pH-Stat Management Reduces the Cerebral Metabolic Rate for Oxygen during Profound Hypothermia (17 degrees Celsius): A Study during Cardiopulmonary Bypass in Rabbits

Background: Greater cerebral metabolic suppression may increase the brain's tolerance to ischemia. Previous studies examining the magnitude of metabolic suppression afforded by profound hypothermia suggest that the greater arterial carbon dioxide tension of pH-stat management may increase metabolic suppression when compared with alpha-stat management.

Methods: New Zealand White rabbits, anesthetized with fentanyl and diazepam, were maintained during cardiopulmonary bypass (CPB) at a brain temperature of 17 degrees Celsius with alpha-stat (group A, n = 9) or pH-stat (group B, n = 9) management. Measurements of brain temperature, systemic hemodynamics, arterial and cerebral venous blood gases and oxygen content, cerebral blood flow (CBF) (radiolabeled microspheres), and cerebral metabolic rate for oxygen (CMRO2) (Fick) were made in each animal at 65 and 95 min of CPB. To control for arterial pressure and CBF differences between techniques, additional rabbits underwent CPB at 17 degrees Celsius. In group C (alpha-stat, n = 8), arterial pressure was decreased with nitroglycerin to values observed with pH-stat management. In group D (pH-stat, n = 8), arterial pressure was increased with angiotensin II to values observed with alpha-stat management. In groups C and D, CBF and CMRO2 were determined before (65 min of CPB) and after (95 min of CPB) arterial pressure manipulation.

Results: In groups A (alpha-stat) and B (pH-stat), arterial pressure; hemispheric CBF (44 plus/minus 17 vs. 21 plus/minus 4 ml *symbol* 100 g sup -1 *symbol* min sup -1 [median plus/minus quartile deviation]; P = 0.017); and CMRO2 (0.54 plus/minus 0.13 vs. 0.32 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.0015) were greater in alpha-stat than in pH-stat animals, respectively. As a result of arterial pressure manipulation, in groups C (alpha-stat) and D (pH-stat) neither arterial pressure (75 plus/minus 2 vs. 78 plus/minus 2 mm Hg) nor hemispheric CBF (40 plus/minus 10 vs. 48 plus/minus 6 ml *symbol* 100 g sup -1 *symbol* min sup -1; P = 0.21) differed between alpha-stat and pH-stat management, respectively. Nevertheless, CMRO2 was greater in alpha-stat than in pH-stat animals (0.71 plus/minus 0.10 vs. 0.45 plus/minus 0.10 ml Oxygen2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.002).     

Rapid Rewarming Causes an Increase in the Cerebral Metabolic Rate for Oxygen that Is Temporarily Unmatched by Cerebral Blood Flow: A Study during Cardiopulmonary Bypass in Rabbits

Background: Jugular venous hemoglobin desaturation during the rewarming phase of cardiopulmonary bypass is associated with adverse neuropsychologic outcome and may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin desaturation. The authors wished to determine if rewarming rate influences the temperature dependence of CBF and CMRO2.

Methods: Anesthetized New Zealand white rabbits, cooled to 25 degrees Celsius on cardiopulmonary bypass, were randomized to one of two rewarming groups. In the fast group (n = 9), aortic blood temperature was made normothermic over 25 min. Cerebral blood flow (microspheres) and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees Celsius during rewarming.

Results: Systemic physiologic variables appeared similar between groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast rewarming group than in the slow group (2.2 +/-0.5 vs. 1.5+/-0.2 ml O2 *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.01), whereas CBF did not differ (48+/-18 vs. 49+/-8 ml *symbol* 100 g sup -1 *symbol* min sup -1, respectively; P = 0.47). Throughout rewarming, CBF increased as a function of brain temperature but was indistinguishable between groups. Cerebral metabolic rate for oxygen differences between groups decreased as brain temperatures increased.     

The Relation between Cerebral Metabolic Rate and Ischemic Depolarization: A Comparison of the Effects of Hypothermia, Pentobarbital, and Isoflurane

Background: Reductions in cerebral metabolic rate may increase the brain's tolerance of ischemia. However, outcome studies suggest that reductions in cerebral metabolic rate produced by anesthetics and by hypothermia may not be equally efficacious. To examine this question, we measured the effects of hypothermia, pentobarbital, and isoflurane on the cerebral metabolic rate for glucose (CMRG) and on the time to the loss of normal membrane ion gradients (terminal ischemic depolarization) of the cortex during complete global ischemia.

