775

Review Article Vasodilators during cerebral aneurysm Kazuo Abe MD surgery

The objective of this review is to review the anaesthetic im- the drugs of choice for induced hypotension. Prostaglandin E t, plications of vasoactive compounds particularly with regard to nicardipine and nitroglycerin have the advantage that they do the cerebral circulation and their clinical importance for the not alter carbon dioxide reactivity. Local cerebral blood flow practicing anaesthetist. Material was selected on the basis of is increased with nitroglycerin, decreased with trimetaphan and validity and application to clinical practice and animal studies unchanged with prostaglandin E~ Intraoperative hypertension were selected only if human studies were lacking. Hypotensive is a dangerous complication occurring during cerebral aneu- drugs have been used to induce hypotension and in the treat- rysm surgery, but its treatment in association with subarachnoid ment of intraoperative hypertension during cerebral aneurysm haemorrhage is complicated in cases of cerebral arterial va- surgery. After subarachnoid haemorrhage, cerebral blood flow sospasm because fluctuations in cerebral blood flow may be is reduced and cerebral vasoreactivity is disturbed which may exacerbated. Hypertension should be treated immediately to re- lead to brain ischaemia. Also, cerebral arterial vasospasm de- duce the risk of rebleeding and intraoperative aneurysmal rup- creases cerebral blood flow, and may lead to delayed ischaemic ture and the choice of drugs is discussed. Although the use brain damage which is a major problem after subarachnoid of induced hypotension has declined, the control of arterial haemorrhage. Recently, the use of induced hypotension has de- with vasoactive drugs to reduce the risk of in- creased although it is still useful in patients with intraoperative traoperative cerebral aneurysm rupture is a useful technique. aneurysm rupture, giant cerebral aneurysm, fragile aneurysms Intraoperative hypertension should be treated immediately but and multiple cerebral aneurysms. In this review, a variety of the cerebral vascular effects of each vasodilator shouM be un- vasodilating agents, prostaglandin E I, sodium nitroprusside, ni- derstood before their use as hypotensive agents. troglycerin, trimetaphan, adenosine, calcium antagonists, and inhalational anaesthetics, are discussed for their clinical use- L'objectif de cet article est de revoir les implications anesth$- fulness. Sodium nitroprusside, nitroglycerin and isoflurane are siques des compos~s vasoactifs particuli~rement en rapport avec la circulation cdr$brale ainsi que leur importance clinique pour l'anesth~siste. Les agents ont ~t~ choisis sur la base de leur Key words validit~ et de leur application it la pratique clinique et des ~tudes ANAESTHETICS,VOLATILES: isoflurane; animales ont ~td choisies seulement en l'absence d~tude sur ANAESTHETICTECHNIQUES; hypotension; 17~omme. Les agents hypotenseurs ont dt~ utilis~s pour induire BLOOD PRESSURE" hypotension; de 1~ypotension et pour traiter 17~ypertensionpreop~ratoire pen- BRAIN: blood flow, carbon dioxide tension; dant la chirurgie d'andvrisme c&~brale. Apr~s une hdmorragie HORMONES: prostaglandin El sous-arachnoMienne, le d~bit sanguin cdr$brale r$duit et la va- SYMPATHETICNERVOUS SYSTEM: ganglionic blockade, somotriciM c&~brale perturb~e peuvent entrafner une isch~mie trimetaphan; c~r$brale. Ainsi, le vasospasme artdriel cdrdbral diminue le d~bit PHARMACOLOGY; adenosine, nitroglycerin, nitroprusside, sanguin cdr~bral et peut conduire it des dommages c&~braux calcium channel blockers, hydralazine, diazoxide, retardes d'isch~mie, problbme majeur aprbs une h~morragie labetalol, esmolol; sous-arachnoMienne. R~cemment, I'utilisation de 171ypotension COMPLICATIONS" intraoperafive hypertension, brain contr61~e s'est rar~fi~e bien qu'elle soit encore utile chez les ischaemia, rebleeding. patients avec une rupture peropdratoire d'an~vrisme, en cos From the Department of Anaesthesia, Osaka Police Hospital. d'an~vrisme c&$bral g~ant, d'an~vrismes fragiles et d'an- Address correspondence to: Dr.Kazuo Abe, Department of ~vrismes cdr~braux multiples. Dans cet article, une varidtd de Anaesthesia, Osaka Police Hospital, 10-31 Kitayama, Tennouji, vasodilatateurs, le prostaglandine E l, le nitroprussiate de so- Osaka 543, Japan. dium, la nitroglycdrine, le trimdtaphan, l'ad~nosine, les anta- Accepted for publication 17th April, 1993. gonistes calciques et les agents d'inhalation son discut~s pour

