Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children

British Journal of Anaesthesia 85 (4): 611±5 (2000)

SHORT COMMUNICATIONS Pulmonary artery catheterization and mortality in critically ill patients² S. D. Murdoch, A. T. Cohen and M. C. Bellamy* Department of Anaesthesia and Intensive Care Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK *Corresponding author Pulmonary artery catheters are widely used in intensive care, but evidence to support their widespread use is sparse. Some published data suggest that greater mortality is associated with use of these catheters. The largest study to date looked at >5500 patients in several centres in America and found a greater 30 day mortality in those patients receiving a pulmonary artery catheter. We tested the hypothesis that, on our intensive care unit, mortality was greater for those patients receiving a pulmonary artery catheter. Using a propensity score to account for severity of illness, the odds ratio for mortality in those patients receiving a pulmonary artery catheter was 1.08 (95% con®dence interval 0.87±1.33). We believe that continued use of the pulmonary artery catheter is safe; a large randomized controlled trial examining outcome is unlikely to provide an adequate answer. Br J Anaesth 2000; 85: 611±5 Keywords: lung, pulmonary artery catheter; intensive care, mortality Accepted for publication: May 2, 2000

Since its introduction in 1970, the pulmonary artery catheter1 has become commonplace in intensive care practice. Pulmonary artery catheterization was ®rst described in 19452 and from then until the 1970s was used in the catheter laboratory as a diagnostic tool. When it became possible to perform the procedure at the bedside in critically ill patients in the intensive care unit, the balloon-tipped pulmonary artery catheter became widely used as a guide to treatment. In 1996, over two million catheters were sold worldwide.3 The effectiveness of new techniques and treatments should ideally be evaluated before they are introduced,4 but this is not always done. The pulmonary artery catheter was not evaluated in this way before being introduced. Despite this, many physicians believe it can guide treatment and provide useful physiological data. Several well conducted studies have shown an improvement in outcome when acting on data provided by the pulmonary artery catheter.5±7 However, greater mortality has been demonstrated in some patients, most notably in those who have had a myocardial infarction.8 9 It has proved dif®cult to conduct a randomized, controlled trial of pulmonary artery catheter use.10 In September 1996, Connors and colleagues published a paper examining the use of the pulmonary catheter in 5735 intensive care patients.11 This multicentre study found

greater mortality in patients receiving a pulmonary artery catheter. The paper was based on data collected as part of the SUPPORT12 study, which was designed to look at decision-making and outcomes in patients with an estimated 6 month mortality of 50%. The study took place between 1989 and 1994 in ®ve American teaching hospitals with patients in one or more of nine disease categories: acute respiratory failure, chronic obstructive pulmonary disease, congestive heart failure, cirrhosis, non-traumatic coma, colon cancer metastatic to the liver, non-small-cell cancer of the lung (stage III or IV) and multiple organ system failure with malignancy or sepsis. Not all patients with these conditions would commonly be given pulmonary catheters in European practice. The statistical techniques used by Connors and colleagues included the propensity score13 to allow comparison between patients receiving or not receiving a pulmonary artery catheter while compensating for severity of illness and treatment selection bias. We examined the effect of the pulmonary artery catheter on intensive care mortality in all adult patients admitted over 7 yr to an intensive care unit in a large British teaching hospital. A propensity score was used to compensate for severity of illness between groups. ²This article is accompanied by Editorial I.

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000

Murdoch et al.

Materials and methods

Table 1 Characteristics of 4182 intensive care patients

Data have been collected prospectively on all patients admitted to the intensive care unit at St James's University Hospital, Leeds, since 1984. The unit is based in a major teaching hospital and accepts patients from all specialties except neurosurgery and cardiothoracic surgery. The unit provides a regional tertiary referral service for patients with respiratory and renal failure, and a supraregional liver failure and transplant programme. We examined patient characteristics, physiological, treatment and outcome data for 4182 patients aged >16 yr admitted between January 1990 and December 1996. Patient characteristics available included age, gender, race (Caucasian or non-Caucasian), length of intensive care stay, the need for readmission, APACHE II (Acute Physiology and Chronic Health Evaluation) score,14 presence of acute renal failure, elective/emergency admission and physician's prediction of death. Treatment variables included insertion of a central venous catheter, insertion of an arterial cannula, treatment with epinephrine, norepinephrine, dopamine or dobutamine (separate variables) and the need for ventilation of the lungs. Outcome data were discharge from the intensive care unit or death on the intensive care unit. APACHE II data were based on the ®rst 24 h of intensive care admission. The physician's prediction of death was a dichotomous variable, with patients being predicted to survive or predicted to die. Following a univariate analysis, 15 variables were entered in a backward stepwise logistic regression analysis. Statistically signi®cant variables, identi®ed from the regression analysis, were used to calculate the propensity score. Variables in the ®nal equation were acute renal failure, need for treatment with epinephrine, norepinephrine, dopamine and dobutamine, monitoring of arterial pressure and central venous pressure, physician's prediction of death and patient age. Variables excluded from the equation included gender, race, APACHE II score, duration of intensive care stay, need for elective (as opposed to emergency) admission and the need for subsequent readmission to the intensive care unit. The signi®cant variables were entered into a logistic regression analysis with pulmonary artery catheter insertion during intensive care stay as the dependent variable. This gave the probability (from 0 to 1) of pulmonary artery catheter insertion occurring during a patient's intensive care stay, the `propensity score'. Statistical analysis was performed using SPSS for Windows version 6, the receiver operator characteristic (ROC) plot was produced by Astute (University of Leeds) on Microsoft Excel 4, all running on Microsoft Windows 98 on a Dan 120 MHz Pentium computer. The accuracy with which a propensity score predicts a treatment option can be tested using the ROC plot. The area under the ROC curve corresponds to the probability of the propensity correctly predicting if a patient receives a treatment or not (in this case a pulmonary artery catheter).

Variable

Age** <50 yr 50±<60 yr 60±<70 yr 70±<80 yr >80 yr Gender Male Female Race Caucasian Non-Caucasian Elective* Emergency* Readmission LOS** APACHE II** CVP* Acute renal failure* Arterial line* Epinephrine* Norepinephrine* Dopamine* Dobutamine* Intubated* Predicted to die* Died*

PA catheter (n=1849)

682 330 404 354 79

(37) (19) (22) (19) (4)

No PA catheter (n=2333)

720 388 565 497 163

(31) (17) (24) (21) (7)

1093 (59) 756 (41)

1364 (58) 969 (42)

1798 (97) 51(3) 192 (10) 1657 (90) 208 (11) 3 (1, 8) 24 (24, 31) 1849 (100) 647 (35) 1849 (100) 829 (45) 614 (33) 1578 (85) 555 (30) 1721 (93) 756 (41) 794 (43)

2274 59 395 1938 253 1 15 1928 174 1953 149 43 1010 163 1654 309 293

(97) (3) (17) (83) (11) (1, 2) (10, 22) (83) (7) (84) (6) (2) (43) (7) (71) (13) (13)

Data presented as number (%) or median (25th and 75th percentiles). *P<0.0001 (chi-squared test).**P<0.0001 (Mann±Whitney U-test).

Bias in the propensity score can be investigated by examining subclasses of data based on the propensity score. If the score is valid it compensates for the covariates; within each class there should be only random differences in the distribution of covariates, which cancel each other out. This means that within each stratum, no factor retains a relationship with the exposure.15 It is suf®cient to look at only ®ve equal groups, known as quintiles.16 Quintiles based on the propensity score were examined to determine the distribution of the predictive variables for pulmonary artery catheter insertion. The predictive value of the propensity in predicting the insertion of the pulmonary artery catheter was tested using a ROC curve.16 The calculated propensity score and pulmonary artery catheterization were then investigated as the two potential predictors of mortality in intensive care, in a logistic regression model. Subgroup analysis of the effect of the pulmonary artery catheter on mortality was performed based on (i) patients' APACHE II score on admission and on (ii) elective compared with emergency admission.

