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Frank M Brunkhorst,
Michael Oppert,
Gernot Marx,
Frank Bloos,
Katrin Ludewig,
Christian Putensen,
Axel Nierhaus,
Ulrich Jaschinski,
Andreas Meier-Hellmann,
Andreas Weyland, [......],
Lorenz Reill,
Harald Fritz,
Michael Kiehntopf,
Evelyn Kuhnt,
Holger Bogatsch,
Christoph Engel,
Markus Loeffler,
Marin H Kollef,
Konrad Reinhart,
Tobias Welte
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ABSTRACT: 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.
To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction.
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.
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.
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.
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).
Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure.
clinicaltrials.gov Identifier: NCT00534287.
JAMA The Journal of the American Medical Association 06/2012; 307(22):2390-9. · 30.03 Impact Factor
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ABSTRACT: Patients with arterial hypertension are characterized by impaired endothelial function and increased cardiovascular risk. Statins have been proposed as a potential treatment option in hypertension, even in those with normal low-density lipoprotein (LDL)-cholesterol levels. We tested whether fluvastatin reduces oxidative stress and inflammation, and improves endothelial function in patients with arterial hypertension and normal LDL-cholesterol.
In a cross-over designed, double-blind randomized trial, 26 patients with arterial hypertension and LDL-cholesterol below 160 mg/dl were treated for 2 weeks with either placebo or fluvastatin 80 mg/day. Endothelium-dependent vasodilation (EDV) was assessed as the forearm blood flow (FBF) response to intra-arterial infusion of acetylcholine (ACH, 12 and 48 μg/min), and endothelium-independent vasodilation (EIV) as the FBF response to nitroprusside (3.2 and 12.8 μg/min). Furthermore, we measured reduced to oxidized glutathione (GSH/GSSG) ratio in red blood cells, total antioxidant capacity in plasma (TAC) and high-sensitivity C-reactive protein (hs-CRP) levels.
Fluvastatin lowered LDL-cholesterol from 118 ± 16 to 90 ± 25 mg/dl (P < 0.0001), but had no effect on blood pressure, high-density lipoprotein (HDL)-cholesterol or triglycerides. EDV and EIV were unaffected by fluvastatin treatment (e.g. increase of FBF 48 μg/min: 339 ± 285% during placebo versus 268 ± 194% during fluvastatin, n.s.). Finally, GSH/GSSG ratio, TAC and hs-CRP levels were similar between fluvastatin and placebo treatment.
Fluvastatin treatment did not improve endothelial function, oxidative stress or inflammation in patients with arterial hypertension and normal LDL-cholesterol levels. These data argue against the usefulness of statins in patients with arterial hypertension in the absence of hypercholesterolemia or other additional risk factors.
Journal of hypertension 09/2011; 29(9):1757-64. · 4.02 Impact Factor
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ABSTRACT: A gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fcγ receptor IIa (FcγRIIa). The R allele is associated with increased binding of CRP and enhanced activation of monocytes. FcγRIIa is also expressed on endothelial cells, and we hypothesized this polymorphism would be associated with alterations of endothelial function.
Genomic DNA was extracted and allele-specific PCR reactions were used to determine the FcγRIIa H131R polymorphism in 78 hypercholesterolaemic subjects. Using strain gauge plethysmography, forearm blood flow (FBF) responses were determined to intra-arterial infusion of acetylcholine (ACH), for endothelium-dependent vasodilatation (EDV), to nitroprusside (NP), for endothelium-independent vasodilatation (EIV), to NG-monomethyl-l-arginine (l-NMMA), for basal NO activity, and to ACH in the presence of l-NMMA, to assess the contribution of NO release to EDV.
Homozygous carriers of the H allele (n=30) had significantly better EDV than homozygous carriers of the R allele (n=15), while heterozygotes showed an intermediate phenotype (n=33) (e.g. % increase of FBF to ACH 48μg/min: 527±359% in H/H versus 452±262% in H/R versus 332±413% in R/R, p=0.0012 by 2-way ANOVA). EIV and basal NO activity were not affected by genotype, and co-infusion of l-NMMA abolished the differences in EDV.
The R allele of the FcγRIIa polymorphism is associated with impaired EDV and reduced NO activity during endothelial cell stimulation. These data suggest that the functional effects of the FcγRIIa H131R gene polymorphism previously observed in vitro translate into clinically relevant alterations of endothelial function in vivo.
