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Ann Thorac Surg 2006;81:625-633
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Cardiac Output Augmentation During Hypoxemia Improves Cerebral Metabolism After Hypothermic Cardiopulmonary Bypass

Jess M. Schultz, MD, Tara Karamlou, MD, Irving Shen, MD, Ross M. Ungerleider, MD *

Division of Pediatric Cardiac Surgery, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon

Accepted for publication June 10, 2005.

* Address correspondence to Dr Ungerleider, Cardiothoracic Surgery, Oregon Health & Science University, Pediatric Cardiac Surgery, Doernbecher Children's Hospital, 3181 SW Sam Jackson Park Rd, DC8S, Portland, OR 97239-3098 (Email: ungerlei{at}ohsu.edu).

Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Comment
 Discussion
 References
 
BACKGROUND: Hypothermic circulatory arrest (HCA) impairs cerebral oxygen delivery (CDO2) and cerebral oxygen consumption (CMRO2), which are further reduced by perioperative hypoxemia. This study investigates if continuous hypothermic low-flow cardiopulmonary bypass (HLF) or intermittent hypothermic low-flow cardiopulmonary bypass (IHLF) can prevent reductions in CDO2 and CMRO2 during hypoxemia.

METHODS: Eighteen neonatal piglets, cooled to 16° to 18°C with cardiopulmonary bypass (CPB), were randomly assigned into three groups: HCA, HLF (50 cc · kg–1 · min–1), or IHLF (1 minute of HLF for every 15 minutes of HCA). After 60 minutes of hypothermia, normothermic CPB (100 cc · kg–1 · min–1) was established and cerebral perfusion data measured at hyperoxemia (PaO2 150 to 250 mm Hg), hypoxemia (PaO2 50 to 60 mm Hg), and severe hypoxemia (PaO2 30 to 40 mm Hg), and with increased CPB flow (200 cc · kg–1 · min–1) during severe hypoxemia.

RESULTS: The CMRO2 (in mL O2 · 100 g–1 · min–1) was lower after HCA (2.5 ± 0.3), compared with HLF (4.1 ± 0.5, p = 0.02) and IHLF (6.2 ± 0.8, p = 0.002). Within groups, the change from hyperoxemia to severe hypoxemia resulted in decreased CMRO2: HCA (1.3 ± 0.2, p = 0.004), HLF (3.0 ± 0.5, p = 0.01), and IHLF (2.9 ± 0.5, p = 0.01). During severe hypoxemia, increasing CPB flow (from 100 cc · kg–1 · min–1 to 200 cc · kg–1 · min–1) improved CMRO2: HCA (1.9 ± 0.5, p = 0.05), HLF (4.2 ± 0.5, p = 0.05), and IHLF (7.4 ± 0.5, p = 0.04).

CONCLUSIONS: Hypoxemia reduces CDO2 and CMRO2 despite the method of hypothermic CPB. Increased CPB flow during hypoxemia can restore both CDO2 and CMRO2 to values found with hyperoxemia and slower CPB flows. Augmenting cardiac output during periods of perioperative hypoxemia may prevent cerebral injury after exposure to hypothermic cardiopulmonary bypass.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Comment
 Discussion
 References
 
Hypothermic circulatory arrest (HCA) is often used in the repair of severe congenital heart defects. Hypothermic circulatory arrest is associated with decreased cerebral perfusion and cerebral oxygen consumption in the perioperative period [1, 2]. Prolonged HCA increases the risk of anoxic brain injury as demonstrated by both histology as well as functional testing [3–5]. To reduce the risks of neurologic injury after HCA, alternative methods of hypothermic cardiopulmonary bypass (CPB) have been advocated, including continuous hypothermic low-flow cardiopulmonary bypass (CLF) and intermittent hypothermic low-flow cardiopulmonary bypass (IHLF) [6–8]

