ORIGINAL ARTICLE
Alfentanil during rapid sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg: tracheal intubation conditions M. H. Abou-Arab1, J. R. Feiner2, O. Spigset3,4 and T. Heier5 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital, Oslo, Norway Anesthesia and Perioperative Care, University of California, UCSF, San Francisco, CA, USA Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Correspondence T. Heier, Department of Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway E-mail: [email protected] Conflicts of interest There is no conflict of interest regarding this study for any of the authors. Funding The study was supported solely by departmental funds. The study is registered with Clinicaltrials.gov (NTC 01518608). Submitted 19 June 2015; accepted 22 June 2015; submission 29 March 2015. Citation Abou-Arab MH, Feiner JR, Spigset O, Heier T. Alfentanil during rapid sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg: tracheal intubation conditions. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12584
Background: Opioids have become an integral part of anaesthesia induction. We aimed to determine the dose of alfentanil needed to obtain perfect tracheal intubation conditions during rapid sequence induction with standard doses of thiopental and rocuronium, where laryngoscopy was initiated 55 s after commencement of drug administration. The influence of covariates (sex, body weight, age, alfentanil plasma concentration at laryngoscopy) was tested. Methods: Eighty-four healthy individuals were randomly assigned to receive one of the seven assessor-blinded alfentanil doses (0, 10, 20, 30, 40, 50 and 60 lg/kg) in conjunction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. For drug administration, 15 s was allowed. Laryngoscopy was initiated 40 s after rocuronium and tracheal intubation concluded within 70 s after commencement of drug administration. Alfentanil doses associated with 50%, 90% and 95% probability of perfect intubation conditions were determined with logistic regression. Multiple logistic regressions were used to test the influence of covariates. The relationship between alfentanil dose and concentration at laryngoscopy was analysed with linear regression. The effects of covariates on plasma concentrations of alfentanil were tested with multiple linear regressions. Results: Perfect intubation conditions of 95% probability was obtained with 56 lg/kg (confidence intervals 44–68). None of the covariates were significant predictors of perfect intubation conditions. Alfentanil plasma concentration correlated with dose and increased with increasing body weight (1.7 ng/ml/kg). Conclusion: Perfect intubation conditions during rapid sequence induction can be obtained with clinically relevant doses of alfentanil in most healthy patients anaesthetized with thiopental 4 mg/ kg and rocuronium 0.6 mg/kg.
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RSII: ALFENTANIL AND INTUBATION
Editorial comment: what this article tells us
In healthy adult subjects, rapid sequence intubation could be performed with optimal conditions in 95% of subjects with induction agents thiopental 4 mg/kg and rocuronium 0.6 mg/kg, as long as there was also a dose of at least 50 lg/kg of alfentanil. It has been suggested that suxamethonium should be replaced with rocuronium during rapid sequence induction of anaesthesia (RSII).1,2 In an RSII study including 133 patients anaesthetized with propofol 2.5 mg/kg and rocuronium 1 mg/kg, perfect intubation conditions were obtained in 66% within 90 s after commencement of drug administration.3 In emergency situations where avoidance of coughing may be important,4–7 an RSII technique that ensures higher probability of optimal intubation conditions may be needed. Also, the anaesthesiologist might prefer to perform tracheal intubation after a shorter apnoea time than in the study by Andrews et al.3 Although an opioid may not be the ideal drug for suppressing the cough reflex,7,8 adding an opioid to the standard induction regimen may serve both these goals.9 We have previously reported 95% probability of perfect intubation conditions 40 s after administration of rocuronium 1 mg/kg, if preceded by alfentanil 36 lg/ kg and thiopental 4 mg/kg.10 However, clinicians may be reluctant to administer higher doses of rocuronium than normally used in elective cases because the surgical procedure may require rapid recovery of muscle strength after administration of the intubating dose, or because the highly effective reversal agent sugammadex is not available. We aimed to determine the dose of alfentanil needed together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg to obtain perfect intubation conditions 40 s after rocuronium. Pharmacokinetics and pharmacodynamics of drugs used in anaesthesia may be influenced by sex, body weight and age.11–15 The central volume of distribution of alfentanil appears to decrease with increasing body weight, and to increase in females compared to males when normalized by body weight.14 Assuming greater average body weight in males than females, the sum of these pharmacokinetic effects suggests that higher maximum blood concentrations of
alfentanil are achieved, and consequently higher likelihood of perfect intubation conditions, in males. As a secondary aim, we investigated if alfentanil blood concentrations during RSII differed between sexes, and if this resulted in a sex-related difference in the probability of perfect intubation conditions. The influence on intubation conditions of body weight, age and alfentanil plasma concentration at laryngoscopy was tested as well. Materials and methods This single centre clinical study was conducted at Oslo University Hospital, a tertiary care surgical hospital. Ethics approval (Ethical Committee #99042) was provided by the Review Board of the Norwegian Committee on Ethics in Human Research (Region Eastern Norway, Chairperson Professor Knut Engedal) on January 21, 2008. A written informed consent was obtained from all participants. Study subjects were enrolled between Jan 2009 and Dec 2012. Eligible study subjects were ASA class 1 patients with Mallampati airway class 1 or 2, scheduled for elective surgery. Exclusion criteria were: age > 55 or < 18 years, BMI > 28 kg m2, presence of gastrooesophageal reflux, neuromuscular disease, use of medication known to interfere with cardiovascular or neuromuscular function, and anticipated difficult airway requiring > 15 s of laryngoscopy. Eighty-four eligible patients, undergoing gastrointestinal or urological procedures, were randomly allocated using random number table to receive one of the seven different doses of alfentanil (0, 10, 20, 30, 40, 50 or 60 lg/kg). The allocation sequence was concealed from the researchers by using numbered, opaque and sealed envelopes containing information on the dose of alfentanil to be used. A nurse anaesthetists not involved in the study picked the envelope that would be assigned to the study subjects, and prepared the drug amount
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16. Fuchs-Buder T, Claudius C, Skovgaard LT, Eriksson LI, Mirakhur RK, Viby-Mogensen J. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007; 51: 789–808. 17. Engelman L. Stepwise logistic regression, BMDP statistical software. Dixon W ed. Berkeley: University of California Press, 1990: 1013–46. 18. Heier T, Caldwell J. Rapid tracheal intubation with large-dose rocuronium: a probability-based approach. Anesth Analg 2000; 90: 175–9. 19. Kirkegaard-Nielsen H, Caldwell JE, Berry PD. Rapid tracheal intubation with rocuronium: a probability approach to determining optimal dose. Anesthesiology 1999; 91: 131–6. 20. Manley B. The bootstrap, randomization, bootstrap and Monte Carlo methods in biology. Manly BFJ ed. London: Chapman and Hall, 1997: 34–68. 21. Crul JF, Vanbelleghem V, Buyse L, Heylen R, van Egmond J. Rocuronium with alfentanil and propofol allows intubation within 45 seconds. Eur J Anaesthesiol Suppl 1995; 11: 111–2. 22. Shafer S, Varvel J. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 1991; 74: 53–63. 23. Miller DR, Martineau RJ, O’Brien H, Hull KA, Oliveras L, Hindmarsh T, Greenway D. Effects of alfentanil on the hemodynamic and catecholamine response to tracheal intubation. Anesth Analg 1993; 76: 1040–6. 24. Hassan HG, el-Sharkawy TY, Renck H, Mansour G, Fouda A. Hemodynamic and catecholamine responses to laryngoscopy with vs. without endotracheal intubation. Acta Anaesthesiol Scand 1991; 35: 442–7.
