What Do We (Really) Know About It?
Matthias W. Koenig, MD
Associate Professor of Pediatrics
Eastern Virginia Medical School
Children’s Hospital of the King’s Daughters
Children’s Specialty Group, Pediatric Anesthesia Division
Vincent J. Kopp, MD
Division of Pediatric Anesthesia
Department of Anesthesiology
University of North Carolina at Chapel Hill School of Medicine
Chapel Hill, North Carolina
Are healthy children who undergo relaxant-free intubation more or less likely to suffer significant ill effects?
When summarizing the Liverpool experience with the use of muscle relaxants in newborns, Stead cited 3 advantages to their use in 1955: effective control of respiration via intubation, optimal surgical conditions, and a reduced requirement for “toxic” anesthetic agents.1 About 30 years later, Frederic A. Berry, MD, described his preference for intubation in his textbook, as follows:
“I prefer to paralyze the infant to facilitate the intubation. If an IV line is in place, 3 to 4 mg/kg of thiopental sodium is administered while the infant is being oxygenated, and the halothane is then begun. Succinylcholine 2 mg/kg is administered IV and the endotracheal tube is inserted.”2
Because Dr Berry’s preferences modeled pediatric anesthesia practice of the time, his endorsement of succinylcholine or other neuromuscular blocking drugs (NMBDs) helped enshrine their use to facilitate infant and pediatric intubation.
However, in a 1999 survey of members of the Society of Pediatric Anesthesia, Politis et al documented the widespread practice of relaxant-free intubation (RFI) techniques in pediatric anesthesia (Table 1).3 This survey revealed that RFI was employed more commonly in nonacademic settings and when providers worked by themselves without an assistant to help accomplish IV placement. The most common motives for choosing an RFI technique, according to the survey participants, are listed in Table 2.3
Why Intubate Children Without Muscle Relaxants?
The perception that muscle relaxants are unnecessary or undesirable for intubation of children is evident in Politis et al’s 1999 survey. We speculate that individual providers came to perceive muscle relaxants unfavorably, based as much on personal clinical experience and practical objectives as on compliance with FDA warnings about succinylcholine or familiarity with publications describing successful RFI techniques.
Getting away with a clinical maneuver such as RFI multiple times until failure results can be self-reinforcing. Unless failure is catastrophic, even failure may not lead to change. Such a dynamic might dominate the pragmatic clinician’s effort to enhance case turnover and cut costs as much as clinical science when it comes to using RFI.
Certainly, concerns over succinylcholine use in children jumped acutely in 1994 after the FDA issued a black box warning that alerted practitioners to the rare risk for hyperkalemic cardiac arrest in patients with undiagnosed muscular dystrophy. Perhaps this concern is legitimately reflected in Politis et al’s survey. The only available alternative muscle relaxants at the time with somewhat comparable pharmacologic profiles were mivacurium and rocuronium. As these substantially more expensive agents were unavailable in 1999 in generic form, providers had an additional nonclinical incentive to avoid relaxants altogether. Additional incentives to avoid NMBDs were supplied by a perceived risk for increased postoperative nausea and vomiting (PONV) after neostigmine use, risk for residual paralysis in the postoperative phase, the added cost of the NMBD and reversal agent, and the potential for allergic reactions to NMBDs.
The link between neostigmine and PONV is controversial, with some studies finding no correlation and others finding weak to moderate correlations. Recent meta-analyses on this subject discount anticholinergic use as a significant PONV risk factor. Applicability of these studies to children, unsurprisingly, is hampered by a lack of pediatric data.4,5
Residual NMBD-induced paralysis is a potentially dangerous complication. Risk factors include use of a long-acting NMBD, such as pancuronium, and the lack of adequate neuromuscular function monitoring. While not entirely fail-safe, NMBD use of short or intermediate duration, judicious intraoperative relaxation, demonstrably qualitative or quantitative neuromuscular recovery, and pharmacologic reversal can reduce the risk for residual paralysis.6
Use of NMBDs and reversal agents can result in increased cost, although all drugs in these classes are available in generic form. To our knowledge, the economic effect of NMBD use versus avoidance has not been formally studied.
Several studies identify NMBDs as common culprits in perioperative allergic reactions. Most reports originate from outside the United States, and variations in local NMBD-use practice patterns and differences in diagnostic workups of suspected NMBD-induced allergy cases may account for some of the international variety in reported incidence figures. The majority of these reactions appear to be of little clinical consequence to patients.7
How Successful Is RFI?
In 2012, Aouad et al reviewed the relevant literature to identify RFI drug combinations that provide “excellent” intubation conditions in at least 80% of pediatric patients.8 The 80% threshold was chosen with reference to succinylcholine as the gold standard for yielding excellent intubation conditions. Six drug combinations met their criteria (Table 3).8 While the authors discriminated from among appropriate studies for analysis, we note several concerns about quantitative assessment of intubation conditions.
