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Ann Thorac Surg 1998;66:2008-2014
© 1998 The Society of Thoracic Surgeons

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Original Articles

Selective convective brain cooling during hypothermic cardiopulmonary bypass in dogs

^a Department of Anesthesiology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA
^b Department of Surgery, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA

Accepted for publication June 6, 1998.

Address reprint requests to Dr Wass, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Neurologic complications, primarily resulting from ischemic insults, represent the leading cause of morbidity and disability, and the second most common source of death, after cardiac operations. Previous studies have reported that increases (as occur during the rewarming phase of cardiopulmonary bypass [CPB]) or decreases in brain temperature of a mere 0.5° to 2°C can significantly worsen or improve, respectively, postischemic neurologic outcome. The purpose of the present study was to evaluate a novel approach of selectively cooling the brain during hypothermic CPB and subsequent rewarming.

Methods. Sixteen dogs were anesthetized with either intravenous pentobarbital or inhaled halothane (n = 8 per group). Normocapnia (alpha stat technique) and a blood pressure near 75 mm Hg were maintained. Temperatures were monitored by placing thermistors in the esophagus (ie, core), parietal epidural space, and brain parenchyma at depths of 1 and 2 cm beneath the dura. During CPB, core temperature was actively cycled from 38°C to 28°C, and then returned to 38°C. Forced air pericranial cooling (air temperature of approximately 13°C) was initiated simultaneous with the onset of CPB, and maintained throughout the bypass period. Brainto-core temperature gradients were calculated by subtracting the core temperature from regional brain temperatures.

Results. In halothane-anesthetized dogs, brain temperatures at all monitoring sites were significantly less than core during all phases of CPB, with one exception (2 cm during systemic cooling). Brain cooling was most prominent during and after systemic rewarming. For example, during systemic rewarming, average temperatures in the parietal epidural space, and 1 and 2 cm beneath the dura, were 3.3° ± 1.3°C (mean ± standard deviation), 3.2° ± 1.4°C, and 1.6° ± 1.0°C, cooler than the core, respectively. Similar trends, but of a greater magnitude, were noted in pentobarbital-anesthetized dogs. For example, during systemic rewarming, corresponding brain temperatures were 6.5° ± 1.7°C, 6.3° ± 1.6°C, and 4.2° ± 1.3°C cooler than the core, respectively.

Conclusions. The magnitude of selective brain cooling observed in both study groups typically exceeded the 0.5° to 2.0°C change previously reported to modulate ischemic injury, and was most prominent during the latter phases of CPB. When compared with previous research from our laboratory, application of cold forced air to the cranial surface resulted in brain temperatures that were cooler than those observed during hypothermic CPB without pericranial cooling. On the basis of the assumption that similar beneficial brain temperature changes can be induced in humans, we speculate that selective convective brain cooling may enable clinicians to improve neurologic outcome after hypothermic CPB.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Improved surgical technique and myocardial protection during cardiopulmonary bypass (CPB) have significantly reduced perioperative cardiac morbidity and mortality [1, 2]. Despite these major advances, ischemia-related neurologic complications associated with CPB appear to be increasing [2–4]. Specifically, neurologic injury represents the leading cause of morbidity and disability, and the second most common source of death, after cardiac operations [1, 2]. Previous studies have reported that increases (as occur during the rewarming phase of CPB [5–7]) or decreases in temperature of 0.5° to 2°C can significantly worsen or improve, respectively, neurologic outcome after focal or global brain ischemia [8–14].

The purpose of the present study was to evaluate a novel approach of selectively cooling the brain during hypothermic CPB. Our approach was based on applying cold forced air to the cranial surface to induce potentially cerebroprotective decreases in brain temperature.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
All pilot and formal studies were approved by the Institutional Animal Care and Use Committee.

Pilot studies
Before initiating our formal studies, pilot studies were performed to design and evaluate several forced air cooling coverlet (ie, helmet) prototypes [15]. The helmet prototype producing the most efficient cooling profile was subsequently used to conduct the formal studies.

