MANUSCRIPT CITATION

Meyer MP, Hou D, Ishrar NN, Dito I, Te Pas AB. Initial Respiratory Support with Cold, Dry Gas versus Heated Humidified Gas and Admission Temperature of Preterm Infants. J Pediatr 2015;166:245-50. e1. PMID 25449225

REVIEWED BY

Professor Hesham Abdel-Hady
Mansoura University Children’s Hospital, Mansoura, Egypt

TYPE OF INVESTIGATION

Therapeutics

QUESTION

In preterm infants <32 weeks’ gestation who required respiratory support after delivery, does the addition of heated humidified gas (HHG) compared to unconditioned, or cold dry gas (CDG) at delivery and until neonatal intensive care unit (NICU) arrival improved admission temperatures, when superimposed upon standard protocols to maintain temperature?

METHODS

• Design: Randomized controlled trial (RCT). Randomization was stratified by center and gestation (28 weeks’). ANZCTR (Australia New Zealand Clinical Trials Registry): 12609000694213
• Allocation: Concealed.
• Blinding: Unblinded.
• Follow-up period: Unclear: Consort diagram indicates it may be death of first-discharge from hospital (~60 days).
• Setting: Two centers in New Zealand (NZ) and the Netherlands (NL).
• Patients: Total sample recruited was 230 deemed by clinical team to require respiratory support at delivery, of whom 203 entered final analysis. Groups were comparable between arms: median (IQR) gestational age: [HHG group: 29 (26-30) weeks, CDG group: 29 (27-30) weeks]; birth weight: [HHG group: 1190 (954-1396) g, CDG group: 1158 (890-1460)], 55% were males, 48% were delivered vaginally, 34% were multiple births, 95% received antenatal steroids, 82% of the HHG group and 76% of the CDG group had 40 seconds DCC, and 3 infants had cord milking. Exclusion criteria included: infants receiving mechanical ventilation for transport, maternal pyrexia (>38°C in labor), and major congenital anomalies.
• Intervention: Randomization to either HHG (n=100), or CDG (n=103) during respiratory support (T-piece resuscitator) at birth and during transport. Standard measures to prevent hypothermia included heated delivery rooms (25-26°C), the use of radiant warmers, body wrap, and head covering.
• Outcomes:
  Primary outcome: Axillary temperature in normothermic range (36.5-37.5°C) on admission to the NICU.
  Secondary outcomes: Measures of respiratory support (receipt of respiratory support during transition and in the NICU, need for mechanical ventilation, surfactant therapy, durations of continuous positive airway pressure and of oxygen therapy; and neonatal morbidities (bronchopulmonary dysplasia defined as respiratory support or oxygen requirement at 36 weeks’ gestation, grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity treated with laser therapy).
• Analysis and Sample Size: A baseline expected rate of admission temperature below normothermic range was 62% at the 2 sites, needing a sample size of 100 infants per site to detect a risk reduction in hypothermia incidence of 30%, or more (power 80% and alpha 0.05).
• Patient follow-up: 89.8% of the patients randomized were included in the primary analysis (intention-to-treat analysis). Loss occurred as 14 infants were excluded from analysis (no consent: 9, no axillary temperature: 5).

MAIN RESULTS

The primary outcome was distributed as follows: Sixty-nine (69%) infants in the HHG group had normothermia compared with 57 (55%) in the CDG group (unadjusted OR 1.8, 95% CI 1.01-3.19 and aOR 2.24, 95% CI 1.17-4.29), absolute benefit increase (ABI):14, 95% CI 0.5% to 27; number needed to treat (NTT): 8, 95% CI 4 to 219. Two (2%) infants in the HHG group had admission temperatures <35.5°C compared with 12 (12%) in the CDG group (p = 0.007), NNT: 11, 95% CI 6 to 35. For infants < 28 weeks’ gestation, 24 of 35 (69%) in the HHG group compared with 16 of 38 (42%) in the CDG group were normothermic on admission (p = 0.03), NNT: 4, 95% CI 2 to 22. The median admission temperatures in the HHG group was 36.7°C (36.4-37.0°C) and 36.6 °C (36.3-37.0°C) in the CDG group (p = 0.27). In the total group, 8 (4%) had temperatures >37.5 °C, the differences between groups for those above the desired range was not statistically different. Respiratory and short-term outcomes were not different. Binary logistic regression showed that humidification and hospital site were significant factors in determining admission temperature in the normothermic range; gestation, antenatal steroid use, mode of delivery, time to admission, sex, and multiple birth were not.