CAN J ANAESTH 1993 / 40: 8 / pp 775-90 776 CANADIAN JOURNAL OF ANAESTHESIA

leur utilit~ cfinique. Le nitroprussiate de sodium, la nitrogly- velop abnormal cerebrovascular reactivity and impaired cerine et l'isoflurane sont les agents de choix pour l~ypotension 2,3 and they may be more susceptible to contrrlke. La prostaglandine E t, la nicardipine et la nitrogly- severe flow reductions during hypotension than normal cerine ont ravantage de ne pas alt~rer la rOactivit~ au dioxyde individuals, 4 resulting in global and or focal ischaemia de carbone. Le d~bit sanguin c~r~bral local est augment~ avec of the brain. 5 During the first two weeks after SAH, la nitroglycerine, diminu~ avec le trim~taphan et inchang~ avec several events may make heavy demands on the capacity la prostaglandine E I. L'hypertension perop~ratoire est une com- of the cerebral vasculature to react adequately. Cerebral plication dangereuse aux cours d'une chirurgie d'an~vrisme arterial vasospasm and rebleeding are major problems cOr~bral, mais son traitement lors d'hdmorragie sous- and cerebral aneurysm surgery is often performed within arachnoMienne se complique dans les cas de vasospasme ar- the same period. Another problem during general anaes- t~riel c~r~bral parce que les fluctuations du d~bit sanguin thesia for aneurysm clipping is intraoperative hyperten- c~r~bral peuvent s'exacerber. L'hypertension devrait 6tre traitke sion. Intraoperative hypertension may increase the risk imm~diatement pour r~duire le risque de resaignement et de of rebleeding and intraoperative aneurysm rupture before rupture perop~ratoire de l'anOvrisme. Le choix des agents est its exposure so that intraoperative blood pressure should discut~. Bien que l'utilisation de l'hypotension contrOl~e est be well controlled. moins fr~quente, le contrrle de la pression art~rielle avec des agents vasoactifs dans le but de r~duire le risque de rupture Pathophysiology perop~ratoire d'anOvrisme c~r~bral est une technique courante. L'hypertension perop~ratoire devrait ~tre traitOe imm~diatement Subarachnoid haemorrhage mais les effets vasculaires c~rObraux de chaque vasodilatateurs Ten percent of all strokes result from subarachnoid haem- devraient 6tre compris avant qu'ils soient utilis~s comme agents orrhage (SAH) which is caused most often by the sudden hypotenseurs. rupture of an intracranial saccular aneurysm. Subarach- noid haemorrhage chiefly afflicts patients between 40 and 60 yr of age and women are affected more often than Contents men. Rupture of an intracranial arterial aneurysm pro- Introduction duces severe focal and generalized disturbances in brain Pathophysiology function (Figure 1). Depending on the surgical risk, pa- - Subarachnoid haemorrhage tients may present a broad spectrum of clinical conditions, - Cerebral vasospasm ranging from non-ruptured aneurysm (grade 0) to deep Cerebral haemodynamics coma (Grade V). 6 Delayed cerebral ischaemia is the - Carbon dioxide reactivity major cause of poor outcome or death after SAH. The - Autoregulation risk of delayed ischaemia and cerebral infarction after - Cerebral blood flow SAH is dependent on many factors, the most important - Cerebral arterial blood flow velocity of which are the amount of blood in the basal cisterns, Induced hypotension the presence of intracranial haematoma and the patient's Hypotensive drugs clinical condition. 7 Subarachnoid haemorrhage from rup- - Prostaglandin El ture of an intracranial arterial aneurysm produces severe - Sodium nitroprusside focal and generalized disturbances in brain function. Rup- - Adenosine ture of a cerebral aneurysm with subsequent arterial - Nitroglycerin bleeding may cause dramatic changes in intracranial pres- - Trimetaphan sure (ICP) 8 (Figure 2). In severe haemorrhage, cerebral - Calcium channel blockers pressure may decrease to low levels with a con- - Isoflurane comitant decrease in cerebral blood flow. Severely ele- - Other vasodilators vated ICP may also lead to brain herniation. Following Clinical implications SAH, dilated ventricles can be seen with computerized tomographic (CT) and scanning at admission can be used During the clipping of cerebral arterial aneurysms, in- to classify the severity of haematoma. Computerized to- duced hypotension is often used to reduce the aneurysmal mographic scanning is valuable in identifying the patient's wall tension to minimize the risk of premature rupture, l risk of brain ischaemia after SAH. 9 A primary concern with the use of hypotension has been Brain damage may be caused by a marked increase that cerebral blood flow (CBF) may decrease to critically in intracranial pressure and mechanical distortion of in- low levels, resulting in ischaemic damage to the brain. tracranial structures resulting from the sudden injection Patients with subarachnoid haemorrhage (SAH) may de- of blood into the subarachnoid space. 10 Some patients Abe: HYPOTENSION AND SAH 777

et al. ~s performed 101 quantitative bedside CBF meas- urements on 40 patients to correlate the severity of SAH with CBE In patients with low-grade SAH, global CBF was within normal limits before and after surgery but increased for two weeks postoperatively, while in the pa- tients with high-grade SAH there was no increase in CBF one week after surgery. Voldby et af. reported that the cerebral metabolic rate of oxygen (CMROz) was more severely reduced than regional CBF during the first two weeks after SAH. 17 The most marked depressions of CMRO2 and regional CBF were seen with the devel- opment of focal neurological deficits. 14,~7 The complications associated with SAH are complex and include cerebral oedema, increased ICP, diffuse cere- bral ischaemia, rebleeding, cerebral arterial vasospasm and hydrocephalus. The presence of oedema, hydroce- phalus, and intracranial hypertension following SAI-I may cause regional CBF and cerebral metabofism to dete- riorate even further. ~8,~9 Neurological status after SAH is evaluated by the classification of Hunt and Hess 2~ FIGURE ! Giantcerebral aneurysm(~) originatingfrom internal (Table I). The Glasgow Outcome Scale 2t is often used carotid artery (lateral view) in a 65-yr-oldwoman. to determine the outcome of patients with head trauma. In general, the probability of survival for each of the grades of the Hunt and Hess system increases with the interval between the initial haemorrhagc and the time that the clinical grade is determined, z2 For example a patient graded I on the first day after the SAH has a 65% chance of survival, whereas a similar grading 21 days later indicates a 95% chance of surviving. 23 The operative results from delayed surgery are not superior to those of early surgery. Ljunggren et aL 24 studying 219 patients, reported good recovery in 76% of patients un- dergoing late surgery (more than eight days after SAH) and in 74% of patients undergoing early surgery group (within 2.5 days of SAH). All patients were grade I-III FIGURE 2 Intraventricularpressure duringrecurrent haemorrhage (Hunt and Hess classification). The Cooperative Aneu- in 57-yr-old man with anteriorcommunicating artery aneurysm.(from rysm Study, performed in 3521 aneurysm patients in 68 Votdby B. Alterationsin vasomotorreactivity in subarachnoid neurosurgical centres, showed that the incidence of re- hemorrhage. In: WoodJH (Ed,). C_.r blood flow. McGraw-Hill bleeding in patients operated upon within the first three Book Company 1987; 404.) days after SAH was lower (6%) than in patients operated upon 7 to 11 days after SAH (14%). 25 Although there have symptoms consistent with hydrocephalus. ;~ The was a reduction in the rebleeding rate after early surgery, most predictable factors for the development of hydroce- the timing of operation did not influence the overall mor- phalus are age, hypertension, CT findings of hydroce- bidity and mortality. However, in the North American phalus, and intraventricular haemorrhage. In order to Subset of the International Cooperative Study, the best reduce ICP and to reduce the risk of brain herniation, results were obtained when surgery was performed within cerebrospinal drainage can be considered, but this is con- three days of SAH. 26 From 1980 through 1983, 772 troversial. 12 Subarachnoid haemorrhage causes a consid- (21.9% of total 3521 patients) patients admitted to 27 erable decrease in both CBF and metabolism. ~3-Js The neurosurgical centers in the United States and Canada reduction in regional CBF and metabolism may oeeur from days 0 to 3 after SAH were enrolled in the study. even in patients in good clinical condition and without Overall outcome in patients planned for surgery on days vasospasm. Patients in poorer clinical condition have 0-3 after SAH was equivalent in terms of mortality to more marked reduction of CBF and metabolism. Mountz patients planned for surgery on days 11-32 after SAH, 778 CANADIAN JOURNAL OF ANAESTHESIA

