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Research JAMA | OriginalInvestigation | CARINGFORTHECRITICALLYILLPATIENT EffectofanEarlyResuscitationProtocolonIn-hospital MortalityAmongAdultsWithSepsisandHypotension ARandomizedClinicalTrial BenAndrews,MD;MatthewW.Semler,MD,MSc;LevyMuchemwa,MBChB;PaulKelly,MD,FRCP;ShabirLakhi,MBChB; DouglasC.Heimburger,MD,MS;ChilesheMabula,MBChB;MwangoBwalya,MBChB;GordonR.Bernard,MD Editorialpage1225 IMPORTANCE Theeffectofanearlyresuscitationprotocolonsepsisoutcomesindeveloping Supplementalcontent countriesremainsunknown. CMEQuizat jamanetwork.com/learning OBJECTIVE Todeterminewhetheranearlyresuscitationprotocolwithadministrationof intravenousfluids,vasopressors,andbloodtransfusiondecreasesmortalityamongZambian andCMEQuestionspage1278 adultswithsepsisandhypotensioncomparedwithusualcare. DESIGN, SETTING, AND PARTICIPANTS Randomizedclinicaltrialof212adultswithsepsis (suspectedinfectionplusⱖ2systemicinflammatoryresponsesyndromecriteria)and hypotension(systolicbloodpressureⱕ90mmHgormeanarterialpressureⱕ65mmHg) presentingtotheemergencydepartmentata1500-bedreferralhospitalinZambiabetween October22,2012,andNovember11,2013.DatacollectionconcludedDecember9,2013. INTERVENTIONS Patientswererandomized1:1toeither(1)anearlyresuscitationprotocolfor sepsis(n = 107)thatincludedintravenousfluidbolusadministrationwithmonitoringof jugularvenouspressure,respiratoryrate,andarterialoxygensaturationandtreatmentwith vasopressorstargetingmeanarterialpressure(ⱖ65mmHg)andbloodtransfusion (forpatientswithahemoglobinlevel<7g/dL)or(2)usualcare(n = 105)inwhichtreating cliniciansdeterminedhemodynamicmanagement. MAINOUTCOMESANDMEASURES Theprimaryoutcomewasin-hospitalmortalityandthesecondary outcomesincludedthevolumeofintravenousfluidreceivedandreceiptofvasopressors. RESULTS Among212patientsrandomizedtoreceiveeitherthesepsisprotocolorusualcare, 3wereineligibleandtheremaining209completedthestudyandwereincludedinthe analysis(mean[SD]age,36.7[12.4]years;117men[56.0%];187[89.5%]positiveforthe humanimmunodeficiencyvirus).Theprimaryoutcomeofin-hospitalmortalityoccurredin51 of106patients(48.1%)inthesepsisprotocolgroupcomparedwith34of103patients AuthorAffiliations:Institutefor GlobalHealth,VanderbiltUniversity (33.0%)intheusualcaregroup(between-groupdifference,15.1%[95%CI,2.0%-28.3%]; MedicalCenter,Nashville,Tennessee relativerisk,1.46[95%CI,1.04-2.05];P = .03).Inthe6hoursafterpresentationtothe (Andrews,Heimburger);Department ofInternalMedicine,Schoolof emergencydepartment,patientsinthesepsisprotocolgroupreceivedamedianof3.5L Medicine,UniversityofZambia, (interquartilerange,2.7-4.0L)ofintravenousfluidcomparedwith2.0L(interquartilerange, 1.0-2.5L)intheusualcaregroup(meandifference,1.2L[95%CI,1.0-1.5L];P < .001).Fifteen Lusaka(Andrews,Muchemwa,Kelly, Lakhi);DivisionofAllergy,Pulmonary, patients(14.2%)inthesepsisprotocolgroupand2patients(1.9%)intheusualcaregroup andCriticalCareMedicine,Schoolof receivedvasopressors(between-groupdifference,12.3%[95%CI,5.1%-19.4%];P < .001). Medicine,VanderbiltUniversity, Nashville,Tennessee(Semler, Bernard);BartsandtheLondon CONCLUSIONS AND RELEVANCE Amongadultswithsepsisandhypotension,mostofwhom SchoolofMedicine,QueenMary werepositiveforHIV,inaresource-limitedsetting,aprotocolforearlyresuscitationwith UniversityofLondon,London, England(Kelly);ZambiaMinistryof administrationofintravenousfluidsandvasopressorsincreasedin-hospitalmortality Health,Lusaka(Mabula,Bwalya). comparedwithusualcare.Furtherstudiesareneededtounderstandtheeffectsof CorrespondingAuthor:GordonR. administrationofintravenousfluidbolusesandvasopressorsinpatientswithsepsisacross Bernard,MD,SchoolofMedicine, differentlow-andmiddle-incomeclinicalsettingsandpatientpopulations. VanderbiltUniversity,116121stAveS, Nashville,TN37232(gordon.bernard @vanderbilt.edu). TRIAL REGISTRATION clinicaltrials.govIdentifier:NCT01663701 SectionEditor:DerekC.Angus,MD, JAMA.2017;318(13):1233-1240.doi:10.1001/jama.2017.10913 MPH,AssociateEditor,JAMA PublishedonlineSeptember27,2017. (angusdc@upmc.edu). (Reprinted) 1233 © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 Research OriginalInvestigation EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia epsis mortality in the developed world steadily de- clined between 2000 and 2012. 1Part of this improve- KeyPoints S ment has been attributed to the implementation Question Doesaresuscitationprotocolwithadministration of sepsis protocols emphasizing early resuscitation with in- ofintravenousfluids,vasopressors,andbloodtransfusion travenousfluidbolusesandvasopressorstoachievehemody- implementedearlyafterpresentationtotheemergency namic targets. 