High-dose Intravenous Dexamethasone in The

HIGH-DOSE DEXAMETHASONE IN ENTERIC ENCEPHALOPATHY

Vol 40 No. 5 September 2009 1065

Correspondence: Dr Mohammod Jobayer Chisti,Clinical Sciences Division, International Centrefor Diarrhoeal Disease Research, Bangladesh(ICDDR,B), 68 Shaheed Tajuddin Ahmed Sarani,Mohakhali, Dhaka 1212, Bangladesh.Tel: + (880-2) 8860523-32 Ext 2334; Fax: + (880-2)8823116 and 9885657E-mail: [email protected]

HIGH-DOSE INTRAVENOUS DEXAMETHASONE IN THEMANAGEMENT OF DIARRHEAL PATIENTS WITH

ENTERIC FEVER AND ENCEPHALOPATHY

Mohammod Jobayer Chisti, Pradip Kumar Bardhan, Sayeeda Huq, Wasif Ali Khan,Ali Miraj Khan, Sharifuzzaman and Mohammed Abdus Salam

Clinical Sciences Division, International Centre for Diarrhoeal Disease Research,Dhaka, Bangladesh

Abstract. We conducted a retrospective chart analysis of diarrheal patients with en-teric fever and encephalopathy (among survivors and non-survivors) to examine therole of high-dose, intravenous dexamethasone as an adjunct to appropriate antimicro-bial therapy in their management. We studied all patients admitted to the Special CareWard (SCW) of Dhaka Hospital between October 2006 and October 2007 with a diag-nosis of encephalopathy in association with enteric fever. Twenty-three cases wereidentified with three mortalities. All bacterial isolates (Salmonella Typhi and SalmonellaParatyphi) were multi-drug resistant. Survivors were significantly more likely to havereceived high dose dexamethasone (100% vs 00%; p < 0.001) and had hypoglycemialess often (6% vs 67%; p = 0.045) compared to those who died. The results suggest highdose intravenous dexamethasone, as an adjunct to appropriate antimicrobial therapy,substantially reduces mortality among diarrheal patients presenting with enteric en-cephalopathy.

INTRODUCTION

Enteric fever is endemic in many devel-oping countries (Choo et al, 1988), and en-cephalopathy (enteric encephalopathy) is acommon feature of severe enteric fever,manifested as altered consciousness, such asdisorientation, confusion, delirium (Nag etal, 1975; Punjabi et al, 1988; Ozen et al, 1993;Mandal, 1996; Dutta et al, 2001). The reportedincidences of enteric encephalopathy varybetween 10% and 30% (Baker, 1981). In the

absence of prompt, appropriate treatmentthe case fatality from enteric encephalopa-thy is high, with cases fatality rates reportedas high as 56% (Hoffman et al, 1984; Dutta etal, 2001). The classic clinical pattern of en-teric fever has changed over time, and theemergence of multi-drug resistance (MDR)enteric fever, associated with higher case-fatality, has complicated the management ofsevere illness (Koul et al, 1991; Sharma andGathwala, 1993; Keusch, 1998; Dutta et al,2001). Steroids have been used alone in themanagement of enteric fever (Smadel et al,1951; Koul et al, 1991) without convincingtherapeutic benefits (Eskes, 1965). However,the use of conventional low dose corticos-teroid therapy in enteric encephalopathyalong with effective antimicrobial therapyhas been reported to produce clinical ben-efits (Zellweger and Idriss, 1960; Midha and

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Singh, 1975); high dose intravenous dexam-ethasone has been reported to substantiallyreduce case mortality as well as morbidityin enteric encephalopathy (Hoffman et al,1984; Punjabi et al, 1988). In our clinicalseting, it is not unusual to encounter patientswith enteric encephalopathy. Based on thefindings of an earlier study (Hoffman et al,1984) our hospital has adopted the use ofintravenous dexamethasone in the treatmentof enteric encephalopathy. However, thereis lack of data regarding the role of highdose dexamethasone in the management ofdiarrheal patients with enteric encephal-opathy, which prompted us to conduct thisanalysis. We did not consider a random-ized, double blind study due to the resultsof the earlier study and because it is a stan-dard practice in our hospital. We conducteda retrospective chart analysis to assess di-arrheal patients with enteric encephalopa-thy treated with high dose dexamethasoneand appropriate antibiotic therapy.

