RANDOMISED CONTROLLED TRIAL OF HELIOX IN NEWBORN INFANTS WITH MECONIUM ASPIRATION SYNDROME

February 14, 2022

MANUSCRIPT CITATION

Ma J, Tang S, Shen L, Chen L, Li X, Li W et al.  A randomized single-center controlled trial of synchronized intermittent mandatory ventilation with heliox in newborn infants with meconium aspiration syndrome. Pediatric Pulmonology.  2021; 1– 7. PMID: 33831271

REVIEWED BY

Anurag Girdhar
Senior Clinical Fellow in Neonatology
Birmingham Women’s Hospital, Birmingham, UK

Harish Kumar
Senior Clinical Fellow in Neonatology
Birmingham Women’s Hospital, Birmingham, UK

Asad Abbas
Neonatal Grid Trainee
University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK.

Anju Singh
Consultant Neonatologist
Birmingham Women’s Hospital, Birmingham, UK

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In infants born between 37+0 – 41+6 weeks gestation who have been diagnosed with meconium aspiration syndrome (MAS) and require mechanical ventilation (MV) (I) is synchronized intermittent mandatory ventilation (SIMV) with heliox more effective than (C) synchronized intermittent mandatory ventilation alone in (O) reducing the length of mechanical ventilation (T) after treatment with heliox lasting 6 hours.

METHODS

  • Design: Prospective, randomised, single-centre.
  • Allocation: The randomisation method and generation of allocation sequence is not specified. Allocation was concealed using serially numbered opaque sealed envelopes.
  • Blinding: Clinicians administering the intervention were not blinded due nature of the intervention. The paper does not specify whether the carers and people analysing the results were blinded.
  • Follow-up period: Neonates were followed up until discharge from the neonatal intensive care unit (NICU).
  • Setting: Single NICU in China.
  • Patients:
    • Included:
      • Infants with gestational age of 37+0 – 41+6
      • Diagnosis of MAS and requiring MV. Intubation standard used was pH <7.2 or PCO2 >60 mmHg (8 kPa) on non-invasive ventilation. MAS was diagnosed in infants born with meconium-stained amniotic fluid and who had respiratory symptoms and radiographic findings of hyperinflation and patchy opacities.
    • Excluded:
      • Infants with congenital or genetic metabolic diseases.
      • Infants with surgical conditions.
  • Intervention:
    • Group I: SIMV with air-oxygen mixture and initial ventilator parameters set as peak inspiratory pressure (PIP) 15-28 cmH2O, peak end expiratory pressures (PEEP) 4-10 cmH2O, respiratory rate of 15-45 breaths/min, the fraction of inspired oxygen (FiO2) was regulated to reach the target oxygen saturation (SpO2) of 90-95%. Of note, the paper does not specify whether the SpO2 was pre or post ductal.
    • Group II: SIMV with same initial ventilator parameters as group I and heliox for six hours followed by SIMV with air oxygen mixture. The concentration of heliox was adjusted according to the condition of the patient and FiO2 was regulated from 0.21 to 1 to reach the target SpO2 of 90-95%.
  • Outcomes:
    • Primary outcomes:
      • PaO2/FiO2 (P/F) after 6 hours of intervention.
      • Time to extubation.
      • Length of hospital stay.
      • It is important to note that only time to extubation was used for sample size estimation.
    • Secondary outcomes:
      • PaO2, pH and PaCO2 at 0, 2, 6, 12, 24 and 48 hours of starting treatment.
      • The inflammatory response indicators – interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), C‐reactive protein (CRP), tumour necrosis factor‐α (TNF‐α) and mycocardial injury markers – CK and CK-MB measured 0 and 6 h after respiratory support
      • The incidence of MV complications, including pneumothorax, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), necrotizing enterocolitis, and intraventricular haemorrhage (IVH).
      • Of note, the length of stay in NICU is included both in primary and secondary outcomes, and complications of MV is included twice in secondary outcomes.
  • Analysis and sample size: Estimating a reduction of 30% in time of ventilation with SIMV and heliox compared to SIMV alone, an alpha level of 5%, power of 80% a sample size of 28 neonates in each arm was calculated. It is not specified whether the dropout rate was included in the sample size calculation. 35 infants were allocated to heliox group and 36 infants were allocated to the control group. All the infants in both groups received the allocated intervention. Student t test was used for continuous variables and Fisher’s exact test for categorical variables. All tests were two-tailed and p value of less than 0.05 was considered significant.
  • Patient follow-up: 35 patients received the intervention with heliox as randomised and 36 patients received the control treatment. The paper does not mention whether there was any loss to follow up and how many infants were included in the final analysis. The CONSORT flow chart is incomplete.