Atherosclerosis 07/2011; 218(2):411-5. · 3.79 Impact Factor
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ABSTRACT: Ischemia-induced reactive hyperemia (RH) is mediated by various factors including release of nitric oxide (NO). The contribution of NO to RH equals the extent of L-NMMA-dependent reduction of forearm blood flow (FBF). Because the optimal duration and location of ischemia that provokes maximum NO activation is unknown, we analyzed which duration and location stimulates most NO release, aiming at developing a noninvasive tool to measure endothelial integrity by NO synthase activity in humans.
FBF was measured by strain gauge plethysmography after ischemia applied at the upper arm and wrist during intra-arterial infusion of L-NMMA or saline. To obtain similar FBF before RH, clamping with sodium nitroprissude was performed. Twenty-eight healthy male volunteers were randomly assigned to two groups (N = 15) undergoing ischemia of 1 and 5 min or 2 and 5 min (N = 13) at both locations.
Peak FBF was not affected by L-NMMA infusion. The change of FBF during L-NMMA expressed as area under the curve (AUC) of the first minute was significantly reduced after 1 (-0.70 +/- 1.63 ml, P < 0.001) and 2 min (1.67 +/- 2.65 ml, P < 0.01) of ischemia applied at wrist level compared to 5 min (7.49 +/- 7.92 ml). Ischemia applied to the upper arm showed no significant differences of FBF after L-NMMA or saline infusion, irrespective of the duration of ischemia.
Our data indicate that only immediately after ischemia the vasodilatatory response is most NO-dependent. RH as a test of NO activity in the forearm microcirculation should be applied at the wrist and last 1 min.
American Journal of Hypertension 08/2010; 23(8):865-9. · 3.18 Impact Factor
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Frank M Brunkhorst,
Christoph Engel,
Max Ragaller,
Tobias Welte,
Rolf Rossaint,
Herwig Gerlach,
Konstantin Mayer, Stefan John,
Frank Stuber,
Norbert Weiler,
Michael Oppert,
Onnen Moerer,
Holger Bogatsch,
Konrad Reinhart,
Markus Loeffler,
Christiane Hartog
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ABSTRACT: To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock.
One-day cross-sectional survey.
Representative sample of German intensive care units stratified by hospital size.
Adult patients with severe sepsis or septic shock.
None.
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 < or = 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 < or = 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 < or = 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.
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.
Critical care medicine 08/2008; 36(10):2719-25. · 6.37 Impact Factor
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ABSTRACT: A 38-year-old patient developed meningitis after a complicated kidney transplantation and organ rejection. Ureaplasma urealyticum was identified as the etiological agent by molecular and microbiological analyses of the cerebrospinal fluid. The patient was successfully treated with doxycycline and chloramphenicol. This is the first report of Ureaplasma urealyticum meningitis in an adult.
Journal of clinical microbiology 04/2008; 46(3):1141-3. · 4.16 Impact Factor
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ABSTRACT: Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor for mortality in septic patients or merely an indicator of disease severity.
A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (< 200 beds; 201-400 beds; 401-600 beds; > 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock.
Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to < 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p< 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p< 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%.
In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.
Nephrology Dialysis Transplantation 03/2008; 23(3):904-9. · 3.40 Impact Factor
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Frank M Brunkhorst,
Christoph Engel,
Frank Bloos,
Andreas Meier-Hellmann,
Max Ragaller,
Norbert Weiler,
Onnen Moerer,
Matthias Gruendling,
Michael Oppert,
Stefan Grond, [......],
Rolf Rossaint,
Tobias Welte,
Martin Schaefer,
Peter Kern,
Evelyn Kuhnt,
Michael Kiehntopf,
Christiane Hartog,
Charles Natanson,
Markus Loeffler,
Konrad Reinhart
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ABSTRACT: 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.
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 Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points.
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 Ringer's lactate.
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.)
