British Journl of Anesthesi 97 (2): 232 7 (2006) doi:10.1093/bj/el116 Advnce Access publiction My 23, 2006 The effects of i.v. fentnyl dministrtion on the minimum lveolr concentrtion of isoflurne in horses S. M. Thomsy 1, E. P. Steffey 2 *, K. R. Mm 3, A. Solno 2 nd S. D. Stnley 1 1 K.L. Mddy Equine Anlyticl Chemistry Lbortory, Cliforni Animl Helth nd Food Sfety Lbortory nd 2 Deprtment of Surgicl nd Rdiologicl Sciences, School of Veterinry Medicine, University of Cliforni, Dvis, CA 95616, USA. 3 Deprtment of Clinicl Sciences, College of Veterinry Medicine nd Biomedicl Sciences, Colordo Stte University, Fort Collins, CO 80523, USA *Corresponding uthor. E-mil: epsteffey@ucdvis.edu Bckground. Fentnyl decreses the minimum lveolr concentrtion (MAC) of inhled nesthetics nd hs been used cliniclly to reduce the requirements of other nesthetic drugs in humns nd smll nimls. We hypothesized tht i.v. fentnyl would decrese the MAC of isoflurne in horses in dose-dependent mnner. Methods. Following determintion of bseline MAC of isoflurne, fentnyl ws dministered i.v. to trget plsm concentrtions of 1, 8 nd 16 ng ml 1. Ech horse ws rndomly ssigned two of three trget concentrtions dministered in scending order. Loding nd infusion doses for ech horse were determined from previously derived individul phrmcokinetic vlues. Isoflurne MAC determintion begn 45 min fter fentnyl dministrtion t ech trget fentnyl concentrtion. Venous blood ws collected t fixed intervls during the infusion for mesurement of plsm fentnyl concentrtions. Results. Men ctul fentnyl plsm concentrtions were 0 (bseline), nd 0.72 (SD 0.26), 8.43 (3.22), nd 13.31 (6.66) ng ml 1 for the trget concentrtions of 1, 8 nd 16 ng ml 1, respectively. The corresponding isoflurne MAC vlues were bseline of 1.57 (0.23), nd 1.51 (0.24), 1.41 (0.23) nd 1.37 (0.09)%, respectively. The fentnyl concentrtions of 0.72 nd 8.43 ng ml 1 did not significntly lter the MAC of isoflurne, but n 18 (7)% ISO-MAC reduction ws observed t the 13.31 ng ml 1 concentrtion. Conclusions. These results cutiously encourge further study of fentnyl s n opioid nesthetic djunct to inhlnt nesthesi in horses. Br J Anesth 2006; 97: 232 7 Keywords: nesthetics voltile, isoflurne; nlgesics opioid, fentnyl; MAC, horse; potency, nesthetic Accepted for publiction: Mrch 21, 2006 Blnced nesthesi is the concomitnt dministrtion of multiple nesthetic drugs so tht no single drug is given t dosge sufficient to produce toxicity during or fter surgery. In humns nd smll nimls, blnced nesthesi with opioids provides periopertive nlgesi nd improves hemodynmics by minimizing the necessry inhltion concentrtion for generl nesthesi. 1 3 Fentnyl, synthetic (m)-receptor gonist, is the most commonly used intropertive opioid nlgesic in humn nd smll niml medicine. 12 I.V. dministrtion of fentnyl hs been reported to decrese the minimum lveolr concentrtion (MAC) of inhltion nesthetics in humns, dogs nd pigs, but its effect in horses hs not been documented. 4 6 However, previous studies demonstrted tht two m-opioid gonists, morphine nd lfentnil, did not consistently lter the MAC of voltile nesthetics in horses. 78 Preliminry clinicl studies evluting the nlgesic efficcy of trnsderml fentnyl in conscious horses suggest tht fentnyl ptches provide significnt nlgesi without undesirble side-effects. 910 Therefore, the purpose of this study ws to determine the effect of three pseudo stedy-stte plsm fentnyl concentrtions on the MAC of isoflurne in horses. We hypothesized tht fentnyl dose-dependently decreses the MAC of isoflurne. Mterils nd methods The study ws pproved by the Institutionl Animl Cre nd Use Committee of the University of Cliforni t Dvis. Ó The Bord of Mngement nd Trustees of the British Journl of Anesthesi 2006. All rights reserved. For Permissions, plese e-mil: journls.permissions@oxfordjournls.org
