Standardization of Care by Defining Endpoints of Resuscitation
M. Mythen, H. Meeran, and M. Grocott
Introduction
The risk of mortality or major morbidity from critical illness remains high. Mor- tality ranges from 5% or more for some major surgical procedures to over 40% for septic shock [1, 2]. Treatment strategies that can reduce this mortality are of obvious importance to patients, health professionals, and resource managers.
Hemodynamic optimization in the form of standardized goal-directed care proto- cols has shown some promising reductions in morbidity and mortality.
The Development of Goal-Directed Therapy
Mortality risk for an individual patient depends on interacting factors. First, on the severity of the acute illness, for example type of surgery, trauma or organ failure score. Second, on the patient’s physiological reserve determined by the presence of pre-existing disease. Critical illness results in a rise in metabolic demand. The ability of the cardiovascular system to meet this demand and avoid tissue hypoxia correlates with survival. Observational studies of critically ill pa- tients demonstrated higher indexes of cardiac output, oxygen delivery (DO2), and oxygen consumption in survivors compared with non-survivors [3–6]. In addi- tion, variables that reflect blood flow and oxygen flux are better predictors of mortality than those more commonly measured such as heart rate, blood pres- sure, central venous pressure (CVP), and hemoglobin [7]. These supranormal values of cardiac output and oxygen transport exhibited by survivors were then suggested as treatment goals [8]. A prospective trial tested this hypothesis and showed a reduction in mortality when supranormal oxygen transport values were used as endpoints for resuscitation of surgical patients [9]. A large number of subsequent studies have been conducted on the theme of supranormal oxygen transport goals or hemodynamic optimization with inconsistent results.
Why is Standardized Hemodynamic Optimization not always Beneficial?
The lack of benefit demonstrated by some studies may have been due to the inclusion of different patient groups, the application of inappropriate treatment
goals or treatment protocols. Previous reviews have been supportive of hemody- namic optimization although pooled results of trials fail to show a significant reduction in mortality [10–14].
The terms ‘goal-directed therapy’, ‘pre-optimization’, or ‘hemodynamic optimi- zation’ lack a precise definition. The effectiveness of this treatment strategy is still controversial. However, there is sufficient evidence to suggest a framework on which to develop current treatment guidelines and future research into hemody- namic resuscitation of the critically ill patient.
Advantages of Standardized Care
The application of evidence-based guidelines to clinical practice has increased in recent years. There are obvious potential advantages of introducing decision- making that is rational and based on evidence. Clinical care can be simplified by the use of treatment algorithms. Standardized algorithms can facilitate coopera- tion between different healthcare professionals. Patients should benefit from the adoption of treatments based on evidence, whereas useless treatments can be discarded. It has been hoped that this approach may also reduce costs for health- care purchasers [15].
Potential Problems with Standardized Care
Unfortunately standardization of care by the use of guidelines and protocols may not necessarily be a success. There are no certainties in clinical care and individual patients may have needs that fall outside standard guidelines. The rigid applica- tion of protocols cannot replace clinical judgment.
For standardized care to be successful either clinically, or in the setting of a research study, it must first be based on sound evidence. Treatment goals must be rational and achievable, validated by their association with improved outcome in previous studies. Standardized treatment algorithms must be previously validated.
In other words, it must have been demonstrated that the treatment is successful in achieving the prescribed goals for all patients, or at least the majority. Research studies must have comparable intervention and control groups and adequate power to show a difference, this is often a problem in critical care based work. A summary of randomized trials of hemodynamic optimization and how they com- pare with this ideal is shown in Table 1a. Clinicians may be cautious in translating the benefits of treatment shown in research studies into everyday practice. Merely taking part in a study tends to result in some improvement in outcome for patients [16]. Implementation of standardized care guidelines requires a process of educa- tion and audit to prove their effectiveness. Finally, powerful social forces and organizational culture may have to be overcome [17, 18].
Endpoints of Resuscitation
A variety of endpoints have been studied in trials of hemodynamic optimization.
