Anaesthesia, 1990, Volume 46, pages 1028-1031
A randomised double-blind study of interpleural analgesia after cholecystectomy
A. LEE, D. BOON, P. BAGSHAW AND P. KEMPTHORNE
Summary Continuous interpleural analgesia provided by 4 hourly injections of 20 ml bupivacaine 0.5% with adrenaline 5 &ml was compared with placebo in a randomised, double-blind study after cholecystectomy. AN patients self-administered intravenous morphine using a patient-controlled analgesia device. There was a highly signijicant difference in mean morphine consumption between the groups (72 mg as compared with 22 mg). Visual analogue pain scores tended to be lower in the bupivacaine group throughout and this was signijicant at 2 hours. Respiratory function measurements were not signijicantly direrent between the groups. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03 pg/ml and no symptoms suggestive of local anaesthetic toxicity occurred. It is concluded that this regimen can provide effective and continuous analgesia after cholecystectomy and that combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the immediate postoperative period. The doses of bupivacaine requiredfor optimal use of the technique lead to signilfcant total plasma bupivacaine concentrations within 24 hours. Key words
Anaesthetic techniques, regional; interpleural. Pain; postoperative.
Pain relief after unilateral thoraco-abdominal operations may be provided by the administration of bupivacaine into the pleural space.’” A duration up to 27 hours after a single injection of 0.5% bupivacaine 20 ml with adrenaline 5 pg/ml has been reported,l but recent studies suggest that analgesia is usually shorter-lived.4.s In our experience, analgesia invariably wears off within 5 hours of administration of the above dose, although 4 hours of pain relief is consistently achieved. Patients who require little or no opioid supplementation may experience extremely painful episodes because the effect of the local anaesthetic wears off rapidly and there is no background analgesia. This intermittent absence of pain relief tends to exaggerate the efficacy of the technique and the possible beneficial effects on respiratory function.2S6It needs to be shown that interpleural analgesia has advantages compared to current regimens before it is adopted for widespread clinical use. The plasma concentrations of bupivacaine attained when interpleural block is maintained using repeated bolus injections of local anaesthetic for prolonged periods remain to be determined.
The aims of this study were to compare interpleural analgesia to placebo in a randomised, double-blind manner and assess whether a combined interpleural and systemic opioid technique provides better pain relief than opioid alone. Local anaesthetic blockade was maintained, and episodes of severe pain were avoided. We examined the effects of interpleural analgesia on respiratory function and measured the plasma concentrations of bupivacaine that may be expected when an intermittent bolus technique is used in an optimal fashion.
Methods Twenty patients (aged 24-70 years, ASA 1 or 2), undergoing cholecystectomy were admitted to the study, which was approved by the local ethics committee. All patients received instruction before operation in the use of the Cardiff Palliator and visual analogue scales for scoring pain. Baseline measurements of FEV,, FVC and the FEV,/ FVC ratio were made with the patient in the sitting position using a wedge spirometer (Vitalograph).
