Does lung ultrasound score predict the need for surfactant in extremely preterm neonates?

MANUSCRIPT CITATION

De Martino L, Yousef N, Ben-Ammar R, et al. Lung Ultrasound Score Predicts Surfactant Need in Extremely Preterm Neonates. Pediatrics. 2018;142(3):e20180463. PMID 30108142.

REVIEWED BY

Grant J. Shafer, MD
Neonatology Fellow
Baylor College of Medicine/Texas Children’s Hospital

Gautham K. Suresh, MD, DM, MS, FAAP
Professor of Pediatrics
Section Head and Service Chief of Neonatology
Baylor College of Medicine/Texas Children’s Hospital

TYPE OF INVESTIGATION

Prognosis

QUESTION

(P) In neonates born at less than or equal to 30 weeks gestation with respiratory distress syndrome (RDS) being treated with continuous positive airway pressure (CPAP) (I) does a modified lung ultrasound score (LUS) adapted for neonates (C) compared to no lung ultrasound score (O) predict the need for treatment and re-treatment with surfactant (T) administered between 0 and 76 hours of life?

METHODS

  • Design: Prospective cohort
  • Allocation: Observational study – does not apply
  • Blinding: Unblinded
  • Follow-up period: Unclear – the study does not report the timeframe for which the patients were followed after admission to the NICU
  • Setting: A single academic tertiary-care referral NICU with ~4,000 deliveries per year between 2015-2016 whose patient population is a mix of inborn and outborn patients
  • Patients:
    • Inclusion Criteria
      • All inborn neonates <30 weeks’ gestational age were eligible to be included in the study
    • Exclusion Criteria
      • Outborn patients
      • Chromosomal abnormalities
      • Complex congenital malformations
      • Congenital lung disease
      • Congenital heart defect
      • Early onset severe sepsis and/or septic shock
      • Need for surgery in the first week of life
      • Administration of surfactant in the delivery room
    • Intervention: A single lung ultrasound study was performed in eligible neonates soon after NICU admission, while they were on CPAP, and before a decision about surfactant administration had been made. The ultrasound was performed by a trained senior neonatology fellow, and a LUS was assigned based on the evaluation of three chest areas on ultrasound – score ranged from 0-18 with a higher score indicating worse lung aeration.
    • Separately, the attending physician for the patient made the determination whether or not to administer surfactant based solely on the patient’s fraction of inspired oxygen (FiO2) requirement – the attending did not have access to the LUS. These cutoffs were based on modified criteria from the European Consensus Guidelines on the Management of Respiratory Distress Syndrome. The FiO2 requirement was >30% for neonates <28 weeks or >40% for neonates >28 weeks. A second dose of surfactant was given if the FiO2 remained higher than the cutoff values at >10 hours after the first dose had been administered.
  • Outcomes
    • Primary outcome: Need for treatment and re-treatment with surfactant therapy.
    • Secondary outcomes: Correlation of LUS with the calculated oxygenation index
  • Analysis and Sample Size: Estimating a rate of surfactant administration of 50% for neonates fulfilling study criteria, and targeting an area under the curve (AUC) of >7 with a Type 1 error of 0.05 and a power of 95%, 100 patients would need to be enrolled. A total of 133 patients were enrolled in the study – the authors choose to enroll this number of patients as this sample size is similiar to previous studies from this institution related to LUS.
    • The study group was further divided into <28 weeks and >28 weeks’ gestational age subgroups. Receiver operating characteristic (ROC) analysis was used to evaluate reliability of LUS to predict the need for treatment and re-treatment surfactant therapy for the study group as a whole as well as the subgroups.
  • Patient follow-up: Of the 133 infants enrolled in the study, 100% were analyzed for the primary outcome.

MAIN RESULTS

Patient Demographic Data

All Patients (n=133) GA <28 Weeks (n=83) GA >28 Weeks (n=50) P-value
Gestation Age, weeks, mean 28 27 29 <0.001
Birth Weight, grams, mean 1043 955 1187 <0.001
Male Sex, n (%) 66 (50) 43 (52) 23 (46) 0.197
Antenatal Steroids, any dose,n (%) 117 (88) 72 (87) 45 (90) 0.576
Antenatal Steroids, full course, n (%) 76 (57) 50 (60) 26 (52) 0.352
Surfactant Replacement, first dose, n (%) 68 (51) 53 (64) 14 (28) <0.001
Surfactant Replacement, second dose, n (%) 19 (14) 18 (22) 1 (2) 0.002
Oxygenation Index, median (interquartile range) 3 (2-5) 4 (3-6) 2 (2-4) 0.013
LUS, median (interquartile range) 8 (4-12) 10 (4-12) 6 (3-11) 0.032

ROC Analysis of Ability of LUS to Predict the Need for a First and Second Dose of Surfactant

All Patients GA <28 Weeks GA >28 Weeks
Need for First Dose of Surfactant
AUC (95% CI, P-value) 0.94 (0.90-0.98, <0.001) 0.93 (0.88-0.98, <0.001) 0.98 (0.94-1, <0.001)
Need for Second Dose of Surfactant
AUC (95% CI, P-value) 0.803 (0.72-0.89, <0.001) 0.78 (0.68-0.88, <0.001) Not performed as only 1 patient required re-treatment

