Controversial therapies in Neonatal Care Julia Trintis, D.O.

Objectives Discuss respiratory failure in premature newborns. Discuss current indications for inhaled nitric oxide therapy in newborns. Discuss chronic lung disease in newborns. Discuss the benefits and hazards of postnatal steroids.

Respiratory Failure: Risk Factors Prematurity Pulmonary Disease Respiratory infections Congenital Anomalies Congenital heart disease Surfactant protein deficiencies

Bronchopulmonary Dysplasia Described by Northway in 1967 Severe chronic lung injury in premature infants who survived hyaline membrane disease Four distinct stages –Respiratory distress syndrome –Alveolar interstitial edema –Extensive bronchial and bronchioalar metaplasia and hyperplasia, Cystic emphysema and overinflation –Massive fibrosis, destruction of alveoli and airways, and consolidation

Evolution of “Bronchopulmonary Dysplasia” Classic BPDNew BPD –Extensive, diffuse fibroproliferationRare fibrosis –Alternating atelectasis with hyperinflationLess heterogeneity –Severe airway epithelial lesionsMild airway epithelial lesions –Marked airway smooth muscle hyperplasiaMilder airway changes

Definition of BPD and Diagnostic Criteria

Epidemiology BPD relatively rare in infants born beyond 32 weeks NICHD ( grams): 22% –Less than 1000 grams: 40% “Although there has been a marked decrease in BPD in larger infants, recent data from Vermont Oxford database and NICHD network indicate that in the years since 1996, there has been no further decrease in the incidence of BPD.” (Taeusch)

Pathogenesis of BPD CP Spear 2006

Strategies for preventing BPD Antenatal steroids Surfactant Permissive hypercapnia Ventilator strategies Reduce “excessive” O2 use Good nutrition Postnatal steroids Inhaled Nitric Oxide???

Current indications for inhaled nitric oxide therapy in newborns Selective pulmonary vasodilator Improves oxygenation and reduces need for ECMO in term infants with PPHN

Inhaled NO Therapy in Premature Newborns Initial reports showed iNO improved oxygenation in preterm infants with severe respiratory failure and with developing or established BPD Kinsella 1999, Banks 1999, Clark 2002

Animal Models Reduces lung inflammation Improves surfactant function Attenuates hyperoxic lung injury Promotes lung growth Kang 2002, Ballard 2006, Cotton 2006

Potential Therapeutic Targets Surfactant function/ production Improve gas exchange Reduce FiO2 Lower pulmonary artery pressure Anti-inflammatory effects Preserve or stimulate angiogenesis and alveolarization in the developing lung

Inhaled NO in Premature Newborns: Randomized Placebo-Controlled Trials AuthorYearPatient #Design Schreiber Early, single center Van Meurs Early, Brief, sick Kinsella Early mild disease Ballard Evolving BPD EUNO Early, mild disease Abman

Schreiber, 2003 Single center study Randomized, double-blind, placebo controlled trial 207 patients Showed reduction in the combined outcome of death and BPD in preterm infants treated with inhaled Nitric Oxide

Van Meurs, 2005 Large, Multicenter study Randomized, double-blind, placebo controlled trial 420 neonates Showed no significant reduction in rates of death or BPD with inhaled nitric oxide in preterm infants with a birth weight of less than 1500 grams

Kinsella, 2006 Large, Multicenter study Randomized, double-blind, placebo controlled trial 793 neonates Low dose inhaled NO (5 ppm) did not reduce the overall incidence of BPD, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury.

Ballard, 2006 Large, Multicenter study Randomized, double-blind, placebo controlled trial 582 neonates Enrolled infants who were ventilator dependent at 7 to 21 days of age. Randomly assigned to 24 day course of nitrogen placebo or inhaled NO at initial dose of 20 ppm NO treatment improved survival at 36 weeks PMA without BPD ( 43.9% vs 36.8%) and reduced the duration of oxygen therapy and hospitalization.

