, and genetic cardiomyopathies, in-cluding those caused by mutations in the lamin A (LMNA) and desmosomal genes.

Combined 18F-fluorodeoxyglucose (FDG) PET-CT did not show FDG avidity but did reveal a trans-

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Figure 1. Electrocardiogram Obtained on Admission, Showing Right Bundle-Branch Block and Right-Axis Deviation.




mural perfusion defect extending from the basal to the midlateral wall, suggesting the formation of an aneurysm (Fig. 3). Tests for T. cruzi with both an immunofluorescence assay and an enzyme-linked immunosorbent assay (ELISA) were positive. The patient was referred to an infectious-disease spe-cialist for the initiation of antiparasitic therapy and was treated with a 60-day course of benznida-zole. At follow-up 9 months later, he remained symptom-free.

Commen ta r y

Approximately 10 million people worldwide are infected with T. cruzi, the parasite responsible for Chagas’ disease,1 which is endemic in rural parts of Latin America.1,2 Although historically Chagas’ disease has been rare in developed countries, its prevalence is expected to increase in the United States and other developed coun-tries as more people emigrate from regions where the disease is endemic.2

Chronic Chagas’ disease, the hallmarks of which are cardiomyopathy, megaesophagus, and

megacolon, occurs in 10 to 30% of infected per-sons, usually manifested 10 to 30 years after initial infection.2 Cardiac manifestations pre-dominate; gastrointestinal manifestations are much less common and are usually restricted to patients in the southern part of South America.3 The mechanism of cardiac damage in Chagas’ disease remains elusive. Inciting factors may represent a response to the persistence of T. cruzi within the myocardium or an autoimmune pro-cess triggered by its presence.1 No matter what the cause, ongoing inflammation results in pro-gressive cardiac dysfunction.

In Chagas’ disease, arrhythmia and conduc-tion abnormalities (particularly right bundle-branch block, left anterior hemifascicular block, and ventricular tachycardia) typically precede overt myocardial dysfunction, apical aneurysm, and the progressive biventricular systolic dys-function that culminates in heart failure.2,4 Pa-tients with advanced disease may die from heart failure, whereas those with earlier stages of car-diac involvement may die from sudden arrhyth-mia. This pattern of conduction disease and ar-rhythmia accompanying or preceding structural heart disease is not unique to Chagas’ disease; it may also be seen in persons with ischemic, in-flammatory, genetic, or infiltrative diseases.5 The diagnosis of Chagas’ disease is generally based on serologic testing for IgG antibodies to T. cruzi antigens in a patient with supportive clinical findings. No one of the available assays (ELISA, immunofluorescence assay, and hemag-glutination assay) has adequate sensitivity and specificity for the diagnosis. Two tests, in which different antigens or techniques are used, are required to make the diagnosis; when the results are discordant, additional testing must be per-formed.3 Potential causes of the clinical mani-festations other than Chagas’ disease should also be ruled out with appropriate testing (e.g., 18F-FDG PET-CT would be used to rule out sar-coidosis).

The best management strategy for chronic Chagas’ cardiac disease remains uncertain. Most management guidelines for Chagas’ cardiomy-opathy are extrapolated from data on ischemic and nonischemic dilated cardiomyopathy.6 Ow-ing to the resource-poor nature of the regions in which Chagas’ disease is endemic, primary data are limited to retrospective studies and small registries. Whereas sustained ventricular tachy-

Figure 2. Electroanatomical Map Showing the Endocardial Surface of the Patient’s Heart.

The representation of the heart in the lower right corner shows the orientation. Normal voltage on the endocardial map is indicated by pink; the voltage is increasingly abnormal as the color changes from blue to green to red. The map reveals a significant scar in the lateral wall of the left ventricle. Red and white spheres indicate points of ablation, and gray spheres indicate a dense scar where pacing could not capture the local tissue.

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cardia is an accepted indication for ICD im-plantation,7 the annual mortality rate is high among patients with Chagas’ disease who have an ICD,8 and there is uncertainty regarding the efficacy of an ICD as compared with amioda-rone (the preferred antiarrhythmic medication for patients with Chagas’ cardiomyopathy).6,9 In patients with Chagas’ disease who have sus-tained ventricular tachycardia, the occurrence of syncope does not appear to portend a poor prognosis,10 but moderate or severe ventricular systolic dysfunction does portend a poor prog-nosis for patients with unsustained or sus-tained ventricular tachycardia11; the relatively preserved ejection fraction in this patient is reassuring. Cardiac transplantation has been successfully performed in a few patients with Chagas’ disease.

