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Morphine, Hypotension, and Adverse Outcomes Among Preterm Neonates: Who’s to Blame? Secondary Results From the NEOPAIN Trial

Richard W. Hall, MD^*, Shari S. Kronsberg, MS, Bruce A. Barton, PhD, Jeffrey R. Kaiser, MD, MA^*, K.J.S. Anand, MBBS, DPhil^*,,||,¶ for the NEOPAIN Trial Investigators Group

^* Department of Pediatrics
Department of Anesthesiology
^|| Department of Neurobiology
^¶ Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Maryland Medical Research Institute, Baltimore, Maryland

	ABSTRACT

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Objectives. Hypotension occurs commonly among preterm neonates, but its cause and consequences remain unclear. Secondary data analyses from the NEOPAIN trial identified the clinical factors associated with hypotension and examined the contributions of morphine treatment or hypotension to severe intraventricular hemorrhage (IVH) (grades 3 and 4), any IVH (grades 1–4), or death.

Methods. In the NEOPAIN trial, 898 ventilated neonates between 23 and 32 weeks of gestation were enrolled, with equal numbers randomized to receive masked morphine or placebo infusions. Additional doses of open-label morphine were administered as necessary by medical staff members. IVH was diagnosed with centralized readings of early and late cranial ultrasonograms. Hypotension was assessed before study drug infusion, during the loading dose, and at 24 and 72 hours during study drug infusion. Logistic regression analyses with stepdown elimination identified the predictor factors associated with the hypotension, severe IVH, any IVH, or death outcomes at each time point.

Results. Hypotension was associated with 23 to 26 weeks of gestation, morphine infusions, severity of illness, additional morphine doses, and prior hypotension. Severe IVH was associated with shorter gestation, higher Clinical Risk Index for Babies scores, no prenatal steroids, pulmonary hemorrhage, hypotension before the loading dose, and morphine doses before intubation and at 25 to 72 hours. Neonatal deaths were associated with 23 to 26 weeks of gestation, higher Clinical Risk Index for Babies scores, pulmonary hemorrhage, patent ductus arteriosus, thrombocytopenia, and hypotension before the loading dose. Morphine infusions were not a significant factor in logistic models for severe IVH, any IVH, or death.

Conclusions. Preemptive morphine infusions, additional morphine, and lower gestational age were associated with hypotension among preterm neonates. Severe IVH, any IVH, and death were associated with preexisting hypotension, but morphine therapy did not contribute to these outcomes. Morphine infusions, although they cause hypotension, can be used safely for most preterm neonates but should be used cautiously for 23- to 26-week neonates and those with preexisting hypotension.

Key Words: morphine • hypotension • preterm neonates • outcomes • pain • intraventricular hemorrhage • drug toxicity

Abbreviations: IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia • OR, odds ratio • CI, confidence interval • CRIB, Clinical Risk Index for Babies • BP, blood pressure • SGA, small for gestational age

Hypotension during the first 3 days of life among preterm neonates has been associated with poor outcomes, including increased mortality rates,¹ intraventricular hemorrhage (IVH),^2,3 and periventricular leukomalacia (PVL).^4,5 Although recent data suggested that the pathogenesis of PVL is related to fetal inflammation and oxidative injury^6,7 and not neonatal hypotension,^8,9 the role of hypotension in the pathogenesis of IVH remains unclear.^4,5 Furthermore, it is not known whether early hypotension is a cause of or simply a marker for poor neurologic outcomes.

The operational definition of hypotension remains controversial, despite the use of published nomograms for blood pressure (BP)¹⁰ and criteria based on gestational age.¹¹ Hypotension occurs commonly among ventilated preterm neonates because of iatrogenic fluid restriction, impaired venous return caused by positive intrathoracic pressure, limited myocardial contractility, decreased adrenocortical responses, and comorbidities such as sepsis and pulmonary hemorrhage. Therefore, although BP is frequently monitored in the NICU, the absolute values of BP that should be treated and the effects of hypotension are in dispute.⁵ Neonatologists remain concerned, however, that systemic hypotension may lead to poor outcomes among preterm neonates, and they treat it aggressively with inotropes,¹² intravenous fluid boluses,^13,14 or corticosteroids.¹⁵

