Subarachnoid haemorrhage: older patients have low cerebral blood flow.

Daily estimations of hemispheral cerebral blood flow using the xenon-133 inhalation technique was made in 116 patients during the first three weeks after subarachnoid haemorrhage. The patients'' cerebral perfusion on average remained less than the normal perfusion expected for their age (based on a single estimation of cerebral blood flow in 67 volunteers). On each separate day after subarachnoid haemorrhage cerebral blood flow was inversely related to the patient''s age. Older patients seem especially at risk of developing cerebral ischaemia after subarachnoid haemorrhage. The clinical outcome was more often unfavourable in older patients--that is, in those who tended to have the lowest cerebral blood flow. Present results support the view that episodes of low cerebral blood flow lead to a poor outcome after subarachnoid haemorrhage. Because of the risk of inducing cerebral ischaemia great care should be exercised by physicians administering hypotensive drugs to older patients after subarachnoid haemorrhage.     

Recovery after subarachnoid haemorrhage.

OBJECTIVE--To determine the implications of subarachnoid haemorrhage for quality of life and aftercare. DESIGN--Prospective follow up study of patients surviving subarachnoid haemorrhage over one year (at discharge, three months, and one year) by examination of cognitive functions (a test battery) and changes in everyday life (semistructured interview). SETTING--Regional neurosurgical unit at a tertiary referral centre. PATIENTS--100 Patients with subarachnoid haemorrhage; 17 were lost during the study because of ineligibility (further surgery, previous head injury, relevant psychiatric history, and cultural differences), loss of contact, and non-compliance; a further 13 patients who developed a neurological deficit were considered separately. MAIN OUTCOME MEASURE--Performance on cognitive test battery and reported changes in quality of life. RESULTS--At discharge patients with and without neurological deficit scored below established norms with most tests, but by three months the difference had resolved in patients without deficit. Reduced quality of life attributable to subarachnoid haemorrhage at one year mainly included less energy (seven patients), adverse emotional changes (five), early retirement, affected social life, and domestic tension (three each). None reported reduced capacity for work. CONCLUSIONS--Patients surviving subarachnoid haemorrhage without neurological symptoms have a good prognosis and should be encouraged to return to a normal lifestyle within about three months.     

Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial.

OBJECTIVE--To determine the efficacy of oral nimodipine in reducing cerebral infarction and poor outcomes (death and severe disability) after subarachnoid haemorrhage. DESIGN--Double blind, placebo controlled, randomised trial with three months of follow up and intention to treat analysis. To have an 80% chance with a significance level of 0.05 of detecting a 50% reduction in an incidence of cerebral infarction of 15% a minimum of 540 patients was required. SETTING--Four regional neurosurgical units in the United Kingdom. PATIENTS--In all 554 patients were recruited between June 1985 and September 1987 out of a population of 1115 patients admitted with subarachnoid haemorrhage proved by the results of lumbar puncture or computed tomography, or both. The main exclusion criterion was admission to the neurosurgical units more than 96 hours after subarachnoid haemorrhage. There were four breaks of code and no exclusions after entry. One patient was withdrawn and in 130 treatment was discontinued early. All patients were followed up for three months and were included in the analysis, except the patient who had been withdrawn. INTERVENTIONS--Placebo or nimodipine 60 mg was given orally every four hours for 21 days to 276 and 278 patients, respectively. Treatment was started within 96 hours after subarachnoid haemorrhage. END POINTS--Incidence of cerebral infarction and ischaemic neurological deficits and outcome three months after entry. MEASUREMENTS--Demographic and clinical data, including age, sex, history of hypertension and subarachnoid haemorrhage, severity of haemorrhage according to an adaptation of the Glasgow coma scale, number and site of aneurysms on angiography, and initial findings on computed tomography were measured at entry. Deterioration, defined as development of a focal sign or fall of more than one point on the Glasgow coma scale for more than six hours, was investigated by using clinical criteria and by computed tomography, by lumbar puncture, or at necropsy when appropriate. All episodes of deterioration and all patients with a three month outcome other than a good recovery were assessed by a review committee. MAIN RESULTS--Demographic and clinical data at entry were similar in the two groups. In patients given nimodipine the incidence of cerebral infarction was 22% (61/278) compared with 33% (92/276) in those given placebo, a significant reduction of 34% (95% confidence interval 13 to 50%). Poor outcomes were also significantly reduced by 40% (95% confidence interval 20 to 55%) with nimodipine (20% (55/278) in patients given nimodipine v 33% (91/278) in those given placebo). CONCLUSIONS--Oral nimodipine 60 mg four hourly is well tolerated and reduces cerebral infarction snd improves outcome after subarachnoid haemorrhage.     

