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Three Part Question

In [neonates] should [premedication be used for semi-urgent intubation] to [decrease the level of distress and optimise the procedure]?

Clinical Scenario

A neonate on the intensive care unit requires semi-urgent intubation. As the procedure is being carried out one of the medical students notices that the neonate is struggling, prolonging the procedure and appeared to be in distress. The medical student asks why no medication was given before the neonate was intubated as this was seen when the procedure was carried out in adults and children.

Search Strategy

Medline 1966 to present
Embase 1980 to 2005 week 27
Cinahl 1982 to June week 4 2005
Using the ovid interface.
[{exp Infant, newborn or neonat$.mp.} AND {exp premdication or premed$.mp. or exp analgesia or analges$.mp. or exp hypnotics and sedatives or sedat$.mp. or exp anesthesia or anaesth$.mp. or exp. Muscle relaxants, central or muscle relax$ or exp fentanyl or fentanyl.mp. or exp morphine or morphine.mp. or exp thiopental or thiopental.mp. or exp atropine or atropine.mp. or exp succinylcholine or succinylcholine.mp. or exp pancuronium or pancuronium.mp. or exp halothane or halothane.mp. or exp alfentanil or alfentanil.mp. or suxamethonium.mp. or sevoflurane.mp.} AND {exp endotracheal intubation or endotracheal intubation.mp. or exp intubation or intubat$.mp.} Limit to English language and Newborn infant (birth to 1 month)]

