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CHEST Point/Counterpoint Editorials
1406 Point/Counterpoint Editorials
Point: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? Yes Abbreviations: CVP 5 central venous pressure ; D o 2 5 systemic oxygen delivery ; EGDT 5 early goal-directed therapy ; GTH 5 global tissue hypoxia ; MAP 5 mean arterial pressure ; OER 5 systemic oxygen extraction ; PDH 5 pyruvate dehydrogenase ; Scv o 2 5 central venous oxygen saturation ; Sv o 2 5 mixed venous oxygen saturation ; o 2 5 oxygen consumption
Quantitative resuscitation in critically ill patients consists of structured cardiovascular interven-
tions, such as intravascular volume expansion and vasoactive agent support, to achieve explicit pre-defi ned physiologic parameters or goals. The con-cept of quantitative resuscitation (also referred to as hemodynamic optimization or goal-directed therapy) as a treatment strategy to improve clinical outcome was fi rst reported in high-risk surgery patients. 1 A recent meta-analysis of randomized clinical trials that compared quantitative resuscitation with stan-dard resuscitation in septic shock found that when therapy was initiated within 24 h of the onset of sep sis (six trials, 740 patients), resuscitation targeting specifi c physiologic end points improved mortality compared with standard resuscitation (39% vs 57%: OR, 0.50; 95% CI, 0.37-0.69). 2 In contrast, when therapy was initiated . 24 h after the onset of sep-sis (three trials, 261 patients), resuscitation target-ing specifi c physiologic end points did not improve mortality (64% vs 58% for standard resuscitation; OR, 1.16; 95% CI, 0.60-2.22). Although the data supporting the use of early quantitative resuscitation are robust, the optimal end points or goals of such therapy are controversial.
Currently, consensus guidelines recommend the use of central venous pressure (CVP), mean arterial pressure (MAP), urine output, and central venous oxygen saturation (Scv o 2 ) as resuscitation goals. 3 These recommendations are based largely on an ED-based clinical trial of quantitative resuscitation for septic
shock, an approach termed “early goal-directed therapy,” which was a single-center study published by Rivers et al 4 in 2001. In this trial, 263 patients with severe sepsis or septic shock were randomly assigned to therapy targeting an Scv o 2 of � 70% or to conven-tional therapy that did not target an Scv o 2 . In both groups, therapy targeted CVP, MAP, and urine out-put. Mortality was signifi cantly lower in the group that targeted an Scv o 2 of � 70% (31% vs 47%). Given that the only difference in the treatment proto-cols in this trial was the Scv o 2 target, the observed treatment effect appears to hinge on achieving this node of the algorithm. In contrast, earlier studies of critically ill patients that targeted mixed venous oxygen saturation (Sv o 2 ) of � 70% found no mor-tality benefi t. 5
Multiple studies have unfortunately documented important barriers to implementing and maintain-ing an ED-based quantitative resuscitation protocol for septic shock. 6 - 8 Among these, the use of a central venous catheter and the need for specialty equip-ment such as a continuous central venous oxygen spectrophotometer, and the training required for it, were major barriers that limited generalizability. To begin to address these barriers, the Lactate Assess-ment in the Treatment of Early Sepsis (LACTATES) randomized multicenter noninferiority trial, the larg-est ED-based early sepsis resuscitation trial com-pleted to date, was designed to compare the use of lactate clearance to Scv o 2 as the fi nal goal of early sepsis resuscitation. 9 In the study, enrolled patients were randomly assigned to one of two groups. Each group received structured quantitative resuscitation while in the ED. The Scv o 2 group (n 5 150) was resuscitated by sequentially providing the therapy needed to meet thresholds of CVP, followed by MAP, and then Scv o 2 of � 70%. The lactate clear-ance group (n 5 150) had similarly targeted thresh-olds in CVP and MAP, and then lactate clearance of � 10% or more. The study protocol was continued until all end points were achieved or for a maximum of 6 h. The published results of this study showed a 6% (95% CI, 2 3% to 14%) in-hospital mortality difference between the two study groups (17% in the lactate clearance group vs 23% in Scv o 2 group), con-fi rming the primary hypothesis of noninferiority.
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There are many evidence-based, data-driven, and log-ical arguments as to why lactate clearance monitor-ing is a superior therapeutic target to oxygen-derived variables such as Scv o 2 . First, the published exper-imental (randomized trial) evidence supporting the use of lactate clearance as a therapeutic target is more robust in terms of the number of multicenter studies. 9 , 10 Similar published experimental evidence supporting Sc vo 2 is derived only from single-center studies. 4 , 11 Furthermore, multicenter studies have failed to show the use of Sv o 2 as a resuscitation goal 5 ; however, unlike Scv o 2 or other oxygen-derived vari-ables, the ability to clear lactate has consistently pre-dicted better survival in published studies of sepsis resuscitation. 12 - 15
Second, elevated lactate levels refl ect the total picture of energy metabolism in the acutely stressed patient with sepsis. Elevated blood lactate has long been known to refl ect anaerobic metabolism from tissue hypoxia in critically ill patients. 16 However, besides these anaerobic processes, aerobic (meta-bolic) mechanisms that affect the host’s effi ciency of energy transfer contribute to lactate production in sepsis. Cytokine-mediated glucose uptake and catecholamine-stimulated Na-K pump overactivity can both result in increased pyruvate production that eventually will overwhelm the catalytic capacity of pyruvate dehydrogenase (PDH) and result in increased lactate because of either mass effect, sepsis-induced PDH dysfunction, or both. This mechanism may explain part of the lactate production observed from the lungs and WBC in response to the infl am-matory stress, rather than tissue hypoxia of sepsis. 17 Additionally, reduced lactate clearance may refl ect globally impaired metabolic function by the liver and kidney, both of which normally contribute to systemic lactate disposal through anaplerosis, a mechanism that carboxylates lactate and delivers it to the tricarboxylic acid cycle , independent of the action of PDH. 18 Recent studies have shown that early lactate clearance is associated with improve-ment in the biomarkers of infl ammation and organ dysfunction. 19 Thus, as opposed to Scv o 2 , which is a rudimentary indicator of only the balance between oxygen supply and demand, lactate clearance bio-logically refl ects more of the general homeostasis of the host and provides more meaningful data about the overall adequacy of the resuscitative processes.
Third, in some circumstances the use of Scv o 2 might erroneously lead a clinician to believe that the physi-ologic status of the patient has improved, when in fact it may not have improved. A recent multicenter study of 619 patients demonstrated that venous hyperoxia (Scv o 2 . 89%) is present in 36% of ED patients with septic shock and is associated with an increased risk of death, and, when adjusted for confounders, venous
hyperoxia was actually associated with a higher risk of death than venous hypoxia (Scv o 2 , 70%). 20 In this situation, high Scv o 2 values represent either an inability to exchange oxygen because of impaired fl ow in the small vessels from dysfunctional vascular autoregulatory mechanisms and functional shunt-ing of oxygen or the inability of cells to use the oxygen because of derangement of cellular respi-ration, so-called “cytopathic hypoxia.” 21 Although the Rivers et al 4 protocol focuses on the correction of a low Scv o 2 level signifying impairment in macrovas-cular oxygen delivery, the algorithm treats venous hyperoxia the same as normoxia (Scv o 2 70%-90%). The finding that a high Scv o 2 is associated with increased mortality reminds us that tissue dysoxia may occur despite adequate global oxygen delivery and that this situation is not identifi ed by the pres ence of normal venous oxygen levels. However, impaired oxygen transfer at any point from the lungs to the nicotinamide adenine dinucleotide dehydrogenase enzyme will cause lactic acidosis, and clearing lac-tate levels almost always signifi es improvement in host oxygen use. 6
Finally, a recently reported secondary analysis of the LACTATES study 9 reported no signifi cant con-cordance in achieving lactate clearance and Scv o 2 goals when measured simultaneously in the same subject, suggesting that these tests may be measuring and/or providing data about physiologically distinct processes. If lactate clearance was , 10%, the mor-tality was 40%, but if the Scv o 2 was , 70%, the mor-tality was 11% (proportion difference 29%; 95% CI, 6%-50%). 22
In conclusion, early sepsis resuscitation remains a dynamic topic of research interest, with many impor-tant questions that have yet to be answered. As sum-marized in this report, the best available evidence suggests that if a clinician has to choose a single goal of early sepsis resuscitation, lactate clearance, as opposed to Scv o 2 , is the more appropriate goal to choose.
Alan E. Jones , MD Jackson, MS
Affi liations: From the Department of Emergency Medicine, University of Mississippi Medical Center . Financial/nonfi nancial disclosures: The author has reported to CHEST the following confl icts of interest: Dr Jones has received funding from the National Institutes of Health to study lactate clearance in sepsis resuscitation. Dr Jones has never been assigned patents, nor has he received patent royalties, honoraria, consulting fees, or other monetary or nonmonetary payments at any time related to the use of lactate or lactate clearance . Correspondence to: Alan E. Jones, MD, Department of Emer-gency Medicine, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216; e-mail: [email protected] © 2011 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.11-2560
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1408 Point/Counterpoint Editorials
References 1 . Shoemaker WC , Appel PL , Kram HB , Waxman K , Lee TS . Pro-
spective trial of supranormal values of survivors as therapeu-tic goals in high-risk surgical patients . Chest . 1988 ; 94 ( 6 ): 1176 - 1186 .
2 . Jones AE , Brown MD , Trzeciak S , et al ; Emergency Medi-cine Shock Research Network investigators . The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis . Crit Care Med . 2008 ; 36 ( 10 ): 2734 - 2739 .
3 . Dellinger RP , Levy MM , Carlet JM , et al ; International Sur-viving Sepsis Campaign Guidelines Committee ; American Association of Critical-Care Nurses ; American College of Chest Physicians ; American College of Emergency Physi-cians ; Canadian Critical Care Society ; European Society of Clinical Microbiology and Infectious Diseases ; European Society of Intensive Care Medicine ; European Respiratory Society ; International Sepsis Forum ; Japanese Association for Acute Medicine ; Japanese Society of Intensive Care Medi-cine ; Society of Critical Care Medicine ; Society of Hospital Medicine ; Surgical Infection Society ; World Federation of Societies of Intensive and Critical Care Medicine . Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 . Crit Care Med . 2008 ; 36 ( 1 ): 296 - 327 .
4 . 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 .
5 . Gattinoni L , Brazzi L , Pelosi P , et al . A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Col-laborative Group . N Engl J Med . 1995 ; 333 ( 16 ): 1025 - 1032 .
