PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1248-e1255 (doi:10.1542/peds.2006-2708)
ARTICLE |
Propofol Compared With the Morphine, Atropine, and Suxamethonium Regimen as Induction Agents for Neonatal Endotracheal Intubation: A Randomized, Controlled Trial
a Department of Newborn Care, Royal Hospital for Women, Randwick, New South Wales, Australia
b School of Women's and Children's Heath, University of New South Wales, Kensington, New South Wales, Australia
c Department of Paediatric Intensive Care, Sydney Children Hospital, Randwick, New South Wales, Australia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. The purpose of this work was to compare the efficacy of propofol, a hypnotic agent, to the regimen of morphine, atropine, and suxamethonium as an induction agent for nonemergency neonatal endotracheal intubation. We hypothesized that propofol aids intubation by allowing the continuation of spontaneous breathing.
PATIENTS AND METHODS. We conducted a randomized, open-label, controlled trial of infants who required nonemergency endotracheal intubation. Primary outcome was successful intubation confirmed by chest auscultation and clinical examination of the infant.
RESULTS. Infants randomly assigned to propofol (n = 33) and the morphine, atropine, and suxamethonium regimen (n = 30) were comparable in median gestational age (27 vs 28 weeks), birth weight (1020 vs 1095 g), weight at intubation (1068 vs 1275 g), and age at intubation (4 vs 3 days). Sleep or muscle relaxation were achieved within 60 seconds in both groups, but time to achieve successful intubation was more than twice as fast with propofol (120 vs 260 seconds). Blood pressure and heart rates were not different, but intraprocedural oxygen saturations were significantly lower in infants on the morphine, atropine, and suxamethonium regimen (trough arterial oxygen saturation: 60% vs 80%). Nasal/oral trauma was less common, and recovery time was shorter (780 vs 1425 seconds) in the propofol group. No significant adverse effects were seen in either group.
CONCLUSIONS. Propofol is more effective than the morphine, atropine, and suxamethonium regimen as an induction agent to facilitate neonatal nasal endotracheal intubation. Importantly, hypoxemia was less severe, probably because of the maintenance of spontaneous breathing. A controlled environment may have promoted the ease of intubation, resulting in less trauma. The shorter duration of action would be advantageous in a compromised infant.
Key Words: propofol • endotracheal intubation • suxamethonium • neonatal • randomized control trial
Abbreviations: MASux—combination of morphine, atropine, and suxamethonium regimen
Endotracheal intubation is a common but necessary procedure in the NICU. Newborn infants are unlikely to be different from older patients, where conscious intubation, regardless of the skill and expertise of the operator, is most likely to cause considerable discomfort and result in adverse physiologic sequelae, such as increased systemic1,2 and intracranial pressures,3 hypoxemia,1,2,4,5 and profound bradycardia.1,2 Studies have unequivocally demonstrated that premedicating infants who require intubation with various forms of induction agents increases the speed of successful intubation and reduces the likelihood of the occurrence of associated adverse sequelae.1,4,6,7
However, there is no consensus as to which types of drugs are best for preintubation medications during the neonatal period. For example, a recent survey8 found that 
14 different combinations of premedication regimes were used in NICUs around the United Kingdom and Australia. Common combinations use an analgesic for pain, a vagolytic to counteract the reflex bradycardia associated with laryngeal stimulation, and a muscle relaxant to ameliorate struggling and to facilitate the intubation process.
