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The Impact of Dopamine on Hemodynamics, Oxygen Metabolism, and Cerebral Resuscitation After Restoration of Spontaneous Circulation in Pigs
The Journal of Emergency Medicine, Vol. 40, No. 3, pp. 348 –354, 2011 Copyright © 2011 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$–see front matter
doi:10.1016/j.jemermed.2009.08.049
Brief Reports
THE IMPACT OF DOPAMINE ON HEMODYNAMICS, OXYGEN METABOLISM, AND CEREBRAL RESUSCITATION AFTER RESTORATION OF SPONTANEOUS CIRCULATION IN PIGS Zhaoxia Liu,
MM,
Chunsheng Li,
MM,
Junyuan Wu,
MM,
Caijun Wu,
MM,
and Guichen Zhang,
MM
Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Reprint Address: Chunsheng Li, MM, Emergency Department, Beijing Chao-Yang Hospital, 8 Road Baijiazhuang, Region Chaoyang, Beijing 100020, China
group and thus, results of the evaluation of nervous system function were better in animals treated with dopamine (p < 0.05). Conclusions: Dopamine improved systemic perfusion, cerebral blood supply, and oxygen metabolism after successful resuscitation from VF in a porcine model. All of these factors have profound effects on the cerebral resuscitation. © 2011 Elsevier Inc.
e Abstract—Background: Restoration of spontaneous circulation after cardiopulmonary resuscitation in cardiac arrest patients does not always signal a completely successful outcome. Functional deficiencies of the nervous system are found in many survivors of cardiac arrest. Objectives: To study the effects of dopamine-induced elevated blood pressure on the hemodynamics, oxygen metabolism, and cerebral resuscitation in different perfusion conditions in a resuscitated animal model. Methods: There were 18 pigs included in the study. Ventricular fibrillation (VF) was induced with a programmed electrical stimulation device. After 4 min of untreated ventricular fibrillation followed by 9 min of CPR, 12 animals were resuscitated successfully, and were then randomly assigned to either the study group (dopamine group) or the control group (normal perfusion group). All animals in the two groups received normal saline through continuous intravenous guttae for 4 h at a rate of 15 mL/kg/h. In the study group, dopamine was added to raise the animals’ blood pressure. Four hours of intensive monitoring was performed for all study animals. Finally, 24-h evaluation of neurological function was conducted in surviving animals in accordance with the standard of the Cerebral Performance Category Score. Results: In animals in the dopamine group, the cardiac output, mean aortic pressure, coronary perfusion pressure, oxygen delivery, and oxygen consumption were higher than those found in the animals in the normal perfusion group (p < 0.05). Oxygen metabolism was remarkably improved in animals in the dopamine group. Furthermore, cerebral perfusion was better in the dopamine group than in the control
RECEIVED: 23 March 2009; FINAL ACCEPTED: 9 August 2009
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e Keywords—Cardiac arrest; cardiopulmonary resuscitation; hemodynamics; restoration of spontaneous circulation
INTRODUCTION Restoration of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR) does not always signal a completely successful outcome. Only if cerebral function is restored is improvement in the quality of life achieved. Although it has been reported that quality of life might be improved by therapeutic hypothermia, study data have shown that 50% of patients die of neurological function disorders among short-term survivors after cardiac arrest; moreover, the neurologic sequela remain in 20 –50% of long-term survivors (1). In this study, CPR was performed in a porcine model of ventricular fibrillation (VF) to evaluate the effects of intravenous (i.v.) dopamine-induced elevated blood pressure on hemodynamics and oxygen metabolism after ROSC. The study was designed to investigate neurolog-
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ical function and determine the effects of different perfusion conditions on cerebral resuscitation in surviving animals.
MATERIALS AND METHODS All animals received humane care in compliance with the principles of laboratory animal use and care formulated by the Administration Office of Laboratory Animals.
Animal Preparation Eighteen healthy male Landrace pigs (weight 30 ⫾ 1 kg) were fasted overnight except for free access to water. Anesthesia was initiated by the intramuscular injection of ketamine (20 mg/kg). The pigs were fastened on the operation table lying on the back. Anesthesia was maintained by ear vein injection of sodium pentobarbital (30 mg/kg). Additional doses of sodium pentobarbital (8 mg/kg/h) were injected intermittently. Fentanyl was administered by continuous infusion (5–10 ug/kg/h). Standard lead II electrocardiography (ECG) was performed to monitor cardiac rhythm (HP M1165 monitor; HewlettPackard, Palo Alto, CA). After tracheal intubation (size 6.5F) during spontaneous respiration, the pigs were ventilated with a volume-controlled ventilator (Siemens Servo 900C; Siemens, Munich, Germany) with FiO2 21% at 12 breaths/min and a tidal volume of 15 mL/kg, adjusted to maintain partial pressure end-tidal carbon dioxide at 35⬃40 mm Hg. A 7F saline-filled central venous catheter (CS-17702-LF, Arrow International, Inc., Wyomissing, PA) was placed into the right atrium through the right external jugular vein and attached to a pressure transducer (Deltran® Pressure Transducers; Utah Medical Products, Midvale, UT). A 6F bipolar pacing catheter (Pacel™ Right Heart Curve, St. Jude Medical, St. Paul, MN) was placed into the right ventricle through the left internal jugular vein. A saline-filled catheter was placed into the common carotid artery and attached to a pressure transducer for continuous arterial pressure monitoring. A Swan-Ganz catheter (Swan-Ganz Oximetery TD catheter, Edwards Lifesciences, Irvine, CA) was inserted via the left femoral vein for continuous pressure monitoring and blood sampling. The SwanGanz catheter was linked to a Vigilance II monitor (Edwards Lifesciences) for hemodynamic monitoring. A 5F fluid-filled angiographic catheter (RQ* 5TIG110M; Outlook Radial Tiger, Terumo Co. Ltd, Tokyo, Japan) was inserted into the aorta through the right femoral artery for continuous arterial pressure monitoring.
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Experimental Procedures The pacing electrode cable was connected to a programmed electronic stimulation device for medical use (Kaifeng Hua-nan Device Co., Ltd., Henan, China), with the following conditions: electronic voltage, 40 v; esophagus output mode S1S2 (300/200 ms) ratio, 8/1; pace width, 10 ms of continuous electronic stimulation up to VF recorded on ECG. Cardiac arrest was defined as a rapid drop in aortic pressure and waveform of VF on ECG. CPR was started after 4 min of VF. During CPR, continuous chest compressions were performed with expired-gas ventilation for 9 min. If ROSC was not achieved, a defibrillation shock was given at 120 J (waveform: Truncated Exponential Biphasic) (2). CPR was performed for 2 min after each defibrillation. During the interval between defibrillation and CPR, no medications were administered to avoid affecting cardiac function or interfering with test results. ROSC was defined as: an unassisted pulse with a systolic arterial pressure ⱖ 50 mm Hg or pulse pressure ⱖ 20 mm Hg lasting for at least 1 min (3). ROSC was successfully achieved in 12 animals. Monitoring was done for 10 min with all of the animals and blood samples collected after vital signs became stable and the baseline data were recorded. Then, the 12 animals were randomly assigned to either the dopamine group (6 animals) or the normal group (6 animals). All animals in both groups received an infusion of normal saline at a rate of 15 mL/kg/h for 4 h, and approximately 1800 mL of normal saline solution was administered in total. In the experimental group, dopamine was added through a venous pump for 4 h to raise the blood pressure and maintain the mean aortic pressure (MAP) at approximately 130% of the baseline MAP after ROSC. The initial dose of dopamine administered was 1 ug/kg/min after ROSC, and was then increased to achieve a MAP targeted value within 0.5 h. The control (normal) group did not receive dopamine. All animals in both groups were monitored for 4 h. During this period of time, the hemodynamics and oxygen metabolism parameters were recorded. The successfully resuscitated animals were put into cages for further observation after 4 h of monitoring immediately after the successful resuscitation and recovery from anesthesia. Finally, the 24-h Cerebral Performance Category (CPC) score was determined (4). At the end of the test, the animals were sacrificed with an overdose of i.v. sodium pentobarbital.
