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INITIAL STUDIES IN MAN WITH A NEW MYONEURAL BLOCKING AGENT (ORG.6368)
Br. J. Anaesth. (1974), 46, 658
INITIAL STUDIES IN MAN WITH A NEW MYONEURAL BLOCKING AGENT (ORG.6368) W. L. M. BAIRD SUMMARY
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
Studies of grip strength in man have indicated that a new steroid compound, ORG.6368, has the features of a myoneural blocking agent. In comparison with the action of pancuronium, the onset is more rapid although the duration is similar. Further investigation is indicated to assess its possible clinical use as a myoneural blocking drug suitable for endotracheal intubation, especially in the emergency induction of anaesthesia. Since the introduction of pancuronium bromide as a neuromuscular blocking drug of short duration a new myoneural blocking drug (Baird and Reid, with a rapid onset of action (Sugrue and Duff, 1967), many related compounds have been examined 1973). In the cat, the blockade was similar to that of in the search for a short-acting, non-depolarizing suxamethonium in rate of onset and duration, with agent with a rapid onset of action (Buckett, Hewett the advantage that it displayed the characteristics and Savage, 1973). The most interesting of these of a non-depolarizing agent. compounds retain the basic androstane nucleus with Therefore, a preliminary investigation of the 2/3, 16j8-quaternary amino groups and differ only action of the drug in man has been carried out by in their substituents at the three and seventeen assessing its effect on the grip strength of conscious carbon atom positions. volunteers. A comparison with pancuronium One compound, dacuronium bromide (fig. 1), bromide, studied similarly, was made. which showed considerable promise in animal METHOD experiments, was less potent, relative to pancuronium, in grip strength studies in man (Stovner, Three healthy, non-obese, male volunteers were 1971, personal communication), and this was con- selected, their ages being 28, 36 and 40 years, and firmed in the anaesthetized human by Norman and their body weights 86, 65 and 70 kg respectively. The technique used to measure grip strength was Katz (1971). similar to that described by Lund and Stovner (1970). The subject lay in the supine position on an examination couch, his right hand holding a sphygmomanometer bulb which was splinted with two pieces of plastic and wrapped with adhesive tape. This arrangement prevented small fibrillatory movements of the fingers from producing an uneven baseline on the tracing. The sphygmomanometer bulb was connected by plastic tubing to an arterial 2Br' AcO pressure transducer (Statham 23db) thence to a FIG. 1. Chemical structure of: (a) pancuronium bromide Philips electromanometer (type 2000) and to a (R=OAc), (b) dacuronium bromide (R=OH) 3 and (c) Devices preamplifier unit and M2 recorder. The ORG.6368 (R=H). recorder speed was 0.1 mm/sec. The sphygmoMore recently, another bisammonio steroid com- manometer bulb and tubing were filled with normal pound in the series, 3a-acetoxy-2j3, 16/?-dipiperi- saline and all air bubbles were carefully excluded. dino-5a-androstane dimethobromide (ORG.6368) A battery-operated timing device was set to emit (fig. lc), has been shown in small animals to be a "bleep" every 30 sec, this being the signal for the subject to exert a maximal squeeze on the sphygmoW. L. M. BAIRD, M.B., CH.B., D.A., F.F.A.R.C.S., University Department of Anaesthesia, Royal Infirmary, Glasgow. manometer bulb. The bulb was squeezed quickly,
INITIAL STUDIES WITH A NEW MYONEURAL BLOCKING AGENT
RESULTS
The drug was a neuromuscular blocking agent as can be seen from the results in table I. The onset of action, measured from the time of injection of the drug into a vein on the dorsum of the hand, until the first sign of diminution of the grip strength, was shorter with ORG.6368 than with pancuronium when compared at doses producing similar degrees of reduction of grip strength (fig. 2). From the data in table I, the time after injection for the maximum percentage reduction in grip strength to be evident averaged 0.6 min (SD 0.21) for
ORG.6368, and 1.4 min (SD 0.30) for pancuronium. These times differ significantly (f=7.11; P<0.01). Although the corresponding maximum reductions in grip strength varied over a wide range, the mean values for the two drugs were virtually identical (57.8% for ORG.6368, 57.1% for pancuronium). However, there was no evidence that recovery to 90% of control, from similar reductions of grip strength, was shorter with ORG.6368. Figure 3 shows the dose response curves for ORG.6368 and pancuronium; the percentage reductions in grip strength were plotted against the dose on a logarithm scale and the regression lines were calculated by the method of least squares. The lines are seen to be approximately parallel, and the responses indicate that the drug has a potency about one-sixth that of pancuronium. No evidence of histamine release such as weal formation was seen near the injection site, and no other untoward effects were noted during or after the investigation. Since fatigue of the forearm muscles might have influenced the results, maximal bulb-squeezing was undertaken by each of the subjects, at 30-sec intervals, for a period of 30 min in the absence of any myoneural blocking agent. In one subject there was no reduction on repeated testing, while the changes in the other two were by 2.5% and 8.0% respectively; changes which are of little significance.
