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.     

Revised resuscitation guidelines: adrenaline versus adrenaline/vasopressin in a pig model of cardiopulmonary resuscitation--a randomised, controlled trial

BACKGROUND: Synergistic effects of adrenaline (epinephrine) and vasopressin may be beneficial during cardiopulmonary resuscitation. However, it is unknown whether either adrenaline alone or an alternating administration of adrenaline and vasopressin is better for restoring vital organ perfusion following basic life support (BLS) according to the revised algorithm with a compression-to-ventilation (c/v) ratio of 30:2. MATERIAL AND METHODS: After 4min of ventricular fibrillation, and 6min of BLS with a c/v ratio of 30:2, 16 pigs were randomised to receive either 45microg/kg adrenaline, or alternating 45microg/kg adrenaline and 0.4U/kg vasopressin, respectively. RESULTS: Coronary perfusion pressure (mean+/-S.D.) 20 and 25min after cardiac arrest was 7+/-4 and 5+/-3mm Hg after adrenaline, and 25+/-2 and 14+/-3mm Hg after adrenaline/vasopressin (p<0.001 and <0.01 versus adrenaline), respectively. Cerebral perfusion pressure was 23+/-7 and 19+/-9mm Hg after adrenaline, and 40+/-10 and 33+/-7mm Hg after adrenaline/vasopressin (p<0.001 and <0.01 versus adrenaline), and cerebral blood flow was 30+/-10 and 27+/-11% of baseline after adrenaline, and 65+/-40 and 50+/-31% of baseline after adrenaline/vasopressin (p<0.05 versus adrenaline), respectively. Return of spontaneous circulation (ROSC) did not differ significantly between the adrenaline group (0/8) and the adrenaline/vasopressin group (3/8). CONCLUSION: Adrenaline/vasopressin resulted in higher coronary and cerebral perfusion pressures, and cerebral blood flow, while ROSC was comparable.     

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.     

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.     

Pulmonary gas exchange after cardiopulmonary resuscitation with either vasopressin or epinephrine

OBJECTIVE: It is well established that epinephrine administered during cardiopulmonary resuscitation results in pulmonary gas exchange disturbances. It is uncertain how vasopressin affects gas exchange after cardiopulmonary resuscitation. DESIGN: Prospective, randomized experimental study. SETTING: Animal research laboratory. SUBJECTS: Twenty domestic pigs. INTERVENTIONS: Animals were subjected to ventricular fibrillation and cardiopulmonary resuscitation by using either vasopressin or epinephrine. Hemodynamic and pulmonary gas exchange (multiple inert gas elimination technique) variables were recorded before cardiopulmonary resuscitation and 10, 30, 60, and 120 mins after return of spontaneous circulation when either epinephrine (control) or vasopressin was used. MEASUREMENTS AND MAIN RESULTS: At 10 mins after return of spontaneous circulation, blood flow to low V /Q lung units was increased in animals treated with epinephrine (17.8 +/- 6 vs. 2.6 +/- 3%, mean +/- sd, p<.01). Resulting carbon dioxide elimination was impaired in animals treated with epinephrine but not in animals treated with vasopressin (PaCO2, 55 +/- 2 vs. 46 +/- 4 torr, p<.05). Thirty minutes after return of spontaneous circulation, blood flow to lung units with a normal VA /Q ratio was reduced in animals treated with epinephrine (79 +/- 1 vs. 84 +/- 12%, p<.05), resulting in a depressed PaO2 (147 +/- 4 vs. 127 +/- 10 torr, p<.05). CONCLUSION: Vasopressin compared with epinephrine for cardiopulmonary resuscitation resulted in better gas exchange variables in the early postresuscitation phase.     

Effects of vasopressin and epinephrine on splanchnic blood flow and renal function during and after cardiopulmonary resuscitation in pigs

