Published online November 1, 2007
PEDIATRICS Vol. 120 No. 5 November 2007, pp. 966-977 (doi:10.1542/peds.2007-0075)
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ARTICLE

Current Definitions of Hypotension Do Not Predict Abnormal Cranial Ultrasound Findings in Preterm Infants

Catherine Limperopoulos, PhDa,b, Haim Bassan, MDa, Leslie A. Kalish, ScDc, Steven A. Ringer, MDd, Eric C. Eichenwald, MDd, Gene Walter, REEGTa, Marianne Moore, BA, RNa, Matthew Vanasse, RRTa, Donald N. DiSalvo, MDe, Janet S. Soul, MD, CMa, Joseph J. Volpe, MDa and Adré J. du Plessis, MBChB, MPHa

a Fetal-Neonatal Neurology Research Group, Department of Neurology
c Clinical Research Program and Department of Pediatrics, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
b Department of Neurology and Neurosurgery and School of Physical and Occupational Therapy, McGill University, Montreal, Quebec, Canada; Departments of
d Newborn Medicine
e Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Hypotension is a commonly treated complication of prematurity, although definitions and management guidelines vary widely. Our goal was to examine the relationship between current definitions of hypotension and early abnormal cranial ultrasound findings.

METHODS. We prospectively measured mean arterial pressure in 84 infants who were ≤30 weeks’ gestational age and had umbilical arterial catheters in the first 3 days of life. Sequential 5-minute epochs of continuous mean arterial pressure recordings were assigned a mean value and a coefficient of variation. We applied to our data 3 definitions of hypotension in current clinical use and derived a hypotensive index for each definition. We examined the association between these definitions of hypotension and abnormal cranial ultrasound findings between days 5 and 10. In addition, we evaluated the effect of illness severity (Score for Neonatal Acute Physiology II) on cranial ultrasound findings.

RESULTS. Acquired lesions as shown on cranial ultrasound, present in 34 (40%) infants, were not predicted by any of the standard definitions of hypotension or by mean arterial pressure variability. With hypotension defined as mean arterial pressure < 10th percentile (<33 mmHg) for our overall cohort, mean value for mean arterial pressure and hypotensive index predicted abnormal ultrasound findings but only in infants who were ≥27 weeks’ gestational age and those with lower illness severity scores.

CONCLUSIONS. Hypotension as diagnosed by currently applied thresholds for preterm infants is not associated with brain injury on early cranial ultrasounds. Blood pressure management directed at these population-based thresholds alone may not prevent brain injury in this vulnerable population.

Key Words: blood pressure • hypotension • cranial ultrasound • prematurity • GM-IVH

Abbreviations: BP—blood pressure • GA—gestational age • GM-IVH—germinal matrix–intraventricular hemorrhage • MAP—mean arterial blood pressure • CV—coefficient of variation • HOI—hypotensive index • CVI—coefficient of variation index • AUROC—area under the receiver operating characteristic curve • SNAP-II—Score for Neonatal Acute Physiology II

Hypotension is commonly diagnosed in preterm infants during the first days of life.1–4 However, there is great inconsistency in the diagnosis and management of hypotension in preterm infants, largely because of the lack of a reliable and consistently applied definition of hypotension. Disparities in the diagnosis of hypotension in preterm infants are in large part attributable to incomplete understanding of the more complex and prolonged circulatory transition from fetal to stable neonatal hemodynamics.1–3,5–7 During this transition, the immature myocardium confronts an abrupt increase in afterload as the low-resistance placental bed is replaced by the high peripheral vascular resistance of the extrauterine circulation. In addition, closure of fetal circulatory pathways (eg, ductus arteriosus) may be more delayed in preterm infants.8 Coincident with this period of systemic circulatory adaptation is a period of particular risk for brain injury in preterm infants.9,10 Consequently, it is not surprising that hemodynamic factors have frequently been associated with the development of early brain injury in the preterm infant.11–16