Despite the method of hypothermic cardiopulmonary bypass utilized, neonates may encounter hypoxemia in the perioperative period. This hypoxemia can arise for a variety of reasons, including: pulmonary dysfunction, intrapulmonary shunting, or the presence of right and left heart mixing lesions. In animals that have not been exposed to hypothermia, homeostatic mechanisms ensure adequate oxygen availability to the brain, even during conditions of profound hypoxemia [9]. Hypothermic circulatory arrest interferes with these mechanisms by reducing both cerebral blood flow and cerebral oxygen extraction, and increasing cerebral vascular resistance during hypoxemia [10, 11]. These effects jeopardize adequate cerebral oxygen availability. It is unknown whether either HLF or IHLF interferes with the homeostatic mechanisms that protect cerebral oxygen availability. If these alternative hypothermic cardiopulmonary bypass techniques also hinder the ability of the cerebral circulation to ensure adequate oxygen availability, then neonates exposed to these strategies could also be at risk of hypoxic brain injury in the perioperative period [12]. This study uses a neonatal pig model to investigate the effects of hypoxemia on cerebral oxygen delivery and cerebral oxygen consumption after exposure to HLF or IHLF. In addition, this study examines the effect of augmenting cardiac output during conditions of hypoxemia on cerebral oxygen delivery and cerebral oxygen consumption, after exposure to HCA, or HLF, or IHLF.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Comment
 Discussion
 References
 
Neonatal piglets (2 to 4 weeks old, weighing 2.62 to 4.35 kg) were studied with approval from the Oregon Health and Sciences Universities' Institutional Animal Care and Use Committee. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985). The piglets were premedicated with intramuscular Telozole (8 mg/kg) and weighed to the nearest 10 grams. A bolus of fentanyl citrate (100 µg/kg) was administered through ear vein access. A surgical tracheostomy was performed, and then anesthesia was maintained with an intravenous fentanyl citrate infusion (100 µg/H), and isoflourane (1.0%) delivered to either the ventilator or the cardiopulmonary bypass oxygenator. Ventilation used oxygen as a carrier gas, with an infant volume cycled ventilator (Harvard Apparatus, Boston, Massachusetts) to keep peak inspiratory pressures less than 25 mm Hg and a positive end expiratory pressure of 5 mm Hg. The fraction of inspired oxygen during ventilation was 100%. An arterial partial pressure of carbon dioxide (PaCO2) of 35 to 45 mm Hg was obtained by adjusting minute ventilation or the rate of the sweep gas of the CBP circuit. Blood gas analyses were performed using an Instrumentation Laboratory Synthesis 10 arterial blood gas apparatus and Model 682 Co-oximeter (Instrumentation Laboratory, Lexington, Massachusetts).

A catheter inserted into the femoral artery and advanced into the descending thoracic aorta was used for arterial blood pressure and blood gas monitoring. A femoral vein catheter, advanced into the right atrium, was used for right atrial pressure monitoring. A nasopharyngeal and a rectal temperature probe were inserted for simultaneous temperature monitoring. The heart was exposed through a median sternotomy, and an ultrasonic flow probe (Transonic Systems, Ithaca, New York) was positioned around the main pulmonary artery to measure cardiac output at baseline before initiation of cardiopulmonary bypass. A silicone elastomer catheter was inserted through the left atrial appendage for microsphere infusion. Each animal was anticoagulated with 500 IU/kg of intravenous heparin. The scalp over the vertex of the animals' skull was raised, and access to the superior sagittal sinus was obtained through two 2-mm burr holes. A fluid filled silicone elastomer catheter was introduced through the posterior burr hole to monitor sagittal sinus pressure. The anterior burr hole was used for sagittal sinus venous blood gas sampling.

Cardiopulmonary Bypass
The extracorporeal circuit included a nonpulsatile Cobe Century roller pump (Cobe, Denver, Colorado), a Polystan Safe Micro neonatal oxygenator venous reservoir (Polystan, Vaerlose, Denmark), and -inch arterial and 1/2-inch venous tubing (Terumo Medical, Somerset, New Jersey). The circuit was primed with fresh, heparinized, whole blood obtained from donor adult pigs and Ringers lactate to obtain a hematocrit of 30%. The primed circuit also included 400 µg of fentanyl citrate and sodium bicarbonate to achieve a pH of 7.40. After instrumentation and baseline data acquisition the piglets received intravenous systemic heparinization (500 U/kg). An 8F arterial canula and 20F venous canula were inserted into the aortic root and right atrial appendage, respectively, through pursestring sutures. Normothermic CPB was established at a rate of 100 mL · kg–1 · min–1. Mechanical ventilation was stopped. Adjustment of the percent oxygen delivered to the oxygenator produced an arterial partial pressure of oxygen (PaO2) of 150 to 250 mm Hg. The animal was perfusion cooled over 20 minutes to a rectal temperature of 18°C using pH-stat blood gas management [13].