25. Egan T, Minto C, Hermann D, Barr J, Muir K, Shafer S. Remifentanil vs alfentanil. Anesthesiology 1996; 84: 821–33. 26. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234–41. 27. Taha S, Siddik-Sayyid S, Alameddine M, Wakim C, Dahabra C, Moussa A, Khatib M, Baraka A. Propofol is superior to thiopental for intubation without muscle relaxants. Can J Anaesth 2005; 52: 249–53. 28. Calvo R, Telletxea S, Leal N, Aguilera L, Suarez E, De La Fuente L, Martin-Suarez A, Lukas JC. Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand 2004; 48: 1038–48. 29. Stanski DR, Hudson RJ, Homer TD, Saidman LJ, Meathe E. Pharmacometrics: pharmacodynamic modeling of thiopental anesthesia. J Pharmacokinet Biopharm 1984; 12: 223–40. 30. Rouby JJ, Andreev A, Leger P, Arthaud M, Landault C, Vicaut E, Maistre G, Eurin J, Gandjbakch I, Viars P. Peripheral vascular effects of thiopental and propofol in humans with artificial hearts. Anesthesiology 1991; 75: 32–42. 31. Sellick BA. Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia. Lancet 1961; 2: 404–6. 32. Ellis DY, Harris T, Zideman D. Cricoid pressure in emergency department rapid sequence tracheal intubations: a risk-benefit analysis. Ann Emerg Med 2007; 50: 653–65. 33. Hartsilver EL, Vanner RG. Airway obstruction with cricoid pressure. Anaesthesia 2000; 55: 208–11. 34. Haslam N, Parker L, Duggan JE. Effect of cricoid pressure on the view at laryngoscopy. Anaesthesia 2005; 60: 41–7.
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0
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0.2 lg/kg was administered if systolic ABP decreased below 70 mmHg. If systolic ABP post intubation increased > 50% of pre-induction values, either thiopental 1 mg/kg or alfentanil 10 lg/kg was allowed. A BIS sensor was attached to the forehead of the patient. Thiopental 1–2 mg/kg was allowed if the BIS value increased above 60 during the first 5 min post intubation. Five min post intubation, the patient received additional anaesthesia-related drugs at the attending anaesthesiologist’s discretion. When laryngoscopy was initiated, i.e. 55 s after commencement of drug administration, an arterial blood sample was taken to determine the plasma concentration of alfentanil. Blood samples were centrifuged immediately and plasma stored at 70°C. Specimens were analysed with liquid chromatography mass spectrometry (LC-MS) after liquid–liquid extraction. Flurazepam was used as the internal standard. The analyses were performed on an Agilent LCMSD 1100 system (Agilent Technologies, Palo Alto, CA, USA), with a Zorbax SB-C18, 150 mm 9 4.6 mm, 5 lm particle size, as analytical column. The mass transitions were m/z 417.2 > 268.2 > 197.1 > 165.1 for alfentanil and m/z 388.1 for flurazepam. The limit of quantification was 1.5 ng/ml and the method was linear at least up to 500 ng/ml. Between-day coefficients of variation were assessed at three different concentrations (low, medium and high), and were < 5% at all concentration levels. Sample size determination Success rates obtained from the different patient groups were not compared, but analysed together in the same modelling process, i.e. using logistic regression. Therefore, traditional power analysis was not applicable. However, a basic requirement for the regression analysis to
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Fig. 1. The figure shows the timeline of events (drug administration, apnoea, tracheal intubation, cuff insufflation) occurring during the RSII procedure.