Methods: As pericranial temperature was varied between 39 and 25 degrees Celsius in normocapnic halothane-anesthetized rats, CMRG (using14 Carbon-deoxyglucose) or the time to depolarization (using a glass microelectrode in the cortex) after a Potassium sup + -induced cardiac arrest was measured. In other studies, CMRG and depolarization times were measured in normothermic animals (37.7 plus/minus 0.2 degree Celsius) anesthetized with high-dose pentobarbital or isoflurane (both producing burst suppression on the electroencephalogram) or in halothane-anesthetized animals whose temperatures were reduced to 27.4 plus/minus 0.3 degree Celsius. These three states were designed to produce equivalent CMRG values.

Results: As temperature was reduced from 39 to 25 degrees Celsius, CMRG decreased from 66 to 21 micro Meter *symbol* 100 g sup -1 *symbol* min1 (Q10 = 2.30), and depolarization times increased from 76 to 326 s. In similarly anesthetized animals at approximately 27 degrees Celsius, CMRG was 32 plus/minus 4 micro Meter *symbol* 100 g sup -1 *symbol* min sup -1 (mean plus/minus SD), whereas in normothermic pentobarbital- and isoflurane-anesthetized rats, CMRG values were 33 plus/minus 3 and 37 plus/minus 4 micro Meter *symbol* 100 g1 *symbol* min sup -1, respectively (P = 0.072 by one-way analysis of variance). Despite these similar metabolic rates, the times to depolarization were markedly different: for hypothermia it was 253 plus/minus 29 s, for pentobarbital 109 plus/minus 24 s, and for isoflurane 130 plus/minus 28 s (P < 0.0001).     

Phenylephrine Increases Cerebral Blood Flow during Low-flow Hypothermic Cardiopulmonary Bypass in Baboons

Background: Although low-flow cardiopulmonary bypass (CPB) has become a preferred technique for the surgical repair of complex cardiac lesions in children, the relative hypotension and decrease in cerebral blood flow (CBF) associated with low flow may contribute to the occurrence of postoperative neurologic injury. Therefore, it was determined whether phenylephrine administered to increase arterial blood pressure during low-flow CPB increases CBF.

Methods: Cardiopulmonary bypass was initiated in seven baboons during fentanyl, midazolam, and isoflurane anesthesia. Animals were cooled at a pump flow rate of 2.5 l *symbol* min-1 *symbol* m-2 until esophageal temperature decreased to 20 degrees C. Cardiopulmonary bypass flow was then reduced to 0.5 l *symbol* min-1 *symbol* m-2 (low flow). During low-flow CPB, arterial partial pressure of carbon dioxide (PCO2) and blood pressure were varied in random sequence to three conditions: (1) PCO2 30-39 mmHg (uncorrected for temperature), control blood pressure; (2) PCO2 50-60 mmHg, control blood pressure; and (3) PCO2 30-39 mmHg, blood pressure raised to twice control by phenylephrine infusion. Thereafter, CPB flow was increased to 2.5 l *symbol* min-1 *symbol* m-2, and baboons were rewarmed to normal temperature. Cerebral blood flow was measured by washout of intraarterial133 Xenon before and during CPB.

Results: Phenylephrine administered to increase mean blood pressure from 23+/-3 to 46+/-3 mmHg during low-flow CPB increased CBF from 14+/-3 to 31+/-9 ml *symbol* min-1 *symbol* 100 g-1, P < 0.05. Changes in arterial PCO2 alone during low flow bypass produced no changes in CBF.     

Pulsatile versus nonpulsatile blood flow in the treatment of acute cerebral ischemia

The effects of pulsatile and nonpulsatile perfusion on local cerebral blood flow (CBF) and on computerized mapping (CME) of electroencephalograms (EEG) in nonischemic and ischemic brain were studied using a canine stroke model. Nine anesthetized mongrel dogs were placed on normothermic right atrial-femoral artery cardiopulmonary bypass at a flow of 100 ml/kg/minute. Local CBF measurements and CME data were collected during nonpulsatile perfusion and maximal pulsatile perfusion. The stroke model was then produced, and local CBF measurements and CME data were again collected during nonpulsatile and pulsatile perfusion. In the nonischemic brain, local CBF increased 19%, from 32 +/- 10 to 38 +/- 11 ml/100 g/minute (P less than 0.01), when perfusion was changed from nonpulsatile flow (pulse pressure less than 4mm Hg) to pulsatile flow (pulse pressure 39 +/- 11 mm Hg). In the ischemic brain, local CBF increased 55%, from 11 +/- 5 to 17 +/- 7 ml/100 g/minute (P less than 0.01), when perfusion was changed from nonpulsatile (pulse pressure less than 3 mm Hg) to pulsatile (pulse pressure 36 +/- 7) flow. EEG power data, expressed as a power ratio index (PRI = low frequency power/high frequency power), improved significantly, from 110 +/- 33 to 101 +/- 41 (P less than 0.01) with pulsatile perfusion. These data demonstrate the importance of pulsatile blood flow in ischemic brain.     

