DOI 10.1378/chest.06-2535 2007;132;1967-1976 Chest

 Arthur P. Wheeler  

Management of Severe SepsisRecent Developments in the Diagnosis and

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Recent Developments in the Diagnosisand Management of Severe Sepsis*

Arthur P. Wheeler, MD, FCCP

The last 5 years have brought dramatic changes to the care of patients with severe sepsis. Whileearly diagnosis remains a challenge and, regrettably, a rapid, sensitive, and specific diagnostictest is still lacking, the methods to identify those critically ill patients who are likely to die havebecome clearer. The presence of multiple organ failure, vasopressor-dependent shock, and highvalues in formalized scoring methods such as the APACHE (acute physiology and chronic healthevaluation) and sequential organ failure assessment systems all have some utility for outcomeprediction for groups of patients. Refinements in long-used supportive practices such as lowertidal volume ventilation and enhanced glucose control have improved outcomes. A growingappreciation of the importance of timely provision of antimicrobial therapy, circulatory resusci-tation, and activated protein C administration have also improved survival. Optimal treatmentcandidates for, and the timing and dose of some treatments (eg, corticosteroids) remaincontroversial and are undergoing additional study. Perhaps the most important change in thecare of patients with severe sepsis is awareness that the syndrome is more common, lethal, andexpensive, than previously appreciated, and as such it warrants an organized approach to careprovided by experts. Although there is still much to learn, numerous studies now indicate thatimprovements in outcomes are possible when treatment protocols that incorporate all knownbeneficial therapies are applied in a timely fashion. (CHEST 2007; 132:1967–1976)

Key words: ARDS; sepsis; septic shock; severe sepsis

Abbreviations: ACTH � adrenocorticotropic hormone; ALI � acute lung injury; APACHE � acute physiology andchronic health evaluation; EGDT � early goal-directed therapy; PAC � pulmonary artery catheter; PEEP � positive end-expiratory pressure; rhAPC � recombinant human activated protein C

S everal aspects of severe sepsis treatment havedramatically changed in the last decade, although

many things remain the same.1 Then, as now, initialtreatment involved obtaining cultures, mechanically

eradicating infection sources, and giving antibioticsdirected at suspected pathogens. Historically, subse-quent management was to support failing organsystems. Patients with respiratory failure were intu-bated and ventilated with a positive end-expiratorypressure (PEEP)-fraction of inspired oxygen combi-nation to maintain a Pao2 of � 60 mm Hg, orhemoglobin saturation of � 90%. A tidal volume of10 to 15 mL/kg was mated to a respiratory ratesufficient to achieve a normal pH and Paco2, whichwere evaluated daily and after almost every ventila-tor change. High airway pressures were tolerated ifnecessary to achieve desired blood gas level targets,and barotrauma was treated with tube thoracostomy.Deep sedation alleviated visible discomfort and madepatients conform to ventilator selections, but even thenchemical paralysis was often administered. Weaningwas an intricate, highly individualized, process of grad-ual ventilator withdrawal.

*From the Medical Intensive Care Unit, Division of Allergy,Pulmonary, and Critical Care, Vanderbilt University, VanderbiltMedical Center, Nashville, TN.Dr. Wheeler has acted as a consultant for Astra-Zeneca, CubistPharmaceuticals, Cumberland Pharmaceuticals, Eli-Lilly, Sanofi-Aventis, and Takeda. He has worked for the speaker’s bureaus ofBoehringer-Ingleheim, Eli Lilly, Pfizer, and Sanofi-Aventis.Manuscript received October 16, 2006; revision accepted June 4,2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Arthur P. Wheeler, MD, FCCP, Director,Medical Intensive Care Unit, Associate Professor of Medicine,Division of Allergy, Pulmonary, and Critical Care, VanderbiltUniversity, T-1217 MCN Vanderbilt Medical Center, Nashville,TN 37232–250; e-mail: art.wheeler@vanderbilt.eduDOI: 10.1378/chest.06-2535

CHEST Recent Advances in Chest Medicine

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Frequently a pulmonary artery catheter (PAC)was inserted to confirm a low intravascular pres-sure and/or low systemic resistance before fluidswere given to achieve an arbitrary pulmonary arteryocclusion pressure (commonly, 18 mm Hg was tar-geted). Persistently hypotensive patients were regularlygiven dopamine, especially if they were oliguric. Forthe treatment of refractory hypotension, norepineph-rine was added to therapy to allow dopamine to remainin a “renal” range. Often, even modest anemia was nottolerated, and many physicians were in the habit oftransfusing at an arbitrary hemoglobin value.

