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Archives of in Childhood 1997;77:F61–F64 F61 Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.77.1.F61 on 1 July 1997. Downloaded from Use of for elective intubation in neonates

G Naulaers, E Deloof, C Vanhole, E Kola, H Devlieger

Abstract to initiate because of The eVectiveness and safety of a short act- respiratory insuYciency or postoperative venti- ing , methohexital, was as- lation, or to prevent an impending blockage of sessed for its use at the time of elective the endotracheal tube. Infants below a intubation in 18 newborn infants with gestational age of 32 weeks were excluded. The severe respiratory or cardiac conditions. 18 infants had a mean gestational age of 36.3 Evaluation included the speed of action weeks (32–42 weeks), a mean postnatal age of and the degree of relaxation, , and 23 days (1–150 days), and a mean weight of sleep in the first five minutes after admin- 2588 g (1390–5000g) at the time of study. istration. All newborn infants were intu- All patients had cardiac and/or respiratory bated in a fully relaxed and somnolent problems. Six patients had cyanotic congenital state. In most infants recovery was com- heart disease. Three patients had respiratory pleted within five minutes. distress syndrome (RDS) with pulmonary A slight to moderate saturation , four patients had bronchopul- drop was observed during the period of monary dysplasia (BPD), one patient had a intubation, especially in patients with diaphragmatic , one patient a oesopha- cyanotic heart disease. The side eVects of geal atresia and one a cystic adenomatoid lung the drug were twitching and a slight drop malformation. in . All intubations were done in the neonatal In conclusion, methohexital seems to be intensive care unit. All patients had intravenous a useful drug for short term anaesthesia in and arterial lines. No other anaesthetic or neonates, during which, short procedures drugs were given during the 24 hours like elective intubation can be safely preceding the intubation. Except for one performed. patient who received multiple doses (three ( 1997;77:F61–F64) Arch Dis Child times) of methohexital, all the other patients received the drug only once. Keywords: methohexital; intubation; anaesthesia Methohexital was given in a dose of 2.6 mg/kg according to the study of Westrin.6 The solution was prepared by mixing 500 mg Intubation of a newborn infant is a diYcult

methohexital sodium with 50 ml physiological http://fn.bmj.com/ procedure, probably uncomfortable for the saline (10 mg/ml). Of this solution, 0.26 ml/kg patient, and is often accompanied by transient was given intravenously. When no central , acidosis, and . In some venous line was available, this solution was dis- units or even intravenous anaesthetics solved in 1 ml of intralipid to diminish are administered to facilitate the procedure. irritation and during , according Others have suggested the administration of 6 atropine to diminish reflex bradycardia. Seda- to the method proposed by Westrin. The drug tion and analgesia with , , was administered as an intravenous bolus and on September 28, 2021 by guest. Protected copyright. and have been described,1 but they flushed with 1 ml of physiological saline. Signs all have the disadvantage of prolonged action of distress and/or pain during injection were and have important side eVects. Three impor- noted. tant alternatives are intravenous anaesthetic Before the injection of methohexital, oxygen drugs like thiopental, methohexital, and propo- was administered to the patient. After metho- fol. Thiopental leads to a slower recovery than hexital had been given the patient was methohexital.2 also has a longer ventilated by face mask. The intubation pro- action and more side eVects than cedure was started as soon as the patient no Department of methohexital.3 Although methohexital was first longer reacted to heel rubbing or the act of Paediatrics, UZ described in 1960,4 its use in infants and inserting the nasotracheal tube. No atropine Gasthuisberg, Leuven, 256 was given to the patient before the intubation. Belgium children was only mentioned recently. To G Naulaers our knowledge, its use has never been reported Sedation, relaxation, and sleep were recorded E Deloof in (preterm) newborn infants. Here, we report by one investigator who was not involved in the C Vanhole procedure. Observations were carried out every E Kola on the eVect of methohexital in terms of seda- H Devlieger tion, relaxation, sleep and cardiovascular minute, for the first five minutes. The degree of eVects in 18 newborn infants who needed an sedation was assessed mainly as the motor Correspondence to: response to external stimuli. As a stimulus H Devlieger, Department of elective intubation. Paediatrics, UZ “heel-rubbing” (rubbing the heel with a swad- Gasthuisberg, Herestraat, Methods dle, as described by Grunau et al7 was used). B-300 Leuven, Belgium. We prospectively studied 18 consecutively seen Four degrees of reactions were defined: Accepted 4 March 1997 infants who needed elective intubation, either “Moves spontaneously,” “moves when F62 Naulaers, Deloof, Vanhole,Kola, Devlieger

