[PROWESS, ENHANCE and ADDRESS: clinical implications for the treatment with drotrecogin alfa (activated)]. / PROWESS, ENHANCE und ADDRESS: klinische konsequenzen für die behandlung mit drotrecogin alfa (aktiviert).

Drotrecogin alfa (activated) (DrotAA) represents a therapeutic advance in the treatment of severe sepsis. In the pivotal PROWESS trial DrotAA had demonstrated a significant decrease in 28-day mortality, most evident in the subgroup of patients at higher risk of death. Thus, DrotAA was licensed throughout Europe for treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The ADDRESS trial was mandated by the FDA to investigate prospectively the treatment effect of DrotAA in patients at low risk of death, e.g. single organ failure. The trial was prematurely stopped due to futility, because no reduction in mortality was observed in this non-indicated patient population. The ENHANCE open-label trial enrolled similar patients to the PROWESS trial and the observed 28-day mortality was consistent with the results seen in the PROWESS trial. Survival rates for patients receiving DrotAA early within 24 h from the first sepsis-induced organ dysfunction were significantly higher than in patients treated later. In this overview we will discuss the results of the ENHANCE and ADDRESS trials in the context of the PROWESS study and clinical implications for the treatment with DrotAA.

Terminal complement complex in septic shock with capillary leakage: marker of complement activation?

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the value of terminal complement complex (C5b-9) plasma levels as a marker for complement activation in septic shock with concomitant capillary leak syndrome. METHODS: In a prospective animal study 10 fasted, anaesthetized, mechanically ventilated and multi-catheterized pigs (20.6 +/- 1.3 kg) were investigated over a period of 8 h. Sepsis was induced by faecal peritonitis (1 g kg(-1) body weight faeces, n = 5) and compared to controls (n = 5). The animals received 6% hydroxyethyl starch 200/0.5 to maintain a central venous pressure of 12 mmHg. To quantify capillary leak syndrome, albumin escape rate was measured using 99mTc-labelled human serum albumin. Plasma levels of terminal complement complex were measured in a double antibody immunoassay (neoepitope-specific MoAb aE 11 as catching antibody). Immunohistological studies of renal specimens were performed to detect terminal complement complex deposition. RESULTS: Albumen escape rate increased in septic animals (+ 52%) compared to controls (+ 3%, P < 0.05). Plasma levels of terminal complement complex decreased during the study period in both groups. In septic animals this finding was accompanied by a significant deposition of terminal complement complex in renal specimens (P < 0.05). CONCLUSION: We found an activation of the complement system proven by marked deposition of terminal complement complex in renal specimen, while its plasma levels decreased during the study period in septic and control animals. These results suggest that in septic shock with capillary leak syndrome plasma level of terminal complement complex may not be a reliable marker of complement activation.

Hydroxyethyl starch and modified fluid gelatin maintain plasma volume in a porcine model of septic shock with capillary leakage.

OBJECTIVE: To compare the effects of different volume replacement therapies on maintenance of plasma volume in septic shock and capillary leakage syndrome. DESIGN AND SETTING: Prospective randomized, controlled animal laboratory study in a university animal laboratory. MEASUREMENTS AND RESULTS: Twenty-five fasted, anaesthetized, mechanically ventilated and multi-catheterized pigs (20.8+/-1.8 kg) received 1 g/kg body weight faeces into abdominal cavity to induce sepsis and were observed over 8 h. Five animals each received volume replacement therapy with modified fluid gelatin 4% or 8% (MFG4%, MFG8%), 6% HES 200/0.5, or Ringer's solution and were compared to controls receiving 6% HES 200/0.5. Infusion rate was titrated to maintain a central venous pressure of 12 mmHg. Plasma volume was determined using (51)Cr-labelled erythrocytes and standard formulae. Albumin escape rate was calculated using technetium (99m)Tc-labelled albumin. Colloid osmotic pressure, systemic haemodynamics and oxygenation were obtained before and 4 and 8 h after induction of sepsis. Plasma volume was reduced in the Ringer's solution group (-46%) but was maintained in HES (+/-0%), MFG4% (+4%), MFG8% (+23%) groups. Albumin escape rate increased in HES (+52%), MFG4% (+47%), MFG8% (+54%) and the Ringer's solution group (+41%) compared to controls. CONCLUSION: In this porcine septic shock model with concomitant capillary leakage syndrome, confirmed by an increased albumin escape rate, the artificial colloids HES, MFG4%, and MFG8% maintained plasma volume and colloid osmotic pressure. These results suggest the intravascular persistency of artificial colloids in the presence of albumin leakage. An editorial regarding this article can be found in the same issue (http://dx.doi.org/10.1007/s00134-002-1283-9)

Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients.

OBJECTIVE: Capillary leakage syndrome (CLS) is a frequent complication in sepsis, characterized by loss of intravasal fluids leading to generalized edema and hemodynamic instability despite massive fluid therapy. In spite of its importance no standardized diagnostic criteria are available for CLS. DESIGN: Prospective clinical study. SETTING: 1,800-bed university hospital PATIENTS: Six septic shock patients with CLS were compared to six control patients. MEASUREMENTS AND RESULTS: CLS was clinically determined by generalized edema, positive fluid balance, and weight gain. Plasma volume was measured by indocyanine green, red blood cell volume by chromium-51 labeled erythrocytes, and colloid osmotic pressure before and 90 min after the administration of 300 ml 20% albumin. Extracellular water (ECW) was measured using the inulin distribution volume and bioelectrical impedance analysis. Red blood cells averaged 20.2 +/- 1.0 ml/ kg body weight in CLS patients and 23.3 +/- 4.1 in controls. ECW was higher in CLS patients than in controls (40.0 +/- 6.9 vs. 21.7 +/- 3.71; p< 0.05). ECW of inulin was correlated with that measured by bioelectrical impedance analysis (r = 0.74, p< 0.01). The increase in colloid osmotic pressure over the 90 min was less in CLS patients than in controls (1.1 +/- 0.3 vs. 2.8 +/- 1.3 mmHg;p< 0.05). CONCLUSION: These results suggest that measurements of an increased ECW using bioelectrical impedance analysis combined with a different response of colloid osmotic pressure to administration of albumin can discriminate noninvasively between patients with and those without CLS.

Septic shock after liver transplantation for Caroli's disease: clinical improvement after treatment with C1-esterase inhibitor.

The extent of complement and contact activation is related to outcome in sepsis. A low functional index of their main blocker C1-esterase inhibitor (C1-INH) is considered as a relative deficiency of C1-INH and might contribute to the development of fatal complications in the intensive care unit. The first results of therapeutic intervention with C1-INH concentrate in septic shock are promising. We report on our experience of C1-INH concentrate administration in a young woman with Caroli's disease as ultimate rescue therapy for septic shock with capillary leakage syndrome after combined liver and kidney transplantation. No focus of infection was detectable and thus surgical intervention was not indicated. Antibiotic therapy at that time included vancomycin, tobramycin, meropenem and fluconazol. Hemodynamic stabilization occurred within hours after administration of C1-INH concentrate. Simultaneously a reduction in vasopressor medication was possible and negative fluid balance was achieved.