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The last 5 years have brought dramatic changes to the care of patients with severe sepsis. Methods to identify those critically ill patients who are likely to die have become clearer. Optimal treatment candidates for, and the timing and dose of some treatments remain controversial.
The last 5 years have brought dramatic changes to the care of patients with severe sepsis. Methods to identify those critically ill patients who are likely to die have become clearer. Optimal treatment candidates for, and the timing and dose of some treatments remain controversial.
The last 5 years have brought dramatic changes to the care of patients with severe sepsis. Methods to identify those critically ill patients who are likely to die have become clearer. Optimal treatment candidates for, and the timing and dose of some treatments remain controversial.
Recent Developments in the Diagnosis and http://chestjournal.org/cgi/content/abstract/132/6/1967 and services can be found online on the World Wide Web at: The online version of this article, along with updated information ). ISSN: 0012-3692. http://www.chestjournal.org/misc/reprints.shtml ( of the copyright holder may be reproduced or distributed without the prior written permission Northbrook IL 60062. All rights reserved. No part of this article or PDF by the American College of Chest Physicians, 3300 Dundee Road, 2007 Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest Copyright 2007 by American College of Chest Physicians on June 27, 2008 chestjournal.org Downloaded from Recent Developments in the Diagnosis and 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. While early diagnosis remains a challenge and, regrettably, a rapid, sensitive, and specific diagnostic test is still lacking, the methods to identify those critically ill patients who are likely to die have become clearer. The presence of multiple organ failure, vasopressor-dependent shock, and high values in formalized scoring methods such as the APACHE (acute physiology and chronic health evaluation) and sequential organ failure assessment systems all have some utility for outcome prediction for groups of patients. Refinements in long-used supportive practices such as lower tidal volume ventilation and enhanced glucose control have improved outcomes. A growing appreciation of the importance of timely provision of antimicrobial therapy, circulatory resusci- tation, and activated protein C administration have also improved survival. Optimal treatment candidates for, and the timing and dose of some treatments (eg, corticosteroids) remain controversial and are undergoing additional study. Perhaps the most important change in the care of patients with severe sepsis is awareness that the syndrome is more common, lethal, and expensive, than previously appreciated, and as such it warrants an organized approach to care provided by experts. Although there is still much to learn, numerous studies now indicate that improvements in outcomes are possible when treatment protocols that incorporate all known beneficial therapies are applied in a timely fashion. (CHEST 2007; 132:19671976) Key words: ARDS; sepsis; septic shock; severe sepsis Abbreviations: ACTH adrenocorticotropic hormone; ALI acute lung injury; APACHE acute physiology and chronic health evaluation; EGDTearly goal-directed therapy; PACpulmonary artery catheter; PEEPpositive end- expiratory pressure; rhAPCrecombinant human activated protein C S everal aspects of severe sepsis treatment have dramatically changed in the last decade, although many things remain the same. 1 Then, as now, initial treatment involved obtaining cultures, mechanically eradicating infection sources, and giving antibiotics directed at suspected pathogens. Historically, subse- quent management was to support failing organ systems. Patients with respiratory failure were intu- bated and ventilated with a positive end-expiratory pressure (PEEP)-fraction of inspired oxygen combi- nation to maintain a Pao 2 of 60 mm Hg, or hemoglobin saturation of 90%. A tidal volume of 10 to 15 mL/kg was mated to a respiratory rate sufficient to achieve a normal pH and Paco 2 , which were evaluated daily and after almost every ventila- tor change. High airway pressures were tolerated if necessary to achieve desired blood gas level targets, and barotrauma was treated with tube thoracostomy. Deep sedation alleviated visible discomfort and made patients conform to ventilator selections, but even then chemical paralysis was often administered. Weaning was 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, Vanderbilt Medical Center, Nashville, TN. Dr. Wheeler has acted as a consultant for Astra-Zeneca, Cubist Pharmaceuticals, Cumberland Pharmaceuticals, Eli-Lilly, Sanofi- Aventis, and Takeda. He has worked for the speakers bureaus of Boehringer-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 permission from 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, Vanderbilt University, T-1217 MCN Vanderbilt Medical Center, Nashville, TN 37232250; e-mail: art.wheeler@vanderbilt.edu DOI: 10.1378/chest.06-2535 CHESTRecent Advances in Chest Medicine www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1967 