2,3 departmentimprovein-hospitalmortalityamongZambianadults withsepsisandhypotensioncomparedwithusualcare? In contrast, mortality from sepsis in low- and middle- income countries remains high and current usual care fre- Findings Inthisrandomizedclinicaltrialthatincluded209adults quently does not include early resuscitation with intrave- withsepsisandhypotensionpresentingtoanemergency nous fluid boluses or vasopressors. 4,5Whether an early departmentinZambia,a6-hoursepsisprotocolemphasizing resuscitation protocol could improve sepsis outcomes in administrationofintravenousfluids,vasopressors,andblood transfusionsignificantlyincreasedin-hospitalmortalitycompared resource-limited settings remains uncertain. Three studies 4-6compared early resuscitation with usual withusualcare(48.1%vs33.0%,respectively). careamongAfricanpatientswithsevereinfectionandyielded Meaning Inresource-limitedsettings,anearlyresuscitation conflicting results. A before-after study in Uganda suggested protocolwithadministrationofintravenousfluids,vasopressors, andbloodtransfusionforadultswithsepsismayincreasemortality decreased mortality with a multicomponent intervention in- comparedwithusualcare. cluding intravenous fluid boluses among adults with sepsis. 5 Arandomizedclinicaltrial(RCT)inZambiaobservednomor- talitybenefitwithaprotocolofearlyintravenousfluidandva- severetachypnea(definedasarterialoxygensaturation<90% sopressor administration among adults with sepsis; how- and respiratory rate >40 breaths per minute). Additional ex- ever, the trial was stopped early for possible harm in the clusion criteria included gastrointestinal bleeding in the ab- subgroupofpatientswithhypoxemiaandtachypnea. 4AnRCT sence of fever, congestive heart failure exacerbation, end- conductedamongchildrenwithseverefebrileillnessinKenya, stage renal disease, elevated jugular venous pressure (JVP), Uganda,andTanzaniademonstratedincreasedmortalitywith incarceration, or the need for immediate surgery. Enroll- 6 intravenous fluid bolus administration. ment occurred within 4 hours of the first eligible blood pres- However, each of these studies 4-6had important limita- sure measurement and within 24 hours of ED registration. 4,6 tions. In particular, both RCTs included patients with non- Study group assignment was generated using computer- specificmarkersoftissuehypoperfusionratherthanonlypa- ized randomization in permuted block sizes of 2, 4, and 6. tientswithsepsisandoverthypotension,forwhomthebenefit Allocationslipswereplacedinsealedopaqueenvelopes,which of early intravenous fluid bolus and vasopressor administra- were opened after informed consent was obtained. Patients, tion may be greatest. treatingclinicians,andclinicalstudypersonnelwereawareof The primary objective of this RCT was to determine group assignment after enrollment. Study personnel respon- whether a sepsis protocol with early administration of intra- sibleforoutcomesassessmentanddataanalysiswereblinded venous fluid boluses, vasopressors, and blood transfusion to group assignment. woulddecreasein-hospitalmortalitycomparedwithusualcare For patients in both groups, treating clinicians deter- among African adults with sepsis and hypotension. minedthelocationofcare(intensivecareunitormedicalward) andantibioticselection(includinguseofempiricalantituber- culousandantimalarialtherapy).Inaddition,adedicatedstudy nurse measured heart rate, systolic and diastolic blood pres- Methods sure, respiratory rate, and oxygen saturation hourly for the 6 The Simplified Severe Sepsis Protocol 2 trial was a parallel- hours after enrollment and supervised the administration of group, nonblinded RCT conducted at a 1500-bed national re- all ordered fluids and medications. 4 ferraluniversityhospitalinZambia. TheUniversityofZambia biomedicalresearchethicscommitteeandtheVanderbiltUni- SepsisProtocolGroup versityinstitutionalreviewboardgrantedethicalapprovaland Patientsrandomizedtothesepsisprotocolreceivedhemody- thetrialwasoverseenbyanindependentdataandsafetymoni- namic management for the first 6 hours after enrollment. An toringboard.Writteninformedconsentwasobtainedfrompa- initial 2-L bolus of intravenous isotonic crystalloid was ad- tientsortheirlegallyauthorizedrepresentativespriortostudy ministered within 1 hour of enrollment, followed by an addi- enrollment. The trial protocol appears in Supplement 1. tional 2 L over the subsequent 4 hours. After each liter of in- From October 22, 2012, through November 11, 2013, we travenous fluid was administered, an investigator or study screened all patients presenting to the emergency depart- nursemeasuredarterialoxygensaturation,respiratoryrate,and ment (ED) between 8 AM on