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MINAXOLONE: A CLINICAL TRIAL IN THE DOG
83.
MINAXOLONE: A CLINICAL TRIAL IN THE DOG -
and
Introduction
The steroid anaesthetic, alphaxolone/alphadolone acetate (Saffan) which is marketed for use mainly in cats, and was until its recent withdrawal used in man (as Althesin), has the disadvantage that it is formulated in a solution containing Cremaphor EL, which can produce anaphylactoid reactions likely to be particularly severe in the dog.
Mixaxolone (IlaN, N-dimethyl-
amino-2-fl ethoxy-3rK-hydroxy-5W-pregnan-20-one-citrate)
is a water soluble
steroid intravenous anaesthetic agent which has undergone extensive clinical trials in man, (Aveling et a1 1979; McNeill et a1 1979, 1981; McNeil et a1 1981; Dundee 1981) where it proved to be an adequate rapidly acting intravenous anaesthetic agent, which most workers considered worthy of further trials. A clinical trial in the dog is reported here.
Patients and Methods
Mioaxolone was used by 6 anaesthetists at 2 centres (Cambridge and London) for anaesthesia in 70 dogs undergoing clinical procedures. Sixteen German Shepherd Dogs and 7 Labrador Retrievers were included, but the trial otherwise represented a wide variety of breeds (25 in total). The trial group included giant dogs such as Deerhounds and Pyrenean
84.
Mountain dogs but nominiature or toy breeds, the smallest adult dog being a Jack Russell Terrier.
bieights ranged from 7 to 62 kg (mean
27 kg), and ages from 3.5 months to 11 years (mean 5.9 years). Three dogs receivedno prernedication, but all others were premedicated with acepromazine maleate (0.02 atropine (0.3
-
- 0.08
mg/kg), and
0.9 mg total dose) given by the intramuscular route
(at least 30 minutes prior to anaesthesia). Anaesthesia was induced by an intravenous dose of Minaxolone The rate of administration varied from 3 to 120 seconds, but once the anaesthetists had become experienced with the drug, an injection time of 5
-
15 seconds was usually employed. In 36 dogs anaesthesia was maintained with increments of
intravenous minaxolone as required.
In 8 of these dogs, endotracheal
intubation was not carried out but the others were all intubated, and if necessary, the inspired gases were supplemented with oxygen.
The
clinical and surgical procedures which were carried out using minoxalone as a sole anaesthetic are listed in Table 1. In 34 cases all of which underwent endotracheal intubation following induction with minaxolone, anaesthesia was maintained with nitrous oxide in oxygen and halothane. Detailed records of the parameters routinely monitored during anaesthesia were kept in all cases. In selected suitable cases more intensive measurement was carried out.
Arterial blood pressure was
measured via a femoral arterial catheter by strain gauge transducers, and arterial blood samples collected anaerobically for blood gas analysis.
Respiratory parameters were measured with a pneumotachygraph
and a Wright's respirometer. Results Induction Intravenous minaxolone invariably gave a smooth induction of anaesthesia, which appeared to occur within a circulation time.
However
85.
in 8 cases it was noted that anaesthesia continued to deepen over the next few minutes.
The speed of injection of the drug had no apparent
influence on the quality of induction, or on the incidence of side effects.
Three dogs did attempt to withdraw their legs during slow
injection (30 seconds), but this was not accompanied by whining, or any other signs of pain. The dose of minaxolone employed for induction in the 70 dogs varied from 0.4 to 2.8 mg/kg.
Endotracheal intubation could be carried
out easily following doses of 0.9 mg/kg, or greater of minaxolone, but with lower doses, although some dogs were intubated with difficulty, anaesthesia was not really adequate for the purpose.
Where intubation
was not attempted, the lower doses were often adequate for very minor procedures. Excitement did not occur with underdosage, and where anaesthesia was inadequate, further increments of minaxolone always led to a satisfactory completion of induction. Table 2 shows the length o f action of the induction dose o f minaxolone in the 36 dogs in which it was the sole agent used.
Although
increased dosage increased the length of action, there were very marked variations in both length and depth of anaesthesia between individual dogs administered similar amounts of minaxolone.