Normal blood pressure (BP) provides appropriate perfusion pressure in end organs to maintain their functional and structural integrity. Hypotension refers to BP levels that are too low to achieve this goal. Although in theory hypotension is an organ-specific diagnosis, the particular vulnerability of the immature brain to hypoperfusion has made brain injury in the preterm infant a leading end point in the pursuit of a reliable clinical definition of hypotension; however, for a number of potential reasons, such a goal has been elusive, and several different definitions of hypotension are in clinical use. In fact, the role of hypotension in prematurity-related brain injury remains a contentious issue, as evidenced by recent calls for a radical reassessment of the diagnosis and management of hypotension in the preterm infant.1,5 To evaluate the association between hypotension and brain injury among critically ill preterm infants, we tested the ability of various definitions of hypotension that are in clinical use to predict early-life ultrasound evidence of brain injury.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
As part of a previous study that investigated cerebral pressure autoregulation in preterm infants,17 we prospectively enrolled a cohort of preterm infants who were ≤30 weeks’ gestational age (GA) and whose hemodynamic instability required an umbilical arterial catheter for continuous BP monitoring. Because we wished to confine our focus to the ultrasound correlates of hemodynamic disturbances during the transitional circulation, we included infants with periods of continuous BP recording during the first 3 days of life. We were interested in the association between actual BP and brain injury and therefore included infants regardless of whether they were being treated for hypotension. We included only infants with at least 1 cranial ultrasound from day 5 to day 10. To exclude the effects of preceding antenatal insults, we excluded infants with cranial ultrasound evidence of long-standing injury (eg, cystic parenchymal lesions). Likewise, to avoid the cumulative effects of later insults (eg, apnea and bradycardia, infection), we confined our ultrasound outcomes to the first 5 to 10 days. We recognize that nonhemorrhagic brain injuries (particularly diffuse white matter injury) may be delayed in their ultrasound appearance and that the effect of less severe insults may be missed by this approach. We also excluded infants with known or suspected cerebral dysgenesis, obvious dysmorphic syndromes, or a known chromosomal disorder. We obtained written informed consent for all patients. The institutional review board of the Brigham and Women's Hospital approved the study.

We categorized our population into 2 GA groups: 23 to 26 weeks and 27 to 30 weeks. We confined our BP analyses to measurements during the first 3 days of life, defined as the first 3 consecutive 24-hour intervals after birth. This restriction was made because the use of intra-arterial monitoring decreases significantly thereafter and because the vast majority of germinal matrix–intraventricular hemorrhage (GM-IVH) occurs during this time.18–22 The BP transducer was maintained at a consistent midthoracic level. We excluded all BP data that were recorded during periods of line clamping (eg, arterial blood gas sampling), as well as during movement of the BP transducer.

BP Measurements
We measured continuous mean arterial BP (MAP) at 2 Hz for up to 12 hours on each of the first 3 days. We divided these continuous MAP data into sequential 5-minute epochs. The mean MAP was calculated for each epoch, as was the coefficient of variation (CV) of all MAP measurements during each epoch. The effects of MAP over the longer term were measured using 2 approaches. First, we summarized these short-term measures of MAP level and MAP variability over longer time periods by deriving the hypotensive index (HOI) and coefficient of variation index (CVI), described later. In addition, a mean MAP was calculated for each of the first 3 days of life by averaging all MAPs recorded during each day; then by averaging the 3 daily mean MAPs, we calculated an overall mean MAP for the 3-day period for each patient.

We then tested 3 definitions of hypotension that are used in clinical practice for their ability to predict early abnormal ultrasound findings. These definitions were MAP of (1) <30 mmHg,23 (2) less than the infant's GA in weeks,24 and (3) <10th percentile of MAP for birth weight and postnatal age based on published normative data.12 For reasons discussed in "Results," we also considered a fourth definition of hypotension: MAP < 10th percentile (33 mmHg) in our overall study population during the first 3 days of life.

We derived the HOI in the following manner. First, consecutive 5-minute epochs from the time of birth were formed for each infant. We excluded epochs that did not have assessable MAPs recorded for at least 4 of the 5 possible minutes. By applying each of the definitions of hypotension to the mean MAP during the 5-minute epoch, each epoch was categorized as either a hypotensive epoch or a nonhypotensive epoch. The HOI was then derived as the proportion of all assessable 5-minute epochs that were hypotensive. Applying this algorithm to the 4 definitions of hypotension yielded 4 HOIs for each infant. We then compared 3-day HOI as well as the 3-day mean MAP between infants with normal versus abnormal cranial ultrasound findings, as defined later. We also calculated HOI during the first 12 hours of life to investigate the possible importance of BP during the very early newborn period.

Similarly, we examined the association between BP variability and abnormal ultrasound findings as follows. First, we calculated the CV of all MAP readings within each epoch. Epochs with a CV of >8% were categorized as having high variability, and a CVI was calculated as the proportion of all assessable epochs with high variability. We also conducted a sensitivity analysis by calculating CVIs after redefining high variability as CV > 6% and CV > 10%. We chose these cut points because they were integer values at high percentiles of all CVs, across all epochs in all infants. The cut points (6%, 8%, and 10%) corresponded to the 80th, 93rd and 98th percentiles, respectively. The CVIs were compared between infants with normal versus abnormal cranial ultrasound findings.

