Department of Pharmacology, University of DurbanWestville, Durban (AD, VR, RM), and Departments of Pharmacology (JHB) and Neurosurgery (JRvD), University of Natal, Wentworth Hospital, Durban, South Africa Neurosurgery 31; 42-51, 1992 ABSTRACT: DESPITE INTENSIVE INVESTIGATION into the cause of cerebral vasospasm (focal ischemic deficit) after subarachnoid hemorrhage, the morbidity and mortality associated with this condition remain high. Various studies have shown levels of catecholamine in plasma and cerebrospinal fluid (CSF) to be increased in subarachnoid hemorrhage, and it is possible that these vasoactive substances play an important role in the subsequent vasospasm. In an attempt to elucidate this possibility, the study presented here was undertaken to investigate the relationship between catecholamine levels in plasma and CSF and focal ischemic deficit (FID); the rupture of aneurysms on blood vessels supplying the hypothalamus as compared with the rupture of aneurysms on blood vessels supplying other areas of the brain; and the clinical outcome of the patients. Concentrations of adrenaline and noradrenaline in plasma and CSF samples obtained from 21 patients who had suffered aneurysmal subarachnoid hemorrhage were determined by a radioenzymatic technique. Significantly higher levels of adrenaline were found at the time of surgery in the CSF of patients with FID. A similar trend, though not statistically significant, was also observed for plasma. Patients with a rupture of aneurysms on blood vessels supplying the hypothalamus showed a tendency towards higher catecholamine levels in plasma and CSF. Subjects with a bad clinical outcome (i.e., those who were severely disabled or had died) had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome (i.e., those with moderate or no disability). Further detailed analysis of the interrelationships showed that, within the group of patients with FID, those with rupture of aneurysms on blood vessels supplying the hypothalamus had significantly higher catecholamine levels in plasma than did those with rupture of aneurysms on other cerebral vessels. Furthermore, in the group of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a bad clinical outcome had significantly higher
KEY WORDS: Aneurysm; Catecholamines; Focal ischemic deficit; Subarachnoid hemorrhage; Vasospasm Despite extensive study of subarachnoid hemorrhage, the incidence of cerebral vasospasm and poor clinical outcome remains high (17,33). Pivotal to this is the fact that, sometimes even after successful surgery, patients develop focal ischemic deficits (FID) with resultant morbidity and mortality. FID are presumably due to decreased oxygen supply to the brain tissue as a result of vasospasm. Although vasospasm is not proven in all cases, in some, angiographic evidence of vasospasm exists. Although the cause of vasospasm is as yet unknown, various vasoactive substances such as catecholamines, serotonin, thromboxane, adenine nucleotides, and oxyhemoglobin have been implicated (11-13,30,31). The possibility that catecholamines may be important is suggested by the fact that elevated levels of catecholamine in plasma have been recorded in patients with vasospasm and in those patients with a poor clinical outcome (15,19). In this respect, damage to the hypothalamus may be an important step in the development of vasospasm. Hypothalamic injury might stimulate a widespread sympathetic discharge (32) , causing increased levels of circulating catecholamines, which in turn might cause cerebral vasospasm (25). The involvement of the hypothalamus is supported by the finding of lesions in the hypothalamus after subarachnoid hemorrhage (5,7), as well as by the more frequent occurrence of vasospasm after the rupture of aneurysms on blood vessels supplying the hypothalamus than after the rupture of aneurysms on blood vessels supplying other areas of the brain (1,5). To further investigate the role of catecholamines in subarachnoid hemorrhage, the relationships between catecholamine levels in plasma and cerebrospinal fluid (CSF) and FID, site of aneurysmal rupture, and clinical outcome were investigated in 21 patients. PATIENTS AND METHODS Twenty-one patients admitted to the Neurosurgical Unit at Wentworth Hospital, Durban, South Africa, for treatment of aneurysmal subarachnoid hemorrhage were entered into the study. Venous blood was collected from the patients before and during surgery, as well as at 6, 24, 48, and 144 hours after surgery. Both ventricular and basal cisternal CSF were obtained at the time of surgery. After surgery, only ventricular CSF was collected at 6, 24, and 48 hours from those patients who had indwelling catheters. In addition, venous blood samples were collected from nine normal, healthy volunteers. All samples were collected in tubes containing a glutathione/ EGTA additive solution to prevent the degradation
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AUTHOR(S): Dilraj, Athmanundh, M.Med.Sc.; Botha, Julia Hilary, Ph.D.; Rambiritch, Virendra, M.Med.Sc.; Miller, Raymond, D.Sc.; van Dellen, James Rikus, F.R.C.S., Ph.D.
catecholamine levels in plasma than did those with a good clinical outcome. These findings lend support to the possibility that damage to the hypothalamus and subsequent elevations in catecholamine levels may be associated with FID and poor clinical outcome.