The animals were packed in ice, and then randomly assigned to one of three groups: in group HCA (n = 6), cardiopulmonary bypass was stopped, the animal was exanguinated into the cardiotomy reservoir; after 60 minutes of hypothermic circulatory arrest, cardiopulmonary bypass was reinstituted and rewarming was initiated. In group HLF (n = 6), hypothermic cardiopulmonary bypass was maintained at 50 mL · kg–1 · min–1 and the heart was packed in ice; after 60 minutes of hypothermic low-flow CPB, flows were returned to normal and rewarming was initiated. In group IHLF (n = 6), cardiopulmonary bypass was stopped (similar to HCA), but 1 minute of hypothermic cardiopulmonary bypass, at 50 mL · kg–1 · min–1, was delivered after every 15 minutes of hypothermic circulatory arrest; after a total of 3 minutes of hypothermic cardiopulmonary bypass and 57 minutes of hypothermic circulatory arrest, CPB was resumed and rewarming was initiated.

All animals were rewarmed to 37°C using cardiopulmonary bypass at 100 mL · kg–1 · min–1 and PaO2 150 to 250 mm Hg over 60 minutes, using alpha-stat blood gas management. Arterial pressures were allowed to drift. The PaCO2 was maintained between 35 and 45 mm Hg and the hematocrit between 28% and 32% throughout the remainder of the study. Measurements were then made at hyperoxemia (PaO2: 150 to 250 mm Hg). The percent oxygen delivered to the oxygenator was then sequentially reduced to obtain the following two data points: moderate hypoxemia (PaO2 50 to 60 mm Hg), and severe hypoxemia (PaO2 30 to 40 mm Hg). The cardiopulmonary bypass flow was then increased to 200 cc · kg–1 · min–1, with the PaO2 30 to 40 mm Hg to obtain the final data point: severe hypoxemia–increased flow.

At each data point, the animals were allowed to stabilize for 30 minutes before data acquisition. Values obtained at each data point included arterial pH, PaO2, PaCO2, hematocrit, hemoglobin (Hb), sagittal sinus pH, sagittal sinus partial pressure of oxygen (PssO2), sagittal sinus partial pressure of carbon dioxide (PssCO2), cardiac output or cardiopulmonary bypass flow, arterial blood pressure, sagittal sinus pressure, right atrial pressure, and cerebral blood flow (CBF).

Cerebral Blood Flow Measurement
At each data collection point, hemodynamic recordings and blood gas analyses were performed immediately before microsphere injection. The reference-sample, microsphere technique, using neutron activated microspheres, 15.5 + 0.1 µm, (BioPal, Boston, Massachusetts) suspended in normal saline containing Tween 80 and 0.01% Thimerosal at a concentration of 2.5 &times 106 microspheres per milliliter, was used to measure cerebral blood flow [14]. One of seven different neutron activated microspheres (198gold, 175ytterbium, 153samarium, 140lanthanum, 154europium, 176lutetium, 160terbium) were used in a random sequence at the five separate data collection points. At baseline, the microspheres were injected through the left atrial catheter. For the later data collection points microspheres were injected using the side port of the aortic cannula. Starting 10 seconds before microsphere injection, a reference blood sample was withdrawn over 2 minutes at a constant rate of 4.89 mL/min from the distal aorta using a Harvard syringe pump (South Natick, Massachusetts). Microsphere injections were made over 60 seconds, and followed by a flush of 5 cc of warmed saline. At the end of the experiment, the brain was removed. The right and left cerebral hemispheres were divided, and separate samples of the right and left frontal lobes were sectioned, weighed to the nearest one hundredth gram, and placed within 5 mL tissue vials (Biopal). The specimen vials containing blood and brain tissue were sent for analysis and CBF calculation (BioPal). Cerebral blood flow (in mL/100 g cerebral tissue) was defined as the average of the right and left CBF measurements.