Measurements Continuous measurements of hemodynamic parameters were recorded by a Swan-Ganz catheter and other artery or vein catheters. Carotid, jugular, and mixed venous
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Table 1. Hemodynamic and Oxygenation Parameters Parameters
Equations
SV (mL/beat) SVR (dynes ⫻ s/cm5 ) PVR (dynes ⫻ s/cm5) CAO2 (mL/dL)
(CO/HR) ⫻ 1000 79.96 ⫻ (MAP ⫺ CVP)/CO 79.96 ⫻ (MPAP ⫺ PAWP)/CO (0.0138 ⫻ Hgb ⫻ SaO2) ⫹ 0.0031 ⫻ PaO2 (0.0138 ⫻ Hgb ⫻ SvO2) ⫹ 0.0031 ⫻ PvO2 CAO2 ⫺ CvO2 CAO2 ⫻ CO ⫻ 10 (C(A-v)O2) ⫻ CO ⫻ 10 (CAO2 ⫺ CvO2)/CAO2) ⫻ 100
CvO2 (mL/dL) C(A-v)O2 (mL/dL) DO2 (mL/min) VO2 (mL/min) ERO2 (%)
SV ⫽ stroke volume; CO ⫽ cardiac output; HR ⫽ heart rate; SVR ⫽ systemic vascular resistance; MAP ⫽ mean aortic pressure; CVP ⫽ central venous pressure; PVR ⫽ pulmonary vascular resistance; MPAP ⫽ mean pulmonary arterial pressure; PAWP ⫽ pulmonary arterial wedge pressure; CAO2 ⫽ arterial oxygen content; Hgb ⫽ hemoglobin; SaO2 ⫽ saturation of blood oxygen of carotid; PaO2 ⫽ arterial partial pressure of oxygen of carotid; CvO2 ⫽ venous oxygen content; SvO2 ⫽ venous oxygen saturation; C(A-v)O2 ⫽ disparity between carotid oxygen content and jugular oxygen content; DO2 ⫽ oxygen delivery, VO2 ⫽ oxygen consumption, ERO2 ⫽ oxygen extraction ratio.
showing a slower response to environmental stimuli; 3 ⫽ severe disability: unable to stand or walk without assistance, not drinking or eating, awake but failing to respond normally to noxious stimuli; 4 ⫽ coma; and 5 ⫽ death).
Statistical Analysis Data are reported as mean and SD. Discrete variables (e.g., normal neurological function at 24 h) were compared with chi-squared test. Continuous variables (including all hemodynamic parameters and blood gas data) were compared with two independent samples t-testing. Data were analyzed using SPSS 11.5 statistics software (SPSS Inc., Chicago, IL). p Value ⬍ 0.05 was considered statistically significant.
RESULTS Nervous System Function Evaluation
blood samples for blood gas analyses and routine blood examinations were drawn at baseline, and after resuscitation at ROSC 0.5 h, ROSC 1 h, ROSC 2 h, and ROSC 4 h. Blood gas analyses were measured with a blood gas analyzer (GEM Premier 3000 blood gas analyzer; Instrumentation Laboratory Inc., Bedford, MA). Routine blood studies were performed at the same time (Sysmex KX-21 Automated Hematology Analyzer; Sysmex Corporation, Kobe, Japan). Cardiac output (CO), mean pulmonary arterial pressure (MPAP), and pulmonary arterial wedge pressure were measured by Swan-Ganz catheter. Aortic systolic pressure (AOS), aortic diastolic pressure (AOD), and MAP were measured by aortic catheter. Carotid systolic pressure (CAS), carotid diastolic pressure (CAD), and carotid mean arterial pressure were measured by carotid catheter. Right atrial systolic pressure and right atrial diastolic pressure were measured by a right atrial catheter. Other variables, including coronary perfusion pressure (CPP), oxygen delivery (DO2), oxygen consumption (VO2), oxygen extraction ratio (ERO2), stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), arterial oxygen content, venous oxygen content, and A-V oxygen content difference (C[a-v]O2) were calculated according to formulas (Table 1). Animals were evaluated at 24 h after resuscitation and awarded a swine CPC score. The CPC evaluation used a 5-point scale to assess neurological function (1 ⫽ normal: no difficulty with standing, walking, eating, or drinking, and alert and fully responsive to environmental stimuli; 2 ⫽ mild disability: able to stand but exhibiting an unsteady gait, drinking but not eating normally, and
In the dopamine group, all 6 animals survived up to 24 h, and the 24-h cerebral function score was CPC grade 1. In the normal perfusion group, however, 5 of 6 animals survived up to 6 h, 4 animals survived up to 24 h, and 24-h cerebral function score was CPC 2 for 3 animals and CPC 1 for 1 animal (p ⬍ 0.05, Table 2).
Hemodynamics and Oxygen Metabolism In the dopamine group, the values of CPP, CO, and SV were much higher than in the normal perfusion group, and the values of heart rate (HR), AOS, AOD, MPAP, CAS, and CAD were correspondingly increased. The SVR was lower in the dopamine group than in the normal perfusion group, and the PVR was similar in the two groups. Compared to the normal perfusion group, values of DO2 in the dopamine group were higher at ROSC
Table 2. The Neurologic Evaluation at 24 Hours After ROSC Comparing the Dopamine Group and the Normal Perfusion Group Survivor 6h 24 h 24 h and “CPC2” neurology 24 h and “CPC1” neurology
DA NP (6 Animals) (6 Animals) p-Value 6 6 6 6
5 4 3 1
1.00 0.45 0.18 0.015*
* p ⬍ 0.05 vs. normal perfusion group. DA ⫽ dopamine group; NP ⫽ normal perfusion group; CPC ⫽ Cerebral Performance Category.
Dopamine Impact after Restoration of Spontaneous Circulation in Pigs
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Table 3. Hemodynamics and Oxygen Metabolism Data, Comparing the Dopamine Group and the Normal Perfusion Group
HR (beats/min) DA NP AOS (mm Hg) DA NP AOD (mm Hg) DA NP MAP (mm Hg) DA NP CAS (mm Hg) DA NP CAD (mm Hg) DA NP MCAP (mm Hg) DA NP CO (L/min) DA NP CPP (mm Hg) DA NP DO2 (mL/min) DA NP VO2 (mL/min) DA NP ERO2 (%) DA NP SV (mL/beat) DA NP SVR (dynes ⫻ s/cm5) DA NP PVR (dynes ⫻ s/cm5) DA NP
n
Pre-arrest
Baseline
6 6
112 ⫾ 10 105 ⫾ 12
123 ⫾ 5 126 ⫾ 4
6 6
126 ⫾ 5 125 ⫾ 8
6 6
ROSC 0.5 h