Sedation lation. This was at a mean of 45 seconds, with 18 an interquartile range of 20 seconds at the 25th Moves quartile, and at 70 seconds at the 75th quartile. 16 spontaneously 14 The exact time of intubation was not noted, Moves when 12 touched but the infants were all intubated within two minutes. 10 Moves when 8 stimulus The influence on body movements, tone, 6 No reaction to and awake/sleep state is shown in fig 1. During 4 stimulus the first two minutes all patients were ad-

Number of patients 2 equately sedated. Sedation was still good in 11/18 patients after three minutes, while 4/18 0 04123 5 patients still did not show any reaction after five Minutes minutes. After 10 minutes all patients were Relaxation moving spontaneously. 18 Relaxation was good during the first two Hypertonic 16 minutes in all patients. After three minutes 14 Mild 12/18 patients were still hypotonic. One patient hypotonic 12 became hypertonic after five minutes, remain- Hypotonic 10 ing hypertonic for one minute. All patients had 8 Normal tonus normal tone after eight minutes. After three minutes 12/18 patients were deep asleep; 5/18 6 patients were still asleep after five minutes. All 4

Number of patients patients were awake after 12 minutes. 2 The influence of and blood 0 04123 5 pressure on is shown in fig 2. Minutes Heart rate was measured during the first 30 minutes. No serious short or long term eVects Sleep 18 on heart rate were noticed. No important Deep asleep 16 change in diastolic and systolic blood pressures 14 Easily woken occurred except for a transient drop in systolic blood pressure between one and three minutes. 12 Awake There were no significant drops in blood pres- 10 sure. 8 Oxygen saturation values varied consider- 6 ably between 0.5 and three minutes as a result 4 of the intubation procedure. Saturation drops Number of patients 2 of more than 10% were found in eight 0 04123 5 patients—namely, all patients with cardiac dis- Minutes ease and all those with pulmonary hyperten- sion. An important variance was also observed Figure 1 EVect of methohexital on sedation, relaxation, and sleep in neonates. between 10 and 15 minutes when the patient touched,” “moves when stimulated” and “no was reconnected to the ventilator. When we http://fn.bmj.com/ reaction to stimulus.” Relaxation was evaluated looked at the group of patients with cyanotic by clinical evaluation of the tone in arms and heart disease, there were very important drops legs. We used the categories “hypotonic,” in saturation. Five of the six patients had a fall “mildly hypotonic,” “normal tone” and in oxygen saturation drop below 85% for more “hypertonic.” Sleep was noted as “awake,” eas- than 30 seconds. In the group with pulmonary ily woken,” and “deep asleep.” Heart rate, disease (including the patients with pulmonary diastolic and systolic blood pressures, and oxy- hypertension) we saw a significant drop in oxy- on September 28, 2021 by guest. Protected copyright. gen saturation were measured using a Siemens gen saturation between 30 and 90 seconds as a Sirecust 3000 monitor and the values were result of the intubation procedure. Four of the recorded every 30 seconds for the first two 12 patients had a saturation below 85% for minutes, every minute up to five minutes, and more than 30 seconds. These were two patients every five minutes thereafter, for the next half with severe BPD and two patients with pul- hour. The median values and the 25th and monary hypertension. 75th interquartile ranges were calculated. A The most important side eVect seen was constant trend measurement was given by the muscle twitching in two patients. The muscle monitor and when there was an important fall twitching was similar to that seen after the in the blood pressure, this was noted. Observa- administration of midazolam. Muscle twitch- tions were made for hiccough, abnormal ing never lasted longer than one minute and behaviour, muscle twitching, convulsions and never re-occurred subsequently. Three patients other side eVects. developed hiccoughs. No significant broncho- spasms were encountered.

