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Ann Thorac Surg 2005;80:1460-1467
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Specific Bypass Conditions Determine Safe Minimum Flow Rate

Vesa Anttila, MD c , d , Ikuo Hagino, MD a , David Zurakowski, PhD b , Yusuke Iwata, MD a , Lennart Duebener, MD a , Hart G.W. Lidov, MD c , Richard A. Jonas, MD a , *

a Department of Cardiovascular Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
b Department of Biostatistics, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
c Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
d Department of Surgery, University Hospital of Oulu, Oulu, Finland

Accepted for publication April 5, 2005.

* Address reprint requests to Dr Jonas, Department of Cardiovascular Surgery, Children's National Medical Center, 111 Michigan Ave, Washington, DC20010 (Email: rjonas{at}cnmc.org).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: The purpose of this study is to define a safe minimum flow rate for specific bypass conditions using continuous monitoring with near-infrared spectroscopy and direct observation of the cerebral microcirculation.

METHODS: Two series of experiments (n = 72 in each) were conducted in which piglets were cooled to a temperature of 15°, 25°, or 34°C on cardiopulmonary bypass with hematocrit 20% or 30%, pH-stat management in all, followed by 1 or 2 hours of reduced flow (10, 25, or 50 mL·kg–1 ·min–1). Animals in series one had a cranial window placed over the parietal cortex to evaluate the microcirculation with intravital microscopy. Plasma was labeled with fluorescein-isothiocyanate-dextran for assessment of functional capillary density (FCD) and microvascular diameter. In series two, near-infrared spectroscopy was utilized to detect tissue oxygenation index (TOI). Outcome measures included histologic and neurologic injury scores.

RESULTS: The TOI during low flow and FCD during rewarming and after weaning from cardiopulmonary bypass were associated with neurologic injury. Failure of FCD to return to baseline during rewarming predicted worse functional and histologic outcome (p < 0.001). Regression analysis indicated that temperature and low-flow rate were multivariable predictors of TOI and FCD during rewarming (p < 0.001).

CONCLUSIONS: Tissue oxygen index derived from near-infrared spectroscopy is a useful real-time monitor for detecting inadequate cerebral perfusion during cardiopulmonary bypass. Minimal safe pump flow rate varies according to the conditions of bypass: using pH stat management and with an hematocrit of either 20% or 30%, a flow rate as low as 10 mL·kg–1 ·min–1 is safe for as long as 2 hours at a temperature of 15°C. However, under the same conditions at 34°C, a flow rate of 10 mL·kg–1 ·min–1 is very likely to be associated with neurologic injury.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Early in the history of open heart surgery, it was apparent that neonates and infants were particularly susceptible to the deleterious effects of cardiopulmonary bypass (CPB). This led Barratt-Boyes and others [1] to popularize the use of deep hypothermic circulatory arrest, which limited exposure to CPB. Although many attempted to define a single safe duration of hypothermic circulatory arrest, we have demonstrated in laboratory studies that the safety of circulatory arrest is strongly influenced by bypass conditions such as pH, hematocrit, and temperature [2–8].

An alternative to deep hypothermic circulatory arrest for reducing the deleterious effects of CPB is to reduce the flow rate [6, 9]. Although some have argued against the concept of "low-flow bypass," the reality is that virtually all CPB is undertaken at a flow rate that is less than a normal cardiopulmonary output, for example, 2.4 L·m–2 ·min–1 (70 mL·kg–1 ·min–1) versus a normal cardiac output of 3.5 L·m–2 ·min–1 (100 mL·kg–1 ·min–1). If hypothermia is employed, it can be argued that even a flow rate of 2.4 L·m–2 ·min–1 is more than necessary for the reduced metabolic demands resulting from hypothermia. Furthermore, there are advantages such as improved intracardiac exposure and reduced cardiotomy suction that have led many centers to use reductions in flow rate of 50% or greater. Until recently, no method of monitoring the safety of reduced flow has been available. However, our own experiments investigating deep hypothermic circulatory arrest and work by others has demonstrated that near-infrared spectroscopy allows real-time monitoring of the brain that could be used to define the adequacy of cerebral oxygenation under conditions of reduced flow [3, 10, 11]. Because the brain is the organ that is most sensitive to oxygen deprivation, adequate cerebral oxygenation should fulfill requirements for whole body oxygenation.