MAIN RESULTS

The demographic and biochemical characteristics of the infants included in the study did not differ significantly between the groups. This included gestational age, sex, mode of delivery, Apgar scores, inflammatory markers and markers for myocardial injury. There is however no information on baseline PaO2/FiO2 (P/F), blood gas indices and ventilatory requirements.

For the primary outcomes, the time to extubation in the heliox group was 78 ± 30 hours versus 114 ± 28.07 hours in the control group. The difference was statistically significant. The P/F was significantly better after 6 hours of treatment in the heliox group and length of hospital stay was also significantly shorter in the heliox group compared to control group. (Table 1)

For secondary outcomes, the blood gas indices of pH, PaO2 and PaCO2 were significantly better in the heliox group at 2, 6 12, 24 and 48 hours compared to control group. There was a significant fall in levels of IL-6, IL-8, TNF‐α at 6 hours, but not in CRP. There was also a significant fall in the levels of CK and CK-MB at 24 hours compared to a baseline of 0 hours (Table 1). There was no significant difference in the incidence of IVH, pneumothorax, BPD and PDA between the two groups.

Table 1: Primary and secondary outcomes

SIMV alone (Mean ± SD) SIMV + Heliox

(Mean ± SD)

P value
PRIMARY OUTCOMES
Time to extubation (Hours) 114 ± 28.07 78 ± 30 <0.001
P/F 260.64 ± 24.83 301 ± 22 <0.001
Length of hospital stay (days) 19.11 ± 4.01 15.3 ± 4.2 <0.001
SECONDARY OUTCOMES
At 6 hours
IL-6 (pg/ml) 20.24 ± 3.22 15.00 ± 2.53 <0.001
IL-8 (pg/ml) 35.84 ± 4.23 20.24 ± 3.22 <0.001
TNF‐α (ng/L) 43.71 ± 3.66 37.72 ± 3.58 <0.001
CRP 5.81 ± 0.65 5.45 ± 0.51 0.012
At 24 hours
CK (U/L) 157.16 ± 15.83 129.2 ± 15.41 0.000
CK-MB (U/L) 24.43 ± 8.65 21.0 ± 3.98 0.041

CONCLUSION

The authors conclude that heliox is superior to an air-oxygen mixture in infants with MAS under the support of SIMV.

COMMENTARY

Helium is a colorless, odorless gas that has no direct pharmacologic or biological effects (1). Helium has one-seventh the density of air. This property allows the gas to achieve a laminar flow even in condition where turbulent flow is expected, for example airway obstruction, which in turn leads to reduced airway resistance and work of breathing (2). Additionally, oxygen and carbon dioxide diffuse faster through helium than through air [1]. Heliox is a mixture of helium (usually 70 to 80 percent) and oxygen (usually 20 to 30 percent) that retains the properties of helium when lower concentrations of oxygen are used (2). In children, Heliox has been used to treat conditions like asthma, bronchiolitis, upper airway obstruction and croup with inconsistent results, and currently there are no evidence-based guidelines for its use (3). There are technical challenges for the use of heliox for mechanical ventilation. Due to its different physical properties, when heliox is used for mechanical ventilation, function of pneumotachometers and flow sensors can be altered. Heliox calibrated ventilators are however available (4).

