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(Circulation. 1995;92:1020-1025.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin II Augments Reflex Activity of the Sympathetic Nervous System During Cardiopulmonary Resuscitation in Pigs
From the Department of Anesthesiology and Critical Care Medicine, University of Ulm, Germany.
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Abstract |
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Background During hypotensive states, angiotensin II augments reflex activity of the sympathetic nervous system. The purpose of the present study was to assess the effects of this vasoconstrictor on myocardial blood flow and plasma catecholamine concentrations during and after CPR.
Methods and Results After 4 minutes of ventricular fibrillation and 3 minutes of open-chest CPR, 14 pigs (24 to 26 kg) were randomized into two groups receiving either saline (n=7) or 0.05 mg/kg angiotensin II (n=7). Arterial plasma catecholamine concentration was measured with high-pressure liquid chromatography. Organ blood flow was measured with radiolabeled microspheres. During CPR, after drug administration, left ventricular myocardial blood flow was significantly higher in the angiotensin II–treated group than in the control group. During CPR, median epinephrine concentrations before and 90 seconds and 5 minutes after drug administration were 63.0, 35.2, and 22.5 ng/mL, respectively, in the control group and 63.2, 139.8, and 154.2 ng/mL, respectively, in the angiotensin II group (P<.001 at 90 seconds and P<.01 at 5 minutes). At the same times, median norepinephrine concentrations were 52.6, 59.8, and 33.9 ng/mL, respectively, in the control group and 42.5, 98.7, and 111.3 ng/mL, respectively, in the angiotensin II group (P<.01 at 5 minutes). Restoration of spontaneous circulation was possible in all of the angiotensin II–treated pigs, whereas only 3 of the 7 saline-treated pigs could be resuscitated. At 5 minutes after successful resuscitation, epinephrine was 6.8 ng/mL in the control group and 16.1 ng/mL in the angiotensin II group (P<.05).
Conclusions During CPR, angiotensin II appears to increase coronary perfusion pressure and myocardial blood flow, not only by direct peripheral arteriolar vasoconstriction via angiotensin II receptors but also by inducing a massive catecholamine release with adrenergic peripheral vasoconstriction.
Key Words: angiotensin • cardiopulmonary resuscitation • nervous system
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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It has recently been demonstrated that angiotensin II, a nonadrenergic vasopressor octapeptide, improves coronary perfusion pressure, myocardial blood flow, and short-term resuscitation success during CPR in a dog and a pig model.1 2 3 Angiotensin II increases total peripheral vascular resistance by receptor-mediated arteriolar vasoconstriction.4 In hypotensive and hypovolemic states, endogenously released angiotensin II augments reflex activity of the sympathetic nervous system.5 In anesthetized animals, the administration of large doses of angiotensin II leads to an increase in plasma catecholamine concentrations from the adrenal medullae and from sympathetic nerve terminals.6 7 The purpose of the present study was to assess the effects of angiotensin II on hemodynamics and on plasma catecholamine concentrations during and after CPR.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Surgical Preparation
The present study was performed on 14 healthy, 12- to 14-week-old domestic pigs weighing 24 to 26 kg. It was approved by our institutional animal investigation committee. The animals had been kept at the local animal care facility according to the guidelines of the American Physiological Society. Animals were fasted overnight for approximately 10 hours before surgery but had free access to water. They were premedicated with azaperon (4 mg/kg IM) and atropine (0.1 mg/kg IM) 1 hour before surgery. Anesthesia was induced with 10 mg/kg metomidate given via an ear vein. The pigs then were placed and fixed in the dorsal recumbent position. Endotracheal tubes were inserted during spontaneous respiration. The animals were ventilated with a Servo ventilator 900 (Servo, Siemens) with 65% nitrous oxide in oxygen at a rate of 24 breaths per minute with tidal volumes adjusted to maintain the arterial PCO2 between 35 and 40 mm Hg. Anesthesia was maintained by a continuous intravenous infusion of metomidate (0.5 mg · kg-1 · h-1) and a single dose of buprenorphine (0.03 mg/kg). Lactated Ringer's solution (6 mL · kg-1 · h-1) was administered continuously throughout the preparation and study period by an infusion pump (Infusomat, Braun). A standard lead II ECG was used to monitor cardiac rhythm.