Calculated Data
Calculated data are as follows:

Arterial oxygen content (in mL O2 /mL of blood) = [(0.0136) • (Hb concentration) • (arterial O2 saturation) + (0.003) • (PaO2)]

Cerebral oxygen delivery (CDO2 [in mL O2/100g tissue/min]) = (arterial oxygen content) • (CBF); sagittal sinus oxygen content (in mL O2 /mL of blood) = [(0.0136) • (Hb concentration) • (sagittal sinus O2 saturation) + (0.003) · (PaO2)]

Cerebral metabolic rate of oxygen consumption (CMRO2 [in mL O2/100 g of tissue/min]) = (arterial oxygen content – sagittal sinus oxygen content) * CBF

Mean arterial pressure (MAP[in mm Hg]) = diastolic arterial pressure + [1/3 • (systolic – diastolic arterial pressure)]

Cerebral perfusion pressure (CPP [in mm Hg]) = mean arterial pressure – sagittal sinus pressure

Cerebral vascular resistance (CVR [in mm Hg • min • 100 g tissue • mL blood) = cerebral perfusion pressure / cerebral blood flow

Cerebral extraction of oxygen (CEO2 [as percent]) = (cerebral metabolic rate of oxygen consumption / cerebral oxygen delivery) • 100.

Statistical Analysis
Before initiation of this study a power calculation was performed: to observe, during severe hypoxemia, an estimated CMRO2 in the IHLF group twice the CMRO2 of the HCA group (mean of HCA estimated at 0.0099 mL O2 · g–1 tissue · min–1 with an expected SD of 0.0059 mL O2 · g–1 tissue · min–1) [10], and {alpha} = 0.05, and ß = 0.80, the study required 6 animals in the HCA group and 6 animals in the IHL group to obtain significance with p less than 0.05 (Sigma Stat; SPSS, Chicago, Illinois) All data are expressed as a mean ± SEM. Significant differences in all data of this experiment were analyzed with a two-way repeated measures analysis of variance, utilizing the Holm-Sidak method, by applying the Sigma-Stat program, version 3.0 (SPSS). Multiple unpaired t tests were used to define statistically significant differences between the variables of the HCA group against the variables of the HLF group and IHLF group. A paired t test was used to detect differences within each group between hyperoxemia, moderate hypoxemia, severe hypoxemia, and severe hypoxemia–increased flow.

Results
Hematocrit, arterial blood gas, and sagittal PaO2 analyses at baseline, hyperoxemia, moderate hypoxemia, severe hypoxemia, and severe hypoxemia-increased flow are listed in Table 1. In all three groups, the experimental protocol did result in significant reductions in the PaO2 at moderate hypoxemia (p < 0.001) severe hypoxemia (p < 0.001), and severe hypoxemia-increased flow (p < 0.001) as compared with hyperoxemia. Further, parallel decreases in PssO2 accompanied the decreasing PaO2. Hemodynamic data at hyperoxemia, moderate hypoxemia, severe hypoxemia, and severe hypoxemia-increased flow are displayed in Table 2. Aside from reduced cerebral pressure in the HCA group compared with the HLF group at severe hypoxemia, the cerebral perfusion pressure was equivalent between groups, at all other experimental points.


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  		Table 1. Hematocrits, Arterial Blood Gas, and Sagittal Sinus Pa02 Analyses at Baseline, Hyperoxemia, Hypoxemia, Severe Hypoxemia, and Severe Hypoxemia Increased Flow for All Animals
 

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  		Table 2. Hemodynamic Data at Baseline, Hyperoxemia, Hypoxemia, Severe Hypoxemia, and Severe Hypoxemia Increased Flow for All Animals
 
Cerebral oxygen handling data are detailed in Table 3. The CBF at baseline for the HCA, HLF, and IHLF groups were similar. The cerebral blood flow within groups did not differ between hyperoxemia, moderate hypoxemia, and severe hypoxemia. However, during severe hypoxemia, the cerebral blood flow of the HLF and IHLF increased with increased CPB flow compared with CPB flow 100 cc · kg–1 · min–1.


