- Email: [email protected]
Counterpoint: Adherence to Early Goal-Directed Therapy
42. Coba V, Andrzejewski T, Huang D, Horst HM. Resuscitation bundle compliance in severe sepsis and septic shock: better late than never still improves survival. Crit Care Med. 2009;37(10):A442-A447. 43. Shorr AF, Micek ST, Jackson WL Jr, Kollef MH. Economic implications of an evidence-based sepsis protocol: can we improve outcomes and lower costs? Crit Care Med. 2007;35(5):1257-1262. 44. Talmor D, Greenberg D, Howell MD, Lisbon A, Novack V, Shapiro N. The costs and cost-effectiveness of an integrated sepsis treatment protocol. Crit Care Med. 2008;36(4): 1168-1174. 45. Cannon C, Holthaus C, Rivers E, et al. Improving outcome in severe sepsis and septic shock: results of a prospective multicenter collaborative. J Emerg Med. 2009;37(2):217-236. 46. Reed K, May R. The First Annual HealthGrade Emergency Medicine in American Hospitals Study. Golden, CO: Health Grades Inc; 2010.
Counterpoint: Adherence to Early Goal-Directed Therapy Does It Really Matter? No. Both Risks and Benefits Require Further Study article published in 2001, patients Inwitha landmark severe sepsis presenting to an ED were more
likely to survive when treated with a multifaceted protocol called early goal-directed therapy (EGDT).1 By 2004, the Surviving Sepsis Campaign (SSC) advocated this approach,2 and soon after, the Institute for Healthcare Improvement, several professional societies, and others urged the adoption of sepsis bundles, including elements derived from EGDT, both to improve patient safety and as a quality measure. Nearly a decade after the original results were published, the medical community’s enthusiasm for EGDT remains tepid. For example, in a survey of 2,461 specialists in emergency medicine, acute medicine, and critical care in the United Kingdom, United States, Australia, and New Zealand, only 0.1% of respondents complied with all SSC 6-h bundle guidelines.3 Only 15% of Australia and New Zealand intensivists target fluid resuscitation to a central venous pressure (CVP) of 8 to 12 mm Hg or transfuse blood for a central venous oxygen saturation (Scvo2) , 70% when the hematocrit is , 30%. In a 2004 survey of academic emergency medicine physicians in the United States, only 7% reported that EGDT was standard treatment.4 A nationwide poll of critical care nurse managers showed that for patients with sepsis and persistent hypotension or lactate . 4 mmolⲐL a central venous catheter would be inserted in only 41% of cases.5 In this issue of CHEST (see page 551), Mikkelsen and colleagues6 show that eligible patients presenting to a single academic ED with severe sepsis had
480
EGDT initiated only 58% of the time and in only 57% of these was the therapy completed.6 Is this another example of failure to translate evidence into practice or informed skepticism? For many intensivists, the evidence supporting EGDT is too weak to justify the expense or the risk to patients. The greatest concerns center around the bundling of therapies in the EGDT protocol, some that may cause harm (central line insertion, blood transfusion) and others that fail to incorporate up-todate views of cardiovascular physiology (targeting a CVP of 8-12 mm Hg) and the unusual nature of subjects enrolled in the EGDT trial. Many intensivists and emergency medicine physicians balk at inserting central venous catheters to comply with a protocol when their clinical gestalt tells them the catheter is unnecessary. New support for this view comes from a study of 300 subjects enrolled in a goal-directed resuscitation trial in three urban EDs. The mortality rate was not reduced by Scvo2 monitoring compared with using lactate clearance (hospital mortality 23% vs 17%; P value not significant).7 The EGDT protocol targets a normal Scvo2, enlisting a sequence of diverse interventions. In comparison with the control group, intervention subjects were given more dobutamine, blood, and fluid.1 For example, of those randomized to EGDT, a stunning 64% were transfused (compared with only 19% of control subjects). It is abundantly clear that RBC transfusion risks nosocomial infection, acute lung injury, and excess deaths.8-11 Transfusion is purported to enhance oxygenation of threatened tissues, but studies in patients who are critically ill generally fail to show this,12,13 perhaps because of poor RBC deformability or low 2,3-diphosphoglycerate concentration in stored blood. While it is possible that the impact of transfusion in the first 6 h of severe sepsis differs from that in general critical illness, there is little reason to believe this would be