Antitrypanosomal medications are now being used in the management of Chagas’ disease. Observational data indicate that their use is as-sociated with a reduced likelihood of progres-sion of cardiomyopathy, although gastrointesti-nal problems may not resolve.1,3,12 Benznidazole and nifurtimox have established antitrypano-somal efficacy; neither agent is widely available in the United States.3,13,14 Benznidazole generally

has fewer side effects than nifurtimox and is recommended as first-line treatment.3,12 Adults younger than 50 years of age who have acute or chronic infection without end-stage cardiac dis-ease should generally be treated with antitrypano-somal medications.3 An ongoing blinded, ran-domized trial of benznidazole (ClinicalTrials.gov number, NCT00123916) should further clarify the role of antitrypanosomal medications in patients with chronic Chagas’ infection and car-diac involvement.15 Anticoagulation is not indi-cated in the absence of intracavitary thrombus.6

Whereas idiopathic ventricular tachycardia was the most likely diagnosis at the time of this patient’s initial presentation, the clinical fea-tures of recurrent arrhythmia and the patient’s region of origin argued for a more complicated process. It is essential in such cases to perform a reassessment for the presence of structural heart disease, which can evolve over time. This case underscores the importance of such a reas-sessment and of the consideration of diseases endemic to a patient’s region of origin.

No potential conflict of interest relevant to this article was reported.


We thank Dr. James Maguire for expert clinical insights.

Figure 3. Images Obtained on 18F-Fluorodeoxyglucose Positron-Emission Tomography and CT, Showing a Transmural Perfusion Defect in the Patient’s Heart.

The arrows point to the perfusion defect in the basal to midlateral left myocardial wall.


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References

1. Control of Chagas’ disease: second report of the WHO Expert Committee. Geneva: World Health Organization, 2002.2. Rassi A Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010;375:1388-402.3. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term follow-up of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001;44:666-75.4. Rassi A Jr, Rassi A, Little WC. Chagas’ heart disease. Clin Cardiol 2000;23:883-9.5. Lakdawala NK, Givertz MM. Dilated cardiomyopathy with conduction disease and arrhythmia. Circulation 2010;122:527-34.6. Andrade JP, Marin Neto JA, Paola AA, et al. I Latin American guidelines for the diagnosis and treatment of Chagas’ heart disease: executive summary. Arq Bras Cardiol 2011;96:434-42.7. Muratore CA, Batista Sa LA, Chiale PA, et al. Implantable cardioverter defi-brillators and Chagas’ disease: results of

the ICD Registry Latin America. Europace 2009;11:164-8.8. Cardinalli-Neto A, Bestetti RB, Cor-deiro JA, Rodrigues VC. Predictors of all-cause mortality for patients with chronic Chagas’ heart disease receiving implant-able cardioverter defibrillator therapy. J Cardiovasc Electrophysiol 2007;18:1236-40.9. Rassi A Jr. Implantable cardioverter-defibrillators in patients with Chagas heart disease: misperceptions, many ques-tions and the urgent need for a random-ized clinical trial. J Cardiovasc Electro-physiol 2007;18:1241-3.10. Leite LR, Fenelon G, Paes AT, de Paola AA. The impact of syncope during clinical presentation of sustained ventricular tachycardia on total and cardiac mortality in patients with chronic Chagasic heart disease. Arq Bras Cardiol 2001;77:439-52.11. Sarabanda AV, Marin-Neto JA. Predic-tors of mortality in patients with Chagas’ cardiomyopathy and ventricular tachycar-dia not treated with implantable cardio-

verter-defibrillators. Pacing Clin Electro-physiol 2011;34:54-62.12. Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 2007;298:2171-81.13. Viotti R, Vigliano C, Lococo B, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznida-zole versus no treatment: a nonrandom-ized trial. Ann Intern Med 2006;144:724-34.14. Viotti R, Vigliano C, Lococo B, et al. Side effects of benznidazole as treatment in chronic Chagas disease: fears and re-alities. Expert Rev Anti Infect Ther 2009; 7:157-63.15. Marin-Neto JA, Rassi A Jr, Avezum A Jr, et al. The BENEFIT trial: testing the hy-pothesis that trypanocidal therapy is ben-eficial for patients with chronic Chagas heart disease. Mem Inst Oswaldo Cruz 2009;104:Suppl 1:319-24. [Erratum, Mem Inst Oswaldo Cruz 2009;104:937.]Copyright © 2013 Massachusetts Medical Society.

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Case 23-2013: A 54-Year-Old Woman with Abdominal Pain, Vomiting, and Confusion

Kamyar Kalantar-Zadeh, M.D., M.P.H., Ph.D., Raul N. Uppot, M.D., and Kent B. Lewandrowski, M.D.

From the Department of Medicine, Univer-sity of California, Irvine, Orange (K.K.-Z.); and the Departments of Radiology (R.N.U.) and Pathology (K.B.L.), Massachusetts General Hospital, and the Departments of Radiology (R.N.U.) and Pathology (K.B.L.), Harvard Medical School — both in Boston.

N Engl J Med 2013;369:374-82. DOI: 10.1056/NEJMcpc1208154Copyright © 2013 Massachusetts Medical Society.

