Stefanutto et al.1 in this issue of Anesthesia & Analgesia continue the long quest to develop an optimal anesthetic induction protocol. A technique that assures good-to-excellent conditions for tracheal intubation upon loss of consciousness, yet assures that if “can't intubate, can't ventilate” (CICV) conditions are encountered, then adequate spontaneous ventilatory exchange will recover before significant arterial oxygen desaturation supervenes.
In healthy patients, apneic intervals of 5 to 7 minutes may elapse before desaturation (<90% arterial saturation) following preoxygenation in the presence of a patent airway,2 – 4 although in patients with decreased functional residual capacity or venous admixture, this interval may be significantly shorter.5 The protocol of Stefanutto et al. was designed so that their subjects retained the greatest chance of maintaining oxygenation during propofol/opioid-induced apnea: they received optimal preoxygenation (end-tidal oxygen >90%), and a tightly fitted facemask with insufflated oxygen flow at 6 L/min was kept in place. Assuming a patent airway, the authors' subjects thus benefited from some degree of “apneic oxygenation.”6
The authors1 chose to avoid the use of succinylcholine to facilitate intubation because there is convincing evidence that significant arterial hemoglobin desaturation may take place before recovery of adequate respiratory mechanics occurs after a traditional “intubating dose” of this relaxant. For example, Heier et al.7 were able to demonstrate that, after induction with thiopental and succinylcholine (no opioid), spontaneous recovery from succinylcholine-induced apnea frequently did not occur quickly enough to prevent arterial desaturation. The present authors hypothesized that perhaps substituting a short-acting opioid in lieu of succinylcholine might result in a shorter apneic interval. In the present investigation, they studied an induction dose of propofol (2.0 mg/kg) combined with 2 different doses of remifentanil.
The first dose they selected, remifentanil 2 μg/kg, resulted in arterial hemoglobin saturations <80% in one-third of subjects, although it offered acceptable intubating conditions in 11 of 12 subjects. This time course of respiratory depression and resulting arterial desaturation is consistent with remifentanil's pharmacokinetic/pharmacodynamic profile.8 In another session, they reduced the dose of remifentanil to 1.5 μg/kg and successfully shortened the apnea time by approximately 1 minute, but 4 of 12 subjects had unacceptable conditions for tracheal intubation. The present study thus demonstrates the limitations of a relaxant-free intubation technique using what are certainly only modest doses of propofol and remifentanil. As pointed out by Sneyd and O'Sullivan,9 in the absence of a good clinical reason for doing so, “attempting tracheal intubation without a neuromuscular blocking agent represents substitution of an inferior technique for one with greater efficacy.”
In the “real world” of unexpected CICV, a patent airway by definition would not be present, and the adequacy of preoxygenation may be questionable. Thus, the study by Stefanutto et al. probably represents a “best case” scenario. Nevertheless, the arterial O2 saturations in 14 of 24 subjects decreased to <90% at some point. Actual patients would likely experience a faster onset of arterial oxygen desaturation during apnea than the present authors observed.
An induction sequence designed to facilitate tracheal intubation ideally should do more than simply induce hypnosis and abet mechanical placement of the endotracheal tube. It should also ensure reflex suppression and cardiovascular stability. Thus, significant reductions in the authors' doses of propofol/opioid may not be realistic. In young, healthy subjects, perhaps the propofol dosage could be decreased to 1.5 mg/kg,10 but doses less than remifentanil 1.0 μg/kg or fentanyl 2 μg/kg are unlikely to suppress the hemodynamic response to intubation. Thus, it appears that muscle relaxant-facilitated intubation is here to stay.