Primary outcomes from the NEOPAIN multicenter trial¹⁶ suggested that morphine analgesia may increase the incidence of severe IVH, particularly among neonates born at 23 to 26 or 27 to 29 weeks of gestation. The increased incidence of hypotension among neonates randomized to the morphine group during the loading dose and during 1 to 24 hours of study drug infusion¹⁶ suggested that adverse neurologic outcomes may be mediated, at least partially, by the hemodynamic effects of morphine therapy.^17,18 After publication of recent trials,^16,19 we were concerned that clinicians might be discouraged from treating ventilated preterm neonates with morphine or other analgesics for fear of promoting hypotension or increasing the risk of adverse neurologic outcomes. Therefore, we performed detailed secondary analyses to identify the clinical factors associated with hypotension among ventilated preterm neonates at different time points during the NEOPAIN trial. Furthermore, we evaluated the association of hypotension and morphine analgesia with severe IVH (grades 3 and 4), any IVH (grades 1–4), and death among these neonates.

	METHODS

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Study Design
Preterm neonates were eligible for the NEOPAIN trial if they were born between 23 and 32 weeks of gestation and required intubation at 72 hours of age. Furthermore, the study drug infusion had to be started within 8 hours after intubation. Neonates with major congenital anomalies, birth asphyxia (5-minute Apgar score of 3 or cord pH of 7.0), intrauterine growth restriction (5th percentile²⁰), or maternal opioid addiction and those participating in other clinical trials were excluded. Written parental consent was obtained for all 898 neonates enrolled from 16 NICUs. The NEOPAIN protocol and consent forms were approved by local ethics committees at each participating site, by an external ethics committee at the coordinating center, and by an independent data and safety monitoring board.

Randomization was performed with an automated telephone response system and was stratified according to the participating NICUs and gestational age (23–26, 27–29, or 30–32 weeks), to ensure equal representation in the morphine and placebo groups. To eliminate bias, all clinical personnel were blinded to the study drug code.

Therapeutic Management
Neonates randomized to the morphine group received a loading dose of morphine (100 µg/kg infused over 1 hour), followed by continuous infusions of 10, 20, or 30 µg/kg per hour for neonates at 23 to 26, 27 to 29, or 30 to 32 weeks of gestation, respectively. These doses were based on morphine pharmacokinetic data available at the time of protocol development.^21,22 Neonates randomized to placebo received a similar-volume loading dose, infusion rate, and weaning protocol. Because of ethical concerns,²³ both randomized groups received additional bolus doses of open-label morphine, on the basis of clinical judgment and specific protocol criteria.

Data Collection
Data collection included baseline clinical and demographic characteristics, primary outcomes including death (defined as death before hospital discharge), severe IVH (defined as grade 3 or 4), and PVL, and secondary clinical outcomes such as hypotension. Two cranial ultrasonograms were performed to assess IVH, one at 4 to 7 days of age for all neonates and the second at 28 to 35 days of age for neonates born at 23 to 29 weeks of gestation or at 14 to 28 days for neonates born at 30 weeks of gestation.^24–26 Two pediatric radiologists, blinded with respect to treatment groups, provided independent interpretations of all ultrasonograms. Discrepancies between the interpretations were adjudicated with standardized criteria, and consensus interpretations were used in this analysis.^24,25,27 The clinical factors defined in Table 1 were selected a priori, on the basis of reported associations with the outcomes of hypotension, severe IVH, any IVH (grades 1–4), or death. Hypotension was defined by the need for treatment, which was defined as the need for intravenous vasopressor support or intravenous fluid boluses of 20 mL/kg, and was evaluated before study drug, during the study drug loading dose, at 1 to 24 hours during study drug infusion, and at 25 to 72 hours during study drug infusion. BP values were assessed by the attending physicians, with umbilical arterial catheters (723 of 885 subjects, 82%), peripheral arterial catheters (53 of 885 subjects, 6%), or noninvasive methods (109 of 885 subjects, 12%); the attending physicians also determined the need for treatment, according to specific clinical criteria at each NICU.