MATERIALS AND METHODS

Patient enrollment

The study participants were patientsadmitted to the Special Care Ward (SCW) ofDhaka Hospital, ICDDR, B; Dhaka,Bangladesh between October 2006 and Oc-tober 2007. Most critically ill patients attend-ing the hospital, over 1,200 per year, aretreated on this ward. The hospital providestreatment for 110,000 diarrheal patients withor without associated complications andwith or without other health problems peryear. The majority of patients came from apoor socio-economic background from ur-ban and suburban Dhaka, the capital city ofBangladesh. A clinical diagnosis of entericencephalopathy was made based on isola-tion of Salmonella Typhi or SalmonellaParatyphi from blood or fecal cultures, andor a positive Widal test and using the

Glasgow Coma Scale (GCS).

Study design

This was a retrospective analysis of datafrom patient records. We identified 23 pa-tients meeting the criteria as a case: diarrhealpatient with enteric fever and features ofencephalopathy. Twenty patients recoveredand three died. We defined enteric fever asa patient with culture proven enteric fever,as defined by isolation of S. Typhi or S.Paratyphi from a blood or fecal culture and/or a positive Widal test. A Widal test wasdeemed positive when the antibody titeragainst somatic antigen (O) was 1:160 orwhen there was a rising titer. A diagnosis ofencephalopathy was made when a patientwith enteric fever had a GCS score 14. Dex-amethasone was administered at a dose of 3mg/kg initially followed by 1 mg/kg every 6hours for the next 48 hours (Hoffman et al,1984; Punjabi et al, 1988). Dehydration wasassessed following modified WHO guide-lines, and when present, was corrected us-ing either oral rehydration salts (ORS) solu-tion or intravenous rehydration fluids asappropriate (Alam and Ashraf, 2003). Weanalyzed the clinical and laboratory charac-teristics of these patients and assessed therole of dexamethasone and other featuresamong survivors and fatalities.

Statistical methods

We developed and pre-tested case re-port forms (CRF) before finalizing them fordata acquisition. All data were entered intoa personal computer (PC) and edited beforeanalysis using SPSS for Windows (version10.2; SPSS, Chicago) and Epi Info (version6.0, USD, Stone Mountain, GA). Differencesin proportions were compared by the 2 testand differences in means were compared byStudents t-test or Mann-Whitney test, asappropriate. A probability of 0.05 was con-sidered statistically significant. Strength ofassociation was determined by calculating



relative risk (RR) and their 95% confidenceintervals (CI). Age, sex, type and durationof diarrhea, dehydration on admission, ex-tent and duration of fever (38C), radialpulse, coated tongue, palpable liver, severesepsis [presence of any two of the follow-ings: tachypnea, tachycardia, temperatureinstability (hypo- or hyperthermia measuredby rectal temperature), abnormal WBC count(>11,000/mm3 ,



Characteristic N =23 (%)

Female 13 (57)Age (months) (Mean SD) 17.5 5.3Poor socio-economic status (monthly income



Characteristic Survivors N (20) (%) Fatalities N (3) (%) RR (95% CI) p-value

Female 10 (50) 3 (100) Unidentified 0.23Age (mean SD) 16.8 5.2 21.7 4.9 Not applicable 0.223GCS score (Mean SD) 12 2 12 2 Not applicable -Type of diarrhea

Acute watery diarrhea 19 (95) 3 (100) - -Invasive diarrhea

Duration of diarrhea (median, range) 48 (3, 240) 24 (24, 24) - -Dehydrating diarrhea (some/severe) 6 (30) 1 (33) 1.11 (0.2-6.3) 1.0Temperature (C) 39.5 1.1 38.5 1.4 Not applicable 0.176Duration of fever (median, range) 7 (3, 20) 7 (6,12) Not applicable 0.830Radial pulse (beats/minute) (Mean SD) 120 13 130 78 Not applicable 0.599Colitis 2 (10) 0 (0) - -Lobar pneumonia 2 (10) 1 (33) 3.3 (0.4-26.5) 0.356Severe sepsis 2 (10) 1 (33) 3.3 (0.42-26.45) 0.356Hypoglycemia (RBS



results were available. The blood cultures oftwo of the fatalities grew S. Paratyphi. Thethird patient had a Widal test suggestive ofenteric fever but a rectal swab culture wasnot performed on this patient.