Finally, we compared abnormal cranial ultrasound findings between preterm infants who were treated for hypotension and those who were not treated. The BP thresholds that are used to guide pressor use in our NICU are GA and postnatal age dependent. Specifically, during the first 48 hours after birth, infants who are <30 weeks’ GA are treated for hypotension when MAP is persistently less than GA (in weeks). Hereafter, treatment is started when the MAP is persistently <2 to 4 mmHg above GA. Inevitably, there are variations in practice, because clinicians take into account not only BP but also other clinical features. The initial treatment of hypotension is usually intravenous fluid (volume expanders) in 1 to 2 boluses of 10 mL/kg each. For persistent hypotension, the first-line pressor medication is dopamine, up to an infusion rate of 30 µg/kg per min. Thereafter, dobutamine, then epinephrine, and finally corticosteroids are used, if needed. Treatment for hypotension was characterized as treatment during each of the first 3 days of life, treatment during any of the first 3 days, and the number of days of treatment. We also evaluated the association between these treatment modalities and BP.

Severity of Illness
To determine the severity of illness in our population during the early neonatal period, we applied the widely used and validated Score for Neonatal Acute Physiology II (SNAP-II)25 using data from the first 12 hours of life. Mean BP forms part of the SNAP-II; therefore, to evaluate illness severity independent of a BP effect, we modified the SNAP-II by calculating the mean MAP for our study population and applying this value for all infants in the BP item of SNAP-II. We used this modified, "BP-neutral" SNAP-II to evaluate the role of illness severity in the treatment of BP, as well as the association between illness severity and abnormal cranial ultrasound findings.

Cranial Ultrasound Criteria
We used as our primary outcome variable predefined features of abnormality on routine cranial ultrasound studies (Acuson Sequoia; Siemens Medical Solutions, Malvern, PA) performed on a clinically scheduled protocol. The Brigham and Women's Hospital NICU uses a clinical protocol for the timing of ultrasound studies (day 3, day 7, and day 30 after birth) in preterm infants. However, additional studies are performed whenever clinically indicated; therefore, in sick populations such as ours, the timing of ultrasound study is seldom consistent. Because the presence of hemorrhagic and major hypoxic-ischemic injuries that occur within the first 3 days should be evident by ultrasound studies performed between 5 and 10 days, we based our outcome analysis on a single ultrasound study performed on or closest to 5 days and before 10 days after birth. The diagnosis of abnormal cranial ultrasound findings was based on a widely used grading scheme9 and made by 2 experienced cranial ultrasound readers (Drs DiSalvo and du Plessis) who were blinded to the clinical and BP data. We defined 3 ultrasound outcome variables: GM-IVH (any grade), parenchymal abnormalities (defined as cerebral and/or cerebellar echodensities), and an overall outcome (GM-IVH and/or parenchymal abnormalities). Echodensities were defined as areas of bright ultrasound signal, approaching or at the density of the choroid plexus and clearly distinct from the surrounding parenchyma. We considered findings to be echodensities only when they were evident on >1 ultrasound slice in the angled sagittal or coronal views. In all cases, regions of echodensity were associated with abnormalities on subsequent ultrasound and/or MRI studies.

Clinical Data Collection
We collected demographic, prenatal, intrapartum, and postnatal data on all infants in a prospective manner using standardized data forms. Demographic data included GA at birth, birth weight, and gender. Maternal data included single versus multiple gestation, pregnancy-induced hypertension, prenatal infection, maternal chorioamnionitis (clinical and/or pathologic diagnosis), and use of tocolysis and antenatal steroids. Clinical chorioamnionitis was entered when this diagnosis was made by the treating obstetrician. Intrapartum factors included mode of delivery, maternal fever (>38°C), vaginal bleeding, Apgar score at 5 minutes, and need for respiratory resuscitation. Early postnatal data collected for the first 3 days of life included arterial blood gases (pH, PCO2, and PO2), blood cell counts and platelets, need for cardiopulmonary support (use of volume expanders and/or pressor-inotropic agents), indomethacin for a patent ductus arteriosus, maximum infant temperature, and infection (confirmed by positive blood, urine, or mucosal culture or clinical suspicion resulting in a full course of antibiotic treatment despite negative cultures).

