1243

CAN J ANESTH 2000 / 47: 12 / pp 1243–1248

Purpose: To evaluate the effects of low-dose olprinone, a phosphodiesterase III inhibitor, on contractility and itsmechanism in nonfatigued and fatigued diaphragm in dogs.Methods: Thirty six pentobarbitone-anesthetized dogs were studied. In Group Ia (n=6), animals without fatigue,received no study drug. In Group Ib (n=6), dogs were given a bolus injection (10 µg·kg–1) followed by continu-ous infusion (0.1 µg·kg–1·min–1) of olprinone. In Groups IIa, IIb, and IIc (n=8 each), diaphragmatic fatigue wasinduced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20-Hz applied for 30min. After producing fatigue, Group IIa received no study drug; Group IIb was infused with olprinone (10 µg·kg–1

loading dose plus 0.1 µg·kg–1·min–1 maintenance dose); Group IIc was infused with nicardipine (5 µg·kg–1·min–1)during olprinone administration. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi).Results: No difference in Pdi was observed between Groups Ia and Ib. After fatigue, in Groups IIa, IIb, and IIc,Pdi at low-frequency (20-Hz) stimulation decreased from prefatigued (baseline) values (P < 0.05), whereas therewas no change in Pdi at high-frequency stimulation (100-Hz). In Group IIb, during olprinone administration, Pdiat both stimuli increased from fatigued values (P < 0.05). In Group IIc, the augmentation of Pdi to each stimulusin fatigued diaphragm by olprinone was abolished with an infusion of nicardipine.Conclusion: Low-dose olprinone does not affect contractility in nonfatigued diaphragm, but increases contrac-tility in fatigued diaphragm via its effect on transmembrane calcium movement in dogs.

Objectif : Évaluer les effets d’une faible dose d’olprinone, un inhibiteur de la phosphodiestérase III, sur la con-tractilité et sur son mécanisme sur le diaphragme fatigué ou non, chez des chiens.Méthode : Trente-six chiens anesthésiés au pentobarbital ont été étudiés. Dans le groupe Ia (n=6), les animauxnon fatigués n’ont pas reçu de médicament à l’étude. Dans le groupe Ib (n=6), les chiens ont reçu l’injection d’unbolus (10 µg·kg–1) d’olprinone, suivie d’une perfusion continue (0,1 µg·kg–1·min–1). Dans les groupes IIa, IIb, et IIc(n=8 chacun), on a induit la fatigue diaphragmatique par une stimulation électrophrénique intermittente supra-maximale bilatérale à une fréquence de 20 Hz appliquée pendant 30 min. Après l’induction de cette fatigue, leschiens du groupe IIa n’ont pas reçu de médicament; ceux du groupe IIb ont reçu une perfusion d’olprinone (10µg·kg–1 en dose de charge plus 0,1µg·kg–1·min–1 comme dose de maintien); ceux du groupe IIc ont reçu de lanicardipine (5 µg·kg –1·min–1) pendant l’administration d’olprinone. La contractilité diaphragmatique a été évaluéepar pression transdiaphragmatique (Pdi).Résultats : Aucune différence de Pdi n’a été observée entre les groupes Ia et Ib. Après la production de fatiguechez les animaux des groupes IIa, IIb, et IIc, la Pdi sous stimulation à basses fréquences (20 Hz) a diminué par rap-port aux valeurs précédant la fatigue (valeurs de base), P < 0,05, tandis qu’il n’y a pas eu de changement de Pdisous stimulation à hautes fréquences (100 Hz). Dans le groupe IIb, pendant l’administration d’olprinone, la Pdi aaugmenté par rapport aux valeurs du muscle fatigué et ce, sous stimulation à toutes les fréquences utilisées (P <0,05). Dans le groupe IIc, l’augmentation de Pdi par l’olprinone pour chaque stimulus du diaphragme fatigué a étéabolie avec une perfusion de nicardipine.Conclusion : Une faible dose d’olprinone n’a pas d’effet sur la contractilité d’un diaphragme non fatigué, maisaccroît celle d’un muscle fatigué par ses effets sur le déplacement du calcium transmembranaire chez les chiens.

