Journal of theVivekananda Institute of Medical Sciences

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Editorial Page No.

Doctor Patient Relationship andDiabetes Mellitus

— Dr. S. Chakrabarti, Dr. J. Roy Chowdhury 5

Original Article:

a) Some Patients with DiabetesPossess Personality Traits ThatEnable Them to Better ControlTheir Disease— Mili Bandyopadhyay

Dr. Anirban MazumdarDr. Sudip Chatterjee 7

b) Multinodular Goiter - A Clinical,Biochemical, Immunological andCytological Study of 100 Cases— Dr. Uttio Gupta

Dr. D. Maji 10

Review Article:

a) Ideal Basal Insulin — Prof. Jayanta Chakraborty 14

b) Hypertension— Dr. N. G. Bhattacharya

Dr. R. N.Chatterjee 21

c) Chronic Hypertension inPregnancy— Dr. Sukanta Misra

Dr. Bijitbaran Chowdhury 27

Journal of theVivekananda Institute of Medical Sciences

Page No.d) Acute Acalculous Cholecystitis :

A Review of Current Trends in Management

— Dr. Himadri SenguptaDr. Soumitra ChandraDr. Zayd Ashok RahmanDr. Hirak Pahari 38

Case Report:

Rare Case of Pallor withAbdominal Distention:Case Report

— Dr. Manomit HaldarProf. Asha MukherjeeDr. Akhilesh VermaDr. Soumitra Masani 44

CME Article :Pictorial CME

— Dr. Semanti ChakrabortyProf. Jayanta Chakraborty 49

Images in Clinical Medicine— Dr. Sudip Chatterjee 52

Buffalo Hump— Prof. D. Maji 53

Tubercular Laryngitis— Prof. B. K. Roychaudhuri

Dr A. RoychoudhuryDr. S. Ghosh 54

Institute News 55

Obituary 56

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Editorial

Doctor Patient Relationship and Diabetes Mellitus

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Introduction:

Relationship and interaction of doctors withpatients and their key caregivers are assumingimportance day by day.

This is of particular relevance in case of chronicillnesses like Diabetes Mellitus where long termmanagement is necessary. American DiabeticAssociation and European Association for studyof Diabetes have highlighted person centeredcare (PCC) in the management of Diabetes.

In India an explosive increase in the number ofDiabetic patients has taken place over recentyears. ICMR sponsored studies observed presenceof 61.3 million of diabetics in India in 2000.They postulated that increased conversion frompre diabetics to diabetics and visceral adipositymight have produced such results. They furtherpredicted that existing 77 million prediabeticsmay soon become full blown diabetics unlessurgent appropriate interventions are taken.

Psychological Factors and PCC:

To combat this bleak scenario it is of utmostimportance to implement PCC in a practical andeffective way. It has to be remembered that Indiais a developing, multicultural and educationallyas well as economically backward country. Sosome amount of understanding of the personalityof the individual patient would help to importbetter patient education and guidance. The studyof personality traits (as published in this issue)of diabetic patients is an important step in thisregard.

Co morbidity of diabetes is known to occur withdepression, anxiety disorders, obsessivecompulsive disorders, obesity, substance abuselike smoking and alcohol. All these cause poorglycemic control. Among type 2 diabetes thosewith depressive symptoms will likely to reportmore stress associated with having the disease,leading to an increase in negative outlook oflife, which in turn will be associated with moreavoidance and passive behaviour. This is avicious cycle since the increase in avoidanceand passive behaviour leads to more depressivesymptoms and greater diabetes related stress.

Moreover certain antipsychotics speciallyclozapine and Olanzapine may lead to obesityand subsequent metabolic syndrome anddiabetes.

Study of personality traits offer new insightsinto variations in glycemic control in patientswith type 2 diabetes undergoing standardmanagement. Patients with type 2 diabetes differfrom control group members in terms of higherlevels of anxiety and depression as well as thetemperament and character traits of fatiguability,resourcefulness and helpfulness.

Concluding Notes:

It may be concluded that some amount ofknowledge about the psychological profile of apatient helps to understand him as an individual.Ideas of his character traits as well as his positiveand negative qualities will help to frame the

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Dr. S. Chakrabarti, MBBS, DPM, MRC (Psych.) Consultant Psychiatrist , RKMSPDr. J. Roy Chowdhury, MD (Psych.) Prof. V.I.M.S., RKMSP

strategies of PCC. Such an endeavor may notneed great knowledge of psychology orpsychiatry, simply sympathetic listening andefforts to understand patients practical problems

References:

1. Roy Chowdhary J, doctor - patient relationship ina multicultural society. Jr Ind Med Assoc 1994;92; 413- 414.

2. Inzacchi SE, Bergenstal RM, Buse JB, DiamontM. Ferrannini E, Nauck M, et al - management ofhyperglycemia in type 2 diabetes : a patient centeredapproach. Position statement of. American DiabeticAssociation (ADA) and the European Associationfor the study do Diabetes (E ASD). Diabetologia2012; 55: 1577 - 96.

will help. Thus a small effort on the part of anempathic physician may help to enhance hispatients quality of life and reduce caregiverburden.

3. Anjana RM, Pradeepa R, Deepa M, Dutta M,Sudha V, Unnikrishnan R, et al-On behalf of theICMR-INDIA B Collaborative study group.Prevalence of Diabetes and Prediabetics (Impairedfasting glucose and / or impaired glucose tolerance)in urban and rural India. Phase 1 results of theICMR-India Diabetes (ICMR-INDIA B) study.

4. Bandopadhyay M, Mazumdar A, Chatterjee S -Some patients with diabetes possess personalitytraits that enable them to better control their diseaseJr Vivek Ind Med Sc.

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Some Patients with Diabetes Possess Personality Traits ThatEnable Them to Better Control Their Disease

Smt. Mili Bandyopadhyay1, Dr. Anirban Mazumdar2, Dr. Sudip Chatterjee3

1Nutritionist, RKMSP, 2Asso. Prof., KPC Medical College, Kolkata.3Prof., Dept. of Medicine, V.I.M.S., RKMSP.

Abstract:

Control of diabetes is a lifelong process whichrequires intensive partnering between the patientand the care giving team. Extensive patienteducation has long been recognized as thecornerstone of successful diabetes management.In busy clinics in resource constrained settingssuch as ours, this is seldom possible due tolimitations of time. We found that some patientsmaintained excellent control over their diabetesin spite of minimal education. These patients didnot differ in age, social class or educationalattainments from other less well controlledpatients. However on administering Sato’ssimplified personality test, significant differencesemerged. The well controlled patients were lessextroverted and less sensitive to external cuesthan age matched controls.

Key Words:

Diabetes; patient behaviour; patient psychology

Introduction:

Good metabolic control in diabetes depends toa large extent on the quality and frequency ofthe interaction the diabetes team has with itspatients. The diabetes clinic in our hospital(RKMSP) caters to patients in socioeconomicclasses 4-5. All services are free and there is anominal charge for patient registration. It isextremely busy and often there is little time forconsultants to talk to patients. The patients pay

subsidized charges for laboratory tests and paystandard charges for medication. In this clinic,we identified a subset of patients who werehighly adherent and maintained clinical standardsclose to ideal at considerable cost and effort. Inthe absence of any special effort on our part, wewanted to know what motivated these patientsto maintain excellent standards of care.

The authors were of the opinion that the diabeteseducation imparted to the patients in the clinicsetting, was suboptimal due to constraints oftime. There was no opportunity for conventionaldiabetes self care concepts to be taught eitherindividually or collectively. Yet many patientsachieved exemplary control. The objective ofthis study was to examine the behavioural traitsof the well controlled patients and to identifythe beneficial skills they possessed.

Material:

The study was conducted on established patientsof the Diabetes OPD of RKMSP between Mayand November 2010. An established patient wasdefined as one who had visited the clinic at least3 times prior to May 2010 and had visited theclinic at least two times during the study period.There were 1084 such patients. Of these 24patients were felt to be ideally controlled basedon American Diabetes Association criteria (1)and gave their consent for further evaluation.Twenty four age and sex matched control patients

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were randomly selected for purposes ofcomparison.

The Eysenck Personality Questionnaire, briefversion was obtained with the help of Dr. ToruSato, Department of Psychology, ShippensburgUniversity, Shippensburg, PA, USA (2). Thiswas translated into the local language (Bengali)and validated. According to Eysenck (3) the basicpersonality traits are extraversion, neuroticismand psychoticism. The original scale measuredthese three components and had a ‘lie scale’ andrequired a yes or no response. Sato’s brief 24question version had a 5 point scoring systemand did not have the lie scale or the psychoticismmeasure and has been well validated. A highscoring subject is likely to be more extravertedand neurotic than a low scoring subject(Appendix-1). The study and the questionnairewere approved by the Institutions’s EthicsCommittee.

Methods:

One of the authors (MB) administered thequestionnaire to the subjects. She was not awareof the status of the subjects whether they werewell controlled or not. Each questionnaire took45 minutes to administer.

Each subject’s age, BP, BMI, HbA1c, LipidProfile fasting and 2hrs post prandial glucosereadings were recorded at each visit. As therewere multiple visits, the highest of the valueswere considered for purposes of analysis.

Statistical analysis was by unpaired Student’s ‘t’test and the level of significance was fixed at =or < 0.05.

Results:

There were 24 patients in each group. Complete

data were obtained in respect of age, Score,FBG, BMI. There was incomplete data forHbA1c and lipid profile. The data aresummarized in Table-1.

The patients in the two groups were comparablein terms of their age and BMI. The wellcontrolled group had significantly better valueswith respect to HbA1c, LDL Cholesterol,triglycerides and their EPQSV score. Wellcontrolled patients had a mean score of 57.9 +-5.6 whereas the poorly controlled patients hada mean score of 68.5 +- 4.4 (p > 0.001). Sato’squestionnaire (Appendix 1) has questions whichalternately tested for extraversion andneuroticism.

Conclusion:

There are many questionnaires on managingdiabetes from the patient’s view point, forexample (4, 5). All these assume that there areno time constraints on the diabetes care team.Unfortunately such time constraints are thereality in public hospitals in India. We foundthat well controlled patients tended to be lessextraverted and less sensitive to external cues.Their excellent control was maintained insubsequent clinic visits after the completion ofthe study.

It was felt that there were some uniquedifferences in behaviour among patients withdiabetes. The differences could be identified ina systematic manner. However it was not feasibleto teach behaviour modification to poorlycontrolled patients with a view to improvingtheir metabolic control.

There have been recent publications (6,7,8)where the value of a patient educationprogramme on diabetes control was evaluated.

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In two studies, there was a positive impact ofthe programme. However in the study conductedon an economically disadvantaged group, therewas no difference (6).

In this study, we found that some patientsinherently maintain good control by virtue of

their personality traits, even in the absence ofan education programme.Acknowledgement:We would like to thank the Secretary,Ramakrishna Mission Seva Pratisthan for hishelp and support. We would like to thank Dr. TSato for sending us the questionnaire.

Table 1: Showing the different parameters between the good control and poor control groups.Values are given with their Standard Deviations and the number of observations is given inparentheses. Student’s ‘t’ test has been used to calculate probability.

Parameter Good Poor p-value

HbA1c (%) 5.94 ± 1.06 (21) 7.79 ± 1.47 (15) >0.001

BMI 24.8 ± 2.5 (24) 25.5 ± 5 (24) 0.49

TG (mg/dl) 109.4 ± 51.5 (24) 168.5 ± 76.2 (19) 0.0043

FBG (mg/dl) 108.2 ± 20.8 (24) 170.6 ± 48.1 (24) >0.001

LDLc (mg/dl) 98 ± 28.8 (24) 133.6 ± 24.4 (19) >0.001

Age (yrs) 52.7 ± 9.1 (24) 47.9 ± 10.2 (24) 0.064

Score 57.9 ± 5.6 (24) 68.5 ± 4.4 (24) >0.001

References:

1. American Diabetes Association. Executivesummary of recommendations 2010. Diab Care2010. 33 : Suppl 1; S4-S10.

2. Sato T. The Eysenck Peronality QuestionnaireBrief Version: Factor structure and reliability. TheJ Psychol 2005 13(6) 545-552.

3. Eysenck SBG, Eysenck HJ, Barrett P. A revisedversion of the Psychotism Scale. Personality and

Individual Differences. 1985 (6) 21-29.

4. Hearnshaw H, Wright K, Dale J, Sturt J, VermiereE, van Royen P. Development and validation ofthe diabetes obstacles questionnaire (DOQ) toassess obstacles in living with type 2 diabetes.Diab Med 2007 (24) 878 – 882.

5. Sridhar GR. Psychiatric co-morbidity and diabetes.Ind J Med Res 2007 Mar 125 (3) 311-320.

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Abstract:

The aims and objectives:

To find out different etiopathogenetic mechanismin cases of Multinodular Goiter (MNG), so thatdefinitive treatment can be planned for eachpatient.

Materials and Method:

Ultrasonography of thyroid was done in all goiterpatients to confirm MNG and subsequently T3,T4, TSH by chemiluminescence method, AntiTPO antibody, FNAC of Thyroid, Tc99 ThyroidScan (in those who had low TSH).

Results:

Among 100 patients of MNG,14% had toxicMNG (who had low TSH and high Tc99 uptakeof thyroid), FNAC revealed colloid goiter 39%,autoimmune thyroiditis 38%, Papillary CAThyroid 8% and Follicular CA Thyroid 1%.Prevalence of malignancy was 9% amongst MNGpatients.

Earlier MNG was considered to be a benigncondition; however of recent several studiesmalignancy found in MNG also.

Conclusion:

Hence, it can be concluded that, risk ofmalignancy in MNG is similar to single thyroidnodule and should be investigated to rule outmalignancy as it has been seen in this study.

Multinodular Goiter - A Clinical, Biochemical,Immunological and Cytological Study of 100 Cases

Dr. Uttio Gupta1, Dr. D. Maji2

1MD PGT, 2Prof., Dept. of Medicine, V.I.M.S., RKMSP

Introduction:

Enlargement of thyroid gland is consideredclinically as goitre. Goitre can be diffuse, orsingle nodular or with multiple nodule the socalled Multinodular Goitre (MNG). MNG hasvaried presentation and different etiopathogenicmechanisms. It can be autoimmune (Hashimoto’sThyroiditis), toxic or non-toxic MNG ormalignancy.

However, the differentiation of these conditionscannot be made reliably on clinical examinationalone. Several diagnostic tests such as thyroidhormone profile, ultrasonography of the thyroidgland, anti-thyroid antibodies and Fine NeedleAspiration Cytology (FNAC) are done for thediagnosis and appropriate management of thepatient1,2,3.

In our study, the aim was to find out theprevalence of different etiopathogenesis andpresentation of MNG on the basis of clinical,biochemical, immunological, imaging andcytological analyses in patients, attendingEndocrine OPD of our hospital, which wouldhelp us to decide the management planaccordingly.