A. Lee, FCAnaes, Senior Registrar, Department of Anaesthetics, Royal Infirmary, Edinburgh EH3 9YW, P. Bagshaw, MD, FRCS, Consultant, Department of Surgery, D. Boon, FFARACS, Consultant, P. Kempthorne, FFARACS, FFARCS, Consultant, Department of Anaesthetics, Christchurch Hospital, Christchurch, New Zealand. Accepted 31 May 1990. 0003-2409/90/121028 +04 $03.00/0
@ 1990 The Association of Anaesthetists of Gt Britain and Ireland
1028
Interpleural analgesia after cholecystectomy Triazolam 0.25mg was given orally one hour before surgery, and anaesthesia was induced with thiopentone and maintained with nitrous oxide 70% and isoflurane 0.5% in oxygen. Alfentanil was administered intravenously at induction, followed by an alfentanil infusion at 1 (pg/kg)/minute; the patients were paralysed with vecuronium and ventilation was controlled. The surgeon did not cross the midline with the skin incision. The alfentanil infusion rate was reduced to 0.5 (pg/kg)/minute 10 minutes before completion of surgery, and after surgery, with the patient still paralysed and anaesthetised, an 18-gauge Tuohy needle was used to insert an extradural catheter interpleurally through the eighth intercostal space, in the posterior axillary line, on the right side. This procedure was performed with the patient in the left lateral position using an air-filled syringe and a loss of resistance technique. The breathing system was disconnected immediately before puncturing the parietal pleura, and the ability to thread 20cm of catheter rapidly was taken as confirmation that the catheter was not sited superficially to the parietal pleura. All anaesthetic agents were discontinued after withdrawing the needle, and residual paralysis was reversed with neostigmine. The patients were randomly allocated to two groups by the hospital pharmacy who provided coded ampoules for interpleural injection. The patients in one group received six doses, each of 20ml 0.9% saline at 4-hourly intervals through the interpleural catheter. The patients in the other group received six doses, each of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml at 4-hourly intervals. All interpleural injections were made by an anaesthetist (A.L.,D.B.) with the patient supine. The upper half of the patient's body was placed in a 30" head-up position one minute after injection. The first interpleural injection was made immediately after catheter insertion with the patient supine on the operating table. The sixth injection was made at 20 hours. All patients were allowed to self-administer 2mg incre, ments of morphine intravenously after operation using a Cardiff Palliator with a lockout interval of 5 minutes. All patients at 24 hours, after completion of the study period, received a seventh interpleural injection of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml. The placement of the catheter was then confirmed by demonstrating loss of cold sensation in several thoracic dermatomes on the right side using an ice cube. Assessments were made by the attending anaesthetist (A.L.,D.B.) at 2, 4, 6, 8, 12 and 20 hours after operation using 10-cm linear visual analogue scales (no pain-the worst pain I can imagine). Respiratory function tests were repeated at 4 and 24 hours after operation with the patient in the sitting position. Venous blood samples were taken before and at 5-minute intervals for 30 minutes after the sixth interpleural injection, and these were stored at
50[
1029
**
1
E 430 0[ c ._ c
**
? 20 H 10 n
0-4
.,
4-8 8-12 12-16 16-20 20-24 T i m e (4 hour periods after operation)
Fig. 1. Morphine consumption during the first 24 hours after surgery (p < 0.01 significant). bupivacaine; m, saline; *p < 0.001; **p < 0.01.
-20°C. The samples from patients who had received placebo were discarded on completion of the study, and samples from patients who received bupivacaine were analysed for plasma bupivacaine concentrations. Any side effects that occurred during the study were recorded. Comparisons were made between groups using Student's t or Mann-Whitney tests with Bonferroni corrections for multiple testing where appropriate.
Results There were no significant differences between the groups in age, height, weight, sex and smoking habits (Table 1). FEV,, FVC and FEVJFVC ratio were within the normal range based on standard tables for all patients, and the groups were comparable. The mean dose of morphine consumed in the first 24 hours after operation was 21.6 mg in the bupivacaine group and 72.4mg in the saline group (p < 0.001). Significantly more morphine was consumed in the saline group in every 4-hour time period up to 16 hours (Fig. 1). Visual analogue scores tended to be higher in the saline group throughout the study (Fig. 2), and this was significant at 2 hours (p c 0.01). There was a highly significant decrease in FEV, and FVC at 4 hours after operation in both groups and this decrease was maintained at 24 hours (Table 2). There were no significant differences in respiratory function tests between the groups at any time. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03pg/ml and occurred between 10 and 30 minutes after injection. The highest
loor
*
Table 1. Demographic data, mean (SD). Age Height Weight Sex Smokers (years) (m) (kg) W / F ) FIN) Bupivacaine group Saline group
50.3 (15.1) 50.1 (14.5)
1.65 (0.08)
1.69 (0.10)
12.1 (12.2) 11.7 (14.6)
3/1
311
416
311
-.-,
Time after operation (hours)
Fig. 2. Visual analogue pain assessments (no pain-the worst pain I can imagine) after surgery. bupivacaine (median/ quart); -n-, saline (median/quart); (*p < 0.01 significant).
