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CME/CE Information

CME/CE Released: 11/04/2015 ; Valid for credit through 11/04/2016

Target Audience

This article is intended for primary care clinicians, critical care medicine specialists, infectious disease specialists,nurses, and other clinicians who care for patients with severe infection.

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The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals inorder to enhance patient care.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Evaluate the association between fever and mortality among patients with severe acute neurologic disease2. Analyze the efficacy of the early application of acetaminophen among patients with suspected infection in

the intensive care unit

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Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

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Robert Morris, PharmD

Associate CME Clinical Director, Medscape, LLC

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CME Author(s)

Charles P. Vega, MD

Clinical Professor of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed the following financial relationships:Served as an advisor or consultant for: Lundbeck, Inc.; McNeil Pharmaceuticals; Takeda Pharmaceuticals North

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Amy Bernard, MS, BSN, RN-BC

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From Medscape Education Clinical Briefs

News Author: Laurie Barclay, MD

CME Author: Charles P. Vega, MD

Clinical Context

The management of fever with antipyretics is automatic for many patients and clinicians. However, the authors of

the current study note that fever may be a helpful part of the immune response, particularly among critically ill

patients. They sought to test this hypothesis by examining patients in the intensive care unit (ICU) with 2 different

types of severe illness of the central nervous system: stroke/traumatic brain injury and meningitis/encephalitis.

Their results, which evaluated more than 1.8 million admissions in 384 ICUs, were published in the May 2015 issue

of Intensive Care Medicine. [1] They found that, compared with normothermia, a peak body temperature below

37˚C or above 39˚C during the first 24 hours of hospital admission was associated with a higher risk for mortality

among patients with stroke or traumatic brain injury. However, fever during the first 24 hours of admission was not

associated with a higher risk for mortality among those patients with central nervous system infection.

If fever is not disadvantageous to patients with severe infection, are clinicians overly vigilant in treating fever with

drugs such as acetaminophen? The current study by Young and colleagues uses a placebo-controlled, blinded

design to evaluate whether the early application of acetaminophen among patients with suspected infection in the

ICU improves outcomes.

Study Synopsis and Perspective

Early use of acetaminophen to treat fever in patients in the ICU with probable infection did not reduce ICU stay or

mortality, according to a binational, blinded, randomized trial published online October 5 in the New England

Journal of Medicine.[2] The publication coincides with presentations at the European Society of Intensive Care

Medicine Congress in Berlin.

"The lack of high-level evidence leaves ICU clinicians uncertain about whether acetaminophen treatment of fever due to probable infection is beneficial, ineffective, or harmful," write Paul Young, MD, from the Intensive Care Unit

of Wellington Regional Hospital and Medical Research Institute of New Zealand, and colleagues.

Inclusion criteria were ICU admission, fever (defined as temperature ≥38°C), and known or suspected infection.

Patients (n=700) were randomly assigned to receive 1 g of intravenous acetaminophen or placebo every 6 hours

until ICU discharge, normalization of temperature, discontinuation of antibiotics, or death.

The acetaminophen and placebo groups did not differ significantly in the primary outcome of ICU-free days, defined

as days alive and free from the need for intensive care, from random selection to day 28. This outcome was 23

days in the acetaminophen group and 22 days in the placebo group (P =.07).

By 90 days, there were 55 deaths in the acetaminophen group (15.9% of 345) and 57 in the placebo group (16.6%

of 344; relative risk, 0.96; 95% confidence interval [CI], 0.66-1.39; P =.84).

Patients who received intravenous acetaminophen had a lower body temperature than those who received placebo

Acetaminophen for ICU Fever Did Not Reduce Stay,Mortality CME/CE

CME/CE Released: 11/04/2015 ; Valid for credit through 11/04/2016

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and did not have significantly more adverse events.

The study drug was discontinued because of liver dysfunction in 28 (8.1%) of 347 patients taking acetaminophen

and in 34 (9.9%) of 344 patients taking placebo (P =.40). One patient taking placebo had a fatal adverse event of

markedly elevated body temperature.

Limitations of this study include short median administration of study drug and lack of data about acetaminophen

use before random selection or after ICU discharge.

"[O]ur results do not preclude the possibility that a more prolonged course of acetaminophen may have a greater

influence on patient-centered outcomes," the study authors conclude.

"[E]arly administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-

free days. There was no significant between-group different in 28-day mortality, 90-day mortality, or survival time to

day 90."

The Health Research Council of New Zealand, the Waikato Medical Research Foundation, the Australian & New

Zealand Intensive Care Foundation, and CSL Bioplasma funded this study. One coauthor has received grant

support, personal fees, and nonfinancial support from Baxter Healthcare, and grant, nonfinancial, and other support

from Fresenius Kabi. The other authors have disclosed no relevant financial relationships.

