The effect of sedative drugs on diaphragmatic contractility in dogs: propofol versus midazolam

Implications: a sedative dose (0.1 mg x kg(-1) x h(-1)) of midazolam, compared with a subhypnotic dose (1.5 mg x kg(-1) x h(-1)) of propofol, decreases the contractility of the diaphragm in dogs.     

Dobutamine increases diaphragmatic contractility in dogs

The effects of dobutamine on diaphragmatic contractility were studied in 24 dogs anaesthetized with secobarbital and receiving mechanical lung ventilation. The phrenic nerves were stimulated supramaximally for two seconds with electrodes placed around the fifth and sixth cervical roots when the airway was closed at the level of FRC. The stimulating frequency ranged from 10 to 100 Hz. Transdiaphragmatic pressure gradient (Pdi) generated by the electrophrenic stimulation was used as an index of diaphragmatic contractility. The electrical activity of the diaphragm during the stimulation (Edi) was also measured with needle electrodes inserted in the right hemidiaphragm percutaneously. During an infusion of dobutamine (10 micrograms.kg-1.min-1 for 20 min), Pdi increased by 15 +/- 2.1% of control value at 20 Hz stimulation (P less than 0.01), and by 13 +/- 1.2% at 100 Hz stimulation (P less than 0.01). The Edi was not altered by dobutamine infusion. This enhancement of Pdi by dobutamine was abolished by simultaneous infusion of nicardipine, a Ca-channel blocker, but was not affected by prostaglandin E1. These results suggest that dobutamine has a stimulating effect on canine diaphragmatic contraction, and this action may be related to the increased inward movement of extracellular calcium.     

Propofol decreases diaphragmatic contractility in dogs

Volatile anesthetics depress diaphragmatic muscle function; however, no data are available regarding the effect of propofol on diaphragmatic contractility. We therefore studied this effect in dogs. Pentobarbital-anesthetized animals were divided into three groups of 10 each. Group I received only maintenance fluid; Group II was infused with a subhypnotic dose of propofol (0.1-mg/kg initial dose plus 1.5-mg x kg(-1) x h(-1) maintenance dose); Group III was infused with an anesthetic dose of propofol (0.1-mg/kg initial dose plus 6.0-mg x kg(-1) x h(-1) maintenance dose). We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). With an infusion of propofol in Groups II and III, Pdi at low-frequency (20-Hz) stimulation decreased from the baseline values (P < 0.05), whereas Pdi at high-frequency (100-Hz) stimulation did not change. Compared with Group I, Pdi at 20-Hz stimulation decreased during propofol administration in Groups II and III (P < 0.05). The decrease in Pdi was more in Group III than in Group II (P < 0.05). We conclude that propofol is associated with a dose-related inhibitory effect on diaphragmatic contractility in dogs. IMPLICATIONS: Propofol is an effective IV anesthetic for the induction and maintenance of anesthesia. Subhypnotic and anesthetic doses of propofol decrease diaphragmatic contractility in dogs.     

High-dose colforsin daropate increases diaphragmatic contractility in dogs

PURPOSE: To evaluate the effects of colforsin daropate, a water-soluble derivate known to improve contractility in fatigued canine diaphragm, at two different doses (low-dose and high-dose) on contractility of the non-fatigued diaphragm of dogs. METHODS: Twenty-four pentobarbitone-anesthetized dogs were divided into three groups of eight each: Group I received no study drug; Group II received low-dose (0.2 microg x kg-1 x min-1) colforsin daropate; Group III received high-dose (0.5 microg x kg-1 x min-1) colforsin daropate. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi). RESULTS: In Group III, with an infusion of high-dose colforsin daropate, Pdi at low-frequency (20 Hz) and high-frequency (100 Hz) stimulation increased from baseline values (P < 0.05). Compared with Group I, Pdi at both stimuli increased during colforsin daropate administration in Group III (P < 0.05). In Group II, with an infusion of low- dose colforsin daropate, Pdi to each stimulus did not change. CONCLUSION: Colforsin daropate, only when administered at high-dose, increases contractility of non-fatigued diaphragm in dogs.     