This study by Ma et al was a prospective randomized controlled comparing the effect of synchronized intermittent mandatory ventilation (SIMV) with heliox for six hours followed by SIMV with air-oxygen mixture versus SIMV with air-oxygen mixture alone on the length of mechanical ventilation in infants with meconium aspiration syndrome. The heliox group received ventilation with helium oxygen mixture, the concentration of oxygen was adjusted to maintain the target saturation. It is not clear what was the concentration of helium that was used for each baby. As the therapeutic effect of heliox depends on the concentration of the helium in the gas mixture the therapeutic effect is likely to diminish with increasing oxygen requirement.

The study showed significant reduction in length of mechanical ventilation, length of hospital stay and better oxygenation in babies treated with heliox. PaO2, pH and PaCO2 measured at 2, 6, 12, 24 and 48 hours were significantly better in the group treated with heliox. In keeping with the current guidance, lower target saturation levels were used. However, no information on baseline ventilatory requirements and oxygenation was provided. There is only one previous small study on 8 neonates with meconium aspiration syndrome. SIMV with heliox for 1 hour allowed the use of significantly lower FiO2, and increase in the PaO2 /FiO2 ratio but no significant difference in oxygenation index (5). In this study, length of mechanical ventilation was not reported. PaO2/FiO2 was used as a measure of oxygenation. As there was wide range of ventilatory pressure used in different infants, oxygenation index would have better reflected the ventilatory requirement.

MAS is often complicated by persistent pulmonary hypertension (PPHN), that require use of pulmonary vasodilators like inhaled nitric oxide (iNO). In this study, echocardiograms to assess PPHN were not performed, and it is not clear if any baby needed treatment for PPHN such as iNO or escalation to extracorporeal membrane oxygenation (ECMO). Delivering iNO in addition to heliox can be even more technically challenging, however, it has been reported in literature. (6)

The inflammatory markers IL-6, IL-8 and TNF‐α were significantly better in the group treated with heliox after 6 hours. In animal models of acute respiratory distress syndrome, helium was shown to have anti-inflammatory properties. It was postulated that this may be related to reduction of shear stress and barotrauma with heliox use and its effect on cell mediated immunity (7). However, this effect was not replicated in subsequent studies (8).

Despite its limitations, this study showed that heliox can be a useful adjunct in the management of MAS. MAS causes airway obstruction and increased airway resistance in addition to parenchymal lung injury. Heliox, due to its physical properties is suited for use in MAS to achieve better gas flow, reduced airway resistance and work of breathing. Further studies that explore the use of Heliox with iNO and the right balance of helium and oxygen to achieve oxygenation, with oxygenation index as a measure of oxygenation are needed.

REFERENCES

  1. Gupta VK, Cheifetz IM. Heliox administration in the pediatric intensive care unit: An evidence-based review. Pediatr Crit Care Med. 2005;6(2):204–11.
  2. Diehl JL, Peigne V, Guérot E, Faisy C, Lecourt L, Mercat A. Helium in the adult critical care setting. Ann Intensive Care. 2011;1(1):24.
  3. Martinón-Torres F. What’s weighing down heliox? Lancet Respir Med. 2015 ;3(1):14–5.
  4. Chowdhury MM, Brown MK, Habibi P. Heliox and ventilatory support: What does it mean for the future of infant care? 2006; 2:194–203.
  5. Szczapa T, Gadzinowski J. Use of heliox in the management of neonates with meconium aspiration syndrome. Neonatology. 2011;100(3):265-270.
  6. Phatak RS, Pairaudeau CF, Smith CJ, Pairaudeau PW, Klonin H. Heliox with inhaled nitric oxide: A novel strategy for severe localized interstitial pulmonary emphysema in preterm neonatal ventilation. Respir Care. 2008; 53:1731–8.
  7. Nawab US, Touch SM, Irwin-Sherman T, Blackson TJ, Greenspan JS, Zhu G, et al. Heliox attenuates lung inflammation and structural alterations in acute lung injury. Pediatr Pulmonol. 2005; 40:524–32.
  8. Beurskens CJ, Wösten-van Asperen RM, Preckel B, Juffermans NP. The potential of heliox as a therapy for acute respiratory distress syndrome in adults and children: a descriptive review. Respiration. 2015; 89:166-174.

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