ROSC 1 h
ROSC 2 h
ROSC 4 h
142 ⫾ 6 136 ⫾ 8
152 ⫾ 6** 140 ⫾ 5
161 ⫾ 13** 129 ⫾ 12
166 ⫾ 7** 125 ⫾ 8
125 ⫾ 5 126 ⫾ 4
144 ⫾ 17* 124 ⫾ 11
162 ⫾ 17** 115 ⫾ 5
174 ⫾ 11** 106 ⫾ 12
175 ⫾ 13** 114 ⫾ 5
101 ⫾ 6 102 ⫾ 6
95 ⫾ 4 92 ⫾ 5
114 ⫾ 11 99 ⫾ 15
124 ⫾ 13** 95 ⫾ 16
131 ⫾ 9** 76 ⫾ 16
132 ⫾ 10** 86 ⫾ 7
6 6
111 ⫾ 7 109 ⫾ 6
105 ⫾ 4 101 ⫾ 6
125 ⫾ 10* 107 ⫾ 12
139 ⫾ 14** 102 ⫾ 11
145 ⫾ 10** 88 ⫾ 15
148 ⫾ 9** 96 ⫾ 6
6 6
— —
120 ⫾ 6 118 ⫾ 6
141 ⫾ 17* 120 ⫾ 11
158 ⫾ 17** 111 ⫾ 5
170 ⫾ 11** 102 ⫾ 12
170 ⫾ 13** 109 ⫾ 5
6 6
— —
93 ⫾ 4 89 ⫾ 5
111 ⫾ 11 96 ⫾ 15
121 ⫾ 13** 92 ⫾ 16
127 ⫾ 9** 75 ⫾ 16
128 ⫾ 10** 82 ⫾ 7
6 6
— —
102 ⫾ 4 99 ⫾ 5
121 ⫾ 13* 104 ⫾ 11
133 ⫾ 14** 98 ⫾ 13
142 ⫾ 10** 84 ⫾ 14
142 ⫾ 10** 91 ⫾ 6
6 6
— —
3.5 ⫾ 0.2 3.5 ⫾ 0.3
4.3 ⫾ 0.3** 2.8 ⫾ 0.1
4.9 ⫾ 0.4** 2.9 ⫾ 0.4
5.0 ⫾ 0.4** 2.8 ⫾ 0.3
5.0 ⫾ 0.2** 3.0 ⫾ 0.2
6 6
— —
89 ⫾ 4 88 ⫾ 5
108 ⫾ 10 94 ⫾ 14
118 ⫾ 12** 89 ⫾ 15
122 ⫾ 10** 80 ⫾ 12
123 ⫾ 11** 82 ⫾ 8
6 6
— —
463 ⫾ 35 480 ⫾ 52
556 ⫾ 43** 375 ⫾ 25
660 ⫾ 56** 381 ⫾ 53
674 ⫾ 53** 362 ⫾ 44
685 ⫾ 44** 400 ⫾ 38
6 6
— —
253 ⫾ 24 266 ⫾ 33
288 ⫾ 35** 191 ⫾ 13
260 ⫾ 37* 204 ⫾ 38
223 ⫾ 27** 169 ⫾ 21
212 ⫾ 19** 163 ⫾ 15
6 6
— —
55 ⫾ 4 55 ⫾ 2
52 ⫾ 3 51 ⫾ 2
39 ⫾ 4* 53 ⫾ 3
33 ⫾ 2* 47 ⫾ 1
31 ⫾ 3* 41 ⫾ 3
6 6
— —
29 ⫾ 2 28 ⫾ 3
30 ⫾ 2** 21 ⫾ 2
32 ⫾ 2** 21 ⫾ 3
31 ⫾ 3** 22 ⫾ 4
30 ⫾ 2** 24 ⫾ 2
6 6
— —
2252 ⫾ 134 2157 ⫾ 145
2209 ⫾ 272** 2871 ⫾ 295
2123 ⫾ 277** 2646 ⫾ 263
6 6
— —
224 ⫾ 68 223 ⫾ 29
276 ⫾ 82 200 ⫾ 51
253 ⫾ 30 233 ⫾ 71
2177 ⫾ 98 2421 ⫾ 433
2222 ⫾ 210 2423 ⫾ 157
336 ⫾ 58 277 ⫾ 83
316 ⫾ 84 238 ⫾ 34
* p ⬍ 0.05 vs. normal perfusion group; **p ⬍ 0.01 vs. normal perfusion group. ROSC ⫽ restoration of spontaneous circulation; DA ⫽ dopamine group; NP ⫽ normal perfusion group; HR ⫽ heart rate; AOS ⫽ aortic systolic pressure; AOD ⫽ aortic diastolic pressure; MAP ⫽ mean aortic pressure; CAS ⫽ carotid systolic pressure; CAD ⫽ carotid diastolic pressure; MCAP ⫽ carotid mean arterial pressure; CO ⫽ cardiac output; CPP ⫽ coronary perfusion pressure; DO2 ⫽ oxygen delivery; VO2 ⫽ oxygen consumption; ERO2 ⫽ oxygen extraction ratio; SV ⫽ stroke volume; SVR ⫽ systemic vascular resistance; PVR ⫽ pulmonary vascular resistance.
0.5 h, 1 h, 2 h, and 4 h; values of ERO2 were lower at ROSC 1 h, 2 h, and 4 h; and values of VO2 were higher at ROSC 0.5 h, 1 h, 2 h, and 4 h (Table 3).
Blood Gas Analyses of Carotid, Jugular, and Mixed Venous Blood Samples In blood gas analysis of carotid artery blood, there was no difference found between the two groups, except for
oxygen partial pressure, which was higher in the dopamine group than in the normal group (p ⬍ 0.05). In the mixed venous blood gas analysis, in the dopamine group, oxygenation was much better than in the carotid blood; in particular, there was higher oxygen partial pressure, lower carbon dioxide partial pressure, higher saturation of blood oxygen and in lactic acid, there was a great disparity between mixed venous blood and carotid blood (p ⬍ 0.05, Table 4). In the carotid and jugular blood gas analysis, in the dopamine group, carotid oxygen content
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Table 4. Blood Gas Analysis and Oxygen Content in Carotid Artery, Jugular, and Mixed Venous Blood, Comparing the Dopamine Group and the Normal Perfusion Group
PaCO2 (mm Hg) DA NP PaO2 (mm Hg) DA NP SaO2 (%) DA NP PvCO2 (mm Hg) DA NP PvO2 (mm Hg) DA NP SvO2 (%) DA NP PCLac (mmol/L) DA NP CAO2 (mL/dL) DA NP C(A-v)O2 (mL/dL) DA NP ERO2 (%) DA NP VALac (mmol/L) DA NP
n
Baseline
ROSC 0.5 h
ROSC 1 h
ROSC 2 h
ROSC 4 h
6 6
45 ⫾ 2 44 ⫾ 2
40 ⫾ 2 38 ⫾ 2
37 ⫾ 1 36 ⫾ 2
35 ⫾ 2 37 ⫾ 2
32 ⫾ 3 33 ⫾ 3
6 6
85 ⫾ 4 83 ⫾ 4
89 ⫾ 2** 83 ⫾ 2
92 ⫾ 2** 88 ⫾ 2
96 ⫾ 2** 91 ⫾ 2
94 ⫾ 3 93 ⫾ 4
6 6
97 ⫾ 1 97 ⫾ 1
97 ⫾ 1 98 ⫾ 1
98 ⫾ 1 97 ⫾ 1
98 ⫾ 1 97 ⫾ 1
98 ⫾ 1 97 ⫾ 1
6 6
44 ⫾ 5 46 ⫾ 5
44 ⫾ 2** 50 ⫾ 2
43 ⫾ 2* 46 ⫾ 2
40 ⫾ 1** 43 ⫾ 1
43 ⫾ 2 42 ⫾ 1
6 6
29 ⫾ 2 30 ⫾ 4
38 ⫾ 4* 33 ⫾ 1
42 ⫾ 2** 36 ⫾ 2
40 ⫾ 2** 36 ⫾ 2
43 ⫾ 2** 38 ⫾ 1
6 6
44 ⫾ 4 43 ⫾ 2
47 ⫾ 3 48 ⫾ 2
60 ⫾ 4** 45 ⫾ 3
66 ⫾ 2** 52 ⫾ 1
68 ⫾ 3** 58 ⫾ 3
6 6
0.6 ⫾ 0.5 0.6 ⫾ 0.2
0.8 ⫾ 0.3 0.4 ⫾ 0.4
1.2 ⫾ 0.2* 0.7 ⫾ 0.4
1.0 ⫾ 0.3* 0.6 ⫾ 0.2
1.1 ⫾ 0.2** 0.5 ⫾ 0.2
6 6
126 ⫾ 6 129 ⫾ 9
124 ⫾ 5 128 ⫾ 4
128 ⫾ 4 124 ⫾ 4
129 ⫾ 2* 125 ⫾ 3
131 ⫾ 4** 126 ⫾ 5
6 6
67 ⫾ 5 70 ⫾ 6
62 ⫾ 5 64 ⫾ 3
72 ⫾ 4* 76 ⫾ 2
40 ⫾ 2** 56 ⫾ 1
38 ⫾ 4** 49 ⫾ 3
6 6
54 ⫾ 4 54 ⫾ 2
50 ⫾ 4 50 ⫾ 2
56 ⫾ 2** 61 ⫾ 2
31 ⫾ 2** 45 ⫾ 1
29 ⫾ 3** 39 ⫾ 3
6 6
0.7 ⫾ 0.6 0.9 ⫾ 0.2
1.2 ⫾ 0.1 1.0 ⫾ 0.5
1.2 ⫾ 0.2* 0.8 ⫾ 0.3
1.1 ⫾ 0.2** 0.5 ⫾ 0.3
1.5 ⫾ 0.2** 0.9 ⫾ 0.2
* p ⬍ 0.05 vs. normal perfusion group; **p ⬍ 0.01 vs. normal perfusion group. DA ⫽ dopamine group; NP ⫽ normal perfusion group; PaH ⫽ PH of carotid blood; PaCO2 ⫽ arterial partial pressure of carbon dioxide of carotid; PaO2 ⫽ arterial partial pressure of oxygen of carotid; ALac ⫽ lactic acid of carotid; SaO2 ⫽ saturation of blood oxygen of carotid; PvH, PvCO2, PvO2, VLac, SvO2 indicate the same meanings about mixed venous blood gas analyses; PCLac ⫽ lactic acid disparity between mixed venous blood and carotid blood; CAO2 ⫽ arterial oxygen content; C(A-v)O2 ⫽ disparity between carotid oxygen content and jugular oxygen content; VALac ⫽ lactic acid disparity between jugular blood and carotid blood.
was higher at ROSC 2 h and 4 h. In the carotid and jugular blood, oxygen content was lower at ROSC 1 h, 2 h, and 4 h; the oxygen extraction ratio of carotid blood was lower at ROSC 1 h, 2 h, and 4 h; and the lactic acid disparity between carotid and jugular blood was greater during the same period (Table 4).