Materials and Methods:

In this study,100 cases of Multinodular Goitre(MNG) were taken from our Ultrasound clinicwho were refereed from the Thyroid clinic of

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Ramakrishna Mission Seva Pratisthan Hospital.From our clinic records it was found that onpalpation of neck only 58% had MNG, 22% haddiffuse goitre and 20% had solitary thyroidnodule. Ultrasonography of thyroid was donewith high frequency transducer (7.5 to 15.0MHz), and 100 sonographically confirmed MNGpatients were included in the study. Subsequentlyother investigations were done.T3, T4, TSH bychemiluminescence method, Anti TPO antibody,FNAC of Thyroid and Tc99 Thyroid Scan (inthose who had low TSH). FNAC were takenfrom at least 4 sites and the cytology results werecategorized into 4 groups-Benign, Follicular,Malignant and inadequate sampling.

Hypothyroidism was defined as serum TSH morethan 5.0 mU/l. Thyrotoxicosis as serum TSHless than 0.35 mU/l and Autoimmune Thyrroiditisas Anti TPO antibody titer more than 30.

The categorical variables are reported as numberand percentage of patients and compared acrossgroups using chi-square test for independenceof attributes. An α level of 5% has been takenand hence any p value <0.05 has been taken assignificant. SPSS software version 16 has beenused for the analysis.

Results and Analysis:

In our study, 29% were in age group of 41-50years, 25% in the 31-40 years age group. Only4% were above 60 years old. So, most of ourpatients with MNG were in fourth and fifthdecade and 82% patients were female and only18% were male.

1. Clinical Goiter Type of All MultinodularGoiter Patients:

On clinical palpation 58% of goiter were

multinodular, 22% diffuse and 20% found assolitary thyroid nodule. But on ultrasonographyall the 100 patients had definite MNG.

Table:1

Goiter type Frequency Percent

Diffuse 22 22

Multinodular 58 58

Solitary Thyroid Nodule 20 20

Total 100 100

2. FNAC Feature of Multinodular Goiter:

In our study of 100 patients of MNG, on FNACexamination colloid goiter has the highestprevalence of 39%, autoimmune thyroiditis 38%,toxic MNG 14%, Papillary CA Thyroid 8% andonly 1% has Follicular CA Thyroid.

Table:2

FNAC of Thyroid Frequency Percent

Autoimmune Thyroiditis 38 38

Colloid Goiter 39 39

Follicular CA Thyroid 1 1

Papillary CA Thyroid 8 8

Toxic MultinodularGoiter 14 14

Total 100 100

3. Features of Tc 99 Uptake Thyroid Scan:

In our study, toxic MNG patients, 31% hadincreased uptake, suggesting MNG withhyperthyroidism, 52% had decreased uptake,suggesting thyroiditis and 17% had patchyuptake.

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Table:3

Uptake on thyroid scan Frequency Percent

Decreased 15 52

Increased 9 31

Patchy 5 17

Total 29 100

Discussion:

We conducted our study in 100 patients whowere found to have MNG after ultrasonographyof neck in patients presenting to our Thyroidclinic with goiter (diffuse, multinodular andsingle nodule) on clinical examination of thyroidgland by palpation.

Tan GH et al opined that prevalence of nodularthyroid disease is greater than 60% in healthyadults screened with sonography4.

Schlumberger MJ et al has written thatultrasonography can confirm presence of thyroidnodule, when clinical findings are equivocal mayreveal presence of non palpable nodules5.

In our study, ultrasonography proven 100 MNGpatients prior clinical palpation only 58% hadmultinodular goiter, 22% had diffuse goitre and20% had solitary thyroid nodule (Table:1). Henceit can be concluded that, ultrasonography is theonly reliable and confirmatory method fordetection of MNG, even if nodule is not palpatedclinically.

Earlier, MNG was considered to be a benigncondition. But in several studies, malignancy isfound in MNG also. In cold single nodule around5-10% have malignancy of which Pap CAThyroid is the commonest.

Tollin SR et al have opined that the risk ofmalignancy in thyroid nodules occurring within

a MNG is similar in frequency with solitarythyroid nodule6.

According to Contempre B et al the possibilityof malignancy should be considered in allpatients with MNG and ultrasonography guidedFNAC and biopsy enhance the diagnosticefficacy7.

Gupta M et al showed that a multitude ofdiagnostic tests like ultrasound, thyroid nuclearscan and FNAC are used for evaluation of thyroidnodule. FNAC is the Gold Standard and othertests should be used in conjunction with FNAC8.

FNAC is the most accurate method for selectingpatients needing thyroid surgery. Most centersutilizing FNA biopsy have achieved a 35–75%reduction in the number of patients requiringsurgery, while still doubling or tripling themalignancy yield at thyroidectomy9-11.

Hanumanthappa M.B. et al in their studyconcluded that, the incidence of malignancy inMNG is quite significant and it is not very lowas was thought before. Due to the risk of occultmalignancy, all the patients with MNG who aretreated conservatively need a close follow upfor malignancy12.

In our study of 100 patients of MNG, on FNACexamination colloid goiter has the highestprevalence of 39%, autoimmune thyroiditis 38%,toxic MNG 14%, Papillary CA Thyroid 8% andonly 1% had Follicular CA Thyroid (Table:2).So, prevalence of malignancy is 9% amongMNG in this study.

Hence it can be concluded that, Ultrasonographyis the only reliable and confirmatory method fordetection of MNG and risk of malignancy inMNG is almost similar in solitary thyroid noduleand should be investigated to rule out malignancyas it has been done in this study.

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Refernces:

1. Tyler DS, Shaha AR, Udelsman RA, ShermanSI, Thompson NW, Moley JF, Evans DB. ThyroidCancer, 1999 update. Ann Surg Oncol 2000;376-98.

2. Wong CK, Wheeler MH, Thyroid Nodules:rational management; Word J Surg 200; 24 :934-41.

3. Roman SA, Endocrine tumours: Evaluation ofthyroid nodule. Curr opin oncol 2003; 15:66-70.

4. Tan GH, Gharib H. Thyroid incidentalomas:management approaches to non palpable nodulesdiscovered incidentally on thyroid imaging. AnnIntern Med. 1997; 126: 226-231.

5. Schlumberger M.J, Filetti S, Hay J. D. Nontoxicdiffuse and nodular goiter and thyroid neoplasia,Williams Textbook of Endocrinology, 12thedition. 2011; 14: 441.

6. Tollin SR, Mery GM. The use of fine needleaspiration biopsy under ultrasound guidance toassess the risk of malignancy in patients with amultinodular goiter, Thyroid 10: 235-241, 2000.

7. Contempre B, Dumont J, Ngo B. Thilly CH,Diplock AT, and Vanderpas J. Effect of seleniumsupplementation in hypothyroid subjects of an

` iodine and selenium deficient area: the possibledanger of indiscriminate supplementation ofiodine deficient subjects with selenium, J ClinEndocrinol Metab 1991; 73: 213-215.

8. Gupta M, Gupta S, Gupta VB. Correlation ofFine Needle Aspiration Cytology withHistopathology in the diagnosis of solitarythyroid nodule. Journal of thyroid researchvolume 2010, Article ID 379051, 5 pages doi:10.4061/2010/379051.

9. Werk EEJ, Vernon BM, Gonzalez JJ. Cancer inthyroid nodules: A community hospital survey,Arch Intern Med, 1984; 144:474–6.

10. Asp AA, Georgitis W,Waldron EJ. Fine needleaspiration of the thyroid: Use in an averagehealth care facility, Am J Med, 1987;83:489–93.

11. Hamberger JI, Consistency of sequential needlebiopsy findings for thyroid nodules: Managementimplications, Arch Intern Med, 1987;147:97–9.

12. Hanumanthappa. M.B, Gopinathan S, SuvarnaR, Rai DG, Shetty G, Shetty A, Shetty B, ShettyN. The Incidence of Malignancy in Multi-nodularGoitre: A Prospective Study at a TertiaryAcademic Centre, Journal of Clinical andDiagnostic Research. 2012 April, Vol-6(2):267-270.

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A significant proportion of patients with type 2diabetes require insulin along the course of thisdisease, characterized by gradual impairment inβ-cell function and loss of β-cell mass,as shownin UKPDS study 50% of beta cells are lost ondiagnosis of type 2 diabetes. Most patients withtype 2 diabetes will eventually require insulintherapy to achieve a goal A1C of < 7% as targetedby the American Diabetes Association (ADA)or ≤ 6.5% as set by the American Association ofClinical Endocrinologists (AACE).

Tight glycemic control was crucial to preventthe microvascular complications of type 1diabetes as evidenced by the landmark trialDiabetic Control and Complications ( DCCT ).Similar inference was also drawn by U.K.Prospective Diabetes Study (UKPDS ), in type2 diabetes, which showed that a similar reductionin complications could be achieved by tightlycontrolling blood glucose. Intensive glycemiccontrol has also been shown to reduce risk ofMacrovascular complications eg.cardiovasculardisease in patients with type 1 diabetes,interestingly enough this has not been statisticallysignificant in patients with type 2 diabetes, inseveral studies.

A major challenge for internists when initiatinginsulin therapy is choosing when to use, whereto use and what to use of the many insulinsavailable today—rapid-acting, short-acting,intermediate-acting, long-acting, ultra long actingand premixed insulins. Insulin initiation isindicated when fasting Plasma fasting glucose

levels are above 250 mg/dl, random glucoselevels are above 300 mg/dl, or the HbA1c isabove ≥10%. Insulin should also be consideredwhenever the HbA1c is persistently above 8.5%,when patients are already on one or more oralantidiabetics..To use insulin therapy mosteffectively, the regimen must be individualized,considering his or her lifestyle needs and physicaland mental status and affordability.1

Once-daily basal insulin, instead of a rapid-acting insulin to be taken before meals or premixed twice daily, is more favourable andapproachable not to speak of the costeffectiveness. Recently published studies havecompared the effects of adding basal versusprandial insulin in patients with type 2 diabeteson oral agents. The Treat to Target in Type 2Diabetes study group found that, althoughprandial insulin improved A1C slightly morethan basal insulin in patients with type 2 diabeteson maximal doses of metformin andsulfonylurea, there were more incidences ofhypoglycemia with the prandial short or rapidacting insulin… 2. Moreover in mild to moderateinsulin requiring patients, a study of ours, hasshown excellent control with once daily basalinsulin.

One should remember that, although it is ofutmost importance to achieve glycemic controland target A1c in the long term, this does nothave to be done in hours or days. In fact, rapidimprovement in glycemic control can actuallybe associated with adverse outcomes in termsof bleeding from proliferative retinopathy or

Ideal Basal InsulinProf. Jayanta Chakraborty

Prof. & HOD of Medicine, Endocrinologist, V.I.M.S., RKMSP.

15

even danger related to frequent hypoglycemia.Therefore, the dictum is, “Start low, and go slow”.

Starting insulin with one or two injections of along acting insulin as basal insulin is an acceptedapproach in the ADA's clinical guidelines.Available basal agents include insulin glargine,insulin detemir, NPH insulin- an intermediate-acting insulin or very recently introduced ultralong acting insulin Degludec.

Alternatives are basal bolus or biphasic premixedinsulin preparations. These may offer theadvantage of providing basal and postprandialcoverage in one injection.

Early premixed insulin formulations combinedneutral protamine hagedorn with regular humaninsulin in a 70/30 proportion (70% neutralprotamine hagedorn, 30% regular). This is astable combination and ensures that the regularinsulin will not be affected by mixing with neutralprotamine hagedorn. Although this provides theconvenience of a basal-bolus regimen, it has thedisadvantages of a prolonged time to peak (oneto five hours). The advent of the rapid-actinganalogues allowed premixed insulins to beadministered more conveniently, within 15minutes of a meal, and to more closely matchtheir peak onset to postprandial glucoseexcursions. The two premixed insulin analogueformulations are: insulin lispro 75/25 (75% lisproprotamine suspension, 25% lispro); and biphasicinsulin aspart 70/30 (70% neutral protamineaspart, 30% aspart); important recent clinicaltrials, INITIATE, randomized 233 insulin-naivepatients with type 2 diabetes who were on oralantidiabetic drugs to either glargine at bedtimeor BIAsp 70/30 twice daily for 28 weeks. Initialmean HbA1c was 9.5% and 8.9% in the BIAspgroup and the glargine group, respectively.Sixty-six percent of patients in the BIAsp group

achieved the HbA1c<7% compared to 40% ofthose in the glargine group. HbA1c reductionwas greater (-2.79%) in the BIAsp groupcompared to the glargine group (-2.36%),especially for subjects with baseline HbA1c8.5%. Minor hypoglycemia was reported by43% and 16%, , in the BIAsp group and theglargine group respectively. The researchersconcluded that twice daily BIAsp 70/30 wassuperior to glargine in achieving target HbA1cin patients failing oral antidiabetic drugs,especially in those with baseline HbA1c>8.5%.But we should not forget the risk of morehypoglycemia with split-mix regimen in thisstudy…12

Two accepted approaches for choosing a doseof basal insulin include starting with a fixeddose of 10 units per day or determining a weight-based dose of 0.2 units /kg of body weight, inpresence of normal renal and hepatic functionand BMI.

Although many diabetologists in India andabroad recommend continuing all oral agents,one should be cautious to the risk ofhypoglycemia with concomitant insulin andsulfonylurea therapy. Metformin and other non-secretogogues may be continued. Patients shouldmonitor and record fasting blood glucose levelsevery morning and should monitor morefrequently if hypoglycemia prevails. Every 3days, if the fasting blood glucose is not in thetarget range the dose of basal insulin can beincreased by 2 units if glucose is relatively closeto the fasting target (e.g. if fasting blood glucoseis 130-180 mg/dl), or 4 units (if fasting bloodglucose is > 180 mg/dl ). If hypoglycemia withblood glucose < 70 mg/dl occurs, basal insulinshould be decreased 4 units or more or stoptemporarily according to the situation.

16

A common mistake with basal insulin dosing isincreasing the dose too much before addingprandial insulin. This does not match thephysiological needs and predisposes patients tofasting hypoglycemia. A rule of thumb is that apatient should not be advanced to more than 0.5units/kg of body weight for basal insulin withoutfirst considering adding a rapid-acting insulin(e.g., 0.1 units/kg) with meals.

If A1C remains elevated = 7% after 2-3 monthson basal insulin, or if prelunch, predinner, orbedtime blood glucose levels are clearly abovethe goal of 70-130 mg/dl despite a fasting glucoselevel at goal, prandial therapy should be initiatedwith rapid or short acting insulin or metformin.

When adding or adjusting prandial insulin, thatpatients should know the importance of frequentblood glucose monitoring. Patients on basal andbolus insulin therapy should monitor bloodglucose no less than four times daily (at mealsand bedtime).

It is often seen that insulin to be given beforeeach meal, this may not be necessary for allpatients. If prelunch blood glucose is consistentlyelevated > 130 mg/dl, add rapid-acting insulinat breakfast. If predinner blood glucose iselevated, add rapid-acting insulin at lunch. Ifbedtime blood glucose is elevated, add rapid-acting insulin at dinner. For each of these doses,one can often begin with 4 units and adjust by2 units every 3 days until blood glucose is inrange.