6 . Carlbom DJ , Rubenfeld GD . Barriers to implementing protocol-based sepsis resuscitation in the emergency department—results of a national survey . Crit Care Med . 2007 ; 35 ( 11 ): 2525 - 2532 .
7 . 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 .
8 . Jones AE , Shapiro NI , Roshon M . Implementing early goal-directed therapy in the emergency setting: the challenges and experiences of translating research innovations into clin-ical reality in academic and community settings . Acad Emerg Med . 2007 ; 14 ( 11 ): 1072 - 1078 .
9 . 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 .
10 . Jansen TC , van Bommel J , Schoonderbeek FJ , et al ; LACTATE study group . Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial . Am J Respir Crit Care Med . 2010 ; 182 ( 6 ): 752 - 761 .
11 . Wang XC , Lü CJ , Gao FQ , Li XH , Yan WF , Ning Fw . Effi cacy of goal-directed therapy in the treatment of septic shock [in Chinese] . Zhongguo Wei Zhong Bing Ji Jiu Yi Xue . 2006 ; 18 ( 11 ): 661 - 664 .
12 . Arnold RC , Shapiro NI , Jones AE , et al ; on behalf of the Emer-gency Medicine Shock Research Network (EMShockNet) Investigators . Multi-center study of early lactate clearance as a determinant of survival in patients with presumed sepsis . Shock . 2008 ; 32 : 36 - 39 .
13 . Nguyen HB , Rivers EP , Knoblich BP , et al . Early lactate clearance is associated with improved outcome in severe sep-sis and septic shock . Crit Care Med . 2004 ; 32 ( 8 ): 1637 - 1642 .
14 . Bakker J , Coffernils M , Leon M , Gris P , Vincent J-L . Blood lactate levels are superior to oxygen-derived variables in pre-dicting outcome in human septic shock . Chest . 1991 ; 99 ( 4 ): 956 - 962 .
15 . Bakker J , Gris P , Coffernils M , Kahn RJ , Vincent J-L . Serial blood lactate levels can predict the development of multiple organ failure following septic shock . Am J Surg . 1996 ; 171 ( 2 ): 221 - 226 .
16 . Weil MH , Afi fi AA . Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock) . Circulation . 1970 ; 41 ( 6 ): 989 - 1001 .
17 . De Backer D . Lactic acidosis . Intensive Care Med . 2003 ; 29 ( 5 ): 699 - 702 .
18 . Russell RR III , Taegtmeyer H . Changes in citric acid cycle fl ux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate . J Clin Invest . 1991 ; 87 ( 2 ): 384 - 390 .
19 . Nguyen HB , Loomba M , Yang JJ , et al . Early lactate clear-ance is associated with biomarkers of infl ammation, coagu-lation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock . J Infl amm (Lond) . 2010 ; 7 : 6 .
20 . Pope JV , Jones AE , Gaieski DF , Arnold RC , Trzeciak S , Shapiro NI ; Emergency Medicine Shock Research Network (EMShockNet) Investigators . Multicenter study of central venous oxygen saturation (ScvO 2 ) as a predictor of mor-tality in patients with sepsis . Ann Emerg Med . 2010 ; 55 ( 1 ): 40 - 46, e1 .
21 . Fink MP . Bench-to-bedside review: cytopathic hypoxia . Crit Care . 2002 ; 6 ( 6 ): 491 - 499 .
22 . Puskarich M , Trzeciak S , Shapiro N , Kline J , Jones AE . Con-cordance and prognostic value of central venous oxygen saturation and lactate clearance in emergency department patients with septic shock . Acad Emerg Med . 2011 ; 18 ( 5 ): S159 - S160 .
Counterpoint: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? No
In 2001, early goal-directed therapy (EGDT ) resulted in a 16% reduction in hospital mortality and,
post hoc, a higher lactate clearance in severe sepsis and septic shock. 1 Multiple studies have confi rmed the validity and generalizability of EGDT, resulting in its adoption into the Surviving Sepsis Campaign Guidelines. 2 , 3 Nguyen et al 4 , 5 examined early lactate clearance and found a signifi cant retrospective associa-tion with infl ammation, apoptosis, coagulation, organ dysfunction, and mortality. Following this rationale, Jones et al 6 modifi ed the EGDT protocol in 2010 using a noninferiority study design and concluded that lactate clearance is equivalent to central venous oxygen saturation (Scv o 2 ) in the management of indi-vidual patients.
Before applying the fi ndings of Jones et al 6 to one’s next patient, compare the baseline characteristics,
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
1408 Point/Counterpoint Editorials
References 1 . Shoemaker WC , Appel PL , Kram HB , Waxman K , Lee TS . Pro-
spective trial of supranormal values of survivors as therapeu-tic goals in high-risk surgical patients . Chest . 1988 ; 94 ( 6 ): 1176 - 1186 .
2 . Jones AE , Brown MD , Trzeciak S , et al ; Emergency Medi-cine Shock Research Network investigators . The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis . Crit Care Med . 2008 ; 36 ( 10 ): 2734 - 2739 .
3 . Dellinger RP , Levy MM , Carlet JM , et al ; International Sur-viving Sepsis Campaign Guidelines Committee ; American Association of Critical-Care Nurses ; American College of Chest Physicians ; American College of Emergency Physi-cians ; Canadian Critical Care Society ; European Society of Clinical Microbiology and Infectious Diseases ; European Society of Intensive Care Medicine ; European Respiratory Society ; International Sepsis Forum ; Japanese Association for Acute Medicine ; Japanese Society of Intensive Care Medi-cine ; Society of Critical Care Medicine ; Society of Hospital Medicine ; Surgical Infection Society ; World Federation of Societies of Intensive and Critical Care Medicine . Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 . Crit Care Med . 2008 ; 36 ( 1 ): 296 - 327 .
4 . 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 .
5 . Gattinoni L , Brazzi L , Pelosi P , et al . A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Col-laborative Group . N Engl J Med . 1995 ; 333 ( 16 ): 1025 - 1032 .
6 . Carlbom DJ , Rubenfeld GD . Barriers to implementing protocol-based sepsis resuscitation in the emergency department—results of a national survey . Crit Care Med . 2007 ; 35 ( 11 ): 2525 - 2532 .
7 . 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 .
8 . Jones AE , Shapiro NI , Roshon M . Implementing early goal-directed therapy in the emergency setting: the challenges and experiences of translating research innovations into clin-ical reality in academic and community settings . Acad Emerg Med . 2007 ; 14 ( 11 ): 1072 - 1078 .
9 . 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 .
10 . Jansen TC , van Bommel J , Schoonderbeek FJ , et al ; LACTATE study group . Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial . Am J Respir Crit Care Med . 2010 ; 182 ( 6 ): 752 - 761 .
11 . Wang XC , Lü CJ , Gao FQ , Li XH , Yan WF , Ning Fw . Effi cacy of goal-directed therapy in the treatment of septic shock [in Chinese] . Zhongguo Wei Zhong Bing Ji Jiu Yi Xue . 2006 ; 18 ( 11 ): 661 - 664 .
12 . Arnold RC , Shapiro NI , Jones AE , et al ; on behalf of the Emer-gency Medicine Shock Research Network (EMShockNet) Investigators . Multi-center study of early lactate clearance as a determinant of survival in patients with presumed sepsis . Shock . 2008 ; 32 : 36 - 39 .
13 . Nguyen HB , Rivers EP , Knoblich BP , et al . Early lactate clearance is associated with improved outcome in severe sep-sis and septic shock . Crit Care Med . 2004 ; 32 ( 8 ): 1637 - 1642 .
14 . Bakker J , Coffernils M , Leon M , Gris P , Vincent J-L . Blood lactate levels are superior to oxygen-derived variables in pre-dicting outcome in human septic shock . Chest . 1991 ; 99 ( 4 ): 956 - 962 .
15 . Bakker J , Gris P , Coffernils M , Kahn RJ , Vincent J-L . Serial blood lactate levels can predict the development of multiple organ failure following septic shock . Am J Surg . 1996 ; 171 ( 2 ): 221 - 226 .
16 . Weil MH , Afi fi AA . Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock) . Circulation . 1970 ; 41 ( 6 ): 989 - 1001 .
17 . De Backer D . Lactic acidosis . Intensive Care Med . 2003 ; 29 ( 5 ): 699 - 702 .
18 . Russell RR III , Taegtmeyer H . Changes in citric acid cycle fl ux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate . J Clin Invest . 1991 ; 87 ( 2 ): 384 - 390 .
19 . Nguyen HB , Loomba M , Yang JJ , et al . Early lactate clear-ance is associated with biomarkers of infl ammation, coagu-lation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock . J Infl amm (Lond) . 2010 ; 7 : 6 .
20 . Pope JV , Jones AE , Gaieski DF , Arnold RC , Trzeciak S , Shapiro NI ; Emergency Medicine Shock Research Network (EMShockNet) Investigators . Multicenter study of central venous oxygen saturation (ScvO 2 ) as a predictor of mor-tality in patients with sepsis . Ann Emerg Med . 2010 ; 55 ( 1 ): 40 - 46, e1 .
21 . Fink MP . Bench-to-bedside review: cytopathic hypoxia . Crit Care . 2002 ; 6 ( 6 ): 491 - 499 .
22 . Puskarich M , Trzeciak S , Shapiro N , Kline J , Jones AE . Con-cordance and prognostic value of central venous oxygen saturation and lactate clearance in emergency department patients with septic shock . Acad Emerg Med . 2011 ; 18 ( 5 ): S159 - S160 .
Counterpoint: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? No
In 2001, early goal-directed therapy (EGDT ) resulted in a 16% reduction in hospital mortality and,
post hoc, a higher lactate clearance in severe sepsis and septic shock. 1 Multiple studies have confi rmed the validity and generalizability of EGDT, resulting in its adoption into the Surviving Sepsis Campaign Guidelines. 2 , 3 Nguyen et al 4 , 5 examined early lactate clearance and found a signifi cant retrospective associa-tion with infl ammation, apoptosis, coagulation, organ dysfunction, and mortality. Following this rationale, Jones et al 6 modifi ed the EGDT protocol in 2010 using a noninferiority study design and concluded that lactate clearance is equivalent to central venous oxygen saturation (Scv o 2 ) in the management of indi-vidual patients.
Before applying the fi ndings of Jones et al 6 to one’s next patient, compare the baseline characteristics,
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accompany venous hyperoxia. The phase of tissue dysoxia can be the result of microcirculatory dys-function causing maldistribution of blood fl ow or mitochondrial dysfunction with defects in substrate utilization. In this phase, improvement in D o 2 may not result in improvement in o 2 .
