Fritz Daudel

Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study.

IntroductionThe inflammatory response to an invading pathogen in sepsis leads to complex alterations in hemostasis by dysregulation of procoagulant and anticoagulant factors. Recent treatment options to correct these abnormalities in patients with sepsis and organ dysfunction have yielded conflicting results. Using thromboelastometry (ROTEM®), we assessed the course of hemostatic alterations in patients with sepsis and related these alterations to the severity of organ dysfunction.MethodsThis prospective cohort study included 30 consecutive critically ill patients with sepsis admitted to a 30-bed multidisciplinary intensive care unit (ICU). Hemostasis was analyzed with routine clotting tests as well as thromboelastometry every 12 hours for the first 48 hours, and at discharge from the ICU. Organ dysfunction was quantified using the Sequential Organ Failure Assessment (SOFA) score.ResultsSimplified Acute Physiology Score II and SOFA scores at ICU admission were 52 ± 15 and 9 ± 4, respectively. During the ICU stay the clotting time decreased from 65 ± 8 seconds to 57 ± 5 seconds (P = 0.021) and clot formation time (CFT) from 97 ± 63 seconds to 63 ± 31 seconds (P = 0.017), whereas maximal clot firmness (MCF) increased from 62 ± 11 mm to 67 ± 9 mm (P = 0.035). Classification by SOFA score revealed that CFT was slower (P = 0.017) and MCF weaker (P = 0.005) in patients with more severe organ failure (SOFA ≥ 10, CFT 125 ± 76 seconds, and MCF 57 ± 11 mm) as compared with patients who had lower SOFA scores (SOFA <10, CFT 69 ± 27, and MCF 68 ± 8). Along with increasing coagulation factor activity, the initially increased International Normalized Ratio (INR) and prolonged activated partial thromboplastin time (aPTT) corrected over time.ConclusionsKey variables of ROTEM® remained within the reference ranges during the phase of critical illness in this cohort of patients with severe sepsis and septic shock without bleeding complications. Improved organ dysfunction upon discharge from the ICU was associated with shortened coagulation time, accelerated clot formation, and increased firmness of the formed blood clot when compared with values on admission. With increased severity of illness, changes of ROTEM® variables were more pronounced.

Pulse pressure variation and volume responsiveness during acutely increased pulmonary artery pressure: an experimental study

IntroductionWe found that pulse pressure variation (PPV) did not predict volume responsiveness in patients with increased pulmonary artery pressure. This study tests the hypothesis that PPV does not predict fluid responsiveness during an endotoxin-induced acute increase in pulmonary artery pressure and right ventricular loading.MethodsPigs were subjected to endotoxemia (0.4 μg/kg/hour lipopolysaccharide), followed by volume expansion, subsequent hemorrhage (20% of estimated blood volume), retransfusion, and additional stepwise volume loading until cardiac output did not increase further (n = 5). A separate control group (n = 7) was subjected to bleeding, retransfusion, and volume expansion without endotoxemia. Systemic hemodynamics were measured at baseline and after each intervention, and PPV was calculated offline. Prediction of fluid-challenge-induced stroke volume increase by PPV was analyzed using receiver operating characteristic (ROC) curves.ResultsSixty-eight volume challenges were performed in endotoxemic animals (22 before and 46 after hemorrhage), and 51 volume challenges in the controls. Endotoxin infusion resulted in an acute increase in pulmonary artery and central venous pressure and a decrease in stroke volume (all P < 0.05). In endotoxemia, 68% of volume challenges before hemorrhage increased the stroke volume by > 10%, but PPV did not predict fluid responsiveness (area under the ROC curve = 0.604, P = 0.461). After hemorrhage in endotoxemia, stroke volume increased in 48% and the predictive value of PPV improved (area under the ROC curve for PPV = 0.699, P = 0.021). In controls after hemorrhage, stroke volume increased in 67% of volume challenges and PPV was a predictor of fluid responsiveness (area under the ROC curve = 0.790, P = 0.001).ConclusionsFluid responsiveness cannot be predicted with PPV during acute pulmonary hypertension in porcine endotoxemia. Even following severe hemorrhage during endotoxemia, the predictive value of PPV is marginal.

Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep.

Adrenomedullin (AM) is a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular homeostasis. In view of the circulatory failure in sepsis, it is still debated as to whether the occurrence of vascular hyporeactivity against AM plays a causative or protective role. This study was designed as a prospective, controlled trial to elucidate the hemodynamic response following a titrating infusion of human AM in healthy and endotoxemic sheep. ANOVA demonstrated that AM infusion produced hypotension and tachycardia, and increased cardiac index in a dose-dependent manner, both in healthy and endotoxemic sheep. In addition, AM application reduced pulmonary vascular resistance index in ovine endotoxemia (P=0.02). These findings confirm that AM produces a hyperdynamic circulation, in the presence and absence of systemic inflammation. Further, exogenous AM could possibly be a useful adjunct in the common setting of sepsis-associated pulmonary hypertension.

