MANUSCRIPT CITATION

Shalish W, Kanbar L, Kovacs L, Chawla S, Keszler M, Rao S, Latremouille S, Precup D, Brown K, Kearney RE, Sant’Anna GM. Assessment of Extubation Readiness Using Spontaneous Breathing Trials in Extremely Preterm Neonates. JAMA Pediatr. 2020;174(2):178–185. doi:10.1001/jamapediatrics.2019.4868. PMID: 31860014.

REVIEWED BY

Nidhi Agarwal
Assistant Professor
Department of Pediatrics
Arkansas Children’s Hospital
University of Arkansas for Medical Sciences
Little Rock, AR, United States

Ankita Shukla
Assistant Professor of Pediatrics,
Arkansas Children’s Hospital
University of Arkansas for Medical Sciences
Little Rock, AR, United States

TYPE OF INVESTIGATION

Clinical prediction guides
Treatment, Diagnosis

QUESTION

In extremely preterm infants with birthweight < 1250 gram who are on mechanical ventilation (P), can a spontaneous breathing trial (SBT) using endotracheal continuous positive airway pressure (I) add to clinical judgement (C) to improve the clinician’s ability to assess extubation readiness (O) prior to their first planned extubation (T).

METHODS

• Design: Multi-center, prospective, single arm observational study
• Allocation: All the infants got intervention. Data from Automated Prediction of Extubation Readiness (APEX) study was used.
• Blinding: Unblinded
• Study period: September 1, 2013 through August 31, 2018
• Follow-up period: 7 days post-extubation
• Setting: Five tertiary-level neonatal intensive care units (NICU) in North America (three in Canada and two in United States)
• Patients:
  • Inclusion Criteria:
    • Extremely preterm neonates with birth weight <1250 g requiring intubation/mechanical ventilation and having a planned elective first extubation
    • Extubation readiness was based on clinical judgment
    • Cardiorespiratory signal acquired before the extubation
  • Exclusion Criteria:
    • Major congenital anomalies
    • Congenital heart disease
    • Cardiac arrhythmias
    • Receiving any vasopressor at time of extubation
    • Receiving any sedatives at time of extubation
    • Extubation from high frequency ventilation
    • Direct extubation to room air, oxyhood or low flow nasal cannula
    • Accidental/unplanned extubation
    • Death prior to extubation
    • Baseline oxygen saturation <85% just before starting the trials
• Intervention: All the subjects underwent 5-minute spontaneous breathing trial (SBT) using ET-CPAP before extubation. The positive end expiratory pressure (PEEP) used during ET-CPAP is equivalent to the conventional mechanical ventilation PEEP. Pressure support and the backup rate were not provided during SBT.
• Outcomes:
  • Primary outcome:
    • Describe the occurrence and cumulative duration of 4 clinical events- apneas requiring stimulation, bradycardias, desaturations, and increase in oxygen supplementation during ET-CPAP trial.
  • Secondary outcomes:
    • To evaluate different SBT combination definitions to predict successful extubation compared to clinical judgment alone
• Analysis and Sample Size: Sensitivity, specificity, positive and negative predictive values of a passed SBT with 95% Confidence Interval were calculated. Based on the sample size and prevalence of successful extubation in the APEX cohort assuming a 2-tailed α = 0.05, the computed SBT sensitivities and specificities would be estimated with approximately 5% and 10% precision respectively. The accuracy of each SBT in estimating success for extubation was calculated by the Youdon index.
• Patient follow-up:
  • 278 neonates with birthweight < 1250 gram received a 5-minute ET-CPAP index test. 25 neonates were excluded [physician changed decision about extubation (7), prolonged interval between index test and reference standard (6), baseline saturation <85% (5), repeat ET-CPAP (3), missing or inadequate clinical data (3), congenital anomaly post extubation (1)]. Out of total 259 extubated neonates (54% male), 184 (71%) had successful extubation. For the cohort (n=259), median gestational age was 26.1 weeks, birth weight 830 grams, postnatal age at extubation was 8 days (IQR  3-26 days). Caffeine was administered to 98% neonates. Post extubation respiratory support was CPAP in 58%, nasal intermittent positive pressure ventilation in 37% and high flow nasal cannula in 5% neonates. ET-CPAP was performed with median PEEP of 5cm H2O (IQR 5-6cm H2O) for 5 minutes with median time lapse of 32 minutes (IQR 21-59 minutes) before extubation. Successful extubation was significantly associated with older gestational age and postmenstrual age, higher birth weight and current weight and less respiratory support at time of extubation.
  • 147 (57%) neonates experienced at least 1 clinical event during ET-CPAP. 39 had only a single clinical event: [desaturations (33), oxygen increase (4), apnea (1), bradycardia (1)]. 19 neonates had all 4 events, while 26 subjects had 3 clinical events where the most common was a combination of bradycardia and desaturations with oxygen increase. The desaturation with increased oxygen was the most common combination (58). Of 259 neonates extubated, seven were excluded due to missing data and 252 (92%) neonates were used in generating 41,602 SBT definitions using various combinations of 4 clinical events. For the SBT combinations, the sensitivity range was 51-100% (median 96%), the specificity range was 0-72% (median 22%), the positive predictive value range was 71-82% (median 75%), the negative predictive value range was 33-100% (median 67%) and the Youden index range was 0- 0.32 (median 0.17) indicating low accuracy.

MAIN RESULTS

CONCLUSION

A spontaneous breathing trial provided marginal additional value to clinical judgment in assessing for extubation readiness. The authors found low accuracy for >41,000 combinations of clinical events during SBT in predicting successful extubation.