Effects of fentnyl on isoflurne in horses Eight helthy, dult horses [4 femles, 4 cstrted mles; men (SD) weight 539 (32) kg nd men (rnge) ge 9 (4 13) yr] were studied on two occsions. Food, but not wter, ws withheld from the horses for 12 h before beginning ech study. Anesthesi nd instrumenttion Ctheters were plced in both externl jugulr veins before induction of nesthesi for i.v. drug dministrtion nd blood collection, respectively. Anesthesi ws induced in unpremedicted horses by dministrtion of isoflurne in oxygen s described elsewhere. 11 Briefly, isoflurne ws delivered to ech horse vi msk connected to lrge niml nesthetic circle system. The horses were in the left lterl recumbency for induction nd mintennce of nesthesi. Orotrchel intubtion ws performed when nesthetic depth ws suitble. Anesthesi ws mintined using intermittent positive pressure ventiltion (Modified Mrk 14, Bird Corp., Plm Springs, CA, USA), with pek irwy pressure of 23 (1) cm H 2 O nd vrible rte of 7 (2) bpm to mintin rteril crbon dioxide tension (P CO2 ) between 45 nd 55 mm Hg. A bse-pex led ECG (Grss Instruments, Quincy, MA, USA) ws used to monitor hert rte (HR) nd rhythm. A clibrted thermistor probe (Yellow Springs Instrument Co., Yellow Springs, OH, USA) ws positioned in the nsophrynx to mesure body temperture which ws mintined constnt t 37.5 (0.4) C using het lmps if it decresed to less thn 37 C or by pouring ethnol on the skin if it incresed to greter thn 38 C. A 20 guge ctheter ws inserted percutneously in the right fcil rtery for direct mesurement of systemic rteril pressure. The ctheter ws connected to strin guge (Model P23D, Division of Mrk IV Industries, Oxnrd, CA, USA) positioned level with the sternum. The strin guge ws clibrted t the beginning of ech experimentl dy using mercury column. The rteril ctheter ws lso used for collection of blood smples for mesurement of P CO2, rteril oxygen tension (P O2 ), ph (ph ), pcked cell volume (PCV) nd totl protein concentrtion (TP). Lctted Ringer s solution ws infused t rte of 2 4 ml kg 1 h 1 vi 16 guge ctheter plced in the left jugulr vein. The urinry bldder ws septiclly ctheterized, nd the ctheter ws connected to receptcle to permit continuous dringe throughout nesthesi nd minimize urinry bldder distention during recumbency nd before nesthetic recovery. Fentnyl delivery nd nesthetic monitoring Individul phrmcokinetic dt obtined from previous study were used to determine the loding nd infusion doses for ech horse. 12 The loding dose ws determined by the following eqution: C T V d(ss), where C T is the trget plsm concentrtion nd V d(ss) is the pprent volume of distribution t stedy stte. The loding dose ws dministered over 12 min to minimize possible centrl nervous system (CNS) excittion nd subsequent locomotor ctivity induced by fentnyl. 