TABLE I Neurological grading system for patients with SAH

Grade Criteria

Grade 1 Asymptomatic or minimal headache and slight nuchal rigidity Grade It Moderate to severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy Grade 111 Drowsiness, confusion, or mild focal deficit Grade IV Stupor, moderate to severe hemiparesis Grade V Deep coma, decerebrate rigidity, moribund appearance

From Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968; 28: 14. but early surgery showed improved recovery. Patients categories: (1) prevention or reversal of the arterial nar- planned for surgery 7-10 days after SAH had nearly rowing, (2) prevention or reversal of the ischaemic neu- twice the mortality of other intervals. These results argue rological deficits, and (3) protection from infarction. 28 Di- for early diagnosis and surgical intervention after SAH. rect pharmacological dilatation of spastic vessels has not been demonstrated but therapy may be directed to prevent Cerebral vasospasm its development or ameliorate the ischaemic consequen- In the past, rebleeding was considered to be one of the ces. 34-36 Several agents have been used to prevent or re- major causes of morbidity and mortality of SAH. Of verse the arterial narrowing. Calcium channel blocking 2265 patients admitted to the Cooperative Aneurysm agents have been used because the contraction of cerebral Study, Kassell et al. reported that 4.1% of patients rebled arterial smooth muscle cells is calcium-dependent and during the first 24 hr after the initial haemorrhage. Re- can be blocked by preventing the influx of extracellular bleeding was documented by bloody spinal fluid or CT calcium. Nimodipine has proved effective both in reduc- scanning. They concluded that rebleeding occurred most ing the mortality rate and in diminishing the severity and commonly during the first 24 hr with a cumulative rate incidence of permanent deficits caused by delayed ischae- of approximately 20% during the first two weeks after mic deterioration. 34.36-38 the initial SAH. 27 Recently, Kassell et al. 28 demonstrated that cerebral vasospasm following aneurysmal SAH was Cerebral haemodynamics one of the most important causes of cerebral ischaemia and was the main cause of death and disability in patients Carbon dioxide reactivity with SAH. Vasospasm, especially of the severe and dif- Cerebral arteries and arterioles react quickly to changes fuse variety, was associated with a reduction in both re- in PaCO2. In the PaCO 2 range 25 to 60 mmHg the re- gional CBF and CMRO2.14,17 mngiographic vasospasm lationship between CBF and PaCO2 is linear, with a flow is defined as a narrowing of the column of dye in the change of about 4% per millimeter of mercury. 39 The major cerebral arteries. The narrowing is time-dependent, vascular reactivity to carbon dioxide is considered to be rarely pronounced before the fourth day after the initial the predominant factor in the regulation of regional CBF haemorrhage and reaches a peak at about the seventh and seems to be a stable phenomenon. Even after severe day. 29-31 Clinical cerebral vasospasm, the syndrome of head trauma or stroke, carbon dioxide reactivity is at the ischaemic consequences of cerebral artery narrowing, least partially preserved, 4~ but Schaltn et al. reported is characterized by an insidious onset of confusion and that loss of carbon dioxide reactivity is a good predictor decreased level of consciousness followed by focal motor of outcome from head injury. 42 Reduction of cerebral and speech impairment and is often heralded by wor- blood flow by hyperventilation is used to control acute sening headache and increasing blood pressure. 28 Cer- increase of intracranial pressure such as epidural haema- ebral arterial spasm, as revealed by angiography, is a toma. Voldby et al. 43 studied cerebral vasomotor reactivity major cause of delayed cerebral ischaemia. 32 Using pos- to hypocapnia in 34 patients between the 3rd and 13th itron emission tomography, Carpenter et al. 33 measured day after rupture of an intracranial aneurysm and re- the regional CMRO2, oxygen extraction fraction and ported that the cerebrovascular response to hyperventi- CBF, and concluded that the initial aneurysm rupture lation was generally preserved. Clinical grading of SAH produced a primary reduction in CMRO2 and that sub- (Hunt and Hess classification) correlates with the disturb- sequent vasospasm caused ischaemia. ance of carbon dioxide reactivity, autoregulation and in- Delayed cerebral ischaemia is the major cause of death traeranial pressure (Table II). In animals, Artru et al. 44 and disability in patients with SAH. The treatment of reported that carbon dioxide responsiveness was abol- cerebral vasospasm may be considered in the following ished during profound hypotension induced with trimet- Abe" HYPOTENSION AND SAH 779

TABLE II ICP and vascular responsiveness after subarachnoid haemorrhage

ICP CO2 response Autoregulation Grade mmHg) ACBF/ A PCO2 ACBF/ A%MABP

II 10 + 3 1.61 5:0.67 -0.042 -I- 0.194 III 18 + 6 1.02 + 0.5 -0.230 -1- 0.514 IV-V 29 -t- 6 0.61 5:0.42 -0.Mzl 5:0.219

Data are mean + SD. Units for CO 2 response are ml- 100 g-Z. min-i change in CBF' mmHg -I change in CO 2. Autoregulation is expressed as ml. 100 g-i. min-~ change in CBF' % change in MAP (a value of 0.000 would be perfect autoregulation, and a more negative number indicates progresssive autoregulatory impairment. From Voldby B, Enevoldsen EM, Jensen FT. Cerebrovascular reactivity in patients with ruptured intmcranial aneurysm. J Neurosurg 1985; 62: 59, and Voldby B, Enevoldsen EM.Intracranial pressure changes following aneurysm rupture. Part I: clinical and angiographic correlations, J Neurosurg 1982; 56: 186. And from Todd MM, Warner DS. Neuroanesthesia: a critical review. In: Rogers MC, Tinker JH, Covino BG, Longnecker DE (Eds.). Principles and Practice of Anesthesiology. Mosby Year Book 1992; 1633.