Insulins available for prandial coverage includeregular insulin-short-acting or the rapid-actinginsulin analogs. The rapid-acting analogs,including aspart, lispro and glulisine, allow acloser approximation of physiological insulinsecretion. They are absorbed more rapidly than

regular insulin, leading to a more rapid onset(5-15 minutes) and peak (about 30-90 minutes)and a shorter duration of action (3-5 hours).Their rapid onset allows them to be given justbefore meals and they should not be given morethan 15 minutes before meals. Regular insulinis less expensive than the analogs. Its onset ofaction occurs in 30-60 minutes, requiring dosing30 minutes before meals for best effect. Regularinsulin peaks at 2-3 hours and has a duration of5-8 hours.

Now coming to the individual basal insulin NPHINSULIN action starts 1-3hrs, peaks at 4-10hrs,duration 10-20hrs. This is a suspension ofcrystalline zinc insulin combined with thepositively charged polypeptide,

Insulin detemir is a soluble, long-acting basalhuman insulin analog. The mean duration ofaction of insulin detemir ranged from 5.7 hoursat the lowest dose to 23.2 hours at the highestdose. The action starts within 2hrs, no peak,ends within 16-24hrs.

The prolonged action of Detemir is mediatedby the slow systemic absorption of insulindetemir molecules from the injection site dueto strong self-association of the drug moleculesand albumin binding. Insulin detemir isdistributed more slowly to peripheral targettissues since insulin detemir in the bloodstreamis highly bound to albumin. Detemir is indicatedfor once or twice daily subcutaneousadministration for patients with type 2 diabetesmellitus who require basal insulin for the controlof hyperglycemia. Detemir is not for intravenousor intramuscular administration. The prolongedduration of activity of insulin detemir isdependent on injection into subcutaneous tissue.Intravenous administration of the usualsubcutaneous dose could result in severe

17

hypoglycemia. Absorption after intramuscularadministration is both faster and more extensivethan absorption after subcutaneous administration.For patients treated with detemir once-daily, thedose should be administered with the eveningmeal or at bedtime. For patients who requiretwice-daily dosing for effective blood glucosecontrol, the evening dose can be administeredeither with the evening meal, at bedtime, or 12hours after the morning dose. For insulin-naïvepatients with type 2 diabetes who are inadequatelycontrolled on oral antidiabetic drugs, Detemirshould be started at a dose of 0.1 to 0.2 U/kgonce-daily in the evening or 10 units once-daily,and the dose adjusted to achieve glycemic targets.Insulin detemir confers a body weight advantageover glargine or NPH…10

Insulin Glargine: Insulin glargine is a humaninsulin analog that has been designed to havelow aqueous solubility at neutral pH. At pH 4,insulin glargine is completely soluble. Afterinjection into the subcutaneous tissue, the acidicsolution is neutralized, leading to formation ofmicroprecipitates from which small amounts ofinsulin glargine are slowly released, resulting ina relatively constant concentration/time profileover 24 hours with no pronounced peak. Thisprofile allows once-daily dosing as a basal insulin.

In clinical studies, the glucose-lowering effecton a molar basis (i.e., when given at the samedoses) of intravenous insulin glargine isapproximately the same as that for human insulin.In euglycemic clamp studies in healthy subjectsor in patients with type 1 diabetes, the onset ofaction of subcutaneous insulin glargine wasslower than NPH insulin. The median timebetween injection and onset of pharmacologicaleffect was 14.5 hours for NPH insulin and 24hours for insulin glargine.

The intended duration of activity of glargine isdependent on injection into subcutaneous tissue.It should not be administered intravenously orvia an insulin pump. Intravenous administrationof the usual subcutaneous dose could result insevere hypoglycemia.

The recommended starting dose of Glargine inpatients with type 2 diabetes who are notcurrently treated with insulin is 10 units (or 0.2Units/kg) once daily, which should subsequentlybe adjusted to the patient's need. The action ofglargine starts within 2-4hrs, no peak, and endsin 24hrs. The longer duration of action (up to24 hours) of glargine is directly related to itsslower rate of absorption and supports once-daily subcutaneous administration. In a studyof Basal Insulin Therapy in Type 2 Diabetes 28-week comparison of insulin glargine and NPHinsulin. To determine the safety and efficacy ofthe long-acting analog insulin glargine comparedwith NPH insulin in patients with type 2 diabeteswho were previously treated with insulin alone.

The treatment groups showed similarimprovements in HbA1c from baseline to endpoint on intent-to-treat analysis. The treatmentswere associated with similar reductions in fastingglucose levels. Overall, mild symptomatichypoglycemia was similar in insulin glarginesubjects (61.4%) and NPH insulin subjects(66.8%). However, nocturnal hypoglycemia inthe insulin glargine group was reduced by 25%during the treatment period. Subjects in theinsulin glargine group experienced less weightgain than those in the NPH group. Theyconcluded, in patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective asonce or twice-daily NPH in improving andmaintaining glycemic control. In addition, insulinglargine demonstrates a lower risk of nocturnal

18

hypoglycemia and less weight gain comparedwith NPH insulin.

In a head to head treat to target, randomizedstudy of 964 patients glargine was required 43.5units to achieve the primary endpoint of HbA1Cof 7% compared to patients on insulin detemirwho received insulin 98.5 units an increase of76%....8 in a cockraine data base study, inNetherlands, Swinnen et al, concluded that “ouranalysis suggest that there is no clinically relevantdifference in efficacy or safety between insulinDetemir and insulin Glargine for targetinghyperglycemia. However, to achieve the sameglycemic control insulin detemir was ofteninjected twice daily in a higher dose but withless weight gain, while insulin glargine wasinjected once daily, with fewer insulin sitereactions. “….7

Insulin Degludec is a ultra-long-acting basalinsulin that forms soluble multihexamers at thesubcutaneous injection site. The differencebetween human insulin and Degludec is thedeletion of residue ThrB30 and the addition ofa fatty diacid moiety, hexadecandioyl, attachedto LysB29, via a glutamic acid spacer. Once thephenol in the pharmaceutical formulation hasdispersed after injection, the acyl side-chaincauses Degludec to self-associate, forming largesoluble multihexamers; creating a subcutaneousdepot. The zinc ions slowly diffuse out from thiscomplex, allowing Degludec monomers todissociate and diffuse into the blood stream at aslow and steady rate. The slowly releasedDegludec monomers may provide a bufferingeffect against changes in absorption rate. Theresultant smooth and stable pharmacokineticprofile at steady state provides a longer durationof action Insulin degludec “sultralong durationof action and low variability, produces a consistent

glucose-lowering activity profile at steady state.Pharmacokinetic data have demonstrated thatDegludec has a terminal half-life ofapproximately 25 hours, twice that of insulinglargine and a duration of action of more than42 hours. This suggests that Degludec injectiontime may be varied from day to day, offeringpatients greater convenience and flexibility,…11.When needed, allowing increased flexibility forpatients leading demanding, unpredictablelifestyles such as shift workers or frequenttravelers crossing time zones. These situationsmay include patients for whom insulin isadministered by a pharmacist or nurse, who maynot be able to visit the patient at the same timeevery day.

Insulin degludec provides comparable glycaemiccontrol to insulin glargine without additionaladverse events and might reduce dosingfrequency due to its ultra-long action profile.Basal-bolus regimens with insulins designedto closely mimic a physiologic profile allowmany patients to reach glycemic targets.However, issues related to variability of actionleading to unexpected hypoglycemia, and theneed to adapt one's lifestyle to the action profileof a prescribed insulin, can prevent theachievement of good glycemic control in a safemanner. Degludec's duration of action exceeds42 hours, providing full 24-hour basal insulincoverage and offering a consistent glucose-lowering effect, thus potentially allowingadministration within a broader dosingwindow…11

Deciding which basal insulin to choose is up tothe diabetologist and the patient. Glargine doesnot have a distinct peak, has onset of actionwithin 2-4 hours, and a duration of action of 20-24 hours and be given every 24 hours at any

19

time of day convenient for the patient. The onsetof detemir's action is 1-3 hours and its durationof action is 18-22 hours. Given this variabilityin duration, some patients may be able to usethis insulin just once per day, whereas-others-will-require-twice-daily-injection.

Compared to these two basal insulins, NPHinsulin has the advantage of lower cost. It is anintermediate-acting product, with onset of activityin 2-4 hours, a peak in 4-10 hours, and a durationof 10-18 hours and most patients are controlledwith once daily or twice daily, though ourexperience favors once daily with good control.When evaluating which basal insulin is preferred,NPH and the long-acting analogue glargine wereconsidered equivalent when used in combination

with short-acting supplemental insulin fortreatment of patients on continuous enteralfeedings, this was the observation in criticalcare setting, published in JCEM….9.And finally the latest addition Degludec withlong action of 42 hrs. and half life of 25 hrs. isno doubt ideal basal insulin. But its prohibitorycost makes the NPH insulin still the ideal basalinsulin for our country, pending themanufacturers curtail the price of Degludec.(NB- This is a review of literature. Author andthe publisher is not responsible for the inferencesof different coments made in the legend by theresearchers. Moreover this should not be usedas treatment guidelines. Readers are to followstandard textbooks for the same)

References:

1. Clinical Diabetes Spring 2009 vol. 27 no. 2 72-76. Initiating and Titrating Insulin in PatientsWith Type 2 Diabetes Joseph A. Henske, MD,Michelle L. Griffith, MD and Michael J. Fowler,MD.

2. Holman RR, Thorne KI, Farmer AJ, Davies MJ,Keenan JF, Paul S, Levy JC, 4-T Study Group :Addition of biphasic, prandial, or basal insulinto oral therapy in type 2 diabetes. N Engl J Med357:1716-1730, 2007

3. Ther Adv Endocrinol Metab. 2012 April; 3(2):55–59. doi: 10.1177/2042018812437181 Efficacyand safety of ultra-long-acting insulin degludecAmmar Wakil and Stephen L. Atkin

4. Lancet 2011 Mar 12;377(9769):924-31. doi:10.1016/S0140-6736(10)623057. Insulindegludec, an ultra-long-acting basal insulin, oncea day or three times a week versus insulin glargineonce a day in patients with type 2 diabetes: a 16-

week, randomised, open-label, phase 2 trial.Zinman B, Fulcher G, Rao PV, Thomas N, EndahlLA, johansen T, Lindh R, Lewin A, RosenstockJ, Pinget M, Mathieu C.

5. doi: 10.2337/diacare.24.4.631 Diabetes CareApril 2001 vol. 24 no. 4 631-636 28-weekcomparison of insulin glargine and NPH insulinJulio Rosenstock, MD1, Sherwyn L. Schwartz,MD2, Charles M. Clark, Jr., MD3, Glen D. Park,PharmD4, David W. Donley, PHD5 and MikeB. Edwards, RPH5

6. doi: 10.2337/diacare.26.11.3080 Diabetes CareNovember 2003 vol. 26 no. 11 3080-3086 TheTreat-to-Target Trial Randomized addition ofglargine or human NPH insulin to oral therapyof type 2 diabetic patients Matthew C. Riddle,MD1, Julio Rosenstock, MD2, John Gerich,MD3 and on behalf of the Insulin Glargine 4002Study Investigators.

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7. Cochrane Database Syst Rev. 2011 jul 6(7) insulindetemir versus insulin glargine for type 2 diabetesmellitus. Swinnen et al.

8. 45th annual meeting of the European associationfor the study of diabetes EASD in Vienna.

9. Larsen and Goldner Severe Insulin Resistance JClin Endocrinol Metab, September 2011, 96(9):2652–2662.

10. J Clin Endocrin Metab. First published ahead ofprint March 22, 2012 as doi:10.1210/jc. 2011-2202, Update on Insulin Therapy for Type 2Diabetes, Thomas Donner and Miguel Mun˜ oz

11. The Journal of Clinical Endocrinology &Metabolism March 1, 2013 vol. 98 no. 3 1154-

1162, Chantal Mathieu, Chantal Mathieu, PriscillaHollander, Bresta Miranda Palma, John Cooper,Edward Franek, David Russell Jones, JensLarsen, soren Can Tamer and Stephen C. Bain,on behalf of the NN1250, (BEGIN: Flex T1)Trial Investigators.

12. Diabetes Care 28:260 –265, 2005, InitiatingInsulin Therapy in Type 2 Diabetes A comparisonof biphasic and basal insulin analogs, PHILIPRASKIN, MD1ELSIE ALLEN, MD2,PRISCILLA HOLLANDER, MD3, ANDREWLEWIN, MD4, ROBERTA. GABBAY, MD,PHD5, PETER HU, PHD2, BRUCE BODE,MD6, ALAN GARBER, MD7, FOR THEINITIATE STUDY GROUP*.

21

HypertensionDr. N. G. Bhattacharya1, Dr. R. N. Chatterjee2

Abstract:

The pathophysiology of hypertension is an areaof active research, attempting to explain causesof hypertension, which is a chronic diseasecharacterized by elevation of blood pressure.Hypertension can be classified as either essentialor secondary. Essential hypertension indicatesthat no specific medical cause can be found toexplain a patient's condition. About 90-95% ofhypertension is essential hypertension.[1][2][3][4]

Secondary hypertension indicates that the highblood pressure is a result of another underlyingcondition, such as kidney disease or tumours(adrenal adenoma or pheochromocytoma).Persistent hypertension is one of the risk factorsfor strokes, heart attacks, heart failure and arterial

1Prof. & HOD, Dept. of Pathology, V.I.M.S., RKMSP, 2MD PGT., Dept. of Pathology, V.I.M.S., RKMSP

aneurysm, and is a leading cause of chronicrenal failure.[5]

Most mechanisms leading to secondaryhypertension are well understood. Thepathophysiology of essential hypertensionremains an area of active research, with manytheories and different links to many risk factors.

Cardiac output and peripheral resistance are thetwo determinants of arterial pressure.[6] Cardiacoutput is determined by stroke volume and heartrate; stroke volume is related to myocardialcontractility and to the size of the vascularcompartment. Peripheral resistance is determinedby functional and anatomic changes in smallarteries and arterioles.

A Diagram Explaining Factors Affecting Arterial Pressure

Regulation of Blood Pressure:

Blood pressure is a function of cardiac outputand peripheral vascular resistance twohemodynamic variables that are influenced by

multiple genetic, environmental, anddemographic factors. The major factors thatdetermine blood pressure variation within andbetween populations include age, gender, bodymass index, and diet, particularly sodium intake.