Laboratory Investigation

Different effects of olpri-none on contractility innonfatigued and fatigueddiaphragm in dogsYoshitaka Fujii MD,

Hidenori Toyooka MD

From the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki305, Japan.

Address correspondence to: Dr. Y. Fujii. Phone: 81-0298-53-3763; Fax: 81-0298-53-3765; E-mail: yfujii@igaku.md.tsukuba.ac.jpAccepted for publication August 31, 2000.

HOSPHODIESTERASE (PDE) IIIinhibitors have been developed, and investi-gated clinically and pharmacologically to eval-uate their therapeutic potential for the

treatment of congestive heart failure.1–3 In addition tothese pharmacological properties, we have shown thatamrinone and milrinone improve diaphragmatic musclefunction,4,5 and that olprinone is more effective thanmilrinone for the improvement of contractility infatigued diaphragm.6 However, high-dose (> 0.3µg·kg–1·min–1) olprinone occasionally causes severehypotension by its direct relaxing effect on vascularsmooth muscle.7 This study was undertaken to deter-mine the effects of low-dose (0.1 µg·kg–1·min–1) olpri-none and its mechanism in nonfatigued and fatigueddiaphragm in dogs.

MethodsThe protocol was approved by our animal researchcommittee, and the care of the animals was in agree-ment with guidelines for ethical animal research.Thirty-six healthy mongrel dogs weighing 10-15 kgwere anesthetized with pentobarbital (25 mg·kg– 1

loading dose plus 2 mg·kg–1·hr– 1maintenance dose) ivto abolish spontaneous movement. No muscle relax-ant was used. Animals were placed in the supine posi-tion, their tracheas were intubated with a cuffedtracheal tube, and the lungs were mechanically venti-lated with a mixture of O2 and air (FIO2=0.4) to main-tain PaO2 > 100 mmHg, PaCO2 35-40 mmHg, andpHa 7.35-7.45. The right femoral artery was cannu-lated to monitor arterial blood pressure and to obtainblood samples for blood gas analysis. The rightfemoral vein was cannulated to administer mainte-nance fluids (10 mL·kg– 1·hr–1 lactated Ringer’s solu-tion), pentobarbital, and bicarbonate to keep theplasma HCO3- concentration within normal ranges.The left femoral vein was cannulated for the adminis-tration of olprinone. A flow-directed pulmonaryartery catheter was advanced via the right externaljugular vein into the pulmonary artery to measure car-diac output (CO) by thermodilution technique.Rectal temperature was monitored continuously andmaintained at 37 ± 1°C.

The phrenic nerves were exposed bilaterally at theneck, and stimulating electrodes were placed aroundthem. Transdiaphragmatic pressure (Pdi) was mea-sured by using two thin-walled latex balloons: onepositioned in the stomach, the other in the middlethird of the esophagus. The balloons were connectedto a differential pressure transducer (TP-604 T;Nihon Kohden, Tokyo, Japan) and an amplifier (Type1257; Nihondenki San-ei, Tokyo, Japan). While one

balloon catheter was open to atmosphere, the positionof the other was changed to obtain appropriate pres-sure. Then the position of the balloons in the esopha-gus and the stomach was confirmed. Supramaximalelectrical stimuli (10-15 volts) of 0.1-msec durationwere applied for two seconds at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation withan electrical stimulator (SEN-3301; Nihon Kohden).Isometric contractility of the diaphragm was evaluatedby the measurement of the maximal Pdi after airwayocclusion at FRC. Transpulmonary pressure (Ptp), thedifference between airway and esophageal pressure,was kept constant (nearly - 5 cm H2O) by maintainingthe same lung volume before each phrenic stimula-tion. End-expiratory diaphragmatic geometry andmuscle fibre length during contraction were kept con-stant by placing a close-fitting plaster cast around theabdomen and lower third of the rib cage. The electri-cal activity of crural (Edi-cru) and costal (Edi-cost)parts of the diaphragm was recorded by two pairs offishhook electrodes placed through a midline laparo-tomy; electrodes were positioned into the anteriorportion of crural part near the central tendon and theanterior portion of costal part (away from the zone ofapposition) in the left hemidiaphragm. Each pair wasplaced in parallel fibres 5-6 mm apart. The abdomenwas then sutured in layers. The signal was rectified andintegrated with a leaky integrator (Type 1322;Nihondenki San-ei) with a time constant 0.1 sec andwas regarded as the integrated diaphragmatic electricalactivity (Edi-cru, Edi-cost).