The mechanism of action of dexametha-sone in enteric encephalopathy is not known.Endotoxins released by S. Typhi and S.Paratyphi stimulate macrophages to pro-duce monokines, arachidonic acid and itsmetabolites, and free oxygen species that areprobably responsible for the toxic effects,particularly in those with enteric encephalo-pathy (Nag et al, 1975; Johnston et al, 1978;Clark et al, 1981). It is possible dexametha-sone either reduces these levels or counter-acts the physiological effects of these pro-ducts or both, and acts as an antioxidant re-sulting in reduced fatalities (Hoffman et al,1984). Cerebellar edema and venous conges-tion of brain cells are often evident in en-teric encephalopathy (Chand and Singh,1988) and high dose dexamethasone mayplay a role in substantially reducing these(Girgis et al, 1993), although this theory hasbeen challenged by another publication(Trevett, 1994). The similar GCS scores (12)among the survivors and the fatalities sug-gests both groups of patients had similarinvolvement of the CNS. Our findings aresimilar to those observed among non-diar-rheal patients with enteric encephalopathy(Hoffman et al, 1984; Punjabi et al, 1988).

Hypoglycemia was common among ourfatalities and is not uncommon in entericfever (Singh and Singh, 2001). We did notfind any published data regarding hypogly-cemia in patients with enteric encephalopa-thy. All three fatalities in our study were fe-males. We do not have a ready explanationfor this observation. This may reflect differ-ences in care seeking behavior among fe-males in our society where they often con-ceal their illness from family members andare less likely to attend health care facilities

until seriously ill. This is supported by thefact they all died before their laboratory testresults were available. The total male to fe-male ratio in our study was 1.3:1, which sup-ports our theory stated above. There was aslight female predominance (57%) in thestudy population, a higher incidence (Chooet al, 1988) of enteric encephalopathy and ahigher case fatality rate (Butler et al, 1991).

All clinical isolates (S. Typhi and S.Paratyphi) were resistant to chloramphenicol,ampicillin and trimethoprim-sulphametho-xazole, were intermediately susceptible tociprofloxacin, and full susceptibility toceftriaxone and cefexime as determined bydisc diffusion method. All the patients weremulti-drug resistant (MDR) cases of entericfever and were treated with parenteralceftriaxone, except for the patient who re-ceived parenteral ciprofloxacin and had a fa-tal outcome, but no significant associationbetween antimicrobial type and morbiditywas observed. An association between entericfever caused by MDR strains and encephal-opathy has been reported (Koul et al, 1991;Kabra et al, 2000; Mahmud et al, 2008).

We observed a coated tongue in two-thirds of our patients and hepatomegaly in13% of them. A coated tongue is thought bysome to be a classical feature of typhoid fe-ver and hepatomegaly has been reportedmore common in patients with MDR ty-phoid fever (Girgis et al, 1993; Dutta et al,2001). We did not observe relative bradycar-dia, leukopenia or lymphocytosis in eithergroup of patients. These findings may rep-resent changing clinical patterns of entericfever (Hoffman et al, 1984; Choo et al, 1988;Koul et al, 1991; Sharma and Gathwala, 1993;Keusch, 1998; Dutta et al, 2001). Two of ourpatients, both among the survivors, devel-oped toxic colitis, a serious complication ofenteric fever (Girgis et al, 1993) and recov-ered without surgical intervention. Thirteenpercent of our patients had radiological lo-



bar consolidation similar to an earlier report(Dutta et al, 2001).

Similar to earlier reports (Bobin et al,1993), we found no influence of age on casefatality. All of our patients were adolescentssimilar to a previous report (Ugwu et al,2005). We observed no differences in peakbody temperature or duration of fever be-tween groups. The consistent finding of per-sistent high fever may represent a conse-quence of the products of macrophagestimulation by the released of endotoxinfrom the pathogens (S. Typhi and S.Paratyphi) (Nag et al, 1975; Johnston et al,1978; Clark et al, 1981). The presence of per-sistent high fever in patients with entericencephalopathy has been reported earlier(Girgis et al, 1993, Jain et al, 1986). Develop-ment of encephalopathy during the firstweek of enteric fever is considered to carrya grave prognosis (Dutta et al, 2001). Noneof our patients receiving high dose dexam-ethasone died, suggesting the beneficial roleof dexamethasone in preventing deaths.

