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From the Department of Anaesthesia, Otolaryngological Clinic, Helsinki University Central Hospital, Haartmaninkatu 4 E, SF-00290 Helsinki, Finland.
Address correspondence to: Dr. Ulla-Maija Klemola. Phone: 358-96988430; Fax: 358-947176024; E-mail: ulla-maija.klemola{at}huch.fi
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Methods: In a randomized, double-blind study 80 healthy children aged three to nine years were assigned to one of four groups (n=20): 2 or 4 µg·kg–1 remifentanil (Re2 or Re4); 2 µg·kg–1 remifentanil and 0.2 mg·kg–1 rocuronium (Re2-Ro0.2); 0.4 mg·kg–1 rocuronium (Ro0.4). After atropine, remifentanil was injected over 30 sec followed by 3.5 mg·kg–1 propofol and rocuronium. After 60 sec, laryngoscopy and intubation were attempted. Intubating conditions were assessed as excellent, good or poor based on ease of ventilation, jaw relaxation, position of the vocal cords, and coughing to intubation.
Results: In all children intubation was successful. Overall intubating conditions were better (P < 0.01), and the frequency of excellent conditions, 85%, was higher (P < 0.01) in the Re4 group than in the Ro0.4 group. No child manifested signs of muscular rigidity. In the remifentanil groups, arterial pressure decreased 11-13% and heart rate 6-9% after anesthetic induction, and remained at that level throughout the study.
Conclusion: The best intubating conditions were produced by the combination of 4 µg·kg–1 remifentanil and 3.5 mg·kg–1 propofol. It provided excellent or good intubating conditions in all children without causing undue cardiovascular depression.
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Introduction |
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Remifentanil is a recently introduced µ-receptor agonist with a unique pharmacokinetic profile. Owing to metabolism by non-specific esterases in blood and tissues, remifentanil is characterised by an extremely rapid clearance and offset of effect.7 Therefore, in contrast to other opioids, the time of recovery is not greatly influenced by the dose.8 Moreover, the onset of effect is rapid, and similar to that of alfentanil.9 Providing an option for intense opioid effect without compromising recovery after short operations, remifentanil might offer benefits over alfentanil especially in ambulatory surgery. In adult patients, intubating conditions after 2 µg·kg–1 remifentanil were inferior to those achieved after 50 µg·kg–1 alfentanil when combined with propofol.4 In order to ensure good intubating conditions a dose of 3-4 µg·kg–1 remifentanil was required.10,11 In children, intubating conditions were similar after 1 µg·kg–1 remifentanil or 15 µg·kg–1 alfentanil followed by propofol.12 However, neither dose appeared optimal regarding intubating conditions.
To determine the optimal dose of remifentanil to facilitate tracheal intubation with propofol in children, we conducted a randomized, controlled study to compare intubating conditions and cardiovascular responses following induction of anesthesia with 3.5 mg·kg–1 propofol, supplemented with either 2 or 4 µg·kg–1 remifentanil, or 0.4 mg·kg–1 rocuronium . In addition, we tested the hypothesis that a small dose of rocuronium, 0.2 mg·kg–1 in this setting might improve intubating conditions.13 This small dose was given in conjunction with remifentanil 2 µg·kg–1.
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Methods |
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All children had EMLA® cream applied over the dorsum of the hand 60 min before venous cannulation. Midazolam, 0.5 mg·kg–1 po, was given as premedication about 20-30 min before anesthesia. Using a sealed envelope method, children were randomized to one of four study groups of 20 children to receive the following in a double-blind manner: 2 µg·kg–1 remifentanil (Re2); 4 µg·kg–1 remifentanil (Re4); 2 µg·kg–1 remifentanil and 0.2 mg·kg–1 rocuronium (Re2-Ro0.2); 0.4 mg·kg–1 rocuronium (Ro0.4). The doses of remifentanil were chosen on the basis of preliminary pilot studies. For every child, an independent assistant nurse prepared four syringes containing the study drugs or saline. Depending on the child's weight, she drew the study drug I, remifentanil, either into a syringe of 5 or 10 ml, and the study drug II, rocuronium, into a syringe of 1 or 2 ml, while filling the other syringe with saline. After drawing the appropriate doses of remifentanil or rocuronium into syringes, she filled the syringes with saline to make up a total volume of 15 ml or 3 ml, respectively. In the operating room, intravenous access was established by inserting a 24-gauge cannula into a vein in the dorsum of the hand. Atropine, 0.015 mg·kg–1 iv, was given to all children. Two minutes after atropine, study drug I was injected over 30 sec. It was followed by 3.5 mg·kg–1 propofol over 20 sec and then study drug II was injected as a rapid bolus.