Twenty-eight dogs were randomized among fourgroups: Groups Ia (n=6), Ib (n=6), IIa (n=8) and IIb(n=8): Group IIc (n=8) was added after the previousresults had been obtained. In Groups Ia and Ib, afterthe baseline measurements of Pdi, Edi-cru, Edi-cost,and hemodynamic variables, including heart rate (HR),mean arterial pressure (MAP), right atrial pressure(RAP), mean pulmonary arterial pressure (MPAP), pul-monary artery occlusion pressure (PAOP), and CO,Group Ia received no study drug; Group Ib was givena bolus injection (10 µg·kg–1) followed by a continuousinfusion (0.1 µg·kg–1·min– 1) of olprinone iv via an infu-sion pump for 30 min. At 30 min after the onset ofolprinone infusion, in Group Ib, Pdi, Edi-cru, Edi-cost,and hemodynamic variables were measured, and COwas evaluated by thermodilution technique. In GroupIa, these measurements were made at 30 min to verifythe stability of this preparation.

In Groups IIa, IIb, and IIc, after measuring prefa-tigued (baseline) values of Pdi, Edi-cru, Edi-cost, andhemodynamic variables, and CO, diaphragmaticfatigue was induced by intermittent supramaximal

1244 CANADIAN JOURNAL OF ANESTHESIA

P

bilateral electrophrenic stimulation applied for 30 minat a frequency of 20-Hz, an entire cycle of four sec-onds, and a duty cycle of 0.5 (i.e., low-frequencyfatigue).8 In Group IIb (10 µg·kg–1 loading dose plus0.1 µg·kg– 1·min–1 maintenance dose), olprinone wascontinuously administered iv via an infusion pump for30 min after the fatigue-producing period. In GroupIIc, nicardipine 5 µg·kg–1·min–1 inhibiting calciuminflux into diaphragm muscle8 was continuouslyinfused iv during olprinone administration afterdiaphragmatic fatigue. At 30 min after the onset of thestudy drug administration, in Groups IIb and IIc, Pdi,Edi-cru, Edi-cost, hemodynamic variables, and COwere measured. In Group IIa, no study drug wasadministered iv, and the same measurements wereperformed as those in Groups IIb and IIc.

All values were expressed as mean ± SD. Statisticalanalysis was performed by ANOVA for repeated mea-surements with Bonferroni adjustment for multiplecomparison and Student’s t test, as appropriate. A Pvalue of < 0.05 was considered significant.

ResultsNo differences in baseline hemodynamic variableswere observed between Groups Ia and Ib. With infu-sion of olprinone in Group Ib, HR and CO increased(P < 0.05) and MAP, MPAP, and PAOP decreased (P< 0.05) from baseline values. No hemodynamicchanges were observed in Group Ia,(Table I).

The Pdi values obtained at each stimulus in GroupsIa and Ib are shown in Table II. No changes in Pdiwere affected by the olprinone administration inGroup Ib. The changes of Edi-cru and Edi-cost(%Edi-cru, %Edi-cost, respectively) from baseline val-ues are also shown in Table II. No changes in %Edi-cru and %Edi-cost were observed throughout theexperiment in either group.

The hemodynamic results of Groups IIa, IIb, andIIc are summarized in Table III. No differences inhemodynamic variables were observed during prefa-tigued (baseline) period among the groups. With aninfusion of olprinone (Group IIb) or combined olpri-none and nicardipine (Group IIc), increases in HRand CO (P < 0.05) and decreases in MAP, MPAP, andPAOP (P < 0.05) compared with baseline values wereobserved. In Group IIa, there were no hemodynamicchanges throughout the experiment.