Arterial Pressure

Cardiac Output

Peripheral Resistance

Stroke Volume

Heart Rate

Vascular Structure

Vascular Function

Myocardial Contractility

Size of the Vascular Compartment

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DECREASED BLOOD PRESSURE

↓Peripheral resistance (dilation)l Nitric oxidel Prostacyclinl Kininsl Atrial natriuretic peptide (ANP)l Neural factors (β-adrenergic)↓

↓↓

↓↓

↓Cardiac outputl Blood volume↓

(ANP)l Heart rate↓l Contracility↓

↓

Blood Pressure

Cardiac outputl Heart ratel Contractionl Blood volume

(aldosterone)

↓↓

↓↓

Peripheral resistance (constriction)l Anglotensin IIl Catecholaminesl Thromboxanel Endothelinl Neural factors (a-adronorgic)

↓↓

↓↓

↓↓

INCREASED BLOOD PRESSURE

Atrial natriuretic peptide

Volume overload

Excretes Na+and water

Bloodvolume

Vasodilation ↓↓BLOOD PRESSURE BLOOD PRESSURE

↓

Normotension

Bloodvolume

↓

(Low volume or low resistancecan also be renal artery stenosis)

Vaso-constriction

Excretes Na+and water

Aldosterone

Anglolension II

Kidney

ReninLiver

Angio-tensinogen

Angiotensin I

Endothelium in many tissues

Angiotensin convertingenzyme

Increased volumel Excess dietary sodiuml Inadequate excretion

(renal failure)l Hyperaldosteronisml Increased sodium resorption

(Gileman, Bartler andLidde syndromes)

Increased resistancel Increased sympathetic tone

(e.g. pheochromopytoma)l Increased renin-angiotensin-

adoslenone axis

A.

B.

23

Effects of Hypertension on Organs:Here's a look at the complications high bloodpressure (hypertension) can cause when it's noteffectively controlled.Damage to Your Arteries:Healthy arteries are flexible, strong and elastic.Their inner lining is smooth so that blood flowsfreely, supplying vital organs and tissues withadequate nutrients and oxygen. If you have highblood pressure, the increased pressure of bloodflowing through your arteries gradually can causea variety of problems, including:Artery Damage and Narrowing:High blood pressure can damage the cells of

your arteries' inner lining. That launches acascade of events that make artery walls thickand stiff, a disease called arteriosclerosis (ahr-teer-e-o-skluh-RO-sis), or hardening of thearteries. Fats from your diet enter yourbloodstream, pass through the damaged cellsand collect to start atherosclerosis (ath-ur-o-skluh-RO-sis). These changes can affect arteriesthroughout your body, blocking blood flow toyour heart, kidneys, brain, arms and legs. Thedamage can cause many problems, includingchest pain (angina), heart attack, heart failure,kidney failure, stroke, blocked arteries in yourlegs or arms (peripheral arterial disease), eyedamage, and aneurysms.

Vascular pathology in hypertention. A, Hyalinearteriolosclerosis. The arteriolar wall is thickenedwith increased protein deposition (hyalinized),and the lumen is markedly narrowed. B,Hyperplastic arteriolosclerosis (onion-skinning;arrow) causing lumenal obliteration (arrow;periodic acid–Schiff stain)

Aneurysm: Over time, the constant pressureof blood moving through a weakened artery cancause a section of its wall to enlarge and forma bulge (aneurysm). An aneurysm (AN-u-rizm)can potentially rupture and cause life-threateninginternal bleeding. Aneurysms can form in anyartery throughout your body, but they're mostcommon in the aorta, your body's largest artery.

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A, View of the base of the brain, dissected toshow the circle of Willis with an aneurysm ofthe anterior cerebral artery (arrow). B, Dissectedcircle of Willis to show large aneurysm. C,Section through a saccular aneurysm showingthe hyalinized fibrous vessel wall (H&E).

Damage to Your Heart:

Your heart pumps blood to your entire body.Uncontrolled high blood pressure can damageyour heart in a number of ways, such as:

Coronary Artery Disease:

Coronary artery disease affects the arteries thatsupply blood to your heart muscle. Arteriesnarrowed by coronary artery disease don't allowblood to flow freely through your arteries. Whenblood can't flow freely to your heart, you canexperience chest pain, a heart attack or irregularheart rhythms (arrhythmias).

Enlarged Left Heart:

High blood pressure forces your heart to workharder than necessary in order to pump blood tothe rest of your body. This causes the left ventricleto thicken or stiffen (left ventricular hypertrophy).

These changes limit the ventricle's ability topump blood to your body. This conditionincreases your risk of heart attack, heart failureand sudden cardiac death.Heart Failure:Over time, the strain on your heart caused byhigh blood pressure can cause your heart muscleto weaken and work less efficiently. Eventually,your overwhelmed heart simply begins to wearout and fail. Damage from heart attacks adds tothis problem.Damage to Your Brain:Just like your heart, your brain depends on anourishing blood supply to work properly andsurvive. But high blood pressure can causeseveral problems, including:Transient Ischemic Attack (TIA):Sometimes called a ministroke, a transientischemic (is-KEM-ik) attack is a brief, temporarydisruption of blood supply to your brain. It'soften caused by atherosclerosis or a blood clot— both of which can arise from high bloodpressure. A transient ischemic attack is often awarning that you're at risk of a full-blown stroke.

25

Stroke:A stroke occurs when part of your brain isdeprived of oxygen and nutrients, causing braincells to die. Uncontrolled high blood pressurecan lead to stroke by damaging and weakening

your brain's blood vessels, causing them tonarrow, rupture or leak. High blood pressurecan also cause blood clots to form in the arteriesleading to your brain, blocking blood flow andpotentially causing a stroke.

A hemorrhagic infarction is present in the inferiortemporal lobe of the left side of this brain. B, Abland infarct with punctate hemorrhages,consistent with ischemia-reperfusion injury, ispresent in the temporal lobe.

Dementia:

Dementia is a brain disease resulting in problemswith thinking, speaking, reasoning, memory,vision and movement. There are a number ofcauses of dementia. One cause, vascular dementia,can result from narrowing and blockage of thearteries that supply blood to the brain. It can alsoresult from strokes caused by an interruption ofblood flow to the brain. In either case, high bloodpressure may be the culprit. High blood pressurethat occurs even as early as middle age canincrease the risk of dementia in later years.

Mild Cognitive Impairment:

Mild cognitive impairment is a transition stagebetween the changes in understanding andmemory that come with aging and the more

serious problems caused by Alzheimer's disease.Like dementia, it can result from blocked bloodflow to the brain when high blood pressuredamages arteries.

Damage to Your Kidneys:

Your kidneys filter excess fluid and waste fromyour blood — a process that depends on healthyblood vessels. High blood pressure can injureboth the blood vessels in and leading to yourkidneys, causing several types of kidney disease(nephropathy). Having diabetes in addition tohigh blood pressure can worsen the damage.

Kidney Failure:

High blood pressure is one of the most commoncauses of kidney failure. That's because it candamage both the large arteries leading to yourkidneys and the tiny blood vessels (glomeruli)within the kidneys. Damage to either makes itso your kidneys can't effectively filter wastefrom your blood. As a result, dangerous levelsof fluid and waste can accumulate. You might

26

ultimately require dialysis or kidneytransplantation.Kidney Scarring (Glomerulosclerosis):Glomerulosclerosis (glo-mer-u-lo-skluh-RO-sis)is a type of kidney damage caused by scarringof the glomeruli (glo-MER-u-li). The glomeruliare tiny clusters of blood vessels within yourkidneys that filter fluid and waste from yourblood. Glomerulosclerosis can leave your kidneysunable to filter waste effectively, leading tokidney failure.Kidney Artery Aneurysm:An aneurysm is a bulge in the wall of a bloodvessel. When it occurs in an artery leading to thekidney, it's known as a kidney (renal) arteryaneurysm. One potential cause is atherosclerosis,which weakens and damages the artery wall.Over time, high blood pressure in a weakenedartery can cause a section to enlarge and form abulge — the aneurysm. Aneurysms can ruptureand cause life-threatening internal bleeding.Hypertenstve Retinopathy:Hypertensive retinopathy is damage to the fromhigh blood pressure. The retina is the layer of

tissue at the back part of the eye. It changeslight and images that enter the eye into nervesignals that are sent to the brain.Causes:High blood pressure can damage blood vesselsin the retina. The higher the blood pressure andthe longer it has been high, the more severe thedamage is likely to be.When you have diabetes, high cholesterol levels,or you smoke, you have a higher risk of damageand vision loss.Rarely, a condition called develops. Bloodpressure readings suddenly become very high.Sometimes, the sudden rise in blood pressurecan cause more severe changes in the eye.Other problems with the retina are also morelikely to occur, such as:l damage to the nerves in the eye due to

poor blood flow.l blockage of the blood supply in the

arteries to the retina.l blockage of the veins that carry blood

away from the retina.

Hypertension can cause damageto the retina of the eye

Retina Hardexudates

MaculaFlamehemorrhage

Cottonwool spots A.D.A.M.

Introduction:

Hypertension is one of the commonest medicaldisorders affecting 10% of all pregnancies aroundthe world.1 Presence of hypertension affects theoutcome of pregnancy adversely by influencingboth maternal and perinatal morbidity andmortality. Hypertensive Disorders in Pregnancy(HDP) are classified into four categories: chronichypertension, gestational hypertension, Pre-eclampsia and pre-eclampsia superimposed onchronic hypertension.2 This citation would discusschronic hypertension during pregnancy, theprevalence of which seems to be increasing asthere is increasing trend of more and more womenopting for childbearing at a relatively older ageand many of them are overweight/obese.Population-based data indicate that approximately1% of pregnancies are complicated by chronichypertension. The prevalence varying accordingto age, race and BMI and the criteria used toestablish the diagnosis.

Physiological Change in BP During Pregnancy:

Usually, there is slight drop in BP in the earlypregnancy possibly mediated through the actionof local mediators like prostacyclin and nitricoxide and reaching the nadir around 20 weeksof gestation. Thereafter, BP continues to risegradually until term when pre-pregnancy levelsare attained. Immediately after delivery, there isa slight drop in BP, followed by slow gradualincrease over a period of few days.

Definition of Hypertension:

Hypertension is defined as SBP of = 140 mmHg or DBP of = 90 mm Hg or both. To establishthe diagnosis of hypertension, these criteriashould be documented on at least two occasions,4 to 6 hours apart. Hypertension is furtherclassified as mild (SBP = 140-159 or DBP =90-109 mm Hg) and severe (SBP = 160 or DBP= 110 mm Hg). For accurate measurement ofBP in pregnant women, there are several generalrecommendations, an essential element for bothdiagnosing and monitoring HDP.

Definition of Chronic Hypertension:

Chronic hypertension during pregnancy isdefined as hypertension present before pregnancyor before 20 weeks of gestation. Women withhistory of pre-pregnancy antihypertensive useand those with persistent hypertension 12 weeksafter delivery are also considered as havingchronic hypertension3. For consideringmanagement, a subgroup4 of women havingcomorbid conditions (such as preexistingdiabetes, renal disease and vascular disease) thatrepresent major cardiovascular risk and impactantihypertensive therapy outside of pregnancywere identified.

Effect of Chronic Hypertension on Pregnancy:

Most women with mild essential hypertensionhave uncomplicated pregnancies. However,chronic hypertension is associated with severaladverse pregnancy outcomes like preterm birth,IUGR, IUD, placental abruption and CS delivery.

27

1 Prof. Obs & Gynae, V.I.M.S., RKMSP 2 Prof. & HOD, Obs & Gynae, V.I.M.S., RKMSP

Chronic Hypertension in PregnancyDr. Sukanta Misra1, Dr. Bijitbaran Chowdhury2

The risk of fetal and maternal complicationsincreases markedly in presence of severehypertension, prolonged hypertension, secondaryhypertension, uncontrolled hypertension orsuperimposed pre-eclampsia.

The risk of SGA increases by almost two timesand the incidence of SGA reaches 50% inpresence of superimposed preeclampsia. Perinatalmortality is increased by two to four times thanin the general population.

Women with uncomplicated chronic hypertensionhave three times the risk of CS delivery andtwice the risk of PPH, compared withnormotensive women. The risk of developingsuperimposed pre-eclampsia is approximately25% with mild hypertension, rising to as high as50% in those with history of pre-eclampsia in aprevious pregnancy, severe hypertension orsecondary hypertension and those with end-organdisease. Compared to normotensive women, thereis fivefold increased risk of complications likematernal mortality, cardiac dysfunction due toventricular hypertrophy, cerebro-vascularaccidents, pulmonary edema and renal failure inwomen with longstanding hypertension andpreexisting co-morbid conditions.

Effects of Pregnancy on Chronic Hypertension:

The physiological changes in pregnancy canaffect chronic hypertension. Increased bloodvolume and decreased colloidal oncotic pressuremay contribute to cardiac decompensation.Decrease in systemic vascular resistance maylead to fall in BP (may be misleading for theclinician) which reaches its nadir at around 16-18 weeks and then increases gradually reachingpre-pregnancy value by third trimester.

Evaluation:

Ideally the evaluation should be performed before

pregnancy or at least as early in pregnancy aspossible. The aim is to identify end organ damageand to look for causes of secondary hypertension.Depending on the severity of hypertension, theevaluation includes assessment of kidney, heart,eye and other organs.

Because kidney is affected early in the diseaseprocess and because proteinuria is the keydiagnostic criteria of super-imposed pre-eclampsia, it is recommended that all womenshould have assessment of renal function whichincludes serum creatinine, BUN, 24 hours urinaryprotein excretion or spot protein / creatinineratio and creatinine clearance. In addition, thosewith long standing hypertension, having risk forIHD, cardiomegaly and retinopathy, need to beevaluated by ECG, echocardiography andophthalmological tests.

Traditionally, pre-eclampsia has been definedas hypertension plus significant proteinuria,defined as = 300 mg of protein in a 24 hoururine sample. Considering the inaccuracies of24 hour urine collection, some guidelines4,6

consider a spot urine protein: creatinine ratio of= 30 mg protein/mmol creatinine as significantproteinuria. Preeclampsia can also occur withoutproteinuria, since there is evidence that end-organ complications can occur withoutproteinuria4,5. Therefore, superimposedpreeclampsia should be suspected in presenceof new onset proteinuria, significant increase inbaseline proteinuria, detection of abnormallaboratory values or development of symptomsof pre-eclampsia3.

The various adverse conditions included in theconsideration of pre-eclampsia are maternal end-organ dysfunction, maternal symptomatology,abnormal maternal laboratory testing andevidence of fetal morbidity4. Adverse conditions

28

that are reflective of maternal end-organdysfunction include eclampsia, pulmonary edema,stroke, placental abruption and severehypertension. Resistant hypertension, defined ashypertension that requires three medications forBP control after 20 weeks gestation is alsoincluded as adverse condition4. The symptom-based adverse conditions include symptoms thatmay reflect occipital cortical or other cerebralischemia or edema (severe headache, visualdisturbance), hepatic capsular irritation (epigastricor right upper quadrant pain) or pulmonary edema(dyspnea). Other maternal symptoms that raisesuspicion for preeclampsia include severe nauseaand vomiting and chest pain. Abnormal maternallaboratory testing reflecting end-organdysfunction includes elevated liver enzymes andthrombocytopenia. Elevated serum creatinineand low serum albumin (< 2.0 g/dl) has beenassociated with an increased risk of pulmonaryedema and other complications4. Signs of fetalmorbidity like oligohydramnios, IUGR, abnormalDoppler umbilical artery velocimetry and IUFDare also included as adverse conditions4,5.Hyperuricemia, although associated with perinatalcomplications is not predictive of adversematernal outcomes4. A serum uric acid level of= 5.5 has a likelihood ratio of 2.5 forsuperimposed preeclampsia3.

