Systemic and regional hemodynamic effects of high-dose epinephrine infusion in hypoxic piglets resuscitated with 100% oxygen

Shock and poor regional perfusion are common in asphyxiated neonates. We compared the systemic and regional hemodynamic effects of high-dose epinephrine (E) with those of dopamine combined with low-dose epinephrine (DE) infusions in a neonatal model of hypoxia-reoxygenation. Neonatal piglets (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously monitor systemic arterial pressure (SAP), pulmonary artery pressure, cardiac index (CI), and blood flows at the left common carotid, superior mesenteric, and renal arteries. Either epinephrine (1 microg.kg(-1).min(-1)) or dopamine (10 microg.kg(-1).min(-1)) and epinephrine (0.2 microg.kg(-1).min(-1)) were given for 2 h in hypoxic piglets resuscitated with 100% oxygen (n = 8 per group) in a randomized blinded fashion. Control piglets received hypoxia and reoxygenation but no catecholamine infusion (n = 7). Alveolar hypoxia (PaO2, 33-37 mmHg) caused reduced CI (89-92 vs. 171-186 mL.kg(-1).min(-1) of baseline, P < 0.05), hypotension (SAP, 28-32 mmHg) with pH 7.05 to 7.10, and decreased regional flows. Upon reoxygenation, CI and SAP improved but gradually deteriorated to 131 to 136 mL.kg(-1).min(-1) and 41 to 49 mmHg at 2 h of reoxygenation, respectively. E and DE administration similarly improved CI (167 +/- 60 and 166 +/- 55 vs. 121 +/- 35 mL.kg(-1).min(-1) of controls) and SAP (53 +/- 7 and 56 +/- 10 vs. 39 +/- 8 mmHg of controls), respectively, and the pulmonary vascular resistance (vs. controls, all P < 0.05). Heart rate and pulmonary artery pressure were not different between groups. Systemic oxygen delivery and consumption were increased in E- and DE-treated groups with no difference in extraction ratio between groups. There were no differences in regional blood flows and oxygen delivery between groups. After hyperlactatemia with hypoxia, plasma lactate levels decreased with no difference between groups. Epinephrine given as the sole agent is as effective as dopamine and low-dose epinephrine combined in treating shock and hypotension that follow the resuscitation of hypoxic neonatal piglets, with no reduction in regional perfusion.     

The hemodynamic effects of dobutamine during reoxygenation after hypoxia: a dose-response study in newborn pigs

Asphyxiated neonates usually have myocardial stunning and hypotension and require inotropic support. A randomized controlled study was designed to examine the dose-response effect of dobutamine (5-20 microg x kg(-1) x min(-1)) on systemic and regional circulations and oxygen metabolism in a neonatal swine model of hypoxia/reoxygenation. Thirty-eight anesthetized newborn piglets were acutely instrumented for continuous monitoring of heart rate, systemic and pulmonary arterial pressures, and pulmonary (surrogate for cardiac index), right common carotid, and superior mesenteric and left renal arterial flows. After stabilization, they were exposed to normocapnic alveolar hypoxia (10%-15% oxygen) for 2 h followed by reoxygenation with 100% oxygen for 1 h, then 21% for 3 h. Piglets were block randomized to receive dobutamine infusion (5, 10, or 20 microg x kg(-1) x min(-1)) or saline (control) at 2 to 4 h of reoxygenation (n = 8 each). A nonasphyxiated, sham-operated group was included (n = 6). Blood samples were collected for blood gas analysis, arterial and venous co-oximetry, and plasma lactate concentration determination. At 2-h reoxygenation after hypoxia, there was hypotension (systemic arterial pressure, 27 to 36 mmHg) and myocardial dysfunction (cardiac index from 178-209 to 134-156 mL x kg(-1) x min(-1)). Cardiac index improved significantly with 20 microg x kg(-1) x min(-1) of dobutamine (P < 0.05) and modestly in the treatment groups of 5 and 10 microg x kg(-1) x min(-1) (P < 0.1) (at 120 min, 172 +/- 35, 160 +/- 30, and 158 +/- 56 mL x kg(-1) x min(-1) vs. 119 +/- 33 mL x kg(-1) x min(-1) of controls, respectively), with corresponding increases in stroke volume. Pulmonary vascular resistance was lower in all dobutamine-treated groups (vs. controls, P < 0.05) There were no differences in heart rate, systemic and pulmonary arterial pressures, systemic vascular resistance, and regional flows between groups. The group of 20 mug.kg.min of dobutamine also had higher systemic oxygen delivery (at 120 min, 18 +/- 5 vs. 11 +/- 3 O(2) mL x kg(-1) x min(-1) of controls, P < 0.05) with no significant differences in systemic oxygen consumption and regional oxygen delivery between groups. After the reoxygenation of newborn piglets with severe hypoxia, high dose of dobutamine is effective to treat myocardial stunning and low cardiac output with no significant effect on blood pressure or regional circulation. Further clinical studies are needed to confirm these findings in the human neonate.     

Dose response of intravenous sildenafil on systemic and regional hemodynamics in hypoxic neonatal piglets

In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.     