For example, the time
before further increments of minaxolone were required following induction with lmg/kg varied from 3 to 25 minutes, whilst in one dog given 0.5 mg/kg no further increments were required for 30 minutes. Some dogs became very deeply anaesthetised by the induction dose, and this deep anaesthesia was often associated with severe respiratory depression. Although this was most likely to occur with the higher doses, it did also occur in 2 cases given 1 mg/kg.
There was
no obvious correlation between the breed of dog, its previous condition, and this sensitivity to the drug.
86.
Side effects
Table 3 shows the side effects noted during induction or maintenance of anaesthesia with minaxolone. Respiratory depression was the most serious side effect. In some cases it was clinically severe, the dogs becoming apnoeic or cyanotic. Such cases were immediately given oxygen supplementation and intermittent positive pressure ventilation if necessary. Apnoea was always associated with maximal depth of anaesthesia so that, although commonest after large doses of the drug, it could occur in a few minutes after induction of anaesthesia so that vigilance by the anaesthetist was needed at this time. Measurement o f respiratory parameters confirmed the existence of respiratory depression in some cases in which it was not clinically apparent. The other common side effect was muscular twitching and tremor, which could occur at any stage of the anaesthetic, and was noted after all but the lower (< 0.8 mg/kg) total dose rates of minaxolone. These twitches did not appear to be related to surgical stimulation, and caused remarkably little inconvenience to the surgeons. One case undergoing anterior cruciate repair violently twitched all muscles other than those of its affected leg, yet the surgeon found surgical conditions perfectly adequate.
The twitches did interfere with radiography,
resulting in several blurred films through movement as the click of the machine appeared to trigger a twitch. Twitching could always be reduced by supplementing anaesthesia with halothane. Cardiovascular effects were minimal. One case had atrioventricular heart block when anaesthetised with minaxolone but heart rhythm reverted to normal on treatment with atropine. This dog had a normal heart rate and rhythm on admission, but had not been checked
subsequent to premedication. One dog, whose heart was monitored by
87.
electrocardiogram during induction of anaesthesia, showed ventricular arrhythmias during endotracheal intubation. Arterial pressure changes were minimal; minaxolone caused a slight fall in blood pressure immediately after administration, but this rapidly returned to normal or became slightly elevated.
Maintenance
Where minaxolone was used as the sole anaesthetic agent, further incremental doses of 0.25 - 0.5 mg/kg were given as required to obtain adequate analgesia and relaxation. Table 4 shows the range of total doses required.
Although the total dose was influenced by the
procedure t o be performed, and the time required, there was again considerable individual variation between the doses required in smaller dogs undergoing identical procedures.
For example, 6 German Shepherd
dogs of similar ages undergoing cryosurgery for anal furunculosis required doses of minaxolone ranging from 0.6 to 2.8 mg/kg (mean 1.7 mgl kg) despite the fact that the procedures took similar periods of time. Three dogs underwent anterior cruciate repair by the same surgeon and required doses ranging from 1.5 to 2.8 mg/kg of minaxolone.
In the majority of
cases where minaxolone was used as the sole agent, analgesia appeared to be excellent, and there was little or no response to surgical stimulation. In one exception, the surgeon complained of movement, despite the fact that the dog was deeply anaesthetised.
The movement may have been due
to the twitches already discussed. In cases where gaseous supplementation of anaesthesia was employed, transition to the volatile agent was smooth and trouble free.
Recoverx The times taken for dogs to lift their heads following the administration of rninaxolone as the sole anaesthetic agent are shown
88.
in Table 4. There was considerable individual variation, and some dogs which regained awareness rapidly subsequently returned to sleep and were able to stand no faster than dogs with an initial slow recovery.
The
time taken for dogs to regain their feet was often influenced by the surgery performed, but most dogs could stand within 2 hours, although in 2 cases, complete recovery was recorded as taking "several hours". The comparatively small number o f cases involved, and the wide individual variation in sensitivity to the drug prevents statistical analysis, but there was no obvious correlation between the speed of recovery, the breed and the original physical status, (fat, thin etc.) of the dog. Recovery times from the last dose administered were not greatly prolonged where anaesthesia had been maintained by incremental doses of minaxolone.