TABLE I. Table shrjiing dose and effect of ORG.6368 and pancuronium on the grip strength of three conscious volunteers.
Subject T.S. (65 kg)
Drug ORG.6368 Pancuronium
Dose (/*g/kg) 90 105 120 15
17.5 20 22
N.D. (86 kg)
ORG.6368
Pancuronium
75 105 130 145
17.5 20
D.S.S. (70 kg)
ORG.6368 Pancuronium
80 105 120 13 15
17.5
% Reduction in grip strength
Onset (min)
43 65 83 27 49 71 91
1 0.5 0.5
13 37 68 87 37 65
0.5 0.5 0.5 0.5
24 70 88 39 55 80
1 0.5 0.5 1.5 1.5
1.5-2 1.5 1 1
1.5-2 1.5-2
1-1.5
Time from injection to maximum reduction (min)
Time to 90% recovery (min)
3 2.5 2.5 4.5 3.5 3.5 4.5
3.5 5.5 10 4 6 8.5 14
3 3 2.5 2.5 3.5 4
0.5 4.5 8 16 3.5 7
4^.5 3 2 4 4 5.5
1.5-2 6 13 3.5 5.5 9.5
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
and the tension was released immediately following maximal effort. After some practice, the height of deflection on the recorder was reproducible for each subject, the study being carried out over several weeks. An indwelling needle (Abbott "Butterfly", 23 gauge) was inserted into a vein on the dorsum of the left hand. After obtaining a series of control responses, the drug was injected and washed through with a constant volume of 4 ml of sterile distilled water. The time taken for injection was maintained constant at 11 sec, and for purposes of measurement the dose was recorded as being given at the time just preceding wash-in. Because of possible emotional effects on pulse rate and arterial pressure, no attempt was made to record circulatory changes on injection of the drug.
659
660
i
BRITISH JOURNAL OF ANAESTHESIA
•A
II 1
1 I t1
i •B
FIG. 2. Comparison of the effects on grip strength of ORG.6368 and pancuronium on the same subject (N.D.). Upper trace shows 68% reduction on injection of ORG.6368 130 />g/kg body weight (A) and lower trace shows 65% reduction on injection of pancuronium 20 /"g/kg (B).
Pancuronium 1-0.93)
% REDUCTION IN GRIP STRENGTH
10
IS
20
FIG. 3. Human grip strength. Dose response curves for pancuronium and ORG.6368.
ACKNOWLEDGEMENTS
DISCUSSION
I wish to record my gratitude to Mr A. G. Gray and his staff for their technical assistance and also to the volunteers for their co-operation. I am indebted to Dr D. S. Savage and his colleagues at Organon Scientific Development Group, Newhouse, Scotland, for their help in this study and for the supply of the drug, ORG.6368.