Search Outcome

Medline search found 459 papers of which 12 were relevant and of a sufficient quality to be included in the paper.
Embase search found a further 1 paper.
Cinahl found no further papers.
2 further relevant papers were found by searching through the references from the papers found.
All three databases were searched again combining the above search strategy with [AND {exp pain or pain.mp.}] No further papers were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lemyre et al, 2004, Canada	34 infants randomly assigned to receive morphine 0.2mg/kg IV or placebo (0.9% Sodium Chloride), for elective intubation	Double blinded Randomised control trial. (Level 1b)	Duration of severe hypoxaemia	No significant difference.	Different levels of experience of people performing the intubations (help called). Variations in time of preoxygenation and hand ventilation. Morphine only used, with known variation in single dose morphine pharmacokinetics in neonates not measured.
			Duration of hypoxaemia	No significant difference.
			Duration of procedure	No significant difference.
			Max increase in mean blood pressure	No significant difference.
			Number of attempts	No significant difference.
			Number where intubation was achieved at first attempt	No significant difference.
			Number where intubation needed a rescue intubator	No significant difference.
			Bradycardia during procedure	No significant difference.
Oei et al, 2002, Australia	20 infants randomised to awake intubation or premedication with morphine 100µg/kg, atropine 10µg/kg and suxamethonium 1mg/kg.	Non-blinded randomised control trial. (Level 1b)	Heart rate	Significantly greater drop in awake infants. (68 ± 47 b.p.m vs 29 ± 39 b.p.m; p=0.017)	Lack of blinding. Small sample size. Groups not completely matched. Two infants had to be moved from the awake group to the premedicated group. In 8 of the intubation attempts the awake infants lowest heart rate and oxygen saturation could not be recorded.
			Oxygen saturation	No significant difference
			Total time taken to complete intubation	Significantly shorter in premedicated infants. (median 60.5 seconds vs 595 seconds; p= 0.016)
			Number of attempts at intubation	More than twice as many attempts in the awake group (p=0.01)
Bhutada et al, 2000, America	30 neonates weighing over 2kg at birth and requiring semi-elective or elective intubation. Randomised into thiopental 6mg/kg or the equivalent volume of physiological saline.	Randomised, placebo controlled trial. (Level 1b)	Heart rate	Significant changes. (mean (SE) -0.5 [4.4] vs 12.0 [3.2] bpm; p< 0.03)	Lack of blinding. Small sample size.
			Heart rate variability	Significantly less variable in study group. (mean (SE) -2.0 [2] vs 19 [5] msec; p, 0.01)
			Transcutaneous oxygen saturation	No significant changes
			Mean blood pressure	Lesser change in mean blood pressure in thiopental group. (mean (SE) -2.9 [1.8] vs 4.4 [1.1] mmHg; p< 0.002)
			Time taken to intubate	Significantly shorter in the thiopental group. (mean (SE) 2.70 [0.37] vs 5.08 [1.10] min; p<0.04)
Cook-Sather et al, 1998, America	76 infants semi-urgently or electively intubated. Three groups identified; one awake, one given a rapid sequence induction with thiopental (5-7 mg/kg) and muscle relaxant succinylcholine (2mg/kg) and one group given a modified rapid sequence induction with thiopental and a muscle relaxant of either succinylcholine, vecuronium (0.1-0.2 mg/kg), rocuronium (0.6-1.0 mg/kg) or atracurium (0.4-0.5 mg/kg)	Prospective, non-randomised, control trial (level 1b)	Number of attempts at intubation	Significantly more attempts in awake group. (8 for awake vs 2 for rapid induction vs 5 for modified induction where multiple attempts needed; p=0.028)	5 infants in the awake group had to be converted to the modified induction group.
			Time taken to complete intubation	Significantly longer in awake group. (median 63 sec for awake vs 30 sec for rapid induction vs 36 sec for modified induction; p=0.004)
			Heart rate	No significant difference
			Oxygen saturation	No significant difference
			Complications	No significant difference
Millar and Bissonette 1994 Canada	14 patients aged 1 to 42 days. Randomised into either awake intubation or thiopentone 5mg/kg and succinylcholine 2 mg/kg.	Randomised control study. (Level 1b)	Heart rate	Significantly elevated heart rate in awake group (+33 bpm; p< 0.05)	Lack of blinding. Small sample size. Patient age range up to 42 days in the article whereas up to 34 days in the abstract. Data from one patient was not included as it was incomplete. Randomization method is not described.
			Systolic arterial blood pressure	No significant differences between the groups.
			Anterior fontanelle pressure	Significantly higher at time of intubation in awake group.(12 mmHg vs 3 mmHg p<0.05)
			Oxygen saturation	No significant differences.
			Cerebral blood flow velocity	No significant differences
			Systolic peak flow velocity	No significant differences
			Mean flow velocity	No significant differences
			Diastolic peak flow velocity	No significant differences
			Cerebrovascular resistance	No significant differences
Pokela and Koivisto, 1994, Finland	20 newborn infants requiring elective tracheal intubation. Randomised to receive pethidine 1mg/kg or alfentanil 20µg/kg plus suxamethonium 1.5mg/kg iv over 1 min. All neonates given glycopyrolate 3-5mg/kg 5 minutes before the procedure	Randomised controlled trial. (Level 1b)	Hypoxemia	Hypoxaemia evident in all neonates in the pethidine group and 7 out of 10 patients in the alfentanil group	Lack of blinding. No method of randomisation documented. Small sample size. No quantification of ease of intubation or trauma to neonate.
			Duration of hypoxemia	Significantly longer in the pethidine group. (4 min vs 1.5mins; p=0.036)
			Time taken to intubate	Significantly longer in the pethidine group (120 seconds vs 60 seconds; p=0.012)
			Success at first attempt	3 /10 intubations successful at first attempt in the pethidine group and 7/10 successful at first attempt in the alfentanil group
			Change in mean arterial pressure	No significant difference
			Change in heart rate	No significant difference
			Change in plasma Beta-endorphin and serum cortisol	No significant difference
			Apnoea	Evident in 3 patients in pethidine group
			Ease of intubation and trauma	Easier and less traumatic in alfentanil group.
Khammash et al, 1993, Canada	28 infants randomised to receive either atropine (0.02mg/kg), atropine and succinylcholine (2 mg/kg), atropine and fentanyl (5 µg/kg) or atropine, succinylcholine and fentanyl before non urgent nasotracheal intubation.	Randomised control trial (Level 1b)	Intubation time	Significantly reduced with succinylcholine and/or fentanyl versus atropine alone. (22±7, 25±10, 27±7 vs 50±22 seconds; p< 0.05)	Small sample size
			Mean arterial pressure	Increased by >20% after intubation in atropine and atropine/ succinylcholine groups (p<0.05)