Formal studies
Formal studies were conducted in 16 purpose-bred hounds using previously described preparatory techniques [16]. Such a study design permitted a direct comparison between the present study in which selective brain cooling was used, and a previous study [16] in which pericranial cooling was not used. To review, all dogs were fasted, but had free access to water, for a minimum of 8 hours before initiating the study. A forelimb vein was cannulated for fluid and drug administration. Anesthesia was induced with either intravenous pentobarbital 30 mg/kg (n = 8) or halothane 2% to 3% inspired in an induction box (n = 8). Once anesthetized, the trachea was intubated, and the lungs were mechanically ventilated (model 900C; Siemens-Elema AB, Solna, Sweden). A tidal volume of 15 to 20 mL/kg was used and the respiratory rate was adjusted to maintain an arterial carbon dioxide tension near 35 mm Hg. The inspired oxygen fraction was adjusted to maintain the arterial oxygen tension near 150 mm Hg. Inspired and end-expired concentrations of oxygen, carbon dioxide, nitrogen, and halothane were quantified using a Rascal II (Albion Instruments, Salt Lake City, UT). Blood gases were measured using the alpha-stat (temperature uncorrected) technique (model BGE; Instrumentation Laboratory, Lexington, MA). Anesthesia was maintained during the preparatory period with additional intravenous pentobarbital or inspired halothane 1.0% to 1.5%. Neuromuscular block was induced and maintained with intravenous. pancuronium. The left femoral artery was cannulated percutaneously with a 4.25-inch 18-gauge catheter (Arrow, Reading, PA) for blood pressure measurements and blood sampling.

Using a sagittal incision, the scalp was reflected laterally from the sagittal ridge. Bilateral parietal burr holes, measuring 1 cm in diameter, were created 1.5 cm lateral to the midline and 3.0 cm rostral to the lambdoidal ridge. Through these burr holes, epidural temperatures were measured by inserting catheter-style thermistors (models 555; YSI, Yellow Springs, OH) 1.5 cm rostral to the anterior margin of each burr hole. In addition, using the same burr holes, intraparenchymal brain temperatures were measured using needle thermistors (model 552; YSI) inserted perpendicular to the parietal cortex surface, to depths of 1 and 2 cm beneath the dura bilaterally. During the pilot studies, we observed the distal tip of the 1- and 2-cm intraparenchymal thermistors were located in subcortical white matter and basal ganglia, respectively. After placement of the intraparenchymal thermistors, the burr holes were sealed with bone wax, and the portion of needle thermistor protruding beyond the dura was thermally insulated with foam tape (Microfoam; 3M, Minneapolis, MN).

Electroencephalographic activity was recorded using gold cup electrodes (model E-6GH; Grass, Quincy, MA) glued to the calvarium. A bifrontal and biparietal electroencephalogram was recorded using a polygraph and a strip recorder (model 8-10; Grass). To minimize insensible heat loss from the calvarium, the scalp was reapproximated toward midline, without disrupting the intraparenchymal needle thermistor trajectory. Any gaps in the suture line were insulated with folded gauze sponges. Before each study, all thermistors were calibrated manually using a mercury thermometer as a reference.

Core temperature was measured using a flexible vinyl thermistor (model 401; YSI) placed in the esophagus to the level of the right atrium. Thermistor position was confirmed by palpation at the time of thoracotomy.

Preparation for CPB was achieved by modifying previously described techniques [17]. Briefly, dogs were placed in the right lateral decubitus position and a left anterolateral thoracotomy was performed in the forth intercostal space. Heparin (Elkins-Sinn, Cherry Hill, NJ) 300 U/kg was administered intravenously before cannulation. A single-stage venous cannula (34F; Bard, Tewksbury, MA) was inserted into the right atrial appendage. Then, to minimize insensible heat loss from the thoracic cavity, the skin margins of the thoracotomy were reapproximated using multiple perforating towel clips. Arterial cannulation was achieved by inserting a 16F catheter (Argyle, St. Louis, MO) into the right common femoral artery. Femoral cannulation was selected to prevent cerebral hyperperfusion associated with inadvertent cannula tip malalignment.