aphan or sodium nitroprusside. We evaluated carbon di- was a close correlation between the degree of cerebral oxide reactivity during deliberate hypotension induced by vasospasm and the impairment of cerebral autoregula- prostaglandin El (PGEI), nitroglycerin (TNG), nicardi- tion, and patients with slight vasospasm and normal rest- pine in patients during cerebral aneurysm surgery. 45-47 ing cerebral blood flow pattern frequently showed focal Nitroglycerin- or nicardipine-induced hypotension did not changes during induced hypotension. Diffuse severe va- change carbon dioxide reactivity during hypotension in sospasm was accompanied by global impairment of au- our studies. 46-47 toregulation. There was a correlation between the pres- ence of cerebral vasospasm and impaired autoregulation Autoregulation and between the degree, extension of vasospasm and the Autoregulation protects the brain against ischaemia severity of autoregulatory impairment. caused by decreased blood pressure. The exact mech- anism of autoregulation is unknown but cerebral resist- Cerebral blood flow ance vessels dilate in response to a decrease in arterial Several methods are available to measure CBF including blood pressure or an increase in intracranial pressure. 2,48 133Xenon inhalation, 55 J33Xenon clearance, 56-57 xenon Cerebral autoregulation is a vulnerable mechanism: im- computed tomographic blood flow mapping, 58 positron pairment of autoregulation has been found in patients emission tomography, 59 and the hydrogen clearance tech- with SAH, 3,49-5~and brain tumour. 39 Severe head injury nique. 60-6z Ishii~3 and Pickard et al. 62 reported that, after is accompanied by marked disturbances of autoregula- SAH, regional CBF was reduced by 25 and 50%, de- tion. 5~ Loss of autoregulation often correlates with pending on the impairment of consciousness. Values for changes in cerebral blood flow in the resting condition regional CBF below 20 but higher 12 ml. I00 g-i. min-l with either hypo- or hyperperfusion, s2 In intracranial were associated with clinical neurological deficits that tumours, autoregulation is impaired in the diseased area were reversible. The values for regional CBF of 12 and its surroundings. 53 After SAH, cerebral blood flow ml. 100 g-t. min-i or less were associated with clinical may be reduced in response to small decreases in blood deficits that were not reversible when the vasospasm re- pressure in patients with cerebral vasospasm. In the first solved. Bell et al. ~3 studied ischaemic cerebral oedema week after SAH, a 10-20% reduction of mean arterial and regional cerebral blood flow in 41 baboons and re- blood pressure using trimetaphan or sodium nitroprusside ported that the threshold of ischaemia is 40.5% of normal decreased CBF in patients with angiographic cerebral ar- cerebral blood flow in cortex and 34.4% of normal flow terial vasospasm, r~ Using the intraarterial 133Xenon in- in subcortical white matter. They concluded that reversal jection method, Voldby et al. 43 studied the effects of hyp- of the neurological deficit and prevention of ischaemic otension on CMRO2, AVDO2, cerebral spinal fluid oedema formation can be expected if cerebral blood flow lactate and intraventricular pressure in 34 patients within can be restored to above the 40% threshold within 30 first 13 days of SAH. Mean arterial blood pressure was minutes. Their results suggest the risk of brain ischaemia reduced between 10 and 20% for five minutes by/v tri- during induced hypotension. In our studies, prostaglandin metaphan or sodium nitroprusside. The severity of an- El (PGE0 did not change LCBF after the induction of giographic cerebral vasospasm was measured by angi- hypotension.45-46 Trimetaphan decreased LCBF at 30 ography immediately after the CBF study and there minutes after the start of agent but increased to the pre- 780 CANADIAN JOURNAL OF ANAESTHESIA treatment level after its discontinuation, 64 whereas nitro- and cerebral vasospasm may disrupt cerebra] autoreg- glycerin increased LCBF at 30 rain after the start and ulation, especially in patients with low classification grade. decreased to the pretreatment level after its discontinua- The safety of systemic hypotension during cerebral aneu- tion. 46 rysm surgery depends on preservation of adequate CBE Cerebral metabolic rate (CMR) is the rate at which Hitchcock et al. studied the outcome in 112 patients op- the brain used or produced metabolic substrates or by- erated upon for clipping of intracranial aneurysms and products, oxygen (CMRO2), glucose (CMR-GIu), or lac- concluded that the incidence of postoperative neurological tate (CMR-Lact). Cerebral metabolic rate plays a major deficits was higher in those patients subjected to intraop- role in the control of cerebral blood flow and is altered erative hypotension below 60 mmHg mean arterial blood by anaesthetics. pressure and the duration of hypotension. 71 The margin of safety is reduced during induced hypotension and Cerebral arterial blood flow velocity therefore the technique should be used only when it may The normal value of mean middle cerebral artery (MCA) benefit the patient and only by those trained and ex- blood flow velocity varies from 35 to 90 cm. see -l and perienced in its use. 5 The competency of cerebral au- an average value is about 60 cm. sec -I during awake toregulation and CBF in aneurysm patients during hyp- and resting states. 65 Elevation of mean MCA velocities otensive anaesthesia is variable. Considerable effort has > 120 cm. see -l has been widely used as the criteria for been directed to determine the ideal drug for induced vasospasm. 66.67 The degree of MCA velocity elevation has hypotension. The three drugs in the most common use been correlated with the clinical symptom caused by de- are TNG, SNP and isoflurane, but there are no pro- layed ischaemia. 66 A rapid increase of velocity may pre- spective studies demonstrating an improved neurologic dict neurological deterioration, but high velocities are outcome with any agents. Lam et al. performed a retro- often unaccompanied by neurological symptoms. 66,68 spective study in 85 patients receiving a combination of Davis et al. compared serial arterial velocities and neu- halothane (0.5-1%), fentanyl and SNP, and in 105 pa- rological deficits in 34 patients after SAH, and reported tients with isoflurane-induced hypotension. Outcome was that eight of 16 patients without delayed ischaemia evaluated as - good: complete recovery except for minor had evidence of vasospasm (MCA velocity >120 cranial nerve dysfunction; satisfactory: major focal neu- cm. sec-~). 69 They concluded that concordant vasospasm rological deficit; poor: vegetative state or death. They con- and hypoperfusion were most often present in patients cluded that there were no differences in outcome between with delayed ischaemia and lateralizing neurological def- the hypotensive methods. 72 icits. Marked reduction in arterial pressure diminishes bleed- ing and on occasion allows the neurosurgeon to regain Induced hypotension during cerebral aneurysm surgery control of an irreversible situation but the neurological Induced hypotension has been used during cerebral aneu- and systemic effects of severe hypotension coupled with rysm surgery to reduce the risk of intraoperative aneur- extreme blood loss should be borne in mind, and normo- ysmal rupture. Intraoperative rupture of a cerebral aneu- tension, normovolaemia, administration of cerebral pro- rysm dramatically interrupts a microsurgical procedure tective agents, and appropriate temporary clipping can and jeopardizes the outcome for the patient. However, be utilized to minimize the risk of cerebral ischaemia. 