We found no association between intra-venous fluid administration and case fatal-ity, suggesting the judicious use of intrave-nous fluid for a specific indication (dehydra-tion or sepsis) does not cause problems, suchas over hydration or pulmonary edema. Allour patients had diarrhea, 30% had dehy-drating diarrhea with vomiting, and 11%had severe colitis as an indication for admin-istration of intravenous fluid.

We did not observe any differences inserum sodium or potassium levels betweenthe groups, but the general finding of hy-ponatremia and hypokalemia in the studypopulation may be due to the fact that nearlyall (96%) had diarrhea and half (50%) hadvomiting. A tendency to have reduced se-rum electrolytes with enteric encephalopa-thy, consequent to disturbances in centralosmoregulation, has been suggested(Zellweger and Idriss, 1960). Our observa-

tions are similar to a number of previousstudies (Marmion, 1952; Watson, 1954;Zellweger and Idriss, 1960).

We found no differences in the durationof diarrhea, dehydration, severe sepsis, andserum creatinine levels between the survi-vors and the fatalities, indicating similarclinical severity between the groups, simi-lar to previous studied (Hoffman et al, 1984,Punjabi et al, 1988).

We observed a serious residual compli-cation in one patient who developed apha-sia that persisted until discharge; we are notsure about the long-term outcome of thiscomplication in the absence of a follow-upassessment. We did not perform an EEG orCT scan of the brain to document thechanges associated with encephalopathy inour patient as has been reported previously(Midha and Singh, 1975; Bansal et al, 1995;Adehossi et al, 2003).

There were other limitations of ourstudy in addition to small sample size. Wehad no routine follow-up of the patients af-ter discharge from the hospital, althoughthey were advised to report back in the eventof encountering a problem. None of the pa-tients returned for follow-up. We did notperform CSF studies in any of our patientsexcept for those presenting with other fea-tures of meningitis (neck rigidity, positiveKernings sign, positive Brudzneskis sign,positive Babinski sign, unconscious) since inthe presence of features of encephalopathy indiagnosed cases of enteric fever we assumedthem to be due to enteric encephalopathy.CSF studies performed in four patients werenormal (clear CSF fluid with normal pres-sure, normal biochemistry results, a leuko-cyte count less than 5/mm3 on a centrifugedsample and no organisms seen on Gramstain or culture). At health facilities withavailable resources to perform CSF studies,they should be performed irrespective of thepresence or absence of meningeal signs.



In conclusion, mild hyponatremia andhypokalemia are frequent findings in diar-rheal patients presenting with enteric en-cephalopathy. Diarrheal patients with MDRenteric fever associated with abnormal men-tal status have better survival when dexa-methasone is administered in high doses inaddition to an effective antimicrobialtherapy. We observed a fatal outcome in allthree cases who did not receive high-dosedexamethasone therapy. We also observedhypoglycemia as a common finding withenteric encephalopathy and its presence hasbeen associated with a higher case fatalityrate. Although our study was not a random-ized, controlled clinical trial, it seems rea-sonable to believe that high dose dexametha-sone therapy as adjunct to appropriate anti-microbial therapy is life-saving for diarrhealpatients with enteric encephalopathy, as hasbeen reported in patients without diarrhealillness. Our data highlights the importanceof excluding hypoglycemia and electrolyteabnormalities and their early detection andaggressive management as a potentially life-saving therapeutic modality.

ACKNOWLEDGEMENTS

This study was supported by theICDDR,B. Current donors providing unre-stricted support include: the AustralianAgency for International Development(AusAID), the Government of the PeoplesRepublic of Bangladesh, the Canadian Inter-national Development Agency (CIDA), theEmbassy of the Kingdom of the NetherlandsDevelopment (EKN), the Swedish Interna-tional Development Cooperation Agency(Sida), the Swiss Agency for the Develop-ment and Cooperation (SDC), and the De-partment for International Development,UK (DFID). The sponsors of the study col-laborated on study design, data collection,and data analysis. We gratefully acknowl-

edge these donors for their support and com-mitment to the Centres research efforts. Wewould like to express our sincere thanks toDr Raihana, the clinical fellows, nurses andother staff of the Special Care Ward. Noneof the staff had any competing interests.

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High-dose Intravenous Dexamethasone in The