The hemodynamic effects of dobutamine infusion in the chronically instrumented newborn piglet

OBJECTIVE: To determine the systemic, pulmonary, mesenteric, and renal hemodynamic effects of short and prolonged infusions of dobutamine. DESIGN: Prospective randomized unblinded study. SETTING: University research laboratory. SUBJECTS: Thirteen newborn (1-3 days old) piglets. INTERVENTIONS: Piglets were instrumented and studied 48 hrs later. Fifteen-minute infusions of dobutamine at 5, 10, 20 and 50 microg/ kg x min were randomly given with 15-min rests between the doses. After a 1-hr hiatus, a dose of 10 microg/kg x min was continuously administered for 2 hrs. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary arterial pressures, cardiac index (thermodilution), and superior mesenteric and renal artery flows were measured. Vascular resistance values were calculated. MAIN RESULTS: Fifteen-minute infusions: Dobutamine dose-dependently increased cardiac index with tachycardia but not stroke volume (from 187 +/- 43 to 238 +/- 51 mL/kg x min at baseline and 50 microg/ kg x min, respectively, p < .05; values expressed as mean +/- SD). Systemic, but not pulmonary, vascular resistance decreased, resulting in a significant decrease in systemic to pulmonary arterial pressure ratio (from 3.8 +/- 0.8 at baseline to 3.2 +/- 1.0 at 50 microg/ kg x min). Superior mesenteric and renal flows were not affected. Two-hour infusion at 10 microg/kg x min: Cardiac index progressively increased from 173 +/- 34 to 240 +/- 58 mL/kg x min at baseline and 120 mins, respectively, (p < .05). The initial tachycardia was transient, and stroke volume was significantly increased at 60 mins and thereafter. Although systemic and pulmonary vascular resistance values fell simultaneously, systemic to pulmonary arterial pressure ratio decreased significantly to 3.4 +/- 0.9 at 120 mins from 3.9 +/- 0.7 at baseline. Superior mesenteric and renal artery flows increased significantly with vasodilation after 60 mins. CONCLUSIONS: Short infusions of dobutamine dose-dependently increase cardiac output due to tachycardia, without significant effect on mesenteric and renal blood flows. Prolonged infusion of dobutamine at 10 microg/kg x min progressively increases cardiac output and stroke volume with transient tachycardia, and increases mesenteric and renal blood flows. Caution is required in the treatment of critically ill neonates with dobutamine, which could also reduce systemic to pulmonary arterial pressure ratio.     

Dose-response effects of milrinone on hemodynamics of newborn pigs with hypoxia-reoxygenation

OBJECTIVE: Neonatal asphyxia causes cardiogenic shock and pulmonary hypertension with decreased brain perfusion. We examined the dose-response of milrinone on systemic, pulmonary, and carotid circulations in a model of neonatal hypoxia-reoxygenation. DESIGN AND SETTING: Controlled, block-randomized study in a university research laboratory. SUBJECTS: Mixed breed piglets (1-3 days, 1.5-2.3 kg). INTERVENTIONS: In acutely instrumented piglets normocapnic alveolar hypoxia (10-15% oxygen) was induced for 2 h followed by reoxygenation with 100% oxygen (1 h) then 21% oxygen (3 h). At 2 h of reoxygenation after a volume loading (10 ml/kg) either saline or milrinone (bolus and infusion at 0.25, 0.5, or 0.75 microg/kg per minute) was given for 2 h in a blinded-randomized fashion (n = 7/group). MEASUREMENTS AND RESULTS: All milrinone-treated groups had higher cardiac output and stroke volume than those of saline-treated hypoxic controls, which showed progressive decline in these measurements. At 2 h of infusion plasma milrinone levels were significantly correlated with cardiac output (r = 0.6), which increased from pretreatment value in the group receiving 0.75 microg/kg per minute. Milrinone maintained mean arterial pressure; heart rate and pulmonary arterial pressure did not differ between groups. Milrinone prevented continued increases in systemic and pulmonary vascular resistances after hypoxia-reoxygenation. Milrinone infusion at higher doses increased common carotid flow. Milrinone-treated piglets had increased systemic and carotid oxygen delivery, with no difference in plasma and myocardial lactate levels among groups. CONCLUSIONS: When used to treat shock in newborn piglets with hypoxia-reoxygenation, milrinone improved cardiac output and carotid flow while maintaining systemic blood pressure. Pulmonary hypertension was not aggravated. Further studies are needed to confirm these findings in asphyxiated neonates.     