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Neurosurgery 1992-98 July 1992, Volume 31, Number 1 42 Levels of Catecholamine in Plasma and Cerebrospinal Fluid in Aneurysmal Subarachnoid Hemorrhage Clinical Study
RESULTS Mean (±SE) levels of adrenaline and noradrenaline in plasma in the nine healthy volunteers were 0.27 (0.03) and 1.23 (0.08) nmol/l respectively. Comparisons between these levels and those of the 21 patients are presented in Tables 1 and 2. The demographic and clinical details of all patients are presented in Table 3. As can be seen, 13 patients developed FID, 15 had rupture of aneurysms on blood vessels supplying the hypothalamus, and 3 had a poor clinical outcome. A comparison of catecholamine levels in plasma and CSF within the three groups yielded the following results. Catecholamine levels and FID The mean adrenaline and noradrenaline levels in plasma and CSF are presented in Tables 4 and 5. Patients with FID had significantly higher adrenaline levels in ventricular CSF (P = 0.02) and cisternal CSF (P = 0.05) at the time of surgery than did patients without FID. Although there was a tendency for levels of both adrenaline and noradrenaline in plasma to be higher in the group of patients with FID than in the group comprising patients without FID, these differences were not statistically significant. Catecholamine levels and site of rupture of aneurysms Patients with rupture of aneurysms on blood vessels supplying the hypothalamus generally had higher levels of adrenaline and noradrenaline in plasma than did those with rupture of aneurysms on other blood vessels (Table 6). Such a trend was only noted in the immediate postoperative period for adrenaline and noradrenaline levels in CSF (Table 7). None of these differences was statistically significant. Catecholamine levels and clinical outcome
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lead independent lives were considered as having a good clinical outcome. Those who were severely disabled or were vegetative and had to lead dependent lives were grouped with those who had died. This group was regarded as having a poor clinical outcome (16). In addition, various other interrelationships were investigated by examining catecholamine levels in certain subgroups of patients. Those of particular interest were the following: 1) all patients with FID. In this subgroup, catecholamine levels were compared between patients who had rupture of aneurysms on blood vessels supplying the hypothalamus and those who had rupture of aneurysms on other cerebral arteries; and 2) all patients with rupture of aneurysms on blood vessels supplying the hypothalamus. In this subgroup, catecholamine levels in those patients with a poor clinical outcome were compared with levels in those patients who had a good clinical outcome. As an extension to the study, an attempt was made to relate catecholamine levels at the time of surgery to time after subarachnoid hemorrhage. The Mann-Whitney U test was used to test the statistical significance of any differences observed.
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of catecholamines. After being mixed thoroughly, the tubes were kept on ice until they were centrifuged at 2000 rpm for 5 minutes at 4°C. All plasma and CSF samples were transferred to duplicate tubes and stored at -80°C until analysis. Adrenaline and noradrenaline were assayed by the radioenzymatic assay of Peuler and Johnson (26) with various modifications. Essentially this assay involves the prior preparation of the enzyme catechol-O-methyl transferase from rat livers by the method of Axelrod and Tomchick (2). This enzyme transfers a radioactive methyl group from S-adenosyl-L-[methyl3H]methionine to endogenous catecholamine molecules to form radioactive catechol derivatives, namely, metadrenaline and normetadrenaline. These derivatives are extracted into an organic phase, back extracted into acid, and separated by thin layer chromatography. Periodate oxidation converts the derivatives to vanillin, which is extracted into toluene and quantitated by liquid scintillation counting. The modifications were as follows: the pretreatment of rats with reserpine and the removal of the adrenal glands before the removal of the livers in order to minimize the amounts of catecholamines in the enzyme preparation (4,24); the use of a methyl donor, S-adenosyl-L-[methyl3H]methionine of higher specific activity (15 Ci/mmol; Amersham International, Amersham, Buckinghamshire, England); the extraction of the radioactive derivatives into diethyl ether and back extraction into hydrochloric acid (6); and the development of the thinlayer chromatography plates in a solution of chloroform, ethanol, and 70% ethylamine (16:3:2) for approximately 1 hour (6). The success of the assay was confirmed by testing for linearity in the range of 1 to 15 nmol/l for adrenaline (r 2 = 0.9908) and 5 to 20 nmol/l for noradrenaline (r 2 = 0.9921). The intra-assay variations for adrenaline and noradrenaline were 8.88 and 10.90%, respectively, whereas the respective interassay variations were 11.23 and 14.79%. The recoveries for both adrenaline and noradrenaline were more than 75%. Levels of catecholamine in plasma and CSF were compared within the following groups: 1) patients who developed FID versus those who did not. Patients with angiographic evidence of vasospasm were grouped with those who developed localizing or lateralizing signs, such as monoplegia and hemiplegia, which could not be directly attributed to the surgical procedures in terms of vascular occlusion or damage. This included the development of confusion. This group of patients was classified as having developed FID; 2) patients with rupture of aneurysms on blood vessels supplying the hypothalamus versus those with rupture of aneurysms on vessels supplying other areas of the brain. Blood vessels considered to be supplying the hypothalamus were the internal carotid artery and the anterior and posterior communicating arteries (3,9,10,23,27,28); and 3) patients with a good clinical outcome versus those with a poor clinical outcome. Patients who had a good recovery or moderate disability and who could
Catecholamine levels, site of aneurysmal rupture, and clinical outcome Considering the subset of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a poor clinical outcome had significantly higher levels of adrenaline in plasma at 6 h (P = 0.005) and 24 hours (P = 0.02) postsurgery than did those with a good clinical outcome (Table 11). Significantly higher levels of noradrenaline in plasma were also measured at 6 (P = 0.043) and 24 hours (P = 0.05) in these patients. Catecholamine levels and interval from subarachnoid hemorrhage to surgery Tables 12 and 13 show that significantly higher levels of noradrenaline in plasma were found in patients who had undergone surgery in the period of 5 to 14 days when compared with those who had undergone early surgery (0-4 days) (P = 0.005). DISCUSSION Postsurgery levels of catecholamine in plasma in patients with subarachnoid hemorrhage were found to be significantly higher than the levels of catecholamine in plasma in the normal, healthy volunteers. This finding is consistent with that of
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Catecholamine levels, site of aneurysmal rupture, and FID FID developed more frequently in patients with rupture of aneurysms on blood vessels supplying the hypothalamus (67%) than in those with rupture of aneurysms on blood vessels supplying other areas of the brain (50%). Considering the subset of all patients with FID, 77% had rupture of aneurysms on vessels supplying the hypothalamus whereas only 23% had rupture of aneurysms on blood vessels supplying other areas of the brain. A further observation in these patients with FID was that those with rupture of aneurysms on blood vessels supplying the hypothalamus showed significantly higher adrenaline and noradrenaline levels in plasma (P = 0.05 and P = 0.035, respectively) at the time of surgery than did those with rupture of aneurysms on vessels supplying other areas of the brain (Table 10).
