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Ann Thorac Surg 1996;61:1699-1707
© 1996 The Society of Thoracic Surgeons
Department of Surgery, Duke University Medical Center, Durham, North Carolina
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Abstract |
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Methods. A group of 1-week-old piglets underwent normothermic cardiopulmonary bypass (group A); three other groups (B, C, and D; n = 6 per group) underwent 60 minutes of DHCA at 18°C and 60 minutes of rewarming. The animals were then treated as follows: Groups A and B received L-
-nitro-arginine-methyl-ester (L-NAME, 50 mg•kg-1); group C, saline solution; and group D, L-arginine (600 mg•kg-1).
Results. In group A, global cerebral blood flow decreased to 37.3% ± 4.2% of baseline after L-NAME administration (p < 0.005). In group B, global cerebral blood flow decreased to 44.6% ± 4.4% of baseline after DHCA and 28.9% ± 3.4% after L-NAME administration (p < 0.001). Following L-arginine treatment after DHCA (group D), global cerebral blood flow increased from 43.8% ± 3.0% of baseline to 61.6% ± 9.1% (p < 0.05); cerebral oxygen metabolism increased from 1.93 ± 0.16 mL•min-1•100 g-1 after DHCA to 2.42 ± 0.25 mL•min-1•100 g-1 (p < 0.05).
Conclusions. Tonal production of nitric oxide is impaired in the brain after DHCA and is partly responsible for the circulatory and metabolic changes observed. Stimulation of nitric oxide production (L-arginine) significantly improved recovery of cerebral blood flow and cerebral oxygen metabolism after DHCA.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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The technique of deep hypothermic circulatory arrest (DHCA) is widely practiced for correction of congenital cardiac defects in neonates and small infants. It provides unparalleled surgical exposure and thereby facilitates complex surgical repairs of the heart and of the great vessels. However, in patients exposed to periods of DHCA, extensive clinical evidence has established that there is a higher incidence of postoperative neurologic disturbance and delayed motor development [1, 2]. Use of DHCA is also associated with cerebral hypoperfusion and impairment of cerebral metabolism during the recovery period [3, 4]. The degree of impairment has been found to be directly proportional to the duration of DHCA [5]. Currently, effective cerebral protection strategies are not available. This is mainly due to a limited understanding of the injury mechanisms. We investigated the hypothesis that impaired tonal production of nitric oxide (NO) in the cerebral circulation is responsible for cerebral hypoperfusion after a period of DHCA.
Furchgott and Zawadzki [6] first described the need for an intact vascular endothelium in the relaxation of rabbit aorta induced by acetylcholine and raised the possibility that this action may be mediated by an endothelium-derived relaxing factor. It was subsequently shown that endothelium-derived relaxing factor is either NO or a labile nitroso- compound such as S-nitrosocysteine. These are produced from L-arginine by the enzyme NO synthase [7].
Nitric oxide has been shown to modulate the vasomotor tone of many vascular beds in the body. There is mounting evidence that NO also participates in maintenance of basal vascular tone in the brain, keeping resistance vessels in a somewhat relaxed state [8]. Impaired NO production has been shown to contribute to impaired vasodilation in many disease states including essential hypertension and diabetes. Furthermore, inhibition of the synthesis of NO has been shown to result in reduction in resting cerebral blood flow in many animal species including newborn piglets [9].
To investigate possible impairment of NO production in the brain after DHCA, we conducted experiments in a neonatal piglet model. In the first study, tonal production of NO in the cerebral circulation was assessed during normothermic cardiopulmonary bypass (CPB), when cerebral blood flow is largely normal, and after recovery from DHCA, when cerebral blood flow is known to be reduced. Nitric oxide is a molecule that is highly reactive and short-lived. Levels are therefore difficult to measure in vivo. As a result, many studies on the basal effects of NO have involved inhibition of its synthesis. N--nitro-L-arginine methyl ester (L-NAME) is an analogue of L-arginine that inhibits NO synthase competitively. The systemic and cerebral vascular effects of this agent were studied.
