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PEDIATRIC ANESTHESIA

The Effect of Hematocrit on Cerebral Blood Flow Velocity in Neonates and Infants Undergoing Deep Hypothermic Cardiopulmonary Bypass

Eva M. Gruber, MD^*, Richard A. Jonas, MD, Jane W. Newburger, MD, David Zurakowski, PhD, Dolly D. Hansen, MD^*, and Peter C. Laussen, MB, BS^*

Departments of *Anesthesiology, Surgery, and Pediatrics, Harvard Medical School; and Departments of *Anesthesia, Cardiovascular Surgery, Cardiology, and Research Computing & Biostatistics, Children’s Hospital, Boston, Massachusetts

Address correspondence and reprint requests to Peter C. Laussen, MB, BS, Department of Anesthesia, Cardiac Anesthesia Service, Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. Address e-mail to laussen{at}a1.tch.harvard.edu

	Abstract

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Varying degrees of hemodilution are used during deep hypothermic cardiopulmonary bypass. However, the optimal hematocrit (Hct) level to ensure adequate oxygen delivery without impairing microcirculatory flow is not known. In this prospective, randomized study, cerebral blood flow velocity in the middle cerebral artery was measured using transcranial Doppler sonography in 35 neonates and infants undergoing surgery with deep hypothermic cardiopulmonary bypass. Patients were randomized to low Hct (aiming for 20%) or high Hct (aiming for 30%) during cooling on cardiopulmonary bypass (CPB). Systolic (V_s), mean (V_m), and diastolic (V_d) cerebral blood flow velocity, as well as pulsatility index (PI = [V_s - V_d]/V_m) and resistance index (RI = [V_s - V_d]/V_s) were recorded at six time points: postinduction, at cannulation, after 10 min cooling on CPB, rewarmed to 35°C on CPB, immediately off CPB, and at skin closure. V_m was significantly lower in the high Hct group compared with that in the low Hct group during cooling (P < 0.01). Postinduction, the high Hct group demonstrated significantly lower V_d immediately off CPB (P < 0.01) and significantly lower V_m and V_s at skin closure (P < 0.001). We conclude that there is an inverse relation between hematocrit and cerebral blood flow velocity during deep hypothermic cardiopulmonary bypass in neonates and infants.

Implications: There is an inverse relation between hematocrit and cerebral blood flow velocity during deep hypothermic cardiopulmonary bypass in neonates and infants. Further studies correlating Hct and cerebral blood flow velocity with cerebral metabolic rate and neurologic outcome are necessary to determine the optimal Hct during deep hypothermic cardiopulmonary bypass.

	Introduction

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Numerous factors may contribute to the risk of neurologic injury after congenital heart surgery and cardiopulmonary bypass (1–3). Hemodilution is used during deep hypothermic cardiopulmonary bypass (DHCPB) to reduce blood viscosity, red cell rigidity, and vascular resistance (4,5). The optimal hematocrit (Hct) level that ensures adequate oxygen delivery without impairing microcirculatory flow is not known for neonates and infants during hypothermic low-flow CPB and circulatory arrest. Therefore, Hct strategies vary widely among centers performing neonatal and infant cardiac surgery. At our institution, a mixture of whole blood has been used to prime the bypass circuit to achieve a Hct of 20% on bypass (6). At Loma Linda University, a blood-free prime is used routinely for neonatal deep hypothermic cardiopulmonary arrest (DHCA) resulting in a Hct <10%, and colloid osmotic pressure is maintained with albumin (7). At other institutions—for example, Marie Lannelongue in Paris—a blood prime is used to achieve a Hct of >30% (8). A recent study using a neonatal swine survivor model suggested that a low Hct may cause inadequate oxygen delivery during early cooling and that the higher Hct achieved with a blood prime is associated with improved cerebral recovery after circulatory arrest (9).