Sepsis may consist of four hemodynamic phases where a decreased Scv o 2 /Sv o 2 always precedes the appearance of lactate, making them complementary and nonexclusive end points, ( Fig 1, Table 1 ). These hemodynamic phases are not always distinct and may overlap depending on the timing and quality of the resuscitation. By characterizing these phases in hemodynamic outcome studies, future trials can be conducted with the appropriate research design and interpreted with clarity, facilitating generalizability and external validation in clinical management. 15
Lactate Kinetics Are Complex and Limit the Interpretation of Lactate Levels and Lactate Clearance in the
Individual Patient
Lactate elevation may indicate stress-induced upreg-ulation in epinephrine-stimulated sodium-potassium adenosine triphosphatase activity in skeletal muscle and inhibition of pyruvate metabolism rather than, or in addition to, the traditionally implicated cellular hypoxia. Other confounding infl uences may include exogenous lactate sources (Ringers lactate or packed RBC transfusions), lactate shuttles and transport, delayed washout from underperfused tissue, variable lactate clearance by a number of organs, and dilution (large-volume resuscitations) ( Fig 2 ). These inter-actions are not in a steady state and depend on the pathophysiology, timing, and quality of the resuscita-tion in the individual case. 16
Normal lactate levels occur in up to 45% of cases of septic shock, and although there is signifi cant vari-ability, the associated mortality can be up to 52%. 9 , 17 - 19 In fact, many patients develop multisystem organ fail-ure and die without ever having increased lactate levels. 9 Thus, lactate has limitations as a tool for risk stratifi cation and as a guide for resuscitation in individual patients. In the Jones et al 6 study, the lactate clearance goal was at least 10% at � 2 h or normality of both initial and subsequent lactates. Nguyen et al, 20 however , found an optimal lactate clearance cutoff of , 10% after 6 h of interven-tion to have a sensitivity of 44.7%, specifi city of 84.4%, and accuracy of only 67.6% for predicting in-hospital mortality. Additionally, lactate clearance was less predictive of outcome in septic shock, the predominant feature of the patients in the Jones et al 6 study. Because of the variable expression of lactate, its complicated kinetics, and the limited accuracy of
early hemodynamic patterns, and therapeutic inter-ventions between those of Jones et al 6 and the EGDT study. 1 Further, review the complexities of lactate kinetics and the weaknesses of a noninferiority study design. 7 Based on these facts, it is clear that lactate clearance and Scv o 2 are not equivalent, but comple-mentary goals for the individual patient.
The Hemodynamic Phases of Severe Sepsis and Septic Shock
The early stages of sepsis are accompanied by cir-culatory insuffi ciency that results from hypovolemia, vasomotor dysfunction, myocardial depression, and increased metabolic demands. In the systemic oxygen delivery (D o 2 )-dependent (hypodynamic) phase, a decrease in D o 2 results in a decrease in Scv o 2 /mixed venous oxygen saturation (Sv o 2 ) and usually an increase in systemic oxygen extraction (OER) or 1 2 Scv o 2 /Sv o 2 ( Fig 1, 8 Table 1 ). When the limits of the OER (anaerobic threshold) are reached, lactate is produced, signifying the development of global tissue hypoxia (GTH). There is signifi cant individual variation in the anaer-obic threshold leading to variable lactate production. 9 This gives rise to why some patients may require nor-mal or elevated D o 2 in order to resolve GTH (decreased Scv o 2 /Sv o 2 and increased lactate) ( Fig 1, Table 1 ). GTH is associated with increased morbidity and mortality if not adequately treated. 10 , 11 Because GTH can occur with normal vital signs, it has been termed “cryptic shock.” 12 GTH or cardiovascular insuffi ciency is a signifi cant part of the natural history of sepsis and responsible for the sudden cardiopulmo-nary deterioration seen in 12% to 21% of patients. 13 , 14 EGDT is associated with a 50% reduction in this adverse event, an issue not addressed by Jones et al. 6
With adequate volume therapy and myocardial reserve, a hyperdynamic or compensated phase fol-lows. During this compensated phase, D o 2 is in the normal or elevated range, systemic oxygen consump-tion ( o 2 ) is increased, and vascular resistance is gen-erally decreased. In contrast to the hypodynamic phase (patients in the Rivers et al 1 study), Jones et al 6 enrolled patients in this phase with a lower systolic BP, normal central venous pressure (CVP), normal Scv o 2 , lower lactate levels, and triple the frequency of vasopressor dependence ( Fig 1 ; Tables 1, 2 ). These patients also had corresponding Simplifi ed Acute Physiology Score II scores and predicted mortality that was nearly 14% lower than that in patients receiv-ing EGDT (34.8% vs 48.4%) and other studies. 2
Pathological D o 2 dependency is a result of a progres-sive impairment of OER, which is accompanied by a markedly increased Scv o 2 /Sv o 2 (venous hyperoxia) and a hyperdynamic circulation. When D o 2 is insuf-fi cient, o 2 decreases, and increased lactate levels
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1410 Point/Counterpoint Editorials
Table 1 —Hemodynamic Phases of Sepsis
Stage Hemodynamic Picture SBP CVP Treatment and Comments
B Hypovolemia Variable ↓ Volume Myocardial suppression Variable ↑ Correct anemia, inotropic therapy A Resuscitated, compensated, and vasodilatory Variable Normal Vasopressors, low-dose corticosteroids C Supranormal D o 2 dependency Variable ↑ to normal Increased o 2 after augmentation of D o 2 D Impairment of tissue O 2 utilization Variable Normal r-APC Decreased o 2 Variable Normal Resuscitated
CVP 5 central venous pressure; D o 2 5 systemic oxygen delivery; r-APC 5 recombinant activated protein C; SBP 5 systolic BP; SvO 2 5 mixed venous oxygen saturation; o 2 5 oxygen consumption.
lactate clearance, Nguyen et al 20 did not recommend lactate clearance as a sole therapeutic end point. Serum lactate levels may rise or fl uctuate during therapy. Of patients with increased initial lactate levels, 41% have delayed peak values (20 � 12 h) after the initial presentation. 11 , 17 Of patients with normal initial lactates, 15% will later demonstrate elevations. These patients have abnormal Scv o 2 (66.7% � 8.6%) at baseline compared with their coun-terparts with normal levels. 17 Lactate levels over time can increase (negative clearance), stay the same, or decrease (positive clearance) after intervention ( Fig 2 ). Not only is the direction of clearance impor tant but also the magnitude of change. There are signifi cantly different clinical and outcome implications in patients whose lactate levels decrease from 10 to 9 mmol/L vs 4 to 3.6 mmol/L. Although both represent clear-ance of 10%, the implications for illness severity and prognostic signifi cance are much different.
What if the Patient Requires More Than Fluid and Vasopressors and the Lactate
Is Still High?
Optimization of preload (CVP) and afterload (mean arterial pressure) were addressed by Jones et al 6 ; however, the remaining components of EGDT, includ-ing optimizing D o 2 (oxygen carrying capacity [sup-plemental oxygen and hemoglobin], cardiac output) and decreasing o 2 (mechanical ventilation and sedation) to prevent delayed cardiopulmonary com-plications, were not elicited or examined. 15 Over the past decade, numerous studies have validated the clinical utility of Scv o 2 in recognizing supply depen-dency, need for a transfusion, detection of myocardial dysfunction, response to oxygen and mechanical ventilation, early cardiopulmonary complications, and overall infl uence on mortality. To establish non-inferiority, lactate clearance has to be appropriately
Figure 1. The hemodynamic phases of sepsis. DO 2 5 systemic oxygen delivery; NI 5 normal; SvO 2 5 mixed venous oxygen saturation; VO 2 5 oxygen consumption. Reprinted with permission from Kruse. 8
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Table 2 —Comparison of Clinical Variables Between Jones et al 6 and Rivers et al 1
Jones et al 6 Rivers et al 1
Lactate Clearance Scv o 2 Guided Standard Therapy EGDT
Comorbidities Congestive heart failure … … 30.2 36.7 Coronary artery disease … … 23.5 26.5 Liver disease … … 23.5 23.1 Alcohol use … … 38.7 38.5 Baseline hemodynamics Lactate, a mmol/L 3.9 � 3.1 4.2 � 3.1 6.9 � 4.5 7.7 � 4.7 CVP, a mm Hg 11 � 6.5 11 � 6.2 6.1 � 7.7 5.3 � 9.3 Systolic BP, a mm Hg 91 � 24.6 92 � 21.0 109 � 34 106 � 36 Scv o 2 a … 74 � 12.3 49.2 � 13.3 48.6 � 11.2 Treatments (0-6-h ranges) RBC transfusions 7 3 18.5 64.1 P Value .2 … , .001 … Vasopressors a 72 75 30.3 27.4 Inotropes 3 5 0.8 13.7 P Value .57 … , .001 … Mechanical ventilation a 27 26 53.8 53.0 6 h hemodynamics Lactate, mmol/L … … 4.9 � 4.7 4.3 � 4.2 P Value .01 Lactate clearance (0-6 h) … … 29 44.2 P Value .01 CVP, mm Hg … … 11.8 � 6.8 13.8 � 4.4 P Value .007 Scv o 2 … … 66.0 � 15.5 77.3 � 10.0 P Value , .001 Sudden cardiopulmonary collapse … … 21.0 10.3 P Value .02 SAPS II scores (baseline) a 44.8 � 18.4 44.1 � 17.3 48.8 � 11.1 51.2 � 11.1 Predicted mortality (approximate) 34.8 32.8 48.4 48.7 Actual in-hospital mortality 23 17 46.5 30.5 P Value NS … .009 …
Data are presented as mean � SD or %. EGDT 5 early goal-directed therapy; NS 5 not signifi cant; SAPS 5 Simplifi ed Acute Physiology Score; Scv o 2 5 central venous oxygen saturation. See Table 1 legend for expansion of other abbreviations. a No statistical signifi cance.
examined in these scenarios in order to be gener-alizable to all hemodynamic phases of sepsis and these facets of care. 7 The discrepancy between Scv o 2 -triggered interventions in the Rivers et al 1 study vs the 30 interventions (10% of patients) guided by lactate clearance refl ects signifi cant differences in hemodynamic phases, patient populations, and frequency and timing of interventions ( Fig 2 ). This undermines the conclusion of equivalency from a noninferiority research design. 7 Patients more likely to require inotropes (congestive heart failure or coronary artery disease) or patients with reduced lactate clearance (liver failure) were not described by Jones et al 6 ( Table 2 ). This lower number of inter-ventions refl ects a lower illness sever ity compared with other studies, 2 the possibility of poor compliance to the protocol, or a study design that is not equiv-alent to EGDT. The threefold greater use of vaso-pressors by Jones et al 6 may have resulted in higher lactate levels (catecholamines), CVP (increased after-
load and venous tone), and Scv o 2 (decreased OER). As a result, triggers for more fl uid administration, RBC transfusion, inotropes, and mechanical ventila-tion may have been obscured by catecholamines. In this vasodilatory phase of sepsis, one would expect a higher use of corticosteroids 3 ; however, they were only used in 37% and 35% of eligible patients in the lactate clearance and Scv o 2 groups, respectively.