View larger version (37K): [in this window] [in a new window]   Fig 1. Incidence of hypotension among treatment groups. The incidence of hypotension at each time point was compared between infants who received open-label morphine or no open-label morphine before treatment (hypotension before study drug [SD]) and between treatment groups that received placebo infusion only, placebo infusion with open-label morphine (AA), morphine infusion only, or morphine infusion with open-label morphine, with 2 tests for independence. Differences in hypotension during the loading dose (0–1 hour of study drug) occurred between the placebo group and all other groups. Rates of hypotension at 1 to 24 hours during study drug infusion were significantly different among all groups except between the placebo plus open-label morphine group and the morphine group.

View larger version (54K): [in this window] [in a new window]   Fig 2. The incidence of hypotension was compared among gestational age strata with 2 tests for all 3 groups (P values in figure) and 2 tests with Yates correction for differences between groups. M indicates morphine infusions; SD, study drug; *, µg/kg per hour.

	RESULTS

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Hypotension before the loading dose was related primarily to severity of illness (measured with the CRIB score), with a protective effect associated with magnesium therapy. Other maternal antihypertensive medications were included in this model but were not significant. Hypotension during the loading dose was associated with gestational age of 23 to 26 weeks, morphine infusions, preexisting hypotension, and use of open-label morphine before the loading dose. Hypotension during 1 to 24 hours of study drug infusion was related to early gestation (23–26 weeks), morphine treatment, severity of illness, occurrence of prior hypotension (before or during the loading dose), lack of maternal steroid therapy, white descent (compared with black), open-label morphine, and neonatal complications (difficult intubation, hypothermia, or neutropenia). Interestingly, hypotension at 25 to 72 hours was not related to gestational age or morphine treatment but was associated with preceding hypotension (at 1–24 hours), patent ductus arteriosus, severity of illness, and open-label morphine use at 25 to 72 hours during study drug infusion. Infants who were small for gestational age (SGA) were less likely to be hypotensive at 1 to 24 hours but were more likely to require treatment at 25 to 72 hours.

Random-effects models were used to test whether the effect of morphine on hypotension varied according to center. This was not found to be significant.

Factors Associated With IVH
Logistic regression models were developed to identify the clinical factors (Table 1) associated with severe IVH (Table 3) or any IVH (Table 4). For the severe IVH outcome (grade 3 or 4 IVH versus grade 1 or 2 or no IVH), logistic regression models revealed that gestational age (23–26 weeks, OR: 6.85–7.70; 27–29 weeks, OR: 3.93–4.21), severity of illness (OR: 2.23–2.58), and lack of prenatal steroid therapy (full course versus none, OR: 2.64–3.14) were significant predictors at all time points when hypotension was assessed (Table 4). Pulmonary hemorrhage was significant at all time points (OR: 5.12–5.38) except at 25 to 72 hours of study drug infusion. Hypotension was a significant predictor of severe IVH only if it occurred before the study drug loading dose (OR: 1.82), whereas hypotension during or after the morphine loading dose or the randomization to morphine treatment did not contribute to the occurrence of severe IVH. The decision to use open-label morphine was a significant predictor of severe IVH only if the open-label morphine was given during 25 to 72 hours of study drug infusion (OR: 1.86; P = .0161).

For neonatal death, logistic regression models identified the clinical factors associated with death, which included gestational age of 23 to 26 weeks (OR: 10.69–11.19), severity of illness (OR: 5.65–7.11), pulmonary hemorrhage (OR: 5.16–6.01), thrombocytopenia (OR: 3.67–4.12), and patent ductus arteriosus (OR: 2.06–2.42). Hypotension before the loading dose was a significant predictor of death (OR: 1.81–2.03), but hypotension occurring at subsequent time points was not significant, despite being forced into the logistic regression model for each time point. It was remarkable that all predictors of neonatal death had similar ORs in each of the logistic models (Table 5). There were no significant effects of randomization to the morphine group or the use of open-label morphine on neonatal death.