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  		Table 3. Cerebral Blood Flow and Oxygen Handling at Baseline, Hyperoxemia, Hypoxemia, Severe Hypoxemia, and Severe Hypoxemia Increased Flow for All Animals
 
After exposure to hypothermia, the cerebral delivery of oxygen was greater in the IHLF and HLF groups than the HCA group at all experimental points (Fig 1). During severe hypoxemia, increasing CPB flow led to increased cerebral delivery of oxygen for all three groups. The cerebral oxygen consumption of the HCA group was lower after hypothermia, compared with baseline (Fig 2). The cerebral oxygen consumption decreased in the IHLF (p = 0.01), HLF (p = 0.01), and HCA (p = 0.004) groups from hyperoxemia to severe hypoxemia. However, increasing CPB flow during severe hypoxemia led to increased cerebral oxygen consumption in the IHLF group (p = 0.04), and a trend towards increased cerebral oxygen consumption in the HLF (p = 0.05) and HCA (p = 0.05) groups. The cerebral vascular resistance of the HCA group was greater after hypothermia, compared with baseline (p = 0.001; Fig 3). However, in general, the cerebral vascular resistance of the IHLF and HLF groups did not change after exposure to hypothermia. Although a trend toward higher cerebral extraction of oxygen was seen in all groups, with worsening hypoxemia, no statistical difference was detected, except between hyperoxemia and severe hypoxemia in the HLF group (p = 0.04).


Figure 1
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  		Fig 1. Cerebral blood flow (CBF [in mL/100 g cerebral tissue/min]) at baseline, and at the experimental time points: hyperoxemia (PaO2 150 to 250 mm Hg), moderate hypoxemia (PaO2 50 to 60 mm Hg) , severe hypoxemia (PaO2 30 to 40 mm Hg), and severe hypoxemia-increased flow (PaO2 30 to 40 mm Hg). After exposure to hypothermia, the CBF of the intermittent hypothermic low-flow (ILF) group (triangles) was higher than the hypothermic circulatory arrest (HCA) group (diamonds) at hyperoxemia (p = 0.04), and hypoxemia (p = 0.04), and severe hypoxemia-increased flow (p = 0.02). The CBF of the hypothermic low-flow (HLF) group (squares) was greater than the HCA group only during hyperoxemia (p = 0.04) and severe hypoxemia-increased flow (p = 0.02). Within groups, increasing cardiopulmonary bypass flow during severe hypoxemia, led to increased CBF for the ILF group (p = 0.04) and the HLF group (p = 0.02).

 

Figure 2
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  		Fig 2. Cerebral delivery of oxygen (CDO2 [in mL O2/100 g cerebral tissue/min]) at baseline, and at the experimental time points: hyperoxemia (PaO2 150 to 250 mm Hg), moderate hypoxemia (PaO2 50 to 60 mm Hg) , severe hypoxemia (PaO2 30 to 40 mm Hg), and severe hypoxemia-increased flow (PaO2 30 to 40 mm Hg). After exposure to hypothermia, the CDO2 of the intermittent hypothermic low-flow (ILF) group (triangles) and the hypothermic low-flow (HLF) group (squares) was higher than that of the hypothermic circulatory arrest (HCA) group (diamonds) at hyperoxemia (p = 0.03 and p = 0.02, respectively), severe hypoxemia (p = 0.03 and p = 0.02, respectively), and severe hypoxemia-increased flow (p = 0.005 and p = 0.02, respectively), Within groups, CDO2 decreased from hyperoxemia to severe hypoxemia in the ILF (p = 0.04), HLF (p = 0.003), and HCA (p = 0.002) groups. Increasing cardiopulmonary bypass flow during severe hypoxemia led to increased CDO2 for the ILF (p = 0.03), CLF (p = 0.03), and HCA (p = 0.04) groups.

 

Figure 3
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  		Fig 3. Cerebral metabolic rate of oxygen consumption (CMRO2 [in mL O2/100 g cerebral tissue/min]) at baseline, and at the experimental time points: hyperoxemia (PaO2 150 to 250 mm Hg), moderate hypoxemia (PaO2 50 to 60 mm Hg), severe hypoxemia (PaO2 30 to 40 mm Hg), and severe hypoxemia-increased flow (PaO2 30 to 40 mm Hg). The CMRO2 of the hypothermic circulatory arrest (HCA) group (diamonds) was significantly less at hyperoxemia than at baseline (p = 0.03). The CMRO2 of the intermittent hypothermic low-flow (ILF) group (triangles) and the hypothermic low-flow (HLF) group (squares) was higher than the HCA group at hyperoxemia (p = 0.002 and p = 0.02, respectively), hypoxemia (p = 0.02 and p = 0.1, respectively), severe hypoxemia (p = 0.01 and p = 0.02, respectively), and severe hypoxemia-increased flow (p = 0.008 and p = 0.02, respectively).