A combination morphine, atropine, and suxamethonium regimen (MASux) is often used as a premedication for intubation. In our previous study, we found that MASux was superior to conscious intubation by increasing the speed and success rate of intubation and by decreasing the incidence of oropharyngeal trauma, a common complication of intubating a struggling, awake infant.6 MASux, however, is time consuming to prepare, especially when needed urgently, because many countries require dual accountability (eg, by 2 registered nurses) for the dispensation of narcotic agents. Furthermore, suxamethonium, a short-acting nondepolarizing muscle relaxant, may cause potentially serious adverse effects, such as hyperkalemia, profound vagotonia, malignant hyperthermia, masseter spasm, and systemic and ocular hypertension.9,10 Furthermore, complete and unexpectedly prolonged muscle relaxation and apnea secondary to paralytic agents, such as suxamethonium or pancuronium, may be detrimental if an airway is unable to be promptly secured.10
Therefore, in this study, we sought to compare the efficacy of a single hypnotic agent, propofol (Diprivan), to MASux as an induction agent for nonemergency neonatal endotracheal intubation. Propofol is a soy-based formula commonly used in short operative procedures for adults and older children.11 Propofol, however, has not been explored for premedication purposes in newborn infants. We chose to explore propofol for this indication because of the convenience of its use as a single agent and its ability to preserve spontaneous respirations while providing hypnosis. We, therefore, hypothesize that propofol is more effective than MASux for nonemergency endotracheal intubation.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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This was a randomized, controlled, open-label study conducted at the Department of Newborn Care at the Royal Hospital for Women in Randwick between March 2004 and December 2005. All of the newborn infants requiring elective or semielective (nonemergency) intubations were eligible if there was sufficient time to obtain informed parental consent. Infants admitted intubated at birth or by retrieval team would not be included unless there was a subsequent need for semielective intubation. Infants with major congenital abnormalities, whose parents had insufficient English-language skills to comprehend all of the explanations or who required emergency intubation (eg, resuscitation in the delivery suite), were excluded from the study. Infants requiring multiple intubations during their hospital stay were allowed to be in the study for only a single intubation. The institutional human research ethics committee approved the study before its commencement. The protocol was registered with the Interdisciplinary Maternal Perinatal Australasian Clinical Trials Network.
The primary purpose of this study was to compare the times required to achieve successful intubation, as well as to compare intraprocedural oxygen saturation, heart rate, and blood pressure changes between the propofol and MASux groups. Additional analyses were also performed on other related factors, as illustrated in Table 1. Random sampling numbers, based on a random number table, were used to assign each infant to blocks of 10 to receive either propofol or MASux after stratification by body weight (<1250 g and >1250 g) at the time of intubation. Group assignments were drawn from consecutively numbered, sealed, opaque envelopes that were opened by the trial team on the infant's admission into the study immediately before intubation. Random sequences and envelopes were prepared by a senior nurse who was entirely uninvolved in the trial.
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Blinding was not possible, because the drugs were very different in appearance: propofol is opaque and white, whereas MASux is a combination of 3 different ampoules of clear liquid. Morphine, an accountable restricted narcotic, was required to be prescribed for each individual patient, as well as to be prepared and accounted for by 2 registered nurses. This administration procedure was the main reason for a lengthy period of drug preparation in this regime. More importantly, the modes of action and the effects of these drugs were also quite different (muscle paralysis versus hypnosis) in assessing infants' readiness for intubation.
Drug Doses and Administration
Propofol
The recommended lowest bolus induction dose for propofol in adults and children >3 years old is 2.5 mg/kg intravenously, with an infusion rate of 1.5 to 3.0 mg/kg per hour for the maintenance of anesthesia during an operative procedure.9 Safety and efficacy in newborn infants have not been well established, and, to date, infusions are not recommended for this group of patients (as development of lactic acidosis documented previously in older patients).12 We, therefore, chose to administer propofol as a single 2.5 mg/kg intravenous dose based on the above recommendations.
After a single intravenous dose of 2.5 mg/kg of propofol, eyelash reflex was tested by the intubator approximately every 10 seconds, the loss of which determined the onset of sleep or hypnosis. A maximum of 2 doses of propofol (2.5 mg/kg each) was allowed. The infant would then default to MASux if sleep had not been achieved in the desired time frame of 3 minutes13 or after the second dose of propofol.
