Acta anaesh scand. 1977, 2 1, 445448
Spinal Anesthesia with Bupivacaine and Tetracaine in Sheep H. JACK ADAMS and DAND.
DOHERTY, JR.
Research Department, Astra Pharmaceutical Products, Inc., Framingham, Massachusetts, USA
Spinal anesthesia was performed in sheep in order to compare hyperbaric solutions of 0.375 and 0.75% bupivacaine and tetracaine. There was no significant difference between the two compounds in the duration of sensory analgesia in the anal regions nor, at 0.75%, in the time required for complete regression of the block. However, at 0.375% the duration of sensory analgesia and motor block in the hind limbs and the time required for complete regression were shorter with bupivacaine. In addition to exhibiting a higher incidence and a longer duration of motor block in the hind limbs, the sheep that received tetracaine were unable to stand on the hind limbs even after complete regression of block had occurred. Although further studies are required to establish the cause of this phenomenon, we suggest this may reflect a block of proprioceptor fibers.
Received I1 January, acceptedfor publication 16 February 1977
Administration of solutions into the sub- brought forward and held with ties so that the hip was arachnoid space is simpler in sheep (LE- flexed and the knee and tarsal joints were extended: this flexes the spine in the lumbosacral region and BEAUX 1975) than in other experimental enlarges the lumbosacral interspace, thereby facilitatanimals such as the dog (REDDERSON et'al. ing placement of the needle in the subarachnoid space. 1974). Spinal anesthesia can be performed A 4- to 6-inch-wide area was clipped from the lower in the restrained but unanesthetized animal, sacral to the upper lumbar region. The lumbosacral and onset and duration of sensory analgesia area was scrubbed with pHisoHex@,rinsed, and then wiped with 70% isopropyl alcohol. The vertebral and motor block can be assessed with a high spines were identified by palpation and marked on the degree of precision. The studies reported skin with indelible ink. here were done to compare onset, duration Spinal block was performed by means of the midline and quality of anesthesia produced by approach for tapping the subarachnoid space. A subarachnoid administration of bupivacaine 22-gauge, 3-inch, clear hub, disposable Yale spinal needle (B-D No. 5171) was inserted, and location of (Marcaine") and tetracaine. the tip in the subarachnoid space was verified by a
MATERIAL AND METHODS The methods for giving spinal (subarachnoid) injections to sheep and for monitoring the blocks have been described by LEBEAUX(1975). Non-pregnant ewes, weighing 40 to 60 kg, were used for these studies. There were five animals per treatment group. No animal was used more than once. Animals were placed in ihe specially-designed stocks, and the hind limbs were
spontaneous flow of CSF when the stylet was withdrawn. An injection was not given unless this flow of CSF occurred. A 2.5 ml sterile disposable glass syringe containing the local anesthetic solution was attached to the spinal needle, and the plunger was withdrawn slightly. A free flow of CSF into the syringe showed that the tip of the needle was still in the subarachnoid space. The solution was then injected over an interval of about 5 s. At the completion of the injection the plunger was again withdrawn slightly to establish whether or not the tip of the needle was still in place. The small amount ( i O . 2 ml) of fluid was
446
H. JACK ADAMS AND D. D. DOHERTY
promptly reinjected, and the needle was withdrawn. As soon as the injection was completed, the hind limbs were untied and allowed to hang free, and testing for the block was started. The presence of sensory analgesia in the anal region and in the hind limbs was assessed by pinching the anus and the corona of each hind limb with an Allis forceps. If the animal did not respond by, for example, a jerking movement of the body, turning of the head, or withdrawal of the limb, we assumed sensory block was present. Since the sheep responds to pinching of the skin with a discrete twitching of the stimulated area, it is possible to follow the dermatomal spread and regression of block on the dorsum. Motor block in the hind limbs was assessed by pinching an unblocked area such as the neck or one of the front limbs and noting whether or not the animal flexed the tarsal joint. Absence of flexion was regarded as motor