The grading of intubation conditions for children relies on scoring systems such as the Helbo-Hansen scale, its Steyn modification, and the Copenhagen scale. All of these scales were originally developed in adult populations. Even allowing for their applicability to infants and children, none has been systematically validated or rated for interobserver reliability to our knowledge (Tables 4 and 5).9-11
Further, given the limited if gross end point being studied—placement of an endotracheal tube between the vocal cords—interpretation of results in some studies raises a number of questions:
- What is the difference between “good” and “excellent” intubation conditions?
- Are “good” and “excellent” intubation conditions equally “acceptable”?
- Do conditions that are “acceptable” to the intubating clinician but produce unacceptable postextubation morbidity really constitute a meaningful end point?
- Should time to success be a scalable factor?
- Should all components of a scoring system carry equal weight when computing an aggregate score?
- What is the importance of the clinician’s intubating experience?
- Should there be a postextubation component included to whatever scale is used in the future?
Aouad et al accounted for some of these limitations, and therefore were able to include only 23 papers out of a larger body of literature.
Given the difficulties with scoring intubation conditions and defining acceptability, another question arises: Is an 80% success rate, historically achieved with succinylcholine, a meaningful surrogate comparator when assessing an RFI technique in a new trial? To ascertain whether RFI techniques are equivalent or superior to any NMBD-based technique, direct comparisons of induction drug “X” plus adjunct drug “A” versus induction drug “X” plus an NMBD are preferable. Aouad et al’s review includes only 6 among the 23 included studies that meet this criterion.
We were unable to identify a single paper that demonstrates superior efficacy—in terms of intubation conditions—of any RFI technique versus an NMBD-based technique. Several authors have concluded that the compared approaches are equivalent based on equal attainment rates of “acceptable” intubation conditions. However, in several of these studies, NMBD use was more likely to produce a higher ratio of “excellent” to “good” conditions when compared with RFI.
Accepting that grading of intubation conditions in any age group has unresolved problems, some adult population studies suggest that the quality of intubating conditions influences postintubation laryngeal morbidity.12,13 Mencke et al performed stroboscopy exams of patients’ vocal cords before intubation, and again—along with hoarseness screening—24 and 72 hours post-extubation.12Quality of intubation conditions in their study showed an inverse relationship to clinical symptoms or pathologic vocal cord findings.
The same authors calculated the number needed to harm by omitting a muscle relaxant as 2.9. As of now, no such data exist in pediatric populations. Nevertheless, we believe that concern about a similar relationship being overlooked or unrecognized in children is appropriate. From this perspective, “excellent” intubation conditions that provide low postextubation morbidity constitute the only meaningful measure of intubation success.
Extrapolation of Study Results
Anecdotes from clinical practice suggest that RFI techniques evaluated systematically are extrapolated to inappropriate patient groups: infants, adolescents, critically ill children, and those with abnormal airway anatomy. Of note, the mean patient age in the relevant literature on RFI techniques is largely between 5 and 8 years of age. As pediatric anesthesia providers know, airway anatomy, physiology, and response to anesthetic drugs among latency-age children differ significantly from infants and adolescents.
We identified only one study that specifically focused on the infant population. In a 2011 prospective study in children aged 1 to 24 months, Devys et al compared intubations after sevoflurane induction followed by placebo, 20 mcg/kg of alfentanil, or 0.3 mg/kg of rocuronium.14 “Excellent” intubation conditions were observed in 64% in the rocuronium group, 30% in the alfentanil group, and 15% in the placebo group. The authors also noted laryngospasm, bronchospasm, and less than 90% saturation in 0% of children intubated with rocuronium, versus 22% with placebo and 27% with alfentanil. They concluded that, in this age group for the purpose of intubation, use of an NMBD might actually be safer than its omission.
Outside anesthesia settings, it is notable that both the American Academy of Pediatrics and the Canadian Paediatric Society have guidance documents on drug use for newborn intubation that recommend NMBD use unless contraindicated by clinical conditions. Although neonatal intensive care intubation indications differ from those in anesthesia practice in the operating room, pediatric anesthesia providers should appreciate that NMDB use for intubations of critically ill neonates is linked to significant reductions of severe desaturation and increased intubation success on first attempt.15,16
At the other extreme of the pediatric age spectrum, size and weight impose an upper limit for RFI techniques. Rising obesity rates among pediatric patients mean more patients 10 to 12 years of age present with an “adult” weight in excess of 154 pounds. However, these children are not adults, as their airways are still growing and developing, especially before puberty. To our knowledge, RFI safety has never been addressed in this patient population. Likewise, how comorbidities or acute cardiorespiratory compromise should affect the decision for or against RFI remains undefined. In our view, the RFI techniques identified by Aouad et al in healthy populations likely have the potential for adverse effects in critically ill children.
