Katrin Bröking

Continuous versus bolus infusion of terlipressin in ovine endotoxemia.

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng·kg−1·min−1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Role of adenosine triphosphate-sensitive potassium channel inhibition in shock states: physiology and clinical implications.

Shock states are associated with an impaired tissue oxygen supply-demand relationship and perturbations within the microcirculation, leading to global tissue hypoxia, finally resulting in multiple-organ failure or even death. Two of the most frequent causes of shock are acute hemorrhage and sepsis. Although the origin and the pathophysiology of hemorrhagic and septic shock are basically different, the involvement of adenosine triphosphate-sensitive potassium (KATP) channels, as an important regulator of vascular smooth muscles tone, plays a pivotal role under both conditions. Because the excessive activation of vascular KATP channels is a major cause of arterial hypotension and vascular hyporesponsiveness to catecholamines, the pharmacological inhibition of KATP channels may represent a goal-directed therapeutic option to stabilize the hemodynamic situation in shock states. Despite promising results of preclinical studies, the efficacy of this innovative therapeutic approach remains to be confirmed in the clinical setting. The differences in the species, the comorbidity, and the difficulty in determining the exact onset of shock in clinical practice and, thus, any duration-related alterations in vascular responses and KATP channel activation may explain the discrepancy between the results obtained from experimental and clinical studies. Currently, two of the most relevant problems related to effective KATP blockade in shock states are represented by (1) the dose itself (benefit-risk ratio) and (2) the route of administration (oral vs. i.v.). This review article critically elucidates the published in vivo studies on the role of KATP channel inhibition in both described shock forms and discusses the advantages and the potential pitfalls related to the treatment of human shock states.

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.

Employing dobutamine as a useful agent to reverse the terlipressin-linked impairments in cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep

Although arginine vasopressin and terlipressin have been identified as useful nonadrenergic agents to increase systemic blood pressure in catchecholamine-resistant septic shock, the impairments in cardiac index (CI) and global oxygen transport may limit their clinical applicability. The present study was designed as a prospective controlled laboratory experiment to investigate the effects of dobutamine as an adjunct to terlipressin infusion on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Nine adult ewes were instrumented for chronic study using an established protocol. After a baseline measurement in the healthy state had been performed, 1 mg terlipressin was given as bolus infusion. Thirty minutes later, dobutamine was continuously infused at incremental doses (2 and 5 &mgr;g·kg−1·min−1, each for 1 h). After 24 h of recovery, a hypotensive-hyperdynamic circulation was induced and maintained by a continuous infusion of Salmonella typhosa endotoxin (10 ng·kg−1·min−1). After 16 h of endotoxemia, the six surviving sheep received terlipressin and dobutamine according to the same protocol that was used in healthy sheep. Compared with baseline, terlipressin infusion was associated with a significant increase in MAP that, however, occurred at the expense of a compromised CI, oxygen delivery index (DO2I), and mixed venous oxygen saturation (SvO2, each P < 0.05). Dobutamine infusion was followed by a dose-dependent increase in CI, DO2I, and SvO2 in both health and endotoxemia (each P < 0.05). Although the higher dosage of dobutamine exerted favorable effects, such as a decrease in pulmonary vascular resistance index (P < 0.05), the associated onset of tachycardia (P < 0.05) and arterial hypotension (P < 0.05) may limit its therapeutic use under septic conditions. This study provides evidence that dobutamine in a dosage of 2 &mgr;g·kg−1·min−1 is useful to reverse the terlipressin-linked depressions in CI, DO2I and SvO2 in ovine endotoxemia without obvious side effects.

Rolle von Levosimendan in der intensivmedizinischen Behandlung des myokardialen Pumpversagens

ZusammenfassungDer „Kalzium-Sensitizer“ Levosimendan steht aktuell im Blickpunkt der intensivmedizinischen Forschung, da er den klassischen Inotropika bei der Therapie der akut dekompensierten Herzinsuffizienz möglicherweise überlegen ist. Seine Wirkung beruht im Wesentlichen auf drei Mechanismen: 1) positive Inotropie durch die Sensibilisierung der kardialen Myofilamente gegenüber Kalziumionen, 2) Vasodilatation durch die Aktivierung adenosintriphosphatsensitiver Kaliumkanäle und 3) Hemmung der Phosphodiesterase-III. In zahlreichen experimentellen und klinischen Untersuchungen sind weitere potenzielle Indikationen für Levosimendan nachgewiesen worden: Kardioprotektion während einer Ischämie, kardiogener Schock, septische Kardiomyopathie und pulmonaler Hypertonus. Dieser Übersichtsartikel stellt Pharmakologie, Wirkmechanismen und mögliche Risiken von Levosimendan unter Berücksichtigung der aktuellen Studienlage kritisch dar.AbstractLevosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.