Dobutamine restores intestinal mucosal blood flow in a porcine model of intra-abdominal hyperpressure

OBJECTIVE: To assess the effects of dopamine and dobutamine administration on the systemic and mesenteric (macro- and microvascular) circulatory disturbances induced by intra-abdominal hyperpressure. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory in a university hospital. SUBJECTS: Twenty-five pigs of either gender, weighing 30-35 kg. INTERVENTIONS: Animals were anesthetized, and their lungs were mechanically ventilated. Pulmonary artery flotation and carotid artery catheters were inserted for hemodynamic monitoring and blood sampling. A perivascular flow probe was placed around the superior mesenteric artery, and a laser Doppler probe was positioned in the lumen of the ileum to measure arterial and intestinal mucosal blood flows, respectively. CO2 was insufflated into the peritoneal cavity to reach an intra-abdominal pressure of 15 mm Hg, and 60 mins later, animals received dopamine (5 microg/kg/min; n = 10), dobutamine (5 microg/kg/min; n = 10), or saline (n = 5) for 30 mins. MEASUREMENTS AND MAIN RESULTS: Peritoneal CO2 insufflation induced significant increases in heart rate, arterial pressure, and systemic vascular resistance with concomitant decreases in cardiac output and superior mesenteric arterial and intestinal mucosal blood flows. Although dobutamine infusion reversed the decrease in cardiac output, it failed to restore superior mesenteric artery blood flow; however, intestinal mucosal blood flow returned to baseline levels. Dopamine also attenuated the decrease in cardiac output, but it had no beneficial effect on splanchnic hemodynamic variables. CONCLUSIONS: Low-dose infusion of dobutamine, but not dopamine, corrects the intestinal mucosal perfusion impairment induced by moderate increases in intra-abdominal pressure.     

Influence of dobutamine on the variables of systemic haemodynamics, metabolism, and intestinal perfusion after cardiopulmonary resuscitation in the rat

BACKGROUND: Global left ventricular dysfunction after successful resuscitation from cardiac arrest may be treated successfully with dobutamine but the effects on intestinal perfusion are unknown. METHODS: In 24 male Sprague-Dawley rats ventricular fibrillation was induced. After 4 min of untreated cardiac arrest, precordial chest compression was performed for 4 min; adrenaline (epinephrine) (90 microg kg(-1)) was injected, followed by defibrillation. Return of spontaneous circulation was achieved in 18 animals, which were allocated to receive saline 0.9% (control group, n = 6), dobutamine at 5 microg kg(-1) min(-1) (n = 6) or dobutamine at 10 microg kg(-1) min(-1) (n = 6). Measurements of haemodynamic variables and intestinal tonometer P(CO2) were made before induction of ventricular fibrillation and 15, 30, 60, and 120 min postresuscitation. RESULTS: At 120 min postresuscitation, mean aortic pressure was 82 +/- 20, 104 +/- 19, and 113 +/- 15 mmHg for the control group, the dobutamine (5 microg kg(-1) min(-1)) group and the dobutamine (10 microg kg(-1) min(-1)) group (P < 0.05 for comparison of the dobutamine (10 microg kg(-1) min(-1)) group versus the control group). Respective abdominal aortic blood flow was 107 +/- 16, 133 +/- 49, and 145 +/- 18 ml min(-1) kg(-1) (P < 0.05 for comparison of the dobutamine (10 microg kg(-1) min(-1)) group versus the control group), and superior mesenteric artery blood flow was 25 +/- 9, 28 +/- 8, and 33 +/- 8 ml min(-1) kg(-1). Arterial lactate was significantly higher (P < 0.05) in the control group (2.3 +/- 0.6 mmol l(-1)) than in the dobutamine (5 microg kg(-1) min(-1)) group (1.6 +/- 0.3 mmol l(-1)) and dobutamine (10 microg kg(-1) min(-1)) group (1.5 +/- 0.3 mmol l(-1)). Tonometrically derived P(CO2) gap was highly elevated at 15 min of postresuscitation and returned to prearrest level at 120 min postresuscitation in all groups. CONCLUSIONS: Dobutamine enhances the recovery of global haemodynamic and metabolic variables early after cardiac arrest.     

Comparison of epinephrine and vasopressin in a pediatric porcine model of asphyxial cardiac arrest

OBJECTIVE: This study was designed to compare the effects of vasopressin vs. epinephrine vs. the combination of epinephrine with vasopressin on vital organ blood flow and return of spontaneous circulation in a pediatric porcine model of asphyxial arrest. DESIGN: Prospective, randomized laboratory investigation using an established porcine model for measurement of hemodynamic variables, organ blood flow, blood gases, and return of spontaneous circulation. SETTING: University hospital laboratory. SUBJECTS: Eighteen piglets weighing 8-11 kg. INTERVENTIONS: Asphyxial cardiac arrest was induced by clamping the endotracheal tube. After 8 mins of cardiac arrest and 8 mins of cardiopulmonary resuscitation, a bolus dose of either 0.8 units/kg vasopressin (n = 6), 200 microg/kg epinephrine (n = 6), or a combination of 45 microg/kg epinephrine with 0.8 units/kg vasopressin (n = 6) was administered in a randomized manner. Defibrillation was attempted 6 mins after drug administration. MEASUREMENTS AND MAIN RESULTS: Mean +/- SEM coronary perfusion pressure, before and 2 mins after drug administration, was 13 +/- 2 and 23 +/- 6 mm Hg in the vasopressin group; 14 +/- 2 and 31 +/- 4 mm Hg in the epinephrine group; and 13 +/- 1 and 33 +/- 6 mm Hg in the epinephrine-vasopressin group, respectively (p = NS). At the same time points, mean +/- SEM left ventricular myocardial blood flow was 44 +/- 31 and 44 +/- 25 mL x min-(1) x 100 g(-1) in the vasopressin group; 30 +/- 18 and 233 +/- 61 mL x min(-1) x 100 g(-1) in the epinephrine group; and 36 +/- 10 and 142 +/- 57 mL x min(-1) x 100 g(-1) in the epinephrine-vasopressin group (p < .01 epinephrine vs. vasopressin; p < .02 epinephrine-vasopressin vs. vasopressin). Total cerebral blood flow trended toward higher values after epinephrine-vasopressin (60 +/- 19 mL x min(-1) x 100 g(-1)) than after vasopressin (36 +/- 17 mL x min(-1) x 100 g(-1)) or epinephrine alone (31 +/- 7 mL x min(-1) x 100 g(-1); p = .07, respectively). One of six vasopressin, six of six epinephrine, and four of six epinephrine-vasopressin-treated animals had return of spontaneous circulation (p < .01, vasopressin vs. epinephrine). CONCLUSIONS: Administration of epinephrine, either alone or in combination with vasopressin, significantly improved left ventricular myocardial blood flow during cardiopulmonary resuscitation. Return of spontaneous circulation was significantly more likely in epinephrine-treated pigs than in animals resuscitated with vasopressin alone.     