DISCUSSION Dopamine is one of the catecholamines that are commonly used in the clinical setting. As a precursor of noradrenaline, dopamine acts on ␣-receptors, -receptors, and two specific dopamine receptors. Hemodynamic instability and left ventricular dysfunction, manifested clinically as arterial hypotension, may result from dopamine administration, especially after restoration of circulation after cardiac arrest and resuscitation. During or after resuscitation,
exogenous epinephrine or other catecholamines are often required to increase coronary perfusion pressure, and to treat post-resuscitation hypotension and post-ischemic myocardial damage or to augment cardiac function and increase DO2 (5–9). In a patient resuscitated from cardiac arrest, hemodynamic instability will affect recovery of neurological function. Some research studies on cerebral blood flow after resuscitation have shown that a short-term episode of transient and multifocal absence of perfusion is followed by hyperemia associated with a high cerebral metabolic rate of oxygen (CMRO2) and glucose. Subsequently, cerebral hypoperfusion with a parallel reduction of CMRO2 develops (10). Under normal conditions, changes in arterial pressure have only a small influence on cerebral blood flow due to reactive dilatation and constriction of cerebral resistance vessels in response to arterial hypotension and hypertension, that is, cerebral
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blood flow autoregulation (11). But some researchers have found that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or is right-shifted. When researchers investigated the autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest, it was found that MAP had to be maintained at a higher level than normal to ensure cerebral perfusion (12). But the optimal MAP for post-cardiac arrest patients has not been defined by prospective clinical trials. Some studies found that level of MAP during the first 2 h after ROSC was correlated with neurological outcome (13). In the present study, all animals that were resuscitated successfully were randomly assigned to one of two groups: the dopamine group or the normal perfusion group. In the dopamine group, animals were administered normal saline solution and dopamine through a venous pump to maintain the MAP at about 130% of the baseline MAP after ROSC. In the normal perfusion group, the animals were administered an equal volume of normal saline solution without dopamine. The findings showed improvement in hemodynamic parameters and in oxygen metabolism in the dopamine group over the normal perfusion group. The improvements in hemodynamic parameters included MAP and carotid blood pressure, which were higher in the dopamine group than in the normal perfusion group (p ⬍ 0.05) in all stages after resuscitation. In other words, a better blood supply to cerebral tissues was achieved in the dopamine group. In a short period of time, the positive inotropism for the heart by dopamine was remarkable, that is, in the dopamine group, the values of CO and SV at ROSC 0.5 h, 1 h, 2 h, and 4 h were higher than those in the normal perfusion group (p ⬍ 0.01), whereas the systemic vascular resistance did not increase (p ⬎ 0.05). However, there was one unfavorable aspect in the dopamine group: heart rate was remarkably higher than in the normal perfusion group. This finding requires further study. The effects of tachycardia and increased oxygen consumption at the myocardium on the restoration of ventricular function after resuscitation as well as the long-term impact require further study. With regard to oxygen consumption, catecholamines could increase oxygen consumption at the myocardium, but they might also increase oxygen consumption by systemic tissues in two ways: cell metabolism induced by adrenergic receptors and effects on the central venous system, and agitation of sympathetic nerves (14). However, if the effect of increasing DO2 is superior to that of VO2, dopamine may improve the general oxygen transportation and oxygenation in tissues. In addition, it has been reported that dopamine could play a beneficial role after cardiac operations in adults and young children (15,16). In this study, DO2 and VO2 were higher in the dopamine group than in the
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normal perfusion group (p ⬍ 0.05), and ERO2 was lower in the dopamine group than in the normal perfusion group (p ⬍ 0.05). Oxygen transportation was better in the dopamine group than in the normal perfusion group. Dopamine may improve the oxygen metabolism of systemic tissues after resuscitation. The results of blood gas analysis in the present study indicate that carotid oxygen content was higher in the dopamine group, carotid-venous oxygen content difference was lower, and the carotid-venous lactic acid content difference was higher (p ⬍ 0.05). Thus, the oxygenation and oxygen utilization were better in the dopamine group than in the normal perfusion group. The improvements in hemodynamics and oxygen metabolism in the dopamine group had beneficial effects on the restoration of neural system function in this resuscitated porcine model. The 24-h cerebral function scores were “normal” for all six animals in the dopamine group, but for only one animal in the normal perfusion group, and there was a significant difference between the two groups (p ⬍ 0.05). The above data suggest that dopamine may improve the cerebral blood supply by raising blood pressure and, further, it may play an active role in the process of cerebral resuscitation. However, due to the limitations in this study, the finding of improved cerebral function will need to be studied for a longer period of time.
Limitations The results of this study, which was performed in an animal model, do not reflect the exact changes and complete outcomes that would occur in the human body under similar physiologic conditions. Moreover, the small number of animals in the sample might preclude finding statistically significant differences in some tests. Additionally, as the electric defibrillation frequency for each animal was different during the period of resuscitation, the possible effects of electronic injuries on myocardial tissue after resuscitation was not considered in the study. The impairments to ventricular function after resuscitation might have been exacerbated by the anesthesia, and that could enhance the effect of the catecholamines.
CONCLUSIONS Dopamine could improve systemic perfusion, and play an active role in improving hemodynamic parameters, as shown in this porcine ROSC model. Dopamine, as a pressor agent, may improve cerebral blood supply and oxygen metabolism after successful resuscitation when it
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is used to increase the aortic blood pressure. All of these factors may have beneficial effects on cerebral function after resuscitation. Acknowledgments—This study would not have been possible without the expertise and support of Doctors Xue Mei, Ziren Tang, Ming Jin and Shuo Wang. Their assistance with this project is greatly appreciated.
REFERENCES 1. Gottschalk A, Burmeister MA, Freitag M, et al. Influence of early defibrillation on the survivor rate and quality of life after CPR in prehospital emergency medical service in a German metropolitan area. Resuscitation 2002;53:15–20. 2. Kern KB, Hilwig RW, Berg RA, et al. Optimizing ventilation in conjunction with phased chest and abdominal compression– decompression (Lifestick™) resuscitation. Resuscitation 2002;52: 91–100. 3. Cavus E, Bein B, Dörges V, et al. Brain tissue oxygen pressure and cerebral metabolism in an animal model of cardiac arrest and cardiopulmonary resuscitation. Resuscitation 2006;71:97–106. 4. Zeiner A, Holzer M, Sterz F, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001;161:2007–12. 5. Kern KB, Elchisak MA, Sanders AB, et al. Plasma catecholamines and resuscitation from prolonged cardiac arrest. Crit Care Med 1989;17:786 –91.
6. Wortsman J, Paradis NA, Martin GB, et al. Functional responses to extremely high plasma epinephrine concentrations in cardiac arrest. Crit Care Med 1993;14:692–7. 7. Kern KB. Postresuscitation myocardial dysfunction. Cardiol Clin 2002;20:89 –101. 8. Crexells C, Bourassa MG, Biron P. Effects of dopamine on myocardial metabolism in patients with ischaemic heart disease. Cardiovasc Res 1973;7:438 – 45. 9. Takamatsu I, Karasawa F, Okuda T. Dopamine may preserve the myocardial oxygen balance better than dobutamine when administered with milrinone. Can J Anaesth 2002;49:968 –72. 10. Sterz F, Leonov Y, Safar P, et al. Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs: reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 1992;24:27– 47. 11. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990;2:161–92. 12. Sundgreen C, Larsen FS, Herzog TM, et al. Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest. Stroke 2001;32;128 –32. 13. Müllner M, Sterz F, Binder M, et al. Arterial blood pressure after human cardiac arrest and neurological recovery. Stroke 1996;27: 59 – 62. 14. Ensinger H, Weichel T, Lindner KH, et al. Effects of norepinephrine, epinephrine, and dopamine infusions on oxygen consumption in volunteers. Crit Care Med 1993;21:1502– 8. 15. Merin G, Bitran D, Uretzky G, et al. The hemodynamic effects of dopamine following cardiopulmonary bypass. Ann Thorac Surg 1977;23:361–3. 16. Kawamura M, Minamikawa O, Yokochi H, et al. Combined use of phenoxybenzamine and dopamine for low cardiac output syndrome in children at withdrawal from cardiopulmonary bypass. Br Heart J 1980;43:388 –92.