The Pdi, %Edi-cru, and %Edi-cost values at differ-ent stages in Groups IIa, IIb, and IIc are shown inTable IV. In each group, after producing fatigue, Pdiat low-frequency (20-Hz) stimulation decreased fromprefatigued (baseline) values (P < 0.05), whereas Pdiat high-frequency (100-Hz) stimulation did not

change. In Group IIb, Pdi at both stimuli increasedfrom fatigued values (P < 0.05) during olprinoneadministration. In Group IIc, the augmentation of Pdiby olprinone in the fatigued diaphragm was abolishedby administering nicardipine. In Group IIa, the speedof recovery from fatigue was relatively slower at 20-Hz stimulation than at 100-Hz stimulation. Nochanges in %Edi-cru and %Edi-cost were observedthroughout the study in any of the groups.

Fujii et al.: OLPRINONE A N D DIAPHRAGMATIC FATIGUE 1245

TABLE I Hemodynamic data and changes in nonfatigueddiaphragm

30 min (Group Ia)Variable Group Baseline Olprinone (Group Ib)

HR Ia 141 ± 10 140 ± 11(bpm) Ib 141 ± 10 149 ± 12*†MAP Ia 123 ± 7 122 ± 8(mmHg) Ib 121 ± 7 112 ± 6*†RAP Ia 5 ± 1 5 ± 2(mmHg) Ib 5 ± 1 5 ± 2MPAP Ia 12 ± 1 12 ± 1(mmHg) Ib 12 ± 2 11 ± 2*†PAOP Ia 8 ± 1 8 ± 2(mmHg) Ib 8 ± 2 7 ± 2*†CO Ia 2.0 ± 0.6 2.0 ± 0.5(L·min- 1) Ib 2.0 ± 0.5 2.5 ± 0.4*†ab

Values are mean ± SD. HR=heart rate, MAP=mean arterial pres-sure, RAP=right atrial pressure, MPAP=mean pulmonary arterialpressure, PAOP=pulmonary artery occlusion pressure, CO=cardiacoutput.*P < 0.05 vs Baseline†P < 0.05 vs Group Ia

TABLE II Changes in Pdi, %Edi-cru, %Edi-cost in nonfatigueddiaphragm

30 min (Group Ia)Variable Frequency Group Baseline Olprinone (Group Ib)

Pdi 20-Hz Ia 15.3 ± 2.0 15.2 ± 1.8Ib 15.2 ± 2.3 15.4 ± 2.1

100-Hz Ia 21.8 ± 2.2 21.9 ± 2.3Ib 21.5 ± 2.1 21.3 ± 2.0

%Edi-cru 20-Hz Ia 100.0 ± 0.0 99.1 ± 5.1Ib 100.0 ± 0.0 100.0 ± 7.3

100-Hz Ia 100.0 ± 0.0 99.1 ± 5.1Ib 100.0 ± 0.0 100.0 ± 7.3

%Edi-cost 20-Hz Ia 100.0 ± 0.0 99.1 ± 5.1Ib 100.0 ± 0.0 100.7 ± 4.9

100-Hz Ia 100.0 ± 0.0 98.7 ± 6.2Ib 100.0 ± 0.0 99.1 ± 5.1

Values are mean ± SD. Pdi=transdiaphragmatic pressure, Edi-cru=electrical activity of the crural part of diaphragm, Edi-cost=electrical activity of the costal part of diaphragm.

1246 CANADIAN JOURNAL OF ANESTHESIA

TABLE III Hemodynamic data and changes in fatigued diaphragm

30 min (Group IIa)Prefatigued Olprinone (Group IIb)

Variable Group (Baseline) Fatigued Olprinone + Nicardipine (Group IIc)

H R IIa 141 ± 11 142 ± 12 141 ± 10(bpm) IIb 142 ± 10 142 ± 11 149 ± 10*†‡

IIc 140 ± 12 141 ± 12 155 ± 11*†‡MAP IIa 124 ± 8 124 ± 7 125 ± 8(mmHg) IIb 123 ± 8 122 ± 8 112 ± 10*†