A membrane oxygenator-heat exchanger (Maxima; Medtronic, Minneapolis, MN), open venous reservoir, serial arterial filter (Pall, Fajardo, Puerto Rico), and standard roller pump were used to provide nonpulsatile perfusion. The pump prime consisted of 1,000 mL of Plasmalyte solution (Baxter, Deerfield, IL).

Once the preparatory period was complete, the anesthetic dose was adjusted to achieve a steady state. Specifically, barbiturate-anesthetized dogs received incremental intravenous pentobarbital in doses of 1 to 5 mg/kg to achieve and maintain electroencephalographic burst suppression, and dogs receiving halothane were maintained at 0.87% end-expired (1.0 minimal alveolar concentration). In addition, the cooling helmet was carefully placed, to avoid movement of the intracranial needle thermistors and accidental hemorrhage in the heparinized dog, around the head and neck.

Before CPB, core and cranial temperatures were maintained at 38.0°C using convection-based surface warming techniques (Bair Hugger; Augustine Medical, Eden Prairie, MN). Fine regional temperature control was attained with supplemental heating lamps and pads. The ambient room temperature was maintained near 22°C during the entire study period. Before and during CPB: (1) the oxygen fraction and total gas flows were adjusted to maintain the arterial oxygen tension >100 mm Hg and the arterial carbon dioxide tension near 35 mm Hg, and (2) sodium bicarbonate was given intravenously as needed to maintain the base deficit at 2 mEq/L. Before CPB, the systemic mean arterial blood pressure (MAP) was allowed to spontaneously equilibrate in halothane-anesthetized dogs. Although baseline values were relatively large, no attempt was made to decrease MAP pharmacologically as it remained within the range of cerebral autoregulation [18]. In contrast, pentobarbital-anesthetized dogs received an intravenous infusion (80 µg/mL) of phenylephrine (ie, a systemic vasoconstrictor that does not directly affect cerebral vascular tone or cerebral blood flow (CBF) [19]) to produce a MAP similar to the halothane group. During CPB, the MAP was maintained near 75 mm Hg in both groups using a phenylephrine infusion as needed.

Atriofemoral CPB was initiated, and after a 15-minute period at 38°C (ie, the "baseline"" phase), core temperature was decreased to 28°C during approximately 23 minutes (ie, the "cooling" phase). After 30 minutes at 28°C (ie, the "stable hypothermia" phase), core temperature was returned to 38°C during approximately 23 minutes (ie, the "rewarming" phase), and maintained there for 60 minutes (ie, the "stable normothermia" phase). Forced air pericranial cooling (air temperature of approximately 13°C) was initiated simultaneous with the onset of CPB and maintained throughout the study period. Mechanical ventilation was terminated after the onset of CPB. During CPB, anesthesia was maintained with either (1) incremental doses of intravenous pentobarbital in an amount sufficient to maintain electroencephalographic burst suppression or (2) 1.0% halothane added to the bypass circuit. Resulting brain temperatures were recorded, and brain-to-core temperature gradients were calculated by subtracting the core temperature from regional brain temperature (derived by averaging right and left values at each brain temperature monitoring site).

At the completion of the study, dogs were euthanized with high-dose pentobarbital (Sleep Away; Fort Dodge Laboratories, Fort Dodge, IA) and discontinuation of CPB.