A double-lumen 7F catheter was advanced by femoral cutdown into the descending aorta for monitoring blood pressure and withdrawing blood samples for blood gas analysis. Reference blood samples for measurement of organ blood flow were withdrawn from a 5F catheter in the descending aorta. Two separate 5F catheters were placed into the right atrium for drug administration and for pressure monitoring. A 5F pulmonary artery catheter (Swan-Ganz, Baxter Edwards Laboratories) was placed under pressure control into the pulmonary artery via a branch of the external jugular vein. A second intravenous bolus of 0.03 mg/kg buprenorphine was administered, and the thorax was opened by median sternotomy. A 7F pigtail catheter with multiple distal side ports was placed under pressure control via femoral cutdown into the left ventricle. This catheter was used to inject iced saline solution (5 mL) to measure cardiac index and radionuclide microspheres to measure myocardial blood flow. The thermistor of the cardiac output computer (model 7905, Hoyer) was placed via femoral artery cutdown in the thoracic aorta. Body temperature was recorded from this thermistor (blood temperature) and maintained between 37.5° and 38.5°C with the use of a heating pad. All catheters were pressure flushed with saline containing 5 U heparin/mL at a rate of 3 mL/h (Intraflo II, Abbott Laboratories). All animals underwent a necropsy to check the correct position of the catheters.
Measurements
Aortic and right atrial pressures were measured
via the
saline-filled catheters with pressure transducers (model 1290A, Hewlett
Packard) that were calibrated to atmospheric pressure at the level of
the right atrium. Pressure tracings were continuously recorded
(model 7758 multichannel recorder, Hewlett Packard), and mean
pressures were obtained by electronic integration. Heart rate was
determined from a simultaneously recorded ECG signal.
Coronary perfusion pressure was defined as the arteriovenous
pressure difference (time-coincident difference between aortic and
right atrial diastolic pressures) and was measured with an
electronic substraction unit. Cardiac output was measured in triplicate
by thermodilution technique with 5 mL saline at 4°C. Saline
injections into the left atrium were given at varying points in time
throughout the respiratory cycle.
Measurements were recorded before arrest and during the period of open-chest CPR with a monitor (model 78342A, Hewlett Packard) and a data acquisition/control unit (model 9133, Hewlett Packard). On-line measurements were performed at 30-second intervals before induction of cardiac arrest and after restoration of spontaneous circulation (ROSC) and at 1-second intervals during CPR. Arterial 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). Arterial glucose and lactate concentrations were determined with a lactate analyzer (2300 STAT glucose/lactate analyzer, Yellow Springs Instruments). Oxygen content was calculated using the following formula: Oxygen Content=Hemoglobinx1.38xSO2±0.0031xPO2.
Plasma
Catecholamine Analysis
Arterial plasma catecholamine
concentrations were measured with high-pressure liquid
chromatography with electrochemical detection (Waters
Associates).8 Immediately after
centrifugation and the addition of an antioxidizing
stabilizer, the plasma was frozen at -76°C until the time of
analysis. The analysis of plasma
catecholamine analysis was based on their selective
isolation by absorption onto surface-activated aluminum oxide
at pH 8.7 (2 mol/L Tris buffer) and subsequent elution with a solution
containing 250 mg EDTA, 500 mg sodium disulfate, and 12.5 mL of 0.2
mol/L acetic acid. This method is sensitive to <10 ng/L of
epinephrine or norepinephrine. Interassay
coefficients of variation were <10% for both epinephrine and
norepinephrine.
Myocardial blood flow was measured by the use of radiolabeled microspheres as previously described.9 Blood flow was measured in the present study before and at 90 seconds and 5 minutes after drug administration during CPR. Microspheres radioactively labeled with 141Ce, 95Nb, or 103Ru (New England Nuclear) had a mean diameter of 15±1.5 µm and a specific activity of 10 mCi/g. Each microsphere vial was placed into a water bath and subjected to ultrasonic vibration for 1 minute before injection. Approximately 5x105 microspheres, diluted in 10 mL 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 was removed. The left ventricular free wall was sectioned into three layers. Aliquots of each tissue were weighed, homogenized, and then placed into vials. Radioactivity from tissues and blood was measured with a gamma scintillation spectrometer (model LB 5300, Berthold).
Experimental Protocol
Before the induction of
cardiocirculatory arrest,
hemodynamic parameters,
arterial and blood gases, and glucose and lactate
concentrations were measured simultaneously. A 50-Hz, 60-V
alternating current was applied via 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 ECG showed ventricular fibrillation.