MASux
This is the standard induction regime used in our NICU. The doses of drugs are as follows (all intravenous): morphine, 100 µg/kg; atropine, 10 µg/kg; and suxamethonium, 2 mg/kg. Two repeat doses of suxamethonium at 1 mg/kg each (maximum total dose of 4 mg/kg per intubation attempt) were administered if muscle relaxation was not achieved in the space of 3 to 5 minutes. Repeat applications of suxamethonium up to a maximum total of 4 mg/kg were allowed (if required) for each intubation attempt.
The Intubation Procedure and Personnel
For nonemergency intubation for prolonged ventilation, nasal intubation was the preferred route in our unit. Each infant was preoxygenated by positive-pressure mask ventilation (delivered by positive end-expiratory pressure-controlled Neopuff) and 100% oxygen before the administration of the induction agents. We do not have nurse practitioners in our NICU, and all of the intubations were conducted by medical officers of varying seniorities. As per our unit policy, each doctor was allowed a maximum of 2 intubation attempts, and each attempt was curtailed if the heart rate decreased below 60 beats per minute and/or the oxygen saturations decreased below 60%. The infant, after cessation of each attempt, was then reventilated by positive-pressure breaths with a mask delivering 100% oxygen. Intubation was then recommence after reestablishment of the heart rate to >120 beats per minute and oxygen saturations to >90%.
The Royal Hospital for Women is a major teaching hospital for pediatric and neonatal subspecialty training. The majority of medical officers in our NICU are therefore seconded on 3-monthly periods from the adjacent Sydney Children's Hospital. The first medical officer to attempt an intubation was usually a registrar (with 
2 previous successful intubation attempts) or, less frequently, a resident who may be having the first hands-on intubation attempt, although with previous exposure to the procedure. Each intubation was personally supervised by doctors who were already technically competent in neonatal intubation (either a neonatal fellow or a consultant neonatologist), and the supervisor would then take over the intubation process after 2 failed attempts from the junior officer. Nasal intubation is the preferred route in the unit. Oral intubations were performed only when emergency airway access was required, such as during resuscitation in the delivery suite or after failures of nasal intubations.
An intubation was considered successful if there was appreciable and bilaterally equal chest movement and air entry in conjunction with rising and stable oxygen saturations and heart rate after insertion of the endotracheal tube. After stabilization, each intubation was then confirmed by a portable chest radiograph, as per routine clinical management.
Timing of Procedures and Data Recording
A clinically uninvolved member of the team, also not a trial investigator, was designated as an observer, data recorder, and timekeeper. The following time periods were recorded: (1) medication preparation time: time from randomization until the medications were ready for administration; (2) time to achieve sleep and muscle relaxation: from administration of medications until onset of sleep/hypnosis (defined as loss of eyelash reflex) or muscle relaxation (defined as loss of voluntary muscle activity); (3) intubation time: from the first insertion of laryngoscope to clinical confirmation of successful intubation after all of the attempts were completed (clinical confirmation of successful intubation is evidenced by adequate chest movement, rising oxygen saturations, and bilaterally equal air entry on auscultation); and (4) recovery time: from onset of sleep and muscle relaxation (above) to return of spontaneous muscle movement.
Information recorded during the intubation process included the number of intubation attempts, additional doses of induction agents required, and the presence of intubation trauma, defined as the presence of blood in the nasal or oropharyngeal areas during or after intubation. Other data collected included head ultrasound appearances, lactate and base deficit levels before and after the intubation, and the severity of illness on admission (according to the Clinical Risk Index for Babies II score).14
The vital signs (including heart rate, oxygen saturations, and blood pressure) of the infants were continuously monitored on Spacelabs modules. Blood pressure was measured by either an indwelling intra-arterial cannula (usually umbilical arteries or radial arteries) or by an appropriately sized Dinamap blood pressure cuff that was inflated every 30 seconds before, during, and after the procedure. Oxygen saturations were also recorded simultaneously with a portable pulse oximeter (Radical, Masimo, Irvine, CA). Records of vital signs were commenced 5 minutes before administration of medications and continued for 5 minutes after complete recovery. Other than time intervals and baseline vital signs, the trough (lowest if any) heart rate, oxygen saturation, and blood pressure during the intubation process and the recovery period were recorded for comparisons.
