(Stroke. 1996;27:1241-1248.)
© 1996 American Heart Association, Inc.
Articles |
Cerebral Oxygenation During Cardiopulmonary Resuscitation With Epinephrine and Vasopressin in Pigs
the Department of Anesthesiology and Critical Care Medicine, University of Ulm (Germany).
Correspondence to Dr Andreas W. Prengel, Universitatsklinik fur Anasthesiologie, Klinikum der Universitat Ulm, Steinhovelstr 9, 89075 Ulm, FRG.
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Background and Purpose Administration of vasopressin during cardiopulmonary resuscitation (CPR) improves vital organ blood flow compared with epinephrine, but the effect of vasopressin on cerebral oxygenation and cerebral venous hypercarbia during CPR has not previously been studied.
Methods Fourteen pigs were allocated to receive either epinephrine (0.2 mg/kg) or vasopressin (0.4 U/kg) after 4 minutes of ventricular fibrillation and 3 minutes of CPR. Cerebral blood flow was determined by radiolabeled microspheres, and arterial and cerebral venous blood gases were measured.
Results Cerebral blood flow, measured before and 90 seconds and 5 minutes after drug administration, was 9 (3; 12), 25 (19; 27), and 18 (10; 23) mL/min per 100 g (median and 25th and 75th percentiles, respectively) in the epinephrine group and 12 (5; 16), 51 (48; 70), and 53 (45; 63) mL/min per 100 g in the vasopressin group (P<.05 at 90 seconds, P<.01 at 5 minutes between groups). Five minutes after drug administration, cerebral venous PCO2 was 63 (59; 68) mm Hg in the epinephrine group and 47 (43; 55) mm Hg in the vasopressin group (P<.01); at the same time cerebral venous pH was 7.18 (7.17; 7.20) and 7.26 (7.22; 7.36) (P<.01) in the epinephrine and vasopressin groups, respectively. Cerebral oxygen extraction ratio, calculated before and 90 seconds and 5 minutes after drug administration, was 0.42 (0.32; 0.57), 0.47 (0.41; 0.57), and 0.56 (0.56; 0.64) in the epinephrine group and 0.43 (0.38; 0.45), 0.38 (0.25; 0.44), and 0.35 (0.33; 0.49) in the vasopressin group (P<.05 at 90 seconds and 5 minutes).
Conclusions Compared with epinephrine, vasopressin not only increases cerebral blood flow but also improves cerebral oxygenation and decreases cerebral venous hypercarbia when administered during CPR in pigs.
Key Words: cardiopulmonary resuscitation • cerebral blood flow • cerebral circulation • heart arrest • pigs
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Introduction |
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One of the most important factors for restoration of spontaneous circulation after cardiac arrest is vital organ blood flow during cardiopulmonary resuscitation (CPR).1 Adrenergic agonists improve vital organ blood flow by increasing perfusion pressure. Nonadrenergic vasopressor drugs such as angiotensin II and vasopressin have recently also been investigated for their effect on vital organ blood flow in pigs. Angiotensin II significantly improved cerebral blood flow when administered during ventricular fibrillation.2 Although it was demonstrated that 0.2 mg/kg epinephrine was the epinephrine dosage at which maximum vital organ blood flow could be achieved in a pig model of ventricular fibrillation, vital organ blood flow was greater after administration of 0.4 or 0.8 U/kg vasopressin than after 0.2 mg/kg epinephrine.3 4 In addition to increasing cerebral perfusion pressure, vasopressin may affect cerebral blood flow by dilation of major cerebral arteries and contraction of intracerebral arterioles.5 6 Preliminary studies have shown that epinephrine and vasopressin in doses of 0.2 mg/kg and 0.4 U/kg, respectively, were equipotent with respect to the increase in cerebral perfusion pressure during closed chest CPR in pigs. After administration of epinephrine during CPR, cerebral venous PCO2 was not affected by the improvement of cerebral blood flow.7 However, the potential effects of vasopressin on cerebral oxygenation and on cerebral venous PCO2 and pH have not been investigated. This study was therefore designed to test whether in comparison to 0.2 mg/kg epinephrine, 0.4 U/kg vasopressin increases cerebral blood flow, improves cerebral oxygenation, and normalizes cerebral venous hypercarbia and acidemia in a pig model of cardiac arrest.