Ventilation was stopped at this point. After 4 minutes of arrest,
open-chest CPR was performed at a rate of 90 compressions per minute
with a thumb of the right hand placed on the lef t ventricle while the
fingers encircled the right ventricle. Mechanical ventilation with an
FIO2 of 1.0 at 24 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 0.05 mg/kg
angiotensin II in 10 mL normal saline (n=7) or 10 mL normal
saline (n=7) given via the right atrial catheter during a period of 5
seconds. During the arrest, the animals were allocated to drug
treatment by random numbers. The investigators were blinded to the use
of drugs. Hemodynamic measurements, measurement of
hemodynamic variables, and acquisition of aortic
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, as well as at 5,
15, 30, and 60 minutes when resuscitation was successful. Immediately
after acquiring the last blood sample during CPR (ie, after a total of
12 minutes of arrest, including 8 minutes of CPR), we attempted to
restore spontaneous circulation with direct-current shocks. Three
direct-current countershocks were initially administered in rapid
succession at an energy setting of 20 J. If ventricular
fibrillation or ventricular tachycardia persisted,
the same drug was administered at the same dose as previously given,
and CPR was reinitiated for an additional 60 seconds. Three DC shocks
(20 J, 20 J, and 40 J) then were delivered again in rapid sequence. The
same protocol (without defibrillation) was used if asystole or
pulseless electrical activity developed. Successful resuscitation was
defined as the presence of coordinated electrical activity, systolic
blood pressure of >90 mm Hg, and diastolic blood pressure
of >40 mm Hg for at least 5 minutes, during which no further
resuscitative measures were applied.
Statistical Analysis
Data are given as median values, with
25th and 75th percentile
values given in parentheses. All data were stored on a computer system
(Hewlett Packard 9000, type 300). Comparison of resuscitation success
between the two groups was assessed with Fisher's exact test. The
Mann-Whitney U test (two-tailed) was used to determine
differences between the groups. For multiple comparisons within one
group, the Bonferroni method was applied. Statistical significance was
considered at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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All animals in the angiotensin II–treated group were successfully resuscitated, whereas spontaneous circulation was restored in only 3 of the 7 control group animals (P<.05). One angiotensin II–treated animal required two additional injections of the same drug and dose as initially given.
Myocardial Perfusion
Coronary artery perfusion pressure is a
major determinant
of myocardial blood flow. During CPR but before drug administration,
this parameter was 27 mm Hg (25 and 32) in the control
group and 26 mm Hg (22 and 37) in the angiotensin
II–treated group (Table 1
). Ninety seconds and 5
minutes after drug administration, coronary perfusion pressure
was 21 mm Hg (19 and 29) and 20 mm Hg (18 and 26) in the control
group pigs and 41 mm Hg (39 and 61) and 26 mm Hg (23 and 35) in
the angiotensin II–treated pigs (P<.001
at 90 seconds and P<.05 at 5 minutes). Before drug
administration during CPR, total myocardial blood flow was 74
mL · min-1 · 100 g-1 (63 and
84) in
the control group and 71 mL · min-1 · 100
g-1 (66 and 86) in the angiotensin II–treated
group. Myocardial blood flow was 67
mL · min-1 · 100 g-1 (53 and
69) at
90 seconds and 55 mL · min-1 · 100
g-1 (44 and 65) at 5 minutes after saline compared with
134 mL · min-1 · 100 g-1 (115
and
136) at 90 seconds and 72 mL · min-1 · 100
g-1 (65 and 81) at 5 minutes after angiotensin
II. There was a significant difference between the two groups at both
points in time (P<.001 at 90 seconds and P<.05
at 5 minutes).
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During CPR, the mean arterial pressure of the
angiotensin II group was significantly higher than in the
control group at both times after drug administration, whereas at 90
seconds after drug administration the cardiac index of the
angiotensin II group was significantly lower (Table 2).
However, there was no difference in
arterial and mixed venous partial pressure of oxygen, in
arterial and mixed venous oxygen content, in arteriovenous
oxygen content difference, or in plasma lactate concentrations. At 5
minutes after drug administration during CPR and at 5 minutes after
ROSC, there was a trend toward a higher glucose concentration in the
angiotensin II–treated animals. Glucose concentrations
were significantly higher at 15 and 30 minutes after ROSC in the
angiotensin II group than in the control group.
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Differences in plasma
catecholamine concentrations between
the two groups are shown in Table 3. Prearrest
epinephrine concentrations were 1.2 ng/mL in both groups.
During CPR before drug administration, epinephrine
concentrations increased dramatically to 63.0 ng/mL in the saline group
and to 63.2 ng/mL in the angiotensin II group. After drug
administration, a significantly higher epinephrine
concentration was measured in the angiotensin II–treated
animals. At 5 minutes after ROSC a significant difference between the
two groups was still present. Before induction of cardiac arrest,
median norepinephrine concentrations were 0.3 ng/mL in the
saline group and 0.5 ng/mL in the angiotensin II group.