	DISCUSSION

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Hypotension occurs commonly among preterm neonates during the first 3 days after birth^1,28 and is associated with adverse clinical outcomes.^29,30 Hypotension is thought to result in ischemia, with potentially detrimental effects on the immature brain.^1,7 Previous studies reported that hypotension in the first 24 hours was affected by multiple clinical factors, including prenatal steroids,^31,32 gestational age,^33,34 severity of illness,^15,30,35 postnatal age in hours,^36,37 and morphine therapy.^38,39 We now know that hypotension can lead to decreased cerebral perfusion among neonates with either impaired or intact cerebral autoregulation.^1,4 Among neonates with impaired autoregulation, cerebral perfusion is pressure passive and hypotension decreases cerebral blood flow. Pressure-passive cerebral blood flow also occurs if BP falls below the lower limit of the ability of neonates to autoregulate cerebral perfusion. Therefore, both situations lead to ischemia of the germinal matrix, which may rupture during reperfusion, leading to IVH.⁴⁰ Despite clinical and physiologic evidence that hypotension may lead to adverse events, its association with IVH and death in clinical studies remains tenuous.⁵

In analyzing the primary outcomes from the NEOPAIN trial, we found significant effects of morphine therapy on the incidence of hypotension among ventilated preterm neonates.¹⁶ An increased incidence of severe IVH occurred among 27- to 29-week neonates randomized to the morphine group, as well as among the neonates who had received open-label morphine. After exclusion of the neonates who received open-label morphine, increased severe IVH was also noted among the neonates randomized to the morphine group and in the 23- to 26-week subgroup in the NEOPAIN trial. Detailed secondary analyses were therefore performed to examine the contributions of morphine infusions and the use of open-label morphine in producing the hypotension measured at various time points during the study. We also evaluated the roles of hypotension and morphine therapy in contributing to IVH or neonatal death in the NEOPAIN trial.

Logistic regression analyses with hypotension as the outcome evaluated the roles of various clinical factors and morphine treatment (Table 2). Hypotension before the study drug loading dose was associated with the severity of illness, as measured with CRIB scores. We were intrigued by the finding of reduced hypotension after the prenatal use of magnesium. Although prenatal magnesium therapy may cause hypotension among the mothers,^41,42 it was reported recently to be neuroprotective for premature neonates.⁴³ Prevention of neonatal hypotension may explain, at least partially, this neuroprotective effect. Alternatively, the prenatal use of magnesium could be a marker for pregnancy-induced hypertension, which has been associated with higher BPs among preterm neonates.⁴³

Hypotension during the loading dose was related to gestational age (23–26 weeks), randomization to the morphine treatment group, and open-label morphine therapy before the loading dose, but the greatest contribution was from hypotension before the loading dose (OR: 4.85; P < .0001). These findings suggest that morphine therapy should be used with great caution among preterm neonates who are hypotensive at baseline, particularly those at the lower gestational ages (23–26 weeks).⁴⁴ Alternative approaches to analgesia and sedation (eg, synchronized ventilation or intravenous ketamine therapy) may be more appropriate for these patients.

Hypotension during 1 to 24 hours of study drug infusion was predicted by well-known risk factors, including severity of illness, white descent, hypothermia, difficulty with intubation, prior exposure to hypotension (before or during the loading dose), and neutropenia (possibly a marker for sepsis). SGA status protected against hypotension during this time period, possibly because it resulted from pregnancy-induced hypertension. It is important to note that preemptive morphine infusions (study drug) and open-label morphine treatment within 24 hours contributed significantly to the hypotension occurring in this time period. This supports our recommendation against the use of morphine among neonates with a history of previous or ongoing hypotension.

Hypotension during 25 to 72 hours was predicted by, in order of clinical importance, hypotension occurring in the previous time period, SGA status, patent ductus arteriosus, increased severity of illness, and use of open-label morphine during this time period but not by gestational age or preemptive morphine treatment. Therefore, the effects of gestational age and morphine, which were both highly associated with hypotension just after birth, had disappeared at 25 to 72 hours. SGA status has been associated with hypotension for as long as 2 years in experimental animals and humans, possibly as a result of altered vascular or cardiac development attributable to increased vascular resistance or nutrient restriction during fetal life.^45,46 This is the first report to describe the timing of hypotension in relation to SGA status.

