Fluid Choices Impact Outcome in Septic Shock

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CURRENTOPINION Fluid choices impact outcome in septic shock

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James J. Douglas and Keith R. Walley

Purpose of review

We discuss the goals of resuscitation, in both the early and the later phases, measures of organ perfusion,fluid responsiveness and the consequences of tissue edema.

Recent findings

The cost of over-aggressive fluid resuscitation is increased organ failure and mortality. In anticipation of theupcoming trials on early goal-directed therapy, we explore strategies to maximize effectiveness ofresuscitation. Furthermore, we review recent data on the choice of fluid therapy.

Summary

Rapid diagnosis and early fluid resuscitation are crucial to patients with septic shock, initially with theprimary goal to relieve the overt tissue hypoxia. Early fluid therapy is important with the caveat thatpatients must show an increase in their cardiac output. Beyond 6–12 h further positive fluid balance maynot usefully improve tissue oxygenation and may be counterproductive.

Keywords

albumin, early goal-directed therapy, edemagenesis, perfusion, resuscitation

INTRODUCTION

Early goal-directed therapy (EGDT) has profoundeffects on clinical outcomes in septic shock patients[1,2,3]. Targeted fluid resuscitation relieves overttissue hypoxia; however, over-aggressive fluidtherapy has deleterious effects on patient outcomes.We discuss goals of resuscitation, both in the early(first 6 h) and in the later phases (6–72 h), measuresof organ perfusion, fluid responsiveness and theconsequences of tissue edema. Furthermore, weexplore new directions in early goal-directedtherapy and the choice of fluid therapy.

Fluid resuscitation has vexed intensivists formany generations and until recently was guidedby expert opinion [4] and loosely based on the1983 Packman and Rackow article [5] that exploredincreases in pulmonary artery wedge pressure lead-ing to an increase in stroke volume index and car-diac index. Ironically, the authors also found a verypoor correlation with wedge pressure and centralvenous pressure (CVP); a debate that persists today.

Centre for Heart Lung Innovation, St. Paul’s Hospital, University of BritishColumbia, Vancouver, British Columbia, Canada

Correspondence to James J. Douglas, MD, Centre for Heart LungInnovation, 1081 Burrard Street, Vancouver, BC, Canada V6Z1Y6.Tel: +1 604 806 8346; fax: +1 604 806 8351; e-mail: [email protected]

Curr Opin Crit Care 2014, 20:378–384

DOI:10.1097/MCC.0000000000000116

EARLY GOAL-DIRECTED THERAPY HASDRIVEN INTEREST IN FLUIDRESUSCITATION

The Rivers et al. 2001 EGDT landmark trial [1] com-pared therapy driven to achieve hemodynamic endpoints versus standard therapy of the late 20th

iams & Wilkins. Unautho

century. Therapy was divided into two periods,the initial 6 h and 6–72 h. In the initial 6 h, morepatients in the EGDT groups achieved CVP, meanarterial pressure (MAP) and urine output goals. Thepatients in the EGDT group had higher centralvenous oxygen saturation (ScvO2) and lower basedeficit at 6 h, implying improved oxygen deliveryand extraction. During the period from 6 to 72 h, thestandard therapy group had a higher heart rate,lactate and base deficit, lower MAP, and a similarCVP. Consequently, the standard therapy groupreceived more fluids, red blood cell transfusions,vasopressors and inotropic support during the 6–72-h period. Overall, from baseline to 72 h, bothgroups received the same total amount of fluids andinotropic support, whereas the standard grouprequired more vasopressors and mechanical venti-lation. The EGDT group showed a 16% absolute riskreduction of mortality compared with the standardtherapy group at 28 days mainly from improved

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KEY POINTS

� Early identification and fluid resuscitation of septicshock patients improves inadequate oxygen deliveryand mortality.

� Fluid resuscitation should be aimed at the least amountof fluid and lowest CVP to achieve an improvement inend organ perfusion (improved ScvO2, lactate or urineoutput).

� Dynamic measure of fluid responsiveness should beused prior to any volume resuscitation.

� Fluid restrictive strategies have shown improvedoutcomes in acute lung injury, kidney injury andsurvival in septic shock patients.