A peripheral 24-G intravenous cannulae was established in each patient and flushed (to ensure patency) with 0.5 mL of normal saline before administration of medications. For each data set, the lactate and base deficit levels were categorized as either normal or increased (2.2 mmol/L and 2.0, respectively), based on our laboratory reference values.
Sample Size and Statistical Analysis
The number of subjects required for this trial was calculated based on findings from our previous study.6 By selecting a power of 0.8 and a 2-tailed 
of .05, 28 infants in each arm were necessary to demonstrate a 30% difference in the time to achieve intubation. Statistical analysis was undertaken on an intention-to-treat basis according to a preestablished analysis plan. This was to allow for possible crossovers to MASux from propofol, should the latter fail to achieve hypnosis.
Results are presented as percentages and medians with interquartile ranges (25th to 75th percentile). The Fisher's exact and Mann-Whitney U tests were used where appropriate. All of the computations were performed using SPSS 10 (SPSS Inc, Chicago, IL) and MedCalc for Windows 5.00.017 (MedCalc Software, Mariakerke, Belgium).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Sixty-seven infants needing semielective intubation were assessed for eligibility by the investigator team. Parents of 4 infants declined consents. Sixty-three infants (33 propofol and 30 MASux) were enrolled. The 2 groups were comparable in gestational ages, Clinical Risk Index for Babies II scores, birth weights, and weights and ages at intubation (Table 1). Most of the infants were intubated for respiratory distress syndrome.
Time Intervals
MASux took 5 times longer (median, interquartile ranges) to prepare than propofol (960, 900–1200 seconds vs 180, 180–210 seconds, respectively; P < .001). Figure 1 shows the time to achieve sleep and muscle relaxation, successful intubation, and recovery. The times to achieve sleep and muscle relaxation (60, 60–120 seconds vs 60, 30]60 seconds, respectively) for MASux versus propofol were comparable (P = .087). Successful intubation was more than twice as fast in the propofol group compared with MASux (120, 60]180 seconds vs 260, 60]435 seconds, respectively; P = .007). Stratifying the time of intubation by the number of intubation attempts showed that intubation times were similar for those who were intubated successfully on first attempt (60, 60–120 seconds vs 60, 52–120 seconds for the 20 propofol and 13 MASux successful first attempts, respectively; P = .641). Intubations that required >1 attempt were significantly faster in the propofol group than the intubation time required for the MASux (180, 120–300 seconds vs 360, 300–750 seconds, respectively; P < .001). Propofol infants regained spontaneous voluntary movements (ie, recovery) almost twice as fast as MASux (780, 360–1110 vs 1425, 645–2250 seconds, respectively; P = .002).
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Details Regarding the Intubation Process
The majority of initial intubation attempts (84%) were performed by registrars who had previously had
2 successful intubation attempts (Table 1). Slightly more MASux infants (17 [57%] vs propofol: 13 [39%]; P = .263) required multiple attempts to achieve successful intubation (median, interquartile range; 2, 1–3 vs 1, 1–2, respectively; P = .082) and, thus, had to be deferred to senior doctors to complete the intubation process (13 [43%] vs 10 [30%]; P = .421).
Vital Signs
Heart rates (Fig 2) and oxygen saturations (Fig 3) decreased in both groups during the intubation process, whereas mean arterial pressures (Fig 4) increased in both groups. Differences in heart rates and mean arterial pressures were not significantly different, but oxygen saturations were significantly lower during intubation in the MASux group (Fig 3). Median (interquartile range) intraprocedural oxygen saturations were 60% (43%–82%) in the MASux group and 80% (67%–88%) in the propofol group (P = .019). Median oxygen saturations at recovery were also significantly higher in the propofol group (median, interquartile: 95%, 92%–98% vs 92%, 90%–96%; P = .008).