73 it is controversial whether induced hypotension is useful Ausman et al. 74 concluded that it may be unreasonable in the prevention and management of intraoperative to make the whole brain hypotensive when only the vessel aneurysmal rupture. Giannotta et al. performed a retro- with the aneurysm needs to be controlled and they rec- spective analysis in 276 consecutive surgical procedures ommended the use of temporary vascular clips. Although for 317 intracranial aneurysms to determine the factors no clinical comparisons between induced hypotension that governed the outcome from intraoperative rupture and temporary vascular clipping have been done, there of aneurysms. There were 16 intraoperative aneurysmal are some advantages to temporary vascular clipping. In ruptures in 108 operations without induced hypotension patients with impaired cerebral autoregulation and de- and 20 ruptures in 168 operations with hypotension, but creased CBF after SAH, temporary vascular clipping may in cases of induced hypotension, 11 of the 20 patients be safer than induced hypotension, because it decreases suffered from permanent deficits or died. However, all flow only to that portion of the brain supplied by the 16 patients of intraoperative ruptures without induced temporarily occluded vessels and maintains collateral hypotension made a good recovery. They concluded that flow, rather than decreasing CBF to the entire brain induced hypotension may not be necessary in the man- through induced hypotension. agement of intraoperative rupture of aneurysm.7~ The Extreme intraoperative hypertension is one of the major argument against induced hypotension is that SAH major problems during cerebral aneurysm surgery. The Abe: HYPOTENSION AND SAH 781 treatment of hypertension in association with SAH is nitrate, sodium thiosulphate, or hydroxycobalamin. The complicated in cases of cerebral vasospasm that may ex- combination of SNP with captopril reduces the dose re- acerbate fluctuations in CBF. It has been reported that quirement of SNP. 81 Sodium nitroprusside markedly in- antihypertensive therapy should be withheld except when creases the intracranial pressure in patients with low in- elevations in blood pressure are extreme because the clear tracranial compliance 82-83 and the effect is even greater benefits have not been shown from reducing CBE 75 than nitroglycerin, u Cerebral vasodilatation induced by SNP is unlikely to affect regional cerebral blood flow Hypotensive drugs which remains unchanged during the hypotension and gross cerebral metabolic disturbance have not been ob- Prostaglandin E~ served. 8s Sodium nitroprusside may induce coagulation The prostaglandins are a large family of naturally oc- disturbances and SNP-induced coagulation abnormalities curring substances with a variety of biological actions. can induce increased bleeding caused by vasodilatation. 86 Prostaglandin El (PGEt) reduces blood pressure by re- Cerebral perfusion is better maintained during drug- laxing vascular smooth muscle, mainly by dilatation of induced hypotension; of the drugs commonly used, per- resistance vessels, but in large doses may exert a pre- fusion is maintained best with SNP. s Cerebral blood flow dominant vasodilator action on the systemic arterial cir- is maintained during SNP-induced hypotension. 87 How- culation so that it induces systemic hypotension. 76,77 In ever, high organ blood flow alone may not guarantee our study, PGEI (initial dose: 0.1 ~g. kg -~- min -I ) was adequate tissue oxygenation and this may be particularly infused continuously to induced systemic hypotension, relevant with SNP because it has no effect on CMRO2 .88 and PGEt did not change LCBF and carbon dioxide reactivity during surgery, but the hypotensive effects of Adenosine PGE~ persisted after its discontinuation. 45,46 Goto et al. Adenosine is an endogenous vasodilatator and is involved also reported prolongation of the hypotensive effect dur- in several vascular beds. It is normally salvaged from ing general anaesthesia, although the blood concentration the tissue and rephosphorylated by ATP-dependent kinase of PGE~ decreased to preadministration levels about ten reactions.89-9~ It has been used to induce hypotension in minutes after the end of infusion. 7s Although PGEI in- cerebral aneurysm surgery due to its rapid onset and hibits platelet aggregation 79 Carlson reported that inhi- stable hypotensive action without rebound hypertension, bition did not occur at clinically used doses of PGE~. s~ and its favourable cardiovascular effects 91,92 with only minor decreases in whole body oxygen consumption, s9 Sodium nitroprusside The effects of this agent are rapidly and spontaneously Sodium nitroprusside (SNP) has been used to induce reversed when its administration is discontinued and it hypotension during cerebral surgery because it has a has no haematological or biochemical toxicity. 89 Lager- rapid onset and a short half-life. Its onset of action is kranser et al. studied the effects of adenosine-induced within 30 sec, and peak hypotensive effect occurs within hypotension on CBE CMRO2 and cerebral lactate pro- two minutes and hypotensive effect disappears within duction in ten patients undergoing cerebral aneurysm three minutes after its discontinuation. Sodium nitroprus- surgery and reported that adenosine-induced hypotension side primarily dilates resistance vessels, and the haemo- at MAP between 40-50 mmHg (5.3-6.7 kPa) did not dynamic response to its administration results from a cause any adverse effects on cerebral circulation or oxy- combination of venous pooling and reduced arterial im- genation. 93 Z'dll et al. 94 reported that adenosine-induced pedance. Sodium nitroprusside must be administered as hypotension during cerebral aneurysm surgery inhibits a continuous infusion. The initial dose is 0.5-1.5 renin release and induces profound decreases in renal ~tg. kg-J min-~ and higher rates are necessary to induce blood flow and glomerular fdtration rate caused predom- hypotension during surgery. The adverse effects of SNP inantly by afferent glomerular arterilar . include cyanide and thiocynate toxicity, rebound hyper- When the adenosine infusion was discontinued, glomer- tension, intracranial hypertension and blood coagulation ular fdtration rate returned to baseline levels. These re- abnormalities. The principal metabolite of nitroprusside, suits suggest that its use should be limited to brief periods cyanide, is converted to thiocyanate in the liver and may of hypotension, and it should not be used in patients accumulate in patients with liver disease. Accumulation with impaired renal function. of cyanide can occur if SNP is infused at rates greater than 2 ~tg. kg -j rain -I . The risk of thiocynate toxicity Nitroglycerin increases when SNP is infused for more than 24 hr, es- Organic nitrates are polyesters of nitric acid, whereas or- pecially if renal function is impaired. Toxic effects may ganic nitrites are esters of nitrous acids. Nitrate esters be prevented or reversed by the administration of sodium are characterized by a sequence of carbon-oxygen- 782 CANADIAN JOURNAL OF ANAESTHESIA