These can be divided into indexes of oxygen transport derived from pulmonary artery catheter (PAC) measurements, measurements of flow in response to circu- lating volume optimization, and markers of tissue perfusion. Table 1b summa- rizes trials with different endpoints and study populations so that they may be compared more easily. This table can be cross-referenced with the more detailed Tables 2a–4b. The intention of these is also to emphasize features of trial design and conduct that are associated with positive outcome.
Oxygen Transport Goals
DO2, oxygen consumption (VO2), and cardiac index (CI) are logical indices to measure because they have been shown to predict survival [7]. The median values for these variables were DO2600 mls/min/m2, VO2170 mls/min/m2, and CI >4.5 l/min/m2in survivors. When these supranormal values have been used as treat- ment goals in randomized controlled trials they have been associated with im- provements in important outcomes such as mortality, complications, and length of intensive care unit (ICU) stay [9, 19–27]. Tables 2a and 2b compare the demo- graphic features and results of studies that use indices of oxygen transport as resuscitation endpoints.
Optimization of Circulatory Volume
Fluid optimization as an endpoint of resuscitation has been shown to reduce length of hospital stay and important complications in patients undergoing a variety of major surgical procedures [28–32]. This is usually achieved with an esophageal Doppler monitor to evaluate changes in flow in response to fluid challenges. The principle this approach shares with PAC-based studies is that hemodynamic resuscitation begins with volume optimization. However, the ap- plication of pre-defined hemodynamic values as goals is avoided, so that the maximum cardiac output achieved by each patient depends upon their own physi- ology. The endpoint of resuscitation is therefore achievable in all patients. The treatment strategy follows a simple, standard fluid challenge algorithm. Patients in the treatment group of these studies have significantly higher cardiac output values, thus demonstrating that the treatment algorithm is effective. Tables 3a and 3b compare these studies in detail.
Surrogate Markers of End-Organ Perfusion
Markers of tissue perfusion have also been used as endpoints for resuscitation.
These include mixed venous oxygen saturation (SvO2), lactate, base excess, and gut mucosal pH using gastric tonometry. The use of these endpoints is attractive,