New England Journal of Medicine 01/2008; 358(2):125-39. · 53.30 Impact Factor
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ABSTRACT: Acute renal failure (ARF) with the concomitant need for renal replacement therapy (RRT) is a common complication of critical care medicine that is still associated with high mortality. Different RRT strategies, like intermittent hemodialysis, continuous venovenous hemofiltration, or hybrid forms that combine the advantages of both techniques, are available and will be discussed in this article. Since a general survival benefit has not been demonstrated for either method, it is the task of the nephrologist or intensivist to choose the RRT strategy that is most advantageous for each individual patient. The underlying disease, its severity and stage, the etiology of ARF, the clinical and hemodynamic status of the patient, the resources available, and the different costs of therapy may all influence the choice of the RRT strategy. ARF, with its risk of uremic complications, represents an independent risk factor for outcome in critically ill patients. In addition, the early initiation of RRT with adequate doses is associated with improved survival. Therefore, the "undertreatment" of ARF should be avoided, and higher RRT doses than those in patients with chronic renal insufficiency, independent of whether convective or diffusive methods are used, are indicated in critically ill patients. However, clear guidelines on the dose of RRT and the timing of initiation are still lacking. In particular, it remains unclear whether hemodynamically unstable patients with septic shock benefit from early RRT initiation and the use of increased RRT doses, and whether RRT can lead to a clinically relevant removal of inflammatory mediators.
Chest 11/2007; 132(4):1379-88. · 5.25 Impact Factor
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Christoph Engel,
Frank M Brunkhorst,
Hans-Georg Bone,
Reinhard Brunkhorst,
Herwig Gerlach,
Stefan Grond,
Matthias Gruendling,
Guenter Huhle,
Ulrich Jaschinski, Stefan John, [......],
Michael Quintel,
Max Ragaller,
Rolf Rossaint,
Frank Stuber,
Norbert Weiler,
Tobias Welte,
Holger Bogatsch,
Christiane Hartog,
Markus Loeffler,
Konrad Reinhart
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ABSTRACT: To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size.
Prospective, observational, cross-sectional 1-day point-prevalence study.
454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003).
Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay.
Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (</= 200 beds: 6% and 11.5 days, universities: 19% and 19.2 days, respectively).
The expected number of newly diagnosed cases with severe sepsis in Germany amounts to 76-110 per 100,000 adult inhabitants. To allow better comparison between countries, future epidemiological studies should use standardized study methodologies with respect to sepsis definitions, hospital size, and daily and monthly variability.
Intensive Care Medicine 04/2007; 33(4):606-18. · 5.40 Impact Factor
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ABSTRACT: Renal replacement therapy (RRT) is increasingly used in intensive care as acute renal failure (ARF) is a common and constantly increasing complication in this setting. Different forms of RRT such as intermittent hemodialysis, continuous hemofiltration, or hybrid forms, which combine advantages of both, are available and will be discussed in this article. As a general survival benefit for neither method has been demonstrated, it is the task of the nephrologist or intensivist to choose the RRT strategy that is most advantageous for each individual patient. The choice of RRT might depend not only on the underlying disease, the time course of the disease, the etiology of ARF, the actual clinical status of the patient but also on the resources available and the cost of therapy. An adequate dose of RRT seems to result in improved survival in patients with ARF. However, clear guidelines on the dose of RRT and the timing of initiation are still lacking. Moreover, it will be discussed whether patients with sepsis and septic shock benefit from early RRT initiation, the use of increased RRT doses, and increased removal of inflammatory mediators by RRT.
Seminars in Dialysis 11/2006; 19(6):455-64. · 2.27 Impact Factor
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ABSTRACT: It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension.
In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively.
Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05).
We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.
American Journal of Hypertension 09/2005; 18(8):1111-7. · 3.18 Impact Factor
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ABSTRACT: Background: It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension.Methods: In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 g/min and 3.2 and 12.8 g/min, respectively.Results: Subjects with essential hypertension had impaired responses to both doses of Ach (% FBF to higher dose of Ach: 325 146 in subjects with essential hypertension v 540 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 108 v 500 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 146 without v 338 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 132 without v 400 185 with VITC, P = .05) and to NP (383 162 v 447 170, P = .05).Conclusions: We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.Keywords: Antioxidants, oxidative stress, endothelium, hypertension
American Journal of Hypertension 07/2005; 18(8):1111-1117. · 3.18 Impact Factor
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ABSTRACT: 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.
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 alpha (TNFalpha), 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), TNFalpha (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).
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.
Journal of Hypertension 05/2005; 23(5):995-1000. · 4.02 Impact Factor
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ABSTRACT: Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete.
We studied 41 patients (52 +/- 11 years) with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL (179 +/- 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C.
After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 microg/min: +15.7 +/- 10.6 vs +10.7 +/- 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 microg/min: +17.7 +/- 10.3 vs +12.4 +/- 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh.
Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.