IIc 125 ± 10 123 ± 11 102 ± 9*†‡§RAP IIa 5 ± 1 5 ± 2 5 ± 2(mmHg) IIb 5 ± 2 5 ± 1 5 ± 2

IIc 5 ± 1 5 ± 2 5 ± 2MPAP IIa 12 ± 1 12 ± 2 12 ± 1(mmHg) IIb 12 ± 1 12 ± 2 11 ± 2*†

IIc 12 ± 2 12 ± 2 11 ± 2*†PAOP IIa 8 ± 1 8 ± 1 8 ± 2(mmHg) IIb 8 ± 2 8 ± 1 7 ± 2*†

IIc 8 ± 2 8 ± 2 7 ± 1*†CO IIa 2.0 ± 0.6 2.1 ± 0.4 2.0 ± 0.4(L·min- 1) IIb 2.0 ± 0.5 2.1 ± 0.6 2.5 ± 0.5*†‡

IIc 2.1 ± 0.4 2.0 ± 0.5 2.8 ± 0.4*†‡

Values are mean ± SD. HR=heart rate, MAP=mean arterial pressure, RAP=right atrial pressure, MPAP=mean pulmonary arterial pressure,PAOP=pulmonary artery occlusion pressure, CO=cardiac output.*P < 0.05 vs Baseline†P < 0.05 vs Fatigued‡P < 0.05 vs Group IIa§P < 0.05 vs Group IIb

TABLE IV Changes in Pdi % Edi-cru, % Edi-cost in fatigued diaphragm

30 min (Group IIa)Prefatigued Olprinone (Group IIb)

Variable Frequency Group (Baseline) Fatigued Olprinone + Nicardipine (Group IIc)

Pdi 20-Hz IIa 15.4 ± 2.5 11.8 ± 2.4* 12.0 ± 2.9*IIb 15.0 ± 2.2 11.4 ± 2.2* 16.0 ± 2.7†‡IIc 15.2 ± 2.4 11.5 ± 2.3* 11.6 ± 2.5*§

100-Hz IIa 21.6 ± 2.9 21.4 ± 3.1 21.5 ± 2.8IIb 21.2 ± 2.4 20.9 ± 2.7 23.8 ± 2.6*†‡IIc 21.3 ± 2.5 21.2 ± 2.5 21.4 ± 2.6§

%Edi-cru 20-Hz IIa 100.0 ± 0.0 98.9 ± 3.2 99.4 ± 1.8IIb 100.0 ± 0.0 98.9 ± 3.2 98.9 ± 3.2IIc 100.0 ± 0.0 99.4 ± 1.8 99.8 ± 2.4

100-Hz IIa 100.0 ± 0.0 99.8 ± 2.4 99.8 ± 2.4IIb 100.0 ± 0.0 98.9 ± 3.2 99.4 ± 1.8IIc 100.0 ± 0.0 98.9 ± 3.2 99.4 ± 1.8

%Edi-cost 20-Hz IIa 100.0 ± 0.0 100.0 ± 6.8 100.0 ± 6.8IIb 100.0 ± 0.0 99.4 ± 1.8 99.8 ± 3.2IIc 100.0 ± 0.0 98.9 ± 5.8 98.9 ± 5.8

100-Hz IIa 100.0 ± 0.0 99.8 ± 3.2 99.8 ± 3.2IIb 100.0 ± 0.0 99.4 ± 1.8 99.4 ± 1.8IIc 100.0 ± 0.0 99.4 ± 1.8 99.4 ± 1.8

Values are mean ± SD. Pdi=transdiaphragmatic pressure, Edi-cru=electrical activity of the crural part of diaphragm, Edi-cost= electricalactivity of the costal part of diaphragm.*P < 0.05 vs Baseline†P < 0.05 vs Fatigued‡P < 0.05 vs Group IIa§P < 0.05 vs Group IIb

DiscussionThe pressure generated by the diaphragm (Pdi) after agiven electrical stimulus depends on its length andgeometry.9 A major determinant of length and geom-etry of the diaphragm is lung volume. In this study,lung volume was strictly controlled, because the air-way was occluded at end-expiratory lung volume dur-ing the measurements and the end-expiratory Ptp wasmonitored and kept constant (nearly-5 cm H2O)before each stimulus. The deformation of thoracoab-dominal structures was also avoided by placing a castaround the abdomen and lower one third of the ribcage. Therefore, changes in Pdi observed in this studycan be regarded as the result of changes in contractil-ity of the diaphragm.