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Comment
Discussion
 References
 
Neurodevelopmental outcomes after the Norwood procedure have shown significant abnormalities for many survivors [15]. Further, results from the recently published Boston Circulatory Arrest Study comparing HCA to continuous HLF identify some degree of neurologic impairment for both groups of patients after 8 years of follow-up [16]. Since the initiation of patient enrollment in that clinical study, numerous experimental studies have contributed much to changing and hopefully improving the effects of HCA on the brain [17–19]. Most previous laboratory studies evaluating the effects of HCA and HLF have utilized normoxemic models, with the PaO2 greater than 80 mm Hg [6, 17, 20, 21]. However, these conditions do not accurately reflect some clinical situations, such as hypoxemia seen after the Norwood procedure, where the average PaO2 is often 35 to 45 mm Hg [22]. This experiment uses an animal model and mechanical circulatory support to change arterial oxygenation and systemic blood flow, in order to approximate the clinical phenomenon of hypoxemia after exposure to HCA, HLF, or IHLF.

Under hypoxemic conditions, CDO2 was lower in the HCA group than either the HLF or IHLF groups. The difference in CDO2 seen between groups arose from disparities in CBF. One cause for the reduced CBF seen after HCA may be the relatively higher CVR that was observed in this group. The cause of elevated CVR after HCA is unclear. Hypothermic circulatory arrest has been demonstrated to cause endothelial dysfunction in cerebral microvessels, which may result in elevated vascular resistance [23]. Additionally, after exposure to HCA, the ability of the cerebral microvasculature to allow adequate oxygen delivery to the cerebrum may be limited during hypoxemic conditions [10, 12]. The results of our study indicate that severe hypoxemia results in decreased CDO2 and CMRO2 after exposure to either HCA, HLF, or IHLF. It is unclear if the decreased cerebral oxygen availability results in reduced metabolic oxygen use, or if reduced oxygen demand causes a reduction in oxygen delivery. Prior studies have demonstrated that decreased CMRO2 correlates with histologic and metabolic findings of neuronal injury [2, 6]. Unfortunately, this study does not provide microscopic or molecular evidence of cerebral injury. The possibility remains that the metabolic effects seen in this study reflect only temporary physiologic derangements, and that these effects will not result in permanent neuronal injury.

Another question raised by this study regards the underlying cause of the reduced CDO2 and CMRO2 seen in all three groups during severe hypoxemia. All of the animals in this study are exposed to both hypothermia and cardiopulmonary bypass. Previous investigations have demonstrated that animals exposed to normothermic cardiopulmonary bypass have cerebral metabolism and oxygen delivery equivalent to animals exposed only to anesthesia [10]. The physiologic effects detailed in this study could result from either hypothermia alone, or the combination of hypothermia and cardiopulmonary bypass.

Unfortunately, this study was not designed to discriminate between the effects of hypothermia and hypothermic CPB on the cerebral vascular response to hypoxemia. Specifically, this study did not contain animals exposed to "normothermic" cardiopulmonary bypass. If included, these animals could have helped determine the effect of hypothermia on CDO2 and CMRO2. Earlier experiments describe the cerebral response of animals exposed to normothermic CPB and hypoxemia [10]. Unfortunately, the exposure time to CPB in this previous study is substantially shorter than the CPB intervals used in our current experiment, which may confound comparisons between these two studies. In addition, the results of this study are limited by some of the experimental conditions. The study design precluded a random sequence of exposure to the different levels of PaO2. In this experiment, animals progressed from a PaO2 of 150 to 250 mm Hg, then moderate and later severe hypoxemia, because of the concern for hypoxic brain injury, which can occur at severe hypoxemia. Although the sequential reduction in PaO2 may have resulted in some the trends in CDO2 and CMRO2 detailed in this study, the effect of early hypoxic brain injury would likely have a much larger impact if the PaO2 of the data collection points were randomized, and some animals exposed to severe hypoxemia during the early data collection points.

