PEDIATRICS Vol. 107 No. 6 June 2001, pp. 1351-1356

Child Health Status, Neurodevelopmental Outcome, and Parental Satisfaction in a Randomized, Controlled Trial of Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn

Marty Ellington Jr, MD, MPH^*, , Deirdre O'Reilly, MD^§, Elizabeth N. Allred, MS^{, ¶}, Marie C. McCormick, MD, ScD^{¶, #}, David L. Wessel, MD^**, and Stella Kourembanas, MD^¶

From the ^* Department of Pediatrics, New York Hospital Medical Center of Queens, New York, New York;  Department of Pediatrics, Weill Medical College of Cornell University, New York, New York; ^§ Department of Pediatrics, University of California-San Francisco, San Francisco, California;  Neuroepidemiology Unit, Children's Hospital of Boston, Boston, Massachusetts; ^¶ Department of Pediatrics, Division of Newborn Medicine, Children's Hospital of Boston, Harvard Medical School, Boston, Massachusetts; ^# Department of Maternal and Child Health, Harvard School of Public Health, Boston, Massachusetts; and the ^** Department of Cardiology, Children's Hospital of Boston, Boston, Massachusetts.

	ABSTRACT

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Objective.  To describe health and neurodevelopmental outcomes and parental satisfaction with hospital care among surviving intervention and control enrollees in a randomized, controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn (PPHN).

Methods.  All surviving enrollees 1 to 4 years of age were eligible for follow-up. Outcomes were assessed by telephone using a trained interviewer and standardized instruments. Domains assessed included parental report of specific conditions and hospital use, rating of general health, cognitive and motor development, behavior problems, temperament, and satisfaction with the hospital stay. Fisher's exact test and the Wilcoxon rank sum test assessed differences between intervention and control infants.

Results.  Interviews were completed on 60 of 83 survivors (72%). Eighteen families (22%) could not be located, 2 (2%) were non-English-speaking, and 3 (4%) declined participation. No postdischarge deaths were ascertained. Among those interviewed, race, income, and education of parents of intervention and controls were comparable, as were entry oxygenation index, extracorporeal oxygenation utilization, and days of hospitalization. No differences were found in pulmonary, neurologic, cognitive, behavioral, or neurosensory outcomes; hospital readmission rates; or parental ratings of child's health. The overall neurologic handicap rate was 15%. The rate of hearing deficit was 7%. The rate of significant behavioral problems was 26%. Levels of satisfaction expressed were high for each group. No differences in parental ratings were found between the 2 groups.

Conclusions.  No adverse health or neurodevelopmental outcomes have been observed among infants treated with nitric oxide for PPHN. The parents of the critically ill infants enrolled in our clinical trial welcomed their child's inclusion and all expressed satisfaction with the care that their child received while at a tertiary care hospital. Enrollment in either arm of this randomized, controlled trial did not seem to affect parental satisfaction with the hospital care that their child received.  Key words:  nitric oxide, parental satisfaction, infant development follow-up, persistent pulmonary hypertension of the newborn, outcome studies.

Infants with persistent pulmonary hypertension of the newborn (PPHN) are critically ill in the neonatal period and are known to be at risk for adverse health and neurodevelopmental outcomes. Published health and neurodevelopmental follow-up studies report that survivors of PPHN are at risk for pulmonary morbidities, hearing and speech loss, cerebral palsy, seizures, stroke, and developmental delay.^1-6 Many of these studies reflect the experience with extracorporeal membrane oxygenation (ECMO), as well as older management approaches. More recent approaches include inhaled nitric oxide, which has proven successful in multicenter trials for the treatment of PPHN and respiratory failure. Inhaled nitric oxide improves oxygenation and reduces the need for ECMO.^7,8 To examine the health and neurodevelopmental outcomes of infants treated with nitric oxide for PPHN, we followed surviving children ages 1 to 4 years who were participants of a randomized, controlled trial of nitric oxide in PPHN.

We also explored parental reactions to participation in randomized, controlled trials. The process of clinical trials requires the informed consent of parents whose critically ill infants may or may not receive the new therapy. Parents have expressed both suspicion of novel therapies as well as a desire for assessment of the safety and efficacy of clinical interventions.⁹ Assessment of parental attitudes toward enrollment in a nonblinded, randomized, controlled study is, therefore, a valuable avenue of investigation. To assess parental reactions to the hospital experience, including participation in the trial, we chose to measure patient satisfaction, because it gauges the parents' reaction to the process of care, importantly, both the technical quality and the interpersonal aspects.^10-12

Our follow-up study of infants enrolled in a clinical trial evaluating the effectiveness of nitric oxide for PPHN sought to determine whether there were differences among intervention and control infants in health and neurodevelopmental outcomes or parental satisfaction with care. We did not anticipate differences in health or neurodevelopmental outcomes; however, we suspected that the parents of infants who did not receive the experimental therapy might be less satisfied with the care that their child received than would be the parents of the infants who did.