Monday and 12 PM on Friday. JVP (details appear in the eMethods in Supplement 2). If the Patientsaged18yearsorolderwereeligibleiftheyhad(1)sep- arterialoxygensaturationdecreasedby3%,therespiratoryrate sis (defined as suspected infection plus ≥2 systemic inflam- increased by 5 breaths per minute, or JVP reached 3 cm or matory response syndrome criteria 7) and (2) hypotension greater above the sternal angle, fluid infusion was discontin- (defined as systolic blood pressure ≤90 mm Hg or mean arte- ued. The sepsis protocol limited intravenous fluid adminis- rial pressure ≤65 mm Hg). Based on the results of a prior trial trationtoatotalof4L,includinganyfluidgivenintheEDprior inthesamesetting, 4weexcludedpatientswithhypoxemiaand to enrollment. 1234 JAMA October3,2017 Volume318,Number13 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia OriginalInvestigation Research Ifmeanarterialpressureremainedlessthan65mmHgaf- All analyses were conducted in a modified intention-to- ter completion of the initial 2-L fluid bolus, a dopamine infu- treat fashion, analyzing patients by the group to which they sion (vasopressor) was initiated via a peripheral intravenous wereassignedandexcludingthosewhowererecognizedasin- line starting at 10 μg/kg/min and titrated to reach a mean ar- eligible immediately after enrollment and who did not re- terialpressureof65mmHgorgreater.Thesepsisprotocolrec- ceivestudyinterventions(Figure1).Continuousvariableswere ommendedbloodtransfusionforpatientswithahemoglobin reported as mean and standard deviation or median and in- level of less than 7 g/dL or with severe pallor. terquartile range (IQR) and categorical variables as frequen- cies and proportions. Between-group differences were ana- lyzedusingthettestforparametriccontinuousvariables,the UsualCareGroup For patients randomized to usual care, treating clinicians de- Mann-Whitney test for nonparametric continuous variables, termined intravenous fluid administration, vasopressor use, the χ2test for categorical variables, and the log-rank test for andbloodtransfusion.Duringusualcareforsepsisinthestudy survival analysis. setting, the volume of intravenous fluid administered in the The primary analysis compared in-hospital mortality be- first 6 hours averages less than 2 L, less than half of patientstweenthesepsisprotocolgroupandtheusualcaregroupusing receive any intravenous fluid bolus, less than 2% of patients theχ 2test.Insecondaryanalyses,wecomparedthesepsispro- receive a vasopressor, and less than 20% of patients receive a tocolgroupwiththeusualcaregroupafteradjustingforbase- bloodtransfusion 4(additionaldetailsappearintheeMethods lineSimplifiedAcutePhysiologyScore3(SAPS-3) 10andinpre- in Supplement 2). specified subgroups defined by the presence of human immunodeficiencyvirusinfection,GlasgowComaScalescore DataCollection at presentation, baseline hemoglobin level, baseline lactate Because most patients were not ambulatory, we measured level, baseline SAPS-3, and baseline JVP. Subgroup analyses upper arm circumference in lieu of weight to assess nutri- used the Mantel-Haenszel test for heterogeneity to assess for 8,9 tional status. Study personnel recorded the volume of subgroup × study group interaction effects on the risk of in- intravenous fluid administered between ED registration and hospital mortality. Analyses were performed using Stata ver- 6 hours after enrollment, 6 to 24 hours after enrollment, and sion 12.1 (StataCorp). 24 to 72 hours after enrollment. Patients were followed up until death or 28 days after enrollment. For patients dis- charged from the hospital, blinded study personnel called the patient or next-of-kin to ascertain vital status at 28 days.Results Additional details regarding data collection appear in the Of 382 patients with sepsis and hypotension, 212 met eligibil- eMethods in Supplement 2. ity criteria, provided consent to participate, and were ran- domized. Immediately after randomization, it was recog- Outcomes nized that 3 patients should have been excluded (age <18 Theprimaryoutcomewasin-hospitalmortality.Secondaryef- years, absence of hypotension, and presence of congestive ficacyoutcomesincluded28-daymortalityandtimetodeath. heart failure), leaving 209 patients who received the study Secondary safety outcomes included the incidence of wors- interventions, completed follow-up, and were included in ening hypoxemia or tachypnea (decrease in arterial oxygen the primary analysis (Figure 1). Data collection concluded saturationof≥3%oranincreaseinrespiratoryrateof≥5breaths December 9, 2013. per minute). Process measures included volume of intrave- Patientsassignedtothesepsisprotocol(n = 