Hypoxemia, hypercapnea, and metabolic acidosisdecrease contractility in the nonfatigued and fatigueddiaphragm.10,11 The PaO2, PaCO2, pHa, and HCO3-concentration were controlled within normal rangesin this study. Therefore, these factors that could haveaffected diaphragmatic contractility were eliminated.

As the dogs were anesthetized with pentobarbital,the combined effects of olprinone and pentobarbitoneon contractility of the diaphragm were examined inthis study. However, it has been reported that pento-barbitone, at the doses used in this experiment, doesnot affect diaphragmatic contractility.1 2 This was alsoin accordance with our results in Group Ia showing nochange in Pdi.

Low-frequency fatigue is of particular clinicalimportance because the spontaneous, natural rate ofphrenic nerve discharge is mainly in the low-frequen-cy ranges (i.e., 5-Hz to 30-Hz).1 3 Therefore, theeffect of olprinone on contractility of fatigueddiaphragm induced by 20-Hz stimulation (i.e., low-frequency fatigue) was examined.

The results of Group IIa, in which Pdi wasobserved without administration of olprinone in thefatigued diaphragm, showed that the speed of recov-ery from fatigue was relatively slower at 20-Hz stimu-lation than at 100-Hz stimulation, and showed thatEdi did not change at any frequency of stimulation.This was in agreement with our previous studies.4–6

We demonstrated that Pdi at 20-Hz and 100-Hzstimulation increased from fatigued values (P < 0.05)with an infusion of olprinone in Group IIb. The exactmechanism by which olprinone improves contractilityin fatigued diaphragm remains unclear. Olprinoneincreases contractility of cardiac muscle by selectivelyinhibiting type III phosphodiesterase and accumulat-ing cAMP intracellularly, which, in turn, induces theactivation of calcium transport from the sacroplasmicreticulum.1 4 To clarify the mechanism responsible for

the effects of olprinone on contractility in fatigueddiaphragm, a combination of olprinone and nicardip-ine, a calcium antagonist which inhibits calcium influxinto diaphragm muscle,8 was administered in thisstudy. Our results of Group IIc showed that augmen-tation of Pdi by olprinone in the fatigued diaphragmwas abolished by administering nicardipine, suggest-ing that olprinone may increase contractility infatigued diaphragm by influencing calcium transportacross the cell membrane.

We have recently shown that contractility infatigued diaphragm increases by 85% at 20-Hz stimu-lation and by 35% at 100-Hz stimulation by adminis-tering high-dose (0.3 µg·kg– 1·min– 1) olprinone.6 Inthis study, diaphragmatic contractility increased by40% and 15% at each stimulus, respectively, with aninfusion of low-dose (0.1 µg·kg–1·min–1) olprinone.Thus, olprinone increases contractility in fatigueddiaphragm in a dose-dependent manner.

Different effects of olprinone on contractility in non-fatigued and fatigued diaphragm were observed in thisstudy. The precise mechanism underlying these findingsis unknown. The contractility of the diaphragmdepends on the energy supplies to the diaphragm,which are related to its blood supply, and CO is one ofthe major factors determining blood flow to thediaphragm.1 3 Diaphragmatic fatigue occurs when theenergy consumption by the muscle is greater than theenergy supplied by the blood.1 5 Thus, the increase inCO observed in Groups IIb (olprinone) and IIc (olpri-none plus nicardipne) may have led to an increase inblood flow to the diaphragm, and thereby may haveincreased contractility in fatigued diaphragm throughan increase in oxygen deliverly to the diaphragm.However, our results showed that augmentation ofcontractility to each stimulus in fatigued diaphragm byolprinone was abolished with an infusion of nicardipine(Group IIc) despite an equal increase in CO and that anincrease in nonfatigued diaphragmatic contractility wasnot observed during olprinone administration (GroupIb). Therefore, an increase in diaphragmatic blood flowinduced by olprinone may be a relatively small factor inaugmenting contractility in fatigued diaphragm. Inaddition, there is a possibility that oxygen requirementsin nonfatigued diaphragm may be below the level ofoxygen delivery.

