- Email: [email protected]
Topical head cooling during rewarming after experimental hypothermic circulatory arrest
Matti Pokela, MD, Janne Heikkinen, MS, Fausto Biancari, MD, PhD, Erkka Ro¨nka¨, MS, Timo Kaakinen, MS, Vilho Vainionpa¨a¨, MD, PhD, Kai T. Kiviluoma, MD, PhD, Pekka Romsi, MD, Enrico Leo, MD, Jorma Hirvonen, MD, PhD, Pasi Lepola, MS, Jussi Rimpila¨inen, MD, PhD, and Tatu S. Juvonen, MD, PhD Departments of Surgery, Anesthesiology, and Forensic Medicine and Laboratory of Clinical Neurophysiology, University of Oulu and Oulu University Hospital, Oulu, Finland
Background. The aim of this study was to evaluate the potential neuroprotective effect of topical head cooling during the first 2 postoperative hours after experimental hypothermic circulatory arrest. Methods. Twenty pigs underwent a 75-minute period of hypothermic circulatory arrest and were randomly assigned to rewarming to 37°C or to undergo topical cooling of the head for 2 hours from the start of rewarming followed by a period of external rewarming to 37°C. Results. The 7-day survival rate was 70% in the control group and 60% in the topical head cooling group. Despite brain tissue oxygenation, intracranial pressures, mixed oxygen venous saturation, oxygen consumption, and extraction tended to be favorable in the topical head cool-
ing group as a clear effect of mild hypothermia. The latter group had significantly higher postoperative brain lactate and pyruvate ratios, and lactate and glucose ratios. Furthermore, the topical head cooling group had worse fluid balance throughout the postoperative period. Brain histopathologic scores were comparable with the study groups, but among 7-days survivors these scores tended to be worse in the topical head cooling group. Conclusions. Topical cooling of the head during the first 2 postoperative hours after experimental hypothermic circulatory arrest does not appear to provide any neuroprotective effect. (Ann Thorac Surg 2003;75:1899 –911) © 2003 by The Society of Thoracic Surgeons
H
of prolonged mild hypothermia after a brief period of cold reperfusion after HCA in a previous experimental study [9]. Unfortunately, the latter strategy was associated with poor outcome, but data indicated that mild hypothermia could preserve its neuroprotective efficacy when mild hypothermia would have been used for a period of less than 4 hours after HCA. Thus the aim of the present study was to investigate whether a short period of mild hypothermia as provided by topical head cooling after HCA may have neuroprotective effects.
ypothermic circulatory arrest (HCA) has been increasingly used as a neuroprotective strategy in the repair of aortic arch diseases and complex congenital cardiac malformations. Recently, some studies provided evidence of a certain superiority of antegrade cerebral perfusion over HCA. However, these observations were derived from retrospective, nonhomogenous series in which HCA was often used in the most critical, clinical situations [1]. Indeed, the latter can be treated with HCA producing excellent results, [2] but time restraint remains the major limitation of HCA. The recent interest in the use of prolonged mild or moderate hypothermia in the management of stroke [3], global cerebral ischemia [4, 5], and brain injury [6], brought new insights into possible technical refinements of hypothermic strategies in cardiac surgery. The evidence of neuroprotective effects of prolonged mild systemic hypothermia in focal and global brain ischemia and brain traumatic injury, and the observation that a brief period of cold reperfusion after HCA may provide some greater benefits than immediate rewarming on reperfusion [7, 8] has led us to adopt a combined strategy
Accepted for publication Dec 31, 2002. Address reprint requests to Prof Juvonen, Division of Cardiothoracic and Vascular Surgery, Oulu University Hospital, PO Box 21, 90029 OYS, Oulu, Finland; e-mail: [email protected].
© 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Twenty female juvenile pigs aged 8 to 10 weeks underwent a 75-minute period of HCA at a core temperature of 20°C. Randomized pigs were then rewarmed to 37°C during 60 minutes of reperfusion (control group) or underwent rewarming for a 60-minute period with topical head cooling by packing the head with three icepacks (topical head cooling group). The topical head cooling was continued for an overall of 2 hours after the start of rewarming.
Preoperative Management All animals received humane care in accordance with the “Principles of Laboratory Animal Care” formulated by 0003-4975/03/$30.00 PII S0003-4975(03)00038-9
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POKELA ET AL TOPICAL COOLING AFTER HCA
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the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council (published by the National Academy Press, revised in 1996). The study was approved by the Research Animal Care and Use Committee of the University of Oulu (Oulu, Finland).
Anesthesia and Hemodynamic Monitoring Anesthesia was induced with ketamine hydrochloride (250 mg intramuscularly) and midazolam (30 mg intramuscularly). A peripheral catheter was inserted into a vein of the right ear for the administration of drugs and to maintain fluid balance with Ringer acetate. Anesthesia was deepened with thiopental sodium (125 to 250 mg intravenously). After an intravenous bolus injection of fentanyl (25 g/kg), anesthesia was maintained by a continuous infusion of fentanyl (25 g/kg/h), midazolam (0.25 mg/kg/h), and pancuronium (0.2 mg/kg/h) throughout the entire experiment. Cefuroxime (1.5 g intravenously) was administered at anesthesia induction and before extubation. After endotracheal intubation the animals were maintained on positive pressure ventilation with 50% oxygen. Electrocardiogram monitoring was started. An arterial catheter was positioned in the left femoral artery and a thermo dilution catheter (CritiCath, 7 French [Ohmeda GmbH & Co, Erlangen, Germany]) was placed through the left femoral vein. Blood, rectal, esophageal, epidural, and intracerebral temperatures were continuously monitored.
Brain Microdialysis and Intracerebral Monitoring A temperature probe was placed into the epidural space through a cranial hole made at the left side of the coronal suture. A catheter for measurement of intracerebral tissue oxygen partial pressure (Revodoxe Brain Oxygen Catheter-Micro-Probe, REF CC1.SB [GMS, Mielkendorf, Germany]) was inserted through a hole located on the right side, 1 cm anteriorly to the coronal suture. An intracerebral microdialysis catheter was inserted through a hole located on the right side, 0.5 cm posteriorly to the coronal suture. Temperature (Thermocouple Temperature Catheter-Micro-Probe, REF C8.B, GMS) and intracranial pressure-monitoring catheter (Codman MicroSensor ICP Transducer, Codman ICP Express Monitor [Codman & Shurtleff, Inc, Raynham, MA]) were placed through a hole located on the left side posteriorly to the coronal suture. A microdialysis catheter (CMA 70 [CMA/Microdialysis, Stockholm, Sweden]) was placed into the brain cortex to a depth of 15 mm below the dura mater. The catheter was connected to a 2.5-mL syringe, which was placed into a microinfusion pump (CMA 106, CMA/Microdialysis) and perfused (flow rate, 0.3 L/min) with Ringer solution (Perfusion Fluid CNS, CMA/Microdialysis). Samples were collected at different time points. The concentrations of cerebral tissue glucose, lactate, pyruvate, glutamate, and glycerol were measured immediately after
Ann Thorac Surg 2003;75:1899 –911
collection with a microdialysis analyzer (CMA 600, CMA/ Microdialysis) by using ordinary enzymatic methods.
Electroencephalography Monitoring Cortical electrical activity was registered from 4 stainlesssteel screw electrodes of 5 mm in diameter implanted in the skull over the parietal and frontal areas of the cortex using a digital electroencephalography (EEG) recorder (Nervus, Reykjavik, Iceland) and an amplifier (Magnus EEG 32/8, Reykjavik, Iceland). Sampling frequency was 256 Hz and bandwidth was 0.03 to 100 Hz. All EEG recordings were referenced to a frontal screw electrode together with a ground screw electrode, which was implanted over the frontal sinuses. Electroencephalography was recorded for 10 minutes to get a base line recording before the cooling period. After HCA, EEG recording was restarted and continued until extubation. Artifact periods were excluded from each 5-minute sample. Recoveries of different wave bands (alpha, beta, and theta) were calculated from all four electrodes by means of nonlinear analysis. The energy recovery of EEG was evaluated by an algorithm based on the nonlinear energy operator [10].
Cardiopulmonary Bypass The heart and great vessels were exposed through a right thoracotomy in the fourth intercostal space. A membrane oxygenator (Midiflow D 705 [Dideco, Mirandola, Italy]) was primed with 1 L of Ringer acetate and heparin (5000 IU). After systemic heparinization (500 IU/kg), the ascending aorta was cannulated with a 16 French arterial cannula, and the right atrial appendage was cannulated with a single 24 French atrial cannula. Nonpulsatile cardiopulmonary bypass (CPB) was initiated (flow rate, 100 mL/kg/min), and the flow was adjusted to maintain a perfusion pressure of 50 mm Hg. The left ventricle was decompressed by a 12 French intracardiac sump cannula. A heat exchanger was used for core cooling. The pH was maintained with ␣-stat principles at 7.40 ⫾ 0.05, with an arterial carbon dioxide tension of 5.3 to 5.5 kPa uncorrected for temperature.
Experimental Protocol After a 60-minute period of cooling to a rectal temperature of 20°C, a 75-minute period of HCA was started. The ascending aorta was cross clamped distally to the aortic cannula. Cardiac arrest was induced by injecting potassium chloride (3 g) through the aortic cannula. During HCA, ice slushes were used continuously for topical cardiac cooling, and the epidural and intracerebral temperatures were maintained at 18°C with ice packs placed over the head. After 75 minutes of HCA, rewarming was started, the left ventricular sump cannula was removed, and furosemide (40 mg), mannitol (15 g), methylprednisolone (80 mg), lidocaine (40 to 150 mg), and calcium chloride (1375 mg) were administered. After weaning from CPB, cardiac support was provided with dopamine. Animals in the topical head cooling group were rewarmed to a rectal temperature of 36°C during 60 min-
utes of reperfusion with their heads packed with three icepacks each. Topical head cooling was continued for an overall of 2 hours after the start of rewarming. Because the animals in the latter group also had a mildly low systemic temperature during topical head cooling, they were rewarmed to 37°C by a heat-exchanger mattress and two heating lamps at the end of the head cooling period. Animals in the control group were rewarmed to a rectal temperature of 37°C during 60 minutes of reperfusion. The heat exchanger and blood temperature gradient were approximately 10°C at the start of rewarming, and the heat exchanger temperature was rarely set to approximately 38°C. The animals of both groups were extubated 8 hours after the start of rewarming when the rectal temperature approximated 37°C and were then moved to a recovery room. During the experiment, hemodynamic and metabolic measurements were recorded. These measurements (pulse rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary capillary wedge pressure, cardiac output, intracranial pressure, intracerebral tissue oxygen partial pressure, temperatures, arterial and venous pH, oxygen and carbon dioxide partial pressure, oxygen saturation, oxygen concentration, hematocrit, hemoglobin, sodium, potassium, and glucose (CibaCorning 288 Blood Gas System [Ciba-Corning Diagnostic Corp, Medfield, MA]), lactate (YSI 1500 analyzer [Yellow Springs Instrument Co, Yellow Springs, OH]), leukocyte differential count (Cell-Dyn analyzer [Abbot, Santa Clara, CA]), and creatine kinase and its isoenzymes (creatine kinase-MM, creatine kinase-MB, creatine kinase-BB [Hydrasys LC-electrophoresis, Hyrys-densitometry, Sebia, France]) were recorded continuously or at baseline, at the end of cooling (at 20°C immediately before institution of HCA), at 30 minutes, 2 hours, 4 hours, and 8 hours after the start of rewarming, and before extubation.