Although majority of the women with chronichypertension have been classified as primary oressential hypertension, in at least 10% cases, anunderlying secondary cause may be present andinclude renal, adrenal, endocrine, collagenvascular diseases, coarctation of aorta and obesity(see box1). The laboratory tests to identify suchcauses should always be performed inconsultation with an appropriate specialist. It islikely that many women have already been

evaluated before pregnancy. Renal artery stenosisshould be considered in young women (< 30years) with severe hypertension, especially ifthere is no family history of hypertension3.Evaluation for pheochromocytoma isrecommended for women with paroxysmalhypertension, frequent hypertensive crises,seizure disorders, anxiety attacks, palpitationsor headaches7.When a woman presenting first time with a veryhigh BP late in pregnancy, it is often difficult todifferentiate severe hypertension fromsuperimposed preeclampsia. However, mostyoung nulliparous women who present withhypertension for the first time during latepregnancy will have preeclampsia. In additionto proteinuria other helpful tests include Hb,haematocrit, platelet count and LFT. Oliguriaand raised Hb and haematocrit usually suggesthaemoconcentration, indicative more ofpreeclampsia. Serum uric acid is more commonlyelevated in preeclampsia. Serum creatinine maybe raised in preeclampsia. Noninvasiveimpedance cardiography is being investigatedfor better differentiating worsening chronichypertension from superimposed preeclampsia.Single biomarkers (soluble fms-like tyrosinekinase-1 and soluble endoglin levels), Dopplerand combination of these tests have althoughbeen suggested as markers to differentiatesuperimposed preeclampsia from chronichypertension, require more studies before beingimplemented in clinical practice. If the morecommon diagnosis of chronic hypertension orpreeclampsia does not apply, the woman shouldbe screened for SLE and primary renal disease3.Preconception/Initial Visit Counseling andEvaluation:Preconception counseling should be provided

29

regarding treatment strategies, risks of medicationand alternatives. Ideally before conception, RAASdrugs should be discontinued and evaluationshould be done to look for evidences of end-organ damage and to identify possible causes forsecondary hypertension. Counseling should alsoinclude emphasizing the benefit of appropriatehealth behavior to optimize pregnancy outcomes.Upon discovery of intrauterine pregnancy, ACEinhibitors and ARBs must be changed toalternative drugs and detailed evaluation mustbe done.

Risk Reduction for Preeclampsia:

a. Aspirin

To reduce the risk of preeclampsia and itscomplications, low-dose aspirin is recommendedfor women who are at high risk for developmentof preeclampsia. The high risk group includeswomen with chronic hypertension, HDP duringa prior pregnancy, chronic kidney disease,autoimmune disorder, pre-existing diabetes.Although there is no clear evidence for a dosagecutoff, low-dose aspirin is commonly defined as75 mg/day. NICE guidelines6 recommend adosage of 81 mg/day. Enteric coated aspirinshould be avoided. Aspirin therapy should beginas early as possible for maximal benefit andshould continue until delivery. Maximum riskreduction is expected if aspirin therapy is initiatedbefore 16 weeks gestation6. WHO recommendsinitiation prior to 20 weeks gestation1. Continuingaspirin therapy until delivery does not increasebleeding complications. It is recommended thataspirin prophylaxis can be given at bedtime4.

b. Others

WHO guidelines1 recommend supplementationwith 1.5-2 grams elemental calcium per day forwomen at high risk for preeclampsia in areas

where dietary calcium intake is low. There isconsensus across guidelines that salt restrictionis not recommended solely to preventpreeclampsia. WHO guidelines1 do notrecommend rest at home for the prevention ofpreeclampsia in women at risk. Low to moderateintensity exercise is of benefit for general health.Poorly controlled chronic hypertension is arelative contraindication8 to aerobic exercise inpregnancy.

Non-Pharmacological Treatment:

There is little evidence that non-pharmacologicaltreatment is of any benefit at all. Women withchronic hypertension should be encouraged tokeep their dietary sodium intake low, either byreducing or substituting sodium salt, becausethis can reduce blood pressure4,6. Whether bedrest is effective or not requires larger trials.However, the issue of DVT as a side effect ofprolonged immobilization should be addressed.

Antihypertensive Therapy:

The goal of BP management is to optimizepregnancy outcome maintaining a balancebetween maternal and fetal/neonatal risk. Asyet, there is no definitive evidence to define theoptimal BP targets and the optimal managementof mild hypertension.

Antihypertensive therapy for mild hypertension(140-159/90-99 mmHg) may decrease therelative risk of maternal severe hypertension,but there is no evidence of a positive impact onadverse maternal or perinatal outcomes. On thecontrary, there is some evidence that such therapymay cause harm, such as an increased risk ofSGA or LBW babies. There is limited, goodquality evidence against treatment of mildhypertension and insufficient evidence regardingthe benefit of treatment in prevention of maternal

30

stroke or other maternal morbidity or in theprevention of adverse neonatal outcomes. Theexisting evidence fails to identify the thresholdfor starting antihypertensive therapy for womenwith mild chronic hypertension. If BP is <150/100 mmHg and there are no complicatingfactors3, it is reasonable to withhold or reducemedication for those on antihypertensive therapy.Women with mild hypertension are, however,candidates for lifestyle modification4,9.

To prevent severe hypertension, antihypertensivetherapy should be reinstituted,6,9 if SBP reaches150-160 mmHg or DBP 100-110 mmHg.Antihypertensives should also be continued9 forthose women with target organ damage or whorequired multiple antihypertensive agents forcontrol of BP before pregnancy.

There is no consensus regarding the optimaltarget for BP control. The target BP varies from130-155/80-105 mm Hg4, if there are nocomorbid conditions, to < 150/100 mmHg6. Forwomen with chronic hypertension and end organdamage, such as renal disease, a target BP of130-139/80-89 mmHg is recommended4.Lowering DBP below 80 mm Hg is notrecommended4,6, because of the risk ofcompromising utero-placental perfusion.

Identification of severe hypertension (SBP = 160or DBP = 110 mmHg or both) in the OPD requiresin-patient admission and immediate managementto lower BP to less than severe levels (< 160/110mmHg), with a caution to avoid a precipitous orextreme drop in BP, to prevent maternal strokeand possibly to avoid IUGR. To avoid prolongedexposure to severe SBP and loss of maternalcerebral vascular autoregulation, the target BPof 140-160/90-100 mmHg is recommended10

and < 150/100 mmHg but DBP not < 80 mmHg6.

Although antihypertensive medications of allclasses have been used in pregnancy, it is difficultto identify a single preferred agent for non-acuteBP management. However, there is consistencyacross the guidelines regarding the acceptabilityof oral labetalol, methyldopa and nifedipine.

Labetalol is preferred due to fewer adverseeffects than methyldopa, and is recommended6,7

as a good option for first line treatment. Thealternatives are methyldopa and nifedipine afterconsideration of maternal, fetal and neonatalside effect profiles. Methyldopa is preferredbecause of stable uteroplacental flow and fetalhemodynamics, as well as an absence of longterm adverse effects in children. However,methyldopa has been associated with seriousadverse effects, like hepatitis, hemolytic anemia,depression, drowsiness and a lupus-likesyndrome. The evidence for long acting calciumchannel blockers is limited, but they appear tobe safe, although there is a theoretical concern7

regarding potential synergy between magnesiumand calcium channel blockers with resultantsevere hypotension.

Regarding β-blockers, although acebutolol,metoprolol, pindolol and propranolol areaccepted by some4 the possible associations ofIUGR with highly selective β-blockers werereported by others5. Atenolol has been associatedwith low birth weight when used from earlypregnancy, and it is not recommended for useduring pregnancy. A possible association ofmetoprolol and IUGR has also been reported,and metoprolol may also exacerbate asthma.Because diuretics can restrict normal plasmavolume expansion of pregnancy, these are notused as first line agents but these are probablysafe7,9. Therefore, thiazide diuretic used beforepregnancy does not need to be discontinued

31

during pregnancy. The possible adverse effectsof thiazide diuretics are hypokalemia andcarbohydrate intolerance. Hydrochlorothiazideand Hydralazine are considered as adjunctiveagents among oral antihypertensives usedcommonly in pregnancy3. A summary of standardand maximum dose ranges of common agents isnoted below. (See table 1).

Severe hypertension with or without preeclampsiarequires urgent treatment. Parenteral hydralazineor labetalol are most commonly used in thissetting, although calcium channel blockers,ketanserin, diazoxide and others have been used3.A systematic review11 of 24 RCTs concludedthat although various drugs are effective, noparticular agent was better than the other. A meta-analysis12 noted that parenteral hydralazine wasless effective than nifedipine in lowering BP totarget range, but hydralazine was more effectivethan labetalol. However hydralazine has moreadverse maternal and perinatal events such asmaternal tachycardia and delayed maternalhypotension than labetalol. Therefore experienceand familiarity of the clinician with a particularagent with its potential feto-maternal adverseeffects should dictate the selection of the agent3.A summary of agents for urgent control of severehypertension in pregnancy is noted below. (Seetable 2).

Because of the increased risk of congenitalabnormality drugs that act on the renin-angiotensin-aldosterone system (RAAS) shouldnot be used during pregnancy. In fact these drugsare contraindicated3 in all trimesters of pregnancy.These drugs include ACE inhibitors, angiotensinreceptor blockers (ARB) and direct renininhibitors. Because = 50% of the pregnanciesare unplanned, these drugs should better beavoided in women of reproductive age group. If

these medications are unavoidable, then thewoman should be counseled regarding the useof effective contraception and also the need fordiscontinuation of the drugs with the use ofalternative ones before planning pregnancy.There is some evidence6 that there may be noadded risk from ACE-inhibitors during the firsttrimester of pregnancy, but the risk is clearlypresent in the second and third trimesters. Thisstudy provides some reassurance to women whobecome pregnant while taking ACE inhibitors.Because of the risk of stillbirth, Prazosin is alsonot recommended4 during pregnancy.

Maternal Surveillance:

Definitive proteinuria testing is recommendedby all the guidelines either by spot urinaryprotein: creatinine ratio or 24-hour urinecollection4,7. Use of an automated reagent stripreading device or urinary protein: creatinineratio twice weekly is recommended6 for womenwith non-severe hypertension. Other thanproteinuria, there is insufficient evidence todefine which lab assessments are most usefulin monitoring women with chronic hypertension.There is poor quality evidence regarding thepredictive value of specific positive tests,although negative tests can be useful. Mostguidelines recommend that women withsuspected preeclampsia should be evaluatedwith a CBC, electrolytes, serum creatinine, andliver function tests. In addition, coagulationstudies (INR and aPTT, fibrinogen), serum uricacid, glucose and urinalysis are alsorecommended by some4. Raised serum uric acidmay be useful in distinguishing preeclampsiain women with chronic hypertension who firstpresent late in pregnancy3. The frequency ofsurveillance in suspected preeclampsia casesshould be dictated by changes in maternal or

32

fetal clinical status4 or if there is ongoing concern6

and these guidelines specify weekly testing forwomen presenting with severe hypertension.

Fetal Surveillance:

Commonly recommended tests of fetal well beingare non-stress test (NST), biophysical profile(BPP) without non-stress test, ultrasoundassessment of fetal growth, amniotic fluidassessment and umbilical artery Dopplervelocimetry. Although DFMC has been included4

in the list, there is no definite cutoff value andmaternal perception of a relative decrease inDFMC may be more important7. All these testsare of low specificity and no single test is superiorto others. Therefore an Individualistic planregarding the nature and timing of fetalmonitoring has been suggested6,7. Most of theincreased morbidity associated with chronichypertension is due to superimposed preeclampsiaor IUGR. Therefore, USG at first trimester fordating and at 18-20 weeks for anomaly scanfollowed by USG for fetal growth at regularintervals is recommended. If IUGR is suspectedtwice weekly NST or BPP and the use ofumbilical artery Doppler velocimetry isappropriate3 . In absence of IUGR orpreeclampsia, these additional tests do notimprove the outcome and therefore isrecommended in selected women. There is noconsensus regarding the timing or frequency ofumbilical artery Doppler velocimetry and it isof limited value after 36 weeks gestation. Formost7 pregnancies, the tests can be initiated at32-34 weeks after due consideration to theseverity of hypertension, risk of fetal death,prognosis of neonatal survival and the potentialfor iatrogenic prematurity from false positiveresults.

Delivery Timing:

No RCTs have evaluated the best time of deliveryfor women with chronic hypertension. Deliveryat term can be expected in those with mildchronic hypertension. Preterm delivery(spontaneous or iatrogenic) is not uncommonamongst women with severe hypertension orhistory of adverse outcome in previouspregnancy. A consensus panel13 recommendfollowing delivery plan: no antihypertensiverequired – 38-39 weeks, hypertension controlledwith medications – 37-39 weeks, hypertensiondifficult to control – 36-37 weeks. However,delivery should be considered at 34 weeks3 inpresence of severe hypertension withsuperimposed preeclampsia. Antenatal steroidsshould be administered according to theinstitutional regime.

Mode of Delivery:

Vaginal delivery is preferred and cervicalripening may be offered4. The increased risk ofbleeding due to thrombocytopenia andcoagulopathy in cases of superimposedpreeclampsia can be avoided by activemanagement of third stage of labour withoxytocin. CS delivery is reserved only forobstetric indications.

Intrapartum:

Antihypertensive therapy should be continuedduring labor and delivery to keep BP at = 160/110mm Hg. In absence of any contraindication,early insertion of an epidural catheter isrecommended as analgesia. If epidural is notpossible patient controlled fentanyl orremifentanil analgesia is recommended5.NSAIDs should be used cautiously3 or mayneed to be avoided altogether4,5 if hypertension

33

is difficult to control, or if there is oliguria,elevated creatinine or platelets < 50 x 109/L.

Anesthesia Concerns:

Despite absence of any good quality evidence,it is likely that women with mild chronichypertension may undergo epidural anaesthesiasafely. GA may pose a risk due to suddensignificant rise of BP during intubation orextubation and difficult or failed intubation dueto laryngeal edema. For fetal or maternalconditions, GA, however, may be indicated5 andrequires early anesthesia notification, aspirationprophylaxis, and attenuation of BP.

Fluid Balance:

Women with severe hypertension or thosecomplicated by cardiovascular or renal diseasesare at increased risk of fluid overload andpulmonary edema, a major cause of maternalmortality in this population. So they requirespecial attention to fluid load and urine output3and any suspected fluid overload should be treatedurgently in collaboration with an intensivist.There is insufficient data regarding the benefitsand potential harms of central invasivehaemodynamic monitoring6,7. Intrapartumoliguria is common, especially with oxytocinusage and if Intrapartum urine output is < 30cc/hr for 2 consecutive hours, up to three bolusesof 500 cc of crystalloid is recommend14. Accuratedetermination of volume status may be requiredin cases of persistent oliguria. The managementof postpartum oliguria varies across theguidelines. Postpartum oliguria is usually due tohypovolemia and initial volume replacementwith 500 cc of crystalloid over 20 minutes isrecommended14, with consideration of packedRBC if oliguria persists and the woman is anemic.In absence of pre-existing renal disease or rising

creatinine, oliguria (15 ml/hr) should betolerated4 for at least the first six hours postpartum.