106)andusual nous fluid administered within 6, 24, and 72 hours; reasons care (n = 103) were similar at baseline (Table 1). Overall, pa- for intravenous fluid discontinuation; and receipt of anti- tientswereyoung(meanage,36.7years[SD,12.4years])with biotics, dopamine, and a blood transfusion. Prospectively high human immunodeficiency virus prevalence (89.5%) collectedadverseeventsincludeddopamineextravasation,tis- and low CD4 lymphocyte counts (median, 66/μL [IQR, sueischemiaornecrosis,iatrogenicpulmonaryedema,andre- 21-143/μL] among patients with human immunodeficiency action to blood transfusion. virus). Median albumin level was 2.2 g/dL (IQR, 1.8-2.7 g/dL) and most patients were malnourished, with a median upper StatisticalAnalysis armcircumferenceof20.1cm(IQR,18.4-22.9cm).Mediansys- Basedonanin-hospitalmortalityrateof65%inapriortrialin tolic blood pressure was 83 mm Hg (IQR, 76-87 mm Hg) with the same setting, 4we calculated that enrolling 212 patients a median lactate level of 4.3 mmol/L (IQR, 2.8-7.7 mmol/L). would provide statistical power of 80% at an α level of .05 to detectanabsoluteriskreductioninmortalityof20%(equiva- DiagnosisandTreatmentofInfection lent to a relative risk [RR] reduction of 30.8% and similar to The most common admitting diagnoses were pneumonia theRRreductionreportedinapriortrial 2).Oneinterimanaly- (49.3%) and suspected tuberculosis (62.7%), with 80 pa- sis was planned, performed, and reviewed by the data and tients (38.3%) having both. Forty-three patients (20.6%) had safety monitoring board after enrollment of 50% of the pa- positive tuberculosis blood cultures. Details of admitting di- tientsusingaconservativeHaybittle-Petoboundary(P < .001) agnosesandmicrobiologicaldataappearineTables1and2in to allow performance of the final analysis using an un- Supplement2.ThemediantimebetweenEDregistrationand changed 2-sided level of significance (P = .05). thefirstdoseofintravenousantimicrobialtherapywassimilar jama.com (Reprinted) JAMA October3,2017 Volume318,Number13 1235 © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 Research OriginalInvestigation EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia Figure1.Screening,Randomization,andFollow-upofPatientsThroughtheTrial 3515 Patientsassessedforeligibility 3133 Excluded(didnotmeetinclusioncriteria) 1813 Didnothavesepsis 1204 Didnothavehypotension 116 Incompletescreening 382 Metinclusioncriteria 170 Excluded 127 Metexclusioncriteria 83 Hypoxemiaandseveretachypnea a 19 Congestiveheartfailure 8 Elevatedjugularvenouspressure 3 End-stagekidneydisease 3 Requiredemergencysurgery 3 Age<18y 3 Gastrointestinalbleeding 1 Incarcerated 4 Otherreasons 43 Eligiblebutnotenrolled 30 Refusedtoparticipate 13 Otherreasons 212 Randomized 107 Randomizedtoreceivesepsisprotocol 105 Randomizedtoreceiveusualcare 106 Receivedsepsisprotocol 103 Receivedusualcareas asrandomized randomized 1 Determinedafterrandomization 2 Determinedafterrandomization tomeetexclusioncriterion tomeetexclusioncriteria (congestiveheartfailure) 1 Age<18y 1 Didnothavehypotension 9 Losttofollow-upafterhospital 6 Losttofollow-upafterhospital discharge discharge 106 Includedinprimaryanalysis 103 Includedinprimaryanalysis a forin-hospitalmortality forin-hospitalmortality Definedasanoninvasively measuredarterialoxygen 97 Includedinanalysisof28-day 97 Includedinanalysisof28-day saturationoflessthan90%and mortality mortality arespiratoryrategreaterthan 40breathsperminute. in the sepsis protocol group and in the usual care group (2.0 orderwasfortheadministrationof3Lofintravenousfluidover vs 1.5 hours, respectively; P = .15). 24 hours (eTable 3 in Supplement 2). Blood pressure generally increased over the first 6 hours HemodynamicInterventions of treatment in both study groups (Table 2). A total of 15 pa- In the 6 hours after presentation to the emergency depart- tients (14.2%) received a dopamine infusion (vasopressor) in ment, patients in the sepsis protocol group received a median the6hoursafterenrollmentinthesepsisprotocolgroupcom- of3.5L(IQR,2.7-4.0L)ofintravenousfluidcomparedwith2.0L paredwith2patients(1.9%)intheusualcaregroup(between- (IQR, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L groupdifference,12.3%[95%CI,5.1%to19.4%];P < .001).The [95%CI,1.0-1.5L];P < .001).Atotalof41patients(38.7%)inthe decreaseinlacticacidconcentrationfrombaselineto6hours sepsisprotocolgroupreceived4Lorgreater of intravenousfluid wasgreaterinthesepsisprotocolgroup(median,−1.2mmol/L; betweenEDregistrationand6hoursafterenrollment.Among IQR,−3.4to0.3mmol/L)thanintheusualcaregroup(median, theremaining65patients(61.3%)inthesepsisprotocolgroup, −0.5 mmol/L; IQR, 2.2 to 1.1 mmol/L) (mean difference, intravenousfluidswerediscontinuedpriortoatotalvolumeof 1.45 mmol/L [95% CI, 0.4 to 2.5 mmol/L]; P = .02). 