A . Lee et al.
1030
Table 2. Respiratory function tests, mean (SD). Bupivacaine group (ml)
Saline group (ml)
Pre-operative values Predicted FEV, Measured FEV, Predicted FVC Measured FVC
2778 3037 3672 3695
(669) (997) (804) (1192)
2924 (567) 3104 (723) 3920 (761) 3839 (981)
4 hours after operation FEV, FVC
1415 (461) 1739 (682)
1697 (467) 2174 (513)
24 hours after operation FEV, FVC
1721 (683) 2112 (802)
1704 (450) 2089 (573)
bupivacaine concentration measured in any patient was 3.91 pg/ml (Fig. 3). No patient had any symptoms suggestive of local anaesthetic toxicity at any time elicited by spontaneous reporting or repeated direct questioning.
Discussion This study confirmed the efficacy of interpleural bupivacaine after cholecystectomy and shows that continuous pain relief can be achieved using an intermittent bolus technique of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml every 4 hours. Combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the first few hours after surgery. Previous studies in postoperative patients with no analgesia have demonstrated a significant decrease in visual analogue pain score after the interpleural administration of local anaesthetic.2S6This confirms the pain relieving effect of interpleural local anaesthetic, but does not show that it is as effective or better than other methods of analgesia. A controlled, double-blind comparison with established analgesic regimens on the day of surgery has not previously been conducted. Studies performed on the day of operation have either been unblinded or have used a local anaesthetic infusion techniq~e.~.~ Continuous infusions may be effective after thoracotomy in children, but appear to be of less use after thoracotomy or cholecystectomy in adults?+ This may be related to the distribution of local anaesthetic in the pleural space. Large bolus doses of solution are retained in the pleural cavity for
’ .a
!5
0
5 10 15 20 25 Time after sixth dose (minutes)
30
Fig. 3. Mean venous plasma bupivacaine concentrations before and after the sixth dose of interpleural bupivacaine (--n-, mean + SD).
appreciable periods of time and spread along the dorsal aspect of the cavity from diaphragm to apex.2 There may be rapid flow of solution to the mediastinal aspect of the pleural cavity with continuous infusion of drug because of the pressure gradients that exist within the cavity.I0 The results from continuous blocks achieved by intermittent bolus techniques may well differ from the effects obtained by infusion of similar doses. The effect of interpleural blockade on respiratory function after upper abdominal surgery is c o n t r o ~ e r s i a l . ~ ~ ~ ~ ~ ~ ~ Some studies have examined the effect of interpleural local anaesthetic in patients with no analgesia at all after an upper abdominal operation and shown that there is a significant improvement in respiratory function.2This does not exclude the possibility that interpleural blockade may have detrimental effects on diaphragmatic function, nor does it show that interpleural analgesia is preferable to systemic opioids. Poorer respiratory function in the presence of interpleural blockade compared to systemic opioids alone has been demonstrated.” However, in that study the patients receiving systemic opioids had better respiratory function than has usually been described after upper abdominal surgery and this may represent a chance finding. We were unable to demonstrate any difference in overall function in the present study compared to patientcontrolled opioid analgesia. More detailed study of respiratory function in the presence of interpleural blockade is indicated, particularly in relation to diaphragmatic function which may be impaired. The venous plasma concentrations of bupivacaine after the sixth dose approached previously reported toxic levels,I2 and were higher than the plasma concentrations reported after one or two doses of interpleural b~pivacaine.