Discussion
Minaxolone proved to be an adequate anaesthetic agent for both induction and maintenance of anaesthesia in the dog.
Recovery times
were rather prolonged, and for this reason minaxolone is unlikely to replace the barbiturate drugs in current use as an induction agent prior t o gaseous anaesthesia, except in the dogs where recovery from barbiturate might be expected to be delayed. However, further doses of minaxolone did not unduly lengthen recovery, and it could be useful as a sole intravenous anaesthetic agent. The commonest side effect of twitching was not a serious disadvantage, except for radiography. This side effect was also noted in man (Aveling et a1 1979) where it was said to occur only at the higher dose ranges.
In our study it was not noted in any of the few
dogs which received a total dose of less than 0.8 mg/kg. The most serious problem in veterinary use was that of respiratory depression, and the danger of this side effect was aggravated by the individual sensitivity of the dogs, and by the fact
89.
that apnoea could occur later than might be expected compared with other intravenous agents.
Respiratory depression did not appear to
be a problem in the trials in man, but again the doses used were much
lower than have been utilised in the dog.
Our results would suggest
that minaxolone should not be used in the dog unless the facilities to give oxygen, and intermittent positive pressure ventilation, are available for emergency use. The delay which was occasionally noted between induction and the attainment o f maximal depth o f anaesthesia was not noted in man. However, it was usually the accompanying respiratory depression which brought this delay to the anaesthetists attention, so again it would be less obvious at the lower dose rates used in the medical trials. Minaxolone would seem worthy of further clinical trials in the dog, particularly to investigate whether the use o f lower initial induction doses might reduce the incidence o f unwanted side effects.
Acknowledgements
The authors wlsh to thank Mrs. P. Taylor, Mr. L. Cullen, Dr. P. Stolk and Dr. K. Cullen for allowing us to utilise their anaesthetic records. Glaxovet provided us with generous supplies of minaxolone.
90.
Aveling,W. et al(1979) The Lancet pp 71-73. Dundee,J.W.
(1981). Editorial.
Anaesthesia, 2, 570-580.
McNeil1,H.G.
et a1 (1379) The Lancet pp 73-74.
McNeil1,H.G.
et a1 (1981) Anaesthesia 2, 592-596.
91.
TABLE 1 PROCEDURES CARRIED OUT UNDER MINAXOLONE ANAESTHESIA
No. -
Procedure Examination under anaesthesia Crysosurgery (for anal furunculosis) Orthopaedic Superficial surgery Teeth extraction Perineal rupture
15 9
6 4 1 1
I
Premeditated dogs Minaxolone (mg/kq) 2 - 2.8 1.6 1.1 1.o
Number 3
-
- 33t
- 25 -- 3015 - 10
26t 25+ 60 14 2 13 16.5 7.5
-
21
3 2
20+ 25+ 60 3 2 7 5 5
3
12
1 1 18
1 3
0.9 0.8 0.5 0.4
Length o f action (mins) Mean Range
No premedication
2.1
- 2.4
35
+ represents still deeply anaesthetised at the end of the procedure
92.
TABLE 3 SIOE EFFECTS DURING MINAXOLONE ANAESTHESIA (Total 70 dogs)
Effect
Number
Twitching/tremor Respiratory depression Cardiac arrhythmias Anaesthesia continued to deepen Leg withdrawal on injection Vocalisation (not intubated) Regurgitation
32 25 2 8 3 3 1
TABLE 4
RECOVERY FROM MINAXOLONE 30 dogs. Minaxolone sole agent
Number 0.8 (0.7
- 0.9)
1.22
(1
-
1.7
(1.6
1.5)
- 2)
2.2 (2-3)
Time to lifting head (mins) From last dose
From induction 107 (65 - 150)
(50 - 120)
16
67 (19 - 90)
51 (13 - 90)
7
88 (30 - 125)
50 (25 - 90)
5
129 (38 - 175)
98 (35 - 175)
1
a5
MINAXOLONE: A CLINICAL TRIAL IN THE DOG -
and
Introduction
The steroid anaesthetic, alphaxolone/alphadolone acetate (Saffan) which is marketed for use mainly in cats, and was until its recent withdrawal used in man (as Althesin), has the disadvantage that it is formulated in a solution containing Cremaphor EL, which can produce anaphylactoid reactions likely to be particularly severe in the dog.