Pr esen tation of C a se

Dr. Sara R. Schoenfeld (Medicine): A 54-year-old woman was admitted to this hospital because of abdominal pain, vomiting, and confusion.

The patient was in her usual health until approximately 3 days before admission, when she reportedly began to feel unwell, with weakness, chills, and skin that was abnormally warm to the touch. She self-administered aspirin, without improvement. During the next 2 days, her oral intake decreased. Approximately 22 hours before presentation, vomiting occurred. Nine hours before presentation, she began to travel home to Italy from the eastern United States. During the next 2 hours, increas-ing abdominal pain occurred, associated with vomiting and shortness of breath, and she took additional aspirin for pain. Approximately 2 hours before presentation, while the patient was in flight, abdominal pain markedly worsened, vomiting in-creased, and she became confused and unresponsive. The flight was diverted to Boston. On examination by emergency medical services personnel, she was non-verbal and was moaning continuously. The blood pressure was 120/70 mm Hg, the pulse 52 beats per minute, and the respiratory rate 26 breaths per minute. The capillary blood glucose level was 116 mg per deciliter (6.4 mmol per liter). She was brought to the emergency department at this hospital by ambulance.

The patient’s history was obtained from her husband through an interpreter. She had non–insulin-dependent (type 2) diabetes mellitus, hypertension, nephro-lithiasis, and chronic kidney disease. Medications included enalapril, metformin, glimepiride, nimesulide, imipramine, aspirin, and ibuprofen. She had no known allergies. She was married and had children. She lived in Italy and did not speak English. She had vacationed in North America for 10 days, traveling to urban areas. She did not smoke, drink alcohol, or use illicit drugs, and there was no history of unusual ingestions.

On examination, the patient was incoherent and appeared agitated and uncom-fortable, with frequent groaning. She was oriented to person only and opened her eyes to command. The blood pressure was 120/70 mm Hg, the pulse 52 beats per minute, the temperature 36.7°C, the respiratory rate 18 breaths per minute, and the oxygen saturation 95% while she was breathing ambient air. The pupils were 3 mm

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in diameter and minimally reactive to light; the oral mucous membranes were dry, and the neck was supple. The abdomen was soft, without distention, rebound tenderness, or guarding. The skin was cool. The remainder of the gen-eral examination was normal. The neurologic examination was limited because of the pa-tient’s inability to follow commands; she with-drew all extremities to pain, and cranial nerves and strength appeared normal. Normal saline was rapidly infused, and dextrose, insulin, on-dansetron, and morphine sulfate were adminis-tered intravenously. An electrocardiogram re-vealed atrial fibrillation at a rate of 115 beats per minute and a QRS duration of 94 msec, with a tremulous baseline possibly obscuring ST-segment depression in the inferior leads. Blood levels of calcium, triglycerides, glycated hemoglobin, and haptoglobin were normal, as were the results of liver-function tests; other test results are shown in Table 1. Placement of an indwelling urinary catheter was followed by placement of intravascular catheters in the right external jugular vein and the femoral artery.

Within 2 hours after the patient’s arrival in the emergency department, tachypnea and increas-ing somnolence developed; results of venous oximetry are shown in Table 1. The trachea was intubated after the administration of etomidate and rocuronium, and 100% oxygen was admin-istered and bicarbonate was infused. A chest radiograph showed no evidence of pneumonia or pleural effusion. There were ill-defined calcifica-tions in the soft tissue of the left breast.

Approximately 3 hours after the patient’s ar-rival, the rectal temperature decreased to 31.7°C and the blood pressure to 84/43 mm Hg. Norepi-nephrine bitartrate and bicarbonate were admin-istered; fluids were warmed before infusion, and a blanket warmer was placed. Dark-brown gas-tric secretions that were positive for occult blood were aspirated through an orogastric tube; the gastric pH was 5.7.

Dr. Raul N. Uppot: Computed tomography (CT) of the abdomen and pelvis without the adminis-tration of intravenous or oral contrast material (Fig. 1) revealed pancreatic edema, peripancreatic fat stranding, a small amount of perihepatic and pericholecystic fluid without biliary ductal dila-tation, some thickened walls in several loops of

small bowel, and an atrophic left kidney contain-ing a nonobstructing calculus. CT of the chest revealed dependent atelectasis, with no focal consolidation, masses, or effusions, and calci-fications of the left breast. CT of the brain was normal.

Dr. Schoenfeld: Cefepime, vancomycin, and met-ronidazole were administered intravenously. Af-ter laboratory results were known, sodium poly-styrene sulfonate was given orally. Toxicologic screening of the blood and urine was negative.

The patient was admitted to the cardiac inten-sive care unit (ICU). Vasopressin, propofol, and calcium were added, and additional bicarbonate and glucose were administered. Eight hours after her presentation, continuous venovenous hemo-filtration with bicarbonate solution was begun. Cultures of the blood and urine were obtained. Fourteen hours after presentation, the urine so-dium level was 136 mmol per liter, and the urine creatinine level was 0.25 mg per milliliter. Echo-cardiography revealed normal global cardiac func-tion, without pericardial effusion.