Data analysis
Physiologic variables were compared between groups (halothane versus pentobarbital) using the two-sample t test. Brain-to-core temperature gradients were calculated by subtracting core temperature from regional brain temperature (derived by averaging right and left values at each brain temperature monitoring site). The effect of anesthetic agent (halothane versus pentobarbital) was assessed separately for each phase of CPB at each temperature monitoring site, using a two-factor repeated measures analysis of variance model. In all cases, brain-to-core temperature gradient was the dependent variable, anesthetic agent was an independent cross-classification factor, and time was the repeated factor. To supplement these analyses, the mean temperature gradient for each phase of CPB was calculated for each regional brain site. For each group the mean temperature gradient was compared to zero using the one-sample t test and the two groups (halothane versus pentobarbital) were compared using the two-sample t test. In all cases, two-sided tests were used with p values less than or equal to 0.05 considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
With the exception of the MAP and hemoglobin concentration (Table 1) before CPB (ie, control), groups were well matched for all systemic physiologic variables throughout the study period. Discrepancies in control MAP and hemoglobin concentration resolved shortly after initiating CPB (Fig 1).

View larger version (29K): [in this window] [in a new window]   Fig 1. Esophageal temperature, systemic mean arterial blood pressure (MAP), and arterial carbon dioxide tension (PaCO2) during simultaneous hypothermic cardiopulmonary bypass and forced air cerebral cooling (air temperature of approximately 13°C). During cardiopulmonary bypass, there were no significant differences between pentobarbital- and halothane-anesthetized groups (n = 8 per group). Vertical bars represent 1.0 standard deviation.

View larger version (31K): [in this window] [in a new window]   Fig 2. Brain-to-core temperature gradients in pentobarbital- or halothane-anesthetized dogs undergoing simultaneous hypothermic cardiopulmonary bypass and forced air cerebral cooling (to approximately 13°C) (n = 8 per group). Core temperature was assessed using a flexible vinyl thermistor placed in the esophagus to the level of the right atrium. Regional brain temperatures were measured using thermistors placed bilaterally (1) in the parietal epidural space, (2) 1 cm beneath the dura, and (3) 2 cm beneath the dura. Resulting core-to-brain temperature gradients were calculated by subtracting core from regional brain temperature (derived by averaging right and left values at each brain temperature monitoring site). Thus, a negative value denotes that the cranial measurement site was cooler than the core.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Brain temperatures with and without forced air pericranial cooling
In a previous study from our laboratory in which forced air cerebral cooling was not used, we reported that when dogs were given halothane 1.0 MAC, the mean brain-to-core temperature gradient was always 0.5°C or less for all cranial temperature monitoring sites during all phases of bypass [16]. Halothane is an anesthetic that should have minimally changed CBF (and hence heat flux between core and brain "compartments") and cerebral metabolic rate (CMR) (and hence endogenous heat production) from the awake state. In contrast, dogs anesthetized with high-dose pentobarbital (ie, an anesthetic that should have diminished CBF and CMR by 50% or more, compared with the awake state), developed brain temperatures that typically lagged behind dynamic alterations in core temperature. For example, during active cooling, although pentobarbital-anesthetized dogs experienced simultaneous decreases in brain and core temperatures, mean brain temperatures typically exceeded the core by 1.7° to 2.2°C [16]. This trend of relative cerebral hyperthermia persisted into the period of stable hypothermia. However, during systemic rewarming, mean brain temperatures were 2.9° to 3.4°C cooler than the core [16]. This trend of relative cerebral hypothermia persisted well into the period in which the core temperature was maintained at 38°C (ie, the stable normothermia phase).

In comparison in the present study, we observed forced air pericranial cooling resulted in brain temperatures that were much cooler than observed in our previous study [16]. For example, in halothane-anesthetized dogs, mean brain temperature temperatures were as much as 2.0° to 2.7°C cooler than the core during the latter two phases of hypothermic CPB (Table 2, Fig 2). In pentobarbital-anesthetized dogs, forced air pericranial cooling attenuated or prevented relative cerebral hyperthermia [16] from occurring during the systemic cooling and stable hypothermia phases of CPB. Specifically, rather than being warmer than core [16], mean brain temperatures were 0.8° to 1.1°C cooler, respectively, than the core (Table 2, Fig 2) in the presence of forced air pericranial cooling. In addition, during and after systemic rewarming, relative cerebral hypothermia was of a greater magnitude (ie, mean brain temperatures were 4.4° to 5.6°C cooler than the core) (Table 2, Fig 2) than previously reported [16].