In conclusion, low-dose (0.1 µg·kg– 1·min– 1) olpri-none does not affect contractility in nonfatigueddiaphragm, but increases contractility in fatigueddiaphragm via its effect on transmembrane calciummovement in dogs.

Fujii et al.: OLPRINONE A N D DIAPHRAGMATIC FATIGUE 1247

References1 LeJemtel TH, Keung E, Sonnenblick EH, et al. Amrinone:

a new non-glycoside, non-adrenergic cardiotonic agenteffective in the treatment of intractable myocardial fail-ure in man. Circulation 1979; 59: 1098–104.

2 Karlsberg RP, DeWood MA, DeMaria AN, Berk MR,Lasher KP. Comparative efficacy of short-term intra-venous infusions of milrinone and dobutamine in acutecongestive herat failure following acute myocardialinfarction. Clin Cardiol 1996; 19: 21–30.

3 Takaoka H, Takeuchi M, Odake M, et al. Comparisonof the effects on arterial-venticular coupling betweenphospodiesterase inhibitor and dobutamine in the dis-eased human heart. J Am Coll Cardiol 1993; 22:598–606.

4 Fujii Y, Toyooka H, Amaha K. Amrinone improvescontractility of fatigued diaphragm in dogs. Can JAnaesth 1995; 42: 80–6.

5 Fujii Y, Takahashi S, Toyooka H. The effects of milri-none and its mechanism in the fatigued diaphragm indogs. Anesth Analg 1998; 87: 1077–82.

6 Fujii Y, Takahashi S, Toyooka H. The effect of olpri-none compared with milrinone on diaphragmatic mus-cle function in dogs. Anesth Analg 1999; 89: 781–5.

7 Kimata S, Hirosawa K, Kasanuki H, et al. Clinicaleffects of olprinone on acute heart failure. Optimaldose-finding study. Jpn J Clin Exp Med 1992; 69:3984–96.

8 Aubier M, Farkas G, DeTroyer A, Mozes R, Roussos C.Detection of diaphragmatic fatigue in man by phrenicnerve stimulation. J Appl Physiol 1981; 50: 538–44.

9 Grassino A, Goldman MD, Mead J, Sears TA.Mechanics of the human diaphragm during voluntarycontraction: statics. J Appl Physiol 1978; 44: 829–39.

10 Esau SA. Hypoxic, hypercapnic acidosis decreases ten-sion and increases fatigue in hamster diaphragmatic mus-cle in vitro. Am Rev Respir Dis 1989; 139: 1410–7.

11 Howell S, Fitzgerald RS, Roussos C. Effects of uncom-pensated and compensated metabolic acidosis oncanine diaphragm. J Appl Physiol 1985; 59: 1376–82.

12 Ide T, Kochi T, Isono S, Mizuguchi T. Effect of sevoflu-rane on diaphragmatic contractility in dogs. AnesthAnalg 1992; 74: 739–46.

13 Roussos C, Macklem PT. The respiratory muscles. NEngl J Med 1982; 307: 786–97.

14 Satoh H, Endoh M. Effects of a new cardiotonic agent1,2-dihydro-6-methyl-2-oxo-5-[imidazol(1,2-a)pyri-dine-6-yl]-3-pyridine carbonitrile hydrochloride mono-hydrate (E-1020) on contractile force and cyclic AMPmetabolism in canine ventricular muscle. Jpn JPharmacol 1990; 52: 215–24.

15 Robertson CH Jr, Foster GH, Johnson RL Jr. The rela-tionship of respiratory failure to the oxygen consump-

tion of, lactate production by, and distribution ofblood flow among respiratory muscles during increas-ing inspiratory resistance. J Clin Invest 1977; 59:31–42.

1248 CANADIAN JOURNAL OF ANESTHESIA