nitrogen. On the other hand, nitro compounds possess Vascular smooth muscle cell carbon-nitrogen bonds. Organic nitrates, nitrites and sev- eral other compounds that are capable of conversion to f Intrace,fu,ar nitric oxide have been termed nitro-vasodilators. Nitro- glycerin (TNG) dilates both veins and arteries directly, i~ NO ~ (Nn~r C~ GMP and has little effect on the smaller resistance vessels of (CN~-FeNO t 1 the body. Nitroglycerin's relaxation of vascular smooth R'-SH R:SS-R' / eGMP ~ r (alldu=~ (Ow~zKI) | KINASE v.~ KINASE muscles stems from the intracellular reaction of organic FI-ONO, nitrates with a sulfydryl moiety on the nitrate receptor IIr,~la~ailrma) Protein ~ p.l=tOlata to form inorganic nitrite. Nitrite is then oxidized to form p-tc~a~n "-"'~ ~ Lightel~aln ~ I..J~ ~lain nitric oxide. Nitric oxide in combination with tissue thiols Ca" forms an activator of guanylate cyclase, the enzyme that catalyzes the formation of cyclic guanylic acid (cGMP) (Figure 3). The increase in cGMP with guanylate cyclase activator is associated with relaxation of vascular smooth FIGURE 3 Schematicdiagram of cellularmechanism of action of nitrogen oxide-containingvasodilators (). The muscle. Nitric oxide is thought to be the active inter- conversion of guanosine triphosphate(GTP) is catalyzedby guanylate mediator for the action of this broad class of agents. 95-96 cyclase. Nitric oxide(NO) derived from the nitrovasodilatorsactivates Perioperatively, intravenous nitroglycerin infusion may the solubleisoenzyme form of guanylatecyclase and results in be used to reduce blood pressure during cerebral aneu- increased cyclicguanylic acid (cGMP) synthesisand cyclicGMP rysm surgery. Cottrell studied the changes in intracranial dependent protein kinase activation.These events result in the dephosphorylationof myosinlight chain and relaxation.From Ignarro pressure in hyperventilated patients undergoing craniot- L J, Lippton H, Edwards JC, et at J PharmacolExp Ther 1981; 218: omy and reported that intracranial pressure increased 739, and Murad E Cyclicguanosine monophosphate as a mediatorof from 14.2 to 30.8 mmHg and cerebral perfusion pressure .J Clin Invest 1986; 78: 3). decreased from 90.2 to 38.2 mmHg. 83 Low intracranial compliance contraindicates the use of TNG prior to dural opening. Langerkranser 97 reported that TNG may cause metaphan is rarely used because of the high incidence increased intracranial pressure, especially in patients with of adverse effects such as bowel and bladder atony and intracranial hypertension, by its venodilatating effects on the rapid development of tachyphylaxis. the cerebral circulation and concluded that, during neu- rosurgical operations, the administration of TNG should, Calcium antagonists if possible, be restricted to the period when the dura is The use of calcium channel blockers has enabled marked open, and the lungs should be moderately hyperventi- progress to be made in studies concerning the role of lated. Maktabi et al. 98 studied the effects of SNP-, TNG- extracellular Ca ++ influx in cardiac and smooth muscle and isoflurane-induced hypotensive anaesthesia on the contraction. Calcium channel blockers, structurally re- cardiovascular system and intrapulmonary shunting in 30 lated to nifedipine, are beneficial in the treatment of hy- patients and reported that was decreased pertension, myocardial ischaemia, and cerebral and cor- more by TNG and isoflurane than with SNP at a mean onary vasospasm during anaesthesia. 1~ The major arterial blood pressure of 40 mmHg. antihypertensive mechanism of calcium antagonists is by decreasing systemic , modified by the ~imetaphan counter-regulatory responses of the and the Trimetaphan (TMP) acts mainly by sympathetic gangli- renin--aldosterone system. 1~ However, the onic blockade as well as by histamine release. 99,1~176A dis- calcium channel blockers, verapamil 1~ and diltiazem ~~ tinct advantage of TMP is that automatic reflexes are may produce severe negative and dromo- blocked. Knight et al. demonstrated that norepinephrine, tropic effects when used to induce systemic hypotension. epinephrine, plasma renin activity, and angiotensin II did Recently, it has been shown that calcium channel blockers not increase as much after TMP as after SNP. ~ol Using also affect the cerebral circulation. Nicardipine, 107,108 ni- a thermal gradient blood flow meter, we measured local modipine, 109 verapami1107 and diltiazem "~ increased cer- cerebral blood flow in 19 patients undergoing cerebral ebral blood flow in animals. Nicardipine is a water- aneurysm clipping during TMP-induced hypotension and soluble, photoresistant di-hydropyridine calcium channel found that local cerebral blood flow was reduced with blocker that causes potent systemic and coronary vaso- TMI~. 63 Turner et al. reported that TMP has little dilator dilatation but does not result in negative inotropic, chro- action on the cerebral vessels, as indicated by the lack notropic, or effects. 11 It has been reported of increase in intracranial pressure with this drug. 102 Tri- that nicardipine increased cerebral blood flow in humans Abe: HYPOTENSION AND SAH 783 and animals. 1~ In our study, nicardipine did not with little effect on pulmonary gas exchange or cardiac change LCBF or carbon dioxide reactivity, but LCBF output, m,m Newman et al. studied the effect of was improved in patients with good presurgical neuro- isoflurane-induced hypotension on CBF and CMRO2 in logical status than in those with poor neurological status. 12 patients undergoing cerebral aneurysm surgery and The hypotensive effect of nicardipine persisted after its concluded that, with regard to global cerebral oxy- discontinuation which is similar to PGE~ 47 The elimi- genation, isoflurane was a safe agent with which to induce nation half-life of nicardipine increased to four to eight hypotension.88 Using thermal diffusion probe, Roth et hours when a continuous intravenous infusion was ad- a/. 124 measured cerebral cortical blood flow and CMRO2 ministered. H2 Anaesthesia and operation may interfere in patients undergoing cerebral aneurysm surgery and with drug disposition, and lead to a decrease in systemic concluded that CBF and oxygen delivery were main- clearance and an increase in plasma concentration. 113 tained during isoflurane-induced hypotension during Consequently, the continuous administration of nicardi- fentanyl-nitrous oxide anaesthesia. Haraldsted et al. 125 pine to induce hypotension during anaesthesia may result studying the cerebral arteriovenous 02 difference during in cumulative effects that persist after discontinuation of in 20 patients undergoing cerebral aneurysm surgery, con- the infusion. It has been reported that the calcium an- cluded that cerebral blood flow and oxygen demand/ tagonists dilate the cerebral resistance vessels and increase supply ratios were maintained favourably during induc- cerebral blood flow. 114 tion of hypotension with isoflurane at concentrations Diltiazem is a benzothiazepine derivative calcium an- <2.5 MAC. Isoflurane causes an increase in intracranial tagonist which acts by interfering with calcium-mediated pressure, 126 plasma epinephrine is decreased but plasma events in excitation-contraction coupling in cardiac and epinephrine and norepinephrine concentrations and smooth muscle. The effectiveness of diltiazem in patients plasma renin activity increased during induced hypoten- with mild to moderate hypertension has been proved in sion in halothane-SNP combined group. It was concluded double-blind comparison with placebo. HS,jl6 Also, dilti- that isoflurane-induced hypotension with isoflurane azem was effective when given intravenously to patients anaesthesia, unlike SNP-induced hypotension with halo- with hypertensive emergencies 117 and/or with postopera- thane anaesthesia, attenuated the stress response. ~27 The tive hypertension. 118 Intravenous diltiazem has been used role of the endothelium in the vascular response to volatile to prevent ischaemia in patients with coronary artery dis- anaesthetics remains controversial. Several studies suggest ease during non-cardiac surgery. ,9 There is some infor- that the volatile anaesthetics may induce endothelium- mation about the cerebral vascular effects of diltiazem dependent relaxation in isolated vascular rings, j28,129 which appears to block receptors and potential dependent Stone et al. studied the endothelium-dependent vascular calcium channels without blocking stretch-induced cal- effects of isoflurane using isolated ring preparations of cium influx. 120 It has been reported that diltiazem pre- rat thoracic aorta and reported that isoflurane causes va- vents or at least minimizes Ca ++ entry into the vascular soconstriction through inhibition of basal EDRF produc- muscle and endothelial cells in the cerebral arteries tion or stimulation of the release of an endothelium- through potential-sensitive and receptor-operated mech- derived vasoconstriction factor at low concentrations and anisms, and that this effect has some selectivity for the that at higher concentrations a direct vasodilating effect cerebral arteries. 121 of anaesthetic predominates. 129 However, the role of the Verapamil is a less potent vasodilator than nicardipine. endothelium in the vascular response to volatile anaes- Prompt reduction of blood pressure can be achieved after thetics remains uncertain. the intravenous administration of verapamil. The cur- rently recommended dosage is 5 to 10 mg, given as an Other vasodilators /v bolus over two minutes. Intravenous administration of verapamil causes a decrease in arterial blood pressure HYDRALAZ1NE due to a decrease in vascular resistance, but the reflex Hydralazine causes direct relaxation of arteriolar smooth tachycardia is blunted by the direct negative chronotropic muscle and most of its effects are confined to the car- effect of verapamil. 113 diovascular system. The decrease in blood pressure is as- sociated with a decrease in vascular resistance in the cor- lsoflurane onary, cerebral and renal circulations. Hydralazine is well The volatile anaesthetic, isoflurane, has been used ex- absorbed through the gastrointestinal tract and the half- tensively to induce hypotension during cerebral aneurysm life is one hour. Hydralazine is administered in doses of surgery because of its rapid onset of action, easy con- 20 to 40 mg/v when there is an urgent need to decrease trollability, and rapid reversal of the cardiovascular effects blood pressure, but the response is very unpredictable on discontinuation. It causes peripheral vasodilatation and prolonged hypotension is not unusual even with doses 784 CANADIAN JOURNAL OF ANAESTHESIA