ARTICLE SUMMARY 1. Why is this topic important? Currently, a key component of post-cardiac arrest syndrome is post-resuscitation brain injury. Although some reports have indicated that therapeutic hypothermia may improve neurological outcome, cerebral resuscitation is still a difficult problem. 2. What does the study attempt to show? This study attempts to show the impact of dopamine on hemodynamic parameters, oxygen metabolism, and cerebral resuscitation after cardiac arrest and resuscitation. 3. What are the key findings? This experimental study of restoration of spontaneous circulation in an animal model of cardiac arrest suggests that changing the total body perfusion with dopamine administration may improve hemodynamics and oxygen metabolism. 4. How is patient care impacted? Dopamine, as a pressor agent, may improve cerebral blood supply and oxygen metabolism after successful resuscitation when it is used to increase the aortic blood pressure. All of these factors may have beneficial effects on cerebral resuscitation after cardiac arrest.
doi:10.1016/j.jemermed.2009.08.049
Brief Reports
THE IMPACT OF DOPAMINE ON HEMODYNAMICS, OXYGEN METABOLISM, AND CEREBRAL RESUSCITATION AFTER RESTORATION OF SPONTANEOUS CIRCULATION IN PIGS Zhaoxia Liu,
MM,
Chunsheng Li,
MM,
Junyuan Wu,
MM,
Caijun Wu,
MM,
and Guichen Zhang,
MM
Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China Reprint Address: Chunsheng Li, MM, Emergency Department, Beijing Chao-Yang Hospital, 8 Road Baijiazhuang, Region Chaoyang, Beijing 100020, China
group and thus, results of the evaluation of nervous system function were better in animals treated with dopamine (p < 0.05). Conclusions: Dopamine improved systemic perfusion, cerebral blood supply, and oxygen metabolism after successful resuscitation from VF in a porcine model. All of these factors have profound effects on the cerebral resuscitation. © 2011 Elsevier Inc.
e Abstract—Background: Restoration of spontaneous circulation after cardiopulmonary resuscitation in cardiac arrest patients does not always signal a completely successful outcome. Functional deficiencies of the nervous system are found in many survivors of cardiac arrest. Objectives: To study the effects of dopamine-induced elevated blood pressure on the hemodynamics, oxygen metabolism, and cerebral resuscitation in different perfusion conditions in a resuscitated animal model. Methods: There were 18 pigs included in the study. Ventricular fibrillation (VF) was induced with a programmed electrical stimulation device. After 4 min of untreated ventricular fibrillation followed by 9 min of CPR, 12 animals were resuscitated successfully, and were then randomly assigned to either the study group (dopamine group) or the control group (normal perfusion group). All animals in the two groups received normal saline through continuous intravenous guttae for 4 h at a rate of 15 mL/kg/h. In the study group, dopamine was added to raise the animals’ blood pressure. Four hours of intensive monitoring was performed for all study animals. Finally, 24-h evaluation of neurological function was conducted in surviving animals in accordance with the standard of the Cerebral Performance Category Score. Results: In animals in the dopamine group, the cardiac output, mean aortic pressure, coronary perfusion pressure, oxygen delivery, and oxygen consumption were higher than those found in the animals in the normal perfusion group (p < 0.05). Oxygen metabolism was remarkably improved in animals in the dopamine group. Furthermore, cerebral perfusion was better in the dopamine group than in the control
RECEIVED: 23 March 2009; FINAL ACCEPTED: 9 August 2009
SUBMISSION RECEIVED:
e Keywords—Cardiac arrest; cardiopulmonary resuscitation; hemodynamics; restoration of spontaneous circulation
INTRODUCTION Restoration of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR) does not always signal a completely successful outcome. Only if cerebral function is restored is improvement in the quality of life achieved. Although it has been reported that quality of life might be improved by therapeutic hypothermia, study data have shown that 50% of patients die of neurological function disorders among short-term survivors after cardiac arrest; moreover, the neurologic sequela remain in 20 –50% of long-term survivors (1). In this study, CPR was performed in a porcine model of ventricular fibrillation (VF) to evaluate the effects of intravenous (i.v.) dopamine-induced elevated blood pressure on hemodynamics and oxygen metabolism after ROSC. The study was designed to investigate neurolog-
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ical function and determine the effects of different perfusion conditions on cerebral resuscitation in surviving animals.
MATERIALS AND METHODS All animals received humane care in compliance with the principles of laboratory animal use and care formulated by the Administration Office of Laboratory Animals.
Animal Preparation Eighteen healthy male Landrace pigs (weight 30 ⫾ 1 kg) were fasted overnight except for free access to water. Anesthesia was initiated by the intramuscular injection of ketamine (20 mg/kg). The pigs were fastened on the operation table lying on the back. Anesthesia was maintained by ear vein injection of sodium pentobarbital (30 mg/kg). Additional doses of sodium pentobarbital (8 mg/kg/h) were injected intermittently. Fentanyl was administered by continuous infusion (5–10 ug/kg/h). Standard lead II electrocardiography (ECG) was performed to monitor cardiac rhythm (HP M1165 monitor; HewlettPackard, Palo Alto, CA). After tracheal intubation (size 6.5F) during spontaneous respiration, the pigs were ventilated with a volume-controlled ventilator (Siemens Servo 900C; Siemens, Munich, Germany) with FiO2 21% at 12 breaths/min and a tidal volume of 15 mL/kg, adjusted to maintain partial pressure end-tidal carbon dioxide at 35⬃40 mm Hg. A 7F saline-filled central venous catheter (CS-17702-LF, Arrow International, Inc., Wyomissing, PA) was placed into the right atrium through the right external jugular vein and attached to a pressure transducer (Deltran® Pressure Transducers; Utah Medical Products, Midvale, UT). A 6F bipolar pacing catheter (Pacel™ Right Heart Curve, St. Jude Medical, St. Paul, MN) was placed into the right ventricle through the left internal jugular vein. A saline-filled catheter was placed into the common carotid artery and attached to a pressure transducer for continuous arterial pressure monitoring. A Swan-Ganz catheter (Swan-Ganz Oximetery TD catheter, Edwards Lifesciences, Irvine, CA) was inserted via the left femoral vein for continuous pressure monitoring and blood sampling. The SwanGanz catheter was linked to a Vigilance II monitor (Edwards Lifesciences) for hemodynamic monitoring. A 5F fluid-filled angiographic catheter (RQ* 5TIG110M; Outlook Radial Tiger, Terumo Co. Ltd, Tokyo, Japan) was inserted into the aorta through the right femoral artery for continuous arterial pressure monitoring.
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Experimental Procedures The pacing electrode cable was connected to a programmed electronic stimulation device for medical use (Kaifeng Hua-nan Device Co., Ltd., Henan, China), with the following conditions: electronic voltage, 40 v; esophagus output mode S1S2 (300/200 ms) ratio, 8/1; pace width, 10 ms of continuous electronic stimulation up to VF recorded on ECG. Cardiac arrest was defined as a rapid drop in aortic pressure and waveform of VF on ECG. CPR was started after 4 min of VF. During CPR, continuous chest compressions were performed with expired-gas ventilation for 9 min. If ROSC was not achieved, a defibrillation shock was given at 120 J (waveform: Truncated Exponential Biphasic) (2). CPR was performed for 2 min after each defibrillation. During the interval between defibrillation and CPR, no medications were administered to avoid affecting cardiac function or interfering with test results. ROSC was defined as: an unassisted pulse with a systolic arterial pressure ⱖ 50 mm Hg or pulse pressure ⱖ 20 mm Hg lasting for at least 1 min (3). ROSC was successfully achieved in 12 animals. Monitoring was done for 10 min with all of the animals and blood samples collected after vital signs became stable and the baseline data were recorded. Then, the 12 animals were randomly assigned to either the dopamine group (6 animals) or the normal group (6 animals). All animals in both groups received an infusion of normal saline at a rate of 15 mL/kg/h for 4 h, and approximately 1800 mL of normal saline solution was administered in total. In the experimental group, dopamine was added through a venous pump for 4 h to raise the blood pressure and maintain the mean aortic pressure (MAP) at approximately 130% of the baseline MAP after ROSC. The initial dose of dopamine administered was 1 ug/kg/min after ROSC, and was then increased to achieve a MAP targeted value within 0.5 h. The control (normal) group did not receive dopamine. All animals in both groups were monitored for 4 h. During this period of time, the hemodynamics and oxygen metabolism parameters were recorded. The successfully resuscitated animals were put into cages for further observation after 4 h of monitoring immediately after the successful resuscitation and recovery from anesthesia. Finally, the 24-h Cerebral Performance Category (CPC) score was determined (4). At the end of the test, the animals were sacrificed with an overdose of i.v. sodium pentobarbital.