Minegishi et al. (22), who showed that patients with subarachnoid hemorrhage who had undergone surgery had significantly higher levels of catecholamine in plasma than did normal, healthy controls. Patients with FID were found to have significantly higher levels of adrenaline in the cisternal and ventricular CSF at the time of surgery than did those patients who did not develop FID. This finding may indicate that elevated adrenaline levels in the CSF at the time of surgery are important in determining subsequent vasospasm. Such a possibility is supported by the observations of Yamashima and Yamamoto (34), who tested the responses of cerebral arteries of dogs to several vasoconstrictors and found adrenaline to be the most potent agent producing vasospasm. Although other workers (15,19) have reported significantly higher levels of both adrenaline and noradrenaline in the plasma of patients with vasospasm, the inability to do the same in this study may be because of the small number of subjects. This problem was also encountered by Minegishi et al. (22) , and as suggested by them, a larger number of subjects may be required to demonstrate statistical significance. Alternatively, it is possible that there is increased sensitivity of cerebral arteries to catecholamines in patients who have vasospasm (8,20, 21,29) . Such increased sensitivity could possibly explain the development of FID in some patients, even though their catecholamine levels were not statistically higher than those who did not develop FID. Although not yet proven in humans, the supersensitivity of cerebral arteries to noradrenaline after experimental subarachnoid hemorrhage has been reported in cats (20,21) and in rabbits (8). These studies revealed a decrease in the noradrenaline content at perivascular nerve endings as well as a reduced reuptake of noradrenaline into the nerve endings, suggesting that the impaired reuptake of noradrenaline might result in a denervation-type supersensitivity of the vascular smooth muscle. The fact that high catecholamine levels were measured in some patients in whom FID was not demonstrated could possibly be explained by spasm of fine arteries supplying the hypothalamus. Such spasm would not have been detected angiographically but has been postulated by Doshi and Neil-Dwyer (7) to alter sympathetic function with a resultant increase in catecholamines. The trend towards higher catecholamine levels seen in patients with rupture of aneurysms on blood vessels supplying the hypothalamus could be consistent with hyperactivity of the sympathetic nervous system. Crompton (5) found that after rupture of aneurysms on blood vessels supplying the hypothalamus, most lesions occurred in the anterior hypothalamus. In general, the anterior hypothalamus influences mainly parasympathetic events whereas the posterior hypothalamus influences mainly sympathetic events. Because the sympathetic and the parasympathetic systems act reciprocally, damage to the anterior hypothalamus would allow a relative hyperactivity of the sympathetic system. A consequence of this could be an increase in
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The 3 patients with a poor clinical outcome had significantly higher levels of adrenaline in plasma measured at 6 (P = 0.005), 24 (P = 0.01), and 48 hours (P = 0.05) after surgery than did the group with a good clinical outcome (Table 8). Significant differences were also noted for noradrenaline levels in plasma at 6 (P = 0.015), 24 (P = 0.04), and 48 hours (P = 0.05) after surgery. Unfortunately, CSF could only be obtained from 1 of the 3 patients who had a poor clinical outcome. Consequently, even though the levels of adrenaline and noradrenaline in this sample at 6 hours postsurgery were much higher than the levels for patients with a good clinical outcome, the single sample in the former group was insufficient for statistical significance to be reached (Table 9). Further detailed analyses of catecholamine levels within certain subgroups revealed the following.
CONCLUSIONS The study presented here has confirmed previous reports by others (15,19) that patients who have a poor clinical outcome have significantly higher levels of catecholamine in plasma than do those with a good clinical outcome. Although CSF from only 1 patient with a poor clinical outcome was available, the immediate postsurgery sample from this patient also contained larger amounts of catecholamine than did the CSF of patients with a good clinical outcome. It is thus possible that catecholamine levels could be used to identify patients likely to have a poor clinical outcome. The investigation into a possible relationship between catecholamines and FID revealed significantly higher levels of catecholamine in CSF at the time of surgery in those patients with FID. This could indicate that elevated catecholamine levels in CSF at the time of surgery may be related to the subsequent development of vasospasm. It is possible that a lack of angiography at appropriate times to determine the severity of spasm or its inability to detect spasm of small vessels prevented further identification of some relationship that may have existed. When considering all of the patients who developed FID, 77% had rupture of aneurysms on blood vessels supplying the hypothalamus. These patients also had significantly higher levels of catecholamine in plasma than did those with rupture of aneurysms on vessels supplying other areas of the brain. It is thus tempting to speculate that rupture of aneurysms on blood vessels supplying the hypothalamus may result in damage to the hypothalamus, a consequent hyperactivity of the sympathetic nervous system with increased catecholamine release, and resultant FID. Although the exact cause of FID in subarachnoid hemorrhage remains unclear, this present study has demonstrated that the hypothalamus, catecholamines, and FID are inextricably linked to the morbidity and mortality of this condition. ACKNOWLEDGMENT This study was supported by grants from the University of Durban-Westville, the University of Natal, and the Medical Research Council of South Africa.
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subarachnoid hemorrhage had the least favorable outcome. The major cause of morbidity and mortality was attributed to vasospasm. It is thus interesting that in this present study, those patients who had undergone surgery between 5 and 14 days after subarachnoid hemorrhage had significantly higher levels of noradrenaline in plasma than did those who had surgery between 0 and 14 days after subarachnoid hemorrhage. In addition, 2 of the 3 patients who had a bad clinical outcome had surgery between 7 and 10 days after hemorrhage. Both of these had noradrenaline levels in plasma almost twice that of the mean levels for the 5- to 14-day group, and they also had evidence of vasospasm and infarction.
