Stefan John

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.)

Impaired endothelial function in arterial hypertension and hypercholesterolemia : potential mechanisms and differences

This review focuses on the role of impaired endothelial function for the developement of atherosclerosis in human arterial hypertension and hypercholesterolemia in vivo. Potential mechanisms underlying impaired endothelial function and decreased bioavailability of nitric oxide under these clinical conditions are discussed and potential differences in these mechanisms between arterial hypertension and hypercholesterolemia are outlined. It further addresses therapeutic strategies aiming to improve the bioavailability of nitric oxide in these patients. The overall conclusion is that the bioavailability of nitric oxide is probably impaired not by a single defect, but by various mechanisms affecting nitric oxide synthesis as well as nitric oxide breakdown. In both diseases, increased superoxide anion production and oxidative stress represents a major mechanism. However, potential differences in the underlying mechanisms of superoxide production or nitric oxide synthesis are evident between arterial hypertension and hypercholesterolemia. Decreased bioavailability of nitric oxide does not only impair endothelium-dependent vasodilation, but also activates other mechanisms that play an important role in the pathogenesis of atherosclerosis. Thus, therapeutic strategies should aim to restore bioavailability of nitric oxide, which has been demonstrated for lipid-lowering therapy in hypercholesterolemia. The mechanisms by which nitric oxide bioavailability can be improved by any drug therapy remain to be elucidated and may provide further insights into the mechanisms that are involved in impaired endothelial function and atherogenesis.

Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical NG, NG-dimethylarginine in human essential hypertension☆

Abstract Background Asymmetrical NG, NG-dimethylarginine (ADMA) is associated with impaired endothelium-dependent vasodilation in humans. Methods Twenty young, male, mildly hypertensive subjects were included in a randomized, double-blind, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or a combination of both drugs (10 and 300 mg/day, respectively) each over 1 week, followed by a 2-week wash-out phase. After each treatment phase, ADMA concentration was measured. Results ADMA concentration was 1.69 ± 0.59 μmol/L in the placebo phase, and was significantly lower in the enalapril, eprosartan, and combination phases (1.41 ± 0.29, 1.42 ± 0.43, and 1.38 ± 0.30 μmol/L, respectively; all P Conclusions Levels of ADMA were reduced with enalapril and eprosartan therapy. Our results suggest a specific action of these drugs on ADMA levels that is independent of BP.

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.

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks

OBJECTIVES We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Practice and perception—A nationwide survey of therapy habits in sepsis*

Objective:To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. Design:One-day cross-sectional survey. Setting:Representative sample of German intensive care units stratified by hospital size. Patients:Adult patients with severe sepsis or septic shock. Interventions:None. Measurements and Main Results:Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses “always” and “frequently” were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation ≤6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% >8 mL/kg predicted body weight. Mean tidal volume was 10.0 ± 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4–6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels ≤8.3 mmol/L and 66.2% were hyperglycemic (blood glucose >8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels ≤8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 ± 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. Conclusions:This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Effect of AT1 receptor blockade on endothelial function in essential hypertension.

BACKGROUND Angiotensin II adversely affects endothelial function and NO availability. We analyzed the effect of AT(1) receptor blockade on endothelium-dependent vasodilation and basal nitric oxide (NO) production and release in hypertensive patients. METHODS AND RESULTS Sixty patients (53 +/- 10 years) with essential hypertension were randomized to 6 weeks of double-blind therapy with either valsartan (80 mg), hydrochlorothiazide (HCTZ) (25 mg), or placebo once daily. Basal NO production and release was assessed by measuring forearm blood flow (FBF) in response to intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and endothelium-dependent vasodilation by measuring FBF in response to intra-arterial administration of acetylcholine, respectively. Intra-arterial infusion of noradrenaline and sodium nitroprusside was used to assess endothelium-independent changes in FBF. Blood pressure (BP) similarly decreased with active treatments (P < .001). After valsartan treatment, the decrease of FBF in response to L-NMMA was augmented (4 micromol/min L-NMMA, -1.3 +/- 1.2 after v -0.5 +/- 1.1 mL/min/100 mL before therapy, P < .02; 8 micromol/min L-NMMA: -1.7 +/- 1.3 after v -1.1 +/- 1.2 mL/min 100 mL before therapy, P < .05). No improvement was found after placebo or HCTZ treatment. Changes in L-NMMA-induced decrease of FBF with valsartan treatment were not related to BP changes. Neither drug substantially modified the response of FBF induced by intra-arterial infusion of acetylcholine, noradrenaline, and sodium nitroprusside. CONCLUSIONS The AT(1) receptor blockade with valsartan improved basal NO production and release. The effect seems to be BP independent, as BP reduction with HCTZ failed to increase NO availability.

Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension.

Background Emerging evidence links inflammation to atherosclerosis (AS). Although some studies have addressed the role of inflammation in patients with arterial hypertension (AH), its overall contribution in AH is far from being understood. Therefore, the present pilot study was designed to examine the role of platelet P-selectin and various inflammatory mediators in young patients with moderate AH without signs of target organ damage. Methods and results Fifteen patients with mild AH [33.8 ± 7.3 years, mean arterial pressure (MAP) 106.6 ± 10.4 mmHg] and 15 healthy normotensive controls (31.7 ± 10.6 years) were examined. Platelet P-selectin was analysed by flow cytometry. Plasma levels of monocyte-chemoattractant-protein-1 (MCP-1), high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, tumour necrosis factor α (TNFα), and IL-10 levels were measured by enzyme immunoassay (EIA). Patients with mild AH showed significantly enhanced expression of platelet P-selectin [17.2 ± 5.4 versus 10.6 ± 4.2 mean fluorescence intensity (MFI), P < 0.001]. P-selectin expression positively correlated with MAP (r = 0.43, P < 0.05). Furthermore, patients with mild AH had significantly enhanced plasma levels of hsCRP (2.7 ± 3.8 versus 0.6 ± 0.9 mg/l, P < 0.01), IL-6 (1.4 ± 0.7 versus 0.6 ± 0.3 pg/ml, P < 0.001), TNFα (2.8 ± 0.7 versus 2.4 ± 0.4 pg/ml, P < 0.05), and MCP-1 (291.3 ± 100.7 versus 214.3 ± 8.3 pg/ml, P < 0.05). IL-6 levels positively correlated with hsCRP levels (r = 0.47, P < 0.05) and mean arterial pressure (MAP) (r = 0.44, P < 0.05). Conclusions This pilot study demonstrates that in an early stage of AH, inflammatory pathways are already activated. Besides pro-inflammatory cytokines, platelets seem to play a significant role in mediating inflammation in AH, which could lead to target organ injury. Further investigations have to clarify the role of early anti-inflammatory therapy, in patients with mild to moderate AH, in alleviating hypertensive target organ damage.

Does Lipoprotein(a) Impair Endothelial Function

OBJECTIVES This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function. BACKGROUND Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed. METHODS Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 microg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl L-arginine (L-NMMA) (1, 2 and 4 micromol/min) in 57 white subjects (mean age +/- SD 37 +/- 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis. RESULTS Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial L-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 +/- 20.3 mg/dl) had a much greater vasoconstrictive response to L-NMMA than patients in the lowest Lp(a) tertile (4.8 +/- 2.5 mg/dl): 2 micromol/min of L-NMMA, -23.6 +/- 22.5% vs. -10.4 +/- 9.1% (p < 0.02); 4 micromol/min of L-NMMA, -27.8 +/- 10.3% vs. -17.6 +/- 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 micromol/min of intraarterial L-NMMA (r = -0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to L-NMMA (p < 0.02). CONCLUSIONS The endothelium-dependent vasoconstrictive response to L-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.

[Prevention, diagnosis, treatment, and follow-up care of sepsis. First revision of the S2k Guidelines of the German Sepsis Society (DSG) and the German Interdisciplinary Association for Intensive and Emergency Care Medicine (DIVI)].

(Orientiert an der Definition der Agency for Health Care Policy and Research fur die „Clinical Practice Guidelines“ der USA): „Leitlinien sind systematisch entwickelte Darstellungen und Empfehlungen mit dem Zweck, Arzte und Patienten bei der Entscheidung uber angemessene Masnahmen der Krankenversorgung (Pravention, Diagnostik, Therapie und Nachsorge) unter spezifischen medizinischen Umstanden zu unterstutzen.“ Leitlinien geben den Stand des Wissens (Ergebnisse von kontrollierten klinischen Studien und Wissen von Experten) uber effektive und angemessene Krankenversorgung zum Zeitpunkt der „Drucklegung“ wieder. In Anbetracht der unausbleiblichen Fortschritte wissenschaftlicher Erkenntnisse und der Technik mussen periodische Uberarbeitungen, Erneuerungen und Korrekturen unternommen werden. Die Empfehlungen der Leitlinien konnen nicht unter allen Umstanden angemessen genutzt werden. Die Entscheidung daruber, ob einer bestimmten Empfehlung gefolgt werden soll, muss vom Arzt unter Berucksichtigung der beim individuellen Patienten vorliegenden Gegebenheiten und der verfugbaren Ressourcen getroffen werden.