RFI techniques in children are popular with anesthesia providers. Because the studies reviewed have design limitations, we have insufficient data to say healthy children of any age range subjected to proper RFI techniques are more or less likely to suffer significant ill effects from such an intubation technique choice.
Practitioners who employ RFI may do so for reasons that have less to do with patient comfort and safety than a perceived need to fulfill another agenda: to avoid succinylcholine, enhance operating room throughput via shortened emergence time, reduce post-anesthesia care unit calls related to PONV, or reduce direct and indirect drug costs. Each has some validity, but none is without some drawback.
Economic factors such as additional drug cost when using NMBDs or the effect of intubation strategy on operating room efficiency have not been evaluated in the literature, and would need to be balanced against the—admittedly equally unquantified—added risk for airway morbidity from omission of NMBDs.
However, we find no evidence that RFI techniques convey a relevant primary medical benefit to the patient: Intubating conditions are not superior when compared with NMBD use; perioperative airway morbidity is not clearly mitigated; and avoidance of NMBD reversal with neostigmine and glycopyrrolate does not confer a significant advantage against vomiting (or nausea, when this symptom can be reported), or reduce the use of other antiemetic strategies, including dexamethasone administration.
Extrapolation of RFI techniques described in healthy preschool and early school-age children to a patient population outside this studied age range and/or with higher assigned American Society of Anesthesiologists physical status classification designation empirically appears to be common. Evidence of efficacy for RFI at the extremes of the pediatric age spectrum is absent. The limited number of studies in infants and neonates suggest otherwise.
Our recommendation is that practitioners should bear these caveats in mind when deciding whom to subject and under what conditions to use RFI techniques that remain largely underevaluated—and their efficacy thus unproven.
- Stead AL. The response of the newborn infant to muscle relaxants.Br J Anaesth. 1955;27(3):124-130.
- Berry FA, ed.Anesthetic Management of Difficult and Routine Paediatric Patients. 2nd ed. London, United Kingdom: Churchill Livingstone; 1986.
- Politis GD, Tobin JR, Morell RC, et al. Tracheal intubation of healthy pediatric patients without muscle relaxant: a survey of technique utilization and perceptions of safety.Anesth Analg. 1999;88(4):737-741.
- Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting.Anesth Analg. 2007;105(6):1615-1628.
- Le TP, Gan TJ. Update on the management of postoperative nausea and vomiting and postdischarge nausea and vomiting in ambulatory surgery.Anesthesiol Clin. 2010;28(2):225-249.
- Plaud B, Debaene B, Donati F, et al. Residual paralysis after emergence from anesthesia.Anesthesiology. 2010;112(4):1013-1022.
- Mertes PM, Aimone-Gastin I, Guéant-Rodriguez RM, et al. Hypersensitivity reactions to neuromuscular blocking agents.Curr Pharm Des. 2008;14(27):2809-2825.
- Aouad MT, Yazbeck-Karam VG, Mallat CE, et al. The effect of adjuvant drugs on the quality of tracheal intubation without muscle relaxants in children: a systematic review of randomized trials.Paediatr Anaesth. 2012;22(7):616-626.
- Helbo-Hansen S, Ravlo O, Trap-Andersen S. The influence of alfentanil on the intubating conditions after priming with vecuronium.Acta Anaesthesiol Scand. 1988;32(1):41-44.
- Steyn MP, Quinn AM, Gillespie JA, et al. Tracheal intubation without neuromuscular block in children.Br J Anaesth. 1994;72(4):403-406.
- Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents.Acta Anaesthesiol Scand. 1996;40(1):59-74.
- Mencke T, Echternach M, Kleinschmidt S, et al. Laryngeal morbidity and quality of tracheal intubation: a randomized controlled trial.Anesthesiology. 2003;98(5):1049-1056.
- Combes X, Andriamifidy L, Dufresne E, et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort.Br J Anaesth. 2007;99(2):276-281.
- Devys JM, Mourissoux G, Donnette FX, et al. Intubating conditions and adverse events during sevoflurane induction in infants.Br J Anaesth. 2011;106(2):225-229.
- Kumar P, Denson SE, Mancuso TJ. Premedication for nonemergency endotracheal intubation in the neonate.Pediatrics. 2010;125(3):608-615.
- Barrington K. Premedication for endotracheal intubation in the newborn infant [in English, French].Paediatr Child Health. 2011;16(3):159-171.