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catecholamine levels in plasma. In 1975, Wilkins (32) proposed that if injury to the hypothalamus influences cerebral vasospasm, then FID should occur most frequently after rupture of aneurysms in locations adjacent to the hypothalamus or on blood vessels that supply the hypothalamus. Although not statistically significant, the results of the study presented here did indeed show that FID developed more frequently in patients with ruptured aneurysms on blood vessels supplying the hypothalamus than in those in whom other vessels were involved (67 versus 50%). Furthermore, considering all patients with FID, 77% of these had suffered rupture of aneurysms on arteries supplying the hypothalamus. These findings are consistent with the observations of Allcock and Drake (1). Those authors found that operations on aneurysms arising from the carotid siphon or anterior cerebral arteries (i.e., vessels supplying the hypothalamus) seemed more likely to provoke FID than did operations on aneurysms arising from the middle cerebral arteries (i.e., vessels supplying other areas of the brain). It is interesting to note that in the study presented here, patients who developed FID after the rupture of aneurysms on vessels supplying the hypothalamus had significantly higher levels of catecholamine in the CSF at the time of surgery than did those who developed FID after the rupture of aneurysms on vessels supplying other areas of the brain. These findings tend to support further the involvement of the hypothalamus and catecholamines in the pathogenesis of FID. A clear relationship between clinical outcome and catecholamine levels in plasma was demonstrated in that patients with a poor clinical outcome had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome. These findings are in agreement with those of others (15,19) , who also demonstrated significant differences in catecholamine levels in plasma between patients with good and poor clinical outcomes. Hence, catecholamine levels could be used as an indication of prognosis in subarachnoid hemorrhage patients and, hence, as a guide to therapeutic approaches in management. The observation that all patients with a poor clinical outcome had suffered rupture of aneurysms on blood vessels supplying the hypothalamus further tends to support the possible involvement of the hypothalamus in the morbidity and mortality associated with subarachnoid hemorrhage. Considering all patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a poor clinical outcome had significantly higher catecholamine levels than did those with a good clinical outcome. This may suggest that high levels of catecholamine in plasma associated with rupture of aneurysms on blood vessels supplying the hypothalamus are a more precise indicator of poor prognosis than are catecholamine levels alone. With respect to the interval from subarachnoid hemorrhage to surgery, Kassell et al. (18) found that patients undergoing surgery for ruptured cerebral aneurysms in the period 7 to 10 days after
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Received, March 6, 1991. Accepted, December 16, 1991. Reprint requests: Athmanundh Dilraj, M.Med.Sc., Department of Pharmacology, University of DurbanWestville, Private Bag X54001, Durban 4000, South Africa.
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COMMENT The study of CSF and plasma adrenaline (epinephrine) and noradrenaline (norepinephrine) is presented by the authors as a logical extension of clinical reports of associating lesions in the hypothalamus with aneurysmal subarachnoid hemorrhage and its subsequent vasospasm. Destructive lesions in the hypothalmic regions associated with parasympathetic activity have been postulated to leave unopposed or to allow hyperactivity of the sympathetic nuclei. Pathological alterations in electrolyte balance, body temperature, and cardiac rhythm are well known to occur after subarachnoid hemorrhage. In fact, patients with cardiac arrythmias and diabetes insipidus secondary to hypothalmic dysfunction after aneurysm rupture have a poor prognosis. Therefore, patients having such a massive output of sympathetic activity would be expected to have elevations in catecholamine levels in plasma as was found by the authors in the study of their 21 patients. Although the authors have taken great care to ensure the validity of their cerebrospinal fluid (CSF) collection and assay methodology (4), other variables that may influence the concentrations of norepinephrine in plasma or CSF include the craniospinal concentration gradient, circadian rhythms, the amount of blood-brain barrier damage, the use of vasopressors and the presence or absence of premorbid systemic arterial hypertension (1-3). Studies involving larger groups of patients would allow the investigators to control for these additional variables. Most important, the authors have associated a poor clinical outcome with significantly elevated catecholamine levels in the plasma, which would indicate that peripheral sympathetic activity would be in itself detrimental or a marker for a dangerous process. Because noradrenaline rather than adrenaline is more important as a central nervous system neurotransmitter and because a relative blood-brain barrier for noradrenaline exists during physiological conditions (2,3), the elevation of adrenaline levels in CSF in patients with subarachnoid hemorrhage may
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and norepinephrine in cerebral vasospasm. Acta Neurochir 63:277-280, 1982. Toda N, Shimizu K, Ohta T: Mechanism of cerebral arterial contraction induced by blood constituents. J Neurosurg 53:312-322, 1980. Voldby B, Engbaek F, Enevoldsen EM: CSF serotonin concentrations and cerebral arterial spasm in patients with ruptured intracranial aneurysm. Stroke 13:184-189, 1982. Wilkins RH: Hypothalamic dysfunction and intracranial arterial spasms. Surg Neurol 4:472-480, 1975. Wilkins RH: Attempted prevention or treatment of intracranial arterial spasm: A survey. Neurosurgery 6:198-210, 1980. Yamashima T, Yamamoto S: Cerebral arterial pathology in experimental subarachnoid hemorrhage. J Neurosurg 58:843-850, 1983.