Postpartum Surveillance:

As BP is often unstable for 1-2 weeks afterdelivery, close monitoring of BP duringpostpartum period is essential. Peak postpartumBP occurs between 3 -5 days after birth. BPshould be monitored at least every 4 hourspostpartum, and women should not be dischargeduntil BP has been well controlled for at least 24hours. Postpartum surveillance also includesconfirmation of the resolution of end-organdysfunction.

Postpartum Antihypertensive Therapy:

There is no reliable data to guide whether or notto continue antenatal antihypertensive therapyand which agent is preferred. WHO guidelines1

recommend antihypertensive treatment in womentreated with antihypertensives during pregnancyand in those who develop severe hypertensionafter delivery. The general consensus is thatsevere hypertension should be treated keepinga target BP of < 140/90 mmHg6. The evidencefor treating non-severe postpartum hypertensionis insufficient. However, in presence of comorbidconditions, they need to be treated, with a targetBP of < 130 /80 mm Hg4.

Although all antihypertensive agents are excretedin breast milk, these are usually acceptable4.Labetalol and propranolol are preferred if betablockers are indicated. Diuretics can decreaselactation, and should be avoided in breastfeedingwomen. To avoid the risk of depression,Methyldopa needs to be discontinued within 2days after birth with resumption of pre-pregnancyantihypertensive drugs6. Regarding ACE/ARBtherapy, the evidences are either against9 theuse or felt to be insufficient to recommend6.

34

Follow up:

Women who required antihypertensives shouldbe reviewed4 2 weeks after delivery for longterm management of hypertension. Follow upby a specialist requires4 the need forantihypertensives and the requisite investigations.They should have annual BP checks andcardiovascular risk assessment, including lipidsand glucose, at least every five years5.

Risk Communication:

Women should be informed of the future riskslike risk of future preeclampsia, and risk of futurehypertension and its complications. The chanceof recurrence of hypertension in subsequentpregnancies is 20-50%. She should also becounseled regarding family planning and offeredan effective birth control method prior todischarge from the hospital. She should beinformed that intervals between pregnancies of< 2 years or > 10 years including weight gainbetween pregnancies are both associated with anincreased risk for preeclampsia and adverseoutcomes. Overweight women should beencouraged4 to attain healthy BMI and to followappropriate health behaviors3.

Take Home Message:

o Ideally a woman with chronic hypertensionshould be evaluated before pregnancy or atleast as early in pregnancy as possible withan aim to identify the cause or any evidenceof end organ damage.

o Women belonging to reproductive age groupshould avoid using ACE-inhibitors and ARBs,if possible; if not, then should use effectivereversible contraception.

o ACE-inhibitors and ARBs are contraindicatedin all trimesters of pregnancy.

o Women with severe hypertension requireantihypertensive medications.

o Labetalol is a good option for first linetreatment.

o Atenolol is not currently recommended forthe treatment of chronic hypertension inpregnancy.

o In pregnant women with uncomplicatedchronic hypertension the aim is to keep BP< 150/100 mm Hg.

o In presence of end-organ damage secondaryto chronic hypertension, the aim is to keepBP < 140/90 mm Hg.

o Treatment should not lower DBP below 80mm Hg.

o Pregnant women with secondary chronichypertension should be referred to aspecialist.

o Women with chronic hypertension shouldreceive antihypertensive treatment dependenton pre-existing treatment, side-effect profiles,and teratogenicity.

o Fetal growth should be evaluated by USG.

o Timing for delivery should be decided bythe gestational age, severity of hypertension,whether controlled or not, evidence of endorgan damage, superimposed preeclampsia,other maternal and fetal adverse effects.

o Mode of delivery should be decided by theobstetric factors.

o After delivery, BP should be checkedregularly and periodically. Antihypertensivesmay need to be initiated to keep BP < 140/90mm Hg.

o Review long term antihypertensives 2 weeksafter birth.

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Secondary Causes ofChronic Hypertension

l Renal Causes:o Chronic glomerulonephritis,o Interstitial nephritis,o Diabetic nephropathy,o Polycystic kidney disease,o Nephropathy due to other causeso Renal artery stenosisl Adrenal Causes:o Pheochromocytomao Primary aldosteronismo Cushing’s syndromel Endocrine Causes:o Hyperthyroidism and thyrotoxicosiso Diabtes Mellitusl Collagen Vascular Diseases:o SLEo Systemic sclerosiso Periarteritis nodosal Coarctation of Aortal Obesity

36

Table 1

Commonly used antihypertensives for non-acute management of chronic hypertension

Agent Dosage /Range Caution? Comment

Labetalol 200 – 800 mg/day, orally, BD/TD Avoid in women with asthma, systolic

Max: 2400 mg/day heart failure and cardiac conduction abnormalities

Nifedipine 30-60 mg/day, orally Correct form should be used(extended release) Max: 120 mg/day Concern for severe hypotension if

Short acting nifedipine is not used concurrently with IV Mg.recommended due to the risk ofhypotension

Methyl Dopa 250-1000 mg/day, orally, BD/TD Drowsiness depression, hepatitis,Max: 3000 mg/day hemolytic anaemia

Evaluation for SecondaryCauses of Chronic Hypertension

l Pheochromocytoma:

o Plasma metanephrines

o 24 hour urinary unconjugatedcatecholamines, VMA

o MRI or CT scan of adrenal gland

l Primary Aldosteronism:

o Serum Potassium

o Plasma rennin activity

o 24 hour urinary aldosteroneexcretion

l Renal Artery Stenosis:

o Renal USG

o Doppler flow study of the renalvessels

o MRI angiography of renal vessels

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Table 2

Antihypertensives for urgent control of severe acute hypertension in pregnancy

Agent Dosage /Range Caution? Comment

Hydralazine 5 mg IV/IM; then 5-10 mg every Long experience of safety and efficacy20-40 minutes or constant infusion of Risk of delayed maternal hypotension,0.5-10 mg/hr fetal bradycardia

Labetalol 20 mg IV, then 20-80 mg every 5-15 Possible less risk of tachycardia andminutes up to a maximum of 300 mg; arrhythmia than with other vasodilatorsor constant infusion of 1-2 mg/min Increasingly preferred as first line agent

Nifedipine 10-30 mg orally; repeat in 45 minutes Possible interference with labor if needed

References:1. WHO recommendations for prevention and

treatment of Preeclampsia and Eclampsia; WHO2011.

2. Report of the National High Blood PressureEducation Program Working Group on HighBlood Pressure in Pregnancy. Am J ObstetGynecol. 2000; 183(1): S1-S22.

3. American College of Obstetricians andGynecologists (ACOG). Practice Bulletin-ChronicHypertension in Pregnancy. February 2012.

4. Society of Obstetricians and Gynaecologists ofCanada (SOGC): Clinical Practice Guideline-Diagnosis, Evaluation and Management of theHypertensive Disorders of Pregnancy. March2008.

5. Society of Obstetric Medicine of Australia andNew Zealand (SOMANZ). Guidelines for theManagement of Hypertensive Disorders ofPregnancy. 2008.

6. Royal Col lege of Obste t r ic ians andGynaecologists. National Institute for Health andClinical Excellence (NICE) Clinical Guideline-Hypertension in Pregnancy: the Management ofHypertensive Disorders during Pregnancy. August2010.

7. American College of Obstetricians andGynecologists (ACOG). Practice Bulletin-

Diagnosis and Management of Preeclampsia andEclampsia. January 2002.

8. American College of Obstetricians andGynecologists (ACOG) Committee Opinion.Exercise during pregnancy and the postpartumperiod. International Journal of Gynecology andObstetrics 2002; 77: 79-81.

9. National High Blood Pressure EducationProgram, National Heart, Lung and BloodInstitute. The Seventh Report of the Joint NationalCommittee on Prevention, Detection, Evaluationand Treatment of High Blood Pressure (JNC7).August 2004.

10. American College of Obstetricians andGynecologists (ACOG). Committee Opinion-Emergent therapy for acute-onset, severehypertension with preeclampsia or eclampsia.December 2011

11. Duley L, Henderson-Smart DJ, Meher S.Cochrane Database of Systematic Reviews 2006,Issue 3.

12. Magee LA, Cham C et al. BMJ 2003; 327 :955-960

13. Spong CY, Mercer BM, D’Alton M et al. ObstetGynecol 2011; 118 : 323-333.

14. American College of Obstetricians andGynecologists/ American Academy of Pediatrics(ACOG/AAP). Guidelines for Perinatal CareSixth Edition 2007.

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Introduction:

Acute acalculous cholecystitis (AAC) maydevelop without gallstones in critically ill patients,and appears to be increasing in incidence1.Duncan first recognized it in 1844 when a fatalcase of acalculous cholecystitis complicating anincarcerated hernia was reported. It is an acutenecroinflammatory disease of the gallbladderwith a multifactorial pathogenesis. It accountsfor approximately 5-10 percent of all cases ofacute cholecystitis and is associated with highmorbidity and mortality rates. The mortality rateremains about 30% because the diagnosis remainschallenging, the affected patients are criticallyill, and the disease itself can progress rapidlydue to a high incidence of gangrene (> 50%) andperforation (> 10%)2.

The proportion of cases occurring in outpatientsis not well-established. In our experience,approximately 10% of the patients attendingOPD with acute cholecystitis are acalculous.This rise in incidence in outpatients may be dueto the increasing use of ultrasound to rule outgallstones in every patient suspected ofgallbladder disease. It is also possible that a fewof these cases are mislabeled as acalculous dueto presence of unappreciated gallstones ormicrocrystals.

Etiopathogenesis:

The critical factor in the pathogenesis of AACis gallbladder ischemia/reperfusion injury. Thisis usually followed by bacterial invasion of

Acute Acalculous Cholecystitis:A Review of Current Trends in Management

Dr. Himadri Sengupta1, Dr. Soumitra Chandra2, Dr. Zayd Ashok Rahman3, Dr. Hirak Pahari4

1Prof. and HOD, 2Asso. Prof., 3Asst. Prof., 4MBBS, DNB — Dept. of Surgery, V.I.M.S., RKMSP

ischemic tissue, like Escherichia coli,Enterococcus faecalis, Klebsiella, Pseudomonas,Proteus species, and Bacteroides. This increasesmucosa l superoxide d ismutase andphospholipase A2 activity along with mucosallipid peroxide content causing a significant hostimmune response, including activation of thecoagulation cascade and platelet-activatingfactor3. There is enough evidence to supportthese observations along with the pathologicobservation of high rates of gallbladder necrosisand perforation4,5,6. When performed on thegallbladder specimen, microangiography hasrevealed significant differences between acutecalculous and AAC7. On one side gallstone-related disease is associated with arterialdilatation and venous filling, while AAC isassociated with multiple arterial occlusions andminimal-to-absent venous filling.

The second most important factor isconcentration and stasis of bile, which caninspissate in the absence of gallbladder emptying.Causes of bile stasis may include volumedepletion or dehydration, use of opioid analgesics(spasm of the sphincter of Oddi), long-termtherapy with total parenteral nutrition (30%)and prolonged positive-pressure ventilation withhigh PEEP8,9. Bile stasis increases thelysophosphatidyl choline concentration in bile,promoting local injury of the mucosa of thegallbladder by disrupting normal water transport.Increase in beta-glucuronidase in bile has alsobeen implicated in causing further injury to the

39

gallbladder10. Serial gallbladder ultrasoundstudies in patients on long-term TPN show thatthe incidence of gallbladder sludge increasesfrom 6% during the first week of TPN to 50%at 4 weeks and nearly 100% at 6 weeks11.Critically ill patients are more predisposedbecause of increased bile viscosity due to feverand dehydration and because of prolongedabsence of oral feeding resulting in a decreaseor absence of cholecystokinin-induced gallbladdercontraction. Interestingly, stimulation ofgallbladder contraction with cholecystokinindoes not prevent AAC in critically ill patients12.

Acute calculus cholecystitis may be acomplication of any major surgery, blunt traumaor major burns. The incidence of AAC followingabdominal aortic reconstruction is 0.5 to 0.9%,with a slight predilection for ruptured aneurysmcases, especially in males13.

AAC is also associated with diabetes, abdominalvasculitis, congestive heart failure, multiple bloodtransfusions, cholesterol embolization, andresuscitation from shock or cardiac arrest (4).Acalculouscholecystitis may also develop fromsecondary infection of the gallbladder, includingCandida infections, Salmonella infections(typhoid), cholera, leptospirosis and tuberculosis(4). Acalculouscholecystitis can also be observedin patients with human immunodeficiency virus(HIV) infection, although it is a late manifestationof this disease14.

Clinical Features:

Patients may present with fever and right upperquadrant tenderness. Patients with sepsis withoutany obvious source must also be considered forthis diagnosis. Complications include gangreneand perforation, which may rarely lead to bleedingor bile embolism15, 16. The gallbladder is usually

distended and may be palpable. Jaundice occursin about 20% of the cases. Most of the patientsare male with a mean age of diagnosis of 47years. However, children may also be affected,especially after a viral illness or during typhoidfever.

Diagnosis:

The diagnosis is challenging, especially in thesetting of a critically ill patient. The differentialdiagnosis of jaundice in the critically ill patientis complex, and includes intrahepatic cholestasisfrom sepsis or drug toxicity and “fatty liver”induced by TPN, in addition to AAC. Rapid andaccurate diagnosis is essential, as ischemia canprogress rapidly to gangrene and perforation.The diagnosis should be considered in everycritically ill patient with a clinical picture ofsepsis and no other obvious source. Physicalexamination and laboratory studies are veryunreliable in this regard17. Bile culture resultsare negative in nearly 50% of patients with AAC,probably because of concurrent antibiotic therapyin these patients. Liver function tests may bederanged.

Ultrasound:

Transcutaneous ultrasound of the gallbladder isthe most common and accurate modality todiagnose AAC in the critically ill patient. Themost reliable criterion is thickening of thegallbladder wall. Deitch18 reported 90%specificity using 3.0 mm and 98.5% specificityusing 3.5 mm wall thickness cutoff, whereassensitivity was 100% at 3.0 mm but only 80%at 3.5 mm. Based on the above findings, Deitchand Engel recommended acceptance ofgallbladder wall thickness of 3.5 mm or greateras definitive evidence of acute cholecystitis,whereas 3.0 mm is suggestive but not

40

conclusive19. False-positives may occur due topresence of s ludge, cholesterolosis ,hypoalbuminemia, nonshadowing stones orascites19. Other features for AAC are the presenceof pericholecystic fluid, intramural gas(emphysematous cholecystits) or a sonolucentintramural layer or “halo” that representsintramural edema.Cholescintigraphy:Hepatobiliary imaging has limited value incritically ill or injured patients20 because of ahigh incidence of false-positive scans, whichmay be due to fasting, liver disease, or TPN. Asensitivity rate as low as 68% has been reportedin studies of hepatobiliary imaging for AAC.Intravenous morphine (0.01 mg/kg) may increasethe accuracy of cholescintigraphy in critically illpatients. Non-visualisation of the gallbladderdespite good hepatic uptake and the entry ofisotope into the small intestine is taken as positiveevidence of cholecystitis. Moreover, increasedpericholecystic activity (the 'rim' sign) canindicate the complication of gangrene, andexceptionally free peritoneal spill will diagnoseperforation of the gall bladder21, 22. However,cholescintigraphy is an excellent choice ofinvestigation with high sensitivity in the outpatientsetting. Gall bladder ejection fraction (GBEF) ismeasured, and a cutoff value of 40% (35%according to some studies) or less is consideredfor this diagnosis to be made. Most studies haveconcluded that the latent period and the patternof gallbladder emptying as well as the onset ofgallbladder filling and biliary-to-bowel transittime are of no significant diagnostic value in thediagnosis of acalculouscholecystitis.Computed Tomography:Computed tomography (CT) is as accurate asultrasound in the diagnosis of AAC in critically

ill patients23. A single retrospective study hascompared all three modalities (ultrasonography,hepatobi l iary scanning, and CT)2 4 ;ultrasonography and CT were comparablyaccurate and superior to hepatobiliary imagingin acute acalculouscholecyctitis. CT scan maybe preferred over ultrasound if other abdominalpathology is more likely.

