O. Picker

Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals

Changes in plasma nitrite concentration in the human forearm circulation have recently been shown to reflect acute changes in endothelial nitric oxide synthase (eNOS)-activity. Whether basal plasma nitrite is a general marker of constitutive NOS-activity in vivo is yet unclear. Due to the rapid metabolism of nitrite in blood and the difficulties in its analytical determination literature data on levels of nitrite in mammals are largely inconsistent. We hypothesized that constitutive NOS-activity in the circulatory system is relatively uniform throughout the mammalian kingdom. If true, this should result in comparable systemic plasma nitrite levels in different species. Using three different analytical approaches we determined plasma nitrite concentration to be in a nanomolar range in a variety of species: humans (305 +/- 23 nmol/l), monkeys (367 +/- 62 nmol/l), minipigs (319 +/- 24 nmol/l), dogs (305 +/- 50 nmol/l), rabbits (502 +/- 21 nmol/l), guinea pigs (412 +/- 44 nmol/l), rats (191 +/- 43 nmol/l), and mice (457 +/- 51 nmol/l). Application of different NOS-inhibitors in humans, minipigs, and dogs decreased NOS-activity and thereby increased vascular resistance. This was accompanied by a significant, up to 80%, decrease in plasma nitrite concentration. A comparison of plasma nitrite concentrations between eNOS(-/-) and NOS-inhibited wild-type mice revealed that 70 +/- 5% of plasma nitrite is derived from eNOS. These results provide evidence for a uniform constitutive vascular NOS-activity across mammalian species.

Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs.

Objective:The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (&mgr;Hbo2) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (&U1E0A;o2) and/or oxygen consumption (&OV0312;o2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. Design:Laboratory experiment. Setting:University animal research laboratory of experimental anesthesiology. Subjects:Chronically instrumented dogs with flow probes for cardiac output measurement. Interventions:Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10 &mgr;g·kg−1, followed by four infusion steps: 0.125–1.0 &mgr;g·kg−1·min−1), milrinone (5.0 &mgr;g·kg−1, followed by 1.25–10 &mgr;g·kg−1·min−1), or dobutamine (2.5–10.0 &mgr;g·kg−1·min−1). Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 mL·kg−1). Measurements and Main Results:We measured &mgr;Hbo2 (reflectance spectrophotometry), &U1E0A;o2, &OV0312;o2, and systemic hemodynamics. Levosimendan significantly increased &mgr;Hbo2 from baseline (∼55% for all groups) to 64 ± 4% and further to 69 ± 2% with volume challenge (mean ± sem). At the systemic level, levosimendan alone only slightly increased &U1E0A;o2 at a stable &OV0312;o2. Milrinone elicited similar systemic effects (&U1E0A;o2, &OV0312;o2, hemodynamics) but failed to increase &mgr;Hbo2. Dobutamine, conversely, increased &mgr;Hbo2 to a similar extent as levosimendan; however, this was accompanied by marked increases in &U1E0A;o2 and &OV0312;o2. The gastric mucosa selectivity of these interventions, expressed as slope of the &mgr;Hbo2/&U1E0A;o2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). Conclusions:Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectively (i.e., at only moderately increased &U1E0A;o2 and stable &OV0312;o2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.

Endocrine and psychological stress responses in a simulated emergency situation

BACKGROUND Several studies have assessed the effects of training using patient simulation systems on medical skills. However, endocrine and psychological stress responses in a patient simulation situation and the relationship between stress reactivity and medical performance have been studied rarely, so far. METHODS Medical students (18 males and 16 females) who had completed at least two months anaesthesiology training participated in the study. In a counterbalanced cross-over design they were subjected to three conditions: rest, laboratory stress (LS; public speaking), and simulated emergency situation (SIM; myocardial ischemia and ventricular fibrillation). Salivary cortisol and psychological responses (visual analogue scales, VAS) were assessed every 15 min from 15 min prior to until 60 min after intervention. Differences between stress and rest conditions were analysed. Medical performance was assessed according to the European Resuscitation Councils Guidelines for Resuscitation. RESULTS As compared to rest, cortisol increased significantly in both stress conditions with different time courses in LS and SIM. Psychological responses in SIM exceeded those in LS. Cortisol increase in LS (r(s)=.486; p=.019) but not in SIM (r(s)=.106; p=.631) correlated significantly with medical performance. DISCUSSION A simulated emergency situation is a profound stressor. The positive relationship between endocrine stress responsiveness in a standard laboratory situation and medical performance in a simulated emergency situation indicates that high stress responsiveness might be a predictor of good performance. At the same time the high stress response might counteract educational efforts associated with training using high-fidelity patient simulation.