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Table 2. A Comparison of Noradrenaline Levels in Plasma between Patients with Subarachnoid Hemorrhage and 9 Normal Subjects with a Mean Level of 1.23 (±0.08) nmol/L
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Table 1. A Comparison of Adrenaline Levels in Plasma Between Patients with Subarachnoid Hemorrhage and 9 Normal Subjects with a Mean Level of 0.27 (±0.03) nmol/L
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Table 3. Demographic and Clinical Details of Patientsa
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Table 5. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid in Patients with and without Focal Ischemic Deficitsa
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Table 4. Adrenaline and Noradrenaline Levels in Plasma in Patients with and without Focal Ischemic Deficits
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Table 7. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 6. Adrenaline and Noradrenaline Levels in Plasma after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 9. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid in Patients with Good and Poor Clinical Outcomea
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Table 8. Adrenaline and Noradrenaline Levels in Plasma in Patients with Good and Poor Clinical Outcomea
Table 12. Adrenaline and Noradrenaline levels at Surgery in Patients with Subarachnoid Hemorrhage with Respect to Time after Hemorrhagea
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Table 11. Adrenaline and Noradrenaline Levels in Plasma in Patients with Good and Poor Clinical Outcome after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamusa
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Table 10. Adrenaline and Noradrenaline Levels in Plasma in Patients with Focal Ischemic Deficits after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 13. Comparison of P Values between Groupsa
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KEY WORDS: Aneurysm; Catecholamines; Focal ischemic deficit; Subarachnoid hemorrhage; Vasospasm Despite extensive study of subarachnoid hemorrhage, the incidence of cerebral vasospasm and poor clinical outcome remains high (17,33). Pivotal to this is the fact that, sometimes even after successful surgery, patients develop focal ischemic deficits (FID) with resultant morbidity and mortality. FID are presumably due to decreased oxygen supply to the brain tissue as a result of vasospasm. Although vasospasm is not proven in all cases, in some, angiographic evidence of vasospasm exists. Although the cause of vasospasm is as yet unknown, various vasoactive substances such as catecholamines, serotonin, thromboxane, adenine nucleotides, and oxyhemoglobin have been implicated (11-13,30,31). The possibility that catecholamines may be important is suggested by the fact that elevated levels of catecholamine in plasma have been recorded in patients with vasospasm and in those patients with a poor clinical outcome (15,19). In this respect, damage to the hypothalamus may be an important step in the development of vasospasm. Hypothalamic injury might stimulate a widespread sympathetic discharge (32) , causing increased levels of circulating catecholamines, which in turn might cause cerebral vasospasm (25). The involvement of the hypothalamus is supported by the finding of lesions in the hypothalamus after subarachnoid hemorrhage (5,7), as well as by the more frequent occurrence of vasospasm after the rupture of aneurysms on blood vessels supplying the hypothalamus than after the rupture of aneurysms on blood vessels supplying other areas of the brain (1,5). To further investigate the role of catecholamines in subarachnoid hemorrhage, the relationships between catecholamine levels in plasma and cerebrospinal fluid (CSF) and FID, site of aneurysmal rupture, and clinical outcome were investigated in 21 patients. PATIENTS AND METHODS Twenty-one patients admitted to the Neurosurgical Unit at Wentworth Hospital, Durban, South Africa, for treatment of aneurysmal subarachnoid hemorrhage were entered into the study. Venous blood was collected from the patients before and during surgery, as well as at 6, 24, 48, and 144 hours after surgery. Both ventricular and basal cisternal CSF were obtained at the time of surgery. After surgery, only ventricular CSF was collected at 6, 24, and 48 hours from those patients who had indwelling catheters. In addition, venous blood samples were collected from nine normal, healthy volunteers. All samples were collected in tubes containing a glutathione/ EGTA additive solution to prevent the degradation
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AUTHOR(S): Dilraj, Athmanundh, M.Med.Sc.; Botha, Julia Hilary, Ph.D.; Rambiritch, Virendra, M.Med.Sc.; Miller, Raymond, D.Sc.; van Dellen, James Rikus, F.R.C.S., Ph.D.
catecholamine levels in plasma than did those with a good clinical outcome. These findings lend support to the possibility that damage to the hypothalamus and subsequent elevations in catecholamine levels may be associated with FID and poor clinical outcome.
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Neurosurgery 1992-98 July 1992, Volume 31, Number 1 42 Levels of Catecholamine in Plasma and Cerebrospinal Fluid in Aneurysmal Subarachnoid Hemorrhage Clinical Study
RESULTS Mean (±SE) levels of adrenaline and noradrenaline in plasma in the nine healthy volunteers were 0.27 (0.03) and 1.23 (0.08) nmol/l respectively. Comparisons between these levels and those of the 21 patients are presented in Tables 1 and 2. The demographic and clinical details of all patients are presented in Table 3. As can be seen, 13 patients developed FID, 15 had rupture of aneurysms on blood vessels supplying the hypothalamus, and 3 had a poor clinical outcome. A comparison of catecholamine levels in plasma and CSF within the three groups yielded the following results. Catecholamine levels and FID The mean adrenaline and noradrenaline levels in plasma and CSF are presented in Tables 4 and 5. Patients with FID had significantly higher adrenaline levels in ventricular CSF (P = 0.02) and cisternal CSF (P = 0.05) at the time of surgery than did patients without FID. Although there was a tendency for levels of both adrenaline and noradrenaline in plasma to be higher in the group of patients with FID than in the group comprising patients without FID, these differences were not statistically significant. Catecholamine levels and site of rupture of aneurysms Patients with rupture of aneurysms on blood vessels supplying the hypothalamus generally had higher levels of adrenaline and noradrenaline in plasma than did those with rupture of aneurysms on other blood vessels (Table 6). Such a trend was only noted in the immediate postoperative period for adrenaline and noradrenaline levels in CSF (Table 7). None of these differences was statistically significant. Catecholamine levels and clinical outcome
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lead independent lives were considered as having a good clinical outcome. Those who were severely disabled or were vegetative and had to lead dependent lives were grouped with those who had died. This group was regarded as having a poor clinical outcome (16). In addition, various other interrelationships were investigated by examining catecholamine levels in certain subgroups of patients. Those of particular interest were the following: 1) all patients with FID. In this subgroup, catecholamine levels were compared between patients who had rupture of aneurysms on blood vessels supplying the hypothalamus and those who had rupture of aneurysms on other cerebral arteries; and 2) all patients with rupture of aneurysms on blood vessels supplying the hypothalamus. In this subgroup, catecholamine levels in those patients with a poor clinical outcome were compared with levels in those patients who had a good clinical outcome. As an extension to the study, an attempt was made to relate catecholamine levels at the time of surgery to time after subarachnoid hemorrhage. The Mann-Whitney U test was used to test the statistical significance of any differences observed.
