Olprinone/dopamine combination for improving diaphragmatic fatigue in pentobarbital-anesthetized dogs

Diaphragmatic fatigue might contribute to the development of respiratory failure. In particular, the spontaneous, natural rate of phrenic nerve discharge occurs mainly in low-frequency ranges making low-frequency fatigue clinically important in both humans and animals. Olprinone, a phosphodiesterase 3 inhibitor, improves contractility in fatigued diaphragm, but is also associated with hypotension. Dopamine might be used concomitantly for treating related hypotension.

The purpose of the study was to assess the effect of olprinoneplus dopamine on diaphragmatic fatigue in pentobarbital-anesthetized dogs.

This nonblinded study was conducted at the Department ofAnesthesiology, Institute of Clinical Medicine, Tsukuba, Japan. Diaphragmatic fatigue (assessed by a decrease in diaphragmatic contractility) was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 minutes. Immediately after the fatigue-producing period, groups 2, 3, and 4 received an initial 10 μg/kg dose of olprinone. Group 2 then received maintenance olprinone of 0.3 μg/kg · min; group 3 received maintenance olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min; and group 4 received maintenance olprinone 0.3 μg/kg · min plus dopamine 5 μg/kg · min. Group 1 received no study drug. Olprinone and dopamine were administered IV for 30 minutes. Diaphragmatic contractility was assessed by measuring the maximal transdiaphragmatic pressure (Pdi) generated by test stimuli after airway occlusion at functional residual capacity. Hypotension induced by the study drugs was defined as a >10 mm Hg decrease in mean arterial pressure (MAP), calculated by diastolic pressure plus ⅓ pulse pressure, from baseline.

Twenty-eight mongrel dogs (18 males and 10 females, weighing 10-15 kg)were used in the study; 7 dogs were randomly assigned to each treatment group. When fatigue was established in each group, mean (SD) Pdi at low-frequency (20 Hz) stimulation decreased significantly from baseline in all groups (group 1: 15.6 [2.2] vs 11.7 [2.4] cm H2O, P = 0.008; group 2: 15.4 [1.5] vs 11.6 [1.3] cm H2O, P= 0.005; group 3:15.5 [2.0] vs 11.6 [1.8] cm H2O, P= 0.006; group 4: 15.7 [1.4] vs 12.0 [1.4] cm H2O, P= 0.008), while no significant change existed in Pdi at high-frequency (100 Hz) stimulation (P = NS). After study drug administration, Pdi in groups 2, 3, and 4 increased significantly from fatigued values at both 20 Hz stimulation (group 2: 11.6 [1.3] vs 21.8 [2.0] cm H2O, P = 0.001; group 3: 11.6 [1.8] vs 22.2 [1.8] cm H2O, P = 0.001; group 4: 12.0 [1.4] vs 25.9 [1.9 ] cm H2O, P = 0.001) and 100 Hz stimulation (group 2: 22.0 [2.2] vs 29.0 [1.9] cm H2O, P = 0.002; group 3: 22.1 [2.0] vs 29.3 [2.2] cm H2O, P = 0.002; group 4: 21.8 [2.2] vs 31.7 [2.4] cm H2O, P= 0.001). The increase in Pdi was significantly larger in group 4 compared with the other 3 groups (all, P < 0.05). Hypotension was not observed in group 4. MAP did not change significantly in group 1 or group 4 compared with baseline or fatigued MAP values (P = NS). Groups 2 and 3 had significant decreases in MAP with treatment compared with values in group 1 and with baseline and fatigued MAP values (all, P < 0.05). The MAP of group 4 was significantly greater than the MAP of groups 2 and 3 with treatment (both, P < 0.05).

Olprinone 0.3 μg/kg sd min plus dopamine 5 μg/kg · min improved contractility in fatigued diaphragms and was not associated with hypotension in these pentobarbital-anesthetized dogs. Olprinone monotherapy and olprinone 0.3 μg/kg · min plus dopamine 2 μg/kg · min might improve contractility significantly. However, it was also associated with significant decreases in MAP.