Lactate clearance is noninferior to central venous oxygen saturation (ScvO2) as a target of early sepsis resuscitation, according to the results of a multicenter, randomized, noninferiority trial reported in the February 24 issue of the Journal of the American Medical Association.
“Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department,” write Alan E. Jones, MD, from the Carolinas Medical Center in Charlotte, North Carolina, and colleagues for the Emergency Medicine Shock Research Network Investigators.
“The Surviving Sepsis Campaign guidelines recommend the use of…ScvO2 or mixed venous oxygen saturation to assess the balance of tissue oxygen delivery and consumption; however, since its publication in 2001 a substantial amount of controversy about this single-center study has been generated in the scientific community….In contrast, lactate clearance, derived from calculating the change in lactate concentration from 2 blood specimens drawn at different times, potentially represents a more accessible method to assess tissue oxygen delivery.”
At 3 participating US urban hospitals, 300 patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 were randomly assigned to 1 of 2 resuscitation protocols. In the ScvO2 group (n = 150), the goal of resuscitation was to normalize central venous pressure and mean arterial pressure and to achieve ScvO2 of 70% or more. In the lactate clearance group (n = 150), the goal of resuscitation was to normalize central venous pressure and mean arterial pressure and to achieve lactate clearance of 10% or more.
Patients in the 2 treatment groups were well matched by demographic factors, comorbid conditions, and physiologic features. The assigned study protocol was continued until all targets were reached or for up to 6 hours. Clinicians who then took over care of the participants were masked to group assignment. The main study endpoint was absolute in-hospital mortality, with the noninferiority threshold set at delta equal to −10%.
No Differences in Treatments
During the initial 72 hours of hospitalization, there were no differences in treatments administered in the 2 groups. In-hospital mortality rate was 23% in the ScvO2 group (n = 34; 95% confidence interval [CI], 17% – 30%) vs 17% (n = 25; 95% CI, 11% – 24%) in the lactate clearance group. Based on intent-to-treat analysis, this 6% difference between mortality rates did not reach the predefined −10% threshold (95% CI for the difference, −3% to 15%). Both groups had similar treatment-related adverse events.
“Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality,” the study authors write. “These data support the substitution of lactate measurements in peripheral venous blood as a safe and efficacious alternative to a computerized spectrophotometric catheter in the resuscitation of sepsis.”
Limitations of this study include lack of blinding of the groups, inability to determine whether an indicated therapeutic action was performed in response to a parameter below the intended goal, lack of generalizability to centers that do not routinely perform early quantitative resuscitation, and possible Hawthorne-like effect.
In an accompanying editorial, Roger J. Lewis, MD, PhD, from the Harbor-UCLA Medical Center in Los Angeles, notes that interpretation of the study findings is somewhat complicated because only 10% of enrolled patients received dobutamine or transfusions, which were the only treatments affected by the resuscitation targets being compared.
“Although using the lactate clearance does not obviate the need for a central venous catheter, it does allow the use of a nonspecialized catheter and does eliminate the need for the associated electronic instrumentation,” Dr. Lewis writes. “[This study] is an important first step to identifying less burdensome approaches to the initial management of critically ill patients with severe sepsis and septic shock. Substantial further progress most likely will depend on appropriately designed, rigorously conducted clinical trials (requiring novel strategies, such as adaptive design) that can efficiently and practically address the complicated questions inherent in identifying the optimal and least burdensome combination of resuscitation targets.”
The National Institutes of Health supported this study and some of its authors. Some of the study authors have disclosed various financial relationships with Critical Biologics Corp, Hutchinson Technology, Brahms and Siemens, Ikaria, Novo Nordisk, Spectral Diagnostics, Edwards Lifesciences, Biosite, and/or Eli Lilly. One of the study authors (Dr. Kline) has disclosed that he is the inventor on a US patent for a breath-based device that monitors patient response to resuscitation.
Dr. Lewis has disclosed that he serves as the chair of the Data and Safety Monitoring Board for the Protocolized Care for Early Septic Shock trial funded by the National Institute of General Medical Sciences, National Institutes of Health, and that he serves as a medical consultant to Berry Consultants, LLC, a statistical consulting group specializing in the use of Bayesian methods in the design and analysis of adaptive clinical trials.
JAMA. 2010;303:739-746, 777-779.