true. Using CVP to guide volume resuscitation fails to acknowledge that this parameter is no better than a coin toss in predicting who will respond to fluids.14 For example, in a series of 150 fluid boluses given to patients with sepsis in an ICU, a CVP , 8 mm Hg had a positive predictive value of only 47%.15 Dynamic physiologic parameters such as pulse pressure variation, brachial artery peak flow velocity variation, inferior vena cava collapsibility, and even passive leg raising are much superior to static predictors such as CVP. Relying on CVP will force excessive fluids on some, while leaving others under-resuscitated. Even if one accepts that EGDT, as a bundle, improved mortality, its applicability to the broad population of patients with sepsis is suspect. The control subjects in the EGDT study strike many intensivists as highly unusual. Most notably, the Scvo2 was 49%, indicating grossly inadequate oxygen transport, results Point/Counterpoint Editorials
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
Figure 1. The APACHE II score and 28-day mortality are plotted for a number of sepsis trials, generally using data from the control arm. The regression line is shown, omitting the data point representing the EGDT trial. APACHE 5 Acute Physiology and Chronic Health Evaluation; EGDT 5 early goal-directed therapy.
counter to most clinicians’ experience in sepsis. Seeking to reproduce this finding, investigators in The Netherlands measured Scvo2 in early critical illness.16 In subjects with sepsis or septic shock, the Scvo2 was 74%, a value more in line with expectations. Pilot data from ongoing EGDT trials also fail to show such a low Scvo2. Perhaps the atypical values in the EGDT trial biased the study in favor of a treatment centered on boosting oxygen transport.
Of greater concern is the curiously high mortality in the control arm of the EGDT trial. Severity-ofillness scores are quite accurate predictors of mortality. From a large number of sepsis trials published in the last 15 years, one can see that Acute Physiology and Chronic Health Evaluation (APACHE) II score and mortality are well correlated (Fig 1, Table 1).17-26 In sharp contrast, the EGDT control group subjects were far more likely to die than control subjects in
Table 1—Sepsis Trials Published in the Last 15 Years Study/Year 17
Abraham et al /1998 Bernard et al18/2001 Abraham et al19/2003 Opal et al20/2004 Panacek et al21/2004
Zeiher et al22/2005 Russell et al23/2008 Brunkhorst et al24/2008 Dellinger et al25/2009 Tidswell et al26/2010 Rivers et al1/2001
Study Therapy
Mean APACHE II Score
28-d Mortality (%)
TNF-a MAb Drotrecogin TFPI PAF-AH Afelimomab Low IL-6 High IL-6 LY315920NAⲐS-5920 VasopressinⲐnorepinephrine InsulinⲐpentastarch GR270773 Eritoran tetrasodium EGDT Intervention Control
28.8 25.0 25.0 21.8
42.8 30.8 33.9 24
24.3 29.2 25.0 27.0 20.2 21.5 24.9
28.6 47.6 31.9 37.3 25.4 26.9 33.3
21.4 20.4
33.3 49.2
APACHE 5 Acute Physiology and Chronic Health Evaluation; EGDT 5 early goal-directed therapy; IL 5 interleukin; PAF-AH 5 platelet-activating factor acetylhydrolase; TFPI 5 recombinant tissue factor pathway inhibitor; TNF-a MAb 5 monoclonal anti-tumor necrosis factor a antibodies. www.chestpubs.org
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other studies. What is it about these subjects (or this treatment center or city) that contributed to such a high rate of death? Questions like this must be dealt with before EGDT can be considered “standard care.” Is it wise to generalize findings from the atypical subjects in this study to the broad population of patients presenting with severe sepsis? More broadly, when should the critical care community adopt the results of any single-center study to change fundamentally how we care for patients? The story of intensive insulin therapy in critical illness offers a cautionary tale: After one study showed a powerful mortality effect,27 professional societies, the SSC, and regulatory agencies advocated intensive glycemic control. Only after hundreds of thousands of patients were so treated did we learn that a single center’s results in atypical subjects (patients in a surgical ICU; extraordinarily high caloric burden through parenteral nutrition) could not be reproduced.28 In fact, it is likely that intensive insulin therapy targeting a blood glucose level of 80 to 110 mgⲐdL causes excess deaths, even when conducted under the auspices of a clinical trial. Examples abound of positive single-center studies later found to be associated with harm.29 Lack of adoption of EGDT does not reflect a complacency borne of inertia. Rather, the critical