So-called stress-dose corticosteroids were often ad-ministered to patients receiving long-term glucocorti-coid therapy, but only rarely would a formal adreno-corticotropic hormone (ACTH) stimulation test beperformed. For many clinicians, nutrition support wasan afterthought, and, if given, was often provided IVbecause it was accepted that the GI tract was nonfunc-tional. A blood glucose level of � 200 mg/dL wassatisfactory. Skin care and patient positioning werelow-priority measures, and preventative treatments fordeep venous thrombosis and GI bleeding were incon-sistently used.

After initial interventions, a conversation with thefamily communicated a “poor prognosis,” the beliefthat severe sepsis was due to “uncontrolled inflam-mation,” and the frustrating fact that there was nospecific treatment. Many clinicians desired a “sepsisdrug,” but pessimism over the prospect was perva-sive given the failures of numerous high-profileclinical trials.

How things have changed! The care of nearlyevery failing organ has improved, new treatmentshave been developed, older therapies have beenrefined, and some long-used treatments are now allbut abandoned. More important than the refinementof individual interventions is a growing awarenessthat it is not one but the sum of all beneficialtreatments delivered in a timely manner that resultsin recovery. Survival now has improved to the pointthat long-term outcomes including quality of life andcost-effectiveness can be studied.2,3

Definition and Case Finding

Despite many advances, some things have notchanged. Clinicians still long for a simple, reliabletest to diagnose severe sepsis because medical history,examination, routine laboratory studies, and radio-graphs often leave the diagnosis in question. Procalci-tonin and C-reactive protein have been advocated fordiagnosis, and while the former has better predictivevalue, neither has gained widespread clinical use.4Measurements of the soluble triggering receptor ex-

pressed on myeloid cells-1 remain experimental.5d-Dimer and interleukin-6 determinations are sensitivebut nonspecific, and the latter test is not clinicallyavailable.6,7 Presently, the value of total protein C levelsas a diagnostic tool for severe sepsis is limited becauseassays are not generally available in a timely fashion andmany patients do not have reduced levels at the time ofdiagnosis; it is more likely that protein C levels willprove useful as a prognostic tool.8 Ongoing studies seekto define a sensitive and specific panel of diagnosticbiomarkers.

The diagnosis of severe sepsis remains ambiguousin some physician’s minds despite a well-acceptedconsensus definition.9 This is especially true for theearly stages of the disease, which can be as subtle asaltered mental status in an elderly patient. In part,diagnostic confusion may stem from multiple defini-tions of “organ failure” or “dysfunction” that are usedin clinical practice, research studies, and consensusguidelines. For example, “renal failure” has beenalternatively defined by urine output, creatininelevel, or the need for renal replacement therapy. Indaily practice, difficulty recognizing the syndrome iscommonly voiced; however, because of the surpris-ingly consistent patient presentation, identification isusually straightforward. When recognized, the typi-cal patient has two or more failing organs, and thelungs and circulatory system are likely to be amongthem.10 These two vital organ failures are usuallymanifested clinically by the use of a ventilator andtherapy with a vasoactive drug. Although using thesesupport technologies does not guarantee that thepatient has severe sepsis, when antibiotics are con-comitantly administered it is not easy to imagine aplausible alternative diagnosis. Granted, seeking thistreatment triad will miss some patients with single-organ failure (eg, coagulopathy) and will delay diag-nosis, but it will eventually find the patients who areat high risk of dying. Earlier identification of high-risk cases can be accomplished in the emergencydepartment by recognizing hypotension or elevatedlactate levels in patients with suspected infections;however, the patient who is being taken care of on ageneral medical or a surgical floor of a hospital oftengoes unnoticed until respiratory or circulatory failureare advanced.11