Measurements Continuous measurements of hemodynamic parameters were recorded by a Swan-Ganz catheter and other artery or vein catheters. Carotid, jugular, and mixed venous
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Table 1. Hemodynamic and Oxygenation Parameters Parameters
Equations
SV (mL/beat) SVR (dynes ⫻ s/cm5 ) PVR (dynes ⫻ s/cm5) CAO2 (mL/dL)
(CO/HR) ⫻ 1000 79.96 ⫻ (MAP ⫺ CVP)/CO 79.96 ⫻ (MPAP ⫺ PAWP)/CO (0.0138 ⫻ Hgb ⫻ SaO2) ⫹ 0.0031 ⫻ PaO2 (0.0138 ⫻ Hgb ⫻ SvO2) ⫹ 0.0031 ⫻ PvO2 CAO2 ⫺ CvO2 CAO2 ⫻ CO ⫻ 10 (C(A-v)O2) ⫻ CO ⫻ 10 (CAO2 ⫺ CvO2)/CAO2) ⫻ 100
CvO2 (mL/dL) C(A-v)O2 (mL/dL) DO2 (mL/min) VO2 (mL/min) ERO2 (%)
SV ⫽ stroke volume; CO ⫽ cardiac output; HR ⫽ heart rate; SVR ⫽ systemic vascular resistance; MAP ⫽ mean aortic pressure; CVP ⫽ central venous pressure; PVR ⫽ pulmonary vascular resistance; MPAP ⫽ mean pulmonary arterial pressure; PAWP ⫽ pulmonary arterial wedge pressure; CAO2 ⫽ arterial oxygen content; Hgb ⫽ hemoglobin; SaO2 ⫽ saturation of blood oxygen of carotid; PaO2 ⫽ arterial partial pressure of oxygen of carotid; CvO2 ⫽ venous oxygen content; SvO2 ⫽ venous oxygen saturation; C(A-v)O2 ⫽ disparity between carotid oxygen content and jugular oxygen content; DO2 ⫽ oxygen delivery, VO2 ⫽ oxygen consumption, ERO2 ⫽ oxygen extraction ratio.
showing a slower response to environmental stimuli; 3 ⫽ severe disability: unable to stand or walk without assistance, not drinking or eating, awake but failing to respond normally to noxious stimuli; 4 ⫽ coma; and 5 ⫽ death).
Statistical Analysis Data are reported as mean and SD. Discrete variables (e.g., normal neurological function at 24 h) were compared with chi-squared test. Continuous variables (including all hemodynamic parameters and blood gas data) were compared with two independent samples t-testing. Data were analyzed using SPSS 11.5 statistics software (SPSS Inc., Chicago, IL). p Value ⬍ 0.05 was considered statistically significant.
RESULTS Nervous System Function Evaluation
blood samples for blood gas analyses and routine blood examinations were drawn at baseline, and after resuscitation at ROSC 0.5 h, ROSC 1 h, ROSC 2 h, and ROSC 4 h. Blood gas analyses were measured with a blood gas analyzer (GEM Premier 3000 blood gas analyzer; Instrumentation Laboratory Inc., Bedford, MA). Routine blood studies were performed at the same time (Sysmex KX-21 Automated Hematology Analyzer; Sysmex Corporation, Kobe, Japan). Cardiac output (CO), mean pulmonary arterial pressure (MPAP), and pulmonary arterial wedge pressure were measured by Swan-Ganz catheter. Aortic systolic pressure (AOS), aortic diastolic pressure (AOD), and MAP were measured by aortic catheter. Carotid systolic pressure (CAS), carotid diastolic pressure (CAD), and carotid mean arterial pressure were measured by carotid catheter. Right atrial systolic pressure and right atrial diastolic pressure were measured by a right atrial catheter. Other variables, including coronary perfusion pressure (CPP), oxygen delivery (DO2), oxygen consumption (VO2), oxygen extraction ratio (ERO2), stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), arterial oxygen content, venous oxygen content, and A-V oxygen content difference (C[a-v]O2) were calculated according to formulas (Table 1). Animals were evaluated at 24 h after resuscitation and awarded a swine CPC score. The CPC evaluation used a 5-point scale to assess neurological function (1 ⫽ normal: no difficulty with standing, walking, eating, or drinking, and alert and fully responsive to environmental stimuli; 2 ⫽ mild disability: able to stand but exhibiting an unsteady gait, drinking but not eating normally, and
In the dopamine group, all 6 animals survived up to 24 h, and the 24-h cerebral function score was CPC grade 1. In the normal perfusion group, however, 5 of 6 animals survived up to 6 h, 4 animals survived up to 24 h, and 24-h cerebral function score was CPC 2 for 3 animals and CPC 1 for 1 animal (p ⬍ 0.05, Table 2).
Hemodynamics and Oxygen Metabolism In the dopamine group, the values of CPP, CO, and SV were much higher than in the normal perfusion group, and the values of heart rate (HR), AOS, AOD, MPAP, CAS, and CAD were correspondingly increased. The SVR was lower in the dopamine group than in the normal perfusion group, and the PVR was similar in the two groups. Compared to the normal perfusion group, values of DO2 in the dopamine group were higher at ROSC
Table 2. The Neurologic Evaluation at 24 Hours After ROSC Comparing the Dopamine Group and the Normal Perfusion Group Survivor 6h 24 h 24 h and “CPC2” neurology 24 h and “CPC1” neurology
DA NP (6 Animals) (6 Animals) p-Value 6 6 6 6
5 4 3 1
1.00 0.45 0.18 0.015*
* p ⬍ 0.05 vs. normal perfusion group. DA ⫽ dopamine group; NP ⫽ normal perfusion group; CPC ⫽ Cerebral Performance Category.
Dopamine Impact after Restoration of Spontaneous Circulation in Pigs
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Table 3. Hemodynamics and Oxygen Metabolism Data, Comparing the Dopamine Group and the Normal Perfusion Group
HR (beats/min) DA NP AOS (mm Hg) DA NP AOD (mm Hg) DA NP MAP (mm Hg) DA NP CAS (mm Hg) DA NP CAD (mm Hg) DA NP MCAP (mm Hg) DA NP CO (L/min) DA NP CPP (mm Hg) DA NP DO2 (mL/min) DA NP VO2 (mL/min) DA NP ERO2 (%) DA NP SV (mL/beat) DA NP SVR (dynes ⫻ s/cm5) DA NP PVR (dynes ⫻ s/cm5) DA NP
n
Pre-arrest
Baseline
6 6
112 ⫾ 10 105 ⫾ 12
123 ⫾ 5 126 ⫾ 4
6 6
126 ⫾ 5 125 ⫾ 8
6 6
ROSC 0.5 h