The primary aim of the present study was define a minimum safe flow rate according to specific bypass conditions in piglets using near-infrared spectroscopy and intravital microscopy. As with our studies of circulatory arrest, we correlated near-infrared spectroscopy monitoring with functional and structural outcomes, namely neurologic and behavioral examination for 4 days postoperatively followed by sacrifice and neuropathologic evaluation. In parallel studies, we examined the microcirculation of the brain during conditions of reduced flow. Although much has been written about hypothermia and its potential effects on the microcirculation, such as capillary plugging secondary to hyperviscosity and red cell rigidity, we had not observed these phenomena in previous work using intravital microscopy. In fact, our previous studies had suggested that hypothermia was protective of the microcirculation [12]. Hemodilution was found to exacerbate the no reflow phenomenon and a higher bypass temperature was associated with increased white cell activation and endothelial adhesion. Therefore, the other principle aim of this study was to investigate whether changes in the microcirculation during low-flow bypass were correlated with neurologic outcome.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Animals
One hundred and forty-four juvenile (6 to 7 weeks old) Yorkshire piglets weighing 13.2 ± 1.1 kg were included in the study. All animals received humane care in accordance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised in 1996.

Surgical Preparation
After premedication with an intramuscular injection of ketamine (20 mg/kg) and xylazine (4 mg/kg) the piglets were intubated and ventilated with 21% oxygen at a respiratory rate between 18 and 20 breaths per minute to achieve an arterial pCO2 of 35 to 40 mm Hg. After induction with fentanyl (25 µg/kg intravenously), anesthesia was maintained with continuous infusion of fentanyl (25 µg·kg–1 ·h–1), midazolam (0.2 mg·kg–1 ·h–1), and pancuronium (0.2 mg·kg–1 ·h–1). Temperature probes were placed into the esophagus and rectum. A cannula (19G Intracath; Becton Dickinson, Sandy, Utah) was inserted in the left superficial femoral artery and advanced into the abdominal aorta for continuous blood pressure monitoring. For anesthesia infusion, a cannula (19G Intracath; Becton Dickinson) was introduced through the right femoral vein into the inferior vena cava. After systemic heparinization (300 IU/kg intravenously) and a right anterolateral thoracotomy in the third intercostal space, an 8F arterial cannula (Bio-Medicus; Medtronic, Eden Prairie, Minnesota) was inserted through the right femoral artery into the abdominal aorta, and a 28F cannula (Harvey; Bard, Tewksbury, Massachusetts) into the right atrium for CPB. Piglets were positioned prone in a stereotactic frame, and a cranial window (15 x 15 mm) was constructed over the parietal cerebral cortex with an electric drill. After incision of the dura, the surface (pial) vessels were visualized. The cranial window was closed with a glass cover slip.

Experimental Protocol
One hundred and forty-four piglets were randomized according to the experimental protocol. A temperature of 15°, 25°, or 34°C was maintained during the low-flow period. Flow rates of 10, 25, or 50 mL·kg–1 ·min–1 were used during the 1 or 2 hour period of low flow. Hematocrit was maintained at either 20% or 30% during the low-flow period. Each combination of temperature, flow rate, hematocrit, and duration of low-flow period (3 x 3 x 2 x 2 = 36 settings) was performed in two series of two independent experiments, resulting in 4 animals randomized to each of the 36 conditions. A power analysis revealed that these sample sizes and conditions would provide 80% power ({alpha} = 0.05, ß = 0.20) to detect significant group differences in neurologic scores based on regression and analysis of variance methods (version 5.0, nQuery Advisor; Statistical Solutions, Boston, Massachusetts).

Arterial pressure was monitored continuously throughout each experiment and was recorded every 15 minutes. Hemoglobin, hematocrit, glucose, lactate, pO2, pCO2, and pH were measured every 15 minutes on CPB, at 30 minutes after CPB, and once an hour until extubation using a blood gas analyzer (Stat Profile 9; Nova, Waltham, Massachusetts).

