Hemodynamic effects of recombinant human activated protein C in patients with septic shock

Purpose

The aim of this study is to examine the effects of recombinant human activated protein C (rhAPC) on hemodynamic parameters in patients with septic shock.

Methods

This is a retrospective study of 2 university-hospital critical care units. Patients with septic shock with pulmonary artery catheterization or transthoracic thermodilution monitoring were studied. We matched patients with septic shock with at least 2 organ failures (18 treated with rhAPC and 18 controls) on sex, age, sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II, and sepsis etiology. We recorded norepinephrine dose and hemodynamic parameters at baseline and 24, 36, and 48 hours after the real or theoretical start of rhAPC treatment.

Results

Mean arterial pressure remained stable in both groups. In rhAPC patients, norepinephrine requirements, initially higher than in controls, were significantly lower at 48 hours, and stroke volume at 24 and 48 hours improved (P < .05).

Conclusion

Recombinant human activated protein C use correlated with improved hemodynamic parameters and decreased norepinephrine requirements. The retrospective nature of the study limits the strength of these findings.     

Rapid and beneficial hemodynamic effects of activated protein C in septic shock patients

Objective Because recombinant human activated protein C (rhAPC) reduces NO production during sepsis, it could improve the vascular tone. We tested whether rhAPC reduces the dose of norepinephrine required to maintain mean arterial pressure (MAP) in septic shock patients.Design and setting Retrospective study in intensive care unit of two university hospitals.Patients Twenty-two septic shock patients with at least two organ failures were retrospectively investigated for MAP and the required dose of norepinephrine before and 24 h after rhAPC administration. A control group of 22 septic shock patients with at least two organ failures who did not receive rhAPC was matched on age, SAPS II, MAP, and norepinephrine dose at the time of the theoretical start of rhAPC.Measurements and results The MAP remained stable and similar in the two groups (86±16 vs. 89±9 mmHg at 24 h). The required dose of norepinephrine increased in the control group (+38%, from –41% to +38%) but decreased in the treated group (–33%, from –74% to +11%).Conclusions rhAPC rapidly improved the vascular tone in septic shock patients as assessed by a decrease in the norepinephrine dose required to maintain arterial pressure.     

Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock

Introduction  

Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo.     

Recombinant human activated protein C attenuates cardiovascular and microcirculatory dysfunction in acute lung injury and septic shock

Introduction

This prospective, randomized, controlled, experimental animal study looks at the effects of recombinant human activated protein C (rhAPC) on global hemodynamics and microcirculation in ovine acute lung injury (ALI) and septic shock, resulting from smoke inhalation injury.

Methods

Twenty-one sheep (37 ± 2 kg) were operatively prepared for chronic study and randomly allocated to either the sham, control, or rhAPC group (n = 7 each). The control and rhAPC groups were subjected to insufflation of four sets of 12 breaths of cotton smoke followed by instillation of live Pseudomonas aeruginosa into both lung lobes, according to an established protocol. Healthy sham animals were not subjected to the injury and received only four sets of 12 breaths of room air and instillation of the vehicle (normal saline). rhAPC (24 μg/kg/hour) was intravenously administered from 1 hour post injury until the end of the 24-hour experiment. Regional microvascular blood flow was analyzed using colored microspheres. All sheep were mechanically ventilated with 100% oxygen, and fluid resuscitated with lactated Ringer's solution to maintain hematocrit at baseline levels.

Results

The rhAPC-associated reduction in heart malondialdehyde (MDA) and heart 3-nitrotyrosine (a reliable indicator of tissue injury) levels occurred parallel to a significant increase in mean arterial pressure and to a significant reduction in heart rate and cardiac output compared with untreated controls that showed a typical hypotensive, hyperdynamic response to the injury (P < 0.05). In addition, rhAPC significantly attenuated the changes in microvascular blood flow to the trachea, kidney, and spleen compared with untreated controls (P < 0.05 each). Blood flow to the ileum and pancreas, however, remained similar between groups. The cerebral blood flow as measured in cerebral cortex, cerebellum, thalamus, pons, and hypothalamus, was significantly increased in untreated controls, due to a loss of cerebral autoregulation in septic shock. rhAPC stabilized cerebral blood flow at baseline levels, as in the sham group.

Conclusions

We conclude that rhAPC stabilized cardiovascular functions and attenuated the changes in visceral and cerebral microcirculation in sheep suffering from ALI and septic shock by reduction of cardiac MDA and 3-nitrotyrosine.     

Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients

Introduction

Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls.

Methods

In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 μg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation.

Results

Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group.

Conclusion

Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.     

Surviving meningococcal septic shock in childhood: long-term overall outcome and the effect on health-related quality of life

Introduction  

The purpose of this study was to evaluate associations between long-term physical and psychological outcome variables in patients who survived meningococcal septic shock (MSS) in childhood.     

Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients

Introduction  

Given the pivotal role of T lymphocytes in the immune system, patients with septic shock may show T cell abnormalities. We have characterised the T cell compartment in septic shock and assess its clinical implications.     