During CPR and at 90 seconds after drug administration, there was no
difference between the two groups, whereas norepinephrine
was significantly higher at 5 minutes after drug administration in the
angiotensin II group.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The nonadrenergic substance angiotensin II is an octapeptide with strong vasoconstricting effects mediated by specific angiotensin II receptors.10 Administration of 0.05 mg/kg angiotensin II during open-chest CPR generated an increase in coronary perfusion pressure and myocardial blood flow. Angiotensin II stimulated the massive release of epinephrine and norepinephrine into the circulation, which in turn might enforce peripheral vasoconstriction, improve vital organ perfusion, and therefore improve resuscitation success.
The vasoconstricting effects of angiotensin II are more potent than those of adrenergic vasoconstrictor hormones.11 Under normal cardiocirculatory conditions, angiotensin II elicits generalized arteriolar vasoconstriction by causing receptor-mediated smooth muscle contraction.12 13 Former studies have shown that the administration of 0.05 mg/kg angiotensin II increases coronary perfusion during open-chest and closed-chest CPR.1 2 After angiotensin II, both coronary venous PCO2 and arteriocoronary venous PCO2 and pH gradients as well as myocardial lactate production were significantly lower, indicating that the angiotensin II–induced increase in myocardial blood flow reduced anaerobic metabolism and therefore normalized these gradients and improved short-term resuscitation success.
Angiotensin II plays an important role in the interaction between the sympathetic nervous system and the renin–angiotensin system.5 It facilitates the release and suppresses the reuptake of norepinephrine from nerve terminals and enhances vascular sensitivity to norepinephrine.14 15 16 17 Furthermore, it stimulates the release of catecholamines from the adrenal medulla, which contains a high density of the angiotensin1-receptor subtype (AT1-receptor), which appears to be responsible for catecholamine release.10 18 Angiotensin II–induced increase in epinephrine secretion is blocked by the specific AT1-receptor antagonist losartan.19 Administration of angiotensin II into the blood flow of the adrenal medulla or into the isolated perfused adrenal gland induces an increased catecholamine secretion.20 21 A comparison with a previous study demonstrates that the supraphysiological dose of 0.05 mg/kg angiotensin II increases plasma epinephrine concentration to a similar extent as high-dose epinephrine as used during CPR to improve vital organ blood flow.8 The higher glucose concentration in the angiotensin II group after ROSC may be mediated by epinephrine-induced gluconeogenesis from the liver,22 skeletal muscle insulin resistance,23 and inhibition of insulin release.24 Norepinephrine plasma concentrations are an indicator of sympathetic nervous system activity,25 although it is influenced not only by the rate of norepinephrine release but also by the reuptake rate of the sympathetic nerve terminal and the metabolic clearance from plasma.26 The endogenously released norepinephrine concentrations are usually below the threshold concentration of 1.8 ng/mL required to cause hemodynamic and metabolic effects.27 The elevation of plasma norepinephrine concentration has been correlated with the severity of heart failure and injury after trauma.28 29
Under normal cardiocirculatory conditions, exogenous angiotensin II in a physiological dose does not lead to an increase in sympathetic nerve activity or circulating catecholamine concentrations.30 31 In contrast, after physiological doses of angiotensin II, sympathetic nerve activity may, mediated by a reflex response, decrease.32 Without this baroreflex buffering, however, approximately half of the vasoconstrictor action of angiotensin II is not mediated by angiotensin receptors but rather by the autonomic nervous system.33 The facilitatory effects of angiotensin II become evident only when concentrations of this vasopressor are raised at the same time as when sympathetic discharge is increased.5
Cardiac arrest and CPR lead to the highest endogenously released catecholamine concentrations that were ever measured in humans and experimental animals.8 34 Administration of 0.05 mg/kg angiotensin II during CPR increases coronary perfusion pressure, myocardial blood flow, and therefore ROSC. In comparison with saline-treated animals, angiotensin II induced a massive increase in plasma epinephrine and norepinephrine concentrations during and after CPR, which in turn might be an important component in the increase of peripheral vascular resistance. The present study underlines the hypothesis that the facilitatory effects of angiotensin II are particularly marked when this vasopressor is administered at the same time as when sympathetic discharge is increased.
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Acknowledgments |
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This study was supported in part by a grant donated by the Laerdal Foundation, Oslo, Norway.
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Footnotes |
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Reprint requests to Dr Karl H Lindner, Universitätsklinik für Anästhesiologie, Klinikum der Universität Ulm, Steinhövelstr. 9, 89075 Ulm, FRG.
Received December 20, 1994; accepted February 10, 1995.
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