European NO (EUNO) trial Large, Multicenter study (35 centers) Randomized, double-blind, placebo controlled trial 800 neonates Preemies weeks GA Mild to moderate respiratory failure Randomized to receive iNO 5ppm or placebo for 7-21 days Results pending – primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age –long-term lung and brain will be followed-up until 7 years of age.

Conclusion: Does inhaled NO have a role in the treatment of preterm infants with respiratory failure? Offering the critically ill, very preterm infant early, sustained low dose prophylactic treatment with NO does not appear to improve survival or BPD. Data on effective dose, duration, time of initiation, and selection of infants most likely to benefit remain unclear. Additional studies need to be performed before the precise role of iNO in preventing BPD can be defined. Long term follow up is essential!

Postnatal Steroids and Chronic Lung Disease: The Good, the Bad, and the Ugly

Chronic lung disease defined as oxygen dependence at 36 weeks postconceptual age or oxygen requirement for >28 days. Associated with: –poor nutrition and growth –poor feeding skills –prolonged hospitalization and episodes of nosocomial infection

Story of steroids: “hastened weaning from ventilator” 1980’s: initial reports suggested short term benefits of steroids in vent dependent children Mammel 1983 –Dexamethasone used with severe BPD –N=6 –Gestational age ranged from 27 to 33 weeks –birth weight from 800 to 1730 g. – Patients received Dexamethasone (0.5 mg/kg/day) or normal saline for the first 3 days, then treatment was crossed over for the next 3 days. –all six patients had improved during dexamethasone therapy Mammel et al. Lancet 1983.

Faster weaning from ventilator and oxygen Cummings, et al 1989 –Double blinded study on 36 preterm infants who were dependent on O2 and mechanical ventilation at 2 weeks –Dexamethasone given for 42 days improved pulmonary and neurodevelopmental outcome at 6 and 15 months of age O’Shea, et al 1993 –Longitudinal follow up on 61 preterm infants –Infants had been treated with 42 day course of dex starting at 2 weeks –Dex associated with fewer days of assisted ventilation but not with improved outcome at age 1

Dexamethasone became widely used to prevent and/or treat CLD –Retrospective study examining the outcome of neonates between 500 g and 749 g showed that 43% of infants born between received dexamethasone vs 84% between –Hack M, Fanaroff AA. Early Hum Dev 1999

The pendulum swings… Dex is good, the more the better All steroids are bad, no babies should get them

1998: Increase in neurodevelopmental dysfunction Yeh, et al large multicenter follow-up study large multicenter follow-up study Outcomes at 2 year corrected age of infants who participated in a double blinded controlled trial of early dexamethasone for the prevention of CLD 133 children marked increase in neurodevelopmental dysfunction in neonates treated with dexamethasone compared with controls marked increase in neurodevelopmental dysfunction in neonates treated with dexamethasone compared with controls Yeh, et al. Pediatrics 1998.

1999: Dexamethasone has some more side effects Shinwell, et al Long term neurodevelopmental outcome of children who participated in early postnatal dexamethasone treatment for prevention of chronic lung disease Dexamethasone treated group associated with: –Hypertension –Hyperglycemia –Gastrointestinal hemorrhage –no reduction in either the incidence or severity of chronic lung disease or mortality Shinwell Es, et al. Arch Dis Child Fetal Neonatal Ed 2000.

More alarming publications on the long term negative effects of dexamethasone appeared Higher incidence of cerebral palsy Higher incidence of cerebral palsy

Reduced brain volumes MRI study at term equivalent age showed reduced brain volumes in infants treated with a moderately low dose of dexamethasone after 28 days of life Parikh, et al. Pediatrics, 2007.

2002 American Academy of Pediatrics stated outside clinical trials, postnatal steroid use should be reserved only for “exceptional clinical circumstances”. “routine use of systemic dexamethasone for the prevention or treatment of CLD in infants with VLBW is not recommended.” “the use of corticosteroids should be limited to exceptions clinical circumstances…parents should be fully informed about the known short-and long-term risks and agree to treatment.” AAP, Committee on Fetus and Newborn. Pediatrics, 2002.