� Albumin provides a higher CVP, MAP with a loweroverall fluid balance in patients with sepsis andimproved survival in those patients with septic shock.

Fluid choices impact outcome in septic shock Douglas and Walley

sudden cardiovascular collapse, whereas death frommultiorgan failure was similar.

Criticism of the EGDT trial centered on theunblinded protocol of the study, its small size andsingle institution nature, the high mortality in thestandard therapy group (46.5%) and abundance ofred blood cell transfusions. However, the resultswere still impressive and upon review are likelyexplained by a couple of simple, yet powerful, facts.First, care began in the emergency department (ED)and emphasized the early identification of high-riskpatients based on blood pressure and lactate. Sec-ond, hemodynamic monitoring is feasible andimproves diagnostic accuracy, rapid access andmonitoring of critically ill patients. Finally, theEGDT group received on average 1500 ml more totalfluid in the first 6 h of treatment, achieving a higherCVP, MAP and urine output. Follow-up meta-analyses of the many subsequent observationalstudies confirmed that early goal-directed resuscita-tion imparted a significant reduction in mortality[odds ratio (OR) 0.64, 95% confidence interval (CI)0.43–0.96] [6]. Moreover, it emphasized the criticalrole in identifying sepsis and septic shock, andrapidly initiating antibiotic and fluid resuscitation.

Sepsis is a form of distributive shock in whichtissue metabolism is impaired by a number of mech-anisms. First, patients present acutely hypovolemicand early fluid resuscitation serves to improve overttissue hypoxia from critical decreases in oxygendelivery. Second, tissue dysoxia may exist afterfluid resuscitation due to inflammation-induceddisruption of oxygen extraction either from oxygendiffusion abnormalities or from mitochondrial dys-function. EGDT studies support the vital need to

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correct the initial phase of intravascular hypovole-mia and inadequate oxygen delivery; however, carehas to be taken not to aggravate the second phase oftissue injury by excessive fluid administration.

ENDPOINTS OF RESUSCITATION

A common fallacy in septic patients is the notion thatfluid resuscitation has succeeded when a numberis reached. The Rivers et al. trial taught us that a time-sensitive protocolized approach based on numericalgoals improves outcomes. Yet, this approach by-passes crucial questions that must be addressedduring fluid resuscitation. First, is end organ per-fusion adequate (so that additional fluid may notbe necessary)? Second, is the patient fluid responsive?Third, what is the cost of giving additional fluids?

Fluid resuscitation early in the management ofseptic shock is aimed at improving cardiac output.Although much maligned over its poor correlationwith fluid responsiveness, central venous access andits transduced pressure still exist as part of the initialresuscitation [7]. The EGDT trial used a CVP of8 mmHg or less to trigger an additional volume bolusduring the initial 6 h. The Surviving Sepsis Campaign(SSC) guidelines propose a goal CVP of 8–12 mmHgand further suggest consideration of a CVP of12–15 mmHg in patients who are mechanicallyventilated, or have known preexisting decreasedventricular compliance, increased abdominal pres-sure or pulmonary arterial hypertension [7]. But thishigher CVP comes at the cost of increased tissueedemagenesis, as described by the Starling equation,so confirmation that a higher CVP increases oxygendelivery and improves organ perfusion and functionis required.

Organ perfusion

The initial profile of sepsis has components of allvarieties of shock, but is often dominated by apicture of a hypodynamic state with low strokevolume. Only after adequate volume resuscitation,does a vasodilatory state with low vascular resistanceemerge. The change also may include macrovascu-lar-to-microvascular shunting and can be associatedwith a histotoxic hypoxia component, elements ofwhich are difficult to identify.

The mean arterial pressure is the driving pres-sure for perfusion for most organs and, althoughautoregulated in tissues such as brain and kidney,when it declines below a lower limit, flow becomesdependent on the MAP [8]. Small studies found nobenefit to higher MAP goals in terms of arteriallactate, urinary output or splanchnic perfusion[9]. The sepsis and mean arterial pressure trial

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compared a MAP target of 80–85 mmHg to65–70 mmHg in septic shock patients and foundno difference in mortality at 28 and 90 days [10

&&

].Newer trials using transcutaneous oxygen saturationin septic patients have shown that increasing MAPcan increase cutaneous microvascular flow and tissueoxygenation, yet prospective trials need to show anoutcome benefit [11].