Postoperative Evaluation The postoperative behavior of the animals was evaluated daily by an experienced observer who was blinded to the study group using a species–specific quantitative behavioral score. The quantified assessment of mental status (0 ⫽ comatose, 1 ⫽ stuporous, 2 ⫽ depressed, and 3 ⫽ normal), appetite (0 ⫽ refuses liquids, 1 ⫽ refuses solids, 2 ⫽ decreased, and 3 ⫽ normal), and motor function (0 ⫽ unable to stand, 1 ⫽ unable to walk, 2 ⫽ unsteady gait, and 3 ⫽ normal) was summed to obtain a final score, with a maximum score of 9 reflecting apparently normal neurologic function and lower values indicating substantial brain damage.
Perfusion Fixation Each surviving animal was electively killed on the seventh postoperative day. Immediately after intravenous injection of pentobarbital (60 mg/kg) and heparin (500 IU/kg), the thoracic cavity was opened and the descending thoracic aorta was clamped. Ringer solution (1 L) was perfused through the ascending thoracic aorta through the upper body, and blood was suctioned from the superior vena cava until the perfusate was clear of blood.
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Then 10% formalin solution (1 L/15 min) was infused through the brain in the same manner to accomplish a perfusion fixation. Immediately thereafter the entire brain was harvested, weighed, and immersed in 10% neutral formalin. The same method of fixation procedure was carried out in those animals that died before the seventh postoperative day.
Histopathologic Analysis The brain was allowed to fix for 1 week en bloc. Thereafter, 3-mm thick coronal samples were sliced from the left frontal lobe, thalamus, and hippocampus, and sagittal samples from the posterior brainstem (medulla oblongata and pons) and cerebellum were obtained. The specimens were fixed in fresh formalin for another week and then processed by rinsing in water for 20 minutes and immersion in 70% ethanol for 2 hours, 94% ethanol for 4 hours, and absolute ethanol for 9 hours. Then the specimens were kept for 1 hour in absolute ethanol-xylene mixture and 4 hours in xylene, and were then embedded in warm paraffin for 6 hours. The specimens were sectioned at 6 m, stained with hematoxylin and eosin, and examined by an experienced senior pathologist (JH) unaware of the experimental design, identity, or fate of the individual animals. The signs of injury were scored as follows: 1 (slight edema, dark or eosinophilic neurons, or cerebellar Purkinje cells); 2 (moderate edema of at least 2 hemorrhagic foci in the section); 3 (severe edema, several hemorrhagic foci, infarct foci [local necrosis]). In case of the presence of more than one of the previously mentioned findings, the score from each region was calculated in a cumulative way. The total regional score was the sum of the scores in each specific brain area (cortex, thalamus, hippocampus, posterior brainstem, and cerebellum).
Statistical Analysis Analyses were performed using the SPSS software (Version 10.0.7 [SPSS Inc, Chicago, IL]). Continuous variables are expressed as the median with interquartile range (IQR) (25th to 75th percentiles). Analysis of variance for repeated measurements was performed. Comparison between relevant time-points and baseline (reference category) was performed by paired sample t test or Wilcoxon matched pairs signed rank test. Differences between groups were determined by t test or by Mann–Whitney U test. The two-tailed Fischer’s exact test was used to determine the significance of mortality rates between groups. The area under the curve was calculated for microdialysis measurements and Kendall’s rank correlation test was used to estimate correlation coefficients. Significance levels are reported for comparisons with a two-tailed p less than 0.05.
Results Comparability of the Study Groups The median weight of pigs was 25.9 kg (IQR, 24.3 to 27.6 kg) in the topical head cooling group and 24.7 kg (IQR,
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Fig 1. Daily score indicating behavioral recovery after 75 minutes hypothermic circulatory arrest. A score of 9 indicates essentially a complete recovery. (Left) Topical cooling group. (Right) Control group.
23.8 to 26.6 kg) in the control group (p ⫽ 0.25). The median CPB cooling time was 63.5 minutes (IQR, 60.0 to 70.0 min) in the topical head cooling group and 62.5 minutes (IQR, 60.0 to 64.0 min) in the control group (p ⫽ 0.39). The median CPB rewarming time was 62.0 minutes (IQR, 60.0 to 67.0 min) in the topical head cooling group and 64.5 minutes (IQR, 63.0 to 70.0 min) in the control group (p ⫽ 0.15). The median total CPB time was 126.5 minutes (IQR, 123.0 to 133.0 min) in the topical head cooling group and 128.0 minutes (IQR, 124.0 to 133.0 min) in the control group (p ⫽ 0.92). During HCA, the temperatures did not differ between the groups.
Mortality and Morbidity The 7-day survival rate was 70% in the topical head cooling group and 60% in the control group. Animals that underwent topical head cooling after HCA tended to have better postoperative behavioral scores throughout the postoperative period than those in the control group, but such differences failed to reach statistical significance (Fig 1). However, such a finding is affected by the occurrence in two animals of the control group with unilateral posterior leg problems related to vascular access complications which prevented their recovery.
Hemodynamic and Metabolic Data Experimental and metabolic data are presented in Table 1, 2 and Figures 2 and 3. There was no significant difference between the study groups in terms of cardiac indexes, heart rate, central venous pressure, arterial and venous pH, arterial oxygen partial pressure, and mixed venous glucose and lactate concentrations. Animals that underwent topical head cooling had significantly lower vascular resistance 30 minutes after the start of rewarming perfusion, which led to a significantly lower perfusion pressure (Table 1). Such a difference tended to persist until the 2-hour postoperative interval. After the start of rewarming, pigs that underwent topical head cooling had lower oxygen extraction and
consumption rates and higher mixed venous saturation levels; this difference was statistically significant at the 2-hour interval (Table 2). Furthermore, animals in the topical head cooling group had lower intracranial temperatures from the start of rewarming until the 4-hour postoperative interval (Fig 2). Rectal and blood temperature were also lower 2 hours after the start of the rewarming (Table 1, Fig 3a, b). It is worth noting that intracranial temperature in the topical head cooling group was still lower after 4 hours of HCA (Fig 1), with the median temperature 1.6 degrees lower than that of the control group. However, the systemic temperatures were similar in both groups (Fig 3a, b). Fluid balance was worse in the topical head cooling group from the 2-hour to 8-hour postoperative interval periods (Table 1). At the 8-hour postoperative interval, hemoglobin value and total leukocyte count were significantly higher in the topical head cooling group (Table 1). Because the central venous pressure was similar between the study groups at this interval, such differences are likely related to a significant tissue edema that occurred in the animals that underwent postoperative topical head cooling (Fig 4). Mixed venous blood creatine-kinase levels did not differ significantly between groups, but the total creatinekinase was slightly higher in the control group (Table 2).
Intracranial Measurements Intracranial measurement data are presented in Figures 5– 6. Brain glucose and glycerol concentration were similar in both study groups throughout the experiment. Brain lactate tended to be higher in the topical head cooling group at the 7-hour and 8-hour intervals after HCA. The peak concentration of brain glutamate was higher in the control group, but the glutamate concentration was higher at the 1.5-hour and 2-hour intervals after HCA in the topical head cooling group (p ⫽ not significant). Brain pyruvate concentrations tended to be lower in the topical head cooling group 2 to 6 hours after
30 Minutes Baseline
4 Hours
8 Hours
p Value Between Groups
After the Start of Rewarming
90 (83–93) 88 (78 –99)
70 (64 –75)a 70 (68 –76)
74 (66 – 82) 95 (85–100)b
88 (83–92) 95 (84 –104)
100 (95–104)a 99 (85–102)
86 (78 –95) 86 (67–94)
p ⫽ 0.206
98 (93–106) 103 (97–116)
0 (0 –20)a 10 (0 –30)
174 (150 –200) 188 (172–207)
134 (118 –143) 120 (118 –156)
142 (126 –153) 150 (125–170)
167 (138 –176) 168 (155–176)
p ⫽ 0.265
4.1 (3.9 –5.0) 4.5 (3.4 –5.0)
p ⫽ 0.583
4.4 (3.7–5.1) 4.3 (3.7– 4.7) 103 (94 –105) 97 (91–101)
2.7 (2.6 –2.9)a 2.8 (2.7–2.8) 69 (66 –72)a 61 (58 – 67)
2.9 (2.6 –3.2)a 2.8 (2.7–3.0) 83 (73– 86)a 77 (65– 82)
3.2 (3.1–3.2)a 3.1 (2.7–3.8) 93 (85–100)a 90 (82–92)
3.4 (3.3– 4.0)a 3.3 (2.9 –3.8) 86 (82–95)a 87 (80 –95)
99 (88 –112) 85 (79 –96)c
p ⫽ 0.094
2,402 (2,087–2,745)a 2,568 (2,435–2,737)
2,297 (2,000 –3,159)a 3,721 (3,333–3,815)a
2,720 (2,508 –3,012)a 3,027 (2,811–3,294)
2,798 (2,584 –2,939)a 2,939 (2,678 –3,510)
1,790 (2,074 –2,264) 1,674 (1,861–2,127)
p ⫽ 0.044
350 (250 – 450) 325 (250 – 450)
3,125 (3,000 –3,600) 3,250 (3,100 –3,600)
3,425 (3,400 – 4,000) 3,475 (3,200 –3,700)
4,500 (3,900 –5,000) 4,275 (3,800 – 4,850)
4,800 (4,200 –5,200) 4,700 (4,700 –5,350)
5,125 (4,300 –5,700) 5,200 (5,000 –5,700)
p ⫽ 0.933
225 (150 –350) 200 (150 –350)
1,300 (1,150 –1,700) 1,400 (1,300 –1,720)
1,900 (1,500 –2,300) 1,775 (1,400 –2,000)
3,275 (3,000 –3,800) 3,650 (3,000 –3,950)
3,975 (3,700 – 4,800) 4,800 (4,460 – 4,950)
4,700 (3,800 –5,150) 5,250 (4,500 –5,600)
p ⫽ 0.455
100 (0 –150) 75 (0 –200)
1,000 (1,750 –2,150)a 1,975 (1,600 –2,200)
1,775 (1,300 –2,000)a 1,750 (1,550 –2,200)
1,225 (700 –1,500)a 650 (100 –1,700)
825 (300 –1,050)d ⫺25 (⫺250 – 650)
575 (200 –950) ⫺75 (⫺200 – 400)
p ⫽ 0.487
37.4 (37.2–38.0) 37.2 (36.8 –37.8)
p ⫽ 0.566
2,133 (1,737–2,242) 2,079 (1,808 –2,382)
36.8 (36.2–37.4) 37.3 (36.9 –37.4)
20.0 (19.4 –20.8) 19.6 (18.5–20.7)
28.1 (27.0 –30.3) 27.4 (26.5–30.7)
34.3 (33.4 –34.6) 35.3 (34.6 –35.9)c
36.8 (35.5–37.2) 36.8 (36.4 –37.5)
1.8 (1.2–7.4) 0.6 (⫺0.5–1.3)c
0.9 (0.7–1.2) ⫺0.2 (⫺0.3– 0.2)b
0.5 (0.3–1.3) 0.1 (0.0 – 0.3)c
1.0 (0.1–1.2) 0.1 (⫺0.1– 0.3)c
p ⫽ 0.016
0.8 (0.4 –1.0) 0.3 (0.1– 0.6)
䡠䡠䡠 䡠䡠䡠
17.3 (14.4 –18.8) 21.2 (18.4 –25.8)
3.6 (2.5–5.0)a 3.0 (2.1– 4.6)
6.9 (6.7–7.5)a 6.9 (6.0 –9.2)
22.7 (19.7–26.7)a 23.6 (21.5–28.6)
30.4 (25.2–33.2)a 28.2 (25.5–36.1)
36.1 (33.6 –39.3)a 30.6 (24.3–36.9)c
p ⫽ 0.004
8.5 (6.8 –10.5) 11.8 (8.8 –12.9)
1.9 (1.2–2.7) 1.8 (1.1–3.0)
3.2 (2.5– 4.3) 3.3 (2.1– 4.4)
16.3 (13.7–19.4) 18.9 (16.3–22.2)
23.3 (19.5–26.6) 22.8 (20.0 –27.7)
29.4 (26.2–33.0) 24.8 (19.9 –30.6)
p ⫽ 0.917
Values are shown as medians with interquartile ranges (25th–75th percentile).
