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* From the Departments of Anesthesia, and
Pharmacology, CHU Dupuytren; and
The Department of Biostatistics, Faculty of Medicine, Hôpital du Cluzeau, Limoges, France.
Address correspondence to: Dr. N. Nathan, Department of Anesthesia, CHU Dupuytren, 2 ave Martin Luther King, 87042 Limoges, France. Phone: 33-555-05-67-91; Fax: 33-555-05-67-92; E-mail: nathan{at}unilim.fr
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Abstract |
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Methods: In this prospective randomized open-label study, 40 ASA I adult patients received alfentanil at the following target-concentrations: zero (Group 0), 25 (Group 25), 50 (Group 50) and 75 ng•mL–1 (Group 75), starting five minutes before induction of anesthesia with 8% sevoflurane in 50% nitrous oxide. The ease of intubation was determined on fixed criteria and scored; arterial pressure, heart rate and bispectral index (BIS) were recorded at one-minute intervals.
Results: Times to allow tracheal intubation were shortened only in Group 75 (94 ± 8 sec) as compared to Group 0 (140 ± 11 sec, P < 0.05). BIS values, tracheal intubation scores and number of attempts were not different between groups. However, more patients suffered from apnea in Group 75. Heart rate and mean arterial pressure remained stable in Group 75 whereas they increased significantly in the three other groups. No patient suffered hypotension.
Conclusion: Adding alfentanil at a 75 ng•mL–1 target-concentration during an inhalation induction with 8% sevoflurane in 50% nitrous oxide allows intubation slightly earlier and provides stable hemodynamic conditions but the incidence of apnea during induction is higher. Lower concentrations are of little clinical interest.
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Introduction |
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Methods |
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). Rocuronium bromide 0.6 mg•kg–1 was injected if one of the following events occurred: apnea and inability to ventilate the patient, laryngospasm or closed vocal cords at time of intubation, cough severe enough to induce hypoxemia (SpO2 < 93%). Heart rate, blood pressure, SpO2, BIS values, respiratory rate and end-tidal sevoflurane concentrations were recorded before and each minute following the beginning of the alfentanil infusion and until the fifth minute following tracheal intubation. Immediately after tracheal intubation, 5 mL of venous blood were collected to measure serum alfentanil concentration by gas chromatography- mass spectrometry (lower limit of detection: 5–10 ng•mL–1, linearity range: 10–500 ng•mL–1).
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error of 0.05 and a ß error of 0.80, a 1.3 min decrease in time to tracheal intubation in one group receiving alfentanil.6 Data are presented as mean ± SD. Differences vs baseline values were used to compare hemodynamic data. Data were compared by ANOVA followed by t tests when normally distributed (P > 0.05 by Bartlett tests) or Mann Whitney U tests otherwise. A Bonferroni correction was used for t tests when ANOVA was not significant. Qualitative data were compared using exact Fisher tests for multiple groups. |
Results |
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). Time to loss of eyelash reflex, to drop a pen and to obtain a BIS < 60 were not influenced by any of the alfentanil concentrations. However criteria for tracheal intubation were reached and intubation performed earlier in patients receiving the highest alfentanil target-concentration (Table III). Once criteria were reached, tracheal intubation was achieved at a similar speed and after a similar number of attempts in the four groups (Tables III and IV). During laryngoscopy, mandible relaxation was rated excellent in all patients whether they received or not an opioid. However, in 5/10 patients receiving the highest alfentanil concentration, vocal cord opening was not optimal and/or apnea lasted more than two minutes. Whatever the target-concentration, alfentanil was unable to suppress the cough reflex following tracheal intubation or cuff inflation (Table IV).
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). Before tracheal intubation, heart rate variations reached 25.4 ± 7.9 min–1 in the control group, 23.1 ± 4.1 min–1 in Group 25 (P > 0.05 as compared to Group 0), 7.5 ± 6.7 min–1 in Group 50 (P = 0.08 vs Group 0) and –1.8 ± 4.7 min–1 in Group 75 (P = 0.005 vs Group 0). Immediately and one minute after tracheal intubation, heart rate increased significantly vs baseline in all groups except in patients receiving the 75 ng•mL–1 alfentanil target-concentration. In these latter patients, heart rate remained stable thereafter and significantly lower than in Group 0 (Figure 1a).