Endocrine effects of dopexamine vs. dopamine in high-risk surgical patients

OBJECTIVES: To compare the endocrine effects of dopexamine and dopamine on prolactin (PRL), dihydroepiandrosterone sulfate (DHEAS), cortisol, thyrotropin (TSH), and peripheral thyroid hormone serum concentrations in surgical patients at risk of developing postoperative complications because of hypoperfusion of various organ systems. DESIGN AND SETTING: A prospective, randomized, placebo-controlled, blinded clinical trial in an adult surgical intensive care unit in a university hospital. PATIENTS: Thirty-two male surgical risk patients undergoing elective major abdominal surgery. INTERVENTIONS: Patients were randomized to receive placebo ( n=8), dopexamine (0.5 microg kg(-1) min(-1), n=8), dopexamine (1 microg kg(-1) min(-1), n=8) or dopamine (5 microg kg(-1) min(-1), n=8) on the first postoperative day. MEASUREMENTS AND RESULTS: All patients received either a placebo or catecholamine infusion for 24 h. Blood samples were obtained every 2 h for the next 2 days. PRL, DHEAS, cortisol, TSH, triiodothyronine, thyroxin, free triiodothyronine, and free thyroxin serum concentrations were determined by radioimmunoassay or luminescence immunoassay. Dopexamine (0.5 microg kg(-1) min(-1)) had no effects on serum concentrations of PRL or TSH. Higher doses of dopexamine (1 microg kg(-1) min(-1)) suppressed PRL secretion significantly, but not TSH. In contrast, infusion of dopamine (5 microg kg(-1) min(-1)) completely inhibited PRL and TSH secretion. DHEAS, cortisol, and thyroid hormone serum concentrations were not affected by either dopexamine or dopamine infusion. Measurements of hemodynamic parameters, peripheral oxygen saturation, diuresis, blood gases, and standard laboratory parameters were repeated hourly. Significant differences were not found between placebo, dopexamine (0.5 microg kg(-1) min(-1)) and dopamine (5 microg kg(-1) min(-1)) group. Dopexamine at 1 microg kg(-1) min(-1) increased the heart rate significantly. CONCLUSIONS: Routine postoperative optimizing of men undergoing abdominal surgical procedures with dopexamine at higher doses or dopamine induces at least partial hypopituitarism, which may possibly affect postoperative morbidity.     

The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients

OBJECTIVES: Dopamine exerts a complicated action on the cardiovascular-renal and neurohumoral systems. We evaluated the effects of the addition of different doses of dopamine on top of treatment with norepinephrine on the haemodynamics, renal function and neurohormones of septic shock patients. DESIGN: Open, uncontrolled, dose-finding study. SUBJECTS: Dopamine was administered, after fluid resuscitation, to septic shock patients who were more than 2 h haemodynamically and pulmonary stable with the use of a constant dose norepinephrine. Patients with a serum creatinine above 180 micromol x l were excluded. METHODS: Dopamine doses of 0, 2, 4, 6 and 0 microg x kg(-1) x min(-1) were given consecutively for 1 h each. Neurohormones were measured hourly after baseline levels had been taken. Systemic haemodynamics were measured using a pulmonary artery (PA) catheter every 30 min, whereas urine collections were examined every hour during the study period. RESULTS AND STATISTICAL ANALYSES: Eight patients (mean age 46 +/- 13 years, M/F 3/5) were included. The median norepinephrine dose at the start of the study was 0.29 microg x kg(-1) x min(-1) (range 0.07-0.48 microg x kg(-1) x min(-1)). Cardiac output (CO) rose during the dopamine infusion for all doses from 7.9 +/- 1.74 l/min to a maximum of 10.1 +/- 1.71 l/min, achieved at the 4 microg x kg(-1) x min(-1) dopamine dose, whereas systemic vascular rate (SVR) decreased slightly for all doses. Heart rate remained unchanged during the 2 microg x kg(-1) x min(-1) dose of dopamine but increased for the 4 and 6 microg x kg(-1) x min(-1) doses from 108 +/- 17 to a maximum of 124 +/- 24 beats/min. Filling pressures remained unchanged whereas the mean arterial blood pressure increased (from 83 +/- 7 to 93 +/- 11 mmHg). Plasma renin activity (PRA) was relatively high (but remained unchanged) as were aldosterone levels. Sodium excretion and diuresis increased for all doses, accompanied by an increase of fractional sodium excretion at the 4 and 6 microg x kg(-1) x min(-1) doses of dopamine. Creatinine clearances remained unchanged. All changed values returned to baseline values after cessation of the dopamine administration. CONCLUSION: During norepinephrine infusion, increasing doses of dopamine from 2 to 6 microg x kg(-1) x min(-1) augments CO, diuresis and sodium excretion in patients treated for septic shock, without changes in creatinine clearance. Higher doses of dopamine (4 and 6 microg x kg(-1) x min(-1)) also induce an increase in heart rate. PRA, aldosterone and norepinephrine levels remain unchanged during dopamine infusion.     