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Surgical Preparation
This study was performed on 14 healthy pigs (crossbreed between Belgian and German domestic pigs) of 27 to 31 kg of body weight between 12 to 14 weeks of age and was approved by our institutional animal investigation committee. The animals were managed in accordance with the guidelines of the American Physiological Society. Before surgery all animals were fasted overnight except for free access to water.
The pigs were premedicated with 4 mg/kg azaperone IM 1 hour before surgical preparation. Anesthesia was induced with 15 mg/kg pentobarbital administered through an ear vein. The pigs were fixed in the dorsal recumbent position, and an endotracheal tube was inserted during spontaneous respiration. Ventilation was performed with a Servo ventilator (Servo 900, Siemens) with 65% nitrous oxide in oxygen at 20 breaths per minute and with a tidal volume adjusted to maintain arterial PCO2 at 35 mm Hg. Anesthesia was maintained by a continuous infusion of pentobarbital (0.4 mg/kg per minute) and a single dose of 0.015 mg/kg buprenorphine. Ringer's solution (6 mL/kg per hour) was administered continuously throughout the preparation and study periods with the use of an infusion pump. A standard lead II electrocardiogram was used to monitor cardiac rhythm.
Various intravascular catheters were advanced by femoral cutdown. For monitoring of arterial blood pressure and withdrawal of blood samples, a double-lumen 5F catheter was advanced into the descending aorta. Reference blood samples for measurement of organ blood flow were withdrawn from a separate 5F catheter placed in the descending aorta. Another 5F catheter was placed into the right atrium for drug administration and monitoring of right atrial pressure.
A 7F pigtail catheter with multiple distal side ports was placed into the left ventricle and used to inject radionuclide microspheres and iced saline solution (5 mL) for measurement of regional blood flow and cardiac output, respectively. For sampling of cerebral venous blood and measurement of sagittal sinus pressure, a burr hole was drilled into the skull over the midline, and a catheter was passed into the sagittal sinus so that the tip was 1.5 cm anterior to the confluence of the sinus. To prevent obstruction, all intravascular catheters were pressure flushed with normal saline containing sodium heparin 5 U/mL at a rate of 3 mL/h (Intraflow II, Abbott Laboratories). For the measurement of body temperature, a thermistor was placed into the abdominal aorta. Body temperature was recorded from this catheter and was maintained between 38.0°C and 39.0°C with the use of a heating pad. After completion of surgical preparation and before induction of cardiac arrest, 300 U/kg sodium heparin IV was administered to prevent intracardiac clot formation. All animals were autopsied to check correct positioning of the catheters and assess damage to the rib cage and internal organs.