The numerous disadvantages and side effects of suxamethonium are well recognized but the advantages of producing total myoneural blockade of rapid onset and of facilitating rapid endotracheal intubation, result in its being the drug of choice in the REFERENCES emergency induction of anaesthesia. While the Baird, W. L. M., and Reid, A. M. (1967). The neuromuscular blocking properties of a new steroid comliterature alludes frequently to the need for a shortpound, pancuronium bromide: a pilot study in man. acting, non-depolarizing neuromuscular blocking Br. J. Anaesth., 39, 775.
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
!l!!! II:
mill
i
agent, it would be a considerable advance to obtain a non-depolarizing myoneural blocker whose action is rapid in onset and of short duration. Further, although the action of suxamethonium begins after about one circulation time, intubation cannot be performed until fasciculations of the head, neck and trunk musculature have ceased. This period of time, from the injection of suxamethonium into a vein on the dorsum of the hand until fasciculations cease, is usually not less than 45 sec. Therefore, a nondepolarizing myoneural blocker which will produce satisfactory intubating conditions by this time, or less, would be desirable. It is known that the rate of onset of action of the existing non-depolarizing neuromuscular blockers depends on the concentration gradient established between the blood and the receptor sites at the myoneural junction (Feldman, 1973), thus very large "swamp" doses of these drugs will permit early intubation. It would be feasible to use such large doses of drugs like gallamine, alcuronium or pancuronium, except that a very deep and prolonged blockade would ensue, while tubocurarine could produce profound hypotension. Recently, a new non-depolarizing drug AH.8165, has been described. It is considered to have a rapid onset of action, and a duration similar to that of pancuronium (Simpson et al., 1972). However, there is the possibility of prolonged blockade with this compound when used in doses which ensure easy intubation (Coleman et al., 1973). The present study indicates that ORG.6368 has a potency approximately one-sixth that of pancuronium in man. This is similar to the findings in cats (Sugrue and Duff, 1973). Also, the drug has a more rapid onset of action than that of pancuronium. However, the short duration of action observed in small animals was not confirmed in these studies of grip strength, where the duration appeared to be about the same as that of pancuronium.
INITIAL STUDIES WITH A NEW MYONEURAL BLOCKING AGENT Buckett, W. R., Hewett, C. L., and Savage, D. S. (1973). Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments. J. med. Chetn. (in press). Coleman, A. J., O'Brien, A., Downing, J. W., Jeal, D. E., Moyes, D. G., and Leary, W. P. (1973). AH.8165: a new non-depolarizing muscle relaxant. Anaesthesia, 28, 262. Feldman, S. A. (1973). Muscle Relaxants, p. 172. London: Saunders. Lund, I., and Stovner, J. (1970). Dose-response curves for tubocurarine, alcuronium and pancuronium. Ada Anaesthesiol. Scand., [Suppl.] 37, 238.
661
Norman, J., and Katz, R. L. (1971). Some effects of the steroidal muscle relaxant, dacuronium bromide, in anaesthetized patients. Br. J. Anaesth., 43, 313. Simpson, B. R., Savage, T. M., Foley, E. I., Ross, L. A., Strunin, L., Walton, B., Maxwell, M. P., and Harris, D. M. (1972). An azobis-arylimidazo-pyridinium derivative: a rapidly acting non-depolarizing muscle relaxant. Lancet, 1, 516. Sugrue, M. F., and Duff, N. (1973). ORG.6368: a competitive steroidal muscle relaxant with a rapid onset and a short duration of action. Naunyn-Schmiedeberg's Archives of Pharmacology, Supplement to Vol. 279, p. 30.