Results Discussion No redness, signs of pain, or any other Intubation is an invasive procedure with problems were noted during or after the injec- important eVects on the respiratory and tion, when administered peripherally. In all cardiovascular system. When the patient is not patients the intubation procedure was initiated sedated, severe problems such as broncho- when the infant no longer reacted to manipu- spasm, pulmonary hypertension, bradycardia F63

Use of methohexital for elective intubation in neonates Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.77.1.F61 on 1 July 1997. Downloaded from

and intubation trauma can occur. Therefore, In this report the usefulness of methohexital as for elective intubations, we give sedation and an adjuvant drug to facilitate intubation of pre- even anaesthesia. Most sedative or term and full term newborn infants has been drugs commonly used in neonatal care have a demonstrated. Good relaxation, sedation, and prolonged eVect. Fentanyl and sufentanyl are sleep during intubation, with a total recovery known to have variable half lives.8 Further- within 10 minutes, were found. Heart rate and more, these drugs have serious side eVects like blood pressure did not vary during the ensuing chest wall rigidity, respiratory depression, 30 minutes, despite the fact no atropine was delayed gastric emptying, decreased gastroin- given.4 This contrasts with other reports in testinal motility, and an increase of the older children and adults where common bile duct pressure.9–15 Morphine is was found after the injection of less frequently used than fentanyl because it methohexital.27–29 The drop in oxygen satura- results in and may produce hista- tion, seen during the first three minutes, espe- mine release.16 are also fre- cially in cardiac patients and patients with quently used. Midazolam has a elimination half severe BPD, can be explained by the intubation life in neonates of 6.5 to 12 hours17 18 and can procedure. produce respiratory depression, hypotension, Intubation of neonates and premature in- and in some patients hyperalgesia and fants is still very diYcult and stressful. In our agitation.19 20 Diazepam also leads to hypoten- study patients with severe cardiac or respira- sion and respiratory depression and its half life tory conditions were intubated by the atten- is substantially prolonged in neonates.21 Lo- ding paediatrician who was in charge of the razepam has an elimination half life of 10 to 20 patient. Similar studies carried out on stable hours and is certainly not appropriate for short patients, like an anaesthetic induction prior to time sedation. Other sedatives like chloral minor , also describe oxygen saturation hydrate and phenobarbital are not potent drops during intubation. In two diVerent enough to relieve discomfort and resistance to hospitals Kong et al30 found that 30% of the the intubation procedure. neonates and small infants experienced desatu- Propofol, thiopental, and methohexital are ration of more than 5% at one or more record- known to be short acting anaesthetics in ings during induction. Lackcock and infants. Propofol causes prolongation of the McNicol31 found that about 40% of the QT–interval and this results in a higher children who where aged under one year incidence of bradycardia or junctional rhythm suVered a maximum fall to less than 90% satu- compared with methohexital or thiopental.5 ration during induction of anaesthesia. During Short acting , especially metho- general anaesthesia 54% of neonates sustained hexital, have recently become the focus of a fall in saturation to 85% or less for at least 30 renewed attention for use in infants and seconds in a group of 13 neonates reported by children. Beskow et al compared methohexital Schulz and colleagues.32 Taylor and Lerman33 with thiopental and found faster recovery after found a decrease in saturation to less than 90% methohexital in infants aged 1 to 12 months.2 in 18% of infants aged under one year. Millar Other reports also mention fewer cardiovas- and Bisonnette34 did not find any decrease in cular side eVects and faster recovery when oxygen saturations in 13 term infants where 22–26 methohexital is compared with thiopental. they practised an awake intubation, but their http://fn.bmj.com/

Heart rate Diastolic blood pressure 200 60 180 50 160 40

140 30 on September 28, 2021 by guest. Protected copyright. 120 20

100 Diastolic blood 10 pressure (mm Hg)

Heart rate (beats/min) 80 0 0 0.5 11.5 2 3 4 5 10 15 20 30 0 0.5 11.5 2 3 4 5 10 15 20 30 Minutes Minutes

Systolic blood pressure Saturation 90 100 80 90 70 80 60 70 50 60 Systolic blood 40 Saturation (%) 50 pressure (mm Hg) 30 40 0 0.5 11.5 2 3 4 5 10 15 20 30 0 0.5 11.5 2 3 4 5 10 15 20 30 Minutes Minutes Pulmonary disease Cyanotic heart disease

Figure 2 Median values, 25th and 75th interquartile ranges of heart rate, systolic and diastolic blood pressure and oxygen saturation before, during, and after methohexital injection. F64