2006 Finer et al prospective evaluation of postnatal steroid administration in California, from April 2002 to March % of children less than or equal to 1500 grams were still receiving steroids. Finer NN, et al. Pediatrics 2006.

Dexamethasone dosing Most previous studies started with a dose of 0.5 mg/kg/day Lower doses (0.15 mg/kg/day) were not associated with adverse neurodevelopmental outcomes in 2 studies – –Stark, et al: Early treatment (n=123) – –Doyle, et al: Later extubation study (n=58) Watterberg

Side effects seen with early Dexamethasone therapy Infection and sepsis HyperglycemiaHypertension Cardiac hypertrophy Delay in weight gain Worse neurodevelopmental outcomes

Not all steroids are the same Hydrocortisone has lower potency Shorter half-life Mineralocorticoid vs glucocorticoid In in vitro neuronal cells, dexamethasone stimulates apoptosis while mineralocorticoids, are protective against apoptosis.

DexamethasoneHydrocortisone Half life hours 8-12 hours SteroidGlucocorticoidMineralocorticoid Preservative Sodium bisulphite No sodium bisulphite ApoptosisStimulatesProtects

Hydrocortisone for chronic lung disease Six reports have been published on postnatal hydrocortisone administration for prevention (n=5) or treatment (n=1) of CLD

1972 First randomized placebo controlled trial of hydrocortisone treatment evaluated the ability of postnatally administered hydrocortisone to alter the course of outcome in infants with hyaline membrane disease. 44 infants (mean gestational age 32.5 weeks) were treated with hydrocortisone or a lactose placebo within 24 h after birth. no remarkable effect on PaO2, PaCO2, need for assisted mechanical ventilation or survival. Baden, et al. Pediatrics 1972.

27 years later…1999 Watterberg et al enrolled 40 preterm infants into a randomised pilot study to test whether hydrocortisone would increase the likelihood of survival without CLD started low-dose hydrocortisone within 48 hours after birth Treated for 12 days Watterberg, et al. Pediatrics 1999.

Results Among those treated with hydrocortisone, 60% survived without supplemental oxygen at 36 weeks’ PMA vs 35% in placebo group. Treatment decreased number of days on: –.40% oxygen –.25% oxygen –Days on ventilator –Oxygen at discharge Adverse short term complications were similar between the two groups –Watterberg KL, Gerdes JS, Gifford KL, et al. Pediatrics 1999

2003 Retrospective matched-cohort study compared 25 preterm infants w/ CLD who were treated with a much higher dose of hydrocortisone with 25 controls From day 7, no significant differences in amount of extra oxygen needed between 2 groups Heide-Jalving, et al. Acta Paediatr 2003.

Watterberg 2004 Multicenter trial Prophylaxis of early adrenal insufficiency to prevent BPD Enrolled mechanically ventilated infants with a birth weight of gram infants between 12 h and 48 h of life

Results Prophylactic treatment of early adrenal insufficiency did not improve survival without CLD or mortality at 36 weeks. Enrollment stopped at 360 infants because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone treated group.

2005 Peltoniemi effect of early hydrocortisone treatment on survival without CLD in infants less than or equal to 30 weeks tendency towards lower CLD in the hydrocortisone treated group Study was discontinued early due to higher incidence of GI perforation Peltoniemi O, Kari MA, Heinonen K, et al. J Pediatr 2005.

2007 Bonasarte et al Double blinded, randomised, placebo controlled trial 50 mechanically ventilated infants Birth weights grams Oxygen free survival was higher in the hydrocortisone treated group No difference in GI perforation between the groups Bonsante F, Latorre G, Iacobelli S, et al. Neonatology 2007

Long term follow-up Few follow-up reports based on the initial 1972 hydrocortisone trial no differences in lung, liver, adrenal, thymus, heart and spleen pathology attributable to steroid treatment Significant association between the occurrence of intraventricular hemorrhage and hydrocortisone treatment Taeusch et al. Pediatrics1973.