Table1a.Anat-a-glancesummaryofstudiesofhemodynamicoptimization. StudyTreatmentgoalsInterventionInterventionStandardizedIntentiontotreat populationa clearlydefinedgroupreceivedgroupachievedenvironmentforanalysis:outcome forbothgroupsmoretreatmenthighergoalvaluestreatmentandfavorstreatment thancontrolsthancontrolscontrolgroups Berlauketal1991[40]S••• Bishopetal1995[27]T••••• Boydetal1993[21]S••••• Conwayetal2002[32]S•••• Ganetal2002[31]S••• Loboetal2000[22]S•••• Mythenetal1995[28]S•••• Polonenetal2000[33]S••••• Riversetal2001[35]C••••• Schultzetal1985[41]S• Shoemakeretal1988[9]S•••• Sinclairetal1997[29]S••• Uenoetal1998[19]S••••• Vennetal2002[30]S•••• Wilsonetal1999[20]S•• Yuetal1998[23]C••••• Aliaetal1999[45]C••
Table1a.Continued StudyTreatmentgoalsInterventionInterventionStandardizedIntentiontotreat populationa clearlydefinedgroupreceivedgroupachievedenvironmentforanalysis:outcome forbothgroupsmoretreatmenthighergoalvaluestreatmentandfavorstreatment thancontrolsthancontrolscontrolgroups Benderetal1997[39]S• Durhametal1996[50]C•• Flemingetal1992[26]T•••• Gattinonietal1995[44]C•••• Hayesetal1994[49]C•••• Ivaturyetal1995[37]T•• Parggeretal1998[36]S•• Sandhametal2003[43]S•• Tuchschmidtetal1992[25]C•••• Valentineetal1998[38]S• Velmahosetal2000[47]T•• Yuetal1993[46]C••• Yuetal1995[48]C•••• Ziegleretal1997[34]S•• (•)Indicatesthepresenceoffeaturesimportantindeterminingthelikelihoodofproducingapositiveoutcome.Studieswithapositiveoutcomearepresented first.a S=surgical,T=trauma,C=mixedcriticalillness
Table1b.Summaryofrandomizedstudiesofstandardizedhemodynamicresuscitationwithvarioustreatmentgoals. StudyStudypopulationInterventiongroupgoalsTreatmentInterventionInterventionMainoutcomeOutcome groupreceivedgroupvariablefavors moretreatmentachievedhigherintervention thancontrolgoalvalues Berlauketal1991[40]VascularsurgeryCI≥2.8l/min/m2 Fluids+/– inotropesYesNotknownMorbidityYesp<<0.05 Bishopetal1995[27]TraumaCI≥4.5l/min/m2 ,Fluids+/–YesYesMortalityYesp=0.02 DO2I≥670l/min/m2 ,inotropes VO2I≥166ml/min/m2 Boydetal1993[11]GeneralsurgeryDO2I>600ml/min/m2 Fluids+/–YesYesMortalityYesp=0.015 inotropes Conwayetal2002[32]GeneralsurgerySVandFTcFluidYesYesMorbidityYesp=0.02 Ganetal2002[31]GeneralsurgeryFTcandSVFluidYesYesLengthYesp=0.03 ofhospitalstay Loboetal2000[22]GeneralsurgeryDO2I>600ml/min/m2 Fluids+/–YesYesMortalityYesp<<0.05 inotropes Mulleretal1999[42]GeneralsurgeryNocleargoalsInotropesYesNocleargoalsSplanchnicYesp<<0.05 oxygenation Mythenetal1995[28]CardiacsurgerySVFluidYesYesMorbidityYesp=0.01 Polonenetal2000[33]CardiacsurgerySvO2>70%,Fluids+/–YesYesLengthofYesp<<0.05 lactate≤2.0mmol/linotropeshospitalstay Riversetal2001[35]SepsisSvO2>70%Fluids+/–YesYesMortalityYesp=0.009 inotropes
Table1b.Continued StudyStudypopulationInterventiongroupgoalsTreatmentInterventionInterventionMainoutcomeOutcome groupreceivedgroupvariablefavors moretreatmentachievedhigherintervention thancontrolgoalvalues Scaleaetal1990[24]TraumaCI>4.0l/min/m2 ,Fluids+/–NoYesMortalityYesp<<0.001 VO2I>170ml/min/m2 inotropes (earlyvslateintervention notarandomized controlledtrial) Schultzetal1985[41]HipsurgeryNormalizationofFluids+/–NotknownNotknownMortality2.9vs29%nop