Results There were 2456 male patients and 1726 females; their median age was 56.3 yr (interquartile range 42.8±70.5 yr),

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Pulmonary artery catheters and mortality

median APACHE II score 19 (interquartile range 12±27) and median length of stay 2 days (interquartile range 1±4 days). Further details of the patients are given in Table 1. Patients who had a pulmonary artery catheter inserted were more likely to be younger, have renal failure, be treated with inotropes, have acute renal failure and have a prolonged stay in intensive care stay. Patients without a pulmonary artery catheter were more likely to be older, admitted electively and have a lower APACHE II score. There was no difference in the two groups with respect to gender, racial origin or previous intensive care unit admission. There was an overall mortality of 1087/4181 (26%), comprising a mortality of 293/2333 (12.6%) in those without a pulmonary artery catheter and 794/1849 (42.9%) in those with a pulmonary artery catheter (chisquared P<0.0001). The pulmonary artery catheter was, therefore, strongly associated with mortality when no adjustment had been made for severity of illness. The propensity score had an area under the ROC curve of 0.88, indicating good predictive value for insertion of the pulmonary artery catheter (Connors and colleagues obtained a propensity score of 0.83). The median propensity score was 0.797 (interquartile range 0.456±0.947) for patients who had a pulmonary artery catheter inserted and 0.176 (interquartile range 0.086± 0.337) for those who did not have a pulmonary artery catheter inserted. The calculated propensity score and pulmonary artery catheterization were then investigated as the two potential predictors of mortality, in intensive care, in a logistic regression model. The cut-off value for the propensity score was 0.5. The propensity score was predictive of death, (odds ratio (OR) 45; 95% con®dence interval (CI) 34.7±58.3). Use of the pulmonary artery catheter was not predictive of death (OR 1.08; 95% CI 0.87±1.33). Analysis of patients according to APACHE II score did not demonstrate a deleterious effect of pulmonary artery catheter use in any group. In patients with an APACHE II score of <20, the presence of a pulmonary artery catheter was not predictive of death (OR 1.14; 95% CI 0.7±2.5), but the propensity score was (OR 75.8; 95% CI 34.8±164.7). In patients with an APACHE II score of 20±25, pulmonary artery catheter insertion was not predictive of death (OR 1.3; 95% CI 0.8±2.15) but the propensity score was (OR 11.27; 95% CI 5.3±24). In patients with an APACHE II score of >25, the pulmonary artery catheter was not predictive of death (OR 0.89; 95% CI 0.64±1.25) but again propensity score was predictive (OR 7.43; 95% CI 4.48±12.3). In patients admitted electively to the intensive care unit, the pulmonary artery catheter was not predictive of death (OR 1.9; 95% CI 0.57±6.14), but propensity score was predictive (OR 330; 95% CI 54.2±2006). Quintile analysis showed that the predictor variables were evenly distributed between interventional groups, with the

exception of central venous and arterial cannulae in the lowest quintile. This is unlikely to be important in the absence of a treatment effect from the pulmonary artery catheter.

Discussion The data we have examined show no increase in mortality in those patients receiving a pulmonary artery catheter, nor do we demonstrate a bene®cial effect of its use. These results were observed after correction for treatment bias using a propensity score. In observational studies, patients are not assigned to treatment groups randomly. It is, therefore, inevitable that some patient variables are over-represented in one group. Consequently, it is dif®cult to interpret direct comparison between the two groups. Previous observational studies found an increase in mortality in patients receiving a pulmonary artery catheter. It has been claimed that patients who were sicker and more likely to die received the pulmonary artery catheter and this underlying severity of disease led to the increase in mortality, rather than the pulmonary artery catheter itself.9 The ideal is a randomized controlled trial, where all variables are represented equally in each treatment group. Where such a trial is not possible, a technique used to overcome this problem is the propensity score, which describes the probability of assignment to a given treatment given a vector of observed covariates. Propensity score is calculated using logistic regression analysis of the variables that lead to a given treatment. It is dependent on identifying variables leading to exposure and is liable to bias owing to failure to include important variables that lead to exposure. In effect, the propensity score represents the probability that a patient will receive a given treatment, taking into account the individual patient's variables that are believed to lead to that treatment. The propensity score can then be used with the treatment it predicts in order to investigate the effect of the treatment, independently of the variables leading to that treatment. The pulmonary artery catheter is a monitoring device; it is generally used to obtain haemodynamic data on patients which may be used to guide treatment. Any possible effect on mortality could result from a direct effect or from the way in which the information obtained from the catheter is used to guide treatment. Direct effects can be divided into the immediate problems of central line insertion (damage to vessels,17 infection,18 cardiac arrhythmias, etc.) and the later risk of infective endocarditis. It is unlikely that these complications are responsible for the increased mortality previously reported with pulmonary artery catheters. The reported increase in mortality with the use of pulmonary artery catheters is probably, therefore, an indirect effect of their use or caused by problems with studying their use. The therapy received by a patient plays a major role in determining the outcome. In therapies based on data

613

Murdoch et al.

obtained from the pulmonary artery catheter, the catheter may act as an indicator of excess mortality of that therapy. It is easier to blame the catheter than the treatment for which it is being used. The use of supranormal oxygen delivery was once an aim of treatment guided by data obtained from the pulmonary artery catheter. A recent study has demonstrated that this therapeutic regimen may be harmful to patients.19 As the Connors study was multicentre and observational, it is possible that, in some patients in that study, the pulmonary artery catheter was used to obtain supranormal oxygen delivery. The use of variables in our propensity score indicating the use of inotropes allows compensation to be made in the ®nal analysis re¯ecting therapeutic intervention. This use of inotropes was recorded at any point during a patient's illness on the intensive care unit, and so re¯ected the change in a patient's condition over time and their response to treatment. The variables used in the construction of the propensity score in the Connors paper did not re¯ect therapeutic intervention but predominantly re¯ected the patient's physiological status on admission to the intensive care unit. Interpretation of the data obtained from the pulmonary artery catheter has been shown to be poor in studies in America20 and Europe.21 There are differences between intensive care practice in France and America,22 and probably also between the UK and USA. It is likely that some patients in the American study would not have been admitted to intensive care in the UK. The SUPPORT study showed differences in medical practice between the ®ve hospitals studied and between different physicians. The results we present are obtained from one intensive care unit, where practice is consultant led and protocol driven. We use pulmonary artery catheters extensively.23 We studied all adult patients admitted to an intensive care unit, classed all patients who had a pulmonary artery catheter inserted at any time in the pulmonary artery group and examined patients' need for cardiovascular and renal support throughout their stay. This provides an overall examination of the effects of the pulmonary artery catheter. Connors and colleagues produced a subgroup analysis based on diagnosis but we did not attempt this because we could not match our groups with those of Connors and colleagues. Smaller groups would have a different propensity score for pulmonary artery catheter insertion (leading to lack of power in the analysis). Modelling treatment effects would also be more dif®cult in small groups of patients. While we have not demonstrated an increase in mortality attributable to the use of pulmonary artery catheters, we have failed to demonstrate a bene®cial effect. This may be because there is no bene®cial effect. It could also be because the bene®t accruing from additional clinical information has little effect on individual patients, but rather informs practice as a whole. Would the results in patients who did not have pulmonary artery catheters have been as good without the accumulated experience resulting from years of using pulmonary artery catheters and familiarity with the

likely haemodynamics in a given clinical situation? If we were to abandon the pulmonary artery catheter, would this skill base decay and, if so, over how long? It is unlikely that a simple head-to-head trial could answer such questions. A randomized, controlled trial of pulmonary artery catheters is required to assess their bene®t, but our results suggest that such a study, even with very large numbers of patients, would have insuf®cient power to demonstrate an effect on mortality. Organizational differences between intensive care units, together with the change in practice that might occur as a result of participation in such a trial, would need to be taken into account in the analysis of such a study.