Hypothermic Modulation of Cerebral Ischemic Injury during Cardiopulmonary Bypass in Pigs

Background: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 [degree sign] Celsius) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia.

Methods: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 [degree sign] Celsius (n = 10), 34 [degree sign] Celsius (n = 10), 31 [degree sign] Celsius (n = 11), or 28 [degree sign] Celsius (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied.

Results: Cerebral oxygen metabolism increased after rewarming from 28 [degree sign] Celsius, 31 [degree sign] Celsius, and 34 [degree sign] Celsius CPB but not in the 37 [degree sign] animals; CMRO2, remained lower with 37 [degree sign] Celsius (1.8 +/- 0.2 ml [center dot] min sup -1 [center dot] 100 g sup -1) than with 28 [degree sign] Celsius (3.1 +/- 0.1 ml [center dot] min sup -1 [center dot] 100 g sup -1; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 [degree sign] Celsius animals. With 28 [degree sign] Celsius and 31 [degree sign] Celsius CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 [degree sign] Celsius and remained significantly greater during reperfusion in the 34 [degree sign] Celsius and 37 [degree sign] Celsius groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 [degree sign] Celsius animals. S-100 protein in cerebrospinal fluid was greater in the 37 [degree sign] Celsius (6 +/- 0.9 micro gram/l) and 34 [degree sign] Celsius (3.5 +/- 0.5 micro gram/l) groups than the 31 [degree sign] Celsius (1.9 +/- 0.1 micro gram/l) and 28 [degree sign] Celsius (1.7 +/- 0.2 micro gram/l) animals.     

Pediatric physiologic pulsatile pump enhances cerebral and renal blood flow during and after cardiopulmonary bypass

Controversy over benefits of pulsatile flow after pediatric cardiopulmonary bypass (CPB) continues. Our study objectives were to first, quantify pressure and flow waveforms in terms of hemodynamic energy, using the energy equivalent (EEP) formula, for direct comparisons, and second, investigate effects of pulsatile versus nonpulsatile flow on cerebral and renal blood flow, and cerebral vascular resistance during and after CPB with deep hypothermic circulatory arrest (DHCA) in a neonatal piglet model. Fourteen piglets underwent perfusion with either an hydraulically driven dual-chamber physiologic pulsatile pump (P, n = 7) or a conventional nonpulsatile roller pump (NP, n = 7). The radiolabeled microsphere technique was used to determine the cerebral and renal blood flow. P produced higher hemodynamic energy (from mean arterial pressure to EEP) compared to NP during normothermic CPB (13 +/- 3% versus 1 +/- 1%, p < 0.0001), hypothermic CPB (15 +/- 4% versus 1 +/- 1%, p < 0.0001) and after rewarming (16 +/- 5% versus 1 +/- 1%, p < 0.0001). Global cerebral blood flow was higher for P compared to NP during CPB (104 +/- 12 ml/100g/min versus 70 +/- 8 ml/100g/min, p < 0.05). In the right and left hemispheres, cerebellum, basal ganglia, and brainstem, blood flow resembled the global cerebral blood flow. Cerebral vascular resistance was lower (p < 0.007) and renal blood flow was improved fourfold (p < 0.05) for P versus NP, after CPB. Pulsatile flow generates higher hemodynamic energy, enhancing cerebral and renal blood flow during and after CPB with DHCA in this model.     

Propofol Linearly Reduces the Vasoconstriction and Shivering Thresholds

Background: Skin temperature is best kept constant when determining response thresholds because both skin and core temperatures contribute to thermoregulatory control. In practice, however, it is difficult to evaluate both warm and cold thresholds while maintaining constant cutaneous temperature. A recent study shows that vasoconstriction and shivering thresholds are a linear function of skin and core temperatures, with skin contributing 20 plus/minus 6% and 19 plus/minus 8%, respectively. (Skin temperature has long been known to contribute [nearly equal] 10% to the control of sweating.) Using these relations, we were able to experimentally manipulate both skin and core temperatures, subsequently compensate for the changes in skin temperature, and finally report the results in terms of calculated core- temperature thresholds at a single designated skin temperature.

Methods: Five volunteers were each studied on 4 days: (1) control; (2) a target blood propofol concentration of 2 micro gram/ml; (3) a target concentration of 4 micro gram/ml; and (4) a target concentration of 8 micro gram/ml. On each day, we increased skin and core temperatures sufficiently to provoke sweating. Skin and core temperatures were subsequently reduced to elicit peripheral vasoconstriction and shivering. We mathematically compensated for changes in skin temperature by using the established linear cutaneous contributions to the control of sweating (10%) and to vasoconstriction and shivering (20%). From these calculated core-temperature thresholds (at a designated skin temperature of 35.7 degrees Celsius), the propofol concentration- response curves for the sweating, vasoconstriction, and shivering thresholds were analyzed using linear regression. We validated this new method by comparing the concentration-dependent effects of propofol with those obtained previously with an established model.