Dopexamine but not dopamine increases gastric mucosal oxygenation during mechanical ventilation in dogs

Objective To compare the effects of dopamine and dopexamine on gastric mucosal oxygenation during mechanical ventilation without and with positive end-expiratory airway pressure (PEEP) and after compensation of the PEEP-induced hemodynamic suppression. Design Randomized controlled animal study. Setting University research department of experimental anesthesiology. Subjects Ten anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. Interventions On different days, the dogs randomly received dopamine (2.5 and 5.0 &mgr;g·kg−1·min−1, n = 10), dopexamine (0.5 and 1.0 &mgr;g·kg−1·min−1) without (n = 8) or with pretreatment with a selective &bgr;2-adrenoceptor antagonist (ICI 118,551, n = 7), or saline (control, n = 7). To simulate common clinical situations, these interventions were performed during different ventilation modes: during mechanical ventilation without and with high levels of PEEP, and after compensation of the PEEP-induced systemic hemodynamic suppression by titrated volume resuscitation with hydroxyethyl starch. Measurements and Main Results We continuously measured microvascular hemoglobin saturation (&mgr;Hbo2) by light-guide spectrophotometry in the gastric mucosa. Dopexamine, but not dopamine, significantly increased gastric mucosal &mgr;Hbo2 by about 20%, regardless of the dose and the ventilation mode. Both catecholamines dose-dependently increased cardiac output and oxygen delivery by up to 75% without effects on systemic oxygen saturation. The effects of dopexamine on &mgr;Hbo2 as well as on cardiac output and oxygen delivery were prevented by selective &bgr;2-adrenoceptor-blockade. Conclusions Dopexamine but not dopamine improved gastric mucosal oxygenation in dogs. This effect was independent of the dosage and the ventilation mode. Thus, dopexamine may reverse a decrease in splanchnic oxygenation induced by ventilation with PEEP. The dopexamine-induced increase in gastric mucosal oxygenation was mediated by &bgr;2-adrenoceptors, which explains the superior effects of dopexamine to dopamine on &mgr;Hbo2. The regional effects of both catecholamines were not mirrored by systemic hemodynamics.

Accuracy and reproducibility of long-term implanted transit-time ultrasound flow probes in dogs

Objective: To assess the accuracy and reproducibility of long-term implanted ultrasound transit-time flow probes for measuring cardiac output. Design: Prospective animal study. Settings: Animal research laboratory in a university department. Animals: Eleven anaesthetised dogs, 24–34 kg. Measurements and results: Flow probes (16–24 mm S-series, Transonic) were implanted around the pulmonary artery for a mean duration of 22 months (range 6–47 months). Comparisons (n = 147) were made between cardiac output thus obtained and that measured by the direct Fick principle using oxygen uptake (Deltatrac II Metabolic Monitor) and the arterial to mixed venous oxygen content difference measured by a galvanic cell (Lex-O2-Con-TL). Measurements were made either during baseline conditions or during pharmacologically altered cardiac output (range 22–180 ml · kg–1· min–1). Regardless of the intervention, the two methods yielded the same results in half of the dogs. In the others, however, cardiac output was underestimated by the flow probes by up to 38 % (probably because of non-perpendicular position of the probe towards the vessel). This difference was constant for the whole range of cardiac output studied and remained constant over the entire observation period for each individual dog, so that a correction factor was used. Thereafter, the mean difference between the two methods was –1.1 ml · kg–1· min–1 with a precision (SD) of 14.2 ml · kg–1· min–1 for all experiments. Conclusions: After in vivo calibration, ultrasound transit-time flow probes measure cardiac output precisely for several years, regardless of the intervention.

Hypercapnic Acidosis Preserves Gastric Mucosal Microvascular Oxygen Saturation in a Canine Model of Hemorrhage.