4 L due to an increase in respiratory rate or a decrease in arte- Duetolimitedintensivecareunitcapacity,208ofthe209 rial oxygen saturation (32 patients [30.2%]), JVP of 3 cm or patients(99.5%)werecaredforonregularmedicalwardswith- greater(9patients[8.5%]),bloodtransfusionthroughanintra- out the availability of mechanical ventilation. More patients venous line (5 patients [4.7%]), and other reasons (4 patients inthesepsisprotocolgroup(35.8%)thanintheusualcaregroup [3.8%]). In the usual care group, only 50 patients (48.3%) re- (22.3%)experiencedadecreaseinoxygensaturationof3%or ceivedanyintravenousfluidbolusandthemostcommonfluid greater or an increase in respiratory rate of 5 breaths or more 1236 JAMA October3,2017 Volume318,Number13 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia OriginalInvestigation Research Table1.BaselineCharacteristicsofthePatients Sepsis Protocol Usual Care (n = 106) (n = 103) Age, mean (SD), y 37.5 (12.9) 35.8 (11.9) Male sex, No. (%) 62 (58.5) 55 (53.4) Abbreviations:ED,emergency a Positive diagnosis for HIV, No. (%) 94 (88.7) 93 (90.3) department;IQR,interquartilerange; Time since HIV diagnosis, median (IQR), d 90 (30-1095) 75 (14-730) SAPS-3,SimplifiedAcutePhysiology Score3. CD4 lymphocyte count, median (IQR), /μL 72 (22-143) 65 (20-159) SIconversionfactors:Toconvert Receiving antiretroviral therapy, No. (%) 56 (52.8) 51 (49.5) creatininetoμmol/L,multiply Duration of antiretroviral therapy, median (IQR), d 105 (42-1460) 195 (30-730) by88.4;lactatetomg/dL,divide History of Mycobacterium tuberculosis infection, No. (%) 49 (46.2) 46 (44.7) by0.111. aOf187patients,162(86.6%)had Receiving treatment for M tuberculosis at presentation, No. (%) 26 (24.5) 24 (23.3) AIDSasdefinedbyaCD4 Physiological variables, median (IQR) lymphocytecountoflessthan Temperature, °C 36.9 (35.5-38.5) 37.7 (35.4-38.5) 200/μLortuberculosisinfection. b Heart rate, beats/min 115 (104-129) 115 (103-130) Objectiveassessmentofthelevelof consciousness(range,3[deep Systolic blood pressure, mm Hg 83 (77-87) 83 (75-87) unconsciousness]to15[normal Diastolic blood pressure, mm Hg 50 (42-54) 48 (42-53) levelofconsciousness]). Respiratory rate, breaths/min 30 (28-38) 32 (28-39) cMeasuredabovetheclaviclewith b thepatientpositionedat45°. Glasgow Coma Scale score <15, No. (%) 32 (30.2) 42 (40.8) Jugular venous pressure by proximity to the sternal angle, No. (%) dAmeasureof22.5cmorless correlateswithabodymassindex ≥4 cm below 34 (32.1) 42 (40.8) (calculatedasweightinkilograms 1-3 cm below 30 (28.3) 22 (21.4) dividedbyheightinmeters At the sternal angle 20 (18.9) 28 (27.2) squared)oflessthan18.5. 8,9 e ≥1 cm above 22 (20.8) 11 (10.7) Aseverityscoreandmortality d estimationtool(range,0-217;higher Upper arm circumference, median (IQR), cm 20.1 (18.0-22.8) 20.1 (18.9-23.0) valuesindicatehigherriskof in-hospitalmortality). Inability to ambulate, No. (%) 66 (62.3) 67 (65.0) Duration of inability to ambulate, median (IQR), d 16.5 (10-35) 10 (7-21) fCalculatedastimefromED registrationtosignedinformed SAPS-3 score, median (IQR)e 55 (50-65) 57 (50-66) consent.Becausethestudynurse Laboratory values beganscreeningforeligiblepatients Whole blood lactate, median (IQR), mmol/L 4.7 (2.8-8.7) 4.0 (2.6-7.0) inthewaitingroompriortoED registration,enrollmentinthestudy Serum creatinine, median (IQR), mg/dL 1.3 (1.0-2.4) 1.3 (0.9-2.7) occurredsimultaneouslywithED Hemoglobin, mean (SD), g/dL 7.8 (0.3) 7.8 (0.3) registrationforsomepatients, Serum albumin, median (IQR), g/dL 2.1 (1.7-2.6) 2.3 (1.9-2.8) producingavalueof0minutesfor thetimefromEDregistrationto Time from ED registration to enrollment, median (IQR), min 71 (5-205) 76 (0-240) studyenrollment. per minute (between-group difference, 13.5% [95% CI, 1.4%- tocol was consistent across prespecified patient subgroups 25.7%]; P = .03) (Table 2). (Figure3).Medianhospitallengthofstaywas5days(IQR,3-8 days)inthesepsisprotocolgroupvs7days(IQR,4-12days)in ClinicalOutcomes the usual care group (P = .01). Rates of adverse events were The primary outcome of in-hospital mortality occurred in 51 similar between groups (eTable 5 in Supplement 2). of 106 patients (48.1%) in the sepsis protocol group vs 34 of 103 patients (33.0%) in the usual care group (between-group difference,15.1%[95%CI,2.0%-28.3%];RR,1.46[95%CI,1.04- Discussion 2.05]; P = .03). Vital status after hospital discharge at day 28 was known for 97 patients in each study group; 28-day mor- This RCT among Zambian adults with sepsis and hypoten- talitywas67.0%withthesepsisprotocolvs45.3%withusual