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Ann Thorac Surg 2002;73:191-197
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Effect of hypothermia on cerebral blood flow and metabolism in the pig

^a Department of Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York, USA
^b Department of Neurosurgery, Mount Sinai Medical Center, New York, New York, USA
^c Department of Biomathematics, Mount Sinai Medical Center, New York, New York, USA

Accepted for publication August 17, 2001.

* Address reprint requests to Dr Griepp, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029, USA
e-mail: marekehrlich{at}hotmail.com

	Abstract

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Background. The pig has become an increasingly popular model for the study of cerebral protection during cardiothoracic surgery in recent years, but little information is available concerning hypothermic porcine physiology. Because the efficacy of cerebral protection depends largely upon metabolic suppression, we studied cerebral oxygen metabolism at various temperatures using two different methods to assess cerebral blood flow (CBF).

Material and Methods. Twelve pigs (7 to 13 kg) underwent cooling on cardiopulmonary bypass to 8°C as recorded by an electrode placed deep in the parenchyma of the brain. CBF was measured in 6 animals using radioactive microspheres and in the other 6 using fluorescent microspheres. CBF, cerebral oxygen consumption, and cerebral vascular resistance were determined at 37°C, 28°C, 18°C, and 8°C.

Results. Both methods produced very similar data. CBF fell steadily with decrease in temperature to 18°C but failed to drop further with more profound hypothermia. With both groups combined, mean cerebral oxygen metabolism was 2.63 mL/100 g per minute at 37°C. Metabolic activity was 50% of base line values at 28°C, 19% at 18°C, and 11% at 8°C. The Q₁₀ value in the pig—the degree of metabolic suppression achieved by a 10°C drop in temperature—is 2.46 (95% confidence interval 2.1 to 2.9); this value is consistent with similar studies in humans.

Conclusions. The presence of significant residual metabolic activity at 18°C suggests that this degree of hypothermia may provide incomplete cerebral protection during prolonged interruption of CBF. This study demonstrates that cooling to temperatures below 18°C in the pig can achieve greater metabolic suppression although it may be associated with loss of cerebral autoregulation.

	Introduction

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Although profound hypothermic circulatory arrest (HCA) is a well-established method for use in surgery for a variety of cardiovascular abnormalities as well as for some neurosurgical procedures, brain damage as a consequence of HCA remains a frequent if often subtle complication. The optimal conditions for maximizing cerebral protection during HCA are not well established. There is still controversy about basic aspects of implementing HCA such as the best temperature at which to arrest the circulation. To allow for the experimental validation of innovative methods involving HCA, a cost-effective and reproducible model is required in which cerebral physiology as well as behavioral responses and histopathology can be studied.

Cerebral blood flow (CBF) was determined in pigs while on cardiopulmonary bypass (CPB) using two different methods. The injection and subsequent detection of radioactively labeled microspheres that lodge in the microcirculation is a reliable and very precise method to determine regional organ blood flow [1]. However, the use of radioactivity has become increasingly problematic owing to restrictive legislation and the high cost of storage and disposal of radioactive tissues, prompting development of different techniques in recent years. One of these new methods, the injection of fluorescently labeled microspheres, has been proposed as a reliable alternative.

The original purpose of this study was twofold: to determine cerebral metabolic activity at different temperatures in the pig and to compare the results using the fluorescent microsphere technique with those obtained with the radioactive microsphere method. Because the results of the two microsphere methods were not significantly different, the data from both groups have largely been combined and the physiologic conclusions emphasized.

	Material and methods

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Preoperative management
All animals received humane care in accordance with "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research, and "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Resources, National Research Council, and published by National Academy Press, revised 1996. The protocol for these experiments was approved by the Mount Sinai Institutional Animal Care and Use Committee.

Animal preparation
Twelve juvenile Yorkshire pigs (Thomas D. Morris, Inc, Reistertown, MD) weighing 7 to 13 kg (mean 10.17 ± 2.26 kg), were used for this study. Anesthesia was induced with ketamine hydrochloride (10 mg/kg intramuscularly). After endotracheal intubation, the pigs were ventilated mechanically with 50% oxygen and 1% to 2% isoflurane to maintain deep anesthesia. Paralysis was achieved with intravenous pancuronium (0.1 mg/kg). The ventilator rate and the tidal volume were adjusted to maintain the arterial carbon dioxide tension at 40 mm Hg. Blood gas analysis was performed using the -stat method: pH during cooling and at microsphere injection times was maintained at 7.4, and carbon dioxide tension at 35 to 45 mm Hg uncorrected for temperature. Arterial oxygen tension was maintained more than 100 mm Hg. Lead II was used for electrocardiographic monitoring. Temperature probes were placed in the esophagus, rectum, and two different regions in the brain. The brain temperatures were determined with an epidural thermal probe (IT-18; Physitemp Instruments Inc, Clifton, NJ) that was positioned under the calvarium; the same probe was used for the so-called "deep brain temperature" but was positioned in the gray matter. An indwelling catheter was inserted in the bladder. Catheters were positioned in the left femoral artery and vein for monitoring purposes and withdrawal of blood samples. A thermodilution catheter (93 A 831 H 5 F; Baxter Healthcare Corp, Irvine, CA) was inserted into the pulmonary artery to measure cardiac output.