Severity of Illness and OutcomePrediction

Studies in the last 5 years have undercut thelong-held belief that microorganism characteristicsare the predominant determinants of prognosis. Theidentity of the infecting organism is of little conse-quence for most patients provided that appropriate,prompt antimicrobial therapy is administered.12–14

1968 Recent Advances in Chest Medicine

The presence of coagulopathy is a powerful pre-dictor of organ failure development and subsequentdeath.15 The occurrence of shock treated with vaso-active drugs and the total number of failing organsystems are also markers of a poor prognosis.16,17 Thesignificance of these organ failures is so entrenchedthat slang is sometimes used to refer to the sickest ofthese patients (eg, “five-organ failures”). In additionto the number of organ failures, the severity of eachor the intensity of support required correlates withoutcome. For example, higher doses of vasoactivedrugs are associated with a worse prognosis thanlower doses or no vasoactive drug therapy at all.18

Understandably, advanced age and the presence ofcancer also worsen the prognosis.19–21

Substudies of large trials have also shown a rela-tionship between the severity-of-illness scores, likethe modified acute physiology and chronic healthevaluation (APACHE) II score and outcome. Suchscoring systems are not designed to predict outcomesin individual patients, and the same score may beassociated with a different mortality rate in differentcountries or even among hospitals within the samecountry.22

The baseline value, or change in plasma lactate,23

interleukin-6, and protein-C level24 have been shownto predict outcome. Of the commonly availableclinical tests, prothrombin time is perhaps the mostuseful laboratory predictor of outcome.13

Pathophysiology

The septic response was once believed to besimply exaggerated inflammation. The last decadehas brought to light a major conceptual advance.Sepsis pathophysiology is very complex and re-mains incompletely understood, but clearly in-volves inflammatory, procoagulant, antifibrino-lytic, and microvascular components25,26 that havebeen nicely summarized elsewhere.27,28

Infection Prevention

For hospitalized patients, many cases of severesepsis can be avoided by meticulous hand washing,precautions for vascular catheter insertion, and ele-vation of the head of the bed. Though these are notnew ideas, they have grown in importance. Soap andwater hand washing is more critical than ever withthe emergence of a virulent strain of Clostridiumdifficile, the spores of which are resistant to alcohol-based hand washes.29,30 The prevention of vascularcatheter-related infection has proven to be an attain-able goal by using a standardized protocol thatincorporates thoughtful site selection and insertionby an experienced operator, using full barrier pre-

cautions with chlorhexidine skin preparation, fol-lowed by careful dressing management.31,32 The useof specialized catheters that are impregnated withantimicrobial agents may also be beneficial in somesettings.33 Despite the seeming simplicity of raisingthe head of the bed to decrease the risk of nosoco-mial pneumonia, practical problems in achieving thedesired degree of elevation persist.34,35 Recent data36

also have indicated that enhanced oral hygiene usinghydrogen peroxide or antimicrobial agents can re-duce the risk of nosocomial pneumonia.

Supportive Care

There are now numerous relatively safe, simple,inexpensive measures to reduce morbidity, and insome cases mortality, in ICU patients that arguablyshould be applied broadly, even if they have not beenproven to reduce the risk of death specifically inpatients with severe sepsis. Many of these measures,including deep venous thrombosis prophylaxis, GIbleeding prophylaxis, conservative transfusion prac-tices, sedation-and-weaning protocols, standardizedenteral feeding protocols, bed-sore and fall preven-tion programs, and strategies to prevent acuterenal failure have been recommended in consen-sus statements.

Potentiality Time-Sensitive Treatments

In the last few years, six beneficial therapies havebeen identified that form the core of the SurvivingSepsis Campaign, a joint effort of numerous profes-sional organizations to expedite and standardize careof the patient with severe sepsis.37 Beneficial treat-ments are advocated collectively in “bundles,” andseveral studies outlined below have examined theeffectiveness of a standardized approach to carecompared to historical control subjects.