ROSC 1 h
ROSC 2 h
ROSC 4 h
142 ⫾ 6 136 ⫾ 8
152 ⫾ 6** 140 ⫾ 5
161 ⫾ 13** 129 ⫾ 12
166 ⫾ 7** 125 ⫾ 8
125 ⫾ 5 126 ⫾ 4
144 ⫾ 17* 124 ⫾ 11
162 ⫾ 17** 115 ⫾ 5
174 ⫾ 11** 106 ⫾ 12
175 ⫾ 13** 114 ⫾ 5
101 ⫾ 6 102 ⫾ 6
95 ⫾ 4 92 ⫾ 5
114 ⫾ 11 99 ⫾ 15
124 ⫾ 13** 95 ⫾ 16
131 ⫾ 9** 76 ⫾ 16
132 ⫾ 10** 86 ⫾ 7
6 6
111 ⫾ 7 109 ⫾ 6
105 ⫾ 4 101 ⫾ 6
125 ⫾ 10* 107 ⫾ 12
139 ⫾ 14** 102 ⫾ 11
145 ⫾ 10** 88 ⫾ 15
148 ⫾ 9** 96 ⫾ 6
6 6
— —
120 ⫾ 6 118 ⫾ 6
141 ⫾ 17* 120 ⫾ 11
158 ⫾ 17** 111 ⫾ 5
170 ⫾ 11** 102 ⫾ 12
170 ⫾ 13** 109 ⫾ 5
6 6
— —
93 ⫾ 4 89 ⫾ 5
111 ⫾ 11 96 ⫾ 15
121 ⫾ 13** 92 ⫾ 16
127 ⫾ 9** 75 ⫾ 16
128 ⫾ 10** 82 ⫾ 7
6 6
— —
102 ⫾ 4 99 ⫾ 5
121 ⫾ 13* 104 ⫾ 11
133 ⫾ 14** 98 ⫾ 13
142 ⫾ 10** 84 ⫾ 14
142 ⫾ 10** 91 ⫾ 6
6 6
— —
3.5 ⫾ 0.2 3.5 ⫾ 0.3
4.3 ⫾ 0.3** 2.8 ⫾ 0.1
4.9 ⫾ 0.4** 2.9 ⫾ 0.4
5.0 ⫾ 0.4** 2.8 ⫾ 0.3
5.0 ⫾ 0.2** 3.0 ⫾ 0.2
6 6
— —
89 ⫾ 4 88 ⫾ 5
108 ⫾ 10 94 ⫾ 14
118 ⫾ 12** 89 ⫾ 15
122 ⫾ 10** 80 ⫾ 12
123 ⫾ 11** 82 ⫾ 8
6 6
— —
463 ⫾ 35 480 ⫾ 52
556 ⫾ 43** 375 ⫾ 25
660 ⫾ 56** 381 ⫾ 53
674 ⫾ 53** 362 ⫾ 44
685 ⫾ 44** 400 ⫾ 38
6 6
— —
253 ⫾ 24 266 ⫾ 33
288 ⫾ 35** 191 ⫾ 13
260 ⫾ 37* 204 ⫾ 38
223 ⫾ 27** 169 ⫾ 21
212 ⫾ 19** 163 ⫾ 15
6 6
— —
55 ⫾ 4 55 ⫾ 2
52 ⫾ 3 51 ⫾ 2
39 ⫾ 4* 53 ⫾ 3
33 ⫾ 2* 47 ⫾ 1
31 ⫾ 3* 41 ⫾ 3
6 6
— —
29 ⫾ 2 28 ⫾ 3
30 ⫾ 2** 21 ⫾ 2
32 ⫾ 2** 21 ⫾ 3
31 ⫾ 3** 22 ⫾ 4
30 ⫾ 2** 24 ⫾ 2
6 6
— —
2252 ⫾ 134 2157 ⫾ 145
2209 ⫾ 272** 2871 ⫾ 295
2123 ⫾ 277** 2646 ⫾ 263
6 6
— —
224 ⫾ 68 223 ⫾ 29
276 ⫾ 82 200 ⫾ 51
253 ⫾ 30 233 ⫾ 71
2177 ⫾ 98 2421 ⫾ 433
2222 ⫾ 210 2423 ⫾ 157
336 ⫾ 58 277 ⫾ 83
316 ⫾ 84 238 ⫾ 34
* p ⬍ 0.05 vs. normal perfusion group; **p ⬍ 0.01 vs. normal perfusion group. ROSC ⫽ restoration of spontaneous circulation; DA ⫽ dopamine group; NP ⫽ normal perfusion group; HR ⫽ heart rate; AOS ⫽ aortic systolic pressure; AOD ⫽ aortic diastolic pressure; MAP ⫽ mean aortic pressure; CAS ⫽ carotid systolic pressure; CAD ⫽ carotid diastolic pressure; MCAP ⫽ carotid mean arterial pressure; CO ⫽ cardiac output; CPP ⫽ coronary perfusion pressure; DO2 ⫽ oxygen delivery; VO2 ⫽ oxygen consumption; ERO2 ⫽ oxygen extraction ratio; SV ⫽ stroke volume; SVR ⫽ systemic vascular resistance; PVR ⫽ pulmonary vascular resistance.
0.5 h, 1 h, 2 h, and 4 h; values of ERO2 were lower at ROSC 1 h, 2 h, and 4 h; and values of VO2 were higher at ROSC 0.5 h, 1 h, 2 h, and 4 h (Table 3).
Blood Gas Analyses of Carotid, Jugular, and Mixed Venous Blood Samples In blood gas analysis of carotid artery blood, there was no difference found between the two groups, except for
oxygen partial pressure, which was higher in the dopamine group than in the normal group (p ⬍ 0.05). In the mixed venous blood gas analysis, in the dopamine group, oxygenation was much better than in the carotid blood; in particular, there was higher oxygen partial pressure, lower carbon dioxide partial pressure, higher saturation of blood oxygen and in lactic acid, there was a great disparity between mixed venous blood and carotid blood (p ⬍ 0.05, Table 4). In the carotid and jugular blood gas analysis, in the dopamine group, carotid oxygen content
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Table 4. Blood Gas Analysis and Oxygen Content in Carotid Artery, Jugular, and Mixed Venous Blood, Comparing the Dopamine Group and the Normal Perfusion Group
PaCO2 (mm Hg) DA NP PaO2 (mm Hg) DA NP SaO2 (%) DA NP PvCO2 (mm Hg) DA NP PvO2 (mm Hg) DA NP SvO2 (%) DA NP PCLac (mmol/L) DA NP CAO2 (mL/dL) DA NP C(A-v)O2 (mL/dL) DA NP ERO2 (%) DA NP VALac (mmol/L) DA NP
n
Baseline
ROSC 0.5 h
ROSC 1 h
ROSC 2 h
ROSC 4 h
6 6
45 ⫾ 2 44 ⫾ 2
40 ⫾ 2 38 ⫾ 2
37 ⫾ 1 36 ⫾ 2
35 ⫾ 2 37 ⫾ 2
32 ⫾ 3 33 ⫾ 3
6 6
85 ⫾ 4 83 ⫾ 4
89 ⫾ 2** 83 ⫾ 2
92 ⫾ 2** 88 ⫾ 2
96 ⫾ 2** 91 ⫾ 2
94 ⫾ 3 93 ⫾ 4
6 6
97 ⫾ 1 97 ⫾ 1
97 ⫾ 1 98 ⫾ 1
98 ⫾ 1 97 ⫾ 1
98 ⫾ 1 97 ⫾ 1
98 ⫾ 1 97 ⫾ 1
6 6
44 ⫾ 5 46 ⫾ 5
44 ⫾ 2** 50 ⫾ 2
43 ⫾ 2* 46 ⫾ 2
40 ⫾ 1** 43 ⫾ 1
43 ⫾ 2 42 ⫾ 1
6 6
29 ⫾ 2 30 ⫾ 4
38 ⫾ 4* 33 ⫾ 1
42 ⫾ 2** 36 ⫾ 2
40 ⫾ 2** 36 ⫾ 2
43 ⫾ 2** 38 ⫾ 1
6 6
44 ⫾ 4 43 ⫾ 2
47 ⫾ 3 48 ⫾ 2
60 ⫾ 4** 45 ⫾ 3
66 ⫾ 2** 52 ⫾ 1
68 ⫾ 3** 58 ⫾ 3
6 6
0.6 ⫾ 0.5 0.6 ⫾ 0.2
0.8 ⫾ 0.3 0.4 ⫾ 0.4
1.2 ⫾ 0.2* 0.7 ⫾ 0.4
1.0 ⫾ 0.3* 0.6 ⫾ 0.2
1.1 ⫾ 0.2** 0.5 ⫾ 0.2
6 6
126 ⫾ 6 129 ⫾ 9
124 ⫾ 5 128 ⫾ 4
128 ⫾ 4 124 ⫾ 4
129 ⫾ 2* 125 ⫾ 3
131 ⫾ 4** 126 ⫾ 5
6 6
67 ⫾ 5 70 ⫾ 6
62 ⫾ 5 64 ⫾ 3
72 ⫾ 4* 76 ⫾ 2
40 ⫾ 2** 56 ⫾ 1
38 ⫾ 4** 49 ⫾ 3
6 6
54 ⫾ 4 54 ⫾ 2
50 ⫾ 4 50 ⫾ 2
56 ⫾ 2** 61 ⫾ 2
31 ⫾ 2** 45 ⫾ 1
29 ⫾ 3** 39 ⫾ 3
6 6
0.7 ⫾ 0.6 0.9 ⫾ 0.2
1.2 ⫾ 0.1 1.0 ⫾ 0.5
1.2 ⫾ 0.2* 0.8 ⫾ 0.3
1.1 ⫾ 0.2** 0.5 ⫾ 0.3
1.5 ⫾ 0.2** 0.9 ⫾ 0.2
* p ⬍ 0.05 vs. normal perfusion group; **p ⬍ 0.01 vs. normal perfusion group. DA ⫽ dopamine group; NP ⫽ normal perfusion group; PaH ⫽ PH of carotid blood; PaCO2 ⫽ arterial partial pressure of carbon dioxide of carotid; PaO2 ⫽ arterial partial pressure of oxygen of carotid; ALac ⫽ lactic acid of carotid; SaO2 ⫽ saturation of blood oxygen of carotid; PvH, PvCO2, PvO2, VLac, SvO2 indicate the same meanings about mixed venous blood gas analyses; PCLac ⫽ lactic acid disparity between mixed venous blood and carotid blood; CAO2 ⫽ arterial oxygen content; C(A-v)O2 ⫽ disparity between carotid oxygen content and jugular oxygen content; VALac ⫽ lactic acid disparity between jugular blood and carotid blood.
was higher at ROSC 2 h and 4 h. In the carotid and jugular blood, oxygen content was lower at ROSC 1 h, 2 h, and 4 h; the oxygen extraction ratio of carotid blood was lower at ROSC 1 h, 2 h, and 4 h; and the lactic acid disparity between carotid and jugular blood was greater during the same period (Table 4).