References

614

1 Swan HJC, Ganz W, Forester J, Marcus H, Diamond G, Chonette D. Catheterizaton of the heart in man using a ¯ow directed balloon tipped catheter. New Engl J Med 1970; 283: 447±51 2 Dexter L, Haynes FW, Burwell CS, Eppinger EC, Seibel RE, Evans JM. Studies of congenital heart disease. I. Techniques of venous catheterization as a diagnostic procedure. J Clin Invest 1947; 26: 547±53 3 Ginosar Y, Sprung CL. The Swan Ganz catheter: twenty ®ve years of monitoring. Crit Care Clin 1996; 12: 771±6 4 Cook DJ, Sibbald WJ, Vincent J-L,Cerra FB. Evidence based critical care medicine: what is it and what can it do for us? Crit Care Med 1996; 24: 334±7 5 Boyd O, Grounds RM, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high risk surgical patients. J Am Med Assoc 1993; 270: 2699±707 6 Wilson J, Woods I, Fawcett J, Whall R, Dibb W, Morris C, McManus E. Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery Br Med J 1999; 318: 1099±103 7 Mimoz O, Rauss A, Rekik N, Brun-Bruission C, Lemaire F, Brochard L. Pulmonary artery catheterization in critically ill patients: a prospective analysis of outcome changes associated with catheter prompted changes in therapy. Crit Care Med 1994: 22; 573±9 8 Gore JM, Goldberg JM, Spodick DH, Alpert JS, Dalen JE. A communitywide assessment of the use of pulmonary artery catheters in patients with myocardial infarction. Chest 1987; 92: 721±7 9 Zion MM, Balkin MM, Rosenmann D et al. Use of the pulmonary artery catheter in patients with acute myocardial infarction. Chest 1990; 98: 1331±5 10 Guyatt G, Ontario Intensive Care Study Group. A randomized controlled trial of right heart catheterization in critically ill patients. J Intensive Care Med 1991; 6: 91±5 11 Connors AF, Speroff T, Dawson NV et al. The effectiveness of right heart catheterisation in the initial care of critically ill patients. J Am Med Assoc 1996; 276: 889±97 12 SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalised patients: the Study to Understand Prognoses and Preferences for Outcome and Risks of Treatments (SUPPORT). J Am Med Assoc 1995; 274: 1591±8 13 Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70: 41±55

Epidural opioids in children

14 Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classi®cation system. Crit Care Med 1985; 13: 818±29 15 Cook EF, Goldman L. Performance of tests of signi®cance based on strati®cation by a mulitvariate confounder score or by a propensity score. J Clin Epidemiol 1989; 42: 317±24 16 Lusted LB. Decision making studies in patient management. New Engl J Med 1971; 284: 416±24 17 Sznajder JI, Zveibil FR, Bitterman H, Weiner P, Bursztein S. Central vein catheterization. Failure and complication rates by three percutaneous approaches. Arch Intern Med 1986; 146: 259±61 18 Mermel LA, Maki DG. Infectious complications of Swan Ganz pulmonary artery catheters: pathogenesis, epidemiology, prevention and management. Am J Respir Crit Care Med 1994; 149: 1020±36

19 Hayes MA, Timmins AC, Yau EHS, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. New Engl J Med 1994; 330: 1717±22 20 Iberti TJ, Fischer EP, Leibowitz AB, Panacek EA, Silverstein JH, Albertson TE. A multicenter study of physicians knowledge of the pulmonary artery catheter. J Am Med Assoc 1990; 264: 2928±32 21 Gnaegi A, Feihl F, Perret C. Intensive care physicians insuf®cient knowledge of right heart catheterization at the bedside: time to act? Crit Care Med 1997; 25: 213±20 22 Knaus WA, Wagner DP, Loirat P. A comparison of intensive care in the USA and France. Lancet 1982; ii: 642±6 23 Vincent JL, Bihari DJ, Suter PM et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) study. J Am Med Assoc 1995; 274: 639±44

British Journal of Anaesthesia 85 (4): 615±7 (2000)

Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children C. Lejus1 *, D. Schwoerer1, I. Furic1, J.-P. Le Moing2, J.-C. Levron2 and M. Pinaud1 1

Department of Anaesthesiology, HoÃtel-Dieu, CHR Nantes, France. 2Janssen Research Foundation, Val de Reuil, France

*Corresponding author: Service d'AnestheÂsie et de ReÂanimation Chirurgicale, HoÃtel-Dieu, F-44093 Nantes cedex 01, France No pharmacokinetic data are available with respect to the plasma concentrations and fentanyl or sufentanil during epidural administration in children. This double-blind randomized study included 12 children (5±12 yr). Patients in group F were given an epidural loading dose of fentanyl 1.5 mg kg±1 and in group S sufentanil 0.6 mg kg±1. Both groups then received a continuous epidural infusion of bupivacaine 5 mg kg±1 day±1 with either fentanyl 5 mg kg±1 day±1 or sufentanil 2 mg kg±1 day±1. An epidural PCA system was also given to the children (bolus: bupivacaine 0.2 mg kg±1 and fentanyl 0.2 mg kg±1 or sufentanil 0.08 mg kg±1). Maximal median concentrations of plasma (0.117±0.247 ng ml±1 for fentanyl and 0.027±0.074 ng ml±1 for sufentanil) were reached approximately 30 and 20 min respectively after the loading doses. These values were similar to those measured after 48 h. Br J Anaesth 2000; 85: 615±7 Keywords: analgesia, postoperative; analgesics opioid, fentanyl; analgesics opioid, sufentanil; analgesic techniques, epidural; children Accepted for publication: March 14, 2000

Epidural bupivacaine has been shown to provide effective postoperative analgesia in paediatric patients. Bupivacaine toxicity may cause convulsions and cardiovascular depression. Therefore, it has been recommended that an opioid should be combined with bupivacaine rather than increasing the infusion rate of bupivacaine. The ef®cacy of a combination of fentanyl with bupivacaine has been reported.1

However, only two studies report the epidural administration of sufentanil in children for postoperative analgesia.2 3 Furthermore, no paediatric data are available about plasma concentrations after continuous and prolonged epidural administration of fentanyl or sufentanil. Therefore, we investigated this in children receiving epidural fentanyl or sufentanil at doses giving similar analgesia.

Ó The Board of Management and Trustees 615 of the British Journal of Anaesthesia 2000

Lejus et al. Table 1 Plasma concentrations (ng ml±1) of fentanyl (children 1±6) and sufentanil (children 7±12) during epidural administration. ND=not determined Fentanyl group