Mixaxolone (IlaN, N-dimethyl-
amino-2-fl ethoxy-3rK-hydroxy-5W-pregnan-20-one-citrate)
is a water soluble
steroid intravenous anaesthetic agent which has undergone extensive clinical trials in man, (Aveling et a1 1979; McNeill et a1 1979, 1981; McNeil et a1 1981; Dundee 1981) where it proved to be an adequate rapidly acting intravenous anaesthetic agent, which most workers considered worthy of further trials. A clinical trial in the dog is reported here.
Patients and Methods
Mioaxolone was used by 6 anaesthetists at 2 centres (Cambridge and London) for anaesthesia in 70 dogs undergoing clinical procedures. Sixteen German Shepherd Dogs and 7 Labrador Retrievers were included, but the trial otherwise represented a wide variety of breeds (25 in total). The trial group included giant dogs such as Deerhounds and Pyrenean
84.
Mountain dogs but nominiature or toy breeds, the smallest adult dog being a Jack Russell Terrier.
bieights ranged from 7 to 62 kg (mean
27 kg), and ages from 3.5 months to 11 years (mean 5.9 years). Three dogs receivedno prernedication, but all others were premedicated with acepromazine maleate (0.02 atropine (0.3
-
- 0.08
mg/kg), and
0.9 mg total dose) given by the intramuscular route
(at least 30 minutes prior to anaesthesia). Anaesthesia was induced by an intravenous dose of Minaxolone The rate of administration varied from 3 to 120 seconds, but once the anaesthetists had become experienced with the drug, an injection time of 5
-
15 seconds was usually employed. In 36 dogs anaesthesia was maintained with increments of
intravenous minaxolone as required.
In 8 of these dogs, endotracheal
intubation was not carried out but the others were all intubated, and if necessary, the inspired gases were supplemented with oxygen.
The
clinical and surgical procedures which were carried out using minoxalone as a sole anaesthetic are listed in Table 1. In 34 cases all of which underwent endotracheal intubation following induction with minaxolone, anaesthesia was maintained with nitrous oxide in oxygen and halothane. Detailed records of the parameters routinely monitored during anaesthesia were kept in all cases. In selected suitable cases more intensive measurement was carried out.
Arterial blood pressure was
measured via a femoral arterial catheter by strain gauge transducers, and arterial blood samples collected anaerobically for blood gas analysis.
Respiratory parameters were measured with a pneumotachygraph
and a Wright's respirometer. Results Induction Intravenous minaxolone invariably gave a smooth induction of anaesthesia, which appeared to occur within a circulation time.
However
85.
in 8 cases it was noted that anaesthesia continued to deepen over the next few minutes.
The speed of injection of the drug had no apparent
influence on the quality of induction, or on the incidence of side effects.
Three dogs did attempt to withdraw their legs during slow
injection (30 seconds), but this was not accompanied by whining, or any other signs of pain. The dose of minaxolone employed for induction in the 70 dogs varied from 0.4 to 2.8 mg/kg.
Endotracheal intubation could be carried
out easily following doses of 0.9 mg/kg, or greater of minaxolone, but with lower doses, although some dogs were intubated with difficulty, anaesthesia was not really adequate for the purpose.
Where intubation
was not attempted, the lower doses were often adequate for very minor procedures. Excitement did not occur with underdosage, and where anaesthesia was inadequate, further increments of minaxolone always led to a satisfactory completion of induction. Table 2 shows the length o f action of the induction dose o f minaxolone in the 36 dogs in which it was the sole agent used.
Although
increased dosage increased the length of action, there were very marked variations in both length and depth of anaesthesia between individual dogs administered similar amounts of minaxolone.