Measurements
We measured sagittal sinus pressure and blood pressure by means of the saline-filled catheters using pressure transducers (model 1290A, Hewlett-Packard) that were calibrated to atmospheric pressure at the level of the right atrium. Pressure tracings were continuously recorded (7758 multichannel recorder, Hewlett-Packard), and mean pressures were obtained by electronic integration. Diastolic coronary perfusion pressure was defined as the difference between aortic and right atrial diastolic pressures. Cerebral perfusion pressure was defined as the difference between aortic and sagittal sinus mean pressures. Heart rate was determined from a simultaneously recorded electrocardiographic signal. Cardiac output was measured in triplicate by the thermodilution technique with a cardiac output computer (model 7905, Hoyer). Heart rate and arterial, central venous, and sagittal sinus pressures were recorded with the use of two monitors (model 78342A, Hewlett-Packard) and a data acquisition/control unit (model 9133, Hewlett-Packard) at intervals of 30 seconds before induction of cardiac arrest and at intervals of 1 second during CPR. Arterial and sagittal sinus blood gases were measured with a blood gas analyzer (IL 1302, Allied Instrumentation Laboratories) and corrected for body temperature. Hemoglobin content and oxygen saturation were measured with a CO oximeter (model 282, Allied Instrumentation Laboratories). Plasma glucose and lactate concentrations were measured by automated enzymatic methods. Oxygen content, cerebral oxygen delivery, and cerebral oxygen consumption were calculated according to the following formulas: Oxygen Content=Hemoglobinx1.38x%Saturation+(0.003xPO2); Cerebral Oxygen Delivery=Cerebral Blood FlowxArterial Oxygen Content; Cerebral Oxygen Consumption=Cerebral Blood FlowxArterial-Sagittal Sinus Oxygen Content Gradient. Cerebral oxygen extraction ratio was calculated by the following formula: Cerebral Oxygen Extraction Ratio=Cerebral Oxygen Consumption/Cerebral Oxygen Delivery. Cerebral metabolic rates of glucose and lactate, respectively, were calculated according to the following formulas: Cerebral Metabolic Rate of Glucose=Cerebral Blood FlowxArterial-Sagittal Sinus Glucose Gradient; Cerebral Metabolic Rate of Lactate=Cerebral Blood FlowxArterial-Sagittal Sinus Lactate Gradient.
Before and 90 seconds and 5 minutes after drug administration during CPR, regional organ blood flow was measured with radiolabeled microspheres according to the technique described by Heymann et al.8 Radioactive-labeled microspheres 141Ce, 95Nb, or 103Ru (New England Nuclear) had a mean diameter of 15±5 µm and a specific activity of 10 mCi/g. Each microsphere vial was placed in a water bath and subjected to ultrasonic vibration for 1 minute before injection. Approximately 5x105 microspheres, diluted in 10 mL normal saline, were then immediately injected into the left ventricle. With an automatic pump (Perfusor, Braun), arterial blood was continuously withdrawn from the descending aorta at a rate of 9.9 mL/min from 10 seconds before to 80 seconds after microsphere injection. At the end of the experiment, the entire heart and brain were removed. The organ tissue was weighed and homogenized, and radioactivity from tissue and blood was measured with a gamma scintillation spectrometer (LB 5300, Berthold).
Experimental Protocol
A 50-Hz, 60-V AC was applied through two subcutaneous needle electrodes to induce ventricular fibrillation. Cardiocirculatory arrest was defined as that point at which the aortic pulse pressure decreased to zero and the electrocardiogram showed ventricular fibrillation. Ventilation was stopped at this point in time. Four minutes after induction of cardiocirculatory arrest, closed chest CPR was begun with a pneumatically driven automatic piston device (Thumper, model 1003, Michigan Instruments). The chest compression rate was 80/min, and the duration of compression was 50% of the total cycle time. The compression pad of the device was wired to the midsternum to ensure a constant contact with the animal's chest wall and to prevent displacement of the pad during CPR. In both groups, a compression force of 500 N was held constant during the course of CPR and resulted in a 25% displacement of the anteroposterior diameter of the animal's chest. Decompression was allowed to occur passively. Mechanical ventilation with an FIO2 of 1.0 at 20 breaths per minute was performed independent of chest compression at a tidal volume shown to result in an arterial PCO2 of 35 mm Hg before induction of cardiac arrest.
After 3 minutes of CPR, animals were randomly assigned to receive either 0.2 mg/kg epinephrine (n=7) or 0.4 U/kg vasopressin (n=7) given through the right atrial catheter over a period of 5 seconds. Both drugs were diluted to 10 mL in 0.9% saline solution. The investigators were blinded to the use of drugs. Hemodynamic measurements and acquisition of blood samples were performed before induction of ventricular fibrillation, before drug administration (ie, after a total of 7 minutes of arrest, including 3 minutes of CPR), and 90 seconds and 5 minutes after drug administration.