Splanchnic vasoregulation during mesenteric ischemia and reperfusion in pigs

We evaluated the hepatic arterial buffer response (HABR) to portal vein (PV) occlusion during 2 h of reduced superior mesenteric arterial blood flow (median 2 mL min(-1) kg(-1), range of 1-3 mL min(-1) kg(-1)) and 1 h of reperfusion in seven pigs and in seven controls. In animals with reduced mesenteric blood flow, celiac trunk blood flow (Qtr) increased during mesenteric hypoperfusion from 4 +/- 1 mL min(-1) kg(-1) (mean +/- SD) to 16 +/- 3 mL min(-1) kg(-1) (P = 0.028), and hepatic arterial blood flow (Qha) increased from 2 +/- 1 to 10 +/- 4 mL min(-1) kg(-1) (P= 0.018). The extra-hepatic fraction of Qtr (Qtr-Qha) also increased (P = 0.028). In controls, Qtr and Qha also increased, but to lower levels. At baseline, acute PV occlusion increased Qha by 5.0 +/- 2.8 mL min(-1) kg(-1) (P < 0.001), whereas Qtr-Qha decreased by 1.6 +/- 1.6 mL min(-1) kg(-1) (P = 0.007). After 120 min of reduced mesenteric blood flow, the HABR was exhausted (change in Qha to PV occlusion of 0.7 +/- 1.6 mL min(-1) kg(-1) [P= 0.27]). The efficacy of the HABR was also reduced in controls animals. Despite increased cardiac output, all flows from the celiac trunk decreased during reperfusion (P = 0.028) and the HABR partially recovered. We conclude that reduced mesenteric perfusion impairs the HABR, which recovers only partially after reperfusion. The distribution of the increased celiac trunk flow secondary to PV occlusion ranges from increased HABR and decreased non-hepatic blood flow (a steal) to decreased hepatic arterial blood flow and increased non-hepatic blood flow (an inverse steal).     

Effects of epinephrine and vasopressin in a piglet model of prolonged ventricular fibrillation and cardiopulmonary resuscitation

OBJECTIVE: We recently demonstrated that vasopressin alone resulted in a poorer outcome in a pediatric porcine model of asphyxial cardiac arrest when compared with epinephrine alone or with epinephrine plus vasopressin in combination. Accordingly, this study was designed to differentiate whether the inferior effects of vasopressin in pediatrics were caused by the type of cardiac arrest. DESIGN: Prospective, randomized laboratory investigation that used an established porcine model for measurement of hemodynamic variables and organ blood flow. SETTING: University hospital laboratory. SUBJECTS: Eighteen piglets weighing 8-11 kg. INTERVENTIONS: After 8 mins of ventricular fibrillation and 8 mins of cardiopulmonary resuscitation, either 0.4 units/kg vasopressin (n = 6), 45 microg/kg epinephrine (n = 6), or a combination of 45 microg/kg epinephrine with 0.8 units/kg vasopressin (n = 6) was administered. Six minutes after drug administration, a second respective bolus dose of 0.8 units/kg vasopressin, 200 microg/kg epinephrine, or a combination of 200 microg/kg epinephrine with 0.8 units/kg vasopressin was given. Defibrillation was attempted 20 mins after initiating cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem left ventricular myocardial blood flow 2 mins after each respective drug administration was 65 +/- 4 and 70 +/- 13 mL x min(-1) x 100 g(-1) in the vasopressin group; 83 +/- 42 and 85 +/- 41 mL x min(-1) x 100 g(-1) in the epinephrine group; and 176 +/- 32 and 187 +/- 29 mL x min(-1) x 100 g(-1) in the epinephrine-vasopressin group (p <.006 after both doses of epinephrine-vasopressin vs. vasopressin and after the first dose of epinephrine-vasopressin vs. epinephrine, respectively). At the same times, mean +/- sem total cerebral blood flow was 73 +/- 3 and 47 +/- 5 mL x min(-1) x 100 g(-1) after vasopressin; 18 +/- 2 and 12 +/- 2 mL x min(-1) x 100 g(-1) after epinephrine; and 79 +/- 21 and 41 +/- 8 mL x min(-1) x 100 g(-1) after epinephrine-vasopressin (p <.025 after both doses of vasopressin and epinephrine-vasopressin vs. epinephrine). Five of six vasopressin-treated, two of six epinephrine-treated, and six of six epinephrine-vasopressin treated animals had return of spontaneous circulation (nonsignificant). CONCLUSIONS: In this pediatric porcine model of ventricular fibrillation, the combination of epinephrine with vasopressin during cardiopulmonary resuscitation resulted in significantly higher levels of left ventricular myocardial blood flow than either vasopressin alone or epinephrine alone. Both vasopressin alone and the combination of epinephrine with vasopressin, but not epinephrine alone, improved total cerebral blood flow during cardiopulmonary resuscitation. In stark contrast to asphyxial cardiac arrest, vasopressin alone or in combination with epinephrine appears to be of benefit after ventricular fibrillation in the pediatric porcine model.     

Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model

OBJECTIVE: To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. DESIGN: Prospective, randomized animal study. SETTING: University research laboratory. SUBJECTS: Five adult female merino sheep. INTERVENTIONS: Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 microg/min) and dopamine (10, 20, 40 microg x kg x min) in 3 x 5 min intervals followed by a 30-min washout period. MEASUREMENTS: Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. MAIN RESULTS: All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146-169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95 % CI, p < 0.05): epinephrine to 41.8% of baseline (11.4-72), norepinephrine to 63 % (27-99) and dopamine to 52.9 % (18.5-87.3). There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The lowest blood concentrations were associated with emergence from anesthesia. Arterial concentrations were inversely related to the simultaneously determined cardiac output (r2 = 0.74, p < 0.0001). Comparison of the data with the predictions of a previously developed recirculatory model of propofol disposition in sheep showed the data were consistent with a mechanism based on increased first pass dilution and clearance of propofol secondary to the increased cardiac output. CONCLUSIONS: Catecholamines produced circulatory changes that reversed propofol anesthesia. These observations have potential clinical implications for the use of propofol in hyperdynamic circulatory conditions, either induced by exogenous catecholamine infusions or pathological states.     

Effects of epinephrine compared with the combination of dobutamine and norepinephrine on gastric perfusion in septic shock

OBJECTIVE: In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock. METHODS: In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan-Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 microg/kg per minute, with 0.2 microg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 microg/kg per minute. RESULTS: Twenty-two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 +/- 3 and 77 +/- 5 mm Hg in the epinephrine and dobutamine-norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine-norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 +/- 1.6 versus 4.2 +/- 1.5 L/min per square meter; P =.078) and oxygen transport (617 +/- 166 versus 481 +/- 229 mL/min per square meter; P =.068). Epinephrine also induced significantly greater values of gastric mucosal blood flow (662 +/- 210 versus 546 +/- 200 units; P =.011) but did not modify indocyanine green clearance. CONCLUSIONS: In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 microg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index.     

Resuscitation from cardiac arrest with adrenaline/epinephrine or vasopressin: effects on intestinal mucosal tonometer pCO(2) during the postresuscitation period in rats

BACKGROUND: The use of vasopressin instead of adrenaline/epinephrine during resuscitation improves vital organ perfusion, but the effects on mesenteric perfusion following successful resuscitation are not fully evaluated. The present study was designed to compare the effects of vasopressin and adrenaline/epinephrine, given to rats during resuscitation from ventricular fibrillation, on to mesenteric ischaemia, as determined by intestinal mucosal tonometer pCO(2) during the postresuscitation period. METHODS AND RESULTS: Male Sprague-Dawley rats (n=28) were allocated randomly to receive vasopressin (0.8 U/kg) or adrenaline/epinephrine (90 microg/kg) after 5 min of ventricular fibrillation. Precordial chest compression was initiated 4 min after the start of ventricular fibrillation, continued for 4 min, and followed by defibrillation. Seven of 14 (vasopressin) and 12 of 14 (adrenaline/epinephrine) rats were successfully defibrillated (P=0.10, Fisher's exact test) and observed for 60 min. Intestinal mucosal tonometer pCO(2) measurements before cardiac arrest and 15, 30, and 60 min following return of spontaneous circulation were 47+/-3, 73+/-8, 63+/-7, and 56+/-6 mmHg in the vasopressin group and 48+/-5, 78+/-7, 67+/-6, and 62+/-6 mmHg in the adrenaline/epinephrine group (P<0.05 at 60 min between vasopressin and adrenaline/epinephrine). Right atrial hemoglobin oxygen saturations at these time points were 73+/-5, 51+/-12, 58+/-11, and 63+/-5% in the vasopressin group and 76+/-7, 44+/-10, 52+/-10 and 54+/-8% in the adrenaline/epinephrine group (P<0.05 at 60 min between vasopressin and adrenaline/epinephrine). CONCLUSIONS: We conclude that in this rat model the administration of vasopressin instead of adrenaline/epinephrine for CPR tends to be associated with lower resuscitation success, but less mesenteric ischaemia during the postresuscitation period in successfully resuscitated rats.     