An ideal neuromuscular blocker used for intubation should have fast onset and either rapid elimination or the potential for prompt and complete antagonism of its effect. Succinylcholine is still the “gold standard” in this regard. After a 1 mg/kg dose, succinylcholine establishes complete block at the adductor pollicis in 70 ± 20 seconds11 and first twitch (T1) height recovers to 10% of control in approximately 6 minutes and to 25% of control in 7 minutes.12,13 Diaphragmatic recovery takes place approximately 2 minutes earlier, and 50% recovery of this muscle's strength is seen in 5 to 6 minutes.14 These data correlate nicely with clinical observations of the return of respiratory efforts. Initial diaphragmatic movement is usually evident by 4.5 to 5.0 minutes after succinylcholine and recordable end-tidal carbon dioxide tracings follow shortly thereafter.7,15,16 Thus, assuming a patent airway and optimal preoxygenation, in healthy subjects, respiratory recovery generally commences just as clinically significant decreases in arterial saturation are about to take place. Reducing the dose of succinylcholine to 0.50 to 0.60 mg/kg will shorten recovery times by approximately 1 minute, but at the price of a reduced incidence of excellent conditions for intubation.17 However, for reasons not always evident, clinically significant desaturation may occur after relatively brief periods of apnea even in apparently healthy young patients.18
Does a better alternative to succinylcholine-facilitated intubation exist? Lee19 has suggested rocuronium-induced block with sugammadex antagonism as a superior and more reliable protocol. Lee et al.20 present data that support this hypothesis. They compared recovery times after succinylcholine 1 mg/kg with those after rocuronium 1.2 mg/kg reversed 3 minutes after administration with sugammadex 16 mg/kg. The time to 10% T1 recovery after succinylcholine was 7.1 ± 1.6 minutes, but only 4.4 ± 0.7 minutes after sugammadex reversal of rocuronium. This presumably implies considerable diaphragmatic recovery within 5 minutes of the time the relaxant was first administered. Unfortunately, Lee and coworkers20 did not measure the time to return to spontaneous respiration in their subjects nor did they report the doses of propofol and opioid administered for induction of anesthesia. As Stefanutto et al.1 have demonstrated, return to spontaneous ventilation (in the absence of neuromuscular blocking drugs) may be delayed after even modest doses of propofol and an opioid. Thus Lee et al.20 leave an important question unanswered. At a time when the majority of patients were no longer paralyzed were respiratory efforts evident?
Lee's study20 involved a rigidly controlled protocol. It was predetermined that sugammadex would be administered 3 minutes after rocuronium and therefore sugammadex was already drawn up and ready to inject. This of course assumes that the drug is immediately available in the operating room. However, economic considerations may preclude this in many institutions.21 To administer approximately 16 mg/kg of sugammadex to a 70-kg patient, a clinician would have to open six 200 mg vials, or three 500 mg vials. This takes time at a moment when the caregiver's attention may be focused on maintaining the airway. In addition, it may take the clinician a finite amount of time to determine that sugammadex is indeed indicated. Finally, all of Lee's patients were intubated within 50-90 seconds so that airway patency and oxygenation was never an issue. It is questionable if similar results can be duplicated in the real world of a CICV situation.22
Finally, a case report by Curtis et al.23 is instructive. These authors attempted tracheal intubation in a patient with a known difficult airway after administering rocuronium 0.6 mg kg−1, propofol 2.5 mg kg−1, and fentanyl 1.2 μg kg−1. After multiple unsuccessful attempts at intubation, sugammadex 16 mg kg−1 was administered. They noted that “…60 seconds [after sugammadex administration] spontaneous chest wall movement was observed with the patient beginning to make respiratory effort and moving her upper limbs. Train-of-four nerve stimulation showed no evidence of fade. An obstructed pattern of breathing was witnessed with no capnography trace or movement of the reservoir bag.”23 This appears to be a classic setup for the onset of negative pressure induced pulmonary edema. Thus an attempted “rescue reversal” of rocuronium or vecuronium with sugammadex in the absence of a patent airway is not risk free.
Even if some “magic bullet” could reliably assure deep paralysis within 60 seconds after its administration, and full recovery of the muscles of respiration 3 minutes later, it must be recognized that neuromuscular blockers are not administered in isolation. Recovery also implies return of spontaneous respiratory efforts and a patent airway. Hence the final question: is “rescue reversal” an obtainable goal? Megadose sugammadex administration following rocuronium clearly can produce a shorter duration of neuromuscular block than is seen after conventional intubating doses of succinylcholine. When CICV situations are anticipated and sugammadex is immediately available, this shortened period of vulnerability would certainly be advantageous. However, multiple factors (human error, airway anatomy, drug availability, etc.) may play a role during crisis situations.24 Thus when unforeseen difficulties in airway management arise, comparable results may not be so favorable. Additional research on this subject is badly needed. The present study by Stefanutto et al.1 provides an excellent model for evaluating intubation sequences when the airway is unprotected and spontaneous recovery of respiratory efforts are desired. Until more data is available, the concept of “rescue reversal” is perhaps best considered to be no more than a pipe-dream.
Name: Aaron F. Kopman, MD.
Contribution: This author helped write the manuscript.
Attestation: Aaron F. Kopman approved the final manuscript.
Name: Jiro Kurata, MD, PHD.
Contribution: This author helped write the manuscript.
Attestation: Jiro Kurata approved the final manuscript.