Dr. Uppot: Ultrasonography of the abdomen re-vealed small-volume ascites, nonspecific thicken-ing of the gallbladder wall, and an atrophic left kidney; there was increased renal parenchymal echogenicity of both kidneys (Fig. 2).

Dr. Schoenfeld: During the first 17 hours, the patient had oliguria, with approximately 125 ml of urine excreted. Additional laboratory tests are shown in Table 1.

A diagnostic test was performed.

Differ en ti a l Di agnosis

Dr. Kamyar Kalantar-Zadeh: The patient was an acutely ill 54-year-old woman with a medical his-tory of type 2 diabetes, hypertension, kidney stones, and chronic kidney disease of unknown severity. She presented to the emergency depart-ment with deteriorating mental state, respiratory distress, and worsening gastrointestinal symp-toms. Laboratory evaluation showed a profound leukocytosis with a left shift (increased levels of immature neutrophil forms circulating in the pe-ripheral blood), an increase in pancreatic enzyme levels, severe metabolic acidosis with a markedly elevated serum lactate level, profound hyperphos-phatemia, and oliguric kidney failure. Although it would be helpful to have a urinalysis, it was not

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performed in the first 24 to 48 hours because of worsening oliguria, the need for other more ur-gent tests, and other priorities.

My initial differential diagnoses include severe lactic acidosis, probably resulting from sepsis, car-diogenic shock, or nonhypoxic causes (e.g., med-

ications and cancer); concurrent acute pancreatitis; and concomitant acute kidney injury, probably su-perimposed on preexisting chronic kidney disease, which could be a result of sepsis, the cardiorenal syndrome, rhabdomyolysis with hyperphosphate-mia, or other causes (Table 2).

Table 1. Laboratory Data.*

VariableReference Range,

Adults† On Admission17 Hr after

Presentation

Hematocrit (%) 36.0–46.0 (women) 44.4 30.0

Hemoglobin (g/dl) 12.0–16.0 (women) 13.4 10.1

White-cell count (per mm3) 4500–11,000 34,800 32,100

Differential count (%)

Neutrophils 40–70 79

Band forms 0–10 2

Lymphocytes 22–44 10

Monocytes 4–11 5

Eosinophils 0–8 1

Myelocytes 0 2

Metamyelocytes 0 1

Platelet count (per mm3) 150,000–400,000 >483,000, with platelet clumps

179,000

Erythrocyte count (per mm3) 4,000,000–5,200,000 4,340,000 3,330,000

Mean corpuscular volume (μm3) 80–100 103 90

Mean corpuscular hemoglobin concentration (g/dl) 31.0–37.0 30.1 33.6

Smear description Toxic granulations and in-creased burr cells pres-ent; 3+ hypochromasia; 1+ macrocytes

Activated partial-thromboplastin time (sec) 21.0–33.0 36.2 26.4

Prothrombin time (sec) 11.0–13.7 15.7 14.3

International normalized ratio for prothrombin time 1.3 1.2

Sodium (mmol/liter) 135–145 146 140

Potassium (mmol/liter) 3.4–4.8 6.3 (not hemolyzed) 3.5

Chloride (mmol/liter) 100–108 83 88

Carbon dioxide (mmol/liter) 23.0–31.9 <2.0 16.0

Urea nitrogen (mg/dl) 8–25 94 58

Creatinine (mg/dl) 0.60–1.50 7.88 3.94

Glucose (mg/dl) 70–110 168 316

Glycated hemoglobin (%) 3.80–6.40 5.70

Protein (g/dl)

Total 6.0–8.3 6.7 4.2

Albumin 3.3–5.0 4.6 2.9

Globulin 2.3–4.1 2.1 1.3

Calcium (mg/dl) 8.5–10.5 9.5 6.6 (7.5 hr after presentation)




Acid–base disorders

Some of the patient’s test results are markedly abnormal. These include a profoundly low blood pH (6.62), a markedly low serum bicarbonate level (<2 mmol per liter; target range, 23 to 25), and a low partial pressure of carbon dioxide (Pco2) (18 mm Hg). Given the severely acidemic pH, which is unusual even for a venous blood sample,1 we should first confirm that this blood-gas analysis is correct. The concentration of hydrogen ions in the patient’s blood is calculated (with the modi-fied Henderson’s equation2) to be 216 nmol per liter, which corresponds to a blood pH between 6.6 and 6.7 and confirms the accuracy of the re-ported blood-gas data and suggests that she had an exceptionally severe metabolic acidosis.