Immediately after the last blood sample during CPR was acquired (ie, after a total of 12 minutes of arrest, including 8 minutes of CPR), DC shocks were applied to restore spontaneous circulation. Initially, three DC countershocks were administered in rapid succession at an energy setting of 3 J/kg. In case of persisting ventricular fibrillation, the same drug was administered at the same dose that had been used before, and after an additional 90-second period of CPR, three countershocks at an energy setting of 5 J/kg were administered in rapid sequence. The same protocol (without defibrillation) was used if asystole or pulseless electric activity occurred. Successful resuscitation was defined as the presence of coordinated electric activity together with a systolic blood pressure greater than 90 mm Hg and a diastolic blood pressure greater than 40 mm Hg for a duration of at least 5 minutes, during which no further resuscitative measures were applied.
Statistical Analysis
Values are expressed as median and 25th and 75th percentiles. For comparisons within groups, the Wilcoxon signed rank test was used to determine differences during CPR before and 90 seconds after drug administration. The Mann-Whitney U test was used to determine differences between groups. Regression analysis was performed to determine correlations between different variables. Statistical significance was considered at P<.05.
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Hemodynamics, acid-base and gas transport variables, and organ blood flow did not differ significantly either before induction of cardiac arrest or during CPR before drug administration. After performance of CPR, two animals in the epinephrine group and seven in the vasopressin group could be successfully resuscitated and survived the 4-hour observation period. Autopsy revealed no damage to the thoracic cage or the internal organs in either group.
Hemodynamics and Left Ventricular Blood Flow
Ninety seconds after drug administration during CPR, mean arterial pressure increased in both the epinephrine and vasopressin groups (P<.05). In comparison to the epinephrine group, the mean arterial pressure of the vasopressin group was greater 5 minutes after drug administration (P<.05). The cardiac index decreased with epinephrine and with vasopressin 90 seconds after drug administration. Between groups, the cardiac index and right atrial pressure were not significantly different at any point in time (Table 1
). Ninety seconds after drug administration, diastolic coronary perfusion pressure was greater than before drug administration in epinephrine- as well as vasopressin-treated animals (P<.05). Compared with epinephrine, diastolic coronary perfusion pressure was greater in vasopressin-treated animals 5 minutes after drug administration (P<.05). In the epinephrine and vasopressin groups, left ventricular blood flow increased 90 seconds after drug administration compared with before drug administration (P<.05). Ninety seconds and 5 minutes after drug administration, left ventricular blood flow was greater in animals subjected to vasopressin compared with epinephrine (P<.01) (Fig 1).
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) and 0.4 U/kg vasopressin (
). Each box plot represents median, 25th and 75th percentiles, and minimum and maximum values. *P<.05 vs epinephrine; 
P<.01 vs epinephrine; 
P<.05 vs before drug administration (DA).
Cerebral Perfusion Pressure and Cerebral Blood Flow
Cerebral perfusion pressure increased in the epinephrine and vasopressin groups 90 seconds after drug administration (P<.05). In comparison to epinephrine, cerebral perfusion pressure was greater in vasopressin-treated animals 5 minutes after drug administration (P<.01). Total cerebral blood flow increased in both groups 90 seconds after drug administration (P<.05) and compared with epinephrine was greater in animals subjected to vasopressin 90 seconds (P<.05) as well as 5 minutes (P<.01) after drug administration (Fig 2). This same pattern of blood flow improvement was found in all investigated regions of the brain (Table 2).
