Elevations of Arterial Blood Pressure and Pressure-Passive Cerebral Circulation.

Concerning the role of elevations in arterial blood pressure, the presence of a pressure-passive cerebral circulation would be expected to lead to an increase in cerebral blood flow in association with increases in blood pressure, with the potential consequence being rupture of vulnerable germinal matrix vessels. The striking increase in cerebral blood flow associated with increases in blood pressure can be shown in real time by near-infrared spectroscopy ( Fig. 24.20 ). A decisive demonstration of the relation between pressure-passive cerebral circulation and the occurrence of IVH was obtained from a classic study of 57 preterm infants supported by mechanical ventilation during at least the first 48 hours of life ( Fig. 24.21 ). Infants in whom ultrasonographic signs of severe IVH developed had prior evidence of a pressure-passive cerebral circulation, whereas those with intact cerebrovascular autoregulation developed either no hemorrhage or only mild hemorrhage (see Fig. 24.21 ). The work of Tsuji and co-workers showed that 47% of infants with impaired cerebrovascular autoregulation developed IVH (or periventricular leukomalacia, or both), whereas only 13% of those with intact autoregulation developed these lesions. Consistent with a potential role for arterial hypertension in this setting is the demonstration of a relationship between maximum systolic blood pressure above a threshold value and subsequent occurrence of IVH. The limit for the highest tolerable peak systolic blood pressure was markedly lower for the smaller infants. A particular role for minute-to-minute alterations in blood pressure has also been demonstrated.

Changes in blood pressure (mean arterial pressure [MAP]) and cerebral perfusion (hemoglobin difference [HbDiff]) during a diaper change.

Simultaneous tracings were obtained from a premature infant (30 weeks of gestational age). Note the marked, parallel increase in cerebral perfusion, determined by near-infrared spectroscopy (NIRS), and in arterial blood pressure, obtained from an umbilical artery catheter.

(Courtesy Dr. Adre du Plessis.)

Cerebral blood flow (CBF) —mean arterial blood pressure (MABP) reactivities (percentage of change in CBF per millimeter of mercury change in MABP) in premature infants before intracranial hemorrhage.

CBF-MABP reactivities were obtained in the first 2 days of life (primarily in the first 24 hours) in 57 mechanically ventilated preterm infants who had normal ultrasound scans at the time of the reactivity measurements and who were followed subsequently by ultrasonography. Groups A, B, and C were determined by the results of the subsequent scans. The average reactivity and 95% confidence limits for each group are shown. Intact autoregulation (i.e., zero value for CBF-MABP reactivity) was present in those infants who had subsequent scans that were normal or showed only mild hemorrhage. Infants who later developed severe hemorrhage had a pressure-passive cerebral circulation.

(Redrawn from Pryds O, Greisen G, Lou H, Friis-Hansen B. Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation. J Pediatr . 1989;115:638–645.)

A more recent study continued to suggest the importance of elevations in cerebral perfusion being associated with high-grade IVH. Thus cranial Doppler studies for middle cerebral artery cerebral blood flow velocity in 185 preterm infants who were receiving mechanical ventilation showed that severe IVH (grades 3 to 4) was associated with an elevation in diastolic closing margin—a measure of cerebral perfusion in diastole that exceeds “cerebral closing margin.” The measures were a complex combination of assumptions based on Doppler-based estimations of cerebrovascular resistance and compliance. This modeling requires replication, but the findings suggest that high-grade IVH was associated with excessive cerebral perfusion. The timing of this elevation in relation to the timing of the IVH was not delineated within the study.

Moreover, as discussed in Chapter 13 , the upper limit of the normal autoregulatory range in the infant is dangerously close to the upper limit of the range of normal blood pressure. Studies in developing animals indicate that the receptor number for specific vasoconstricting prostaglandins, which are important in setting the upper limit of the autoregulatory range in the adult, are low early in maturation and thereby impair protection of the cerebral circulation from increases in blood pressure.

Whether the pressure-passive cerebral circulatory state relates to dysfunctional autoregulation per se, to maximal vasodilation caused by hypercarbia or hypoxemia (or both), to the cranial trauma of even a normal vaginal delivery, to dopamine therapy for hypotension, or to normal arterial blood pressures in the premature infant that are dangerously close to the upslope of a normal autoregulatory curve remains unclear. Experimental support for these several possibilities is available (see Chapter 13 ). Whatever the mechanism, however, the balance of current data imparts particular importance to events that cause elevations in arterial blood pressure, especially abrupt elevations, in the small premature infant.

Causes of Increased Arterial Blood Pressure in the Human Newborn.

The causes of abrupt elevations in arterial blood pressure sometimes shown to be accompanied by increased cerebral blood flow velocity by the Doppler technique, or increased cerebral blood volume by near-infrared spectroscopy in the premature infant, are clearly important to detect (and to prevent, whenever possible; Table 24.6 ). These causes include the following: such physiological events as rapid eye movement (REM) sleep and the first minutes and hours after birth; such caretaking concomitants as inadvertent noxious stimulation, abdominal examination, handling (see Figs. 24.10 and 24.22 ), instillation of mydriatics, and tracheal suctioning ( Fig. 24.23 ); systemic complications such as pneumothorax and rapid infusion of colloid; and neurological complications such as seizures.

Increases of arterial blood pressure in the small premature infant.

Continuous recording of mean aortic pressure in a 20-hour-old premature infant weighing 880 g. Note the marked and sustained increase with manipulation. The infant subsequently developed an intraventricular hemorrhage.

(From Lou HC, Lassen NA, Friis-Hansen B. Is arterial hypertension crucial for the development of cerebral haemorrhage in premature infants? Lancet. 1979;1:1215–1217.)

Changes in blood pressure with tracheal suctioning in premature infants.

Note the increase in blood pressure that accompanied suctioning in all but one infant.

Although the degree to which these events contribute to the pathogenesis of IVH requires further quantitation and probably depends on concomitant clinical circumstances, particular importance can be attributed to pneumothorax . In one earlier study of nine infants, pneumothorax was accompanied consistently by abrupt elevations of systemic blood pressure and cerebral blood flow velocity, and these circulatory changes were followed within hours by IVH. Studies in newborn dogs documented abrupt increases in arterial blood pressure on rapid evacuation of pneumothorax. Thus both clinical and experimental data emphasize the potentially deleterious circulatory effects of neonatal pneumothorax.

The complexity of interaction between respiratory and cardiovascular factors in the pathway to IVH is also notable with regard to pneumothorax. A major reduction in the risk of pneumothorax occurred following the administration of exogenous surfactant therapy. Indeed, the administration of surfactant reduced the risk of pneumothoraxes by almost 50% (RR 0.63; 95% CI, 0.53 to 0.75). However, despite this reduction in pneumothorax with surfactant administration, there has been no reduction in the incidence of IVH. One possible explanation for this lack of reduction in IVH may relate to changes in cardiovascular and respiratory stability during surfactant administration. As early as 1992, it was noted that during surfactant administration adverse changes in systemic and cerebral oxygenation could be seen. This has been replicated with less severe impact in recent years, with 62% of premature infants displaying reductions in cerebral electrophysiological activity with intubation and surfactant administration. Thus surfactant administration may have a double-edge effect with a positive impact, with reduction of pneumothorax being offset by a potential negative effect of reduced cerebral perfusion during its administration. To determine the impact of therapies during this period of physiological instability in the preterm infant, monitoring of cerebral perfusion can provide much-needed guidance.

Relevant Experimental Studies: Role of Hypertension.

The particular importance of abrupt increases in systemic blood pressure, and cerebral blood flow in pathogenesis has been demonstrated conclusively in elegant experimental studies in the newborn beagle puppy and in the preterm sheep fetus. The newborn puppy, which has been studied most extensively, has a subependymal germinal matrix approximately comparable to that of the human premature infant of 30 to 32 weeks of gestation. Germinal matrix hemorrhage–IVH is produced most readily in this animal by a sequence of hypotension and hypertension produced by blood removal and volume reinfusion ( Fig. 24.24 ). The marked increase in germinal matrix flow provoked by hypertension has been demonstrated strikingly by autoradiography ( Fig. 24.25 ).

Intraventricular hemorrhage in the newborn beagle puppy.

Gross intraventricular hemorrhage with dilation of the lateral ventricle (arrow) in cerebrum of a 24-hour-old puppy subjected to hypertension.

(From Goddard J, Lewis RM, Armstrong DL, Zeller RS. Moderate, rapidly induced hypertension as a cause of intraventricular hemorrhage in the newborn beagle model. J Pediatr . 1980;96:1057–1060.)

Increase in blood flow to germinal matrix with increase in arterial blood pressure in the newborn dog.