Results: The concentration-response slopes for sweating and vasoconstriction were virtually identical to those reported previously. Propofol significantly decreased the core temperature triggering vasoconstriction (slope = 0.6 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.98 plus/minus 0.02) and shivering (slope = 0.7 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.95 plus/minus 0.05). In contrast, increasing the blood propofol concentration increased the sweating threshold only slightly (slope = 0.1 plus/minus 0.1 degree Celsius *symbol* micro gram sup -1 *symbol* ml sup -1; r2 = 0.46 plus/minus 0.39).     

Consequences of Electroencephalographic-suppressive Doses of Propofol in Conjunction with Deep Hypothermic Circulatory Arrest

Background: Some patients who undergo cerebral aneurysm surgery require cardiopulmonary bypass and deep hypothermic circulatory arrest. During bypass, these patients often are given large doses of a supplemental anesthetic agent in the hope that additional cerebral protection will be provided. Pharmacologic brain protection, however, has been associated with undesirable side effects. These side effects were evaluated in patients who received large doses of propofol.

Methods: Thirteen neurosurgical patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest to facilitate clip application to a giant or otherwise high-risk cerebral aneurysm. Electroencephalographic burst suppression was established before bypass with an infusion of propofol, and the infusion was continued until the end of surgery. Hemodynamic and echocardiographic measurements were made before and during the prebypass propofol infusion and again after bypass. Emergence time also was determined.

Results: Prebypass propofol at 243 plus/minus 57 micro gram *symbol* kg sup -1 *symbol* min sup -1 decreased vascular resistance from 34 plus/minus 8 to 27 plus/minus 8 units without changing heart rate, arterial or filling pressures, cardiac index, stroke volume, or ejection fraction. Propofol blood concentration was 8 plus/minus 2 micro gram/ml. Myocardial wall motion appeared hyperdynamic at the end of cardiopulmonary bypass, and all patients were weaned therefrom without inotropic support. After bypass, vascular resistance decreased further, and cardiovascular performance was improved compared to baseline values. Nine of the 13 patients emerged from anesthesia and were able to follow commands at 3.1 plus/minus 1.4 h. Three others had strokes and a fourth had cerebral swelling.     

Beneficial effect of balloon-induced pulsatility on brain oxygenation in hypothermic cardiopulmonary bypass

BACKGROUND: Sufficient O2 delivery to meet the demand is an important factor for protecting the brain during cardiopulmonary bypass (CPB). This study was designed to investigate the influences of temperature, pulsatility of blood flow (intra-aortic balloon pump-induced) and flow rate during CPB on the cerebral oxygenation. METHODS: Patients were divided into five groups. Normothermia (36 degrees C): pulsatile (n=8, 2.5 L/min/m2), nonpulsatile (n=12, 2.5 L), and nonpulsatile perfusion (n=12, 2.8 L); hypothermia (30 degrees C): pulsatile (n=9, 2.5 L) and nonpulsatile perfusion (n=11, 2.5 L). The oxygen saturation (SjVO2), lactate and CPK-BB levels in the jugular venous blood were measured. RESULTS: In all of the normothermic groups, the SjVO2 value decreased during the CPB (p<0.1-0.01). No remarkable change was observed in the hypothermic groups, with the exception during the rewarming period in the nonpulsatile group. A higher SjVO2 and a lower frequency of SjVO2 values <50% were observed in the hypothermic pulsatile group, as compared with those in the normothermic groups (p<0.05). The levels of CPK-BB were nearly the same, however the levels of lactate were higher in the normothermic pulsatile and nonpulsatile (2.5 L) groups (p<0.05). CONCLUSIONS: We concluded that the hypothermic CPB was advantageous over normothermic CPB in regard to the SjVO2 levels and lactate production. The beneficial effect of intra-aortic balloon pump assist was only obtained in the hypothermic CPB.     