For example, the time
before further increments of minaxolone were required following induction with lmg/kg varied from 3 to 25 minutes, whilst in one dog given 0.5 mg/kg no further increments were required for 30 minutes. Some dogs became very deeply anaesthetised by the induction dose, and this deep anaesthesia was often associated with severe respiratory depression. Although this was most likely to occur with the higher doses, it did also occur in 2 cases given 1 mg/kg.
There was
no obvious correlation between the breed of dog, its previous condition, and this sensitivity to the drug.
86.
Side effects
Table 3 shows the side effects noted during induction or maintenance of anaesthesia with minaxolone. Respiratory depression was the most serious side effect. In some cases it was clinically severe, the dogs becoming apnoeic or cyanotic. Such cases were immediately given oxygen supplementation and intermittent positive pressure ventilation if necessary. Apnoea was always associated with maximal depth of anaesthesia so that, although commonest after large doses of the drug, it could occur in a few minutes after induction of anaesthesia so that vigilance by the anaesthetist was needed at this time. Measurement o f respiratory parameters confirmed the existence of respiratory depression in some cases in which it was not clinically apparent. The other common side effect was muscular twitching and tremor, which could occur at any stage of the anaesthetic, and was noted after all but the lower (< 0.8 mg/kg) total dose rates of minaxolone. These twitches did not appear to be related to surgical stimulation, and caused remarkably little inconvenience to the surgeons. One case undergoing anterior cruciate repair violently twitched all muscles other than those of its affected leg, yet the surgeon found surgical conditions perfectly adequate.
The twitches did interfere with radiography,
resulting in several blurred films through movement as the click of the machine appeared to trigger a twitch. Twitching could always be reduced by supplementing anaesthesia with halothane. Cardiovascular effects were minimal. One case had atrioventricular heart block when anaesthetised with minaxolone but heart rhythm reverted to normal on treatment with atropine. This dog had a normal heart rate and rhythm on admission, but had not been checked
subsequent to premedication. One dog, whose heart was monitored by
87.
electrocardiogram during induction of anaesthesia, showed ventricular arrhythmias during endotracheal intubation. Arterial pressure changes were minimal; minaxolone caused a slight fall in blood pressure immediately after administration, but this rapidly returned to normal or became slightly elevated.
Maintenance
Where minaxolone was used as the sole anaesthetic agent, further incremental doses of 0.25 - 0.5 mg/kg were given as required to obtain adequate analgesia and relaxation. Table 4 shows the range of total doses required.
Although the total dose was influenced by the
procedure t o be performed, and the time required, there was again considerable individual variation between the doses required in smaller dogs undergoing identical procedures.
For example, 6 German Shepherd
dogs of similar ages undergoing cryosurgery for anal furunculosis required doses of minaxolone ranging from 0.6 to 2.8 mg/kg (mean 1.7 mgl kg) despite the fact that the procedures took similar periods of time. Three dogs underwent anterior cruciate repair by the same surgeon and required doses ranging from 1.5 to 2.8 mg/kg of minaxolone.
In the majority of
cases where minaxolone was used as the sole agent, analgesia appeared to be excellent, and there was little or no response to surgical stimulation. In one exception, the surgeon complained of movement, despite the fact that the dog was deeply anaesthetised.
The movement may have been due
to the twitches already discussed. In cases where gaseous supplementation of anaesthesia was employed, transition to the volatile agent was smooth and trouble free.
Recoverx The times taken for dogs to lift their heads following the administration of rninaxolone as the sole anaesthetic agent are shown
88.
in Table 4. There was considerable individual variation, and some dogs which regained awareness rapidly subsequently returned to sleep and were able to stand no faster than dogs with an initial slow recovery.
The
time taken for dogs to regain their feet was often influenced by the surgery performed, but most dogs could stand within 2 hours, although in 2 cases, complete recovery was recorded as taking "several hours". The comparatively small number o f cases involved, and the wide individual variation in sensitivity to the drug prevents statistical analysis, but there was no obvious correlation between the speed of recovery, the breed and the original physical status, (fat, thin etc.) of the dog. Recovery times from the last dose administered were not greatly prolonged where anaesthesia had been maintained by incremental doses of minaxolone.