*.~J~J~ Symptoms suggestive of local anaesthetic toxicity were specifically sought and were not present at any time. The lack of toxic effects at these plasma concentrations is related to the marked increase in plasma alpha,-acid glycoprotein known to occur after surgery.” This protein provides the main binding sites for bupivacaine and with an increased availability of binding sites the total plasma bupivacaine concentration may increase without an increase in free drug concentration. Similar plasma concentrations have been reported during extradural infusions, again without clinical evidence of systemic toxicity.16The rate of rise of plasma concentration is important and the gradual increase that occurs in the clinical setting compared to the acute rise in volunteer studies helps to account for the lack of systemic effects.,’ Continuous administration of bupivacaine at these doses for periods exceeding 48 hours should be viewed with some caution. Increases in the total plasma bupivacaine concentration to values exceeding 5 pg/ml have been measured during postoperative extradural infusions that have been in progress for over 2 days.[* No clinical evidence of bupivacaine toxicity was reported, but these patients had relatively stable and low plasma concentrations of bupivacaine for the first 48 hours. Measurement of the free drug concentration was not performed during these late increases in total concentration, but would have been of value. The necessity for frequent top-ups limits the use of intermittent interpleural techniques, and studies conducted in a double-blind manner have confirmed that the duration expected from a single bolus is around 4 h o u r ~ . ~Further ,~J~ investigation of interpleural local anaesthetic infusions is
Interpleural analgesia after cholecystectomy desirable, but they may not prove to be as useful as intermittent bolus techniques. It is concluded that continuous, effective analgesia can be maintained by regular interpleural injections of bupivacaine after cholecystectomy and that analgesia superior to that obtainable from systemic opioids alone is possible. Significant total plasma bupivacaine concentrations are present after 24 hours.
Acknowledgment We should like to thank Astra Pharmaceutical, New Zealand for measurement of plasma bupivacaine concentrations.
References 1. REIESTADF, STROMSKAG KE. Interpleural catheter in the management of postoperative pain. A preliminary report. Regional Anesthesia 1986; 11: 89-91. 2. BRISMARB, PEITERSONN, TOKICSL, STRANDBERG A, HEDENSTIERNA G. Postoperative analgesia with intrapleural of bupivacaine-adrenaline. Acta administration . Anaesthesiologica Scandinavica 1987; 31: 5 15-20. 3. LANDESBERG G, MERETYK S,LANKOVSKY Z, SHAPIRO A. Intraoperative intrapleural catheter placement for continuous bupivacaine administration. European Journal of Anaesrhesiology 1990; 7: 149-52. 4. VADEBONCOUER TR, RIEGLER FX, GAUTTRS, WEINBERG GL. A randomized, double-blind comparison of the effects of interpleural bupivacaine and saline on morphine requirements and pulmonary function after cholecystectomy. Anesthesiology 1989; 71: 339-43. 5. BLAKE DW, DONNANG, NOVELLAJ. Interpleural administration of bupivacaine after cholecystectomy: a comparison with intercostal nerve block. Anaesthesia and Intensive Care 1989; 17: 269-74. KE, REIESTADF, HOLMQVIST ELO, OGENSTAD S. 6. STROMSKAG Intrapleural administration of 0.25%, 0.375% and 0.5% bupivacaine with epinephrine after cholecystectomy. Anesthesia and Analgesia 1988; 67: 430-4. 7. SCOTTNB, MWENSENT, BIGLER D, KEHLETH. Comparison of the effects of continuous intrapleural vs epidural
103 1