Study Highlights

Patients eligible for study participation were at least 16 years old and were receiving antimicrobial treatment

of a known or suspected infection. All included patients had a temperature of 38˚C or higher in the 12 hours

before study enrollment.

Patients with acute brain disorders and severe liver dysfunction were excluded from the study protocol.

Participants were randomly assigned to receive 1 g of intravenous acetaminophen or a dextrose solution

(control) every 6 hours. Their randomly selected regimen could be continued for up to 28 days, but it was

stopped with resolution of fever, discharge from the ICU, or death.

Rescue physical cooling was permitted, as was ad hoc use of acetaminophen after the study treatment was

completed.

The main study outcome was the number of ICU-free days during a 4-week period. ICU-free days were

defined as the total number of days of life outside the ICU after random selection.

Researchers also followed mortality rates and the duration of patients' stay in the ICU. Finally, they followed

participants' body temperatures and safety outcomes as well.

700 patients were enrolled from 23 ICUs participating in the research. Baseline characteristics between the

acetaminophen group and the control group were similar. The mean age of participants was 58 years, and

65% were men. An estimated 83% of participants had severe sepsis.

The most common sites of infection were the lung and abdomen. A causative organism was discovered in62% of patients.

The median number of doses of the study drugs was 8. The mean daily peak body temperature and mean

daily temperature of participants in the acetaminophen group were lower than those in the control group.

The odds ratio for study drug discontinuation from resolution of fever was 1.45 (95% CI, 0.99-2.12) in

comparing the acetaminophen group vs the control group.

The numbers of ICU-free days in the acetaminophen group and the control group were 23 and 22,

respectively, a nonsignificant difference.

Mortality rates at day 28 and day 90 were also similar between the groups.

The length of ICU stay was slightly more than 4 days and was similar in both treatment groups.

However, survivors who received acetaminophen had a shorter length of ICU stay compared with survivors

who received the dextrose solution. Conversely, the ICU stay was longer in the acetaminophen group vs the

control group in an analysis of patients who died.

Rates of liver dysfunction necessitating withdrawal of the study drug occurred in 8.1% of participants in the

acetaminophen group and in 9.9% of patients in the control group.





Clinical Implications

A previous study f ound that early f ever was associated with increased mortality rates among ICU patients

with stroke or traumatic brain injury, but not among those with meningitis or encephalitis.

The current study by Young and colleagues demonstrates that the early application of acetaminophen

among febrile ICU patients with suspected infection improves mean body temperature values but does not

result in fewer ICU days or lower mortality rates at 28 or 90 days.

Implications for the Healthcare Team: The current study reminds us that all members of the healthcare teamshould question potential canards widely applied to patient care, but without solid evidence for their efficacy.

The routine use of acetaminophen for fever among febrile patients in the ICU is a more questionable

practice now.

CME Test

To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

You are seeing a 58-year-old man admitted to the ICU for suspected sepsis with an unknown

source. His temperature after arrival in the unit is 39.2˚C. According to the previous study by the

authors of the current research, fever is most likely to promote a higher risk for death among

patients with which of the following diagnoses?

Any severe central nervous system disease

Traumatic brain injury or stroke

Meningitis

Encephalitis

You initiate treatment with acetaminophen intravenously every 6 hours for this patient. Accordingto the current study by Young and colleagues, which of the following outcomes is most likely to be

achieved with this approach to treatment?

Lower mean daily body temperature

Reduced number of days in the ICU

Reduced 28-day mortality rate

Reduced 90-day mortality rate

Save and Proceed

This article is a CME/CE certified activity. To earn credit for this activity visit:


References

1. Intensive Care Med . 2015;41:823-832. http://link.springer.com/article/10.1007%2Fs00134-015-3676-6

2. N Engl J Med . Published online October 5, 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1508375

Disclaimer

The educational activity presented above may involve simulated case-based scenarios. The patients depicted inthese scenarios are fictitious and no association with any actual patient is intended or should be inferred.






The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that supporteducational programming on medscape.org. These materials may discuss therapeutic products that have not beenapproved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcareprofessional should be consulted before using any therapeutic product discussed. Readers should verify allinformation and data before treating patients or employing any therapies described in this educational activity.

Medscape Education © 2015 Medscape, LLC

This article is a CME/CE certified activity. To earn credit for this activity visit:http://www.medscape.org/viewarticle/852913

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Acetaminophen for ICU Fever Did Not Reduce Stay, Mortality (Printer-friendly)