CORRESPONDENCE Sir,—I have read the letter of Dr Selwyn Crawford (fir. J. Anaesih. (1974), 46, 82) concerning the inadvertent continuous spinal in an obstetric patient and was impressed by the logical questions raised. I should like to suggest a possible explanation for this event. It was reported that the specific gravity of 0.25% bupivacaine without adrenaline is 1.003 at 20 °C and 0.998 at 37°C, suggesting that 0.25% bupivacaine is hypobaric for practical purposes (as the specific gravity would be less than 1.003 with small rise in the temperature of the injected bupivacaine). When 7 ml of 0.25% bupivacaine was injected intrathecally while the patient was reclining (she must have been comfortably resting her head on few pillows) and "slightly propped up", the spinal block extended from T l to the perineum. On this occasion probably the patient was not turned to either side soon enough for a bilateral block to be established. The spinal block would not have regressed to T i l until 4 hours for the patient to complain of the uterine pain. It is interning to recall that when inadvertent massive spinal occurs while attempting extradural, the resulting apnoea requires ventilation for the duration of 2.5-4 hours. This time varies in direct proportion to the volume of the injected local anaesthetic, its nature and concentration. The subsequent intrathecal injections of smaller dose of bupivacaine would provide only a limited spinal block and comprising a hypobaric solution, would result in unilateral block on the upper side, in this case on the right as the patient preferred lying on her left. Turning the patient from side to side would not appreciably alter the predominance of unilateral block if the posture changed after fixation of the drug. It is evident that 2-4 ml of 0.25% bupivacaine injected intrathecally produced block up to T i l and slight regression of the block allowed return of normal function of T i l as a sensory pathway for the uterus. This required further injections at intervals of 70-75 min to relieve the uterine pain of the first-stage labour. However, the patient remained comfortable for many hours after the forceps delivery as (probably) the spinal block regression was not complete for return of sensation in the saddle area, i.e. saddle block duration being 4 hours following her last "top-up". One would naturally question such a long duration of saddle block with bupivacaine, a drug recognized to provide analgesia for only 2 hours. However, the patient had injections of 4 ml of the drug at 3.10 and 4.35 hours. In my experience it is possible to prolong the duration of spinal block in the saddle area including groin, from 2 to 4 hours in the case of heavy cinchocaine by a saturation technique. What happens is as follows:
Heavy cinchocaine (0.5% cinchocaine with 6% glucose) is injected intrathecally with the patient sitting up. After 10 minutes the patient is returned to a reclining position with two pillows under the head. Dose injected Duration of analgesia 1 ml 2 hours 3 ml 4-5 hours The saturation technique has been used successfully for extensive surgical procedures such as bilateral block dissection of inguinal nodes and radical amputation of carcinoma of the penis. Sedation of the patients was very light. I suggest that the pain across the shoulder and down each arm was of cardiac origin, triggered off by severe arterial hypotension. The relative cardiac ischaemia took 4 days to settle down before the symptoms disappeared. I know little of the interscapular pain which occurs in association widi an epidural drip as I have no experience with extradural infusion of Hartmann's solution. However, I note the patient had excruciating pain across the back of the shoulders and down each arm coinciding with the hypotension which followed the initial intrathecal bupivacaine, the symptoms persisting subsequently with varying intensity during labour and disappearing on the 5th day. This pain could not be attributed to the extradural drip as the infusion of Hartmann's solution had to be discontinued after 9 hours following dislodgement of the catheter.
N. H. DOCTOR
Hackney, London Sir,—I am grateful to Dr Doctor for his comments, with several of which I am in sympathy. However, I am doubtful that what used to be termed "hypobaricity" influences the direction and spread of the injection solution to any great extent (Macintosh and Lee, 1973). I was surprised that the effect of the bupivacaine persisted for such a short time (after all, it is said to persist for 7-8 hours when applied to the brachial plexus), but your correspondent apparently takes the opposite view. Perhaps others who have used the drug for spinal analgesia can provide some further information. I am very doubtful that the pain across the shoulders and down the arms was anginal. Angina is surely rarely provoked by a fall of systolic pressure from 130 mm Hg to 80 mm Hg, and furthermore the pain (across the shoulders) persisted intermittently for several days, during which time the patient was fully mobile and normotensive. J. SELWYN CRAWFORD
Birmingham REFERENCE
Macintosh, R. R., and Lee, J. A. (1973). Lumbar Puncture and Spinal Analgesia (3rd edn) p. 133Edinburgh: Churchill Livingstone.
