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J Thorac Cardiovasc Surg 1994;108:907-912
© 1994 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

Chronic nonpulsatile blood flowI. Cerebral autoregulation in chronic nonpulsatile biventricular bypass: Carotid blood flow response to hypercapnia

Cleveland, Ohio

Supported by funding from the G. Herold and Leila Y. Mathers Charitable Foundation.

Received for publication July 30, 1993. Accepted for publication Nov. 29, 1993. Address for reprints: Ryuji Tominaga, MD, Division of Cardiovascular Surgery, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, 3-1-1 Maedashi, Higashi-ku, Fukuoka, 812, Japan.

Abstract

To investigate the response of the carotid blood flow and general circulation to hypercapnia in chronic nonpulsatile blood flow, we performed 18 carbon dioxide gas inhalation studies on three calves undergoing a centrifugal biventricular bypass with ventricular fibrillation. An ultrasonic flow probe was put on the carotid artery during biventricular bypass pump implantation, and pump flows were maintained at 90, 100, and 120 ml/kg per minute for 1 week each. The carbon dioxide inhalation studies were performed twice a week. Hypercapnia was induced by administering pure carbon dioxide gas through a nasal tube at flow rates of 0, 5, 7.5, 10, 12.5, and 15 L/min for 5 minutes each at three different nominal pump flow rates, and the resultant arterial blood gas and hemodynamic changes were recorded. No significant correlation existed between the carotid blood flow and mean aortic pressure, which varied from 70 to 140 mm Hg, but the carotid blood flow correlated significantly (p < 0.01) with the systemic pump flow rate. A significant (p < 0.01) linear relationship was found between the carotid blood flow and arterial carbon dioxide tension. For each 1 mm Hg change in arterial carbon dioxide tension, there was a 2.8% change in the carotid blood flow. The percent changes in the carotid blood flow in response to arterial carbon dioxide tension were calculated as 2.9%, 3.7%, and 2.5% for each 1 mm Hg change in arterial carbon dioxide tension at pump flows of 90, 100 and 120 ml/kg per minute. No significant differences in the carotid blood flow response to hypercapnia were detected among the three systemic pump flow rates. These results thus suggested that chronic nonpulsatile blood flow had no detrimental effects on cerebral autoregulation. (J THORACCARDIOVASCSURG1994;108:907-12)

Nonpulsatile, centrifugal blood pumps are recently finding a wider use in the clinical setting because of their simplicity of application and cost effectiveness. ¹ Animals have been maintained for up to 99 days with chronic nonpulsatile blood flow, ² indicating that both adaptation to and survival with this nonphysiologic flow regimen is possible. However, no detailed physiologic study during chronic nonpulsatile blood flow has yet been performed. In addition, no reports have been published on the response of the cerebral flow to varying arterial carbon dioxide tension (PaCO₂) in an animal model of chronic nonpulsatile blood flow. The purpose of this study is thus to clarify the effects of a chronic nonpulsatile bypass flow on the cerebral blood flow, as well as the response to varying PaCO₂ levels.

MATERIAL AND METHODS

Detailed descriptions of the operative technique and equipment used for this laboratory's model of prolonged nonpulsatile biventricular bypass in the calf have been previously reported. ³ In summary, three healthy Holstein calves, 4 months old, body weight 91.3 ± 1.7 kg (89.8 to 93.6 kg), were used in the study. The preanesthetic medication consisted of 0.4 mg atropine sulfate administered intramuscularly. Anesthesia was induced with halothane and nitrous oxide and maintained with 1% to 1.5% halothane. No paralytic agents were used. Antibiotics, cephapirin sodium (Cefadyl) 2 gm intravenously and gentamicin 160 mg intramuscularly, were begun the night before the operation and were continued 7 days after the operation. After surgical hemostasis had been achieved, a continuous heparin infusion was used throughout the experiment and was titrated to maintain an activated coagulation time between 200 and 250 seconds.

The cannulation sites were retrograde across the pulmonary valve for the right inflow and through the left atrial appendage and mitral orifice for the left inflow. The retrograde pulmonary approach to the right ventricle represented a surgical modification to the former penetration of the myocardial wall. The right and left arterial returns were through grafts anastomosed end to side to the pulmonary artery and aorta, respectively. The cannulas were attached to Hemadyne centrifugal blood pumps (Medtronic, Inc., Minneapolis, Minn.), mounted to a harness on the animal's back. Fluid-filled pressure monitoring and sampling catheters were placed in the right atrium, the pulmonary artery, the left atrium, the internal mammary artery, and the jugular vein. An ultrasonic flow probe (Transonic Systems Inc., Ithaca, N.Y.) was implanted on the calf left carotid artery while transit-time ultrasonic flow probes were clamped on the outflow cannulas to determine the left and right pump flows. The waveforms and numerical hemodynamic data were recorded hourly, as were the respiration rate, body temperature, animal position up or down, and fluid input/output. The body weight was measured at least twice a week. During the first postoperative week, the calf's natural heart continued to beat and the centrifugal device idled at 3 to 5 L/min to prevent any internal clotting. On the seventh day, the animal's heart was fibrillated and the device was set at one of three flow levels (90, 100, or 120 ml/kg per minute).