Cerebral blood flow decreases with time whereas cerebral oxygen consumption remains stable during hypothermic cardiopulmonary bypass in humans

Recent investigations demonstrate that cerebral blood flow (CBF) progressively declines during hypothermic, nonpulsatile cardiopulmonary bypass (CPB). If CBF declines because of brain cooling, the cerebral metabolic rate for oxygen (CMRO2) should decline in parallel with the reduction in CBF. Therefore we studied the response of CBF, the cerebral arteriovenous oxygen content difference (A-VDcereO2) and CMRO2 as a function of the duration of CPB in humans. To do this, we compared the cerebrovascular response to changes in the PaCO2. Because sequential CBF measurements using xenon 133 (133Xe) clearance must be separated by 15-25 min, we hypothesized that a time-dependent decline in CBF would accentuate the CBF reduction caused by a decrease in PaCO2, but would blunt the CBF increase associated with a rise in PaCO2. We measured CBF in 25 patients and calculated the cerebral arteriovenous oxygen content difference using radial arterial and jugular venous bulb blood samples. Patients were randomly assigned to management within either a lower (32-48 mm Hg) or higher (50-71 mm Hg) range of PaCO2 uncorrected for temperature. Each patient underwent two randomly ordered sets of measurements, one at a lower PaCO2 and the other at a higher PaCO2 within the respective ranges. Cerebrovascular responsiveness to changes in PaCO2 was calculated as specific reactivity (SR), the change in CBF divided by the change in PaCO2, expressed in mL.100 g-1.min-1.mm Hg-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Vasoconstrictive Agents Added to Lidocaine on Intravenous Lidocaine-induced Convulsions in Rats

Background: Epinephrine is reported to decrease the threshold of intravenous lidocaine-induced convulsions. However, the mechanism underlying this effect is not clear. Therefore, we carried out a study to examine the role of vasopressor-induced hypertension.

Methods: Fifty-six awake Wistar rats were assigned to seven groups of eight. All groups received a continuous intravenous infusion of lidocaine at a rate of 4 mg *symbol* kg sup -1 *symbol* min sup -1 until generalized convulsions occurred. The control group (group C) received plain lidocaine. The acute hypertensive groups received lidocaine with epinephrine (group E), norepinephrine (group N), or phenylephrine (group P) to increase mean arterial blood pressure (MAP) to 150 plus/minus 5 mm Hg. Sodium nitroprusside (SNP) was added to prevent an increase in mean arterial pressure in the remaining three groups (vasopressor-SNP groups).

Results: The acute hypertensive groups required significantly smaller cumulative doses of lidocaine to produce convulsions compared with control (C - 41.5 plus/minus 2.9 > E - 24.1 plus/minus 2.7, N = 27.1 plus/minus 2.8, P = 26.7 plus/minus 2.5 mg *symbol* kg sup -1; values are mean plus/minus SD, P < 0.01) In addition, plasma lidocaine concentrations (C = 11.0 plus/minus 0.7 > E = 7.4 plus/minus 0.5, N = 7.9 plus/minus 0.6, P = 8.1 plus/minus 0.8 micro gram *symbol* ml sup -1, P < 0.01) and brain lidocaine concentrations (C = 50.9 plus/minus 4.5 > E = 32.6 plus/minus 4.2, N - 34.5 plus/minus 4.8, P - 37.1 plus/minus 4.5 micro gram *symbol* g sup -1, P < 0.01) were less in the acute hypertensive groups at the onset of convulsions. In the vasopressor-SNP groups, the plasma and brain lidocaine concentrations at the onset of convulsions returned to the control values, although epinephrine and norepinephrine, but not phenylephrine, still decreased cumulative convulsant doses of lidocaine significantly (P < 0.01) compared with control (E + SNP = 30.8 plus/minus 2.9 < N + SNP = 34.8 plus/minus 2.8, P < 0.01) < P + SNP = 40.2 plus/minus 3.0 mg *symbol* kg sup -1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups.     

The Effects of Pulsatile Versus Nonpulsatile Perfusion on Blood Viscoelasticity Before and After Deep Hypothermic Circulatory Arrest in a Neonatal Piglet Model

Blood trauma increases blood viscoelasticity by increasing red cell aggregation and plasma viscosity and by decreasing cell deformability. During extracorporeal circulation, the mode of perfusion (pulsatile or nonpulsatile) may have a significant impact on blood trauma. In this study, a hydraulically driven dual chamber pulsatile pump system was compared to a standard nonpulsatile roller pump in terms of changes in the blood viscosity and elasticity during cardiopulmonary bypass (CPB) and pre and post deep hypothermic circulatory arrest (DHCA). Piglets, with an average weight of 3 kg, were used in the pulsatile (n = 5) or nonpulsatile group (n = 5). All animals were subjected to 25 min of hypothermia, 60 min of DHCA, 10 min of cold reperfusion, and 40 min of rewarming with a pump flow of 150 ml/kg/min. A pump rate of 150 bpm, pump ejection time of 120 ms, and stroke volume of 1 ml/kg were used during pulsatile CPB. Arterial blood samples were taken pre-CPB (36 degrees C), during normothermic CPB (35 degrees C), during hypothermic CPB (25 degrees C), pre-DHCA (18 degrees C), post-DHCA (19 degrees C), post-rewarming (35 degrees C), and post-CPB (36 degrees C). Viscosity and elasticity were measured at 2 Hz and 22 degrees C and at strains of 0.2, 1, and 5 using the Vilastic-3 Viscoelasticity Analyzer. Results suggest that the dual chamber neonate-infant pulsatile pump system produces less blood trauma than the standard nonpulsatile roller pump as indicated by lower values of both viscosity and elasticity during CPB support.     