A further study was conducted to assess the effects of L-arginine on the recovery of cerebral blood flow and cerebral oxygen metabolism (CMRO2) after DHCA. Although intravascular administration of L-arginine has no significant effect on cerebral blood flow in the normal brain [10], it has been shown to increase blood flow in areas of focal cerebral ischemia caused by unilateral common carotid and middle cerebral artery occlusions, thereby reducing infarct size [11]. Furthermore, L-arginine can completely reverse blood flow changes caused by competitive NO synthase inhibitors such as L-NAME [12]. These processes are thought to result from an increase in substrate availability for the L-arginine-NO pathway.
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Material and Methods |
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Anesthesia was induced with an intramuscular injection of ketamine (50 mg•kg-1) and acepromazine (15 µg • kg-1). Intravenous methylprednisolone (30 mg • kg-1) was administered via a 24-gauge cannula in the marginal vein of the pinna. Orotracheal intubation was performed and mechanical ventilation (Infant Ventilator; Sechrist Industries, Anaheim, CA) was commenced to achieve an arterial oxygen tension of 150 to 250 mm Hg and an arterial carbon dioxide tension of 35 to 45 mm Hg. The animals were paralyzed with intravenous pancuronium (300 µg•kg-1) and anesthetized with fentanyl (100 µg•kg-1). Thereafter, anesthesia was maintained with a continuous infusion of fentanyl (25 µg•kg-1•h-1). An 18-gauge cannula was placed in the descending aorta via the left femoral artery for blood pressure monitoring and arterial blood sampling. The animal's temperature was monitored throughout the study by an indwelling nasopharyngeal temperature probe (Yellow Springs Instrument Inc, Yellow Springs, OH). Temperature was maintained at 36°C except for the period of induced hypothermia.
The heart was exposed through a median sternotomy. Cardiac instrumentation consisted of a 3F micromanometer (Millar Instruments Inc, Houston, TX) inserted into the superior vena cava for central venous pressure monitoring and placement of an 8-mm flow probe (Transonic Systems, Ithaca, NY) around the proximal pulmonary artery for cardiac output monitoring.
Sagittal Sinus Access
The animals were anticoagulated with intravenous heparin (500 IU/kg) before access of the sagittal sinus. A 1-cm strip of scalp was raised in the midline over the vertex of the skull. Two separate 2-mm burr holes were made over the superior sagittal sinus for repeated sagittal sinus venous blood sampling and continuous sagittal sinus venous pressure monitoring with a 3F micromanometer (Millar Instruments Inc).
Cardiopulmonary Bypass and Circulatory Arrest
An 8F arterial cannula and a 20F venous cannula (Electro-Catheter Corp, Rahway, NJ) were inserted through pursestring sutures into the ascending aorta and the right atrium, respectively. Cardiopulmonary bypass was commenced at a flow rate of 150 mL•kg-1•min-1. The pump-oxygenator system consisted of a Stöckert-Shiley (Irvine, CA) nonpulsatile roller pump and a Cobe VP-CML membrane oxygenator (Denver, CO). No arterial filter was used. The circuit was primed with heparinized fresh blood from a donor pig. Ringer's lactate and sodium bicarbonate solutions were added to the prime to achieve a hematocrit of 0.25 and a pH of 7.4 at 37°C. The total prime volume was approximately 650 mL. The temperature of the perfusate was controlled with the integral heat exchanger in the venous reservoir of the oxygenator and a Bio-Medicus water bath system (Minneapolis, MN). Animals undergoing DHCA were cooled to a nasopharyngeal temperature of 18°C over a standard duration of 20 minutes by the circulation of ice water through the heat exchanger. At the end of the cooling period, the perfusate was drained from the animal via both cannulas into the venous reservoir over 1 minute. When DHCA was established, the aortic and right atrial cannulas were clamped. After 60 minutes of DHCA, the aortic and venous cannulas were unclamped. Perfusion was reestablished at 150 mL•kg-1•min-1 with the perfusate initially at room temperature (20°C to 22°C). Rewarming was accomplished by circulating warm water to the heat exchanger in the venous reservoir. A nasopharyngeal temperature of 36°C was generally reached by 45 minutes of reperfusion. During cooling and rewarming, blood gases were managed according to the ``alpha-stat'' strategy. The arterial pH was maintained at 7.35 to 7.45 and carbon dioxide tension at 35 to 45 mm Hg measured at 37°C and uncorrected for the temperature of the animal. Arterial oxygen tension was kept between 150 and 250 mm Hg and hematocrit between 0.23 and 0.28. Sodium bicarbonate (8.4%) was given when necessary but not immediately before cerebral blood flow measurements. At the end of the study, the animals were killed by a bolus injection of fentanyl and cessation of CPB.