In normothermic neonates and infants, there is an inverse relationship between Hct and cerebral blood flow velocity (CBFV) (10), but the effect of hypothermia on this relation is not known. Further, a persistent decrease in CBFV has been demonstrated in neonates and infants after DHCPB (11,12). Initial cold perfusion with delayed rewarming (13) and pH-stat blood gas management (14) have been reported to improve recovery of CBFV after DHCA. The Hct level during DHCPB is an additional factor that may influence recovery of CBFV. The purpose of this study was to assess two different Hct strategies during cooling on CBFV in neonates and infants undergoing DHCPB.

	Methods

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After institutional review board approval and parental informed consent were obtained, 35 neonates and infants undergoing heart surgery using deep hypothermia were prospectively studied. Patients were randomized to low Hct (aiming for 20%) or high Hct (aiming for 30%) during cooling on CPB.

Anesthesia was induced with fentanyl 25 µg/kg, and neuromuscular blockade was obtained with pancuronium 0.2 mg/kg. After nasotracheal intubation, controlled mechanical ventilation was initiated to maintain normocarbia. Additional doses of fentanyl 25 µg/kg were given before sternotomy and on rewarming. A radial arterial catheter was inserted for measurement of systemic arterial pressure and intermittent blood sampling. Tympanic, esophageal, and rectal temperatures were monitored continuously.

A 2-MHz, range-gated, pulsed-wave transcranial Doppler sonographic probe was placed over either the left or the right temporal window (Medasonics CDS; Medasonics Inc., Fremont, CA) to measure CBFV in the proximal (M1) segment of the middle cerebral artery. To ensure a reproducible window, the signal from the artery was adjusted to be accompanied by retrograde anterior cerebral flow (A1 segment). After achieving an acceptable waveform, the probe position was secured with an adhesive tape and a protective cage over the transducer. An investigator who was not responsible for the anesthetic management of the infant recorded all measurements. Systolic (V_s), mean (V_m), and diastolic (V_d) velocity, as well as pulsatility index (PI = [V_s - V_d]/V_m) and resistance index (RI = [V_s - V_d]/V_s were recorded at six time points: postinduction (T1), at cannulation (T2), 10 min after cooling on CPB (T3), rewarmed to 35°C on CPB (T4), immediately off CPB (T5), and at skin closure (T6). In addition, mean arterial pressure (MAP), PaCO₂, pH, bypass flow rates, and tympanic, esophageal, and rectal temperatures were recorded at the same times.

A nonpulsatile roller pump with a membrane oxygenator was used, and the circuit was primed with Plasma-Lyte A (Baxter, Deerfield, IL), pH 7.4, and blood to achieve the desired Hct during cooling. Hemofiltration during rewarming was performed in all patients to achieve a Hct of 30% before coming off bypass. pH-stat blood gas management was used in all patients during hypothermia.

Two-sample Student’s t-tests were used to compare baseline CBFV measurements for age, weight, duration of bypass, MAP, pH, PaCO₂, bypass flow rate, V_s, V_m, V_d, PI, and RI between the two Hct groups. Categorical variables including gender, diagnosis, and DHCA were compared by using the Pearson 2 test with Yates’ correction. Because no significant baseline differences were found for each of the CBFV outcomes (P > 0.50 in each case), raw measurements were analyzed at each data collection point. Each CBFV variable conformed to a normal (Gaussian) distribution according to the Wilk-Shapiro test (15). Therefore, two-way repeated-measures analysis of variance (ANOVA) (16) was used to assess differences in CBFV outcomes between groups across time, and data are expressed as the mean ± SE. Using a profile analysis strategy, an interaction test was used to indicate whether the slopes were parallel. Assuming equal slopes, main effect tests were used to assess whether the two Hct groups differed in level. A significant interaction (unequal slopes) would indicate that the changes in CBFV over the time points differed between the groups. In this case, the effect of time was evaluated separately for each group, and groups were compared at each time point using two-sample t-tests. Within each Hct group, paired t-tests were used to evaluate changes in CBFV outcomes between T1 and T6 and between T1 and T5. A Bonferroni correction was used to take into account the post hoc multiple time point comparisons. Therefore, a two-tailed P < 0.01 was considered statistically significant throughout. Data analysis was performed using the SPSS statistical package (version 8.0; SPSS Inc., Chicago, IL).