Laparoscopy:

Although reports are limited to small series andthere has been no randomized trial, laparoscopyhas been reported to be successful for both thediagnosis and therapy of AAC25. For criticallyill patients, laparoscopy can be performed underlocal anesthesia and intravenous sedation.Laparoscopy is possible in patients who haveundergone recent abdominal surgery if “gasless”techniques are used. Diagnostic accuracy is high,and both laparoscopic cholecystostomy andcholecystectomy have been performed.

Treatment:

The main treatment for AAC is cholecystectomy.Drainage of pericholecystic fluid collectionsmay be done, and other acute problems that maymimic acute cholecystitis (e.g., perforated ulcer,cholangitis, pancreatitis) must be ruled out.Cholecystostomy can be a life saving alternativein the patient considered too unstable to undergogeneral anesthesia26. Successful cholecystostomyis followed by cholangiography after the patienthas recovered. If gallstones are absent (trueAAC), cholecystectomy is usually not indicatedand the catheter can be removed27. However,definite statistical data is lacking whether or notinterval cholecystectomy is of any role afterpercutaneous cholecystostomy in the treatmentof AAC. One possible solution could be toperform a cholescintigraphy to assess the GBEF

41

after an interval of 6 weeks and performcholecystectomy if the GBEF is less than 40%.Most studies are of the opinion that oncerecovered from AAC while critically ill, thegallbladder function improves and intervalcholecystectomy is usually not required.Percutaneous cholecystostomy is gainingacceptance of late as an alternative to openprocedures. Although randomized trials have notbeen published, class II and III of evidence lendscredence to the procedure. The advantages ofpercutaneous cholecystostomy are bedsideapplicability, local anesthesia, and avoidance ofan open procedure. In 85% cases, the patient hasbeen noted to improve. If there is no improvementwithin 24 hours, an open procedure should beperformed. Causes of failure include gangrene,catheter dislodgment, bile leakage and wrongdiagnosis. In the largest reported series, majorcomplications were reported in 8.7% cases,including dislodgment of the catheter, acuterespiratory distress, bile peritonitis, hemorrhage,cardiac arrhythmia, and hypotension due toprocedure-rela ted bacteremia. Minorcomplications occurred in an additional 3.9%cases28. Catheters are usually removed afterapproximately 3 weeks in critically ill patientswith AAC who have undergone percutaneouscholecystostomy. This allows for the developmentof a mature track from the skin to the gallbladder.

Antibiotic therapy is an important adjunct to theremoval or drainage of AAC. The most commonbacteria isolated from bile in acute cholecystitisare E. coli, Klebsiella and Enterococcus faecalis,thus antibiotic therapy is directed against theseorganisms. Pseudomonas, staphylococci(MRSA/VRSA), Enterobacter species, anaerobicorganisms (Clostridium, Bacteroides), and fungimay be found.

In patients with AAC who are high-risk surgicalcandidates (i.e. end-stage liver disease),endoscopic gallbladder stent placement has beenreported as an effective palliative treatment.This involves placement of a double pigtail stentbetween the gallbladder and the duodenumduring ERCP.

Summary:

Acalculous cholecystitis is an acute necro-inflammatory disease of the gallbladder with amultifactorial pathogenesis. It accounts forapproximately 10 percent of all cases of acutecholecystitis and is associated with highmorbidity and mortality rates. Acalculous-cholecystitis is typically seen in patients whoare hospitalized and critically ill, though it mayalso be seen in the outpatient setting.Ultrasonography is typically the first test obtainedwhen acalculouscholecystitis is suspected.Advantages of ultrasonography are that it isnoninvasive, can be done at the bedside, andhas good sensitivity and specificity fordiagnosing acalculouscholecystitis. The role ofcholescintigraphy is unclear in the critically illpatient, but it has a high sensitivity in theoutpatient setting. Once the diagnosis isestablished, prompt treatment is imperativebecause without it, gallbladder gangrene maydevelop and can result in gallbladder perforation.Treatment is by cholecystectomy or percutaneouscholecystostomy, if general anesthesia is notfeasible. Patients with acalculouscholecystitiswho fail to improve or worsen followingcholecystostomy require cholecystectomy. Thereis no documented role of in tervalcholecystectomy for patients who have recoveredfrom AAC.

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References:

1. Johanning JM, Bruenberg JC. The changing face ofcholecystectomy. Am Surg. 1998 Jul;64(7):643-7;discussion 647-8.

2. Kalliafas S, Ziegler DW, Flancbaum L, Choban PS.Acute acalculouscholecystitis: incidence, risk factors,diagnosis, and outcome. Am Surg. 1998 May;64(5):471-5.

3. Kaminski DL, Andrus CH, German D, Deshpande YG.The role of prostanoids in the production of acuteacalculouscholecystitis by platelet-activating factor.Ann Surg. 1990 Oct;212(4):455-61.

4. Barie PS. Acalculous and postoperative cholecystitis.In: Barie PS, Shires GT, editors. Surgical intensivecare. Boston: Little Brown & Co; 1993; 837–57.

5. Venkataramani A, Strong RM, Anderson DS, GilmoreIT, Stokes K, Hofmann AF. Abnormal duodenal bilecomposition in patients with acalculous chroniccholecystitis. Am J Gastroenterol. 1998 Mar;93(3):434-41.

6. Janowitz P, Kratzer W, Zemmler T, et al. Gallbladdersludge: spontaneous course and incidence ofcomplications in patients without stones.Hepatology.1994 Aug;20(2):291-4.

7. Hakala T, Nuutinen PJ, Ruokonen ET, Alhava E.Microangiography in acute acalculouscholecystitis. BrJ Surg. 1997 Sep;84(9):1249-52.

8. Roslyn JJ, Pitt HA, Mann LL, Ament ME, DenBestenL. Gallbladder disease in patients on long-termparenteral nutrition. Gastroenterology. 1983Jan;84(1):148-54.

9. Johnson EE, Hedley-Whyte J. Continuous positive-pressure ventilation and choledochoduodenal flowresistance. J Appl Physiol. 1975 Dec;39(6):937-42.

10. Kouroumalis E, Hopwood D, Ross PE, Milne G,Bouchier IA. Gallbladder epithelial acid hydrolases inhuman cholecystitis. J Pathol. 1983 Feb;139(2):179-91.

11. Messing B, Bories C, Kunstlinger F, Bernier JJ. Doestotal parenteral nutrition induce gallbladder sludgeformation and lithiasis? Gastroenterology. 1983May;84(5 Pt 1):1012-9.

12. Merrill RC, Miller-Crotchett P, Lowry P. Gallbladderresponse to enteral lipids in injured patients. ArchSurg. 1989 Mar;124(3):301-2.

13. Herlin P, Ericsson M, Holmin T, Jönsson PE. Acuteacalculouscholecystitis following trauma. Br J Surg.1982 Aug;69(8):475-6.

14. Wind P, Chevallier JM, Jones D, Frileux P, CugnencPH. Cholecystectomy for cholecystitis in patients withacquired immune deficiency syndrome. Am J Surg.1994 Sep;168(3):244-6

15. Brady E, Welch JP. Acute hemorrhagic cholecystitiscausing hemobilia and colonic necrosis. Dis ColonRectum. 1985 Mar;28(3):185-7.

16. Proia AD, Fetter BF, Woodard BH, Stickel DL, MeyersWC. Fatal pulmonary bile embolism following acuteacalculouscholecysti t is . Arch Surg. 1986Oct;121(10):1206-8.

17. Fabian TC, Hickerson WL, Mangiante EC. Post-traumatic and postoperative acute cholecystitis. AmSurg. 1986 Apr;52(4):188-92.

18. Deitch EA, Engel JM.Acute acalculouscholecystitis.Ultrasonic diagnosis. Am J Surg. 1981 Aug;142(2):290-2.

19. Deitch EA, Engel JM.Ultrasound in elective biliarytract surgery. Am J Surg. 1980 Aug;140(2):277-83.

20. Shuman WP, Rogers JV, Rudd TG, Mack LA, PlumleyT, Larson EB. Low sensitivity of sonography andcholescintigraphy in acalculouscholecystitis. AJR AmJ Roentgenol. 1984 Mar;142(3):531-4.

21. Bushnell DL, Perlman SB, Wilson MA, Polcyn RE.The rim sign: association with acute cholecystitis. JNucl Med. 1986 Mar;27(3):353-6.

22. Swayne LC. Acute acalculouscholecystitis: sensitivityin detection using technetium-99m iminodiaceticacid-cholescintigraphy. Radiology. 1986 Jul;160(1): 33-8.

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23. Mirvis SE, Whitley NN, Miller JW. CT diagnosis ofacalculouscholecystitis.J Comput Assist Tomog.1987;11:83–7.

24. Mirvis SE, Vainright JR, Nelson AW. The diagnosisof acute acalculouscholecystitis: A comparison ofsonography, sc int igraphy, and CT. AJR.1986;147:1171–5.

25. Almeida J, Sleeman D, Sosa JL, Puente I, McKenneyM, Martin L. Acalculouscholecystitis: The use ofdiagnostic laparoscopy. J Laparoendosc Surg. 1995Aug;5(4):227-31.

26. Glenn F. Cholecystostomy in the high-risk patientwith biliary tract disease. Ann Surg. 1977 Feb;185(2): 185-91.

27. Pearse DM, Hawkins IF Jr, Shaver R, Vogel S.Percutaneous cholecystostomy in acute cholecystitisand common duct obstruction. Radiology. 1984Aug;152(2):365-7.

28. VanSonneberg E, D'Agostino HB, Goodacre BW,Sanchez RB, Casola G. Percutaneous gallbladderpuncture and cholecystostomy: Results, complications,and caveats for safety. Radiology. 1992 Apr;183(1):167-70.

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Rare Case of Pallor with Abdominal Distention: Case ReportDr. Manomit Haldar1; Prof. Asha Mukherjee2; Dr. Akhilesh Verma3; Dr. Soumitra Masani4

1, 2, 3, 4 V.I.M.S., RKMSP

Introduction:

Extra-nodal lymphoma in the gastrointestinaltract occurs in 10-30% of all patients with NHL1.The stomach, small bowel, pharynx, large boweland esophagus is affected in decreasing order offrequency2.

The cecum and the rectum are the mostcommonly involved part of the large bowel. Thepattern of the large bowel involvement includebulky polypoidal mass, infiltrative tumor andaneurysmal dilatation7. Bowel obstruction is

uncommon at presentation despite significantlymphomatous infiltration of the bowel wallbecause of the absent desmoplastic reaction9.In contrast to gastrointestinal adenocarcinoma,lymphoma is more likely to involve multipleand longer segments of gut and is less likely tocause bowel obstruction. Our patient presentedwith diffuse colonic wall thickening, 3 mostcommon causes of which are Diverticulitis,Carcinoma and Inflammatory bowel disease.Lymphoma presenting with such an extensiveand diffuse thickening of whole large gut is ararest presentation.

Case History:

5yrs. 5 months old girl admitted on 26.06.2013with complains of progressive distention ofabdomen for last 1 month. She was also havingalteration of bowel motion with passage ofoccational blackish stool. For the last weekmother also noticed decreased urine output andperiorbital and pedal edema. There was nohistory of vomiting, hematemesis or passage offresh blood. On examination there was severepallor, hugely distended abdomen (abdominalgirth 61cm), no hepatosplenomegaly, no ascites.

Investigations:

On 14.06.2013 (before admission at RKMSP)Hb-5gm/dL; PCV-16.50%; MCV-54.7fL; MCH-16.9pg; TLC-10, 600/cmm (N50L45M2E3B0);Platelet count-5.32 lakhs/cmm; ESR-35 mm in1st hour, Peripheral smear not suggestive; Reticcount-3.5%.

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DCT-Neg; On HPLC no abnormal Hb band seen;Serum Bilirubin-0.5mg/dl (conjugated 0.2 andunconjugated 0.3); Serum urea 25mg/dL,creatinine 0.5mg/Dl; total protein 3.9gm/dL(Alb2.2 and Glb 1.7); SGPT-32U/L; AlkalinePhosphatase-170U/L; GOT-28U/L. Serum iron26mcg/dl; Ferritin 13.5ng/ml; TIBC-252 mcg/dl;Urine and stool RE was normal. USG of wholeabdomen revealed a mild hepatomegaly, multipledilated bowel loops with small amount of freefluid.Child received one unit of PRBC transfusionfrom outside before admission, after all thesetests.After admission, we found Hb-11.4gm/dL; TLC-10,100(N48L40M4E8B0); Platelet-5,32,000; urea20, creatinine 0.5, Na-136; K-4.3; total protein4.1gm/dl (Alb-1.9 and Glb-2.2); Stool for OBTcame Positive twice on 28/6 and 29/6.Urine C/Sshowed a growth of E.coli. Mantoux test was

Neg, gastric aspirate (morning sample) on bothdays came Neg.

USG whole abdomen detected a gross diffusecolonic wall thickening with minimal ascites.There was also a hepatomegaly with focalhypoechoic lesion in the left lobe. Ascitic fluidwas so minimal that it could not be aspiratedfor study under USG guidance.

2nd Line Investigation:

All the primary investigations failed to detectthe cause of gutwall thickening. Proper biopsyfrom gutwall was needed, but there was risk ofanesthetia and OT procedure. Finally USG-guided FNAC was taken from bowel-wall.Microscopy showed scattered malignant cells.Those cells had large hyperchromatic nucleiwith irregular nuclear membrane and scantyamount of cytoplasm, background showedlymphoglandular bodies.

[Chest X-Ray Shows No MediastinalLymphadenopathy.]

[St. X-Ray Abdomen:Distended Bowel Loops.]

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[CECT Abdomen: DiffuseThickening of The Entire LargeGut, Excluding The Rectum.]

[CECT Abdomen:Abdomen Full of Guts.]

[CECT Abdomen:Abdomen Full of Guts.]