Dobutamine reverses the vasopressin-associated impairment in cardiac index and systemic oxygen supply in ovine endotoxemia

IntroductionArginine vasopressin (AVP) is increasingly used to treat sepsis-related vasodilation and to decrease catecholamine requirements. However, AVP infusion may be associated with a marked decrease in systemic blood flow and oxygen transport. The purpose of the present study was to evaluate whether dobutamine may be titrated to reverse the AVP-related decrease in cardiac index (CI) and systemic oxygen delivery index (DO2I) in an established model of ovine endotoxemia.MethodsTwenty-four adult ewes were chronically instrumented to determine cardiopulmonary hemodynamics and global oxygen transport. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation and death of five sheep. After 16 hours of endotoxemia, the surviving ewes (n = 19; weight 35.6 ± 1.5 kg (mean ± SEM)) were randomized to receive either AVP (0.04 Umin-1) and dobutamine (n = 8) or the vehicle (normal saline; n = 6) and compared with a third group treated with AVP infusion alone (n = 5). Dobutamine infusion was started at an initial rate of 2 μg kg-1min-1 and was increased to 5 and 10 μg kg-1 min-1 after 30 and 60 minutes, respectively.ResultsAVP infusion increased mean arterial pressure (MAP) and systemic vascular resistance index at the expense of a markedly decreased CI (4.1 ± 0.5 versus 8.2 ± 0.3 l min-1 m-2), DO2I (577 ± 68 versus 1,150 ± 50 ml min-1 m-2) and mixed-venous oxygen saturation (SvO2; 54.5 ± 1.8% versus 69.4 ± 1.0%; all p < 0.001 versus control). Dobutamine dose-dependently reversed the decrease in CI (8.8 ± 0.7 l min-1 m-2 versus 4.4 ± 0.5 l min-1 m-2), DO2I (1323 ± 102 versus 633 ± 61 ml min-1 m-2) and SvO2 (72.2 ± 1.7% versus 56.5 ± 2.0%, all p < 0.001 at dobutamine 10 μg kg-1 min-1 versus AVP group) and further increased MAP.ConclusionThis study provides evidence that dobutamine is a useful agent for reversing the AVP-associated impairment in systemic blood flow and global oxygen transport.

Continuously infused glipizide reverses the hyperdynamic circulation in ovine endotoxemia.

In advanced sepsis, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Although activation of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, previous studies demonstrated only a transient increase in mean arterial pressure (MAP) after bolus administration of KATP channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea glipizide, a KATP channel inhibitor, may reverse cardiovascular dysfunctions in sepsis permanently. Eighteen adult sheep were instrumented for chronic study. After a baseline measurement in healthy ewes, endotoxin (Salmonella typhosa, 10 ng kg−1 min−1) was continuously infused for 19 h. After 16 h of endotoxemia, the surviving sheep (n = 14) were randomly assigned to be treated with either glipizide (5 mg/kg, followed by a continuous infusion of 8 mg kg−1 h−1) or placebo (normal saline; each n = 7). Measurements of cardiopulmonary hemodynamics, global oxygen transport, acid-base status, and urine output were performed in the healthy state, after 16 h of endotoxemia, and during 3 h of glipizide infusion. Continuous infusion of glipizide reversed the endotoxin-induced hyperdynamic circulation, as indicated by significant increases in MAP and systemic vascular resistance index, as well as decreases in cardiac index and heart rate (P < 0.001 each). In addition, glipizide increased urine output as compared with untreated controls (P < 0.001). The anticipated decrease in glucose plasma levels was prevented by infusion of glucose 5%. From these results, we conclude that continuous glipizide infusion may represent a useful therapeutic option in the treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Role of Levosimendan in intensive care treatment of myocardial insufficiency