	Results

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Demographic data and CPB variables are presented in Table 1. There was no significant difference between the groups in terms of age, weight, duration of CPB, and DHCA time. There were no significant differences between groups with respect to MAP, bypass flow rates, pH, PaCO₂, tympanic temperature, and nadir temperature on bypass (Table 2). Hct was significantly different between the groups 10 min after cooling according to the study protocol.

View larger version (20K): [in this window] [in a new window]   Figure 1. Time course for mean cerebral blood flow velocity during the study period. * Significant difference between the high and low hematocrit (Hct) groups (P < 0.01). Significant difference between skin closure and postinduction for the high Hct group (P < 0.001). CPB = cardiopulmonary bypass.

View larger version (18K): [in this window] [in a new window]   Figure 2. A, Time course for systolic cerebral blood flow velocity during the study period. Significant difference between skin closure and postinduction for the high hematocrit (Hct) group (P = 0.001). B, Time course for diastolic cerebral blood flow velocity during the study period. Significant difference between off cardiopulmonary bypass (CPB) and postinduction for the high Hct group (P = 0.01).

V_d revealed no significant interaction between group and time (P = 0.80) and no group effect (P = 0.74), but a significant time effect (P = 0.002). Compared with T1, the lowest V_d was observed immediately after CPB (T5) (low Hct: 15 ± 2.1 cm/s; P = 0.03 and high Hct: 13 ± 2.4 cm/s; P < 0.01) and increased slightly at the time of skin closure for both groups. V_d was significantly lower at T5 compared with T1 only within the high Hct group (P < 0.01). No significant differences were detected between T6 and T1 for the high (P = 0.08) or low (P = 0.49) Hct groups.

All patients in both groups demonstrated antegrade diastolic flow prebypass. All patients in the low Hct group had recovery of diastolic flow postbypass; however, two patients in the high Hct group had absent or retrograde diastolic flow at T5.

PI and RI did not show any significant interaction between group and time (P = 0.53), which indicates that the two groups showed similar changes in PI and RI from T1 to T6. There were no significant differences for either index within each Hct group.

After DHCPB, there were no significant differences between the groups with respect to Hct, MAP, PaCO₂, arterial pH, and tympanic, esophageal, and rectal temperatures.

	Discussion

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In normothermic neonates and infants up to 10 wk of age, an inverse relationship between Hct and both V_s and V_m has been described (10). An inverse association in V_m was also seen in our study during deep hypothermia. There were no significant differences in CBFV over time between the two Hct groups after bypass, but within the high Hct group, the V_s and V_m remained significantly lower at completion of surgery compared with the baseline values.

Variables other than Hct that affect cerebral blood flow were controlled in our study. There were no significant differences in MAP or flow rates during the cooling phase between the two groups. Similarly, there were no differences in PaCO₂, pH, or temperature gradients during bypass to account for the difference in perfusion detected by CBFV between the two Hct groups.

A possible explanation for the decrease in CBFV in the high Hct group after DHCPB in our study may be a delayed recovery of cerebral vasoreactivity in the high Hct group. The lower V_s and V_m after separation from DHCPB in children has been previously reported and ascribed to a decrease in cerebral perfusion secondary to an increase in cerebral vascular resistance (12,17,18). Jonassen et al. (12) reported a significantly lower V_m compared with pre-CPB values in infants after deep hypothermia with low-flow CPB or circulatory arrest. In contrast, van der Linden et al. (17) reported a return of CBFV to baseline values after low-flow CPB in pediatric patients. However, in both of these studies, -stat blood gas management was used, and the Hct varied between 40% and 28% from pre-CPB to post-CPB.