Surrogate measures of organ perfusion

The Rivers et al. trial [1] emphasized the measure-ment and response to ScvO2 monitoring to detectimbalances between oxygen delivery and oxygenconsumption. Manuevers to increase ScvO2 inclu-ded increasing oxygen delivery by inspired oxygenconcentration, red blood cell transfusion and ino-tropic support or decreasing oxygen consumptionusing mechanical ventilation, sedation and evenparalysis. A number of trials have shown a corre-lation between mixed venous oxygen saturationmeasured in the pulmonary artery (SvO2) and ScvO2

with a difference of approximately 5% betweenthem [1]. A meta-analysis of 21 sepsis bundle studiesfound that achievement of a ScvO2 greater than 70%as part of the 6-h resuscitation bundle was associatedwith greater than two times likelihood of survival[2]. Lactate at 6 h, ScvO2 at 48 h and MAP at bothtime points were independently associated withmortality and ScvO2 and MAP less than 65 hadthe highest predictive value as measured by areaunder a receiver operating characteristic curve. Popeet al. [12] performed a secondary analysis of fourprospective studies of EGDT and found low ScvO2

(suggesting inadequate oxygen delivery relative todemand) and excessively high ScvO2 (>90%,suggesting histoxic hypoxia) recorded in the EDwere associated with increased mortality.

Elevated lactate is associated with early morta-lity in critically ill patients [13,14]. In severe sepsispatients the reported prevalence of elevated lactatealone upon admission is 5.4% which increases to16.6% in the presence of hypotension [15].Mortality in these two groups was 30% and46.1%, respectively. Addition of lactate clearanceto the primary SSC bundle observed improved out-comes when lactate was 1 mmol/l or less or whenlactate decreased significantly within 12 h [16].Despite the prevalence of elevated lactate in septicpatients, it is the acidosis and not the hyperlactate-mia that predicts mortality [17]. Jones et al. [18]performed a noninferiority study comparing severesepsis and septic shock patients with one of tworesuscitation strategies after normalization of MAPand CVP: ScvO2 at least 70% or lactate clearancegreater than 10% over 6 h [18]. Interestingly, there

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was no observed difference in the treatments in theinitial 72 h and no difference in mortality.

Although there is significant overlap in the util-ity of both ScvO2 and lactate measures, certainfeatures of each provide bedside assistance. ScvO2

provides immediate feedback on the oxygen con-sumption or oxygen delivery relationship; however,interpretation may be required depending on thephase of sepsis. ScvO2 levels below 50–60% areinterpreted as evidence of inadequate oxygen deliv-ery with respect to oxygen demand. However, highScvO2 levels (>80–90%) may indicate adequateoxygen delivery, but may also indicate histotoxichypoxia and impaired tissue-oxygen extractioncapacity. Furthermore, high ScvO2 (>90%) is associ-ated with increased mortality [12] and is currentlywithout a known effective therapy. Lactate levelsand metabolism involve complex kinetics andreflect whole body metabolism. As such the sensi-tivity to regional insults may be poor, resulting indelayed or missed diagnosis [19]. There is only amodest correlation between a ScvO2 at least 70%goal and a lactate clearance at least 10% goal, withthe later more strongly associated with survival [20].Although the Jones trial declared noninferiority of alactate clearance goal compared with a ScvO2 goal,certain points need to be remembered. The patientsin the Jones trial were less sick, with lower lactate andhigher ScvO2 at baseline, and required less thera-peutic intervention compared with the originalEGDT trial. We conclude that measurement andtrending of ScvO2 and lactate are complementaryand not mutually exclusive. Future studies target-ing microcirculatory perfusion derangements mayimprove understanding and treatment of othercryptic changes that can accompany sepsis.