To evaluate laboratory results as binary covariates, we used clinically meaningful cut points to categorize each variable as follows: minimum pH < 7.2, minimum PO2 < 45 mmHg, minimum PCO2 < 30 mmHg, maximum PCO2 > 60 mmHg, maximum white blood cell count > 20000/µL, minimum hemoglobin level < 10 g/dL, and minimum platelet count < 100000/µL.

Statistical Methods
The association between a BP index (eg, HOI) and each cranial ultrasound outcome variable was assessed by comparing the index distribution between infants with versus without the abnormal ultrasound finding using the 2-sample Wilcoxon test. To express the magnitude of these associations on a scale that is directly comparable across different indices, we also report the area under the receiver operating characteristic curve (AUROC), which is closely related to the Wilcoxon test and has the following interpretation. The AUROC is the probability that an infant with the abnormality has a higher index value than an infant without the abnormality. An AUROC of 0.50 suggests that the index has no predictive value, and an AUROC of >0.50 suggests a positive association. Because higher values of HOI or CVI are hypothesized to confer higher risk whereas lower values of BP confer higher risk, we reversed the scale when analyzing mean MAP so that AUROCs of >0.50 are always interpretable as an association in the hypothesized direction.

To compare mean MAP across days 1 through 3 and between GA strata, we fit a repeated measures model with day of life as the repeated factor and GA as a fixed factor. We used an autoregressive correlation structure. We then constructed Wald tests from linear contrasts to compare days within each GA stratum and to compare GA strata within each day.

Mean MAPs were compared across subgroups defined by pressor-inotrope use, volume expander use, and SNAP-II categories using the 2-sample t test or analysis of variance. Comparisons of HOIs were made with the Wilcoxon or Kruskal-Wallis test. Percentages of patients with cranial ultrasound outcomes were compared across covariate subgroups with Fisher's exact test. For continuous covariates, we tested associations with outcomes by comparing the covariate distributions in infants with versus without the outcome using the 2-sample Wilcoxon test.

We evaluated whether a covariate confounded the association between HOI or mean MAP and cranial ultrasound outcome as follows. We considered only covariates that had suggestive associations with outcomes as indicated by P < .10. We then compared the association evaluated in unadjusted analysis (using the Wilcoxon test) with the same association evaluated in adjusted analyses, where we adjusted for each of the covariates using a van Elteren test. The van Elteren test is a stratified version of the Wilcoxon test.26 All tests are 2-sided and P < .05 is considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Included in the analysis were 84 infants who met our entry criteria.

Baseline Characteristics
Table 1 summarizes the clinical characteristics of pregnancy, labor, and delivery. Preterm infants ranged in GA from 23 to 30 weeks and in birth weight from 460 to 1490 g. By our inclusion criteria, umbilical arterial lines were present in all infants for BP management. The mean age at onset of BP recording was 11.5 hours; however, studies started within 12 hours in 50 (60%) of 84 patients and within 24 hours of birth in all but 2. Although we aimed to record 12 hours of continuous MAP data per day during the first 3 days of life, personnel and equipment availability, as well as artifact removal and exclusion of incompletely recorded epochs, reduced the MAP data that were available for analysis. Reliable BP data were available on days 1 through 3 from 82, 78, and 60 infants for a mean (range) of 5.20 (0.25–12.75), 5.20 (0.67–11.75), and 5.10 (1.25–7.80) hours, respectively.


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  		TABLE 1 Clinical Characteristics of Pregnancy, Labor, and Delivery

 
Abnormal Cranial Ultrasound Findings
The mean age at the target cranial ultrasound study was 7.4 days. On this ultrasound study, abnormalities were identified in 34 (40%) of 84 preterm infants. Thirty-one (37%) developed GM-IVH grades 1 through 3. Because 3 cranial ultrasound studies had suboptimal cerebellar views, 81 cranial ultrasound studies were assessable for parenchymal abnormalities, 14 (17%) of which had cerebral echodensities and/or cerebellar lesions (9 cerebral only, 4 cerebellar only, and 1 both).

Relationship of MAP With GA and Postnatal Age
Table 2 describes the relationship among mean MAP, GA, and postnatal age during each of the first 3 days and for the overall 3-day period. Generally, those in the lower GA group had lower mean MAP, although this was statistically significant only on days 2 and 3 (P = .001 for both). There was also a statistically significant increase in mean MAP during the first 3 days of postnatal life (P = .01 among infants with GA 23–27 weeks, P < .001 among infants with GA 27–30 weeks). However, the increase in MAP during the 3 days was much less than that previously reported,12 and we were not able to estimate daily 10th percentiles with precision adequate for creating separate daily criteria for hypotension; therefore, we used the overall 3-day data set to derive the 10th percentile of mean MAP.