ZusammenfassungDer „Kalzium-Sensitizer“ Levosimendan steht aktuell im Blickpunkt der intensivmedizinischen Forschung, da er den klassischen Inotropika bei der Therapie der akut dekompensierten Herzinsuffizienz möglicherweise überlegen ist. Seine Wirkung beruht im Wesentlichen auf drei Mechanismen: 1) positive Inotropie durch die Sensibilisierung der kardialen Myofilamente gegenüber Kalziumionen, 2) Vasodilatation durch die Aktivierung adenosintriphosphatsensitiver Kaliumkanäle und 3) Hemmung der Phosphodiesterase-III. In zahlreichen experimentellen und klinischen Untersuchungen sind weitere potenzielle Indikationen für Levosimendan nachgewiesen worden: Kardioprotektion während einer Ischämie, kardiogener Schock, septische Kardiomyopathie und pulmonaler Hypertonus. Dieser Übersichtsartikel stellt Pharmakologie, Wirkmechanismen und mögliche Risiken von Levosimendan unter Berücksichtigung der aktuellen Studienlage kritisch dar.AbstractLevosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.

Sleep Disturbances after Posterior Scoliosis Surgery with an Intraoperative Wake-up Test Using Remifentanil

Background:The intraoperative wake-up test is a standard procedure for early recognition of neurologic complications after posterior correction of idiopathic scoliosis. In this prospective, single-blinded cohort study, the impact of the wake-up test and the opioid used for anesthesia on the quality of the patients’ sleep after scoliosis surgery was investigated up to 12 months postoperatively. Methods:Patients were classified into three groups: posterior instrumentation with wake-up test using remifentanil, anterior instrumentation without wake-up test using sufentanil, and posterior instrumentation with wake-up test using sufentanil. The quality of sleep was assessed using the Pittsburgh Sleep Quality Index questionnaire preoperatively as well as 3, 6, and 12 months postoperatively. In addition, data were collected on patients’ age, weight, and sex, as well as the duration of the operation and anesthesia, amount of blood loss, specific opioid dosages, and wake-up test times. Statistical analysis was conducted using the Mann–Whitney, Kruskal–Wallis, and Wilcoxon tests. Results:There were no differences between groups with regard to baseline characteristics. No explicit recall was assessed through all groups. At 3 and 6 months postoperatively, the sleep quality in the posterior–remifentanil group was significantly poorer than preoperatively and compared with the anterior– and posterior–sufentanil groups. No significant differences in wake-up test times between groups undergoing posterior instrumentation occurred. Conclusions:This study suggests that patients undergoing scoliosis surgery with an intraoperative wake-up test using remifentanil had impaired sleep quality that lasted up to 6 months postoperatively. No deterioration in sleep quality was observed with sufentanil. Large randomized trials are now needed to confirm these preliminary results.

Hemodynamic effects of titrated norepinephrine in healthy versus endotoxemic sheep.

In patients with sepsis and systemic inflammatory response syndrome, hemodynamic support is often complicated by a vascular hyporesponsiveness to exogenously administered norepinephrine. Although norepinephrine tachyphylaxis represents a significant clinical problem, the relationship between norepinephrine dosages and mean arterial pressure (MAP) in the presence of systemic inflammation is still not fully understood. This study was, therefore, designed as a prospective, controlled laboratory trial to elucidate the hemodynamic response to incremental norepinephrine doses in healthy and endotoxemic sheep. ANOVA demonstrated that a significantly higher mean infusion rate of norepinephrine was needed to increase MAP by 20 mmHg in endotoxemic versus healthy control sheep (P = 0.007). Whereas the goal-MAP was reached in 100% of healthy controls, it was achieved in only 80% during endotoxemia. Cardiac index increased significantly in healthy, but not in endotoxemic, sheep. Our findings confirm the presence of vascular hyporesponsiveness to norepinephrine in endotoxemia. In addition, this study demonstrates that the presence of systemic inflammation leads to an early hyporesponsiveness against norepinephrine which was caused by a drug-independent mechanism rather than a tachyphylaxis due to long-term administration of norepinephrine.