Cardiopulmonary Bypass Technique
The CPB circuit consisted of a roller-pump (Cardiovascular Instrument, Wakefield, Massachusetts), membrane oxygenator (Minimax; Medtronic, Anaheim, California), and sterile tubing with 40-µm arterial filter. Fresh whole blood from a donor pig was transfused into the prime as required to adjust hematocrit level to either 20% or 30%. Methylprednisolone (30 mg/kg), furosemide (0.25 mg/kg), sodium bicarbonate 7.4% (10 mL), and cephazolin sodium (25 mg/kg) were added to the prime before the start of CPB. The pH stat strategy was used (sweep gas 95% O2 / 5% CO2). The gas flow was adjusted to achieve an arterial pCO2 of 40 to 45 mm Hg (corrected to nasopharyngeal temperature). After baseline recordings, CPB with a flow rate of 100 mL·kg–1 ·min–1 was started, and the animals were perfused for 10 minutes at normothermia (esophageal temperature 37°C). Ventilation was stopped after the establishment of CPB. The piglets underwent 40 minutes of cooling on CPB to an esophageal temperature of 15°, 25°, or 34°C. During cooling period, the temperature gradient between esophageal temperature and ingoing blood was kept less than 10°C to allow gradual cooling and to prevent gaseous emboli. The duration of cooling period was kept equal in all experimental settings. After cooling, low-flow perfusion at 10, 25, or 50 mL·kg–1 ·min–1 flow rate was initiated for 1 or 2 hours. Before rewarming, sodium bicarbonate 7.4% (10 mL), methylprednisolone (30 mg/kg), furosemide (0.25 mg/kg), and mannitol (0.5 g/kg) were administered into the pump. During 40 minutes of rewarming to keep the temperature gradient less than 10°C, animals were warmed to 37°C with a flow rate of 100 mL·kg–1 ·min–1. The heart was defibrillated, if necessary, at an esophageal temperature of 30°C. Ventilation (100% oxygen) was started 10 minutes before weaning from CPB. Protamine (5 mg/kg) was administered intravenously after the animal was hemodynamically stable. The wounds were closed in a sterile fashion.

Animals remained sedated and paralyzed by a continuous infusion of fentanyl (50 µg·kg–1 ·h–1), midazolam (0.2 mg·kg–1 ·h–1), and pancuronium (0.2 mg·kg–1 ·h–1), and were mechanically ventilated (21% oxygen) and monitored continuously for 12 hours after operation. The chest tubes were removed and animals were extubated.

Intravital Fluorescence Microscopy
An epifluorescence microscope (Model MZFL III; Leica, Heerbrugg, Switzerland) with a 100 W mercury gas discharge lamp equipped with a rapid filter exchanger was placed over the cranial window. The microscope was equipped with a blue filter set (450 to 490 nm excitation per >515-nm emission wavelength) for visualization of fluorescein fluorescence.

The microscope images from the charge-coupled device (CCD) video camera (Dage-300-RC; Dage-MTI, Michigan City, Indiana) were time-stamped using a time-code generator (VTG-33, For-A. Tokyo, Japan). The images were transferred to a high-resolution 12-inch monitor (Dage HR-1000; Dage-MTI) and videotaped. A Scion LG-3 frame grabber card (Scion Corporation, Frederick, Maryland) and computer-assisted image analysis system (NIH Image; National Institutes of Health, Bethesda, Maryland) were used for subsequent offline analysis. The final magnification on the monitor was x400.

To visualize microvascular functional capillary density (FCD), defined as total length of erythrocyte-perfused capillaries per observation area, and diameter of arteries and venules, plasma was labeled with 1 mL fluorescein-isothiocyanate (FITC)-Dextran 5% (150 kD; Sigma Chemical, St. Louis, Missouri) before each subsequent measurement. The FITC fluorescence was excited using the blue filter set. The FCD and diameter of 60- to 100-µm arterial and venous cerebrocortical microvessels were measured from video still images using an image analysis program. On average, 4 to 5 arterioles and 3 to 4 venules per observation area were measured.

Intravital fluorescence microscopy was performed at baseline; at 10 minutes of normothermic CPB; at 20 minutes of cooling; at the end of cooling; at 15, 30, 45 minutes, and at the end of low-flow period; at 15, 30, and 40 minutes of reperfusion; and at 30 and 60 minutes after weaning from CPB. The duration of brain tissue epi-illumination was limited to less than 1 minute to avoid thermal injury of tissue, and it was always shut off between video recordings.