The patient had a markedly elevated anion gap of 61 mmol per liter (reference range, 8 to 12), in-dicating that she had a profound anion-gap meta-


VariableReference Range,

Adults† On Admission17 Hr after

Presentation

Phosphorus (mg/dl) 2.6–4.5 19.3

Magnesium (mmol/liter) 0.7–1.0 1.1

Lactate dehydrogenase (U/liter) 110–210 515

Lipase (U/liter) 13–60 595 88

Amylase (U/liter) 3–100 386 276

Lactate (mmol/liter) 0.5–2.2 20.3 13.7

Troponin T (ng/ml) <0.03 0.03

Creatine kinase (U/liter) 40–150 656

Osmolality (mOsm/kg of water) 280–296 354 (11 hr after presentation)

Blood gases

Fraction of inspired oxygen 0.21 (ambient air) 0.40

Source Venous Unspecified

pH 7.30–7.40 (venous); 7.32–7.45 (unspecified)

6.62 7.38

Partial pressure of carbon dioxide (mm Hg) 38–50 (venous); 35–50 (unspecified)

18 27

Partial pressure of oxygen (mm Hg) 35–50 (venous); 40–90 (unspecified)

73 156

Base excess (mmol/liter) −35.1 −8.6

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to milli-moles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to milligrams per deciliter, divide by 0.4114. To convert the values for lactate to milligrams per deciliter, divide by 0.1110.

† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

Figure 1. Abdominal Imaging.

A CT scan of the abdomen and pelvis, without intrave-nous or oral contrast material, reveals pancreatic ede-ma and peripancreatic fat stranding and fluid (arrows), features consistent with acute pancreatitis. No pseudo-cyst or gallstones were visualized.

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bolic acidosis. Conditions causing this degree of acidosis include lactic acidosis, aspirin overdose, methanol or ethylene glycol toxicity, diabetic keto-acidosis, and uremia. Lactic acidosis in this pa-tient was corroborated by a markedly elevated serum lactate level (>20 mmol per liter); other causes of metabolic acidosis could not be sub-stantiated by the test results.

Estimating this patient’s osmolal gap is an-other way to refine the differential diagnosis. She had a mildly elevated osmolal gap (the difference between the measured and calculated serum osmolality) of 18 mOsm per kilogram of water (reference range, 5 to 15). A slightly elevated or borderline high osmolal gap is usually caused by either lactic acidosis or ketoacidosis; methanol or ethylene glycol ingestion often leads to a more

profound rise in the osmolal gap, making such ingestion a less likely diagnosis in this case.

Furthermore, the patient’s anion gap is ap-proximately 50 mmol per liter above the normal level, and the serum bicarbonate level is ap-proximately 20 mmol per liter below the normal level (i.e., the deviation from normal of the an-ion gap is more than two times as high as the deviation from normal of the bicarbonate level). This suggests that she could have a concomitant metabolic alkalosis, probably because of repeated vomiting and loss of hydrochloric acid. Never-theless, the patient’s profound hyperphosphate-mia may have contributed to the disproportion-ately high anion gap.3

Respiratory acid–base disorders

Does this patient have a concurrent respiratory acid–base disorder? We would expect that for each 10 mmol per liter decrease from normal in the bicarbonate level, a compensatory decrease in the Pco2 of at least 12 mm Hg would ensue.4 Since the patient’s serum bicarbonate level was 22 mmol per liter lower than the target level of 24 mmol per liter, the expected drop in the Pco2 should have been approximately 26 mm Hg. In-deed, despite her acute illness and altered mental state, she was capable of lowering the Pco2 by 22 mm Hg (from a normal value of 40 mm Hg to 18 mm Hg), probably by breathing deeply and in-creasing her respiratory rate in an attempt to compensate for the marked decrease in the serum bicarbonate level. Her remarkable and effective compensatory hyperventilation, classically known as Kussmaul respiration, is often perceived by cli-nicians as “respiratory distress.”5 In addition, the chest radiograph obtained on the patient’s arrival in the emergency department was normal, pro-viding further support that she probably had no respiratory disease. Her need for intubation and mechanical ventilation was probably the result of her worsening mental state, which could have been aggravated by the administration of mor-phine in association with renal insufficiency.6

severe Acidemia

Many, if not all, features of this patient’s presen-tation can be explained by profound acidemia (Fig. 3). Altered mental status, including lethargy, stupor, and even coma, can be a direct consequence of acidosis.7 Acidemia may lead to increased vaso-dilatation and warm skin, which the patient had

A

B

Figure 2. Renal Imaging.

An ultrasonographic study of the abdomen shows an atrophic left kidney (Panel A) and increased renal pa-renchymal echogenicity of both kidneys (Panels A and B), features suggestive of chronic renal disease.




reported during the 3 days before hospitalization. However, by the time the patient arrived at the emergency department, the acidosis had dramat-ically worsened and had most likely led to her paradoxical hypothermia, which is a known com-plication of profound acidosis.7 She also had some of the cardiovascular consequences of acidosis, including cardiac failure and catecholamine re-lease, which led to arrhythmia and respiratory compromise. Her atrial fibrillation could be a di-rect complication of acute acidemia.