The authors aimed to clarify the effects of hypercapnic acidosis and its timing on gastric mucosal oxygenation in a canine model of hemorrhage. This was designed as a prospective, controlled, randomized animal study set in a university research laboratory. Five chronically instrumented dogs were used. Dogs were repeatedly anesthetized (sevoflurane 1.5 MAC), mechanically ventilated, and randomized to each of the following protocols. In a control series (CON), animals underwent hemorrhage during normoventilation (etCO2, 35 mmHg). In a second series, hypercapnia (etCO2, 70 mmHg) was applied before onset of hemorrhage (prophylactic hypercapnia), whereas in the third series, hypercapnia was applied after hemorrhage (therapeutic hypercapnia, THE). Microvascular oxygenation (&mgr;HbO2) of the gastric mucosa was continuously assessed by tissue reflectance spectrophotometry. Cardiac output was continuously measured, and oxygen delivery (DO2) was intermittently calculated. In CON, hemorrhage decreased DO2 (from 11 ± 3 mL·kg−1·min−1 to 8 ± 2 mL·kg−1·min−1 and 8 ± 2 mL·kg−1·min−1 after 30 and 75 min, respectively) and &mgr;HbO2 (from 57% ± 4% to 43% ± 11% and 50% ± 11%). Prophylactic hypercapnia attenuated the effects of hemorrhage on DO2 (12 ± 2 mL·kg−1·min−1 to 10 ± 2 mL·kg−1·min−1 and 11 ± 2 mL·kg−1·min−1) and preserved &mgr;HbO2 (52% ± 3% to 47% ± 5% and 57% ± 3%). Initial effects of hemorrhage in THE were comparable to CON (DO2 from 11 ± 2 mL·kg−1·min−1 to 8 ± 1 mL·kg−1·min−1; &mgr;HbO2 from 56% ± 7% to 43% ± 9%), but after application of hypercapnic acidosis, baseline levels were restored (DO2 10 ± 3 mL·kg−1·min−1; &mgr;HbO2 52% ± 14%). Hypercapnic acidosis applied before or after hemorrhage (THE) preserves microvascular mucosal oxygenation. If these experimental findings may be transferred to the clinical setting, deliberate hypercapnic acidosis could serve to augment oxygenation of the splanchnic region in states of compromised circulation, e.g., hemorrhage.

Desflurane increases heart rate independent of sympathetic activity in dogs

Background and objective: Desflurane has been shown to increase sympathetic activity and heart rate (HR) in a concentration-dependent manner. Nevertheless, desflurane, like all other volatile anaesthetics, increased HR in parallel to vagal inhibition in a previous study. Therefore, our hypothesis is that desflurane elicits tachycardia by vagal inhibition rather than by activation of the sympathetic nervous system. Methods: Six dogs were studied awake and during desflurane anaesthesia (1 and 2 MAC) alone, after pretreatment with propranolol (2 mg kg−1 followed by 1 mg kg−1 h−1), or after pretreatment with atropine (0.1 mg kg−1 followed by 0.05 mg kg−1 h−1). The effects on HR and HR variability were compared by an analysis of variance (P < 0.05). HR variability was analysed in the frequency domain as power in the high-(0.15-0.5 Hz, vagal activity) and low-frequency range (0.04-0.15 Hz, sympathetic and vagal activity). Results: HR increased during 2 MAC of desflurane from about 60 (awake) to 118 ± 2 beats min−1 (mean ± SEM) in controls and to 106 ± 3 beats min−1 in dogs pre-treated with propranolol. In contrast, pretreatment with atropine increased HR from 64 ± 2 to 147 ± 5 beats min−1 (awake) and HR decreased to 120 ± 5 beats min−1 after adding desflurane. High-frequency power correlated inversely with HR (r2 = 0.95/0.93) during desflurane alone and in the presence of β-adrenoceptor blockade, with no significant difference between regression lines. There was no correlation between these variables during atropine/desflurane. Conclusions: The increase in HR elicited by desflurane mainly results from vagal inhibition and not from sympathetic activation.

Sevoflurane and propofol anaesthesia differentially modulate the effects of epinephrine and norepinephrine on microcirculatory gastric mucosal oxygenation