Child 1

Child 2

Child 3

Child 4

Child 5

Child 6

Age (yr) Surgery No. PCEA boluses

11 Foot 6

8 Pelvis 27

9 Pelvis 13

9 Foot 8

8 Foot 9

6 Tibia 1

5 min 10 min 20 min 30 min 60 min 120 min 6h 24 h 48 h

0.058 0.085 0.16 0.181 0.155 0.058 0.074 0.098 0.142

0.118 0.172 0.221 0.222 0.249 0.208 0.191 0.245 0.261

0.064 0.155 0.184 0.217 0.133 0.141 0.104 0.106 0.221

0.213 0.363 0.43 0.381 0.347 0.25 0.16 0.24 0.172

< 0.05 0.067 0.117 0.12 0.099 0.085 0.184 0.14 0.229

0.073 0.118 0.188 0.247 0.236 0.177 0.216 ND ND

Sufentanil group

Child 7

Child 8

Child 9

Child 10

Child 11

Child 12

Age (yr) Surgery No. PCEA boluses

7 Pelvis 10

6 Pelvis 8

11 Foot 3

11 Foot 1

5 Foot 10

8 Tibia 5

0.022 < 0.02 0.041 0.042 0.032 <0.02 <0.02 <0.02 0.024

<0.02 <0.02 <0.02 <0.02 <0.02 <0.02 <0.02 0.049 ND

0.026 0.046 0.022 0.048 0.045 0.037 0.036 0.049 0.058

<0.02 0.022 0.027 0.025 0.018 0.026 0.025 0.039 0.06

0.061 0.069 0.07 0.05 0.028 <0.02 <0.02 <0.02 0.051

0.047 0.059 0.074 0.07 0.058 0.04 0.03 0.038 ND

Time

Time 5 min 10 min 20 min 30 min 60 min 120 min 6h 24 h 48 h

Methods and results After approval of the study by the Ethical Human Studies Committee of our University Hospital and written parental consent had been obtained, 12 children (5±12 yr) scheduled for postoperative epidural analgesia after orthopaedic surgery were enrolled in this prospective, randomized, double-blind clinical trial. Twenty minutes after premedication with midazolam 0.3 mg kg±1, anaesthesia was induced by inhalation of halothane or sevo¯urane. Endotracheal intubation was facilitated with atracurium 5 mg kg±1 and anaesthesia was maintained with an expired fraction of 0.8% iso¯urane in nitrous oxide/oxygen (FIO2=0.5). Ventilation was controlled in order to maintain normocapnia. Children were placed in the lateral position for insertion of a lumbar epidural catheter before surgery. The epidural test dose consisted of 0.5% bupivacaine 0.1 ml kg±1 with epinephrine (1/200 000). Before surgery, all children received a bolus dose of 0.75 ml kg±1 of a 50/50% mixture of 0.5% bupivacaine and 1% lidocaine, with epinephrine. The patients were allocated randomly to receive either fentanyl (group F) or sufentanil (group S). Patients were given an epidural dose of fentanyl 1.5 mg kg±1 in group F and of sufentanil 0.6 mg kg±1 in group S. Immediately after

the epidural loading dose had been given, a continuous epidural infusion was started with bupivacaine 5 mg kg±1 day±1 plus fentanyl 5 mg kg±1 day±1 in group F and sufentanil 2 mg kg±1 day±1 in group S. In the recovery room, after tracheal extubation and once the children were completely awake, an epidural patient-controlled analgesia (PCEA) system was given to the children. They could self-administer boluses of bupivacaine 0.2 mg kg±1 with fentanyl 0.2 mg kg±1 or sufentanil 0.08 mg kg±1 in groups F and S respectively. Lock-out time was 1 h, with a maximal number of two boluses per 4 h. The maximal daily total doses of epidural bupivacaine, fentanyl and sufentanil were 7.4 mg kg±1, 7.4 mg kg±1 and 2.96 mg kg±1 respectively. The continuous and PCEA epidural administration was planned for the 48 h after operation. Randomization was performed by the pharmacist of the hospital, who prepared the vial of opioids for the double-blind procedure. Measurements of plasma fentanyl and sufentanil plasma were performed on venous samples withdrawn 5, 10, 20, 30 and 60 min and 2, 6, 24 and 48 h after the loading dose in six patients from each group, using a radioimmunological method. The limit of quanti®cation was 0.020 ng ml±1 for sufentanil and 0.05 ng ml±1 for fentanyl. Pain was evaluated

616

Epidural opioids in children

every 3 h with a standard visual analogue pain scale graded from 0 to 100, except when the child was asleep. The ®rst evaluation was performed by the child on arrival in the surgical ward. The number of PCEA-satis®ed demands for the 48 h after operation was recorded. Patient characteristics are presented in Table 1. Epidural analgesia was interrupted prematurely in children 6 and 8 at the 15 and 20th hour respectively because of accidental removal of the epidural catheter. In one other child (number 12), the study was stopped at the 30th hour because of a surgical complication. Among the 52 plasma determinations performed in group F and the 51 performed in group S, 1 and 14 respectively were below the limit of quanti®cation (P<0.001). The maximum concentrations (0.117± 0.247 ng ml±1 for fentanyl and 0.027 and 0.074 ng ml±1 for sufentanil) had been reached by approximately 30 min after the loading dose for fentanyl and by 20 min for sufentanil. Analgesia was excellent in both groups. The median (25±75%) number of self-administered boluses was similar in the two groups: 8.5 (5±11) in group F and 6.5 (4± 7.25) in group S.

In the ®rst report of epidural administration of sufentanil in children, the slope of the carbon dioxide ventilatory response curve decreased signi®cantly from 1.1 before sufentanil to 0.68 litre min±1 mm Hg±1 30 min after epidural administration.2 A higher dose (0.75 mg kg±1) than that used in our study was administered, and the plasma concentrations were low (0.1 ng ml±1). The low concentrations of sufentanil and fentanyl measured in our study do not eliminate completely the possibility of respiratory depression, and monitoring the sedation score and respiratory rate remains absolutely necessary. Nevertheless, fentanyl and sufentanil are highly lipidsoluble opioids and migrate less than morphine in the cerebral spinal ¯uid. They are less likely to cause delayed respiratory depression after epidural administration.

Acknowledgements The work was supported by Janssen-Cilag France.

References

Comments The initial systemic absorption of sufentanil is very rapid. The relative delay of the peak plasma concentration of sufentanil observed in our patients was similar to that reported previously in adults.4 The plasma concentrations of fentanyl or sufentanil reached with our epidural regimens were very low, with little suggestion of accumulation at 24 and 48 h. The excellent quality of analgesia associated with very low plasma concentrations of sufentanil suggest a spinal action of sufentanil. Other investigators have reported plasma concentrations of sufentanil or fentanyl below the minimal effective concentration necessary for systemic analgesia after epidural injection.5 With intravenous infusion, a serum sufentanil concentration above 0.03 ng ml±1 seems to be necessary for analgesia.6 7 However, it has been suggested that the epidural and i.v. doses of sufentanil required for analgesia are similar.8 The plasma concentrations of sufentanil and fentanyl that are not associated with risk of respiratory depression are not well established. The target concentration of fentanyl for analgesia is considered to be above 1.5 ng ml±1 and thus induces signi®cant alteration in the carbon dioxide response.9 A 38% decrease in the carbon dioxide response slope has been reported in association with a mean plasma concentration of 0.95 (SD 0.2) ng ml±1.10 Respiratory depression has been described in one adult despite a plasma concentration below 1 ng ml±1, whereas infants and children in the same study had respiratory depression only when the fentanyl concentration exceeded 1 ng ml±1.11 For sufentanil, a plasma concentration >0.25 ng ml±1 is considered to be ef®cacious with self-spontaneous ventilation when administered i.v. 617

1 Lùvstad RZ, Halvorsen P, Raeder JC, Steen PA. Post-operative epidural analgesia with low dose fentanyl, adrenaline and bupivacaine in children after major orthopaedic surgery. A prospective evaluation of ef®cacy and side effects. Eur J Anaesth 1997; 14: 583±9 2 Benlabed M, Ecoffey C, Levron JC, Flaisler B, Gross JB. Analgesia and ventilatory response to CO2 following epidural sufentanil in children. Anesthesiology 1987; 67: 948±51 3 Kokki H, Tuovinen K, Hendolin H. The effect of intravenous ketoprofen on postoperative epidural sufentanil analgesia in children. Anesth Analg 1999; 88: 1036±41 4 Ionescu TI, Taverne RHT, Houveling PL, Drost RH, Nuijten S, Van Rossum J. Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery. Br J Anaesth 1991; 66: 458±64 5 Geller E, Chrubasik J, Graf R, Chrubasik S, Schulte-MoÈnting J. A randomized double-blind comparison of epidural sufentanil versus intravenous sufentanil of epidural fentanyl analgesia after major abdominal surgery. Anesth Analg 1993; 76: 1243±50 6 Scott JC, Cooke JE, Stanski DR. Electroencephalographic quanti®cation of opioid effect: comparative pharmacodynamic of fentanyl and sufentanil. Anesthesiology 1991; 74: 34±42 7 Lehmann KA, Gerhard A, Horrichs-Haermayer G, Grond S, Zech D. Postoperative patient-controlled analgesia with sufentanil: analgesic ef®cacy and minimum effective concentrations. Acta Anaesthesiol Scand 1991; 35: 221±6 8 Cohen SE, Tan S, White PF. Sufentanil analgesia following cesarean section: epidural versus intravenous administration. Anesthesiology 1988; 68: 129±34 9 Cartwright P, Prys-Roberts C, Gill K, Dye A, Staffort M, Gray A. Ventilatory depression related to plasma fentanyl concentrations during and after anesthesia in humans. Anesth Analg 1983; 62: 966±74 10 Renaud B, Brichant JF, Clergue F, Chauvin M, Levron JC, Viars P. Ventilatory effects of continuous epidural infusion of fentanyl. Anesth Analg 1988; 67: 971±5 11 Hertzka R, Gaunlett IS, Fischer DM, Spellman MJ. Fentanyl induced ventilatory depression: effect of age. Anesthesiology 1989; 70: 213±8