administration of 0.5% bupivacaine on pain, metabolic response and pulmonary function following cholecystectomy. Acta Anaesthesiologica Scandinavica 1989; 3 3 535-9. 8. ROSENBERG PH,SCHEININ BMA, LEPANTAM MJA, LINDFORS 0. Continuous intrapleural infusion of bupivacaine for analgesia after thoracotomy. Anesthesiology 1987; 67: 81 1-3. WB, KNOXRF, FENNESEY PV, GOLDSTEIN M. 9. MCILVAINE Continuous infusion of bupivacaine via intrapleural catheter for analgesia after thoracotomy in children. Anesthesiology 1988; 69: 261-4. 10. MISEROCCHI G, PISTOLFSIM, MINIATIM, BELLINACR, NEGRINI D, GIUNTINI C. Pleural liquid pressure gradients and intrapleural distribution of injected bolus. Journal of Applied Physiology 1984; 56: 526-32. 11. OXORNDC,WHATLEY GS. Post-cholecystectomy pulmonary function following interpleural bupivacaine and intramuscular pethidine. Anaesthesia and Intensive Care 1989; 17: 440-3. 12. JORFELDT L, LOF~TROM B, PERNOWB, PERSONB, WAHRENJ, WIDMANB. The effects of local anaesthetics on the central circulation and respiration in man and dog. Acia Anaesthesiologica Scandinavica 1968; 1 2 153-69. 13. SELTZERJL, LARIJANI GE, GOLDBERG ME, MARR AT. Intrapleural bupivacaine-a kinetic and dynamic evaluation. Anesthesiology 1987; 67: 798-800. FM. 14. KAMBAMJR, HAMMONJ, PARRISWCV, LUPINETTI Intrapleural analgesia for post-thoracotomy pain and blood levels of bupivacaine following intrapleural injection. Canadian Journal of Anaesthesia 1989; 36: 106-9. 15. WULF H, WINCKLERK, MAIER C, HEINZOW B. Pharmacokinetics and protein binding of bupivacaine in postoperative epidural analgesia. Acta Anaesthesiologica Scandinavica 1988; 3 2 530-4. JE, ARMITAGE EN. Postoperative pain 16. Ross RA, CLARKE prevention by continuous epidural infusion. A study of the clinical effects and the plasma concentrations obtained. Anaesthesia 1980; 35: 663-8. 17. SCOTTDB. Evaluation of the toxicity of local anaesthetic agents in man. British Journal of Anaesthesia 1975; 47: 56-61. 18. RICHTER 0, KLEINK, ABELJ, OHNESORGE FK, WUST HJ, THIESSENFMM. The kinetics of bupivacaine (Carbostesin) plasma concentrations during epidural anesthesia following intraoperative bolus injection and subsequent continuous infusion. International Journal of Clinical Pharmacology, Therapy and Toxicology 1984; 2 2 61 1-7. 19. SCHEININ B, LINDGREN L, ROSENBERG PH. Treatment of postthoracotomy pain with intermittent instillations of intrapleural bupivacaine. Acta Anaesthesiologica Scandinavica 1989; 3 3 156-9.
A randomised double-blind study of interpleural analgesia after cholecystectomy
A. LEE, D. BOON, P. BAGSHAW AND P. KEMPTHORNE
Summary Continuous interpleural analgesia provided by 4 hourly injections of 20 ml bupivacaine 0.5% with adrenaline 5 &ml was compared with placebo in a randomised, double-blind study after cholecystectomy. AN patients self-administered intravenous morphine using a patient-controlled analgesia device. There was a highly signijicant difference in mean morphine consumption between the groups (72 mg as compared with 22 mg). Visual analogue pain scores tended to be lower in the bupivacaine group throughout and this was signijicant at 2 hours. Respiratory function measurements were not signijicantly direrent between the groups. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03 pg/ml and no symptoms suggestive of local anaesthetic toxicity occurred. It is concluded that this regimen can provide effective and continuous analgesia after cholecystectomy and that combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the immediate postoperative period. The doses of bupivacaine requiredfor optimal use of the technique lead to signilfcant total plasma bupivacaine concentrations within 24 hours. Key words
Anaesthetic techniques, regional; interpleural. Pain; postoperative.