13 The fentnyl loding doses dministered were 0.28 (0.10), 3.03 (0.85) nd 4.69 (2.14) mg kg 1 for the trget plsm concentrtions of 1, 8 nd 16 ng ml 1, respectively. The infusion rte per minute ws determined by the eqution: C T Cl, where Cl is totl body clernce, nd ws begun immeditely fter loding dose dministrtion ws completed. The fentnyl infusions dministered were 0.006 (0.002), 0.059 (0.018) nd 0.113 (0.037) mg kg 1 min 1 for the trget plsm concentrtions of 1, 8 nd 16 ng ml 1, respectively. Ech horse ws rndomly ssigned two of three trget concentrtions of 1 (n=6), 8(n=5), nd 16 (n=5) ng ml 1 nd the trget concentrtions were rrnged in scending order. Isoflurne MAC ws determined in duplicte t ech fentnyl concentrtion for every niml. 11 Vlues for phryngel temperture, HR, systolic rteril pressure (SAP), distolic rteril pressure (DAP), nd men rteril pressure (MAP) nd long nd short xes of the pupil were recorded immeditely before nd t the conclusion of the fentnyl loding dose, then every 15 min. Blood smples (12 ml) were collected from the right jugulr ctheter immeditely before nd t the conclusion of the loding dose, then every 15 min. All blood smples were trnsferred to tube contining sodium heprin, centrifuged for 10 min, nd the plsm collected nd frozen t 20 C for future determintion of fentnyl concentrtion by previously described method using liquid chromtogrphy mss spectrometry. 12 Arteril blood ws collected in heprinized syringes immeditely before nd t the conclusion of the fentnyl loding dose, then every 30 min. Smples were nlysed immeditely for mesurement of P O2, P CO2, nd ph (ABL 330, Rdiometer Americ, Clevelnd, OH, USA), s well s PCV nd TP. Results for P O2, P CO2, nd ph were corrected to the horse s phryngel temperture. During recovery from nesthesi, severl vribles were monitored including time to trchel tube removl, time to stnding, number of ttempts to stnding nd totl recovery time. Once the horse ttined stnding position, venous blood smple ws collected for future plsm fentnyl determintion. MAC determintion Approximtely 1 h fter nesthetic induction, determintion of predrug (bseline) MAC ws begun using previously described techniques. 11 Briefly, end-tidl isoflurne concentrtion ws mintined constnt for t lest 20 min nd nesthetic step chnges were usully ner 10%, but no more thn 15% of the previous concentrtion. End-expired gs smples were obtined by intermittent mnul collection from nylon ctheter positioned ner the cudl tip of the trchel tube. Isoflurne ws mesured by n infrred gs nlyser (LB-2 nesthetic nlyser, Sensormedics Corp., Anheim, CA, USA) tht ws clibrted before the strt of ech experiment ginst multi-point clibrtion stndrds 233
Thomsy et l. (Primry gs stndrds, Mtheson Gs Products, Newrk, CA, USA). Clibrtion checks were lso performed throughout the dy of ech experiment. The concentrtion of O 2 nd CO 2 in the trchel tube were lso intermittently monitored by the use of clibrted polrogrphic (OM-11, Sensormedics Corp., Anheim, CA, USA) nd infrred (LB-2 CO 2 nlyser, Sensormedics Corp., Anheim, CA, USA) nlysers, respectively. A response ws judged s positive if some purposeful movement such s lifting or rotting of the hed or neck occurred in response to up to 60 s of electricl stimultion (50 V, 5 Hz, 10 ms) of orl mucous membrnes. Isoflurne MAC ws defined s the verge of the isoflurne concentrtions, llowing nd preventing gross purposeful movement in response to electricl stimultion. Bseline MAC ws determined in triplicte nd the men ws reported. To determine the effect of noxious stimultion on crdiopulmonry mesurements, six vlues for HR, SAP, MAP nd DAP over three breths were obtined immeditely before nd fter noxious stimultion. Sttisticl nlysis Sttisticl nlyses were conducted