block. Since the spread and intensity of spinal block may not be the same for both sides, the left and right hind limbs and the areas just to the left and right of the vertebral column were tested, and the results obtained for the two sides recorded separately. In general, animals were checked a t 5-minute intervals for the first half hour and then at 15-minute intervals after that, until complete recovery of the several variables had occurred: i.e., motor activity in the hind limbs and sensory analgesia in the hind limbs, the anal region, and the cutaneous dermatomes of the dorsum. The duration of the block was taken as the interval between onset (loss of sensory or motor function) and recovery of the function. When recovery had occurred in these several variables, the animal was removed from the stock and placed in one of the pens. The observen noted whether or not the animal was able to support itself on its hind limbs and, if so, whether or not it was ataxic. Animals that were ataxic or unable to use their hind limbs sufficiently to enable them to stand were checked later that day and, if necessary, again the following morning to ascertain whether or not motor function in the hind limbs had returned to normal. Freshly prepared sterile solutions of bupivacaine and tetracaine, adjusted to about p H 7 and made hyperbaric by the presence of 5% glucose, were available in multiple dose vials. The vials were coded so that the personnel giving the injections and observing the animals were unaware of the contents until the studies were completed and the code was revealed. Personnel were instructed to note whether or not DreciDitation. manifested as cloudiness or “milkiness”, occurred when CSF was drawn into the syringe containing local anesthetic solution. Data obtained for the right and left sides were combined for calculation of mean durations of block in the hind limbs and the mean times required for complete regression of block. Frequency of block, expressed as per cent, was calculated from the ratio
. .
of the number of successful blocks over the total number of possible blocks, the right and left sides being treated independently. Statistical significance was tested by means of a n analysis of variance.
RESULTS The data are summarized in Table 1. Complete onset of block in all cases occurred within 5 min after the injection. Although mean duration of sensory analgesia in the anal region was shorter with bupivacaine, there was no statistically significant difference between bupivacaine and tetracaine at either concentration. Failure to show a difference between the two concentrations of drug may be due, for example, to the small number of animals in each group, the anatomy of the sheep, its ventral recumbent position during and after the spinal injection, the use of hyperbaric solutions, or some combination of these factors. The mean time required for complete regression was shorter for 0.75% bupivacaine than Sor 0.75% tetracaine, but, again, the difference was not statistically significant. This agrees with the results of a clinical study reported by PFLUGet al. (1976), who found that in their patients the time required for complete regression was the same for bupivacaine and tetracaine. However, we found in our study that, at 0.375%, the time for complete regression was significantly shorter with bupivacaine. Furthermore, the duration of sensory analgesia in the hind limbs was, at both concentrations, significantly shorter with bupivacaine. This confirms our previous observa;ions (unpublished) that in sheep the duration of spinal anesthesia with bupivacaine is shorter than with mg doses Of tetracaine. As in the clinical study (PFLUGet a]. 1976), bupivacaine produced less motor block than tetracaine, and the mean duration Of motor with bupivacaine was about one-half the duration with tetracaine.
SPINAL BUPIVACAINE AND TETRACAINE IN SHEEP
447
Table 1 Frequency and duration of block (see text). Meansfs.e. mean are given for durations and are in minutes. Frequency of block shown in parentheses. Highest segmental level of block most frequently observed is shown in brackets. Drug concentrations are as HCl salt. Treatment
Variable Sensory analgesia, anal region Sensory analgesia, hind limbs Motor blockade, hind limbs Complete regression
1
Bupivacaine 0.375% 2 1 ~ ( 100%)
7
P N.S.
I
Tetracaine 0.375%
262 f 62 (100%)
+
I
Bupivacaine 0.75%
185f 17
I
P
1
Tetracaine 0.75%
N,S.