American heart journal 03/2005; 149(3):473. · 4.65 Impact Factor
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ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is a rare haematological disease of unknown aetiology. This thrombotic microangiopathy is characterized by microvascular lesions with platelet aggregation. It is found in adults and can be associated with pregnancy, cancer, autoimmune diseases, bone marrow transplantation, drugs and bacterial as well as viral infections. The therapy requires a multi-disciplinary team approach involving dentistry. Even if TTP is immediately treated in an adequate manner, it still shows a mortality of up to 20%.
To define a specific treatment concept for periodontal disease and decayed teeth in patients suffering from TTP based on the experiences gained from two cases.
The two patient cases revealed a possible association of TTP with dental foci. Because of the severity and mortality of this disease, both prognosis evaluation and treatment standards of periodontologically compromised or decayed teeth have to be strictly followed in patients suffering from TTP. In order to avoid recurrence of TTP, it seems important to remove radically teeth of questionable prognosis.
Journal Of Clinical Periodontology 12/2004; 31(11):1019-23. · 3.00 Impact Factor
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ABSTRACT: Objectives: Thrombotic thrombocytopenic purpura (TTP) is a rare haematological disease of unknown aetiology. This thrombotic microangiopathy is characterized by microvascular lesions with platelet aggregation. It is found in adults and can be associated with pregnancy, cancer, autoimmune diseases, bone marrow transplantation, drugs and bacterial as well as viral infections. The therapy requires a multi-disciplinary team approach involving dentistry. Even if TTP is immediately treated in an adequate manner, it still shows a mortality of up to 20%.Aim: To define a specific treatment concept for periodontal disease and decayed teeth in patients suffering from TTP based on the experiences gained from two cases.Conclusion: The two patient cases revealed a possible association of TTP with dental foci. Because of the severity and mortality of this disease, both prognosis evaluation and treatment standards of periodontologically compromised or decayed teeth have to be strictly followed in patients suffering from TTP. In order to avoid recurrence of TTP, it seems important to remove radically teeth of questionable prognosis.
Journal Of Clinical Periodontology 09/2004; 31(11):1019 - 1023. · 3.00 Impact Factor
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ABSTRACT: In the coronary and the forearm circulations, endothelium-dependent vasomotion is impaired in smokers, but can be augmented by -arginine or vitamin C. We examined whether smoking similarly affects the renal circulation.
In 20 smokers (age 26 +/- 4 years) and in 20 non-smokers (age 28 +/- 3 years) changes of renal plasma flow (RPF), glomerular filtration rate (GFR), blood pressure and heart rate in response to the subsequent intravenous infusions of N(G)-monomethyl--arginine (L-NMMA), -arginine and -arginine plus vitamin C were studied by use of a constant infusion input clearance technique.
Systemic haemodynamic parameters did not differ between smokers and non-smokers during each experimental phase. At baseline, RPF and GFR were similar between the groups. The infusion of L-NMMA led to a similar decrease of RPF, while GFR did not change in either group. During the infusion of -arginine RPF increased similarly. Finally, the co-infusion of -arginine plus vitamin C led to a significantly greater increase of RPF (+277 +/- 395 vs +79 +/- 76 ml/min, P = 0.03) and GFR (+12.1 +/- 10.6 vs +3.4 +/- 11.2 ml/min, P = 0.02) in smokers as compared to non-smokers.
L-NMMA-induced vasoconstriction of the renal vasculature was similar in smokers compared to non-smokers. -arginine alone induced a similar increase of RPF. The co-infusion of vitamin C and -arginine led to a greater increase of RPF and GFR in smokers. This might suggest that oxidative stress is increased in the renal vasculature of smokers.
Nephrology Dialysis Transplantation 09/2003; 18(8):1512-7. · 3.40 Impact Factor
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ABSTRACT: Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.
Clinical Science 07/2003; 105(1):97-103. · 4.61 Impact Factor
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ABSTRACT: This review focuses on the role of impaired endothelial function for the development 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. It further addresses therapeutic strategies aimed at improving 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 represent a major mechanism. Decreased bioavailability of nitric oxide not only impairs 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 and blood pressure control in hypertension. In addition, antioxidative strategies will represent a major therapeutic tool against atherosclerotic diseases in the future. Statins and blockers of the renin-angiotensin system seem to have such antioxidative effects independent from their effects on lipid profiles or blood pressure control.
Current Hypertension Reports 07/2003; 5(3):199-207. · 2.50 Impact Factor