Near-Infrared Spectroscopy
A pair of fiberoptic optodes was attached to the head of the animal with a probe holder after induction of anesthesia. The optodes spacing was 4.0 cm in a coronal plane. These two optodes, a transmitter, and a receiver of laser light of near-infrared wavelength, were connected to near-infrared spectroscopy (NIRO300; Hamamatsu Photonics K.K., Hamamatsu City, Japan). The receiving optode incorporates three detectors allowing assessment at three different pathlengths. This device calculated the relative concentration changes in oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HHb), and the tissue oxygenation index (TOI), which was calculated from the ratio of oxygenated to total hemoglobin determined at three different pathlengths. Data were recorded every 10 seconds after induction of anesthesia and for 3 hours after weaning from CPB. The average TOI for a selected period was used for further analysis.

Postoperative Evaluation
After the operation, neurologic and behavioral evaluations were performed at 24 hours intervals by a senior veterinarian masked to the experimental protocol beginning on postoperative day 1. Neurologic scoring was adapted from the neurologic deficit score (NDS [500 = brain dead, 0 = normal]) [13].

Histopathologic Analysis
Piglets were sedated by intramuscular induction by ketamine (20 mg/kg) and xylazine (4 mg/kg) and anesthetized by intravenous fentanyl (50 µg/kg). After a midline sternotomy, heparin (300 IU/kg) was administered, and a cannula was inserted into the left common carotid artery. The aortic arch was clamped, and 1 L Plasmalyte solution (Baxter) was infused through the left common carotid artery. Blood was suctioned from the superior vena cava until the perfusate was clear of blood. Then 3 L 10% formalin solution was perfused through the brain in the same manner to accomplish a perfusion fixation. The entire head of piglet was immersed into 10% formalin for a week, and the brain was harvested and fixed with 10% formalin solution for the histologic assessment [14].

The preparation of cerebral specimens and details of analyses used have been described previously [2, 14]. Specimens from six regions of the brain (neocortex, hippocampus, dentate gyrus, caudate nucleus, thalamus, and cerebellum) were examined. Histologic damage was scored using the following criteria: 5 = cavitated lesions with necrosis, 4 = significant damage to neurons, 3 = large clusters of injured neurons, 2 = small clusters of damaged neurons, 1 = isolated neuronal damage, and 0 = normal. A single neuropathologist (H.G.W.L.) examined all specimens in a masked fashion.

Statistical Analysis
The Shapiro-Wilk test indicated that TOI, FCD, and NDS followed a normal distribution and were summarized using the mean ± SD. Histologic data showed nonnormality due to skewness and were therefore expressed using the median and interquartile range. Repeated-measures analysis of variance (ANOVA) was used to evaluate changes over time and to compare rates of change between the groups [15]. One-way ANOVA with Bonferroni t tests were used to detect differences in TOI, FCD, and NDS between experimental conditions, whereas the nonparametric Mann-Whitney U test was used to compare histologic data [16]. The Pearson correlation coefficient (r) was used as a measure of linear association between TOI, FCD, and NDS. Least-squares regression analysis was applied to derive equations using TOI and FCD to predict NDS [17]. All reported p values are two-tailed. The SPSS statistical package was utilized analysis of the data (version 12.0; SPSS, Chicago, Illinois).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
There were no statistically significant differences at baseline (before CPB) between experimental conditions regarding hematocrit, blood gases, mean arterial pressure, whole body lactate, near-infrared spectroscopy measurements, or FCD.