OBJECTIVE: To compare the effects of vasopressin versus epinephrine on splanchnic blood flow during and after cardiopulmonary resuscitation (CPR), and to evaluate the effects of these vasopressors on renal function in the postresuscitation phase. DESIGN: Prospective, randomized laboratory investigation using an established porcine CPR model with instrumentation for continuous measurement of splanchnic and renal blood flow. SETTING: University hospital experimental laboratory. SUBJECTS: A total of 12 anesthetized, 12- to 16-wk-old domestic pigs weighing 30-35 kg. INTERVENTIONS: After 4 mins of cardiac arrest, and 3 mins of CPR, 12 pigs were randomly assigned to receive either 0.4 units/kg vasopressin (n = 6) or 45 microg/kg epinephrine (n = 6). Defibrillation was performed 5 mins after drug administration; all animals were observed for 6 hrs after return of spontaneous circulation (ROSC). MEASUREMENTS AND MAIN RESULTS: Mean +/- SEM superior mesenteric artery blood flow was significantly (p < .05) lower after vasopressin compared with epinephrine at 90 secs after drug administration (13+/-3 vs. 129+/-33 mL/min); at 5 mins after drug administration (31+/-18 vs. 155+/-39 mL/min); at 5 mins after ROSC (332+/-47 vs. 1087+/-166 mL/min); and at 15 mins after ROSC (450+/-106 vs. 1130+/-222 mL/min); respectively. Mean +/- SEM left renal and hepatic artery blood flow after ROSC was comparable in both groups ranging between 120-290 mL/min (renal blood flow), and 150-360 mL/min (hepatic blood flow), respectively. Median urine output after ROSC showed no difference between groups, and highest values (180-220 mL/hr) were observed in the first 60 mins after ROSC. Median calculated glomerular filtration rate showed no difference between groups with values ranging between 30 and 80 mL/min in the postresuscitation phase. Calculated fractional sodium excretion and osmolar relationship between urea and plasma indicated no evidence for renal tubular dysfunction. CONCLUSIONS: In the early postresuscitation phase, superior mesenteric blood flow was temporarily impaired by vasopressin in comparison with epinephrine. With respect to renal blood flow and renal function after ROSC, there was no difference between either vasopressor given during CPR. Vasopressin given during CPR did not result in an antidiuretic state in the postresuscitation phase.     

Combination drug therapy with vasopressin,adrenaline (epinephrine) and nitroglycerin improves vital organ blood flow in a porcine model of ventricular fibrillation

There is increasing evidence that the combination of epinephrine (adrenaline) with vasopressin may be superior to either epinephrine or vasopressin alone for treatment of cardiac arrest. However, the optimal combination, and dosage of cardiovascular drugs to minimize side effects, and to improve outcome has yet to be found. We therefore evaluated whether the combination of vasopressin plus epinephrine plus nitroglycerin (EVN), would improve vital organ blood flow during cardiopulmonary resuscitation (CPR) when compared with epinephrine (EPI) alone. After 4 min of ventricular fibrillation (VF) and 4 min of standard CPR, pigs were randomized to the combination of epinephrine (45 microg/kg) plus vasopressin (0.4 U/kg) plus nitroglycerin (7.5 microg/kg; n=12), or epinephrine (40 microg/kg; n=12) alone. Cerebral and myocardial blood flow was measured with radiolabeled microspheres. Defibrillation was attempted after 19 min of VF including 15 min of CPR. Mean+/-SEM coronary perfusion pressures were significantly (P < 0.01) higher 5 min after EVN vs. EPI alone (34+/-3 vs. 24+/-3 mmHg, respectively). At the same time, mean+/-SEM left ventricular, and global cerebral blood flow was also significantly (P < 0.05) higher after EVN vs. EPI alone (0.78+/-0.11 vs. 0.48+/-0.08 ml/min/g; and 0.37+/-0.05 vs. 0.22+/-0.0 3 ml/min/g, respectively). Spontaneous circulation was restored in 11 of 12 animals in the EVN group vs. 6 of 12 swine after EPI alone (P = N.S.). In conclusion, the combination of EVN significantly improved vital organ blood flow during CPR compared with EPI alone. Addition of nitroglycerin to the combination of low dose epinephrine with vasopressin during cardiac arrest may be beneficial.     