Absent or even retrograde V_d has been reported after DHCA in infants, and it has also been ascribed to an increase in cerebral vascular resistance or intracranial pressure (19). In our study, V_d was absent immediately after separation from bypass in two patients, neither of whom underwent circulatory arrest. Diastolic CBFV had returned to baseline level in both groups by completion of surgery.

Although the V_m and V_s were significantly lower after DHCPB within the high Hct group, there were no statistically significant differences over time between the two Hct groups. Further, there were no significant differences in the RI and PI between groups. These indices have been used to relate the blood velocity waveform to resistance to blood flow (20), although changes in the viscoelastic properties of blood, systemic vascular resistance, and cardiac output all influence the pulsatility of the blood waveform. A direct correlation with cerebral vascular resistance was not possible to determine in this study.

In this study, there were no differences between groups after DHCPB that could account for the decrease in V_m and V_s in the high Hct group. Although cardiac output and systemic vascular resistance were not measured in this study, the return to baseline RI and PI after DHCPB in both groups indicates that there was probably no significant change in cerebral vascular resistance after DHCPB to account for the lower V_m and V_s.

The duration of cooling and rewarming was identical for both groups. In a previous study by Rodriguez et al. (13), a period of hypothermic cerebral reperfusion after DHCA was associated with improved recovery of CBFV. In our study, only eight patients underwent DHCA for a relatively short duration, and there were no differences in CBFV within and between groups when those patients were excluded from analysis. In addition, all other patients were perfused at flow rates previously shown not to be associated with neurologic injury (21). Therefore, it is unlikely that the flow rates on CPB and rate of rewarming contributed significantly to the observed changes in CBFV.

The marked hemodilution used during DHCPB may compromise cerebral oxygenation. Although hemodilution increases cerebral blood flow by reducing viscosity, the decrease in arterial oxygen content may be significant. A higher Hct during cooling and deep hypothermic circulatory arrest has been associated with improved neurologic recovery in a survivor swine model (9). In this model, the oxyhemoglobin and cytochrome aa₃ signal as measured by near infrared spectroscopy (NIRS) during cooling and subsequent DHCA demonstrated continued oxygen extraction in the higher Hct group. Animals with higher Hct also demonstrated less evidence of neurologic injury on postoperative examination and less histologic injury compared with those animals with lower Hct in this study. The higher Hct may therefore provide an additional source of oxygen for use during low-flow bypass and DHCA, which suggests that red blood cells continue to release oxygen throughout the arrest period and that higher hemoglobin levels may act as a reservoir of oxygen.

A lower Hct during cooling, combined with left shift of the oxyhemoglobin dissociation curve, may result in reduced O₂ delivery. Therefore, the higher CBFV seen in the low Hct group after DHCA may reflect a relative cerebral hyperemia compared with the high Hct group. Such a response in hemodiluted animals during reperfusion after circulatory arrest has been previously described (22) and demonstrated by NIRS in our swine survivor model of DHCPB (9).

CBFV does not reflect actual cerebral blood flow, and cerebral metabolic rate was not measured in this study. We were therefore unable to determine whether there was a change in O₂ delivery and extraction between the two Hct strategies, and correlating changes in CBFV to altered flow-metabolism is speculative. Studies specifically correlating CBFV at different Hct levels with NIRS evaluation of redox state and cerebral blood flow would be useful in this regard and are in progress. Finally, we do not know whether the different Hct strategies altered neurologic outcome. A specific neurologic examination was not performed, but no patients had clinical evidence of seizures in the immediate postoperative period. Long-term neurologic or developmental examinations were not performed.

In summary, we demonstrated an inverse relationship between CBFV and Hct during DHCPB, although there was no significant difference between high and low Hct in the recovery of CBFV after DHCPB. Further studies correlating Hct and CBFV with cerebral metabolism of oxygen, oxygen use by NIRS, and long-term neurologic outcome are necessary to determine the optimal Hct during DHCPB.

	Footnotes

 
Presented in abstract form at the 1998 American Society of Anesthesiologists annual meeting, Orlando, FL.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999