Functional Capillary Density
Functional capillary density increased in all animals from baseline (100%) to normothermic CPB (108% ± 6%), but there were no differences between the groups. At the end of cooling, FCD was significantly lower in animals at 15°C (93% ± 4%) compared with the 34°C group (98% ± 2%; p < 0.05). The FCD was lower after 34°C low-flow period during the entire rewarming period and after weaning from the pump compared with 15°C and 25°C (p < 0.05). The FCD was lower after the low-flow period with 10 mL·kg–1 ·min–1 flow rate compared with 25 and 50 mL·kg–1 ·min–1 flow rate (p < 0.05). For animals subjected to a temperature of 34°C during the low-flow period, the subgroup with the lowest flow rate (10 mL·kg–1 ·min–1) had significantly lower FCD values compared with all other groups (p < 0.001). During rewarming and after weaning from CPB, FCD correlated inversely with functional outcome (NDS) and histologic score (p < 0.05). Univariate analysis showed that temperature and flow rate (p < 0.001, F-tests), but not hematocrit (p = 0.41, t test) were associated with FCD during rewarming and after CPB. Moreover, temperature and flow rate were found to be significant multivariable predictors of FCD during rewarming (F = 31.0, p < 0.001, and F = 30.6, p < 0.001, respectively). This analysis showed a moderate interaction between temperature and flow rate. As depicted in Figure 1, at temperatures of 15° and 25°C, an increase in flow rate from 25 to 50 mL·kg–1 ·min–1 did not improve FCD because it was already at the 100% baseline level. However, failure of FCD to return to baseline during rewarming was associated with worse functional and histologic outcome (p < 0.001). There were no statistically significant differences in neurologic or histologic outcome between the 20% and 30% hematocrit groups, although during normothermic bypass, rewarming and after weaning from pump the 30% hematocrit group scored slightly better in terms of outcome.



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  		Fig 1. Functional capillary density (FCD): FCD was lower after 34°C low-flow period to 15°C and 25°C (*p < 0.05). FCD was lower after low-flow period with 10 mL/kg/min flow rate compared to 25 and 50 mL/kg/min flow rate (*p < 0.05). For animals subjected to temperature of 34°C during the low-flow period, the subgroup with the lowest flow rate (10 mL·kg–1 ·min–1) had significantly lower FCD values compared with all other groups (p < 0.001). Temperature and flow rate were found to be significant multivariable predictors of FCD during rewarming (F = 31.0, p < 0.001, and F = 30.6, p < 0.001, respectively).

 
Microvascular Diameter
The diameter of arterial cerebrocortical microvessels increased significantly in all groups at the end of normothermic CPB compared with baseline (prebypass; p < 0.01). During the low-flow period, animals perfused at 15°C and flow rate of 10 mL·kg–1 ·min–1 had significantly smaller mean arterial diameter (80% ± 30%) compared with all other groups except animals perfused at 15°C and flow rate of 25 mL·kg–1 ·min–1 (99% ± 28%; p < 0.05). During rewarming and after weaning from CPB, there were no significant group differences. At 40 minutes of rewarming and after weaning from CPB, arterial diameters did not significantly differ from baseline within any group.

Near-Infrared Spectroscopy
Univariate analysis indicated that temperature and flow rate had a significant impact on TOI (p < 0.001, ANOVA, F tests). However, duration of low flow and hematocrit level did not affect TOI (p = 0.49 and p = 0.07, t tests, respectively). Multivariate analysis detected highly significant effects of temperature (F = 54.5, p < 0.001) and flow rate (F = 32.5, p < 0.001) on TOI with no significant interaction between temperature and flow rate (Fig 2).



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  		Fig 2. Tissue oxygenation index (TOI): univariate analysis indicated that temperature and flow rate had a significant impact on TOI (p < 0.001, ANOVA, F test). However, regarding the duration of low flow or hematocrit, there were no significant differences (p = 0.49 and p = 0.07, t tests, respectively). Multivariate analysis detected a highly significant effect for temperature (F = 54.5, p < 0.001) and flow rate (F = 32.5, p < 0.001) on TOI. No temperature and flow rate interactions were found (p = 0.21). (*p < 0.05.)

 
Morbidity and Mortality
All animals were stable during the surgical procedures and survived to at least the first postoperative day. In series one, 69 of the 72 animals survived 4 days after surgery and were electively sacrificed. One animal subjected to a temperature of 34°C and 2-hour duration of flow rate 10 mL·kg–1 ·min–1 died of severe brain damage on postoperative day 1, and another animal in the same group was sacrificed after repeated seizures on postoperative day 2. Also one animal with the temperature of 34°C and 1 hour duration of flow rate 25 mL·kg–1 ·min–1 was sacrificed on postoperative day 2 owing to ischemia-related abdominal problems.

In the near-infrared spectroscopy study, 66 of the 72 animals survived 4 days after surgery. Four animals assigned to a temperature of 34°C and 2-hour flow at 10 mL·kg–1 ·min–1 were sacrificed 12 to 14 hours after surgery owing to inability to wean the respirator with lack of spontaneous breathing. Two animals, both assigned to 34°C and 1 hour of duration of flow rate of 10 mL·kg–1 ·min–1, were sacrificed on postoperative days 2 and 3, respectively, owing to respiratory failure with repeated seizures.