physiologicalprofileinotropesvaluegiven. fromPACstudies. Valuesnotspecified. Shoemakeretal1988[9]GeneralsurgeryCI3.5–4.5l/min/m2 ,Fluids+/–sNotknownYesMortalityYesp<<0.01 DO2I>600ml/min/m2 ,inotrope VO2I>170ml/min/m2 Sinclairetal1997[29]HipsurgerySVandFTcFluidYesYesLengthofYesp<0.05 hospitalstay Uenoetal1998[19]HepaticsurgeryCI3.5–4.5l/min/m2 ,Fluids+/–YesYesLiverfunctionYesp<0.05 DO2I>600ml/min/m2 ,inotropes VO2I>170ml/min/m2 Vennetal2002[30]HipsurgerySV,FTc,CVPFluidYesYesTimetofitnessYesp=0.008 fordischarge Wilsonetal1999[20]GeneralsurgeryDO2I>600ml/min/m2 Fluids+/–YesYesMortalityYesp=0.007 inotropes
Table1b.Continued StudyStudypopulationInterventiongroupgoalsTreatmentInterventionInterventionMainoutcomeOutcome groupreceivedgroupvariablefavors moretreatmentachievedhigherintervention thancontrolgoalvalues Yuetal1998[23]MixedcriticalDO2I≥600l/min/m2 Fluids+/–YesYesMortalityYesp=0.01 illness≥50yearsoldinotropes Aliaetal1999[45]SepsisDO2I>600ml/min/m2 Fluids+/–YesNoMortalityNo inotropes Benderetal1997[39]VascularsurgeryCI≥2.8l/min/m2 Fluids+/–YesNotknownMortalityNo inotropes Durhametal1996[50]MixedcriticalDO2I>600ml/min/m2 ,Fluids+/–NotknownNoMortalityNo illnessVO2I>170ml/min/m2 inotropes Flemingetal1992[26]TraumaCI≥4.52l/min/m2 ,Fluids+/–YesYesMortalityNo DO2I≥670l/min/m2 ,inotropes VO2I≥166ml/min/m2 Gattinonietal1995[44]MixedcriticalCI≥4.5l/min/m2 Fluids+/–YesOnlyinMortalityNo illnessorSvO2≥70%inotropesCIgroup Hayesetal1994[49]MixedcriticalCI≥4.5l/min/m2 ,Fluids+/–YesYesMortalityNo illnessDO2I≥600l/min/m2 ,inotropes VO2I≥170ml/min/m2 Ivaturyetal1995[37]TraumapHi≥7.30Fluids+/–NotknownYesMorbidityNo orDO2I≥600l/min/m2 inotropes andVO2I≥150ml/min/m2 Parggeretal1998[36]VascularsurgerypHi≥7.32Fluids+/–YesNoMorbidityNo inotropes
Table1b.Continued StudyStudypopulationInterventiongroupgoalsTreatmentInterventionInterventionMainoutcomeOutcome groupreceivedgroupvariablefavors moretreatmentachievedhigherintervention thancontrolgoalvalues Sandhametal2003[43]GeneralsurgeryDO2I550–600ml/min/m2 Fluids+/–YesNotknownMortalityNo CI3.5–4.5l/min/m2 inotropes Tuchschmidtetal1992SepsisCI≥6.0l/min/m2 Fluids+/–YesYesMortalityNo [25]inotropes Valentineetal1998[38]VascularsurgeryCI≥2.8l/min/m2 Fluids+/–YesNotknownMorbidityNo inotropes Velmahosetal2000[47]TraumaCI≥4.5l/min/m2, Fluids+/–NoNotknownMortalityNo DO2I>600ml/min/m2 ,inotropes VO2I>170ml/min/m2 Yuetal1993[46]MixedcriticalDO2I≥600l/min/m2 Fluids+/–YesNoMortalityNo illnessinotropes Yuetal1995[48]MixedcriticalDO2I≥600l/min/m2 Fluids+/–YesNoMortalityNo illnessinotropes Ziegleretal1997[34]VascularsurgerySvO2≥65%Fluids+/–YesYesMorbidityNo inotropes Studieswithpositiveoutcomesarepresentedfirst.Abbreviations:CI=cardiacindex,DO2I=oxygendeliveryindex,VO2I=oxygenconsumptionindex, SV=strokevolume,FTc=correctedflowtime,pHi=gastricmucosalpH,SvO2=mixedvenousoxygensaturation,PAC=pulmonaryarterycatheter,vs=versus.