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of catecholamines. After being mixed thoroughly, the tubes were kept on ice until they were centrifuged at 2000 rpm for 5 minutes at 4°C. All plasma and CSF samples were transferred to duplicate tubes and stored at -80°C until analysis. Adrenaline and noradrenaline were assayed by the radioenzymatic assay of Peuler and Johnson (26) with various modifications. Essentially this assay involves the prior preparation of the enzyme catechol-O-methyl transferase from rat livers by the method of Axelrod and Tomchick (2). This enzyme transfers a radioactive methyl group from S-adenosyl-L-[methyl3H]methionine to endogenous catecholamine molecules to form radioactive catechol derivatives, namely, metadrenaline and normetadrenaline. These derivatives are extracted into an organic phase, back extracted into acid, and separated by thin layer chromatography. Periodate oxidation converts the derivatives to vanillin, which is extracted into toluene and quantitated by liquid scintillation counting. The modifications were as follows: the pretreatment of rats with reserpine and the removal of the adrenal glands before the removal of the livers in order to minimize the amounts of catecholamines in the enzyme preparation (4,24); the use of a methyl donor, S-adenosyl-L-[methyl3H]methionine of higher specific activity (15 Ci/mmol; Amersham International, Amersham, Buckinghamshire, England); the extraction of the radioactive derivatives into diethyl ether and back extraction into hydrochloric acid (6); and the development of the thinlayer chromatography plates in a solution of chloroform, ethanol, and 70% ethylamine (16:3:2) for approximately 1 hour (6). The success of the assay was confirmed by testing for linearity in the range of 1 to 15 nmol/l for adrenaline (r 2 = 0.9908) and 5 to 20 nmol/l for noradrenaline (r 2 = 0.9921). The intra-assay variations for adrenaline and noradrenaline were 8.88 and 10.90%, respectively, whereas the respective interassay variations were 11.23 and 14.79%. The recoveries for both adrenaline and noradrenaline were more than 75%. Levels of catecholamine in plasma and CSF were compared within the following groups: 1) patients who developed FID versus those who did not. Patients with angiographic evidence of vasospasm were grouped with those who developed localizing or lateralizing signs, such as monoplegia and hemiplegia, which could not be directly attributed to the surgical procedures in terms of vascular occlusion or damage. This included the development of confusion. This group of patients was classified as having developed FID; 2) patients with rupture of aneurysms on blood vessels supplying the hypothalamus versus those with rupture of aneurysms on vessels supplying other areas of the brain. Blood vessels considered to be supplying the hypothalamus were the internal carotid artery and the anterior and posterior communicating arteries (3,9,10,23,27,28); and 3) patients with a good clinical outcome versus those with a poor clinical outcome. Patients who had a good recovery or moderate disability and who could
Catecholamine levels, site of aneurysmal rupture, and clinical outcome Considering the subset of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a poor clinical outcome had significantly higher levels of adrenaline in plasma at 6 h (P = 0.005) and 24 hours (P = 0.02) postsurgery than did those with a good clinical outcome (Table 11). Significantly higher levels of noradrenaline in plasma were also measured at 6 (P = 0.043) and 24 hours (P = 0.05) in these patients. Catecholamine levels and interval from subarachnoid hemorrhage to surgery Tables 12 and 13 show that significantly higher levels of noradrenaline in plasma were found in patients who had undergone surgery in the period of 5 to 14 days when compared with those who had undergone early surgery (0-4 days) (P = 0.005). DISCUSSION Postsurgery levels of catecholamine in plasma in patients with subarachnoid hemorrhage were found to be significantly higher than the levels of catecholamine in plasma in the normal, healthy volunteers. This finding is consistent with that of
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Catecholamine levels, site of aneurysmal rupture, and FID FID developed more frequently in patients with rupture of aneurysms on blood vessels supplying the hypothalamus (67%) than in those with rupture of aneurysms on blood vessels supplying other areas of the brain (50%). Considering the subset of all patients with FID, 77% had rupture of aneurysms on vessels supplying the hypothalamus whereas only 23% had rupture of aneurysms on blood vessels supplying other areas of the brain. A further observation in these patients with FID was that those with rupture of aneurysms on blood vessels supplying the hypothalamus showed significantly higher adrenaline and noradrenaline levels in plasma (P = 0.05 and P = 0.035, respectively) at the time of surgery than did those with rupture of aneurysms on vessels supplying other areas of the brain (Table 10).
