Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes.

OBJECTIVES: In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. STUDY DESIGN: A total of 385 neonates who received >/=50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. RESULTS: The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43-6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%-100%), paralysis (73%; range: 33%-98%), and inotrope administration (84%; range: 46%-100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%-81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%-33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. CONCLUSIONS: Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies.

Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial.

BACKGROUND: Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease. METHODS: We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age. FINDINGS: The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%). INTERPRETATION: Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury.

Impact of prolonged saline solution prime exposure on integrity of extracorporeal membrane oxygenation circuits.

OBJECTIVE: Our purpose was to evaluate the safety of the common practice of preparing extracorporeal membrane oxygenation (ECMO) circuits in advance with saline solution priming by analysis of the surfaces of circuit components and analysis of the prime solution for toxic contaminations. STUDY DESIGN: In vitro analysis of eight ECMO circuits exposed to saline prime solution for 0, 2, or 4 weeks was performed with scanning electron microscopy. Prime solution analyzed for contamination with aluminum, silicone, and diethylhexylphthalate. RESULTS: The silicone membrane and heat exchanger demonstrated surface degradation in contact with saline solution. The prime solution showed increasing concentrations of both aluminum and silicone but not diethylhexylphthalate over time. CONCLUSIONS: Advance preparation of ECMO circuits by prepriming with normal saline solution leads to significant circuit degradation. Prepriming should be avoided.

Treatment of persistent pulmonary hypertension of the newborn without hyperventilation: an assessment of diffusion of innovation.

OBJECTIVE: The treatment of neonates with persistent pulmonary hypertension of the newborn (PPHN) is controversial with no consensus on diagnostic criteria or treatments. Hyperventilation has been the therapeutic mainstay. However, two widely variant alternative approaches have been proposed: ventilation without induced alkalosis, or more aggressive therapies such as high frequency ventilation or extracorporeal membrane oxygenation. We wished to determine the extent to which these alternative treatments have diffused into practice. METHODS: A forced choice questionnaire was mailed to a sample representing 10% of 3740 practicing neonatologists. Sixty percent of those surveyed responded. Data on treatment practices was tabulated. Subanalyses with respect to training era, practice site, and geographic region were performed. RESULTS: In patients with meconium aspiration syndrome, without evidence of PPHN, 36% described their initial management as hyperventilation. If PPHN was confirmed, hyperventilation was used in 90% of patients by 44% of the respondents. Muscular paralysis and inotropic support were also used frequently. Alkali and vasodilator infusion were used less frequently. The gentle ventilation strategy proposed by Wung and James at Columbia Babies Hospital was used infrequently by 47% of respondents. Gentle ventilation was used more frequently by board-certified neonatologists than those not certified. No significant differences in practice were identified by geographic region or era of training. When standard treatment failed, only 40% of the respondents utilized rescue treatments such as high frequency ventilation or extracorporeal membrane oxygenation. CONCLUSIONS: This study documents that gentle ventilation, an easily and inexpensively adopted innovation, has not diffused into practice significantly while more expensive high technology treatments, such as high frequency ventilation and extracorporeal membrane oxygenation, have penetrated more significantly.

Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes.

OBJECTIVE: To compare the survival, neurodevelopmental, and health outcomes of children with severe respiratory illness treated with and without extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective collection of clinical and demographic data of all neonates reaching illness severity criteria, with follow-up at 8 and 20 months of age. Patients were assigned to treatment by the attending physician. PATIENTS: Consecutive sample of 74 neonates during a 24-month period with an alveolar-to-arterial gradient exceeding 620 for 8 or more hours. RESULTS: Eighteen (69%) of 26 neonates treated with conventional therapy survived to 20 months, in comparison with 43 (90%) of 48 neonates treated with ECMO. The conventionally treated group had significantly more chronic lung disease, longer duration of oxygen therapy, more chronic reactive airway disease, and more rehospitalizations than those treated with ECMO. Hospital charges were similar in the two groups. Macrocephaly was noted in 24% of those treated with ECMO and in none of the conventional group. Of those completing evaluation, 4 (24%) of 17 conventionally treated survivors and 20 (26%) of 38 ECMO-treated survivors had neurodevelopmental impairment. CONCLUSION: Survivors of severe neonatal respiratory illness have significant pulmonary and neurodevelopmental impairment, regardless of the treatment used. Neonates treated with ECMO had neurodevelopmental outcomes similar to those of patients treated conventionally, but better pulmonary outcomes.

Persistent pulmonary hypertension of the newborn. The black box revisited.

Our understanding and therapy of PPHN, as in many other aspects of neonatology, have been clouded by our understandable fear for our patients and our wish to provide excellent care. We can no longer accept therapies that are well intentioned but unstudied. It is time that thoughtful, well-designed studies be conducted to lead us into the next century. The controversies surrounding treatment can be answered in multicentered trials. We must accept this challenge.

The natural history of direct hyperbilirubinemia associated with extracorporeal membrane oxygenation.

OBJECTIVE: To determine the incidence and natural history of direct hyperbilirubinemia in neonates treated with extracorporeal membrane oxygenation. DESIGN: A prospective series of patients. SETTING: A level 3 neonatal intensive care unit and center for extracorporeal membrane oxygenation in Ohio. PARTICIPANTS: Sixty-seven consecutive patients treated with extracorporeal membrane oxygenation in 33 months. INTERVENTION: None. MEASUREMENTS/RESULTS: Twenty-six (39%) developed direct hyperbilirubinemia. In 14 (54%), bilirubin levels were mildly elevated and occurred only during extracorporeal membrane oxygenation therapy. Levels were more severely elevated in the remaining 12 patients (46 +/- 10 mumol/L [2.7 +/- 0.6 mg/dL] vs 159 +/- 101 mumol/L [9.3 +/- 5.9 mg/dL], P less than .0001). Duration and severity of hyperbilirubinemia were correlated. Hyperbilirubinemia resolved in all patients by 9 weeks after extracorporeal membrane oxygenation therapy. No structural abnormalities or infectious agents were identified as causes. Aluminum levels were evaluated for 40 patients, were not in the toxic range, and did not correlate with hyperbilirubinemia. Multiple linear regression analysis suggested that hyperbilirubinemia in these cases resulted from interaction of injuries, with the primary contributor being hemolysis during extracorporeal membrane oxygenation. CONCLUSIONS: Direct hyperbilirubinemia occurs frequently in patients treated with extracorporeal membrane oxygenation and may be severe. However, direct hyperbilirubinemia typically resolves without short-term sequelae. Hemolysis may be an important contributing factor.

Carotid reconstruction in the neonate following ECMO.

Permanent ligation of the carotid artery remains a major objection to the use of extra corporeal membrane oxygenation (ECMO) in infants with severe cardiorespiratory disorders. Because reconstruction of the carotid artery is highly desirable, we began a study to evaluate the feasibility and risks of carotid artery repair following decannulation. All infants placed on ECMO from December 1988 to January 1990 were evaluated for carotid artery reconstruction. During this period 18 infants underwent carotid reconstruction and 8 infants were deemed unsuitable candidates. Patency of the right common carotid artery was demonstrated in 14 of the 18 infants with good bilateral anterior and middle cerebral artery flow. Seven infants have had MRA evaluation at 6 months and have demonstrated no significant change from their discharge study. These preliminary findings suggest that carotid reconstruction can be performed safely with no apparent morbidity in the majority of infants placed on ECMO, but long-term follow-up data concerning patency rate and neurological status must be obtained before this technique is applied to all infants with this problem.