Once the child became unconscious, ease of ventilation via a facemask was scored as easy (=1), satisfactory (=2) or impossible (=3). Sixty seconds after study drug II, laryngoscopy and intubation were attempted by an experienced anesthesiologist (U-MK or AH) using a Macintosh laryngoscope blade of appropriate size, and an uncuffed orotracheal tube the internal diameter of which was calculated using the formula, 4.0 + age/ 4 mm. The intubating conditions were assessed and scored for four variables: jaw relaxation (jaw mobile= 1, partly mobile=2, or immobile=3), position of the vocal cords (open=1, midposition=2, or tightly closed=3), and patient response to intubation (no coughing=1, one or two coughs=2, or persistent coughing=3). Using the above criteria intubating conditions were assessed as excellent (all criteria scored as 1), good (criteria scored as 1 or 2) or poor (any of the criteria scored as 3). Tracheal intubation was not attempted if the vocal cords were judged to be tightly closed in order to avoid injury to them. Children whose tracheas could not be intubated after receiving the assigned induction drugs were so noted, and were given 0.5 mg·kg–1 rocuronium.
Monitors included an automated arterial pressure cuff, ECG, peripheral pulse oximeter (Sp02), and capnometer. Control values of arterial pressure (MAP), heart rate, and Sp02 were obtained after atropine. Thereafter, the measurements were performed after anesthetic induction, and immediately after intubation.
Parametric data were analysed by one-way analysis of variance. Differences among groups were evaluated using Student's unpaired t test. Student's paired t test was used for changes within each patient. Chi-square test or Fisher's exact test, when appropriate, was used for nonparametric data. Bonferroni correction was performed for multiple comparisons. Significance was defined as P < 0.05.
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Results |
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). The ease of mask ventilation was scored as easy in all children except in one in the Re2 group when it was satisfactory. No child appeared to manifest signs of opioid-induced rigidity at any time. In all children, intubation was successful at the first attempt. Overall intubating conditions were (P < 0.01) better, and the number of patients showing excellent conditions (mask ventilation easy, jaw relaxed, vocal cords open, and no coughing) was higher in the Re4 group (P < 0.01) than in the Ro0.4 group (Figure). The jaw was judged to be mobile in all children. The vocal cords were open in 70%, 95%, 95% or 100% in the Re2, Re4, Re2-Ro0.2 or Ro0.4 groups, respectively. In the groups receiving rocuronium, vocal cords were judged more frequently (P < 0.05) to be open than in the Re2 or Re4 groups. The patient response after intubation was judged to be excellent with no coughing in 70%, 90%, 70% or 30% in the Re2, Re4, Re2-Ro0.2 or Ro0.4 groups, respectively. There was a difference between the Re4 and the Ro0.4 group (P < 0.01).
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. After anesthetic induction, MAP decreased 11-13% in the groups receiving 2 (P < 0.05) or 4 µg·kg–1 remifentanil (P < 0.01), and increased 18% in the Ro0.4 group (P < 0.05). However, the differences among the groups were not statistically significant. After intubation, MAP remained at the same level in the remifentanil groups but increased in the Ro0.4 group (P < 0.05) which differed from the Re4 group (P < 0.001). After induction, heart rate decreased 6-9% in the remifentanil groups (P < 0.05) but was similar to preinduction values after intubation. In the Ro0.4 group, heart rate increased after intubation (P < 0.01), and the difference from the other groups was significant (P < 0.001 to the Re2 or Re4 group; P < 0.05 to the Re2-Ro0.2 group). Peripheral oxygen saturation remained over 95% in all children throughout the investigation.
