Andreas Meier-Hellmann

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis

BACKGROUND The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringers lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringers lactate. CONCLUSIONS The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.

Objective: Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high‐dose supplementation of sodium‐selenite would improve the outcome of patients with severe sepsis and septic shock. Design: Prospective randomized, placebo‐controlled, multiple‐center trial. Setting: Eleven intensive care units in Germany. Patients: Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70. Interventions: Patients received 1000 &mgr;g of sodium‐selenite as a 30‐min bolus injection, followed by 14 daily continuous infusions of 1000 &mgr;g intravenously, or placebo. Measurements and Main Results: The primary end point was 28‐day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum gluthation‐peroxidase‐3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention‐to‐treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium‐treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39–1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28‐day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32–1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score ≥102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase‐3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high‐dose sodium‐selenite treatment. Conclusions: The adjuvant treatment of patients with high‐dose sodium‐selenite reduces mortality rate in patients with severe sepsis or septic shock.

Epinephrine impairs splanchnic perfusion in septic shock

OBJECTIVE To assess the effects of epinephrine on splanchnic perfusion and splanchnic oxygen uptake in patients with septic shock. DESIGN Prospective, controlled trial. SETTING University hospital intensive care unit (ICU). PATIENTS Eight patients with septic shock, according to the criteria of the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference, requiring treatment with vasopressors. INTERVENTIONS We compared in crossover design a 2-hr infusion of epinephrine with dobutamine plus norepinephrine in eight ICU patients with septic shock. Systemic and splanchnic hemodynamics and oxygen transport were measured before and during treatment with epinephrine. MEASUREMENTS AND MAIN RESULTS There was essentially no effect of epinephrine on the global parameters, except for increased lactate concentrations. There were marked effects on the regional variables; epinephrine caused lower splanchnic flow and oxygen uptake, lower mucosal pH, and higher hepatic vein lactate. CONCLUSION We conclude that undesirable splanchnic effects on patients in whom that region is particularly fragile should be considered when using epinephrine for septic shock treatment.

High-dose vasopressin is not superior to norepinephrine in septic shock.

ObjectiveWe examined the effects of arginine vasopressin, when substituted for norepinephrine as a vasopressor in septic shock, on global and hepatosplanchnic hemodynamic and oxygen transport variables. DesignExperimental study. SettingIntensive care unit. SubjectsTwelve septic shock patients. InterventionsNorepinephrine was replaced by vasopressin in a dose sufficient to keep mean arterial blood pressure constant. Blood flow, oxygen delivery, and oxygen consumption of the hepatosplanchnic region (calculated by a hepatic venous catheter technique using the Fick principle during continuous infusion of indocyanine green), global hemodynamics (by thermodilution), and gastric regional Pco2 gap (by air tonometry) were calculated during infusion of norepinephrine (mean, 0.56 &mgr;g·kg−1·min−1; range, 0.18–1.1 &mgr;g·kg−1·min−1) and again 2 hrs after replacement by vasopressin (mean, 0.47 IU/min; range, 0.06–1.8 IU/min). Measurements and Main ResultsCardiac index decreased significantly from 3.8 ± 1.3 to 3.0 ± 1.1 L·min−1·m−2, heart rate decreased from 96 ± 14 to 80 ± 16 min−1 (p < .01), and global oxygen uptake decreased from 248 ± 67 to 218 ± 75 mL/min (p < .05). Absolute splanchnic blood flow tended to increase, although not significantly, whereas fractional splanchnic blood flow increased from 10.8 ± 7.6 to 25.9 ± 16.6% of cardiac output (p < .05). Gastric regional Pco2 gap increased from 17.5 ± 26.6 to 36.5 ± 26.6 mm Hg (p < .01). ConclusionVasopressin, in doses sufficient to replace the vasopressor norepinephrine, had mixed effects in septic shock patients. Hepatosplanchnic blood flow was preserved during substantial reduction in cardiac output. An increased gastric Pco2 gap suggests that the gut blood flow could have been redistributed to the disadvantage of the mucosa. Based on these limited data, it does not appear beneficial to directly replace norepinephrine with vasopressin in septic shock.

Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: results from a prospective, randomized, double-blind study.

