('1,n Pbannacol"MI. l'll);
2~2.u
1990
01 12-S961/90/OOOl-ONO!S02,SOlO CI ADIS f'rnI umlted All n,llIS rncrved. ~~
C linical Pharmacokinetics After Repeated Intrapleural Bupivacaine Administration D. Debruyne. M .A. MOlilill, J. Tarljere, M.-C. BigOI, J.-L. Gerard and H. Bricard LaboralOry of Pharmacology and [kpanment of Anaesthcsiology. Unt\'erslly Hospital Centre of Caen. Caen. France
Pallents (n .. 14) who underv.ent thOracOiom y dunn, su~ery of the oesophagus for eancer recelyed an Initial mtrapleural dose of 10mi buplvacaine hydrochloride 2.5 mil ml followed by repeated admlnlstrallon every 8 hours from the first to the founh postopera ti ve day. The mean ( :t: SDj peak plasma drug co ncentration (em,,) [352 :!: 120 "II L]. lime 10 peak (1m .. ) [0.83 1: O.5 Ih]. and first-order absorption rale constant (k.1 [S.46 1: 4.95 h- t] after t~ t ..-elfth dose .. ere s.gntfi{'8nlly different from the Cm ., (206 :t: 81 ,,&ILl. tma~ (1.8 :t: I.2hl. and k. (1.8 :!: 1.47 h-tl determined all er the first dose. Halfhfe (l.S 1: 2.2hl and mean eoncen tratlon (204 :t lOS ,,&lL) were not Signtficantly different on the founh day from those on the first (4. 1 :t 2.6h and 142 1: 71 ,,&lL. respectiyely). No sharp peak colTtsponding to sytemie 10;\icity and no accumulation could be e;\pected With these low doses. administered at shon mtervals and providing good pam relief in this sUfl.lcal scnts.
The intrapleural administration of local anaesthetics, especially bupiyacaine (Covi no 1988). is currently used to relieve postoperative pain in patients undergoing abdominal or in trathoracic surgery. In previous studies. blood bupivacaine concentrations were determined following administration of a bolus in adults (Bnsmar et al . 1987; Seltzer et al. 1987; Stromskag et al. 1987) and after infusion in children (Mcilvaine et al. 1988). The organ isalion of a clinical trial. designed to evaluate pain relief after oesophageal surgery for canttr in patien ts who undef'Ao"ent thoracotomy. provides accurate pharmacokinctic data on bupivacaine concentrations following intrapleural administration of low doses for several days. A comparison of the main
pharmacokinetic parameter5 determined after the t.....elfth administration with respect to the fir5t dose is discussed and the risk of cumulative toxicily due to repeatcd administration by this route [considered by Lee and Abram (1987)1 is assessed.
Subject! lind CliniclIl Protocol The participants in this study were 14 patien ts ( 12 male. 2 female). mean age 56 ± 12 years. who
underwent thoracotomy during oesophageal sur· gcry for ca ncers. The preoperative functional res. piratory val ues .....ere 2.8 ± O.4L and 2.2 ± O.2L for yital capacity and timed vital capacity. respec· tiyely. No cardiopu lmonary or respiratory disturbances were evident. The anaesthetic medication
Pharmacoklnellcs After Intrapleural Bupl"acamr
adnllmstered was dropendol (19 := 2mg). numtrazepam (5 ::: Img) or fentan)l (1.9 :t 0.9mg). The surgical procedure consisted of Oi."sogastrectom) or ocsophagcctom~ requiring a thoracotom~. An mtrapieural catheter .... as mstalled 10 the eighth mtercostal space tx-forc the thoracotom) \~as closed. On thc first postoperatlH' da}. 10 mmutes be· fore e:\tubatlOn. 10mi of bupl\acame h}drochloride 2.5 mg/ml \\1!h epmephnne (adrenalml') 5 I'g/ ml was mluall} admmlstered as an mtrapleural bolus. follo\\ed b~ repeated admmistration e\'e~ 8 hours for 4 da}s. No analgcSlc themp) other than (exccpllonall)) mtra\enous flunitrazepam 0.5mg was adminlstcTed at the latest 5 hours before extubation to relle\e pam be,..~een the end of the operation and the first mjectlon of bupl\acame. on account of the residual effect of anaesthetic drugs. On the followmg da)s. "'here bupl\acame analgesia was madequate. Intramuscular propacetamol hydrochlonde (0.5 to Ig on the first and second days. 0.25 to 0.5g on the third and fourth da)s) was also given to 4 patients on request. Blood samples were collected from an ann vein before and al 0.25. 0.5. I. 1.5. 2. 3. 5 and 8 hours after the fi rst mtra· pleural bupi,acame mjectlon. and at the same times after the t\\elfth administration on the fourth da) . 6 patients were punctured after the first and twelfth doses: -I pauents "'ere punctured on I) after the first injcction. and -I onl} after the twelfth . .\]] blood samples ",erc Immedlatel) centrifuged and serum samples kept frozen untIl analysed I to 7 da}s later. Thcrapeullc eOkac) "'as measured usmg a "5ual analogue S