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  		TABLE 2 MAP According to GA and Postnatal Age

 
Relationship Between Hypotension and Early Abnormal Cranial Ultrasound Findings
When the criterion for hypotension was based on the 3 existing definitions (MAP [1] <30 mmHg,23 [2] less than the infant's GA,24 and [3] <10th percentile of MAP for birth weight and postnatal age based on published normative data12), there was a substantial number of infants with HOIs equal to 0 (ie, no 5-minute epochs of hypotension [36%, 81%, and 48%, respectively]). For example, 81% of infants had 0 epochs with mean MAP less than their GA. Furthermore, on the basis of the HOI derived for each of these thresholds, we found no significant associations between HOI and abnormal cranial ultrasound findings (Table 3).


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  		TABLE 3 AUROC and P Value for Testing Association Between BP Index and Cranial Ultrasound Outcome, by GA Category

 
Our population of infants likely differed in important ways (including overall systemic morbidity) from infants that were used to generate existing normative BP databases12,23,27; therefore, given the lack of association between hypotension defined by these criteria and abnormal cranial ultrasound findings in our infants, we considered a fourth definition of hypotension, MAP <33 mmHg, which is the 10th percentile of the overall 3-day mean MAP in our population, and derived the hypotensive index for this threshold (HOI-33). Using this criterion, 19% of the infants had HOI-33 equal to 0 (ie, no hypotensive 5-minute epochs). We also considered the overall mean MAP for days 1 through 3 of life and the CVI as potential correlates of abnormal cranial ultrasound findings. For the remainder of our analyses, we used 33 mmHg as the threshold of hypotension and HOI-33 as the hypotensive index.

AUROCs for the different hypotensive indices and for the overall mean MAP and CVI are shown in Table 3. The results are stratified by GA (23–26 weeks: n = 44; 27–30 weeks: n = 40). High HOI-33 and low overall mean MAP are each associated with abnormal cranial ultrasound outcomes; however, the association is confined to the GA group of ≥27 weeks. The similar AUROC values for these 2 measures of BP suggest that they perform very similarly as correlates of abnormal cranial ultrasound findings. None of the HOI using cut points based on published normative data was associated with abnormal cranial ultrasound findings. The CVI based on a CV = 8% cut point was also not associated with abnormal cranial ultrasound findings (Table 3). In a sensitivity analysis, CVIs using larger and smaller cut point values were also not predictive of abnormal cranial ultrasound findings (data not shown).

To examine features of BP confined to the earliest hours, we calculated HOI and CVI using only data from the first 12 hours after birth (n = 50). If the early BPs were associated with abnormal outcomes, then one might expect that the AUROCs based on BP indices calculated from these first hours would be larger than the AUROCs calculated from the entire 3-day period. Generally, we did not see such a pattern, and in no case was an early HOI or CVI significantly higher among infants with abnormal cranial ultrasound outcomes (Table 3). In a related analysis, we calculated the daily mean MAP separately in infants with versus without abnormal ultrasound findings (Fig 1). We did not find a larger difference on day 1, as would be expected if the earliest BPs were best able to predict outcomes.


Figure 1
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  		FIGURE 1 Mean MAP on each of days 1, 2, and 3 of life in patients with and without each ultrasound outcome. A, IVH; B, parenchymal; C, overall. Error bars are ±SD.

 
Effects of Volume Expander and Pressor-Inotrope Use
For our analysis of volume expanders, we focused on dosages of >10 mL/kg per day, which were administered to 63 (75%) of our infants, whereas 60 (71%) infants required pressor-inotrope support at some point during the 3-day study period. Dopamine was the first-line pressor-inotrope used in all infants. During the 3-day study period, 1 infant also received dobutamine (days 1 and 2), 1 received epinephrine (day 1), and 2 received hydrocortisone (1 on day 2 only and the other on days 1 and 2). Only 1 patient received 3 pressors (days 1 and 2). Given the small number of patients on multiple pressor support, additional analysis was not conducted. The numbers of infants who required volume expanders and pressor-inotropes on each study day, as well as the numbers of infants who were treated for 1, 2, or all 3 days with each of these interventions, are shown in Table 4. As shown in Table 4, infants who were treated with volume expanders or pressor-inotropes had significantly lower mean MAP values for each of the study days and for the study period overall.