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a p ⬍ 0.01 interaction between time versus baseline and other intervals in the study groups. p value between groups is according to the tests of between-subjects effects. Fluid balance ⫽ intravenous fluids given b c d — cumulative diuresis; p ⬍ 0.05 difference between study groups at each interval; p ⬍ 0.05 interaction between time versus baseline and other intervals in the study groups; p ⬍ 0.01 difference between study groups at each interval.
POKELA ET AL TOPICAL COOLING AFTER HCA
Mean arterial pressure (mm Hg) Topical head cooling Control Heart rate (beats/min) Topical head cooling Control Cardiac index (L/min/m2) Topical head cooling Control Hemoglobin (g/L) Topical head cooling Control Vascular resistance (dyn 䡠 d seq 䡠 d cm⫺5) Topical head cooling Control Fluid (mL) Topical head cooling Control Urine (mL) Topical head cooling Control Fluid balance (mL) Topical head cooling Control Rectal temperature (°C) Topical head cooling Control Gradient between blood and intracranial temperature (°C) Topical head cooling Control Total leukocytes count (⫻ 109/L) Topical head cooling Control Neutrophil count (1 ⫻ 109/L) Topical head cooling Control
End of Cooling
2 Hours
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Table 1. Experimental Data
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Table 2. Metabolic Data
Baseline Arterial pH Topical head cooling Control PaCO2 (kPa) Topical head cooling Control PvCO2 (kPa) Topical head cooling Control Pao2 (kPa) Topical head cooling Control Venous glucose (mmol/L) Topical head cooling Control Venous lactate (mmol/L) Topical head cooling Control SvO2 (%) Topical head cooling Control O2 consumption (mL/min/m2) Topical head cooling Control O2 extraction (mL/dL) Topical head cooling Control Creatine-kinase total (U/mL) Topical head cooling Control Creatine-kinase BB (U/mL) Topical head cooling Control
End of Cooling
2 Hours
4 Hours
8 Hours
After the Start of Rewarming
P Value Between Groups
7.51 (7.49 –7.55) 7.53 (7.48 –7.55)
7.42 (7.39 –7.45)a 7.41 (7.38 –7.46)
7.36 (7.33–7.40)a 7.35 (7.32–7.36)
7.42 (7.41–7.44)a 7.42 (7.42–7.45)
7.49 (7.47–7.50)b 7.47 (7.47–7.50)
7.49 (7.47–7.52) 7.50 (7.49 –7.53)
p ⫽ 0.439
4.9 (4.6 –5.2) 4.8 (4.3–5.2)
5.0 (4.5–5.5) 4.9 (4.4 –5.3)
5.0 (4.7–5.2)a 4.7 (4.4 –5.0)
5.8 (5.5– 6.1)b 5.4 (5.0 –5.6)c
5.4 (5.1–5.5) 5.3 (4.7–5.5)
5.0 (4.7–5.5) 4.8 (4.7–5.2)
p ⫽ 0.620
6.0 (5.7– 6.2) 6.0 (5.6 – 6.3)
6.1 (5.3– 6.5) 5.8 (5.7– 6.2)
6.3 (6.0 – 6.7) 6.4 (6.0 – 6.7)
7.1 (6.8 –7.6)a 7.0 (6.8 –7.3)
6.7 (6.4 – 6.8)a 6.4 (6.2– 6.9)
6.2 (5.4 – 6.6) 6.1 (5.9 – 6.4)
p ⫽ 0.617
64.6 (59.1– 69.1)a 68.6 (55.0 –72.4)
84.7 (78.7– 89.7)a 80.3 (68.3– 82.6)
30.6 (28.6 –35.4)a 30.7 (29.2–34.6)
31.4 (27.4 –34.2)a 29.8 (27.3–31.0)
p ⫽ 0.596
38.6 (36.5– 40.5) 34.5 (31.9 –37.2)
122 (117–126)a 127 (122–132)
5.2 (4.9 –5.5) 5.4 (5.1–5.9)
5.9 (4.9 – 6.7)b 5.9 (5.2–7.0)
14.4 (12.3–15.7)a 14.6 (10.4 –17.0)
9.4 (8.3–10.5)a 9.1 (7.9 –9.6)
9.1 (7.9 –9.6)a 7.9 (7.5– 8.6)
7.9 (7.7– 8.8)a 7.4 (6.8 – 8.4)
p ⫽ 0.298
0.9 (0.9 –1.1) 1.0 (0.8 –1.0)
1.4 (1.1–1.5)a 1.4 (1.2–1.7)
3.8 (3.5–5.1)a 4.5 (3.8 – 4.8)
2.9 (1.8 –3.1)a 2.5 (2.1–2.6)
0.9 (0.8 –1.1) 1.0 (0.9 –1.2)
1.0 (0.8 –1.3) 1.0 (0.9 –1.3)
p ⫽ 0.458
84.9 (80.2– 86.3) 81.1 (79.1– 87.9)
99.7 (99.5–99.8)a 99.7 (99.6 –99.7) 51 (40 –56)a 54 (49 – 68)
131 (128 –144) 126 (104 –142) 3.0 (2.5–3.5) 3.2 (2.5–3.3) 1,039 (815–1,322) 1,239 (950 –1,508) 170 (138 –204) 130 (116 –181)
76.1 (67.5– 80.2)a 71.1 (67.7–75.9) 112 (96 –126) 115 (102–141)
82.5 (75.1– 85.0)a 67.8 (64.1– 80.8)c 125 (118 –154) 170 (126 –179)c
67.9 (64.3– 69.9)a 64.7 (58.7–71.9) 158 (135–175)a 157 (150 –175)
1.9 (1.5–1.9)a 1.9 (1.8 –2.1)
4.1 (3.3– 4.4)a 4.1 (3.8 – 4.9)
4.0 (3.7– 4.6)a 5.4 (4.3– 6.0)c
4.3 (4.1– 4.9)a 4.8 (4.0 –5.3)
1,953 (1,584 –2,972)a 2,359 (2,049 –2,639)
3,658 (2,268 – 4,730)a 3,618 (3,139 –3,981)
7,374 (6,160 –9,703)a 9,120 (8,835–9,919)
8,290 (7,479 – 8,826)a 9,709 (8,566 –10,072)
135 (130 –166) 109 (105–120)
134 (127–170) 145 (113–159)
353 (293– 413)a 384 (339 – 417)
77.2 (68.8 – 83.3)a 69.0 (64.0 –71.4) 162 (141–180)a 180 (160 –201) 4.2 (2.8 –5.0)a 4.4 (3.8 – 4.6) 7,093 (6142–9,293)a 9,317 (8375–10,876)
380 (257–521)a 284 (252–358)
174 (125–211) 185 (178 –265) b
p ⫽ 0.017
p ⫽ 0.355
p ⫽ 0.150
p ⫽ 0.147
p ⫽ 0.908
p ⬍ 0.05 interaction between time
Values are shown as medians with interquartile ranges (25th–75th percentile). PaCO2 ⫽ arterial carbon dioxide partial pressure; pressure; SvO2 ⫽ mixed venous oxygen saturation.
Pao2 ⫽ arterial oxygen partial pressure;
PvCO2 ⫽ mixed venous carbon dioxide partial pressure;
PvO2 ⫽ mixed venous oxygen partial
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p ⬍ .01 interaction between time versus baseline and other intervals in the study groups. p value between groups is according to the tests of between-subjects effects. c versus baseline and other intervals in the study groups. p ⬍ 0.05 difference between study groups at each interval.
a
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HCA. The brain lactate and pyruvate ratio was significantly higher in the topical head cooling group from the 6-hour to 8-hour interval after HCA (p ⫽ 0.02) (Fig 6). Similarly, the brain lactate and glucose ratio was also higher 7 hours after HCA (p ⫽ 0.036) and tended to be significantly higher at the 6-hour and 8-hour interval after HCA (Fig 6). Brain tissue oxygen partial pressure values tended to be higher in the topical head cooling group at the 1-hour to 3-hour interval after HCA and the difference was statistically significant 2.5 hours after HCA. However, during the late two study intervals, brain tissue oxygen partial pressure increased and tended to be higher in the control group, although the difference did not reach statistical significance (Fig 6). Intracranial pressure values tended to be lower in the topical head cooling group from the 3-hour to 8-hour postoperative interval.
Histopathologic Data
Fig 2. Median brain temperatures in pigs during the experiment. *p less than 0.05; **p less than 0.01 difference between study groups at a certain interval. (HCA ⫽ hypothermic circulatory arrest.)
No statistically significant differences were observed in the overall histopathologic scores between these two study groups, with a mean score of 9.6 in the topical head cooling group and 9.5 in the control group (Table 3). Among the survivors, the topical head cooling group had a slightly higher mean overall histopathologic score (9.5
Fig 3. Median brain and blood temperatures (25th to 75th percentile) in both study groups during the experimental protocol. (a) Topical cooling group. (b) Control group. (HCA ⫽ hypothermic circulatory arrest.)
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CARDIOVASCULAR Fig 4. (a) Central venous pressure, (b) fluid balance, (c) mean arterial pressure, and (d) vascular resistance. **p less than 0.01 difference between study groups at a certain interval.
vs 6.8; p ⫽ 0.3) (Table 3). The histopathological score of posterior brainstem was significantly higher in the topical head cooling group (mean 1.0 vs 0.2; p ⫽ 0.026).