Apnea period
Tracheal intubation
Induction
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TIMELINE OF RSII PROCEDURE (s)
work properly is that the success rate of the binary variable, i.e. obtaining either perfect (success) or less than perfect (failure) intubation conditions, increases gradually with increasing doses of the study drug.17 The inclusion of a wide range of study drug doses accommodates this requirement. The probability approach employed has been used successfully in previous studies.10,18,19 Statistics Demographic data between alfentanil dose groups were compared by ANOVA and Chisquare test. The relationship between alfentanil dose and probability of obtaining perfect intubation condition was analysed using logistic regression,17 equation: Fraction of success ¼ m3 þ ð1 m3ÞðA=ðA þ 1ÞÞ A is EXP (m1 + m2 (dose)), m1 and m2 are the inbuilt parameters of the logistic regression program, and m3 an additional parameter allowing for the proportion of patients who is scored as a success when no alfentanil is used. The doses of alfentanil that gave 50%, 90% and 95% probability of success (ED50, ED90 and ED95 respectively) and their 95% confidence intervals (CIs) were determined using inverse prediction.20 Multivariate logistic regression was used to analyse the effect of alfentanil dose, sex, body weight, age and alfentanil plasma concentration at laryngoscopy on the success rate of perfect intubation conditions. The relationship between alfentanil dose and concentration was analysed by linear regression. To examine for a possible non-linear relation-
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ship, a polynomial term (dose2) was added and tested for statistical significance. Multiple linear regressions were used to determine whether sex, body weight or age affected alfentanil blood concentration. To determine if lack of perfect intubation conditions in a particular individual was caused by a low alfentanil blood concentration, concentrations obtained within each alfentanil dose group were compared between patients with perfect intubation condition and those without, using Mann–Whitney U-test. Data were analysed using JMP 10.0 (SAS Institute, Cary, NC, USA) and Stata 12.0 (StataCorp, College Station, TX, USA). Differences were considered significant if P < 0.05. Results Eighty-eight patients were enrolled. Three study subjects were excluded due to technical problems (with insertion of the arterial line in 10, 20 and 50 lg/kg dose groups respectively), and one because of unanticipated difficult tracheal intubation (60 lg/kg dose group). No differences were found in sex distribution, body weight or age between the different alfentanil dose groups (Table 1). Success rates of perfect intubation conditions across alfentanil dose groups are presented in Table 1. The relationship between alfentanil dose and the probability of obtaining perfect intubation conditions was statistically significant (P < 0.0001, Fig. 2). Our best estimates of the ED50, 90 and 95 values, irrespective of sex, were 22 (CI 14–30), 51 (CI 41–61) and 56 (CI 44–68) lg/kg respectively. The ED50, 90 and 95 values for males and females separately, were 27 (CI 19–35) and 18 (CI 10–26), 52 (CI 42–62) and 36 (CI 26–46), and 62 (CI 50–74) and 44 (34–54) lg/kg respectively (P = 0.15). Neither body weight (P = 0.76), age (P = 0.58) or alfentanil plasma concentration at laryngoscopy (P = 0.91) were significant predictors of perfect intubation conditions. When adding both alfentanil dose and concentration to the multivariate model, only alfentanil dose was a significant predictor. A significant linear relationship was found between alfentanil dose and alfentanil concentration (Fig. 3, P < 0.0001). The polynomial term
Fig. 2. The figure shows the logistic regression between alfentanil dose and fractional success (probability of success) of obtaining perfect intubation conditions. The relationship was statistically significant (P < 0.0001). The estimated ED50, ED90 and ED95 were 22 (CI 14–30), 51 (CI 41–61) and 56 (CI 44–68) lg/kg respectively. X-error bars represent the 95% confidence intervals.
Fig. 3. The graph shows the linear relationship between alfentanil dose and concentration. Open diamonds represent mean values at each alfentanil dose including all study subjects, and the error bars are standard deviations. The relationship was statistically significant (P < 0.0001). Individual data points at each alfentanil dose are shown separately for males (closed circles) and females (open circles). For clarity reasons, the data points are displaced slightly to the right (males) and left (females). Acta Anaesthesiologica Scandinavica 59 (2015) 1278–1286
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Table 2 Comparison of patients with (success) and without (failure) perfect intubation conditions. Numbers are mean SD. Success Age (years) 39.0 11.0 Weight (kg) 75.2 10.8 No of Males (M)/No 25 M/25 F of Females (F) Alfentanil dose group (mg/kg) vs. concentration (ng/ml) 0 0 10 66 6 20 144 21 30 241 83 40 283 72 50 295 64 60 427 109
Failure
All
P value (success vs. failure)
41.9 8.3 74.1 12.8 18 M/16 F
40.2 10.1 74.7 11.6 43 M/41 F
0.25 0.51 –
0 70 146 236 227 317 –
0 69 145 239 274 297 427
0.86 0.75 0.87 0.28 0.66 –
did not indicate that the relationship was better described with a non-linear function. The alfentanil plasma concentration increased with 1.7 ng/ml/kg increase in body weight (P = 0.0084). Sex did not affect alfentanil concentration (P = 0.33), even when adjusting for body weight (P = 0.32). Age was not a statistically significant factor either alone (P = 0.082) or when including body weight (P = 0.17). The average alfentanil plasma concentrations were similar in patients with and without perfect intubation conditions (Table 2). Systolic ABP < 90 mm Hg post intubation occurred in eight study subjects and < 70 mmHg in one (in the alfentanil 10 lg/kg group). Four patients needed additional anaesthetics post intubation due to exaggerated arterial blood pressure response, three in the alfentanil 0 lg/ kg and one in the alfentanil 10 lg/kg groups. Discussion RSII with propofol 2.5 mg/kg and rocuronium 0.6 lg/kg provides acceptable intubation conditions in a high percentage of patients if 90 s is allowed to complete tracheal intubation.3 In certain situations, it may be preferable to establish airway control within a shorter time range, especially in patients with high probability of regurgitation or development of hypoxaemia during the apnoea period. Previous studies show that acceptable tracheal intubation conditions can be achieved 40–45 s after rocuronium
0 22 91 70 94
0 18 63 73 75 62 109
0.6 lg/kg in most patients if alfentanil 20– 30 lg/kg is part of an induction regimen with standard doses of either propofol or thiopental.9,21 In the present study, we have shown that even perfect intubation conditions can be obtained, but that the average alfentanil dose must be increased to 56 lg/kg. Alfentanil 50– 60 lg/kg might be considered a relatively large dose of this drug. However, our data show that such doses can safely be administered as rapid boluses in healthy individuals because none of the study subjects receiving 50 or 60 lg/kg needed treatment for hypotension. Prolonged respiratory depression might be a concern when alfentanil 50–60 lg/kg is administered, but alfentanil distributes rapidly,22 and therefore its plasma concentration should decline below the threshold for spontaneous ventilation within 30 min after a bolus dose of this magnitude.23 The ED95 to obtain perfect intubation conditions obtained in the present study is significantly greater than that determined in our previous investigation (36 lg/kg, 95% CI 33– 39) using an identical study design except for a larger rocuronium dose (1 lg/kg).10 Therefore, it appears that decreasing the dose of rocuronium from 1.0 to 0.6 mg/kg has a great influence on the intubation conditions during RSII when laryngoscopy is initiated 40 s later. The alfentanil blood concentration at laryngoscopy increased with increasing body weight, consistent with previous findings that the drug’s central volume of distribution
