Observations on the effects of intrathecal papaverine in experimental vasospasm

Transcription

1 Observations on the effects of intrathecal papaverine in experimental vasospasm MASAHIRO OGATA:, M.D., B. M. MARSHALL:, M.D., ANn W. M. LOUGHEED, M.D. Division of Neurosurgery, Department o/ Surgery and Department o/ Anesthesia, University of Toronto, Canada Subarachnoid hemorrhage was produced in monkeys by injecting fresh arterial blood. Serial angiographic studies of the basilar artery then showed vasospasm, occurring as a biphasic response similar to that seen following subarachnoid hemorrhage in man. Papaverine had previously been found to be the most potent vasodilator for topical use to release spasm resulting from experimentally induced subarachnoid hemorrhage. This drug was therefore administered, in various dilutions, as a slow infusion into the subarachnoid space of these monkeys. In a concentration of 0.03%, papaverine proved to be effective in reducing the vasospasm without toxicity. KEY WORDS papaverine vasospasm subarachnoid hemorrhage toxic effect concentration biphasie response I N preliminary experiments we reevaluated various known aspects of experimental cerebral vasospasm. The experimental model used was the basilar artery in the cat, and in the monkey similar to that described by Echlin.'-' The single and repeated stimuli studied were electrical, mechanical (using a small radio amplifier of original design), thermal (17 ~ 7 ~ 0~ arterial blood, serum, and plasma (Fig. 1). The spasm produced by fresh whole blood had the best characteristics for study of the effect of vasodilating agents. Arterial spasm resulting from this stimulus, although less in degree than that obtained from an electrical or mechanical source, was more consistent in character, much more prolonged in duration, and caused no apparent damage to the vessel. A study of the cerebral vasodilator effect of papaverine in various dilutions, Rogitine 0.5% and Vasodilan 0.5% applied topically, showed that papaverine was the mos! effective. These observations led to the study in this paper. The effect of an intrathecal infusion of papaverine on the release of vasospa:m was observed, and histological studies were made at postoperative intervals to record local toxic effects. Materials and Methods Rhesus monkeys weighing 6 to 8 kg were anesthetized with intraperitoneal Nembutal (30 mg/kg), with intravenous supplement IOO BEFORE STIMULATION 3 MIN 60 MIN 6 HR t ; 1 t FIG. 1. Degree of spasm (%) after hemorrhagic stimulation.. 20 J. Neurosurg. / Volume 38 / January, 1973

2 Intrathecal papaverine in experimental vasospasm as required. Pulse rate, systemic blood pressure, cerebrospinal fluid pressure, and endtidal COs concentration were continuously monitored. Arterial pco~ and po., were checked at intervals. A small burr hole was made over the Sylvian fissure with a dental drill. After dissection of dura and arachnoid, one or two polyethylene tubes were inserted into the subarachnoid space along the Sylvian fissure to approach the circle of Willis. These tubes were fixed to the surrounding tissue and the proximal ends buried under the skin. The skin overlying the tube was opened and resutured at the time of each injection. The stimulus used to induce arterial spasm was whole arterial blood. The animals own fresh arterial blood (usually 1.3 ml/kg, without any added agents) was injected over 5 to I0 minutes into the subarachnoid space via the polyethylene tube. This large amount of blood was found necessary to produce signs of listlessness, crouching, unsteadiness and refusal to eat, thus simulating human cases of severe subarachnoid hemorrhage with spasm, and also to leave blood clot around the artery at the time of sacrifice. Radiological observation of the basilar artery was done by brachial angiography with an arterial cannula usually from the left side. The contrast medium was Renografin 60, a dose of 1 ml/kg with an injection time of 1.5 sec. The diameter of the basilar artery and vertebral arteries was measured at standard points by magnification, and a photographic record made. Variation in diameter of the basilar artery on sequential angiograms was found to be negligible if the animals were under a comparable general anesthesia with a constant end-tidal COs concentration. Angiography was performed immediately prior to the introduction of the artificial subarachnoid hemorrhage (SAH) and subsequently at post-sah intervals of 10 to 30 min, 60 min, 24 hr, 3 to 4 days, and 6 to 8 days. Cases in which spasm was demonstrated angiographically at one week after the initial hemorrhage were immediately treated with varying concentrations of papaverine given intrathecally, and the roentgenological study was continued for a second week. The papaverine used to treat the spasm was diluted with normal saline to concentra- tions of 3%, 0.3%, 0.03%, 0.003% and %. The two stronger solutions were injected via the tubes to a total of 0.3 ml/kg at a rate of 0.1 ml/min. The weaker dilutions were infused slowly into the subarachnoid space in a continuous drip, 23 ml for the most concentrated solution to 140 ml for the more dilute solution, over a period of two hours. During this period an equal amount of fluid was allowed to drain from the cisternal puncture. At varying intervals after each experiment was completed, the animals were sacrificed and studied for macroscopic and histological changes in the brain and dura. Results Induced Spasm Of the 15 monkeys selected for this experiment, Monkey 1 was eliminated due to technical difficulties. Therefore the monkeys are numbered 2 to 15. Ten of the 14 remaining monkeys showed spasm of the basilar artery following the induced SAH. Seven of these l0 animals were then treated with papaverine. The clinical state of the animals following the SAIl was characterized by listlessness, refusal to eat, crouching, and unsteadiness. There were minor changes in cardiac rate and rhythm, and in CSF pressure, but no specific neurological deficits. The variable nature of the course of spasm is noted in Fig. 2. Two monkeys, Nos. 8 and 13, showed spasm only after a second SAH was introduced on the third or fourth day. One animal, Monkey 14, having apparently recovered spontaneously from the effects of the SAH, did not show recurrence of spasm when a second SAIl was introduced on the seventh day. In four animals, Monkeys 3, 4, 6, and 9, the spasm subsided significantly during the observation period and then recurred by the sixth to eighth day (Fig. 3 : Monkey 4). In Monkey 6, a further SAH was attempted on the seventh day, and a larger than usual amount of blood was injected into the subarachnoid space. This caused a morbid deterioration in the condition of the animal similar to that seen in a spontaneous SAH, and the animal subsequently died. In three animals, Monkeys 2, 5, and 12, no significant change in spasm J. Neurosurg. / Volume 38 / January,