EEG Findings There were no statistical, significant differences between the two groups. All three wave analyses showed faster EEG recovery in the control group during the first postoperative hours; however, later EEG recovery was similar in both groups (Fig 7). Animals that died had lower EEG energies at the 3-hour and 6-hour intervals after HCA (89 vs 206 mV2; p ⫽ 0.01; and 211 vs 625 mV2; p ⫽ 0.05; respectively).
Comment The evidence of reduction in oxygen consumption under hypothermia during the last decades has led to the use of different hypothermic strategies during cardiac surgery in order to protect the brain, heart, and other organs susceptible to hypoperfusion and transient ischemia.
HCA represents the clearest evidence of the protective effect of deep hypothermia on the brain. However, mild hypothermia also preserves its protective effect on neurons, and this has led to extensive experimental and clinical investigations of the neuroprotective effects of prolonged hypothermia in fields other than cardiac surgery with encouraging results [3– 6]. Recent studies have also shown that selective hypothermia by topical cooling can be effective in protecting the brain after global brain ischemia [5, 11] and spinal cord ischemia [12, 13], thus potentially decreasing the potential troublesome adverse effects of systemic hypothermia. During the last few years, some authors [7, 8] in different settings have shown that cold reperfusion after HCA may provide further neuroprotection, thus extending the efficacy of deep hypothermia. Indeed a policy of uncomplete rewarming to 32°C to 33°C after HCA is routinely adopted by some authors with good clinical results [1]. In a previous study of ours [9], a 5-minute period of cold reperfusion at 20°C after HCA followed by a 14-hour period of mild hypothermia did not show any significant
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Fig 5. Medians (25th to 75th percentile) of (a– e) brain microdialysis measurements and (f) intracranial pressure. (HCA ⫽ hypothermic circulatory arrest.)
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CARDIOVASCULAR Fig 6. Median (25th and 75th percentiles) (right) brain lactate and glucose ratio, (middle) lactate and pyruvate ratio, and (left) brain tissue O2 partial pressures. *p less than 0.05. (HCA ⫽ hypothermic circulatory arrest.)
neuroprotective efficacy and was associated with unfavorable changes in cerebral and systemic hemodynamic and metabolic measurements. Nevertheless, data from the latter study suggested that postoperative mild hypo-
thermia may still be effective when used for less than 4 hours. The perceived efficacy of short-term postoperative mild hypothermia, topical brain cooling, and the need to
Table 3. Histopathologic Scores
Protocol Topical head cooling group
Mean Mean (only survivors) Control group
Mean Mean (only survivors) p value p value for survivors
Pig Number
Survival (days)
Cortex Score
Thalamus Score
Hippocampus Score
Posterior Brainstem Score
Cerebellum Score
Total Score
1 2 3 4 5 6 7 8 9 10
1 1 6 7 7 7 7 7 7 7
1 2 3 4 5 6 7 8 9 10
0 1 1 2 7 7 7 7 7 7
2 3 1 2 2 2 7 7 6 4 3.4 4.0 3 2 4 3 2 2 5 7 5 2 3.7 4.2 NS NS
1 2 2 0 0 2 1 2 2 0 1.3 1.1 2 2 4 3 0 1 1 1 1 1 1.5 0.7 NS NS
1 2 2 0 2 2 2 3 5 0 2 2.1 3 1 3 2 1 0 1 1 2 1 1.4 0.8 NS NS
1 5 3 0 1 1 1 1 2 0 1.6 1.0 2 2 4 2 0 0 0 0 1 1 1.1 0.2 NS 0.026
1 2 1 1 1 1 1 2 2 1 1.4 1.4 3 2 5 2 1 1 1 0 2 2 1.8 1.0 NS NS
6 14 9 2 6 8 12 15 17 5 9.6 9.5 13 9 20 12 4 4 8 9 11 7 9.5 6.8 NS NS
Signs of brain ischemic injury were scored as follows: 1 ⫽ dark or eosinophilic neurons or cerebellar Purkinje cells, edema; 2 ⫽ moderate edema, hemorrhages; 3 ⫽ severe edema, infarct foci. The total score is the sum of scores of each specific brain area.
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Fig 7. Electroencephalogram (EEG) (right) beta and (left) theta wave energy (mV2) with mean line and standard error of mean in the study groups.
reduce the adverse effects of systemic hypothermia led us to plan the present study using short-term postoperative topical head cooling. Despite such good premises and its efficacy in decreasing the brain temperature of more than 2°C as compared with controls, topical cooling of the brain failed to provide better results, but rather seems to be associated with some detrimental effects. Such a method was associated with favorable mixed oxygen venous saturation, oxygen extraction and oxygen consumption rates, brain oxygenation, total creatinekinase concentration, and intracranial pressure. These effects are intrinsically related to the ability of hypothermia to reduce tissue metabolism, but its duration seems to be rather short [9]. The present study provided some data to support the hypothesis of derangements occurring in the brain undergoing mild hypothermia after a period of severe HCA. In fact, the occurrence of significantly higher brain lactate and pyruvate ratios and brain lactate and glucose ratios a few hours after the end of topical cooling of the head coincided with a certain “resistance” of the brain to increase its temperature (Figs 2, 3). Although postoperative mild hypothermia may maintain the reduced metabolism state of the brain, it is possible that this is paid back by a severe alteration of brain vasoregulatory mechanisms. After the end of topical head cooling, the animals were rewarmed to 37°C, but a blood-brain temperature difference persisted, probably because of a relative hypoperfusion caused by vasoconstrictive mechanisms. We do not have data on cerebral blood flow rates, but the significant increase in brain lactate and pyruvate ratios and brain lactate and glucose ratios during the last study intervals support a hypothesis of possible cerebral derangements after mild hypothermia after HCA. It is worth noting that the alteration in vasoregulation, to a much less extent, may have also occurred in control animals as their brain temperatures decreased after the end of rewarming. Ehrlich and colleagues [7] reported the beneficial effects of cold reperfusion after experimental HCA. However, such a strategy was evaluated in an acute porcine
model, thus preventing a thorough evaluation of the impact of hypothermic strategy after HCA on the postoperative survival and neurologic outcome. The authors showed that a brief period of hypothermia after the end of HCA is associated with a decrease in intracranial pressure. Indeed we also showed that intracranial pressure is a determinant of postoperative outcome after experimental HCA in a chronic porcine model [14]. However, as shown in our previous study, a decrease of intracranial pressure related to the use of mild hypothermia is not necessarily associated with better outcome [9]. In fact we observed a certain rebound increase of intracranial pressure after the end of prolonged systemic postoperative mild hypothermia associated with unfavorable metabolic derangements and poorer outcome [9], which suggests that postoperative mild hypothermia is associated with unfavorable vasoregulatory changes that may cause severe metabolic alterations despite results in decreased intracranial pressure. Furthermore, despite our attempt to limit cooling to the head, in the present study we have observed that topical head cooling also has a certain effect in decreasing blood and rectal temperatures (Table 1, Fig 3). This can be caused by either a direct cooling effect on the blood or an alteration in peripheral vasoregulation. Since systemic mild hypothermia may potentially have an adverse impact on the outcome of patients undergoing surgery [15, 16], a decrease in core temperature associated with such a regionally limited cooling method is an undesirable effect. This does not negate the beneficial effect of mild systemic or selective hypothermia in the setting of stroke and global hypoxia that occurred during normothermia as extensively demonstrated by several studies. However, HCA is a particularly different setting as it may probably result not only in severe global cerebral ischemia but also in other derangements of cerebral metabolism and vasoregulation, thus offering a different basis for possible therapeutic use of mild hypothermia. Insler and colleagues [16] also observed a significant negative impact of mild hypothermia after coronary artery bypass
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surgery, thus further suggesting that any hypothermic state after rewarming can be significantly detrimental in cardiac surgery patients. In conclusion, the present experimental study demonstrated that a short-term period of topical head cooling does not provide any neuroprotective effect after HCA. It confirmed the validity of the strategy for prompt rewarming to 36.5°C after a period of HCA, and maintenance of a temperature of 37°C by external warming during the intensive care unit stay [17].
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6. 7. 8.
9.
This study was supported by grants from the Oulu University Hospital, the Finnish Foundation for Cardiovascular Research, and the Sigrid Juselius Foundation. We express our gratitude to Seija Selja¨ npera¨ , RN, and Veikko La¨ hteenma¨ ki, RN, for their technical assistance; Pasi Ohtonen, MS, for statistical analysis; the Laboratory of the Oulu University Hospital for analyzing the blood samples; and the personnel of the Animal Research Center, Oulu University, and its director, Hanna-Marja Voipio, DVM, PhD, for providing facilities.
10. 11.
12. 13.
References 1. Hagl C, Ergin MA, Galla JD, et al. Neurologic outcome after ascending aorta-aortic arch operations: effect of brain protection technique in high-risk patients. J Thorac Cardiovasc Surg 2001;121:1107–21. 2. Westaby S, Saito S, Katsumata T. Acute type A dissection: conservative methods provide consistently low mortality. Ann Thorac Surg 2002;73:707–13. 3. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998;29:2461–6. 4. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549 –56. 5. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in
14. 15.
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newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102:885–92. Marion DW, Penrod LE, Kelsey SF, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336:540 –6. Ehrlich MP, McCullough J, Wolfe D, et al. Cerebral effects of cold reperfusion after hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2001;121:923–31. Rodriguez RA, Austin EH 3rd, Audenaert SM. Postbypass effects of delayed rewarming on cerebral blood flow velocities in infants after total circulatory arrest. J Thorac Cardiovasc Surg 1995;110:1686 –91. Romsi O, Heikkinen J, Biancari F, et al. Prolonged mild hypothermia after experimental hypothermic circulatory arrest in a chronic porcine model. J Thorac Cardiovasc Surg 2002;123:724 –34. Sa¨ rkela¨ M, Mustola S, Seppa¨ nen T, et al. Automatic analysis and monitoring of burst suppression in anesthesia. J Clin Monit Comput 2002;17:125–34. Tooley J, Satas S, Eagle R, Silver IA, Thoresen M. Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets. Pediatrics 2002; 109:643–9. Ueno T, Furukawa K, Katayama Y, Itoh T. Protection against ischemic spinal cord injury: one-shot perfusion cooling and percutaneous topical cooling. J Vasc Surg 1994;19:882–7. Motoyoshi N, Sakurai M, Hayashi T, et al. Establishment of a local cooling model against spinal cord ischemia representing prolonged induction of heat shock protein. J Thorac Cardiovasc Surg 2001;122:351–7. Pokela M, Romsi P, Biancari F, et al. Increase of intracranial pressure after hypothermic circulatory arrest in a chronic porcine model. Scand Cardiovasc J 2002;36:302–7. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med 1996;334: 1209 –15. Insler SR, O’Connor MS, Leventhal MJ, Nelson DR, Starr NJ. Association between postoperative hypothermia and adverse outcome after coronary artery bypass surgery. Ann Thorac Surg 2000;70:175–81. Coselli JS, LeMaire SA. Temperature management after hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2002;123:621–3.