Frequently a pulmonary artery catheter (PAC) was inserted to confirm a low intravascular pres- sure and/or low systemic resistance before fluids were given to achieve an arbitrary pulmonary artery occlusion pressure (commonly, 18 mm Hg was tar- geted). Persistently hypotensive patients were regularly given dopamine, especially if they were oliguric. For the treatment of refractory hypotension, norepineph- rine was added to therapy to allow dopamine to remain in a renal range. Often, even modest anemia was not tolerated, and many physicians were in the habit of transfusing 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 be performed. For many clinicians, nutrition support was an afterthought, and, if given, was often provided IV because it was accepted that the GI tract was nonfunc- tional. A blood glucose level of 200 mg/dL was satisfactory. Skin care and patient positioning were low-priority measures, and preventative treatments for deep venous thrombosis and GI bleeding were incon- sistently used. After initial interventions, a conversation with the family communicated a poor prognosis, the belief that severe sepsis was due to uncontrolled inflam- mation, and the frustrating fact that there was no specific treatment. Many clinicians desired a sepsis drug, but pessimism over the prospect was perva- sive given the failures of numerous high-profile clinical trials. How things have changed! The care of nearly every failing organ has improved, new treatments have been developed, older therapies have been refined, and some long-used treatments are now all but abandoned. More important than the refinement of individual interventions is a growing awareness that it is not one but the sum of all beneficial treatments delivered in a timely manner that results in recovery. Survival now has improved to the point that long-term outcomes including quality of life and cost-effectiveness can be studied. 2,3 Definition and Case Finding Despite many advances, some things have not changed. Clinicians still long for a simple, reliable test 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 for diagnosis, and while the former has better predictive value, neither has gained widespread clinical use. 4 Measurements of the soluble triggering receptor ex- pressed on myeloid cells-1 remain experimental. 5 d-Dimer and interleukin-6 determinations are sensitive but nonspecific, and the latter test is not clinically available. 6,7 Presently, the value of total protein Clevels as a diagnostic tool for severe sepsis is limited because assays are not generally available in a timely fashion and many patients do not have reduced levels at the time of diagnosis; it is more likely that protein C levels will prove useful as a prognostic tool. 8 Ongoing studies seek to define a sensitive and specific panel of diagnostic biomarkers. The diagnosis of severe sepsis remains ambiguous in some physicians minds despite a well-accepted consensus definition. 9 This is especially true for the early stages of the disease, which can be as subtle as altered mental status in an elderly patient. In part, diagnostic confusion may stem from multiple defini- tions of organ failure or dysfunction that are used in clinical practice, research studies, and consensus guidelines. For example, renal failure has been alternatively defined by urine output, creatinine level, or the need for renal replacement therapy. In daily practice, difficulty recognizing the syndrome is commonly voiced; however, because of the surpris- ingly consistent patient presentation, identification is usually straightforward. When recognized, the typi- cal patient has two or more failing organs, and the lungs and circulatory system are likely to be among them. 10 These two vital organ failures are usually manifested clinically by the use of a ventilator and therapy with a vasoactive drug. Although using these support technologies does not guarantee that the patient has severe sepsis, when antibiotics are con- comitantly administered it is not easy to imagine a plausible alternative diagnosis. Granted, seeking this treatment triad will miss some patients with single- organ failure (eg, coagulopathy) and will delay diag- nosis, but it will eventually find the patients who are at high risk of dying. Earlier identification of high- risk cases can be accomplished in the emergency department by recognizing hypotension or elevated lactate levels in patients with suspected infections; however, the patient who is being taken care of on a general medical or a surgical floor of a hospital often goes unnoticed until respiratory or circulatory failure are advanced. 11 Severity of Illness and Outcome Prediction Studies in the last 5 years have undercut the long-held belief that microorganism characteristics are the predominant determinants of prognosis. The identity of the infecting organism is of little conse- quence for most patients provided that appropriate, prompt antimicrobial therapy is administered. 1214 1968 Recent Advances in Chest Medicine The presence of coagulopathy is a powerful pre- dictor of organ failure development and subsequent death. 15 The occurrence of shock treated with vaso- active drugs and the total number of failing organ systems are also markers of a poor prognosis. 