Real-World Clinical Practice
Central venous catheterization is recommended for patients with septic shock, and this was indeed the practice in the Jones et al 6 study. However, this study often is misinterpreted to imply that lactate clearance precludes the need for central venous catheterization altogether. This could result in a delay in a safer route for administration of vasopressors and achievement of EGDT goals within 6 h. The Surviving Sepsis Campaign recommendations include intermittent
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
1412 Point/Counterpoint Editorials
Figure 2. The kinetics, diagnostic, and therapeutic clinical scenarios of lactate. EGDT 5 early goal-directed therapy; PRBC 5 packed RBC; ScvO 2 5 central venous oxygen saturation. See Figure 1 legend for expansion of other abbreviation.
or continuous Scv o 2 sampling. 3 It is a simple matter to add intermittent Scv o 2 to lactate measurements in the absence of continuous monitoring. Bundle compliance and socioeconomic costs improve signifi -cantly with continuous monitoring. 21
Conclusions
Scv o 2 provides immediate feedback to the o 2 /D o 2 relationship but requires interpretation that depends on the phase of sepsis. Lactate is a delayed indicator of tissue perfusion and is subject to complex kinetics that are never clear in the individual case. Lactate levels may be normal or fl uctuate, leading to inappro-priate risk stratifi cation and therapy. Lactate clear-ance and Scv o 2 , therefore, are complementary and not mutually exclusive end points.
Emanuel P. Rivers , MD, MPH, FCCP Detroit, MI
Ronald Elkin , MD San Francisco, CA
Chad M. Cannon , MD Kansas City, KS
Affi liations: From the Department of Emergency Medicine and Surgery (Dr Rivers), Henry Ford Hospital, Wayne State University; Department of Medicine (Dr Elkin), Pulmonary and Critical Care Medicine, California Pacifi c Medical Center; and Department of Emergency Medicine (Dr Cannon), University of Kansas Hospital. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: In the past 3 years, Dr Rivers has received funding from the National Institutes of Health, Aggennix AG, and Alere Corporation. He has been a one-time consultant for Aggennix AG; Eisai Co, Ltd; Idaho Technologies Inc; AstraZeneca; Massimo; and Sangard. He is a consultant to the Institute of Medicine, National Academies. The EGDT study was performed without external industry support or funding of any kind. Any intellectual properties associated with Dr Rivers’ research are exclusively owned by Henry Ford Hospital. Dr Rivers holds no past or present intellectual proper-ties and has never received royalties or stock interest related to technologies in EGDT research and practice. Dr Elkin has received funding from the Gordon and Betty Moore Foundation, been a one-time consultant for Eisai Co, Ltd, and participated on the speaker’s bureau for Edwards Lifesciences LLC on three occasions. Dr Cannon has been a one-time consultant for Aggennix AG and Eisai Co, Ltd. Correspondence to: Emanuel P. Rivers, MD, MPH, FCCP, Department of Emergency Medicine, Wayne State University, 270 Clara Ford Pavilion, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202; e-mail: [email protected] © 2011 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.11-2563
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Rebuttal From Dr Jones
In their counterpoint, Dr Rivers and colleagues 1 present the theoretical view that patients with
septic shock present in very distinct “hemodynamic phases” and that Jones et al 2 enrolled patients in a different phase of septic shock than did Rivers et al. 3 According to their theory, decreased central venous oxygen saturation (Scv o 2 ) always precedes the appear-ance of lactate—a concept not observed in my clin-ical practice. Clinicians who routinely care for the critically ill encounter patients with elevated lac-tate and normal Scv o 2 . Furthermore, as shown in Table 1 , 2 - 10 the hemodynamic patterns of the sub-jects enrolled by Rivers et al 3 are markedly different from any other reported populations of patients with septic shock treated with quantitative resuscitation. The study by Rivers et al 3 patients had much higher lactate, much lower Scv o 2 , and much higher mor-tality than described elsewhere. Possible explana-tions for this discrepancy may include that patients with septic shock in Detroit between 1997 and 2000 were markedly different than any other septic shock population reported in the world’s literature and/or that systematic selection bias was a signifi cant problem in the their study. In such a scenario, their results have questionable external validity. Support-ing either of these assertions is the fact that mor-tality in the control group of the Rivers et al 3 study was 20% higher than any septic shock mortality reported in the recent literature, leaving one to question exactly what care they received. 3 Little evidence supports the contention that Jones et al 2 enrolled patients in a different phase of septic shock
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 . Rivers EP . Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientifi c proof speaks for itself . Chest . 2010 ; 138 ( 3 ): 476 - 485 .
3 . Dellinger RP , Levy MM , Carlet JM , et al ; International Surviving Sepsis Campaign Guidelines Committee ; American Association of Critical-Care Nurses ; American College of Chest Physicians ; American College of Emergency Physicians ; Canadian Critical Care Society ; European Society of Clinical Microbiology and Infectious Diseases ; European Society of Intensive Care Medicine ; European Respiratory Society ; Inter-national Sepsis Forum ; Japanese Association for Acute Med-icine ; Japanese Society of Intensive Care Medicine ; Society of Critical Care Medicine ; Society of Hospital Medicine ; Surgical Infection Society ; World Federation of Societies of Intensive and Critical Care Medicine . Surviving Sepsis Cam-paign: international guidelines for management of severe sepsis and septic shock: 2008 . Crit Care Med . 2008 ; 36 ( 1 ): 296 - 327 .
4 . Nguyen HB , Rivers EP , Knoblich BP , et al . Early lactate clearance is associated with improved outcome in severe sep-sis and septic shock . Crit Care Med . 2004 ; 32 ( 8 ): 1637 - 1642 .
5 . Nguyen HB , Loomba M , Yang JJ , et al . Early lactate clear-ance is associated with biomarkers of infl ammation, coagu-lation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock . J Infl amm (Lond) . 2010 ; 7 : 6 .
6 . 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 .
7 . Piaggio G , Elbourne DR , Altman DG , Pocock SJ , Evans SJ ; CONSORT Group . Reporting of noninferiority and equiv-alence randomized trials: an extension of the CONSORT statement . JAMA . 2006 ; 295 ( 10 ): 1152 - 1160 .
8 . Kruse J . Lactic acidosis, part 1: understanding pathogenesis and causes. As mechanisms are elucidated, some assumptions are being revised. J Crit Illness . 1999 ; 14 ( 8 ): 456 - 466 .
9 . Levraut J , Ichai C , Petit I , Ciebiera JP , Perus O , Grimaud D . Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients . Crit Care Med . 2003 ; 31 ( 3 ): 705 - 710 .
10 . Astiz ME , Rackow EC , Kaufman B , Falk JL , Weil MH . Relationship of oxygen delivery and mixed venous oxygena-tion to lactic acidosis in patients with sepsis and acute myo-cardial infarction . Crit Care Med . 1988 ; 16 ( 7 ): 655 - 658 .
11 . Rivers EP , Kruse JA , Jacobsen G , et al . The infl uence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock . Crit Care Med . 2007 ; 35 ( 9 ): 2016 - 2024 .
12 . Rady MY , Rivers EP , Nowak RM . Resuscitation of the crit-ically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate . Am J Emerg Med . 1996 ; 14 ( 2 ): 218 - 225 .
13 . Brun-Buisson C , Doyon F , Carlet J , et al ; French ICU Group for Severe Sepsis . Incidence, risk factors, and out-come of severe sepsis and septic shock in adults. A multi-center prospective study in intensive care units . JAMA . 1995 ; 274 ( 12 ): 968 - 974 .
14 . Carr GE , Edelson DP , Yuen TC , et al . In-hospital cardiac arrest among patients with coexisting pneumonia: a report from the American Heart Association’s Get With The Guidelines–Resuscitation Program . Am J Respir Crit Care Med . 2011 ; 183 : A6339 .
15 . Sevransky JE , Nour S , Susla GM , Needham DM , Hollenberg S , Pronovost P . Hemodynamic goals in randomized clinical trials in patients with sepsis: a systematic review of the literature . Crit Care . 2007 ; 11 ( 3 ): R67 .
16 . Mizock BA . The hepatosplanchnic area and hyperlactatemia: A tale of two lactates . Crit Care Med . 2001 ; 29 ( 2 ): 447 - 449 .
17 . Hernandez G , Castro R , Romero C , et al . Persistent sepsis-induced hypotension without hyperlactatemia: is it really sep-tic shock? J Crit Care . 2010 ; 26 ( 4 ): 435.e9 - e14 .
18 . Dugas A , Mackenhauer J , Joyce N , et al . Prevalence and char-acteristics of non-lactate and lactate expressors in septic shock [abstract] . Crit Care Med . 2009 ; 37:A227 .
19 . Cannon CM ; Multicenter Severe Sepsis and Septic Shock Collaborative Group . The GENESIS Project (GENeralization of Early Sepsis InterventionS): a multicenter quality improve-ment collaborative . Acad Emerg Med . 2010 ; 17 ( 11 ): 1258 .
20 . Nguyen HB , Rivers EP , Havstad S , et al . Critical care in the emergency department: a physiologic assessment and out-come evaluation . Acad Emerg Med . 2000 ; 7 ( 12 ): 1354 - 1361 .
21 . Ising P , Smith TW , Simpson SQ . Effect of intermittent vs con-tinuous ScvO2 monitoring on sepsis bundle compliance and mortality [abstract] . Chest . 2009 ; 136 ( 4 ): 21S .
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Rebuttal From Dr Jones
In their counterpoint, Dr Rivers and colleagues 1 present the theoretical view that patients with
septic shock present in very distinct “hemodynamic phases” and that Jones et al 2 enrolled patients in a different phase of septic shock than did Rivers et al. 3 According to their theory, decreased central venous oxygen saturation (Scv o 2 ) always precedes the appear-ance of lactate—a concept not observed in my clin-ical practice. Clinicians who routinely care for the critically ill encounter patients with elevated lac-tate and normal Scv o 2 . Furthermore, as shown in Table 1 , 2 - 10 the hemodynamic patterns of the sub-jects enrolled by Rivers et al 3 are markedly different from any other reported populations of patients with septic shock treated with quantitative resuscitation. The study by Rivers et al 3 patients had much higher lactate, much lower Scv o 2 , and much higher mor-tality than described elsewhere. Possible explana-tions for this discrepancy may include that patients with septic shock in Detroit between 1997 and 2000 were markedly different than any other septic shock population reported in the world’s literature and/or that systematic selection bias was a signifi cant problem in the their study. In such a scenario, their results have questionable external validity. Support-ing either of these assertions is the fact that mor-tality in the control group of the Rivers et al 3 study was 20% higher than any septic shock mortality reported in the recent literature, leaving one to question exactly what care they received. 3 Little evidence supports the contention that Jones et al 2 enrolled patients in a different phase of septic shock
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 . Rivers EP . Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientifi c proof speaks for itself . Chest . 2010 ; 138 ( 3 ): 476 - 485 .