Blood pressure was elevated by infusion of phenylephrine. Blood flow to the germinal matrix was measured by ¹⁴ C-iodoantipyrine autoradiography.

(From Pasternak JF, Groothuis DR. Autoregulation of cerebral blood flow in the newborn beagle puppy. Biol Neonate . 1985;48:100–109.)

Rapid Volume Expansion.

The role of rapid volume expansion (see Table 24.4 ) involves not only the administration of blood or other colloid, as described in relation to systemic hypertension, but also the administration of hyperosmolar materials, such as hypertonic sodium bicarbonate. Pressure-passive cerebral circulation may not be the sole or even the principal means by which such infusions may lead to IVH, particularly in the case of sodium bicarbonate. Although the dangers of rapid infusion of hyperosmolar solutions had been noted for many years, an association of IVH in the premature infant administered sodium bicarbonate was emphasized initially by Simmons and co-workers from study of an autopsy population. The association was later confirmed in a CT study of premature infants, and the importance of rapidity of infusion was made apparent. Conflicting reports on the pathogenetic role of sodium bicarbonate relate in part to the failure to take into account such factors as rapidity of administration and also to the problems of extrapolating data to living infants from studies of dead infants, particularly in the case of IVH. At any rate, the mechanism for the effect of rapid infusion of hyperosmolar sodium bicarbonate on intracranial hemorrhage may relate in part to the abrupt elevation of arterial pressure of carbon dioxide (Pa co ₂ ) that results in the poorly ventilated or nonventilated patient from the buffering effect of the bicarbonate. The elevated Pa co ₂ would then act on cerebral arterioles, by causing an increase in perivascular hydrogen ion (H ⁺ ) concentration, to increase cerebral perfusion as outlined next.

Hypercarbia.

The role of hypercarbia in causing increases in cerebral blood flow of pathogenetic importance for IVH may be appreciable in selected infants. Hypercarbia, a common accompaniment of respiratory distress syndrome, respiratory complications, apneic episodes, and so forth, has been demonstrated conclusively to be a potent means for increasing cerebral blood flow in experimental studies (see Chapter 13 ). Indeed, careful studies of mechanically ventilated preterm infants show a pronounced reactivity of cerebral blood flow to changes in Pa co ₂ (≈30% increase in cerebral blood flow per kilopascal [kPa] increase in Pa co ₂ ) after the first 24 hours of life. Notably, in the first 24 hours of life, this normal reactivity was attenuated markedly (≈10% increase in cerebral blood flow per kPa increase in Pa co ₂ ) in mechanically ventilated infants with normal subsequent ultrasonograms, but it was actually absent in infants with subsequent severe IVH. This observation suggested that, in the first day of life at least, hypercarbia of at least a moderate degree may not be a major pathogenetic factor for severe IVH in mechanically ventilated infants. A similar lack of correlation between hypercarbia and IVH is apparent in several other studies. An increased risk for IVH after hypercarbia, however, is suggested in several other reports, including three that used multivariate analysis. In a particularly large study ( n = 463), hypercarbia (defined as Pa co ₂ >60 mm Hg) showed a positive relation with IVH. In a later study of permissive hypercapnia to 45 to 55 mm Hg (vs. 35 to 45 mm Hg in the control group) in ventilated premature infants, no statistically significant difference in IVH was noted between the groups, although the incidence of severe IVH was 29% in the permissive hypercapnia group versus 20% in the control group (not statistically significant). Thus a role for hypercarbia in the pathogenesis of IVH may require particularly marked elevations of Pa co ₂ . Consistent with this speculation is the demonstration that hypercapnia leads to clearly impaired autoregulation at Pa co ₂ levels above 45 mm Hg ( Fig. 24.26 ). Such levels were shown to be significantly associated with the occurrence of severe IVH and periventricular hemorrhagic infarction in a study of 58 infants.

Impaired autoregulation with hypercapnia.

Estimated mean slopes and 95% confidence intervals of the autoregulatory plateau for arterial carbon dioxide tension (Pa co ₂ ) values 30, 35, 40, 45, 50, 55, and 60 mm Hg for 43 very low birthweight infants. Bars indicate 95% confidence intervals for the mean slopes of the autoregulatory plateaus for Pa co ₂ 30 ( n = 82), 35 ( n = 94), 40 ( n = 100), 45 ( n = 103), 50 ( n = 100), 55 ( n = 90), and 60 mm Hg ( n = 83). The horizontal line at slope 0 indicates intact autoregulation. The estimated means of the slope of the autoregulatory plateau (cm/sec* mm Hg ⁻¹ ) increased as Pa co ₂ increased ( P = .004).

(From Kaiser JR, Gauss CH, Williams DK. The effects of hypercapnia on cerebral autoregulation in ventilated very low birthweight infants. Pediatr Res . 2005;58:931–935.)

Decreased Hemoglobin.

The role of decreased hematocrit in causing increases in cerebral blood flow of pathogenetic importance for IVH may be greater than was previously suspected. Thus, as described in Chapter 13 , an inverse correlation exists in the human infant between hemoglobin concentration and cerebral blood flow, as well as between the concentration of adult versus fetal hemoglobin (higher hemoglobin oxygen affinity) and cerebral blood flow. In one study of premature infants in the first days of life, cerebral blood flow increased by 12% per 1-mM decrease in hemoglobin. The inverse relationship between hematocrit and cerebral blood flow described previously in experimental studies has been suggested to result from changes in arterial oxygen content or blood viscosity. Because alterations in newborn hematocrit to less than 60% have little influence on blood viscosity, the major factor in the studies of human infants is considered to be related to arterial oxygen content and thereby cerebral oxygen delivery. Cerebral blood flow presumably increases to maintain cerebral oxygen delivery at a constant level. Consistent with this possibility, apparently stable premature infants with low hematocrits (<21%) had clinically unsuspected high cardiac output. The adaptive response of increased cerebral blood flow may become maladaptive if certain vulnerable capillary beds (e.g., in the germinal matrix) are exposed to the elevated cerebral blood flow. When one considers that iatrogenic blood loss, owing to repeated blood sampling, and low initial blood volume are common in sick premature infants, especially during the periods of highest risk for occurrence of IVH, the role of decreased hematocrit as a cause of IVH could be considerable.

Potentially consistent with supporting the role of anemia in the risk for IVH, a recent study demonstrated an increased risk of severe IVH among VLBW infants following a red cell transfusion within the first 72 hours of birth. This finding remained significant after controlling for confounding variables (RR, 2.02 [95% CI, 1.54 to 3.33]). The authors were unable to determine the underlying mechanism, given the retrospective nature of the review, but one possibility for the increased risk is concomitant anemia requiring transfusion, rather than the transfusion itself. However, the infants developing IVH may have been sicker and thus at greater risk. Indeed, although there was no difference in coagulation measures, the infants with IVH received more frozen plasma and platelet transfusions and had longer ampicillin courses, higher nucleated RBC counts, more vasopressor use, and a higher mortality rate.

Relevant in this context are results of studies of the timing of cord clamping. Delayed cord clamping (DCC; 30 seconds), compared with immediate cord clamping (6 to 7 seconds), is associated with a slightly higher baseline hematocrit (49% vs. 46%), higher mean blood pressure (33.8 vs. 31.9 mm Hg), increased superior vena caval flow, and a significantly reduced risk for IVH (14% vs. 36%). This reduction in IVH with DCC is supported by a meta-analysis of the randomized trials in preterm infants, although it is noteworthy that the largest studies included involve larger preterm infants with birthweights greater than 1500 g. Because of these benefits in preterm infants and the advantages of increasing iron stores in healthy term-born infants, the American College of Obstetricians and Gynecologists recommended a delay in umbilical cord clamping in vigorous term and preterm infants for at least 30 to 60 seconds after birth.

Blood Glucose.

Decreased blood glucose now should be considered in the evaluation of pathogenetic factors for IVH in view of the observation that cerebral blood flow increases twofold to threefold when blood glucose declines to levels lower than 1.7 mM in the premature infant. Blood glucose levels lower than 1.7 mM in premature infants are not unusual in the first days of life in many NICUs (see Chapter 25 ).