Donitriptan selectively decreases jugular venous oxygen saturation in the anesthetized pig: further insights into its mechanism of action relevant to headache relief

The effects of donitriptan on systemic arterial-jugular venous oxygen saturation difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 microg/kg, n = 7) were cumulatively infused over 15 min/dose. The involvement of 5-hydroxytryptamine(1B) (5-HT(1B)) receptors was assessed in the presence of the 5-HT(1B/1D) receptor antagonist, GR 127935. Donitriptan decreased markedly and dose dependently jugular venous oxygen saturation [ED(50) 0.5 (0.3-1.1) microg/kg], in parallel with increases in carotid vascular resistance [ED(50) 0.9 (0.7-1.1) microg/kg]. Since arterial oxygen saturation and partial pressure remained unchanged, donitriptan significantly increased arteriovenous oxygen saturation difference from 0.63 microg/kg (maximal variation: 57 +/- 18%, P < 0.05 compared with vehicle). Unexpectedly, donitriptan from 2.5 microg/kg induced marked and significant increases in carbon dioxide partial pressure (pVCO(2)) in venous blood (maximal increase 18.8 +/- 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR 127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the increase in carotid vascular resistance and reduced the increases in pVCO(2) induced by donitriptan. The results demonstrate that donitriptan, via 5-HT(1B) receptor activation, decreases the oxygen saturation of venous blood draining the head, concomitantly with cranial vasoconstriction. Since donitriptan also increased pVCO(2), an effect upon cerebral oxygen consumption and metabolism is suggested in addition to cranial vasoconstriction, which may be relevant to its headache-relieving effects.     

Effects of combined administration of vasopressin, epinephrine, and norepinephrine during cardiopulmonary resuscitation in pigs

OBJECTIVE: Synergistic effects of epinephrine and vasopressin may be of benefit during cardiopulmonary resuscitation. However, cerebral perfusion was decreased when epinephrine was combined with vasopressin compared with vasopressin alone. Although a combined infusion of norepinephrine and vasopressin improves hemodynamic variables compared with norepinephrine alone during sepsis, it is unknown whether norepinephrine in addition to vasopressin and epinephrine changes vital organ perfusion during cardiopulmonary resuscitation. DESIGN: Prospective, randomized animal study. SETTING:: University hospital research laboratory. SUBJECTS: Twenty-one domestic pigs. INTERVENTIONS: After 4 mins of ventricular fibrillation and 3 mins of basic life support, the pigs were randomly assigned to receive either 200 microg/kg epinephrine, 0.4 units/kg vasopressin alone, or 45 microg/kg norepinephrine plus 45 microg/kg epinephrine plus 0.4 units/kg vasopressin before defibrillation. MEASUREMENTS AND MAIN RESULTS: Organ perfusion was determined by radiolabeled microspheres. Myocardial blood flow (mean +/- sem) before and 90 secs and 5 mins after drug administration was 8 +/- 2, 25 +/- 6, and 7 +/- 1 mL/min/100 g after high-dose epinephrine, 12 +/- 1, 75 +/- 7, and 60 +/- 10 mL/min/100 g after vasopressin, and 9 +/- 2, 95 +/- 26, and 46 +/- 15 mL/min/100 g after vasopressin/epinephrine/norepinephrine, respectively (p < .05 at 90 secs and 5 mins vasopressin vs. epinephrine and vasopressin/epinephrine/norepinephrine vs. epinephrine). At the same time points, cerebral blood flow was 8 +/- 2, 23 +/- 3, and 17 +/- 3 mL/min/100 g after epinephrine, 11 +/- 3, 55 +/- 7, and 52 +/- 7 mL/min/100 g after vasopressin, and 11 +/- 4, 67 +/- 13, and 53 +/- 12 mL/min/100 g after vasopressin/epinephrine/norepinephrine, respectively (p < .05 at 90 secs and 5 mins vasopressin vs. epinephrine and vasopressin/epinephrine/norepinephrine vs. epinephrine). Two of seven animals in the epinephrine group, four of seven animals in the vasopressin/epinephrine/norepinephrine group, and seven of seven animals in the vasopressin group could be successfully resuscitated (p < .05 vasopressin vs. epinephrine). CONCLUSIONS: Vasopressin with or without epinephrine and norepinephrine resulted in higher myocardial and cerebral perfusion than epinephrine alone, but there was no benefit in adding norepinephrine to vasopressin and epinephrine with regard to cardiac and cerebral blood flow during cardiopulmonary resuscitation.     