3 M. Ogata, B. M. Marshall and W. M. Lougheed ~ [ : < li 1 f--after SAH --1 rafter-papaverine, ~ o o "" ~- ". c, "-:='-" " ~ i,// T. ~ D 130 i_ 2ndSAH ".,oo~o [ "T-'~o.,..FTEE~'~---~''''~" S 70 _ I ~0MI~:AErER /,~%~'\ F.! 0.03% F o~%_s... P /03~, \1o.o.3%r o o S ALL "1- "l" BETTER -H" BAD.~ m m NO CHANGE + -I- -- BAD -I BETTER F r-, LB.S./ 0.03% P *~, P X ~~ *% ~~ -I--I-- BETTER...,:,.--~"... ::... i... :... (~) L... -~ 2nd SAH]~ % ~FIB. E.B.S. FTER,., L I 20 MIN' AFTER~.~ ~176 "1(" t..'- I- ~ OOM'N'AETEmn~AHI ~ E-'~./~.~ A LITTLE BETTER MEDULLAE,~ INJURY -, (~ L "~'''~'- ~.~ SA, TONSILLAR HERNIATION FIG. 2. Clinical course and size of artery in 10 monkeys that developed spasm. The diameter of the artery is recorded in percentages of normal (100%). was noted from the time of onset, up to the sixth or eighth day. In summary, spasm induced by artificial SAH was variable. It usually appeared within a few minutes of the stimulus but often was temporary; in some animals it was continuous from its initial onset, in others it subsided and recurred and in some it did not appear until a few days after the initial stimulus. Effect oj Papaverine Seven of the 10 animals were treated with varying amounts of papaverine. The administration of the papaverine appeared to have a beneficial clinical effect, but the results of the clinical observations were sufficiently variable to preclude drawing specific conclu- sions from such a small series. The animals appeared to be less lethargic and to have a return of appetite following administration of papaverine. During, and for a few hours after, injection of the agent, transient slowing of pulse rate and a rise in CSF pressure were noted in some animals. The specific effects of the various dilutions of papaverine upon the vessel in spasm are recorded in Fig. 2. Papaverine 3.0%, 0.3 ml /kg was used in one experiment (Monkey 3). This animal appeared to suffer some toxic effects from the agent. The vessel became markedly dilated, and this state persisted beyond the first hour. Some spasm had returned at 24 hours. No spasm was noted in this animal on the fourth day after treatment. 22 J. Neurosurg. / Volume 38 / ]anuary, 1973