Cerebral Blood Flow Measurement
All cerebral blood flow measurements were determined by the reference-sample, radiolabeled microspheres technique [13] during CPB at 36°C. Suspensions of microspheres with a diameter of 15.5 ± 0.1 µm (Du Pont de Nemours & Co, Wilmington, DE) were made up in 10% Dextran and 0.01% TWEEN 80 with 106 microspheres per milliliter. Up to five different isotopes (gadolinium 153, tin 113, niobium 95, ruthenium 103, and scandium 46) were used in each piglet, and these were injected in a random sequence. For each flow measurement, 106 microspheres were injected into a side port of the arterial tubing 30 cm proximal to the aortic cannula over 30 seconds and washed through with 5 mL of warm saline solution. A reference blood sample was withdrawn from the distal aorta at a constant rate of 3 mL•min-1 with a Harvard syringe pump (South Natick, MA), commencing 10 seconds before the microsphere injection and continued for a total of 2 minutes. At the end of the experiment, the brain was removed and divided into left and right cerebral hemispheres, basal ganglia, cerebellum and brain stem (midbrain, pons, and medulla oblongata). After measurement of fresh weights, the brain parts were dissolved in 2 molar potassium hydroxide solution and analyzed in a gamma counter (Auto-Gamma 5530; Packard Instrument Co, Meriden, CT) to estimate the quantity of each type of radiolabeled microsphere present in the specimen together with the reference blood samples. The withdrawal rate of the reference blood sample and the ratio of counts from a brain part to the reference blood sample allowed calculation of regional cerebral blood flow. These are expressed in milliliters per minute per 100 grams of brain by normalizing for fresh tissue weight. The weighted sum of regional cerebral blood flow allowed calculation of global cerebral blood flow.
Cerebral perfusion pressure (CPP) was taken as the difference between the mean arterial pressure and the sagittal sinus venous pressure. Cerebral vascular resistance was the ratio of cerebral perfusion pressure to global cerebral blood flow (in units of millimeters of mercury•minute•100 grams per milliliter). Systemic vascular resistance was taken as the ratio between the systemic perfusion pressure and the total bypass pump flow rate (systemic vascular resistance = [mean arterial pressure - right atrial pressure]/[pump flow rate] in units of millimeters of mercury•minute•kilogram per milliliter).