243+31 (100%)
( 100%)
112+ 15 (90%)
< 0.001
255 27 (80%)
198f25 (100%)
< 0.01 > 0.001
313+29 (100%)
82+ 18 (50%)
< 0.05 > 0.01
179f53 (50%)
66f8 (70%)
< 0.05 >o.c1
166+26 (100%)
0.001
DISCUSSION The data show that, depending upon the variable examined, the investigators could conclude that duration of spinal anesthesia with bupivacaine was either equal to or shorter than that of tetracaine. Clearly, the duration of sensory analgesia and of motor block in the hind limbs was shorter with bupivacaine. Even more striking than this difference in duration of motor block was the observation that when the animals were removed from the stocks after complete recovery from the spinal block, all those that had received tetracaine were unable to stand on their hind limbs, whereas only one of the sheep that had received the higher dose of bupivacaine was so affected. Unable to use their hind limbs to support their hind quarters, these animals remained in a recumbent position until sufficient recovery occurred to permit them to stand. This required a minimum of 7 to 8 h after administration of the local anesthetic agent, but all these animals exhibited completely normal stance and gait the following morning, i.e., 24 h after beinginjected. Theanimals
+
{W
241+ 1 1 Sl}
had, at the time they were removed from the stocks, recovered motor function in the hind limbs and were able to flex and extend both the hip and tarsal joints. In fact, two of the animals that received 0.375% tetracaine never exhibited block of flexion of the tarsal joint, the end-point we defined for ascertaining the presence or absence of motor block. Nevertheless, these animals could not stand on their hind limbs when removed from the stocks. This phenomenon cannot, therefore, be explained simply as a block of the motor fibers innervating the hind limbs, and it may be, for example, that the block of proprioceptive pathways is in part responsible for it. Whatever the explanation, the fact remains that tetracaine produced a higher incidence of motor block and motor block of longer duration than did bupivacaine at equal mg doses.
REFERENCES REDDERSON, C. L., UY,D. & ANTON,A. H. (1974) New techniques for spinal anesthesia in the dog. Anesthesiology 40, 187.
448
H . JACK ADAMS AND D. D. DOHERTY
LEBEAUX, M. I. (1975) Sheep: a model for testing spinal and epidural anesthetic agents. Lab. Animal Sci. 25, 629. PPLUG,A. E., AASIIEIM, G. M. & BECK,H. A. (1976) Spinal anesthesia: bupivacaine versus tetracaine. Anesth. Analg. Curr. Res. 55, 489.
Address:
H. Jack Adams, Ph,D. Research Department Astra Pharmaceutical Products, Inc. Framingham Massachusetts
U.S.A.
Spinal Anesthesia with Bupivacaine and Tetracaine in Sheep H. JACK ADAMS and DAND.
DOHERTY, JR.
Research Department, Astra Pharmaceutical Products, Inc., Framingham, Massachusetts, USA
Spinal anesthesia was performed in sheep in order to compare hyperbaric solutions of 0.375 and 0.75% bupivacaine and tetracaine. There was no significant difference between the two compounds in the duration of sensory analgesia in the anal regions nor, at 0.75%, in the time required for complete regression of the block. However, at 0.375% the duration of sensory analgesia and motor block in the hind limbs and the time required for complete regression were shorter with bupivacaine. In addition to exhibiting a higher incidence and a longer duration of motor block in the hind limbs, the sheep that received tetracaine were unable to stand on the hind limbs even after complete regression of block had occurred. Although further studies are required to establish the cause of this phenomenon, we suggest this may reflect a block of proprioceptor fibers.