Sagittal sinus cannulation
Sagittal sinus cannulation was performed before cannulation for CPB. A midline scalp incision was made and the underlying periosteum removed to facilitate identification of the coronal and sagittal sutures. Under 2.5-fold magnification, a 3-mm cutting burr was used to remove the bone over the sinus. A 24-gauge catheter was inserted into the sagittal sinus to permit both sampling of cerebral venous blood and monitoring of cerebral venous pressure.

Cardiopulmonary bypass and cooling
After heparinization (300 IU/kg), nonpulsatile CPB was instituted employing single-cannula drainage of the right atrium with return of the arterial perfusate through a cannula in the ascending aorta. Membrane oxygenators (VPCML Plus; Cobe Cardiovascular Inc, Arvada, CO) were primed with a solution containing homologous blood (universal donor), 5% albumin, furosemide (1 mg/kg), heparin (2,000 IU), 1% dextrose in 0.9% saline solution, and KCl (1 mEq/kg). Nonpulsatile cardiopulmonary bypass was initiated at a flow rate of 100 mL · kg^-1 · min^-1, and then adjusted to maintain a mean blood pressure of 50 mm Hg. Hematocrit was maintained between 0.18 and 0.22. Arterial oxygen tension was adjusted to exceed 200 mm Hg. Using -stat blood gas monitoring, cooling was carried out to achieve a deep brain temperature of 28°C, 18°C, and 8°C. Each data point during cooling was recorded after a period of stabilization at the appropriate temperature for 5 minutes; the total duration of cooling to achieve a deep brain temperature of 8°C averaged 90 minutes.

Study protocol
Measurements of CBF, cerebral vascular resistance (CVR), cerebral oxygen metabolism (CMRO₂), and cerebral oxygen extraction were undertaken 5 times in the pigs assessed using radioactive microspheres, and 4 times in the group in which fluorescent microspheres were used. (The base line measurement was repeated to enhance accuracy using radioactive microspheres, but this measurement could be carried out only once in the other group because of the limited availability of different fluorescent microspheres.) Measurement 1 was at base line, at 37°C, before CPB; measurement 2 was at 28°C deep brain temperature; measurement 3 was at 18°C deep brain temperature; and measurement 4 was at 8°C deep brain temperature. The mean value of the two base line measurements in the radioactively labeled microspheres group was used at 37°C.

Cerebral blood flow and cerebrovascular resistance
Cerebral blood flow was measured in the first group using radionuclide-labeled microspheres as originally described by Rudolph and Heymann [1] and as described by us in previous studies [2, 3]. Briefly, approximately 0.8 to 1.2 x 10⁶ microspheres 15 ± 0.5 m in diameter, labeled Ru 103, Sn 113, Cr 51, Co 57, Nb 95, and Sc 46 (New England Nuclear, Wilmington, DE), were injected and flushed with 5 mL of saline solution into a left ventricular catheter (10 F) before CPB, and into the arterial cannula during CPB; in the animals in which fluorescent microspheres were used, the same procedure was followed with 4 different-colored fluorescent microspheres (orange-high, red-low, blue-high, violet-low; Triton Technology, Mettler-Toledo, Greifensee, Switzerland), also 15 m in diameter. Blood reference samples were withdrawn from the femoral arterial line at a constant rate (2.29 mL/min) with a Harvard withdrawal pump (Instech Laboratories, Plymouth Meeting, PA) beginning 15 seconds before microsphere injection and ending 105 seconds after injection.

After the last microsphere injection at 8°C, the animals were sacrificed using sodium pentobarbital (30 mg/kg) and KCl (6 mEq/kg). In all 12 animals, the brain was removed and weighed. Radionuclide determination was made using a gamma counter (Auto-Gamma, Packard Instruments, Downers Grove, IL). Fluorescent analysis was carried out by flow cytometry (IMT).

Cerebral blood flow and the other reported metabolic factors using radioactive microspheres were calculated by using the following equation (the same principles underlie the method used to calculate flows and resistances using fluorescent microspheres):

Cerebral vascular resistance was calculated by using the following equation:

where MAP is mean arterial pressure and MSSP is mean sagittal sinus pressure.