Cerebral Oxygen Handling
Arterial and sagittal sinus blood samples were taken just before each microsphere injection for estimation of oxygen tension, carbon dioxide tension, oxygen saturation, pH, and base excess using a GEM-Stat Blood Gas/Electrolyte Monitor (Mallinckrodt Sensor Systems Inc, Ann Arbor, MI). Hemoglobin levels (in grams per deciliter) were measured from arterial blood samples (482 Co-Oximeter; Instrumentation Laboratory Corp, Lexington, MA). Cerebral delivery of oxygen (CDO2 in milliliters per minute per 100 grams), cerebral metabolic rate of oxygen (CMRO2 in milliliters per minute per 100 grams), and cerebral oxygen extraction ratio (CEO2 as a percent) were calculated as follows: CDO2 = cerebral blood flow•arterial oxygen content, CMRO2 = cerebral blood flow•(arterial oxygen content - sagittal sinus venous oxygen content), and CEO2 = (CMRO2/CDO2)•100%. The oxygen content (milliliters of O2 per milliliter of blood) was calculated by the following formula: O2 content = 0.01 x [(1.36)(hemoglobin)(oxygen saturation) + (0.003)(oxygen tension)].
Experimental Protocol and Data Collection
The animals were stabilized on normothermic CPB for a minimum of 20 minutes before the baseline cerebral blood flow measurement was taken. Animals undergoing DHCA had a post-DHCA measurement taken at 60 minutes after the start of reperfusion when the animals were fully rewarmed and stable. Two experimental studies were undertaken:
L-NAME STUDY.
The effects of L-NAME (50 mg•kg-1) during CPB and after DHCA were studied in 12 piglets. Group A (n = 6) underwent normothermic CPB without DHCA. After the initial baseline cerebral blood flow measurement, a bolus of L-name was administered into the arterial tubing proximal to the aortic cannula over 1 minute. group b (n = 6) underwent normothermic cpb, 60 minutes of dhca, and reperfusion. the bolus of L-name was given after the post-dhca cerebral blood flow measurement. in addition to baseline measurements, microsphere injections were made at 15-minute intervals up to 1 hour after the bolus of L-name in group a and at 30, 45, and 60 minutes after the administration of L-name in group b. the pump flow was continuously adjusted to provide a constant cpp of 60 mm hg for 15 minutes before baseline cerebral blood flow measurements and after the administration of L-name.
L-ARGININE STUDY.
The effects of L-arginine on the brain after DHCA were studied. Twelve piglets underwent CPB, 60 minutes of DHCA, and reperfusion. After the post-DHCA cerebral blood flow measurement, the animals were randomized into two groups. Group C (n = 6) received an infusion of saline solution into the arterial tubing at 1 mL•min-1. Group D (n = 6) received an infusion of L-arginine solution at 1 mL•min-1. The L-arginine solution was made up to provide a dose of 30 mg•kg-1•min-1. The infusions were continued for 20 minutes, and further cerebral blood flow measurements were taken at the end of this period in each group. The pump flow was continuously adjusted to provide a constant CPP of 50 mm Hg for 15 minutes before baseline cerebral blood flow measurements and also throughout the respective infusions.
Statistical Analysis
All results are reported as mean ± standard error of the mean and were analyzed by a statistical analysis system (Statview 4.1; Abacus Concepts, Inc, Berkley, CA). For the L-NAME study, an unpaired t test was used to compare variable means between groups. A paired t test was used to compare variable means within each group before administration of L-NAME and 45 minutes after L-NAME administration. In the L-arginine study, an unpaired t test was used to compare variable means between groups. Repeated-measures analysis of variance was used to compare hemodynamic and blood gas variables between the three measurement timepoints within each group. When the analysis of variance was significant, multiple paired comparisons were made with the Scheffé F procedure. A paired t test was used to compare data before and after infusion within each group. Statistical significance was tested at the 95% confidence level.
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Results |
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EFFECTS OF CIRCULATORY ARREST ON THE BRAIN.
In group B, a period of DHCA resulted in significant reductions in global cerebral blood flow from 57.6 ± 5.0 to 24.7 ± 0.6 mL•min-1•100 g-1 (p = 0.0014). The reduction in blood flow to the cerebral hemispheres was more severe than that to other brain regions. However, the post-DHCA blood flow in all brain regions were significantly less than the pre-DHCA baselines (p < 0.025) (Fig 1
). Deep hypothermic circulatory arrest also resulted in significant changes in cerebral oxygen handling with reduced CDO2 and CMRO2 and an elevated CEO2 (Fig 2).