Increased blood glucose has also been evaluated as a potential risk factor for IVH. In a recent case-control study of high-grade IVH ( n = 70) compared with no IVH ( n = 108), infants with IVH had significantly more hyperglycemic events (2.9 ± 1.7 vs. 2.4 ± 1.8 events, P < .05) with longer duration (22.2 ± 14.2 vs. 14.1 ± 12.5 hours, P < .001) and a higher hyperglycemic index (1.0 ± 0.9 vs. 1.4 ± 1.0, P = .003). Respiratory distress syndrome, hypotension, and thrombocytopenia increased the adjusted OR for IVH. Hypoglycemia was not independently associated with IVH. Conversely, the increase in hyperglycemic duration most prominently increased the aOR for severe IVH (OR = 10.33; 95% CI, 10.0 to 10.6; P = .033). To avoid hyperglycemia, insulin therapy is often initiated. However, an important randomized controlled trial of tight glycemic control with insulin versus standard care documented a nonsignificant trend toward an increase in the incidence of grade III/IV IVH in the insulin-treated group (insulin 6/38 infants, 14%, vs. standard care 3/43, 7%, P = .35). The insulin-treated group did have more episodes of hypoglycemia. Thus avoidance of protracted hyperglycemia and hypoglycemia may be most prudent as further data are collected on this clinical factor.

Finally, it has been suggested that alterations in the osmotic gradient may occur with hyperglycemia and other metabolic derangements, such as hypernatremia, leading to an increase in the intravascular pressure relative to the surrounding extravascular tissue that may predispose to IVH. Several cohort studies have shown that those states associated with an alteration in the osmotic balance, such as hyperglycemia and hypernatremia (even high sodium intake in the absence of hypernatremia), are associated with an increased risk for IVH. However, the retrospective nature of these studies cannot delineate the underlying mechanism for this increased risk.

Importance of Venous Anatomy.

The particular importance of increased venous pressure in the pathogenesis of IVH relates in part to the venous anatomy in the region of the germinal matrix (see Fig. 24.6 ). Thus the direction of deep venous flow takes a peculiar U-turn in the subependymal region at the level of the foramen of Monro (i.e., the most common site of germinal matrix hemorrhage). Also at this site is the point of confluence of the medullary, thalamostriate, and choroidal veins to form, in sequence, the terminal vein and then the internal cerebral vein, which ultimately empties into the vein of Galen.

Labor and Delivery.

Concerning labor and delivery, marked increases in cerebral venous pressure must be common accompaniments. Indeed, in one study of 46 infants, when measurement of “fetal head compression pressure” was determined by a compression transducer positioned between the fetal head and the wall of the uterus, the overall mean pressure was 158 mm Hg. Deformations of the particularly compliant premature skull are likely to accentuate the increases in venous pressure caused by normal labor. Indeed, the deleterious effects of labor (see later discussion) appear to be most pronounced in the most premature infants. The skull deformations can lead to obstruction of major venous sinuses and presumably increased venous pressure. Support for this notion has been provided by studies of blood flow velocity in the sagittal sinus, cerebral blood volume, and intracranial pressure during such manipulations as external pressure on the skull or rotation of the neck. These effects may be expected to be greater with breech delivery. Available data are somewhat inconsistent concerning a relationship between such factors as presence or absence of labor, duration of labor, mode of delivery, and the occurrence of IVH, although in general the studies were not designed to address these issues specifically and were retrospective. The inconsistency of the data, however, does not rule out a contributory role of intrapartum events in causation of IVH in certain infants. Thus, in a study that addressed the role of presence or absence of labor, duration of labor, mode of labor, and potential confounders in a multivariate analysis, Leviton and co-workers showed that infants delivered vaginally were more likely to develop IVH than those delivered abdominally, that labor longer than 12 hours increased risk of IVH regardless of the mode of delivery, and that the occurrence of labor before abdominal delivery increased the incidence of IVH by 2 to 4 times, depending on the duration of labor ( Table 24.7 ). In a separate study of 201 VLBW infants, multivariate analysis also indicated an increased risk (2.2-fold) of IVH for infants delivered vaginally, a very low risk (7%) for infants delivered abdominally with no labor, and an increased risk among infants delivered abdominally for labor greater than 10 hours in duration (40%). Subsequent investigations of 229 and 254 infants, respectively, show an increased risk of IVH occurring in the first 3 to 12 hours of life as a function of active labor and vaginal delivery. Finally, a multicenter study of 4795 infants of less than 1500 g birthweight showed an incidence of grade III and IV IVH in 19% of vaginally delivered infants and 11% of those delivered by cesarean section without labor. On balance, these data suggest that labor and delivery influence the risk of IVH in premature infants and have implications concerning a potential role for cesarean section in prevention (see later discussion).

The most recent studies of mode of delivery relative to IVH have continued to demonstrate conflicting results, with several finding no association with method of delivery. A recent study of 158 infants born at less than 1500 g found that there was an increased risk of mild IVH among infants with vaginal delivery versus cesarean section before the second stage of labor. The studies that did not report an association between mode of delivery and IVH did not comment on the duration of labor or the stage during which the cesarean section was performed, possibly explaining the discrepancies in the literature. Of note, it has been recently shown that head position, both before delivery and in the neonatal nursery, may also alter cerebral venous drainage. One study with near-infrared spectroscopy showed that cerebral venous drainage may be impaired in prone or side positions.

Hypoxic-Ischemic Injury.

With perinatal asphyxial events, circulatory collapse may lead to hypoxic-ischemic cardiac failure and, as a consequence, increased cerebral venous pressure. The cardiac disturbance is caused by injury of papillary muscle, subendocardial tissue, and myocardium. The importance of increased venous pressure in association with asphyxia in the causation of IVH was shown in experimental studies of preterm fetal sheep. Thus it seems likely that increased venous pressure could contribute to the propensity to IVH observed after serious asphyxia. Consistent with this notion are the strong relationships among such factors as severe umbilical cord acidemia, low Apgar scores, the need for neonatal resuscitation, and the occurrence of severe IVH (see later). Other factors associated with asphyxia, such as ischemic injury to the germinal matrix and hypercarbia, are also likely important.

Respiratory Disturbances.

Concerning respiratory disturbances , available data suggest that such factors as positive-pressure ventilation with relatively high peak inflation pressure, tracheal suctioning, abnormalities of the mechanics of respiration, and pneumothorax may be major causes of increased cerebral venous pressure in the premature infant. Thus, extending earlier observations, Cowan and Thoresen used Doppler measurements of blood flow velocity in the superior sagittal sinus to demonstrate a striking sensitivity of the venous circulation to the level of peak inflation pressure; the smallest infants exhibited the most marked effects.

The possibility of a particular importance for venous abnormalities in causation of IVH was raised by a study of intubated preterm infants with respiratory distress syndrome under conditions in which dangerous alterations in arterial blood pressure occur (i.e., elevations with tracheal suctioning and fluctuations with breathing out of synchrony with the ventilator ). The effects on the venous circulation were dramatic. With elevations in arterial blood pressure produced by tracheal suctioning, pronounced changes in venous pressure also occurred ( Fig. 24.27A ). Moreover, because the magnitude and the direction of the changes in venous pressure often were not similar to those in arterial pressure, striking changes in perfusion pressure resulted (see Fig. 24.27B ). Similarly, because fluctuations in arterial blood pressure were associated with noncoordinated fluctuations in venous pressure ( Fig. 24.28A ), pronounced and continuous alterations in perfusion pressure resulted (see Fig. 24.28B ). Thus, under both circumstances, decreases in perfusion pressure by as much as 10 to 20 mm Hg were followed in seconds by abrupt, similar increases in perfusion pressure. Because these changes occur essentially on a beat-to-beat basis, it is unlikely that autoregulation, even if functional, could protect critical capillary beds by causing the changes in arteriolar diameter necessary to maintain constant cerebral blood flow under such circumstances. Thus the previously established role for disturbed mechanics of respiration with fluctuations in arterial blood pressure in the causation of IVH (see Table 24.5 ) may be mediated as much by alterations on the venous side of the cerebral circulation as by alterations on the arterial side. A similar conclusion can be drawn for the previously established role in the causation of IVH of abruptly increased arterial blood pressure with pneumothorax, because this respiratory complication has been shown to cause abruptly increased venous pressure as well. A study of 58 cases of severe IVH with periventricular hemorrhagic infarction showed a significant relationship of pneumothorax with the occurrence of the lesion.

Venous pressure response to suctioning.

(A) Simultaneous venous pressure and arterial blood pressure tracings from a premature infant during tracheal suctioning (arrowhead) . Note the pronounced increases in venous pressure after onset of suctioning. (B) Graphic plot of calculated changes in perfusion pressure during the same suctioning episode.

(Adapted from Perlman JM, Volpe JJ. Are venous circulatory abnormalities important in the pathogenesis of hemorrhagic and/or ischemic cerebral injury? Pediatrics . 1987;80:705–711.)

Correlation of fluctuations in arterial and venous pressure.

(A) Simultaneous venous pressure and arterial blood pressure tracings from an infant with fluctuating blood pressure. Note that the marked fluctuations in arterial pressure are associated with marked fluctuations in venous pressure. (B) Graphic plot of calculated changes in perfusion pressure in the same infant.