3 . Dellinger RP , Levy MM , Carlet JM , et al ; International Surviving Sepsis Campaign Guidelines Committee ; American Association of Critical-Care Nurses ; American College of Chest Physicians ; American College of Emergency Physicians ; Canadian Critical Care Society ; European Society of Clinical Microbiology and Infectious Diseases ; European Society of Intensive Care Medicine ; European Respiratory Society ; Inter-national Sepsis Forum ; Japanese Association for Acute Med-icine ; Japanese Society of Intensive Care Medicine ; Society of Critical Care Medicine ; Society of Hospital Medicine ; Surgical Infection Society ; World Federation of Societies of Intensive and Critical Care Medicine . Surviving Sepsis Cam-paign: international guidelines for management of severe sepsis and septic shock: 2008 . Crit Care Med . 2008 ; 36 ( 1 ): 296 - 327 .
4 . Nguyen HB , Rivers EP , Knoblich BP , et al . Early lactate clearance is associated with improved outcome in severe sep-sis and septic shock . Crit Care Med . 2004 ; 32 ( 8 ): 1637 - 1642 .
5 . Nguyen HB , Loomba M , Yang JJ , et al . Early lactate clear-ance is associated with biomarkers of infl ammation, coagu-lation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock . J Infl amm (Lond) . 2010 ; 7 : 6 .
6 . 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 .
7 . Piaggio G , Elbourne DR , Altman DG , Pocock SJ , Evans SJ ; CONSORT Group . Reporting of noninferiority and equiv-alence randomized trials: an extension of the CONSORT statement . JAMA . 2006 ; 295 ( 10 ): 1152 - 1160 .
8 . Kruse J . Lactic acidosis, part 1: understanding pathogenesis and causes. As mechanisms are elucidated, some assumptions are being revised. J Crit Illness . 1999 ; 14 ( 8 ): 456 - 466 .
9 . Levraut J , Ichai C , Petit I , Ciebiera JP , Perus O , Grimaud D . Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients . Crit Care Med . 2003 ; 31 ( 3 ): 705 - 710 .
10 . Astiz ME , Rackow EC , Kaufman B , Falk JL , Weil MH . Relationship of oxygen delivery and mixed venous oxygena-tion to lactic acidosis in patients with sepsis and acute myo-cardial infarction . Crit Care Med . 1988 ; 16 ( 7 ): 655 - 658 .
11 . Rivers EP , Kruse JA , Jacobsen G , et al . The infl uence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock . Crit Care Med . 2007 ; 35 ( 9 ): 2016 - 2024 .
12 . Rady MY , Rivers EP , Nowak RM . Resuscitation of the crit-ically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate . Am J Emerg Med . 1996 ; 14 ( 2 ): 218 - 225 .
13 . Brun-Buisson C , Doyon F , Carlet J , et al ; French ICU Group for Severe Sepsis . Incidence, risk factors, and out-come of severe sepsis and septic shock in adults. A multi-center prospective study in intensive care units . JAMA . 1995 ; 274 ( 12 ): 968 - 974 .
14 . Carr GE , Edelson DP , Yuen TC , et al . In-hospital cardiac arrest among patients with coexisting pneumonia: a report from the American Heart Association’s Get With The Guidelines–Resuscitation Program . Am J Respir Crit Care Med . 2011 ; 183 : A6339 .
15 . Sevransky JE , Nour S , Susla GM , Needham DM , Hollenberg S , Pronovost P . Hemodynamic goals in randomized clinical trials in patients with sepsis: a systematic review of the literature . Crit Care . 2007 ; 11 ( 3 ): R67 .
16 . Mizock BA . The hepatosplanchnic area and hyperlactatemia: A tale of two lactates . Crit Care Med . 2001 ; 29 ( 2 ): 447 - 449 .
17 . Hernandez G , Castro R , Romero C , et al . Persistent sepsis-induced hypotension without hyperlactatemia: is it really sep-tic shock? J Crit Care . 2010 ; 26 ( 4 ): 435.e9 - e14 .
18 . Dugas A , Mackenhauer J , Joyce N , et al . Prevalence and char-acteristics of non-lactate and lactate expressors in septic shock [abstract] . Crit Care Med . 2009 ; 37:A227 .
19 . Cannon CM ; Multicenter Severe Sepsis and Septic Shock Collaborative Group . The GENESIS Project (GENeralization of Early Sepsis InterventionS): a multicenter quality improve-ment collaborative . Acad Emerg Med . 2010 ; 17 ( 11 ): 1258 .
20 . Nguyen HB , Rivers EP , Havstad S , et al . Critical care in the emergency department: a physiologic assessment and out-come evaluation . Acad Emerg Med . 2000 ; 7 ( 12 ): 1354 - 1361 .
21 . Ising P , Smith TW , Simpson SQ . Effect of intermittent vs con-tinuous ScvO2 monitoring on sepsis bundle compliance and mortality [abstract] . Chest . 2009 ; 136 ( 4 ): 21S .
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1414 Point/Counterpoint Editorials
Table 1 —Summary of Initial Clinical Characteristics and Mortality Rates of Recent Studies of Quantitative
Resuscitation for Septic Shock
Study No. Lactate, mmol/L Scv o 2 ,% Mortality, %
Rivers et al 3 EGDT group 130 7.7 48.6 30.5 Control group 133 6.9 49.2 46.5 Jones et al 2 Scv o 2 group 150 4.2 74 23 LC group 150 3.9 … 17 Shapiro et al 4 116 4.4 72 20 Jones et al 5 77 3.6 69-81 18 Nguyen et al 6 197 3.4-4.4 62-69 … Kortgen et al 7 30 2.6 … 27 van Beest et al 8 125 2.7 74 26 Peake et al 9 324 6.9 a … 23 Xiao-Zhi et al 10 16 5.3 66 18
The most abnormal values in each column are present in bold and italic text. EGDT 5 early goal-directed therapy; LC 5 lactate clearance; Scv o 2 5 central venous oxygen saturation. a Only 98 had lactate measured.
than did Rivers et al, 3 because the population enrolled by Jones et al 2 used inclusion cri teria identical to the Rivers et al 3 study. Furthermore, the population in the Jones et al 3 study appears to be an accurate con-temporaneous population from three US EDs; it has characteristics, including mortality rates, nearly iden-tical to those described from other studies ( Table 1 ).
Rivers et al 3 have raised the issue of potential methodologic limitations. They state that one must consider “weaknesses of the non inferiority study design” in the Jones et al 2 study. However, our study did not show equivalence (not worse than and not better than) but rather noninferiority (not worse than and maybe better than). This study design is the only design that could test the hypothesis at hand and, furthermore, the methodologic quality of a noninferiority and superiority randomized con-trolled trial is the same if properly conducted. So it is unclear exactly what “weaknesses” in our study are being criticized. On the other hand, there appear to be real methodologic concerns in the Rivers et al 3 trial. They failed to follow recommendations by not reporting whether any patients were randomized but not analyzed or performing an intention-to-treat analysis that could easily change the statistically sig-nifi cant results of the trial.
Finally, the counterpoint 1 states that 45% of patients with septic shock present with a normal lactate and suggest that because of this, lactate is an incon-sistent guide of resuscitation. 1 In fact, . 65% of patients in contemporaneous studies present with an Scv o 2 . 70%, and using their argument, these data make Scv o 2 an even more inconsistent resuscitative guide, particularly given that there is no therapy for markedly elevated and pathologic Scv o 2 (ie, . 90%). 2 , 5
Because data from an experimental clinical trial are the only way to scientifi cally deduce the clinical effi -cacy of lactate clearance vs Scv o 2 and because data from a large multicenter clinical trial demonstrated that lactate clearance is not inferior to Scv o 2 as an end point of early sepsis resuscitation, as described herein, lactate clearance has principles that may make it the more appropriate end point to choose.
Alan E. Jones , MD Jackson, MS
Affi liations: From the Department of Emergency Medicine, University of Mississippi Medical Center . Financial/nonfi nancial disclosures: The author has reported to CHEST the following confl icts of interest: Dr Jones has received funding from the National Institutes of Health to study lactate clearance in sepsis resuscitation. Dr Jones has never been assigned patents, received patent royalties, honoraria, consulting fees, or other monetary or nonmonetary payments at any time related to the use of lactate or lactate clearance . Correspondence to: Alan E. Jones, MD, Department of Emer-gency Medicine, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216; e-mail: [email protected] © 2011 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.11-2597
References 1 . Rivers EP , Elkin R , Cannon CM . Counterpoint: should lac-
tate clearance be substituted for central venous oxygen satura-tion as goals of early severe sepsis and septic shock therapy? No . Chest . 2011 ; 140 ( 6 ): 1408 - 1413 .
2 . 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 .
3 . 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 .
4 . Shapiro NI , Howell MD , Talmor D , et al . Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol . Crit Care Med . 2006 ; 34 ( 4 ): 1025 - 1032 .
5 . Jones AE , Focht A , Horton JM , Kline JA . Prospective exter-nal validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock . Chest . 2007 ; 132 ( 2 ): 425 - 432 .
6 . Nguyen HB , Corbett SW , Steele R , et al . Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality . Crit Care Med . 2007 ; 35 ( 4 ): 1105 - 1112 .
7 . Kortgen A , Niederprüm P , Bauer M . Implementation of an evidence-based “standard operating procedure” and outcome in septic shock . Crit Care Med . 2006 ; 34 ( 4 ): 943 - 949 .
8 . van Beest PA , Hofstra JJ , Schultz MJ , Boerma EC , Spronk PE , Kuiper MA . The incidence of low venous oxygen satura tion on admission to the intensive care unit: a multi-center observa-tional study in The Netherlands . Crit Care . 2008 ; 12 ( 2 ): R33 .
9 . Peake SL , Bailey M , Bellomo R , et al ; ARISE Investigators, for the Australian and New Zealand Intensive Care Society Clinical Trials Group . Australasian resuscitation of sepsis evaluation (ARISE): a multi-centre, prospective, inception cohort study . Resuscitation . 2009 ; 80 ( 7 ): 811 - 818 .