Although we need to rule out cardiogenic or septic shock, which could explain the acute kid-ney injury, severe acidosis could lead to a decline

in the glomerular filtration rate (GFR).7 Given the patient’s reported medical history of chronic kidney disease, probably caused by diabetic or tubulointerstitial nephropathy or hypertensive nephrosclerosis and the administration of an an-giotensin-converting–enzyme (ACE) inhibitor and nonsteroidal antiinflammatory drugs (NSAIDs), she was probably susceptible to the development of superimposed acute kidney injury from any of these events.8 Her gastrointestinal manifestations were impressive and most likely were due to a concurrent acute pancreatitis. Nevertheless, we should note again that acidemia could cause gastric atony, nausea, vomiting, and abdominal

Table 2. Differential Diagnoses.

Diagnosis Findings More Consistent with Diagnosis Findings Less Consistent with Diagnosis

Sepsis (e.g., pyelonephritis and intraabdominal infection, such as emphysematous pyelonephritis)

Leukocytosis, lactic acidosis (type A), hypothermia, altered mental state

Initial normal blood pressure, no identifi-able source of infection

Cardiogenic shock (e.g., acute coronary syndrome)

Lactic acidosis (type A), arrhythmias, pre-existing vascular calcification, pulmo-nary edema

Initial normal blood pressure, normal tropo-nin level, normal echocardiogram, hypo-thermia, profound leukocytosis

Metformin-associated lactic acidosis

Metformin therapy, lactic acidosis (type B), profound acidemia, altered mental state, preexisting renal insufficiency

Profound leukocytosis, prominent gastro-intestinal symptoms

Cancer (e.g., lymphoma and leukemia)

Hyperphosphatemia (possible tumor lysis syndrome), leukocytosis (with leuke-moid reaction), lactic acidosis (type B), kidney failure

Prominent gastrointestinal symptoms, no other identifiable clues to malignant conditions

Overdose of salicylates (e.g., acetylsalicylic acid)

History of aspirin intake, anion-gap acidosis, hyperventilation

No respiratory alkalosis, too-severe lactic acidosis, no initial respiratory alkalosis, negative toxicologic screening

Intoxication with ethylene gly-col, methanol, or paralde-hyde

Anion-gap acidosis, altered mental state, worsening kidney function

Negative toxicologic screening, too-small osmolal gap, too-severe lactate acidosis

Mesenteric ischemia Severe gastrointestinal symptoms, leuko-cytosis, hypothermia, lactic acidosis (type A), altered mental state

Upper gastrointestinal bleeding, non-supporting imaging studies

Rhabdomyolysis Hyperphosphatemia, large anion gap, increased creatine kinase level

Profound leukocytosis, no other support-ing clues

Diabetic ketoacidosis History of diabetes, abdominal pain, anion-gap acidosis

Normal glucose level, normal glycated hemoglobin, high lactate level (too high for diabetic ketoacidosis)

Acute pancreatitis Gastrointestinal symptoms, elevated amylase and lipase levels, evidence on imaging studies

A pattern of abdominal pain not typical for pancreatitis

Acute kidney injury, super-imposed on chronic kidney disease

History of chronic kidney disease, history of nephrolithiasis with atrophic left kidney, type 2 diabetes, history of intake of an angiotensin-converting–enzyme inhibi-tor and nonsteroidal antiinflammatory drugs, hyperkalemia, hyperphosphate-mia, low urinary creatinine level

Normal hemoglobin level

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pain. Finally, the remarkable leukocytosis with a left shift can also be explained by severe acido-sis9; however, an infectious disease is a more likely explanation, as are malignant conditions such as leukemia and lymphoma.

Anion-gap metabolic acidosis

What could explain anion-gap metabolic acidosis with an elevated serum lactate level in this patient? One possible cause of a classic (type A) lactic aci-dosis is impaired tissue perfusion that typically happens in patients with septic or cardiogenic shock or during cardiopulmonary arrest. However, another likely cause of anion-gap metabolic aci-dosis in this patient is nonhypoxic (type B) lactic acidosis. Impaired lactate metabolism can occur in association with the administration of certain medications (e.g., metformin, salicylate, isoniazid, and zidovudine) or in association with certain cancers (e.g., lymphoma and leukemia), among other reasons.10 This patient had been taking met-formin, which, like other biguanides (e.g., phen-formin and buformin), can lead to the increased generation and accumulation of lactate by re-

ducing gluconeogenesis and glycogenolysis, in-hibiting oxygen consumption, and impairing mitochondrial function in the liver and other organs.11 In fact, phenformin and buformin were removed from the market because they are as-sociated with an unacceptably high risk of lactic acidosis.12