FLUID RESPONSIVENESS

Now well documented is the inability of the CVPto predict volume responsiveness. CVP is oftenthought of as a surrogate for right ventricular end-diastolic volume which, in turn, is an indicator ofpreload responsiveness. The flaw lies not only in thecurvilinear shape of the ventricular diastolic pres-sure–volume curve, but also in alterations in ven-tricular compliance that occur during critical illnessdue to pressures transmitted from adjacent compart-ments. Mark and Cavallazzi [21] performed a meta-analysis of 43 studies from the ICU and operatingroom and found a correlation coefficient betweenbaseline CVP and change in stroke volume indexand cardiac index of 0.18, indicating essentiallyno relationship.

A common approach in the ICU is a fluid chal-lenge. Osman et al. [22] evaluated 150 fluid




challenges among 96 patients and found that thecardiac index improved in only 65 cases. The CVPwas similar in responders and nonresponders inwhom a CVP less than 8 and pulmonary arteryocclusion pressure less than 14 predicted volumeresponsiveness of only 47% and 54%, respectively,similar to flipping a coin.

Cyclic changes in intrathoracic pressure duringmechanical ventilation change ventricular preloadand, to a lesser extent, afterload. Higher intrathora-cic pressure during ventilator inspiration impedesvenous return with a corresponding decrease instroke volume and pulse pressure [23]. Studies exam-ining these dynamic ventilation-induced changesfound that pulse pressure variation and strokevolume variation are useful in predicting respon-siveness to volume administration (sensitivity,specificity and diagnostic OR 0.89, 0.88 and 59.9for pulse pressure variation and 0.82, 0.86 and27.3 for stroke volume variation, respectively)[24]. As an extension, use of the pulse oximeterplethysmographic waveform has been used to pre-dict fluid responsiveness with good correlation andagreement with the pulse pressure variation [25].Drawbacks of these strategies include the need forabsence of significant arrhythmias and mechanicalventilation using tidal volumes of 8–10 ml/kg inpatients without spontaneous breathing, whichconflicts with lung protective ventilation and strat-egies at minimizing sedation.

Doppler echocardiography assessment of theaortic blood velocity over the respiratory cycle fol-lows the same principle as arterial waveform analysis.Using either esophageal Doppler monitoring ortransesophageal echocardiography of ventilator-induced variation in aortic blood flow has been usedto predict fluid responsiveness [26,27]. Similar toarterial changes during positive pressure ventilation,superior and inferior vena cava diameter has beenused to predict fluid responsiveness. Using focusedechocardiography, inspiratory increases in inferiorvena cava diameter greater than 12% in one studyand 18% in another had greater than a 90% sensi-tivity and specificity for fluid responsiveness [28,29].A recent study looking at end-expiratory occlusionduring mechanical ventilation showed that anincrease in cardiac output or arterial pulse pressureby more than 5% predicted fluid responsiveness withgood accuracy [30].

Spontaneously breathing patients can beassessed using a passive leg raise. Lifting the legspassively to a 458 angle has been shown to predictchanges in aortic blood flow to the same extent as a500 ml bolus even in patients with cardiac arrhy-thmias and spontaneous ventilation. It is importantto assess this method with real-time evaluation



of cardiac output or stroke volume. Newer tech-niques including transpulmonary thermodulitionto measure the stroke volume (PiCCO, FloTrac-Vig-ileo) allow this assessment, and increases in pulsecontour cardiac output at least 10% predict volumeresponsiveness. Other techniques to assess the res-ponse to a passive leg raise can use bioimpedance-based systems (e.g., noninvasive cardiac outputmonitoring measuring changes in signal amplitude[31]).

FLUID CONSEQUENCES

Recent evidence is emerging, suggesting that over-exuberant fluid resuscitation is detrimental. Boydet al. [14] demonstrated higher mortality with amore positive fluid balance at 12 h and day 4. Lowestmortality at 12 h was observed in those with a CVPless than 8 mmHg, followed by 8–12 mmHg andlastly greater than 12 mmHg had the highestmortality. No correlation between CVP and fluidbalance was seen on days 1–4. The fluid expansionas supportive therapy trial group explored fluidbolus therapy versus no fluid bolus therapy inAfrican children admitted to hospitals with severefebrile illness and impaired perfusion. The trial [32]was stopped early after preliminary results showedan increased 48-h and 4-week mortality in the fluidbolus group. Post-trial exploration revealed thatdespite a greater perfusion increase at 1 h in thebolus arm, a higher proportion of terminal eventswere caused by cardiovascular collapse at 48 h [33].