Pure carbon dioxide gas was given through the small tube that was put in the nose of the calf. The calf was allowed to breathe without any airway resistance. The carbon dioxide gas flow rate was increased by 2.5 L/min increments from 0 to 15 L/min, imposed for 5 minutes each. All hemodynamic parameters, including the right atrial pressure, left atrial pressure, pulmonary arterial pressure, systemic arterial pressure, pump flow rate, and carotid flow rate were recorded at each nasal carbon dioxide gas flow rate. Blood samples were obtained from the pulmonary artery and systemic artery through indwelling catheters and blood gas analysis was performed. A carbon dioxide gas inhalation study was done on the ninth to thirty-second (mean 22.1 ± 7.8 days) postoperative days, which was at 3 to 26 days (mean 16.2 ± 1.8 days) after ventricular fibrillation at the three different flow rates. In all, 18 studies (six studies at each pump flow rate) were performed in the three calves. The mean hematocrit value was 30% ± 2.7% (28.9% ± 2.7%, 31.3% ± 2.4%, and 29.7% ± 2.4% at pump flows of 90, 100, and 120 ml/kg per minute respectively) during the carbon dioxide inhalation study.

The animals were kept in an air conditioned room in a cage that was cleaned every day, and they were given water and free access to food. All animal handling and experimentation were conducted in a gentle manner to minimize the stress and discomfort of the calves. All protocols were written according to Food and Drug Administration guidelines for laboratory animal care, the guiding principles of the American Physiological Society, and were approved by the Cleveland Clinic Foundation Institutional Animal Care and Use Committee.

All data were represented as the mean ± standard deviation. Statistical significance was evaluated with a two-tailed paired t test, and p < 0.05 was considered to be statistically significant. The transonic flow probe was removed en bloc with the carotid artery at autopsy and calibrated with calf blood to check the accuracy of the system. This check revealed no change in accuracy after more than a 4-week implantation.

RESULTS

No significant correlation existed between the carotid blood flow and mean aortic pressure (representative data from one calf are shown in Fig. 1), but a significant (p < 0.01) correlation was observed between the carotid flow and left pump flow rate (Fig. 2).

View larger version (24K): [in this window] [in a new window]   Fig. 1. Correlation between carotid blood flow and systemic arterial pressure during long-term chronic nonpulsatile blood flow. No significant correlation was observed.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Correlation between carotid blood flow and systemic pump flow rate during chronic nonpulsatile biventricular bypass with ventricular fibrillation. Carotid blood flow correlated significantly to left pump flow rate.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Carotid blood flow response to hypercapnia during chronic nonpulsatile blood flow. A significant (p < 0.01) linear relationship was obtained between carotid blood flow and PaCO2. Each data point was picked up from the data at each nasal carbon dioxide gas flow rate. Small bars indicate standard deviation.

View larger version (67K): [in this window] [in a new window]   Fig. 4. Correlation between carotid blood flow and PaCO2 at each systemic pump flow rate. Pump flow rate at 90 ml/kg per minute (A), 100 ml/kg per minute (B), and 120 ml/kg per minute (C). Significant linear correlations were obtained at each pump flow rate. Small bars indicate standard deviation.

Because of their efficacy and simplicity, centrifugal pumps have been used as a circulatory assist device for the patient with severe postoperative low cardiac output syndrome. ¹ However, the long-term use of centrifugal pumps, especially as in the case of a totally implantable artificial heart, has been rarely reported. One of the reasons that nonpulsatile centrifugal pumps have not been used for long-term circulatory support is that the effects of chronic nonpulsatile blood flow on organ function, especially on cerebral blood flow, were believed to be detrimental.

Nonpulsatile blood flow was reported to decrease cerebral blood flow and cerebral metabolic rate by approximately 30% as compared with pulsatile flow during normothermic cardiopulmonary bypass. ⁴ The responses of cerebral blood flow to PaCO₂, mean aortic pressure, and systemic flow rate during hypothermic nonpulsatile cardiopulmonary bypass have been investigated intensively both in animal models ^5-8 and in clinical studies. ^9-13 The response of cerebral blood flow to changes in PaCO₂ was reported to be well maintained in nonpulsatile hypo thermic cardiopulmonary bypass despite the various methods used for cerebral blood flow measurements; however, cerebral blood flow autoregulation is still controversial. These experiments were done either in short-term animal studies or in a short-term clinical cardiopulmonary bypass for cardiac surgery. In chronic nonpulsatile blood flow, in which some unknown compensation mechanisms are at work, no one has yet investigated the autoregulation of cerebral blood flow or the response to hypercapnia.