Determinants of brain temperature
It has been theorized that brain temperature results from three major factors: CBF (ie, heat flux between the brain and core), CMR (ie, endogenous heat production), and heat exchange with the environment [8, 20]. The importance of each "compartment" has previously been reviewed [8].

In our present and previous [16] studies, we pharmacologically altered two of the temperature compartments (ie, CBF and CMR). In both studies, although not quantified, we speculate the larger brain-to-core temperature gradients observed in pentobarbital-anesthetized dogs were predominantly related to the ability of the barbiturates to decrease CBF profoundly relative to halothane. Hence, pentobarbital would have served to partially isolate the systemic and cerebral circulations, thus making brain temperature less influenced by blood temperature and more influenced by environmental (pericranial) temperature.

Temperature modulation of ischemic brain injury
Previous studies have demonstrated mild alterations in brain temperature (ie, 0.5° to 2°C) at the time of, or immediately after, an ischemic insult can significantly affect neurologic outcome [8–14]. This effect has been demonstrated in laboratory animals exposed to either focal [9] or global [10] brain ischemia. In addition, in humans experiencing an ischemic stroke, postischemic neurologic outcome has been reported to be significantly affected by mild temperature changes [11–14].

During cardiac operation, the brain does not benefit from cold-induced brain protection: (1) before the initiation of bypass (ie, during manipulation and cannulation of the aorta), and (2) during the latter phases of, and immediately after, the rewarming phase of hypothermic CPB [5–7]. These three phases of bypass are often associated with cerebral ischemic events [21]. In addition, several groups of investigators have reported the occurrence of cerebral hyperthermia (well within the range previously reported to adversely affect postischemic neurologic outcome) during the latter phases of CPB [5–7]. For example, Cook [5] and Newman [6] and their colleagues reported cerebral temperatures of 39°C and 40°C, respectively, during and after the rewarming phase of hypothermic CPB. As might be expected, bypass-related cerebral hyperthermia has been reported to correlate with cerebral venous oxygen desaturation and worsening of neurologic function after bypass [6, 22].

Taken together, cerebral hyperthermia may be responsible, in part, for neurologic and neuropsychologic changes observed after CPB. In response to this clinical concern, we evaluated the efficacy of selective forced air cerebral cooling in a canine model of hypothermic CPB. When extrapolated to humans undergoing hypothermic CPB, we speculate that forced air cerebral cooling may provide a novel, noninvasive approach of providing brain protection during periods in which the brain otherwise does not benefit from hypothermia-mediated protection (eg, before initiation of bypass, and during and immediately after the rewarming phase of hypothermic CPB).

Mechanisms of brain protection by mild hypothermia
The physiologic basis by which small temperature changes produce significant alterations in postischemic neurologic outcome has not been fully elucidated. However, proposed mechanisms have previously been discussed [8]. Briefly, these include alterations in (1) CMR; (2) membrane stability (including the blood–brain barrier); (3) membrane depolarization; (4) temperature-induced ion homeostasis (including calcium fluxes); (5) neurotransmitter release or reuptake (eg, glutamate or aspartate); (6) enzyme function (eg, phospholipase, xanthine oxidase, or nitric oxide synthase activity); and (7) free radical production or endogenous scavenging [8].