This patient had a high risk of metformin ac-cumulation, given her history of chronic kidney disease, and this is corroborated by seemingly normalized glucose and glycated hemoglobin levels, which probably resulted from the progres-sion of renal insufficiency.13,14 The profound aci-demia with a massive decrease in the serum bi-carbonate level and a markedly elevated serum lactate level is consistent with other reports of metformin-associated acidosis.11,15 A case series comparing metformin-associated acidosis with other types of lactic acidosis, such as those as-sociated with postcardiac arrest, septic shock, cardiogenic shock, mesenteric ischemia, and hemorrhagic shock, described only metformin as being associated with a mean blood pH below 7.0, as in this patient.16 Survival rates associated

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Author

Fig #

Title

ME

DEArtist

Issue date

COLOR FIGURE

Draft 5Kalantar-Zadeh

Knoper

Central Nervous System

Skin

GastrointestinalRenal

Cardiovascular

Respiratory

Blood

Endocrine

WeaknessAltered sensoriumLethargyStupor and coma

Increased respiratory rateIncreased tidal volumeRespiratory alkalosisDecreased venous compliancePulmonary edema

Reduced left ventricular contractilityDecreased cardiac outputIncreased catecholamine release

Hypotension

Arrhythmias

Gastric atonyNausea and vomitingAbdominal painDecreased hepatic blood flow

Leukocytosis with left shift

Insulin resistanceIncreased calcium release from boneIncreased protein catabolism

Decreased GFR (tubuloglomerular feedback)Increased urinary calcium excretionHyperkalemiaHyperphosphatemia

Increased peripheral vasodilatation

Warm skin(warm shock)

Hypothermia

Figure 3. Clinical Manifestations of Acidemia.

GFR denotes glomerular filtration rate.




with the toxic effects of metformin are generally better, despite a more severe acidemia, than the rates associated with other causes of lactic aci-dosis.16 Therefore, I expect and certainly hope that this patient survived, especially since she under-went continuous venovenous hemodiafiltration therapy for oliguric renal failure, which could also effectively lower the metformin level despite its large volume of distribution.11,17 Not many labo-ratories can measure metformin levels rapidly; if such testing is available, it is usually performed as a late confirmatory test.17

In my experience and on the basis of the data reviewed in the literature,16,17 metformin overdose or accumulation as the cause of lactic acidosis is highly likely in any patient who has most or all of the following five criteria even if the metformin level is not known: a history of metformin ad-ministration (e.g., in a patient with type 2 diabe-tes), a markedly elevated lactate level (>15 mmol per liter) and a large anion gap (>20 mmol per li-ter), severe acidemia (pH <7.1), a very low serum bicarbonate level (<10 mmol per liter), and a his-tory of renal insufficiency (estimated GFR, <45 ml per minute per 1.73 m2 of body-surface area; or serum creatinine level, >2.0 mg per deciliter [>177 μmol per liter]).

This patient has all these features. The acute pancreatitis also could have been caused by met-formin accumulation.12,18 Therefore, I expect that the diagnostic test in this case was a high met-formin level or maybe a novel surrogate of the metformin level that I am not aware of.

Dr. Eric S. Rosenberg (Pathology): Dr. Schoenfeld, what was your initial impression when you evalu-ated this patient?

Dr. Schoenfeld: Our initial impression was that the renal failure was due to a combination of factors, including poor oral intake and multiple nephrotoxic agents, including an ACE inhibitor and NSAIDs. We believed that the lactic acidosis was probably a result of metformin accumulation in association with the renal failure. Given the CT findings of peripancreatic fat stranding and pancreatic edema, we wondered whether the initial insult may have been pancreatitis, which led to the abdominal pain, nausea, and reduced oral intake. However, we could not be certain that pancreatitis was the primary insult; alterna-tively, the abdominal pain and pancreatitis could have been a result of severe acidemia and the toxic effects of metformin.

Clinic a l Di agnosis

Lactic acidosis caused by the toxic effects of met-formin.

DR . K A M Y A R K A L A N TA R-Z A DEH’S DI AGNOSIS

Type B lactic acidosis caused by metformin ac-cumulation.

Pathol o gic a l Discussion

Dr. Kent B. Lewandrowski: The patient’s plasma metformin level was 23 μg per milliliter (refer-ence range, 1 to 2), which explains her presenta-tion. The clinical thinking at the time was that her exposure to multiple nephrotoxic drugs, in-cluding aspirin, ibuprofen, and enalapril, result-ed in acute kidney injury. Metformin is excreted unmetabolized in the urine. Therefore, the pa-tient’s impaired renal function resulted in the ac-cumulation of metformin in the plasma, causing lactic acidosis. In patients who have toxic effects of metformin, the mechanism of lactic acidosis is multifactorial, including enhanced conversion of glucose to lactate in the small intestine and in-hibition of gluconeogenesis by lactate, pyruvate, and alanine. As in this patient, the toxic effects of metformin typically present with nausea and abdominal pain,19 and the mortality rate is high, approaching 50%. The diagnosis requires a high index of suspicion and a consideration of clinical and laboratory findings and the patient’s medica-tion history. Measurement of a metformin level will firmly establish the diagnosis; however, this approach is usually impractical because few hospi-tals offer this test in-house and obtaining results from a reference laboratory may take several days.