Received I1 January, acceptedfor publication 16 February 1977
Administration of solutions into the sub- brought forward and held with ties so that the hip was arachnoid space is simpler in sheep (LE- flexed and the knee and tarsal joints were extended: this flexes the spine in the lumbosacral region and BEAUX 1975) than in other experimental enlarges the lumbosacral interspace, thereby facilitatanimals such as the dog (REDDERSON et'al. ing placement of the needle in the subarachnoid space. 1974). Spinal anesthesia can be performed A 4- to 6-inch-wide area was clipped from the lower in the restrained but unanesthetized animal, sacral to the upper lumbar region. The lumbosacral and onset and duration of sensory analgesia area was scrubbed with pHisoHex@,rinsed, and then wiped with 70% isopropyl alcohol. The vertebral and motor block can be assessed with a high spines were identified by palpation and marked on the degree of precision. The studies reported skin with indelible ink. here were done to compare onset, duration Spinal block was performed by means of the midline and quality of anesthesia produced by approach for tapping the subarachnoid space. A subarachnoid administration of bupivacaine 22-gauge, 3-inch, clear hub, disposable Yale spinal needle (B-D No. 5171) was inserted, and location of (Marcaine") and tetracaine. the tip in the subarachnoid space was verified by a
MATERIAL AND METHODS The methods for giving spinal (subarachnoid) injections to sheep and for monitoring the blocks have been described by LEBEAUX(1975). Non-pregnant ewes, weighing 40 to 60 kg, were used for these studies. There were five animals per treatment group. No animal was used more than once. Animals were placed in ihe specially-designed stocks, and the hind limbs were
spontaneous flow of CSF when the stylet was withdrawn. An injection was not given unless this flow of CSF occurred. A 2.5 ml sterile disposable glass syringe containing the local anesthetic solution was attached to the spinal needle, and the plunger was withdrawn slightly. A free flow of CSF into the syringe showed that the tip of the needle was still in the subarachnoid space. The solution was then injected over an interval of about 5 s. At the completion of the injection the plunger was again withdrawn slightly to establish whether or not the tip of the needle was still in place. The small amount ( i O . 2 ml) of fluid was
446
H. JACK ADAMS AND D. D. DOHERTY
promptly reinjected, and the needle was withdrawn. As soon as the injection was completed, the hind limbs were untied and allowed to hang free, and testing for the block was started. The presence of sensory analgesia in the anal region and in the hind limbs was assessed by pinching the anus and the corona of each hind limb with an Allis forceps. If the animal did not respond by, for example, a jerking movement of the body, turning of the head, or withdrawal of the limb, we assumed sensory block was present. Since the sheep responds to pinching of the skin with a discrete twitching of the stimulated area, it is possible to follow the dermatomal spread and regression of block on the dorsum. Motor block in the hind limbs was assessed by pinching an unblocked area such as the neck or one of the front limbs and noting whether or not the animal flexed the tarsal joint. Absence of flexion was regarded as motor block. Since the spread and intensity of spinal block may not be the same for both sides, the left and right hind limbs and the areas just to the left and right of the vertebral column were tested, and the results obtained for the two sides recorded separately. In general, animals were checked a t 5-minute intervals for the first half hour and then at 15-minute intervals after that, until complete recovery of the several variables had occurred: i.e., motor activity in the hind limbs and sensory analgesia in the hind limbs, the anal region, and the cutaneous dermatomes of the dorsum. The duration of the block was taken as the interval between onset (loss of sensory or motor function) and recovery of the function. When recovery had occurred in these several variables, the animal was removed from the stock and placed in one of the pens. The observen noted whether or not the animal was able to support itself on its hind limbs and, if so, whether or not it was ataxic. Animals that were ataxic or unable to use their hind limbs sufficiently to enable them to stand were checked later that day and, if necessary, again the following morning to ascertain whether or not motor function in the hind limbs had returned to normal. Freshly prepared sterile solutions of bupivacaine and tetracaine, adjusted to about p H 7 and made hyperbaric by the presence of 5% glucose, were available in multiple dose vials. The vials were coded so that the personnel giving the injections and observing the animals were unaware of the contents until the studies were completed and the code was revealed. Personnel were instructed to note whether or not DreciDitation. manifested as cloudiness or “milkiness”, occurred when CSF was drawn into the syringe containing local anesthetic solution. Data obtained for the right and left sides were combined for calculation of mean durations of block in the hind limbs and the mean times required for complete regression of block. Frequency of block, expressed as per cent, was calculated from the ratio
. .
of the number of successful blocks over the total number of possible blocks, the right and left sides being treated independently. Statistical significance was tested by means of a n analysis of variance.