Effects of vasopressin on adrenal gland regional perfusion during experimental cardiopulmonary resuscitation

OBJECTIVE: Despite the important role of the adrenal gland during cardiac arrest, little is known about changes in the adrenal medullary or cortical blood flow in this setting. This study was designed to assess regional adrenal gland perfusion in the medulla and cortex during cardiopulmonary resuscitation (CPR), and after administration of adrenaline (epinephrine) versus vasopressin versus saline placebo. METHODS: After 4 min of untreated ventricular fibrillation, and 3 min of basic life support CPR, 19 animals were randomly assigned to receive either vasopressin (0.4 U/kg; n=7), adrenaline (45 microg/kg; n=6) or saline placebo (n=6), respectively. Haemodynamic variables, adrenal, and renal blood flow were measured after 90 s of CPR, and 90 s and 5 min after drug administration. RESULTS: All values are given as mean+/-S.E.M. Blood flow in the adrenal medulla was significantly higher 90 s after adrenaline when compared with saline placebo in the right adrenal medulla (210+/-14 vs. 102+/-5 ml/min per 100 mg), and in the left adrenal medulla (218+/-14 vs. 96+/-3 ml/min per 100 mg). Blood flow in the adrenal medulla was significantly higher 90 s and 5 min after vasopressin when compared with adrenaline in the right (326+/-22 mg vs. 210+/-14 ml/min per 100 mg, and 297+/-17 vs. 103+/-5 ml/min per 100 mg), and in the left medulla (333+/-25 vs. 218+/-14 ml/min per 100 mg, and 295+/-14 vs. 111+/-7 ml/min per 100 mg). Ninety seconds and five minutes after vasopressin, and 90 s after adrenaline, adrenal cortex blood flow was significantly higher when compared with saline placebo. After 12 min of cardiac arrest, including 8 min of CPR, seven of seven pigs in the vasopressin group, one of six pigs in the adrenaline group, but none of six placebo were successfully defibrillated. CONCLUSION: Both vasopressin and adrenaline produced significantly higher medullary and cortical adrenal gland perfusion during CPR than did a saline placebo; but vasopressin resulted in significantly higher medullary adrenal gland blood flow when compared with adrenaline.     

Vasopressin versus epinephrine during cardiopulmonary resuscitation: a randomized swine outcome study.

In animal models, vasopressin improves short-term outcome after cardiopulmonary resuscitation (CPR) for ventricular fibrillation compared to placebo, and improves myocardial and cerebral hemodynamics during CPR compared to epinephrine. This study was designed to test the hypothesis that vasopressin would improve 24-h neurologically intact survival compared to epinephrine. After a 2-min untreated ventricular fibrillation interval followed by 6 min of simulated bystander CPR, 35 domestic swine (weight, 25+/-1 kg) were randomly provided with a single dose of vasopressin (20 U or approximately 0.8 U kg(-1) intravenously) or with epinephrine (0.02 mg kg(-1) intravenously every 5 min). Ten minutes after initial medication administration (18 min after induction of ventricular fibrillation), standard advanced life support was provided, starting with defibrillation. Animals that were successfully resuscitated received 1 h of intensive care support and were observed for 24 h. Coronary perfusion pressures were higher in the vasopressin group 2 and 4 min after vasopressin administration (28+/-2 versus 18+/-1 mm Hg, P<0.01, and 26+/-3 versus 18+/-2 mm Hg, P<0.05, respectively). The vasopressin group tended to be successfully defibrillated on the first attempt more frequently (8/18 versus 3/17, P = 0.15). Return of spontaneous circulation (ROSC) was attained in 12/18 (67%) vasopressin-treated pigs versus 8/17 (47%) epinephrine-treated pigs, P = 0.24. Twenty-four hour neurologically normal survival occurred in 11/18 (61%) versus 7/17 (41%), respectively, P = 0.24. In conclusion, vasopressin administration during CPR improved coronary perfusion pressure, but did not result in statistically significant outcome improvement.     

Vasopressin versus continuous adrenaline during experimental cardiopulmonary resuscitation

OBJECTIVE: To evaluate the effects of a bolus dose of vasopressin compared to continuous adrenaline (epinephrine) infusion on vital organ blood flow during cardiopulmonary resuscitation (CPR). METHODS: Ventricular fibrillation was induced in 24 anaesthetised pigs. After a 5-min non-intervention interval, CPR was started. After 2 min of CPR the animals were randomly assigned to receive either vasopressin (0.4 U/kg) or adrenaline (bolus of 20 microg/kg followed by continuous infusion of 10 microg/(kg min)). Defibrillation was attempted after 9 min of CPR. RESULTS: Vasopressin generated higher cortical cerebral blood flow (P < 0.001) and lower cerebral oxygen extraction (P < 0.001) during CPR compared to continuous adrenaline. Coronary perfusion pressure during CPR was higher in vasopressin-treated pigs (P < 0.001) and successful resuscitation was achieved in 12/12 in the vasopressin group versus 5/12 in the adrenaline group (P = 0.005). CONCLUSIONS: In this experimental model, vasopressin caused a greater increase in cortical cerebral blood flow and lower cerebral oxygen extraction during CPR compared to continuous adrenaline. Furthermore, vasopressin generated higher coronary perfusion pressure and increased the likelihood of restoring spontaneous circulation.     