Antimicrobial Therapy

It makes sense to obtain cultures of blood andother suspect body fluids before the institution ofantimicrobial therapy, provided the process does notunduly delay treatment. Cultures are most usefulwhen a highly sensitive organism that can be treatedwith a simplified regimen is grown, or when anunexpected or highly resistant organism requiringthe modification of empiric therapy is recovered.Despite prompt collection in the absence of antibi-otics, findings from cultures of samples taken fromall sites remain negative in up to 20% of patients, andblood culture findings are positive in only approxi-mately one third of patients.38 Even though themajority of culture findings are negative, blood and

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spinal fluid cultures are most useful because whenthey grow an organism, it likely represents a true-positive result, compared to urine or sputum culturesin which contamination is much more common.

While it is seemingly preposterous to question theimportance of antimicrobial agents or source control,data supporting these treatments are not of the samescientific rigor as those for other sepsis therapies. Itis implausible that a randomized study will be con-ducted comparing the outcomes of patients operatedon for a ruptured appendix vs those subjected to asham operation. Likewise, the lack of equipoisedictates a study in which patients are randomized toreceive placebo vs optimal antimicrobial therapy; orprompt vs intentionally delayed treatment will notoccur. Hence, inferring an antimicrobial therapybenefit hinges on comparing the outcomes of pa-tients who receive timely, adequate, sometimescalled appropriate, antimicrobial therapy to those ofpatients who receive something less.

The problem inherent to all such nonrandomizedstudies is that there may be some unknown patientfactor or characteristic of the setting in which pa-tients are treated influencing outcomes that is inde-pendent of antibiotic selection (ie, unmeasured co-variates). Some possibilities are obvious. Patientsreceiving inadequate therapy may have fungal dis-ease or highly resistant bacteria, making the initialantibiotic choices wrong. This situation often resultsfrom patient characteristics such as immune compro-mise or chronic illness with repeated antimicrobialexposure.39–41 Another possibility relates to systemperformance. For example, outcomes could be bet-ter when patients are treated in hospitals with rapidaccess to physicians and nurses and efficient labora-tory and radiology services, all of which are factorsthat could result in faster diagnosis and appropriateantibiotic therapy.42 Attempts to control for theseand other differences cannot eliminate the possibilitythat patient groups may differ in ways that cannot bediscerned.

Despite study limitations, the ability of antimicro-bial agents to effectively treat infection before thedevelopment of organ failure is well accepted.43–45

Until the past few years, there was little evidencethat antimicrobial therapy conferred a significantbenefit to patients with established organ failure,46

but now a large retrospective analysis47 has sug-gested that time to treatment with antibiotics, evenafter the onset of shock, is a predictor of survival. Inthis analysis,47 meaningful survival differences wereobserved with as little as a 1-h delay in antimicrobialtherapy. These data are perhaps the best that willever exist to support guidelines recommendingbroad, rapid antimicrobial administration. Thesefindings will be controversial as some argue it will

lead to overuse and perhaps to the inappropriateprescription of antibiotics. In addition, there is anemerging body of literature48 to suggest that dees-calating antibiotic therapy when culture findings arenegative is a beneficial practice.

Hemodynamic Management

In the last few years, physicians treating patientswith severe sepsis have been reminded of whattrauma and burn physicians have espoused fordecades, which is that rapidly identifying patientswith inadequate circulation and providing promptresuscitation is a critical determinant of outcome.Although numerous studies, including the largerandomized Saline versus Albumin Fluid Evalua-tion study,49 have failed to definitively prove thesuperiority of colloids or crystalloids, studies insevere sepsis consistently indicate that substantialvolumes (6 to 10 L of crystalloid or its colloidequivalent) are required to restore and maintainnormal intravascular pressures.11