Oral Clonidine Premedication Blunts the Heart Rate Response to Intravenous Atropine in Awake Children

Background: Clonidine, which is known to have analgesic and sedative properties, has recently been shown to be an effective preanesthetic medication in children. The drug may cause side effects, including bradycardia and hypotension. This study was conducted to evaluate the ability of intravenous atropine to increase the heart rate (HR) in awake children receiving clonidine preanesthetic medication.

Methods: We studied 96 otherwise healthy children, 8-13 yr old, undergoing minor surgery. They received, at random, oral clonidine 2 or 4 micro gram *symbol* kg sup -1 or placebo 105 min before scheduled induction of anesthesia. Part I (n = 48, 16 per group): When hemodynamic parameters after insertion of a venous catheter had been confirmed to be stable, atropine was administered in incremental doses of 2.5, 2.5, and 5 micro gram *symbol* kg sup -1 every 2 min. The HR and blond pressure were recorded at 1-min intervals. Part II (n = 48, 16 per group): After the recording of baseline hemodynamic values, successive doses of atropine (5 micro gram *symbol* kg sup -1 every 2 min, to 40 micro gram *symbol* kg sup -1), were administered until HR increased by 20 beats *symbol* min sup -1. The HR and blood pressure were recorded at 1-min intervals.

Results: Part I: The increases in HR in response to a cumulative dose of atropine 10 micro gram *symbol* kg sup -1 were 33 plus/minus 3%, 16 plus/minus 3%, and 8 plus/minus 2% (mean plus/minus SEM) in children receiving placebo, clonidine 2 micro gram *symbol* kg sup -1, and clonidine 4 micro gram *symbol* kg sup -1, respectively (P < 0.05). Part II: The HR in the control group increased by more than 20 beats *symbol* min sup -1 in response to atropine 20 micro gram *symbol* kg sup -1 or less. In two patients in the clonidine 4 micro gram *symbol* kg sup -1 group, HR did not increase by 20 beats *symbol* min sup -1 even after 40 micro gram *symbol* kg sup -1 of atropine.     

Myocardial Effects of Propofol in Hamsters with Hypertrophic Cardiomyopathy

Background: Propofol is a short-acting intravenous induction agent that induces cardiovascular depression but without significant effect no intrinsic myocardial contractility in various species. However, its effects on diseased myocardium remain unknown.

Methods: The effects of propofol (1, 3, and 10 micro gram *symbol* ml sup -1) on the intrinsic contractility of left ventricular papillary muscles from normal hamsters and those with hypertrophic cardiomyopathy (strain BIO 14.6, aged 6 months) were investigated in vitro (Krebs-Henseleit solution, 29 degrees Celsius, pH 7.40, Calcium sup +1 2.5 mmol *symbol* l [1], stimulation frequency 3/min).

Results: Cardiac hypertrophy (143 plus/minus 13%, P < 0.001) was observed in cardiomyopathic hamsters. The contractility of papillary muscles from hamsters with cardiomyopathy was less than that of controls, as shown by the decrease in maximum shortening velocity (29%, P < 0.03) and active isometric force (-51%, P < 0.03) and active isometric force (-51%, P < 0.001). Propofol did not induce any significant effect on contraction, relaxation, and contraction-relaxation coupling under low and high loads in normal hamsters. The effects of propofol were not significantly different between normal hamsters and those with cardiomyopathy. A slight but significant increase in maximum unloaded shortening velocity was observed in cardiomyopathic hamsters at 3 micro gram *symbol* ml sup -1 (4 plus/minus 6%, P < 0.05) and 10 micro gram *symbol* ml sup -1 (7 plus/minus 6%, P < 0.05).     

Effect of Halothane Anesthesia on Glucose Utilization and Production in Adolescents

Background: It should be possible to avoid variations in plasma glucose concentration during anesthesia by adjusting glucose infusion rate to whole-body glucose uptake. To study this hypothesis, we measured glucose utilization and production, before and during halothane anesthesia.

Methods: After an overnight fast, six adolescents between 12 and 17 yr of age were infused with tracer doses of [6,6-sup 2 H2]glucose for 2 h before undergoing anesthesia, and the infusion was continued after induction, until the beginning of surgery. Plasma glucose concentration was monitored throughout, and free fatty acids, lactate, insulin, and glucagon concentrations were measured before and during anesthesia.