Table2a.Demographicfeaturesofstudiesusingoxygentransportvaluesasendpointsofresuscitation. StudyInclusionTimingofStudyStudyTreatmentTreatmentTreatmentsEnviron-Environ- criteriainterventionmonitormonitorgoalsgoalsmentment Interventioncontrolinterventioncontroltreatmentcontrol groupgroupgroupgroup Aliaetal1999EstablishedWithin6hrsofPACPACDO2I>600DO2I>130Crystalloid,ICUICU [45]criticalillness:studyentryml/min/m2 ml/min/m2 dopamine, Severesepsisuntil96hrsnorepinephrine, orsepticdobutamine shock Benderetal1997InfrarenalPreoperativelyPACCVPPAOPNotspecifiedCrystalloid,ICUICU [39]aorticoruntil16hrs8–15mmHg,dopamine,beforebefore lowerlimbaftersurgeryCI≥l/min/m2,blood,andafterandafter electiveSVR<1100nitrates.surgerysurgery vasculardyne-s/cm5 surgery Berlauketal1991Lowerlimb3hrsPACCVPPAOPCI≥2.8NotspecifiedFluid,ICUICU [40]vascularpreoperativelyl/min/m2 ,dopamine,beforebefore surgeryuntilendSVR<1100dobutamine,andafterandafter ofsurgerydyne-s/cm5 nitrates.surgerysurgery Bishopetal1995Trauma6hrsafterPACCVPCI≥4.5l/minCVP8-12,Fluid,ICUICU [27]excludingsurgeryor/m2 ,DO2I≥SAP>120blood, headinjury12hrsafter670l/min/m2 ,mmHg,dobutamine admissionVO2I≥166HR<110/min, until48hrsml/min/m2 urine 30–50ml/hr
Table2a.Continued StudyInclusionTimingofStudyStudyTreatmentTreatmentTreatmentsEnviron-Environ- criteriainterventionmonitormonitorgoalsgoalsmentment Interventioncontrolinterventioncontroltreatmentcontrol groupgroupgroupgroup Boydetal1993HighriskPreoperativelyPACPACDO2I>600PAOPGelofusine,ICUICU [11]surgerybyuntil24hrsml/min/m2 12–14mmHg,blood, ShoemakeraftersurgeryHb≥12g/dldopexamine criteria Durhametal1996EstablishedStudyentryPACPACDO2I>600OptimalCIFluid,blood,ICUICU [50]criticalillness:untilPACml/min/m2 ,(minimumdobutamine, Trauma,nolongerVO2I>1703.5)usingdopamine, sepsis,shock,requiredml/min/m2 PAOPuptonitrates renalfailure,18mmHg, respiratoryHb11g/dl failure Flemingetal1992TraumaWithin6hrsPACCVPCI≥4.52SAP120mmHg,Fluid,blood,ICUICU [26]ofadmissionl/min/m2 ,Hb≥10g/dl,dobutamine orsurgeryDO2I≥670CVP8–12 for48hrsl/min/m2 ,mmHg VO2I≥166 ml/min/m2 GattinoniHighriskWithin48hrsPACPACCI≥4.5CI≥2.5–3.5Fluid,blood,ICUICU etal1995[44]surgerybyofadmissionl/min/m2 l/min/m2 dobutamine, Shoemakerfor5daysorSv≥Ο270%dopamine, criteria,sepsis,norepinephrine, respiratoryepinephrine, failureornitrates trauma
Table2a.Continued StudyInclusionTimingofStudyStudyTreatmentTreatmentTreatmentsEnviron-Environ- criteriainterventionmonitormonitorgoalsgoalsmentment Interventioncontrolinterventioncontroltreatmentcontrol groupgroupgroupgroup Hayesetal1994EstablishedWithin24hrsPACPACCI≥4.5CI>2.8Fluid,blood,ICUICU [49]criticalillness:ofICUl/min/m2 ,l/min/m2 dopamine High-riskadmission,DO2I≥dobutamine, surgeryby(excepttwo600l/min/m2 ,norepinephrine Shoemakerpatients).VO2I≥170 criteria,Lengthofml/min/m2 sepsis,treatment trauma,unspecified. respiratory failure. Withfailure tomeetgoals withvolume alone. Loboetal2000HighriskPreoperativePACPACDO2I>600DO2IFluid,blood,ICUICU [22]electiveuntil24hrsml/min/m2 520–600dobutamine, surgeryafterml/min/m2 dopamine, operationnitrates SandhamASAIIIStartedbeforePACNotDO2INotspecifiedFluid,ICUICU etal2003[43]orIVoperation,butspecified550–600inotropes, majorlengthoftreat-ml/min/m2 ,blood surgerymentunclearCI3.5–4.5l /min/m2