Naulaers, Deloof, Vanhole,Kola, Devlieger Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.77.1.F61 on 1 July 1997. Downloaded from

exclusion criteria included the presence of methohexitone for induction of anaesthesia in children. Acta Anaesthesiol Scand 1993;37:419-23. known intracranial, cardiovascular, or laryn- 4 Taylor C, Stoelting VK. Methohexital sodium: A new ultra- geal pathology. Barrington et al35 also found a short acting barbiturate. 1960;21:29-34. 5 Crumrine RS, Yodlowski EH. Assessment of neuromuscular significant fall in transcutaneous oxygen in 20 function in infants. Anesthesiology 1981;54:29-32. preterm newborn infants randomly assigned to 6 Westrin P. Methohexital dissolved in lipid emulsion for intravenous induction of in infants and receive either atropine alone or atropine plus children. Anesthesiology 1992;76:917-21. succinylcholine before nasotracheal intubation. 7 Grunau RVE, Craig KD. Pain expression in neonates: facial All these studies were carried out in neonates action and cry. Pain 1987;28:395-410. 8 Gauntlett IS, Fischer DM, Hertzka RE, et al. Pharmacoki- without severe cardiorespiratory problems. In netics of fentanyl in neonatal humans and lambs : eVects of age. Anesthesiology 1988;69:683-7. our study patients with cyanotic heart disease, 9 Comstock MK, Carter JG, Moyers JR, Stevens WC. Rigid- severe BPD, and pulmonary hypertension had ity and hypercarbia associated with high dose fentanyl the most important drop in oxygen saturation. induction of anesthesia. Anesth Analg 1981;60:362-3. 10 Mentor ML, Schwalb AJ, Lieberman RW. Rapid high-dose Only in the group of patients with cardiac fentanyl induction for CABG. Anesthesiology 1980;53:S95. problems was a second period of low saturation 11 Scamman FL. Fentanyl-O2-N2O rigidity and pulmonary compliance. Anesth Analg 1983;62:332-4. observed at the time the patient was recon- 12 Hill AB, Nahrwold ML, de Rosayro AM, et al. Prevention of nected to the ventilator. rigidity during fentanyl-oxygen induction of anesthesia. Anesthesiology 1981;55:452-4. No serious side eVects were encountered. 13 Bailey PL, Wilbrink J, Zwanikken P, et al. induc- Myoclonic jerks, similar to those described tion with fentanyl. Anesth Analg 1985;64:48-53. 14 Marat I, Levron JC, Berg A, Saint-Maurice C. EVects of with midazolam, were seen in three patients. fentanyl on baroreceptor reflex control of heart rate in No baby developed convulsions and all pa- newborn infants. Anesthesiology 1988;68:717-32. 15 Friesen RH, Henry DB. Cardiovascular changes in preterm tients had a normal neurological outcome. No neonates receiving isoflurane, , fentanyl, and investigations were carried out to evaluate the . Anesthesiology 1986;64:238-42. 16 Rosow CE, Moss J, Philbin DM, Savarese JJ. Histamine eVect on cerebral circulation in these neonates. release during morphine and fentanyl anesthesia. Anesthe- We cautiously recommend methohexital as a siology 1982;56:93-6. drug for a short induction of anaesthesia in 17 Jacqz-Aigrain E, Wood C, Robieux I. of midazolam in critically ill neonates. Eur J Clin Pharmacol neonates. We used it for elective intubation, but 1990;39:191-2. 18 Jacqz-Aigrain E, Daoud P, Burtin P, Mahezzi S, Beaufils F. other procedures such as the insertion of a Pharmacokinetics of midazolam during continuous infu- chest tube or of a deep venous catheter could sion in critically ill neonates. Eur J Clin Pharmacol 1992; also benefit from the use of this drug. The drug 42:329-32. 19 Burtin P, Daoud P, Jacqz-Aigrain E, et al. Hypotension with produces quick and short term anaesthesia midazolam and fentanyl in the newborn. Lancet 1991; without significant side eVects and with a stable 337:1545-6. 20 Niv D, Davidovich S, Geller E, Urca G. Analgesic and cardiovascular system. We must, however, hyperalgesic eVects of midazolam : dependence on route of await further investigations concerning ED50- administration. Anesth Analg 1988;67:1169-73. 21 Morselli P L, Principi N, Tognoni G. Diazepam elemination values for neonates and premature infants in premature and full term infants, and children. J Perina- before advising the regular and/or repeated use tol 1973;1:133-41. 