16,17 The significance of these organ failures is so entrenched that slang is sometimes used to refer to the sickest of these patients (eg, five-organ failures). In addition to the number of organ failures, the severity of each or the intensity of support required correlates with outcome. For example, higher doses of vasoactive drugs are associated with a worse prognosis than lower doses or no vasoactive drug therapy at all. 18 Understandably, advanced age and the presence of cancer also worsen the prognosis. 1921 Substudies of large trials have also shown a rela- tionship between the severity-of-illness scores, like the modified acute physiology and chronic health evaluation (APACHE) II score and outcome. Such scoring systems are not designed to predict outcomes in individual patients, and the same score may be associated with a different mortality rate in different countries or even among hospitals within the same country. 22 The baseline value, or change in plasma lactate, 23 interleukin-6, and protein-C level 24 have been shown to predict outcome. Of the commonly available clinical tests, prothrombin time is perhaps the most useful laboratory predictor of outcome. 13 Pathophysiology The septic response was once believed to be simply exaggerated inflammation. The last decade has 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 components 25,26 that have been nicely summarized elsewhere. 27,28 Infection Prevention For hospitalized patients, many cases of severe sepsis can be avoided by meticulous hand washing, precautions for vascular catheter insertion, and ele- vation of the head of the bed. Though these are not new ideas, they have grown in importance. Soap and water hand washing is more critical than ever with the emergence of a virulent strain of Clostridium difficile, the spores of which are resistant to alcohol- based hand washes. 29,30 The prevention of vascular catheter-related infection has proven to be an attain- able goal by using a standardized protocol that incorporates thoughtful site selection and insertion by an experienced operator, using full barrier pre- cautions with chlorhexidine skin preparation, fol- lowed by careful dressing management. 31,32 The use of specialized catheters that are impregnated with antimicrobial agents may also be beneficial in some settings. 33 Despite the seeming simplicity of raising the head of the bed to decrease the risk of nosoco- mial pneumonia, practical problems in achieving the desired degree of elevation persist. 34,35 Recent data 36 also have indicated that enhanced oral hygiene using hydrogen 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 in some cases mortality, in ICU patients that arguably should be applied broadly, even if they have not been proven to reduce the risk of death specifically in patients with severe sepsis. Many of these measures, including deep venous thrombosis prophylaxis, GI bleeding prophylaxis, conservative transfusion prac- tices, sedation-and-weaning protocols, standardized enteral feeding protocols, bed-sore and fall preven- tion programs, and strategies to prevent acute renal failure have been recommended in consen- sus statements. Potentiality Time-Sensitive Treatments In the last few years, six beneficial therapies have been identified that form the core of the Surviving Sepsis Campaign, a joint effort of numerous profes- sional organizations to expedite and standardize care of the patient with severe sepsis. 37 Beneficial treat- ments are advocated collectively in bundles, and several studies outlined below have examined the effectiveness of a standardized approach to care compared to historical control subjects. Antimicrobial Therapy It makes sense to obtain cultures of blood and other suspect body fluids before the institution of antimicrobial therapy, provided the process does not unduly delay treatment. Cultures are most useful when a highly sensitive organism that can be treated with a simplified regimen is grown, or when an unexpected or highly resistant organism requiring the modification of empiric therapy is recovered. Despite prompt collection in the absence of antibi- otics, findings from cultures of samples taken from all sites remain negative in up to 20% of patients, and blood culture findings are positive in only approxi- mately one third of patients. 38 Even though the majority of culture findings are negative, blood and www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1969 spinal fluid cultures are most useful because when they grow an organism, it likely represents a true- positive result, compared to urine or sputum cultures in which contamination is much more common. While it is seemingly preposterous to question the importance of antimicrobial agents or source control, data supporting these treatments are not of the same scientific rigor as those for other sepsis therapies. It is implausible that a randomized study will be con- ducted comparing the outcomes of patients operated on for a ruptured appendix vs those subjected to a sham operation. Likewise, the lack of equipoise dictates a study in which patients are randomized to receive placebo vs optimal antimicrobial therapy; or prompt vs intentionally delayed treatment will not occur. Hence, inferring an antimicrobial therapy benefit hinges on comparing the outcomes of pa- tients who receive timely, adequate, sometimes called appropriate, antimicrobial therapy to those of patients who receive something less. The problem inherent to all such nonrandomized studies is that there may be some unknown patient factor 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. Patients receiving inadequate therapy may have fungal dis- ease or highly resistant bacteria, making the initial antibiotic choices wrong. This situation often results from patient characteristics such as immune compro- mise or chronic illness with repeated antimicrobial exposure. 