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Adverse Events Related to the Induction Agents
Seven infants on MASux (23%) and 2 infants on propofol (6%) sustained intubation-related trauma (P = .117). Serum lactate was analyzed before and after intubation as part of arterial blood gas measurements in 15 infants on MASux and 18 infants on propofol. Only 1 infant on MASux had an increase in lactate levels >2.2 mmol/L. None of the infants became apneic after propofol induction, but 1 infant developed masseter spasm after suxamethonium administration. This complication was self-limiting, and intubation proceeded uneventfully after a period of manual insufflation. No other adverse effects were seen. No infant developed severe (grades 3 or 4) intraventricular hemorrhage after any of the intubation attempts.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Our study has shown that propofol, a hypnotic agent, is overall superior to MASux for the facilitation of elective neonatal endotracheal intubation. Propofol was also found to be more convenient and significantly faster to prepare than the combination of MASux, because it does not need dilution and is a single agent that is injected directly into the patient from a warmed ampoule. The speed of preparation of any induction agent is particularly important during emergencies. More importantly, intraprocedural oxygenation was maintained better in the propofol group, because spontaneous infant breathing was maintained. These favorable conditions facilitated the ease of the procedure so that that intubation was achieved faster with less trauma.
Suxamethonium, a nondepolarizing neuromuscular blocker, is a commonly used paralytic for neonatal intubation induction because of its speed and short duration of action.15 It may have potential significant adverse effects, including vagotonia (and, therefore, bradycardia), masseter spasm, rarely acute hyperkalemia, and malignant hyperthermia in genetically susceptible subjects, as well as increased systemic and intraocular pressures, prolonged muscle paralysis, 9,10 and postadministration tetany.16 The dose of suxamethonium recommended for neonatal rapid sequence intubation is 2 to 3 mg/kg, a higher dose than that commonly used for adults probably because the neonate has a disproportionately larger volume of distribution and neuromuscular junction immaturity.17,18 Conversely, high doses of suxamethonium may result in muscle rigidity, and lower doses, such as 0.6 mg/kg, have been suggested to circumvent this problem.17 However, a number of infants (7 of 30 infants [23%]) required repeated doses to achieve muscle relaxation in our study, and lower doses of suxamethonium may not be as effective in the neonatal population. Masseter spasm, as witnessed in 1 patient in the MASux group, was not an issue in the propofol group.
Regardless of the type of induction agent used, the maximum benefits and attenuation of the adverse physiologic responses of intubation would only be achieved if the infant is adequately muscle relaxed before the procedure.18 Some agents that have been explored for this purpose include thiopental,19 suxamethonium,6,20 pancuronium,2 and mivacurium,20 all of which have proved to be superior to awake intubation. However, each of these agents, as a consequence of their mode of action, causes apnea, which may then result in profound hypoxemia if the operator is unable to promptly secure an airway in the infant.
Nevertheless, many NICUs continue to practice awake or conscious intubation for a variety of reasons. First, there is no firm consensus as to which combination of premedication is best, and many NICUs are located in teaching hospitals where inexperienced operators may not be able to promptly procure a patent airway. Analgesia or sedatives such as morphine or benzodiazepines15 have been used alone to facilitate intubation without muscle relaxation. However, even morphine has been shown to be relatively ineffective in ameliorating the pain response generated by supposedly innocuous procedures, such as heel pricks, in preterm infants.12 A struggling infant may then p aradoxically make the intubation procedure more difficult for the inexperienced operator. As illustrated in our setting, a teaching hospital, where the majority of intubators are relatively inexperienced, optimal intubation conditions may increase the success rate of first-time intubations, and, indeed, there was less need for assistance from senior doctors in the propofol group.