care community has judged EGDT to be insufficiently validated. Skepticism arises from the single-center nature of the only positive, prospective trial; uncertainty regarding the individual components of a complex, bundled protocol; and concern about the appropriateness of drawing general inferences from an unusual subject pool. The equipoise found among intensivists is reflected in the three large, ongoing, multicenter trials seeking to confirm or refute the original EGDT trial results. These include the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial (1,600 subjects), the Protocolized Care for Early Septic Shock (ProCESS) trial centered in Pittsburgh (1,935 subjects), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (1,260 subjects). The investigators, the hundred or so institutional review boards, and the subjects choosing to consent for these studies surely are not taking lightly their responsibilities to balance risks and benefits. Further study is warranted because EGDT may yet be proved to be life saving. Meanwhile, however, it is premature to widely promulgate this protocol based on fragile evidence. Gregory A. Schmidt, MD, FCCP Iowa City, IA Affiliations: From the Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa. 482
Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companiesⲐorganizations whose products or services may be discussed in this article. Correspondence to: Gregory A. Schmidt, MD, FCCP, Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, C304-GH, Iowa City, IA 52242; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-1400
References 1. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 2. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004;30(4):536-555. 3. Reade MC, Huang DT, Bell D, et al; British Association for Emergency Medicine; UK Intensive Care Society; UK Society for Acute Medicine; Australasian Resuscitation in Sepsis Evaluation Investigators; Protocolized Care for Early Septic Shock Investigators. Variability in management of early severe sepsis. Emerg Med J. 2010;27(2):110-115. 4. Jones AE, Kline JA. Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med. 2005;33(8):1888-1889. 5. Durthaler JM, Ernst FR, Johnston JA. Managing severe sepsis: a national survey of current practices. Am J Health Syst Pharm. 2009;66(1):45-53. 6. Mikkelsen ME, Gaieski DF, Goyal M, et al. Factors associated with nonadherence with early goal-directed therapy in the ED. Chest; 2010;138(3):551-558. 7. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746. 8. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004; 32(1):39-52. 9. Taylor RW, O’Brien J, Trottier SJ, et al. Red blood cell transfusions and nosocomial infections in critically ill patients. Crit Care Med. 2006;34(9):2302-2309. 10. Shorr AF, Jackson WL, Kelly KM, Fu M, Kollef MH. Transfusion practice and blood stream infections in critically ill patients. Chest. 2005;127(5):1722-1728. 11. Zilberberg MD, Stern LS, Wiederkehr DP, Doyle JJ, Shorr AF. Anemia, transfusions and hospital outcomes among critically ill patients on prolonged acute mechanical ventilation: a retrospective cohort study. Crit Care. 2008;12(2):R60. 12. Creteur J, Neves AP, Vincent JL. Near-infrared spectroscopy technique to evaluate the effects of red blood cell transfusion on tissue oxygenation. Crit Care. 2009;13(Suppl 5):S11. 13. Sakr Y, Chierego M, Piagnerelli M, et al. Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med. 2007;35(7):1639-1644. 14. Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest. 2008;133(1):252-263. 15. Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med. 2007;35(1):64-68. Point/Counterpoint Editorials
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16. van Beest PA, Hofstra JJ, Schultz MJ, Boerma EC, Spronk PE, Kuiper MA. The incidence of low venous oxygen saturation on admission to the intensive care unit: a multicenter observational study in The Netherlands. Crit Care. 2008;12(2):R33. 17. Abraham E, Anzueto A, Gutierrez G, et al; NORASEPT II Study Group. Double-blind randomized controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock. Lancet. 1998;351(9107):929-933. 18. Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 19. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003; 290(2):238-247. 20. Opal S, Laterre P-F, Abraham E, et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase 3, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med. 2004;32(2):332-341. 21. Panacek EA, Marshall JC, Albertson TE, et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab9)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004; 32(11):2173-2182. 