Midazolam versus propofol for reducing contractility of fatigued canine diaphragm

The effects of midazolam and propofol on the contractility offatigued canine diaphragm were examined. Diaphragmatic fatiguewas induced by intermittent supramaximal bilateral electrophrenicstimulation at a frequency of 20 Hz applied for 30 min.After fatigue had been induced, group I (n=10) receivedno study drug, group II (n=10) was given a propofol infusion(0.1 mg kg^–1 loading dose plus 1.5 mg kg^–1 h^–1maintenance dose) and group III (n=10) was given a midazolaminfusion (0.1 mg kg^–1 loading dose plus 0.1 mg kg^–1 h^–1maintenance dose). Diaphragmatic contractility was assessedby measuring transdiaphragmatic pressure (P_di). After the fatigue-inducingperiod in each group, P_di at low-frequency (20 Hz) stimulationwas lower than the baseline values (P<0.05), whereas no changein P_di at high-frequency (100 Hz) stimulation was observed.In group II, P_di at 20 Hz stimulation was lower than fatiguedvalues (P<0.05); P_di at 100 Hz stimulation did not change.In group III, P_di at both stimulation frequencies was lowerthan fatigued values (P<0.05). Compared with group I, P_diat 20 Hz stimulation was lower than fatigued values (P<0.05)during administration of the study drug in groups II and III.The decrease in P_di was greater in group III than in group II(P<0.05). In conclusion, midazolam compared with propofolis associated with an inhibitory effect on contractility inthe fatigued canine diaphragm. Br J Anaesth 2001; 86: 879–81     

Effect of sevoflurane on diaphragmatic contractility in dogs.

The effect of sevoflurane on diaphragmatic contractility was investigated in 12 anesthetized, mechanically ventilated dogs with the thorax opened. Animals were divided into two groups of six each: the sevoflurane and time control groups. We assessed contractility by the transdiaphragmatic pressure (Pdi) during supramaximal stimulation of the phrenic nerve at frequencies of 0.5, 10, 20, 50, and 100 Hz under quasiisometric conditions. The integrated electrical activity (Edi) of the crural and costal parts of the diaphragm (Edi cru, Edi cost) was also measured. In the sevoflurane group, diaphragmatic contractility was determined during three levels of anesthesia, specifically 0, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC). Measurements were made at the start of the stimulation (initial) and at the end of the 2-s period (2-s). Increasing the depth of sevoflurane anesthesia did not cause any significant differences in Pdi and Edi at 0.5-, 10-, and 20-Hz stimulation. By contrast, at 50- and 100-Hz stimulation, initial Pdi during 1.0 and 1.5 MAC sevoflurane exposure decreased significantly compared with the 0 MAC value (P less than 0.05). In addition, there was a statistical difference in 2-s Pdi between 1.0 and 1.5 MAC at 100-Hz stimulation (P less than 0.05). The Edi cru showed similar changes in Pdi at both measurements, whereas there was no remarkable change in Edi cost. There was no significant change either in Pdi or in Edi with respect to time in the time control group. We conclude from these results that sevoflurane impairs diaphragmatic contractility through its inhibitory effect on neuromuscular transmission, predominantly of the crural part.     

Recovery of costal and crural diaphragmatic contractility from partial paralysis

Since the two muscles (costal and crural) that constitute the diaphragm are separate and histologically different, their individual recovery pattern from neuromuscular blockade also may be different. Therefore, we studied the recovery of force and shortening in the in vivo diaphragm from atracurium-induced neuromuscular blockade in seven pentobarbital anesthetized dogs to assess segmental differences. Transdiaphragmatic pressure (Pdi), shortening of costal and crural segments, integrated electromyogram (EMG), and tidal volume (VT) were measured during spontaneous breathing. After atracurium had reduced VT to 30% of control, breathing parameters were followed until recovered to 90% of control values. In addition, force-frequency curves generated by supramaximal tetanic stimuli of the phrenic nerve were measured. Recovery times for tidal Pdi, tidal EMG, tidal shortening, low-frequency shortening, and twitch Pdi were twice as fast as for VT (40 +/- 4 min), reflecting a slower rate of recovery of accessory inspiratory muscles. High-frequency recovery was typically slower than that of VT. During tidal breathing and tetanic stimulation, costal and crural shortening recovered simultaneously. On the other hand, comparison between costal and crural by analysis of pressure-shortening relationships showed a segmental difference (crural shortened 30% more than costal at the same Pdi), which implied reduced afterload on the crural segment. However, since shortening and pressure were linearly related during paralysis and recovery, measurements of Pdi alone can accurately reflect changes in contractile mass when heterogeneity and afterload are controlled.     