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). Immediately after tracheal intubation, the mean arterial pressure increase was significant in all patients except in those receiving 75 ng•mL–1 alfentanil plasma-target-concentration. In these patients, arterial pressure remained stable until the fourth minute following tracheal intubation (Figure 1b). The systolic and diastolic arterial pressure variations were similar to those observed for mean arterial pressure (not shown). No decrease in arterial pressure or heart rate higher than 30% of preanesthetic values were observed. However 8/10 patients of Group 0, 9/10 of Group 25, 6/10 of Group 50 and 4/10 of Group 75 increased their heart rate or arterial pressure above 30% of baseline. In Group 75, this increase, only observed after tracheal intubation, was always brief. BIS values are reported in Figure 2 and alfentanil concentrations in Table III.
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Discussion |
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Our study shows that the addition of alfentanil 75 ng•mL–1 to a sevoflurane induction hastens slightly, approximately by 30%, the occurrence of a BIS < 60 and tracheal intubation. Unexpectedly, this effect was slight with no clear dose-effect relationship between the time to obtain the appropriate criteria for intubation and the various concentrations of alfentanil. Indeed, the addition of high opioid doses during steady state conditions reduces by approximately 50% to 80% the various MACs of sevoflurane, which should accelerate induction and tracheal intubation. For example, 3 ng•mL–1 fentanyl reduced by 66% the MAC and by 83% the MAC-BAR of sevoflurane.14 Sevoflurane ED95 for tracheal intubation is reduced by 50% and reaches 3.2% when a 1 µg•kg–1 bolus of remifentanil is associated with sevoflurane.9 While maintaining a steady state concentration of sevoflurane, the MAC for tracheal intubation is reduced by 42% when adding 1 µg•kg–1 fentanyl.8 The maintenance of a steady state concentration of sevoflurane used in these previous studies is relevant only for maintenance of anesthesia but not for induction. In the present study, we chose a different approach, maintaining alfentanil at steady state concentrations. Indeed, during an inhalation induction, end-tidal, blood and cerebral concentrations of sevoflurane increase rapidly with, approximately, a two-minute half time to equilibrium between blood and brain.15 This suggests that, during a mask induction, it is probably not possible to reduce the time to tracheal intubation to less than two minutes, without a risk of awareness. This may explain why, during an inhalation induction, alfentanil cannot reduce the time to loss of consciousness.11 Alfentanil pre-treatment was, as well, unable to reduce consistently the time to obtain a BIS < 60 probably because of this lag and because alfentanil plasma concentrations as high as 50 ng•mL–1 have no effect on BIS during sevoflurane anesthesia.10
Errors of the pharmacokinetic model due to low target-concentrations of alfentanil may also explain the lack of a dose-effect on intubation times. Low opioid target-concentrations were chosen to preserve spontaneous ventilation because of a synergistic effect between alfentanil and sevoflurane on respiratory depression.10 Unequal mean prediction errors of alfentanil concentrations may have attenuated the dose-effect relationship. Although the Scott pharmacokinetics model performs well to predict alfentanil concentrations during maintenance, this model has not been validated during the induction of anesthesia.16,17 Unfortunately no model specific to induction is available.
Clinical interpretation of the criteria used to decide on tracheal intubation may also have influenced our results. During an inhalation induction, intubation is performed either after a fixed delay and/or according to (subjective) clinical signs such as mandible relaxation and Guedel criteria. A minimal five-minute delay is usually recommended before intubation is attempted.6 The time to allow intubation was much shorter in this study, even in patients not receiving alfentanil, probably because fixed criteria were used. These were, perhaps, insufficient to evaluate the depth of anesthesia even if they predict the success of laryngeal mask insertion with a sensitivity of 100%.1,18 Although this study was unblinded, the same number of attempts, as well as the same time to tracheal intubation, suggest that the criteria were followed equally in all groups. The high incidence of cough after tracheal intubation and after cuff inflation indicates that the airway remained highly reactive whatever the concentration of alfentanil. The maintenance of such a high tracheal reactivity during induction with high concentrations of sevoflurane contradicts a previous report where 1 MAC of sevoflurane was able to suppress the cough response to cuff inflation during maintenance in 30/32 patients.19
Whereas beneficial on heart rate and time to allow tracheal intubation, the highest concentration of alfentanil was associated with a 50% incidence of prolonged apnea. This apnea occurred mainly after tracheal intubation and, fortunately, was not associated with hypoxemia. This effect of opioids is well-known but was not expected with the low doses of alfentanil used in this study (about 10 µg•kg–1 alfentanil had been administered in ten minutes at the time of tracheal intubation in Group 75). Furthermore, at the highest alfentanil target-concentration, vocal cord opening was incomplete in half the cases and severe cough was observed. As a consequence, neuromuscular blockade remained necessary in three patients receiving the highest alfentanil concentration.