	METHODS

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From September 1992 through January 1997, 90 infants admitted to Children's Hospital with PPHN were randomized with parental consent to receive conventional therapy or conventional therapy plus nitric oxide. Entry criteria included respiratory failure, as defined by ventilatory support requiring 100% oxygen with persistent hypoxia, and documented pulmonary hypertension by echo or ductal shunting. During this period, nitric oxide was used only within protocol. All analysis was performed following intent-to-treat criteria. No parents refused participation in the trial and there were no withdrawals for any reason. Protocols and results of this study have been published elsewhere.^13,14

We attempted to contact the 83 survivors at 1 to 4 years of age using mail and telephone search strategies described previously.¹⁵ Forty-three children had received nitric oxide, and 40 received conventional therapy. The Children's Hospital Committee on Clinical Investigation approved the study.

Data Collection

Study data were collected through a telephone interview using a questionnaire. The interviewer was blinded to treatment group. Interviews required ~20 minutes to complete. Specific items included:

1. Specific morbidities: questions patterned after the National Health Interview Survey to assess for the presence or absence of morbidities previously reported among surviving infants with PPHN, ie, hearing deficits, visual deficits (blindness or problems seeing), cerebral palsy, hyperactivity, mental retardation, seizures, speech disorders, asthma, stroke, microcephaly, and hydrocephalus.^16-18
2. Perinatal history and the health care utilization of the child after the initial hospitalization.^16-18
3. Parental ratings of their child's current and past health: General Health Rating Scale, which consists of 7 Likert scale items developed for use in the National Health Insurance Study.^1618-20
4. Sociodemographic characteristics of the family: ethnicity, income, and education of the responding caretaker.
5. Cognitive development: Motor and Social Development Scale previously fielded as part of the 1981 Child Health Supplement to the National Health Interview Survey (specific questions include: 0-3 months, "Have child's eyes ever followed a moving object at all?"; 10-12 months, "Has your child ever said recognizable words such as "mama' or "dada'?"; 1 year 10 months to 3 years 11 months, "Has child ever walked upstairs by himself/herself without holding a rail?"). Developmental quotients (DQs) were assigned based on published normative values.²¹
6. Behavior problems: Richman-Graham Behavior Screening Questionnaire, which is a 20-item, survey eliciting parental perceptions of the frequency of their child's expression of 12 problematic behaviors. This instrument provides a measure of the prevalence of behavioral difficulties in children ages 2 to 4 years with a score of 0 to 2 for each behavior. A total score of 10 or more is suggestive of clinically significant behavioral disturbance.^22-25
7. The Bates Temperament Scale, an 11-item instrument used to assess the affective response to stimuli in children 1 to 2 years of age.²⁶ Scores range from 5 to 55, with higher scores suggestive of a difficult temperament.
8. Parent satisfaction: Patient Satisfaction Questionnaire (PSQ) of the Medical Outcomes Trust consisting of Likert scale items with each item scored 1 to 5, with higher scores suggesting higher satisfaction.¹⁰ The PSQ is normed for adults assessing satisfaction with their own care. We modified the PSQ to a 30-item survey and used it to assess parental satisfaction with their child's care. In addition, we formulated 2 similar-style questions to assess parental satisfaction with their child receiving care in an institution that enrolled their critically ill infant in a clinical trial. The questions specifically queried whether the parent "appreciated being in an institution that offered experimental therapies" or believed that the "doctors were experimenting on infants."

Analyses

Patient's whom we successfully interviewed were compared with those with whom we were unsuccessful by severity of illness measures and available sociodemographic factors. The nitric oxide and control groups were compared for differences in sociodemographic factors and characteristics of the neonatal hospitalization. Statistical significance was determined using the Wilcoxon rank sum test and Fisher's exact test. Multivariate regression was performed to determine whether socioeconomic factors contributed to variation in health, developmental, and satisfaction outcomes.