(Adapted from Perlman JM, Volpe JJ. Are venous circulatory abnormalities important in the pathogenesis of hemorrhagic and/or ischemic cerebral injury? Pediatrics . 1987;80:705–711.)

Importance of Pressure-Passive Cerebral Circulation.

Decreases in cerebral blood flow, occurring either prenatally (perhaps primarily intrapartum) or postnatally, may play an important role in pathogenesis of IVH in certain infants. The principal consequence of the decreased cerebral blood flow is injury of germinal matrix vessels, which rupture subsequently on reperfusion. The importance of vascular border zones and end zones in the matrix, as well as the intrinsic vulnerability of the matrix vessels to oxygen deprivation, is emphasized later (see the section on vascular factors ). As indicated earlier, hemorrhagic hypotension preceding volume reexpansion is the optimal means to produce IVH experimentally in the newborn beagle puppy. In the premature infant, decreases in cerebral blood flow are most likely with perinatal hypoxia-ischemia and with various postnatal events that result in systemic hypotension. Because of the pressure-passive cerebral circulation in sick premature infants, this hypotension can lead to a decrease in cerebral blood flow. Recall that a detailed study of 90 premature infants in the first 5 days of life showed that more than 95% had pressure-passive periods, with a mean total time of pressure-passivity of 20%.

Perinatal Hypoxic-Ischemic Events.

Although it is not an obligatory event for development of IVH, the infant with prior perinatal asphyxia clearly has an increased likelihood of developing IVH, and, in our experience, the hemorrhage in such infants tends to be relatively large. Indeed, a study of 58 infants with periventricular hemorrhagic infarction found a strong association of the lesion with fetal distress and the need for emergency cesarean section, low Apgar scores, and the need for respiratory resuscitation. Perinatal hypoxic-ischemic events presumably explain, at least in part, the relation between low Apgar scores, early acidosis, early use of bicarbonate or pressors, hypocarbia, and the subsequent overall occurrence of IVH, particularly lesions that develop in the first 12 hours. ^a

a References .

More recent studies have documented a high incidence of seizures in the preterm infant in the first 72 hours of life, accompanied by a strong association with the presence of IVH. In one study, 95 VPT infants underwent aEEG monitoring during the first 72 hours of life. The overall incidence of seizures in this sample was 48%. High seizure burden was associated with increased risk of IVH throughout each of the 3 days of monitoring. The seizures observed in this very preterm cohort demonstrated a similar evolution in the timeline to the seizures of a term infant suffering from hypoxic-ischemic encephalopathy (HIE) with the highest median seizure burden during the 0- to 24-hour period. These observations support a potential role of perinatal asphyxia in the pathway to IVH.

Postnatal Ischemic Events.

The importance of postnatal decreases in cerebral blood flow in the pathogenesis of IVH has been shown by studies using a combination of noninvasive methods to evaluate the cerebral circulation. Notably, however, a relationship with decreases in mean arterial blood pressure , when infants who developed IVH were compared with infants who did not develop IVH, was not uniformly shown. Thus the changes in cerebral hemodynamics could occur without pronounced disturbances of mean arterial blood pressure . These findings of a lack of association between mean arterial blood pressure and IVH were recently replicated. Rhee and co-workers documented no relationship between systemic blood pressure and risk for IVH but did document a relationship between measures of cerebral blood flow with IVH. This finding continues to emphasize the inability of systemic measures of blood pressure to define the adequacy of cerebral perfusion. Because impaired autoregulation and fluctuations in blood pressure are both frequent but not necessarily constant in the sick preterm infant, intermittent declines in cerebral blood flow could occur without pronounced changes in mean blood pressure. Thus continuous measurements of the cerebral circulation are critical in determining changes in cerebral blood flow in the sick, ventilated infant .

Nevertheless the importance of postnatal decreases in arterial blood pressure in the pathogenesis of IVH is suggested by several studies in which arterial blood pressure was monitored continuously from birth or the first hours of life. In a study of approximately 25,000 VLBW infants, severe IVH was 3 times more common in those infants requiring cardiopulmonary resuscitation (15.3%) at delivery than in those not requiring resuscitation (4.9%). A relationship between arterial hypotension and subsequent occurrence of IVH has been documented frequently. Although the possibility of ischemic insult to germinal matrix in the postnatal period is obvious in association with such occurrences as severe apnea, myocardial failure, sepsis, and so forth, sharp decreases in blood pressure have also been shown to precede the more widely recognized increases provoked by ordinary caretaking procedures. By continuous monitoring of arterial blood pressure during such procedures as auscultation of the chest, taking of temperature, and suctioning, the increases in blood pressure previously noted were shown to be preceded by a decrease in blood pressure. The decreases were most pronounced in the infants requiring the most intensive ventilatory support. The biphasic response of decrease and then increase in blood pressure is qualitatively similar to the sequence required to produce IVH in the beagle puppy (see earlier). The rebound elevation of cerebral blood flow velocity observed after apnea and bradycardia is relevant in this context.

Of particular importance concerning a role for postnatal ischemia is the demonstration by near-infrared spectroscopy in 24 preterm infants in the first 24 hours of life that cerebral blood flow was significantly lower in infants with subsequent demonstration of IVH (median, 7.0 mL/100 g/min) than in those without IVH (median, 12.2 mL/100 g/min). In addition supportive of a relationship between postnatal ischemic events and the occurrence of IVH is the demonstration of decreased cardiac output in the first 36 hours of life in infants who developed the lesion, especially with severe IVH. Similarly, the occurrence of periventricular hemorrhagic infarction with severe IVH was strongly associated with metabolic acidosis in the first days of life and a need for pressor support and volume expanders. Finally, the beneficial effect of delayed versus immediate clamping of the umbilical cord on the incidence of IVH is considered to be likely caused in considerable part by stabilization of cerebral blood flow and prevention of ischemia. However, as mentioned earlier, the interrelationships between cerebral hypoperfusion and IVH appear complex, with an early ischemic period potentially increasing the vulnerability for reperfusion injury to the germinal matrix. These evolutions can only be evaluated with the presence of monitoring of both systemic and cerebral hemodynamics simultaneously.

The contributory role of maternal intrauterine infection and fetal systemic inflammation in the pathogenesis of IVH likely is mediated by effects on the cerebral circulation. Although data are not entirely consistent concerning a relationship between chorioamnionitis and the occurrence of IVH, several reports indicate an association with IVH of elevated levels of specific cytokines, especially interleukin-6 (IL-6), in cord or early neonatal blood. Infants with chorioamnionitis and fetal cord vasculitis had higher IL-6 levels and likelihood of IVH than those with fetal vasculitis alone. The findings suggest that maternal intrauterine infection that leads to a systemic fetal inflammatory response is critical. Indeed, a recent large study of periventricular hemorrhagic infarction ( n = 58) found no association with maternal fever, maternal infection, or pathologically confirmed chorioamnionitis. The principal mechanism of the fetal/neonatal cytokine effect is likely circulatory disturbance. Thus decreased arterial blood pressure, often requiring pressor support, has been shown in the infants with elevated IL-6. IL-6, like several other cytokines, has vasodilator properties that likely lead to the decreased blood pressure and presumably cerebral blood flow ( Fig. 24.29 ). Whether IL-6 or related cytokines impair cerebrovascular autoregulation is plausible but not yet shown.

Relationship between mean arterial blood pressure (BP) and interleukin-6 (IL-6) concentration.

Mean BP was inversely correlated ( R ² = 0.21, P < .01) with log IL-6. Solid square, chorioamnionitis; open square, no chorioamnionitis.

(From Yanowitz TD, Jordan JA, Gilmour CH, Towbin R, et al. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res . 2002;51:310–316.)

Platelet-Capillary Function.

Regarding platelet-capillary function, an earlier prospective study is of particular interest. Forty percent of infants of less than 1500 g birthweight exhibited platelet counts less than 100,000/mm ³ , and most of these thrombocytopenic infants had abnormal bleeding times. The incidences of IVH in thrombocytopenic versus nonthrombocytopenic infants were 78% versus 48% for those weighing less than 1000 g. Additional analysis for other factors potentially important for causation of IVH suggested that the presence of thrombocytopenia was an independent pathogenetic factor. Subsequent work has both confirmed and refuted a role for thrombocytopenia in the pathogenesis of IVH.

