Infants of all gestations, admitted to McMaster University Medical Center level III NICU and considered likely to need an elective oral or nasotracheal intubation during their hospital stay, were candidates for inclusion in this study. Families were approached for consent as soon as possible after birth when an elective intubation during their hospital stay seemed likely: if their infant(s) was less than 30 weeks gestation, already ventilated (as endotracheal tubes are frequently changed after 10 days if clinical deterioration from a respiratory standpoint), was on NCPAP for respiratory distress or was needing an elective surgery. Others were approached when an elective intubation was needed. At the time of this study, our unit was a 33-bed level 3 NICU, caring for both inborn and outborn patients, and the referral center for 25000 annual deliveries, with 900–1000 admissions per year.
Infants were excluded if they met any of the following conditions: 1) absence of an intravenous access, 2) upper airway anomaly potentially leading to a difficult intubation, 3) cyanotic heart disease, 4) upper gastrointestinal obstruction (which would require a rapid sequence intubation) or 5) concurrent opioid administration.
Infants requiring an elective intubation were randomly assigned to receive either morphine 0.2 mg/kg IV or placebo (0.9% NaCl), given over 1 minute, followed 5 minutes later by the intubation. This larger dose of morphine was chosen for the perceived acuity of pain produced by an intubation; a larger dose may be more effective to decrease the struggling by infants during the procedure, which is caused by pain. Infants were randomized according to a computer-generated random number table with random block sizes. Morphine and placebo were supplied in identical unidose vials, labeled PIN Rx, which were prepared by one pharmacist according to the randomization sequence and placed in sealed, consecutively numbered envelopes, which were opened just before intubation. Thus, randomization occurred just prior to intubation.
Three to four minutes after receiving the study medication, infants were preoxygenated with 100% 02 and hand-ventilated with a self-inflatable bag for 1–2 minutes prior to intubation. Infants having their endotracheal tube replaced were ventilated through their existing tube until it was removed. Vital signs (HR, BP, Sp02) were captured to a laptop computer from the infant's monitor (PC Express, Spacelabs Inc., Redmond WA) every 5 seconds (except blood pressure which was obtained with a self inflating cuff every minute) using Procom Plus Communication Software, from the time the study medication was given (which was considered the baseline) to 5 minutes after the infant's vital signs returned to pre-procedure values. One of three investigators, not involved in the procedure collected the following data manually: duration of the procedure (defined as the time between insertion of the laryngoscope in the mouth to confirmation of endotracheal tube placement by auscultation) and the number of intubation attempts (defined as number of times the laryngoscope was inserted in the mouth). If there was more than one attempt, the clock continued between attempts and was stopped only when tube placement was confirmed by auscultation. In our NICU, the preferred method of intubation is via the nasotracheal route if mechanical ventilation is expected for more than a few hours.
All team members performed the intubations: staff neonatologists a, neonatal fellows b, pediatric residents c, clinical nurse specialists d, clinical nurse specialist students e and transport nurses f. After 2 unsuccessful attempts by a junior team member (c,d,e,f), a more experienced intubator (a,b) was called.
Institutional ethics committee approval and informed consent from the parents were obtained for this study.
The study aimed to test the hypothesis that morphine 0.2 mg/kg would decrease fluctuations in vital signs, shorten the duration of the procedure and reduce the number of attempts. The primary outcome was the duration of severe hypoxemia, defined as Sp02 < 85% with a HR< 90/min. This was felt to be the most undesirable side effect of endotracheal intubation as cerebral blood flow in neonates is highly dependent upon heart rate. Secondary outcomes included: (1) duration of the procedure, (2) duration of hypoxemia (Sp02 < 85%), (3) number of attempts, (4) maximum change in blood pressure from baseline, (5) occurrence of bradycardia (HR<90/min).
The study group's impression was that a majority of infants experience some degree of severe hypoxemia during an elective intubation, which was clinically undesirable. It was estimated to be 30 seconds, based on experience. In order to detect a one standard deviation difference in duration of severe hypoxemia between the 2 groups (α = 0.05, 2-sided, β = 0.2), 17 patients per group were required.
Because the distribution of the main outcome was skewed and groups were small, continuous variables were compared using the Mann-Whitney U test. Dichotomous variables were compared using Fisher's exact test or Chi-square test. A p value < 0.05 (2-sided) was considered significant for the primary outcome; p < 0.01 was considered significant for secondary outcomes to account for multiple analyses in a small sample. Level of experience of the intubator, birth weight and gestational age were separately explored as potential confounders of the primary outcome using ANOVA or linear regression.