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Rebuttal From Dr Rivers et al
An End Point Must Be Consistently Present to Be Generalized
Levraut et al 1 stated, “It is common knowledge that many septic patients develop multiple organ
failure and die despite normal blood lactate levels.” Below the critical systemic oxygen delivery, central venous oxygen saturation (Scv o 2 ) decreases; however, lactate level elevation may not occur. More impor-tantly, an Scv o 2 � 70% is not the only goal, as achieve-ment of all early goal-directed therapy (EGDT) goals actually resulted in an Scv o 2 � 77.3%. According to Dr Jones, 2 a study by Gattinoni et al 3 did not show an outcome benefi t of reaching a mixed venous oxygen saturation of 70% up to 48 h after ICU admission. However, Chamberlain et al 4 found in a meta-analysis that patients resuscitated to this end point within a more reasonable 6 h were twice as likely to survive than those without it.
A Repeat Look at a Previously Quoted Study
Dr Jones 2 cites the study by Jansen et al 5 as sup-portive of lactate clearance, but not all patients in that study were septic. Furthermore, the reduction of lac-tate was no faster when the control group therapy was compared with the lactate-guided aggressive resus-citation group. In fact, these authors concluded that “this observation might actually argue against lactate level as a target of hemodynamic therapy. However, given that Scv o 2 monitoring was mandatory in the lactate group and control group, we cannot exclude the possibility that this had an impact on the observed outcome difference.” 5
Does Noninferiority Mean Equivalency? Be Careful What You Read
Noninferiority is a double negative that may confuse clinicians because of the complexity of study design. Noninferiority trials are contro versial and diffi cult to design, conduct, analyze, and interpret for trialists, clinicians, reviewers, and editors. 6 The low number of interventions observed by Jones et al 7 bias toward the conclusion of noninferiority. Thus, for appropriate interpretation, one must be aware of and apply the CONSORT (Consolidated Standards of Reporting Trials) recommendations on noninferiority and equiva-lence trials ( Table 1 ). 6 - 10
Responding to Perceived Barriers
Barriers specifi ed by Dr Jones 2 are unacceptable as excuses for our failure to save lives. We do not avoid complex interventions for trauma, stroke, or myocar-dial infarction. Severe sepsis carries a mortality risk far in excess of these acknowledged emergencies. Surely, placement of central lines, as well as contin-uous or intermittent venous saturation measurement, should be well within the capabilities of competent emergency and critical care practitioners.
Conclusion
Today’s clinical tools for assessing tissue perfusion, including Scv o 2 and lactate level, have benefi ts and limitations. Scv o 2 has a half-life of seconds, providing value as an early goal of resuscitation with interpre-tation potentially confounded by changes in systemic oxygen delivery, tissue extraction, and distribution of blood fl ow at both the macrocirculatory and microcir-culatory levels. Serum lactate levels may remain nor-mal before and throughout resuscitation or fl uctuate due to the complexities of lactate kinetics, causing one to question the clinical usefulness of lactate clearance. Moreover, a 10% drop in serum lactate level has different implications if the initial value is 12 mmol/L rather than 4 mmol/L . The concept of lac-tate clearance as the single goal of resuscitation is, therefore, fl awed and potentially dangerous. Today’s prudent clinician will use both normalization of Scv o 2 and lactate levels to guide resuscitation rather than rely on one parameter alone.
Emanuel P. Rivers , MD, MPH, FCCP Detroit, MI
Ronald Elkin , MD San Francisco, CA
Chad M. Cannon , MD Kansas City, KS
Affi liations: From the Department of Emergency Medicine and Surgery (Dr Rivers), Henry Ford Hospital, Wayne State University; Department of Medicine (Dr Elkin), Pulmonary and Critical Care Medicine, California Pacifi c Medical Center; and Department of Emergency Medicine (Dr Cannon), University of Kansas Hospital. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: In the past 3 years, Dr Rivers has received funding from the National Institutes of Health, Aggennix AG, and Alere Corporation. He has been a one-time consultant for Aggennix AG; Eisai Co, Ltd; Idaho Technologies Inc; AstraZeneca; Massimo; and Sangard. He is a consultant to the Institute of Medicine, National Academies. The Early Goal-Directed Therapy (EGDT) study was performed without external industry support or funding of any kind. Any intellectual properties associated with Dr Rivers’ research are exclusively owned by Henry Ford Hospital. Dr Rivers holds no past or present intellectual properties and has never received royalties or stock interest related to technologies in EGDT research and practice. Dr Elkin has received funding from the Gordon and Betty Moore Foundation, has been a one-time consultant for Eisai Co, Ltd, and participated on the speaker’s bureau for Edwards Lifesciences LLC on three occasions. Dr Cannon has been a one-time consultant for Aggennix AG and Eisai Co, Ltd.
10 . Wang XZ , Lü CJ , Gao FQ Li XH , Yan WF , Ning FY . Effi cacy of goal-directed therapy in the treatment of septic shock [in Chinese] . Zhongguo Wei Zhong Bing Ji Jiu Yi Xue . 2006 ; 18 ( 11 ): 661 - 664 .
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Rebuttal From Dr Rivers et al
An End Point Must Be Consistently Present to Be Generalized
Levraut et al 1 stated, “It is common knowledge that many septic patients develop multiple organ
failure and die despite normal blood lactate levels.” Below the critical systemic oxygen delivery, central venous oxygen saturation (Scv o 2 ) decreases; however, lactate level elevation may not occur. More impor-tantly, an Scv o 2 � 70% is not the only goal, as achieve-ment of all early goal-directed therapy (EGDT) goals actually resulted in an Scv o 2 � 77.3%. According to Dr Jones, 2 a study by Gattinoni et al 3 did not show an outcome benefi t of reaching a mixed venous oxygen saturation of 70% up to 48 h after ICU admission. However, Chamberlain et al 4 found in a meta-analysis that patients resuscitated to this end point within a more reasonable 6 h were twice as likely to survive than those without it.
A Repeat Look at a Previously Quoted Study
Dr Jones 2 cites the study by Jansen et al 5 as sup-portive of lactate clearance, but not all patients in that study were septic. Furthermore, the reduction of lac-tate was no faster when the control group therapy was compared with the lactate-guided aggressive resus-citation group. In fact, these authors concluded that “this observation might actually argue against lactate level as a target of hemodynamic therapy. However, given that Scv o 2 monitoring was mandatory in the lactate group and control group, we cannot exclude the possibility that this had an impact on the observed outcome difference.” 5
Does Noninferiority Mean Equivalency? Be Careful What You Read
Noninferiority is a double negative that may confuse clinicians because of the complexity of study design. Noninferiority trials are contro versial and diffi cult to design, conduct, analyze, and interpret for trialists, clinicians, reviewers, and editors. 6 The low number of interventions observed by Jones et al 7 bias toward the conclusion of noninferiority. Thus, for appropriate interpretation, one must be aware of and apply the CONSORT (Consolidated Standards of Reporting Trials) recommendations on noninferiority and equiva-lence trials ( Table 1 ). 6 - 10
Responding to Perceived Barriers
Barriers specifi ed by Dr Jones 2 are unacceptable as excuses for our failure to save lives. We do not avoid complex interventions for trauma, stroke, or myocar-dial infarction. Severe sepsis carries a mortality risk far in excess of these acknowledged emergencies. Surely, placement of central lines, as well as contin-uous or intermittent venous saturation measurement, should be well within the capabilities of competent emergency and critical care practitioners.
Conclusion
Today’s clinical tools for assessing tissue perfusion, including Scv o 2 and lactate level, have benefi ts and limitations. Scv o 2 has a half-life of seconds, providing value as an early goal of resuscitation with interpre-tation potentially confounded by changes in systemic oxygen delivery, tissue extraction, and distribution of blood fl ow at both the macrocirculatory and microcir-culatory levels. Serum lactate levels may remain nor-mal before and throughout resuscitation or fl uctuate due to the complexities of lactate kinetics, causing one to question the clinical usefulness of lactate clearance. Moreover, a 10% drop in serum lactate level has different implications if the initial value is 12 mmol/L rather than 4 mmol/L . The concept of lac-tate clearance as the single goal of resuscitation is, therefore, fl awed and potentially dangerous. Today’s prudent clinician will use both normalization of Scv o 2 and lactate levels to guide resuscitation rather than rely on one parameter alone.
Emanuel P. Rivers , MD, MPH, FCCP Detroit, MI
Ronald Elkin , MD San Francisco, CA
Chad M. Cannon , MD Kansas City, KS
Affi liations: From the Department of Emergency Medicine and Surgery (Dr Rivers), Henry Ford Hospital, Wayne State University; Department of Medicine (Dr Elkin), Pulmonary and Critical Care Medicine, California Pacifi c Medical Center; and Department of Emergency Medicine (Dr Cannon), University of Kansas Hospital. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: In the past 3 years, Dr Rivers has received funding from the National Institutes of Health, Aggennix AG, and Alere Corporation. He has been a one-time consultant for Aggennix AG; Eisai Co, Ltd; Idaho Technologies Inc; AstraZeneca; Massimo; and Sangard. He is a consultant to the Institute of Medicine, National Academies. The Early Goal-Directed Therapy (EGDT) study was performed without external industry support or funding of any kind. Any intellectual properties associated with Dr Rivers’ research are exclusively owned by Henry Ford Hospital. Dr Rivers holds no past or present intellectual properties and has never received royalties or stock interest related to technologies in EGDT research and practice. Dr Elkin has received funding from the Gordon and Betty Moore Foundation, has been a one-time consultant for Eisai Co, Ltd, and participated on the speaker’s bureau for Edwards Lifesciences LLC on three occasions. Dr Cannon has been a one-time consultant for Aggennix AG and Eisai Co, Ltd.
10 . Wang XZ , Lü CJ , Gao FQ Li XH , Yan WF , Ning FY . Effi cacy of goal-directed therapy in the treatment of septic shock [in Chinese] . Zhongguo Wei Zhong Bing Ji Jiu Yi Xue . 2006 ; 18 ( 11 ): 661 - 664 .
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
1416 Point/Counterpoint Editorials
(Con
tinu
ed)
Tabl
e 1 —
CO
NSO
RT
Che
ckli
st f
or R
epor
ting
Non
infe
rior
ity
or E
quiv
alen
ce T
rial
s in
Riv
ers
et a
l 8 a
nd J
ones
et
al 7
C
omm
enta
ry
Topi
cR
equi
rem
ents
and
Con
side
ratio
nsJo
nes
et a
l 7,10
R
iver
s et
al 8
Bac
kgro
und
Scie
ntifi
c ba
ckgr
ound
and
exp
lana
tion
of
ra
tiona
le, i
nclu
ding
the
ratio
nale
for
usin
g a
noni
nfer
iori
ty o
r eq
uiva
lenc
e de
sign
.