While subsequent work has both confirmed and refuted a role for thrombocytopenia in the pathogenesis of IVH, the most recent studies have tended to support an association. The largest of these evaluated 655 infants born at less than 32 weeks’ gestational age, 44% of whom had thrombocytopenia. Within this cohort there was a 30% (85/286) incidence of IVH in those with thrombocytopenia versus 14% (53/369) in those with a normal platelet count. Interestingly there was no correlation between the severity of thrombocytopenia and the incidence of IVH; rather the relationship was dichotomous. Similarly no protective effect was demonstrated with increased platelet transfusion, as might be expected if there was a linear correlation with platelet count. In an alternate cohort of 251 neonates, Rastogi and colleagues found no significant difference in severe IVH with or without thrombocytopenia in isolation, but the odds of a severe IVH were increased fourfold if there was a sudden drop in the platelet count. The odds increased to 14 times the baseline if this sudden decline occurred from a baseline of thrombocytopenia. The exact mechanism between IVH and thrombocytopenia has not yet been elucidated. Some evidence suggests that premature infants demonstrate elevated levels of prostacyclin before the occurrence of IVH. Because prostaglandins have an impact not only on platelet function but also on such factors as cerebral blood flow and free radical production that also may be important in pathogenesis of IVH, it is not clear to what extent effects on platelet-capillary function were independently related to causation of IVH.

Perhaps relevant to the possibility of disturbed platelet function (rather than platelet count) in some infants before the occurrence of IVH is the study by Rennie and co-workers of circulating levels of the principal metabolite of prostacyclin in preterm infants. Prostacyclin is a potent perturbant of platelet-capillary function and is produced in elevated amounts, probably by lung, in respiratory distress syndrome and with mechanical ventilation. Evidence was obtained for elevated levels of prostacyclin before the occurrence of IVH. Because prostaglandins additionally have an impact on such factors as cerebral blood flow and free radical production that also may be important in the pathogenesis of IVH, it is not clear to what extent effects on platelet-capillary function were independently related to causation of IVH. More data are needed on these issues.

Coagulation.

Disagreement exists concerning the role of coagulopathy in causation of IVH. It could be postulated that prothrombotic disturbances (e.g., factor V Leiden mutation, prothrombin mutation) would increase IVH by provoking deep venous thrombosis or would decrease IVH by preventing extension of small hemorrhages. Because disturbances of coagulation are not uncommon in preterm infants with other provocative factors for IVH (e.g., serious respiratory distress syndrome, asphyxia) or may occur secondary to major hemorrhage, an independent pathogenetic role for such disturbances has been difficult to establish. Although administration of fresh frozen plasma was shown in one study to decrease the incidence of IVH, no effect on coagulation measures accompanied the apparent beneficial effect. Moreover, a later investigation failed to show a beneficial effect of prophylactic early fresh frozen plasma in premature infants. Administrative of antithrombin III, known to be low in premature infants, did not alter the incidence of IVH in a randomized study.

Recent reports have examined the potential role of mutations in coagulation proteins as possible risk modifiers for IVH. Several common mutations in coagulation proteins are associated with increased tendency to thrombotic events. Those that have been investigated most included factor XIII Val34Leu mutation, factor V Leiden, factor II (prothrombin) G20210A, and MTHFR C677T. Factor XIII stabilizes the fibrin clot, and thus it is hypothesized that low levels of factor XIII may predispose to IVH. Low factor XIII levels in preterm infants may contribute to the relatively higher fibrinolytic activity documented in preterm infants. Two recent studies, however, failed to find any association between factor XIII-Val34Leu mutation and IVH. Factor V Leiden is a common mutation in the white population and is associated with thrombotic events, with decreased inactivation of factor V leading to increased thrombin generation. The role of factor V Leiden in risk of IVH is unclear. Results have been conflicting with some studies suggesting a significant role for factor V Leiden in the risk of IVH, while others suggest no role, or a mixed pattern, whereby the mutation is associated with low-grade IVH (grade I or II), but a reduced risk of severe IVH.

There have been similarly conflicting findings for prothrombin G20210A mutations and the development of IVH. Two mutations (C677T and A1298C) in the 5,10-methylene tetrahydrofolate reductase (MTHFR) gene lead to hyperhomocysteinemia under conditions of decreased folate or B ₁₂ concentrations and an increased risk of thrombosis. Although no consistent association has been found with this mutation and IVH, a recent report by Ment and co-workers did find a significantly increased association of this polymorphism among preterm infants, specifically with grade II–IV IVH.

Potential Role of Drugs.

The possibility that maternal ingestion of certain drugs , such as aspirin, can result in impaired neonatal hemostasis and provoke IVH was suggested by two earlier reports. It is not likely, however, that such factors play a major independent role. Similarly, retrospective data suggest that the use of heparin as an intravascular flush to maintain patency of umbilical artery catheters increases the risk of IVH by fourfold. Whether this effect is related to a disturbance of coagulation or to selection bias because of the use of heparin in sick premature infants who develop IVH for other reasons is unclear. A subsequent report also suggested an increasing risk for IVH in premature infants as a function of the daily dose of heparin. More data are needed.

Prevention of Premature Birth.

The most decisive way to prevent IVH would be to prevent premature birth. Those pathogenetic factors referable to the regulation of cerebral blood flow and the microvascular network of the germinal matrix of the premature brain obviously cannot be altered after birth. Indeed, the magnitude of the problem of IVH relates directly to the fact that annually more than 300,000 premature infants (birthweight <2500 g) are born in the United States (≈8% of the 4,000,000 births yearly), and more important, approximately 60,000 of these infants weigh less than 1500 g at birth. Notably, in the United States, the rate of very low birthweight (i.e., <1500 g) infants has actually increased from 1.17% to 1.42% in the past 30 years.

Attempts at prevention of premature birth have been based on three major approaches, operating in sequence: (1) identification of the woman at high risk for premature delivery; (2) management of such a woman with a combination of patient education, treatment of infection, comprehensive health care, and early detection of premature labor; and (3) early treatment of premature labor, primarily with tocolytic agents. Despite comprehensive prevention programs and aggressive use of tocolytic agents, or both, results have not shown consistent benefit. ^a

a References .

Of particular interest has been the beneficial effect of progesterone or 17-alpha-hydroxyprogesterone caproate (17P) in reduction of preterm delivery. In one large multicenter, randomized clinical trial of 17P begun at 16 to 20 weeks of gestation in women with a history of previous preterm delivery, the rate of preterm delivery in the 17P-treated group was 36% versus 55% in the placebo group. Notably, the incidence of IVH in these infants who weighed less than 2500 g at birth was 1.3% in the 17P-treated group versus 5.2% in the placebo group. A more recent study of 45 singleton pregnancies randomized after successful tocolysis and arrest of preterm labor included 22 women who received 17 P and 23 placebo. The mean gestational age at delivery ( P = .07) and the interval from treatment to delivery ( P = .2) were not affected by 17 P. However, significantly fewer women in the 17 P group delivered at less than 34 weeks (14 vs. 21, P = .03). There was also a significant reduction in the risk of neonatal sepsis ( P = .04) and grade III/IV IVH ( P = .02) in the 17 P group.

Transportation in Utero.

If premature labor and delivery cannot be prevented, then the pregnant woman should be transported to a perinatal center specializing in high-risk deliveries. Infants thus transported in utero have a considerably lower incidence of IVH than apparently similar infants transported after delivery. Whether this difference relates to inherently lower risk in pregnant women who are transported compared with those who are not transported, the type of management of labor and delivery, neonatal resuscitation factors, complications during transport, or a combination of these factors is not yet clear.

Prenatal Pharmacological Interventions.

Because of the possibility that factors related to labor and delivery or to the immediate postnatal period may play a role in the pathogenesis of IVH, a preventive intervention that could be instituted in the presence of impending premature delivery has been sought. Antenatal administration of glucocorticoids , usually betamethasone or dexamethasone, currently is the most clearly beneficial antenatal intervention to decrease the incidence of all varieties of IVH ( Table 24.19 ). The beneficial effect was observed initially in studies of the use of antenatal glucocorticoids to promote fetal lung maturation. An early brief report suggested that this therapy resulted in a decreased incidence of IVH postnatally. In a subsequent careful study, the incidence of germinal matrix hemorrhage–IVH was twofold to threefold lower in infants whose mothers received a complete course of steroids antenatally, compared with infants whose mothers received no steroids or an incomplete course. Similar beneficial effects of glucocorticoid have been well documented. Multivariate analysis suggested that the effect was not related to a lower incidence of complications of respiratory distress syndrome, although the severity of the respiratory disease was less in the treated infants. A large amount of subsequent work demonstrated the beneficial effect of antenatal glucocorticoids ( Fig. 24.37 ). The beneficial effect has been observed most decisively after a complete course of treatment (maternal receipt of two or more doses of glucocorticoid within a week of delivery with an interval of 12 hours from the last dose [or 24 hours from the first dose] to delivery) but also has been observed with a partial course (less than two doses in the week before delivery). ^a

a References .

Intraventricular hemorrhage and antenatal steroids.

