Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants.

IMPORTANCE: Extremely preterm infants may experience intermittent hypoxemia or bradycardia for many weeks after birth. The prognosis of these events is uncertain. OBJECTIVE: To determine the association between intermittent hypoxemia or bradycardia and late death or disability. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of data from the inception cohort assembled for the Canadian Oxygen Trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel, including 1019 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days who were born between December 2006 and August 2010 and survived to a postmenstrual age of 36 weeks. Follow-up assessments occurred between October 2008 and August 2012. EXPOSURES: Episodes of hypoxemia (pulse oximeter oxygen saturation <80%) or bradycardia (pulse rate <80/min) for 10 seconds or longer. Values were sampled every 10 seconds within 24 hours after birth until at least 36 weeks' postmenstrual age. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death after 36 weeks' postmenstrual age, motor impairment, cognitive or language delay, severe hearing loss, or bilateral blindness at 18 months' corrected age. Secondary outcomes were motor impairment, cognitive or language delay, and severe retinopathy of prematurity. RESULTS: Downloaded saturation and pulse rate data were available for a median of 68.3 days (interquartile range, 56.8-86.0 days). Mean percentages of recorded time with hypoxemia for the least and most affected 10% of infants were 0.4% and 13.5%, respectively. Corresponding values for bradycardia were 0.1% and 0.3%. The primary outcome was ascertained for 972 infants and present in 414 (42.6%). Hypoxemic episodes were associated with an estimated increased risk of late death or disability at 18 months of 56.5% in the highest decile of hypoxemic exposure vs 36.9% in the lowest decile (modeled relative risk, 1.53; 95% CI, 1.21-1.94). This association was significant only for prolonged hypoxemic episodes lasting at least 1 minute (relative risk, 1.66; 95% CI, 1.35-2.05 vs for shorter episodes, relative risk, 1.01; 95% CI, 0.77-1.32). Relative risks for all secondary outcomes were similarly increased after prolonged hypoxemia. Bradycardia did not alter the prognostic value of hypoxemia. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants who survived to 36 weeks' postmenstrual age, prolonged hypoxemic episodes during the first 2 to 3 months after birth were associated with adverse 18-month outcomes. If confirmed in future studies, further research on the prevention of such episodes is needed.

Inhaled nitric oxide use in newborns.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator that plays a major role in regulating vascular muscle tone. It has emerged as a treatment for hypoxemic respiratory failure in newly born infants that is associated with persistent high pulmonary vascular pressure and resultant right-to-left shunting of blood (persistent pulmonary hypertension of the newborn). Current evidence shows that iNO improves oxygenation and decreases the combined outcome of death or need for extracorporeal membrane oxygenation in infants ≥35 weeks' gestational age at birth. Its role in managing preterm infants <35 weeks' gestational age is not yet established. iNO is safe when administered in tertiary care settings using strict protocols and monitoring. The recommended starting dose is 20 ppm with gradual reduction of the dose following improvement in oxygenation.

L'oxyde nitrique inhalé (iNO) est un vasodilatateur pulmonaire qui joue un rôle majeur dans la régulation du tonus musculaire vasculaire. Il a émergé comme traitement de l'insuffisance respiratoire hypoxémique chez les nouveau-nés ayant une pression vasculaire pulmonaire qui demeure élevée et entraîne une dérivation droite-gauche du sang (hypertension pulmonaire persistante du nouveau-né). Les données probantes actuelles révèlent que l'iNO améliore l'oxygénation et réduit l'issue combinée de décès ou d'administration d'oxygénation extracorporelle chez les nourrissons d'au moins 35 semaines d'âge gestationnel. Son rôle dans la prise en charge des nourrissons prématurés de moins de 35 semaines d'âge gestationnel n'est pas encore établi. L'iNO est sécuritaire lorsqu'il est administré dans des établissements de soins tertiaires selon des protocoles et une surveillance stricts. La dose de départ recommandée, de 20 parties par million, est réduite graduellement lorsque l'oxygénation s'améliore.

Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up.

OBJECTIVE: To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension. STUDY DESIGN: Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months. RESULTS: The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4). CONCLUSIONS: Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.

The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants.

OBJECTIVE: To determine whether extremely low birth weight infants (ELBW) transfused at lower hemoglobin thresholds versus higher thresholds have different rates of survival or morbidity at discharge. STUDY DESIGN: Infants weighing <1000 g birth weight were randomly assigned within 48 hours of birth to a transfusion algorithm of either low or high hemoglobin transfusion thresholds. The composite primary outcome was death before home discharge or survival with any of either severe retinopathy, bronchopulmonary dysplasia, or brain injury on cranial ultrasound. Morbidity outcomes were assessed, blinded to allocation. RESULTS: Four hundred fifty-one infants were randomly assigned to low (n = 223) or high (n = 228) hemoglobin thresholds. Groups were similar, with mean birth weight of 770 g and gestational age of 26 weeks. Fewer infants received one or more transfusions in the low threshold group (89% low versus 95% high, P = .037). Rates of the primary outcome were 74.0% in the low threshold group and 69.7% in the high (P = .25; risk difference, 2.7%; 95% CI -3.7% to 9.2%). There were no statistically significant differences between groups in any secondary outcome. CONCLUSIONS: In extremely low birth weight infants, maintaining a higher hemoglobin level results in more infants receiving transfusions but confers little evidence of benefit.

Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure.

AIM: To determine relationships between ototoxic drugs and 4-y sensorineural hearing loss (SNHL) in near-term and term survivors of severe neonatal respiratory failure. METHODS: All 81 survivors of the Canadian arm of the Neonatal Inhaled Nitric Oxide Study (mortality 32, loss to follow-up 9) received loop diuretics, aminoglycosides, and neuromuscular blockers (NMB), and 50 received vancomycin as neonates. Prospective, longitudinal secondary outcome using audiological tests diagnosed late-onset, progressive SNHL in 43 (53%); not flat (sloping) in 29, flat (severe to profound) in 14. Risk for SNHL was determined. RESULTS: A combination of duration of diuretic use of >14 d and average NMB dose of >0.96 mg/kg/d contributed to SNHL among survivors (odds ratio 5.2; 95% CI 1.6, 16.7). Markers of illness severity did not contribute. Dosage or duration of aminoglycosides use did not relate to SNHL. Cumulative dosages and duration of use of diuretics; NMB; use of vancomycin; and overlap of diuretics with NMB, aminoglycosides, and vancomycin individually linked to SNHL (p<0.001). CONCLUSION: Overuse of loop diuretics and/or NMB contributes to SNHL after neonatal respiratory failure; markers of illness severity or the appropriate administration of aminoglycosides do not.

Actuarial survival of a large Canadian cohort of preterm infants.

BACKGROUND: The increased survival of preterm and very low birth weight infants in recent years has been well documented but continued surveillance is required in order to monitor the effects of new therapeutic interventions. Gestation and birth weight specific survival rates most accurately reflect the outcome of perinatal care. Our aims were to determine survival to discharge for a large Canadian cohort of preterm infants admitted to the neonatal intensive care unit (NICU), and to examine the effect of gender on survival and the effect of increasing postnatal age on predicted survival. METHODS: Outcomes for all 19,507 infants admitted to 17 NICUs throughout Canada between January 1996 and October 1997 were collected prospectively. Babies with congenital anomalies were excluded from the study population. Gestation and birth weight specific survival for all infants with birth weight < 1,500 g (n = 3419) or gestation < or = 30 weeks (n = 3119) were recorded. Actuarial survival curves were constructed to show changes in expected survival with increasing postnatal age. RESULTS: Survival to discharge at 24 weeks gestation was 54%, compared to 82% at 26 weeks and 95% at 30 weeks. In infants with birth weights 600-699, survival to discharge was 62%, compared to 79% at 700-799 g and 96% at 1,000-1,099 g. In infants born at 24 weeks gestational age, survival was higher in females but there were no significant gender differences above 24 weeks gestation. Actuarial analysis showed that risk of death was highest in the first 5 days. For infants born at 24 weeks gestation, estimated survival probability to 48 hours, 7 days and 4 weeks were 88 (CI 84, 92)%, 70 (CI 64, 76)% and 60 (CI 53, 66)% respectively. For smaller birth weights, female survival probabilities were higher than males for the first 40 days of life. CONCLUSION: Actuarial analysis provides useful information when counseling parents and highlights the importance of frequently revising the prediction for long term survival particularly after the first few days of life.

A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure.

OBJECTIVE: Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes. METHODS: Neonates who were born at > or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) > or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. RESULTS: The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups. CONCLUSION: iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure.

Late-onset, progressive sensorineural hearing loss after severe neonatal respiratory failure.

OBJECTIVES: To determine the prevalence of sensorineural hearing loss (SNHL) at the age of 4 years among survivors of severe neonatal respiratory failure with and without congenital diaphragmatic hernia and to document the occurrence of late-onset or progressive SNHL among the survivors. DESIGN: Prospective, longitudinal secondary outcome study. SETTING: Multicenter Canadian study in 9 tertiary referral centers. PATIENTS: Eighty-one (89%) of ninety 4-year-old survivors born from 1994 to 1996 of > or =34 weeks gestation at birth with severe neonatal respiratory failure (2 oxygenation indices > or =25 at least 15 minutes apart). MAIN OUTCOME MEASURES: Repeated audiologic measurements from birth to the age of 4 years with documentation of the entire cohort at 2 and 4 years of age. RESULTS: Forty-three (53%) of 81 tested 4-year-old survivors had SNHL; 28 (42%) of 66 without congenital diaphragmatic hernia and 15 (100%) of 15 with congenital diaphragmatic hernia. High-frequency SNHL occurred in 65% of the patients. Of the 43 children with SNHL at 4 years, 30 (70%) had loss at 2 years, and 18 (60%) of these 30 had progressive loss between 2 and 4 years of age. For 13 children with SNHL onset after 2 years of age, the loss was less severe with lesser involvement of the lower frequencies. CONCLUSION: Survivors of severe neonatal respiratory failure frequently develop late-onset SNHL that may be progressive. Urgent investigation is required to enable further understanding and prevention of this problem. Severe neonatal respiratory failure should be an indication for long-term audiologic surveillance.