British Journal of Anaesthesia 85 (4): 618±20 (2000)

Peribulbar anaesthesia with 1% ropivacaine and hyaluronidase 300 IU ml±1: comparison with 0.5%bupivacaine/2% lidocaine and hyaluronidase 50 IU ml±1 D. K. Woodward1*, A. T. S. Leung2, M. W. I. Tse2, R. W. K. Law2, D. S. C. Lam2 and W. D. Ngan Kee1 1

Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. 2Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China *Corresponding author: 32 Lemont Road, Shef®eld S17 4HA, UK The low toxicity of ropivacaine makes it attractive for peribulbar anaesthesia. However, its motor-sparing properties are undesirable when akinesia is important. Hyaluronidase (300 IU ml±1) promotes the onset and quality of peribulbar blockade when used with other agents. We investigated the onset and quality of ocular akinesia in 80 patients randomized to receive 1% ropivacaine plus hyaluronidase 300 IU ml±1 (group 1), or bupivacaine 0.5%/ Lidocaine 2% plus 50 IU ml±1 hyaluronidase (group 2). Ocular akinesia was scored from 0 (no movement) to 8 (full movement) every 2 min for 20 min. The groups showed no difference in the rate of onset or degree of akinesia achieved (analysis of variance with repeated measures; P=0.34). Sixty per cent of patients in group 1 and 55% in group 2 achieved akinesia scores of <4 by 6 min (c2 test; P=0.5). We conclude that both peribulbar solutions produce equivalent onset and quality of ocular akinesia. Br J Anaesth 2000; 84: 618±20. Keywords: anaesthetics local, ropivacaine; anaesthetics local, lidocaine± bupivacaine Accepted for publication: April 11, 2000

Ropivacaine has the potential advantage of reduced cardiovascular and neurological toxicity compared with other local anaesthetics that are commonly used for peribulbar anaesthesia. However, the motor sparing attributed to ropivacaine1 is a potential disadvantage that might reduce the onset or extent of motor block required for ophthalmic surgery. Previously it was found that combining a high concentration of hyaluronidase (300 IU ml±1) with a bupivacaine/lidocaine mixture improved the onset and quality of peribulbar block.2 However, there are few data on the addition of high concentrations of hyaluronidase to ropivacaine. Therefore, we compared a mixture of 1% ropivacaine with hyaluronidase 300 IU ml±1 with our standard 1:1 mixture of 0.5% bupivacaine/2% lidocaine with hyaluronidase 50 IU ml±1. The onset and quality of block were compared.

Methods and results After having obtained Research Ethics Committee approval, we recruited 80 consecutive ASA I±III Chinese outpatients undergoing phacoemulsi®cation cataract surgery in a

randomized double-blind study. Patients refusing consent, taking anticoagulants, allergic to amide local anaesthetics or hyaluronidase, or with a single eye, were excluded. After they had given written informed consent, the patients were randomized to receive peribulbar anaesthesia using either 1% ropivacaine with hyaluronidase 300 IU ml±1 (group 1) or a 1:1 mixture of 0.5% bupivacaine/2% lidocaine with adrenaline 1:200 000 and hyaluronidase 50 IU ml±1 (group 2). Intravenous access and standard monitoring were established, and one drop of 1% tetracaine was administered topically. Anaesthetic solutions were prepared individually immediately before injection. The investigators performing the injections (M.W.I.T.) and assessments (D.K.W.) were blinded to the solutions used. A two-injection technique was used, consisting of inferolateral and superior injections using a 22 mm, 25 gauge needle. Local anaesthetic was injected until peribulbar fullness was observed or to a maximum of 8 ml. Ocular pressure of 30 mm Hg was applied for 20 min, and was removed at 2 min intervals to assess residual ocular movement. Movement in the superior, inferior, medial and lateral directions was scored as 0 (no

Ó The Board of Management and Trustees 618 of the British Journal of Anaesthesia 2000

Peribulbar anaesthesia

Eighty-®ve per cent of patients in group 1 and 87.5% in group 2 reported no or mild discomfort during injection (P=0.8), and only 5% in each group reported severe discomfort. During surgery, there was no complaint of discomfort in 75% of patients in each group. The remainder complained of mild discomfort, and one patient in group 1 reported moderate discomfort.

Comment

Fig 1 Onset of akinesia in patients receiving ropivacaine (group 1) and bupivacaine plus lidocaine (group 2).

movement), 1 (up to 2 mm movement) or 2 (>2 mm movement); this gave a range from 0 (complete akinesia) to 8 for each assessment.3 Surgery started after 20 min. Patients were asked to grade discomfort during injection and during surgery on a 5-point ordinal scale (none, mild, moderate, severe, worst ever). The surgeon graded operating conditions on a 10 cm visual analogue scale (VAS; 0=impossible, 10=ideal). The principal end-point was the rate of onset and the quality of ocular akinesia. Previously, successful block was de®ned as an ocular mobility score <4.3 Prospective power analysis showed that a sample size of 40 patients per group would have 80% power at the 0.05 level of signi®cance to detect a 30% difference in the proportion of patients with an ocular mobility score <4 at 6 min, assuming an expected proportion of approximately 84% in the control group.3 Data were analysed using analysis of variance for repeated measures, Student's t test, the c2 test and the Mann± Whitney U test as appropriate. Values of P<0.05 were considered statistically signi®cant. Patient characteristics were similar between groups. Both groups had approximately twice as many women as men, with a mean age of 76 (SD 9) yr in group 1 and 74 (8) yr in group 2. The mean volume of anaesthetic injected was similar (6.7 (0.7) ml in group 1 and 6.7 (0.8) ml in group 2). There were no differences between groups in the rate of onset of block or the degree of akinesia achieved (P=0.34; Fig. 1). Sixty per cent of patients in group 1 and 55% in group 2 achieved akinesia scores of <4 at 6 min (P=0.5). Because of discomfort during surgery, one patient in group 1 required additional topical anaesthesia, while two patients required topical anaesthesia and two required subtenon's injection in group 2. These differences were not statistically signi®cant. Operating condition scores were similar (group 1, 7.6 (2.2) cm; group 2, 7.1 (2.9) cm; P=0.6).

We found that 1% ropivacaine with 300 IU ml±1 hyaluronidase gave onset and quality of peribulbar block equivalent to 0.5%bupivacaine/2%lidocaine with 50 IU ml±1 hyaluronidase. Before commencing our study, the only published data on peribulbar ropivacaine were comparisons of ropivacaine/ lidocaine with bupivacaine/lidocaine mixtures.3 We wished to determine whether ropivacaine as the sole anaesthetic could provide satisfactory akinesia for ocular surgery, particularly as other clinical applications have demonstrated motor sparing properties.1 However, before commencing the study, our impression with 1% ropivacaine was that onset of akinesia was delayed. Previous ®ndings demonstrate that a high concentration of hyaluronidase (300 IU ml±1) in peribulbar local anaesthesia promotes the speed of onset and quality of block,2 hence we opted for a combination of 1% ropivacaine and high-dose hyaluronidase. This was compared with our standard peribulbar local anaesthetic mixture as the control. After we had commenced our study, a number of other studies of peribulbar ropivacaine combined with hyaluronidase 0±75 IU ml±1 were published, and they found this to be as effective as 0.75% bupivacaine or 0.5% bupivacaine/2% lidocaine mixtures.4 5 6 Differences in methods between studies make direct comparison dif®cult. These include site(s) of injection, akinesia scoring methods, the de®nition of successful block, indications for and methods of supplementation, and the type of surgery. We used a two-injection technique according to our routine practice. Our method of assessing ocular mobility was simple and semiquantitative. We felt this was more objective and reproducible than qualitative methods. Our surgeons tolerated considerable eye movement. This was largely because we studied patients undergoing phacoemulsi®cation, which is increasingly being performed under topical anaesthesia alone. An `unsuccessful block' therefore related in practice to problems with analgesia rather than akinesia, with a correspondingly low supplementation rate compared with some other studies.4 Only one other study has been published using 300 IU ml±1 peribulbar hyaluronidase.2 No adverse effects speci®cally related to hyaluronidase were reported. Although we found that adding this dose of hyaluronidase to 1% ropivacaine resulted in an effective mixture for peribulbar block, the successful use of ropivacaine alone, or with lower concentrations of hyaluronidase, has now been

