Gunter Hempelmann

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

Objective To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. Design Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. Setting Thirty-eight intensive care units in the United States and Europe. Patients Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. Interventions Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). Measurements and Main Results There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p = .037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p = .026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%;p = .39). Conclusions Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.

Is continuous cardiac output measurement using thermodilution reliable in the critically ill patient

Objective: Evaluation of continuous cardiac output monitoring based on the thermodilution technique in the critically ill. Design: Prospective clinical investigation. Setting: A surgical intensive care unit of a university hospital. Patients: Thirty‐five critically ill patients (trauma and/or sepsis patients), who needed pulmonary artery catheterization. The patients were prospectively studied according to the following groups: a) patients with a heart rate of >120 beats/min; b) those patients with a cardiac output of >10 L/min; c) patients with a cardiac output of <4.5 L/min; d) patients with a rectal temperature of >39.0°C; and e) patients with a pulmonary artery catheter inserted for >4 days. Interventions: Therapies were carried out according to modern intensive care medicine protocols by physicians who were not involved in the study. Measurements: Cardiac output was monitored continuously using a new, modified pulmonary artery catheter. This catheter has a heating filament by which energy is transmitted to the circulating blood (modified thermodilution technique). A bedside microprocessor calculated cardiac output using a new algorithm. Standard bolus thermodilution technique (10 mL of ice‐cold saline solution) was used to compare the continuous cardiac output measurement with the intermittent bolus cardiac output measurement. Main Results: A total of 404 pairs of intermittent (bolus) cardiac output and continuous cardiac output measurements were obtained from the 35 patients. The bias (mean difference between bolus cardiac output measurement and continuous cardiac output measurement) of all measurements was 0.03 ± 0.52 L/min and the 95% confidence limit (mean difference ± 2 sd) was ‐1.01/1.06 L/min. Also, continuous cardiac output measurement agreed closely with bolus cardiac output measurement (bias was 0.16 ± 0.57 L/min in the cardiac output of >10 L/min group; bias was ‐0.17 ± 0.50 L/min for the cardiac output of <4.5 L/min group). Increased temperature and prolonged length of stay did not influence the agreement of continuous cardiac output measurement with bolus cardiac output measurement (bias was 0.09 ± 0.51 L/min in the >39°C rectal temperature group). Conclusions: Continuous monitoring of cardiac output using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise in the critically ill patient when compared with the “standard” intermittent bolus thermodilution technique. The continuous monitoring technique enhances our armamentarium for more intensive monitoring of these patients under a variety of circumstances. (Crit Care Med 1994; 22:1913–1918)

Changes in blood lymphocyte populations after multiple trauma: Association with posttraumatic complications

OBJECTIVE To study the frequency of several lymphocyte subsets, circulating cytokines, and prostaglandin plasma values at their time course over a period of 14 days in severely injured trauma patients in relation to the development of sepsis and multiple organ failure (MOF). DESIGN Prospective study. SETTING An operative intensive care unit (ICU) of a university hospital. PATIENTS Sixty-eight consecutive severely injured trauma patients. INTERVENTIONS Patients were separated into patients without sepsis and MOF (group 1, n = 51), and patients who developed sepsis and MOF (group 2, n = 17) during their stay in the ICU. Therapy was adjusted to the standards of modern intensive care management by physicians who were not involved in the study. MEASUREMENTS AND MAIN RESULTS In arterial blood samples, the profile of lymphocyte subset frequencies was performed by flow cytometry and, together with interleukin (IL)-1, IL-10, tumor necrosis factor (TNF)-alpha soluble TNF-alpha receptor 1 (sTNF-alpha r1 [p55]), and prostaglandin E2 (PGE2alpha)-alpha, serially measured after arrival in the ICU (baseline value) and during the next 14 days. Mean plasma IL-1 (29.3 +/- 5.8 [SD] pg/mL), TNF-alpha (138.5 +/- 22.4 pg/mL), and soluble TNF-alpha r1 (6.1 +/- 0.3 ng/mL) values were significantly higher in group 2 patients before clinical evidence of sepsis and MOF. With the onset of severe infections in group 2 patients, IL-1, TNF-alpha, and sTNF-alpha r1 values decreased, while immunosuppressive IL-10 (191.7 +/- 29.1 pg/mL) and PGE2alpha (87.7 +/- 20.4 pg/mL) values further increased and remained elevated during the time course. Analysis of lymphocyte subsets revealed a fall in total lymphocyte levels, in CD4+ T lymphocytes, and natural killer (NK) cells, but no change in CD8+ T lymphocyte subset. Despite a marked change in the T helper (CD4+) to T suppressor (CD8+) ratio (from 1:1.72 to 1:1.10), patients without MOF (group 1) had no significant difference in any of the markers tested compared with baseline values. In addition to the inverse CD4+/CD8+ T cell ratio (from 1:1.75 to 1:0.91) and increased activated T cells, each of these markers was significantly elevated and peaked before the onset of MOF in group 2 patients. CONCLUSIONS A severely depressed cellular immune response associated with increased suppressive mediators might be closely related to the development of severe sepsis and MOF in trauma patients. Therefore, an in-depth understanding of the deficits in host defense following multiple trauma will provide the basis for therapeutic interventions.

Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons.

BackgroundTetrodotoxin-resistant Na+ channels play an important role in generation and conduction of nociceptive discharges in peripheral endings of small-diameter axons of the peripheral nervous system. Pathophysiologically, these channels may produce ectopic discharges in damaged nociceptive fibers, leading to neuropathic pain syndromes. Systemically applied Na+ channel–blocking drugs can alleviate pain, the mechanism of which is rather unresolved. The authors investigated the effects of some commonly used drugs, i.e., lidocaine, mexiletine, carbamazepine, amitriptyline, memantine, and gabapentin, on tetrodotoxin-resistant Na+ channels in rat dorsal root ganglia. MethodsTetrodotoxin-resistant Na+ currents were recorded in the whole-cell configuration of the patch-clamp method in enzymatically dissociated dorsal root ganglion neurons of adult rats. Half-maximal blocking concentrations were derived from concentration–inhibition curves at different holding potentials (−90, −70, and −60 mV). ResultsLidocaine, mexiletine, and amitriptyline reversibly blocked tetrodotoxin-resistant Na+ currents in a concentration- and use-dependent manner. Block by carbamazepine and memantine was not use-dependent at 2 Hz. Gabapentin had no effect at concentrations of up to 3 mm. Depolarizing the membrane potential from −90 mV to −60 mV reduced the available Na+ current only by 23% but increased the sensitivity of the channels to the use-dependent blockers approximately fivefold. The availability curve of the current was shifted by 5.3 mV to the left in 300 &mgr;m lidocaine. ConclusionsLess negative membrane potential and repetitive firing have little effect on tetrodotoxin-resistant Na+ current amplitude but increase their sensitivity to lidocaine, mexiletine, and amitriptyline so that concentrations after intravenous administration of these drugs can impair channel function. This may explain alleviation from pain by reducing firing frequency in ectopic sites without depressing central nervous or cardiac excitability.

Influence of different intravascular volume therapies on platelet function in patients undergoing cardiopulmonary bypass

The influence of four different kinds of intravascular volume replacement on platelet function was investigated in 60 patients undergoing elective aortocoronary bypass grafting using cardiopulmonary bypass (CPB). In a randomized sequence, high-molecular weight hydroxyethyl starch solution (HMW-HES, mean molecular weight [Mw] 450,000 d), low-molecular weight HES (LMW-HES, Mw 200,000 d), 3.5% gelatin or 5% albumin were infused preoperatively to double reduced filling pressure (pulmonary capillary wedge pressure [PCWP] < 5 mm Hg). Fifteen untreated patients served as a control. Platelet function was assessed by aggregometry using turbidometric technique (inductors: ADP, epinephrine, collagen). Maximum aggregation, maximum gradient of aggregation, and platelet volume were measured before, during, and after CPB until the first postoperative day. HMW-HES 840 +/- 90 mL, LMW 850 +/- 100 mL, gelatin 950 +/- 110 mL, and albumin 810 +/- 100 mL were given preoperatively. Maximum platelet aggregation (ranging from -23% to -44% relative from baseline value) and maximum gradient of platelet aggregation (ranging from -26% to -45% relative from baseline values) were reduced only in the HMW-HES patients. After CPB, aggregometry also was impaired most markedly in these patients. The other volume groups showed less reduction in platelet aggregation and were similar to the untreated control. On the first postoperative day, aggregation variables had returned almost to baseline in all patients. Platelet volume was the same among the groups within the investigation period. Postbypass blood loss was highest in the HMW-HES group (890 +/- 180 mL). There was significant (P < 0.04) correlation in this group between blood loss and change in platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients

A single base pair insertion/deletion (4G/SG) promoter polymorphism in the plasminogen-activator-inhibitor-1 (PAI-1) gene is thought to play a part in prognosis after severe trauma. We investigated the relation between outcome of severe trauma, PAI-1 concentrations, and PAP-1 genotype in 61 patients who had been severely injured. 11 (58%) of 19 patients with genotype 4G/4G did not survive, whereas only eight (28%) of 29 patients with heterozygous genotype 4G/SG, and two (15%) of 13 patients with genotype 5G/5G died. The PAI-1 4G allele is associated with high concentrations of PAI-1 in plasma and a poor survival rate after severe trauma.

Normothermic versus hypothermic cardiopulmonary bypass: Do changes in coagulation differ?

BACKGROUND The differences between hypothermic and normothermic cardiopulmonary bypass (CPB) on platelet function and endothelial-related coagulation (eg, the thrombomodulin/protein C/protein S system) should be investigated. METHODS According to a randomized sequence, 30 patients undergoing aortocoronary bypass grafting underwent either hypothermic (rectal temperature, 27 degrees C to 28 degrees C, n = 15) or normothermic CPB (rectal temperature, more than 35 degrees C, n = 15). Arterial blood samples were taken after induction of anesthesia (baseline values), before, during, and immediately after CPB, 5 hours after CPB, and on the morning of the first postoperative day. Circulating thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from these samples. Platelet function was assessed by aggregometry (turbidometric technique) induced by adenosine diphosphate (2 mumol/L), collagen (4 micrograms/L), and epinephrine (25 mumol/L). RESULTS Hypothermic patients showed a significantly higher blood loss and need for homologous blood than the normothermic patients. Thrombomodulin plasma level increased more in the hypothermic (from 28 +/- 5 ng/mL to 60 +/- 10 ng/mL) than in the normothermic group (from 28 +/- 7 ng/mL to 41 ng/mL); p < 0.05). Both protein C and (free) protein S were reduced significantly in the hypothermic (protein C, from 88% +/- 25% to 60% +/- 11%; protein S, from 71% +/- 10% to 40% +/- 8%) than in the normothermic patients. Platelet aggregation was significantly more decreased in the hypothermic (adenosine diphosphate, maximum decrease by -43% relative to baseline) than in the normothermic patients (adenosine diphosphate, maximum decrease by -22% relative to baseline). In the hypothermic CPB group, platelet aggregation had recovered incompletely, whereas in the normothermic patients platelet aggregation even slightly exceeded baseline values. CONCLUSIONS Hypothermic CPB resulted in more pronounced alterations of platelet aggregation and endothelial-related coagulation than normothermic CPB. Plasma levels of soluble thrombomodulin were more increased in hypothermic than in normothermic CPB indicating more extensive endothelial damage or activation associated with hypothermic CPB.

Alterations of acute phase reaction and cytokine production in patients following severe burn injury

To determine the acute immunologic reaction, mediated by cytokines, interleukines (ILs) and growth factors and the susceptibility to infections and sepsis after severe burn injury a prospective, single unit, longitudinal study of acute phase reactants and mediators who performed. After approval by the ethics committee of our hospital, we investigated the plasma concentrations of IL-2, -6, -8, -10, and -13, the soluble IL-2 receptor (sIL-2R), and the acute phase proteins procalcitonin (PCT) and C-reactive protein (CRP) at admission and every 3 days in 24 patients over a time course of 28 days after thermal injury and categorized by percent burn: < or =30% (group 1; n=12) and >30% (group 2; n=12). Shortly after burn injury we found higher concentrations of IL-2, -6, -10 and PCT in those patients >30% TBSA. During the study period, we found significant higher levels of acute phase proteins, IL-6 and -8 in patients >30% TBSA. The incidence of SIRS and MODS was three times increased in patients >30% TBSA. Our results show different patterns of cytokines and acute phase proteins in patients with different burned surface areas over a long time and continuous monitoring of a more distinct inflammatory response in these patients.

