Should premedication be used for semi‐urgent or elective intubation in neonates?

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

Structured clinical question

In neonates undergoing semi‐urgent intubation [patients] should premedication [intervention] be used to facilitate easier intubation with less physiological stress [outcome]?

Search strategy and outcome

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$.mp.} AND {exp premedication or premed$.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).

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 one paper.

Cinahl found no further papers.

Two 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.

See table 4.

Table 4 Premedication for semi‐urgent intubation.

Citation, country	Study group	Study type (level of evidence)	Outcome	Key results	Study weaknesses
Lemyre et al (2004), Canada1	34 infants randomly assigned to receive morphine 0.2 mg/kg IV or placebo (0.9% sodium chloride), for elective intubation	Double blind 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
			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), Australia2	20 infants randomised to awake intubation or premedication with morphine 100 μg/kg, atropine 10 μg/kg and suxamethonium 1 mg/kg	Non‐blinded randomised control trial (level 1b)	Heart rate	Significantly greater drop in awake infants. (68±47 bpm v 29±39 bpm; 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 v 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), America3	30 neonates weighing over 2 kg at birth and requiring semi‐elective or elective intubation. Randomised into thiopental 6 mg/kg or the equivalent volume of physiological saline	Randomised, placebo controlled trial (level 1b)	Heart rate	Significant changes (mean (SE) −0.5 [4.4] v 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 v 19 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] v 4.4 [1.1] mmHg; p<0.002)
			Time taken to intubate	Significantly shorter in the thiopental group (mean (SE) 2.70 [0.37] v 5.08 [1.10] min; p<0.04)
Cook‐Sather et al (1998), America4	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 (2 mg/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 v 2 for rapid induction v 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 s for awake v 30 s for rapid induction v 36 s for modified induction; p = 0.004)
			Heart rate	No significant difference
			Oxygen saturation	No significant difference
			Complications	No significant difference
Millar and Bissonette (1994), Canada5	14 patients aged 1 to 42 days. Randomised into either awake intubation or thiopentone 5 mg/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. Randomisation method is not described
			Systolic arterial blood pressure	No significant differences between the groups
			Anterior fontanelle pressure	Significantly higher in awake group.(12 mmHg v 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), Finland6	20 newborn infants requiring elective tracheal intubation. Randomised to receive pethidine 1 mg/kg or alfentanil 20 μg/kg plus suxamethonium 1.5 mg/kg iv over 1 min. All neonates given glycopyrrolate 3–5 mg/kg 5 minutes before the procedure	Randomised controlled trial (level 1b)	Hypoxaemia	Hypoxaemia evident in all neonates in the pethidine group and 7 of 10 patients in the alfentanil group	Lack of blinding. No method of randomisation documented. Small sample size. No quantification of ease of intubation
			Duration of hypoxaemia	Significantly longer in the pethidine group (4 min v 1.5 min; p = 0.036)
			Time taken to intubate	Significantly longer in the pethidine group (120 seconds v 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 β‐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), Canada7	28 infants randomised to receive atropine (0.02 mg/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 v 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
Barrington et al (1989), Canada8	20 preterm neonates undergoing semi‐elective intubation were randomised to awake and non‐paralysed group or awake and paralysed with succinylcholine (2 mg/kg) group. Both received atropine (20 µg/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 non‐randomised 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 v 55±23 torr p<0.05)
			Blood pressure	Elevated 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 v 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
Charlton and Greenhough (1988), UK9	45 neonates needing semi‐urgent or elective intubation for surgery. Patients were randomised into awake intubation group, N2O and halothane inhalation group, or 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. Randomisation not detailed.
Stow et al (1988), Canada10	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 v 15 mmHg; p<0.05)	Lack of blinding. Small sample size. Randomisation was not described. Groups not matched for post‐conceptual age or weight
			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), America11	12 preterm neonates randomised into Group 1 (received atropine 0.02 mg/kg IV or Group 2 (received atropine 0.02 mg/kg IV, pancuronium 0.1 mg/kg IV, and 1 of 4 anaesthetics: 0.75% isoflurane, 0.5% halothane, 20 µg/kg fentanyl, or 2 mg/kg ketamine	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 v +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), Canada12	30 neonates requiring semi‐urgent or elective intubation, 10 with either no drugs (control), atropine 0.01 mg/kg IV, or atropine 0.01 mg/kg IV and pancuronium 0.1 mg/kg IV	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 v 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 v 19.8 cm in control group v 24.8 cm in atropine group; p<0.05)
Raju et al (1980), America13	Two groups of neonates and infants, one group (n = 4) intubated awake second group (n = 5) given halothane, nitrous oxide, 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 H2O; 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. Randomisation method not described. Not all neonates (7 days to 10 months)
Barrington and Byrne (1998), Canada14	269 consecutive nasotracheal intubations carried out on infants aged from 30 minutes–192 days. Premedication was given (atropine 20 µg/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. Large age range
			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, self limiting in the other
Naulaers (1997), Belgium15	18 infants (gestational age 32–42 weeks postnatal age 1–150 days) weighing 1390–5000 g all received methohexital 2.6 mg/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. 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

Commentary

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 UK'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 200.¹⁶ Premedication is more commonly used for term rather than preterm neonates.^16–18

Recent research and debate has focused on 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 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,^{5 8 10–13} higher blood pressure,^{3 7 11} and more variable heart rate^{2 3 5 12} than premedicated intubation. In addition, the increased time taken to intubate^{2–4 6 7} and the greater number of attempts associated with awake intubation^{2 4 6} may compound these factors and lead to increased morbidity. Studies using thiopentone show significantly lower intracranial pressure, significantly more stable heart rate, and 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.^{3–5 10} Studies using opiates 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.^{6 7} They also show that morphine and pethidine are not the drugs of choice.^{1 6} This is likely to be due to their variable pharmacokinetics and pharmacodynamics in neonates.¹⁶ 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.^{7 8 12 13} Chest wall rigidity was reported in three of seven neonates given fentanyl without a muscle relaxant in one randomised controlled trial,⁷ and in four neonates in one cohort study, resolving with suxamethonium in three cases and self limiting in the other.¹⁴ No other studies reported this adverse event when an opiate is used with a muscle relaxant.

Current evidence suggests that for routine semi‐urgent intubation of neonates, the use of premedication is a more effective technique, with less potentially harmful physiological fluctuations, than traditional awake intubation.

CLINICAL BOTTOM LINE

• Routine premedication for semi‐urgent or elective intubation in neonates produces more optimal intubation conditions (fewer attempts and shorter times) and less potentially harmful physiological fluctuations and pain. (Grade B)

• A potent opiate (fentanyl or alfentanil) or thiopentone with a muscle relaxant is the intubating drug combination of choice. (Grade B)

• More clinical trials are required to determine the optimal premedication strategy.