Andre Holder

A dream deferred: the rise and fall of recombinant activated protein C

Expanded abstractCitationRanieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD: Drotrecogin alfa (activated) in adult patients with septic shock. N Engl J Med 2012, 366: 2055-2064.BackgroundThere have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock.MethodsObjective: To test the hypothesis that DrotAA, as compared with placebo, would reduce mortality in patients with septic shock.DesignA randomized, double-blind, placebo-controlled, multicenter trial, conducted from March 2008 through August 2011. Patients were followed until either 90 days or death.SettingPatients were enrolled from 208 sights in Europe, North and South America, Australia, New Zealand, and India.SubjectsSubjects included 1,697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours.InterventionDrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours.OutcomesDeath from any cause 28 days after randomization.ResultsAt 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval (CI), 0.92 to 1.28; P = 0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P = 0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P = 0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P = 0.81).ConclusionsDrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.

Using What You Get: Dynamic Physiologic Signatures of Critical Illness

The development and resolution of cardiopulmonary instability take time to become clinically apparent, and the treatments provided take time to have an impact. The characterization of dynamic changes in hemodynamic and metabolic variables is implicit in physiologic signatures. When primary variables are collected with high enough frequency to derive new variables, this data hierarchy can be used to develop physiologic signatures. The creation of physiologic signatures requires no new information; additional knowledge is extracted from data that already exist. It is possible to create physiologic signatures for each stage in the process of clinical decompensation and recovery to improve outcomes.

Inhaled Carbon Monoxide Protects against the Development of Shock and Mitochondrial Injury following Hemorrhage and Resuscitation

Aims Currently, there is no effective resuscitative adjunct to fluid and blood products to limit tissue injury for traumatic hemorrhagic shock. The objective of this study was to investigate the role of inhaled carbon monoxide (CO) to limit inflammation and tissue injury, and specifically mitochondrial damage, in experimental models of hemorrhage and resuscitation. Results Inhaled CO (250 ppm for 30 minutes) protected against mortality in severe murine hemorrhagic shock and resuscitation (HS/R) (20% vs. 80%; P<0.01). Additionally, CO limited the development of shock as determined by arterial blood pH (7.25±0.06 vs. 7.05±0.05; P<0.05), lactate levels (7.2±5.1 vs 13.3±6.0; P<0.05), and base deficit (13±3.0 vs 24±3.1; P<0.05). A dose response of CO (25–500 ppm) demonstrated protection against HS/R lung and liver injury as determined by MPO activity and serum ALT, respectively. CO limited HS/R-induced increases in serum tumor necrosis factor-α and interleukin-6 levels as determined by ELISA (P<0.05 for doses of 100–500ppm). Furthermore, inhaled CO limited HS/R induced oxidative stress as determined by hepatic oxidized glutathione:reduced glutathione levels and lipid peroxidation. In porcine HS/R, CO did not influence hemodynamics. However, CO limited HS/R-induced skeletal muscle and platelet mitochondrial injury as determined by respiratory control ratio (muscle) and ATP-linked respiration and mitochondrial reserve capacity (platelets). Conclusion These preclinical studies suggest that inhaled CO can be a protective therapy in HS/R; however, further clinical studies are warranted.

Applied Physiology at the Bedside to Drive Resuscitation Algorithms

EMODYNAMIC INSTABILITY is associated with significant morbidity and mortality. Goal-directed therapeutic algorithms have been used in various clinical settings to reverse or prevent organ damage and death that could occur with a low oxygen delivery state. Most current resuscitative algorithms use static physiologic measures to determine if a patient will respond to proven therapies. While static parameters are useful in identifying the potential for clinical instability, they cannot tell how patients will respond to an intervention. Applied physiology, through the use of functional hemodynamic monitoring, can predict the body’s reaction to therapy because it is based on cardiovascular dynamics. A growing body of evidence supports the use of applied physiologic principles in goal-directed therapeutic algorithms for appropriate and effective resuscitation/optimization. Over time, applied physiology should be incorporated into standardized protocol-driven care to improve outcomes in patients experiencing or at risk for hemodynamic instability. Patients who are at risk for clinical decompensation should be identified as early as possible to prevent subsequent morbidity and mortality. Many of the available tools and parameters that could be used to identify and manage instability do not take the dynamic nature of disease into account. The use of applied physiologic techniques allows clinicians to perform an intervention in an unstable patient and follow the changes in bedside hemodynamics. This is possible by identifying each of the components of cardiovascular function that may be contributing to clinical instability, including volume responsiveness, vasomotor tone, and contractility. The practice of applied physiology also requires a framework to maximize clinical utility; goal-directed therapeutic algorithms can provide such a framework. The objectives of this review were (1) to demonstrate that static physiologic indices are good diagnostic tools to identify occult organ hypoperfusion and hemodynamic compromise, but that they have limited utility in subsequent management; (2) to summarize existing applied physiologic techniques, the principles behind their utility, and discuss advantages and disadvantages of each; (3) to show that goal-directed therapeutic algorithms for addressing imminent or existing hemodynamic compromise can be a useful tool in the management of the critically ill; and (4) to demonstrate that the integration of applied physiologic techniques into goal-directed therapy can improve the implementation of those algorithms, and together they can improve outcomes in those experiencing and at risk for clinical instability. Although this discussion can be applied to any condition that causes imminent or existing hemodynamic instability like sepsis or trauma, this review will focus on perioperative care.

Early Identification of Occult Bleeding Through Hypovolemia Detection

Clinically occult hypovolemia is a significant problem facing hospitalized patients. Tachycardia may occur before hypotension or signs of end-organ injury are apparent, but it is non-specific, often overlooked and may be attributed to other less serious causes. Unless clinicians have a high index of suspicion for subclinical hypovolemia, at-risk patients may progress to overt tissue hypoperfusion, displaying hyperlactatemia and hypotension. Delaying definitive care to reverse both hypovolemia and its causes may have a negative impact on patient outcome. Clinicians need tools to accurately diagnose patients with occult hypovolemia so that these patients receive appropriate resuscitation and definitive care in a timely fashion. We believe that any instrument used to detect clinically occult hypovolemia must use dynamic changes in physiologic parameters. We will review the merit of commonly and less commonly used hemodynamic parameters, measures of global and tissue blood flow and metabolic function, and features embedded within waveform data to identify occult hypovolemia. We will also provide an overview of new approaches to parsimoniously select parameters most predictive of early hypovolemia. All of these parameters and features can be applied to identify any disease process causing occult hypovolemia, e. g., sepsis, bleeding; we will focus on the early identification of occult bleeding.