Analysing ventricular fibrillation ECG-signals and predicting defibrillation success during cardiopulmonary resuscitation employing N(alpha)-histograms.

Mean fibrillation frequency may predict defibrillation success during cardiopulmonary resuscitation (CPR). N(alpha)-histogram analysis should be investigated as an alternative. After 4 min of cardiac arrest, and 3 versus 8 min of CPR, 25 pigs received either vasopressin or epinephrine (0.4, 0.4, and 0.8 U/kg vasopressin versus 45, 45, and 200 microg/kg epinephrine) every 5 min with defibrillation at 22 min. Before defibrillation, the N(alpha)-parameter histogramstart/histogramwidth and the mean fibrillation frequency in resuscitated versus non-resuscitated pigs were 2.9+/-0.4 versus 1.7+/-0.5 (P=0.0000005); and 9.5+/-1.7 versus 6.9+/-0.7 (P=0.0003). During the last minute prior to defibrillation, histogramstart/histogramwidth of > or =2.3 versus mean fibrillation frequency > or =8 Hz predicted successful defibrillation with subsequent return of a spontaneous circulation for more than 60 min with sensitivity, specificity, positive predictive value and negative predictive value of 94 versus 82%, 96 versus 89%, 98 versus 93% and 90 versus 74%, respectively. We conclude, that N(alpha)-analysis was superior to mean fibrillation frequency analysis during CPR in predicting defibrillation success, and distinction between vasopressin versus epinephrine effects.     

Vasopressors are essential during cardiopulmonary resuscitation in rats: Is vasopressin superior to adrenaline?

BACKGROUND: Vasopressors are recommended for cardiopulmonary resuscitation (CPR) after cardiac arrest. In order to assess possible benefits regarding neurological recovery, vasopressin versus adrenaline and the combination of both was tested against placebo in a cardiac arrest model in rats. METHODS: Under anaesthesia with halothane and N2O, cardiac arrest was initiated via transoesophageal electrical fibrillation. After 7 min of global ischaemia, CPR was performed by external chest compression combined with defibrillation. Animals were randomly assigned to three groups receiving adrenaline, vasopressin and a combination of both (n = 15 per group) versus placebo (n = 8). At 1, 3 and 7 days animals were tested according to a neurological deficit score (NDS). After 7 days of reperfusion, coronal brain sections were analysed by Nissl- and TUNEL-staining. Viable as well as TUNEL-positive neurons were counted in the hippocampal CA-1 sector. For statistical analysis, the log rank and the Kruskal-Wallis ANOVA test were used. All data are given as mean+/-S.D.; a p-value <0.05 was considered significant. RESULTS: Mean arterial blood pressure (MAP) measured in the aorta did not differ between the vasopressor groups, whereas placebo animals had significantly lower levels. Survival to 7 days revealed significant differences between the placebo (n = 0/8) and all vasopressor groups (adrenaline, 10/15; adrenaline/vasopressin, 8/15; vasopressin, 12/15). Histological deficit scoring by quantitative analysis of the Nissl- and TUNEL-staining showed no difference in the amount of viable and apoptotic neurons in the vasopressin group (viable: 33+/-18; apoptotic: 63+/-23) versus the adrenaline group (viable: 21+/-12; apoptotic: 67+/-17) and the adrenaline/vasopressin group (viable: 31+/-26; apoptotic: 61+/-27). Neurological deficit scoring did not show any differences between the vasopressor groups. CONCLUSION: Administration of arginine-vasopressin during CPR does not improve behavioural and cerebral histopathological outcome, compared to the use of adrenaline or the combination of both vasopressors, after cardiac arrest in rats.     