Results: Despite the use of a glucose-free maintenance solution, plasma glucose concentration increased slightly but significantly 5 min after induction (5.3 plus/minus 0.4 vs. 4.5 plus/minus 0.4 mmol *symbol* 1 sup -1 , P < 0.05). This early increase corresponded to a significant increase in endogenous glucose production over basal conditions (4.1 plus/minus 0.4 vs. 3.6 plus/minus 0.2 mg *symbol* kg sup -1 *symbol* min sup -1, P < 0.05), with no concomitant change in peripheral glucose utilization. Fifteen minutes after induction, both glucose utilization and production rates decreased steadily and were 20% less than basal values by 35 min after induction (2.9 plus/minus 0.3 vs. 3.6 plus/minus 0.2 mg *symbol* kg sup -1 *symbol* min sup -1, P < 0.05). Similarly, glucose metabolic clearance rate decreased by 25% after 35 min. Despite the increase in blood glucose concentration, anesthesia resulted in a significant decrease in plasma insulin concentration.     

The Type of Aortic Cannula and Membrane Oxygenator Affect the Pulsatile Waveform Morphology Produced by a Neonate-Infant Cardiopulmonary Bypass System In Vivo

Although the debate still continues over the effectiveness of pulsatile versus nonpulsatile perfusion, it has been clearly proven that there are several significant physiological benefits of pulsatile perfusion during cardiopulmonary bypass (CPB) compared to nonpulsatile perfusion. However, the components of the extracorporeal circuit have not been fully investigated regarding the quality of the pulsatility. In addition, most of these results have been gathered from adult patients, not from neonates and infants. We have designed and tested a neonate-infant pulsatile CPB system using 2 different types of 10 Fr aortic cannulas and membrane oxygenators in 3 kg piglets to evaluate the effects of these components on the pulsatile waveform produced by the system. In terms of the methods, Group 1 (Capiox 308 hollow-fiber membrane oxygenator and DLP aortic cannula with a very short 10 Fr tip [n =2]) was subjected to a 2 h period of normothermic pulsatile CPB with a pump flow rate of 150 ml/kg/min. Data were obtained at 5, 30, 60, 90, and 120 min of CPB. In Group 2 (Capiox 308 hollow-fiber membrane oxygenator and Elecath aortic cannula with a very long 10 Fr tip [n =7]) and Group 3 (Cobe VPCML Plus flat sheet membrane oxygenator and DLP aortic cannula with a very short 10 Fr tip [n =7]), the subjects' nasopharyngeal temperatures were reduced to 18°C followed by 1 h of deep hypothermic circulatory arrest (DHCA) and then 40 min rewarming. Data were obtained during normothermic CPB in the pre- and post-DHCA periods. The criteria of pulsatility evaluations were based upon pulse pressure (between 30 and 40 mm Hg), aortic dp/dt (greater than 1000 mm Hg/s), and ejection time (less than 250 ms). The results showed that Group 1 produced flow which was significantly more pulsatile than that of the other 2 groups. Although the same oxygenator was used for Group 2, the quality of the pulsatile flow decreased when using a different aortic cannula. Group 3 did not meet any of the criteria for physiologic pulsatility. In conclusion these data suggest that in addition to a pulsatile pump, the aortic cannula and the membrane oxygenator must be chosen carefully to achieve physiologic pulsatile flow during CPB.     

Glycine Receptor Antagonism: Effects of ACEA-1021 on the Minimum Alveolar Concentration for Halothane in the Rat

Background: Glycine and glutamate binding sites are allosterically coupled at the N-methyl-n-aspartate (NMDA) receptor complex. Previous studies have shown that antagonism of glutamate at the NMDA receptor reduces the minimum alveolar concentration (MAC) for volatile anesthetics. 5-Nitro-6, 7-dichloro-2, 3-quinoxalinedione (ACEA-1021) is a competitive antagonist at the glycine recognition site of the NMDA receptor. The purpose of this study was to determine whether glycine receptor antagonism also reduces volatile anesthetic requirements in the rat.

Methods: In experiment 1, Sprague-Dawley rats were anesthetized with halothane in 50% Oxygen2 -balance Nitrogen2 and their lungs mechanically ventilated. They were randomly assigned to one of three groups according to the dose of ACEA-1021 administered (0, 20, or 40 mg/kg intravenously; n = 6). The bolus dose of ACEA-1021 was followed by a continuous intravenous infusion of vehicle or ACEA-1021 at 14 mg *symbol* kg sup -1 *symbol* h sup -1. Halothane MAC was then determined by the tail-clamp method. In experiment 2, awake rats were randomly assigned to groups according to the same dosages of ACEA-1021 as in experiment 1. Arterial CO2 tension and mean arterial pressure were recorded before and 5 and 30 min after the start of the infusion. The infusion was then stopped, and the time to recovery of the righting reflex was recorded.