Plasma Concentrations of Digoxin after Oral Administration in the Fasting and Postprandial State

After the oral administration of 0·5 mg of digoxin in tablet form to fasting subjects peak plasma levels were reached in 30 to 60 minutes. Levels then fell to reach a plateau at six to eight hours. When the same dose was given after food the peak plasma concentrations were significantly lower, but the concentrations reached in samples obtained from two to eight hours after the dose did not differ appreciably from corresponding samples obtained in the fasting experiments.In a four-week cross-over study of 21 patients on maintenance therapy, digoxin taken regularly in the fasting state produced plasma concentrations similar to those obtained when the drug was taken after meals.The rapid appearance of digoxin in the blood suggests that the oral route of administration is adequate for most patients who require rapid digitalization, and the timing of maintenance dosage in relation to meals is unimportant.     

Developement and quality control of a radioimmunoassay for measurement of endogenous digoxin

It has been suggested that sodium renal excretion is regulated, at least partially, by a factor with natriuretic properties called digoxin-like factor (DLF). As this substance crossreacts with digoxin antibodies, it was measured with a radioimmunoassay used to determine exogenous digoxin. Methodological conditions and quality control to determine DLF in plasma and urine have been established. Good correlation coefficients in specificity as well as dilution studies were obtained. Within--and between--assay coefficients of variations indicate good reproducibility. Moreover, changes in plasma DLF levels were detected in patients with cirrhosis or with renal failure, diseases which thrive on alterations in salt and water metabolism. In conclusion, this radioimmunoassay method for measuring DLF may be useful to investigate the role of this factor in several physiological and pathological conditions.     

Digoxin-like immunoreactivity: is it still worth measuring?

On the assumption that digoxin-like immunoreactivity may represent digitalis-like sodium pump inhibitors in the mammalian body, many investigators have used radioimmunoassay for digoxin to monitor such factors during the past decade. The presence of digoxin-like immunoreactivity has been confirmed by numerous studies using biochemical, immunological or morphological methods. Very recently, ouabain or a very similar substance, which did not cross-react with antidigoxin antibodies, was identified from the human plasma as the long-sought sodium pump inhibitor. However, it is yet to be determined whether sodium pump inhibitory activity in the circulation results from one substance or several. Some researchers still insist on the possible physiological roles of digoxin-like immunoreactivity which may or may not be related to the regulation of sodium pump. These issues are critically reviewed in this article.     

The presence of an extractable substance in the CSF of humans with cerebral vasospasm after subarachnoid haemorrhage that correlates with phosphatase inhibition

The cellular events leading to cerebral vasospasm after subarachnoid haemorrhage are poorly understood, although an increase in smooth muscle myosin light chain phosphorylation has been observed. This study set out to determine if phosphatase inhibition may be involved in the pathological maintenance of tension observed during vasospasm. We found that 1 nM okadaic acid, a type 2A protein phosphatase inhibitor, elicited an increase in rate of O(2) consumption in the porcine carotid artery similar to that by cerebrospinal fluid (CSF) from vasospastic patients (CSF(V), n=5) (control 0.23+/-0.03, CSF(V) 0.84+/-0.16 and okadaic acid 0.85+/-0.02 micromol min(-1) g dwt(-1)). It was also observed that phosphatase inhibition with 1 nM okadaic acid significantly slowed relaxation after a stretch in a similar fashion to CSF(V) haemorrhage. CSF from vasospastic subarachnoid haemorrhage patients, but not from those without vasospasm, contains an extractable substance which modulates myosin light chain phosphorylation in vitro. A phosphatase preparation obtained from the porcine carotid artery dephosphorylated 63+/-2% of the phosphorylated (MLC(20)) substrate in vitro, and non-vasospastic CSF treated enzyme dephosphorylated 60+/-2.6%. Okadaic acid inhibited phosphatase dephosphorylated only 7.5+/-1% of the substrate where CSF(V) treated enzyme dephosphorylated 22+/-2.8% of the substrate. We conclude that inhibition of smooth muscle phosphatase may be involved in the mechanisms associated with cerebral vasospasm after subarachnoid haemorrhage.     

Subarachnoid haemorrhage above the age of 59: are intracranial investigations justified?