Inte
rmitt
ent o
r co
ntin
uous
Scv
o 2 a
s pa
rt o
f EG
DT
and
reco
mm
ende
d by
the
SSC
9 is
not g
ener
aliz
able
bec
ause
of
the
follo
win
g is
sues
:
•
The
nee
d fo
r sp
ecia
lty e
quip
men
t and
trai
ning
, su
ch a
s co
ntin
uous
Scv
o 2 s
pect
roph
otom
eter
an
d ca
thet
er.
• T
his
tech
nolo
gy is
des
crib
ed a
s “t
echn
ical
ly d
iffi c
ult,
unav
aila
ble
in m
any
tert
iary
car
e E
Ds,
too
com
plex
, co
stly
and
take
s tim
e aw
ay fr
om th
e pa
tient
.”
•
Scv o
2 is
a “c
ontr
over
sial
” m
etho
d of
det
erm
inin
g tis
sue
oxyg
en d
eliv
ery.
Ass
umpt
ion,
LC
is e
quiv
alen
t to
Scv o
2 :
•
Incr
ease
d la
ctat
e le
vels
are
ubi
quito
us in
all
patie
nts
with
sev
ere
seps
is a
nd s
eptic
sho
ck.
Bac
kgro
und
of E
GD
T 8 :
• It
has
bee
n re
plic
ated
in v
ario
us m
ultip
le
stud
ies
com
pris
ing
. 4
0 st
udie
s to
talin
g .
10,
000
patie
nts.
• R
educ
es a
bsol
ute
mor
talit
y by
16%
-18%
in
patie
nts
of e
qual
illn
ess
seve
rity
. •
It is
cos
t eff
ectiv
e an
d de
crea
ses h
ealth
-car
e re
sour
ce c
onsu
mpt
ion.
• T
he S
cv o 2 t
echn
olog
y is
. 4
0 y
old,
requ
ires
se
cond
s to
cal
ibra
te, a
nd is
opt
iona
l with
in
term
itten
t sam
plin
g ac
cord
ing
to th
e SS
C
reco
mm
enda
tions
.
Rat
iona
le fo
r a
noni
nfer
iori
ty d
esig
n:
•
To e
stab
lish
equi
pois
e be
caus
e co
mpa
ring
EG
DT
to
a c
ontr
ol g
roup
in a
pro
spec
tive
rand
omiz
ed
tria
l with
info
rmed
con
sent
wou
ld b
e un
ethi
cal
base
d on
rob
ust e
vide
nce
of p
revi
ous
stud
ies.
Met
hods
Inte
rven
tions
Prec
ise
deta
ils o
f the
inte
rven
tions
inte
nded
for
each
gro
up, d
etai
ling
whe
ther
the
refe
renc
e tr
eatm
ent i
n th
e no
ninf
erio
rity
or
equi
vale
nce
tria
l is
iden
tical
(or
very
sim
ilar)
to th
at in
any
tr
ial(s
) tha
t est
ablis
hed
effi c
acy
and
how
and
w
hen
they
wer
e ac
tual
ly a
dmin
iste
red.
LC
trig
gere
d in
terv
entio
ns:
EG
DT
trig
gere
d in
terv
entio
ns o
ver
6 h:
•
Supp
lem
enta
l oxy
gen
• B
lood
tran
sfus
ions
to h
emat
ocri
t of 3
0%
• D
obut
amin
e to
a 1
0% d
ecre
ase
in L
C
• F
luid
ther
apy
• Va
sopr
esso
r th
erap
y
• B
lood
tran
sfus
ions
•
Inot
rope
s us
e
•
Mec
hani
cal v
entil
atio
n
•
Prev
entio
n of
sud
den
card
iopu
lmon
ary
com
plic
atio
ns
O
bjec
tives
Spec
ifi c
obje
ctiv
es a
nd h
ypot
hese
s, in
clud
ing
the
hy
poth
esis
con
cern
ing
noni
nfer
iori
ty o
r eq
uiva
lenc
e.O
bjec
tive:
• To
add
ress
the
pote
ntia
l util
ity o
f LC
as
a su
bstit
ute
for
Scv o
2 .
Hyp
othe
sis:
•
Targ
etin
g L
C a
s th
e m
arke
r of
ade
quac
y of
D o
2 was
no
ninf
erio
r to
the
curr
ently
rec
omm
ende
d Sc
v o 2
mon
itori
ng fo
r th
e ou
tcom
e of
in-h
ospi
tal m
orta
lity.
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
CHEST / 140 / 6 / DECEMBER, 2011 1417www.chestpubs.org
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
C
omm
enta
ry
Topi
cR
equi
rem
ents
and
Con
side
ratio
nsJo
nes
et a
l 7,10
R
iver
s et
al 8
Oth
er o
bjec
tives
:
•
Disa
ssem
ble
a pr
otoc
ol “t
oo c
ompl
ex” f
or th
e pr
ovid
ers o
f car
e.
• Pr
ove
evid
ence
that
che
ckin
g se
rial
lact
ates
is e
asie
r an
d a
relia
ble
equi
vale
nt to
Scv
o 2 .
• F
ind
a si
mpl
er a
nd m
ore
gene
raliz
able
met
hod
to m
onito
r th
e ad
equa
cy o
f D o
2 as
a re
sear
ch im
pera
tive
in th
e tr
eatm
ent
of p
atie
nts
with
sev
ere
infe
ctio
n.
O
utco
mes
Cle
arly
defi
ned
prim
ary
and
seco
ndar
y ou
tcom
e m
easu
res,
de
taili
ng w
heth
er th
e ou
tcom
es in
the
noni
nfer
iori
ty
or e
quiv
alen
ce tr
ial a
re id
entic
al (o
r ve
ry s
imila
r) to
th
ose
in a
ny tr
ial(s
) tha
t est
ablis
hed
effi c
acy
of th
e re
fere
nce
trea
tmen
t and
, whe
n ap
plic
able
, any
m
etho
ds u
sed
to e
nhan
ce th
e qu
ality
of m
easu
rem
ents
(e
g, m
ultip
le o
bser
vatio
ns, t
rain
ing
of a
sses
sors
).
• T
he p
rimar
y en
d po
int w
as a
bsol
ute
in-h
ospi
tal m
orta
lity
rate
.
• Se
cond
ary
end
poin
ts w
ere
ICU
leng
th o
f sta
y, h
ospi
tal
leng
th o
f sta
y, v
entil
ator
-fre
e da
ys, a
nd n
ew o
nset
mul
tiple
or
gan
failu
re.
• O
ther
end
poi
nts
asse
ssed
wer
e th
e nu
mbe
r of
res
usci
tativ
e go
als
achi
eved
, adm
inis
tere
d tr
eatm
ents
, and
pre
defi n
ed
prot
ocol
-rel
ated
ser
ious
adv
erse
eve
nts.
Sam
ple
size
an
d st
atis
tical
m
etho
ds
How
sam
ple
size
was
det
erm
ined
, det
ailin
g w
heth
er it
was
cal
cula
ted
usin
g a
noni
nfer
iorit
y or
equ
ival
ence
cr
iteri
on a
nd s
peci
fyin
g th
e m
argi
n of
equ
ival
ence
with
th
e ra
tiona
le fo
r its
cho
ice.
Whe
n ap
plic
able
, exp
lana
tion
of a
ny in
teri
m a
naly
ses a
nd st
oppi
ng ru
les (
and
whe
ther
re
late
d to
a n
onin
feri
ority
or
equi
vale
nce
hypo
thes
is).
• U
sing
a on
e-sid
ed te
st o
f non
infe
riorit
y, as
sum
ing
a co
ntro
l gr
oup
mor
talit
y ra
te o
f 25%
and
a 5
.05,
a sa
mpl
e siz
e of
15
0 pe
r gr
oup
gave
71%
pow
er to
det
erm
ine
the
inte
rven
tion
did
not i
ncre
ase
mor
talit
y by
. 1
0%.
Prev
ailin
g m
orta
lity
in p
revi
ous b
efor
e an
d af
ter
in
terv
entio
n st
udie
s sho
w a
hig
her m
orta
lity. 8
• B
asel
ine
mor
talit
y of
47.
6% �
5%
•
Aft
er in
terv
entio
n m
orta
lity
of
27.5
% �
13%
•
The
req
uire
d si
ze o
f non
infe
rior
ity tr
ials
is u
sual
ly
larg
er th
an th
at fo
r su
peri
ority
tria
ls. 6
B
lindi
ng
(mas
king
)W
heth
er p
artic
ipan
ts, t
hose
adm
inist
erin
g th
e
inte
rven
tions
, and
thos
e as
sess
ing
the
outc
omes
wer
e bl
inde
d to
gro
up a
ssig
nmen
t. W
hen
rele
vant
, how
the
succ
ess
of b
lindi
ng w
as e
valu
ated
.
• B
lindi
ng d
oes
not p
rote
ct a
gain
st b
ias
near
ly a
s w
ell
in a
non
infe
rior
ity tr
ial a
s it
does
in a
sup
erio
rity
tria
l.
Res
ults
Part
icip
ant
fl ow
and
re
crui
tmen
t
Flo
w o
f par
ticip
ants
thro
ugh
each
sta
ge (a
dia
gram
is
st
rong
ly r
ecom
men
ded)
. Spe
cifi c
ally
, for
eac
h gr
oup
repo
rt th
e nu
mbe
rs o
f par
ticip
ants
rand
omly
ass
igne
d,
rece
ivin
g in
tend
ed tr
eatm
ent,
com
plet
ing
the
tria
l pr
otoc
ol, a
nd a
naly
zed
for
the
prim
ary
outc
ome.
D
escr
ibe
prot
ocol
dev
iatio
ns fr
om tr
ial a
s pl
anne
d,
toge
ther
with
rea
sons
.
One
sho
uld
avoi
d fe
atur
es th
at m
ight
dilu
te tr
ue d
iffer
ence
s be
twee
n
EG
DT
and
LC
, the
reby
enh
anci
ng th
e ri
sk o
f err
oneo
usly
co
nclu
ding
non
infe
rior
ity:
• Po
or a
dher
ence
to th
e pr
otoc
ol
• D
ropo
uts
• R
ecru
itmen
t of p
atie
nts u
nlik
ely
to n
eed
or re
spon
d to
inte
rven
tions
(lo
w il
lnes
s se
veri
ty a
nd m
orta
lity)
trea
tmen
t cro
ssov
ers.