CONCLUSION

In this unblinded multicenter RCT, adding HHG during respiratory support in preterm infants from birth increased the incidence of normothermia at admission to NICU.

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COMMENTARY

Maintaining normothermia in preterm infants after birth remains a challenge even after best current methods to prevent heat loss in the delivery room e.g. warming the delivery room and use of radiant warmers and polyethylene occlusive wrap during stabilization. Hypothermia at NICU admission remains common and is a risk factor for death [1,2] and even after best quality initiative are instituted may remain a burden.[3] The use of CDG during stabilization of the preterm infants in the delivery room may adversely affect lung function.[4,5] The standard practice in NICUs is to use HHG, however, there are no recommendations for conditioning gases during newborn stabilization.

Meyer and colleagues[6] have demonstrated that the use of HHG during preterm infants stabilization improves temperature on admission to NICU. The benefit of HHG seems to be more in infants < 28 weeks, although the study was not powered to detect differences in this small subgroup of patients. The use of HHG was safe and did not increase the risk for hyperthermia. This trial was clinically relevant, and it appears safe to add HHG to delivery room interventions for preterm infants. While the study was unblinded, bias was reduced by an endpoint of robust determination (axillary temperature). A potential problem of interpretation, was that delivery room interventions (use of servo, wrapping and DCC) and methods of transport (radiant warmer versus preheated incubator) differed between the two centers, and may have influenced temperature on admission to the NICU. In a secondary analysis, only site and humidification were sources to explain admission temperatures outside defined ranges.

Although the authors did not observe differences in short-term morbidity, mortality, and respiratory outcomes between the groups, their study was not powered to detect differences between groups in these outcomes. Firm recommendations for clinical practice cannot be given at this time based on the limited evidence currently available. Two approaches can be taken: Either further adequately powered multicenter RCTs are urgently needed to confirm the value of using HHG during delivery room stabilization on clinically more relevant outcomes such as mortality and long-term neurodevelopmental outcome. Or it could be argued that a good physiological surrogate has been shown of sufficient meaningful importance, to obviate the need for further trials. However ideally, new trials would better describe optimal methods for heating and humidification of inspired gases in the delivery room setting, and also include economic evaluations to study the cost implications of these interventions. Such studies should target preterm infants < 28 weeks gestation who are at the greatest risk for hypothermia and its complications and consequently, might benefit most from this intervention.

REFERENCES

1. de Almeida MF, Guinsburg R, Sancho GA, et al. Hypothermia and early neonatal mortality in preterm infants. J Pediatr 2014;164:271-5. e1.
2. McCall EM, Alderdice F, Halliday HL, Jenkins JG, Vohra S. Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants. Cochrane Database Syst Rev 2010:CD004210.
3. DeMauro SB, Douglas E, Karp K, et al. Improving delivery room management for very preterm infants. Pediatrics 2013;132:e1018-25.
4. Schulze A. Respiratory gas conditioning in infants with an artificial airway. Semin Neonatol 2002;7:369-77.
5. Tarnow-Mordi WO, Reid E, Griffiths P, Wilkinson AR. Low inspired gas temperature and respiratory complications in very low birth weight infants. J Pediatr 1989;114:438-42.
6. Meyer MP, Hou D, Ishrar NN, Dito I, Te Pas AB. Initial Respiratory Support with Cold, Dry Gas versus Heated Humidified Gas and Admission Temperature of Preterm Infants. J Pediatr 2015;166:245-50. e1.