For patients who are hypotensive or who havepersistent lactate elevations after administration ofan initial fluid bolus, the use of an explicit hemody-namic protocol reduces hospital mortality by asmuch as 16%.11 This early goal-directed therapy(EGDT) differs in numerous respects from olderunsuccessful studies50,51 in which attempts weremade to boost oxygen delivery often long afterorgans had failed. Although the difference in out-comes might simply be prompt implementation, it ispossible that some or all protocol elements may beessential. This strategy uses therapy with vasopres-sors to achieve a mean arterial pressure of � 65 mmHg after central venous pressure is raised to 8 to 12mm Hg with fluids. A key distinction between this andother approaches is the measurement of superior venacaval oxygen saturation, targeting a value � 70%. Thisgoal is pursued by RBC transfusion for anemic patients(hematocrit, � 30%) and dobutamine therapy for pa-tients above that threshold. The application of theserules for a mere 6 h reportedly reduces the following:mortality; the fraction of patients requiring mechanicalventilation and therapy with vasopressors; time in thehospital; and costs.11

Like many therapies for severe sepsis, controversyand questions surround this approach. For example,how does the protocol recommendation for transfu-sion reconcile with studies suggesting that a lowertransfusion target may be acceptable or even bene-ficial? The answer is not known; however, becausethese patients are hemodynamically unstable, theydiffer significantly from hemodynamically stable par-ticipants who have been studied in previous transfu-

1970 Recent Advances in Chest Medicine

sion protocols.52 Curious physicians seek to identifywhich “one” protocol component is beneficial. Whilethis may be a germane research question, for thepracticing clinician trying to decide which protocolcomponent is critical it is of questionable impor-tance, considering that the protocol is brief andemploys generally conventional, inexpensive inter-ventions. However, one important unanswered ques-tion is what is the maximum time window for theapplication of this protocol beyond which benefitwanes? This question is especially important giventhat studies50 in which later attempts to modifyoxygen delivery may have been harmful. Despiteimpressive results, this protocol has not been widelyadopted.53 Potential reasons for nonadoption of theresults are the relatively small number of patientsstudied and the single-center, nonblinded design.Yet, other potential reasons for nonimplementationare an uncooperative or inadequately staffed emer-gency department; the added expense of saturationmeasuring catheters; general opposition to standard-ization of care; and uncertainty over which protocolelement is responsible for benefits.

After initial resuscitation, data from the Fluid andCatheter Treatment Trial54 indicate that among pa-tients with acute lung injury (ALI) a more conserva-tive approach to fluid management is prudent. Al-though not exclusively a study of severe sepsis, nearlytwo thirds of participants met the criteria for severesepsis (pneumonia and ALI or sepsis as the ALI riskfactor). The application of an explicit hemodynamicmanagement protocol that targets a central venouspressure (� 4 mm Hg) or pulmonary capillary occlu-sion pressure (� 8 mm Hg) after the resolution ofshock resulted in a significantly less positive netfluid balance during the first week of treatment.Although the nominally lower mortality rate (ap-proximately 3%) was not significantly different,fluid-conservative patients had more ventilator andICU-free days and a reduced duration of mechanicalventilation among survivors. These goals were reachedwithout increased risk of renal insufficiency or hypo-tension.54 Which tool is used to measure the vascularpressure used to drive the protocol (ie, central venouscatheter vs PAC) did not seem to matter, except withregard to complications where PAC-randomized pa-tients had roughly twice as many nonfatal catheter-related complications.55

Some investigators have questioned how theEGDT approach, advocating early and aggressivefluid administration, reconciles with this more con-servative approach to fluid management. Perhapsthe best explanation was articulated in an editorial56

accompanying the Fluid and Catheter TreatmentTrial publication, which posits the phase of illness asthe critical difference. A liberal fluid approach ap-

pears to be beneficial over the first 6 h of shock aspart of early goal-directed therapy, and a conserva-tive approach yields better outcomes after shockresolution.

Although several studies now suggest that therapywith dopamine does not offer significant protectionof the kidney at risk from shock or sepsis,57 it is stillbeing used by some for that purpose. Unfortunately,few data suggest that one vasopressor is superior toanother, but small randomized studies58 have sug-gested that norepinephrine is more likely to rapidlyachieve a desired BP target than other vasopressors,and do so with less tachycardia. The Sepsis Occur-rence in Acutely ill Patients study59 has suggestedthat the use of dopamine in uncontrolled practice isassociated with a higher mortality than the use ofnorepinephrine; however, studies of vasopressor useare ongoing.