INVITED COMMENTARY Perioperative cerebral protection in aortic operations requiring deep hypothermic circulatory arrest (DHCA) to avoid stroke and severe neurocognitive dysfunction remains one of the biggest concerns for cardiovascular surgeons. No matter how much attention has been paid to avoiding emboli during such operations, stroke can still accidentally occur, possibly due to disease-related factors. Neurocognitive dysfunction is multifactorial and more complicated. Possible causes of neurocognitive dysfunction are reported to be cerebral ischemia and the consequent accumulation of anaerobic metabolic substances, reactive hyperemia immediately after reperfusion, release of toxic amino acids, and explosive exacerbation of inflammatory responses that are related to contact between blood and the bypass circuit, and are considerably suppressed under deep hypothermia. All of these factors may contribute to consequent cerebral edema in the primarily damaged region and secondary © 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
damage in surrounding penumbra through a compartment phenomenon. A large number of experimental and clinical investigations addressing the beneficial and adverse effects of DHCA have been performed in the last decade. Currently, more attention is being shifted to the rewarming, or postischemia reperfusion, phase after DHCA. Pokela and colleagues have already presented the negative impacts of prolonged (14 hours) mild hypothermia (32°C) after DHCA through similarly well-designed experimental protocols as the present study [1]. They performed another in-depth investigation addressing the impact of a much shorter period (2 hours) of mild topical hypothermia by head cooling. Contrary to previously published articles that support the significance of post-DHCA mild hypothermia for the reduction of cerebral complications [2, 3], they did not demonstrate a significant neuroprotective effect of shortperiod topical hypothermia. Why are these results con0003-4975/03/$30.00 PII S0003-4975(03)00356-4
Background. The aim of this study was to evaluate the potential neuroprotective effect of topical head cooling during the first 2 postoperative hours after experimental hypothermic circulatory arrest. Methods. Twenty pigs underwent a 75-minute period of hypothermic circulatory arrest and were randomly assigned to rewarming to 37°C or to undergo topical cooling of the head for 2 hours from the start of rewarming followed by a period of external rewarming to 37°C. Results. The 7-day survival rate was 70% in the control group and 60% in the topical head cooling group. Despite brain tissue oxygenation, intracranial pressures, mixed oxygen venous saturation, oxygen consumption, and extraction tended to be favorable in the topical head cool-
ing group as a clear effect of mild hypothermia. The latter group had significantly higher postoperative brain lactate and pyruvate ratios, and lactate and glucose ratios. Furthermore, the topical head cooling group had worse fluid balance throughout the postoperative period. Brain histopathologic scores were comparable with the study groups, but among 7-days survivors these scores tended to be worse in the topical head cooling group. Conclusions. Topical cooling of the head during the first 2 postoperative hours after experimental hypothermic circulatory arrest does not appear to provide any neuroprotective effect. (Ann Thorac Surg 2003;75:1899 –911) © 2003 by The Society of Thoracic Surgeons
H
of prolonged mild hypothermia after a brief period of cold reperfusion after HCA in a previous experimental study [9]. Unfortunately, the latter strategy was associated with poor outcome, but data indicated that mild hypothermia could preserve its neuroprotective efficacy when mild hypothermia would have been used for a period of less than 4 hours after HCA. Thus the aim of the present study was to investigate whether a short period of mild hypothermia as provided by topical head cooling after HCA may have neuroprotective effects.
ypothermic circulatory arrest (HCA) has been increasingly used as a neuroprotective strategy in the repair of aortic arch diseases and complex congenital cardiac malformations. Recently, some studies provided evidence of a certain superiority of antegrade cerebral perfusion over HCA. However, these observations were derived from retrospective, nonhomogenous series in which HCA was often used in the most critical, clinical situations [1]. Indeed, the latter can be treated with HCA producing excellent results, [2] but time restraint remains the major limitation of HCA. The recent interest in the use of prolonged mild or moderate hypothermia in the management of stroke [3], global cerebral ischemia [4, 5], and brain injury [6], brought new insights into possible technical refinements of hypothermic strategies in cardiac surgery. The evidence of neuroprotective effects of prolonged mild systemic hypothermia in focal and global brain ischemia and brain traumatic injury, and the observation that a brief period of cold reperfusion after HCA may provide some greater benefits than immediate rewarming on reperfusion [7, 8] has led us to adopt a combined strategy
Accepted for publication Dec 31, 2002. Address reprint requests to Prof Juvonen, Division of Cardiothoracic and Vascular Surgery, Oulu University Hospital, PO Box 21, 90029 OYS, Oulu, Finland; e-mail: [email protected].
© 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Twenty female juvenile pigs aged 8 to 10 weeks underwent a 75-minute period of HCA at a core temperature of 20°C. Randomized pigs were then rewarmed to 37°C during 60 minutes of reperfusion (control group) or underwent rewarming for a 60-minute period with topical head cooling by packing the head with three icepacks (topical head cooling group). The topical head cooling was continued for an overall of 2 hours after the start of rewarming.
Preoperative Management All animals received humane care in accordance with the “Principles of Laboratory Animal Care” formulated by 0003-4975/03/$30.00 PII S0003-4975(03)00038-9
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the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council (published by the National Academy Press, revised in 1996). The study was approved by the Research Animal Care and Use Committee of the University of Oulu (Oulu, Finland).
Anesthesia and Hemodynamic Monitoring Anesthesia was induced with ketamine hydrochloride (250 mg intramuscularly) and midazolam (30 mg intramuscularly). A peripheral catheter was inserted into a vein of the right ear for the administration of drugs and to maintain fluid balance with Ringer acetate. Anesthesia was deepened with thiopental sodium (125 to 250 mg intravenously). After an intravenous bolus injection of fentanyl (25 g/kg), anesthesia was maintained by a continuous infusion of fentanyl (25 g/kg/h), midazolam (0.25 mg/kg/h), and pancuronium (0.2 mg/kg/h) throughout the entire experiment. Cefuroxime (1.5 g intravenously) was administered at anesthesia induction and before extubation. After endotracheal intubation the animals were maintained on positive pressure ventilation with 50% oxygen. Electrocardiogram monitoring was started. An arterial catheter was positioned in the left femoral artery and a thermo dilution catheter (CritiCath, 7 French [Ohmeda GmbH & Co, Erlangen, Germany]) was placed through the left femoral vein. Blood, rectal, esophageal, epidural, and intracerebral temperatures were continuously monitored.
Brain Microdialysis and Intracerebral Monitoring A temperature probe was placed into the epidural space through a cranial hole made at the left side of the coronal suture. A catheter for measurement of intracerebral tissue oxygen partial pressure (Revodoxe Brain Oxygen Catheter-Micro-Probe, REF CC1.SB [GMS, Mielkendorf, Germany]) was inserted through a hole located on the right side, 1 cm anteriorly to the coronal suture. An intracerebral microdialysis catheter was inserted through a hole located on the right side, 0.5 cm posteriorly to the coronal suture. Temperature (Thermocouple Temperature Catheter-Micro-Probe, REF C8.B, GMS) and intracranial pressure-monitoring catheter (Codman MicroSensor ICP Transducer, Codman ICP Express Monitor [Codman & Shurtleff, Inc, Raynham, MA]) were placed through a hole located on the left side posteriorly to the coronal suture. A microdialysis catheter (CMA 70 [CMA/Microdialysis, Stockholm, Sweden]) was placed into the brain cortex to a depth of 15 mm below the dura mater. The catheter was connected to a 2.5-mL syringe, which was placed into a microinfusion pump (CMA 106, CMA/Microdialysis) and perfused (flow rate, 0.3 L/min) with Ringer solution (Perfusion Fluid CNS, CMA/Microdialysis). Samples were collected at different time points. The concentrations of cerebral tissue glucose, lactate, pyruvate, glutamate, and glycerol were measured immediately after
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collection with a microdialysis analyzer (CMA 600, CMA/ Microdialysis) by using ordinary enzymatic methods.
Electroencephalography Monitoring Cortical electrical activity was registered from 4 stainlesssteel screw electrodes of 5 mm in diameter implanted in the skull over the parietal and frontal areas of the cortex using a digital electroencephalography (EEG) recorder (Nervus, Reykjavik, Iceland) and an amplifier (Magnus EEG 32/8, Reykjavik, Iceland). Sampling frequency was 256 Hz and bandwidth was 0.03 to 100 Hz. All EEG recordings were referenced to a frontal screw electrode together with a ground screw electrode, which was implanted over the frontal sinuses. Electroencephalography was recorded for 10 minutes to get a base line recording before the cooling period. After HCA, EEG recording was restarted and continued until extubation. Artifact periods were excluded from each 5-minute sample. Recoveries of different wave bands (alpha, beta, and theta) were calculated from all four electrodes by means of nonlinear analysis. The energy recovery of EEG was evaluated by an algorithm based on the nonlinear energy operator [10].
Cardiopulmonary Bypass The heart and great vessels were exposed through a right thoracotomy in the fourth intercostal space. A membrane oxygenator (Midiflow D 705 [Dideco, Mirandola, Italy]) was primed with 1 L of Ringer acetate and heparin (5000 IU). After systemic heparinization (500 IU/kg), the ascending aorta was cannulated with a 16 French arterial cannula, and the right atrial appendage was cannulated with a single 24 French atrial cannula. Nonpulsatile cardiopulmonary bypass (CPB) was initiated (flow rate, 100 mL/kg/min), and the flow was adjusted to maintain a perfusion pressure of 50 mm Hg. The left ventricle was decompressed by a 12 French intracardiac sump cannula. A heat exchanger was used for core cooling. The pH was maintained with ␣-stat principles at 7.40 ⫾ 0.05, with an arterial carbon dioxide tension of 5.3 to 5.5 kPa uncorrected for temperature.
Experimental Protocol After a 60-minute period of cooling to a rectal temperature of 20°C, a 75-minute period of HCA was started. The ascending aorta was cross clamped distally to the aortic cannula. Cardiac arrest was induced by injecting potassium chloride (3 g) through the aortic cannula. During HCA, ice slushes were used continuously for topical cardiac cooling, and the epidural and intracerebral temperatures were maintained at 18°C with ice packs placed over the head. After 75 minutes of HCA, rewarming was started, the left ventricular sump cannula was removed, and furosemide (40 mg), mannitol (15 g), methylprednisolone (80 mg), lidocaine (40 to 150 mg), and calcium chloride (1375 mg) were administered. After weaning from CPB, cardiac support was provided with dopamine. Animals in the topical head cooling group were rewarmed to a rectal temperature of 36°C during 60 min-
utes of reperfusion with their heads packed with three icepacks each. Topical head cooling was continued for an overall of 2 hours after the start of rewarming. Because the animals in the latter group also had a mildly low systemic temperature during topical head cooling, they were rewarmed to 37°C by a heat-exchanger mattress and two heating lamps at the end of the head cooling period. Animals in the control group were rewarmed to a rectal temperature of 37°C during 60 minutes of reperfusion. The heat exchanger and blood temperature gradient were approximately 10°C at the start of rewarming, and the heat exchanger temperature was rarely set to approximately 38°C. The animals of both groups were extubated 8 hours after the start of rewarming when the rectal temperature approximated 37°C and were then moved to a recovery room. During the experiment, hemodynamic and metabolic measurements were recorded. These measurements (pulse rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary capillary wedge pressure, cardiac output, intracranial pressure, intracerebral tissue oxygen partial pressure, temperatures, arterial and venous pH, oxygen and carbon dioxide partial pressure, oxygen saturation, oxygen concentration, hematocrit, hemoglobin, sodium, potassium, and glucose (CibaCorning 288 Blood Gas System [Ciba-Corning Diagnostic Corp, Medfield, MA]), lactate (YSI 1500 analyzer [Yellow Springs Instrument Co, Yellow Springs, OH]), leukocyte differential count (Cell-Dyn analyzer [Abbot, Santa Clara, CA]), and creatine kinase and its isoenzymes (creatine kinase-MM, creatine kinase-MB, creatine kinase-BB [Hydrasys LC-electrophoresis, Hyrys-densitometry, Sebia, France]) were recorded continuously or at baseline, at the end of cooling (at 20°C immediately before institution of HCA), at 30 minutes, 2 hours, 4 hours, and 8 hours after the start of rewarming, and before extubation.