	RESULTS

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Characteristics of Sample

Interviews were completed on 60 of 83 of the survivors (72%); 35 intervention infants and 25 controls. Eighteen families (22%) were not located, 2 (2%) were non-English-speaking, and 3 (4%) declined participation. No postdischarge deaths were ascertained. No differences were seen between respondents and nonrespondents in mean entry oxygenation index, ECMO use, sex, insurance status, or distance from Children's Hospital. Respondents, however, were more likely to have received nitric oxide (Table 1).

The vast majority of caretakers interviewed were biologic parents. There were 2 exceptions: a foster mother and a female relative, each of whom had been the caretaker since discharge from the hospital. No differences emerged in sex, mean entry oxygenation index, ECMO use, length of stay, or age at interview between intervention and control infants. There were likewise no differences in race, income, or education of the parents of intervention and control infants (Table 2).

Health Outcomes

The intervention and control groups were similar in pulmonary, neurologic, or neurosensory outcomes and in hospital readmission rates (Table 3). Likewise, parents of each group reported that their children's health, behavior, temperament, and cognitive development were similar. The vast majority of respondents (65%) reported that their child did not have any morbidities. Twenty-seven percent reported at least 1 hospital readmission. The overall neurologic handicap rate reported by respondents was 15%. The rate of hearing deficit reported was 7%. The rate of hearing or speech disability reported was 18%. Visual disability was reported by 8% of respondents. Ten percent of respondents recalled that their child was discharged from the hospital from the initial hospitalization on oxygen, and 18% reported that their child had suffered from asthma at some point since discharge. The rate of significant behavioral problems reported was 26%.

Satisfaction

A high level of satisfaction with the tertiary care received was expressed. No difference between the 2 groups in parental ratings of overall satisfaction with hospital care was seen (Table 3). Furthermore, there was no difference in parental satisfaction between the parents of infants who had undergone ECMO or the parents of infants who reported current morbidities. No respondent agreed that "doctor's experimented on infants," and all respondents agreed that they "appreciated being at an institution that offered experimental therapies."

Multivariate linear regression was performed to determine whether level of parental education or family income contributed any variation to the comparisons of parental health ratings, cognitive development, behavior and temperament, and parental satisfaction with care. Level of parental income was significantly associated with cognitive development but not other outcomes. In no case did the association with study status change with entry of parental education into the models.

	DISCUSSION

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As we hypothesized, no differences in the neurodevelopmental or health outcomes were seen for surviving infants with PPHN with or without nitric oxide treatment. In addition, contrary to our expectation, we have found that enrollment in either arm of this nonblinded, randomized, controlled trial did not affect parental satisfaction with the hospital care that their child received.

Our follow-up study suggests that nitric oxide therapy does not pose any additional risk of adverse health or neurodevelopmental outcomes compared with conventional therapy for PPHN. In fact, the decrease observed in hypoxemia and ECMO use among infants with PPHN suggests the potential for an overall improvement in the outcome of infants with PPHN as a result of nitric oxide therapy.^7,8,13,14

Comparison of our findings with previously reported health and neurodevelopmental outcomes is difficult because of inconsistency in outcome measures across studies and small sample size, particularly in the pre-ECMO era. However, when neurodevelopmental disability is defined as presence of cerebral palsy, DQ < 70, or seizures, disability rates are in the range of 0% to 36%.^1-627-37 Early studies (pre-1990) reported a higher rate of poor outcomes. Our neurodevelopmental disability rate of 15% is consistent with the more recent reports of outcomes of ECMO, as well as the recent report by Rosenberg et al,³⁸ in which 12% of nitric-treated PPHN survivors had severe neurodevelopmental disabilities. Rosenberg et al,³⁸ however, does not include seizure disorders in the definition of neurodevelopmental disabilities.

Poor neurosensory outcomes, defined as hearing, speech, or visual impairment, received significant attention in published reports of the 1980s. Reported rates of impairment were variable, ranging from 5% to 53%, with a predominance of hearing loss and abnormal speech patterns.^{3,6,27,30,31,3335-37} Rates of visual impairment ranged from 0% to 13%.^27,32,35 Our finding of 18% prevalence of hearing or speech problems reflects this previous literature. Our findings are also consistent with Rosenberg et al,³⁸ of 6% hearing loss because parents reported hearing problems in 7% of our study sample.

Pulmonary sequelae, defined as reactive airway disease, chronic lung disease, and rehospitalization for respiratory illnesses, ranged from 25% to 30%.^2,6,32 Our findings of pulmonary sequelae are also consistent with the previous literature.