Out of 186 patients aged over 59 referred to a neurosurgical department after spontaneous subarachnoid haemorrhage, 143 underwent cerebral angiography; only 28 (15%) of the patients had surgery, of whom 16 were independent one year later. The doubtful benefit of surgery and the small proportion of patients who underwent surgery have economic and ethical implications; in particular, neurosurgical beds and neuroradiological facilities should not be occupied by such patients if this delays the admission of younger patients and those requiring investigation of intracranial space-occupying and spinal lesions.     

Diurnal variation in incidence of stroke: Oxfordshire community stroke project.

OBJECTIVE--To determine whether diurnal variation occurs in the onset of stroke. DESIGN--Community based study over four years. SETTING--Oxfordshire, United Kingdom. SUBJECTS--105,000 people, of whom 675 had a first ever stroke. 545 had a cerebral infarction, 66 had primary intracerebral haemorrhage, 33 had subarachnoid haemorrhage, and in 31 the type of stroke was not known. MAIN OUTCOME MEASURES--Time of stroke and degree of activity at onset. RESULTS--In the 578 patients for whom it was known whether onset occurred while asleep or awake, the proportion with onset during sleep was 25% (135/545) for cerebral infarction, 17% (11/66) for primary intracerebral haemorrhage, and 0% (0/33) for subarachnoid haemorrhage. This difference persisted if patients in whom it was not known whether they were asleep or awake at onset were classed as asleep. For all stroke types together there was a significant (chi 2 = 218.7, p less than 0.001) diurnal variation with a morning peak between 0800 and 1000, which persisted even after allowing for strokes first noted on waking by redistributing the hour of onset through the preceding eight hours (chi 2 = 47, p less than 0.001). A significant diurnal variation was also found in the onset of cerebral infarction (peak 0800-1000, chi 2 = 208.4, p less than 0.001). Fewer patients had other forms of stroke and the diurnal variations for primary intracerebral haemorrhage (peak 1000-1200) and subarachnoid haemorrhage (peaks 0800-1000 and 1800-2000) were not significant. There seemed to be a second smaller peak for all types of stroke. CONCLUSIONS--All types of stroke are most likely to occur after waking in the morning. The cause of the circadian variation requires further study.     

Experience with nimodipine treatment of vascular spasm after subarachnoid hemorrhage]

Pathogenesis of vasospasms following subarachnoid haemorrhage and possible therapeutic efficacy of nimodipine (calcium channel blocking agent) are discussed. The authors present their own experience in the treatment of 209 patients with subarachnoid haemorrhage with nimodipine. Collected clinical results suggest the necessity of the combined treatment of vasospasm following subarachnoid haemorrhage with nimodipine, hypervolemia, and hypertensive agents.     

Cardiovascular investigations of an endogenous digoxin-like factor

A circulating factor with digoxin immunoreactivity has been demonstrated. Elevated levels of this substance appear to be present after volume expansion and salt loading, and in some forms of hypertension. The potentially causative role for this factor in hypertension can be demonstrated by the normalization of blood pressure after antidigoxin antibody infusions in low-renin and sodium-dependent hypertension. The possibility that renal excretory defects may be the initiating event to elevate endogenous digoxin is suggested by studies with normotensive humans and monkeys with renal disease. In the latter case cardiovascular deficits were noted that were analogous to those detected in renal hypertensive monkeys with elevated endogenous digoxin. Considered together, these results suggest the existence of a natriuretic and hypertensive substance that plays a role in body fluid homeostasis and blood pressure regulation.     

Further Haemorrhage after Admission to Hospital for Gastrointestinal Haemorrhage

During 1967 and 1968 817 episodes of acute alimentary tract haemorrhage were treated in Aberdeen hospitals. In 229 cases further haemorrhage occurred in hospital, with a mortality of 28·8%; the mortality among patients who did not have this complication was 7·8%. This was true of any kind of further haemorrhage. As judged by transfusion requirements and mortality the severity of the further haemorrhage was unaffected by its occurrence as haematemesis and melaena or as melaena only or by whether it took place before or after 48 hours from the time of admission. The occurrence of further haemorrhage did not appear to be affected by the sex or blood group of patients, by aspirin ingestion, or by a history of a previous haemorrhage.The effects of the occurrence of further haemorrhage, of the age being over 60 years, or of coincidental disease being present were of descending importance in regard to mortality.Among 151 patients with peptic ulcer and further haemorrhage half required urgent surgery and 20% died. Further haemorrhage is a dangerous condition and its occurrence should immediately signal the need for vigilance and for urgent consultation between physician and surgeon. Any delay in treatment entails increased mortality.     