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). this necessitated gradual reductions in bypass pump flow rate to maintain a constant cpp for subsequent cerebral blood flow measurements according to the protocol. in both groups of animals with or without dhca, maximal systemic and cerebral vascular effects were recorded at 45 minutes after L-name was given representing maximal inhibition of no synthase activity. therefore, data from this time point were used for all analyses as they represented the state of maximal inhibition of no synthase. at this point, blood flow to all brain regions was significantly reduced in both groups (p < 0.005) and systemic vascular resistance was significantly greater than those obtained before L-name was given (p < 0.005). The effects of L-name on regional cerebral blood flow and cerebral oxygen handling during normothermic cpb and after dhca are shown in figures 2 and 3
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EFFECTS OF CIRCULATORY ARREST ON THE BRAIN.
In the L-arginine study, global cerebral blood flow was significantly reduced after 60 minutes of circulatory arrest in both groups of piglets (paired t test p < 0.0001) (Figure 4). There were no differences in cerebral blood flow and cerebral oxygen handling between the two groups before and after circulatory arrest prior to the administration of the respective infusions (data not shown). The effects of DHCA on cerebral oxygen handling in group D are shown in Figure 5.
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). the increases were statistically significant in the basal ganglia, cerebellum, and brain stem (paired t test p < 0.05). The increases in blood flow to the cerebral hemisphere did not reach statistical significance (paired t test p = 0.075). Postarginine global cerebral blood flow was significantly greater than that before the start of the infusion (paired t test p = 0.048), and cerebral vascular resistance was significantly reduced (p = 0.014) (Table 2). In fact, postarginine blood flow to the cerebellum and brain stem recovered to levels that were not significantly less than the baseline values before DHCA (paired t test p > 0.15). The effects of L-arginine infusion on cerebral oxygen handling are shown in figure 5. both cdo2 and cmro2 were significantly increased (paired t test p < 0.05). In the control group C, infusion of saline solution after DHCA had no effect on cerebral blood flow or cerebral oxygen handling (see Table 2).
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Comment |
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After DHCA, when global and regional cerebral blood flow were already below the pre-DHCA baseline, L-NAME caused further reductions in blood flow to all brain regions. These further reductions were small compared with those in the non-DHCA animals. This suggests that even though tonal NO production was still present in all brain regions after DHCA, the amount produced was probably reduced. At 45 minutes after L-NAME administration, when maximal effects were observed in both groups of piglets, blood flow to the basal ganglion, cerebellum, and brain stem were similar between groups A and B. This implies that impaired NO production alone could have accounted for the reduced blood flow in these regions after DHCA. On the other hand, blood flow to the cerebral hemispheres was still significantly less in the post-DHCA animals than the non-DHCA animals. It is therefore likely that some mechanism in addition to impaired NO production is operating to limit cerebral blood flow to the cerebral hemispheres during the recovery period after DHCA. The fact that L-NAME further reduced CDO2 and CMRO2 in piglets after DHCA suggests that the brain remained dependent on the production of NO to maintain cerebral perfusion and oxygen metabolism, albeit at a reduced level.
A number of different NO synthase inhibitors have been used experimentally. A recent review article on this subject concluded that L-NAME is one of the most specific inhibitors of NO synthase and favored its use for the study of the cerebral circulation [8]. From preliminary experiments, it was evident that administration of L-NAME resulted in severe generalized systemic vasoconstriction. If the bypass pump flow rate was kept constant, it would have resulted in severe hypertension. In turn, it would have caused marked increases in CPP. Unpublished work from our laboratory using this model has shown that blood flow to different regions of the brain was affected to different degrees by changes in CPP. Furthermore, the cerebral vascular responses to changes in CPP during CPB without DHCA were different from those after DHCA. To assess the effects of L-NAME on the systemic circulation and on the cerebral circulation independent of changes in CPP, we designed the protocol to maintain a constant CPP by adjustments to the bypass pump flow rate.