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
THE STRANGE CASE OF THE (INADVERTENT) CONTINUOUS SPINAL
INITIAL STUDIES IN MAN WITH A NEW MYONEURAL BLOCKING AGENT (ORG.6368) W. L. M. BAIRD SUMMARY
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
Studies of grip strength in man have indicated that a new steroid compound, ORG.6368, has the features of a myoneural blocking agent. In comparison with the action of pancuronium, the onset is more rapid although the duration is similar. Further investigation is indicated to assess its possible clinical use as a myoneural blocking drug suitable for endotracheal intubation, especially in the emergency induction of anaesthesia. Since the introduction of pancuronium bromide as a neuromuscular blocking drug of short duration a new myoneural blocking drug (Baird and Reid, with a rapid onset of action (Sugrue and Duff, 1967), many related compounds have been examined 1973). In the cat, the blockade was similar to that of in the search for a short-acting, non-depolarizing suxamethonium in rate of onset and duration, with agent with a rapid onset of action (Buckett, Hewett the advantage that it displayed the characteristics and Savage, 1973). The most interesting of these of a non-depolarizing agent. compounds retain the basic androstane nucleus with Therefore, a preliminary investigation of the 2/3, 16j8-quaternary amino groups and differ only action of the drug in man has been carried out by in their substituents at the three and seventeen assessing its effect on the grip strength of conscious carbon atom positions. volunteers. A comparison with pancuronium One compound, dacuronium bromide (fig. 1), bromide, studied similarly, was made. which showed considerable promise in animal METHOD experiments, was less potent, relative to pancuronium, in grip strength studies in man (Stovner, Three healthy, non-obese, male volunteers were 1971, personal communication), and this was con- selected, their ages being 28, 36 and 40 years, and firmed in the anaesthetized human by Norman and their body weights 86, 65 and 70 kg respectively. The technique used to measure grip strength was Katz (1971). similar to that described by Lund and Stovner (1970). The subject lay in the supine position on an examination couch, his right hand holding a sphygmomanometer bulb which was splinted with two pieces of plastic and wrapped with adhesive tape. This arrangement prevented small fibrillatory movements of the fingers from producing an uneven baseline on the tracing. The sphygmomanometer bulb was connected by plastic tubing to an arterial 2Br' AcO pressure transducer (Statham 23db) thence to a FIG. 1. Chemical structure of: (a) pancuronium bromide Philips electromanometer (type 2000) and to a (R=OAc), (b) dacuronium bromide (R=OH) 3 and (c) Devices preamplifier unit and M2 recorder. The ORG.6368 (R=H). recorder speed was 0.1 mm/sec. The sphygmoMore recently, another bisammonio steroid com- manometer bulb and tubing were filled with normal pound in the series, 3a-acetoxy-2j3, 16/?-dipiperi- saline and all air bubbles were carefully excluded. dino-5a-androstane dimethobromide (ORG.6368) A battery-operated timing device was set to emit (fig. lc), has been shown in small animals to be a "bleep" every 30 sec, this being the signal for the subject to exert a maximal squeeze on the sphygmoW. L. M. BAIRD, M.B., CH.B., D.A., F.F.A.R.C.S., University Department of Anaesthesia, Royal Infirmary, Glasgow. manometer bulb. The bulb was squeezed quickly,
INITIAL STUDIES WITH A NEW MYONEURAL BLOCKING AGENT
RESULTS
The drug was a neuromuscular blocking agent as can be seen from the results in table I. The onset of action, measured from the time of injection of the drug into a vein on the dorsum of the hand, until the first sign of diminution of the grip strength, was shorter with ORG.6368 than with pancuronium when compared at doses producing similar degrees of reduction of grip strength (fig. 2). From the data in table I, the time after injection for the maximum percentage reduction in grip strength to be evident averaged 0.6 min (SD 0.21) for
ORG.6368, and 1.4 min (SD 0.30) for pancuronium. These times differ significantly (f=7.11; P<0.01). Although the corresponding maximum reductions in grip strength varied over a wide range, the mean values for the two drugs were virtually identical (57.8% for ORG.6368, 57.1% for pancuronium). However, there was no evidence that recovery to 90% of control, from similar reductions of grip strength, was shorter with ORG.6368. Figure 3 shows the dose response curves for ORG.6368 and pancuronium; the percentage reductions in grip strength were plotted against the dose on a logarithm scale and the regression lines were calculated by the method of least squares. The lines are seen to be approximately parallel, and the responses indicate that the drug has a potency about one-sixth that of pancuronium. No evidence of histamine release such as weal formation was seen near the injection site, and no other untoward effects were noted during or after the investigation. Since fatigue of the forearm muscles might have influenced the results, maximal bulb-squeezing was undertaken by each of the subjects, at 30-sec intervals, for a period of 30 min in the absence of any myoneural blocking agent. In one subject there was no reduction on repeated testing, while the changes in the other two were by 2.5% and 8.0% respectively; changes which are of little significance.