Effect of recombinant activated protein C and low-dose heparin on neutrophil-endothelial cell interactions in septic shock

OBJECTIVE: To examine the effects of recombinant activated protein C (rhAPC) and low-dose heparin on neutrophil-platelet-endothelial cell interactions in septic shock. DESIGN: Controlled experiments using phase contrast microscopy to study neutrophil, platelet, and endothelial cell interactions in flowing cell suspensions under simulated physiologic conditions. SETTING: University research laboratory. PATIENTS: Adult patients with septic shock and normal volunteers. INTERVENTIONS: Neutrophils and platelets removed from control subjects were stimulated with plasma and serum from 21 patients in septic shock and perfused over endothelial cells. Activated protein C, low-dose heparin, and low-dose heparin with rhAPC were added to cells suspended in septic plasma. Neutrophil rolling velocity and the number of neutrophils adherent to endothelial cells and in aggregates were determined. Flow cytometric analysis of CD11b/CD63 cells was used to identify platelet-neutrophil aggregates. MEASUREMENTS AND MAIN RESULTS: Activated protein C significantly decreased neutrophil adhesion and aggregation and increased rolling velocity in cells stimulated with both septic serum and septic plasma. Significant decreases in platelet-neutrophil aggregates induced by septic plasma were also observed. Low-dose heparin alone had no effects on these variables. The addition of low-dose heparin to cells suspended in septic plasma and rhAPC attenuated the benefits observed with rhAPC alone in each of these variables. CONCLUSIONS: These data suggest that the in vitro addition of rhAPC decreases sepsis-induced interactions between isolated platelets, neutrophils, and endothelial cells. Low-dose heparin attenuates the benefits observed with rhAPC. The changes in neutrophil-endothelial cell interactions demonstrated with rhAPC may play a role in preserving microvascular patency in patients with septic shock.     

Prevalence and characteristics of nonlactate and lactate expressors in septic shock

Purpose

The study's objective was to determine the proportion and patient characteristics of patients in vasopressor-dependent septic shock who presented without lactatemia.

Methods

A retrospective review of patients presenting to an urban tertiary-care emergency department between December 2007 and September 2008 was conducted. Patients with a final diagnosis of septic shock requiring vasopressors were divided, based on initial lactate, to nonlactate expressors (0-2.4 mmol/L), intermediate (2.5-3.9 mmol/L), and high (>4.0 mmol/L) lactate groups.

Results

Among 123 patients with vasopressor-dependent septic shock, 55 (45%) were nonlactate expressors (lactate ≤2.4 mmol/L). Acute liver injury, history of liver disease, and presence of bacteremia were associated with elevated lactate.

Conclusion

Almost one-half of patients with vasopressor-dependent septic shock did not express lactate on presentation, although a high mortality rate remains in this population. We found a significant association between lactate expressors and liver disease and between lactate expressors and positive blood cultures. The use of lactatemia as the sole indicator of need for additional intravenous fluid or an end point of resuscitation in septic shock may be inadequate.     

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status

Introduction  

In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock.     

The incidence of relative adrenal insufficiency in patients with septic shock after the administration of etomidate

Introduction  

Etomidate blocks adrenocortical synthesis when it is administered intravenously as a continuous infusion or a single bolus. The influence of etomidate administration on the incidence of relative adrenal insufficiency in patients with septic shock has not been formally investigated. The objective of this study was to determine the incidence of relative adrenal insufficiency in patients with septic shock after etomidate administration compared with patients with septic shock who did not receive etomidate.     

Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study

Introduction  

The use of low-dose steroid therapy in the management of septic shock has been extensively studied. However, the association between the timing of low-dose steroid therapy and the outcome has not been evaluated. Therefore, we evaluated whether early initiation of low-dose steroid therapy is associated with mortality in patients with septic shock.     

Time to antibiotics for septic shock: evaluating a proposed performance measure

Purposes

International guidelines recommend antibiotics within 1 hour of septic shock recognition; however, a recently proposed performance measure is focused on measuring antibiotic administration within 3 hours of emergency department (ED) arrival. Our objective was to describe the time course of septic shock and subsequent implications for performance measurement.

Basic procedures

Cross-sectional study of consecutive ED patients ultimately diagnosed with septic shock. All patients were evaluated at an urban, academic ED in 2006 to 2008. Primary outcomes included time to definition of septic shock and performance on 2 measures: antibiotics within 3 hours of ED arrival vs antibiotics within 1 hour of septic shock definition.

Main findings

Of 267 patients with septic shock, the median time to definition was 88 minutes (interquartile range, 37-156), and 217 patients (81.9%) met the definition within 3 hours of arrival. Of 221 (83.4%) of patients who received antibiotics within 3 hours of arrival, 38 (17.2%) did not receive antibiotics within 1 hour of definition. Of 207 patients who received antibiotics within 1 hour of definition, 11.6% (n = 24) did not receive antibiotics within 3 hours of arrival. The arrival measure did not accurately classify performance in 23.4% of patients.

Principal conclusions

Nearly 1 of 5 patients cannot be captured for performance measurement within 3 hours of ED arrival due to the variable progression of septic shock. Use of this measure would misclassify performance in 23% of patients. Measuring antibiotic administration based on the clinical course of septic shock rather than from ED arrival would be more appropriate.     