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Cerebral Acid-Base Status and Metabolism
Five minutes after drug administration, sagittal sinus PCO2 was smaller and sagittal sinus pH was greater in vasopressin-treated animals compared with epinephrine-treated animals (P<.01). At the same time, the sagittal sinus O2 content was greater and the arterial-sagittal sinus O2 gradient was smaller in animals subjected to vasopressin than in those subjected to epinephrine (P<.05). The sagittal sinus-arterial PCO2 gradient [P(ss-a)CO2] was lower in the vasopressin group 5 minutes after drug administration compared with epinephrine, while the arterial-sagittal sinus pH gradient did not differ between groups at any time. With epinephrine (P<.05) but not with vasopressin, the arterial-sagittal sinus pH gradient further increased significantly 90 seconds after compared with before drug administration (Table 3). Ninety seconds after drug administration, cerebral O2 delivery and consumption were greater and O2 extraction was less in vasopressin-treated compared with epinephrine-treated animals. Five minutes after drug administration, cerebral O2 consumption was not significantly different between groups, but O2 delivery was greater and O2 extraction less with vasopressin than epinephrine (Fig 3). None of the animals in the epinephrine group and all but one animal in the vasopressin group had oxygen delivery indices greater than 4 mL/min per 100 g 90 seconds and 5 minutes after drug administration (Fig 4). During CPR before drug administration, in the epinephrine group (r2=.83, P<.01) as well as the vasopressin group (r2=.96, P<.001) there were significant correlations between cerebral oxygen delivery and consumption. Ninety seconds and 5 minutes after drug administration, in the epinephrine group (r2=.64, P<.05 and r2=.82, P<.01) but not the vasopressin group (r2=.46 and r2=.35) cerebral oxygen delivery and consumption were significantly correlated. Five minutes after drug administration, there was a significant negative correlation between total cerebral blood flow and the P(ss-a)CO2 in the vasopressin group (r2=.64, P<.05). No such correlation was found in the epinephrine group. Compared with epinephrine, the cerebral metabolic rate of glucose was greater in the vasopressin group 5 minutes after drug administration (P<.05).
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Discussion |
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Comparison of the hemodynamic effects of epinephrine and vasopressin administered during CPR revealed a sustained effect on mean arterial pressure in those animals treated with vasopressin. This long-lasting effect on arterial blood pressure is the most probable reason for the intergroup differences in coronary as well as cerebral perfusion pressure at 5 minutes after drug administration. In this study, as in a previous study comparing different doses of vasopressin with epinephrine, vital organ blood flow was greater 5 minutes after administration of 0.4 U/kg vasopressin compared with 0.2 mg/kg epinephrine.4
While at 90 seconds after drug administration myocardial and cerebral blood flow were significantly higher after vasopressin administration compared with epinephrine, between both groups myocardial (P=.06) and cerebral perfusion pressure (P=.95) did not differ significantly. A relatively small sample size may have prevented diastolic coronary perfusion pressure being statistically significant between groups at this time, but mechanisms other than increased cerebral perfusion pressure must be discussed as potential reasons for the marked increase in cerebral blood flow. In cats vasopressin selectively dilated large cerebral arteries.9 In isolated canine basilar arteries, vasopressin induced concentration-dependent inhibition of myogenic tone,10 and cerebral blood flow increased by 100% after administration of vasopressin in dogs.11 In a canine model, it was demonstrated that the vasopressin-induced dilatation of basilar arteries was suppressed by preadministration of NG-monomethyl-L-arginine, which inhibits the synthesis of nitric oxide.12 In guinea pigs, vasopressin-immunoreactive nerve fibers surrounding cerebral arteries may play a role in cerebral circulation.13 During stable hemodynamic conditions, the overall effect of vasopressin on cerebral blood flow may be considered the summation of increased flow, resulting from large vessel dilatation by the release of nitric oxide from the endothelium, and of decreased flow in contracted small vessels.14 15 The results of the present study indicate that under CPR conditions, the effect of exogenously administered vasopressin (0.4 U/kg) on cerebral circulation is increased blood flow in all investigated regions of the brain.