22 Schrum SF, Hannallah RS, Verghese PM, Welborn LG, of this drug for diVerent procedures. The dose Norden J M, Ruttiman U. Comparison of propofol and we used is recommended by Westrin et al4 for thiopental for rapid anesthesia induction in infants. Anesth Analg 1994;78:482-5. infants, but we do not know the exact 23 Valtonen M, Iisalo E, Kanto J, Tikkanen J. Comparison ED50-values for neonates or premature babies. between propofol and thiopentone for induction of anaes- thesia in children. Anaesthesia 1988;43:696-9. The redistribution could be diVerent, taking 24 Hiller AU. Comparison of cardiovascular changes during into account the higher percentage of extracel- anaesthesia and recovery from propofol-alfentanyl- and thiopentone-halothane-nitrous oxide anaesthe- lular fluid in this group of patients. The imma- sia in children undergoing otolaryngological surgery. Acta http://fn.bmj.com/ turity of cytochrome P450 in these patients will Anaesthesiol Scand 1993;37:737-41. 25 Aun CS, Sung RY, O’Meara ME, Short TG, Oh TE. also have an important role. In our group of Cardiovascular eVects of i.v. induction in children: patients we did not see any eVects after 10 comparison between propofol and thiopenthone. Br J Anaesth 1993;70:647-53. minutes, but we do not know what the eVect 26 Runcie CJ, Mackenzie SJ, Arthur DS, Morton NS. will be after repeated doses of methohexital. In Comparison of recovery from anaesthesia induced in chil- dren with either propofol or thiopentone. Br J Anaesth the patient in whom methohexital was used on 1993;70: 192-5. three separate occasions, no diVerent eVects 27 McCollum JS, Dundee JW. Comparison of induction char- on September 28, 2021 by guest. Protected copyright. were observed in subsequent administrations. acteristics of four intravenous anaesthetic agents. Anaes- thesia 1986;41:998-1000. Further investigations, especially on the 28 Raeder JC, Misvaer G. Comparison of propofol induction eVect of brain circulation in preterm infants with thiopentone or methohexitone in short outpatient general anaesthesia. Acta Anaesthesiol Scand 1988;32:607- and the eVect of repeated use in the same 13. patient, must be carried out, before this drug 29 Gold MI, Abraham EC, Herrrington C. A controlled inves- tigation of propofol, thiopentone and methohexitone. Can can be used regularly in the neonatal intensive J Anaesth 1987;34:478-83. care unit. Furthermore, we think there is still a 30 Kong AS, Brennan L, Morgan-Hughes J. An audit of induc- tion of anaesthesia in neonates and small infants using need for basic research on the eVect of intuba- . Anaesthesia 1992;47:896-99. tion of very sick premature and term neonates 31 Laycock GJA, McNicoll LR. Hypoxaemia during induction of anaesthesia - an audit of children who underwent as most of the studies are done in stable general anaestheia for routine elective surgery. Anaesthesia patients in perfect circumstances (induction of 1988;43:981-4. 32 Schulz C, Lenz G, Madee S, Schulze M. Frequency of anaesthesia for minor surgery) and not in the hypoxic episodes during general anaesthesia in children. acute neonatal intensive care setting. Cahiers d’Anesthesiologie (Paris) 1989;37:403-7. 33 Taylor RH, Lerman J. Induction, maintenance and recovery characteristics of desflurane in infants and children. Can J 1 Truog R, Anand KJ. Management of pain in the postopera- Anaesth 1992;39:6-13. tive neonate. Clin Perinatol 1989;16:61-78. 34 Millar C, Bissonnette B. Awake intubation increases intrac- 2 Beskow A, Werner O, Westrin P. Faster recovery after ranial pressure without aVecting cerebral blood flow veloc- anesthesia in infants after intravenous induction with ity in infants. Can J Anaesth 1994;41:281-7. methohexital instead of thiopental. Anesthesiology 35 Barrington KJ, Finer NN, Etches PC. Succinylcholine and 1995;83:976-9. atropine for of the newborn infant before 3 Saarnivaara L, Hiller A, Oikkonen M. QT-interval, heart nasotracheal intubation: A randomized, controlled trial. rate and arterial pressures using propofol, thiopentone or Crit Care Med 1989;17:1293-6.