Reliability of LUS to Predict Surfactant Treatment and Re-treatment

All Patients
LUS Sensitivity, % (95% CI) Specificity, % (95% CI)
Surfactant First Dose
>6 90 (80-96) 80 (68-89)
>8 82 (71-90) 92 (83-98)
Surfactant Second Dose
>10 84 (60-97) 70 (61-78)
GA <28 Weeks
Surfactant First Dose Sensitivity, % (95% CI) Specificity, % (95% CI)
>6
>7 87 (75-96) 80 (61-92)
Surfactant Second Dose 83 (70-92) 87 (69-96)
>10
83 (59-96) 66 (53-77)
GA >28 Weeks
Surfactant First Dose Sensitivity, % (95% CI) Specificity, % (95% CI)
>6 100 (77-100) 80 (73-92)
>8 100 (77-100) 94 (81-99)

LUS and Correlation with Oxygenation Index

All Patients GA <28 Weeks GA >28 Weeks
Spearman coefficient or ƿ (P-value) 0.6 (<0.001) 0.5 (<0.001) 0.6 (<0.0001)

CONCLUSION

The authors conclude that a LUS assigned by a trained operator can accurately predict the need for treatment – and to a lesser degree re-treatment – with surfactant therapy in <30 week gestation neonates with RDS on CPAP and no other major abnormalities. A LUS between 6 and 8 provides the best sensitivity and specificity for predicting the need for a first dose surfactant, while a LUS of >10 predicts the need for a second dose.

COMMENTARY

Study Description: Respiratory distress syndrome (RDS) is almost universal in the extremely preterm neonate, and select patients benefit from timely administration of surfactant therapy (1). Use of lung ultrasonography to assign a semi-quantitative lung ultrasound score (LUS) may predict which neonates will require surfactant therapy (2). This was a prospective cohort diagnostic accuracy study to assess the ability of the LUS to predict the need for surfactant treatment and re-treatment in neonates <30 weeks’ gestational age with RDS on continuous positive airway pressure (CPAP). Patients had a lung ultrasound performed to assign a LUS, then need for treatment and re-treatment with surfactant relied solely on the inspired fraction of oxygen (FiO2) requirement (3).

Critical Appraisal: We evaluated the study using the QUADAS-2 tool– see attached supplement (4). Patients were enrolled consecutively with appropriate inclusion/exclusion criteria. The study was well-powered.

The index test was the LUS with no pre-specified thresholds. Of note, lung ultrasonography is the first-line imaging to evaluate RDS at this institution. The ultrasound operator was not blinded to the patient’s FiO2 requirement, which increases the risk of bias, although previous studies demonstrated good inter-rater reliability under similar conditions (2).  The physician was blinded to the LUS results, however, when determining the need for surfactant therapy based on the FiO2 reference standard. The authors report that a lung ultrasound was performed on average at 30 minutes of life, and that the first dose of surfactant was administered at a mean of four hours of life, but it is unclear how the long the patient had to exceed the FiO2 requirement before a decision was made to treat.

Receiver operating characteristic analysis demonstrated good predictive value with an area under the curve >0.9 across all gestational ages. It was closer to 0.8, however, when predicting the need for re-treatment. LUS cut-offs also predicted the need for treatment and re-treatment with surfactant. The authors did not provide clinical characteristics for patients requiring treatment or re-treatment versus no treatment, so it is unclear if there were confounding factors. For example, only 60% of study patients received a full antenatal steroid course, but the authors did not report if this varied between the treatment versus no treatment groups. The secondary outcome correlating LUS with oxygenation index demonstrated good agreement.

Overall, the results support the reliability of the LUS to predict the need for surfactant treatment in this population.

Practice Implications: This study’s primary limitation is applicability. While the authors used low FiO2 cutoffs (30% for < 28 weeks and 40% for > 28 weeks) to administer surfactant, the FiO2 requirement constituting CPAP failure varies in the literature from 30-75% (1,5,6) – restricting the applicability of these results to institutions which utilize similar thresholds. Additionally, although other studies report good reliability of the LUS (3,7,8),  a recent systemic review by Hiles, et al,  found only moderate quality evidence to support its use (9). Thus, more research is needed prior to universal implementation, so for now this study’s results are limited to NICUs with similar expertise.

REFERENCES

  1. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev 2012; 11: CD001456.
  2. Brat R, Yousef N, Klifa R, Reynaud S, Shankar Aguilera S, De Luca D. Lung Ultrasonography Score to Evaluate Oxygenation and Surfactant Need in Neonates Treated With Continuous Positive Airway Pressure. JAMA Pediatr 2015; 169: e151797.
  3. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2016 Update. Neonatology 2017; 111: 107-125.
  4. Whiting PF, Rutjes AWS, Westwood ME, Mallett S, Deeks JJ, Reitsma JB et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155: 529-536.
  5. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG et al. Early CPAP versus Surfactant in Extremely Preterm Infants. N Engl J Med 2010; 362: 1970-1979.
  6. Wright CJ, Polin RA. Noninvasive Support: Does It Really Decrease Bronchopulmonary Dysplasia? Clin Perinatol 2016; 43: 783-798.
  1. Copetti R, Cattarossi L, Macagno F, Violino M, Furlan R. Lung Ultrasound in Respiratory Distress Syndrome: A Useful Tool for Early Diagnosis. Neonatology 2008; 94: 52-59.
  2. Raimondi F, Migliaro F, Sodano A, Ferrara T, Lama S, Vallone G et al. Use of Neonatal Chest Ultrasound to Predict Noninvasive Ventilation Failure. Pediatrics 2014; 134: e1089-1094.
  3. Hiles M, Culpan A, Watts C, Munyombwe T, Wolstenhulme S. Neonatal respiratory distress syndrome: Chest X-ray or lung ultrasound? A systematic review. Ultrasound 2017; 25: 80-91.

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