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Discussion |
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Excellent intubating conditions were found in 85% of the patients after 4 µg·kg–1 remifentanil whereas , in the control group where propofol was supplemented with 0.4 mg·kg–1 rocuronium, the corresponding number was 30%. The difference among the groups was due to slight coughing occurring in 70% of the patients in the control group. The vocal cords were more frequently judged to be open in the groups receiving rocuronium than without it. Thus, our results were similar to those showing a rapid onset of action for rocuronium at the laryngeal muscles.13,14 Barclay et al. demonstrated that the vocal cords were open in 90% of patients after propofol combined with 0.1 or 0.3 mg·kg–1 rocuronium.13 After 0.25 mg·kg–1 rocuronium, the onset time to maximum neuromuscular block of the laryngeal adductor muscles was 1.6 min.14 However, for doses producing complete neuromuscular block the onset time decreased as the dose of rocuronium increased but remained similar with lower doses insufficient to produce complete block.15
In clinical practice, we considered it reasonable to take advantage of the observations that intubating conditions were acceptable after relatively low doses of rocuronium.13,16 Pollard et al. showed that the trachea could be intubated in all patients at 60 sec after 0.45 mg·kg–1 rocuronium with satisfactory intubating conditions. The authors recommended this dose as appropriate for day case patients undergoing very short procedures. In children aged two to ten years, 0.4 mg·kg–1 rocuronium was shown to be the ED95 value17 but, for a mean onset time of 46-48 sec at the adductor pollicis, a dose of 0.6-0.8 mg·kg–1 was required.17,18 In consideration of the wide interindividual variability, the duration of action of this dose is too long for most of the procedures characteristic of our clinical practice. In the present study, 0.4 mg·kg–1 rocuronium after propofol resulted in good jaw relaxation and open vocal cords in all children. Hence, rather than inadequate muscle relaxation, the slight coughing observed in the group might be a question of the depth of anesthesia. As a practical conclusion, we emphasise the advantages associated with combinations of an hypnotic and an opioid instead of an hypnotic alone when treating noxious stimulation.19 Succinylcholine with its very rapid onset and offset of action has been popular in both pediatric and adult anesthesia for nearly five decades. However, because of its many problems, we have followed those clinicians and investigators who have encouraged it be avoided in pediatric anesthetic practice except in emergency situations.1
Concerning the optimal dose of remifentanil combined with propofol to facilitate tracheal intubation without the use of muscle relaxants, our results are in agreement with those obtained in adult patients. Alexander et al. demonstrated that 4 or 5 µg·kg–1 remifentanil improved intubating conditions compared with 3 µg·kg–1.11 Further, Stevens et al. reported that 3-4 µg·kg–1 remifentanil provided satisfactory intubating conditions more reliably than 1-2 µg·kg–1 remifentanil.10 In both studies, remifentanil was combined with 2 mg·kg–1 propofol. In the present study, a dose of 3.5 mg·kg–1 propofol was chosen because children require a larger induction dose than adults. Moreover, children less than five years of age seem to need a higher dose than older children.20 In the younger children, the increased propofol requirement seems to be due to pharmacokinetic differences whereas the volume of the central compartment and the systemic clearance were both greater than those reported in older children and adults.21
Consequently, we find it difficult to agree with the conclusion made by Robinson et al. that remifentanil does not appear to offer any advantage when compared with alfentanil for routine use in children aged two to 12 yr.12 By taking remifentanil as being 15 times more potent than alfentantanil, they found intubating conditions after 1 µg·kg–1 remifentanil comparable with those provided by 15 µg·kg–1 alfentanil when both were followed by 4 mg·kg–1 propofol. By scrutinizing their results, however, it seems that neither dose was optimal. In adults, intubating conditions after propofol combined with 2 µg·kg–1 remifentanil were inferior to those after 50 µg·kg–1 alfentanil.4 Thus, it seems that the study design and the conclusion made by Robinson et al. was based on an incorrect estimate of potency of the drugs. Depending on the chosen endpoint, remifentanil has been found to be 20 to 40 times more potent than alfentanil.22,23 However, in this context, a more useful approach for defining the optimal dose of remifentanil might start from the recognition of its unique pharmacokinetic properties. In contrast to alfentanil, remifentanil, with its very rapid elimination, allows a greater margin to dosing, since the time to recovery is not influenced by dose.9