sion,mostofwhomhadbeendiagnosedwithHIV,foundthat care (between-group difference, 21.6% [95% CI, 8.0%- a protocol for early resuscitation with intravenous fluid bo- 35.3%]; RR, 1.48 [95% CI, 1.14-1.91]; P = .002). In the multi- luses and vasopressors increased mortality compared with variableanalysisadjustingforSAPS-3atenrollment,riskofin- usual care. The sepsis protocol resulted in greater intrave- hospital mortality (RR, 1.45 [95% CI, 1.04-2.02]; P = .03) and nousfluidadministration,vasopressoruse,andlactateclear- 28-day mortality (RR, 1.41 [95% CI, 1.08-1.84]; P = .01) was ance but caused more frequent worsening of hypoxemia and greaterinthesepsisprotocolgroupthanintheusualcaregroup. tachypnea and higher rates of in-hospital and 28-day mortal- In the time-to-event analysis, the probability of survival was ity. These findings may have important implications for lowerinthesepsisprotocolgroupthanintheusualcaregroup the clinical care of patients with sepsis in low- and middle- (P = .02) (Figure 2 and eTable 4 in Supplement 2). Increased incomecountriesandforfutureresearchinearlysepsisman- in-hospitalmortalityamongpatientsassignedtothesepsispro- agement across settings. jama.com (Reprinted) JAMA October3,2017 Volume318,Number13 1237 © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 Research OriginalInvestigation EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia Table2.ElementsofSepsisResuscitation Sepsis Protocol Usual Care (n = 106) (n = 103) P Value a Intravenous fluid administration, median (IQR), L 6 h 3.5 (2.7 to 4.0) 2.0 (1.0 to 2.5) <.001 24 h 4.0 (3.0 to 5.0) 3.0 (2.0 to 4.3) <.001 72 h 5.0 (3.5 to 6.5) 4.0 (3.0 to 6.0) .33 Dopamine (vasopressor) administration, No. (%) During first 6 h 15 (14.2) 2 (1.9) .001 During hospitalization 22 (20.8) 7 (6.8) .004 Abbreviations:IQR,interquartile Blood transfusion, No. (%) range;SpO ,2xygensaturationby During first 6 h 17 (16.0) 13 (12.6) .48 pulseoximeter. During hospitalization 37 (34.9) 31 (30.1) .46 SIconversionfactor:Toconvert lactatetomg/dL,divideby0.111. Time to antibiotics, median (IQR), h 2.0 (0.7 to 4.1) 1.5 (0.5 to 2.8) .15 a Physiological variables, median (IQR) Representsthecumulativevolume ofcrystalloidsolutionsadministered Systolic blood pressure 2 h after enrollment, mm Hg 89 (85 to 95) 88 (83 to 92) .09 betweenemergencydepartment Diastolic blood pressure 2 h after enrollment, mm Hg 55 (48 to 59) 54 (47 to 61) .99 registrationandthe3timepoints. Systolic blood pressure 6 h after enrollment, mm Hg 95 (90 to 104) 96 (90 to 105) .95 b Respiratorycompromisewas Diastolic blood pressure 6 h after enrollment, mm Hg 61 (55 to 67) 61 (55 to 65) .82 prospectivelydefinedasanincrease inrespiratoryrateofatleast5 Whole blood lactate, median (IQR), mmol/L 3.3 (2.1 to 5.4) 3.9 (2.1 to 6.6) .25 breathsperminutevsbaselineora decreaseinoxygensaturationof Change in lactic acid concentration from baseline to 6 h−1.2 (−3.4 to 0.3) −0.5 (−2.2 to 1.1) .02 after enrollment, mmol/L morethan3%frombaseline. Respiratory rate increased by ≥5 breaths/min or S2O 38 (35.8) 23 (22.3) .03 Classificationofrespiratory decreased by ≥3%, No. (%)b compromiseaseitherresolvingby6 Resolved by 6 h after enrollment 20 (18.9) 8 (7.8) .02 hoursafterenrollmentorpersisting beyond6hoursafterenrollment Persistent beyond 6 h after enrollment 18 (17.0) 15 (14.6) .63 wasperformedposthoc. Figure2.Kaplan-MeierPlotoftheProbabilityofSurvivalUntilDay28 administration of inotropes to achieve central venous oxy- gen saturation of 70% or greater. AfterEnrollment Threerecentmulticentertrials 12-14foundnodifferencebe- 1.0 tween EGDT and usual care, but may have achieved smaller between-group differences in fluid administration due to in- 0.8 a corporationofearlyfluidadministrationintousualsepsiscare v Usual care 3,11,15 S0.6 inresource-intensesettings. Incontrast,thecurrentstudy o is the third RCT to suggest that early resuscitation for African t Sepsis protocol i0.4 patientswithinfectionandhypoperfusionmayincreasemor- a 4,6 r tality compared with usual care. P0.2 Severalpotentialexplanationsexistforthediscordancein findings between the EGDT trial and the more recent African 0 Log-rank P=.02 trials. Similar to the Fluid Expansion As Supportive Therapy 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 (FEAST)trial 6 andthepriorSimplifiedSevereSepsisProtocol Days 4 No. at risk trial, patientsinthecurrentstudywerepredominantlyyoung, Sepsis protoco106 56 43 38 malnourished individuals at risk for tuberculosis and ma- Usual care 103 71 63 60 laria.Inthispatientpopulation,rapidadministrationofintra- Vitalstatuswasknownthroughstudyday28for194patients(94.2%).The venousfluidbolusesmaypredisposetopulmonaryedemaand mediandurationoffollow-upwas28days(interquartilerange,28-28days)in respiratoryfailure,conferringhighmortalityintheabsenceof bothstudygroups.Verticalticksonthecurvesindicatecensoringduetolossto ventilator support. 