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decreases with increasing body weight.14 The average male therefore acquire higher blood concentration of alfentanil than the average female when the drug is administered on mg per kg basis, simply because the body mass is greater. However, in the present study, this did not translate into a higher probability of perfect intubation conditions in males. A plausible reason for this finding is that the stimulus intensity during tracheal intubation increases with increasing body weight as well, and because there is a relationship between the magnitude of noxious stimuli and the release of catecholamines,24 the effect of a greater alfentanil plasma concentration is balanced out. Our results are rather consistent with the assumption that females might need less alfentanil than males to obtain perfect intubation conditions (ED95 62 vs. 44 lg/kg). Although this apparent sex-related difference did not reach the significance level (P = 0.15), the reason might well be a type II error due to the relatively low number of subjects included. As expected, alfentanil dose and alfentanil concentration at laryngoscopy correlated (Fig. 3), but only alfentanil dose was a significant predictor of perfect intubation conditions. There are plausible pharmacokinetic–pharmacodynamic reasons for this apparent discrepancy. First, during the initial minutes after an intravenous drug bolus, a concentration hysteresis exists between blood stream and effect site, implying that the alfentanil plasma concentrations at laryngoscopy obtained in the present study did not reflect that of the central nervous system.22,25 Second, this single, non-steadystate measurement of the alfentanil plasma concentration does not take into account the individual variability in drug sensitivity, which is the ultimate pharmacodynamic factor contributing to drug effect.26. Alfentanil dose is likely a better predictor of drug effect than non-steadystate alfentanil plasma concentration because a drug’s dose–effect relationship accounts for both pharmacokinetics (i.e. drug concentration in the blood stream) and pharmacodynamics (i.e. drug sensitivity). Therefore, in a clinical perspective, measurements of plasma concentrations of alfentanil at the time of laryngoscopy, if they were available, do not appear to concur any advantage when an optimal regimen for
alfentanil administration is to be decided (Fig. 3). The same pharmacokinetic–pharmacodynamic factors may also explain why alfentanil plasma concentrations were similar in patients with and without perfect intubation conditions (Table 2). An identical plasma drug concentration obtained at laryngoscopy in two different individuals after bolus administrations of alfentanil will likely be associated with dissimilar effect site concentrations due to inter-individual variability in the blood–brain equilibration rate (hysteresis), and consequently with different magnitude of airway responses to tracheal intubation. And again, inter-individual differences in sensitivity to alfentanil will certainly also contribute to response variability, even if the effect site concentrations were similar. In the present study, thiopental was used for sedation during induction of anaesthesia. Many clinicians prefer propofol, even in emergency situations, due to its superior muscle relaxing effect.27 We chose to use thiopental because it has faster onset than propofol,28,29 and less potential for hypotension and bradycardia.30 Thiopental may therefore be considered a safer hypnotic agent than propofol when the drugs are administered as rapid boluses. We believe our study design was appropriate to answer our primary research question, i.e. determination of the alfentanil dose needed to obtain perfect intubation conditions under RSII settings. First, we took advantage of one of the alfentanil’s onset characteristics, i.e. that the effect site concentration is at its peak approximately 60 s after a bolus injection,25 and designed an induction regimen where the noxious stimulation of the airway occurred between 55 and 70 s after drug administration. Second, as our research question could not be addressed properly by using a group comparison technique, we applied a probability approach, a technique that allows for the inclusion of a wide range of doses of the study drug. Our approach has also been used successfully in dose–response studies previously.10,18,19 We further believe that the estimated alfentanil dose to obtain perfect intubation conditions in 95% of the individuals is reliable. First, logistic regression is frequently used in the anaesthetic literature to describe relationships Acta Anaesthesiologica Scandinavica 59 (2015) 1278–1286
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between drug dose and binary variables. Second, the basic requirement for the regression analysis to work properly, a gradual increase in success rate with increasing drug dose, was met in this study. Although generally recommended in emergency situations,31 cricoid pressure was not applied in the present study. The main reason was that studies have shown that this procedure may impede visualization of larynx or even obstruct the airway.32–34 Omitting use of this procedure therefore secured as uniform intubation conditions as possible. The present study has one major limitation. The data obtained are only directly applicable to healthy individuals without difficult airways. Unfortunately, ethical considerations precluded inclusion of study subjects with significant organ dysfunction because, due to the study design, such participants might have been exposed to a potentially harmful drug regimen, i.e. either a relatively large dose of alfentanil or no alfentanil at all. In conclusion, when alfentanil 56 lg/kg, thiopental 4 mg/kg and rocuronium 0.6 mg/kg are administered in rapid succession, perfect intubation conditions are obtained in most patients 40 s after rocuronium.
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16. Fuchs-Buder T, Claudius C, Skovgaard LT, Eriksson LI, Mirakhur RK, Viby-Mogensen J. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007; 51: 789–808. 17. Engelman L. Stepwise logistic regression, BMDP statistical software. Dixon W ed. Berkeley: University of California Press, 1990: 1013–46. 18. Heier T, Caldwell J. Rapid tracheal intubation with large-dose rocuronium: a probability-based approach. Anesth Analg 2000; 90: 175–9. 19. Kirkegaard-Nielsen H, Caldwell JE, Berry PD. Rapid tracheal intubation with rocuronium: a probability approach to determining optimal dose. Anesthesiology 1999; 91: 131–6. 20. Manley B. The bootstrap, randomization, bootstrap and Monte Carlo methods in biology. Manly BFJ ed. London: Chapman and Hall, 1997: 34–68. 21. Crul JF, Vanbelleghem V, Buyse L, Heylen R, van Egmond J. Rocuronium with alfentanil and propofol allows intubation within 45 seconds. Eur J Anaesthesiol Suppl 1995; 11: 111–2. 22. Shafer S, Varvel J. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 1991; 74: 53–63. 23. Miller DR, Martineau RJ, O’Brien H, Hull KA, Oliveras L, Hindmarsh T, Greenway D. Effects of alfentanil on the hemodynamic and catecholamine response to tracheal intubation. Anesth Analg 1993; 76: 1040–6. 24. Hassan HG, el-Sharkawy TY, Renck H, Mansour G, Fouda A. Hemodynamic and catecholamine responses to laryngoscopy with vs. without endotracheal intubation. Acta Anaesthesiol Scand 1991; 35: 442–7.