This study confirms previous investigations showing that a large PCO2 gradient exists between venous and arterial blood during CPR, not only for the body as a whole but also for individual organs.16 17 18 An increased PCO2 gradient between mixed venous and arterial blood is a marker of low-flow states,18 and mixed venous hypercarbia may be considered to represent tissue PCO2 under low-flow conditions.19 Since mixed venous PCO2 does not mirror the PCO2 of individual tissues, sagittal sinus blood was taken to represent cerebral acid-base status. Ninety seconds after drug administration, the P(ss-a)CO2 of both groups was not statistically different compared with that before drug administration. Five minutes after drug administration, the P(ss-a)CO2 of the vasopressin group was significantly less compared with the epinephrine group and was even less than that before drug administration. While during the early period after drug administration greater absorption of tissue-stored CO2 into the blood may have prevented a decrease in P(ss-a)CO2, in the later phase, ie, 5 minutes after drug administration, the sustained improvement of cerebral blood flow in the vasopressin group may well have caused the reduction of P(ss-a)CO2 compared with the epinephrine group. Unlike the case with epinephrine, in which the effectiveness of this drug in terms of improving cerebral blood flow could not be evaluated by measuring PCO2 values in cerebral venous blood,5 the effectiveness of vasopressin in terms of increasing cerebral blood flow seems to be strong enough to significantly influence cerebral venous PCO2 values during CPR.
During CPR after administration of vasopressin, cerebral blood flow values of approximately 50 mL/min per 100 g and cerebral oxygen consumption of approximately 2 mL/min per 100 g were close to those values that have been reported in anesthetized pigs during stable circulatory conditions.20 21 Although there is no evidence that during CPR epinephrine influences cerebral oxygen consumption independent of its action in raising arterial blood pressure,22 oxygen extraction in this as in another study has been shown to increase continuously during CPR with epinephrine in pigs.21 In contrast, after vasopressin administration, when oxygen delivery was at a significantly higher level, oxygen extraction decreased during CPR. Since 5 minutes after drug administration cerebral glucose utilization was greater in the vasopressin group than in the epinephrine group, there is no evidence that cerebral metabolism was more reduced after vasopressin administration than after administration of epinephrine. In the vasopressin group, the lack of any correlation between oxygen delivery and consumption may indicate that oxygen delivery is sufficiently high to enable consumption to be independent of delivery. Taken together, these results suggest that in the vasopressin group the observed decrease in oxygen extraction represents improved cerebral oxygenation compared with epinephrine.
Our study is limited in several ways. Since oxygen delivery and consumption were calculated with cerebral blood flow as a shared variable, there is a potential for mathematical coupling of measurement errors and thus of overestimating correlations between oxygen delivery and consumption. On the other hand, mathematical coupling would have biased correlations in both groups. Oxygen delivery and consumption were not found to be correlated at either 90 seconds or 5 minutes after administration of vasopressin, suggesting that mathematical coupling does not explain the observed correlations between cerebral oxygen delivery and consumption in the epinephrine group. Potential influences of barbiturate administration as well as of other anesthetic drugs prevent conclusions on the meaning of the absolute oxygen transport and acid-base values. Apart from vasopressor therapy, however, the animals of both groups were treated in the same manner, and therefore the observed intergroup differences are independent of the anesthetics used. In this study, arginine vasopressin was administered exogenously during CPR. However, in contrast to most species, pigs secrete lysine vasopressin rather than arginine vasopressin. In piglets, lysine vasopressin dilated pial arterioles during normotension but constricted pial arterioles that were previously di-lated.23 Since the affinity of lysine vasopressin recep-tors for arginine vasopressin may differ from that of arginine vasopressin receptors, dose responses obtained in pigs cannot be translated to humans. However, since humans have arginine vasopressin receptors, it is suggested that the circulatory effects of arginine vasopressin administered to humans will be more pronounced than those in pigs. Finally, since we did not evaluate cerebral function after restoration of spontaneous circulation, we cannot state whether the improvement in cerebral oxygenation and cerebral acid-base status after administration of vasopressin might have had an impact on cerebral outcome after restoration of spontaneous circulation.
In conclusion, this study shows that compared with epinephrine, the effectiveness of vasopressin in increasing cerebral blood flow when given during CPR results in improved cerebral oxygenation and acid-base status.
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Acknowledgments |
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This study was supported in part by a grant from the Laerdal Foundation, Stavanger, Norway.
