Cerebral Blood Flow Is Independent of Mean Arterial Blood Pressure in Preterm Infants Undergoing Intensive Care

DISCUSSION

This study found no significant difference in CBF between infants with MABP ≥30 mm Hg and those with MABP in the range 23.7 to 29.9 mm Hg.

The Hbo ₂ technique for measuring CBF in the newborn has been validated against the intravenous¹³³Xenon clearance method.^{10 11} The assumptions underlying the method have been discussed elsewhere.¹² All methods for CBF measurement in newborns have limitations in accuracy, which is reflected in the intraindividual variability. However, the range of CBF values we obtained was similar to those measured in very preterm infants using both ¹³³Xenon clearance¹³and positron emission tomography.¹⁴

Our results indicate that infants with MABP in the lower range are able to maintain a satisfactory CBF, suggesting that autoregulation was intact. We did, however, demonstrate a positive correlation with TcPco ₂. These findings are consistent with previously published studies of CBF measured shortly after birth in spontaneously-breathing and mechanically-ventilated preterm infants using ¹³³Xenon clearance.^{13 15} This was a cross-sectional rather than a longitudinal study, which was not designed to detect whether a small subgroup of the sickest infants had a pressure passive circulation. Although the power of the study was insufficient to detect a difference in CBF between the two groups of less than 7.5 mL · 100 g⁻¹ · min⁻¹(P < .05), there was no trend for a lower CBF in the low MABP group. By contrast the study was able to demonstrate the expected correlation of CBF with Paco ₂.

Animal models used to study the effects of hypotension on CBF have shown that although autoregulation may be intact, preterm animals have a reduced range during which autoregulation occurs. The lower limit of autoregulation is the same in the term and the preterm fetal lamb;^{16 17} however, the resting MABP in the preterm lamb lies closer to the lower limit of autoregulation, making it more susceptible to cerebral ischemia. Similar studies in human infants are not possible and the limits of autoregulation in the preterm neonate have not been determined. CBF velocity measurements using Doppler ultrasound have suggested loss of autoregulation in the preterm infant,^{2 18} although such studies are difficult to interpret because of changes in the diameter of insonated vessels.¹⁹

It is generally assumed that there must be a critical level of CBF required to maintain cellular integrity and homeostasis, but this level has not yet been established in preterm infants. Initial reports suggested that a CBF of less than 10 mL · 100 g⁻¹ · min⁻¹ was associated with neurologic impairment.²⁰ However more recent studies have shown that a CBF as low as 5 mL · 100 g⁻¹ · min⁻¹ can be compatible with a normal neurologic and cognitive outcome.^{14 21} Visual evoked potentials have been shown to be preserved in infants with CBF as low as 4.3 mL · 100 g⁻¹ · min⁻¹.¹⁵ In our study 11 infants had a CBF measurement below 10 mL · 100 g⁻¹ · min⁻¹. Of these, only 4 were in the group with lower blood pressure; 5 died and 3 developed ultrasound evidence of cerebral injury.

Blood pressure nomograms as a function of birth weight have been published for term and preterm infants.^{6 22-25} However there are discrepancies between different studies, probably because of differences in the clinical treatment of preterm infants. Some studies of infants with a birth weight of <1500 g have shown that a MABP of less than 30 mm Hg was more than 2 SD below the mean MABP,^{6 25} but the concept of a normal range for MABP in preterm infants undergoing intensive care is problematic. A MABP lower than 30 mm Hg for any significant period has been associated with periventricular hemorrhage,^{4 6 22} cerebral ischemic lesions, and death.⁴ Although there is evidence of a statistical association between low MABP and adverse outcome, there may not be a causal link. The statistical association may simply reflect the fact that the sickest infants tend to have the lowest blood pressures. It is therefore not surprising that the treatment of blood pressure in preterm infants varies widely. It is common practice in many neonatal intensive care units to maintain the MABP more than 30 mm Hg using plasma expanders or pressor agents to ensure adequate perfusion to vital organs, particularly the brain.

An alternative recommendation from the Joint Working Group of the British Association of Perinatal Medicine was that the MABP in mm Hg should not fall below the gestational age of the infant in weeks.²⁶ This recommendation was based on a consensus decision and there are no studies to confirm these lower limits of MABP. In our study 9 infants had a MABP lower than their gestational age. The mean CBF (±SD) in this group was 15.2 ± 7.7 mL · 100 g⁻¹ · min⁻¹ compared with 14.6 ± 7.0 mL · 100 g⁻¹ · min⁻¹in the remainder. Our study does not support the assumption that a MABP in the range of 23.7 to 29.9 mm Hg is necessarily associated with a reduction in cerebral perfusion. Fluid overload and edema are frequent results of excessive use of plasma expanders. The direct effects of pressor agents such as dopamine on cerebral vasculature in preterm infants have not been fully investigated. Recent evidence has demonstrated that these agents may have a vasoconstrictive action²⁷ and may even reduce cerebral perfusion.^{28 29} Although dopamine causes a rise in MABP this may be a result of either improved left ventricular output³⁰ or of increased systemic vascular resistance. Hence, therapeutic measures such as inotrope infusions to maintain MABP more than arbitrary levels may be inappropriate and even harmful.

Our data show a strong dependence of CBF on Paco ₂ and emphasize the need to monitor Paco ₂ continuously and to use ventilatory strategies that minimize the risk of hypocarbia.