22. Zeiher BG, Steingrub J, Laterre P-F, et al. LY315920NAⲐS-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit Care Med. 2005;33(8):1741-1748. 23. Russell JA, Walley KR, Singer J, et al. Vasopressin vs norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. 24. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139. 25. Dellinger RP, Tomayko JF, Angus DC, et al. Efficacy and safety of a phospholipid emulsion (GR270773) in gramnegative severe sepsis: results of a phase 2 multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit Care Med. 2009;37(11):2929-2938. 26. Tidswell M, Tillis W, LaRosa SP, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38(1):72-83. 27. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367. 28. Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13): 1283-1297. 29. Bellomo R, Warrillow SJ, Reade MC. Why we should be wary of single-center trials. Crit Care Med. 2009;37(12): 3114-3119.
Rebuttal From Dr Rivers goal-directed therapy (EGDT) is not only a Early life-saving intervention but also a systems-based
approach similar to that used for acute myocardial infarction, stroke, and trauma. Instead of a similar universal adoption, debate continues with a myopic focus on its integrated components (which have been around for . 60 years), which have been addressed in a www.chestpubs.org
previously published rebuttal.1 Physical examination or gestalt does not accurately assess hemodynamic status.2 A low central venous oxygen saturation (Scvo2) of 28% to 73% in the ICU is not only common but also predictive of outcome.3 Antibiotics, an unquestionable therapy, can result in lethal complications and have never undergone a randomized multicenter trial. The bottom line is that EGDT decreases hospital length of stay, exposure to more interventions, and, thus, hospital-related complications. Comparing EGDT to a heterogeneous mix of studies with different times of enrollment (which affects Acute Physiology and Chronic Health Evaluation [APACHE] II scores), interventions (glucose control), and stages of oxygen delivery dependency (lactate clearance equates with Scvo2) represents tangential associations leading to misinterpretations. Propagating these misinterpretations creates doubt and leads to inertia. This inertia leaves the enthusiastic clinician in search of best-practice guidance from the “experts” feeling uncertain, apathetic, and tepid. Surveys and studies (independent of current investigators of EGDT trials) of ED and ICU physicians indicate that the majority (77%) of programs either are planning to implement or presently utilizing EGDT.4,5 A study of 40 hospitals comprising 1,719 preimplementation and 2,319 postimplementation patients found an inhospital mortality rate of 44% and 23%, respectively.6 In another study, 1,554 preimplementation and 4,801 postimplementation patients had an inhospital mortality of 42.8% and 28.7%, respectively.7 These two studies comprise . 10,000 patients of every race, academic and community setting, and geographic region.6,7 In a metaanalysis, EGDT was found not only to robustly decrease mortality rates (56.6% to 39.4%)8 but also to confirm that a high baseline mortality is not unique to original EGDT study.8 In 1997, funding for a study of EGDT with pilot data was denied by peer-funding agencies. However, with the support of a hospital dedicated to quality improvement, it was completed without any extramural or industry support. Ironically, some of the investigators who now advocate for more studies of EGDT with public funding were the same reviewers who denied the study funding in 1997. If the contributors to the original EGDT study would have given up and waited for multicenter trials, EGDT would not be saving lives today. Thus, single-center studies continue to have a significant impact on medical practice and must continue. There are . 150,000 severe sepsis and septic shock deaths every year in the United States, which means that an estimated 1.5 million patients have died since the EGDT study was completed. With full implementation of EGDT, one life could have been saved CHEST / 138 / 3 / SEPTEMBER, 2010
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Counterpoint: Adherence to Early Goal-Directed Therapy Does It Really Matter? No. Both Risks and Benefits Require Further Study article published in 2001, patients Inwitha landmark severe sepsis presenting to an ED were more