25. Egan T, Minto C, Hermann D, Barr J, Muir K, Shafer S. Remifentanil vs alfentanil. Anesthesiology 1996; 84: 821–33. 26. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234–41. 27. Taha S, Siddik-Sayyid S, Alameddine M, Wakim C, Dahabra C, Moussa A, Khatib M, Baraka A. Propofol is superior to thiopental for intubation without muscle relaxants. Can J Anaesth 2005; 52: 249–53. 28. Calvo R, Telletxea S, Leal N, Aguilera L, Suarez E, De La Fuente L, Martin-Suarez A, Lukas JC. Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand 2004; 48: 1038–48. 29. Stanski DR, Hudson RJ, Homer TD, Saidman LJ, Meathe E. Pharmacometrics: pharmacodynamic modeling of thiopental anesthesia. J Pharmacokinet Biopharm 1984; 12: 223–40. 30. Rouby JJ, Andreev A, Leger P, Arthaud M, Landault C, Vicaut E, Maistre G, Eurin J, Gandjbakch I, Viars P. Peripheral vascular effects of thiopental and propofol in humans with artificial hearts. Anesthesiology 1991; 75: 32–42. 31. Sellick BA. Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia. Lancet 1961; 2: 404–6. 32. Ellis DY, Harris T, Zideman D. Cricoid pressure in emergency department rapid sequence tracheal intubations: a risk-benefit analysis. Ann Emerg Med 2007; 50: 653–65. 33. Hartsilver EL, Vanner RG. Airway obstruction with cricoid pressure. Anaesthesia 2000; 55: 208–11. 34. Haslam N, Parker L, Duggan JE. Effect of cricoid pressure on the view at laryngoscopy. Anaesthesia 2005; 60: 41–7.
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Alfentanil during rapid sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg: tracheal intubation conditions M. H. Abou-Arab1, J. R. Feiner2, O. Spigset3,4 and T. Heier5 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital, Oslo, Norway Anesthesia and Perioperative Care, University of California, UCSF, San Francisco, CA, USA Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
Correspondence T. Heier, Department of Anesthesia, Division of Emergencies and Critical Care Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway E-mail: [email protected] Conflicts of interest There is no conflict of interest regarding this study for any of the authors. Funding The study was supported solely by departmental funds. The study is registered with Clinicaltrials.gov (NTC 01518608). Submitted 19 June 2015; accepted 22 June 2015; submission 29 March 2015. Citation Abou-Arab MH, Feiner JR, Spigset O, Heier T. Alfentanil during rapid sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg: tracheal intubation conditions. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12584
Background: Opioids have become an integral part of anaesthesia induction. We aimed to determine the dose of alfentanil needed to obtain perfect tracheal intubation conditions during rapid sequence induction with standard doses of thiopental and rocuronium, where laryngoscopy was initiated 55 s after commencement of drug administration. The influence of covariates (sex, body weight, age, alfentanil plasma concentration at laryngoscopy) was tested. Methods: Eighty-four healthy individuals were randomly assigned to receive one of the seven assessor-blinded alfentanil doses (0, 10, 20, 30, 40, 50 and 60 lg/kg) in conjunction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. For drug administration, 15 s was allowed. Laryngoscopy was initiated 40 s after rocuronium and tracheal intubation concluded within 70 s after commencement of drug administration. Alfentanil doses associated with 50%, 90% and 95% probability of perfect intubation conditions were determined with logistic regression. Multiple logistic regressions were used to test the influence of covariates. The relationship between alfentanil dose and concentration at laryngoscopy was analysed with linear regression. The effects of covariates on plasma concentrations of alfentanil were tested with multiple linear regressions. Results: Perfect intubation conditions of 95% probability was obtained with 56 lg/kg (confidence intervals 44–68). None of the covariates were significant predictors of perfect intubation conditions. Alfentanil plasma concentration correlated with dose and increased with increasing body weight (1.7 ng/ml/kg). Conclusion: Perfect intubation conditions during rapid sequence induction can be obtained with clinically relevant doses of alfentanil in most healthy patients anaesthetized with thiopental 4 mg/ kg and rocuronium 0.6 mg/kg.
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RSII: ALFENTANIL AND INTUBATION
Editorial comment: what this article tells us
In healthy adult subjects, rapid sequence intubation could be performed with optimal conditions in 95% of subjects with induction agents thiopental 4 mg/kg and rocuronium 0.6 mg/kg, as long as there was also a dose of at least 50 lg/kg of alfentanil. It has been suggested that suxamethonium should be replaced with rocuronium during rapid sequence induction of anaesthesia (RSII).1,2 In an RSII study including 133 patients anaesthetized with propofol 2.5 mg/kg and rocuronium 1 mg/kg, perfect intubation conditions were obtained in 66% within 90 s after commencement of drug administration.3 In emergency situations where avoidance of coughing may be important,4–7 an RSII technique that ensures higher probability of optimal intubation conditions may be needed. Also, the anaesthesiologist might prefer to perform tracheal intubation after a shorter apnoea time than in the study by Andrews et al.3 Although an opioid may not be the ideal drug for suppressing the cough reflex,7,8 adding an opioid to the standard induction regimen may serve both these goals.9 We have previously reported 95% probability of perfect intubation conditions 40 s after administration of rocuronium 1 mg/kg, if preceded by alfentanil 36 lg/ kg and thiopental 4 mg/kg.10 However, clinicians may be reluctant to administer higher doses of rocuronium than normally used in elective cases because the surgical procedure may require rapid recovery of muscle strength after administration of the intubating dose, or because the highly effective reversal agent sugammadex is not available. We aimed to determine the dose of alfentanil needed together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg to obtain perfect intubation conditions 40 s after rocuronium. Pharmacokinetics and pharmacodynamics of drugs used in anaesthesia may be influenced by sex, body weight and age.11–15 The central volume of distribution of alfentanil appears to decrease with increasing body weight, and to increase in females compared to males when normalized by body weight.14 Assuming greater average body weight in males than females, the sum of these pharmacokinetic effects suggests that higher maximum blood concentrations of