Unadjusted odds ratio and 95% confidence intervals for the occurrence of severe intraventricular hemorrhage after antenatal steroid treatment (vs. no treatment) in three separate studies of infants of less than 1500 g birthweight (the National Institute of Child Health and Human Development Neonatal Research Network [NICHD], the Vermont-Oxford Trials Network [VTOX], and the database of Ross Laboratories [Ross]). The total number of infants was approximately 18,000.

(Data from Wright LL, Horbar JD, Gunkel H, Verter J, et al: Evidence from multicenter networks on the current use and effectiveness of antenatal corticosteroids in low birth weight infants. Am J Obstet Gynecol . 1995;173:263–269.)

Repeated antenatal glucocorticoid courses have not been recommended as routine clinical practice because of adverse effects on fetal growth and cerebral cortical maturation documented in animals and humans. However, one randomized clinical trial ( n = 982) showed benefit of repeat doses for respiratory outcome but no additional benefit concerning incidence of IVH. Another, smaller trial ( n = 249) of mothers who received a course of betamethasone followed by a single booster dose of betamethasone just before preterm birth showed a trend for worse survival and increased respiratory disease but no effect on incidence of IVH for those receiving the booster dose of betamethasone versus placebo.

The most recent Cochrane review of single versus repeated course of antenatal corticosteroids included 10 trials, with a total of 4733 women and 5700 infants. The comparison was between treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment. Repeated corticosteroid reduced the risk of respiratory distress syndrome (RR 0.83; 95% CI, to 0.91). There was no effect on the incidence of IVH. Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference [MD] −75.79 g; 95% CI, –117.63 to –33.96; nine trials, 5626 infants). At early childhood follow-up, no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments. Finally, twin gestations may not show the same beneficial effects of antenatal corticosteroids, with a recent study showing no difference in respiratory distress syndrome or other neonatal morbidities, including IVH.

The basis for the beneficial effect of antenatal steroids may relate to the improved cardiovascular stability in the treated infants. Thus antenatal steroid therapy is associated with less need for blood pressure support and less hypotension postnatally. That this beneficial postnatal hemodynamic effect could be related to improved placental blood flow (and thereby less likelihood of impairment of the infant’s cerebrovascular autoregulation) seems possible because antenatal betamethasone has been shown to lead to a decrease in placental vascular resistance. Perhaps relevant in this context is the observation that antenatal steroid administration is associated with a reduced incidence of cystic periventricular leukomalacia postnatally. The possibility also exists that the therapy leads to the beneficial effect on IVH in part by stimulation of maturation of brain structures (e.g., germinal matrix).

In conclusion, antenatal corticosteroids reduce the risk for IVH in singleton preterm infants, particularly when a completed course is given and betamethasone is the agent administered. The biological basis for this benefit remains unclear. Optimal preparations, dosing, and timing to delivery remain worthy of investigation, particularly in the setting of multiple births.

Antenatal administration of phenobarbital led to interesting results in five studies. Initial studies raised the possibility that antenatal phenobarbital may have a small protective effect against IVH. However, later work failed to show a significant protective effect. Currently this approach appears not to be beneficial for the prevention of IVH.

Because the function of vitamin K–dependent coagulation factors in preterm infants is approximately 30% to 60% of the function in adults, vitamin K was administered intramuscularly to women in premature labor at least 4 hours before delivery in an attempt to prevent IVH. The incidence of IVH in the prenatally treated infants was 5%, compared with 33% in the control infants. Although the infants treated prenatally with vitamin K had normal prothrombin activity (compared with 67% of normal in control infants), no statistically significant relationship existed between prothrombin activity and the occurrence of IVH. In a subsequent larger study ( n = 100), antenatal administration of vitamin K resulted in a lower incidence of total IVH (16% vs. 36% in control infants) and of severe IVH (0% vs. 11% in control infants). However, uncertainty concerning the role of vitamin K per se persists, despite these interesting data. Moreover, two later studies of antenatal vitamin K administration, combined in one of the studies with antenatal phenobarbital administration, showed no significant beneficial effect on hemostasis or incidence and severity of IVH. Thus, on balance, it does not appear that antenatal vitamin K is useful for the prevention of IVH.

As described in Chapter 16 , some data, although not consistent, indicate that the use of antenatal magnesium sulfate (principally for tocolysis) is followed by a lower incidence of cerebral palsy in the premature infants so treated. Although one preliminary report suggested that antenatal magnesium sulfate therapy results in a lower incidence of “grade III or IV IVH,” most data do not show a beneficial effect on IVH or cerebral palsy, or both. More concerning, some reports noted an increase in perinatal and postnatal mortality after antenatal magnesium administration. Other studies did not show this increased mortality. A more recent report showed a decreased incidence of IVH after the combination of antenatal magnesium and aminophylline, but the population was not randomized, and the numbers of infants with IVH were small (1 of 78 in the treated group and 7 of 68 in the control group). A review of the nine best trials concluded that antenatal magnesium sulfate has no beneficial effect on “the risk of neonatal morbidity.”

Optimal Management of Labor and Delivery—Delivery Mode.

As discussed earlier concerning pathogenesis, potentially deleterious effects of labor and delivery relate principally to the easily deformed, particularly compliant skull of the premature infant. Such deformations presumably could lead to dangerous elevations of venous pressure and perhaps to an impairment of cerebrovascular autoregulation (analogous to that observed in adult patients with head trauma). Prolonged labor and breech delivery would be considered most likely to lead to such hemodynamic effects, and some, but not all, work supports this contention. ^a

a References .

Delayed Cord Clamping.

DCC by 30 to 120 seconds rather than immediate clamping has been reported to be associated with less need for transfusion and lower rate of IVH. In December 2012, the American College of Obstetricians and Gynecologists recommended a delay of 30 to 60 seconds in umbilical cord clamping for all preterm deliveries. Most recently in January 2017, the American College of Obstetricians and Gynecologists recommended a delay in umbilical cord clamping in vigorous term and preterm infants who do not require resuscitation for at least 30 to 60 seconds after birth.

Although DCC has been associated with a decrease in the overall incidence of IVH, it has not been shown to have a beneficial effect on severe IVH, and thus its clinical application has not been uniformly embraced. It is also worthy of note that both the ACOG and ILCOR recommendations are in vigorous preterm infants. There are no data on DCC in the premature infant in need of resuscitation.

With regard to subsequent outcomes, a recent randomized controlled trial reported the effects of placental transfusion on neonatal and 18-month outcomes in preterm infants with singleton fetuses ( n = 208) between 24 weeks of gestation and 32 weeks of gestation. There were no differences in the number of infants who received phototherapy, days of phototherapy, delivery room resuscitation, Neonatal Acute Physiology scores at 12 hours of age, and the rates of IVH or late-onset sepsis between the groups. However, at 18 to 22 months, DCC was found to be protective against motor scores less than 85 on the Bayley Scales of Infant Development. The authors concluded that although DCC did not alter the incidence of IVH or late-onset sepsis in preterm infants, it improved motor function at 18 to 22 months’ corrected age.

Umbilical Cord Milking.

An alternative to DCC is umbilical cord milking (UCM), a procedure that can be performed in 20 seconds. UCM is performed by holding the infant at or 20 cm below the level of the placenta. The cord is pinched as close to the placenta as possible and milked toward the infant for 2 seconds. The cord is then released and allowed to refill with blood for 1 to 2 seconds between each milking motion, a process repeated a total of 4 times. After completion, the cord is clamped and the newborn handed to the resuscitation team. Milking the cord 4 times provides a similar amount of placental-fetal blood as with DCC for 30 seconds.

A recent meta-analysis of UCM, including seven randomized clinical trials involving 501 infants delivered at less than 33 weeks, demonstrated that infants who underwent UCM had a higher hemoglobin level and lower risk of oxygen requirement at 36 weeks and IVH of all grades compared with those who underwent immediate cord clamping. A recent pilot study of 75 extremely premature neonates (born at a gestational age <29 weeks) randomly assigned to receive UCM or immediate cord clamping also demonstrated a 50% reduction in total IVH with UCM. Moreover, in another recent retrospective study of 318 infants born at less than 30 weeks, UCM was associated with reductions in IVH, necrotizing enterocolitis, and death before hospital discharge. Concerning the mechanism of benefit from UCM, a further study that enrolled 197 infants (mean gestational age 28 ± 2 weeks) reported a higher hemoglobin level at birth, improved hemodynamics (higher blood flow and improved blood pressure), and improved urine output with UCM compared with DCC in preterm infants delivered by cesarean section. The authors also noted SVC flow and higher right ventricular output in infants treated with UCM.

A concern has been raised over UCM relating to the rapidity of the delivery of the bolus of blood. Rapid changes in venous pressure during UCM were addressed in an early trial that demonstrated no greater increase in venous pressures with UCM compared with uterine contractions or a newborn cry during intact placental circulation. A recent meta-analysis evaluating the safety and efficacy of UCM at birth concluded that there was a lower risk of oxygen requirement at 36 weeks and IVH of all grades.