4 follow-upafterhospitaldischarge. Despite excluding 20% of otherwise eligible patients for hypoxemia and severe tachypnea, nearly one-third of pa- Despiteinternationalrecommendationsforfluidbolusand tientsinthesepsisprotocolgrouprequireddiscontinuationof vasopressor administration in the treatment of sepsis- intravenous fluids due to decreased oxygen saturation or in- induced hypotension, 11supportive data are scarce. The Early creasedrespiratoryrate.Nearlyallpatientsinthecurrenttrial Goal-DirectedTherapy(EGDT)trial, 2 whichinvolved263adults were cared for on the medical ward without access to me- with sepsis at a single ED in the United States, reported re- chanical ventilation compared with the 30% to 70% of pa- duced mortality with administration of intravenous fluid bo- tientswhoreceivedmechanicalventilationintheEGDTtrials, 2,12-14 luses per protocol to achieve central venous pressure of which were performed in high-income countries. 8 mm Hg to 12 mm Hg, vasopressors to achieve mean arterial Resourcelimitationsmandatedthattheresuscitationtar- pressureof65mmHgto90mmHg,andbloodtransfusionor gets in the sepsis protocol in the current trial differ from the 1238 JAMA October3,2017 Volume318,Number13 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia OriginalInvestigation Research Figure3.RiskofIn-hospitalMortalitybySubgroupforPatientsTreatedWiththeSepsisProtocolvsUsualCare In-hospital Mortality, No. of Patients No. (%) Sepsis Usual Sepsis Usual Relative Risk Favors Favors P Value for Protocol Care Protocol Care (95% CI) Sepsis Protocol Usual Care Interaction HIV Positive 94 93 46 (48.9) 29 (31.2) 1.57 (1.09-2.26) .09 Negative 9 9 3 (33.3) 5 (55.6) 0.75 (0.23-2.44) Glasgow Coma Scale Score 13-15 86 78 36 (41.9) 17 (21.8) 1.92 (1.18-3.13) 9-12 7 17 4 (57.1) 10 (58.8) 0.97 (0.46-2.07) .01 3-8 11 5 10 (90.9) 5 (100.0) 0.91 (0.75-1.10) Hemoglobin, g/dL <7 35 35 15 (42.9) 11 (31.4) 1.37 (0.82-2.29) ≥7 48 50 21 (43.8) 16 (32.0) 1.36 (0.73-2.54) .99 b Simplified Acute Physiology Score 3 <56 54 48 23 (42.6) 16 (33.3) 1.28 (0.77-2.12) ≥56 52 55 28 (53.8) 18 (32.7) 1.65 (1.04-2.59) .47 Capillary Blood Lactic Acid, mmol/L <4 42 49 16 (38.1) 12 (24.5) 1.55 (0.83-2.91) ≥4 61 51 33 (54.1) 20 (39.2) 1.38 (0.91-2.08) .75 Jugular Venous Pressure, 2m H O ≤–2 47 50 28 (59.6) 17 (34.0) 1.75 (1.11-2.75) .29 >–2 59 53 23 (39.0) 17 (32.1) 1.22 (0.73-2.01) Overall 106 103 51 (48.1) 34 (33.0) 1.46 (1.04-2.05) 0.1 1.0 10 Relative Risk (95% CI) b Thesepsisprotocolincreasedtheoverallabsoluteriskofin-hospitalmortality Aseverityscoreandmortalityestimationtool(range,0-217;highervalues by15.1%(95%CI,2.0%-28.3%)comparedwithusualcare. indicatehigherriskofin-hospitalmortality). a c Objectiveassessmentofthelevelofconsciousness(range,3[deep Measuredabovetheclaviclewiththepatientpositionedat45°.Forexample, unconsciousness]to15[normallevelofconsciousness]). becausemostpatientsinthetrialhaddepletedvolumelevels,themedian jugularvenouspressurewasaround2cmH Obelowtheclavicleor−2cmH O. 2 2 2 EGDT algorithm. In the absence of access to central venous tion of clinical outcomes by blinded study personnel. Unlike 12-14 catheterization, the protocol in the current study prescribed recenttrialsinhigh-incomecountries, usualcareinthecur- aninitial2-Lintravenousfluidbolusduringthefirsthourand rent study setting involved limited early fluid or vasopressor usedJVPmeasurementandrespiratoryexaminationtodeter- administration. As a result, the differences in the volume of mine when fluid administration should be discontinued. It is intravenous fluid received and receipt of vasopressors be- possible that JVP did not serve as a reliable surrogate mea- tweenpatientsinthesepsisprotocolgroupandtheusualcare 16 sure of central venous pressure or that central venous pres- group were greater than in any prior sepsis resuscitation 2,12-14 sure itself was an inaccurate indicator of developing volume trial, strengtheningcausalinferencesbetweenstudygroup overload. 