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Discussion:

The gastrointestinal tract is the most frequentsite of extra-nodal involvement by Non-Hodgkin’s lymphoma. Some patients haveprimary gastrointestinal lymphoma with diseasearising from the alimentary tract, but others havegeneralized lymphoma with associatedgastrointestinal involvement. In both forms thestomach is the most commonly involved,followed by the small intestine, pharynx, colonand rarely esophagus.3

Exposure to antigens usually occurs at epithelialsurfaces of the body including the gastrointestinaltract, respiratory tract, mammary glands andconjunctiva.4 Lymphoid tissue in these exposedareas is described as mucosa-associated lymphoidtissue(MALT). This tissue can confer localimmunologic protection independent of thegeneral immune system.5 Gut associatedlymphoid tissue forms the largest portion of theMALT-system and is the largest immunologicorgan in the body(even larger than the Spleen).

The colon is a much less common site ofgastrointestinal lymphoma, than is the stomachor small intestine. Primary Non-Hodgkin’slymphoma of the colon usually involves thececum or the rectum6. Patients with this conditioncan have polypoid, infiltrative or cavitary lesion.7The infiltrative form is characterized by a longsegment of concentric narrowing with smoothoverlying mucosa and thickened irregular haustralfolds, caused by infiltration of submucosa by

tumor.7 The differential diagnosis of cavitatoryform of lymphoma includes a malignant stromaltumor or a perforated colonic carcinoma.

In contrast, the generalized lymphoma involvingthe colon is usually manifested by innumerablesmall, sessile nodules involving long segmentsof the colon or even the entire colon.8 Thismultinodular form of colonic lymphoma can beconfused with a familial polyposis syndrome orlymphoid hyperplasia. The disseminatedlymphoma of small intestine characteristicallyinvolves long segment of bowel,9 but obstructionis uncommon, because the infiltrating tumorweakens the muscularis propria and does notelicit a desmoplastic response.9 It can bedifferentiated from adenocarcinoma by the lengthof narrowed segment, the degree of narrowingand the absence of significant obstruction.

Gastrointestinal non-Hodgkin lymphomas areusually B-cell in origin,10 but lymphomasassociated with celiac disease may be of T-cellorigin.11 NHL complicating celiac diseaseinvolves the proximal jejunam.

A study conducted in Finland, during 1978-88,showed most frequently the disease occurred inmiddle aged patients,12 where the stage of thedisease was the most important prognostic factor.Five-year survival was 92% in stage-1 disease.The importance of our case is that such anextensive colonic infiltration at 5 yrs of age isa rare presentation.

References:

1. Vinnicombe SJ, Rejnek RH. Extranodalmanifestation of lumphoma.Imaging1999; 11:240-268.

2. Levine MS, Rubesin SE, Pantongrag-Brown L,Buck JL, Herlinger H. Non-Hodgkin's lymphomaof the gastrointestinal tract: radiographic findings.AJR 1997; 168:165 –172.

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3. Berg JW. Primary lymphomas of thegastrointestinal tract. Natl Cancer Inst Monogr1969; 32 : 211-215.

4. Keren DF. Structure and function of theimmunologic system of the gastrointestinal tract.In: Ming S-C, Goldman H, eds. Pathology ofgastrointestinal tract. Philadelphia: Saunders.1992: 69-80.

5. Lewin K, Riddell RH, Weinstein W N.Immunodeficiency disorders. Gastrointestinalpathology and its clinical implications. NewYork:Ygaku-shoin,1992:104-111.

6. Zomoza J, Dodd GD. Lymphoma of thegastrointestinal tract. Semin Roentgenol, 1980;15 : 272-287.

7. Rubesin SE, Furth EE. Other tumors. In: GoreRM, Levine MS, Laufer I, eds. Textbook ofgastrointestinal radiology. Philadelphia:Saunders.1994 : 1200-1227.

8. Williams SM, Bark RN, Hamen RK. Radiologicfeatures of multinodular lymphoma of the colon.AJR 1984; 143 : 87-91.

9. Rubesun SE, Gilchrist AM, Bronner M et al.Non-Hodhkins Lymphoma of the small intestine.Radio Graphics1990; 10 : 985-998.

10. Papadimitriou CS, Papacharalampus NX, KittasC. Primary gastrointestinal lymphoma: amorphologic and immunohistochemical study.Cancer 1995; 55 : 870-879.

11. Egan LJ, Walsh SV, Stevens FM, Connolly CE,Egan EL, McCarthy CF. Celiac associatedlymphoma. J Clin Gastroenterol 1995; 21 :123-129.

12. Jaser N. Primary gastrointestinal non-Hodgkin’slymphomas. Clinical presentations and resultsof treatment. Ann Chir Gynaecol 1993; 82 (1): 7-16.

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WHAT IS THE DIGNOSIS ?

Pictorial CMEDr. Semanti Chakraborty1, Prof. Jayanta Chakraborty2

1Senior Resident, 2Prof. & HOD of Medicine & Endocrinologist, V.I.M.S., RKMSP

l Answer is Acromegaly.l The patient came with mild headache and

dysuria. X-ray skull reveals hypertrophiedparanasal sinuses, frontal bossing andthickened Calvarium.

l Acromegaly is due to anterior pituitary tumorsecreting GH or very rarely due to

hypothalamic or ectopic secretion ofGH/GHRH

l GHRH secretion may occur from bronchialcarcinoid, small cell lung cancer, pancreaticislet cell tumor, adrenal adenoma,pheochromocytoma and medullary thyroidcarcinoma.

l Some genetic syndromes like Mc CuneAlbright syndrome, Carney’s syndrome.Familial acromegaly, MEN 1 produces excessGH secretion.

l In > 65% of cases macroadenoma is present,so pressure effects of enlarged pituitary iscommon. Headache and visual field defectsare common….1

l In children tall stature, gigantism as it iscalled is usual manifestation. Children whoare more than three standard deviations (SD)above normal mean height for age, or morethan 2 SDs over their adjusted mean parentalheight.….1

l In adults the dignosis is often delayed untilflorid facial or acral features are present.

l Patient may attend neurologist for headache,cranial nerve palsy or carpal tunnel syndrometo ophthalmologist for visual field defect, todental surgeon for dental malocclusion orprognathism.

l May attend rheumatologist for arthritis.Cardiomegaly, diastolic dysfunction,hypertension may draw cardiologist attention.

50

Sleep apnea may necessitate pulmonologistreferral. A dermatologist may come in thepicture for skin tag or hyperhidrosis. Femalesubjects often consult gynecologist formenstrual disorders or galactorrhoea. Wehave seen a teacher consulting initially anotorhinolaryngologist for deep and labouredvoice. And finally the endocrinologist maydiagnose from hyperglycemia, insulinresistance or during evaluation of MEN 1syndrome.

l Dignosis is suspected by GH nadir during anoral OGTT of greater than 1ug/L or1ng/ml…1. However, Endocrine societyguideline recommends consideration oflowering this cutoff to 0.4 ng/mL because ofthe increased sensitivity of current GHassays…2. Age specific serum IGF-1 levelare high and help in diagnosis. False-positiveelevations of serum IGF-I levels may be seenin pregnancy, during which the placenta makeslarge quantities of a smaller yet biologicallyactive GH molecule. IGF-I levels should becompared with age-dependent normative datagenerated across all age-groups in bothsexes..2. Confirmation by pituitary-hypothalamic imaging or very rarely forectopic secretion by PET, MRI, CT scan…1.Growth hormone-staining of histopathologymaterial and pituitary somatostatin reseptorsubtype, in biopsy material help to predictresponse to somatostatin analogue therapy.

Treatment:

l The goals of therapy for acromegaly are to(1) control biochemical indices of activity,(2) control tumor size and prevent local masseffects, (3) reduce signs and symptoms ofdisease, (4) prevent or improve medical

comorbidities, and (5) prevent early mortality…2. The primary mode of therapy is surgery,which is recommended for all patients withmicroadenomas and for all patients who havemacroadenomas with associated mass effects.In patients with macroadenomas withoutmass effects, and with low likelihood ofsurgical cure, a role for surgical de-bulkingof macroadenomas to improve the responseto subsequent medical therapy has beenadvocated, as well as primary medical therapyalone. Medical therapy is generally used inthe adjuvant sett ing as well asradiotherapy...2.

Somatostatin Analogues (SSA):

The use of SSAs in the management ofacromegaly is based principally on the inhibitoryeffects of native somatostatin on GH secretion.Although the initial formulations for SSAs(octreotide) were administered subcutaneouslyup to 3 or 4 times a day, the newer formulationsare longer acting and Could be used oncemonthly or longer. Such as Sandostatin LARand Lanreotide. But short-acting subcutaneouslyadministered octreotide should be given for 2weeks 3 times daily before initiation of treatmentwith the long-acting octreotide LAR orLanreotide in order to assess the response toand systemic tolerability of octreotide. SSAssuccessfully reduce GH and IGF-I levels in 50%to 70% of patients…2

Sandostatin-LAR is an effective and well-tolerated treatment for patients with acromegaly.Undoubtedly the initial indication forSandostatin-LAR will be in the patient who isnot cured after surgery and radiotherapy, but itmay be used as a primary treatment in someacromegalics…3

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GH Receptor Antagonist:

Pegvisomant is a recombinantly derivedanalogue of human GH that acts as a highlyselective GH receptor antagonist. Treatmentwith pegvisomant results in a dose-dependentreduction of serum IGF-I levels but anincrease in circulating GH levels. Therefore,serum IGF-I, and not GH, is used to monitorthe biochemical response to therapy. Patientsreceiving this GH receptor antagonist require

close observation with serial MRI scans,such as at 6-month intervals during the firstyear of management and then at annualintervals Pegvisomant therapy is associatedwith abnormal results of LFTs…2.

Radiation Therapy:

l Pituitary irradiation in acromegaly isgenerally considered an adjunctive therapyin patients not fully responding to surgicaland medical treatments …2.

References:

1. Williams Textbook of Endocrinology. 11th.Edition, saunders, Elsevier.

2. A m e r i c a n A s s o c i a t i o n o f C l i n i c a lEndocrinologists Medical Guidelines for ClinicalPractice AACE Acromegaly Task Force, Chair,Laurence Katznelson, MD, Departments ofMedicine and Neurosurgery, Stanford University,

Stanford, California,Endocr. Pract.2011;17,suppl.4.

3. J Clin Endocrinol Metab. 1995 Nov; 80 (11) :3267-72. Depot long-acting somatostatinanalog (Sandostatin-LAR) is an effectivetreatment for acromegaly. Stewart PM, KaneK, SE, LancranjanI, Sheppard MC.

Images in Clinical MedicineDr. Sudip Chatterjee

CT scan of a 57 year old male who presented in adrenal crisis. The scan shows bilateralenlarged hypodense adrenals. FNAC found Histoplasmosis. The patient received a courseof Itraconazole and is now well on steroid replacement.

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Prof., Dept. of Medicine & Endocrinologist, V.I.M.S., RKMSP

53

Buffalo hump refers to a lump of fat that develops at the top of the back between the shoulders. Itcan arise from a variety of conditions that are characterized by an increase in central fat distribution.Originally described as clinical feature of Cushings Syndrome, but is now more commonly seenwith Obesity. Some consider it to be a clinical sign of insulin resistance. When found in a patient;blood pressure to be measured, other features of Cushings Syndrome to be looked for and bloodsugar and basal Cortisol should be measured. The most common cause of Cushings Syndrome inclinical practice is the prolonged use of oral corticosteroid drugs, which are prescribed to treatdifferent conditions, including inflammatory diseases.

Courtesy : Prof. D. Maji (Dept. of Medicine)

Buffalo Hump

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Tubercular LaryngitisProf. B. K. Roychaudhuri, Dr. A. Roychoudhury, Dr. S. Ghosh

Dept. of ENT and Head-Neck Surgery, V.I.M.S., RKMSP

Case report:

32 years old male patient with hoarseness,diagnosed to have tubercular laryngitis and treatedwith antitubercular drugs.

Pre Therapy Photographs

Fig 1: Abducted vocal folds before therapy

Post Therapy Photographs (after 6 months)

Fig 2: Adducted vocal folds before therapy

Fig 3: Pre-therapy X-Ray Chest showingpatchy opacities involving Left upper lobe

Fig 4: Normal adducted vocal folds

Fig 5: Normal abducted vocal folds

Fig 6 : X-Ray Chest showing normal lungfields with residual fibrosis

Fig. 7: A happy patient after therapy

55

Institute News

The 27th Annual Scientific Conference of theinstitute has been organized successfully by Dr.Himadri Sengupta, Executive President on 26th,27th & 28th July, 2013. The conference waspreceded by a pre-conference workshop on 25thJuly, 2013.

This year our nursing and paramedical stafforganized a joint scientific conference on 26thJuly, 2013. The whole day seminar was dividedin different important sessions. Participants fromvarious institute attended that whole day seminar.

The three day annual scientific conference startedfrom 26th July. The programme includedinteresting sessions like panel discussion, debate,award paper session, mediquiz etc. AnnualScientific Oration was delivered by Prof. AmbarChakraborty, Dayananda Oration was given byProf. P. B. Dutta and Gahananda oration waspresented by Prof. Adarsh Chaudhuri, New Delhi.

1. A Video discussion on Cataract Surgery wasorganized by the Dept. of Opthalmology on26.08.2013.

2. A CME on the Management of InfertileCouple was organized by South KolkataMedical Association (Branch of IMA) incollaboration with this Institute on 05.11.2013.

3. A two days’ Workshop on Live Phonosurgery

& Hands on Cadaver dissection organizedby the Department of E.N.T. and Head &Neck surgery was held on 21 & 22 November,2013, where a good number of participantsfrom this institute and outside attended.

Achievements:

Prof. Arabinda Mukherjee of Neurologydepartment has been elected as “President Elect”of Indian Academy of Neurology, Prof. samarBanerjee of the Department of Medicine hasbeen elected as President of Research Societyfor study on diabetes in India (RSSDI) and Prof.Ashoke Ganguly department of Dermatologyhas been awarded FRCP. Prof. Dilip Kr.Mazumdar, Dept. of Medicine has recently beenappointed as overseas Regional Advisor for EastRegion of India in addition to his commitmentsfor West Bengal by the Council of Royal Collegeof Physicians of Edinburgh.

Dr. Sudip Chatterjee published 4 articles inimportant journals this year & contributedchapters in 2 text books. He also deliveredlectures at RIMS Imphal, Endocrine Societyconference at Sanfransico, ENICON at Bhopal& presented paper in Medicon International,Kolkata. He was one of the faculty at Ideacon2013 conference.

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We express deep sorrow at the passing away of —

t DR. SANTOSH KUMAR DUTTA, Senior Specialist

in Radiodiagnosis on 27th April, 2013.

t DR. SHIBANI KAR, Consultant in Obs & Gynae on

30th June, 2013.

t DR. SUNIL KRISHNA GHOSH, Hony. Consultant

in Opthalmology on 11th November, 2013.

We remember with respectful gratitude the dedicated

and selfless services rendered by them during their long

association with this Institute.

We whole heartedly pray to the Allmighty for the

eternal peace of the departed soul.

Editorial Board

Journal of the Vivekananda Institute of Medical Sciences