Pain relief after unilateral thoraco-abdominal operations may be provided by the administration of bupivacaine into the pleural space.’” A duration up to 27 hours after a single injection of 0.5% bupivacaine 20 ml with adrenaline 5 pg/ml has been reported,l but recent studies suggest that analgesia is usually shorter-lived.4.s In our experience, analgesia invariably wears off within 5 hours of administration of the above dose, although 4 hours of pain relief is consistently achieved. Patients who require little or no opioid supplementation may experience extremely painful episodes because the effect of the local anaesthetic wears off rapidly and there is no background analgesia. This intermittent absence of pain relief tends to exaggerate the efficacy of the technique and the possible beneficial effects on respiratory function.2S6It needs to be shown that interpleural analgesia has advantages compared to current regimens before it is adopted for widespread clinical use. The plasma concentrations of bupivacaine attained when interpleural block is maintained using repeated bolus injections of local anaesthetic for prolonged periods remain to be determined.
The aims of this study were to compare interpleural analgesia to placebo in a randomised, double-blind manner and assess whether a combined interpleural and systemic opioid technique provides better pain relief than opioid alone. Local anaesthetic blockade was maintained, and episodes of severe pain were avoided. We examined the effects of interpleural analgesia on respiratory function and measured the plasma concentrations of bupivacaine that may be expected when an intermittent bolus technique is used in an optimal fashion.
Methods Twenty patients (aged 24-70 years, ASA 1 or 2), undergoing cholecystectomy were admitted to the study, which was approved by the local ethics committee. All patients received instruction before operation in the use of the Cardiff Palliator and visual analogue scales for scoring pain. Baseline measurements of FEV,, FVC and the FEV,/ FVC ratio were made with the patient in the sitting position using a wedge spirometer (Vitalograph).
A. Lee, FCAnaes, Senior Registrar, Department of Anaesthetics, Royal Infirmary, Edinburgh EH3 9YW, P. Bagshaw, MD, FRCS, Consultant, Department of Surgery, D. Boon, FFARACS, Consultant, P. Kempthorne, FFARACS, FFARCS, Consultant, Department of Anaesthetics, Christchurch Hospital, Christchurch, New Zealand. Accepted 31 May 1990. 0003-2409/90/121028 +04 $03.00/0
@ 1990 The Association of Anaesthetists of Gt Britain and Ireland
1028
Interpleural analgesia after cholecystectomy Triazolam 0.25mg was given orally one hour before surgery, and anaesthesia was induced with thiopentone and maintained with nitrous oxide 70% and isoflurane 0.5% in oxygen. Alfentanil was administered intravenously at induction, followed by an alfentanil infusion at 1 (pg/kg)/minute; the patients were paralysed with vecuronium and ventilation was controlled. The surgeon did not cross the midline with the skin incision. The alfentanil infusion rate was reduced to 0.5 (pg/kg)/minute 10 minutes before completion of surgery, and after surgery, with the patient still paralysed and anaesthetised, an 18-gauge Tuohy needle was used to insert an extradural catheter interpleurally through the eighth intercostal space, in the posterior axillary line, on the right side. This procedure was performed with the patient in the left lateral position using an air-filled syringe and a loss of resistance technique. The breathing system was disconnected immediately before puncturing the parietal pleura, and the ability to thread 20cm of catheter rapidly was taken as confirmation that the catheter was not sited superficially to the parietal pleura. All anaesthetic agents were discontinued after withdrawing the needle, and residual paralysis was reversed with neostigmine. The patients were randomly allocated to two groups by the hospital pharmacy who provided coded ampoules for interpleural injection. The patients in one group received six doses, each of 20ml 0.9% saline at 4-hourly intervals through the interpleural catheter. The patients in the other group received six doses, each of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml at 4-hourly intervals. All interpleural injections were made by an anaesthetist (A.L.,D.B.) with the patient supine. The upper half of the patient's body was placed in a 30" head-up position one minute after injection. The first interpleural injection was made immediately after catheter insertion with the patient supine on the operating table. The sixth injection was made at 20 hours. All patients were allowed to self-administer 2mg incre, ments of morphine intravenously after operation using a Cardiff Palliator with a lockout interval of 5 minutes. All patients at 24 hours, after completion of the study period, received a seventh interpleural injection of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml. The placement of the catheter was then confirmed by demonstrating loss of cold sensation in several thoracic dermatomes on the right side using an ice cube. Assessments were made by the attending anaesthetist (A.L.,D.B.) at 2, 4, 6, 8, 12 and 20 hours after operation using 10-cm linear visual analogue scales (no pain-the worst pain I can imagine). Respiratory function tests were repeated at 4 and 24 hours after operation with the patient in the sitting position. Venous blood samples were taken before and at 5-minute intervals for 30 minutes after the sixth interpleural injection, and these were stored at
50[
1029
**
1
E 430 0[ c ._ c
**
? 20 H 10 n
0-4
.,
4-8 8-12 12-16 16-20 20-24 T i m e (4 hour periods after operation)
Fig. 1. Morphine consumption during the first 24 hours after surgery (p < 0.01 significant). bupivacaine; m, saline; *p < 0.001; **p < 0.01.