This study is the first trial to investigate the effect of varying levels of chronic nonpulsatile blood flow on cerebral blood flow. No significant increase in carotid arterial blood flow was observed when the mean arterial pressure changed from approximately 70 to 140 mm Hg. From these data, autoregulation of the cerebral blood flow appears to be preserved even after prolonged nonpulsatile blood flow. This autoregulation of carotid blood flow has a lower limit as well as an upper limit, and these limits vary with PaCO₂. ¹⁴ The lower limit of autoregulation, that is, the lower limit of maintenance of unchanged flow, which in normotensive individuals lies at a mean arterial blood pressure of about 60 to 70 mm Hg, can be as high as 110 or even 130 mm Hg with increased sympathetic nerve activity in hypertensive individuals. ^15,16 A previous study suggested increased sympathetic nerve activity ² during a prolonged period of nonpulsatile blood flow, which might affect the lower and upper limits of cerebral autoregulation. However, further investigation should still be done to determine the precise lower pressure limit of cerebral blood flow autoregulation in chronic nonpulsatile blood flow to determine whether a significant difference exists between pulsatile and nonpulsatile blood flow.

The relationship between cerebral blood flow and systemic blood flow is still controversial. Soma and associates ¹⁷ demonstrated that the cerebral blood flow measured with the argon gas inhalation technique during moderate hypothermic cardiopulmonary bypass significantly correlated with the extracorporeal circulation flow. On the other hand, Govier and coworkers ¹⁸ reported insignificant changes in the regional cerebral blood flow determined by the clearance of xenon gas with a varying pump flow during hypothermic nonpulsatile cardiopulmonary bypass. In this study, a weak but significant increase in the carotid blood flow according to the increase in the pump flow rate was observed after ventricular fibrillation. However, the percent increase in the carotid flow was not the same as that in the pump flow. When the pump flow increased to 50% of the control value, the cerebral blood flow increased only by 35%. Presumably, this result might suggest that cerebral autoregulation against systemic blood flow changes was retained during prolonged nonpulsatile perfusion.

This study had several limitations. First, no precise data on the distribution of the carotid arterial blood flow in calves are available. When the animal began to chew its cud, the carotid flow always increased, which meant a chewing muscle was perfused with the carotid artery. Even though no quantitative study was done, dye injected into the carotid artery at autopsy revealed flow distribution to the pial arterioles from the carotid artery. Thus carotid blood flow was measured only in the absence of the effect of chewing. The second factor was the brevity of the experimental study. A carbon dioxide inhalation study was done twice a week at three different flow settings in three animals. Six data points were considered to be independent and the statistical analysis was done on these data. Because the animals' conditions changed daily, we believe that the data obtained on different days can be considered to be independent.

Variations in the PaCO₂ can exert a profound influence on the cerebral blood flow. Hypercapnia causes intense cerebral vasodilation, whereas hypocapnia causes such extensive constriction that the limit of brain hypoxia is reached. In normal waking or anesthetized human beings not undergoing cardiopulmonary bypass, the cerebral blood flow change per millimeter of mercury of PaCO₂ has been established to be about 3% to 4%. ^12,19 In this study, the percent change in the carotid blood flow was 2.8%/mm Hg change in PaCO₂, which was lower but similar to the previously reported cerebral blood flow data despite a different method of cerebral blood flow estimation. A significant linear relationship was found between the carotid blood flow and PaCO₂ when PaCO₂ was changed from approximately 40 to 70 mm Hg during chronic nonpulsatile flow. Because the pump flow rate was not affected by the increase in PaCO₂, this linear increase was considered to be due to the cerebral response to hypercapnia per se. A significant linear relationship between the carotid blood flow and PaCO₂ was also seen when the data were analyzed at each of the three nominal systemic flows. The regression line obtained from the data for a nominal flow rate of 120 ml/kg per minute shifted upward when it was compared with that of a nominal flow rate of 90 ml/kg per minute, but no statistically significant differences in the carotid blood flow existed when compared with those at each nasal carbon dioxide gas flow rate. These results thus suggest that the cerebral blood flow during prolonged periods of a nonpulsatile biventricular bypass was adequately autoregulated to changes in both the systemic pump flow and PaCO₂. Anderson and associates ²⁰ reported the detrimental effect of nonpulsatility in the blood flow on cerebral autoregulation. Using pigs, they investigated the effects of flow pulsatility during normothermic cardiopulmonary bypass on the relationship between brain glucose consumption and regional blood flow. In nonpulsatile cardiopulmonary bypass, the regional blood flow remained normal but the average glucose consumption declined, indicating a perfusion in excess of metabolic demand. They thus suggested that the nonpulsatile blood flow affected the metabolic flow regulation in the brain by interfering with the myogenic contractility of the cerebral arterioles. Murkin and associates ⁴ also demonstrated that nonpulsatile cardiopulmonary bypass per se had an effect on the cerebral blood flow and cerebral oxygen consumption, reducing both by approximately 30%. Previous studies, indicative of a detrimental effect in the nonpulsatile blood flow, were performed under general anesthesia, which can affect the cerebral arteriolar response to hypercapnia. ²¹ In this study, we could not find any deleterious effect in a prolonged nonpulsatile blood flow either through daily observation of the animal or through a carbon dioxide inhalation study. We therefore concluded that cerebral autoregulation was normally well maintained during prolonged nonpulsatile blood flow in waking animals. However, further studies are still being planned to obtain more precise information on the flow/metabolic coupling in the brain during normothermic nonpulsatile blood flow either with or without anesthesia.

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