			Complications	Chest wall rigidity was found in 3 of the infants in the atropine and fentanyl alone group
Charlton and Greenhough, 1988, UK	45 neonates needing semi-urgent or elective intubation for surgery. Patients were randomised into awake intubation group, after N2O and halothane inhalation group, or after thiopentone and muscle relaxant (atracurium or pancuronium) group.	Randomised control study. (level 1b)	Blood pressure and Heart rate	No significant changes in outcome between awake or anaesthetised groups.	Lack of blinding. Not randomised or matched for atropine administration. Small sample size. No preterm neonates. Method of randomization is not detailed. Data from 2 neonates in the thiopentone group were not included for diastolic pressure. Heart rate data from 1 infant and 3 of the neonates in the thiopentone group were not included.
Stow et al, 1988, Canada	24 infants (less than 8 weeks post-natal age) electively intubated either awake or premedicated with sodium thiopentone 5 mg/kg and suxamethonium 2 mg/kg. Both groups were given atropine 0.02 mg/kg IV.	Control trial. (Level 1b)	Anterior fontanelle pressure (AFP)	Lesser increase in the premedicated than the awake groups. (30 mmHg vs 15 mmHg; p<0.05)	Lack of blinding could introduce bias. Small sample size. No randomisation was discussed or described. Groups not matched for post-conceptual age or weight. Infants
			Heart rate	No significant changes
			Systolic arterial pressure	Decreased significantly in the premedicated infants during anaesthesia. (from 92.5 mm Hg to 77.8 mmHg; p< 0.05)
Friesen et al, 1987, America	12 preterm neonates randomised into: Group 1 (received atropine 0.02 mg/kg IV or Group 2 (received atropine 0.02mg/kg IV, 0.1mg/kg IV pancuronium and 1 of 4 anaesthetics: 0.75% isoflurane (3 pats), 0.5% halothane (1 pat) 20µg/kg fentanyl (1 pat) and 2mg/kg ketamine (1 pat)	Randomised control trial. (Level 1b)	Anterior Fontanelle Pressure (AFP)	Increased significantly in group 1 (from 7.7 to 23.8 cm H2O; p< 0.05), it did not change significantly in group 2. The changes in AFP were significantly different between group 1 and group 2 (+197% change vs +25% change; p<0.05).	Small sample size. Lack of blinding.
			Mean blood pressure	Significant increase in systolic blood pressure (average of 20%) in group 1(p< 0.05). Blood pressure did not change significantly in group 2.
Kelly et al, 1984, Canada	30 neonates requiring semi-urgent or elective intubation, 10 with either no drugs (control), atropine 0.01mg/kg IV or atropine 0.01 mg/kg IV pancuronium 0.1mg/kg IV.	Non-blinded prospective randomised control trial. (Level 1b)	Heart rate	Decrease was significantly greater for control and atropine groups than pancuronium group 52.2 bpm and 36.2 vs 7.3; p<0.01)	Lack of blinding. Small sample size.
			Transcutaneous oxygen saturation	No difference between the groups.
			Blood pressure	No reported difference between the groups.
			Intracranial pressure	Significant increase in all groups. Increase was significantly less in the atropine plus pancuronium group than in the other two groups.(11.6 cm vs 19.8 cm in control group vs 24.8 cm in atropine group; p<0.05)
Raju et al, 1980, America	Two groups of neonates and infants, one group (n=4) intubated awake second group (n=5) given halothane, N2O2 and D-tubocurare muscle relaxant then intubated.	Control study. (Level 1b)	Intracranial pressure	Significant increase from the baseline in both groups after intubation. (increase of 70.65±8.2 cm H2 O; p<0.001 for awake and 19.45±5.1 cm H2O; p<0.05 for D-tubocurare) Significantly higher in infants intubated awake than those who received D-tubocurare (p< 0.001).	Small number of infants studied. Lack of blinding. Infants not matched for postnatal age or preoperative intracranial pressure. Randomization is not mentioned. Not all neonates (7 days to 10 months). The numbers of patients included in the study vary throughout the article.
Barrington et al, 1989, Canada	20 preterm neonates undergoing semi-elective intubation were randomised to awake and non-paralysed group or awake and paralysed with succinylcholine (2mg/kg) group. Both received atropine (20µg/kg).	Randomised control trial. (Level 1b)	Heart rate	No significant changes	Lack of blinding. Randomisation did not produce well matched groups with respect to the number of infants undergoing a tube change compared to the number undergoing initial intubation so an additional 5 nonrandomised infants undergoing awake intubation were included. Postnatal ages of succinylcholine group were significantly greater.
			Transcutaneous oxygen tension	Significant fall in both groups during intubation. Higher for the awake and paralysed group than for the awake and non-paralysed group (86 ± 46 torr vs 55 ± 23 torr p< 0.05)
			Blood Pressure	Raised in both groups. No significant difference during intubation between the groups.
			Intracranial pressure	Significantly greater rise in awake and non paralysed group than the awake and paralysed group.(41.4 ± 23.3 H2O vs 36.8 ± 11.6 cm H2O; p< 0.05)
			Cerebral perfusion pressure	Increased significantly in awake and paralysed group (mean 39.4 mmHg to 54.2 mmHg) versus the awake and non paralysed group.
Naulaers, 1997, Belgium	18 infants (gestational age 32-42 weeks postnatal age 1-150 days) weighing 1390-5000g all received methohexital 2.6mg/kg IV	Cohort study. (Level 2b)	Sedation	All patients adequately sedated within 2 minutes. 11/18 still sedated at 3 minutes and 4/18 at 5 minutes. All patients moving spontaneously by 10 minutes	Small sample size. No control group used. Infants not matched for gestational age, postnatal age or weight. One patient received three doses of the drug, all others received one. Some of the data collected relies on opinion which may vary. Results were not assessed for significance.
			Relaxation	All patients adequately relaxed within 2 minutes. 12/18 still hypotonic at 3 minutes. 1 patient became hypertonic at 5 minutes, this lasted for 1 minute.
			Sleep	12/18 patients were in a deep sleep after 3 minutes, 5/18 patients still asleep after 5 minutes. By 12 minutes all patients were awake.
Barrington and Byrne, 1998, Canada	269 consecutive nasotracheal intubations carried out on infants aged from 30 minutes – 192 days. Premedication was given (atropine 20µg/kg, fentanyl 3-4 µg/kg and succinylcholine 2 mg/kg) if an IV was in place and if intubation was not an absolute emergency.	Cohort study (Level 2b)	Premedication Used	Of the 269 intubations performed premedication was used in 253 cases and not used in 16 cases.	No control group
			Success rate	253 premedicated intubations, 194 without incident, 28 required 2 attempts and 9 required a second attempt with smaller tube.
			Incidence of complications and adverse events	4 infants developed chest wall rigidity, resolved with succinylcholine in 3 cases.