-20°C. The samples from patients who had received placebo were discarded on completion of the study, and samples from patients who received bupivacaine were analysed for plasma bupivacaine concentrations. Any side effects that occurred during the study were recorded. Comparisons were made between groups using Student's t or Mann-Whitney tests with Bonferroni corrections for multiple testing where appropriate.
Results There were no significant differences between the groups in age, height, weight, sex and smoking habits (Table 1). FEV,, FVC and FEVJFVC ratio were within the normal range based on standard tables for all patients, and the groups were comparable. The mean dose of morphine consumed in the first 24 hours after operation was 21.6 mg in the bupivacaine group and 72.4mg in the saline group (p < 0.001). Significantly more morphine was consumed in the saline group in every 4-hour time period up to 16 hours (Fig. 1). Visual analogue scores tended to be higher in the saline group throughout the study (Fig. 2), and this was significant at 2 hours (p c 0.01). There was a highly significant decrease in FEV, and FVC at 4 hours after operation in both groups and this decrease was maintained at 24 hours (Table 2). There were no significant differences in respiratory function tests between the groups at any time. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03pg/ml and occurred between 10 and 30 minutes after injection. The highest
loor
*
Table 1. Demographic data, mean (SD). Age Height Weight Sex Smokers (years) (m) (kg) W / F ) FIN) Bupivacaine group Saline group
50.3 (15.1) 50.1 (14.5)
1.65 (0.08)
1.69 (0.10)
12.1 (12.2) 11.7 (14.6)
3/1
311
416
311
-.-,
Time after operation (hours)
Fig. 2. Visual analogue pain assessments (no pain-the worst pain I can imagine) after surgery. bupivacaine (median/ quart); -n-, saline (median/quart); (*p < 0.01 significant).
A . Lee et al.
1030
Table 2. Respiratory function tests, mean (SD). Bupivacaine group (ml)
Saline group (ml)
Pre-operative values Predicted FEV, Measured FEV, Predicted FVC Measured FVC
2778 3037 3672 3695
(669) (997) (804) (1192)
2924 (567) 3104 (723) 3920 (761) 3839 (981)
4 hours after operation FEV, FVC
1415 (461) 1739 (682)
1697 (467) 2174 (513)
24 hours after operation FEV, FVC
1721 (683) 2112 (802)
1704 (450) 2089 (573)
bupivacaine concentration measured in any patient was 3.91 pg/ml (Fig. 3). No patient had any symptoms suggestive of local anaesthetic toxicity at any time elicited by spontaneous reporting or repeated direct questioning.
Discussion This study confirmed the efficacy of interpleural bupivacaine after cholecystectomy and shows that continuous pain relief can be achieved using an intermittent bolus technique of 20 ml 0.5% bupivacaine with adrenaline 5 pg/ml every 4 hours. Combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the first few hours after surgery. Previous studies in postoperative patients with no analgesia have demonstrated a significant decrease in visual analogue pain score after the interpleural administration of local anaesthetic.2S6This confirms the pain relieving effect of interpleural local anaesthetic, but does not show that it is as effective or better than other methods of analgesia. A controlled, double-blind comparison with established analgesic regimens on the day of surgery has not previously been conducted. Studies performed on the day of operation have either been unblinded or have used a local anaesthetic infusion techniq~e.~.~ Continuous infusions may be effective after thoracotomy in children, but appear to be of less use after thoracotomy or cholecystectomy in adults?+ This may be related to the distribution of local anaesthetic in the pleural space. Large bolus doses of solution are retained in the pleural cavity for
’ .a
!5
0
5 10 15 20 25 Time after sixth dose (minutes)
30
Fig. 3. Mean venous plasma bupivacaine concentrations before and after the sixth dose of interpleural bupivacaine (--n-, mean + SD).