619

Abdi et al.

reported.4 5 6 Huha et al. 6 found that plasma concentra-tions of ropivacaine approached the reported greatest tolerated concentration in four of 11 patients using 1% ropivacaine and hyaluronidase 7.5 IU ml±1. The pharmacokinetic effects of higher hyaluronidase concentrations are unknown. In conclusion, we have found that 1% ropivacaine with hyaluronidase 300 IU ml±1 is a suitable mixture for peribulbar block, with onset and quality of anaesthesia similar to those achieved with bupivacaine/lidocaine. Further work is required to determine the effect of high concentrations of hyaluronidase on plasma concentrations of ropivacaine and the duration of block.

Acknowledgements We would like to thank Ms E. Wong, Ms J. Liu and the nursing staff of the Li Ka Shing ophthalmology theatres for their invaluable assistance in this investigation.

References 1 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 300±7 2 Dempsey GA, Barrett PJ, Kirby IJ. Hyaluronidase and peribulbar block. Br J Anaesth 1997; 78: 671±4 3 Gillart T, Barrau P, Bazin JE, Roche G, Chiambaretta F, Schoef¯er P. Lidocaine plus ropivacaine versus lidocaine plus bupivacaine peribulbar anaesthesia by single medial injection. Anesth Analg 1999; 89: 1192±6 4 Corke PJ, Baker J, Cammack R. Comparison of 1% ropivacaine and a mixture of 2% lignocaine and 0.5% bupivacaine for peribulbar anaesthesia in cataract surgery. Anaesth Intens Care 1999; 27: 249±52 5 Gioia L, Prandi E, Codenotti M, Casati A, Fanelli G, Torri TM, et al. Peribulbar anesthesia with either 0.75% ropivacaine or a 2% lidocaine and 0.5% bupivacaine mixture for vitreoretinal surgery: a double-blinded study. Anesth Analg 1999; 89: 739±42 6 Huha T, Ala-Kokko TI, SalomaÈki T, Alahuhta S. Clinical ef®cacy and pharmacokinetics of 1% ropivacaine and 0.75% bupivacaine in peribulbar anaesthesia for cataract surgery. Anaesthesia 1999; 54: 137±41

British Journal of Anaesthesia 85 (4): 620±3 (2000)

Lack of pre-emptive analgesic effects of local anaesthetics on neuropathic pain S. Abdi1*, D. H. Lee2, S. K. Park2 and J. M. Chung2 1

Department of Anesthesiology and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. 2Marine Biomedical Institute and Departments of Anatomy, Neurosciences, Physiology, and Biophysics, The University of Texas Medical Branch, Galveston, TX 77555, USA

*Corresponding author: Department of Anesthesia and Critical Care, Clinics 3, Massachusetts General Hospital, Harvard Medical School, 32 Fruit Street, Boston, MA 02114, USA We investigated the signi®cance of pre-emptive analgesia using a well-known model of neuropathic pain in rats. Lignocaine, bupivacaine or saline was applied locally to the left L5±L6 spinal nerve before or 4 days after nerve injury. Mechanical allodynia was then evaluated before and after injury. Pre- and post-injury treatment with local anaesthetics both resulted in a two- to threefold increase in the pain threshold, as manifested by a signi®cant increase in von Frey measurements. However, this effect lasted only 24 h. Our study in rats questions the bene®cial effect of a single dose of local anaesthetic as pre-emptive analgesia. Br J Anaesth 2000; 85: 620±3. Keywords: anaesthetics local, bupivacaine; anaesthetics local, lignocaine; pain, neuropathic; rats Accepted for publication: April 10, 2000

Pre-emptive analgesia, the administration of analgesics before tissue damage, aims to reduce both postoperative pain and the subsequent development of chronic pain

after surgery. Studies in animals have shown that tissue damage produces signi®cant changes in neuronal processing, including central sensitization, alteration in

Ó The Board of Management and Trustees 620 of the British Journal of Anaesthesia 2000

Pre-emptive analgesia for neuropathic pain

neuronal phenotype and the loss of neurons in the dorsal root ganglion with associated synaptic plasticity.1 Both basic science and recent clinical studies have shown that such changes may be attenuated to varying degrees if analgesic agents are administered before tissue injury.2 Local anaesthetics are useful in alleviating both acute and chronic pain through their inhibitory actions on sodium channels. The use of local anaesthetic agents in pre-emptive analgesia has been investigated in two in¯ammatory models of acute pain, the formalin test and the carrageenan test. However, very few investigations have used animal models of neuropathic pain.3 The purpose of our study was to test the ef®cacy of the direct application of two commonly used local anaesthetics, lignocaine and bupivacaine, onto the nerves before or after injury, using the Chung model of segmental spinal nerve injury.4 In this model, rats develop neuropathic pain with behavioural evidence of hyperalgesia and allodynia within 24 h of nerve ligation, which peaks within 7 days and may persist for several weeks.4

Methods and results The experiments were approved by the Animal Care and Use Committee of The University of Texas Medical Branch and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Thirty male Sprague±Dawley rats (Harlan Sprague± Dawley, Harlan Industries, Indianapolis, IN), weighing 150±200 g, were used. One week after the animals had been acclimatized to the laboratory conditions, baseline (before surgery) quantitative von Frey measurements were recorded and the animals were randomly assigned to one of three experimental groups: group I, saline; group II, 2% lignocaine and group III, 0.5% bupivacaine. Animals in each of the three groups were treated with either of the local anaesthetics or saline before nerve injury. Then the animals were prepared for measurements of chronic neuropathic pain behaviour, as described by Kim and Chung.4 Brie¯y, the rats were anaesthetized with halothane in oxygen (halothane concentration of 2 vol% for induction and 0.8 vol% for maintenance). Animals were placed in the prone position, skin in®ltration was done with saline (group I), 2% lignocaine (group II) or 0.5% bupivacaine (group III), and midline skin incisions at L4±S2 were made, followed by separation of the paraspinal muscles from spinous processes. The transverse process of L6 was then carefully removed. Once the left L5 and L6 spinal nerves had been identi®ed, they were bathed with saline (group I), 2% lignocaine (group II) or 0.5% bupivacaine (group III) for 10 min. The left L5±L6 spinal nerves were then ligated tightly with 6±0 silk thread, and the wound was closed. At the end of surgery, anaesthesia was discontinued and the animals were awakened and placed back into their cages with food pellets and water ad libitum under the same environmental conditions as previously. The mechanical allodynia thresh-

old was measured using von Frey ®laments, as described below, every day for 7 days. To avoid the effects of the circadian cycle, all studies were performed during the same period (9 a.m. to 12 p.m.) on each of the experimental days. Fourteen additional Sprague±Dawley rats were used to study the effect of 0.5% bupivacaine or saline when applied 4 days after injury. These animals were surgically prepared for the study in the same manner as the animals discussed above, except that their ligated L5±L6 spinal nerves had to be exposed again under anaesthesia in order to in®ltrate the nerves with saline (group IV) or 0.5% bupivacaine (group V) 4 days after ligation.

