Remifentanil is too potent to be given by bolus

Editor—We read with interest the study evaluating bolus injection of remifentanil in spontaneously breathing human volunteers by Egan and colleagues.1 Using a randomized, double-blind, placebo- controlled, dose-escalation, crossover study design, a total of 64 healthy subjects received remifentanil or placebo by bolus injection (1–3 s) in a fixed unit dose separated by a 1 h washout period. Groups of six subjects were studied at the initial dose of 25 µg and at subsequent doses of 25 µg increments until a total of four out of the six subjects in any one group had experienced respiratory depression, or the maximum dose of 200 µg had been reached. From their extensive investigation, the authors were able to conclude that bolus injection of remifentanil would be potentially safe and effective in clinical situations, despite the fact that a number of the volunteers in their study had what can be considered serious respiratory depression and apnoea. Unsurprisingly, these events were more evident in the elderly group, which overall received lower doses of remifentanil; however, some younger age group subjects also experienced respiratory depression, again at a relatively low dose of remifentanil. The authors' definition of an adverse event was related to the respiratory intervention scale, which, rather generously in our opinion, defines respiratory depression as an <85% for >5 s.

The UK data sheet indicates that remifentanil may be administered as a bolus of 0.5–1.0 µg kg–1 min–1 over not less than 30 s during induction of anaesthesia. Even under these controlled conditions, this practice has not found wide acclaim because of the associated incidence of hypotension and bradycardia.2 3 Where remifentanil is used, a titrated infusion is increasingly preferred. A bolus of remifentanil is not recommended in spontaneously breathing anaesthetized patients or in sedated ICU patients. Indeed, the product licence for remifentanil in the ICU stipulates remifentanil infusion for mechanically ventilated patients only. Whereas we would advocate use of a remifentanil infusion in a variety of settings and different patient groups, particularly in spontaneously breathing patients where lack of accumulation and titratability can make it a superior choice of analgesia, its use in bolus form is unpredictable and associated with a host of uncontrollable and undesirable effects.

Overall, the conclusions reached by Egan and colleagues are not reflective of their study results, and should do little to convince the readership that bolus administration of remifentanil is a safe and effective means of analgesia in spontaneously breathing patients.

A. Mallick and S. Elliot

Leeds, UK


 
Editor—We thank Dr Mallick and colleagues for their comments regarding the use of remifentanil by bolus injection, as discussed in our manuscript.1 They correctly underscore the potential dangers of the technique.

As noted in our manuscript, the primary side-effect of concern in association with remifentanil bolus injection in spontaneously ventilating patients is respiratory depression (and apnoea). Rapid onset opioids like remifentanil are especially troublesome in this regard because the carbon dioxide ventilation–response curve (i.e. the relationship between minute volume and ) is altered before the patient's rises sufficiently to sustain ventilatory drive.4

Our manuscript was not intended to minimize these risks. On the contrary, the study was intended to provide a scientific foundation to begin understanding and characterizing these risks. While the respiratory depression observed in all subjects in our study was easily managed with simple clinical manoeuvres (i.e. prompting to breathe and the administration of supplemental oxygen), some subjects, particularly older ones, exhibited substantial respiratory depression even at low doses. The degree of respiratory depression we observed cannot be considered trivial by any means.

As noted in the original manuscript, from a clinical perspective, the ‘take home’ messages from our study are: (i) that bolus dose remifentanil does indeed produce substantial respiratory depression; (ii) that this respiratory depression is highly variable and is typically more serious in older subjects; (iii) that the respiratory depression can be managed with simple clinical manoeuvres; (iv) that practitioners should be expert at the administration of remifentanil by infusion before attempting bolus injection techniques; and (v) that practitioners administering remifentanil by bolus injection should be experts at the recognition of inadequate ventilation and airway management.

At least in part, our investigation was motivated by the increasing use of bolus dose remifentanil in the USA. Bolus injection of remifentanil in various clinical settings, for example analgesia for eye blocks, awake laryngoscopy, and shock wave lithotripsy,58 is commonplace. Our study aimed to better understand and define this practice.

T. D. Egan and S. E. Kern

Salt Lake City, UT, USA

References

1 Egan TD, Kern SE, Muir KT, White J. Remifentanil by bolus injection: a safety, pharmacokinetic, pharmacodynamic, and age effect investigation in human volunteers. Br J Anaesth 2004; 92: 335–43[Abstract/Free Full Text]

2 Hall AP, Thompson JP, Leslie NAP, Fox AJ, Kumar N, Rowbotham DJ. Comparison of different doses of remifentanil on cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth 2000; 84: 100–2[Abstract]

3 Bowdle TA, Camporesi EM, Maysick L, et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg 1996: 83: 1292–97[Abstract]

4 Bouillon T, Bruhn J, Radu-Radulescu L, Andresen C, Cohane C, Shafer SL. A model of the ventilatory depressant potency of remifentanil in the non-steady state. Anesthesiology 2003; 99: 779–87[CrossRef][ISI][Medline]

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6 Johnson KB, Swenson JD, Egan TD, Jarrett R, Johnson M. Midazolam and remifentanil by bolus injection for intensely stimulating procedures of brief duration: experience with awake laryngoscopy. Anesth Analg 2002; 94: 1241–3[Abstract/Free Full Text]

7 Joo HS, Perks WJ, Kataoka MT, Errett L, Pace K, Honey RJ. A comparison of patient-controlled sedation using either remifentanil or remifentanil-propofol for shock wave lithotripsy. Anesth Analg 2001; 93: 1227–32[Abstract/Free Full Text]

8 Sa Rego MM, Inagaki Y, White PF. Remifentanil administration during monitored anesthesia care: are intermittent boluses an effective alternative to a continuous infusion? Anesth Analg 1999; 88: 518–22[Abstract/Free Full Text]