The Cardiac Electrophysiology of Postresuscitation Hypokalemia in Dogs

Hypokalemia has been observed in man after out-of-hospital ventricular fibrillation and after cardioversion from ventricular tachycardia in the electrophysiology laboratory, and also in dogs following ventricular fibrillation (maximal effect 45-60 minutes after resuscitation). Since the electrophysiological effects of postresuscitation hypokalemia are unknown, we evaluated the effects of this hypokalemia on ventricular fibrillation thresholds (group 1) and on right ventricular effective refractory periods (group 2). In both groups, anesthetized dogs with normal hearts were divided into experimental animals that had 2 minutes of ventricular fibrillation followed by cardioversion without medications and control animals without ventricular fibrillation. In group 1, we measured serum potassium before ventricular fibrillation (or time 0 in control dogs) and then measured potassium and ventricular fibrillation threshold at 45, 60, 75, and 90 minutes after baseline. In group 2 animals we measured right ventricular effective refractory periods and serum potassium at baseline and sequentially from 7 to 180 minutes after resuscitation. In group 1, the maximum change in potassium from baseline was -0.8 +/- 0.3 mEq/L at 60 minutes after resuscitation as compared to -0.1 +/- 0.3 mEq/L in control animals at 60 minutes (P less than 0.01). At 60 minutes, ventricular fibrillation threshold was 8 +/- 3 mA in ventricular fibrillation animals and 7 +/- 3 mA in control animals (P = NS). In group 2 animals, the maximum change in serum potassium also occurred 60 minutes after resuscitation and was -0.8 +/- 0.3 mEq/L as compared to -0.2 +/- 0.2 mEq/L in control animals (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation

OBJECTIVE: Epinephrine given during closed-chest resuscitation increases blood flow across the coronary and cerebral circuits. However, epinephrine worsens reperfusion arrhythmias and intensifies postresuscitation myocardial dysfunction. We investigated whether cariporide-a selective sodium-hydrogen exchanger isoform-1 inhibitor-could ameliorate such adverse effects without diminishing its vasopressor actions. DESIGN: Randomized animal study. SETTING: University-based animal laboratory. SUBJECTS: Twenty-four anesthetized male domestic pigs (29-43 kg). INTERVENTIONS: Ventricular fibrillation was electrically induced and left untreated for 8 mins. Pigs were randomized to receive after 2 mins of chest compression a 3 mg/kg bolus of cariporide (n = 8), a 0.02 mg/kg bolus of epinephrine (n = 8), or a combination of cariporide and epinephrine (n = 8). Additional doses of epinephrine were given if the coronary perfusion pressure decreased below 15 mm Hg. Successfully resuscitated pigs were observed for 72 hrs. MEASUREMENTS AND MAIN RESULTS: The averaged coronary perfusion pressure was higher in the epinephrine (34 +/- 11 mm Hg, p = .001) and cariporide/epinephrine (35 +/- 10 mm Hg, p < .001) groups compared with the cariporide group (15 +/- 6 mm Hg). All pigs in the epinephrine and cariporide/epinephrine groups but only six in the cariporide group were successfully resuscitated and survived 72 hrs. During the immediate postresuscitation period, four of eight pigs in the epinephrine group had episodes of recurrent ventricular fibrillation or pulseless ventricular tachycardia requiring additional electrical shocks (7.0 +/- 6.4) but none in the cariporide and cariporide/epinephrine groups (chi-square, p = .008). Myocardial dysfunction occurred early after return of spontaneous circulation but only in the epinephrine group. CONCLUSIONS: The combined administration of cariporide and epinephrine prompted adequate pressor effects during chest compression and facilitated reestablishment of cardiac activity without episodes of recurrent ventricular fibrillation or transient myocardial dysfunction as with epinephrine alone.     

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.     

Effects of epinephrine and vasopressin on cerebral microcirculatory flows during and after cardiopulmonary resuscitation