to ssess the effects of fentnyl concentrtion on isoflurne MAC, temperture, pupil re, PCV, TP, P O2, P CO2 nd ph. A mixed-effect sttisticl model using SAS (version 9.1, Cry, NC) tht included the ctegoricl, fixed effect of tretment (trget fentnyl concentrtion djusted by ctul fentnyl concentrtion), nd rndom horse effect ws used to ssess whether fentnyl hd significnt effect on the bove vribles. For crdiovsculr vribles (HR, SAP, MAP, DAP), n dditionl ctegoricl vrible (stimulus) ws dded to the mixed-effect model. Significnce ws set t P<0.05. Dt re reported s men (SD). Results Fentnyl plsm concentrtions were stble over time s shown in Figure 1. Actul fentnyl plsm concentrtions were 0.72 (0.26), 8.43 (3.22) nd 13.31 (6.66) ng ml 1 for the trget concentrtions of 1, 8 nd 16 ng ml 1, respectively. The MAC of isoflurne in this study ws 1.57 (0.23), 1.51 (0.24), 1.41 (0.23) nd 1.37 (0.09)% t fentnyl plsm concentrtions of 0, 0.72, 8.43 nd 13.31 ng ml 1, respectively, s shown in Figure 2. The fentnyl concentrtions of 0.72 nd 8.43 ng ml 1 did not significntly lter the MAC of isoflurne, but sttisticlly significnt 18 (7)% reduction ws observed t the 13.3 ng ml 1 fentnyl concentrtion s shown in Figure 3. PCV, TP, P O2 nd pupil size were not significntly ltered by fentnyl dministrtion, but P CO2 nd ph were significntly different (Tble 1). Fentnyl dministrtion hd significnt effect on HR nd MAP, while noxious stimultion hd significnt effect on MAP but not HR s shown in Figure 4. Totl nesthesi time, determined s the time from horse s first breth of isoflurne to the time the brething circuit ws disconnected from the trchel tube, ws 464 (69) min nd time to trchel tube removl ws 30 (13) min. All individuls in both experiments recovered from nesthesi in 38 (31) min without serious compliction. Recovery behviour ws vrible with medin 2 (rnge 1 5) ttempts to ttin stnding position. One horse exhibited recovery behviours tht hve been previously ssocited with opioid dministrtion to horses. The horse went from 40 Plsm fentnyl concentrtion (ng ml 1 ) 30 20 10 0 Strt CRI MAC determintion 1 ng ml 1 8 ng ml 1 16 ng ml 1 0 10 20 30 40 50 Time (min) 60 70 80 90 Fig 1 Men (+SD) plsm fentnyl concentrtion vs time fter loding dose dministered over 12 min, then CRI to trget three different fentnyl concentrtions in eight horses (n=4 6 t ech dt point). 234
Effects of fentnyl on isoflurne in horses 2.0 1.8 Isoflurne MAC (%) 1.6 1.4 1.2 1.0 0 5 10 15 20 25 Fentnyl plsm concentrtion (ng ml 1 ) Fig 2 Isoflurne MAC t different plsm fentnyl concentrtions in eight horses. 10 5 % Reduction isoflurne MAC 0 5 10 15 20 25 30 0 5 10 15 20 Fentnyl plsm concentrtion (ng ml 1 ) Fig 3 Percentge reduction in isoflurne MAC [men (SD)] t three different plsm fentnyl concentrtions in eight horses. *P<0.05 from bseline. lterl recumbency to stnding t 13 min, then frnticlly ttempted to circle in both directions nd fell down severl times. Plsm fentnyl concentrtion immeditely fter stnding ws 2.78 (1.47) ng ml 1. Discussion The MAC for isoflurne [1.57 (0.23)%] determined in this study ws similr to tht reported in previous studies of horses. 711 Mesured plsm fentnyl concentrtions of 0.72 nd 8.43 ng ml 1 did not hve consistent or significnt effect on the MAC of isoflurne. However, fentnyl t 13.31 ng ml 1 significntly decresed the MAC of isoflurne in comprison to bseline, 0.72 nd 8.43 ng ml 1 of fentnyl. The 18% reduction in isoflurne requirement observed with 13.31 ng ml 1 of fentnyl is similr to tht found for swine 6 (14 ng ml 1 fentnyl decresed isoflurne MAC by 25%), but is smll in comprison to other species studied. For exmple, fentnyl t pproximtely 6 10 ng ml 1 decresed the MAC of isoflurne by 53% in dogs nd fentnyl t 10 ng ml 1 decresed the MAC of isoflurne by 82% in humns. 45 Perhps 235