Postoperative Evaluation The postoperative behavior of the animals was evaluated daily by an experienced observer who was blinded to the study group using a species–specific quantitative behavioral score. The quantified assessment of mental status (0 ⫽ comatose, 1 ⫽ stuporous, 2 ⫽ depressed, and 3 ⫽ normal), appetite (0 ⫽ refuses liquids, 1 ⫽ refuses solids, 2 ⫽ decreased, and 3 ⫽ normal), and motor function (0 ⫽ unable to stand, 1 ⫽ unable to walk, 2 ⫽ unsteady gait, and 3 ⫽ normal) was summed to obtain a final score, with a maximum score of 9 reflecting apparently normal neurologic function and lower values indicating substantial brain damage.
Perfusion Fixation Each surviving animal was electively killed on the seventh postoperative day. Immediately after intravenous injection of pentobarbital (60 mg/kg) and heparin (500 IU/kg), the thoracic cavity was opened and the descending thoracic aorta was clamped. Ringer solution (1 L) was perfused through the ascending thoracic aorta through the upper body, and blood was suctioned from the superior vena cava until the perfusate was clear of blood.
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Then 10% formalin solution (1 L/15 min) was infused through the brain in the same manner to accomplish a perfusion fixation. Immediately thereafter the entire brain was harvested, weighed, and immersed in 10% neutral formalin. The same method of fixation procedure was carried out in those animals that died before the seventh postoperative day.
Histopathologic Analysis The brain was allowed to fix for 1 week en bloc. Thereafter, 3-mm thick coronal samples were sliced from the left frontal lobe, thalamus, and hippocampus, and sagittal samples from the posterior brainstem (medulla oblongata and pons) and cerebellum were obtained. The specimens were fixed in fresh formalin for another week and then processed by rinsing in water for 20 minutes and immersion in 70% ethanol for 2 hours, 94% ethanol for 4 hours, and absolute ethanol for 9 hours. Then the specimens were kept for 1 hour in absolute ethanol-xylene mixture and 4 hours in xylene, and were then embedded in warm paraffin for 6 hours. The specimens were sectioned at 6 m, stained with hematoxylin and eosin, and examined by an experienced senior pathologist (JH) unaware of the experimental design, identity, or fate of the individual animals. The signs of injury were scored as follows: 1 (slight edema, dark or eosinophilic neurons, or cerebellar Purkinje cells); 2 (moderate edema of at least 2 hemorrhagic foci in the section); 3 (severe edema, several hemorrhagic foci, infarct foci [local necrosis]). In case of the presence of more than one of the previously mentioned findings, the score from each region was calculated in a cumulative way. The total regional score was the sum of the scores in each specific brain area (cortex, thalamus, hippocampus, posterior brainstem, and cerebellum).
Statistical Analysis Analyses were performed using the SPSS software (Version 10.0.7 [SPSS Inc, Chicago, IL]). Continuous variables are expressed as the median with interquartile range (IQR) (25th to 75th percentiles). Analysis of variance for repeated measurements was performed. Comparison between relevant time-points and baseline (reference category) was performed by paired sample t test or Wilcoxon matched pairs signed rank test. Differences between groups were determined by t test or by Mann–Whitney U test. The two-tailed Fischer’s exact test was used to determine the significance of mortality rates between groups. The area under the curve was calculated for microdialysis measurements and Kendall’s rank correlation test was used to estimate correlation coefficients. Significance levels are reported for comparisons with a two-tailed p less than 0.05.
Results Comparability of the Study Groups The median weight of pigs was 25.9 kg (IQR, 24.3 to 27.6 kg) in the topical head cooling group and 24.7 kg (IQR,
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Fig 1. Daily score indicating behavioral recovery after 75 minutes hypothermic circulatory arrest. A score of 9 indicates essentially a complete recovery. (Left) Topical cooling group. (Right) Control group.
23.8 to 26.6 kg) in the control group (p ⫽ 0.25). The median CPB cooling time was 63.5 minutes (IQR, 60.0 to 70.0 min) in the topical head cooling group and 62.5 minutes (IQR, 60.0 to 64.0 min) in the control group (p ⫽ 0.39). The median CPB rewarming time was 62.0 minutes (IQR, 60.0 to 67.0 min) in the topical head cooling group and 64.5 minutes (IQR, 63.0 to 70.0 min) in the control group (p ⫽ 0.15). The median total CPB time was 126.5 minutes (IQR, 123.0 to 133.0 min) in the topical head cooling group and 128.0 minutes (IQR, 124.0 to 133.0 min) in the control group (p ⫽ 0.92). During HCA, the temperatures did not differ between the groups.
Mortality and Morbidity The 7-day survival rate was 70% in the topical head cooling group and 60% in the control group. Animals that underwent topical head cooling after HCA tended to have better postoperative behavioral scores throughout the postoperative period than those in the control group, but such differences failed to reach statistical significance (Fig 1). However, such a finding is affected by the occurrence in two animals of the control group with unilateral posterior leg problems related to vascular access complications which prevented their recovery.
Hemodynamic and Metabolic Data Experimental and metabolic data are presented in Table 1, 2 and Figures 2 and 3. There was no significant difference between the study groups in terms of cardiac indexes, heart rate, central venous pressure, arterial and venous pH, arterial oxygen partial pressure, and mixed venous glucose and lactate concentrations. Animals that underwent topical head cooling had significantly lower vascular resistance 30 minutes after the start of rewarming perfusion, which led to a significantly lower perfusion pressure (Table 1). Such a difference tended to persist until the 2-hour postoperative interval. After the start of rewarming, pigs that underwent topical head cooling had lower oxygen extraction and
consumption rates and higher mixed venous saturation levels; this difference was statistically significant at the 2-hour interval (Table 2). Furthermore, animals in the topical head cooling group had lower intracranial temperatures from the start of rewarming until the 4-hour postoperative interval (Fig 2). Rectal and blood temperature were also lower 2 hours after the start of the rewarming (Table 1, Fig 3a, b). It is worth noting that intracranial temperature in the topical head cooling group was still lower after 4 hours of HCA (Fig 1), with the median temperature 1.6 degrees lower than that of the control group. However, the systemic temperatures were similar in both groups (Fig 3a, b). Fluid balance was worse in the topical head cooling group from the 2-hour to 8-hour postoperative interval periods (Table 1). At the 8-hour postoperative interval, hemoglobin value and total leukocyte count were significantly higher in the topical head cooling group (Table 1). Because the central venous pressure was similar between the study groups at this interval, such differences are likely related to a significant tissue edema that occurred in the animals that underwent postoperative topical head cooling (Fig 4). Mixed venous blood creatine-kinase levels did not differ significantly between groups, but the total creatinekinase was slightly higher in the control group (Table 2).
Intracranial Measurements Intracranial measurement data are presented in Figures 5– 6. Brain glucose and glycerol concentration were similar in both study groups throughout the experiment. Brain lactate tended to be higher in the topical head cooling group at the 7-hour and 8-hour intervals after HCA. The peak concentration of brain glutamate was higher in the control group, but the glutamate concentration was higher at the 1.5-hour and 2-hour intervals after HCA in the topical head cooling group (p ⫽ not significant). Brain pyruvate concentrations tended to be lower in the topical head cooling group 2 to 6 hours after
30 Minutes Baseline
4 Hours
8 Hours
p Value Between Groups
After the Start of Rewarming
90 (83–93) 88 (78 –99)
70 (64 –75)a 70 (68 –76)
74 (66 – 82) 95 (85–100)b
88 (83–92) 95 (84 –104)
100 (95–104)a 99 (85–102)
86 (78 –95) 86 (67–94)
p ⫽ 0.206
98 (93–106) 103 (97–116)
0 (0 –20)a 10 (0 –30)
174 (150 –200) 188 (172–207)
134 (118 –143) 120 (118 –156)
142 (126 –153) 150 (125–170)
167 (138 –176) 168 (155–176)
p ⫽ 0.265
4.1 (3.9 –5.0) 4.5 (3.4 –5.0)
p ⫽ 0.583
4.4 (3.7–5.1) 4.3 (3.7– 4.7) 103 (94 –105) 97 (91–101)
2.7 (2.6 –2.9)a 2.8 (2.7–2.8) 69 (66 –72)a 61 (58 – 67)
2.9 (2.6 –3.2)a 2.8 (2.7–3.0) 83 (73– 86)a 77 (65– 82)
3.2 (3.1–3.2)a 3.1 (2.7–3.8) 93 (85–100)a 90 (82–92)
3.4 (3.3– 4.0)a 3.3 (2.9 –3.8) 86 (82–95)a 87 (80 –95)
99 (88 –112) 85 (79 –96)c
p ⫽ 0.094
2,402 (2,087–2,745)a 2,568 (2,435–2,737)
2,297 (2,000 –3,159)a 3,721 (3,333–3,815)a
2,720 (2,508 –3,012)a 3,027 (2,811–3,294)
2,798 (2,584 –2,939)a 2,939 (2,678 –3,510)
1,790 (2,074 –2,264) 1,674 (1,861–2,127)
p ⫽ 0.044
350 (250 – 450) 325 (250 – 450)
3,125 (3,000 –3,600) 3,250 (3,100 –3,600)
3,425 (3,400 – 4,000) 3,475 (3,200 –3,700)
4,500 (3,900 –5,000) 4,275 (3,800 – 4,850)
4,800 (4,200 –5,200) 4,700 (4,700 –5,350)
5,125 (4,300 –5,700) 5,200 (5,000 –5,700)
p ⫽ 0.933
225 (150 –350) 200 (150 –350)
1,300 (1,150 –1,700) 1,400 (1,300 –1,720)
1,900 (1,500 –2,300) 1,775 (1,400 –2,000)
3,275 (3,000 –3,800) 3,650 (3,000 –3,950)
3,975 (3,700 – 4,800) 4,800 (4,460 – 4,950)
4,700 (3,800 –5,150) 5,250 (4,500 –5,600)
p ⫽ 0.455
100 (0 –150) 75 (0 –200)
1,000 (1,750 –2,150)a 1,975 (1,600 –2,200)
1,775 (1,300 –2,000)a 1,750 (1,550 –2,200)
1,225 (700 –1,500)a 650 (100 –1,700)
825 (300 –1,050)d ⫺25 (⫺250 – 650)
575 (200 –950) ⫺75 (⫺200 – 400)
p ⫽ 0.487
37.4 (37.2–38.0) 37.2 (36.8 –37.8)
p ⫽ 0.566
2,133 (1,737–2,242) 2,079 (1,808 –2,382)
36.8 (36.2–37.4) 37.3 (36.9 –37.4)
20.0 (19.4 –20.8) 19.6 (18.5–20.7)
28.1 (27.0 –30.3) 27.4 (26.5–30.7)
34.3 (33.4 –34.6) 35.3 (34.6 –35.9)c
36.8 (35.5–37.2) 36.8 (36.4 –37.5)
1.8 (1.2–7.4) 0.6 (⫺0.5–1.3)c
0.9 (0.7–1.2) ⫺0.2 (⫺0.3– 0.2)b
0.5 (0.3–1.3) 0.1 (0.0 – 0.3)c
1.0 (0.1–1.2) 0.1 (⫺0.1– 0.3)c
p ⫽ 0.016
0.8 (0.4 –1.0) 0.3 (0.1– 0.6)
䡠䡠䡠 䡠䡠䡠
17.3 (14.4 –18.8) 21.2 (18.4 –25.8)
3.6 (2.5–5.0)a 3.0 (2.1– 4.6)
6.9 (6.7–7.5)a 6.9 (6.0 –9.2)
22.7 (19.7–26.7)a 23.6 (21.5–28.6)
30.4 (25.2–33.2)a 28.2 (25.5–36.1)
36.1 (33.6 –39.3)a 30.6 (24.3–36.9)c
p ⫽ 0.004
8.5 (6.8 –10.5) 11.8 (8.8 –12.9)
1.9 (1.2–2.7) 1.8 (1.1–3.0)
3.2 (2.5– 4.3) 3.3 (2.1– 4.4)
16.3 (13.7–19.4) 18.9 (16.3–22.2)
23.3 (19.5–26.6) 22.8 (20.0 –27.7)
29.4 (26.2–33.0) 24.8 (19.9 –30.6)
p ⫽ 0.917
Values are shown as medians with interquartile ranges (25th–75th percentile).