Results: In experiment 1, ACEA-1021 decreased halothane MAC (mean + SD) in a dose-dependent manner (control, 0.95 plus/minus 0.15 vol%; ACEA-1021 20 mg/kg, 0.50 plus/minus 0.14 vol%; ACEA-1021 40 mg/kg, 0.14 plus/minus 0.16 vol%; P < 0.01). In experiment 2, arterial CO2 tension was increased by ACEA-1021 (control, 38 plus/minus 3 mmHg; ACEA-1021 20 mg/kg, 43 plus/minus 3 mmHg; ACEA-1021 40 mg/kg, 48 plus/minus 2 mmHg; P < 0.01). Mean arterial pressure was not affected by any dose of ACEA-1021. The righting reflex was abolished in rats receiving ACEA-1021 40 mg/kg only and recovered 30 plus/minus 7 min after discontinuation of the infusion.     

Human Chest Wall Function while Awake and during Halothane Anesthesia: II. Carbon Dioxide Rebreathing

Background: Changes in the distribution of respiratory drive to different respiratory muscles may contribute to respiratory depression produced by halothane. The aim of this study was to examine factors that are responsible for halothane-induced depression of the ventilatory response to carbon dioxide rebreathing.

Methods: In six human subjects, respiratory muscle activity in the parasternal intercostal, abdominal, and diaphragm muscles was measured using fine-wire electromyography electrodes. Chest wall motion was determined by respiratory impedance plethysmography. Electromyography activities and chest wall motion were measured during hyperpnea produced by carbon dioxide rebreathing while the subjects were awake and during 1 MAC halothane anesthesia.

Results: Halothane anesthesia significantly reduced the slope of the response of expiratory minute ventilation to carbon dioxide (from 2.88 plus/minus 0.73 (mean plus/minus SE) to 2.01 plus/minus 0.45 l *symbol* min sup -1 *symbol* mmHg sup -1). During the rebreathing period, breathing frequency significantly increased while awake (from 10.3 plus/minus 1.4 to 19.7 plus/minus 2.6 min sup -1, P < 0.05) and significantly decreased while anesthetized (from 28.8 plus/minus 3.9 to 21.7 plus/minus 1.9 min sup -1, P < 0.05). Increases in respiratory drive to the phrenic motoneurons produced by rebreathing, as estimated by the diaphragm electromyogram, were enhanced by anesthesia. Anesthesia attenuated the response of parasternal electromyography and accentuated the response of the transversus abdominis electromyography to rebreathing. The compartmental response of the ribcage to rebreathing was significantly decreased by anesthesia (from 1.83 plus/minus 0.58 to 0.48 plus/minus 0.13 l *symbol* min sup -1 *symbol* mmHg sup -1), and marked phase shifts between ribcage and abdominal motion developed in some subjects. However, at comparable tidal volumes, the ribcage contribution to ventilation was similar while awake and anesthetized in four of the six subjects.     

New Technology Mimics Physiologic Pulsatile Flow During Cardiopulmonary Bypass

The Ventri Flo True Pulse Pump (Design Mentor, Inc., Pelham, NH, USA) is the first blood pump designed to mimic human arterial waveforms in a standard oxygenation circuit. Our aim was to demonstrate the feasibility and safety of this pump in preparation for future studies to determine possible clinical advantages. We studied four piglets (41.4–46.2 kg): three with an implanted Ventri Flo pulsatile pump and one with the nonpulsatile ROTAFLOW pump (MAQUET Holding B.V. & Co. KG, Rastatt, Germany) as a control. Hemodynamics was monitored during 6‐h cardiopulmonary bypass (CPB) support and for 2 h after weaning off CPB. The Ventri Flo demonstrated physiologic arterial waveforms with arterial pulse pressure of 24.6 ± 5.7 mm Hg. Pump flows (2.0 ± 0.1 L/min in ROTAFLOW; 1.9 ± 0.1 L/min in Ventri Flo ) and plasma free hemoglobin levels (27.9 ± 12.5 mg/dL in ROTAFLOW; 28.5 ± 14.2 mg/dL in Ventri Flo ) were also comparable, but systemic O₂ extraction (as measured by arterial minus venous O₂ saturation) registered slightly higher with the Ventri Flo (63.2 ± 6.9%) than the ROTAFLOW (55.4 ± 6.5%). Histological findings showed no evidence of ischemic changes or thromboembolism. This pilot study demonstrated that the Ventri Flo system generated pulsatile flow and maintained adequate perfusion of all organs during prolonged CPB.