Morphine inhibits NF-κB nuclear binding in human neutrophils and monocytes by a nitric oxide-dependent mechanism

Background The transcription factor NF-&kgr;B plays a pivotal role in gene expression of inflammatory mediators such as cytokines or adhesion molecules. NF-&kgr;B–mediated transcriptional activation of these genes is inhibited by nitric oxide (NO) in a variety of cells, including monocytes. Morphine mediates NO release in a naloxone antagonizable manner in monocytes and neutrophils. Methods The influence of morphine on NF-&kgr;B activation was investigated in a whole-blood flow cytometric assay. A specific antibody against the p65 subunit of NF-&kgr;B was used and detected by fluoresceine-isothiocyanate–labeled anti–immunoglobulin G. Nuclei were stained with propidium iodide. Leukocyte subpopulations were evaluated by gating on neutrophils and monocytes. The median fluorescence channel was determined. Different morphine concentrations (50 nm, 50 &mgr;m, 1 mm) and incubation intervals (10–150 min) were used. Results Morphine inhibits lipopolysaccharide-induced NF-&kgr;B nuclear binding in human blood neutrophils and monocytes in a time-, concentration-, and naloxone-sensitive–dependent manner. Similar effects were achieved with the NO donor S-nitroso-N-acetyl-pencillamine and the antioxidant N-acetyl-cysteine. The NO synthase inhibitors N&ohgr;-nitro-l-arginine-methyl-esther and N&ohgr;-nitro-l-arginine completely abolished the morphine-induced attenuation of NF-&kgr;B nuclear binding, demonstrating that the inhibitory action is mediated by NO release. Conclusion Morphine causes immunosuppression, at least in part, via the NO-stimulated depression of NF-&kgr;B nuclear binding.

Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord

Background The dorsal horn of the spinal cord is a pivotal point for transmission of neuronal pain. During spinal and epidural anesthesia, the neurons of the dorsal horn are exposed to local anesthetics. Unfortunately, little is known about the action of local anesthetics on the major ionic conductances in dorsal horn neurons. In this article, the authors describe the effects of bupivacaine, lidocaine, and mepivacaine on voltage‐gated Na sup + and K sup + currents in the membranes of these neurons. Methods The patch‐clamp technique was applied to intact dorsal horn neurons from laminae I‐III identified in 200‐micro meter slices of spinal cord from newborn rats. Under voltage‐clamp conditions, the whole‐cell Na sup + and K sup + currents activated by depolarization were recorded in the presence of different concentrations of local anesthetics. Results Externally applied bupivacaine, lidocaine, and mepivacaine produced tonic block of Na sup + currents with different potencies. Half‐maximum inhibiting concentrations (IC50) were 26, 112, and 324 micro Meter, respectively. All local anesthetics investigated also showed a phasic, that is, a use‐dependent, block of Na sup + channels. Rapidly inactivating K sup + currents (KA currents) also were sensitive to the blockers with IC50 values for tonic blocks of 109, 163, and 236 micro Meter, respectively. The block of KA currents was not use dependent. In contrast to Na sup + and KA currents, delayed‐rectifier K sup + currents were almost insensitive to the local anesthetics applied. Conclusions In clinically relevant concentrations, local anesthetics block Na sup + and KA currents but not delayed‐rectifier K sup + currents in spinal dorsal horn neurons. The molecular mechanisms of Na sup + and K sup + channel block by local anesthetics seem to be different. Characterization of these mechanisms could be an important step in understanding the complexity of local anesthetic action during spinal and epidural anesthesia.