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  		TABLE 4 MAP and HOI-33 by Pressor-Inotrope Use and Volume Expander Use

 
Next, we considered the association between volume expanders and pressor-inotrope support, and abnormal cranial ultrasound findings. The use of volume expanders was not significantly associated with any abnormal cranial ultrasound finding on day 1 or with either GM-IVH or parenchymal echodensities on day 2; however, volume expander use on day 2 was significantly associated with overall abnormal ultrasound findings (P = .03), and volume expander use on day 3 was significantly associated with all 3 abnormal ultrasound outcomes (P < .005 for each outcome). There was no significant association between abnormal cranial ultrasound findings and pressor-inotrope treatment (any versus no treatment) or treatment on any of the 3 study days.

Influence of Other Clinical Variables on the Relationship Between MAP and Abnormal Cranial Ultrasound Finding
The population selected for this study (preterm infants who required umbilical arterial BP monitoring) represents a particularly sick population, often with multiorgan dysfunction; therefore, we examined the role of selected clinical and laboratory variables in the relationship between MAP and abnormal cranial ultrasound findings. Thirty (36%) infants were treated on ≥1 days during the study period with indomethacin for patent ductus arteriosus. Neonatal infection was diagnosed in 4 (5%) infants during the study period. Arterial blood gas analyses during the first 3 days of life, shown as median (range), were minimum pH 7.2 (6.8–7.4), minimum PO2 (mmHg) 42.6 (23.3–63.5), minimum PCO2 (mmHg) 31.9 (17.2–47.9), and maximum PCO2 (mmHg) 61.6 (36.5–169.5). The median (range) of the maximum white blood count (103/µL) was 11.3 (3.3–72.0) and of minimum platelets (103/µL) was 168 (59–439). We selected only clinical variables with P < .10 when evaluated as a predictor of abnormal cranial ultrasound findings. Only GA, 5-minute Apgar, minimum pH, minimum PO2, maximum PCO2, minimum hemoglobin, minimum platelet count, and maximum temperature met this criterion. We then repeated the comparisons between abnormal cranial ultrasound findings and each of HOI and mean MAP over days 1 through 3 after stratifying by each of these covariates. In all cases, the stratified P values were similar to the crude (unadjusted) P values, suggesting that none of these variables seemed to exert a confounding effect on the relationship between BP and abnormal cranial ultrasound finding.

To assess the level of illness severity at the onset of these studies, we performed the SNAP-II during the first 12 hours after birth. The mean (± SD) SNAP-II of 23.2 (± 12.4) underscores the high level of illness severity in our population.28 The modified SNAP-II (using the same population mean MAP of 35 mmHg for BP scores in all patients) was 16.0 (± 11.5). We dichotomized patients into those with low (<20) and high (≥20) modified SNAP-II. Infants with higher modified SNAP-II had significantly lower mean MAP on day 1 (34.9 vs 36.9 mmHg; P = .03) and a significantly lower overall mean MAP over days 1 through 3 (35.9 vs 38.5 mmHg; P = .007). When SNAP-II and modified SNAP-II were assessed for their relationships with cranial ultrasound outcomes (Table 5), abnormal outcomes were more strongly associated with high modified SNAP-II (P = .01–.05) than with the unmodified SNAP-II (P = .05–.25), suggesting that the association is driven by factors other than BP. Finally, we assessed the relationship between BP and cranial ultrasound outcomes separately in patients with high versus low modified SNAP-II (Table 6). As with GA, for which this association was found only in infants with older GA, the association between BP and abnormal cranial ultrasound findings was present only in infants with lower illness severity.


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  		TABLE 5 SNAP-II for the First 12 Hours of Life and Cranial Ultrasound Outcome

 

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  		TABLE 6 AUROC and P Value for Testing Association Among HOI-33, Mean MAP, and Cranial Ultrasound Outcome Stratified by Modified SNAP-II

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Hypotension is frequently diagnosed in the early days after preterm birth.1–3 Because this is also a high-risk period for brain injury in preterm infants,11,12,29 it is not surprising that a number of studies have associated hypotension with abnormal cranial ultrasound findings.11,12,27,30 Several mechanisms have been proposed to underlie this association. Decreases in BP within the range of functioning cerebral pressure autoregulation trigger cerebral vasodilation, thereby increasing cerebral blood volume. When BP falls below the lower threshold of the autoregulatory plateau, there are 2 major risks for the brain. First, there is a significantly increased risk for cerebral hypoperfusion and ischemia.31–33 Second, the cerebral pressure passivity that results exposes the cerebral vasculature to greater variability in blood flow with changes in BP.34–37 Together, these mechanisms are known to mediate cerebrovascular injury through hypoperfusion-reperfusion mechanisms, as demonstrated in earlier animal studies.38,39 Preventing these developments is a major impetus behind the current practice in most NICUs,1,5,11,12,23,30 including our own, of diagnosing and promptly treating hypotension in the preterm infant. However, the lower threshold of the autoregulatory plateau or even the existence of such a plateau in the preterm infant remains a contentious issue.40–44