3941 Another possibility relates to system performance. For example, outcomes could be bet- ter when patients are treated in hospitals with rapid access to physicians and nurses and efficient labora- tory and radiology services, all of which are factors that could result in faster diagnosis and appropriate antibiotic therapy. 42 Attempts to control for these and other differences cannot eliminate the possibility that patient groups may differ in ways that cannot be discerned. Despite study limitations, the ability of antimicro- bial agents to effectively treat infection before the development of organ failure is well accepted. 4345 Until the past few years, there was little evidence that antimicrobial therapy conferred a significant benefit to patients with established organ failure, 46 but now a large retrospective analysis 47 has sug- gested that time to treatment with antibiotics, even after the onset of shock, is a predictor of survival. In this analysis, 47 meaningful survival differences were observed with as little as a 1-h delay in antimicrobial therapy. These data are perhaps the best that will ever exist to support guidelines recommending broad, rapid antimicrobial administration. These findings will be controversial as some argue it will lead to overuse and perhaps to the inappropriate prescription of antibiotics. In addition, there is an emerging body of literature 48 to suggest that dees- calating antibiotic therapy when culture findings are negative is a beneficial practice. Hemodynamic Management In the last few years, physicians treating patients with severe sepsis have been reminded of what trauma and burn physicians have espoused for decades, which is that rapidly identifying patients with inadequate circulation and providing prompt resuscitation is a critical determinant of outcome. Although numerous studies, including the large randomized Saline versus Albumin Fluid Evalua- tion study, 49 have failed to definitively prove the superiority of colloids or crystalloids, studies in severe sepsis consistently indicate that substantial volumes (6 to 10 L of crystalloid or its colloid equivalent) are required to restore and maintain normal intravascular pressures. 11 For patients who are hypotensive or who have persistent lactate elevations after administration of an initial fluid bolus, the use of an explicit hemody- namic protocol reduces hospital mortality by as much as 16%. 11 This early goal-directed therapy (EGDT) differs in numerous respects from older unsuccessful studies 50,51 in which attempts were made to boost oxygen delivery often long after organs had failed. Although the difference in out- comes might simply be prompt implementation, it is possible that some or all protocol elements may be essential. This strategy uses therapy with vasopres- sors to achieve a mean arterial pressure of 65 mm Hg after central venous pressure is raised to 8 to 12 mm Hg with fluids. A key distinction between this and other approaches is the measurement of superior vena caval oxygen saturation, targeting a value 70%. This goal is pursued by RBC transfusion for anemic patients (hematocrit, 30%) and dobutamine therapy for pa- tients above that threshold. The application of these rules for a mere 6 h reportedly reduces the following: mortality; the fraction of patients requiring mechanical ventilation and therapy with vasopressors; time in the hospital; and costs. 11 Like many therapies for severe sepsis, controversy and questions surround this approach. For example, how does the protocol recommendation for transfu- sion reconcile with studies suggesting that a lower transfusion target may be acceptable or even bene- ficial? The answer is not known; however, because these patients are hemodynamically unstable, they differ 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 identify which one protocol component is beneficial. While this may be a germane research question, for the practicing clinician trying to decide which protocol component is critical it is of questionable impor- tance, considering that the protocol is brief and employs generally conventional, inexpensive inter- ventions. However, one important unanswered ques- tion is what is the maximum time window for the application of this protocol beyond which benefit wanes? This question is especially important given that studies 50 in which later attempts to modify oxygen delivery may have been harmful. Despite impressive results, this protocol has not been widely adopted. 