4 Intrathecal papaverine in experimental vasospasm Papaverine 0.3% (0.3 ml/kg), used on one occasion, had a specific effect on the vessel similar to that resulting from the 3.0% solution. None of the untoward systemic effects were noted in this animal however. Papaverine 0.03 % was used in five experiments in a slow continuous infusion. On each occasion this treatment resulted in either a marked decrease in the degree of spasm or caused an actual dilatation of the vessel (Fig. 4). No untoward generalized reaction to the drug or the method of treatment was noted. Papaverine of 0.003% and % concentrations was infused in one animal. The weaker concentration had no visible effect. The stronger concentration caused a transient decrease in the degree of spasm. Pathological Studies The animals were sacrificed after completion of treatment on the third, seventh, or fifteenth day. Macroscopic and microscopic examinations of the local area and of specific regions throughout the brain were carried out. It was noted during the treatment phase that papaverine 3.0% formed a white precipitate when in contact with CSF. The weaker concentrations did not form visible precipitates. The microscopic examinations of tissue from animals that had received 3.0% and 0.3% papaverine concentrations showed only aseptic meningeal response and this in fact could have resulted from the injection of blood. With 0.03%, 0.003% and % papaverine concentrations, the leptomenin- geal response was very mild. In no group was there any significant lesion in the parenchyma. Discussion Intracranial artery spasm has been produced artificially in various ways to study the natural history of the problem. Simeone, et al., 3 discussed prolonged experimental cerebral vasospasm in the carotid system of monkeys. This spasm was produced by arterial puncture, and the technique caused spasm in over 65% of cases. Wilkins and Levitt a in their experimental studies on vasospasm note the variability of spasm and its apparent immunity to changes in po~, pco2, and ph. Weir, et al., 4 concluded that repeated injections of blood produced an effect by "cumulative structural damage rather than by heightened vasospastic response to repeated SAH." Most experimental models demonstrate the immediate onset of spasm after SAH and some have observed a biphasic response2 Others have failed to obtain a biphasic response? It is possible that the initial spasm could have been missed since angiograms have rarely been performed within the first few hours after SAH. Spasm at five to seven days could be part of a biphasic response. In this series we were successful in producing an immediate spasm in seven out of 14 cases, it was still present, one week after the initial injection of blood. In another animal, the spasm appeared initially, but had subsided at the one week interval. In two other animals, a second injection of blood at Day 3 or 4 was required to produce any measurable spasm. Thus in 10 of 14 cases, Fro. 3. Monkey 4. Arteriographic record of spasm of the basilar artery. LeJt to right: 1) Basilar artery before SAH. 2) Spasm 10 rain after SAH (arrows). 3) Spasm disappeared 3 days after SAH. 4) Spasm returned 6 days after SAH (arrows). 5) The artery was dilated 30 min after irrigation with 0.003% papaverine (70 ml/2 hr). 1. Neurosurg. / Volume 38 / January,

5 M. Ogata, B. M. Marshall and W. M. Lougheed FIG. 4. Monkey 12. Arteriographic record of spasm of the basilar artery. From top to bottom, lejt to right: 1) Basilar artery before SAH. 2) Spasm 25 min after SAH (arrows). 3) Seven days after SAH, slightly less spasm. 4) After irrigation with 0.03% papaverine (23 ml/2 hr), artery was dilated. 5) One hour after irrigation; artery is still moderately dilated. 6) Three hours after irrigation, artery appears normal. 7) One day after irrigation, spasm has returned (arrows). 8) Seven days after irrigation, no spasm can be seen. spasm occurred, and in seven of the 14 cases the spasm was still present up to the seventh or eighth day. In the discussion and summary of intracranial artery spasm in humans. Wilkins, et al./noted the variability of the time of onset of spasm. In clinical cases however, it is doubtful if many angiographic studies have been made within 1 hour of the time of hemorrhage. Also, since pre-sah angiograms would rarely be available, small degrees of spasm might not be recognized. These variable factors noted in the clinical material might well represent the variable degree of spasm noted in following our experimental material. Thus, assuming that our pre-sah angiograms represented a "normal" vessel, our ex- perimental model mimicked the characteristics of a spontaneous SAH with sufficient regularity to be a useful experimental tool. Subarachnoid injection of papaverine in the intact monkey in dilutions of 0.3% to 0.03% was free of toxic effects and proved effective in releasing the experimentally induced spasm. This effect however, was transient, lasting up to 24 hours. Because of the complexity of this experiment, a large series of animals could not be done. Therefore we cannot predict exactly how long the beneficial effects might last. It appears, however, that the papaverine is diluted or neutralized or removed after a few hours and that the artery then still possesses the ability to go back into spasm. It seems likely that if papaverine is to be an effective agent in the Neurosurg. / Volume 38 / January, 1973

6 Intrathecal papaverine in experimental vasospasm treatment of experimental cerebral vasospasm it must be injected into the subarachnoid space either intermittently or continuously in the appropriate concentrations. Obviously the proof of this assumption requires a larger series of animals because of the variability in the experimental model. Acknowledgment The authors wish to express their thanks to Mrs. Mimi Reid, Research Editor, Division of Neurosurgery, Toronto General Hospital, for her assistance in the preparation of this manuscript. References 1. Brawley BW, Strandness DE Jr, Kelly WA: The biphasic response of cerebral vasospasm in ex- perimental subarachnoid hemorrhage. J Neoro. surg 28"1-8, Echlin FA: Spasm of basilar and vertebral arteries caused by experimental subarachnoid hemorrhage. J Neurosurg 23:1-11, Simeone FA, Ryan KG, Cotter JR: Prolonged experimental cerebral vasospasm. J Neurosurg 29: , Weir B, Erasmo R, Miller J, et al: Vasospasm in response to repeated subarachnoid hemorrhages in the monkey. J Neurosurg 33: , Wilkins RH, Alexander JA, Odom GL: Intracranial arterial spasm: a clinical analysis. J Neurosurg 29: , Wilkins RH, Levitt P: Intracranial arterial spasm in the dog: a chronic experimental model. J Neurosurg 33: , 1970 Address reprint requests to: W. M. Lougheed, M.D., F.R.C.S.(C), Neurosurgical Office, 11th Floor, Norman Urquhart Wing, Toronto General Hospital, Toronto 2, Canada. J. Neurosurg. / Volume 38 / January,