Dr. Schoenfeld: The patient was admitted to the cardiac ICU, and continuous venovenous hemo-filtration was continued. Within the first 24 hours after admission, her mental status improved dra-matically. She was extubated 1 day after admis-sion. Within the next 48 hours, her metabolic abnormalities started to normalize and she be-gan to make copious amounts of urine. At that point, continuous venovenous hemofiltration was discontinued and she was weaned off vasopressin. Out of concern for infection, she had been started on broad-spectrum antibiotics at the time of ad-mission, but after 48 hours, cultures of blood and

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case records of the massachusetts gener al hospital

urine remained negative and the antibiotics were discontinued. She was transferred to the general medical unit, where her hypertension was man-aged with a calcium-channel blocker. Her renal function completely normalized. She was dis-charged from the hospital 1 week after admis-sion, and she returned home to Italy. We received notification from her primary care doctor 1 week later that she was doing well and had resumed her normal daily activities.

Fina l Di agnosis

Toxic effects of metformin.This case was presented as part of the Harvard Medical School

postgraduate course Internal Medicine: Comprehensive Review and Update, directed by Ravi I. Thadhani, M.D., M.P.H., Sekar Kathiresan, M.D., and Dennis Ausiello, M.D.

Dr. Uppot reports receiving payment for reviewing testimony for a legal case involving renal biopsy. No other potential conflict of interest relevant to this article was reported.


1. Adrogué HJ, Rashad MN, Gorin AB, Yacoub J, Madias NE. Assessing acid-base status in circulatory failure: differences between arterial and central venous blood. N Engl J Med 1989;320:1312-6.2. Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004;17:455-65.3. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162-74.4. Kurtz I. Clinical approach to the diag-nosis of acid-base disorders. Can Med As-soc J 1979;121:157-8.5. Adolf Kussmaul (1822-1902) — coun-try doctor to clinical professor. JAMA 1964;189:58-9.6. Fainsinger RL, Miller MJ, Bruera E. Morphine intoxication during acute re-versible renal insufficiency. J Palliat Care 1992;8:52-3.7. Cogan MG, ed. Fluid & electrolytes:

physiology & pathophysiology. San Ma-teo, CA: Appleton & Lange, 1991:203-24.8. Rifkin DE, Coca SG, Kalantar-Zadeh K. Does AKI truly lead to CKD? J Am Soc Nephrol 2012;23:979-84.9. Tullis JL. The leukocytosis of diabetic acidosis. Am J Med Sci 1948;215:424-6.10. Caspar CB, Oelz O. Lactic acidosis in malignant lymphoma. Am J Med 1991; 91:197-8.11. Vecchio S, Protti A. Metformin- induced lactic acidosis: no one left behind. Crit Care 2011;15:107.12. Fimognari FL, Corsonello A, Pastorell R, Antonelli-Incalzi R. Metformin-induced pancreatitis: a possible adverse drug ef-fect during acute renal failure. Diabetes Care 2006;29:1183.13. Kovesdy CP, Park JC, Kalantar-Zadeh K. Glycemic control and burnt-out diabe-tes in ESRD. Semin Dial 2010;23:148-56.14. Kalantar-Zadeh K. A critical evalua-tion of glycated protein parameters in advanced nephropathy: a matter of life or death: A1C remains the gold standard

outcome predictor in diabetic dialysis pa-tients. Counterpoint. Diabetes Care 2012; 35:1625-8.15. Protti A, Russo R, Tagliabue P, et al. Oxygen consumption is depressed in pa-tients with lactic acidosis due to bigua-nide intoxication. Crit Care 2010;14:R22.16. Friesecke S, Abel P, Roser M, Felix SB, Runge S. Outcome of severe lactic acido-sis associated with metformin accumula-tion. Crit Care 2010;14:R226.17. Nguyen HL, Concepcion L. Metfor-min intoxication requiring dialysis. He-modial Int 2011;15:Suppl 1:S68-S71.18. Mallick S. Metformin induced acute pancreatitis precipitated by renal failure. Postgrad Med J 2004;80:239-40.19. Chu J, Stolbach A. Metformin poison-ing. In: UpToDate, 7.0 ed. Waltham, MA: UpToDate, 2012 (http://www.uptodate .com/contents/metformin-poisoning? source=search_result&search= Metformin+poisoning&selectedTitle= 1%7E5).Copyright © 2013 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].

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Documents

NEJM Readers’ Choice Clinical Care CollectionBack to Table of Contents 4 nejm readers’ choice clinical care collection The NEW ENGLAND JOURNAL of MEDICINE n engl j med 369;20 nejm.org