53 Potential reasons for nonadoption of the results are the relatively small number of patients studied and the single-center, nonblinded design. Yet, other potential reasons for nonimplementation are an uncooperative or inadequately staffed emer- gency department; the added expense of saturation measuring catheters; general opposition to standard- ization of care; and uncertainty over which protocol element is responsible for benefits. After initial resuscitation, data from the Fluid and Catheter Treatment Trial 54 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, nearly two thirds of participants met the criteria for severe sepsis (pneumonia and ALI or sepsis as the ALI risk factor). The application of an explicit hemodynamic management protocol that targets a central venous pressure ( 4 mm Hg) or pulmonary capillary occlu- sion pressure ( 8 mm Hg) after the resolution of shock resulted in a significantly less positive net fluid 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 and ICU-free days and a reduced duration of mechanical ventilation among survivors. These goals were reached without increased risk of renal insufficiency or hypo- tension. 54 Which tool is used to measure the vascular pressure used to drive the protocol (ie, central venous catheter vs PAC) did not seem to matter, except with regard to complications where PAC-randomized pa- tients had roughly twice as many nonfatal catheter- related complications. 55 Some investigators have questioned how the EGDT approach, advocating early and aggressive fluid administration, reconciles with this more con- servative approach to fluid management. Perhaps the best explanation was articulated in an editorial 56 accompanying the Fluid and Catheter Treatment Trial publication, which posits the phase of illness as the critical difference. A liberal fluid approach ap- pears to be beneficial over the first 6 h of shock as part of early goal-directed therapy, and a conserva- tive approach yields better outcomes after shock resolution. Although several studies now suggest that therapy with dopamine does not offer significant protection of the kidney at risk from shock or sepsis, 57 it is still being used by some for that purpose. Unfortunately, few data suggest that one vasopressor is superior to another, but small randomized studies 58 have sug- gested that norepinephrine is more likely to rapidly achieve a desired BP target than other vasopressors, and do so with less tachycardia. The Sepsis Occur- rence in Acutely ill Patients study 59 has suggested that the use of dopamine in uncontrolled practice is associated with a higher mortality than the use of norepinephrine; however, studies of vasopressor use are ongoing. The last few years have produced numerous re- ports that some septic shock patients have low levels of vasopressin 60 and that fixed-dose replacement can reduce 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 (data not published), have been presented and do not suggest a significant generalized benefit from vaso- pressin therapy. Hence, until the final results are available, this author advocates caution in the use of vasopressin since it is a potent vasoconstrictor that may lead to splanchnic ischemia. Normal Tidal Volume Ventilation Some degree of ALI develops in most patients with 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 body weight reduces absolute mortality by 9% compared to ventilation with a traditional tidal volume of 12 mL/kg. The beneficial effects of this strategy were confirmed among patients with sepsis as the risk factor for ALI. 63 In this approach, ventilation with 6 mL/kg predicted body weight was used initially, but tidal volumes were reduced to as low as 4 mL/kg if needed to maintain plateau pressures at 30 cm H 2 O. Although volume-cycled ventilation was used, it is reasonable to think that a pressure-cycled ap- proach could yield similar results, provided that inflation pressures are set to deliver a tidal volume of 6 mL/kg and corresponding plateau pressures are not 30 cm H 2 O. 64 Contrary to speculation, no data have suggested that there is a known safe plateau pressure or that there is an optimal tidal volume between 6 and 12 mL/kg. 65 It is important to recog- www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1971 nize that these studies also remind physicians that tidal volume is determined predominately by height not actual body weight, and that 6 mL/kg is not a small tidal volume, but rather a normal tidal volume, just one that has not traditionally been used. Data from clinical practice also now suggest that the use of a higher tidal volume in patients with ALI is associ- ated with worse outcomes 66 and lung injury is more likely to develop in patients without ALI who have received ventilation with higher tidal volumes. 