Respiratory depression under long-term sedation with sufentanil, midazolam and clonidine has no clinical significance

OBJECTIVE: Assessment of respiratory depression caused by long-term sedation with sufentanil, midazolam and clonidine. DESIGN: Retrospective assessment using data from a patient data management system. SETTING: University hospital anaesthesiological ICU. PATIENTS: Three hundred ninety-five surgical and trauma patients with an ICU stay of more than 48 h. INTERVENTION: None. MEASUREMENTS AND RESULTS: Arterial blood partial pressure of carbon dioxide (PCO2) was evaluated during mechanically assisted spontaneous ventilation (continuous positive airway pressure, synchronised intermittent mandatory ventilation, mandatory minute ventilation, bilevel positive airway pressure). Continuous sedation with sufentanil, midazolam or clonidine or a combination of those drugs was administered to achieve a Ramsay score between 2 and 4. Spontaneously breathing patients without continuous sedation and patients on controlled mechanical ventilation (and sedation) served as control groups. Mean arterial PCO2 from spontaneously breathing patients without continuous sedation was 39.5 +/- 7.3 torr compared with 42.7 +/- 6.8 torr under sufentanil (median 0.44 microg x kg(-1) x h(-1), 98 % of observations between 0.1 and 2.1 microg x kg(-1) x h(-1)), 41.5 +/- 6.1 torr under sufentanil (median 0.90 microg x kg(-1) x h(-1) (0.1-2.8)) plus midazolam (median 45 microg x kg(-1) x h(-1) (7-170)) and 39.8 +/- 5.6 torr under a combination of sufentanil (median 1.15 microg x kg(-1) x h(-1) (0.2-3.6)), midazolam (median 45 microg x kg(-1) x h(-1) (11-216)) and clonidine (median 1.3 microg x kg(-1) x h(-1) (0.2-2.5)). Mean arterial PCO2 from patients on controlled mechanical ventilation was 39.9 +/- 6.1 torr. CONCLUSION: Patients under continuous sedation with sufentanil exhibit a statistically significant rise in arterial PCO2, however this respiratory depression is only slight and has no clinical significance. Mechanically assisted spontaneous ventilation modes can safely be used under continuous sedation with sufentanil, midazolam or clonidine.     

Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition

BACKGROUND/OBJECTIVE: The efficacy of a direct factor (F)Xa inhibitor, ZK-807834, was compared with indirect inhibition by enoxaparin for inhibition and deaggregation of acute platelet-rich thrombi in a well-characterized porcine carotid injury model. METHODS: A crush injury was performed on a randomly chosen carotid artery and the thrombus allowed to propagate for 30 min. Pigs then received intravenous drug for 35 min: ZK-807834-Dose 1 (40 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion, n=6); ZK-807834-Dose 2 (20 microg kg(-1) bolus + 0.75 microg kg(-1) min(-1) infusion; n=6); enoxaparin (1 mg kg(-1) bolus; n=6); or saline (n=6). Five minutes after drug initiation, the contralateral artery was injured. Thrombus size was monitored by scintillation detection of autologous 111In-platelets. RESULTS: The prothrombin time ratio was 2.2 +/- 0.1; 1.4 +/- 0.3; 1.2 +/- 0.9 and 1.1 +/- 0.2, respectively. ZK-807834-Dose 1 significantly inhibited carotid platelet deposition (525 +/- 226 x 10(6) cm(-2); P = 0.008), whereas ZK-807834-Dose 2 (2325 +/- 768) and enoxaparin (1236 +/- 383) were not different from saline (2776 +/- 642). Thrombus deaggregation was greatest for animals receiving ZK-807834-Dose 1 (473 +/- 185). Neither ZK-807834-Dose 2 (1588 +/- 480) nor enoxaparin (1618 +/- 686) was different from saline control (2222 +/- 598). CONCLUSIONS: Direct FXa inhibition with ZK-807834, at a prothrombin time ratio of 2.2, effectively inhibits thrombosis and promptly deaggregates thrombi induced by arterial injury. In contrast, indirect FXa inhibition with enoxaparin was ineffective.     

Norepinephrine and vital organ blood flow

OBJECTIVE: To test whether norepinephrine (NE) infusion at 0.4 microg kg(-1) min(-1) adversely affects regional blood flow in the normal mammalian circulation. DESIGN AND SETTING: Randomized cross-over experimental animal study in a university-affiliated physiology institute. SUBJECTS: Six merino ewes. INTERVENTIONS: Staged insertion of transit-time flow probes around the ascending aorta and circumflex coronary, superior mesenteric and left renal arteries. In conscious animals with chronically embedded flow probes randomization to either 6 h of placebo (saline) or drug (NE at 0.4 microg kg(-1) min(-1)). MEASUREMENTS AND RESULTS: Compared to placebo, NE significantly increased mean arterial pressure (84.4 vs. 103.8 mmHg), heart rate (61.0 vs. 74.6 bpm) and cardiac output (3.76 vs. 4.78 l/min). These changes were associated with an increase in coronary blood flow (24.2 vs. 37.4 ml/min) and renal blood flow (215.2 vs. 282.0 ml/min) but no change in mesenteric blood flow. The increase in renal and coronary blood flow was associated with an increase in regional conductance (regional vasodilatation), while mesenteric conductance fell (mesenteric vasoconstriction). Urine output (91+/-17 vs. 491+/-360 ml/h) and creatinine clearance (61+/-18 vs. 89+/-12 ml/min) increased during NE infusion. CONCLUSIONS: NE infusion does not induce vital organ ischaemia in the normal mammalian circulation. Furthermore, it results in a significant increase in coronary and renal blood flow with a concomitant improvement in urine output and creatinine clearance.