Siriraj stroke score and validation study to distinguish supratentorial intracerebral haemorrhage from infarction.

OBJECTIVES--To develop a simple, reliable, and safe diagnostic tool for acute stroke syndromes in a setting where computerised brain scanning was not readily available and to validate its accuracy with regard to pathological types of stroke. DESIGN--13 clinical variables that potentially might differentiate supratentorial cerebral haemorrhage from infarction were recorded and tested by multivariate analysis in a prospective study of 174 patients with acute stroke. In developing the Siriraj stroke score stepwise discriminant analysis of the variables was followed by a linear discriminant equation to differentiate between supratentorial haemorrhage and infarction. The score obtained was validated against scores in 206 other patients with stroke, computerised brain scans being used for definitive diagnosis. SETTING--Siriraj Hospital Medical School, Mahidol University, Bangkok. SUBJECTS--Prospective study: 174 consecutive patients with acute supratentorial stroke syndrome (not subarachnoid haemorrhage) admitted to Siriraj Hospital during 1984-5; validation study: 206 patients admitted to Siriraj Hospital or another hospital for supratentorial intracerebral haemorrhage or infarction. RESULTS--The Siriraj stroke score was developed and calculated as (2.5 x level of consciousness) + (2 x vomiting) + (2 x headache) + (0.1 x diastolic blood pressure) - (3 x atheroma markers) - 12. A score above 1 indicates supratentorial intracerebral haemorrhage, while a score below -1 indicates infarction. The score between 1 and -1 represents an equivocal result needing a computerised brain scan or probability curve to verify the diagnosis. In the validation study of the Siriraj stroke score the diagnostic sensitivities of the score for cerebral haemorrhage and cerebral infarction were 89.3% and 93.2% respectively, with an overall predictive accuracy of 90.3%. CONCLUSION--The Siriraj stroke score is widely accepted and applied in hospitals throughout Thailand as a simple and reliable bedside method for diagnosing acute stroke.     

CANADIAN MEDICAL NEWS

Using the radioimmunoassay technique for measuring serum digoxin, it was found that patients who were given 0.25 mg. digoxin orally per day had a mean serum level of 0.83 ± 0.06 ng. per ml. In patients given 0.5 mg. daily the mean level was 1.30 ± 0.14 ng. A higher 24-hour urinary excretion of digoxin was associated with the higher serum levels in the latter group. Individuals who exhibited electrocardiographic evidence of digoxin toxicity had a mean serum level of 2.81 ± 0.21 ng. The majority of patients with high serum levels had evidence of impaired renal function, and it is in this clinical situation that knowledge of serum digoxin levels is likely to be most helpful in determining dose schedules.The method is specific, sensitive and reproducible. Repeated measurements on the same patient on maintenance therapy showed little variation. To obtain dependable serum levels blood should be drawn at least five hours after oral, and three hours after intravenous administration.     

Measurement of Plasma Digoxin Concentration by Radioimmunoassay

A rapid, sensitive, and precise method for measuring the plasma digoxin concentration has been developed with the radioimmunoassay technique. Seventy patients receiving digoxin were shown to have plasma digoxin concentrations between 0·4 and 5 ng./ml. Preliminary studies show that though there is a positive correlation between total daily dose and the plasma digoxin concentration, the relationship is not close, and a relatively wide range of plasma digoxin concentrations appear to be consistent with effective digitalization.     

Oral contraceptives and fatal subarachnoid haemorrhage.

A case-control study was conducted of the deaths from subarachnoid haemorrhage (SAH) in women aged 15-44 in England and Wales in 1976. There was a small excess of oral contraceptive use by the women who died from SAH compared with their generally healthy practice-matched controls; this was not, however, statistically significant. Out of 134 women who died from SAH, 34 had a history of hypertension compared with only six of their controls. Renal disease and pre-eclamptic toxaemia were more commonly associated with hypertension in the dead women than in controls. No change in the annual mortality from SAH has been observed in the past 20 years such as might have been expected if the risks were high. Although current or past use of oral contraceptives may have increased the blood pressure and risk of SAH in a few women, the most important factor in determining this risk was hypertension. SAH should thus probably not be regarded as serious cause for concern in healthy non-hypertensive women using oral contraceptives.     