Retrospective review of the Acute RespiratoryDistress Syndrome Network ventilator-tidal volumetrial revealed that negative cumulative fluid balanceat 4 days was associated with more ventilator andICU free days and lower odds ratio of mortality [34].Another prospective trial in patients with acute lunginjury found a conservative strategy of fluid man-agement improved oxygenation and shortenedmechanical ventilation and ICU care [35]. A numberof studies looking at restrictive versus liberal strat-egies of fluid administration perioperatively haveshown lower rates of postoperative complicationsand mortality in the former [36,37].

Sepsis-induced acute kidney injury (AKI) is notonly the result of hypoperfusion, but the interactionbetween inflammation and oxidative stress, micro-vascular dysfunction and adaptive changes in tubularepithelium [38]. A recent retrospective study lookingat kidney injury and hemodynamics found that ahigher CVP was associated with risk of developingnew or persistent AKI [39

&

,40]. Analysis of the SepsisOccurrence in Acutely Ill Patients trial showed that inpatients with AKI, mean fluid balance remainedan independent risk factor for mortality [41]. In



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the Randomized Evaluation of Normal vs. Aug-mentedLevel study in critically ill patients, a negativemean daily fluid balance was associated withincreased renal replacement free days, ICU free daysand survival [42].

In summation, we are left with the need forrapid diagnosis and early fluid resuscitation,possibly primarily to relieve overt tissue hypoxia.Beyond the initial fluid loading during the first6–12 h, further positive fluid balance may be coun-terproductive. EGDT, now in its teenage years, is stillbeing questioned; however, there can be no doubtthat an imperative to diagnose and respond quicklyto septic patients is vital to their survival. Perhaps, itis necessary to make a clear distinction betweenfluid resuscitation during the first 6 h and the fol-lowing 6–72 h in which the end-point goals are verydifferent and are based on clear evidence that fur-ther fluids will improve organ function.

FUTURE TRIALS OF GOAL-DIRECTEDTHERAPY

Despite widespread acceptance and early imple-mentation into the Surviving Sepsis Campaignguidelines, aspects of EGDT are debated. For thesereasons, three separate groups designed and finishedor are near completion of multicenter randomizedcontrolled trials of EGDT; the UK ProMISe, Austral-asia ARISE and USA ProCESS trials. These studiespresented a number of interesting questions. First,sites were selected on the basis of an absence ofroutine protocolized ED sepsis care. All three studiesare superiority trials, enrolled from the ED within2 h of meeting criteria. Trained teams are activatedto deliver the EGDT on the basis of the originalEGDT trial with two arms (usual versus EGDT) inthe ARISE and ProMISe and three arms [usual, EGDTand protocolized standard care (PSC)] in the Pro-CESS trial. The trials are powered to detect at 6–8%absolute risk reduction in hospitals or 90-daymortality, which will be challenging because of abaseline mortality of septic shock of 25–30% [43].The only one released to date is the ProCESS trial inwhich the protocol-based regimens (standard careand EGDT) both received more fluids and hadhigher MAPs and use of vasopressors at the end ofthe 6-h resuscitation periods compared with usualcare [44]. Interestingly, there was no difference in60-day and 90-day mortality between the groups,yet the usual care group had a lower incidence ofacute renal failure requiring renal replacement.

Publication of the other two control trials ofEGDT may shed even more light on what elementsand quantities of EGDT are crucial. Even more chal-lenging is the observation that ‘usual care’ is now



quite different from the previous century (whenEGDT was conducted) and now incorporates manyelements of EGDT.