Received January 15, 1996; revision received March 11, 1996; accepted March 25, 1996.
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References |
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Lindner KH, Prengel AW, Pfenninger EG, Lindner IM, Strohmenger HU, Georgieff M, Lurie KG. Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation. 1995;91:215-221.
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Suzuki Y, Satoh S, Oyama H, Takayasu M, Shibuya M. Regional differences in the vasodilator response to vasopressin in canine cerebral arteries in vivo. Stroke. 1993;24:1049-1054.
6. Takayasu M, Kajita Y, Suzuki Y, Shibuja M, Sugita K, Ishikawa T, Hidaka H. Triphasic response of rat intracerebral arterioles to increasing concentrations of vasopressin in vitro. J Cereb Blood Flow Metab. 1993;13:304-309.[Medline] [Order article via Infotrieve]
7. Lindner KH, Ahnefeld FW, Bowdler IM, Prengel AW. Influence of epinephrine on systemic, myocardial, and cerebral acid-base status during cardiopulmonary resuscitation. Anesthesiology. 1991;74:333-339.[Medline] [Order article via Infotrieve]
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Faraci FM, Mayhan WG, Schmid PG, Heistad DD. Effects of arginine vasopressin on cerebral microvascular pressure. Am J Physiol. 1988;255:H70-H76.
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Katusic ZS, Shepherd JT, Vanhoutte PM. Vasopressin causes endothelium-dependent relaxations of the canine basilar artery. Circ Res. 1984;55:575-579.
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Hurn PD, Wilson DA, Hansen RB, Hanley DF, Traystman RJ. Vasopressin and oxytocin: modulators of neurohypophysial blood flow. Am J Physiol. 1993;265:H2027-H2035.
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13. Itakura T, Okuno T, Ueno M, Nakakita K, Nakai K, Naka Y, Imai H, Kamei I, Komai N. Immunohistochemical demonstration of vasopressin nerve fibers in the cerebral artery. J Cereb Blood Flow Metab. 1988;8:606-608.[Medline] [Order article via Infotrieve]
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Faraci FM, Heistad DD. Regulation of cerebral blood vessels by humoral and endothelium dependent mechanisms. Hypertension. 1991;17:917-922.
15. Tsugane S, Suzuki Y, Kano T, Takayasu M, Shibuya M, Sugita K. Differing effects of vasopressin on regional cerebral blood flow of dogs following intracisternal vs. intra-arterial administration. Life Sci. 1993;15:241-246.
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Von Planta M, Weil MH, Gazmuri MJ, Bisera J, Rackow EC. Myocardial acidosis associated with CO2 production during cardiac arrest and resuscitation. Circulation. 1989;80:684-692.
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Editorial Comment
Anesthesiology/Critical Care, The Johns Hopkins Medical Institutions, Baltimore, Md
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Clinical studies indicate that early defibrillation is one of the most critical factors for reducing cerebral ischemic damage after ventricular fibrillation.1R In experimental studies, the success of defibrillation is associated with increasing coronary blood flow to at least 20 mL/min per 100 g during cardiopulmonary resuscitation (CPR).2R However, basic life support CPR generally generates coronary and cerebral blood flow less than 20 mL/min per 100 g and thereby extends the period of ischemia.3R Advanced life support CPR has relied on early administration of epinephrine to selectively constrict peripheral vascular beds, raise arterial pressure, and redirect the limited cardiac output generated by chest compressions to heart and brain, where
-adrenergic vasoconstriction is less prominent.2R In an attempt to maximize this redistribution, high doses of epinephrine have been tried in clinical trials, but high doses generally have not been found to be superior to standard doses of epinephrine.4R Whether high doses of epinephrine exert an adverse cellular or metabolic effect in the ischemic myocardium remains an unresolved issue. In a recent study, Lindner et al5R observed that bolus injection of 0.4 U/kg vasopressin during CPR in pigs resulted in greater coronary and cerebral blood flow than bolus injection of epinephrine. The greater flow 5 minutes after injection was attributable to the more prolonged increase in arterial