The effects of propofol and midazolam on canine left ventricular contractility

Pronounced decrease in arterial blood pressure during propofol or midazolam infusion for sedation of critically ill patients, has raised the possibility that they have a direct negative inotropic action. Accordingly, in the current study, changes in the left ventricular (LV) contractility were examined during i.v. infusion of these two sedatives in anesthetized dogs. Myocardial contractility was assessed with the slope (Ees) of the LV end-systolic pressure-volume relationship and the slope (Msw) of the LV end-diastolic volume-stroke work relationship. Propofol was administered at 5, 10 and 20 mg.kg-1.h-1, and midazolam at 0.3, 0.6 and 1.2 mg.kg-1.h-1 over 60 min. Propofol caused dose-dependent decrease in Ees (55 +/- 7 during the low dose to 27 +/- 3 mmHg.ml-1 during the high dose, P < 0.05) and in Msw (91 +/- 8 during the low dose to 67 +/- 6 erg.cm-3 x 10(-3) during the high dose, P < 0.05). Midazolam, also, decreased in Ees and Msw significantly. No significant differences were observed between three different doses of midazolam. It is concluded that propofol shows the dose-dependent inhibition of myocardial contractility, but midazolam induces dose-independent inhibition.     

RETRACTED ARTICLE: Effect of xenon on diaphragmatic contractility in dogs

PURPOSE: This study was undertaken to examine the effect of xenon on diaphragmatic contractility in pentobarbitone- anesthetized, mechanically ventilated dogs. METHODS: Twenty-one dogs were randomly allocated to three groups (n=7 of each): Group I received oxygen 100%; Group II received xenon 30% in oxygen; Group III received xenon 60% in oxygen. Diaphragmatic contractility was assessed by measuring transdiaphragmatic pressure (Pdi) generated during supramaximal stimulation of phrenic nerves at the neck at low-frequency (20-Hz) and high-frequency (100-Hz) stimulation, after maintaining 60 min of stable condition. RESULTS: With inhalation of xenon at two different concentration (30% and 60%), no changes were observed in Pdi at either concentration. There was no difference in Pdi among the three groups. CONCLUSION: Increasing the concentration of xenon to 60% has no effect on diaphragmatic contractility in dogs. This suggests that xenon may be used safely as an anesthetic with respect to respiratory muscle function.     

Different effects of halothane and enflurane on diaphragmatic contractility in vivo

We examined the effects of halothane and enflurane on diaphragmatic contractility in 12 anesthetized, mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. Animals were randomly assigned to two groups, a halothane group (n = 6) and an enflurane group (n = 6). The Pdi stimulus-frequency relationship was compared at anesthetic levels of 1, 1.5, and 2 MAC (minimum alveolar concentration) in each group. The sequence of changing anesthetic concentration was randomized. In addition, the Pdi-frequency relationship was also compared between 1 MAC of halothane and enflurane in 8 of 12 dogs. In animals anesthetized with enflurane, Pdi significantly decreased with 50- and 100-Hz stimulation in the presence of increasing MAC values, whereas Pdi at 10-Hz stimulation was not affected by the depth of anesthesia. Pdi with 20-Hz stimulation during 2 MAC enflurane also decreased significantly below Pdi levels seen at 1 and 1.5 MAC. By contrast, with halothane there was no difference in Pdi at any of the stimulation frequencies during any of the three levels of anesthesia. There was no statistical difference, however, between Pdi-frequency relationships during 1 MAC of halothane and enflurane in eight animals. From these results, we conclude that halothane does not impair diaphragmatic contractility any more than enflurane does, but enflurane decreases force generation of the diaphragm at high stimulation frequencies in a dose-related fashion. This depressant effect of enflurane occurs mainly through the impairment of neuromuscular transmission and/or membrane excitability.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effects of xenon and nitrous oxide on diaphragmatic contractility in dogs