CHOICE OF FLUIDS

Although the need for early fluid resuscitation inseptic patients is accepted, the choice of fluid therapyremains controversial. Crystalloids include varioussalt concentrations of isotonic saline (0.45%, 0.9%,3%) and the balanced salt solutions (Hartmans,Ringers lactate, PlasmaLyte). Crystalloids are inex-pensive, rapidly expand the intra and extravascularfluid compartments, improve end organ perfusionand have minimal risks of anaphylactoid reactions[45]. The colloids are a heterogeneous group of fluids,including albumin, gelatins, hydroxyethyl starch(HES) and dextran containing fluids. Colloids rapidlyimprove intravascular volume and oncotic pressure;thereby resuscitation may require less time and vol-ume. Colloid resuscitation can improve oxgygentransport, myocardial contractility and cardiacoutput [46]; however, until recently no data haveclearly demonstrated their superiority in critically illpatients in terms of pulmonary edema, length of stayor mortality [47].

The Cochrane review [48] from 1998 comparedalbumin to crystalloids in 30 randomized controlledtrials in critically ill patients with hypovolemia,burns or hypoalbuminemia and found that thepooled relative risk of death was significantly higherwith albumin. The crystalloid versus hydroxyethylstarch trial compared crystalloid versus HES andfound no difference in 90-day mortality, but despitean overall lower rate of AKI there was more need forrenal replacement therapy in the HES group [49].The 6S trial group compared hydroxyethyl starch toRinger’s acetate in patients with severe sepsis forICU fluid resuscitation [50]. The group that receivedHES had an increased risk of death at 90 days andwere more likely to require renal replacementtherapy.

The saline versus albumin fluid evaluation trialcompared albumin to saline for initial fluid resusci-tation in ICU patients and showed no difference inthe rates of organ failure, ICU time, renal replace-ment or mortality [47]. However, when the investi-gators performed a subgroup analysis of patientswith severe sepsis the adjusted odds ratio for deathwas 0.71 (95% CI: 0.52–0.97; P¼0.03) for albumin[51]. The CRISTAL trial compared a number ofcolloids to crystalloids as part of a multicountrycollaboration to assess primarily death at 28 daysand a number of secondary outcomes [52]. Overall,there was no difference at 28 days; however, 90-daymortality was lower among patients receiving




colloids. Interestingly, the colloid group also hadsignificantly more days alive without mechanicalventilation and alive without vasopressor therapy atboth 7 and 28 days. The recent Albumin Replace-ment in Patients with Severe Sepsis or Septic Shocktrial [53

&&

] randomized severe septic and septicshock patients to albumin or crystalloids for earlyfluid resuscitation (6–24 h) and to infusions of albu-min to maintain levels of 30 g/l or less. Patientsreceiving albumin had higher MAP and CVP anda lower fluid balance with the same mortality. How-ever, when only the patients with septic shock wereobserved, the albumin patients had a 6.3% higherprobability of survival at 90 days (P¼0.04) (website:http://www.criticalcarecanada.com/presentations/2013/albios_trial_%E2%80%93_albumin_in_sepsis.pdf.).

One of the criticisms of the Rivers et al. trialincluded the aggressive use of red blood cell trans-fusions for low ScvO2. Although packed red cells areuseful means of volume expansion, their use innonhemorrhagic patients is controversial. Restric-tive strategies aimed at hemoglobin greater than7.0 g/dl showed improved mortality in the lessacutely ill (APACHE II score � 20) or less than55 years of age and similar mortality to those withsignificant cardiac disease compared with hemo-globins of 10 g/dl or less [54].

Currently, the data suggest that fluid resuscita-tion in septic shock patients with albumin providessome improvement in survival and potentiallyventilator and vasopressor free days. With moredata soon to be available, the momentum mayshift again; however, the purpose will be the same:early responsible fluid resuscitation improves out-comes.

CONCLUSION

Despite decades of research into mechanisms andmany failed trials of therapeutics, mortality fromseptic shock still remains shockingly high. EDGTwas one of the first modalities to provide somebenefit, yet questions remain whether they arethe right goals. There can be no question that earlyidentification and adequate fluid resuscitation iscrucial and that over-aggressive fluid resuscitationleads to complications; however, where that break-ing point is remains unclear.

Acknowledgements

Support: Canadian Institutes of Health Research.

Conflicts of interest

Both authors state no conflict of interest.



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Fluid Choices Impact Outcome in Septic Shock