Behavioral outcomes have not previously been described among survivors of PPHN. Parental reports of difficult temperament among 1- to 2-year-olds are similar to published norms.²⁶ Rates of clinically significant behavior problems among 2- to 4-year-olds, however, were higher than the prevalence of 14% in reference populations.²⁴ We found that 16% of intervention patients and 40% of controls exhibited problem behaviors, although median scores did not differ. The prevalence of behavior problems deserves additional examination in future outcome studies of PPHN survivors.

Parental reports of current health are similar to reference populations.¹⁹ There are, however, striking differences between parental reports of susceptibility to illness and previous health between our group of infants and the reference populations. Consistent with their life-threatening neonatal experiences, parents rated their child's past health more poorly than published norms.

In summary, the health and neurodevelopmental outcomes of our cohort are consistent with the experience reported among PPHN survivors. There was no difference in outcome among those treated with nitric oxide and those receiving conventional medical therapy.

Our study also provides encouragement for tertiary care centers engaging in the clinical investigation of new therapies and technologies. To our knowledge, no studies of patient satisfaction with participation in clinical trials have been published. We found that most parents expressed high levels of satisfaction with the care received at a tertiary care center using investigational therapies with no difference between the groups in level of satisfaction. No one expressed distrust of physicians with regard to research, and all parents appreciated that their critically ill infant was cared for at an institution that offered experimental therapies.

Our study also provides additional experience with using survey methodologies in the follow-up of critically ill neonatal intensive care unit graduates at risk for health, neurodevelopmental, and behavioral morbidities. Although telephone interviews and other survey techniques do not replace direct patient examination and observation, these methodologies might prove valuable adjuncts for infant follow-up programs confronting funding limitations.

We must also acknowledge the limitations of our study. First, although our cohort of 60 infants is larger than most previously published cohorts, our power to detect differences in health and neurodevelopmental outcomes between intervention and control infants is limited. For example, a full standard deviation difference in the mean scores of DQ would have been needed to achieve statistical significance. Thus, although we have shared the striking differences in the numbers of intervention and control infants with DQs < 70, we must emphasize that our study does not detect differences in the median DQs of the 2 groups. Second, the timing of assessment has implications for interpreting the results. For example, we could not assess for any learning difficulties, which may become evident as our cohort reaches school age. Third, our study relies on parental report during telephone interview. Although this approach is validated and would not affect the detection of severe disabilities, mild neurologic deficits may be underestimated. Additionally, we were unable to elicit information concerning the infants' growth and head circumference. This information is often part of infant follow-up studies. Fourth, parental satisfaction with care might be influenced by the child's current health status, although in our small sample we detected no such influence. Alternatively, the survival of a child with life-threatening illness may lead to high satisfaction irrespective of treatment or outcome. Finally, we ethically could not assess the satisfaction with care of the parents of children who died. Differences in reaction to study status may be more pronounced among those whose children did not survive.

	CONCLUSION

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We detected no excess adverse health or neurodevelopmental outcome among PPHN survivors treated with nitric oxide compared with those treated with conventional therapies. Parents of the critically ill infants enrolled in our clinical trial welcomed their child's inclusion. Most parents subsequently expressed satisfaction with the tertiary care that their child received. Given that in our trial inhaled nitric oxide reduced the need for ECMO and did not adversely affect platelet function, our results suggest no adverse sequelae from exposure to nitric oxide.^14,39 Furthermore, our results argue for more attention to outcomes, such as behavior and satisfaction with care, in randomized, controlled trials.

	ACKNOWLEDGMENTS

This program was supported by the National Institute of Child Health and Human Development Grant T32HD07392 and a grant from Ohmeda. Dr Wessel was supported by Grant FD-R00133136 from the Food and Drug Administration. Dr Kourembanas was supported by Grants R01 HL55454 and P50HL46491 from the American Heart Association and the National Institutes of Health. Data collection was performed at Children's Hospital, Boston, Massachusetts.

We thank David Gemmel and Melissa Himes of the Research Department of Western Reserve Health Care for their assistance in the editing and preparation of this manuscript.

	FOOTNOTES

Received for publication Feb 4, 2000; accepted Oct 10, 2000.

Reprint requests to (M.E.) Department of Pediatrics, New York Hospital Medical Center of Queens, 56-45 Main St, Flushing, New York 11355. E-mail: mae9011{at}nyp.org

	ABBREVIATIONS

PPHN, persistent pulmonary hypertension of the newborn; ECMO, extracorporeal membrane oxygenation; DQ, developmental quotient; PSQ, Patient Satisfaction Questionnaire.

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