Objectives: Deactivation of endotheliumderived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an impairment in microcirculatory blood flow. We investigated whether treatment with the sulfhydryl donor and oxygen radical scavenger, N‐acetylcysteine, would improve wholebody oxygen consumption (&OV0312;o2), gastric intramucosal pH, and veno‐arterial CO2 gradient (veno‐arterial Pco2) during septic shock. Design: Prospective, randomized, doubleblind study conducted over 2 yrs. Setting: Septic shock patients admitted to the intensive care unit. Patients: Fifty‐eight patients requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to septic shock, were included in this study. All patients were examined within 72 hrs after the onset of sepsis. They were optimally resuscitated by conventional means with volume and inotropic agents, and exhibited stable clinical conditions (hemodynamic values, body temperature, hemoglobin, Fio2). Interventions: A gastric tonometer was inserted to measure the gastric intramucosal pH. Subjects randomly received either 150 mg/kg of intravenous N‐acetylcysteine or placebo over a 15‐min period, then a continuous infusion of 12.5 mg/hr of N‐acetylcysteine or placebo over ˜90 mins. Measurements: Infusion measurements were begun 60 mins after the beginning of infusion and lasted ˜30 mins. The infusion was then discontinued and 2 hrs later the final measurements were taken. Main Results: Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II scores, Multiple Organ Failure scores) did not differ significantly, nor did pre‐ and 2‐hr postinfusion measurements differ between any of the groups. Thirteen (45%) patients responded (i.e., showed an increase in &OV0312;o2 >10%, reaching a mean of 19%) to the N‐acetylcysteine infusion. The N‐acetylcysteine responders also showed an increase in gastric intramucosal pH, a decrease in veno‐arterial Pco2, an increase in oxygen delivery, cardiac index, stroke index, and left ventricular stroke work index, as well as a significant decrease in systemic vascular resistance in comparison to baseline. The N‐acetylcysteine nonresponders, as well as the patients in the placebo group, did not show any significant changes in any of these variables. The N‐acetylcysteine responders had a higher survival rate (69%) than the nonresponders (19%) and were studied earlier after onset of sepsis (37 hrs) than the nonresponders (61 hrs). The only significant difference between the entire N‐acetylcysteine group (which included responders plus nonresponders) and the placebo group was an increased &OV0312;o2 in the entire N‐acetylcysteine group during infusion measurements. Conclusions: N‐acetylcysteine provided a transient improvement in tissue oxygenation in about half of the septic shock patients, as indicated by an increase in &OV0312;o2 and gastric intramucosal pH and a decrease in veno‐arterial Pco2. The higher survival rate in the N‐acetylcysteine responders and the fact that half of the patients receiving N‐acetylcysteine did not respond, suggests that, in some patients, sepsis irreversibly damages the microvasculature to the extent that N‐acetylcysteine has no effect. If analyzed by intention to treat, the N‐acetylcysteine did not produce effects that were significantly different from the placebo. Whether the N‐acetylcysteine challenge was merely diagnostic or whether N‐acetylcysteine can be effective in the treatment of sepsis deserves further investigation. (Crit Care Med 1994; 22:1738–1746)

N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study.

ObjectiveIn septic shock, decreased splanchnic blood flow is reported, despite adequate systemic hemodynamics. N-acetylcysteine (NAC) was found to increase hepatosplanchnic blood flow in experimental settings. In septic shock patients, NAC improved the clearance of indocyanine green and the relationship of systemic oxygen consumption to oxygen demand. We investigated the influence of NAC on liver blood flow, hepatosplanchnic oxygen transport-related variables, and liver function during early septic shock. DesignProspective, randomized, double-blind study. SettingSeptic shock patients admitted to an interdisciplinary surgical intensive care unit. PatientsWe examined 60 septic shock patients within 24 hrs after onset of sepsis. They were conventionally resuscitated with volume and inotropes and were in stable condition. A gastric tonometer was inserted into the stomach and a catheter into the hepatic vein. Microsomal liver function was assessed by using the plasma appearance of monoethylglycinexylidide (MEGX). InterventionsSubjects randomly received either a bolus of 150 mg/kg iv NAC over 15 mins and a subsequent continuous infusion of 12.5 mg/kg/hr NAC over 90 mins (n = 30) or placebo (n = 30). Measurements and Main ResultsMeasurements were performed before (baseline) and 60 mins after beginning the infusion (infusion). After NAC, a significant increase in absolute liver blood flow index (2.7 vs. 3.3 L/min/m2;p = .01) and cardiac index (5.0 vs. 5.7 L/min/m2;p = .02) was observed. Fractional liver blood flow index (cardiac index-related liver blood flow index) did not change. The difference between arterial and gastric mucosal carbon dioxide tension decreased (p = .05) and MEGX increased (p = .04). Liver blood flow index and MEGX correlated significantly (rs = .57;p ≤ .01). ConclusionsAfter NAC treatment, hepatosplanchnic flow and function improved and may, therefore, suggest enhanced nutritive blood flow. The increase of liver blood flow index was not caused by redistribution to the hepatosplanchnic area, but by an increase of cardiac index. Because of its correlation with liver blood flow index, MEGX may be helpful in identifying patients who benefit from NAC treatment in early septic shock.

Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor-α and interleukin-6 in patients with sepsis

OBJECTIVES To determine correlations and predictive strength of surrogate markers (body temperature, leukocyte count, C-reactive protein [CRP], and procalcitonin [PCT]) with elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in septic patients. DESIGN Prospective consecutive case series. SETTING Surgical intensive care unit (ICU) of a university hospital. PATIENTS A total of 175 patients experiencing intensive care unit stays >48 hrs categorized for sepsis according to ACCP/ SCCM Consensus Conference criteria. MEASUREMENTS AND MAIN RESULTS CRP and PCT were both significantly correlated with TNF-alpha and IL-6. Based on the area-under-the-curve of the receiver operating characteristics curves, predicting capability was highest for PCT (0.814 for TNF-alpha >40 pg/mL and 0.794 for IL-6 >500 pg/mL), moderate with CRP (0.732 and 0.716, respectively), and lowest for leukocyte count (0.493 and 0.483, respectively) and body temperature (0.587 and 0.589, respectively). Sensitivity, specificity, positive, and negative predictive values and test effectiveness all followed this same pattern of being highest for PCT followed by CRP, with leukocyte count and body temperature being lowest. CONCLUSION PCT may be an early and better marker of elevated cytokines than the more classic criteria of inflammation.

Platelet and leukocyte activation correlate with the severity of septic organ dysfunction.

This study was conducted to investigate the extent of platelet-leukocyte adhesion and platelet, monocyte, and neutrophil activation in septic patients and to analyze whether these variables correlate with the severity of sepsis. Forty-seven patients consecutively admitted to the operative ICU of a University Medical Centre and 12 control patients prior to elective surgery were included in this prospective cohort study. Patients were evaluated daily for sepsis criteria and sepsis-associated organ failure assessment (SOFA) score was used to describe the extent of sepsis-associated organ failure. Indicators for cell activation (CD62P on platelets and CD11b on neutrophils and monocytes) and binding of platelets to neutrophils and monocytes were analyzed by flow cytometry. CD62P was increased on platelets from patients with sepsis compared with patients who did not have sepsis. Patients with sepsis also had higher CD11b expression on neutrophils and monocytes. Statistical analyses revealed a positive correlation between platelet CD62P expression and severity of sepsis, as well as a positive correlation between the SOFA score and CD11b on monocytes. No correlation was found between the SOFA score and CD11b on neutrophils. Higher values for platelet-neutrophil adhesion were observed in patients with uncomplicated sepsis compared either with controls or to patients with septic shock. An inverse relation between severity of sepsis and extent of platelet-neutrophil adhesion was also obvious from correlation analysis. The results indicate that flow cytometry can be used to measure these parameters of cell activation in sepsis and that activation of platelets and monocytes as well as adhesion of platelets to neutrophils does play a role in the development of organ dysfunction.

Effect of Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Trial

CONTEXT Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00534287.

Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine

OBJECTIVE To assess the effects of dopexamine on splanchnic blood flow and splanchnic oxygen uptake in septic patients. DESIGN A prospective, controlled trial. SETTING A ten-bed intensive care unit (ICU) in a university hospital. PATIENTS Twelve patients with severe sepsis (according to the criteria of the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus conference) being stabilized by volume loading and treated to an elevated oxygen delivery by dobutamine infusion. INTERVENTIONS Infusion of increasing dosages of dopexamine (0.5, 1.0, 2.0, and 4.0 microg/kg/min). MEASUREMENTS AND MAIN RESULTS Systemic and splanchnic hemodynamic and oxygen transport parameters as well as gastric mucosal pH (pHi) were measured. A hepatic venous catheter technique with indocyanine green dye dilution was used to determine splanchnic blood flow. Dopexamine increased global and splanchnic oxygen delivery without affecting oxygen consumption (VO2). Splanchnic blood flow increased proportionally to cardiac output, indicating that there was no selective effect of dopexamine on the splanchnic flow. Dopexamine decreased pHi in a dose-dependent fashion in all 12 patients. CONCLUSIONS In hemodynamically stable, hyperdynamic septic patients being treated with dobutamine, dopexamine has no selective effect on splanchnic blood flow. In fact, a decreased pHi suggests a harmful effect on gastric mucosal perfusion.