Thomsy et l. Tble 1 Minimum lveolr concentrtion (MAC), temperture, pupil re, pcked cell volume (PCV), totl protein (TP), rteril ph (ph ), nd rteril oxygen nd crbon dioxide tensions (P CO2 P O2 ) in eight isoflurne-nesthetized horses t fentnyl concentrtions (FC) of 0, 0.72, 8.43 nd 13.31 ng ml 1. Dt re men (SD). *P<0.05 from 0 FC. P<0.05 from 0.72 FC. P<0.05 from 8.43 FC A 50 40 Fentnyl concentrtion (ng ml 1 ) 0(n=8) 0.72 (n=6) 8.43 (n=5) 13.31 (n=5) MAC (%) 1.57 (0.23) 1.51 (0.24) 1.41 (0.23) 1.37 (0.09)*,, Temperture ( C) 37.4 (0.4) 37.6 (0.3) 37.7 (0.6)* 37.5 (0.4)* Pupil re (mm 2 ) 1100 (250) 870 (90) 1000 (300) 1100 (350) PCV (%) 31 (2) 32 (2) 33 (6) 30 (3) TP (mg dl 1 ) 5.6 (0.2) 5.7 (0.3) 5.7 (0.4) 5.3 (0.4) P O2 (mm Hg) 417 (167) 439 (137) 438 (155) 359 (142) P CO2 (mm Hg) 45.6 (4.1) 47.7 (3.2)* 47.4 (3.2) 48.4 (2.6)*, ph (units) 7.42 (0.02) 7.40 (0.03) 7.40 (0.04) 7.40 (0.02)*, Hert rte (bets min 1 ) 30 20 10 expectedly, the effect of morphine on isoflurne nesthetic requirement in swine, dogs nd primtes is lso qulittively nd quntittively similr to tht for fentnyl (i.e. primtes>dogs>swine). However, with the sme dose of morphine (2 mg kg 1 ) the response of the isoflurnenesthetized horse ws more vrible thn tht noted in these other species nd included increses in MAC. 7 Resons for the vried response in the horse to morphine remin specultive. 713 Regrdless, our present finding of uniform decrese in MAC provides some encourgement for further study of fentnyl s n nesthetic djuvnt in horses. This is further supported by previous report of smll but mesurble increse in nociceptive threshold in wke horses dministered 10 mg kg 1 i.v. fentnyl 14 or pproximtely twice the loding dose given to chieve plsm fentnyl concentrtion of 13.31 ng ml 1 in this study. Bseline crdiovsculr prmeters were typicl of horses nesthetized with low dose (1.0 MAC) of isoflurne in O 2. 15 16 Administrtion of fentnyl ws ssocited with significnt nd dose-dependent increse in MAP, SAP nd DAP. For exmple, MAP ws 85 (9), 89 (6), 100 (7) nd 104 (11) mm Hg t fentnyl concentrtions of 0, 0.72, 8.43 nd 13.31 ng ml 1, respectively. Temporl effects my contribute to the observed increse in MAP, but MAP hs been reported to increse fter the first hour of nesthesi then stbilize fter 2 4 h of nesthesi. 17 As fentnyl dministrtion did not begin until 3.6 (0.8) h fter the strt of nesthesi, it is unlikely tht temporl effects could completely explin the increse in MAP. A smll but sttisticlly significnt increse in HR from bseline of 32 (3) to 34 (5) nd 35 (4) bets min 1 ws noted for the fentnyl concentrtions of 8.43 nd 13.3 ng ml 1, respectively. Other studies hve noted n increse in MAP nd HR fter the dministrtion of opioids to nesthetized horses nd postulted tht it my be becuse of CNS stimultion nd subsequent incresed sympthetic tone. 78 Fentnyl concentrtions were vrible mong studied horses despite using individul phrmcokinetic dt from previous study to determine loding nd infusion B Men rteril pressure (mm Hg) 140 120 100 80 60 40 20 0 Pre-stimulus Post-stimulus 0 0.72 8.47 13.3 Fentnyl concentrtion (ng ml 1 ) doses (Fig. 3). 