67 Given that a normal-tidal-volume strategy has no added cost, does not require additional sedation or paralysis, 68 and is quick and simple to implement for the majority patients, it represents a reasonable starting point for ventilation of ALI patients. Because low-level PEEP has inhibited atelectasis formation and has attenuated the development of ALI in animal models of lung injury, 69,70 some nominal level of PEEP (approximately 5 cm H 2 O) should probably be supplied to all patients. Beyond this minimal recommendation, the selection of PEEP and inspired oxygen concentration should maintain saturations in the range of 88 to 95% (or an equivalent Pao 2 range) while avoiding potentially toxic inspired oxygen concentrations and excessive lung stretch. Nei- ther higher levels of PEEP nor the titration of PEEP to lung compliance or lower inflection point of the pres- sure-volume curve (or Pflex) values have been consis- tently shown to produce superior outcomes compared to a simpler approach, provided that tidal volumes are reduced. 71 Ventilation strategies that give a high prior- ity to recruitment clearly can improve radiographic images of the lung and indexes of oxygenation, but, to date, have not translated into improved patient out- comes. 72 Glucocorticoids and Mineralocorticoids for Septic Shock Numerous trials 73 using short courses of high- dose corticosteroids in patients with severe sepsis have failed to improve survival. Nonetheless, in the last few years interest in lower doses of glucocorticoids has been revived as a concept termed relative adrenal insufficiency. In a widely discussed study 74 of septic shock, approximately 300 patients who were identified within 8 h of shock onset were randomized to receive hydrocor- tisone plus fludrocortisone or placebo for 7 days. When evaluating all patients, the time to death may have been altered somewhat, but there was no difference in the 28-day, ICU, hospital, or 1-year mortality rate between treated patients and pla- cebo recipients. Subsequent analyses found that for patients who failed to increase their total plasma cortisol levels by at least 9 g/dL following administration of a 250-g ACTH stimulation dose, there was approximately a 10% absolute reduction in adjusted mortality associated with treatment. 74 The smaller group of responders to ACTH had a nominally higher mortality rate if they were treated compared to those receiving placebo, although this difference was not statisti- cally significant. This study caused controversy and stimulated ad- ditional study. Since the benefit appears confined to ACTH nonresponders, perhaps the most pressing unanswered question is whether it is necessary to conduct an ACTH stimulation test. This is a signifi- cant issue in many hospitals, where the results of cortisol tests are not available for days. Another problem is clinician skepticism about whether pa- tients with high baseline cortisol values could benefit from receiving even more glucocorticoid therapy merely because they failed to raise plasma cortisol levels after the administration of ACTH. Along those lines, some researchers 75 have claimed that a more relevant provocation test may be 1 g of ACTH. Some publications 76 illustrating a poor correlation between free and total cortisol levels have ques- tioned the soundness of using total cortisol level as a marker. Some physicians have also expressed doubt regarding the need to include fludrocortisone be- cause of the volume of fluids that has been admin- istered. The outcomes of patients who were given various doses of corticosteroids in usual practice may be substantially different. When examined as part of a trial of activated protein C, corticosteroid-treated patients had a lower survival rate than those not treated with corticosteroids regardless of treatment with activated protein C. 77 Despite these questions, a number of clinicians have adopted glucocorticoid therapy for the treatment of patients with severe sepsis without shock, or with shock of prolonged duration, perhaps based on the recommendations of some authors for broad use. 78 Hopefully, the final results of a follow-up study 79 of glucocorticoid supplementation in patients with septic shock will help to clarify the role of cortico- steroids. Unfortunately, preliminary results suggest little benefit. Nevertheless, for the time being it seems prudent to this author to administer glucocor- ticoids and mineralocorticoids to ACTH (250 g) nonresponders with early shock that is refractory to fluid administration, since that is how the primary study showing benefit was conducted. Omitting the mineralocorticoid or the ACTH stimulation test with the assumption that they are unimportant implies that one can discern which component of a complex protocol accounts for the benefit. 1972 Recent Advances in Chest Medicine 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 the outcomes of heterogeneous populations of critically ill patients are worse if they are hyperglycemic. 80 Now this concept has been extended to patients with or at risk of severe sepsis. In a prominent study 81 of approximately 1,500 postoperative patients, a proto- col in which glucose was targeted to a range of 80 to 110 mg/dL gained substantial benefits compared to patients with less stringent control. An ICU and hospital mortality rate reduction of slightly 3% was observed, with the greatest differences seen in the sickest patients. 