Generally, muscular rigidity may be associated with rapid infusions of large doses of potent opioids.24 After remifentanil, muscular rigidity was demonstrated in 11-32% of patients with target concentrations escalating from 2.0 to 16.0 ng·ml–1.25 However, none of our benzodiazepine premedicated patients exhibited signs of opioid-induced muscular rigidity such as a stiff chest. The lungs of all children could be ventilated without difficulty, and there was no jaw rigidity. Our results are in agreement with those obtained previously, in which drug combination and dosage were similar to ours.10,11 The absence of signs of rigidity in our patients might have been due to the moderate injection rate of remifentanil. It has been suggested that the incidence and severity are dependent not only on the dose but the rate of administration.24 Further, pretreatment with a benzodiazepine is effective in preventing opioid-induced muscle rigidity.26
With regard to cardiovascular variables, there was a marked similarity between the changes caused by the different doses of remifentanil both after induction and intubation. Indeed, it has been shown that after remifentanil the decreases in arterial pressure and heart rate of about 20% were independent of the dose from 2 to 30 µg·kg–1.27 In the present study, the mean reduction in MAP after anesthetic induction, 11-13%, was of a similar magnitude as that reported by Robinson et al. after 1 µg·kg–1 remifentanil,12 but considerably less than that after 2 or 4 µg·kg–1 remifentanil shown by Alexander et al.4,11 In the present study, pretreatment with atropine might have constituted a link for the absence of cardiovascular depression. Without a concurrent anticholinergic agent remifentanil was associated with bradycardia or hypotension, or both, in 30-50% of healthy patients during anesthetic induction and intubation.10,11,28 On this basis, we considered the administration of an anticholinergic agent necessary, which might have contributed also to the observed stability of heart rate in our study in contrast to the results obtained without using an anticholinergic agent. In the present study, the cardiovascular intubation response was totally prevented in the groups receiving 2 or 4 µg·kg–1 remifentanil. This result is consistent with those obtained by others.4,10,11
It is concluded that the administration of 4 µg·kg–1 remifentanil in combination with 3.5 mg·kg–1 propofol provided excellent to good conditions for tracheal intubation thereby allowing successful tracheal intubation in all premedicated children aged three to nine years with favourable airway anatomy. Moreover, the combination of 2 or 4 µg·kg–1 remifentanil with propofol prevented the cardiovascular response to intubation. The technique may be appropriate when rapid return of spontaneous ventilation is aimed at, or if neuromuscular blockade is undesirable or not required for the planned surgical procedure.
Accepted for publication May 14, 2000.
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2 Saarnivaara L, Klemola U-M. Injection pain, intubating conditions and cardiovascular changes following induction of anaesthesia with propofol alone or in combination with alfentanil. Acta Anaesthesiol Scand 1991; 35: 19–23.[Medline]
3
Scheller MS, Zornow MH, Saidman LJ. Tracheal intubation without the use of muscle relaxants: a technique using propofol and varying doses of alfentanil. Anesth Analg 1992; 75: 788–93.
4 Alexander R, Booth J, Olufolabi AJ, El-Moalem HE, Glass PS. Comparison of remifentanil with alfentanil or suxamethonium following propofol anaesthesia for tracheal intubation. Anaesthesia 1999; 54: 1032–6.[Medline]
5 Hiller A, Klemola UM, Saarnivaara L. Tracheal intubation after induction of anaesthesia with propofol, alfentanil and lidocaine without neuromuscular blocking drugs in children. Acta Anaesthesiol Scand 1993; 37: 725–9.[Medline]
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McConaghy P, Bunting HE. Assessment of intubating conditions in children after induction with propofol and varying doses of alfentanil. Br J Anaesth 1994; 73: 596–9.