In this study of prolonged high-frequency aortic BP recordings in sick preterm infants during the first 3 days of life, we demonstrated that none of the more commonly used clinical definitions of hypotension12,23,24 reliably predicted early abnormal cranial ultrasound findings. Unlike previous studies that focused on relatively limited aspects of BP, we evaluated the role of BP on early cranial ultrasound outcome in several different ways. Specifically, we explored the effects of MAP variability, mean MAP during 5-minute epochs, and mean MAP during the study period, as well as the cumulative duration of hypotension expressed as the HOI for each definition. Like others,11,12,27,45 we found a statistically significant increase in MAP with increasing GA and postnatal age; however, the 2- to 3-mmHg increase in MAP during the first 72 postnatal hours was substantially less than that previously reported.12,23,27 This more modest postnatal increase in MAP was largely attributed to higher starting BPs on the first day, possibly as a result of more liberal early initiation of pressors-inotropes in our unit compared with other centers.23,27

The hypotension thresholds tested in this study either are based on statistical normality in large populations12,46–48 or originate from populations with levels of systemic morbidity different from ours2,12,23,27,49; therefore, we tested an MAP threshold at the 10th percentile (ie, 33 mmHg) for our own cohort. Although this threshold predicted abnormal cranial ultrasound findings in infants between 27 and 30 weeks’ gestation and those with lower illness severity (by the SNAP-II),25 it failed to do so in the smallest, sickest infants (ie, those most vulnerable to brain injury).

We also assessed the effect of rapid BP changes by examining the association between BP variability and abnormal cranial ultrasound findings. Several previous studies had shown an association between BP variability and GM-IVH.11,23,27,50–52 Watkins et al12 found higher BP variability in infants with GM-IVH, but this was not statistically significant. Although the average BP variability did not predict GM-IVH in the study by Bada et al,11 longer durations of high or low variability were predictive of GM-IVH. However, like others,12,13 we found no significant association between BP variability and early abnormal cranial ultrasound findings.

Because appropriate BP targets for intervention remain poorly defined in preterm infants,1,5,53,54 it is not surprising that pressor-inotrope practices for this population vary widely between and even within centers.1,3,54 Despite 3 decades of pressor-inotrope use in the NICU, there is still no direct evidence that current treatment for hypotension decreases mortality or morbidity in the preterm infant.1,5,53 Several authors have challenged the current approaches to management of hypotension in the preterm newborn and, on the basis of an increase in adverse outcome among infants with treated hypotension, have suggested that treatment may contribute to brain injury.1,4,45 In our study, volume expander use after the first day was associated with abnormalities on cranial ultrasound, but no significant association was seen with pressor-inotrope use. As in previous studies,4,45 infants who received volume expanders or pressors-intropes had significantly lower BPs. In fact, the HOI-33 measures in Table 4 show that infants who were treated with pressors-inotropes had mean MAP values during the study period that were below our population's 10th percentile >15-fold longer than untreated infants. Although these observations may of course reflect confounding by indication, the prompt treatment of hypotension in our NICU, the expected rapid response to pressors-inotropes, and the duration of treatment (58% of treated infants received pressors-inotropes for >1 day) suggest other possible explanations. First, it is possible that infants who are prone to hypotension are poorly responsive to current therapies. Second, the BP targets pursued or the vigor of that pursuit may be inadequate.

There are several potential explanations for why we, unlike others,11,12,27,30 found no significant association between currently applied definitions of hypotension and early abnormal cranial ultrasound findings. First, the severity of illness in our population, as indicated by the high SNAP-II, may be higher than that in previous studies23,27; therefore, factors other than hypotension may have contributed to the development of abnormal cranial ultrasound findings. Consistent with this, the modified SNAP-II, which did not account for BP, was more closely associated with abnormal cranial ultrasound findings than the unmodified score. Second, it is possible that our techniques for BP measurement and analysis were not sufficiently sensitive to detect an association. Previous studies were limited by small patient numbers30,46,55 or differed from our study in their methods of BP measurement and analysis.12,23,27,45 The techniques for BP measurement in previous studies12,23,30 have ranged from isolated measurements taken hourly to every 24 hours, to BP averaged over extended periods. Our goal was to capture BP behavior across a broad temporal spectrum by using high-frequency measurements and then generating measures of rapid, short-term, and long-term BP changes; however, despite this comprehensive analysis of MAP, our recordings were not continuous throughout the 3 days, and it is possible that injurious hemodynamics that are responsible for abnormal cranial ultrasound findings may have gone undetected during off-hours in our study.