Behavioural tests All animals were tested for quantitative changes in pain threshold, as measured by the use of von Frey ®laments. Before the von Frey measurements were made, each rat was placed on a metal mesh ¯oor and covered with a plastic box (838318 cm) and allowed 30 min to acclimatize. Thereafter, light mechanical stimuli using suf®cient force to cause light buckling of the ®lament was applied to the plantar surface of the left foot using different strengths of von Frey ®laments (Stoelting, Woodale, IL, USA). In brief, von Frey ®laments with incremental stiffness (0.3±15 g) were applied serially to the paw in ascending or descending order of stiffness depending on the foot withdrawal response of the rat. The maximum and minimum cut-offs were at 15 and 0.3 g respectively. A single trial of stimuli consisted of ®ve applications of a von Frey ®lament every 4 s to the plantar surface of the left hind paw perpendicularly for about 3±4 s. Brisk foot withdrawals (at least three times out of ®ve applications) in response to normally innocuous mechanical stimuli using von Frey ®laments were considered positive; no response was considered negative. Depending on the positive or negative response, subsequent ®laments were applied in order of descending and ascending intensity respectively. The baseline threshold value of von Frey measurement was 12.6 (SEM 1.1), 12.8 (0.8), 13.7 (0.7), 15 (0) and 15 (0) g for groups I, II, III, IV and V respectively. All the animals developed signi®cant mechanical allodynia 24 h after spinal nerve ligation (Fig. 1). Pretreatment with either lignocaine or bupivacaine (groups II and III respectively) increased the threshold of mechanical allodynia compared with the control group (group I). However, this effect lasted only 24 h. Similarly, when bupivacaine was used after injury, its effect in alleviating mechanical allodynia lasted only 24 h. Neither pretreatment nor post-treatment with saline altered the development of mechanical allodynia.

Comment Tissue and nerve damage and the subsequent transmission of neural impulses from the surgical site to the spinal cord mark the beginning of a process of central neural

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Fig 1 The effects of treatment with 2% lignocaine and 0.5% bupivacaine before injury (A) and 0.5% bupivacaine treatment after injury (B) on mechanical allodynia. Nerve injury was induced by tightly ligating the left L5±L6 spinal nerves in rats. All the data are expressed as mean 6 SEM. Statistical analysis was done by analysis of variance followed by Dunnett's post hoc test and Student's t-test where appropriate.*Signi®cant difference (P<0.05) compared with the saline control group. BL, Baseline, before surgery.

sensitization that may be enhanced by other noxious perioperative events. The segmental spinal nerve injury model (Chung's model) is a well-established model used to induce neuropathic pain behaviour in rats. However, a meticulous surgical technique must be used in order to minimize the damage to the L4 spinal nerve, which can affect locomotor activity and the withdrawal response to various stimuli. Although no animal was excluded from this study because of dragging of the left hind limb (a sign of a damaged L4 spinal nerve), ®ve rats were excluded from the study because of abnormal presurgical baseline von Frey measurements. Although both pretreatment with 2% lignocaine or 0.5% bupivacaine and post-treatment with 0.5% bupivacaine slightly attenuated mechanical allodynia, all the animals remained signi®cantly allodynic throughout the experimental period. This effect lasted only 24 h, which, although it is a short time, is considerably longer than expected from the half-life of the drugs. These results are consistent with the ®ndings of Dougherty and colleagues,3 who studied the differential in¯uence of local anaesthetic upon two models of experimentally induced peripheral mononeuropathy in the rat, the partial constriction neuropathy (PCN) model and the partial transection neuropathy (PTN) model. They found that the PCN but not the PTN model showed an increase in pain threshold to the local application of anaesthetics at the

time of injury. This was consistent with the previous observations made by Gonzales-Darder, whereby autotomy in rats was diminished in magnitude but unchanged in onset after application of anaesthetic to the sciatic nerve before transection.5 Furthermore, Mao and colleagues6 reported that a single perineural injection of bupivacaine (0.5%) on day 3 after nerve ligation reduced thermal hyperalgesia when assessed 24 h after injection, and that this effect lasted for under 48 h. This is consistent with our ®ndings in the present study (Fig. 1B), even though we in®ltrated the nerves with local anaesthetic 10 min before injuring (ligating) them in addition to 4 days afterwards. In clinical studies, Nikolajsen and colleagues7 reported that perioperative epidural block that was started about 18 h before the amputation and continued into the postoperative period did not prevent phantom or stump pain. Although the role of pre-emptive analgesia in neuropathic pain is still not clear, we speculate that it may not prevent the barrage of neural discharges necessary for the development of neuropathic pain at the time of injury. In the present study, although the use of the local anaesthetics before nerve injury seems to have delayed the transmission of pain impulses to the central nervous system, it did not prevent the occurrence of neuropathic pain. Thus, the important question remains: when is the best time to administer local anaesthetics in order to derive the maximum bene®t from their pre-emptive analgesic effects? In conclusion, our present pilot study suggests that the application of a single dose of local anaesthetic onto an injured nerve may not be a clinically effective means of preventing neuropathic pain. Therefore, further blinded studies are necessary to ascertain the combination of dosage, time frame and route of administration of local anaesthetics that is most effective in preventing neuropathic pain.

Acknowledgement This research was supported by The National Institutes of Health Grants NS 31680 and NS 11255.

References

622

1 Woolf CJ, Chong MS. Preemptive analgesiaÐtreating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: 362±79 2 Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. J Am Med Assoc 1998; 279: 1076±82 3 Dougherty PM, Garrison CJ, Carlton SM. Differential in¯uence of local anaesthetic upon two models of experimentally induced peripheral mononeuropathy in the rat. Pain 1992; 570: 109±15 4 Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355±63 5 Gonzales-Darder JM, Barbera J, Abellan MJ. Effects of prior anaesthesia on autotomy following sciatic transection in rats. Pain 1986; 24: 87±91

Comparison of intubating conditions

6 Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy. Brain Res 1992; 576: 254±62

7 Nikolajsen L, Ilkjaer S, Christensen JH, Kroner K, Jensen TS. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 1997; 350: 1353±7

British Journal of Anaesthesia 85 (4): 623±5 (2000)

Comparison of intubating conditions following propofol and succinylcholine with propofol and remifentanil 2 mg kg±1 or 4 mg kg±1 I. A. McNeil, B. Culbert and I. Russell Department of Anaesthesia, Hull Royal In®rmary, Anlaby Road, Hull HU3 2JZ, UK We evaluated the intubating conditions, haemodynamic responses and duration of apnoea in 60 healthy adult patients after propofol 2 mg kg±1 combined with either a bolus of remifentanil 2 mg kg±1 or 4 mg kg±1, or succinylcholine 1 mg kg±1. Patients intubated following remifentanil showed dose-dependent intubating conditions, similar at 4 mg kg±1 to the conditions produced with succinylcholine. Post-induction mean arterial pressure decreased from baseline values by 21% (P<0.0001), 28% (P<0.0001) and 8% (P>0.05) in the remifentanil 2 mg kg±1, remifentanil 4 mg kg±1 and succinylcholine 1 mg kg±1 groups, respectively. The mean (SD) duration of apnoea following induction was 9.3 (2.6) min and 12.8 (2.9) min in the remifentanil 2 mg kg±1 and 4 mg kg±1 groups, and 6.0 (0.9) min in the succinylcholine group (P<0.001 between groups). Br J Anaesth 2000; 85: 623±5 Keywords: analgesics opioid, remifentanil; anaesthetics i.v., propofol; neuromuscular block, succinylcholine; intubation tracheal Accepted for publication: May 18, 2000

Neuromuscular blocking drugs, particularly succinylcholine, may cause serious side effects but remain in clinical use to facilitate tracheal intubation due to a lack of suitable alternatives.1 A combination of propofol and alfentanil has been demonstrated to reliably facilitate intubation without the use of neuromuscular blocking agents.2 3 Remifentanil is a new potent fentanyl derivative with a unique metabolic pro®le and plasma clearance considerably faster than alfentanil.4 These properties make remifentanil the opioid of choice to facilitate tracheal intubation, and subsequently allow a rapid return of spontaneous respiration and airway re¯exes. In this study, we have compared the intubating conditions, haemodynamic changes and duration of apnoea in healthy adults following induction of anaesthesia with propofol in combination with either succinylcholine or varying doses of remifentanil.