7 Rosow CE. An overview of remifentanil. Anesth Analg 1999; 89: S1–3.
8 Kapila A, Glass PSA, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995; 83: 968–75.[Medline]
9 Egan TD, Minto CF, Herman DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil. Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996; 84: 821–33.[Medline]
10 Stevens JB, Wheatley L. Tracheal intubation in ambulatory surgery patients: using remifentanil and propofol without muscle relaxants. Anesth Analg 1998; 86: 45–9.[Abstract]
11 Alexander R, Olufolabi AJ, Booth J, El-Moalem HE, Glass PS. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia 1999; 54: 1037–40.[Medline]
12 Robinson DN, O'Brien K, Kumar R, Morton NS. Tracheal intubation without neuromuscular blockade in children: a comparison of propofol combined either with alfentanil or remifentanil. Paediatr Anaesth 1998; 8: 467–71.[Medline]
13
Barclay K, Eggers K, Asai T. Low-dose rocuronium improves conditions for tracheal intubation after induction of anaesthesia with propofol and alfentanil. Br J Anaesth 1997; 78: 92–4.
14
Meistelman C, Plaud B, Donati F. Rocuronium (ORG 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis in humans. Can J Anaesth 1992; 39: 665–9.
15 Wright PMC, Caldwell JE, Miller RD. Onset and duration of rocuronium and succinylcholine at the adductor pollicis and laryngeal adductur muscles in anesthetized humans. Anesthesiology 1994; 81: 1110–5.[Medline]
16 Pollard BJ, Chetty MS, Wilson A, Healy TEJ. Intubation conditions and time-course of action of low-dose rocuronium bromide in day-case dental surgery. Eur J Anaesthesiol 1995; 12(Suppl11): 81–3.
17 Woolf RL, Crawford MW, Choo SM. Dose-response of rocuronium bromide in children anesthetized with propofol. Anesthesiology 1997; 87: 1368–72.[Medline]
18 Woelfel SK, Brandom BW, Cook DR, Sarner JB. Effects of bolus administration of ORG-9426 in children during nitrous oxide-halothane anesthesia. Anesthesiology 1992; 76: 939–42.[Medline]
19 Hug CC Jr. Propofol requirements versus stimulus intensity (Editorial). Anesthesiology 1997; 87: 201–2.[Medline]
20
Aun CST, Short SM, Leung DHY, Oh TE. Induction dose-response of propofol in unpremedicated children. Br J Anaesth 1992; 68: 64–7.
21 Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a single dose in children aged 1-3 years with minor burns. Comparison of three data analysis approaches. Anesthesiology 1996; 84: 526–32.[Medline]
22
Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (G187084B). Anesth Analg 1993; 77: 1031–40.
23 Glass PSA, Iselin-Chaves IA, Goodman D, Delong E, Hermann DJ. Determination of the potency of remifentanil compared with alfentanil using ventilatory depression as the measure of opioid effect. Anesthesiology 1999; 90: 1556–63.[Medline]
24
Thompson JP, Rowbotham DJ. Remifentanil – an opioid for the 21st century (Editorial). Br J Anaesth 1996: 76: 341–3.
25 Lang E, Kapila A, Shlugman D, Hoke JF, Sebel PS, Glass PSA. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996: 85: 721–8.[Medline]
26 Sanford TJ Jr, Weinger MB, Smith NT, et al. Pretreatment with sedative-hypnotics, but not with nondepolarizing muscle relaxants, attenuates alfentanil-induced muscle rigidity. J Clin Anesth 1994: 6: 473–80.[Medline]
27 Sebel PS, Hoke JF, Westmoreland C, Hug CC Jr, Muir KT, Szlam F. Histamine concentrations and hemodynamic responses after remifentanil. Anesth Analg 1995: 80: 990–3.[Abstract]
28
Thompson JP, Hall AP, Russell J, Cagney B, Rowbotham DJ. Effect of remifentanil on the haemodynamic response to orotrahceal intubation. Br J Anaesth 1998; 80: 467–9.
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P < 0.01 higher frequency of excellent conditions than in the Ro0.4 group.