alfentanil are achieved, and consequently higher likelihood of perfect intubation conditions, in males. As a secondary aim, we investigated if alfentanil blood concentrations during RSII differed between sexes, and if this resulted in a sex-related difference in the probability of perfect intubation conditions. The influence on intubation conditions of body weight, age and alfentanil plasma concentration at laryngoscopy was tested as well. Materials and methods This single centre clinical study was conducted at Oslo University Hospital, a tertiary care surgical hospital. Ethics approval (Ethical Committee #99042) was provided by the Review Board of the Norwegian Committee on Ethics in Human Research (Region Eastern Norway, Chairperson Professor Knut Engedal) on January 21, 2008. A written informed consent was obtained from all participants. Study subjects were enrolled between Jan 2009 and Dec 2012. Eligible study subjects were ASA class 1 patients with Mallampati airway class 1 or 2, scheduled for elective surgery. Exclusion criteria were: age > 55 or < 18 years, BMI > 28 kg m2, presence of gastrooesophageal reflux, neuromuscular disease, use of medication known to interfere with cardiovascular or neuromuscular function, and anticipated difficult airway requiring > 15 s of laryngoscopy. Eighty-four eligible patients, undergoing gastrointestinal or urological procedures, were randomly allocated using random number table to receive one of the seven different doses of alfentanil (0, 10, 20, 30, 40, 50 or 60 lg/kg). The allocation sequence was concealed from the researchers by using numbered, opaque and sealed envelopes containing information on the dose of alfentanil to be used. A nurse anaesthetists not involved in the study picked the envelope that would be assigned to the study subjects, and prepared the drug amount
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16. Fuchs-Buder T, Claudius C, Skovgaard LT, Eriksson LI, Mirakhur RK, Viby-Mogensen J. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007; 51: 789–808. 17. Engelman L. Stepwise logistic regression, BMDP statistical software. Dixon W ed. Berkeley: University of California Press, 1990: 1013–46. 18. Heier T, Caldwell J. Rapid tracheal intubation with large-dose rocuronium: a probability-based approach. Anesth Analg 2000; 90: 175–9. 19. Kirkegaard-Nielsen H, Caldwell JE, Berry PD. Rapid tracheal intubation with rocuronium: a probability approach to determining optimal dose. Anesthesiology 1999; 91: 131–6. 20. Manley B. The bootstrap, randomization, bootstrap and Monte Carlo methods in biology. Manly BFJ ed. London: Chapman and Hall, 1997: 34–68. 21. Crul JF, Vanbelleghem V, Buyse L, Heylen R, van Egmond J. Rocuronium with alfentanil and propofol allows intubation within 45 seconds. Eur J Anaesthesiol Suppl 1995; 11: 111–2. 22. Shafer S, Varvel J. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology 1991; 74: 53–63. 23. Miller DR, Martineau RJ, O’Brien H, Hull KA, Oliveras L, Hindmarsh T, Greenway D. Effects of alfentanil on the hemodynamic and catecholamine response to tracheal intubation. Anesth Analg 1993; 76: 1040–6. 24. Hassan HG, el-Sharkawy TY, Renck H, Mansour G, Fouda A. Hemodynamic and catecholamine responses to laryngoscopy with vs. without endotracheal intubation. Acta Anaesthesiol Scand 1991; 35: 442–7.
25. Egan T, Minto C, Hermann D, Barr J, Muir K, Shafer S. Remifentanil vs alfentanil. Anesthesiology 1996; 84: 821–33. 26. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234–41. 27. Taha S, Siddik-Sayyid S, Alameddine M, Wakim C, Dahabra C, Moussa A, Khatib M, Baraka A. Propofol is superior to thiopental for intubation without muscle relaxants. Can J Anaesth 2005; 52: 249–53. 28. Calvo R, Telletxea S, Leal N, Aguilera L, Suarez E, De La Fuente L, Martin-Suarez A, Lukas JC. Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand 2004; 48: 1038–48. 29. Stanski DR, Hudson RJ, Homer TD, Saidman LJ, Meathe E. Pharmacometrics: pharmacodynamic modeling of thiopental anesthesia. J Pharmacokinet Biopharm 1984; 12: 223–40. 30. Rouby JJ, Andreev A, Leger P, Arthaud M, Landault C, Vicaut E, Maistre G, Eurin J, Gandjbakch I, Viars P. Peripheral vascular effects of thiopental and propofol in humans with artificial hearts. Anesthesiology 1991; 75: 32–42. 31. Sellick BA. Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia. Lancet 1961; 2: 404–6. 32. Ellis DY, Harris T, Zideman D. Cricoid pressure in emergency department rapid sequence tracheal intubations: a risk-benefit analysis. Ann Emerg Med 2007; 50: 653–65. 33. Hartsilver EL, Vanner RG. Airway obstruction with cricoid pressure. Anaesthesia 2000; 55: 208–11. 34. Haslam N, Parker L, Duggan JE. Effect of cricoid pressure on the view at laryngoscopy. Anaesthesia 2005; 60: 41–7.
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0
5
Airway control
10
15
0.2 lg/kg was administered if systolic ABP decreased below 70 mmHg. If systolic ABP post intubation increased > 50% of pre-induction values, either thiopental 1 mg/kg or alfentanil 10 lg/kg was allowed. A BIS sensor was attached to the forehead of the patient. Thiopental 1–2 mg/kg was allowed if the BIS value increased above 60 during the first 5 min post intubation. Five min post intubation, the patient received additional anaesthesia-related drugs at the attending anaesthesiologist’s discretion. When laryngoscopy was initiated, i.e. 55 s after commencement of drug administration, an arterial blood sample was taken to determine the plasma concentration of alfentanil. Blood samples were centrifuged immediately and plasma stored at 70°C. Specimens were analysed with liquid chromatography mass spectrometry (LC-MS) after liquid–liquid extraction. Flurazepam was used as the internal standard. The analyses were performed on an Agilent LCMSD 1100 system (Agilent Technologies, Palo Alto, CA, USA), with a Zorbax SB-C18, 150 mm 9 4.6 mm, 5 lm particle size, as analytical column. The mass transitions were m/z 417.2 > 268.2 > 197.1 > 165.1 for alfentanil and m/z 388.1 for flurazepam. The limit of quantification was 1.5 ng/ml and the method was linear at least up to 500 ng/ml. Between-day coefficients of variation were assessed at three different concentrations (low, medium and high), and were < 5% at all concentration levels. Sample size determination Success rates obtained from the different patient groups were not compared, but analysed together in the same modelling process, i.e. using logistic regression. Therefore, traditional power analysis was not applicable. However, a basic requirement for the regression analysis to
20
25
30
35
40
45
50
55
60
Cuff insufflation
Laryngoscopy
Rocuronium
Thiopental
Alfentanil
Fig. 1. The figure shows the timeline of events (drug administration, apnoea, tracheal intubation, cuff insufflation) occurring during the RSII procedure.