likely to survive when treated with a multifaceted protocol called early goal-directed therapy (EGDT).1 By 2004, the Surviving Sepsis Campaign (SSC) advocated this approach,2 and soon after, the Institute for Healthcare Improvement, several professional societies, and others urged the adoption of sepsis bundles, including elements derived from EGDT, both to improve patient safety and as a quality measure. Nearly a decade after the original results were published, the medical community’s enthusiasm for EGDT remains tepid. For example, in a survey of 2,461 specialists in emergency medicine, acute medicine, and critical care in the United Kingdom, United States, Australia, and New Zealand, only 0.1% of respondents complied with all SSC 6-h bundle guidelines.3 Only 15% of Australia and New Zealand intensivists target fluid resuscitation to a central venous pressure (CVP) of 8 to 12 mm Hg or transfuse blood for a central venous oxygen saturation (Scvo2) , 70% when the hematocrit is , 30%. In a 2004 survey of academic emergency medicine physicians in the United States, only 7% reported that EGDT was standard treatment.4 A nationwide poll of critical care nurse managers showed that for patients with sepsis and persistent hypotension or lactate . 4 mmolⲐL a central venous catheter would be inserted in only 41% of cases.5 In this issue of CHEST (see page 551), Mikkelsen and colleagues6 show that eligible patients presenting to a single academic ED with severe sepsis had
480
EGDT initiated only 58% of the time and in only 57% of these was the therapy completed.6 Is this another example of failure to translate evidence into practice or informed skepticism? For many intensivists, the evidence supporting EGDT is too weak to justify the expense or the risk to patients. The greatest concerns center around the bundling of therapies in the EGDT protocol, some that may cause harm (central line insertion, blood transfusion) and others that fail to incorporate up-todate views of cardiovascular physiology (targeting a CVP of 8-12 mm Hg) and the unusual nature of subjects enrolled in the EGDT trial. Many intensivists and emergency medicine physicians balk at inserting central venous catheters to comply with a protocol when their clinical gestalt tells them the catheter is unnecessary. New support for this view comes from a study of 300 subjects enrolled in a goal-directed resuscitation trial in three urban EDs. The mortality rate was not reduced by Scvo2 monitoring compared with using lactate clearance (hospital mortality 23% vs 17%; P value not significant).7 The EGDT protocol targets a normal Scvo2, enlisting a sequence of diverse interventions. In comparison with the control group, intervention subjects were given more dobutamine, blood, and fluid.1 For example, of those randomized to EGDT, a stunning 64% were transfused (compared with only 19% of control subjects). It is abundantly clear that RBC transfusion risks nosocomial infection, acute lung injury, and excess deaths.8-11 Transfusion is purported to enhance oxygenation of threatened tissues, but studies in patients who are critically ill generally fail to show this,12,13 perhaps because of poor RBC deformability or low 2,3-diphosphoglycerate concentration in stored blood. While it is possible that the impact of transfusion in the first 6 h of severe sepsis differs from that in general critical illness, there is little reason to believe this would be true. Using CVP to guide volume resuscitation fails to acknowledge that this parameter is no better than a coin toss in predicting who will respond to fluids.14 For example, in a series of 150 fluid boluses given to patients with sepsis in an ICU, a CVP , 8 mm Hg had a positive predictive value of only 47%.15 Dynamic physiologic parameters such as pulse pressure variation, brachial artery peak flow velocity variation, inferior vena cava collapsibility, and even passive leg raising are much superior to static predictors such as CVP. Relying on CVP will force excessive fluids on some, while leaving others under-resuscitated. Even if one accepts that EGDT, as a bundle, improved mortality, its applicability to the broad population of patients with sepsis is suspect. The control subjects in the EGDT study strike many intensivists as highly unusual. Most notably, the Scvo2 was 49%, indicating grossly inadequate oxygen transport, results Point/Counterpoint Editorials
Downloaded from chestjournal.chestpubs.org by Kimberly Henricks on September 15, 2010 © 2010 American College of Chest Physicians
Figure 1. The APACHE II score and 28-day mortality are plotted for a number of sepsis trials, generally using data from the control arm. The regression line is shown, omitting the data point representing the EGDT trial. APACHE 5 Acute Physiology and Chronic Health Evaluation; EGDT 5 early goal-directed therapy.