In summary, during 8% sevoflurane inhalation induction, a 75 ng•mL–1 alfentanil plasma target-concentration provides better stability of heart rate and arterial pressure than lower concentrations. Time to allow tracheal intubation is shortened slightly with the 75 ng•mL–1 alfentanil target-concentration. However alfentanil is unable to suppress cough reflex and the incidence of apnea is increased. The use of alfentanil 75 ng•mL–1 may be of clinical interest in patients at risk of cardiac complications. According to the Scott pharmacokinetics model, such a target-concentration may be obtained in 1.5 min after a 7 µg•kg–1 alfentanil infusion.
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Footnotes |
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References |
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2 Joo HS, Perks WJ. Sevoflurane versus propofol for anesthetic induction: a meta-analysis. Anesth Analg 2000; 91: 213–9.
3 Vakkuri AP, Lindgren L, Korttila KT, Yli-Hankala AM. Transient hyperdynamic response associated with controlled hypocapneic hyperventilation during sevoflurane-nitrous oxide mask induction in adults. Anesth Analg 1999; 88: 1384–8.
4 Vial G, Nathan N, Benrhaiem M, Peyclit A, Feiss P. Paroxystic systemic hypertension during inhalation induction with sevoflurane 8% (Letter). Can J Anesth 2000; 47: 191–2.
5 Hall JE, Ebert TJ, Harmer M. Induction characteristics with 3% and 8% sevoflurane in adults: an evaluation of the second stage of anaesthesia and its haemodynamic consequences. Anaesthesia 2000; 55: 545–50.[Medline]
6 Muzi M, Robinson BJ, Ebert TJ, O’Brien TJ. Induction of anesthesia and tracheal intubation with sevoflurane in adults. Anesthesiology 1996; 85: 536–43.[Medline]
7 Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998; 88: 18–24.[Medline]
8 Katoh T, Nakajima Y, Moriwaki G, et al. Sevoflurane requirements for tracheal intubation with and without fentanyl. Br J Anaesth 1999; 82: 561–5.
9 Cros AM, Lopez C, Kandel T, Sztark F. Determination of sevoflurane alveolar concentration for tracheal intubation with remifentanil, and no muscle relaxant. Anaesthesia 2000; 55: 965–9.[Medline]
10 Dahan A, Nieuwenhuijs D, Olofsen E, Sarton E, Romberg R, Teppema L. Response surface modeling of alfentanil-sevoflurane interaction on cardiorespiratory control and bispectral index. Anesthesiology 2001; 94: 982–91.[Medline]
11 Muzi M, Colinco MD, Robinson BJ, Ebert TJ. The effects of premedication on inhaled induction of anesthesia with sevoflurane. Anesth Analg 1997; 85: 1143–8.[Abstract]
12 Wang JY, Winship SM, Thomas SD, Gin T, Russel GN. Induction of anaesthesia in patients with coronary artery disease: a comparison between sevoflurane-remifentanil and fentanyl-etomidate. Anaesth Intensive Care 1999; 27: 363–8.[Medline]
13 Nathan N, Vial G, Benrhaiem M, Peyclit A, Feiss P. Induction with propofol target-concentration infusion vs. 8% sevoflurane inhalation and alfentanil in hypertensive patients. Anaesthesia 2001; 56: 251–7.[Medline]
14 Katoh T, Kobayashi S, Suzuki A, Iwamoto T, Bito H, Ikeda K. The effect of fentanyl on sevoflurane requirements for somatic and sympathetic responses to surgical incision. Anesthesiology 1999; 90: 398–405.[Medline]
15 Olofsen E, Dahan A. The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram. Anesthesiology 1999; 90: 1345–53.[Medline]
16 Raemer DB, Buschman A, Varvel JR, et al. The prospective use of population pharmacokinetics in a computer-driven infusion system for alfentanil. Anesthesiology 1990; 73: 66–72.[Medline]
17 Barvais L, Cantraine F, D’Hollander A, Coussaert E. Predictive accuracy of continuous alfentanil infusion in volunteers: variability of different pharmacokinetic sets. Anesth Analg 1993; 77: 801–10.
18 Drage MP, Nunez J, Vaughan RS, Asai T. Jaw thrusting as a clinical test to assess the adequate depth of anaesthesia for insertion of the laryngeal mask. Anaesthesia 1996; 51: 1167–70.[Medline]
19 Klock PA Jr, Czeslick EG, Klafta JM, Ovassapian A, Moss J. The effect of sevoflurane and desflurane on upper airway reactivity. Anesthesiology 2001; 94: 963–7.[Medline]
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