Apnea period
Tracheal intubation
Induction
65
70
TIMELINE OF RSII PROCEDURE (s)
work properly is that the success rate of the binary variable, i.e. obtaining either perfect (success) or less than perfect (failure) intubation conditions, increases gradually with increasing doses of the study drug.17 The inclusion of a wide range of study drug doses accommodates this requirement. The probability approach employed has been used successfully in previous studies.10,18,19 Statistics Demographic data between alfentanil dose groups were compared by ANOVA and Chisquare test. The relationship between alfentanil dose and probability of obtaining perfect intubation condition was analysed using logistic regression,17 equation: Fraction of success ¼ m3 þ ð1 m3ÞðA=ðA þ 1ÞÞ A is EXP (m1 + m2 (dose)), m1 and m2 are the inbuilt parameters of the logistic regression program, and m3 an additional parameter allowing for the proportion of patients who is scored as a success when no alfentanil is used. The doses of alfentanil that gave 50%, 90% and 95% probability of success (ED50, ED90 and ED95 respectively) and their 95% confidence intervals (CIs) were determined using inverse prediction.20 Multivariate logistic regression was used to analyse the effect of alfentanil dose, sex, body weight, age and alfentanil plasma concentration at laryngoscopy on the success rate of perfect intubation conditions. The relationship between alfentanil dose and concentration was analysed by linear regression. To examine for a possible non-linear relation-
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ship, a polynomial term (dose2) was added and tested for statistical significance. Multiple linear regressions were used to determine whether sex, body weight or age affected alfentanil blood concentration. To determine if lack of perfect intubation conditions in a particular individual was caused by a low alfentanil blood concentration, concentrations obtained within each alfentanil dose group were compared between patients with perfect intubation condition and those without, using Mann–Whitney U-test. Data were analysed using JMP 10.0 (SAS Institute, Cary, NC, USA) and Stata 12.0 (StataCorp, College Station, TX, USA). Differences were considered significant if P < 0.05. Results Eighty-eight patients were enrolled. Three study subjects were excluded due to technical problems (with insertion of the arterial line in 10, 20 and 50 lg/kg dose groups respectively), and one because of unanticipated difficult tracheal intubation (60 lg/kg dose group). No differences were found in sex distribution, body weight or age between the different alfentanil dose groups (Table 1). Success rates of perfect intubation conditions across alfentanil dose groups are presented in Table 1. The relationship between alfentanil dose and the probability of obtaining perfect intubation conditions was statistically significant (P < 0.0001, Fig. 2). Our best estimates of the ED50, 90 and 95 values, irrespective of sex, were 22 (CI 14–30), 51 (CI 41–61) and 56 (CI 44–68) lg/kg respectively. The ED50, 90 and 95 values for males and females separately, were 27 (CI 19–35) and 18 (CI 10–26), 52 (CI 42–62) and 36 (CI 26–46), and 62 (CI 50–74) and 44 (34–54) lg/kg respectively (P = 0.15). Neither body weight (P = 0.76), age (P = 0.58) or alfentanil plasma concentration at laryngoscopy (P = 0.91) were significant predictors of perfect intubation conditions. When adding both alfentanil dose and concentration to the multivariate model, only alfentanil dose was a significant predictor. A significant linear relationship was found between alfentanil dose and alfentanil concentration (Fig. 3, P < 0.0001). The polynomial term
Fig. 2. The figure shows the logistic regression between alfentanil dose and fractional success (probability of success) of obtaining perfect intubation conditions. The relationship was statistically significant (P < 0.0001). The estimated ED50, ED90 and ED95 were 22 (CI 14–30), 51 (CI 41–61) and 56 (CI 44–68) lg/kg respectively. X-error bars represent the 95% confidence intervals.
Fig. 3. The graph shows the linear relationship between alfentanil dose and concentration. Open diamonds represent mean values at each alfentanil dose including all study subjects, and the error bars are standard deviations. The relationship was statistically significant (P < 0.0001). Individual data points at each alfentanil dose are shown separately for males (closed circles) and females (open circles). For clarity reasons, the data points are displaced slightly to the right (males) and left (females). Acta Anaesthesiologica Scandinavica 59 (2015) 1278–1286
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Table 2 Comparison of patients with (success) and without (failure) perfect intubation conditions. Numbers are mean SD. Success Age (years) 39.0 11.0 Weight (kg) 75.2 10.8 No of Males (M)/No 25 M/25 F of Females (F) Alfentanil dose group (mg/kg) vs. concentration (ng/ml) 0 0 10 66 6 20 144 21 30 241 83 40 283 72 50 295 64 60 427 109
Failure
All
P value (success vs. failure)
41.9 8.3 74.1 12.8 18 M/16 F
40.2 10.1 74.7 11.6 43 M/41 F
0.25 0.51 –
0 70 146 236 227 317 –
0 69 145 239 274 297 427
0.86 0.75 0.87 0.28 0.66 –
did not indicate that the relationship was better described with a non-linear function. The alfentanil plasma concentration increased with 1.7 ng/ml/kg increase in body weight (P = 0.0084). Sex did not affect alfentanil concentration (P = 0.33), even when adjusting for body weight (P = 0.32). Age was not a statistically significant factor either alone (P = 0.082) or when including body weight (P = 0.17). The average alfentanil plasma concentrations were similar in patients with and without perfect intubation conditions (Table 2). Systolic ABP < 90 mm Hg post intubation occurred in eight study subjects and < 70 mmHg in one (in the alfentanil 10 lg/kg group). Four patients needed additional anaesthetics post intubation due to exaggerated arterial blood pressure response, three in the alfentanil 0 lg/ kg and one in the alfentanil 10 lg/kg groups. Discussion RSII with propofol 2.5 mg/kg and rocuronium 0.6 lg/kg provides acceptable intubation conditions in a high percentage of patients if 90 s is allowed to complete tracheal intubation.3 In certain situations, it may be preferable to establish airway control within a shorter time range, especially in patients with high probability of regurgitation or development of hypoxaemia during the apnoea period. Previous studies show that acceptable tracheal intubation conditions can be achieved 40–45 s after rocuronium
0 22 91 70 94
0 18 63 73 75 62 109
0.6 lg/kg in most patients if alfentanil 20– 30 lg/kg is part of an induction regimen with standard doses of either propofol or thiopental.9,21 In the present study, we have shown that even perfect intubation conditions can be obtained, but that the average alfentanil dose must be increased to 56 lg/kg. Alfentanil 50– 60 lg/kg might be considered a relatively large dose of this drug. However, our data show that such doses can safely be administered as rapid boluses in healthy individuals because none of the study subjects receiving 50 or 60 lg/kg needed treatment for hypotension. Prolonged respiratory depression might be a concern when alfentanil 50–60 lg/kg is administered, but alfentanil distributes rapidly,22 and therefore its plasma concentration should decline below the threshold for spontaneous ventilation within 30 min after a bolus dose of this magnitude.23 The ED95 to obtain perfect intubation conditions obtained in the present study is significantly greater than that determined in our previous investigation (36 lg/kg, 95% CI 33– 39) using an identical study design except for a larger rocuronium dose (1 lg/kg).10 Therefore, it appears that decreasing the dose of rocuronium from 1.0 to 0.6 mg/kg has a great influence on the intubation conditions during RSII when laryngoscopy is initiated 40 s later. The alfentanil blood concentration at laryngoscopy increased with increasing body weight, consistent with previous findings that the drug’s central volume of distribution