TABLE Ill Parenteralmedications used in the treatment of hypertensiveemergencies

Duration Drug Administration* Onset of action Dosage Adverse effects and comments

Sodium /v infusion Immediate 2-3 min 0.5-10~tg kg-I min-] Hypotension,nausea, vomiting, apprehension. Risk nitroprusside (initial dose, 0.25 of thiocyanate and cyanide toxicity is increased in ~tg" kg-I- min-t for renal and hepatic insufficiency,respectively; levels eclampsia and renal should be monitored. Must be shielded from light. insufficiency) Diazoxide /v bolus 1-5 rnin 6-12 hr 50-100mg every 5-10 Hypotension, tachycardia, nausea, vomiting, fluid min, up to 600 mg retension, hyperglycemia.May exacerbate myocardial ischemia, failure, or aortic /v infusion 10-30 mg" min-l dissection. May require concomitant use of a 13- antagonist. Labetalol /v bolus 5-10 min 3-6 hr 20-80 mg every 5-10 Hypotension, heart block, heart failure, min, up to 300 mg bronchospasm, nausea, vomiting, scalp tingling, paradoxical pressor response. May not be effective in patients receivinget- or 13-antagonists. /v infusion 0.52-2 mg' rain-j Nitroglycerin /v infusion 1-2 min 3-5 min 5-100 ~.g' min-t Headache, nausea, vomiting. Tolerance may develop with prolonged use. Trimetaphan /v infusion 1-5 min 10 min 0.5-5 mg" min-I Hypotension, urinary retention, ileus, respiratory arrest, mydriasis,cycloplegia, dry mouth. More effective if patient's head is elevated. Hydralazine (for /v bolus 10-20 rain 3-6 hr 5-10 mg every 20 min (if Hypotension, fetal distress, tachycardia, headache, treatment of no effect after 20 mg, try nausea, vomiting, local thrombo phlebitis;infusion eclampsia) another agent) site should be changed after 12 hr. Nicardipine~ /v infusion 1-5 rain 3-6 hr 5 mg" hr-I, increased by Hypotension, headache, tachycardia, nausea, 1-2.5 mg- hr-l every 15 vomiting. min, up to 15 mg' hr-I