Although morphine analgesia was associated with the increased occurrence of early hypotension, additional analyses revealed that morphine therapy had no significant effects on IVH or neonatal death, except that open-label morphine during 25 to 72 hours after starting study drug infusion was associated with severe IVH. We think that open-label morphine during this late period was most likely given to treat the symptoms of neurologic irritability associated with early IVH.

These results differed from primary outcomes of the NEOPAIN trial because we adjusted for the various clinical risk factors and hypotension occurring at different time points. Therefore, we think that these analyses reflect more accurately the association of hypotension, morphine, and adverse sequelae. These analyses showed that use of preemptive morphine analgesia was no longer significant in the logistic regression models tested for the outcomes of severe IVH, any IVH, or death (Tables 3, 4, and 5, respectively). Morphine therapy may accentuate preexisting hypotension, but it also blunts the physiologic responses to pain leading to the BP fluctuations associated with IVH.^44,47 Therefore, morphine infusions may be used judiciously for normotensive preterm neonates.

Severe IVH was related to the CRIB score,⁴⁸ lower gestational age,⁴⁹ pulmonary hemorrhage,⁵⁰ lack of prenatal steroids,⁵¹ analgesia before tracheal intubation, and hypotension before the loading dose. In contrast, any IVH was related to preexisting hypotension and hypotension within the first 24 hours, as well as additional risk factors such as chorioamnionitis and neonatal sepsis.⁵² This assessment suggests that systemic hypotension may be partially responsible for IVH. IVH has been postulated classically as a venous disturbance, but these data support the emerging concept that IVH may also be related to arterial dysfunction (hypotension). Although morphine therapy does not increase short-term adverse effects among preterm neonates, long-term studies are needed to address this important concern.⁵³

Limitations of this study include the lack of cranial ultrasonography before study drug infusion, use of the decision to treat rather than numerical values for defining hypotension, and a quasi-retrospective study design. Because there were no baseline cranial ultrasound findings, we can only suggest an association between hypotension and IVH. Furthermore, we can only speculate that some of the infants who received open-label morphine were reflecting an increased irritability attributable to intracranial hemorrhage, which is well described in the literature.³⁹ Currently, there is no consensus regarding the definition of hypotension with numerical criteria. Therefore, the decision to treat might also be considered a strength of this study, because most neonatologists use clinical criteria such as history, peripheral perfusion, skin color, oxygen requirements, and urine output to determine treatment in actual practice. This study was a retrospective analysis and was not designed to assess hypotension. However, because hypotension is a common complication of morphine therapy, it was well documented in this data set at several time points and led to a careful analysis of this adverse outcome.

First, this study design has several strengths. First, this is the largest study to date that has examined the association between early hypotension and subsequent adverse outcomes among preterm neonates. Second, these data were obtained from 16 participating centers, 4 of which were outside the United States, which strengthens the generalizability of these results. Third, a major strength was the centralized interpretation of cranial ultrasonograms, so that IVH was assessed uniformly for all study participants, with stringent criteria. Lastly, the use of logistic regression analyses with such a large number of patients better enabled us to eliminate other "markers" for hypotension when assessing clinical factors associated with hypotension, IVH, or death.

	CONCLUSIONS

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Although morphine therapy is associated with hypotension among ventilated preterm neonates, it does not increase the risk of severe IVH, any IVH, or death. Only hypotension occurring before the loading dose in this study was associated with these adverse outcomes among preterm neonates. Because morphine predisposes patients to hypotension, which has other adverse effects, we recommend that it be used with caution among 23- to 26-week neonates and those with preexisting hypotension.

	ACKNOWLEDGMENTS

 
This study was supported by the National Institute for Child Health and Human Development (grant HD36484 to K.J.S.A. and grant HD36270 to B.A.B.).

We gratefully acknowledge the contributions of all of the physicians, nurses, and other professionals at the participating institutions and the parents who gave consent for this study.

	FOOTNOTES

 
Accepted Jan 4, 2005.

Reprint requests to (R.W.H.) University of Arkansas for Medical Sciences, Slot 512B, 4301 West Markham St, Little Rock, AR 72205. E-mail: hallrichardw{at}uams.edu

No conflict of interest declared.

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