The onset of action of L-NAME was rapid in the systemic circulation, with the systemic vascular resistance almost reaching a plateau after 15 minutes. However, effects on the cerebral circulation had a slower time course, and maximal cerebrovascular effects were only reached at 45 minutes after administration of L-NAME in the study animals. This is important as measurements taken too soon after the administration of L-NAME would have underestimated the basal production of NO in the brain. The slow time course of L-NAME in the brain observed in this study is consistent with other reports in the literature, where maximal cerebrovascular effects were only observed 45 to 60 minutes after an intravenous dose of L-NAME [16].
The second study in this report demonstrated that an infusion of L-arginine improved cerebral blood flow in neonatal piglets after DHCA. Global cerebral blood flow increased from 43.8% ± 3.2% to 61.6% ± 9.1% of the pre-DHCA baseline. The vascular effects of L-arginine were most striking in the cerebellum and brain stem, where posttreatment blood flow returned to levels that were not significantly different from those obtained at the baseline before DHCA. The smallest increase in blood flow was seen in the cerebral hemispheres, but blood flow in this region was still significantly greater than in the corresponding region in the control group after a saline infusion. The increased cerebral perfusion with L-arginine infusion was accompanied by significant increases in CDO2 and CMRO2.
The fact that cerebral blood flow increased in response to L-arginine suggests that NO synthase in the cerebral vasculature is not saturated with substrate after DHCA. This ameliorating effect of L-arginine in cerebral hypoperfusion after DHCA is consistent with reports that suggest that L-arginine improved regional blood flow within areas of focal cerebral ischemia induced by vascular occlusions [11]. It is most likely to be related to increases in precursor levels for the L-arginine-NO pathway. Similar increases in cerebral blood flow in areas of focal ischemia have also been reported from the use of NO donors such as sodium nitroprusside [17]. Thus, the mechanism for improvements observed with L-arginine is likely to be related to NO-mediated vasodilation. The source of NO responsible for maintenance of resting cerebral blood flow remains to be elucidated. Nitric oxide synthase is present in vascular endothelial cells as well as in neurons, astrocytes, and perivascular nerves [18]. The site for the conversion of L-arginine into NO in the brain is probably the vascular endothelium, although the participation of glial cells and perivascular nerves cannot be ruled out [8].
It is interesting that L-arginine has no dilating effect on the normal systemic or cerebral circulation [10] and yet it was effective in improving recovery of cerebral blood flow after DHCA. In isolated canine basilar arteries and sheep middle cerebral arteries, anoxia produces endothelium-dependent contractions that were thought to be related to reduced production of endothelial-relaxing vascular factor [19, 20]. Furthermore, reperfusion after ischemia is known to produce oxygen free radicals that can interfere with endothelium-dependent relaxation [21]. The mechanisms involved are thought to include direct injury to the endothelium and destruction of NO by oxygen free radicals after its release into the extracellular environment [22]. All of these processes may contribute toward cerebral hypoperfusion after DHCA. It is probable that by increasing substrate availability, L-arginine stimulated production of NO in injured endothelial cells that may have impaired NO synthase activity. This would supplement reduced levels of NO in the subendothelial space and help restore a more dilated vascular tone in the cerebral circulation.
The fact that blood flow in different brain regions recovered to disparate levels with infusion of L-arginine again raised the possibility that different mechanisms may be involved in the post-DHCA cerebral hypoperfusion depending on the brain region. Possibilities include impairment of another vasodilator mechanism such as adenosine or prostacyclin. Alternatively, it may be due to increased levels of vasoconstrictors such as endothelins or thromboxane A2. Significant involvement of one or more of these other mechanisms in addition to impaired tonal production of NO may explain the regional differences in recovery of cerebral blood flow after a period of DHCA. Results from the L-NAME study are consistent with the finding that L-arginine had the smallest effect in restoring blood flow to the cerebral hemispheres. An alternative explanation for this regional effect of L-arginine is that the degree of impairment of the NO synthase pathway may be more severe in the cerebral hemisphere and simply increasing substrate availability was insufficient to restore NO production to normal levels in this region.