Cerebral metabolism
Sagittal sinus and arterial samples were obtained simultaneously for calculation of cerebral oxygen extraction (arteriovenous oxygen content difference). Cerebral metabolic rate of oxygen (CMRO₂) was determined as follows:

Arterial and venous blood pH, oxygen tension, carbon dioxide tension, hematocrit, oxygen content, and glucose levels were measured using the Ciba-Corning 800 Series blood gas analyzer (Ciba Corning, East Walpole, MA).

Temperature coefficient
The temperature coefficient (Q₁₀), a well-described physiologic variable denoting the change in a metabolic variable corresponding to a 10°C change in temperature, was also determined. The Q₁₀ was derived for each microsphere method as follows. (1) For each animal, x, an estimate was obtained of the slope (m_x) of the line expressing the natural logarithm of the CMRO₂ as a function of the temperature, t, while cooling:

(2) m = the mean slope among all the animals in the group. (3) Q₁₀ = exp(10 m), the ratio of CMRO₂ (x,t) to CMRO2 (x,t - 10), evaluated at the mean slope, m.

Statistical analysis
Values are expressed as the mean ± standard deviation. Differences between groups were tested by t tests, the Wilcoxon rank sum test, or repeated measures ANOVA. The p values are shown for all the tests with p less than 0.10.

	Results

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All animals were hemodynamically stable without the use of vasoactive or inotropic agents during the time all intraoperative measurements were made. The mean weight in the group of pigs in whom radioactive microspheres was used was 8.5 ± 1.09 kg: they were significantly smaller (p = 0.003 by t test) than the usual size of those in whom fluorescent microspheres were used, mean 11.8 ± 1.83 kg (mean ± SD) to minimize the cost of disposal. There were no significant differences in cardiac index between groups: 0.20 ± 0.12 versus 0.14 ± 0.05.

Table 1 displays the values that were obtained at the time of each data collection for three different body temperatures, arterial pH, arterial oxygen and carbon dioxide tension, and hematocrit. There were no clinically significant differences between the two groups in the temperatures at different sites, in arterial oxygen and carbon dioxide tensions, or in the hematocrit values, although all these variables changed significantly over time. Arterial pH showed a significantly higher value at base line in the fluorescent microsphere group, corresponding to a slightly lower pCO₂, cerebral blood flow, and higher vascular resistance: none of these latter differences were significant, and in both groups all values were well within the normal physiologic range.

View larger version (30K): [in this window] [in a new window]   Fig 1. Cerebral blood flow (CBF) on cardiopulmonary bypass, measured in all 12 pigs as described in the text. Data are from Table 2. When the percentage of base line CBF is calculated for each pig at each temperature, for the two groups of pigs combined mean percentage of base line CBF (95% confidence limits) is 62% (42%, 83%) of base line at 28°C; 36% (26%, 46%) of base line at 18°C; and 43% (30%, 55%) of base line at 8°C.

View larger version (34K): [in this window] [in a new window]   Fig 2. Cerebral vascular resistance (CVR) on cardiopulmonary bypass measured in all 12 pigs as described in the text. Data are from Table 2.

View larger version (27K): [in this window] [in a new window]   Fig 3. Cerebral oxygen consumption (CMRO2) on cardiopulmonary bypass measured in all 12 pigs as described in the text. Data are from Table 3. When the percentage of base line CMRO2 is calculated for each pig at each temperature, for the two groups of pigs combined mean percentage of base line CMRO2 (95% confidence limits) is 50% (35%, 65%) of base line at 28°C; 19% (13%, 25%) of base line at 18°C; and 11% (6%, 16%) of base line at 8°C.

CBF/CMRO₂
If the ratio of cerebral blood flow to cerebral oxygen metabolism at base line is considered ideal, representing optimal autoregulation of cerebral blood flow in accordance with metabolic needs, then as seen in Figure 4 autoregulation is well preserved at 28°C. It is slightly less consistent at 18°C, and quite often unreliable at 8°C.

View larger version (24K): [in this window] [in a new window]   Fig 4. The ratio of cerebral blood flow (CBF) to cerebral oxygen consumption (CMRO2) in all 12 pigs studied. If the base line ratio is assumed to represent ideal autoregulation of cerebral blood flow to satisfy metabolic demands, then progressive loss of autoregulation is seen below 28°C and there is marked variability among animals in the degree to which autoregulation is preserved at 8°C, and often so-called luxury perfusion.