Early Goal-directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department

Objectives: To describe our experience with early goal‐directed therapy (EGDT), corticosteroid administration, and recombinant human activated protein C (rhAPC) administration in patients with severe sepsis or septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥25 in the emergency department (ED). Methods: This was a retrospective case series of a prospectively maintained ED sepsis registry. Data are presented as median (25th, 75th percentile). The setting was an academic tertiary ED with approximately 60,000 annual patient visits. Patients with severe sepsis or septic shock and an APACHE II score ≥25 entered in an ED sepsis registry over a four‐month period were included. Patients who received rhAPC in the intensive care unit were excluded. Central venous catheterization for central venous pressure and central venous oxygen saturation monitoring, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, inotropes, corticosteroids, and rhAPC were initiated by the emergency physicians and continued in the intensive care unit by intensivists. Results: Twenty‐four patients were enrolled. Patient characteristics were as follows: age, 79.5 (68.0, 83.5) years; APACHE II score, 31.5 (29.8, 36.0); ED length of stay, 6.5 (4.0, 10.5) hours; predicted mortality, 76.7% (71.9, 86.4); and in‐hospital mortality, 45.8%. All patients received broad‐spectrum antibiotics, 54.2% completed EGDT, 33.3% received corticosteroids, and 33.3% received rhAPC. Time of antibiotic administration was 1.5 (1.0, 2.0) hours, time of central venous pressure/central venous oxygen saturation monitoring was 1.0 (0.5, 2.5) hour, and time of rhAPC administration was 9.5 (6.8, 10.5) hours after patients met criteria for severe sepsis or septic shock. In‐hospital mortality of patients who received rhAPC in addition to other therapies was 25.0%. Conclusions: EGDT, corticosteroid administration, and rhAPC administration are feasible in the ED setting. While these evidence‐based therapies individually have been shown to improve outcomes for patients with severe sepsis or septic shock, further studies are needed to examine their combined effectiveness during the early stages of this disease.     

Plasma from septic shock patients induces loss of muscle protein

Introduction  

ICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.     

Effects on management and outcome of severe sepsis and septic shock patients admitted to the intensive care unit after implementation of a sepsis program: a pilot study

Introduction  

The application in clinical practice of evidence-based guidelines for the management of patients with severe sepsis/septic shock is still poor in the emergency department, while little data are available for patients admitted to the intensive care unit (ICU). The aim of this study was to evaluate the effect of an in-hospital sepsis program on the adherence to evidence-based guidelines and outcome of patients with severe sepsis/septic shock admitted to the ICU.     

Erythrocyte selenium concentration predicts intensive care unit and hospital mortality in patients with septic shock: a prospective observational study

Introduction

Selenoenzymes can modulate the extent of oxidative stress, which is recognized as a key feature of septic shock. The pathophysiologic role of erythrocyte selenium concentration in patients with septic shock remains unknown. Therefore, the objective of this study was to evaluate the association of erythrocyte selenium concentration with glutathione peroxidase (GPx1) activity, GPx1 polymorphisms and with ICU and hospital mortality in septic shock patients.

Methods

This prospective study included all patients older than 18 years with septic shock on admission or during their ICU stay, admitted to one of the three ICUs of our institution, from January to August 2012. At the time of the patients’ enrollment, demographic information was recorded. Blood samples were taken within the first 72 hours of the patients’ admission or within 72 hours of the septic shock diagnosis for determination of selenium status, protein carbonyl concentration, GPx1 activity and GPx1 Pro198Leu polymorphism (rs 1050450) genotyping.

Results

A total of 110 consecutive patients were evaluated. The mean age was 57.6 ± 15.9 years, 63.6% were male. Regarding selenium status, only erythrocyte selenium concentration was lower in patients who died in the ICU. The frequencies for GPx1 Pro198Leu polymorphism were 55%, 38% and 7% for Pro/Pro, Pro/Leu and Leu/Leu, respectively. In the logistic regression models, erythrocyte selenium concentration was associated with ICU and hospital mortality in patients with septic shock even after adjustment for protein carbonyl concentration and acute physiology and chronic health evaluation II score (APACHE II) or sequential organ failure assessment (SOFA).

Conclusions

Erythrocyte selenium concentration was a predictor of ICU and hospital mortality in patients with septic shock. However, this effect was not due to GPx1 activity or Pro198Leu polymorphism.     

Dopexamine and norepinephrine versus epinephrine on gastric perfusion in patients with septic shock: a randomized study [NCT00134212]

Introduction  

Microcirculatory blood flow, and notably gut perfusion, is important in the development of multiple organ failure in septic shock. We compared the effects of dopexamine and norepinephrine (noradrenaline) with those of epinephrine (adrenaline) on gastric mucosal blood flow (GMBF) in patients with septic shock. The effects of these drugs on oxidative stress were also assessed.     

Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness

Introduction  

The objective of the present study was to compare the health-related quality of life (HR-QoL) of survivors from severe sepsis and septic shock with HR-QoL in others who survived critical illness not involving sepsis.