Comment(s)

Intubation is a potentially painful and distressing procedure. It is suggested that such physiological distress may increase neonatal morbidity. Premedication for intubation with potent opiates or anaesthetic agents and muscle relaxants is the routine for children and infants. Premedication is not common practice for the intubation of neonates, Whyte et al in 1998 revealed that only 14% of the United Kingdom's neonatal units had a written policy for premedication for semi-urgent or elective intubation. Only 37% of the neonatal units surveyed routinely used sedation prior to intubation, and those that did used drug doses that varied by factors up to 200 (Bhat). Premedication is more commonly used for term rather than preterm neonates.(Bhat, Whyte). Recent research and debate has focused upon whether premedication of the neonate for a routine semi-urgent intubation, (that is when intravenous access is available and difficult intubation is not expected) may be a more humane, safer and a more effective method than awake intubation. From the available evidence it is clear that awake intubation is associated with a significantly higher intracranial pressure (Millar, Barrington 1989, Stow, Friesen, Kelly, Raju), higher blood pressure (Bhutada, Khammash, Friesen) and more variable heart rate (Oei, Bhutada, Khammash, Kelly) than premedicated intubation. In addition the increased time taken to intubate (Oei, Bhutada, Cook-Sather, Pokela, Khammash) and the greater number of attempts associated with awake intubation (Oei, Cook-Sather, Pokela) may compound these factors and lead to increased morbidity. Thiopentone studies show significantly lower intracranial pressure, significantly more stable heart rate, lower blood pressure, fewer attempts to intubate are needed and the time taken to intubate is shorter in neonates premedicated with thiopentone than in control neonates (Bhutada, Cook-Sather, Millar, Stow). Opiate studies show a significantly lower blood pressure and shorter duration of hypoxia during intubation and shorter length of time taken to intubate with a potent opiate than in control neonates (Pokela, Khammash). They also show that morphine and pethidine are not the drugs of choice (Lemyre, Pokela). This is likely to be due to their variable pharmokinetics and pharmodynamics in neonates (Bhat). Muscle relaxant studies show a significantly lower intracranial pressure, improved cerebral perfusion pressure, less heart rate variability and a shorter time needed to intubate in neonates premedicated with a muscle relaxant than in control neonates (Khammash, Barrington 1989, Kelly, Raju). Chest wall rigidity was reported in three of seven neonates given fentanyl without a muscle relaxant in one randomised controlled trial (Khammash) and four neonates in one cohort study (Barrington). No studies reported this adverse event when an opiate was used with a muscle relaxant. Current best evidence suggests that for routine semi-urgent intubation of neonates, the use of premedication is a more effective technique, and less distressing to the neonate, with less potentially harmful physiological fluctuations, than traditional awake intubation.