Despite these limitations, a number of conclusions can be reached from the data obtained in this experiment. First, severe hypoxemia (PaO2 30 to 40 mm Hg) after hypothermic CPB produces significant impairment to cerebral blood flow, cerebral oxygen delivery, and cerebral metabolism, compared with values seen at hyperoxemia, regardless of the CPB strategy (HCA, HLF, IHLF) utilized. Second, after HLF and IHLF, the cerebral metabolic activity and oxygen delivery during hypoxemia is higher than that observed after exposure to uninterrupted HCA. Third, it appears that the cerebral oxygen delivery and consumption of a brain exposed to hypoxemia after HCA are flow independent, as these values did not appreciably increase with increased total systemic flow. In contrast, after HLF or IHLF and during severe hypoxemia, both cerebral oxygen delivery and consumption appeared to be flow dependent, because with increased systemic flow, the brain experienced increased blood flow, oxygen delivery, and oxygen consumption. In this experiment, hypoxemic brains exposed to IHLF appeared to be more responsive to increased systemic flow than those brains exposed to HLF. However, these results did not reach statistical significance. Further studies comparing these two CPB strategies are needed to define if any physiologic differences occur during hypoxemia.

In conclusion, the infant exposed to hypoxemia after uninterrupted HCA, can have significantly impaired cerebral energetics which do not respond to cardiac output support. The combination of perioperative hypoxemia after the use of uninterrupted HCA may create the potential for substantial brain injury. The infant with hypoxemia after exposure to HLF or IHLF appears to have impaired cerebral energetics which can respond to cardiac output support. Low cardiac output in these hypoxemic patients, may make the brain more vulnerable to injury despite the more "favorable" CPB strategy used. Cardiac output support may be beneficial in protecting brains of hypoxemic patients from injury [24].


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Comment
 Discussion
References
 
DR ANTONIO CORNO (Lausanne, Switzerland): You performed a very nice study, extensive, on the differences between deep hypothermia with circulatory arrest and low flow/intermittent flow. I'm quite sure you agree, then, that no one of these techniques clinically provides the best type of perfusion. If you look at the book of physiology, the best perfusion, is written, it is with normal flow, normal temperature, normal oxygen content and possibly no hemodilution. I wonder why—it is a provocative question—you, like the people in Los Angeles, Boston, and Philadelphia, are using a tremendous amount of resources—time, effort, people, money, knowledge—to study different types of perfusion which are known to be suboptimal, instead of studying the normothermia, high flow, no hemodilution. It's like, if you allow the comparison, studying if one brand of cigarette is less dangerous than another one and not to compare with breathing fresh air. Thank you.

DR SCHULTZ: I think that is an excellent point. Without a doubt, hypothermia, in and of itself, will create some discomfort and some problems when we're looking at overall brain perfusion. However, it also has provided many advantages historically that have been proven time and time again. Specifically, it allows exposure in the operative field. When you're talking about circulatory arrest and a difficult repair, the cannulas can be removed in order to facilitate the repair. I'm not sure that this could be accomplished using a normothermic regional bypass strategy for cerebral perfusion.

In consequence, the other two methods do require occasional intermittent perfusion. In the intermittent hypothermic low-flow group, though, you still have the opportunity to remove these cannulas and reinsert them when you're planning on doing the reperfusion during the hypothermic interval.

I'm afraid I can't answer your question with regard to the hypothermic low-flow animals that received continuous perfusion, however.

DR WILLIAM DOUGLAS (Lexington, KY): I enjoyed your study very much. I have two questions for you. You didn't talk about PO2. Now, when we're talking about cerebral blood flow, I think most of us are used to thinking about bearing with CO2 instead of oxygen, so do you have any data on the reactivity to CO2?

And also, I think your institution is one of those that are using mechanical support devices after the Norwood procedure. If you're suggesting that the cerebral blood flow is dependent on PO2, are you suggesting that instead of putting patients on a ventricular assist device after a Norwood that they should be put on ECMO?

DR SCHULTZ: Those are both two excellent points. First, regarding the PCO2, in this particular study we maintain the PCO2 under very tight control, specifically between 38 and 42, to try to maintain it with a mean of around 40.

Unfortunately, we did not study it; and we all know that it's a very powerful vasodilator in the cerebral be. Previous studies have identified that sometimes the animals after circulatory arrest have a reduced ability to respond to PCO2; however, other studies have been contradictory. Unfortunately, I can't answer the question. I can only tell you for our study we made sure that we tried to keep very tight control because we did not want to confound this issue.

Regarding the second question, it is, in our opinion, of greater benefit to be able to maintain the lower arterial oxygen content in the perioperative period in these patients simply because inserting an oxygenator into the VAD circuit would add also the complications of requiring anticoagulation, which raises the possibility of intercerebral hemorrhage. It also adds to the overall difficulty of the procedure. We feel, at least with the method that we're using for brain protection intraoperatively, we can use the VAD in the perioperative period to provide adequate oxygen delivery to these infants in order to maintain adequate neurologic outcomes.