Frequency and impact of brain injury after hypothermic cardiopulmonary bypass
With the advent of improved cardiac outcome after cardiac operation, increased attention has been directed at improving neurologic outcome after CPB. It is well appreciated that patients undergoing CPB-facilitated heart operations often sustain postoperative alterations in neurologic or neuropsychologic function [2–4, 6, 21–25]. For example, in a prospective multicenter study, Roach and colleagues [4] evaluated the affect of elective coronary artery bypass grafting on neurologic outcome in 2,108 patients. In this study, patients were stratified into two adverse neurologic outcome categories: type I (defined as death attributable to stroke or hypoxic encephalopathy, nonfatal stroke, transient ischemic attack, or stupor or coma at the time of discharge) or type II (defined as a new deterioration in intellectual function, confusion, agitation, disorientation, memory deficit, or seizure without evidence of focal injury). They reported that a total of 6.1% (3.1% type I and 3.0% type II) of patients had adverse neurologic outcomes [4]. When compared with patients not experiencing neurologic injury, type I and II outcomes were associated with a 5- to 10-fold increase in in-hospital mortality, 2- to 4-fold increase in average length of postsurgical hospital stay, and 3- to 6-fold increase in discharge to a skilled nursing facility or rehabilitation center [4]. It also has been reported that the mortality rate for patients sustaining a CPB-related stroke is approximately 20% to 25% (with a mean age, at the time of death, of 65 years) [3, 4]. In addition to severe neurologic injury, patients undergoing bypass-facilitated heart operations often sustain neuropsychologic deficits (ie, cognitive changes) [6, 21–25]. For example, Mills [21] reported neuropsychologic deficits (ie, cognitive changes) in 60% to 80% and 20% to 40% of patients at 1 and 8 weeks after coronary artery bypass grafting, respectively [21]. Taken together, neurologic injury is probably the most common source of morbidity, and the second most frequent cause of death, after cardiac operations [2–4, 21].

The potential magnitude of this problem of great concern. For example, it has been estimated that approximately 800,000 myocardial revascularization procedures are performed throughout the world annually [4]. Assuming data from the above cited investigators are applicable throughout the world, approximately 50,000 patients will sustain major neurologic deficits related to CPB, and up to 640,000 individuals will experience bypass-mediated neuropsychologic injury each year. The downstream effect of brain injury after CPB imposes an immense fiscal (ie, an estimated 2 to 4 billion dollars per year [4]), and emotional burden on the families and society that must care for these patients.

Cause of cardiopulmonary bypass-related brain injury
The cause of CPB-related brain injury is believed to be of an ischemic origin. Specifically, during CPB, it is believed that brain injury is produced by showers of air and particulate emboli washed into the cerebral circulation (ie, multifocal ischemia) and low flow states (ie, global ischemia accompanying severe systemic hypotension or cardiac arrest) [21–25].

Limitations
Potential limitations of our study design have been discussed in a previous study from our laboratory in which we used similar methodologies [15]. Briefly, issues addressed include our decision not to quantify changes in brain temperature associated with pharmacologic alterations in CBF and CMR, and the appropriateness of extrapolating our data to humans despite potential differences in cerebral anatomy and physiology between the two species.

In conclusion, the magnitude of selective brain cooling observed in both study groups typically exceeded the 0.5° to 2.0°C change previously reported to modulate ischemic injury, and was most prominent during the latter phases of CPB (ie, a time in which ischemic brain injury is likely [21]). When compared with previous research from our laboratory, application of cold forced air to the cranial surface resulted in brain temperatures that were cooler than, and presumably more cerebroprotective than, those observed during hypothermic CPB without pericranial cooling. On the basis of the assumption that similar beneficial brain temperature changes can be induced in humans, we speculate that selective convective brain cooling may enable clinicians to provide cerebral protective therapy during periods in which the brain typically does not benefit from hypothermia during ischemic insults.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank William Anding, Richard Koenig, Marilyn Oeltjen, and Rebecca Wilson for their technical assistance in the Cardiovascular Surgery and Neuroanesthesia Research Laboratories. Dr Wass was awarded a Research Fellow Scholarship and Grant, from Augustine Medical, Inc., to support this research project. All scholarship and grant monies were received by the Mayo Foundation for Research and Education.

	References

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