Methods and results With Ethics Committee approval and written informed consent, 60 ASA 1 and 2 non-obese, elective surgical

patients, aged between 18 and 65 yr who required intubation for their proposed surgery were studied. Those on obstetric, neurosurgical or ophthalmic lists, those with Mallampati scores greater than 2 or with gastro-oesophageal re¯ux were excluded. Patients were randomized into three groups by opening unmarked envelopes indicating the induction regime as follows: PS=propofol 2 mg kg±1 and succinylcholine 1 mg kg±1; PR 2=propofol 2 mg kg±1 and remifentanil 2 mg kg±1; and PR 4=propofol 2 mg kg±1 and remifentanil 4 mg kg±1. No patients were prescribed sedative premedication. Intravenous access was established, but no ¯uids were given. Mean arterial pressure (MAP), heart rate (HR), oxygen saturation and end-tidal carbon dioxide (FE¢CO ) were monitored during induction using the Datex Cardiocap. Patients were not preoxygenated, but received oxygen from the end of a Bain system held 5±10 cm caudal to the chin. In group PS, propofol 2 mg kg±1 was given over 60 s followed immediately by succinylcholine 1 mg kg±1. In groups PR 2 and PR 4, propofol 2 mg kg±1 was followed immediately by remifentanil 2 or 4 mg kg±1, with each drug administered over 30 s. After induction, mask ventilation

Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000 623

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McNeil et al.

was initiated with 2% sevo¯urane in 50% nitrous oxide in oxygen at a total ¯ow of 8 litres min±1 and continued in group PS until fasciculation had ceased, and for 30 s in both remifentanil groups. At this point an experienced, blinded anaesthetist took over airway control and attempted tracheal intubation of the patient. During laryngoscopy, each patient was assessed for ®ve variables: jaw mobility; mask ventilation; vocal cord visibility; vocal cord position; and patient movement during intubation. The criteria used for ranking these variables are shown in Table 1. Following intubation, patients were hand ventilated with a Bain breathing system at ®ve breaths per minute. If FE¢CO levels reached 8 kPa in any patient, ventilation was increased to prevent any further rise. Duration of apnoea was recorded in patients as the period from the beginning of the propofol injection until the ®rst recognizable breath. If spontaneous respiration had not resumed within 15 min (so as not to delay operating time), this time was recorded as the duration of apnoea. Data were analysed using one-way analysis of variance with Tukey's multiple comparisons (age, weight, duration of apnoea and MAP changes between groups), the paired ttest (MAP and HR changes within groups) and the Kruskal± Wallis test with Dunn's multiple comparisons (intubation scores). A value of P<0.05 was considered statistically signi®cant. We studied 17 patients in group PS, 20 in group PR 4 and 23 in group PR 2. One patient in group PR 4 was an unexpected dif®cult intubation and was withdrawn from the study. Patients in all three groups were similar in age and weight. Mean (SD, range) patient age in groups PS, PR 4 and PR 2 were 44 (15, 18±65) yr, 40 (13, 18±61) yr and 39 (11, 18±62) yr, respectively. Mean patient weight in groups PS, PR 4 and PR 2 were 75 (10, 49±92) kg, 71 (12, 50±94) kg and 76 (15, 55±100) kg, respectively. All subjects in the study were successfully intubated except for two, both in group PR2. In one of these patients vocal cord relaxation was insuf®cient to allow passage of a tracheal tube, and purposeful movement continued following induction in

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another. Subsequently, both patients were intubated following the administration of atracurium 0.5 mg kg±1. Scores in the three groups, for each of the ®ve intubation characteristics graded in the study are shown in Fig. 1. While there were no differences between groups for the intubation characteristic scores of jaw mobility (P>0.05), ease of mask ventilation (P>0.05) or vocal cord visibility (P>0.05), signi®cant differences were found between groups for the characteristics of vocal cord position (P<0.05) and movement during intubation (P<0.001). Although multiple comparisons demonstrated no signi®cant differences between pairs of groups for vocal cord position (P>0.05), movement during intubation was found to be signi®cantly more likely in group PR 2 than in either of the other groups (P<0.05). Mask ventilation was described as `dif®cult' in one patient in group PR 2 and `impossible' in

Fig 1 Percentage of patients in groups and the scores attained for each of ®ve intubation characteristics. Groups: PS=propofol 2 mg kg±1 and succinylcholine 1 mg kg±1; PR4=propofol 2 mg kg±1 and remifentanil 4 mg kg±1; and PR2=propofol 2 mg kg±1 and remifentanil 2 mg kg±1. Intubation characteristics: JM, jaw mobility; MV, mask ventilation; CV, vocal cord visibility; CP, vocal cord position; PM, patient movement.

Table 1 Intubating conditions scoring system Intubation characteristic

Criteria

Score

Jaw mobility

Jaw mobile Jaw partly mobile Jaw immobile Mask ventilation easy Mask ventilation dif®cult Mask ventilation impossible Vocal cords and arytenoids completely visible Vocal cords and arytenoids partly visible Vocal cords or arytenoids not seen Vocal cords open Vocal cords mid-position Vocal cords closed No movement during intubation One or two coughs during intubation Persistent coughing or purposeful movement

1 2 3 1 2 3 1 2 3 1 2 3 1 2 3

Mask ventilation Vocal cord visibility Vocal cord position Patient movement

624

Comparison of intubating conditions

one patient in group PR 4, but neither subject experienced oxygen desaturation, and both were successfully intubated. Baseline preinduction values of MAP and HR were similar in all three groups (P>0.05). Postinduction MAP values decreased from baseline in groups PR 2, PR 4 and PS by 21% (P<0.0001), 28% (P<0.0001) and 8% (P>0.05), respectively. While the difference in post-induction MAP values between groups PR2 and PR4 was not signi®cant (P>0.05), post-induction MAP values were signi®cantly lower in both remifentanil groups compared with group PS (P<0.001). Values of post-induction HR decreased from baseline in groups PR 2 and PR 4 by 14% (P<0.01) and 19% (P<0.001), and increased in group PS by 15% (P<0.01). One patient in group PR 4, whose heart rate fell to 35 beats min±1, was treated with glycopyrrolate 500 mg. The mean (SD) times, recorded from the beginning of the propofol injection until the ®rst recognizable breath, were 6.0 (0.9) min in group PS, 9.3 (2.6) min in group PR 2 and 12.8 (2.9) min in group PR 4 (P<0.001 between all groups).

Comment Our study has demonstrated that in healthy adults, with normal airway anatomy, a combination of propofol 2 mg kg±1 and remifentanil 2 or 4 mg kg±1 produces dosedependent intubating conditions which at the higher remifentanil dose are similar to those produced with succinylcholine 1 mg kg±1. Unfortunately, using a suf®ciently high dose of remifentanil to consistently ensure optimum intubating conditions is not without problem. We found signi®cant, dose-related cardiovascular depression associated with the use of a large dose of remifentanil. These levels of hypotension were well tolerated by the subjects in our study, but how they might be tolerated in those less healthy is unproven. High doses of potent opioids are also well recognized to cause muscle rigidity, and in this respect remifentanil is no exception.5 In our study, two patients receiving remifentanil were dif®cult to hand ventilate, and this dif®culty may well have been due to opioid-induced rigidity.

For an opioid to replace succinylcholine in a rapid sequence induction it should provide optimum intubating conditions, and also allow a rapid return of spontaneous respiration and airway re¯exes. Although we demonstrated that patients intubated following remifentanil 4 mg kg±1 and succinylcholine 1 mg kg±1 had similar intubating conditions, the mean duration of apnoea was more than twice as long in the remifentanil group (12.8 vs 6.0 min in the succinylcholine group). The period of apnoea, following a suf®cient dose of remifentanil to ensure optimum intubating conditions, would be unacceptable in rapid sequence induction should intubation fail. Although the opioid antagonist, naloxone, could be administered in these circumstances, the degree to which it might lessen apnoea is as yet undetermined. Our study indicates a role for remifentanil and propofol as an effective method of tracheal intubation. We hope our described technique will be considered an alternative to the use of neuromuscular blocking drugs for procedures requiring tracheal intubation but not muscle relaxation during surgery, and in situations where the use of neuromuscular blocking agents is contraindicated.

References

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