Minegishi et al. (22), who showed that patients with subarachnoid hemorrhage who had undergone surgery had significantly higher levels of catecholamine in plasma than did normal, healthy controls. Patients with FID were found to have significantly higher levels of adrenaline in the cisternal and ventricular CSF at the time of surgery than did those patients who did not develop FID. This finding may indicate that elevated adrenaline levels in the CSF at the time of surgery are important in determining subsequent vasospasm. Such a possibility is supported by the observations of Yamashima and Yamamoto (34), who tested the responses of cerebral arteries of dogs to several vasoconstrictors and found adrenaline to be the most potent agent producing vasospasm. Although other workers (15,19) have reported significantly higher levels of both adrenaline and noradrenaline in the plasma of patients with vasospasm, the inability to do the same in this study may be because of the small number of subjects. This problem was also encountered by Minegishi et al. (22) , and as suggested by them, a larger number of subjects may be required to demonstrate statistical significance. Alternatively, it is possible that there is increased sensitivity of cerebral arteries to catecholamines in patients who have vasospasm (8,20, 21,29) . Such increased sensitivity could possibly explain the development of FID in some patients, even though their catecholamine levels were not statistically higher than those who did not develop FID. Although not yet proven in humans, the supersensitivity of cerebral arteries to noradrenaline after experimental subarachnoid hemorrhage has been reported in cats (20,21) and in rabbits (8). These studies revealed a decrease in the noradrenaline content at perivascular nerve endings as well as a reduced reuptake of noradrenaline into the nerve endings, suggesting that the impaired reuptake of noradrenaline might result in a denervation-type supersensitivity of the vascular smooth muscle. The fact that high catecholamine levels were measured in some patients in whom FID was not demonstrated could possibly be explained by spasm of fine arteries supplying the hypothalamus. Such spasm would not have been detected angiographically but has been postulated by Doshi and Neil-Dwyer (7) to alter sympathetic function with a resultant increase in catecholamines. The trend towards higher catecholamine levels seen in patients with rupture of aneurysms on blood vessels supplying the hypothalamus could be consistent with hyperactivity of the sympathetic nervous system. Crompton (5) found that after rupture of aneurysms on blood vessels supplying the hypothalamus, most lesions occurred in the anterior hypothalamus. In general, the anterior hypothalamus influences mainly parasympathetic events whereas the posterior hypothalamus influences mainly sympathetic events. Because the sympathetic and the parasympathetic systems act reciprocally, damage to the anterior hypothalamus would allow a relative hyperactivity of the sympathetic system. A consequence of this could be an increase in
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The 3 patients with a poor clinical outcome had significantly higher levels of adrenaline in plasma measured at 6 (P = 0.005), 24 (P = 0.01), and 48 hours (P = 0.05) after surgery than did the group with a good clinical outcome (Table 8). Significant differences were also noted for noradrenaline levels in plasma at 6 (P = 0.015), 24 (P = 0.04), and 48 hours (P = 0.05) after surgery. Unfortunately, CSF could only be obtained from 1 of the 3 patients who had a poor clinical outcome. Consequently, even though the levels of adrenaline and noradrenaline in this sample at 6 hours postsurgery were much higher than the levels for patients with a good clinical outcome, the single sample in the former group was insufficient for statistical significance to be reached (Table 9). Further detailed analyses of catecholamine levels within certain subgroups revealed the following.
CONCLUSIONS The study presented here has confirmed previous reports by others (15,19) that patients who have a poor clinical outcome have significantly higher levels of catecholamine in plasma than do those with a good clinical outcome. Although CSF from only 1 patient with a poor clinical outcome was available, the immediate postsurgery sample from this patient also contained larger amounts of catecholamine than did the CSF of patients with a good clinical outcome. It is thus possible that catecholamine levels could be used to identify patients likely to have a poor clinical outcome. The investigation into a possible relationship between catecholamines and FID revealed significantly higher levels of catecholamine in CSF at the time of surgery in those patients with FID. This could indicate that elevated catecholamine levels in CSF at the time of surgery may be related to the subsequent development of vasospasm. It is possible that a lack of angiography at appropriate times to determine the severity of spasm or its inability to detect spasm of small vessels prevented further identification of some relationship that may have existed. When considering all of the patients who developed FID, 77% had rupture of aneurysms on blood vessels supplying the hypothalamus. These patients also had significantly higher levels of catecholamine in plasma than did those with rupture of aneurysms on vessels supplying other areas of the brain. It is thus tempting to speculate that rupture of aneurysms on blood vessels supplying the hypothalamus may result in damage to the hypothalamus, a consequent hyperactivity of the sympathetic nervous system with increased catecholamine release, and resultant FID. Although the exact cause of FID in subarachnoid hemorrhage remains unclear, this present study has demonstrated that the hypothalamus, catecholamines, and FID are inextricably linked to the morbidity and mortality of this condition. ACKNOWLEDGMENT This study was supported by grants from the University of Durban-Westville, the University of Natal, and the Medical Research Council of South Africa.
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subarachnoid hemorrhage had the least favorable outcome. The major cause of morbidity and mortality was attributed to vasospasm. It is thus interesting that in this present study, those patients who had undergone surgery between 5 and 14 days after subarachnoid hemorrhage had significantly higher levels of noradrenaline in plasma than did those who had surgery between 0 and 14 days after subarachnoid hemorrhage. In addition, 2 of the 3 patients who had a bad clinical outcome had surgery between 7 and 10 days after hemorrhage. Both of these had noradrenaline levels in plasma almost twice that of the mean levels for the 5- to 14-day group, and they also had evidence of vasospasm and infarction.