BACKGROUND: Xenon at two different concentrations (30%, 60%) has no effect on diaphragmatic contractility. This study was undertaken to compare the effects of xenon and nitrous oxide (N2O), a commonly used and well-established gas anesthetic, on diaphragmatic contractility in dogs. METHODS: Twenty-one pentobarbitone-anesthetized dogs were randomly divided into three groups of seven each: group 1 received xenon 30% (0.25 MAC) in oxygen; group 2 received N2O 47% (0.25 MAC) in oxygen; and group 3 received N2O 60% (0.32 MAC) in oxygen. Diaphragmatic contractility was assessed by transdiaphragmatic pressure (Pdi) at low- (20-Hz) and high-frequency (100-Hz) stimulation, after maintaining 60 min of stable condition. The integrated electrical activity of diaphragm (Edi) to each stimulus was measured. RESULTS: With an inhalation of xenon 30%, N2O 47%, or N2O 60%, Pdi and Edi at both stimuli did not change. No difference in Pdi or Edi was observed among the groups. CONCLUSION: When used at clinical concentration, xenon or N2O does not affect contractility and electrical activity of the diaphragm in dogs.     

The recovery profile of reduced diaphragmatic contractility induced by propofol in dogs

Propofol decreases contractility of the diaphragm, but no data are available for its effects on recovery. We studied the recovery profile of reduced diaphragmatic contractility induced by propofol in dogs. Animals were divided into 4 groups of 7 each. Group I, without fatigue, received only maintenance fluid; Group II, without fatigue, was infused with propofol; Group III, with fatigue, received no study drug; Group IV, with fatigue, was infused propofol. Propofol at an anesthetic dose (0.1 mg/kg initial dose plus 6.0 mg x kg(-1) x h(-1)) was administered for 60 min. In Groups III and IV, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at 20-Hz for 30 min. We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). In group II, Pdi at low-frequency (20-Hz) stimulation decreased to less than baseline (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. At 10 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to baseline. When fatigue was established, in Groups III and IV, Pdi at 20-Hz stimulation decreased to less than baseline (P < 0.05), whereas Pdi at 100-Hz stimulation did not change. After administering propofol in Group IV, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). At 20 min after the end of propofol administration, Pdi at 20-Hz stimulation returned to fatigued values. We conclude that reduced contractility in nonfatigued and fatigued canine diaphragm induced by propofol recovers within 20 min after the cessation of administration.     

RETRACTED ARTICLE: Dobutamine increases contractility of fatigued diaphragm in dogs: The relationship between dose and diaphragmatic contractility

The dose-related effects of dobutamine (DOB) on the contractility of fatigued diaphragm were studied in 16 anesthetized, mechanically ventilated dogs. The animals were divided into two groups of eight: the control (group C) and the DOB (group D). Diaphragmatic fatigue was induced by intermittent supramaximal electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Diaphragmatic contractility was assessed from changes in transdiaphragmatic pressure (P_di). After the induction of diaphragmatic fatigue, P_di at low-frequency (20-Hz) stimulation decreased significantly compared with the prefatigue values (P<0.05), whereas no change in P_di was observed at high-frequency (100-Hz) stimulation. In group D, after producing fatigue, P_di at 20-Hz stimulation increased significantly with a continuous infusion of DOB (5 and 10 μg·kg⁻¹·min⁻¹) i.v. (P<0.05). The P_di at 100-Hz stimulation increased significantly with administration of DOB 10 μg·kg⁻¹·min⁻¹ i.v. (P<0.05). There was a significant correlation between dose of DOB and P_di at both stimuli (P<0.05). In group C, the speed of P_di recovery at 20-Hz stimulation was relatively slower. The integrated diaphragmatic electric activity (E_di) in each group did not change at any frequency of stimulation throughout the study. It is concluded that DOB increases the contractility of fatigued diaphragm in a dose-dependent manner.     