81 Although this was not a study of 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, failed to show an overall mortality benefit even though intensive insulin therapy reduced renal injury and lessened time on the ventilator in the ICU and in the hospital. Debate followed the observation that pa- tients with shorter stays ( 3 days) may actually have an increased mortality rate from treatment, whereas benefit was observed for those with longer stays. The relevance of this finding to practitioners caring for patients with severe sepsis is questionable because they rarely stay 3 days. Because it is hard to think of a reason that patients would benefit from hyperglycemia of a significant degree, 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 questions remain 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 target and protocol that maximizes benefit while minimiz- ing hypoglycemia? Although it is not certain, a protocol may be even more important if corticoste- roids are utilized as part of therapy for shock. It appears that the benefit results from the glucose control, not the dose of insulin administered. 83,84 Drotrecogin Alfa Activated The last few years have seen release of the first drug for the treatment of severe sepsis. Drotrecogin alfa activated, also known as recombinant human activated protein C (rhAPC) has been shown in a large randomized, multicenter, placebo-controlled trial 85 to reduce the absolute mortality of patients with severe sepsis by approximately 6%. Long-term follow-up demonstrated a persistent survival benefit 2 to 3 years after treatment. 86 In addition, treated patients had a shorter time spent receiving therapy with vasopressors and ventilation compared to pla- cebo. 87 When defined as a modified APACHE II score of 25, the absolute mortality reduction in high-risk-of-death patients was 13%. Similar to the EGDT and glucocorticoid studies, designating a subgroup with a larger survival benefit than the whole dictates that there must be a complementary group with a lesser benefit. Subsequent study of a heterogeneous group of low-risk-of-death patients confirmed that such patients do not experience a survival 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 of intracranial hemorrhage is in the range of 0.1 to 0.3%. Preliminary reports 89 have indicated that in a relatively small study of a heterogeneous group of children no survival benefit was observed. Similar to the temporal effect seen in studies of antimicrobial therapy, a large open-label trial and a multihospital case series 90 found a that patients treated with rhAPC within the first day after severe sepsis developed had a higher survival rate compared to the second day. Earlier treatment was also asso- ciated with less time receiving ventilation in the ICU and in the hospital. The results of a large retrospec- tive analysis 91 of all patients treated in controlled trials in the first 24 h of sepsis to those treated in the second 24 h of sepsis support the observation that earlier treatment is better than later treatment. For many clinicians, the survival benefit, and data sug- gesting that a shorter time spent receiving mechan- ical ventilation in patients with shock in the ICU and in the hospital compared to those receiving placebo, is not sufficiently compelling to justify the costs of rhAPC, despite numerous analyses suggesting cost- effectiveness. 92,93 Changing Practice Perhaps the most exciting development is the demonstration by numerous institutions that a stan- dardized procedure or protocol can be used to improve process and outcomes, including survival and time spent on the ventilator, in the ICU and in the hospital. Collectively, hospitals initiating proto- cols have shown that best practices are achieved in a higher fraction of patients, and the time to begin almost all beneficial treatments decreases; with early intervention, many other treatments such as pulmo- nary artery catheterization and mechanical ventila- tion decrease in use. For institutions that have www.chestjournal.org CHEST / 132 / 6 / DECEMBER, 2007 1973 investigated, 9497 costs are reduced by protocol- directed care. Reports 98 are now emerging that the failure to meet the treatment goals of the early or late phase of the surviving sepsis bundles results in increased mortality. Although some have questioned the motivation for recommendations and protocol development, published data 9498 support the find- ing that a bundled approach to care is associated with 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 the underlying inflammatory and coagulopathic process. Although the treatments advocated today are almost certainly not the best that will ever be known, they are the best known now. Daily clinicians are faced with the following simple choice: ignore existing evidence because it may have some flaws and is incomplete in favor of non-evidence-based practice, or promptly provide all the treatments we now know to increase our patients chance of survival unless there is a compelling reason not to do so. References 1 Marini JJ, Wheeler AP. Critical care medicine: the essentials. 2nd ed. Baltimore, MD: Williams and Wilkens, 1997 2 Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syn- drome. N Engl J Med 2003; 348:683694 3 Angus DC, Laterre PF, Helterbrand J, et al. 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