*/v denotes intravenous. 1"Not yet approved by the Food and Drug Administrationfor this use. From Calhoun LA, Oparil S. Treatment of hypertensivecrisis. New Engl J Med 1990; 223:1179.

as low as 10 mg. James et al. studied the effect of LABETALOL hydralazine-induced hypotension during enflurane anaes- Labetalol acts as a competitive antagonist at both eq- thesia in patients during neurosurgical operations, and and 13radrenergic receptors. The actions on both eq and reported that hydralazine is a simple, smooth, predictable, 13j adrenergic receptors induces a decrease in blood pres- nontoxic technique to induce hypotension during neu- sure in patients with hypertension. Orlowski et al. ad- rovascular operations. 130 ministered labetalol to 15 postoperative neurosurgical pa- tients who had undergone neurovascular surgery. The DIAZOXIDE patients had been treated initially with SNP to maintain Initially, diazoxide was developed as an oral antihyper- reasonable arterial blood pressure, but because of ex- tensive drug, but it induced unacceptable side effects (hy- cessive SNP dose requirements, intravenous labetalol was perglycaemia, hypertrichosis). It was given parenterally administered. Mean intracranial pressure decreased from for the treatment of hypertensive emergencies, but sodium 11.3 + 6.1 mmHg with SNP to 8.6 + 3.1 mmHg after nitroprusside has replaced diazoxide as the drug of choice conversion to labetalol. 132 for hypertensive cases. Although the plasma half-life of diazoxide is 20 to 60 hr, the duration of the hypotensive ESMOLOL response is variable and can be as short as four hours Esmolol is a selective 131 antagonist with a very short or as long as 20 hr. The main indication for diazoxide duration of action and has a half-life of about eight min- is the treatment of hypertensive emergencies. However, utes. It has been reported that esmolol and labetalol were excessive hypotension may induce cardiac or cerebral useful in controlling systolic blood pressure in emergen- damage. The most common side effects caused by diaz- cies and in the recovery room in patients undergoing in- oxide are salt and water retention and hyperglycaemia. 131 tracranial surgery 133 (Table III). Abe: HYPOTENSION AND SAH 785

Clinical implications drugs that dilate cerebral vessels and increase cerebral The use of induced hypotension has declined because blood flow may also cause an immediate increase in in- it may induce or exacerbate brain ischaemia during aneu- tracranial pressure and create the potential for cerebral rysm surgery, but intraoperative rupture of a cerebral herniation. 135 aneurysm, especially if rupture occurs before its exposure In our studies, arterial blood pressure was reduced im- may induce catastrophic result. A recent retrospective mediately after the start of hypotensive drugs, but the study suggests the usefulness of temporal clipping than hypotensive effect of PGEI and nicardipine infusion per- induced hypotension. 70 The use of temporal clipping to sisted after their discontinuation. PGE~ and nicardipine decompress aneurysms, or to treat intraoperative aneu- do not change LCBF; trimetaphan decreases LCBF and rysm rupture has been preferred to induced hypotension nitroglycerine increases LCBE We confirmed that PGEt, recently. However, it is unclear whether improvement in TMP, TNG and nicardipine did not change carbon di- outcome results from the use of temporary clips or the oxide reactivity during surgery but carbon dioxide reac- increase in surgical experience and expertise. 134 Prolonged tivity had a close correlation with presurgical neurological temporary occlusion can be unforgiving when the oc- status. cluded vessel supplies numerous small perforators such as the carotid birfucation, the M1 segment of middle Conclusion cerebral artery, or the anterior communicating artery. Induced hypotension has been used to decrease the risk These arterial segments supply perforating vessels without of intraoperative aneurysmal rupture but the use of it collateral circulation. The other difficulty that arises from is declining because of brain ischaemia. But intraoper- temporal clipping is the physical and anatomical limi- ative hypertension should be treated immediately to re- tations of applying multiple clips in a confined space, duce the risk of rebleeding. Profound hypotension should particularly with basilar aneurysms in which space is usu- be avoided. A drug that does not change CBF during ally the limiting factor. Complete dissection of an aneu- cerebral aneurysm surgery should be used to induce hyp- rysm neck by surgical clipping and without injury to otension. surrounding brain or blood vessels, is the goal of aneu- rysm surgery. In cases of giant cerebral aneurysm, fragile Acknowledgements aneurysm or multiple cerebral aneurysms, induced hyp- I thank Professor Ikuto Yoshiya MD, PhI~ and Yasuhiro otension may be recommended to prevent the intraop- Shimada MD, PhO, Dept of Anaesthesia Osaka University erative rupture, but long-term hypotension or profound Medical School and Nagoya University Medical School hypotension may induce cerebral ischaemia after surgery for their valuable advice. and provoke end-organ ischaemia or infarction. Thus, profound and long-term hypotension should be avoided. References During cerebral aneurysm surgery, the effect of vasod- 1 Lam AM. Induced hypotension. Can Anaesth Soc J 1984; ilators on cerebral vasculature should be kept in mind. 31: $56-$62. 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Any drug used for the 4 Symon L Disordered cerebro-vascular physiologyin treatment of intraoperative hypertension carries the risk aneurysmal subarachnoid haemorrhage. Aeta Neurochir of decreasing cerebral blood flow below the lower limit (Wien) 1978; 41: 7-22. of autoregulation to induce cerebral ischaemia or infarc- 5 McDowall DG. Induced hypotension and brain ischaemia. tion. Vasoactive drugs have less effects in the cerebral Br J Anaesth 1985; 57: 110-9. circulation than in other vascular beds, in part because 6 Hunt WE, Kosnik El.. Timing and perioperative care in of the protective effect of the blood-brain barrier, but intracranial aneurysm surgery. Clin Neurosurg 1974; 21: drugs that penetrate the blood-brain barrier and dilate 78-89. the cerebral vessels (e.g., hydralazine, sodium nitroprus- 7 Disney L, Weir B, Grace M. 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