Continuous thoracic epidural anesthesia improves gut mucosal microcirculation in rats with sepsis.

Microcirculatory dysfunction contributes significantly to tissue hypoxia and multiple organ failure in sepsis. Ischemia of the gut and intestinal hypoxia are especially relevant for the evolution of sepsis because the mucosal barrier function may be impaired, leading to translocation of bacteria and toxins. Because sympathetic blockade enhances intestinal perfusion under physiologic conditions, we hypothesized that thoracic epidural anesthesia (TEA) may attenuate microcirculatory perturbations during sepsis. The present study was designed as a prospective and controlled laboratory experiment to assess the effects of continuous TEA on the mucosal microcirculation in a cecal ligation and perforation model of sepsis in rats. Anesthetized Sprague-Dawley rats underwent laparotomy and cecal ligation and perforation to induce sepsis. Subsequently, either bupivacaine 0.125% (n = 10) or isotonic sodium chloride solution (n = 9) was continuously infused via the thoracic epidural catheter for 24 h. In addition, a sham laparotomy was carried out in eight animals. Intravital videomicroscopy was then performed on six to ten villi of ileum mucosa. The capillary density was measured as areas encircled by perfused capillaries, that is, intercapillary areas. The TEA accomplished recruitment of microcirculatory units in the intestinal mucosa by decreasing total intercapillary areas (1,317 ± 403 vs. 1,001 ± 236 μm2) and continuously perfused intercapillary areas (1,937 ± 512 vs. 1,311 ± 678 μm2, each P < 0.05). Notably, TEA did not impair systemic hemodynamic variables beyond the changes caused by sepsis itself. Therefore, sympathetic blockade may represent a therapeutic option to treat impaired microcirculation in the gut mucosa resulting from sepsis. Additional studies are warranted to assess the microcirculatory effects of sympathetic blockade on other splanchnic organs in systemic inflammation.

Delayed Onset of Malignant Hyperthermia in Desflurane Anesthesia

IMPLICATIONS Animal-experimental studies demonstrate desfluranes trigger effect for malignant hyperthermia (MH). In contrast to other anesthetics, the time interval from exposure to the occurrence of symptoms is much longer with desflurane. This case report focuses on MH induced by desflurane alone.

Thoracic epidural anesthesia reverses sepsis-induced hepatic hyperperfusion and reduces leukocyte adhesion in septic rats

IntroductionLiver dysfunction is a common feature of severe sepsis and is associated with a poor outcome. Both liver perfusion and hepatic inflammatory response in sepsis might be affected by sympathetic nerve activity. However, the effects of thoracic epidural anesthesia (TEA), which is associated with regional sympathetic block, on septic liver injury are unknown. Therefore, we investigated hepatic microcirculation and inflammatory response during TEA in septic rats.MethodsForty-five male Sprague-Dawley-rats were instrumented with thoracic epidural catheters and randomized to receive a sham procedure (Sham), cecal ligation and puncture (CLP) without epidural anesthesia (Sepsis) and CLP with epidural infusion of 15 ul/h bupivacaine 0.5% (Sepsis + TEA). All animals received 2 ml/100 g/h NaCl 0.9%. In 24 (n = 8 in each group) rats, sinusoidal diameter, loss of sinusoidal perfusion and sinusoidal blood flow as well as temporary and permanent leukocyte adhesion to sinusoidal and venolar endothelium were recorded by intravital microscopy after 24 hours. In 21 (n = 7 in each group) separate rats, cardiac output was measured by thermodilution. Blood pressure, heart rate, serum transaminase activity, serum TNF-alpha concentration and histologic signs of tissue injury were recorded.ResultsWhereas cardiac output remained constant in all groups, sinusoidal blood flow increased in the Sepsis group and was normalized in rats subjected to sepsis and TEA. Sepsis-induced sinusoidal vasoconstriction was not ameliorated by TEA. In the Sepsis + TEA group, the increase in temporary venolar leukocyte adherence was blunted. In contrast to this, sinusoidal leukocyte adherence was not ameliorated in the Sepsis + TEA group. Sepsis-related release of TNF-alpha and liver tissue injury were not affected by Sepsis + TEA.ConclusionsThis study demonstrates that TEA reverses sepsis-induced alterations in hepatic perfusion and ameliorates hepatic leukocyte recruitment in sepsis.

Short-term effects of glipizide (an adenosine triphosphate-sensitive potassium channel inhibitor) on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep.

ABSTRACT In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific KATP channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific KATP channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng·kg−1·min−1) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 ± 3 mmHg vs. 101 ± 2 mmHg, P < 0.05) and sheep with endotoxemia (86 ± 3 mmHg vs. 93 ± 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.

Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia

Since arginine vasopressin (AVP)may reduce cardiacout-put and, in proportion, oxygen delivery, we studied the efficacy of dopexamine (DPX) as an adjunct to AVP infusion. After1 h of continuous AVP infusion (0.04U/min)in healthy sheep(n = 7),DPX was additionally administered in incremental doses (1, 5, and 10 μg · kg−1 · min−1; each dose for 30 min). After a 24-h period of recovery, endotoxin was continuously infused in the same sheep to induce and maintain a hypotensive/hyperdynamic circulation. After 16 h of endotoxemia, AVP and DPX were given as described previously. AVP infusion increase dsystemic vascular resistance index and decreased cardiac index in both healthy and endotoxemic conditions (P < 0.001 each). This was accompanied by an augmented pulmonary vascular resistance index in endotoxemia (159 ± 13 dynes · cm−5 · m−2 versus 202 ± 16 dynes · cm−5 · m−2) and a decrease in oxygen delivery index (health: 842 ± 66 mL · min−2 · m−2 versus 475 ± 38 mL · min−2 · m−2; endotoxemia: 1073 ± 49 mL · min−2 · m−2 versus 613 ± 44 mL · min−2 · m−2) and mixed venous oxygen content (health: 63% ±2% versus 47% ± 2%; endotoxemia: 68% ± 2% versus 51% ± 3%; P < 0.001 each). Small doses of DPX (1 and 5 μg · kg−1 · min−1) improved not only the AVP-associated depressions in cardiac index, oxygen delivery index, and mixed venous oxygen content, but also the pulmonary vasopressive effect in both groups. While large-dose DPX (10 μg · kg−1 · min−1) also reduced mean pulmonary arterial pressure in endotoxemia (27 ± 1 mm Hg versus 23 ± 1 mm Hg; P < 0.05 versus baseline), mean arterial blood pressure decreased (105 ± 4 mm Hg versus 80 ± 3 mm Hg) and heart rate increased (84 ± 4 bpm versus 136 ± 9 bpm; P < 0.001 versus AVP alone), thereby limiting its therapeutic use.

Effects of thoracic epidural anesthesia on hemodynamics and global oxygen transport in ovine endotoxemia.

ABSTRACT Besides providing effective analgesia, thoracic epidural anesthesia (TEA) has been shown to decrease perioperative morbidity and mortality. Because of its vasodilatory properties in association with the sympathetic blockade, however, TEA may potentially aggravate cardiovascular dysfunctions resulting from sepsis and systemic inflammatory response syndrome. The objective of the present study was to assess the effects of TEA on hemodynamics, global oxygen transport, and renal function in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 18), Salmonella typhosa endotoxin was centrally infused at incremental doses to induce and maintain a hypotensive-hypodynamic circulation using an established protocol. The animals were then randomly assigned to one of two groups. In the treatment group, continuous TEA was initiated with 0.1 mL·kg−1 of 0.125% bupivacaine at the onset of endotoxemia and maintained with 0.1 mL·kg−1·h−1. In the control group, the same amount of isotonic sodium chloride solution was injected through the epidural catheter. In the animals surviving the entire experiment (n = 7 per group), cardiac index and mean arterial pressure decreased in a dose-dependent manner during endotoxin infusion. In the TEA group, neither systemic hemodynamics nor global oxygen transport were impaired beyond the changes caused by endotoxemia itself. Urinary output was increased in the TEA group as compared with the control group (P < 0.05). In this model of endotoxic shock, TEA improved renal perfusion without affecting cardiopulmonary hemodynamics and global oxygen transport.

Endogenous carbon monoxide production correlates weakly with severity of acute illness

Background and objective: The enzyme haeme oxygenase‐1 is highly inducible by oxidative agents. Its product carbon monoxide is thought to exert anti‐inflammatory properties. We recently showed, that critically ill patients produce higher amounts of carbon monoxide compared to healthy controls. In the present study we compare endogenous carbon monoxide production with the severity of illness of intensive care unit patients. Methods: Exhaled carbon monoxide concentration was measured in 95 mechanically ventilated, critically ill patients (mean age ± SD, 59.5 ± 15.7) on a carbon monoxide monitor. Measurements were taken every hour for 24 h in each patient. Data were analysed using Mann‐Whitney rank sum test. Correlation analysis was performed with the Spearmans rank order correlation. Results: Carbon monoxide production correlated weakly with the multiple organ dysfunction score (R = 0.27; P = 0.009). Patients suffering from cardiac disease (median 22.5, interquartile range 16.2‐27.4 μL kg−1 h−1 vs. median 18.2, interquartile range 14.2‐21.8 μL kg−1 h−1, P = 0.008) and critically ill patients undergoing dialysis (median 25.0, interquartile range 21.4‐30.2 μL kg−1 h−1, vs. median 19.4, interquartile range 14.7‐23.3 μL kg−1 h−1, P = 0.004) produced significantly higher amounts of carbon monoxide compared to critically ill controls. Conclusion: The findings suggest that endogenous carbon monoxide production might reflect the severity of acute organ dysfunction.