appreciable periods of time and spread along the dorsal aspect of the cavity from diaphragm to apex.2 There may be rapid flow of solution to the mediastinal aspect of the pleural cavity with continuous infusion of drug because of the pressure gradients that exist within the cavity.I0 The results from continuous blocks achieved by intermittent bolus techniques may well differ from the effects obtained by infusion of similar doses. The effect of interpleural blockade on respiratory function after upper abdominal surgery is c o n t r o ~ e r s i a l . ~ ~ ~ ~ ~ ~ ~ Some studies have examined the effect of interpleural local anaesthetic in patients with no analgesia at all after an upper abdominal operation and shown that there is a significant improvement in respiratory function.2This does not exclude the possibility that interpleural blockade may have detrimental effects on diaphragmatic function, nor does it show that interpleural analgesia is preferable to systemic opioids. Poorer respiratory function in the presence of interpleural blockade compared to systemic opioids alone has been demonstrated.” However, in that study the patients receiving systemic opioids had better respiratory function than has usually been described after upper abdominal surgery and this may represent a chance finding. We were unable to demonstrate any difference in overall function in the present study compared to patientcontrolled opioid analgesia. More detailed study of respiratory function in the presence of interpleural blockade is indicated, particularly in relation to diaphragmatic function which may be impaired. The venous plasma concentrations of bupivacaine after the sixth dose approached previously reported toxic levels,I2 and were higher than the plasma concentrations reported after one or two doses of interpleural b~pivacaine.*.~J~J~ Symptoms suggestive of local anaesthetic toxicity were specifically sought and were not present at any time. The lack of toxic effects at these plasma concentrations is related to the marked increase in plasma alpha,-acid glycoprotein known to occur after surgery.” This protein provides the main binding sites for bupivacaine and with an increased availability of binding sites the total plasma bupivacaine concentration may increase without an increase in free drug concentration. Similar plasma concentrations have been reported during extradural infusions, again without clinical evidence of systemic toxicity.16The rate of rise of plasma concentration is important and the gradual increase that occurs in the clinical setting compared to the acute rise in volunteer studies helps to account for the lack of systemic effects.,’ Continuous administration of bupivacaine at these doses for periods exceeding 48 hours should be viewed with some caution. Increases in the total plasma bupivacaine concentration to values exceeding 5 pg/ml have been measured during postoperative extradural infusions that have been in progress for over 2 days.[* No clinical evidence of bupivacaine toxicity was reported, but these patients had relatively stable and low plasma concentrations of bupivacaine for the first 48 hours. Measurement of the free drug concentration was not performed during these late increases in total concentration, but would have been of value. The necessity for frequent top-ups limits the use of intermittent interpleural techniques, and studies conducted in a double-blind manner have confirmed that the duration expected from a single bolus is around 4 h o u r ~ . ~Further ,~J~ investigation of interpleural local anaesthetic infusions is
Interpleural analgesia after cholecystectomy desirable, but they may not prove to be as useful as intermittent bolus techniques. It is concluded that continuous, effective analgesia can be maintained by regular interpleural injections of bupivacaine after cholecystectomy and that analgesia superior to that obtainable from systemic opioids alone is possible. Significant total plasma bupivacaine concentrations are present after 24 hours.
Acknowledgment We should like to thank Astra Pharmaceutical, New Zealand for measurement of plasma bupivacaine concentrations.
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