12 However, ctul plsm fentnyl concentrtions were unchnged in individuls over time during the determintion of MAC s shown in Figure 1. In ddition, low intr-individul vribility between doses ws noted. Fctors tht my hve contributed to the vribility between ctul nd trget plsm fentnyl concentrtions include high inter-individul nd intr-individul vribility in the disposition of fentnyl, differences in concentrtion of isoflurne between the present nd previous study where the phrmcokinetics were determined, nd poor performnce of the phrmcokinetic models. *,b,c Fig 4 Men (+SD) HR (A) nd MAP (B) in eight isoflurnenesthetized horses immeditely before nd fter noxious stimultion t fentnyl concentrtions (FC) of 0, 0.72, 8.43 nd 13.31 ng ml 1. P<0.05 from 0 FC. b P<0.05 from 0.72 FC. c P<0.05 from 8.43 FC. *P<0.05 from pre-noxious stimultion. 236
Effects of fentnyl on isoflurne in horses A smll but sttisticlly significnt increse in temperture ws noted between bseline nd the fentnyl concentrtions of 8.43 nd 13.31 ng ml 1. In this study, n ttempt ws mde to tightly regulte phryngel temperture between 37 nd 38 C becuse hlothne MAC hs been shown to increse linerly by 8% per C from 37.3 to 40.7 C in dogs. 18 Two horses required ctive cooling by pplying ethnol to the skin when their tempertures reched 38.2 C but no horse ttined temperture higher thn 38.6 C. In spontneously ventilted isoflurne-nesthetized horses, morphine incresed P CO2 to 102 mm Hg. 7 As hypercpni hs been shown to decrese hlothne MAC in dogs, 19 horses were mechniclly ventilted in this study to mintin normocpni nd prevent hypoventiltion from confounding the effects of fentnyl on isoflurne MAC. As desired, P CO2 ws mintined between 45 nd 55 mm Hg. However, P CO2 ws slightly but significntly incresed from bseline of 45.6 to 47.7 mm Hg nd 48.4 mm Hg for the 0.72 nd 13.31 ng ml 1 fentnyl concentrtions, respectively. We consider these chnges in P CO2 to be of no consequence to the mgnitude of isoflurne MAC determined in this study. However, it is of interest tht during these studies, smll upwrd djustments in mechnicl ventiltion were required to mintin P CO2 within our trget rnge s the dose of fentnyl incresed. Such observtions my be ttributble to norml vribility or my represent smll chnges in metbolic output ssocited with incresed opioid-induced sympthetic tone, nd re consistent with previously noted chnges in HR nd MAP. 78 All horses recovered from nesthesi without serious compliction. Seven of eight recoveries were similr to those previously described for horses recovering from inhltion nesthesi. 20 One horse showed some signs consistent with opioid stimultion during recovery. 78 There ws no correltion between overll recovery score nd plsm fentnyl concentrtion t the time of recovery. Fentnyl concentrtions declined rpidly from 11.0 (6.52) to 2.78 (1.47) ng ml 1 64 (20) min fter discontinution of the fentnyl continuous-rte infusion (CRI). In conclusion, this study is both similr to nd in conflict with current knowledge of opioid ction in horses, but suggests tht there my be therpeutic rnge of fentnyl tht consistently decreses nesthetic requirement. Accordingly, this study encourges further investigtion of the use of fentnyl s prt of blnced nesthetic technique in horses. The results of this study further suggest tht the nesthetic potency of fentnyl in horses is similr to swine, but less thn tht of humns or dogs. 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