RESULTS The data are summarized in Table 1. Complete onset of block in all cases occurred within 5 min after the injection. Although mean duration of sensory analgesia in the anal region was shorter with bupivacaine, there was no statistically significant difference between bupivacaine and tetracaine at either concentration. Failure to show a difference between the two concentrations of drug may be due, for example, to the small number of animals in each group, the anatomy of the sheep, its ventral recumbent position during and after the spinal injection, the use of hyperbaric solutions, or some combination of these factors. The mean time required for complete regression was shorter for 0.75% bupivacaine than Sor 0.75% tetracaine, but, again, the difference was not statistically significant. This agrees with the results of a clinical study reported by PFLUGet al. (1976), who found that in their patients the time required for complete regression was the same for bupivacaine and tetracaine. However, we found in our study that, at 0.375%, the time for complete regression was significantly shorter with bupivacaine. Furthermore, the duration of sensory analgesia in the hind limbs was, at both concentrations, significantly shorter with bupivacaine. This confirms our previous observa;ions (unpublished) that in sheep the duration of spinal anesthesia with bupivacaine is shorter than with mg doses Of tetracaine. As in the clinical study (PFLUGet a]. 1976), bupivacaine produced less motor block than tetracaine, and the mean duration Of motor with bupivacaine was about one-half the duration with tetracaine.
SPINAL BUPIVACAINE AND TETRACAINE IN SHEEP
447
Table 1 Frequency and duration of block (see text). Meansfs.e. mean are given for durations and are in minutes. Frequency of block shown in parentheses. Highest segmental level of block most frequently observed is shown in brackets. Drug concentrations are as HCl salt. Treatment
Variable Sensory analgesia, anal region Sensory analgesia, hind limbs Motor blockade, hind limbs Complete regression
1
Bupivacaine 0.375% 2 1 ~ ( 100%)
7
P N.S.
I
Tetracaine 0.375%
262 f 62 (100%)
+
I
Bupivacaine 0.75%
185f 17
I
P
1
Tetracaine 0.75%
N,S.
243+31 (100%)
( 100%)
112+ 15 (90%)
< 0.001
255 27 (80%)
198f25 (100%)
< 0.01 > 0.001
313+29 (100%)
82+ 18 (50%)
< 0.05 > 0.01
179f53 (50%)
66f8 (70%)
< 0.05 >o.c1
166+26 (100%)
0.001
DISCUSSION The data show that, depending upon the variable examined, the investigators could conclude that duration of spinal anesthesia with bupivacaine was either equal to or shorter than that of tetracaine. Clearly, the duration of sensory analgesia and of motor block in the hind limbs was shorter with bupivacaine. Even more striking than this difference in duration of motor block was the observation that when the animals were removed from the stocks after complete recovery from the spinal block, all those that had received tetracaine were unable to stand on their hind limbs, whereas only one of the sheep that had received the higher dose of bupivacaine was so affected. Unable to use their hind limbs to support their hind quarters, these animals remained in a recumbent position until sufficient recovery occurred to permit them to stand. This required a minimum of 7 to 8 h after administration of the local anesthetic agent, but all these animals exhibited completely normal stance and gait the following morning, i.e., 24 h after beinginjected. Theanimals
+
{W
241+ 1 1 Sl}
had, at the time they were removed from the stocks, recovered motor function in the hind limbs and were able to flex and extend both the hip and tarsal joints. In fact, two of the animals that received 0.375% tetracaine never exhibited block of flexion of the tarsal joint, the end-point we defined for ascertaining the presence or absence of motor block. Nevertheless, these animals could not stand on their hind limbs when removed from the stocks. This phenomenon cannot, therefore, be explained simply as a block of the motor fibers innervating the hind limbs, and it may be, for example, that the block of proprioceptive pathways is in part responsible for it. Whatever the explanation, the fact remains that tetracaine produced a higher incidence of motor block and motor block of longer duration than did bupivacaine at equal mg doses.
REFERENCES REDDERSON, C. L., UY,D. & ANTON,A. H. (1974) New techniques for spinal anesthesia in the dog. Anesthesiology 40, 187.
448
H . JACK ADAMS AND D. D. DOHERTY
LEBEAUX, M. I. (1975) Sheep: a model for testing spinal and epidural anesthetic agents. Lab. Animal Sci. 25, 629. PPLUG,A. E., AASIIEIM, G. M. & BECK,H. A. (1976) Spinal anesthesia: bupivacaine versus tetracaine. Anesth. Analg. Curr. Res. 55, 489.
Address:
H. Jack Adams, Ph,D. Research Department Astra Pharmaceutical Products, Inc. Framingham Massachusetts
U.S.A.