2~2.u
1990
01 12-S961/90/OOOl-ONO!S02,SOlO CI ADIS f'rnI umlted All n,llIS rncrved. ~~
C linical Pharmacokinetics After Repeated Intrapleural Bupivacaine Administration D. Debruyne. M .A. MOlilill, J. Tarljere, M.-C. BigOI, J.-L. Gerard and H. Bricard LaboralOry of Pharmacology and [kpanment of Anaesthcsiology. Unt\'erslly Hospital Centre of Caen. Caen. France
Pallents (n .. 14) who underv.ent thOracOiom y dunn, su~ery of the oesophagus for eancer recelyed an Initial mtrapleural dose of 10mi buplvacaine hydrochloride 2.5 mil ml followed by repeated admlnlstrallon every 8 hours from the first to the founh postopera ti ve day. The mean ( :t: SDj peak plasma drug co ncentration (em,,) [352 :!: 120 "II L]. lime 10 peak (1m .. ) [0.83 1: O.5 Ih]. and first-order absorption rale constant (k.1 [S.46 1: 4.95 h- t] after t~ t ..-elfth dose .. ere s.gntfi{'8nlly different from the Cm ., (206 :t: 81 ,,&ILl. tma~ (1.8 :t: I.2hl. and k. (1.8 :!: 1.47 h-tl determined all er the first dose. Halfhfe (l.S 1: 2.2hl and mean eoncen tratlon (204 :t lOS ,,&lL) were not Signtficantly different on the founh day from those on the first (4. 1 :t 2.6h and 142 1: 71 ,,&lL. respectiyely). No sharp peak colTtsponding to sytemie 10;\icity and no accumulation could be e;\pected With these low doses. administered at shon mtervals and providing good pam relief in this sUfl.lcal scnts.
The intrapleural administration of local anaesthetics, especially bupiyacaine (Covi no 1988). is currently used to relieve postoperative pain in patients undergoing abdominal or in trathoracic surgery. In previous studies. blood bupivacaine concentrations were determined following administration of a bolus in adults (Bnsmar et al . 1987; Seltzer et al. 1987; Stromskag et al. 1987) and after infusion in children (Mcilvaine et al. 1988). The organ isalion of a clinical trial. designed to evaluate pain relief after oesophageal surgery for canttr in patien ts who undef'Ao"ent thoracotomy. provides accurate pharmacokinctic data on bupivacaine concentrations following intrapleural administration of low doses for several days. A comparison of the main
pharmacokinetic parameter5 determined after the t.....elfth administration with respect to the fir5t dose is discussed and the risk of cumulative toxicily due to repeatcd administration by this route [considered by Lee and Abram (1987)1 is assessed.
Subject! lind CliniclIl Protocol The participants in this study were 14 patien ts ( 12 male. 2 female). mean age 56 ± 12 years. who
underwent thoracotomy during oesophageal sur· gcry for ca ncers. The preoperative functional res. piratory val ues .....ere 2.8 ± O.4L and 2.2 ± O.2L for yital capacity and timed vital capacity. respec· tiyely. No cardiopu lmonary or respiratory disturbances were evident. The anaesthetic medication
Pharmacoklnellcs After Intrapleural Bupl"acamr
adnllmstered was dropendol (19 := 2mg). numtrazepam (5 ::: Img) or fentan)l (1.9 :t 0.9mg). The surgical procedure consisted of Oi."sogastrectom) or ocsophagcctom~ requiring a thoracotom~. An mtrapieural catheter .... as mstalled 10 the eighth mtercostal space tx-forc the thoracotom) \~as closed. On thc first postoperatlH' da}. 10 mmutes be· fore e:\tubatlOn. 10mi of bupl\acame h}drochloride 2.5 mg/ml \\1!h epmephnne (adrenalml') 5 I'g/ ml was mluall} admmlstered as an mtrapleural bolus. follo\\ed b~ repeated admmistration e\'e~ 8 hours for 4 da}s. No analgcSlc themp) other than (exccpllonall)) mtra\enous flunitrazepam 0.5mg was adminlstcTed at the latest 5 hours before extubation to relle\e pam be,..~een the end of the operation and the first mjectlon of bupl\acame. on account of the residual effect of anaesthetic drugs. On the followmg da)s. "'here bupl\acame analgesia was madequate. Intramuscular propacetamol hydrochlonde (0.5 to Ig on the first and second days. 0.25 to 0.5g on the third and fourth da)s) was also given to 4 patients on request. Blood samples were collected from an ann vein before and al 0.25. 0.5. I. 1.5. 2. 3. 5 and 8 hours after the fi rst mtra· pleural bupi,acame mjectlon. and at the same times after the t\\elfth administration on the fourth da) . 6 patients were punctured after the first and twelfth doses: -I pauents "'ere punctured on I) after the first injcction. and -I onl} after the twelfth . .\]] blood samples ",erc Immedlatel) centrifuged and serum samples kept frozen untIl analysed I to 7 da}s later. Thcrapeullc eOkac) "'as measured usmg a "5ual analogue S