Clinical Bottom Line

Current evidence suggests that for routine semi-urgent intubation, premedication as opposed to awake intubation: Produces more optimal intubation conditions (fewer attempts and shorter times) Produces less potentially harmful physiological fluctuations and pain A potent opiate (fentanyl or alfentanil) or thiopentone with a muscle relaxant is the intubating drug combination of choice. More clinical trials are required to determine the optimal premedication strategy.

References

1. Lemyre B, Doucette J, Kalyn A et al. Morphine for elective endotracheal intubation in neonates: A randomized trial. BMC Pediatrics. 2004; 4: 6p.
2. Oei J, Hari R, Butha T, Lui K. Facilitation of neonatal nasotracheal intubation with premedication: A randomized controlled trial. Journal of Paediatrics & Child Health. 2002; 38(2): 146-50.
3. Bhutada A, Sahni R, Rastogi S et al. Randomised controlled trial of thiopental for intubation in neonates. Archives of Disease in Childfood Fetal & Neonatal Edition. 2000; 82(1): F34-7.
4. Cook-Sather SD, Tulloch HV, Cnaan A et al. A comparison of awake versus paralyzed tracheal intubation for infants with pyloric stenosis. Anesthesia & Analgesia. 1998; 86(5): 945-51.
5. Millar C, Bissonnette B. Awake intubation increases intracranial pressure without affecting cerebral blood flow velocity in infants. Canadian Journal of Anaesthesia. 1994; 41(4): 281-7.
6. Pokela ML, Koivisto M. Physiological changes, plasma beta-endorphin and cortisol responses to tracheal intubation in neonates. Acta Paediatrica. 1994; 83(2): 151-6.
7. Khammash HM, O'Brein K, Dunn MS, et al. Blunting of hypertensive response to endotracheal intubtion in neonates by premedication. Pediatr Res. 1993; 33(4): 218A.
8. Charlton AJ, Greenhough SG. Blood pressure response of neonates to tracheal intubation. Anesthesia & Analgesia. 1987; 66(9): 874-8.
9. Stow PJ, Mcleod ME, Burrows FA, et al. Anterior fontanelle pressure responses to tracheal intubation in the awake and anaesthetized infant. British Journal of Anaesthesia. 1988; 60: 167-170.
10. Friesen RH, Honda AT, Thieme RE. Changes in anterior fontanel pressure in preterm neonates during tracheal intubation. Anaesthesia & Analgesia. 1987; 66(9): 874-8.
11. Kelly M, Funer N. Nasotracheal intubation in the neonate: Physiological responses and the effects of atropine and pancuronium. Journal of Pediatrics. 1984; 105(2): 303-9.
12. Raju TN, Vidyasagar D, Torres C et al. Intracranial pressure during intubation and anaesthesia in infants. Journal of Pediatrics. 1980; 96(5): 860-2.
13. Barrington KJ, Finer NN. Etches PC. Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial. Critical Care Medicine. 1989; 17(12): 1293-6 .
14. Naulaers G, Deloof E, Vanhole C et al. Use of methohexital for elective intubation in neonates. Archives of Disease in Childhood Fetal & Neonatal Edition. 1997; 77(1): F61-4 .
15. Bhat R, Chari G, Gulati A et al. Pharmokinetics of a single dose of morphine in preterm infants during the first week of life. Journal of Pediatrics. 1990; 117: 477-81.
16. Barrington KJ, Byrne PJ. Premedication for neonatal intubation. American Journal of Perinatology. 1998; 15(4); 213-6.
17. Hancock S, Newell S, Briefley J, Berry A. Premedication for neonatal intubation: Current practice in Australia and the United Kingdom. Archives of Disease in Childhood Fetal & Neonatal Edition. 2000; 83(1):F77.
18. Whyte S, Birrell G, Wyllie J, Woolf A. Premedication before intubation in UK neonatal units. Archives of Disease in Childhood Fetal & Neonatal Edition. 2000; 82(1): F38-F41.