The last few years have produced numerous re-ports that some septic shock patients have low levelsof vasopressin60 and that fixed-dose replacement canreduce or eliminate the need for therapy with cat-echolamines.61 Preliminary data from a large, ran-domized study evaluating norepinephrine vs vaso-pressin, the Vasopressin and Septic Shock Trial (datanot published), have been presented and do notsuggest a significant generalized benefit from vaso-pressin therapy. Hence, until the final results areavailable, this author advocates caution in the use ofvasopressin since it is a potent vasoconstrictor that maylead to splanchnic ischemia.

Normal Tidal Volume Ventilation

Some degree of ALI develops in most patientswith severe sepsis. In a study of ALI patients,62

investigators established that the use of a “normal”tidal volume (6 mL/kg) indexed to predicted bodyweight reduces absolute mortality by 9% comparedto ventilation with a traditional tidal volume of 12mL/kg. The beneficial effects of this strategy wereconfirmed among patients with sepsis as the riskfactor for ALI.63 In this approach, ventilation with 6mL/kg predicted body weight was used initially, buttidal volumes were reduced to as low as 4 mL/kg ifneeded to maintain plateau pressures at � 30 cmH2O. Although volume-cycled ventilation was used,it is reasonable to think that a pressure-cycled ap-proach could yield similar results, provided thatinflation pressures are set to deliver a tidal volume of� 6 mL/kg and corresponding plateau pressures arenot � 30 cm H2O.64 Contrary to speculation, no datahave suggested that there is a known “safe” plateaupressure or that there is an optimal tidal volumebetween 6 and 12 mL/kg.65 It is important to recog-

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nize that these studies also remind physicians thattidal volume is determined predominately by heightnot actual body weight, and that 6 mL/kg is not asmall tidal volume, but rather a normal tidal volume,just one that has not traditionally been used. Datafrom clinical practice also now suggest that the use ofa higher tidal volume in patients with ALI is associ-ated with worse outcomes66 and lung injury is morelikely to develop in patients without ALI who havereceived ventilation with higher tidal volumes.67

Given that a normal-tidal-volume strategy has noadded cost, does not require additional sedation orparalysis,68 and is quick and simple to implement forthe majority patients, it represents a reasonablestarting point for ventilation of ALI patients.

Because low-level PEEP has inhibited atelectasisformation and has attenuated the development ofALI in animal models of lung injury,69,70 somenominal level of PEEP (approximately 5 cm H2O)should probably be supplied to all patients. Beyondthis minimal recommendation, the selection of PEEPand inspired oxygen concentration should maintainsaturations in the range of 88 to 95% (or an equivalentPao2 range) while avoiding potentially toxic inspiredoxygen concentrations and excessive lung stretch. Nei-ther higher levels of PEEP nor the titration of PEEP tolung compliance or lower inflection point of the pres-sure-volume curve (or Pflex) values have been consis-tently shown to produce superior outcomes comparedto a simpler approach, provided that tidal volumes arereduced.71 Ventilation strategies that give a high prior-ity to “recruitment” clearly can improve radiographicimages of the lung and indexes of oxygenation, but, todate, have not translated into improved patient out-comes.72

Glucocorticoids and Mineralocorticoidsfor Septic Shock

Numerous trials73 using short courses of high-dose corticosteroids in patients with severe sepsishave failed to improve survival. Nonetheless, inthe last few years interest in lower doses ofglucocorticoids has been revived as a concepttermed relative adrenal insufficiency. In a widelydiscussed study74 of septic shock, approximately300 patients who were identified within 8 h ofshock onset were randomized to receive hydrocor-tisone plus fludrocortisone or placebo for 7 days.When evaluating all patients, the time to deathmay have been altered somewhat, but there was nodifference in the 28-day, ICU, hospital, or 1-yearmortality rate between treated patients and pla-cebo recipients. Subsequent analyses found thatfor patients who failed to increase their total

plasma cortisol levels by at least 9 �g/dL followingadministration of a 250-�g ACTH stimulationdose, there was approximately a 10% absolutereduction in adjusted mortality associated withtreatment.74 The smaller group of responders toACTH had a nominally higher mortality rate ifthey were treated compared to those receivingplacebo, although this difference was not statisti-cally significant.