The increase in CMRO2 after the L-arginine infusion in this study was likely to be secondary to the increase in cerebral blood flow and CDO2 because it was accompanied by a small reduction in CEO2. If the primary effect of L-arginine were an increased CMRO2, one would have expected an increase in CEO2 instead. In this study, the L-arginine infusion was commenced at 1 hour after the start of reperfusion, when cerebral hypoperfusion was already established. It may in fact be more beneficial to commence the L-arginine infusion at the start of reperfusion to try to prevent or reduce the degree of hypoperfusion at the outset. By optimizing CDO2 at an earlier stage after DHCA, even better recovery of CMRO2 may be possible. The total dose of L-arginine administered over the 20-minute infusion period was approximately 600 mg•kg-1. Most other studies have reported that a dose of 300 to 400 mg•kg-1 was sufficient to reverse the effects of high-dose NO synthase inhibition. One report used a much higher dose of L-arginine at 900 mg•kg-1. It would be interesting to see whether a higher dose of L-arginine or longer period of infusion would further improve the recovery of cerebral perfusion and cerebral oxygen metabolism.
There are obvious limitations with this type of acute functional study involving the brain because no attempt was made to correlate the perfusion and metabolic improvements with neurologic outcome. Longer-term studies in a suitable experimental model should be performed before more definite conclusions can be made regarding the role of L-arginine in resuscitation of the brain after DHCA. Better knowledge of injury mechanisms will enable development of more effective cerebral protection strategies and allow safer application of DHCA.
In summary, this study demonstrated the importance of tonal release of NO in the systemic as well as the cerebral circulation in neonatal piglets during CPB. Inhibition of NO synthase led to severe and sustained generalized vasoconstriction. In the brain, this was sufficient to reduce cerebral blood flow to the extent that oxygen metabolism in the brain became seriously compromised. A period of DHCA did not have any significant effect on the tonal release of NO in the systemic circulation. However, tonal release of NO was much reduced in all regions of the brain after DHCA. This probably contributed to the low cerebral blood flow observed in the recovery period after DHCA. By increasing substrate availability with L-arginine, recovery of cerebral blood flow after DHCA was significantly improved. This was accompanied by significant improvement in CMRO2 toward baseline levels.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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Address reprint requests to Dr Tsui, Department of Cardiothoracic Surgery, Papworth Hospital, Papworth Everard, Cambridgeshire, CB3 8RE, United Kingdom.
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G. Nollert, M. Nagashima, J. Bucerius, T. Shin'oka, H. G. W. Lidov, A. d. Plessis, and R. A. Jonas OXYGENATION STRATEGY AND NEUROLOGIC DAMAGE AFTER DEEP HYPOTHERMIC CIRCULATORY ARREST. II. HYPOXIC VERSUS FREE RADICAL INJURY J. Thorac. Cardiovasc. Surg., June 1, 1999; 117(6): 1172 - 1179. [Abstract] [Full Text] [PDF]
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D. Segawa, N. Hatori, H. Yoshizu, Y. Uriuda, M. Shimizu, and S. Tanaka The effect of nitric oxide synthase inhibitor on reperfusion injury of the brain under hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., April 1, 1998; 115(4): 925 - 930. [Abstract] [Full Text] [PDF]
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p = 0.013 versus group A by unpaired t test) whereas no significant difference was found between the two groups in blood flow to the basal ganglion, cerebellum, and brain stem (*p > 0.39 by unpaired t test).