TABLE I. Table shrjiing dose and effect of ORG.6368 and pancuronium on the grip strength of three conscious volunteers.
Subject T.S. (65 kg)
Drug ORG.6368 Pancuronium
Dose (/*g/kg) 90 105 120 15
17.5 20 22
N.D. (86 kg)
ORG.6368
Pancuronium
75 105 130 145
17.5 20
D.S.S. (70 kg)
ORG.6368 Pancuronium
80 105 120 13 15
17.5
% Reduction in grip strength
Onset (min)
43 65 83 27 49 71 91
1 0.5 0.5
13 37 68 87 37 65
0.5 0.5 0.5 0.5
24 70 88 39 55 80
1 0.5 0.5 1.5 1.5
1.5-2 1.5 1 1
1.5-2 1.5-2
1-1.5
Time from injection to maximum reduction (min)
Time to 90% recovery (min)
3 2.5 2.5 4.5 3.5 3.5 4.5
3.5 5.5 10 4 6 8.5 14
3 3 2.5 2.5 3.5 4
0.5 4.5 8 16 3.5 7
4^.5 3 2 4 4 5.5
1.5-2 6 13 3.5 5.5 9.5
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
and the tension was released immediately following maximal effort. After some practice, the height of deflection on the recorder was reproducible for each subject, the study being carried out over several weeks. An indwelling needle (Abbott "Butterfly", 23 gauge) was inserted into a vein on the dorsum of the left hand. After obtaining a series of control responses, the drug was injected and washed through with a constant volume of 4 ml of sterile distilled water. The time taken for injection was maintained constant at 11 sec, and for purposes of measurement the dose was recorded as being given at the time just preceding wash-in. Because of possible emotional effects on pulse rate and arterial pressure, no attempt was made to record circulatory changes on injection of the drug.
659
660
i
BRITISH JOURNAL OF ANAESTHESIA
•A
II 1
1 I t1
i •B
FIG. 2. Comparison of the effects on grip strength of ORG.6368 and pancuronium on the same subject (N.D.). Upper trace shows 68% reduction on injection of ORG.6368 130 />g/kg body weight (A) and lower trace shows 65% reduction on injection of pancuronium 20 /"g/kg (B).
Pancuronium 1-0.93)
% REDUCTION IN GRIP STRENGTH
10
IS
20
FIG. 3. Human grip strength. Dose response curves for pancuronium and ORG.6368.
ACKNOWLEDGEMENTS
DISCUSSION
I wish to record my gratitude to Mr A. G. Gray and his staff for their technical assistance and also to the volunteers for their co-operation. I am indebted to Dr D. S. Savage and his colleagues at Organon Scientific Development Group, Newhouse, Scotland, for their help in this study and for the supply of the drug, ORG.6368.
The numerous disadvantages and side effects of suxamethonium are well recognized but the advantages of producing total myoneural blockade of rapid onset and of facilitating rapid endotracheal intubation, result in its being the drug of choice in the REFERENCES emergency induction of anaesthesia. While the Baird, W. L. M., and Reid, A. M. (1967). The neuromuscular blocking properties of a new steroid comliterature alludes frequently to the need for a shortpound, pancuronium bromide: a pilot study in man. acting, non-depolarizing neuromuscular blocking Br. J. Anaesth., 39, 775.