Another potential reason that early life BP changes were not predictive of abnormal cranial ultrasound findings in our study may relate to the difficulty of making a precise temporal association between BP changes and injury. It is possible that hemodynamic changes that are responsible for brain injury in the preterm infant are brief and intermittent. Because the onset of brain injury in sick preterm infants is usually clinically subtle or silent and clinical protocols usually separate cranial ultrasound by at least days, injurious short-term hemodynamic changes may be averaged out during prolonged recordings during the high-risk period for brain injury. We used cranial ultrasound as our principal outcome measure12,23,27 because it remains the only bedside imaging technique currently available and therefore the only technique for brain imaging during the acute period of critical illness in sick preterm infants. Cranial ultrasound reliably detects the onset of hemorrhage but is both insensitive and delayed in its detection of hypoxic-ischemic injury56–58; therefore, although it is likely that we captured major focal parenchymal lesions as echodensities on cranial ultrasound, it is possible that lesser and more diffuse degrees of white matter injury went undetected. Furthermore, because the cranial ultrasound in our study was clinically indicated, it was not performed at consistent times; however, all infants had ultrasound studies between 5 and 10 days, and because this period is beyond the greatest risk for especially GM-IVH, we based our cranial ultrasound outcome on this study.

Recent studies have suggested that BP may not reliably reflect brain perfusion during critical early periods in the transition from fetal to premature neonatal hemodynamics.59–62 These studies used superior vena cava blood flow as a surrogate for cerebral blood flow, and because the validity of this technique is untested, the relevance of a pressure-flow disconnect to our findings remains unclear. Finally, other mechanisms of brain injury, such as those mediated by circulating inflammatory substances63–68 or abnormalities in circulating carbon dioxide,43,69–73 have been proposed as principal mediators of brain injury in the preterm infant. These issues remain unresolved and in need of additional study.

One major factor that is overlooked in the debate about the relation between BP and brain injury in preterm infants is the dynamic yet tenuous nature of intrinsic cerebrovascular control in these patients.17 The interaction between immature systemic and cerebral hemodynamics during the period of circulatory transition is likely to be extremely complex and remains very difficult to study continuously at the bedside of sick preterm infants. In a recent study,17 we used continuous direct measurements of BP time-locked to continuous near-infrared spectroscopy measures of cerebral hemodynamics to demonstrate a high prevalence and fluctuating nature of cerebral blood flow pressure passivity in sick preterm infants. Most important, the relationship between cerebral pressure passivity and BP was unpredictable, with pressure passivity occurring during both normal and hypotensive BP levels (as currently defined) in the same infant over time.17 These findings emphasize the dynamic nature of the cerebral pressure autoregulatory plateau and suggest that factors other than BP may influence the BP thresholds for cerebral pressure passivity. These questions are under investigation.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In this study we failed to find an association between various widely used definitions of hypotension in preterm infants and the emergence of early brain injury as detected by cranial ultrasound. This lack of association was particularly true of the smallest, sickest, and therefore most vulnerable infants. These findings suggest that adherence to current population-based guidelines for the diagnosis and management of hypotension might not be effective in preventing brain injury in sick preterm infants. On the basis of our previous work,17 we propose that this lack of association is attributable to the influence of factors other than BP on cerebral autoregulation. Without the ability to measure cerebrovascular responses continuously, identifying and applying optimal BP levels to prevent brain injury across whole populations of sick infants or even in the individual infant may be an exercise in futility.


   ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health grant P01NS38475, the LifeBridge Fund, the Caroline Levine Foundation, the Trust Family Foundation, and a postdoctoral fellowship (to Dr Limperopoulos) from the Canadian Institutes of Health Research.

We thank Shaye Moore for assistance with manuscript preparation and the patients and families for participation in this study.


   FOOTNOTES
 
Accepted May 7, 2007.

Address correspondence to Adré J. du Plessis, MBChB, MPH, Department of Neurology, Fegan 11, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: adre.duplessis{at}childrens.harvard.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
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 RESULTS
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