This study caused controversy and stimulated ad-ditional study. Since the benefit appears confined toACTH nonresponders, perhaps the most pressingunanswered question is whether it is necessary toconduct an ACTH stimulation test. This is a signifi-cant issue in many hospitals, where the results ofcortisol tests are not available for days. Anotherproblem is clinician skepticism about whether pa-tients with high baseline cortisol values could benefitfrom receiving even more glucocorticoid therapymerely because they failed to raise plasma cortisollevels after the administration of ACTH. Along thoselines, some researchers75 have claimed that a morerelevant provocation test may be 1 �g of ACTH.Some publications76 illustrating a poor correlationbetween free and total cortisol levels have ques-tioned the soundness of using total cortisol level as amarker. Some physicians have also expressed doubtregarding the need to include fludrocortisone be-cause of the volume of fluids that has been admin-istered.

The outcomes of patients who were given variousdoses of corticosteroids in usual practice may besubstantially different. When examined as part of atrial of activated protein C, corticosteroid-treatedpatients had a lower survival rate than those nottreated with corticosteroids regardless of treatmentwith activated protein C.77 Despite these questions,a number of clinicians have adopted glucocorticoidtherapy for the treatment of patients with severesepsis without shock, or with shock of prolongedduration, perhaps based on the recommendations ofsome authors for broad use.78

Hopefully, the final results of a follow-up study79

of glucocorticoid supplementation in patients withseptic shock will help to clarify the role of cortico-steroids. Unfortunately, preliminary results suggestlittle benefit. Nevertheless, for the time being itseems prudent to this author to administer glucocor-ticoids and mineralocorticoids to ACTH (250 �g)nonresponders with early shock that is refractory tofluid administration, since that is how the primarystudy showing benefit was conducted. Omitting themineralocorticoid or the ACTH stimulation test withthe assumption that they are unimportant impliesthat one can discern which component of a complexprotocol accounts for the benefit.

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Glucose Control

Substantial data indicate that long-term inade-quate glycemic control in diabetic patients is associ-ated with poor long-term prognosis and that theoutcomes of heterogeneous populations of criticallyill patients are worse if they are hyperglycemic.80

Now this concept has been extended to patients withor at risk of severe sepsis. In a prominent study81 ofapproximately 1,500 postoperative patients, a proto-col in which glucose was targeted to a range of 80 to110 mg/dL gained substantial benefits compared topatients with less stringent control. An ICU andhospital mortality rate reduction of slightly � 3%was observed, with the greatest differences seen inthe sickest patients.81 Although this was not a studyof patients with established severe sepsis, the sug-gestion that glucose control could reduce the inci-dence of sepsis and improve outcomes is reasonable.

Many were disappointed when subsequent stud-ies,82 including one of medical ICU patients, failedto show an overall mortality benefit even thoughintensive insulin therapy reduced renal injury andlessened time on the ventilator in the ICU and in thehospital. Debate followed the observation that pa-tients with shorter stays (� 3 days) may actually havean increased mortality rate from treatment, whereasbenefit was observed for those with longer stays. Therelevance of this finding to practitioners caring forpatients with severe sepsis is questionable becausethey rarely stay � 3 days.