1. Stefanutto B, Feiner JR, Krombach J, Brown R, Caldwell JE. Hemoglobin desaturation after propofol/remifentanil-induced apnea: a study of the recovery of spontaneous ventilation in healthy volunteers. Anesth Analg 2012;114:980–6
2. Teller LE, Alexander CM, Frumin MJ, Gross JB. Pharyngeal insufflation of oxygen prevents arterial desaturation during apnea. Anesthesiology 1988;69:980–2
3. Taha SK, El-Khatib MF, Baraka AS, Haidar YA, Abdallah FW, Zbeidy RA, Siddik-Sayyid SM. Effect of suxamethonium vs rocuronium on onset of oxygen desaturation during apnoea following rapid sequence induction. Anaesthesia 2010;65:358–61
4. Tang L, Li S, Huang S, Ma H, Wang Z. Desaturation following rapid sequence induction using succinylcholine vs. rocuronium in overweight patients. Acta Anaesthesiol Scand 2011;55:203–8
5. Benumof JL, Dagg R, Benumof R. Critical hemoglobin desaturation will occur before return to an unparalysed state following 1 mg/kg intravenous succinylcholine. Anesthesiology 1997;87:979–82
6. Frumin MJ, Epstein RM, Cohen G. Apneic oxygenation in man. Anesthesiology 1959;20:789–98
7. Heier T, Feiner JR, Lin J, Brown R, Caldwell JE. Hemoglobin desaturation following succinylcholine-induced apnea: a study of the recovery of spontaneous ventilation in healthy volunteers. Anesthesiology 2001;94:754–9
8. 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
9. Sneyd JR, O'Sullivan E. Tracheal intubation without neuromuscular blocking agents: is there any point? Br J Anaesth 2010;104:535–7
10. Peacock JE, Spiers SP, McLauchlan GA, Edmondson WC, Berthoud M, Reilly CS. Infusion of propofol to identify smallest effective doses for induction of anaesthesia in young and elderly patients. Br J Anaesth 1992;69:363–7
11. Kopman AF, Zhaku B, Lai KS. The “intubating dose” of succinylcholine: the effect of decreasing doses on recovery time. Anesthesiology 2003;99:1050–4
12. Viby-Mogensen J. Correlation of succinylcholine duration of action with plasma cholinesterase activity in subjects with the genotypically normal enzyme. Anesthesiology 1980;53:517–20
13. Pansard JL, Chauvin M, Lebrault C, Gauneau P, Duvaldestin P. Effect of an intubating dose of succinylcholine and atracurium on the diaphragm and the adductor pollicis muscle in humans. Anesthesiology 1987;67:326–30
14. Dhonneur GD, Kirov K, Slavov V, Duvaldestin P. Effects of an intubating dose of succinylcholine and rocuronium on the larynx and diaphragm: an electromyographic study in humans. Anesthesiology 1999;90:951–5
15. El-Orbany M, Joseph NJ, Salem MR, Klowden AJ. The neuromuscular effects and tracheal intubation conditions after small doses of succinylcholine. Anesth Analg 2004;98:1680–5
16. Hayes AH, Breslin DS, Mirakhur RK, Reid JE, O'Hare RA. Frequency of haemoglobin desaturation with the use of succinylcholine during rapid sequence induction of anaesthesia. Acta Anaesthesiol Scand 2001;45:746–9
17. Naguib M, Samarkandi A, Riad W, Alharby SW. Optimal dose of succinylcholine revisited. Anesthesiology 2003;99:1045–9
18. Naguib M, Abdulhamid S, Khaled A, Waleed R, Salah A. Succinylcholine dosage and apnea-induced hemoglobin desaturation in patients. Anesthesiology 2005;102:35–40
19. Lee C. Goodbye to suxamethonium! Anaesthesia 2009;64:73–81
20. Lee C, Jahr JS, Candiotti CA, Warriner B, Zornow MH, Naguib M. Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine. Anesthesiology 2009;110:1020–5
21. Chambers D, Pauldenm, Paton M, Heirs M, Duffy S, Hunter JM, Schupher M, Woolacott N. Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment. Br J Anaesth 2010;105:568–75
22. Bisschops MM, Holleman C, Huitink JM. Can sugammadex save a patient in a simulated ‘cannot intubate, cannot ventilate' situation? Anaesthesia 2010;65:936–41
23. Curtis R, Lomax S, Patel B. Use of sugammadex in a 'can't intubate, can't ventilate' situation. Br J Anaesth 2012 . [Epub ahead of print]
24. Huitink JM, Bisschops M. Sugammadex and rescue reversal: a reply. Anaesthesia 2011;66:141