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decreases with increasing body weight.14 The average male therefore acquire higher blood concentration of alfentanil than the average female when the drug is administered on mg per kg basis, simply because the body mass is greater. However, in the present study, this did not translate into a higher probability of perfect intubation conditions in males. A plausible reason for this finding is that the stimulus intensity during tracheal intubation increases with increasing body weight as well, and because there is a relationship between the magnitude of noxious stimuli and the release of catecholamines,24 the effect of a greater alfentanil plasma concentration is balanced out. Our results are rather consistent with the assumption that females might need less alfentanil than males to obtain perfect intubation conditions (ED95 62 vs. 44 lg/kg). Although this apparent sex-related difference did not reach the significance level (P = 0.15), the reason might well be a type II error due to the relatively low number of subjects included. As expected, alfentanil dose and alfentanil concentration at laryngoscopy correlated (Fig. 3), but only alfentanil dose was a significant predictor of perfect intubation conditions. There are plausible pharmacokinetic–pharmacodynamic reasons for this apparent discrepancy. First, during the initial minutes after an intravenous drug bolus, a concentration hysteresis exists between blood stream and effect site, implying that the alfentanil plasma concentrations at laryngoscopy obtained in the present study did not reflect that of the central nervous system.22,25 Second, this single, non-steadystate measurement of the alfentanil plasma concentration does not take into account the individual variability in drug sensitivity, which is the ultimate pharmacodynamic factor contributing to drug effect.26. Alfentanil dose is likely a better predictor of drug effect than non-steadystate alfentanil plasma concentration because a drug’s dose–effect relationship accounts for both pharmacokinetics (i.e. drug concentration in the blood stream) and pharmacodynamics (i.e. drug sensitivity). Therefore, in a clinical perspective, measurements of plasma concentrations of alfentanil at the time of laryngoscopy, if they were available, do not appear to concur any advantage when an optimal regimen for
alfentanil administration is to be decided (Fig. 3). The same pharmacokinetic–pharmacodynamic factors may also explain why alfentanil plasma concentrations were similar in patients with and without perfect intubation conditions (Table 2). An identical plasma drug concentration obtained at laryngoscopy in two different individuals after bolus administrations of alfentanil will likely be associated with dissimilar effect site concentrations due to inter-individual variability in the blood–brain equilibration rate (hysteresis), and consequently with different magnitude of airway responses to tracheal intubation. And again, inter-individual differences in sensitivity to alfentanil will certainly also contribute to response variability, even if the effect site concentrations were similar. In the present study, thiopental was used for sedation during induction of anaesthesia. Many clinicians prefer propofol, even in emergency situations, due to its superior muscle relaxing effect.27 We chose to use thiopental because it has faster onset than propofol,28,29 and less potential for hypotension and bradycardia.30 Thiopental may therefore be considered a safer hypnotic agent than propofol when the drugs are administered as rapid boluses. We believe our study design was appropriate to answer our primary research question, i.e. determination of the alfentanil dose needed to obtain perfect intubation conditions under RSII settings. First, we took advantage of one of the alfentanil’s onset characteristics, i.e. that the effect site concentration is at its peak approximately 60 s after a bolus injection,25 and designed an induction regimen where the noxious stimulation of the airway occurred between 55 and 70 s after drug administration. Second, as our research question could not be addressed properly by using a group comparison technique, we applied a probability approach, a technique that allows for the inclusion of a wide range of doses of the study drug. Our approach has also been used successfully in dose–response studies previously.10,18,19 We further believe that the estimated alfentanil dose to obtain perfect intubation conditions in 95% of the individuals is reliable. First, logistic regression is frequently used in the anaesthetic literature to describe relationships Acta Anaesthesiologica Scandinavica 59 (2015) 1278–1286
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between drug dose and binary variables. Second, the basic requirement for the regression analysis to work properly, a gradual increase in success rate with increasing drug dose, was met in this study. Although generally recommended in emergency situations,31 cricoid pressure was not applied in the present study. The main reason was that studies have shown that this procedure may impede visualization of larynx or even obstruct the airway.32–34 Omitting use of this procedure therefore secured as uniform intubation conditions as possible. The present study has one major limitation. The data obtained are only directly applicable to healthy individuals without difficult airways. Unfortunately, ethical considerations precluded inclusion of study subjects with significant organ dysfunction because, due to the study design, such participants might have been exposed to a potentially harmful drug regimen, i.e. either a relatively large dose of alfentanil or no alfentanil at all. In conclusion, when alfentanil 56 lg/kg, thiopental 4 mg/kg and rocuronium 0.6 mg/kg are administered in rapid succession, perfect intubation conditions are obtained in most patients 40 s after rocuronium.
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References 1. Engbaek J, Viby-Mogensen J. Can rocuronium replace succinylcholine in a rapid-sequence induction of anaesthesia? Acta Anaesthesiol Scand 1999; 43: 1–3. 2. Goulden M, Hunter J. Rapacuronium: do we have a replacement for succinylcholine? Br J Anaesth 1999; 82: 489–92. 3. Andrews J, Kumar N, van den Broom R. A large simple randomized trial of rocuronium versus succinylcholine in rapid-sequence induction of anesthesia along with propofol. Acta Anaesthesiol Scand 1999; 43: 4–8. 4. Bilotta F, Branca G, Lam A, Cuzzone V, Doronzio A, Rosa G. Endotracheal lidocaine in preventing endotracheal suctioning-induced changes in cerebral hemodynamics in patients with severe head trauma. Neurocrit Care 2008; 8: 241–6. 5. Gemma M, Tommasino C, Cerri M, Giannotti A, Piazzi B, Borghi T. Intracranial effects of
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