Lumbar puncture in spontaneous subarachnoid haemorrhage.

Seventy-four patients with proved spontaneous subarachnoid haemorrhage were studied. Sixty-four underwent computed tomography and 55 underwent lumbar puncture. Seven cases deteriorated dramatically after lumbar puncture, six of these showing evidence of cerebral dislocation on further investigation. Four of the seven had not undergone computed tomography and three underwent computed tomography after lumbar puncture. Computed tomography of the brain could determine patients at risk of coning. It is suggested that computed tomography is the investigation of choice after spontaneous subarachnoid haemorrhage and that lumbar puncture, if still then necessary, should be avoided until computed tomography has been undertaken.     

Acute cerebral artery constriction in the spontaneously hypertensive rat following blood and plasma administration into the subarachnoid space

The purpose of the present study was to demonstrate, using a vascular casting technique, acute vasoconstrictive changes in the cerebral vasculature 1 h following whole-blood or plasma infusion into the subarachnoid space of conscious spontaneously hypertensive rats. Vascular casts from animals infused (over 20 min) with 0.45 ml of heparinized autologous arterial blood or plasma exhibited incomplete filling, while casts from saline-infused controls exhibited virtually no filling defects. Significant elevations in intracranial pressure were noted in blood, but not in plasma- or saline-infused rats. Two characteristic forms of constriction occurred, depending upon the vessel lumen diameter. Vessels with lumen diameters >100 µm were flattened longitudinally with deep endothelial nuclear imprints, while smaller vessels had focal circular constrictions resembling beads. Arterial cast filling terminated in vessels with lumen diameters from 70 to 20 µm with focal signs of constriction at or near the point of cast termination. The results indicate that the presence of both blood and plasma in the subarachnoid space produces acute small-artery constriction. This phenomenon is due to a noncellular blood component and does not correlate with increases in intracranial pressure.     

Toxicity of myoglobin and haemoglobin: oxidative stress in patients with rhabdomyolysis and subarachnoid haemorrhage

Haemolytic events, such as those following rhabdomyolysis and subarachnoid haemorrhage, often result in pathological complications such as vasoconstriction. Haem-protein cross-linked myoglobin and haemoglobin are generated by ferric-ferryl redox cycling, and thus can be used as markers of oxidative stress. We have found haem-protein cross-linked myoglobin in the urine of patients suffering from rhabdomyolysis and haem-protein cross-linked haemoglobin in the cerebrospinal fluid of patients following subarachnoid haemorrhage. These findings provide strong evidence that these respiratory haem proteins can be involved in powerful oxidation processes in vivo. We have previously proposed that these oxidation processes in rhabdomyolysis include the formation of potent vasoconstrictor molecules, generated by the myoglobin-catalysed oxidation of membranes, inducing nephrotoxicity and renal failure. Haem-protein cross-linked haemoglobin in cerebrospinal fluid suggests that a similar mechanism of lipid oxidation is present and that this may provide a mechanistic basis for the delayed vasospasm that follows subarachnoid haemorrhage.     

Comparative effects of cardiac receptors and sinoaortic baroreceptors on elevations of plasma vasopressin and renin activity elicited by haemorrhage

Increases in plasma vasopressin and renin activity that occur in response to haemorrhage have been attributed in part to reflex effects from cardiac receptors and sinoaortic baroreceptors, but the relative importance of these different receptors in causing humoral changes during haemorrhage in conscious dogs has not been reported. We investigated this question by hemorrhaging 6 sham-operated (SO), 6 cardiac-denervated (CD), 4 sinoaortic-denervated (SAD), and 4 combined sinoaortic and cardiac-denervated (SACD), conscious dogs. Blood was removed at a rate of 0.9 ml/kg X min. Plasma vasopressin and renin samples were taken during a control period and after 10, 20, and 30 ml/kg of blood had been removed. Results (mean +/- SE) are shown in the tables below. (table; see text) These experiments illustrate that: resting plasma levels of vasopressin and renin in conscious dogs are unaffected by the denervation procedures used in these experiments, the increase in plasma vasopressin that occurs during haemorrhage is mediated largely via cardiac receptors, with a considerably smaller contribution from the sinoaortic baroreceptors, during moderately severe haemorrhage (30 ml/kg) vasopressin secretion can be increased by a mechanism independent of sinoaortic and cardiac reflexes, the increase in plasma renin activity that occurs during haemorrhage is not dependent upon either cardiac or sinoaortic reflexes.