Neurologic and Behavioral Evaluations
The NDS showed relatively rapid recovery in all surviving animals except animals subjected to a temperature of 34°C and flow rate 10 mL·kg–1 ·min–1 (condition 7, Table 1). During rewarming and after weaning from bypass, the FCD was inversely correlated with functional outcome (NDS) during the entire postoperative period (Pearson r = -0.46 to -0.66, p < 0.001; Pearson r = -0.68 to -0.80, p < 0.001, respectively). Multiple linear regression indicated that FCD is a predictor of NDS (postoperative day 1) independent of flow rate and temperature. The fitted regression equation for predicting NDS (^) in points from %FCD (x) is: ^ = 260 – 2.2x. For example, when FCD is 90, the estimated NDS = 260 – 2.2 x 90 = 62 points (Fig 3).


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  		Table 1. Regional Histologic Scores and Neurologic Deficit Scores by Temperature and Flow Rate During Low-Flow Bypass
 


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  		Fig 3. During rewarming, the functional capillary density (FCD) was negatively correlated with functional outcome (neurologic deficit score [NDS]) on postoperative day 1 (POD1). (r = -0.66, p < 0.001). Multiple regression indicated that FCD is a predictor of NDS (POD1) independent of flow rate and temperature. The fitted regression equation (solid line) for predicting NDS (^) in points from FCD (x) is: ^ = 260 – 2.2x.

 
Similarly, multiple regression indicted that TOI is a predictor of NDS (postoperative day 1) independent of flow rate and temperature. The fitted regression equation for predicting NDS (^) in points from %TOI (x) is: ^ = 315 – 3.5x. For example, when TOI is 60, NDS = 315 – 3.5 x 60 = 105 points (Fig 4).



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  		Fig 4. An inverse correlation was found between the tissue oxygenation index (TOI) and the neurologic deficit score (NDS) on postoperative day 1 (POD1; r = -0.45, p < 0.001). Multiple regression analysis indicated that TOI is a predictor of NDS (POD1) independent of flow rate and temperature. The fitted regression equation (solid line) for predicting NDS (^) in points from TOI (x) is: ^ = 315 – 3.5x.

 
Histologic Assessment
Temperature and flow rate were highly significant multivariable predictors of both total histologic score and NDS (p < 0.001). Table 1 presents the histologic results for each region of the brain according to temperature and flow rate conditions. Overall, there was essentially no damage to the cerebrum except for animals subjected to a temperature of 34°C and flow rate 10 mL·kg–1 ·min–1. Mean NDS is also shown for these nine conditions and reveals a significantly worse score for condition 7 (34°C and flow rate 10 mL·kg–1 ·min–1) than for any of the other conditions (p < 0.05 for each). As illustrated by the boxplots in Figure 5, total histologic score in this group was significantly higher than all other groups combined (median scores of 11 versus 0, p < 0.001, Mann-Whitney U test). Table 2 presents the F-tests and corresponding p values based on the multivariable analyses for total histologic score and NDS testing according to hematocrit, duration of low flow, temperature, and flow rate. There is no significant effect of hematocrit, but a longer duration of low flow was associated with higher NDS scores (F = 13.0, p < 0.001).



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  		Fig 5. No damage was found in the cerebrum, except in animals undergoing a bypass temperature of 34°C and a flow rate 10 mL·kg–1 ·min–1(ml/kg/min). The total histologic score in this group was significantly higher compared with other groups (median scores, 11 versus 0; p < 0.001).

 

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  		Table 2. Multivariable Predictors of Histologic and Neurologic Deficit Scores
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
This study demonstrates that the conditions of CPB influence the safe minimum flow rate. For example using the pH stat strategy and a hematocrit of 20% or 30%, a flow rate as low as 10 mL·kg–1 ·min–1 appears to be safe for as long as 2 hours at a temperature of 15°C. On the other hand, with the same conditions at 34°C, flow rates of 25 or 50 mL·kg–1 ·min–1 can result in neurologic injury, and a profound degree of injury is sustained using 34°C with a flow rate of 10 mL·kg–1 ·min–1.