Bas
elin
e
da
ta o
f the
pa
rtic
ipan
ts
Bas
elin
e de
mog
raph
ic a
nd c
linic
al c
hara
cter
istic
s
of e
ach
grou
p. E
ligib
ility
cri
teri
a fo
r pa
rtic
ipan
ts
(det
ailin
g w
heth
er p
artic
ipan
ts in
the
noni
nfer
iorit
y or
equ
ival
ence
tria
l are
sim
ilar
to th
ose
in a
ny
tria
l[s] t
hat e
stab
lishe
d ef
fi cac
y of
the
refe
renc
e tr
eatm
ent)
and
the
sett
ings
and
loca
tions
whe
re
the
data
wer
e co
llect
ed.
At b
asel
ine
com
pare
d to
the
Riv
ers
et a
l 8 stu
dy, J
ones
et a
l 7 pat
ient
s
wer
e ch
arac
teri
zed
by:
• Yo
unge
r ag
e
•
Few
er c
omor
bidi
ties
• L
ower
illn
ess
seve
rity
•
Low
er m
orta
lity
risk
•
Low
er la
ctat
e le
vels
•
Hig
her
Scv o
2 (no
rmal
ran
ge)
• H
ighe
r C
VP
(nor
mal
ran
ge)
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
1418 Point/Counterpoint Editorials
Tabl
e 1—
Con
tinu
ed
C
omm
enta
ry
Topi
cR
equi
rem
ents
and
Con
side
ratio
nsJo
nes
et a
l 7,10
R
iver
s et
al 8
N
umbe
rs
anal
yzed
Num
ber
of p
artic
ipan
ts (d
enom
inat
or) i
n ea
ch g
roup
incl
uded
in e
ach
anal
ysis
and
whe
ther
“in
tent
ion-
to-t
reat
” an
d/or
alte
rnat
ive
anal
yses
wer
e co
nduc
ted.
St
ate
the
resu
lts in
abs
olut
e nu
mbe
rs w
hen
feas
ible
(e
.g.,
10 o
f 20,
not
50%
).
Jone
s et
al 7 r
epor
ted
30 in
terv
entio
ns in
300
pat
ient
s ra
ndom
ized
:
• 10
% (n
5 2
9) g
ot to
the
poin
t in
the
prot
ocol
whe
re o
ne
of th
e tw
o tr
eatm
ents
bei
ng e
valu
ated
wer
e ad
min
iste
red
(Scv
o 2 ;
n 5
13)
and
(LC
; n 5
16)
.
O
utco
mes
and
es
timat
ion
For
eac
h pr
imar
y an
d se
cond
ary
outc
ome,
a s
umm
ary
of
res
ults
for
each
gro
up a
nd th
e es
timat
ed e
ffec
t siz
e an
d its
pre
cisi
on (e
g, 9
5% C
I). F
or th
e ou
tcom
e(s)
for
whi
ch n
onin
feri
ority
or
equi
vale
nce
is h
ypot
hesi
zed,
a
fi gur
e sh
owin
g co
nfi d
ence
inte
rval
s an
d m
argi
ns
of e
quiv
alen
ce m
ay b
e us
eful
.
Patie
nts
wer
e tr
eate
d in
the
ED
from
the
time
of r
ando
miz
atio
n un
til a
ll
trea
tmen
t goa
ls w
ere
achi
eved
or
6 h
had
elap
sed:
6-h
end
poin
ts a
re p
rovi
ded
in th
e R
iver
s et
al 8
st
udy.
•
No
6-h
hem
odyn
amic
end
poi
nts
are
repo
rted
.
•
Alth
ough
hem
atoc
rit w
as a
ther
apeu
tic e
nd p
oint
, no
data
w
ere
repo
rted
in r
each
ing
this
end
poi
nt in
eith
er g
roup
.
•
The
re w
as n
o m
etho
d to
ass
ess
whe
ther
an
indi
cate
d th
erap
eutic
act
ion
was
per
form
ed in
res
pons
e to
a
para
met
er b
elow
the
inte
nded
goa
l.
Adv
erse
eve
nts
All
impo
rtan
t adv
erse
eve
nts
or s
ide
effe
cts
in e
ach
in
terv
entio
n gr
oup.
Del
ayed
hem
odyn
amic
det
erio
ratio
n w
as n
ot r
epor
ted.
Del
ayed
hem
odyn
amic
det
erio
ratio
n is
an
im
port
ant f
eatu
re in
up
to 2
0% o
f pat
ient
s w
hich
was
red
uced
to 1
0% w
ith E
GD
T.
In
terp
reta
tion
and
gene
raliz
abili
ty
Gen
eral
izab
ility
(ext
erna
l val
idity
) of t
he tr
ial fi
ndi
ngs.
• L
C c
anno
t be
used
in p
atie
nts
with
non
elev
ated
lact
ate
leve
ls.
•
LC
is u
npro
ven
in p
atie
nts
with
mor
e co
mpl
ex p
rese
ntat
ions
w
ho r
equi
re m
ultip
le in
terv
entio
ns.
O
vera
ll ev
iden
ceG
ener
al in
terp
reta
tion
of th
e re
sults
in th
e
cont
ext o
f cur
rent
evi
denc
e.
•
Thi
s st
udy
is u
nder
pow
ered
to p
rovi
de e
noug
h ev
iden
ce
to u
se L
C a
s a
repl
acem
ent o
f Scv
o 2 .
Add
ition
al
cont
ribu
tions
U
ntes
ted
hypo
thes
isC
linic
ians
mus
t be
confi
den
t tha
t the
new
trea
tmen
t
wou
ld h
ave
been
sho
wn
to b
e ef
fi cac
ious
if a
pl
aceb
o-co
ntro
lled
tria
l had
bee
n pe
rfor
med
.
• Is
ther
e an
out
com
e di
ffer
ence
bet
wee
n a
LC
from
10
to
9 vs
4 to
3.6
, bot
h 10
% c
lear
ance
but
diff
eren
t out
com
es?
• H
ow m
any
lact
ate
leve
ls w
ere
requ
ired
per
pat
ient
to
com
plet
e th
erap
y an
d th
e tim
e du
ratio
n?
• Is
LC
cos
t eff
ectiv
e as
sho
wn
in E
GD
T?
• W
hat i
s th
e te
chno
logy
ass
essm
ent c
ompa
ring
the
clin
ical
ut
ility
of a
pre
calib
rate
d Sc
v o 2 a
nd h
ourl
y or
eve
n m
ore
freq
uent
lact
ate
leve
ls?
C
ompe
ting
inte
rest
sT
his
may
pot
entia
lly in
fl uen
ce th
e ed
itori
al
pr
oces
s an
d in
terp
reta
tion
of th
e re
sults
.
•
The
sec
tion
edito
r of
the
jour
nal w
here
Jon
es e
t al 7
is p
ublis
hed
is a
pri
ncip
le in
vest
igat
or fo
r co
mpe
ting
rese
arch
on
EG
DT.
• T
he a
utho
r of
the
acco
mpa
nyin
g ed
itori
al is
par
ticip
atin
g in
com
petin
g re
sear
ch o
n E
GD
T. 10
CO
NSO
RT
5 C
onso
lidat
ed S
tand
ards
of
Rep
ortin
g Tr
ials
; CV
P 5
cent
ral v
enou
s pr
essu
re; D
o 2 5
syst
emic
oxy
gen
deliv
ery;
EG
DT
5 e
arly
goa
l dir
ecte
d th
erap
y; L
C 5
lact
ate
clea
ranc
e; S
cv o
2 5 ce
ntra
l ve
nous
oxy
gen
satu
ratio
n; S
SC 5
surv
ivin
g se
psis
cam
paig
n.
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from
CHEST / 140 / 6 / DECEMBER, 2011 1419www.chestpubs.org
Correspondence to: Emanuel P. Rivers, MD, MPH, FCCP, Department of Emergency Medicine, Wayne State University, 270 Clara Ford Pavilion, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202; e-mail: [email protected] © 2011 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.11-2599
References 1 . Levraut J , Ichai C , Petit I , Ciebiera JP , Perus O , Grimaud D .
Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients . Crit Care Med . 2003 ; 31 ( 3 ): 705 - 710 .
2 . Jones AE . Point: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? Yes . Chest . 2011 ; 140 ( 6 ): 1406 - 1408 .
3 . Gattinoni L , Brazzi L , Pelosi P , et al . A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collabo-rative Group . N Engl J Med . 1995 ; 333 ( 16 ): 1025 - 1032 .
4 . Chamberlain DJ , Willis EM , Bersten AB . The severe sepsis bundles as processes of care: a meta-analysis [published online ahead of print February 14, 2011] . Aust Crit Care .
5 . Jansen TC , van Bommel J , Schoonderbeek FJ , et al ; LACTATE study group . Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized con-trolled trial . Am J Respir Crit Care Med . 2010 ; 182 ( 6 ): 752 - 761 .
6 . Piaggio G , Elbourne DR , Altman DG , Pocock SJ , Evans SJ ; CONSORT Group . Reporting of noninferiority and equiva-lence randomized trials: an extension of the CONSORT statement . JAMA . 2006 ; 295 ( 10 ): 1152 - 1160 .
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 . Rivers EP . Point: adherence to early goal-directed therapy: does it really matter? Yes. After a decade, the scientifi c proof speaks for itself . Chest . 2010 ; 138 ( 3 ): 476 - 480 .
9 . Dellinger RP , Levy MM , Carlet JM , et al ; International Sur-viving Sepsis Campaign Guidelines Committee ; American As-sociation of Critical-Care Nurses ; American College of Chest Physicians ; American College of Emergency Physicians ; Cana-dian Critical Care Society ; European Society of Clinical Micro-biology and Infectious Diseases ; European Society of Intensive Care Medicine ; European Respiratory Society ; International Sepsis Forum ; Japanese Association for Acute Medicine ; Japanese Society of Intensive Care Medicine ; Society of Crit-ical Care Medicine ; Society of Hospital Medicine ; Surgical Infection Society ; World Federation of Societies of Intensive and Critical Care Medicine . Surviving Sepsis Campaign: inter-national guidelines for management of severe sepsis and septic shock: 2008 . Crit Care Med . 2008 ; 36 ( 1 ): 296 - 327 .
10 . Lewis RJ . Disassembling goal-directed therapy for sepsis: a fi rst step . JAMA . 2010 ; 303 ( 8 ): 777 - 779 .
© 2011 American College of Chest Physicians at Mount Sinai School of Medicine on December 9, 2011chestjournal.chestpubs.orgDownloaded from