24 survivors examined at 1 year of age Griffiths Developmental Scale showed a normal developmental quotient in both groups normal developmental quotient in both groups substantial difference in the results for the gross motor development with a lower mean score for the hydrocortisone group

Van de Heide et al 25 preterm infants treated with high-dose hydrocortisone age of 5–7 years this group did not differ from a non-treated control group with regard to: –neurological outcome –psychomotor development –school performance

Watterberg et al 294 survivors, 252 (86%) infants who participated in prophylactic hydrocortisone trial evaluated at the age of 20.0 months incidence of cerebral palsy was similar significantly smaller percentage of infants treated with hydrocortisone had a Mental Developmental Index below 70

Lodygensky and Rademaker 2005 Follow up study 23 preterm-born children received hydrocortisone treatment for chronic lung disease starting dose of 5 mg/kg/day, tapered over a minimum of 3 weeks 35 children not treated 35 children not treated quantitative MRI and neurocognitive assessment at 8 years of age Both groups had similar volumes of grey matter, white matter, cerebral fluid and hippocampus

Rademaker preterm-born children treated with hydrocortisone for CLD were compared with 164 children who did not receive steroids during their admission to the NICU mean IQ, and visual-motor integration and memory test results, were similar in the hydrocortisone-treated and non-treated groups

Karemaker et al retrospective matched-cohort long-term effects on behavior and motor skills in school age (7–10 years) children who received either dexamethasone or hydrocortisone for CLD dexamethasone group had more neuromotor problems than children in the control group

Puzzled yet?

Summary In long-term follow-up studies at 5–8 years of age preterm infants not treated with hydrocortisone compared with those who were treated for CLD, no differences have been found: –in neurocognitive or motor outcome –incidence of brain abnormalities on MRI

Summary 2 prophylactic hydrocortisone studies, stopped early due to increased incidence of spontaneous GI perforation with combined indomethacin tx two publications reported an increased risk of disseminated Candida infections in infants treated with hydrocortisone

Summary Moderately early steroid treatment can result in reductions in: –Failure to extubate –CLD –Neonatal mortality Risks of short term and potentially long term adverse effects –Limited long term outcomes, especially in school age children

Summary modify the dosage Limit the drug–drug interactions Scrutinise patient selection in corticosteroid trials on very high-risk infants in early life infants in early life Treat beyond 2 weeks of postnatal age to avoid the interactive effect of hydrocortisone with indometacin

Questions?

References Mammel MC, Green, Johnson, et al. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1983; 1: Yeh, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350: Yeh, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 1998;101:E7. Shinwell Es, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed AAP, Committee on Fetus and Newborn. Pediatrics, Finer NN, et al. Pediatrics Parikh, et al. Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants. Pediatrics, 2007; 119: Baden, et al. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 1972, 50: Heide-Jalving M, Kamphuis PJ, van der Laan MJ, et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatr 2003;92:827–35. effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone? Acta Paediatr 2003;92:827–35. Watterberg KL, Gerdes JS, Gifford KL, et al. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics1999;104:1258–63. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990s. Early Hum Dev 1999;53:193–218.

References cont. Watterberg KL, Gerdes JS, Gifford KL, et al. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics 1999;104:1258–63. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004;114:1649–57. Peltoniemi O, Kari MA, Heinonen K, et al. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005;146:632–7. Bonsante F, Latorre G, Iacobelli S, et al. Early low-dose hydrocortisone in very preterm infants: a randomized, placebo- controlled trial. Neonatology 2007;91:217–21 Taeusch HW Jr, Wang NS, Baden N, et al. A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome: II. Pathology. Pediatrics 1973;52:850–4.