17Thefactthatmorethan30%ofpatientstreatedwith and clinical outcomes. the sepsis protocol developed worsening respiratory func- tion but less than 10% developed JVP elevation suggests that Limitations JVP cannot be safely used as an end point for fluid adminis- Thisstudyalsohasseverallimitations.First,moderatesizeand tration in this context. conductatasinglecentermayexaggeratetheobservedtreat- 5 A before-after study in Uganda reported the safety and menteffect.However,anybaselineimbalancesbetweengroups efficacy of fluid boluses guided by blood pressure measure- that occurred despite randomization appeared to be rela- mentratherthanJVP,butthebefore-afterdesignandthepres- tivelysmall(eg,between-groupdifferenceinbaselinelacticacid enceofadedicatedmedicalofficerfortheinterventiongroup concentration of 0.7 mmol/L), and likely do not explain the makecomparisonwiththecurrentstudychallenging.Theonly between-group differences in clinical outcomes. Second, al- vasopressor available in the setting of the current study was though study enrollment occurred shortly after arrival in the dopamine. Recent studies have demonstrated better clinical ED, the onset of infection for many patients may have oc- outcomes with norepinephrine than with dopamine 18-20 and curreddaystoweeksbeforepresentation.Third,patients,treat- increaseddopamineadministrationinthesepsisprotocolgroup ing clinicians, and clinical study personnel were not blinded may have contributed to increased mortality. togroupassignment.Fourth,thesepsisprotocolreliedonde- Thisstudyhasseveralimportantstrengths.Thedesignin- terminationofJVP,asemireproducibleskill,anddatawerenot cluded randomization to balance baseline confounders, con- collected on the concordance of JVP measurement between cealed allocation to prevent selection bias, monitoring by an study personnel. Fifth, secondary multivariable analyses re- independent data and safety monitoring board, and collec- lied on the SAPS-3, which has not been validated as a marker jama.com (Reprinted) JAMA October3,2017 Volume318,Number13 1239 © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024 Research OriginalInvestigation EffectsofanEarlyResuscitationProtocolonSepsisMortalityinZambia 10 forseverityofillnessinthestudysetting. Sixth,only1of209 dynamic,cellular,andclinicaleffectsofintravenousfluidbo- patientswascaredforinanintensivecareunit.Althoughthis lus and vasopressor administration in sepsis are needed. reflects the reality of medical care in most hospitals in sub- SaharanAfrica,itlimitsthegeneralizabilitytomoreresource- intense settings. 6 Conclusions CoupledwiththeresultsoftheFEASTtrial andtheprior 4 SimplifiedSevereSepsisProtocoltrial, thefindingsofthecur- Among adults with sepsis and hypotension, most of whom rent study suggest that in settings without routine access to werepositiveforHIV,inaresource-limitedsetting,aprotocol mechanicalventilation,therisksofintravenousfluidbolusad- forearlyresuscitationwithadministrationofintravenousflu- ministration for patients acutely ill from infection may out- ids and vasopressors increased in-hospital mortality com- weigh the benefits. These findings also increase the uncer- pared with usual care. Further studies are needed to under- tainty regarding the ideal approach to intravenous fluid standtheeffectsofadministrationofintravenousfluidboluses administration during early sepsis management in high- andvasopressorsinpatientswithsepsisacrossdifferentlow- incomesettings.Furthertrialscarefullyexaminingthehemo- andmiddle-incomeclinicalsettingsandpatientpopulations. ARTICLEINFORMATION MeetingPresentation:Presentedinpart circumferenceandbodymassindexininpatients.PLoS AcceptedforPublication:July21,2017. attheEuropeanSocietyofIntensiveCare One.2016;11(8):e0160480. Medicine30thAnnualCongress;September27, PublishedOnline:September27,2017. 2017;Vienna,Austria. 10. MorenoRP,MetnitzPGH,AlmeidaE,etal. doi:10.1001/jama.2017.10913 SAPS3—fromevaluationofthepatientto AdditionalContributions:Wethankthe evaluationoftheintensivecareunit:part2. AuthorContributions:DrAndrewshadfullaccess individualsworkingatthemicrobiologylaboratory IntensiveCareMed.2005;31(10):1345-1355. toallofthedatainthestudyandtakes responsibilityfortheintegrityofthedataandthe ofZambiaUniversityTeachingHospitaland 11. DellingerRP,CarletJM,MasurH,etal.Surviving EugeneSilomba,BS(AIDSReliefZambia), SepsisCampaignguidelinesformanagementof accuracyofthedataanalysis. fortheiruncompensatedcontributions Conceptanddesign:Andrews,Muchemwa,Kelly, tomakingthistrialpossible. severesepsisandsepticshock[publishedcorrection Heimburger,Bernard. appearsinCritCareMed.2004;32(6):1448].Crit Acquisition,analysis,orinterpretationofdata: CareMed.2004;32(3):858-873. REFERENCES Andrews,Semler,Muchemwa,Lakhi,Heimburger, 12. YealyDM,KellumJA,HuangDT,etal. Mabula,Bwalya,Bernard. 1. 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BenítezBritoN,SuárezLlanosJP,FuentesFerrerM, etal.Relationshipbetweenmid-upperarm 1240 JAMA October3,2017 Volume318,Number13 (Reprinted) jama.com © 2017 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Claire Perrott on 02/06/2024