The potential for developing hyperbilirubinemia is another issue of concern with UCM. A Cochrane review found that none of the infants with elevated bilirubin levels required phototherapy treatment or exchange transfusions. However, in populations more susceptible to neonatal hyperbilirubinemia, especially those of Asian ethnicity, careful monitoring of the serum bilirubin level is warranted.

According to the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations and subsequent review of both DCC and cord milking in preterm newborns in the 2015 Umbilical Cord Management in the International Liaison Committee on Resuscitation (ILCOR) systematic review, DCC for longer than 30 seconds was proposed as reasonable for both term and preterm infants who do not require resuscitation at birth. However, it was felt that there was insufficient evidence to recommend “delayed” cord clamping for infants who required resuscitation at birth, and more randomized trials involving such infants were needed. ILCOR also suggested that cord milking should not be routinely used for infants born at less than 29 weeks of gestation outside of a research setting because of concerns over rapid volume changes. Further studies are warranted to elucidate this issue, because cord milking may improve the initial mean blood pressure, hematologic indices, and reduce intracranial hemorrhage. However, there is currently no evidence with regard to improvements in long-term outcomes.

Temperature Stabilization.

Unless significant preventative efforts are made, periviable newborns will quickly lose heat in the delivery room by evaporation of amniotic fluid from the baby’s body, by conduction of heat from the body touching cooler surfaces, by convection to cooler surrounding air, and by radiation to cooler objects in the vicinity. For every 1°C below 36°C on admission temperature, mortality increases by 28%. The periviable infant should be placed in a high diathermancy food-grade polyethylene bag or wrap without initial drying up to the level of the shoulders. Multiple studies have shown that plastic bags and wraps improve temperature on admission to the NICU, but as of yet there are no studies powered for important clinical outcomes, such as mortality or IVH.

Although normothermia may reduce cold stress , there are few studies to support an association of admission temperature or admission hypothermia to an increased risk for IVH. A single observational study of 271 VLBW infants showed that after correction for confounders by multivariate logistic regression analysis admission hypothermia (at ≤35.5 and at ≤35°C) was not associated with IVH.

Newborn Resuscitation.

Consideration of the intravascular pathogenetic factors makes it clear that certain practices in newborn resuscitation may increase the likelihood of IVH in the premature infant ( Table 24.20 ). In particular, overly rapid infusion of volume expanders or of hypertonic solutions, such as sodium bicarbonate, should be avoided.

Concerning cerebrovascular autoregulation, the most important admonition in neonatal resuscitation is to establish adequate ventilation promptly to prevent hypoxemia and hypercarbia, two alterations that result readily in pressure-passive cerebral circulation. Because of the latter facts and because hyperventilation in animals and humans sufficient to decrease Pa co ₂ to approximately 25 mm Hg restores autoregulation after hypoxia, two retrospective studies of hyperventilation in the first 2 hours of life and the subsequent occurrence of IVH were conducted. The data in the initial study suggested that Pa co ₂ values less than 35 mm Hg led to a decrease in incidence of subsequent IVH, but a subsequent study failed to confirm this observation. Currently, it seems prudent to recommend that adequate ventilation be established promptly in the resuscitation of the newborn infant, and that hypoxemia and hypercarbia be avoided. However, this goal does not require systematic early intubation of all ELBW infants (≤1000 g) at the slightest signs of respiratory distress. An individualized approach to intubation is important. It is also important that if continuous positive airway pressure (CPAP) is to be used as the principal mode of ventilator support, an adequate but not excessive end expiratory pressure must be provided, with the goal of avoiding overdistention or elevated intrathoracic pressures.

Correction of Fluctuating Cerebral Blood Flow Velocity.

The nearly invariable relationship between fluctuating cerebral blood flow velocity in the ventilated premature infant with respiratory distress syndrome and the subsequent occurrence of IVH (see Table 24.5 ) led to a search for interventions that could prevent this hemodynamic disturbance. Muscle paralysis with pancuronium bromide was found to be highly effective for the rapid conversion of the fluctuating pattern to a stable velocity ( Fig. 24.38 ). Moreover, muscle paralysis eliminated the fluctuations in venous pressure that accompany the cerebral arterial fluctuations (see earlier discussion). Thus a prospective, randomized study of muscle paralysis from the first day of life to 72 hours of age in ventilated premature infants with the fluctuating hemodynamic disturbance was undertaken. All the control infants (i.e., nonparalyzed) developed IVH, consistent with previous observations. After completion of the controlled study, a second study in 72 ventilated premature infants with the fluctuating circulatory abnormality for the first 72 hours of life showed a prominent reduction in IVH, including especially severe IVH.

Effect of muscle paralysis on fluctuating cerebral blood flow velocity from a ventilated, preterm infant with respiratory distress syndrome.

Before paralysis, the constantly fluctuating peak systolic and end-diastolic flow velocities are apparent. After paralysis was induced by pancuronium, the fluctuating pattern was eliminated.

Importantly, the fluctuations were related to the infant breathing out of synchrony with the ventilator, inducing a pulses paradoxus –like effect. Paralysis eliminated the infant’s own breathing activity with immediate stabilization of the blood pressure and fluctuating cerebral blood flow velocity patterns. Over the last 10 years, several clinical and therapeutic factors have reduced the occurrence of this potential deleterious relationship. First, the near-universal use of antenatal glucocorticoids has reduced the severity of respiratory distress syndrome and improved the stability of the infant’s blood pressure. Consequently, there has been a lesser requirement for volume expanders and/or inotrope use. Second, the early use of surfactant replacement therapy for infants with evidence of respiratory distress syndrome has facilitated the earlier extubation of infants, reducing the severity of their respiratory instability and the length of time that the infant is ventilated. Third, modern ventilators now have sophisticated feedback strategies that facilitate the infant’s breathing in synchrony with the ventilator. In this regard, in a report in 2015 of 47,816 VLBW infants in the Vermont Oxford Network, only 50% of these infants ever received any positive pressure ventilation. Sixty percent of infants were ventilated for less than 24 hours, and 80% for less than 7 days. Thus it is the most immature and sick infants (<20% of VLBW infants) who may remain ventilator dependent during the first few critical days when the risk for IVH is highest and reducing fluctuations in systemic and cerebral perfusion are most often considered.

For those infants who may appear irritable , the use of sedatives is a clinical option. In our own experience and that of the more recent published literature, the need for muscle paralysis now is rare. Of note, however, the use of opiates and benzodiazepines has increased dramatically over the past two decades in some centers ( Fig. 24.39 ). The factors responsible for this increase in use are unclear, but it has not been driven by clear data indicating that such practice reduces the risk for IVH.

Opioid and benzodiazepine administration compared with ampicillin and inotrope administration over time.

(From Zimmerman KO, Smith PB, Benjamin DK, Laughon M, Clark R, Traube C, Sturmer T. Hornik CP. Sedation, analgesia, and paralysis during mechanical ventilation of preterm infants. J Pediatr . 2017;180:99–104, figure 2.)

In view of the increased use of sedation rather than paralysis, it is plausible that the use of such sedatives may reduce the tendency for fluctuating cerebral blood flow associated with handling, painful procedures, and/or mechanical fighting of the ventilator, thereby leading to lower rates of IVH. Nevertheless, the impact of opioids on acute brain injury and long-term neurodevelopment in mechanically ventilated preterm neonates has been examined in two large randomized controlled trials, where no difference in the composite outcome of severe IVH, PVL, or death was detected. It is worthy of note that infants that required additional boluses of morphine in the morphine group demonstrated an increased risk for IVH. However, long-term follow-up was also concerning, as it revealed conflicting results regarding the neurodevelopmental impact of early morphine exposure in preterm neonates. Even though the randomized Neurologic Outcomes and Preemptive Analgesia in Neonates study (NEOPAIN) showed no difference in overall intelligence between groups, morphine exposure was associated with a smaller head circumference, impaired short-term memory, and social problems at 5 to 7 years of age compared with the placebo group. An understanding of how to best target sedation and/or paralysis is limited in these studies because of a lack of knowledge of cerebral perfusion and autoregulation. If accurate monitoring of cerebral perfusion were achievable, then a more rational targeted approach would identify which infant might benefit from sedation/paralysis to minimize any fluctuations in cerebral blood flow.

Correction or Prevention of Other Major Hemodynamic Disturbances.