We found that propofol induced satisfactory hypnosis in less than a minute and that spontaneous respiration was maintained throughout the intubation procedure at the chosen intravenous dose of 2.5 mg/kg. The continuation of spontaneous respiration may have allowed the infants in the propofol group to maintain intraprocedural oxygenation better than the suxamethonium group. There was no precedent for this particular dosage in the newborn (and especially low birth weight) infant, and this dose was chosen because it was the lowest limit of the range recommended for adult and pediatric patients.9 The treatment failures with this dose was comparable to the MASux group. We also found that a single dose of propofol was adequate to complete the majority of intubation attempts without adverse effects that have been noted in adults, such as hypotension, vagotonia, or apnea.9 In addition, none of the infants suffered intraventricular hemorrhage. Lactic acidosis, an adverse effect of prolonged infusions in older patients, was not noted, but we would strongly caution against using propofol as an infusion in newborn infants until further evidence is available, because severe complications, such as zinc deficiency, metabolic acidosis, rhabdomyolysis, hyperkalemia, renal failure, and death have been reported in adult patients administered with propofol infusions >5 mg/kg per hour for >58 hours.21
Unfortunately, neither of these regimes may be administered without intravenous access. Propofol, in particular, may cause severe pain if it extravasates into tissues.9 There is, therefore, a need to explore agents that may be administered by nonintravenous routes in case patent venous access cannot be obtained. For example, ketamine can be administered intramuscularly,9 and nitrous oxide can be inhaled22 (although the latter requires special dispensing equipment).
Therefore, until evidence for nonintravenous induction agents is available, we strongly condone the use of intravenous premedications for this purpose, because the noxious effects of conscious intubation are well documented and undisputed. Although adults and older children who require this procedure are often anesthetized or sedated, similar practice is not routine in the newborn population, and, indeed, in a 10-day prospective survey of 75 neonatal and PICUs in France, Simon et al23 found that only 37.1% of neonates (as opposed to 67.3% of infants and 91.7% of children) received premedication before intubation, and premedication was particularly infrequently used for the youngest and smallest infants, who are theoretically at greatest risk of developing adverse physiologic sequelae, such as intraventricular hemorrhage.
This may be because of a misconception that newborn infants are less susceptible to pain when compared with older infants or adults, but substantial evidence shows that even fetuses respond adversely to noxious stimuli by 20 weeks' gestational age,24,25 that thalamocortical connections responsible for pain perception are present from 26 weeks' gestation,24 and that repeated noxious stimuli may cause longer-term behavioral changes.26 Another reason may be because the operator, with adequate assistance, can easily overcome the struggling efforts of small newborn infants during a noxious procedure. A further reason may be, as discussed previously, a natural trepidation to use muscle relaxation in case a patent airway is unable to be obtained.
Our study is, therefore, the first to compare a hypnotic to a combination of analgesics and muscle relaxants for newborn semielective endotracheal intubation, and we have found that propofol is superior to the MASux as an induction agent to facilitate the procedure. Propofol also offered additional advantages, such as maintenance of spontaneous respiration, less profound hypoxemia, and less procedure-related trauma compared with MASux. Faster recovery could also be an advantage in a compromised infant or in a case of difficult intubation. We, therefore, recommend further large-scale studies with adequate sample size to assess the short- and long-term safety of propofol, especially for more urgent neonatal endotracheal intubations.
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FOOTNOTES |
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Accepted Nov 28, 2006.
Address correspondence to Kei Lui, MBBS, FRACP, MD, Department of Newborn Care, Royal Hospital for Women, Barker Street, Randwick, New South Wales 2031, Australia. E-mail: kei.lui{at}sesiahs.health.nsw.gov.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
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 K. Allegaert, M. Y. Peeters, R. Verbesselt, D. Tibboel, G. Naulaers, J. N. de Hoon, and C. A. Knibbe Inter-individual variability in propofol pharmacokinetics in preterm and term neonates Br. J. Anaesth., December 1, 2007; 99(6): 864 - 870. [Abstract] [Full Text] [PDF]
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eLetters:
Read all eLetters
- Further studies needed to establish safety profile
- Santanu Sen
- Pediatrics Online, 17 Jun 2007 [Full text]
- propofol disposition in neonates: interindividual variability is to be anticipated
- karel allegaert
- Pediatrics Online, 5 Jul 2007 [Full text]
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