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a p ⬍ 0.01 interaction between time versus baseline and other intervals in the study groups. p value between groups is according to the tests of between-subjects effects. Fluid balance ⫽ intravenous fluids given b c d — cumulative diuresis; p ⬍ 0.05 difference between study groups at each interval; p ⬍ 0.05 interaction between time versus baseline and other intervals in the study groups; p ⬍ 0.01 difference between study groups at each interval.
POKELA ET AL TOPICAL COOLING AFTER HCA
Mean arterial pressure (mm Hg) Topical head cooling Control Heart rate (beats/min) Topical head cooling Control Cardiac index (L/min/m2) Topical head cooling Control Hemoglobin (g/L) Topical head cooling Control Vascular resistance (dyn 䡠 d seq 䡠 d cm⫺5) Topical head cooling Control Fluid (mL) Topical head cooling Control Urine (mL) Topical head cooling Control Fluid balance (mL) Topical head cooling Control Rectal temperature (°C) Topical head cooling Control Gradient between blood and intracranial temperature (°C) Topical head cooling Control Total leukocytes count (⫻ 109/L) Topical head cooling Control Neutrophil count (1 ⫻ 109/L) Topical head cooling Control
End of Cooling
2 Hours
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Table 1. Experimental Data
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Table 2. Metabolic Data
Baseline Arterial pH Topical head cooling Control PaCO2 (kPa) Topical head cooling Control PvCO2 (kPa) Topical head cooling Control Pao2 (kPa) Topical head cooling Control Venous glucose (mmol/L) Topical head cooling Control Venous lactate (mmol/L) Topical head cooling Control SvO2 (%) Topical head cooling Control O2 consumption (mL/min/m2) Topical head cooling Control O2 extraction (mL/dL) Topical head cooling Control Creatine-kinase total (U/mL) Topical head cooling Control Creatine-kinase BB (U/mL) Topical head cooling Control
End of Cooling
2 Hours
4 Hours
8 Hours
After the Start of Rewarming
P Value Between Groups
7.51 (7.49 –7.55) 7.53 (7.48 –7.55)
7.42 (7.39 –7.45)a 7.41 (7.38 –7.46)
7.36 (7.33–7.40)a 7.35 (7.32–7.36)
7.42 (7.41–7.44)a 7.42 (7.42–7.45)
7.49 (7.47–7.50)b 7.47 (7.47–7.50)
7.49 (7.47–7.52) 7.50 (7.49 –7.53)
p ⫽ 0.439
4.9 (4.6 –5.2) 4.8 (4.3–5.2)
5.0 (4.5–5.5) 4.9 (4.4 –5.3)
5.0 (4.7–5.2)a 4.7 (4.4 –5.0)
5.8 (5.5– 6.1)b 5.4 (5.0 –5.6)c
5.4 (5.1–5.5) 5.3 (4.7–5.5)
5.0 (4.7–5.5) 4.8 (4.7–5.2)
p ⫽ 0.620
6.0 (5.7– 6.2) 6.0 (5.6 – 6.3)
6.1 (5.3– 6.5) 5.8 (5.7– 6.2)
6.3 (6.0 – 6.7) 6.4 (6.0 – 6.7)
7.1 (6.8 –7.6)a 7.0 (6.8 –7.3)
6.7 (6.4 – 6.8)a 6.4 (6.2– 6.9)
6.2 (5.4 – 6.6) 6.1 (5.9 – 6.4)
p ⫽ 0.617
64.6 (59.1– 69.1)a 68.6 (55.0 –72.4)
84.7 (78.7– 89.7)a 80.3 (68.3– 82.6)
30.6 (28.6 –35.4)a 30.7 (29.2–34.6)
31.4 (27.4 –34.2)a 29.8 (27.3–31.0)
p ⫽ 0.596
38.6 (36.5– 40.5) 34.5 (31.9 –37.2)
122 (117–126)a 127 (122–132)
5.2 (4.9 –5.5) 5.4 (5.1–5.9)
5.9 (4.9 – 6.7)b 5.9 (5.2–7.0)
14.4 (12.3–15.7)a 14.6 (10.4 –17.0)
9.4 (8.3–10.5)a 9.1 (7.9 –9.6)
9.1 (7.9 –9.6)a 7.9 (7.5– 8.6)
7.9 (7.7– 8.8)a 7.4 (6.8 – 8.4)
p ⫽ 0.298
0.9 (0.9 –1.1) 1.0 (0.8 –1.0)
1.4 (1.1–1.5)a 1.4 (1.2–1.7)
3.8 (3.5–5.1)a 4.5 (3.8 – 4.8)
2.9 (1.8 –3.1)a 2.5 (2.1–2.6)
0.9 (0.8 –1.1) 1.0 (0.9 –1.2)
1.0 (0.8 –1.3) 1.0 (0.9 –1.3)
p ⫽ 0.458
84.9 (80.2– 86.3) 81.1 (79.1– 87.9)
99.7 (99.5–99.8)a 99.7 (99.6 –99.7) 51 (40 –56)a 54 (49 – 68)
131 (128 –144) 126 (104 –142) 3.0 (2.5–3.5) 3.2 (2.5–3.3) 1,039 (815–1,322) 1,239 (950 –1,508) 170 (138 –204) 130 (116 –181)
76.1 (67.5– 80.2)a 71.1 (67.7–75.9) 112 (96 –126) 115 (102–141)
82.5 (75.1– 85.0)a 67.8 (64.1– 80.8)c 125 (118 –154) 170 (126 –179)c
67.9 (64.3– 69.9)a 64.7 (58.7–71.9) 158 (135–175)a 157 (150 –175)
1.9 (1.5–1.9)a 1.9 (1.8 –2.1)
4.1 (3.3– 4.4)a 4.1 (3.8 – 4.9)
4.0 (3.7– 4.6)a 5.4 (4.3– 6.0)c
4.3 (4.1– 4.9)a 4.8 (4.0 –5.3)
1,953 (1,584 –2,972)a 2,359 (2,049 –2,639)
3,658 (2,268 – 4,730)a 3,618 (3,139 –3,981)
7,374 (6,160 –9,703)a 9,120 (8,835–9,919)
8,290 (7,479 – 8,826)a 9,709 (8,566 –10,072)
135 (130 –166) 109 (105–120)
134 (127–170) 145 (113–159)
353 (293– 413)a 384 (339 – 417)
77.2 (68.8 – 83.3)a 69.0 (64.0 –71.4) 162 (141–180)a 180 (160 –201) 4.2 (2.8 –5.0)a 4.4 (3.8 – 4.6) 7,093 (6142–9,293)a 9,317 (8375–10,876)
380 (257–521)a 284 (252–358)
174 (125–211) 185 (178 –265) b
p ⫽ 0.017
p ⫽ 0.355
p ⫽ 0.150
p ⫽ 0.147
p ⫽ 0.908
p ⬍ 0.05 interaction between time
Values are shown as medians with interquartile ranges (25th–75th percentile). PaCO2 ⫽ arterial carbon dioxide partial pressure; pressure; SvO2 ⫽ mixed venous oxygen saturation.
Pao2 ⫽ arterial oxygen partial pressure;
PvCO2 ⫽ mixed venous carbon dioxide partial pressure;
PvO2 ⫽ mixed venous oxygen partial
Ann Thorac Surg 2003;75:1899 –911
p ⬍ .01 interaction between time versus baseline and other intervals in the study groups. p value between groups is according to the tests of between-subjects effects. c versus baseline and other intervals in the study groups. p ⬍ 0.05 difference between study groups at each interval.
a
POKELA ET AL TOPICAL COOLING AFTER HCA
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HCA. The brain lactate and pyruvate ratio was significantly higher in the topical head cooling group from the 6-hour to 8-hour interval after HCA (p ⫽ 0.02) (Fig 6). Similarly, the brain lactate and glucose ratio was also higher 7 hours after HCA (p ⫽ 0.036) and tended to be significantly higher at the 6-hour and 8-hour interval after HCA (Fig 6). Brain tissue oxygen partial pressure values tended to be higher in the topical head cooling group at the 1-hour to 3-hour interval after HCA and the difference was statistically significant 2.5 hours after HCA. However, during the late two study intervals, brain tissue oxygen partial pressure increased and tended to be higher in the control group, although the difference did not reach statistical significance (Fig 6). Intracranial pressure values tended to be lower in the topical head cooling group from the 3-hour to 8-hour postoperative interval.
Histopathologic Data
Fig 2. Median brain temperatures in pigs during the experiment. *p less than 0.05; **p less than 0.01 difference between study groups at a certain interval. (HCA ⫽ hypothermic circulatory arrest.)