COMMENTARY

Despite ongoing medical advances, extremely premature infants continue to have substantial morbidities and mortality.  Prolonged mechanical ventilation has been associated with bronchopulmonary dysplasia and neurodevelopmental delays,^1,2 and is a major reflection of increased healthcare costs.³ Rate of extubation failure in preterm infants is 40-50% and many providers strive to find the appropriate time for extubation since reintubation attempts are associated with increased mortality and worsening of respiratory status, along with risks for severe intracranial bleed.^4,5

Extubation readiness is primarily steered by clinical judgement and is supported by measures like spontaneous breathing trials (SBT), minute ventilation tests,and the extubation predictor calculator.^6,7 In neonates, even though SBT is a common practice, success of its applicability is debated. Selection of ‘extubation ready’ candidates for SBT using clinical judgement leads to inherent test-referral bias that overvalues sensitivity and misjudges diagnostic accuracy. Historically, SBT practice is not standardized for its duration and provision of level of support, which may greatly influence the outcomes.⁸

This report, performed as a secondary analysis to the APEX study, used a recent approach of SBT with ET-CPAP of 5-6 cmH2O for 5-minute just prior to extubation. Failed outcome was defined as the need for reintubation within 7 days.⁹ Similar to prior studies, the successful extubation group had higher gestational age, birth weight, postmenstrual age and lower pre-extubation oxygen requirement. Also, the successful extubation group compared to the failure group had fewer clinical events during ET-CPAP (51% vs 72%) and had less incidence of early termination of SBT (3% vs 20%).

This is a unique study where ET-CPAP clinical events are described as independent predictors for successful extubation, to bridge the knowledge gap about SBT. None of >41,000 combinations had superior predictive accuracy for successful extubation without high false positive rates. Apnea with 15% increase in baseline oxygen had the highest Youdon index of only 0.32 (sensitivity 93%, specificity 39%). Another major strength is the large number of subjects (n= 259) in a multicenter trial. Unlike other studies, there was no preset criteria to extubate, but all subjects got extubated. Additional analyses were performed to overcome potential biases from variations in the observation window from time of extubation, and higher and lower gestational ages of the neonates.

As a major limitation, the study does not account for clinical judgement selection bias where only those neonates who are “ready for extubation” underwent SBT. A more appropriate design would be diagnostic randomized controlled trial where intubated neonates are randomized to be or not to be assessed by SBT at pre-determined intervals. This will be of more clinical relevance and provide robust data on important clinical outcomes. In neonates, a major factor to failed extubation not accounted for could be the interval of time on PEEP support while ET-CPAP is administered. SBT does not have consistent criteria to define outcomes and adds little value to safe and reliable decision making. SBT tests do not identify clinically ‘not ready’ neonates and do not apply independently in the absence of clinical judgement. Prospectively, a study to include outcome data of unsuccessful extubation would help in better understanding of SBT failed attempts. The study uses automated algorithmic approach to identify clinical events to predict successful extubation. Alternatively, Bayesian approach incorporating prior probability of extubation success based on weight, gestation etc can be used to assess the same.

Considering that SBT does not add any further value to clinical decision-making, clinicians must weigh prudently the risk of exposing neonates to subthreshold support that may lead to adverse clinical events and lung atelectasis, thus, limiting its applicability in extremely premature infants.

REFERENCES

1. Miller JD, Carlo WA. Pulmonary complications of mechanical ventilation in neonates. Clin Perinatol. 2008;35:273–81.
2. Jensen EA, DeMauro SB, Kornhauser M, Aghai ZH, Greenspan JS, Dysart KC. Effects of multiple ventilation courses and duration of mechanical ventilation on respiratory outcomes in extremely low-birth-weight infants. JAMA Pediatr. 2015;169:1011–7.
3. Van Katwyk S, Augustine S, Thébaud B, Thavorn K. Lifetime patient outcomes and healthcare utilization for Bronchopulmonary dysplasia (BPD) and extreme preterm infants: a microsimulation study. BMC Pediatr. 2020 Mar 25;20(1):136
4. Berger J, Mehta P, Bucholz E, Dziura J, Bhandari V. Impact of early extubation and reintubation on the incidence of bronchopulmonary dysplasia in neonates. Am J Perinatol. 2014;31:1063–72.
5. Chawla S, Natarajan G, Shankaran S, Carper B, Brion LP, Keszler M, et al. Markers of successful extubation in extremely preterm infants, and morbidity after failed extubation. J Pediatr. 2017;189:113-e.112.
6. Nakato AM, Ribeiro DF, Simão AC, Da Silva RP, Nohama P. Impact of Spontaneous Breathing Trials in Cardiorespiratory Stability of Preterm Infants. Respir Care. 2021 Feb;66(2):286-291. doi: 10.4187/respcare.07955. Epub 2020 Sep 29. PMID: 32994356.
7. Gupta, D., Greenberg, R.G., Sharma, A. et al.A predictive model for extubation readiness in extremely preterm infants. J Perinatol 39, 1663–1669 (2019).
8. Manley BJ, Doyle LW, Owen LS, Davis PG. Extubating Extremely Preterm Infants: Predictors of Success and Outcomes following Failure. J Pediatr. 2016 Jun;173:45-9. doi: 10.1016/j.jpeds.2016.02.016. Epub 2016 Mar 5. PMID: 26960919.
9. Shalish, W., Kanbar, L.J., Rao, S. et al.Prediction of Extubation readiness in extremely preterm infants by the automated analysis of cardiorespiratory behavior: study protocol. BMC Pediatr 17, 167 (2017).