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catecholamine levels in plasma. In 1975, Wilkins (32) proposed that if injury to the hypothalamus influences cerebral vasospasm, then FID should occur most frequently after rupture of aneurysms in locations adjacent to the hypothalamus or on blood vessels that supply the hypothalamus. Although not statistically significant, the results of the study presented here did indeed show that FID developed more frequently in patients with ruptured aneurysms on blood vessels supplying the hypothalamus than in those in whom other vessels were involved (67 versus 50%). Furthermore, considering all patients with FID, 77% of these had suffered rupture of aneurysms on arteries supplying the hypothalamus. These findings are consistent with the observations of Allcock and Drake (1). Those authors found that operations on aneurysms arising from the carotid siphon or anterior cerebral arteries (i.e., vessels supplying the hypothalamus) seemed more likely to provoke FID than did operations on aneurysms arising from the middle cerebral arteries (i.e., vessels supplying other areas of the brain). It is interesting to note that in the study presented here, patients who developed FID after the rupture of aneurysms on vessels supplying the hypothalamus had significantly higher levels of catecholamine in the CSF at the time of surgery than did those who developed FID after the rupture of aneurysms on vessels supplying other areas of the brain. These findings tend to support further the involvement of the hypothalamus and catecholamines in the pathogenesis of FID. A clear relationship between clinical outcome and catecholamine levels in plasma was demonstrated in that patients with a poor clinical outcome had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome. These findings are in agreement with those of others (15,19) , who also demonstrated significant differences in catecholamine levels in plasma between patients with good and poor clinical outcomes. Hence, catecholamine levels could be used as an indication of prognosis in subarachnoid hemorrhage patients and, hence, as a guide to therapeutic approaches in management. The observation that all patients with a poor clinical outcome had suffered rupture of aneurysms on blood vessels supplying the hypothalamus further tends to support the possible involvement of the hypothalamus in the morbidity and mortality associated with subarachnoid hemorrhage. Considering all patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a poor clinical outcome had significantly higher catecholamine levels than did those with a good clinical outcome. This may suggest that high levels of catecholamine in plasma associated with rupture of aneurysms on blood vessels supplying the hypothalamus are a more precise indicator of poor prognosis than are catecholamine levels alone. With respect to the interval from subarachnoid hemorrhage to surgery, Kassell et al. (18) found that patients undergoing surgery for ruptured cerebral aneurysms in the period 7 to 10 days after
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Received, March 6, 1991. Accepted, December 16, 1991. Reprint requests: Athmanundh Dilraj, M.Med.Sc., Department of Pharmacology, University of DurbanWestville, Private Bag X54001, Durban 4000, South Africa.
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COMMENT The study of CSF and plasma adrenaline (epinephrine) and noradrenaline (norepinephrine) is presented by the authors as a logical extension of clinical reports of associating lesions in the hypothalamus with aneurysmal subarachnoid hemorrhage and its subsequent vasospasm. Destructive lesions in the hypothalmic regions associated with parasympathetic activity have been postulated to leave unopposed or to allow hyperactivity of the sympathetic nuclei. Pathological alterations in electrolyte balance, body temperature, and cardiac rhythm are well known to occur after subarachnoid hemorrhage. In fact, patients with cardiac arrythmias and diabetes insipidus secondary to hypothalmic dysfunction after aneurysm rupture have a poor prognosis. Therefore, patients having such a massive output of sympathetic activity would be expected to have elevations in catecholamine levels in plasma as was found by the authors in the study of their 21 patients. Although the authors have taken great care to ensure the validity of their cerebrospinal fluid (CSF) collection and assay methodology (4), other variables that may influence the concentrations of norepinephrine in plasma or CSF include the craniospinal concentration gradient, circadian rhythms, the amount of blood-brain barrier damage, the use of vasopressors and the presence or absence of premorbid systemic arterial hypertension (1-3). Studies involving larger groups of patients would allow the investigators to control for these additional variables. Most important, the authors have associated a poor clinical outcome with significantly elevated catecholamine levels in the plasma, which would indicate that peripheral sympathetic activity would be in itself detrimental or a marker for a dangerous process. Because noradrenaline rather than adrenaline is more important as a central nervous system neurotransmitter and because a relative blood-brain barrier for noradrenaline exists during physiological conditions (2,3), the elevation of adrenaline levels in CSF in patients with subarachnoid hemorrhage may
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and norepinephrine in cerebral vasospasm. Acta Neurochir 63:277-280, 1982. Toda N, Shimizu K, Ohta T: Mechanism of cerebral arterial contraction induced by blood constituents. J Neurosurg 53:312-322, 1980. Voldby B, Engbaek F, Enevoldsen EM: CSF serotonin concentrations and cerebral arterial spasm in patients with ruptured intracranial aneurysm. Stroke 13:184-189, 1982. Wilkins RH: Hypothalamic dysfunction and intracranial arterial spasms. Surg Neurol 4:472-480, 1975. Wilkins RH: Attempted prevention or treatment of intracranial arterial spasm: A survey. Neurosurgery 6:198-210, 1980. Yamashima T, Yamamoto S: Cerebral arterial pathology in experimental subarachnoid hemorrhage. J Neurosurg 58:843-850, 1983.
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Table 2. A Comparison of Noradrenaline Levels in Plasma between Patients with Subarachnoid Hemorrhage and 9 Normal Subjects with a Mean Level of 1.23 (±0.08) nmol/L
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Table 1. A Comparison of Adrenaline Levels in Plasma Between Patients with Subarachnoid Hemorrhage and 9 Normal Subjects with a Mean Level of 0.27 (±0.03) nmol/L
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Table 3. Demographic and Clinical Details of Patientsa
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Table 5. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid in Patients with and without Focal Ischemic Deficitsa
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Table 4. Adrenaline and Noradrenaline Levels in Plasma in Patients with and without Focal Ischemic Deficits
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Table 7. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 6. Adrenaline and Noradrenaline Levels in Plasma after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 9. Adrenaline and Noradrenaline Levels in Cerebrospinal Fluid in Patients with Good and Poor Clinical Outcomea
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Table 8. Adrenaline and Noradrenaline Levels in Plasma in Patients with Good and Poor Clinical Outcomea
Table 12. Adrenaline and Noradrenaline levels at Surgery in Patients with Subarachnoid Hemorrhage with Respect to Time after Hemorrhagea
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Table 11. Adrenaline and Noradrenaline Levels in Plasma in Patients with Good and Poor Clinical Outcome after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamusa
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Table 10. Adrenaline and Noradrenaline Levels in Plasma in Patients with Focal Ischemic Deficits after Rupture of Aneurysms on Blood Vessels Supplying the Hypothalamus and Other Areas of the Braina
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Table 13. Comparison of P Values between Groupsa
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