BACKGROUND Adequate gastrointestinal mucosal oxygenation is regarded to be crucial in the prevention and therapy of critical illness. Epinephrine and norepinephrine are used for perioperative haemodynamic support. However, their per se effects on gastromucosal haemoglobin oxygenation (μHbO(2)) remain unclear. Moreover, respective effects of epinephrine and norepinephrine may be affected by the type of underlying anaesthesia. Thus, we studied the effects of epinephrine and norepinephrine during anaesthesia with sevoflurane or propofol on regional gastromucosal μHbO(2) and systemic O(2)-derived variables. METHODS In a double-randomized cross-over study, chronically instrumented dogs (n=6 per group) were anaesthetized randomly with sevoflurane or propofol, ventilated, and then randomly received either epinephrine or norepinephrine (0, 0.05, 0.1, and 0.2 µg kg(-1) min(-1)). We measured gastromucosal μHbO(2), systemic haemodynamics, and O(2)-derived variables. RESULTS During sevoflurane anaesthesia, norepinephrine markedly increased μHbO(2) (P<0.0001) and systemic oxygen transport (DO(2)) (P=0.0006). In contrast, epinephrine failed to increase μHbO(2), despite doubling DO(2) (P=0.0002). During propofol anaesthesia, in contrast to sevoflurane, neither epinephrine nor norepinephrine affected μHbO(2), although epinephrine, but not norepinephrine, again resulted in markedly increased DO(2) (P<0.0001). CONCLUSIONS The effects of epinephrine and norepinephrine depended on the type of anaesthesia. In addition, regional effects (i.e. μHbO(2)) were not predictable from systemic effects (i.e. DO(2)).

Endogenous Endothelin and Vasopressin Support Blood Pressure During Epidural Anesthesia in Conscious Dogs

We studied whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during high epidural anesthesia when efferent sympathetic drive is diminished. On different days, six awake dogs underwent each of the following five interventions: blockade of vasopressin V1a receptors using [d (CH2)5Tyr(Me2)]AVP, (40 &mgr;g/kg) or endothelin receptors using tezosentan (3 mg/kg followed by 3 mg · kg−1 · h−1) with or without epidural anesthesia (1% lidocaine, intraindividual dose did not differ between experiments), and epidural saline (n = 5). The effects of endothelin- or vasopressin-receptor blockade were analyzed (means ± sem) and compared by an analysis of variance for repeated measures (paired Student’s t-test, &agr;-adjusted, P < 0.05). Vasopressin-receptor blockade decreased blood pressure (10 ± 2 mm Hg) only in the presence of epidural anesthesia, whereas endothelin-receptor blockade reduced blood pressure both in the presence and absence of epidural anesthesia (12 ± 3 versus 10 ± 1 mm Hg). During baseline and each intervention, plasma concentrations of vasopressin and big-endothelin were measured and compared by a Wilcoxon’s rank sum test;P < 0.05. Vasopressin concentrations increased during epidural anesthesia and after additional endothelin receptor blockade, but big-endothelin concentrations remained unchanged during each intervention. We conclude that vasopressin acts as a reserve system, as it stabilizes blood pressure specifically during epidural anesthesia, whereas the unchanged concentrations of big-endothelin indicate that the endothelin system is not specifically activated to support blood pressure during epidural anesthesia.

Fenoldopam--but not dopamine--selectively increases gastric mucosal oxygenation in dogs.

ObjectiveTo compare the effects of fenoldopam and dopamine on gastric mucosal and systemic oxygenation, and to identify the receptors involved. DesignRandomized controlled animal study. SettingUniversity research department of experimental anesthesiology. SubjectsSeven anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. InterventionsOn different days, the dogs received in random order either the selective DA1-agonist fenoldopam (0.1 and 1.0 &mgr;g·kg−1·min−1, with or without DA1-blocker pretreatment), dopamine (2.5 and 5.0 &mgr;g·kg−1·min−1, with or without &agr;1-blocker pretreatment), or saline (control). Measurements and Main ResultsWe continuously measured regional microvascular hemoglobin oxygen saturation (&mgr;HbO2) in gastric mucosa by reflectance spectrophotometry, and systemic oxygen delivery. Fenoldopam increased gastric mucosal &mgr;HbO2 by approximately 20%, and this effect was prevented by selective DA1-receptor blockade. In contrast, dopamine neither alone nor during &agr;1-blockade altered &mgr;HbO2. With respect to systemic measures of oxygen transport, fenoldopam had negligible effects, whereas dopamine (with and without &agr;1-blocker pretreatment) dose-dependently increased cardiac output and systemic oxygen delivery by approximately 30%. ConclusionsFenoldopam dose-dependently increased microvascular oxygenation of the gastric mucosa without changing systemic oxygen transport, i.e., this drug acted selectively on the splanchnic mucosa. The increase in gastric mucosal oxygenation was mediated by DA1-receptors. In contrast, dopamine markedly increased systemic oxygen transport, but did not affect microvascular oxygenation of gastric mucosa. This lacking effect on gastric mucosal oxygenation was not caused by &agr;1-mediated vasoconstriction. The regional effects of both catecholamines could not be deduced from systemic hemodynamics and oxygenation.