counter to most clinicians’ experience in sepsis. Seeking to reproduce this finding, investigators in The Netherlands measured Scvo2 in early critical illness.16 In subjects with sepsis or septic shock, the Scvo2 was 74%, a value more in line with expectations. Pilot data from ongoing EGDT trials also fail to show such a low Scvo2. Perhaps the atypical values in the EGDT trial biased the study in favor of a treatment centered on boosting oxygen transport.
Of greater concern is the curiously high mortality in the control arm of the EGDT trial. Severity-ofillness scores are quite accurate predictors of mortality. From a large number of sepsis trials published in the last 15 years, one can see that Acute Physiology and Chronic Health Evaluation (APACHE) II score and mortality are well correlated (Fig 1, Table 1).17-26 In sharp contrast, the EGDT control group subjects were far more likely to die than control subjects in
Table 1—Sepsis Trials Published in the Last 15 Years Study/Year 17
Abraham et al /1998 Bernard et al18/2001 Abraham et al19/2003 Opal et al20/2004 Panacek et al21/2004
Zeiher et al22/2005 Russell et al23/2008 Brunkhorst et al24/2008 Dellinger et al25/2009 Tidswell et al26/2010 Rivers et al1/2001
Study Therapy
Mean APACHE II Score
28-d Mortality (%)
TNF-a MAb Drotrecogin TFPI PAF-AH Afelimomab Low IL-6 High IL-6 LY315920NAⲐS-5920 VasopressinⲐnorepinephrine InsulinⲐpentastarch GR270773 Eritoran tetrasodium EGDT Intervention Control
28.8 25.0 25.0 21.8
42.8 30.8 33.9 24
24.3 29.2 25.0 27.0 20.2 21.5 24.9
28.6 47.6 31.9 37.3 25.4 26.9 33.3
21.4 20.4
33.3 49.2
APACHE 5 Acute Physiology and Chronic Health Evaluation; EGDT 5 early goal-directed therapy; IL 5 interleukin; PAF-AH 5 platelet-activating factor acetylhydrolase; TFPI 5 recombinant tissue factor pathway inhibitor; TNF-a MAb 5 monoclonal anti-tumor necrosis factor a antibodies. www.chestpubs.org
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other studies. What is it about these subjects (or this treatment center or city) that contributed to such a high rate of death? Questions like this must be dealt with before EGDT can be considered “standard care.” Is it wise to generalize findings from the atypical subjects in this study to the broad population of patients presenting with severe sepsis? More broadly, when should the critical care community adopt the results of any single-center study to change fundamentally how we care for patients? The story of intensive insulin therapy in critical illness offers a cautionary tale: After one study showed a powerful mortality effect,27 professional societies, the SSC, and regulatory agencies advocated intensive glycemic control. Only after hundreds of thousands of patients were so treated did we learn that a single center’s results in atypical subjects (patients in a surgical ICU; extraordinarily high caloric burden through parenteral nutrition) could not be reproduced.28 In fact, it is likely that intensive insulin therapy targeting a blood glucose level of 80 to 110 mgⲐdL causes excess deaths, even when conducted under the auspices of a clinical trial. Examples abound of positive single-center studies later found to be associated with harm.29 Lack of adoption of EGDT does not reflect a complacency borne of inertia. Rather, the critical care community has judged EGDT to be insufficiently validated. Skepticism arises from the single-center nature of the only positive, prospective trial; uncertainty regarding the individual components of a complex, bundled protocol; and concern about the appropriateness of drawing general inferences from an unusual subject pool. The equipoise found among intensivists is reflected in the three large, ongoing, multicenter trials seeking to confirm or refute the original EGDT trial results. These include the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial (1,600 subjects), the Protocolized Care for Early Septic Shock (ProCESS) trial centered in Pittsburgh (1,935 subjects), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (1,260 subjects). The investigators, the hundred or so institutional review boards, and the subjects choosing to consent for these studies surely are not taking lightly their responsibilities to balance risks and benefits. Further study is warranted because EGDT may yet be proved to be life saving. Meanwhile, however, it is premature to widely promulgate this protocol based on fragile evidence. Gregory A. Schmidt, MD, FCCP Iowa City, IA Affiliations: From the Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa. 482
Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companiesⲐorganizations whose products or services may be discussed in this article. Correspondence to: Gregory A. Schmidt, MD, FCCP, Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, C304-GH, Iowa City, IA 52242; e-mail: [email protected] © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-1400
References 1. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 2. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med. 2004;30(4):536-555. 3. Reade MC, Huang DT, Bell D, et al; British Association for Emergency Medicine; UK Intensive Care Society; UK Society for Acute Medicine; Australasian Resuscitation in Sepsis Evaluation Investigators; Protocolized Care for Early Septic Shock Investigators. Variability in management of early severe sepsis. Emerg Med J. 2010;27(2):110-115. 4. Jones AE, Kline JA. Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med. 2005;33(8):1888-1889. 5. Durthaler JM, Ernst FR, Johnston JA. Managing severe sepsis: a national survey of current practices. Am J Health Syst Pharm. 2009;66(1):45-53. 6. Mikkelsen ME, Gaieski DF, Goyal M, et al. Factors associated with nonadherence with early goal-directed therapy in the ED. Chest; 2010;138(3):551-558. 7. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746. 8. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004; 32(1):39-52. 9. Taylor RW, O’Brien J, Trottier SJ, et al. Red blood cell transfusions and nosocomial infections in critically ill patients. Crit Care Med. 2006;34(9):2302-2309. 10. Shorr AF, Jackson WL, Kelly KM, Fu M, Kollef MH. Transfusion practice and blood stream infections in critically ill patients. Chest. 2005;127(5):1722-1728. 11. Zilberberg MD, Stern LS, Wiederkehr DP, Doyle JJ, Shorr AF. Anemia, transfusions and hospital outcomes among critically ill patients on prolonged acute mechanical ventilation: a retrospective cohort study. Crit Care. 2008;12(2):R60. 12. Creteur J, Neves AP, Vincent JL. Near-infrared spectroscopy technique to evaluate the effects of red blood cell transfusion on tissue oxygenation. Crit Care. 2009;13(Suppl 5):S11. 13. Sakr Y, Chierego M, Piagnerelli M, et al. Microvascular response to red blood cell transfusion in patients with severe sepsis. Crit Care Med. 2007;35(7):1639-1644. 14. Durairaj L, Schmidt GA. Fluid therapy in resuscitated sepsis: less is more. Chest. 2008;133(1):252-263. 15. Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med. 2007;35(1):64-68. Point/Counterpoint Editorials
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16. van Beest PA, Hofstra JJ, Schultz MJ, Boerma EC, Spronk PE, Kuiper MA. The incidence of low venous oxygen saturation on admission to the intensive care unit: a multicenter observational study in The Netherlands. Crit Care. 2008;12(2):R33. 17. Abraham E, Anzueto A, Gutierrez G, et al; NORASEPT II Study Group. Double-blind randomized controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock. Lancet. 1998;351(9107):929-933. 18. Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 19. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003; 290(2):238-247. 20. Opal S, Laterre P-F, Abraham E, et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase 3, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med. 2004;32(2):332-341. 21. Panacek EA, Marshall JC, Albertson TE, et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab9)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004; 32(11):2173-2182. 22. Zeiher BG, Steingrub J, Laterre P-F, et al. LY315920NAⲐS-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit Care Med. 2005;33(8):1741-1748. 