DR JOHN MAYER (Boston, MA): I think this is interesting validation of a concept that's been around for a little while, that at least part of the injury associated with ischemia and reperfusion is a vascular injury and not necessarily a parenchymal neuronal or parenchymal myocardial cell injury.

I'm interested in whether or not you have any data or speculations on more precisely what the mechanisms are for dysfunction in the vasculature after these kinds of interventions.

DR SCHULTZ: Unfortunately, this study is not refined enough in order to adequately investigate on a microvasculature level where the disregulation is occurring. That definitely is an area that needs to be investigated in the future.

Further, I would say that we could use more of a gross investigation to examine other possibilities, such as was mentioned earlier, altering the PACO2 or altering the overall vascular ability of the bed to dilate with other mechanisms such as nitroglycerin. It needs further study; but we did not incorporate it within this study, no.

DR MARSHALL JACOBS (Philadelphia, PA): I compliment you on a really elegant study design and a very nice experiment, you and your coauthors.

I guess my question is more naive than Dr Mayer's, but it has to do with the behavior of the vasculature. You showed data pertaining to cerebral vascular resistance and you showed data pertaining to flow, which you doubled from 100 mL/kg to 200 mL/kg. And I didn't have my adding machine and couldn't figure out the blood pressure. What happens to the blood pressure in this experimental preparation when you double the cardiac output? And to what extent do you think regulation or autoregulation is preserved or disturbed, and how might that impact on your observations?

DR SCHULTZ: Would it be possible for us to bring the talk up again. I have the cerebral perfusion pressure, but we didn't include it within the talk.

DR JACOBS: Did I just miss it? Did you show it?

DR SCHULTZ: No, I didn't include it actually within the talk itself. It was on a slide afterwards. We were anticipating that somebody might ask this question.

What we actually found is that within the groups there was no statistical difference in the overall cerebral perfusion pressure. However, as Dr Jacobs pointed out, increase in the total systemic flow did have a marked impact upon the overall mean arterial pressure, and we did see an overall increase in the cerebral perfusion pressure in these animals. However, and it's likely due to the overall statistical size of the study, the only one that generated a statistical difference within groups between those two points, hypoxemia at 100 cc, hypoxemia at 200 cc, was in the circulatory arrest animals. The other animals, there was just enough overlap within the groups that we weren't able to generate a statistical difference. But I agree with you, I think it's an important consideration.

DR SCOTT M. BRADLEY (Charleston, SC): It wasn't the main point of your talk, but another interesting piece of information in your results is that when you made these pigs hypoxic, cerebral blood flow either did not increase, or actually seemed to decrease. Do you know what happens to cerebral blood flow in normal pigs, or pigs that have been on bypass but without circulatory arrest, when you take their PO2 down to 40?

DR SCHULTZ: We, last year, presented a study in this forum. What we found was that if they're not exposed to hypothermic circulatory arrest, normal pigs, and normal pigs that have been exposed to cardiopulmonary bypass, have essentially the same response. They're able to substantially increase their cardiac output, their cerebral blood flow, and decrease their cerebrovascular resistance.

I think it's an important thing to point out. In those two groups that were reacting more normally, they weren't acting completely normally. They weren't able to substantially decrease their cerebrovascular resistance and allow their cerebral blood flow, which was substantially different than the study that was presented earlier.

DR CHRISTIAN BRIZARD (Melbourne, Australia): I wonder if we are missing an important piece of information: did you measure in your experiment the intracranial pressure. Could it allow differentiating a modification of the vascular reactivity from a compression of the intra cranial vessel by cerebral edema?

DR SCHULTZ: Unfortunately, we did not put any intraparenchymal catheters or pressure transducers in. We worried about the possibility of creating a hemorrhage, which would have a devastating outcome upon the preparation.

All I can tell you is the sagittal sinus pressures, although not completely accurate for intraparenchymal pressures, do reflect them somewhat. With the higher flow rates on the data at the end of the study, we did see an elevation in the sagittal sinus pressure; however, at the other time points after exposure there really wasn't that much of a change.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Comment
 Discussion
 References
 

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