As indicated in the earlier discussion of pathogenesis, increases and decreases in cerebral arterial blood flow and increases in cerebral venous pressure can be involved in the pathogenesis of IVH. Thus care must be taken to prevent sharp elevations in blood pressure and cerebral blood flow with excessive handling, tracheal suctioning, rapid infusions of blood or other colloid, exchange transfusions, apneic spells, seizures, pneumothorax, and hypercarbia. As noted earlier, the use of antenatal corticosteroids, coupled with targeted surfactant replacement therapy, has reduced many of these events, particularly pneumothorax. Fluctuating Pa co ₂ or hypocarbia also should be avoided. Several smaller retrospective studies suggested that alterations in various monitoring and caretaking procedures, resulting in minimal stimulation , led to a decrease in incidence of IVH. However, out of necessity, the use of historic controls made it difficult to specify the most important alterations. A subsequent prospective study in which infants were randomly assigned to a carefully quantitated reduced manipulation protocol ( n = 62) or to standard care ( n = 94) did not show a significant difference in incidence of IVH (30% in study infants, 37% in control infants).

In an attempt to avoid (rapid) fluctuations in CBF during routine care, several nursing interventions have been proposed. These nursing interventions are especially important during the first 72 hours after birth because most GMH-IVH develops during this time frame. The first of these interventions consists of positioning the head of the infant in a neutral (i.e., midline) position, enabling optimal cerebral venous drainage through the internal jugular veins. As a consequence, hampered venous drainage and ultimately bleeding is believed to be prevented. Low-quality evidence obtained in very small studies indicates that there is no significant effect on cerebral oxygenation by head rotation and/or head tilting in preterm infants. One study performed by Liao and co-workers revealed a small, statistically significant, one-sided decrease in rScO ₂ after head rotation to the left. However, this decline of only 1% is unlikely to be of clinical significance. The second proposed intervention consists of elevating the head of the incubator 15 to 30 degrees upward (i.e., tilting) to facilitate venous outflow from the brain by promoting hydrostatic cerebral venous drainage.

Finally, elevations in venous pressure must be avoided by prompt treatment of myocardial impairment (e.g., in the asphyxiated infant) and factors that may increase intrathoracic pressure and thereby cerebral venous pressure, such as pneumothorax and vigorous tracheal suctioning. A more extensive evaluation of myocardial function by functional echocardiography may assist in the decision to reduce cardiovascular afterload or manage preload. Management that is limited to evaluation of a single mean arterial blood pressure will likely result in inadequate or inappropriate therapy.

The role of surfactant per se in prevention of the hemodynamic disturbances associated with mechanical ventilation of infants with respiratory distress syndrome and thereby IVH is not entirely clear. Thus a series of earlier studies using one of at least seven different preparations of surfactant in prophylactic or rescue trials resulted in findings that were not entirely uniform. In general, however, neonatal mortality rates, severity of respiratory distress, and air-block complications (e.g., pneumothorax) were reduced. The incidence and severity of IVH most often were either unchanged or reduced. The occurrence, albeit unusual, of increased incidence of IVH in surfactant-treated infants and the failure of a consistent decrease in incidence of IVH (despite a decrease in respiratory disease) in such infants led to the suspicion that surfactant treatment may have deleterious cerebral hemodynamic effects. Available data suggest that surfactant therapy may cause a transient increase in cerebral blood flow velocity and cerebral blood volume and electroencephalographic depression, but the effects are generally not marked. Moreover, no clinical or biochemical evidence of deleterious effects (e.g., serum CK-BB levels) has been demonstrated. In addition, the combined use of antenatal glucocorticoids and postnatal surfactant has added benefits concerning the prevention of IVH.

Alternative methods of mechanical ventilation (i.e., high-frequency oscillatory ventilation or high-frequency jet ventilation) are not clearly superior to conventional ventilation regarding the incidence of IVH. Indeed, in initial work, the incidence of severe IVH was higher in infants treated with high-frequency oscillatory ventilation (26%) than in infants treated with conventional mechanical ventilation (18%), and the neurological outcome was poorer in the former group of infants. A subsequent multicenter study showed a similarly higher incidence of IVH (36% vs. 20%), but four later studies showed no increase in incidence of IVH in infants treated with high-frequency oscillatory ventilation. A significantly deleterious effect concerning IVH also was not observed in two studies of high-frequency jet ventilation, although an increase in the incidence of cystic periventricular leukomalacia was documented in one report. More data are needed on these issues. Most frequently, early nasal CPAP is being used in the delivery room or early in the neonatal course. A meta-analysis of 2364 infants comparing CPAP with mechanical ventilation, CPAP resulted in a small but clinically significant reduction in the incidence of BPD at 36 weeks (typical RR 0.89; 95% CI, 0.79 to 0.99) and death or BPD (typical RR 0.89; 95% CI, 0.81 to 0.97). There was no difference in the rates of IVH. Early CPAP did appear to be associated with a higher risk for pneumothorax if surfactant therapy was not administered.

The use of inhaled nitric oxide for premature infants with severe respiratory failure, related most often to severe respiratory distress syndrome, currently is under active investigation. The gas is used for pulmonary benefits related to its strong pulmonary vasodilator properties. Thus far, no consistent significant differences in the rate of IVH in infants treated with nitric oxide have been reported. One controlled study of 793 infants 34 weeks of gestational age or younger described a decline in grade 3 or 4 hemorrhage in infants treated with nitric oxide from the first days of life but only in infants of birthweight 750 to 999 g. Another report described improved neurodevelopmental outcome in infants treated with inhaled nitric oxide, but the neuropathological basis for the improvement was not clear.

Correction of Abnormalities of Coagulation.

Although in selected infants abnormalities of coagulation (or of platelet-capillary interactions) may play a role in the pathogenesis of IVH, it is unclear whether interventions to correct or prevent such abnormalities are indicated for all premature infants. Thus in one controlled study of the administration of fresh frozen plasma (10 mL/kg) to premature infants on admission to the nursery and again at 24 hours of life, treated infants exhibited a decrease in the overall incidence of IVH (14% vs. 41% in untreated infants). However, no difference in incidence of severe IVH was noted, and no clear effect on coagulation variables could be demonstrated. The possibility was raised that the fresh frozen plasma exerted its benefit by “stabilizing the circulation” rather than by an effect on coagulation. Two later studies of administration of fresh frozen plasma showed no benefit regarding prevention or extension of IVH or on neurological outcome at 2 years. Thus, at present, no clear indication exists for the routine administration of fresh frozen plasma postnatally to premature infants for prevention of IVH.

Indomethacin.

In the last edition of this book, we reviewed 19 controlled studies of indomethacin as a means to prevent IVH. The drug was studied particularly for prophylaxis, rather than treatment, of patent ductus arteriosus, and it was generally administered initially before 12 hours of age. A summary of the pooled results showed that indomethacin administration led to a decrease in the incidence of overall IVH (RR, 0.88; 95% CI, 0.80 to 0.96) and of severe IVH (RR, 0.66; 95% CI, 0.53 to 0.82). In the largest early series ( n = 431), Ment and co-workers observed a decrease in the incidence of total IVH (18% to 12%) and grade IV IVH (4.5% to 0.5%). However, in this study, early-onset IVH was excluded, and the marked preponderance of grade IV IVH relative to grade III IVH (10 : 1) in the control population was unusual and raised the possibility of an undefined unusual characteristic of the control population. Indeed, in centers where the incidence of grades III and IV IVH in the control population was greater than 10%, indomethacin administration was shown to lead to a significant reduction in these severe hemorrhages (OR, 0.54; 95% CI, 0.36 to 0.82; P < .005), whereas in centers where the incidence was less than 10%, indomethacin did not lead to a significant reduction (OR, 0.72; 95% CI, 0.39 to 1.33; P < .3).

An interesting development in this area was the repeat analysis of the data from the earlier study of Ment and co-workers ( n = 431; Table 24.21 ). Thus the beneficial effect of indomethacin on IVH was shown in male but not female patients. A repeat analysis of the later larger study of prophylactic indomethacin ( n = 1202) showed a weak differential effect of indomethacin by sex; for severe IVH, the incidences in indomethacin-treated versus placebo groups were 9.8% versus 11.7% (OR, 0.46 to 1.44) for female patients but 8.6% versus 14.7% (OR, 0.31 to 0.94) for male patients. Thus, on balance, in the total experience with indomethacin, a generally favorable preventive effect of the drug on IVH seems apparent, particularly or exclusively in male patients . Follow-up of the large series of infants studied by Ment and co-workers showed no difference in the development of ultrasonographically demonstrated cystic periventricular leukomalacia or in incidences of cerebral palsy or of cognitive impairment at 36 months of age. Other investigators also have shown no beneficial long-term neurodevelopmental effects. However, again, when male and female patients are analyzed separately, a clear cognitive benefit is apparent in male but not female patients ( Table 24.22 ).

TABLE 24.21

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