pressure with vasopressin, presumably reflecting its long circulating half-life during CPR. In the present study, in which the same model of 4 minutes of cardiac arrest followed by 3 minutes of CPR was used, Prengel et al confirmed that bolus injection of 0.4 U/kg of vasopressin produced a greater increase in both coronary and cerebral blood flow. In addition, there are several new and interesting findings in the present study. First, blood flow was increased not only at 5 minutes when perfusion pressure was greater with vasopressin, but also 90 seconds after injection when coronary and cerebral perfusion pressures were nearly equivalent with epinephrine and vasopressin injection. This finding implies that coronary and cerebral arterioles are not maximally dilated during the subnormal perfusion pressures generated by chest compressions after a period of no flow. As discussed by the authors, there is experimental evidence that vasopressin can act as a vasodilator in cerebral arterioles. Second, the greater blood flow in brain with vasopressin administration occurred throughout the neuroaxis. Third, the greater cerebral blood flow provided for a greater cerebral O2 consumption. The greater O2 consumption was not the result of an overstimulation of metabolism because cerebral O2 extraction fell and O2 uptake became independent of O2 delivery. Therefore, these promising results indicate that vasopressin may possess some advantages over epinephrine in restoring regional cerebral blood flow and metabolism during CPR until spontaneous circulation can be restored. Because the ventricles of all pigs receiving vasopressin could be defibrillated, vasopressin does not appear to exert an adverse effect on the defibrillating threshold.
There are also some limitations of the study to consider before these findings are extended to humans. First, the pigs were young and healthy, whereas cardiac arrest in patients is associated with a wide spectrum of atherosclerotic disease. The increase in blood flow with either epinephrine or vasopressin may be highly variable and produce a large variability in successful defibrillation and neurological outcome, as typically seen in clinical trials. Second, the pressor drugs in the present study were injected at 3 minutes of CPR after a period of 4 minutes of arrest. With longer periods of arrest and CPR, the pressor effect may be diminished. Third, arginine vasopressin was injected, whereas the pig secretes lysine vasopressin. The dose-response curve to arginine vasopressin in the pig may differ from that in humans and other species in which arginine vasopressin is the endogenous form. Fourth, endogenous plasma vasopressin concentration in cardiac arrest victims may be increased 50- to 100-fold, and exogenous administration may have only a marginal effect.6R Despite these limitations, the present results with arginine vasopressin in the pig are promising and warrant further investigation.
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1R. Weaver WD, Copass MK, Bufi B, Ray R, Hallstrom AP, Cobb LA. Improved neurologic recovery and survival after early defibrillation. Circulation. 1984;69:943-948.
2R.
Michael JR, Guerci AD, Koehler RC, Shi A-Y, Tsitlik J, Chandra N, Niedermeyer E, Rogers MC, Traystman RJ, Weisfeldt ML. Mechanisms by which epinephrine augments cerebral and myocardial perfusion during cardiopulmonary resuscitation in dogs. Circulation. 1984;69:822-835.
3R. Koehler RC, Eleff SM, Traystman RJ. Global neuronal ischemia and reperfusion. In: Paradis NA, Halperin HR, Nowak RM, eds. Cardiac Arrest: The Science and Practice of Resuscitation Medicine. Baltimore, Md: Williams & Wilkins; 1996:113-145.
4R. Brown CG, Martin DR, Pepe PE, Stueven H, Cummins RO, Gonzales E, Jastremski M. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med. 1992;327:1051-1055.[Abstract]
5R. Lindner KH, Prengel AW, Pfenninger EG, Linder IM, Strohmenger H-U, Georgieff M, Lurie KG. Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in dogs. Circulation. 1995;91:215-221.
6R. Lindner KH, Strohmenger HU, Ensinger H, Hetzel WD, Ahnefeld FW, Georgieff M. Stress hormone response during and after cardiopulmonary resuscitation. Anesthesiology. 1992;77:662-668.[Medline] [Order article via Infotrieve]
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