Discussion
Minaxolone proved to be an adequate anaesthetic agent for both induction and maintenance of anaesthesia in the dog.
Recovery times
were rather prolonged, and for this reason minaxolone is unlikely to replace the barbiturate drugs in current use as an induction agent prior t o gaseous anaesthesia, except in the dogs where recovery from barbiturate might be expected to be delayed. However, further doses of minaxolone did not unduly lengthen recovery, and it could be useful as a sole intravenous anaesthetic agent. The commonest side effect of twitching was not a serious disadvantage, except for radiography. This side effect was also noted in man (Aveling et a1 1979) where it was said to occur only at the higher dose ranges.
In our study it was not noted in any of the few
dogs which received a total dose of less than 0.8 mg/kg. The most serious problem in veterinary use was that of respiratory depression, and the danger of this side effect was aggravated by the individual sensitivity of the dogs, and by the fact
89.
that apnoea could occur later than might be expected compared with other intravenous agents.
Respiratory depression did not appear to
be a problem in the trials in man, but again the doses used were much
lower than have been utilised in the dog.
Our results would suggest
that minaxolone should not be used in the dog unless the facilities to give oxygen, and intermittent positive pressure ventilation, are available for emergency use. The delay which was occasionally noted between induction and the attainment o f maximal depth o f anaesthesia was not noted in man. However, it was usually the accompanying respiratory depression which brought this delay to the anaesthetists attention, so again it would be less obvious at the lower dose rates used in the medical trials. Minaxolone would seem worthy of further clinical trials in the dog, particularly to investigate whether the use o f lower initial induction doses might reduce the incidence o f unwanted side effects.
Acknowledgements
The authors wlsh to thank Mrs. P. Taylor, Mr. L. Cullen, Dr. P. Stolk and Dr. K. Cullen for allowing us to utilise their anaesthetic records. Glaxovet provided us with generous supplies of minaxolone.
90.
Aveling,W. et al(1979) The Lancet pp 71-73. Dundee,J.W.
(1981). Editorial.
Anaesthesia, 2, 570-580.
McNeil1,H.G.
et a1 (1379) The Lancet pp 73-74.
McNeil1,H.G.
et a1 (1981) Anaesthesia 2, 592-596.
91.
TABLE 1 PROCEDURES CARRIED OUT UNDER MINAXOLONE ANAESTHESIA
No. -
Procedure Examination under anaesthesia Crysosurgery (for anal furunculosis) Orthopaedic Superficial surgery Teeth extraction Perineal rupture
15 9
6 4 1 1
I
Premeditated dogs Minaxolone (mg/kq) 2 - 2.8 1.6 1.1 1.o
Number 3
-
- 33t
- 25 -- 3015 - 10
26t 25+ 60 14 2 13 16.5 7.5
-
21
3 2
20+ 25+ 60 3 2 7 5 5
3
12
1 1 18
1 3
0.9 0.8 0.5 0.4
Length o f action (mins) Mean Range
No premedication
2.1
- 2.4
35
+ represents still deeply anaesthetised at the end of the procedure
92.
TABLE 3 SIOE EFFECTS DURING MINAXOLONE ANAESTHESIA (Total 70 dogs)
Effect
Number
Twitching/tremor Respiratory depression Cardiac arrhythmias Anaesthesia continued to deepen Leg withdrawal on injection Vocalisation (not intubated) Regurgitation
32 25 2 8 3 3 1
TABLE 4
RECOVERY FROM MINAXOLONE 30 dogs. Minaxolone sole agent
Number 0.8 (0.7
- 0.9)
1.22
(1
-
1.7
(1.6
1.5)
- 2)
2.2 (2-3)
Time to lifting head (mins) From last dose
From induction 107 (65 - 150)
(50 - 120)
16
67 (19 - 90)
51 (13 - 90)
7
88 (30 - 125)
50 (25 - 90)
5
129 (38 - 175)
98 (35 - 175)
1
a5