Dose-response and onset/offset characteristics of rapacuronium

BACKGROUND: A rigorous study of the dose-response relation of rapacuronium has, to our knowledge, yet to be performed. In addition, there is little information available regarding the onset or offset profile of rapacuronium when administered in subparalyzing doses. These issues necessitate further study. METHODS: Forty-seven adult patients, American Society Anesthesiologists physical status I or II, were studied. Tracheal intubation was accomplished without muscle relaxants. Anesthesia was maintained with use of nitrous oxide, propofol, and alfentanil. The electromyogram of the first dorsal interosseous muscle was measured using a monitor. Single stimuli at 0.10 Hz were administered. A single dose of rapacuronium was administered. After log-dose or logit transformation of the data, the best-fit line of regression was determined using the method of least squares. For each subject, the authors estimated the 50% effective dose (ED50) and 95% effective dose (ED95) from the Hill equation using the slope obtained from regression analysis. The onset times to 50 and 90% of peak effect were estimated in a subset of 10 individuals in which peak twitch depression decreased to the range of 90-99%. RESULTS: The calculated ED50 and ED95 values for rapacuronium were 0.39 +/- 0.08 (SD) and 0.75 +/- 0.16 mg/kg, respectively. After a single ED95 dose, 90% of the drug's peak effect was evident in 77 +/- 17 s. After this dose, rapacuronium has a clinical duration of 6.1 +/- 1.1 min. CONCLUSIONS: The authors found the ED95 of rapacuronium to be substantially less than suggested by previous estimates. Rapacuronium has an onset profile that is not different from that previously reported for succinylcholine. The rate of spontaneous recovery was faster after rapacuronium than the authors previously observed after mivacurium administration but was slower than after succinylcholine, using an identical protocol.     

Olprinone for the treatment,but not prevention,of fatigue-induced changes in guinea-pig diaphragmatic contractility

Olprinone, a phosphodiesterase III inhibitor, improves the contractility in fatigued diaphragm in vivo, but no data are available for the treatment and prevention of fatigue-induced changes in vitro. We therefore examined the efficacy of Olprinone for the treatment and prevention of fatigue-induced changes in guinea-pig diaphragmatic contractility. The guinea-pig diaphragm strips were randomly allocated according to dose of Olprinone (0, 10(-6), 10(-5), and 10(-4) M) (n = 7 each) and were stimulated directly in an organ bath. Diaphragmatic contractility was measured by assessing twitch tension and force at 20-Hz and 100-Hz stimulation. Diaphragmatic fatigue was induced by generating rhythmic, repetitive contractions produced by 20-Hz stimulation for 5 min. In the first experiment, after the fatigue-producing period, Olprinone was administered to the organ bath for 5 min. In the second experiment, Olprinone was pretreated for 5 min, and then diaphragmatic fatigue was produced. In Experiment 1, after a fatigue-producing period, tetanic force to each stimulus decreased from baseline values (P < 0.05). Olprinone 10(-5)-10(-4) M caused an increase in force at both stimuli from fatigued values (P < 0.05). In Experiment 2, no change in tetanic force was observed by pretreatment with Olprinone (0-10(-4) M). After producing fatigue, tetanic force to each stimulus decreased from baseline values (P < 0.05). These results suggest that Olprinone 10(-5)-10(-4) M improves the fatigue-induced changes in guinea-pig diaphragmatic contractility and that pretreatment with Olprinone does not prevent diaphragmatic fatigability. IMPLICATIONS: Olprinone is effective for the treatment, but not prevention, of fatigue-induced changes in guinea-pig diaphragmatic contractility.     

Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model

BACKGROUND: Respiratory failure with diaphragmatic fatigability is common in patients suffering sepsis or septic shock. However, the development and progress of diaphragmatic fatigability remains poorly understood, and no method has been established to treat fatigability. In this study, we hypothesize that neutrophil activation contributes to the development of diaphragmatic fatigability. We also sought to investigate whether a phosphodiesterase inhibitor, olprinone, improves diaphragmatic fatigability associated with abdominal sepsis and inhibits an increase in myeloperoxidase activity in diaphragmatic muscle. METHODS: Male Wistar rats were randomly assigned to a sham group, coecal legation perforation group (CLP), and a phosphodiesterase inhibitor (PDE) pretreated group. At 16 h after surgical procedure, the left hemidiaphragm was removed for the measurement of diaphragmatic contractility and fatigability. In addition, for the measurement of serial changes in myeloperoxidase activity, the right hemidiaphragm was also removed at 4, 8 or 16 h after the surgical procedure in each group. RESULTS: In a septic model involving rats, we observed that diaphragmatic muscles were fatigable and myeloperoxidase activity increased. We also demonstrated that intraperitoneal administration of olprinone improves diaphragmatic fatigability and inhibits an increase in myeloperoxidase activity induced by abdominal sepsis. CONCLUSION: Olprinone represents a potential therapy for cases of respiratory failure with diaphragmatic fatigability resulting from inhibition of neutrophil activation.