Downloaded from http://bja.oxfordjournals.org/ at University of Chicago on July 24, 2015
!l!!! II:
mill
i
agent, it would be a considerable advance to obtain a non-depolarizing myoneural blocker whose action is rapid in onset and of short duration. Further, although the action of suxamethonium begins after about one circulation time, intubation cannot be performed until fasciculations of the head, neck and trunk musculature have ceased. This period of time, from the injection of suxamethonium into a vein on the dorsum of the hand until fasciculations cease, is usually not less than 45 sec. Therefore, a nondepolarizing myoneural blocker which will produce satisfactory intubating conditions by this time, or less, would be desirable. It is known that the rate of onset of action of the existing non-depolarizing neuromuscular blockers depends on the concentration gradient established between the blood and the receptor sites at the myoneural junction (Feldman, 1973), thus very large "swamp" doses of these drugs will permit early intubation. It would be feasible to use such large doses of drugs like gallamine, alcuronium or pancuronium, except that a very deep and prolonged blockade would ensue, while tubocurarine could produce profound hypotension. Recently, a new non-depolarizing drug AH.8165, has been described. It is considered to have a rapid onset of action, and a duration similar to that of pancuronium (Simpson et al., 1972). However, there is the possibility of prolonged blockade with this compound when used in doses which ensure easy intubation (Coleman et al., 1973). The present study indicates that ORG.6368 has a potency approximately one-sixth that of pancuronium in man. This is similar to the findings in cats (Sugrue and Duff, 1973). Also, the drug has a more rapid onset of action than that of pancuronium. However, the short duration of action observed in small animals was not confirmed in these studies of grip strength, where the duration appeared to be about the same as that of pancuronium.
INITIAL STUDIES WITH A NEW MYONEURAL BLOCKING AGENT Buckett, W. R., Hewett, C. L., and Savage, D. S. (1973). Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments. J. med. Chetn. (in press). Coleman, A. J., O'Brien, A., Downing, J. W., Jeal, D. E., Moyes, D. G., and Leary, W. P. (1973). AH.8165: a new non-depolarizing muscle relaxant. Anaesthesia, 28, 262. Feldman, S. A. (1973). Muscle Relaxants, p. 172. London: Saunders. Lund, I., and Stovner, J. (1970). Dose-response curves for tubocurarine, alcuronium and pancuronium. Ada Anaesthesiol. Scand., [Suppl.] 37, 238.
661
Norman, J., and Katz, R. L. (1971). Some effects of the steroidal muscle relaxant, dacuronium bromide, in anaesthetized patients. Br. J. Anaesth., 43, 313. Simpson, B. R., Savage, T. M., Foley, E. I., Ross, L. A., Strunin, L., Walton, B., Maxwell, M. P., and Harris, D. M. (1972). An azobis-arylimidazo-pyridinium derivative: a rapidly acting non-depolarizing muscle relaxant. Lancet, 1, 516. Sugrue, M. F., and Duff, N. (1973). ORG.6368: a competitive steroidal muscle relaxant with a rapid onset and a short duration of action. Naunyn-Schmiedeberg's Archives of Pharmacology, Supplement to Vol. 279, p. 30.