No statistically significant differences were observed in the overall histopathologic scores between these two study groups, with a mean score of 9.6 in the topical head cooling group and 9.5 in the control group (Table 3). Among the survivors, the topical head cooling group had a slightly higher mean overall histopathologic score (9.5
Fig 3. Median brain and blood temperatures (25th to 75th percentile) in both study groups during the experimental protocol. (a) Topical cooling group. (b) Control group. (HCA ⫽ hypothermic circulatory arrest.)
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CARDIOVASCULAR Fig 4. (a) Central venous pressure, (b) fluid balance, (c) mean arterial pressure, and (d) vascular resistance. **p less than 0.01 difference between study groups at a certain interval.
vs 6.8; p ⫽ 0.3) (Table 3). The histopathological score of posterior brainstem was significantly higher in the topical head cooling group (mean 1.0 vs 0.2; p ⫽ 0.026).
EEG Findings There were no statistical, significant differences between the two groups. All three wave analyses showed faster EEG recovery in the control group during the first postoperative hours; however, later EEG recovery was similar in both groups (Fig 7). Animals that died had lower EEG energies at the 3-hour and 6-hour intervals after HCA (89 vs 206 mV2; p ⫽ 0.01; and 211 vs 625 mV2; p ⫽ 0.05; respectively).
Comment The evidence of reduction in oxygen consumption under hypothermia during the last decades has led to the use of different hypothermic strategies during cardiac surgery in order to protect the brain, heart, and other organs susceptible to hypoperfusion and transient ischemia.
HCA represents the clearest evidence of the protective effect of deep hypothermia on the brain. However, mild hypothermia also preserves its protective effect on neurons, and this has led to extensive experimental and clinical investigations of the neuroprotective effects of prolonged hypothermia in fields other than cardiac surgery with encouraging results [3– 6]. Recent studies have also shown that selective hypothermia by topical cooling can be effective in protecting the brain after global brain ischemia [5, 11] and spinal cord ischemia [12, 13], thus potentially decreasing the potential troublesome adverse effects of systemic hypothermia. During the last few years, some authors [7, 8] in different settings have shown that cold reperfusion after HCA may provide further neuroprotection, thus extending the efficacy of deep hypothermia. Indeed a policy of uncomplete rewarming to 32°C to 33°C after HCA is routinely adopted by some authors with good clinical results [1]. In a previous study of ours [9], a 5-minute period of cold reperfusion at 20°C after HCA followed by a 14-hour period of mild hypothermia did not show any significant
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Fig 5. Medians (25th to 75th percentile) of (a– e) brain microdialysis measurements and (f) intracranial pressure. (HCA ⫽ hypothermic circulatory arrest.)
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CARDIOVASCULAR Fig 6. Median (25th and 75th percentiles) (right) brain lactate and glucose ratio, (middle) lactate and pyruvate ratio, and (left) brain tissue O2 partial pressures. *p less than 0.05. (HCA ⫽ hypothermic circulatory arrest.)
neuroprotective efficacy and was associated with unfavorable changes in cerebral and systemic hemodynamic and metabolic measurements. Nevertheless, data from the latter study suggested that postoperative mild hypo-
thermia may still be effective when used for less than 4 hours. The perceived efficacy of short-term postoperative mild hypothermia, topical brain cooling, and the need to
Table 3. Histopathologic Scores
Protocol Topical head cooling group
Mean Mean (only survivors) Control group
Mean Mean (only survivors) p value p value for survivors
Pig Number
Survival (days)
Cortex Score
Thalamus Score
Hippocampus Score
Posterior Brainstem Score
Cerebellum Score
Total Score
1 2 3 4 5 6 7 8 9 10
1 1 6 7 7 7 7 7 7 7
1 2 3 4 5 6 7 8 9 10
0 1 1 2 7 7 7 7 7 7
2 3 1 2 2 2 7 7 6 4 3.4 4.0 3 2 4 3 2 2 5 7 5 2 3.7 4.2 NS NS
1 2 2 0 0 2 1 2 2 0 1.3 1.1 2 2 4 3 0 1 1 1 1 1 1.5 0.7 NS NS
1 2 2 0 2 2 2 3 5 0 2 2.1 3 1 3 2 1 0 1 1 2 1 1.4 0.8 NS NS
1 5 3 0 1 1 1 1 2 0 1.6 1.0 2 2 4 2 0 0 0 0 1 1 1.1 0.2 NS 0.026
1 2 1 1 1 1 1 2 2 1 1.4 1.4 3 2 5 2 1 1 1 0 2 2 1.8 1.0 NS NS
6 14 9 2 6 8 12 15 17 5 9.6 9.5 13 9 20 12 4 4 8 9 11 7 9.5 6.8 NS NS
Signs of brain ischemic injury were scored as follows: 1 ⫽ dark or eosinophilic neurons or cerebellar Purkinje cells, edema; 2 ⫽ moderate edema, hemorrhages; 3 ⫽ severe edema, infarct foci. The total score is the sum of scores of each specific brain area.
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Fig 7. Electroencephalogram (EEG) (right) beta and (left) theta wave energy (mV2) with mean line and standard error of mean in the study groups.
reduce the adverse effects of systemic hypothermia led us to plan the present study using short-term postoperative topical head cooling. Despite such good premises and its efficacy in decreasing the brain temperature of more than 2°C as compared with controls, topical cooling of the brain failed to provide better results, but rather seems to be associated with some detrimental effects. Such a method was associated with favorable mixed oxygen venous saturation, oxygen extraction and oxygen consumption rates, brain oxygenation, total creatinekinase concentration, and intracranial pressure. These effects are intrinsically related to the ability of hypothermia to reduce tissue metabolism, but its duration seems to be rather short [9]. The present study provided some data to support the hypothesis of derangements occurring in the brain undergoing mild hypothermia after a period of severe HCA. In fact, the occurrence of significantly higher brain lactate and pyruvate ratios and brain lactate and glucose ratios a few hours after the end of topical cooling of the head coincided with a certain “resistance” of the brain to increase its temperature (Figs 2, 3). Although postoperative mild hypothermia may maintain the reduced metabolism state of the brain, it is possible that this is paid back by a severe alteration of brain vasoregulatory mechanisms. After the end of topical head cooling, the animals were rewarmed to 37°C, but a blood-brain temperature difference persisted, probably because of a relative hypoperfusion caused by vasoconstrictive mechanisms. We do not have data on cerebral blood flow rates, but the significant increase in brain lactate and pyruvate ratios and brain lactate and glucose ratios during the last study intervals support a hypothesis of possible cerebral derangements after mild hypothermia after HCA. It is worth noting that the alteration in vasoregulation, to a much less extent, may have also occurred in control animals as their brain temperatures decreased after the end of rewarming. Ehrlich and colleagues [7] reported the beneficial effects of cold reperfusion after experimental HCA. However, such a strategy was evaluated in an acute porcine
model, thus preventing a thorough evaluation of the impact of hypothermic strategy after HCA on the postoperative survival and neurologic outcome. The authors showed that a brief period of hypothermia after the end of HCA is associated with a decrease in intracranial pressure. Indeed we also showed that intracranial pressure is a determinant of postoperative outcome after experimental HCA in a chronic porcine model [14]. However, as shown in our previous study, a decrease of intracranial pressure related to the use of mild hypothermia is not necessarily associated with better outcome [9]. In fact we observed a certain rebound increase of intracranial pressure after the end of prolonged systemic postoperative mild hypothermia associated with unfavorable metabolic derangements and poorer outcome [9], which suggests that postoperative mild hypothermia is associated with unfavorable vasoregulatory changes that may cause severe metabolic alterations despite results in decreased intracranial pressure. Furthermore, despite our attempt to limit cooling to the head, in the present study we have observed that topical head cooling also has a certain effect in decreasing blood and rectal temperatures (Table 1, Fig 3). This can be caused by either a direct cooling effect on the blood or an alteration in peripheral vasoregulation. Since systemic mild hypothermia may potentially have an adverse impact on the outcome of patients undergoing surgery [15, 16], a decrease in core temperature associated with such a regionally limited cooling method is an undesirable effect. This does not negate the beneficial effect of mild systemic or selective hypothermia in the setting of stroke and global hypoxia that occurred during normothermia as extensively demonstrated by several studies. However, HCA is a particularly different setting as it may probably result not only in severe global cerebral ischemia but also in other derangements of cerebral metabolism and vasoregulation, thus offering a different basis for possible therapeutic use of mild hypothermia. Insler and colleagues [16] also observed a significant negative impact of mild hypothermia after coronary artery bypass
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POKELA ET AL TOPICAL COOLING AFTER HCA
CARDIOVASCULAR
surgery, thus further suggesting that any hypothermic state after rewarming can be significantly detrimental in cardiac surgery patients. In conclusion, the present experimental study demonstrated that a short-term period of topical head cooling does not provide any neuroprotective effect after HCA. It confirmed the validity of the strategy for prompt rewarming to 36.5°C after a period of HCA, and maintenance of a temperature of 37°C by external warming during the intensive care unit stay [17].
Ann Thorac Surg 2003;75:1899 –911
6. 7. 8.
9.
This study was supported by grants from the Oulu University Hospital, the Finnish Foundation for Cardiovascular Research, and the Sigrid Juselius Foundation. We express our gratitude to Seija Selja¨ npera¨ , RN, and Veikko La¨ hteenma¨ ki, RN, for their technical assistance; Pasi Ohtonen, MS, for statistical analysis; the Laboratory of the Oulu University Hospital for analyzing the blood samples; and the personnel of the Animal Research Center, Oulu University, and its director, Hanna-Marja Voipio, DVM, PhD, for providing facilities.
10. 11.
12. 13.
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INVITED COMMENTARY Perioperative cerebral protection in aortic operations requiring deep hypothermic circulatory arrest (DHCA) to avoid stroke and severe neurocognitive dysfunction remains one of the biggest concerns for cardiovascular surgeons. No matter how much attention has been paid to avoiding emboli during such operations, stroke can still accidentally occur, possibly due to disease-related factors. Neurocognitive dysfunction is multifactorial and more complicated. Possible causes of neurocognitive dysfunction are reported to be cerebral ischemia and the consequent accumulation of anaerobic metabolic substances, reactive hyperemia immediately after reperfusion, release of toxic amino acids, and explosive exacerbation of inflammatory responses that are related to contact between blood and the bypass circuit, and are considerably suppressed under deep hypothermia. All of these factors may contribute to consequent cerebral edema in the primarily damaged region and secondary © 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
damage in surrounding penumbra through a compartment phenomenon. A large number of experimental and clinical investigations addressing the beneficial and adverse effects of DHCA have been performed in the last decade. Currently, more attention is being shifted to the rewarming, or postischemia reperfusion, phase after DHCA. Pokela and colleagues have already presented the negative impacts of prolonged (14 hours) mild hypothermia (32°C) after DHCA through similarly well-designed experimental protocols as the present study [1]. They performed another in-depth investigation addressing the impact of a much shorter period (2 hours) of mild topical hypothermia by head cooling. Contrary to previously published articles that support the significance of post-DHCA mild hypothermia for the reduction of cerebral complications [2, 3], they did not demonstrate a significant neuroprotective effect of shortperiod topical hypothermia. Why are these results con0003-4975/03/$30.00 PII S0003-4975(03)00356-4