View larger version (19K): [in this window] [in a new window]   Fig 5. Data from each of the 12 pigs were used to determine the temperature coefficient (Q10) using both radioactive and fluorescent microspheres. (LN(CMRO2) = natural logarithm of oxygen consumption. Squares on solid lines = radioactive microspheres; circles on dashed lines = fluorescent microspheres.)

	Comment

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We found a significant reduction of CMRO₂ in the pig at a deep brain temperature of 8°C compared with 18°C using the time-honored radioactive microsphere method for calculating cerebral blood flow. The finding that residual cerebral metabolism is still 24% of base line values at 18°C is somewhat alarming, inasmuch as most estimates of the theoretic safety of relatively long ischemic times under hypothermia assume a much greater reduction of metabolic rate than we were able to document in this study. The data suggest that hypothermia to a level of 18°C may provide less complete cerebral protection during interrupted or severely reduced CBF than has often been assumed, and that HCA can probably be tolerated without cerebral injury only for durations of circulatory arrest less than 30 minutes, given the assumption that 5 minutes of ischemia can be withstood safely at base line temperatures. As a further lowering of metabolic rate could be achieved with cooling to 8°C, it seems logical to suppose that more profound hypothermia might provide better cerebral protection during more prolonged periods of HCA.

The residual cerebral metabolism at 18°C in this pig model was somewhat lower than that in a study performed by our laboratory in dogs, in which cerebral activity at 18°C was as high as 40% of base line values; this difference may reflect a species-specific variability [3]. In the current study, the metabolic coefficient for the pig brain during cooling to deep hypothermic temperatures—the Q₁₀—was 2.46: this result is similar to calculations from a recent clinical study in which the Q₁₀ in 37 patients was found to be 2.3 [8] and suggests that earlier estimates showing higher degrees of metabolic suppression achieved by hypothermia based on less reliable methods for estimating cerebral blood flow may have been too optimistic. The observation that oxygen extraction is not minimal at 18°C but rather continues to fall as cooling continues also confirms the idea that further metabolic suppression can be achieved using more profound hypothermia.

The metabolic data from this experiment strongly suggest that cooling to 18°C does not provide as great a reduction of cerebral activity as can be obtained from cooling to more profoundly hypothermic temperatures and therefore is unlikely to provide as complete a degree of cerebral protection as can be obtained at lower temperatures. However, cooling below 18°C is associated with a greater loss of autoregulation. The so-called luxury perfusion that results when cerebral blood flow exceeds metabolic demands presents a theoretical increase in the risk of cerebral emboli.

A secondary observation from this study is that fluorescent microsphere calculations of cerebral blood flow correlate well with radioactive microsphere determinations. Since its first use in 1967 by Rudolph and Heymann to determine the circulation of lambs in utero, the radioactive microsphere technique has been validated in many studies [4, 5] and is currently regarded as the gold standard for blood flow measurements in experimental cardiovascular research, but promising and less costly alternatives have now become available. Hale and colleagues [9] introduced a method utilizing colored microspheres more than 10 years ago, and fluorescent microspheres have recently been demonstrated to be reliable for the determination of blood flow in various organs such as kidneys and heart [6, 7]. Several studies have now shown good correlations between blood flow values obtained with simultaneously injected colored and radioactive microspheres [6, 9], and fluorescent microspheres have been validated for use in nonischemic and ischemic myocardium [6].

The microsphere methods used in this study to estimate cerebral blood flow showed excellent agreement, indicating that the fluorescent microsphere technique can be used to determine cerebral blood flow accurately. The more significant fall in cerebral metabolism seen between 18°C and 8°C using radioactive microspheres may reflect more thorough cooling at low temperatures in the animals in whom the radioactive microspheres were used: they were significantly smaller, had a slightly more acidic initial pH, and consistently a somewhat lower cerebral vascular resistance. But the ultimate degree of metabolic suppression achieved in both groups was the same, arguing that differences in the rapidity with which maximal metabolic suppression is achieved can be overcome by cooling that is sufficiently profound and sustained.

In conclusion, this study revealed that significant residual metabolic activity is still present at a deep brain temperature of 18°C, suggesting that this degree of hypothermia may provide less complete cerebral protection during interrupted or severely reduced CBF than has often been assumed. Further metabolic suppression can be achieved with cooling to lower temperatures, albeit with greater loss of cerebral autoregulation. The metabolic consequences of hypothermia in the pig are very similar to previous observations in dogs and humans, suggesting that the pig may be an appropriate model for use in future studies evaluating strategies for cerebral protection during cardiothoracic surgery. [10]

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This work was supported by grant HL 45636 from the National Institutes of Health and by the Nat Lapkin Foundation.

The authors thank Richard Smith, Richard Henry, and Russell Jenkins for invaluable technical assistance.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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