CORRESPONDENCE Sir,—I have read the letter of Dr Selwyn Crawford (fir. J. Anaesih. (1974), 46, 82) concerning the inadvertent continuous spinal in an obstetric patient and was impressed by the logical questions raised. I should like to suggest a possible explanation for this event. It was reported that the specific gravity of 0.25% bupivacaine without adrenaline is 1.003 at 20 °C and 0.998 at 37°C, suggesting that 0.25% bupivacaine is hypobaric for practical purposes (as the specific gravity would be less than 1.003 with small rise in the temperature of the injected bupivacaine). When 7 ml of 0.25% bupivacaine was injected intrathecally while the patient was reclining (she must have been comfortably resting her head on few pillows) and "slightly propped up", the spinal block extended from T l to the perineum. On this occasion probably the patient was not turned to either side soon enough for a bilateral block to be established. The spinal block would not have regressed to T i l until 4 hours for the patient to complain of the uterine pain. It is interning to recall that when inadvertent massive spinal occurs while attempting extradural, the resulting apnoea requires ventilation for the duration of 2.5-4 hours. This time varies in direct proportion to the volume of the injected local anaesthetic, its nature and concentration. The subsequent intrathecal injections of smaller dose of bupivacaine would provide only a limited spinal block and comprising a hypobaric solution, would result in unilateral block on the upper side, in this case on the right as the patient preferred lying on her left. Turning the patient from side to side would not appreciably alter the predominance of unilateral block if the posture changed after fixation of the drug. It is evident that 2-4 ml of 0.25% bupivacaine injected intrathecally produced block up to T i l and slight regression of the block allowed return of normal function of T i l as a sensory pathway for the uterus. This required further injections at intervals of 70-75 min to relieve the uterine pain of the first-stage labour. However, the patient remained comfortable for many hours after the forceps delivery as (probably) the spinal block regression was not complete for return of sensation in the saddle area, i.e. saddle block duration being 4 hours following her last "top-up". One would naturally question such a long duration of saddle block with bupivacaine, a drug recognized to provide analgesia for only 2 hours. However, the patient had injections of 4 ml of the drug at 3.10 and 4.35 hours. In my experience it is possible to prolong the duration of spinal block in the saddle area including groin, from 2 to 4 hours in the case of heavy cinchocaine by a saturation technique. What happens is as follows:
Heavy cinchocaine (0.5% cinchocaine with 6% glucose) is injected intrathecally with the patient sitting up. After 10 minutes the patient is returned to a reclining position with two pillows under the head. Dose injected Duration of analgesia 1 ml 2 hours 3 ml 4-5 hours The saturation technique has been used successfully for extensive surgical procedures such as bilateral block dissection of inguinal nodes and radical amputation of carcinoma of the penis. Sedation of the patients was very light. I suggest that the pain across the shoulder and down each arm was of cardiac origin, triggered off by severe arterial hypotension. The relative cardiac ischaemia took 4 days to settle down before the symptoms disappeared. I know little of the interscapular pain which occurs in association widi an epidural drip as I have no experience with extradural infusion of Hartmann's solution. However, I note the patient had excruciating pain across the back of the shoulders and down each arm coinciding with the hypotension which followed the initial intrathecal bupivacaine, the symptoms persisting subsequently with varying intensity during labour and disappearing on the 5th day. This pain could not be attributed to the extradural drip as the infusion of Hartmann's solution had to be discontinued after 9 hours following dislodgement of the catheter.
N. H. DOCTOR
Hackney, London Sir,—I am grateful to Dr Doctor for his comments, with several of which I am in sympathy. However, I am doubtful that what used to be termed "hypobaricity" influences the direction and spread of the injection solution to any great extent (Macintosh and Lee, 1973). I was surprised that the effect of the bupivacaine persisted for such a short time (after all, it is said to persist for 7-8 hours when applied to the brachial plexus), but your correspondent apparently takes the opposite view. Perhaps others who have used the drug for spinal analgesia can provide some further information. I am very doubtful that the pain across the shoulders and down the arms was anginal. Angina is surely rarely provoked by a fall of systolic pressure from 130 mm Hg to 80 mm Hg, and furthermore the pain (across the shoulders) persisted intermittently for several days, during which time the patient was fully mobile and normotensive. J. SELWYN CRAWFORD
Birmingham REFERENCE
Macintosh, R. R., and Lee, J. A. (1973). Lumbar Puncture and Spinal Analgesia (3rd edn) p. 133Edinburgh: Churchill Livingstone.
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THE STRANGE CASE OF THE (INADVERTENT) CONTINUOUS SPINAL