Because it is hard to think of a reason that patientswould benefit from hyperglycemia of a significantdegree, it makes sense to follow the recommenda-tions for maintaining glucose levels at � 150 mg/dL,and maybe even in the range of 80 to 110 mg/dL.Despite rapid widespread adoption, many questionsremain regarding glucose control, the most impor-tant of which are the following: does glycemic con-trol improve the outcomes of patients with estab-lished sepsis, and what is the optimal glucose targetand protocol that maximizes benefit while minimiz-ing hypoglycemia? Although it is not certain, aprotocol may be even more important if corticoste-roids are utilized as part of therapy for shock. Itappears that the benefit results from the glucosecontrol, not the dose of insulin administered.83,84

Drotrecogin Alfa Activated

The last few years have seen release of the firstdrug for the treatment of severe sepsis. Drotrecoginalfa activated, also known as recombinant humanactivated protein C (rhAPC) has been shown in alarge randomized, multicenter, placebo-controlledtrial85 to reduce the absolute mortality of patients

with severe sepsis by approximately 6%. Long-termfollow-up demonstrated a persistent survival benefit2 to 3 years after treatment.86 In addition, treatedpatients had a shorter time spent receiving therapywith vasopressors and ventilation compared to pla-cebo.87 When defined as a modified APACHE IIscore of � 25, the absolute mortality reduction in“high-risk-of-death” patients was 13%. Similar to theEGDT and glucocorticoid studies, designating asubgroup with a larger survival benefit than thewhole dictates that there must be a complementarygroup with a lesser benefit. Subsequent study of aheterogeneous group of “low-risk-of-death” patientsconfirmed that such patients do not experience asurvival benefit but still incur the roughly 1 to 2%increase in serious bleeding risk compared to placebo.88

In controlled trials,85,88 the increase in the risk ofintracranial hemorrhage is in the range of 0.1 to0.3%. Preliminary reports89 have indicated that in arelatively small study of a heterogeneous group ofchildren no survival benefit was observed.

Similar to the temporal effect seen in studies ofantimicrobial therapy, a large open-label trial and amultihospital case series90 found a that patientstreated with rhAPC within the first day after severesepsis developed had a higher survival rate comparedto the second day. Earlier treatment was also asso-ciated with less time receiving ventilation in the ICUand in the hospital. The results of a large retrospec-tive analysis91 of all patients treated in controlledtrials in the first 24 h of sepsis to those treated in thesecond 24 h of sepsis support the observation thatearlier treatment is better than later treatment. Formany clinicians, the survival benefit, and data sug-gesting that a shorter time spent receiving mechan-ical ventilation in patients with shock in the ICU andin the hospital compared to those receiving placebo,is not sufficiently compelling to justify the costs ofrhAPC, despite numerous analyses suggesting cost-effectiveness.92,93

Changing Practice

Perhaps the most exciting development is thedemonstration by numerous institutions that a stan-dardized procedure or protocol can be used toimprove process and outcomes, including survivaland time spent on the ventilator, in the ICU and inthe hospital. Collectively, hospitals initiating proto-cols have shown that best practices are achieved in ahigher fraction of patients, and the time to beginalmost all beneficial treatments decreases; with earlyintervention, many other treatments such as pulmo-nary artery catheterization and mechanical ventila-tion decrease in use. For institutions that have

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investigated,94–97 costs are reduced by protocol-directed care. Reports98 are now emerging that thefailure to meet the treatment goals of the early orlate phase of the surviving sepsis bundles results inincreased mortality. Although some have questionedthe motivation for recommendations and protocoldevelopment, published data94–98 support the find-ing that a “bundled” approach to care is associatedwith improved outcomes.

Conclusion

The last 5 years have produced significant im-provements in the care of patients with severe sepsis,including organ support and direct treatment of theunderlying inflammatory and coagulopathic process.Although the treatments advocated today are almostcertainly not the best that will ever be known, theyare the best known now. Daily clinicians are facedwith the following simple choice: ignore existingevidence because it may have some flaws and isincomplete in favor of non-evidence-based practice,or promptly provide all the treatments we now knowto increase our patient’s chance of survival unlessthere is a compelling reason not to do so.

References1 Marini JJ, Wheeler AP. Critical care medicine: the essentials.

2nd ed. Baltimore, MD: Williams and Wilkens, 19972 Herridge MS, Cheung AM, Tansey CM, et al. One-year

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1976 Recent Advances in Chest Medicine

DOI 10.1378/chest.06-2535 2007;132;1967-1976 Chest

Arthur P. Wheeler Sepsis

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