23. Russell JA, Walley KR, Singer J, et al. Vasopressin vs norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. 24. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-139. 25. Dellinger RP, Tomayko JF, Angus DC, et al. Efficacy and safety of a phospholipid emulsion (GR270773) in gramnegative severe sepsis: results of a phase 2 multicenter, randomized, placebo-controlled, dose-finding clinical trial. Crit Care Med. 2009;37(11):2929-2938. 26. Tidswell M, Tillis W, LaRosa SP, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38(1):72-83. 27. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-1367. 28. Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13): 1283-1297. 29. Bellomo R, Warrillow SJ, Reade MC. Why we should be wary of single-center trials. Crit Care Med. 2009;37(12): 3114-3119.
Rebuttal From Dr Rivers goal-directed therapy (EGDT) is not only a Early life-saving intervention but also a systems-based
approach similar to that used for acute myocardial infarction, stroke, and trauma. Instead of a similar universal adoption, debate continues with a myopic focus on its integrated components (which have been around for . 60 years), which have been addressed in a www.chestpubs.org
previously published rebuttal.1 Physical examination or gestalt does not accurately assess hemodynamic status.2 A low central venous oxygen saturation (Scvo2) of 28% to 73% in the ICU is not only common but also predictive of outcome.3 Antibiotics, an unquestionable therapy, can result in lethal complications and have never undergone a randomized multicenter trial. The bottom line is that EGDT decreases hospital length of stay, exposure to more interventions, and, thus, hospital-related complications. Comparing EGDT to a heterogeneous mix of studies with different times of enrollment (which affects Acute Physiology and Chronic Health Evaluation [APACHE] II scores), interventions (glucose control), and stages of oxygen delivery dependency (lactate clearance equates with Scvo2) represents tangential associations leading to misinterpretations. Propagating these misinterpretations creates doubt and leads to inertia. This inertia leaves the enthusiastic clinician in search of best-practice guidance from the “experts” feeling uncertain, apathetic, and tepid. Surveys and studies (independent of current investigators of EGDT trials) of ED and ICU physicians indicate that the majority (77%) of programs either are planning to implement or presently utilizing EGDT.4,5 A study of 40 hospitals comprising 1,719 preimplementation and 2,319 postimplementation patients found an inhospital mortality rate of 44% and 23%, respectively.6 In another study, 1,554 preimplementation and 4,801 postimplementation patients had an inhospital mortality of 42.8% and 28.7%, respectively.7 These two studies comprise . 10,000 patients of every race, academic and community setting, and geographic region.6,7 In a metaanalysis, EGDT was found not only to robustly decrease mortality rates (56.6% to 39.4%)8 but also to confirm that a high baseline mortality is not unique to original EGDT study.8 In 1997, funding for a study of EGDT with pilot data was denied by peer-funding agencies. However, with the support of a hospital dedicated to quality improvement, it was completed without any extramural or industry support. Ironically, some of the investigators who now advocate for more studies of EGDT with public funding were the same reviewers who denied the study funding in 1997. If the contributors to the original EGDT study would have given up and waited for multicenter trials, EGDT would not be saving lives today. Thus, single-center studies continue to have a significant impact on medical practice and must continue. There are . 150,000 severe sepsis and septic shock deaths every year in the United States, which means that an estimated 1.5 million patients have died since the EGDT study was completed. With full implementation of EGDT, one life could have been saved CHEST / 138 / 3 / SEPTEMBER, 2010
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