DISCUSSION Dopamine is one of the catecholamines that are commonly used in the clinical setting. As a precursor of noradrenaline, dopamine acts on ␣-receptors, -receptors, and two specific dopamine receptors. Hemodynamic instability and left ventricular dysfunction, manifested clinically as arterial hypotension, may result from dopamine administration, especially after restoration of circulation after cardiac arrest and resuscitation. During or after resuscitation,
exogenous epinephrine or other catecholamines are often required to increase coronary perfusion pressure, and to treat post-resuscitation hypotension and post-ischemic myocardial damage or to augment cardiac function and increase DO2 (5–9). In a patient resuscitated from cardiac arrest, hemodynamic instability will affect recovery of neurological function. Some research studies on cerebral blood flow after resuscitation have shown that a short-term episode of transient and multifocal absence of perfusion is followed by hyperemia associated with a high cerebral metabolic rate of oxygen (CMRO2) and glucose. Subsequently, cerebral hypoperfusion with a parallel reduction of CMRO2 develops (10). Under normal conditions, changes in arterial pressure have only a small influence on cerebral blood flow due to reactive dilatation and constriction of cerebral resistance vessels in response to arterial hypotension and hypertension, that is, cerebral
Dopamine Impact after Restoration of Spontaneous Circulation in Pigs
blood flow autoregulation (11). But some researchers have found that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or is right-shifted. When researchers investigated the autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest, it was found that MAP had to be maintained at a higher level than normal to ensure cerebral perfusion (12). But the optimal MAP for post-cardiac arrest patients has not been defined by prospective clinical trials. Some studies found that level of MAP during the first 2 h after ROSC was correlated with neurological outcome (13). In the present study, all animals that were resuscitated successfully were randomly assigned to one of two groups: the dopamine group or the normal perfusion group. In the dopamine group, animals were administered normal saline solution and dopamine through a venous pump to maintain the MAP at about 130% of the baseline MAP after ROSC. In the normal perfusion group, the animals were administered an equal volume of normal saline solution without dopamine. The findings showed improvement in hemodynamic parameters and in oxygen metabolism in the dopamine group over the normal perfusion group. The improvements in hemodynamic parameters included MAP and carotid blood pressure, which were higher in the dopamine group than in the normal perfusion group (p ⬍ 0.05) in all stages after resuscitation. In other words, a better blood supply to cerebral tissues was achieved in the dopamine group. In a short period of time, the positive inotropism for the heart by dopamine was remarkable, that is, in the dopamine group, the values of CO and SV at ROSC 0.5 h, 1 h, 2 h, and 4 h were higher than those in the normal perfusion group (p ⬍ 0.01), whereas the systemic vascular resistance did not increase (p ⬎ 0.05). However, there was one unfavorable aspect in the dopamine group: heart rate was remarkably higher than in the normal perfusion group. This finding requires further study. The effects of tachycardia and increased oxygen consumption at the myocardium on the restoration of ventricular function after resuscitation as well as the long-term impact require further study. With regard to oxygen consumption, catecholamines could increase oxygen consumption at the myocardium, but they might also increase oxygen consumption by systemic tissues in two ways: cell metabolism induced by adrenergic receptors and effects on the central venous system, and agitation of sympathetic nerves (14). However, if the effect of increasing DO2 is superior to that of VO2, dopamine may improve the general oxygen transportation and oxygenation in tissues. In addition, it has been reported that dopamine could play a beneficial role after cardiac operations in adults and young children (15,16). In this study, DO2 and VO2 were higher in the dopamine group than in the
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normal perfusion group (p ⬍ 0.05), and ERO2 was lower in the dopamine group than in the normal perfusion group (p ⬍ 0.05). Oxygen transportation was better in the dopamine group than in the normal perfusion group. Dopamine may improve the oxygen metabolism of systemic tissues after resuscitation. The results of blood gas analysis in the present study indicate that carotid oxygen content was higher in the dopamine group, carotid-venous oxygen content difference was lower, and the carotid-venous lactic acid content difference was higher (p ⬍ 0.05). Thus, the oxygenation and oxygen utilization were better in the dopamine group than in the normal perfusion group. The improvements in hemodynamics and oxygen metabolism in the dopamine group had beneficial effects on the restoration of neural system function in this resuscitated porcine model. The 24-h cerebral function scores were “normal” for all six animals in the dopamine group, but for only one animal in the normal perfusion group, and there was a significant difference between the two groups (p ⬍ 0.05). The above data suggest that dopamine may improve the cerebral blood supply by raising blood pressure and, further, it may play an active role in the process of cerebral resuscitation. However, due to the limitations in this study, the finding of improved cerebral function will need to be studied for a longer period of time.
Limitations The results of this study, which was performed in an animal model, do not reflect the exact changes and complete outcomes that would occur in the human body under similar physiologic conditions. Moreover, the small number of animals in the sample might preclude finding statistically significant differences in some tests. Additionally, as the electric defibrillation frequency for each animal was different during the period of resuscitation, the possible effects of electronic injuries on myocardial tissue after resuscitation was not considered in the study. The impairments to ventricular function after resuscitation might have been exacerbated by the anesthesia, and that could enhance the effect of the catecholamines.
CONCLUSIONS Dopamine could improve systemic perfusion, and play an active role in improving hemodynamic parameters, as shown in this porcine ROSC model. Dopamine, as a pressor agent, may improve cerebral blood supply and oxygen metabolism after successful resuscitation when it
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is used to increase the aortic blood pressure. All of these factors may have beneficial effects on cerebral function after resuscitation. Acknowledgments—This study would not have been possible without the expertise and support of Doctors Xue Mei, Ziren Tang, Ming Jin and Shuo Wang. Their assistance with this project is greatly appreciated.
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6. Wortsman J, Paradis NA, Martin GB, et al. Functional responses to extremely high plasma epinephrine concentrations in cardiac arrest. Crit Care Med 1993;14:692–7. 7. Kern KB. Postresuscitation myocardial dysfunction. Cardiol Clin 2002;20:89 –101. 8. Crexells C, Bourassa MG, Biron P. Effects of dopamine on myocardial metabolism in patients with ischaemic heart disease. Cardiovasc Res 1973;7:438 – 45. 9. Takamatsu I, Karasawa F, Okuda T. Dopamine may preserve the myocardial oxygen balance better than dobutamine when administered with milrinone. Can J Anaesth 2002;49:968 –72. 10. Sterz F, Leonov Y, Safar P, et al. Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs: reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 1992;24:27– 47. 11. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990;2:161–92. 12. Sundgreen C, Larsen FS, Herzog TM, et al. Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest. Stroke 2001;32;128 –32. 13. Müllner M, Sterz F, Binder M, et al. Arterial blood pressure after human cardiac arrest and neurological recovery. Stroke 1996;27: 59 – 62. 14. Ensinger H, Weichel T, Lindner KH, et al. Effects of norepinephrine, epinephrine, and dopamine infusions on oxygen consumption in volunteers. Crit Care Med 1993;21:1502– 8. 15. Merin G, Bitran D, Uretzky G, et al. The hemodynamic effects of dopamine following cardiopulmonary bypass. Ann Thorac Surg 1977;23:361–3. 16. Kawamura M, Minamikawa O, Yokochi H, et al. Combined use of phenoxybenzamine and dopamine for low cardiac output syndrome in children at withdrawal from cardiopulmonary bypass. Br Heart J 1980;43:388 –92.
ARTICLE SUMMARY 1. Why is this topic important? Currently, a key component of post-cardiac arrest syndrome is post-resuscitation brain injury. Although some reports have indicated that therapeutic hypothermia may improve neurological outcome, cerebral resuscitation is still a difficult problem. 2. What does the study attempt to show? This study attempts to show the impact of dopamine on hemodynamic parameters, oxygen metabolism, and cerebral resuscitation after cardiac arrest and resuscitation. 3. What are the key findings? This experimental study of restoration of spontaneous circulation in an animal model of cardiac arrest suggests that changing the total body perfusion with dopamine administration may improve hemodynamics and oxygen metabolism. 4. How is patient care impacted? Dopamine, as a pressor agent, may improve cerebral blood supply and oxygen metabolism after successful resuscitation when it is used to increase the aortic blood pressure. All of these factors may have beneficial effects on cerebral resuscitation after cardiac arrest.