This study has confirmed that the tissue oxygenation index as derived from near-infrared spectroscopy is a useful real-time monitor for determining the safety of a reduced flow rate under specific bypass conditions. The TOI was found by multiple regression analysis to be a predictor of functional outcome as determined by NDS on postoperative day 1, independent of flow rate and temperature.

This study has confirmed that perfusion temperature has a powerful impact on the safe minimum flow rate. Interestingly, there was no difference in the safe minimum flow rate whether that flow rate was maintained for 1 hour or 2 hours. Also, there were no differences in the safe minimum flow rates based on the levels of hematocrit chosen in this study. However, unlike our previous laboratory studies which included an extremely low hematocrit of 10%, the spread of hematocrit in this study was less, namely, 20% versus 30%. This laboratory result contrasts with the findings of a recent prospective clinical randomized trial which detected differences in developmental outcome despite a difference of only 6% in hematocrit between hematocrit 21% and 27% [18]. As with the clinical trial, all animals in the present study were perfused using the pH stat strategy.

Analysis of the microcirculation in this study has produced some particularly interesting findings. Most important, it was found that the functional capillary density both during rewarming and after weaning from CPB correlated with both functional and structural neurologic outcome. Failure of functional capillary density to return to baseline also predicted worse functional and structural outcome. Perfusion at a higher temperature and with a lower flow rate predicted decreased functional capillary density during rewarming by multivariate analysis. For example, at 34°C with a flow rate of 10 mL·kg–1 ·min–1, functional capillary density during rewarming and after weaning from bypass was markedly decreased. This is consistent with our observation in a previous study of deep hypothermic circulatory arrest. In that study, decreased FCD during rewarming was associated with a lower hematocrit [19]. We hypothesized that reduced FCD during rewarming is a consequence of hypoxic endothelial injury. This may partially be a consequence of white cell mediated injury in that a higher perfusion temperature was associated increased white cell activation as demonstrated by greater numbers of rolling and adherent leukocytes.

Our previous studies using intravital microscopy in a piglet model were acute studies and did not allow us to correlate changes in the microcirculation with subsequent structural and functional neurologic outcomes [19, 20]. That a strong correlation was demonstrated in the current study between functional capillary density during rewarming and after weaning from CPB highlights the importance of changes in the microcirculation that occur in response to manipulations of CPB. Thus, protection of microvascular integrity during CPB should be a goal of future endeavors.

Another finding pertaining to the microcirculation was that arterial diameter increased during the cooling period in all animals and was not dependent on temperature. During low flow, the arterial diameter decreased significantly in animals at a temperature of 15°C and low-flow rate of 10 mL·kg–1 ·min–1 and remained at baseline in animals at 25 mL·kg–1 ·min–1. This finding most likely reflects the decreased metabolic demands of the brain at lower temperature, which is associated with a lower total cerebral flow. In addition, previous studies have demonstrated that under conditions of CPB autoregulation is lost, and flow is highly dependent on perfusion flow rate.

The histologic damage noted in this study was in general milder than that seen in our previous studies using hypothermic circulatory arrest. Only the combination of a temperature of 34°C and flow rates of 10 and 25 mL·kg–1 ·min–1 resulted in ischemia severe enough to produce important histologic damage in all regions of the brain that were studied. This result is consistent with previous work by Swain and colleagues [9] using magnetic resonance spectroscopy. They demonstrated that at deep hypothermia, a CPB flow rate as low as 10 mL·kg–1 ·min–1 maintains cerebral high-energy phosphates and intracellular pH [9]. Nevertheless, we found that temperature and flow rate were significant multivariable predictors of histologic damage. Histologic damage was most commonly found in the cerebellum. The explanation as to why injury should have been found most commonly in the cerebellum is unclear, although it may be related to the prone position of animals in the intravital microscopy series of experiments.

In conclusion, this study highlights the importance of monitoring cerebral oxygenation during CPB since the minimal safe pump flow rate varies according to the conditions of bypass. The tissue oxygen index derived from near-infrared spectroscopy is a useful absolute measure of adequacy of cerebral perfusion and allows real-time adjustment of either the flow rate or bypass conditions to correct inadequate cerebral oxygenation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Barratt-Boyes BG, Simpson M, Neutze JM. Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass Circulation 1971;43(Suppl 1):25-30.
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