OBJECTIVES: Both epinephrine and vasopressin increase aortic and carotid arterial pressure when administered during cardiopulmonary resuscitation. However, we recently demonstrated that epinephrine reduces cerebral cortical microcirculatory blood flow. Accordingly, we compared the effects of nonadrenergic vasopressin with those of epinephrine on cerebral cortical microvascular flow together with cortical tissue Po2 and Pco2 as indicators of cortical tissue ischemia. DESIGN: Randomized, prospective animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Domestic pigs. MEASUREMENTS AND MAIN RESULTS: The tracheae of ten domestic male pigs, weighing 40 +/- 2 kg, were noninvasively intubated, and the animals were mechanically ventilated. A frontoparietal bilateral craniotomy was created. Microcirculatory blood flow was quantitated with orthogonal polarization spectral imaging. Blood flow velocity in pial and cortical penetrating vessels measuring <20 microm was graded from 0 (no flow) to 3 (normal). Cerebral cortical tissue carbon dioxide and oxygen tensions (Pbco2 and Pbo2) were measured concurrently using miniature optical sensors. Ventricular fibrillation, induced with an alternating current delivered to the right ventricular endocardium, was untreated for 3 mins. Animals were then randomized to receive central venous injections of equipressor doses of epinephrine (30 microg/kg) or vasopressin (0.4 units/kg) at 1 min after the start of cardiopulmonary resuscitation. After 4 mins of cardiopulmonary resuscitation, defibrillation was attempted. Spontaneous circulation was restored in each animal. However, postresuscitation microvascular flows and Pbo2 were greater and Pbco2 less after vasopressin when compared with epinephrine. We observed that a significantly greater number of cortical microvessels were perfused after vasopressin. CONCLUSIONS: Cortical microcirculatory blood flow was markedly reduced after epinephrine, resulting in a greater severity of brain ischemia after the restoration of spontaneous circulation in contrast to the more benign effects of vasopressin.     

Comparison of epinephrine with vasopressin on bone marrow blood flow in an animal model of hypovolemic shock and subsequent cardiac arrest

OBJECTIVE: The intraosseous route is an emergency alternative for the administration of drugs and fluids if vascular access cannot be established. However, in hemorrhagic shock or after vasopressors are given during resuscitation, bone marrow blood flow may be decreased, thus impairing absorption of intraosseously administered drugs. In this study, we evaluated the effects of vasopressin vs. high-dose epinephrine in hemorrhagic shock and cardiac arrest on bone marrow blood flow. 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: Fourteen pigs weighing 30 +/- 3 kg. INTERVENTIONS: Radiolabeled microspheres were injected to measure bone marrow blood flow during a prearrest control period and during hypovolemic shock produced by rapid hemorrhage of 35% of the estimated blood volume. In the second part of the study, ventricular fibrillation was induced; after 4 mins of untreated cardiac arrest and 4 mins of standard cardiopulmonary resuscitation, a bolus dose of either 200 microg/kg epinephrine (n = 6) or 0.8 units/kg vasopressin (n = 6) was administered. Defibrillation was attempted 2.5 mins after drug administration, and blood flow was assessed again at 5 and 30 mins after successful resuscitation. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem bone marrow blood flow decreased significantly during induction of hemorrhagic shock from 14.4 +/- 4.1 to 3.7 +/- 1.8 mL.100 g-1.min-1 in the vasopressin group and from 18.2 +/- 4.0 to 5.2 +/- 1.0 mL.100 g-1.min-1 in the epinephrine group (p =.025 in both groups). Five minutes after return of spontaneous circulation, mean +/- sem bone marrow blood flow was 3.4 +/- 1.1 mL.100 g-1.min-1 after vasopressin and 0.1 +/- 0.03 mL.100 g-1.min-1 after epinephrine (p =.004 for vasopressin vs. epinephrine). At the same time, bone vascular resistance was significantly (p =.004) higher in the epinephrine group when compared with vasopressin (1455 +/- 392 vs. 43 +/- 19 mm Hg. mL-1.100 g.min, respectively). CONCLUSIONS: Bone blood flow responds actively to both the physiologic stress response of hemorrhagic shock and vasopressors given during resuscitation after hypovolemic cardiac arrest. In this regard, bone marrow blood flow after successful resuscitation was nearly absent after high-dose epinephrine but was maintained after high-dose vasopressin. These findings emphasize the need for pressurized intraosseous infusion techniques, because bone marrow blood flow may not be predictable during hemorrhagic shock and drug therapy.     

Epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest

Although vasopressin has been reported to be more effective than epinephrine for cardiopulmonary resuscitation in ventricular fibrillation animal models, its efficacy in asphyxia model remains controversy. The purpose of this study was to investigate the effectiveness of vasopressin vs epinephrine on restoration of spontaneous circulation (ROSC) in a rabbit model of asphyxia cardiac arrest. Cardiac arrest was induced by clamping endotracheal tube. After 5 minutes of basic life-support cardiopulmonary resuscitation, animals who had no ROSC were randomly assigned to receive either epinephrine alone (epinephrine group; 200 microg/kg) or vasopressin alone (vasopressin group; 0.8 U/kg). The coronary perfusion pressure (CPP) was calculated as the difference between the minimal diastolic aortic and simultaneously recorded right atrial pressure. Restoration of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of 60 mm Hg or higher for 5 minutes or longer. We induced arrest in 62 rabbits, 15 of whom had ROSC before drug administration and were excluded from analysis. The remaining 47 rabbits were randomized to epinephrine group (n = 24) and vasopressin group (n = 23). Before and after drug administration, CPP in epinephrine group increased significantly (from -4 +/- 4 to 36 +/- 9 mm Hg at peak value, P = .000), whereas CPP in vasopressin group increased only slightly (from 9 +/- 5 to 18 +/- 6 mm Hg at peak value, P = .20). After drug administration, 13 of 24 epinephrine rabbit had ROSC, and only 2 of 23 vasopressin rabbit had ROSC (P < .01). Consequently, we conclude that epinephrine, but not vasopressin, increases survival rates in this adult rabbit asphyxia model.     

Effects of naloxone on the adrenomedullary response during and after cardiopulmonary resuscitation in dogs

To determine the effects of naloxone, an opiate antagonist, on the adrenomedullary response to cardiac arrest, plasma epinephrine and norepinephrine levels were measured before, during, and after cardiac arrest in dogs. Ventricular fibrillation was induced in 12 dogs anesthetized with pentobarital sodium (30 mg/kg) and standard American Heart Association cardiopulmonary resuscitation (CPR) was begun using a mechanical device. At 6.5 minutes of CPR, naloxone (10 mg/kg) or 0.9% saline (10 ml) was given intravenously. At 12 minutes of CPR, the cardiac ventricles were electrically defibrillated. Plasma epinephrine and norepinephrine levels were measured before ventricular fibrillation; at 2.5, 4.5, 9.5, and 11.5, minutes of CPR; and at 5, 10, 15, and 20 minutes after resuscitation. Epinephrine and norepinephrine increased from prearrest levels of 3.66 +/- 0.67 (+/- SE) and 24.02 +/- 3.67 ng/ml to 66.67 +/- 9.65 and 74.00 +/- 9.91 ng/ml, respectively, at 4.5 minutes of CPR. After resuscitation, norepinephrine levels remained slightly elevated, while epinephrine fell to prearrest levels. Naloxone did not cause a significant change in either epinephrine or norepinephrine from 6.5 minutes of CPR (time of treatment) through 20 minutes postresuscitation. In addition, naloxone had no effect on either the end-diastolic pressure difference during CPR or resuscitation outcome. We conclude that cardiac arrest causes significant increases in plasma epinephrine and norepinephrine levels, which remain elevated for the duration of the arrest, and that naloxone has no effect on these levels.     

Continued circulatory support: effect of epinephrine or dopamine on 24-hour survival and neurologic function in dogs

The effects on 24-h survival and neurologic function were compared following continued postresuscitation circulatory support with epinephrine or dopamine. Cardiopulmonary arrest was induced by ventricular fibrillation. After 10 min, resuscitation efforts were initiated including i.v. infusion of either epinephrine (6 micrograms/kg per min, 11 dogs) or dopamine (10 micrograms/kg per min, 14 dogs) for continued circulatory support. There was no difference detected in duration of circulatory support, although dogs receiving epinephrine required more lidocaine (3.3 +/- 0.4 vs. 1.8 +/- 0.3 mg/kg, P = 0.005). Likewise, there was no statistically significant difference detected in MAP or HR between groups at any time tested. However, dogs receiving epinephrine had significantly worse neurologic function at 6 and 12 h postarrest. Mean survival time (20.3 +/- 1.2 vs. 15.3 +/- 1.9 h, P = 0.028) and overall survival (P = 0.027, survival curve analysis) were significantly longer for dogs receiving dopamine. Plasma glucose in the first 6 h postarrest was significantly higher in dogs receiving epinephrine (P = 0.006). These results suggest that the use of epinephrine for continued vasopressor support in cardiopulmonary resuscitation may contribute to decreased survival and poorer neurologic function in this controlled experimental setting. It is reasonable to propose that similar responses to these commonly used circulatory support agents occur clinically. Therefore, continued vasopressor support with dopamine rather than epinephrine may be justified in the setting of cardiac resuscitation.