atrial-natriuretic-factor and Subarachnoid-Hemorrhage

Patients with hyponatremia of central origin were treated with a mineralocorticoid, and the pathogenetic mechanism of the hyponatremia was assessed based on the therapeutic effect obtained. The subjects were 14 patients (6 with subarachnoid hemorrhage, 3 with hypertensive intracerebral hemorrhage, 2 with cerebral infarct and 3 with head injury) who developed hyponatremia, as a complication during their hospital stay for their intracranial lesions from April to December 1992. Patients with serum Na levels below 135 mEq/l for more than 2 days with no other discernible etiology were defined as having hyponatremia of central origin. The mineralocorticoid used was fludrocortisone acetate, and as a rule administration was started the day after the onset of hyponatremia. When improvements occurred within 3 days, in 3 to 7 days, or 8 days or more efficacy was rated "excellent", "good" or "poor", respectively. The mean interval until the onset of hyponatremia was 10.4 days, its mean duration was 5.7 days, and the mean minimum serum sodium level was 129.5 mEq/l. The dose of fludrocortisone administration was 0.1 mg/day except for one patient who was treated with 0.3 mg/day. The mean period of administration was 3.7 days (range: 3 to 6 days), and the route was via a stomach tube in 5 cases and oral in 9 cases. The therapeutic effect was excellent in 9 cases, good in 3 cases and poor in 2 cases, the efficacy rate being 86%. None of the patients manifested side effects. Plasma atrial natriuretic peptide levels were above 100 pg/ml in 2 patients and 50-100 pg/ml in 8 patients and neither of the former 2 patients exhibited "excellent" efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Brain Diseases; Cerebral Hemorrhage; Cerebral Infarction; Female; Fludrocortisone; Humans; Hyponatremia; Male; Middle Aged; Sodium; Subarachnoid Hemorrhage

Topics: Atrial Natriuretic Factor; Female; Humans; Hyponatremia; Male; Subarachnoid Hemorrhage

Serum atrial natriuretic peptide (ANP) that is elevated after aneurysmal subarachnoid hemorrhage (SAH) causes diuresis and natriuresis (cerebral salt wasting) and might exacerbate delayed ischemic neurological deficit (DIND). We investigated relationships among hyponatremia, serum ANP elevation, and the onset of DIND after SAH.. Thirty-nine consecutive patients (15 women and 24 men) with SAH were assigned to a normonatremia group or a group that developed hyponatremia after SAH. Serum ANP and brain natriuretic peptide were assessed after SAH. All patients remained normovolemic and normotensive. We attributed DIND to vasospasm only in the absence of other causes and when supported by cerebral angiography.. Hyponatremia developed after SAH in 11 patients (28.2%), among whom serum ANP concentrations at 0 and 3 days thereafter were significantly increased. Furthermore, DIND developed in five (45.5%) and two (7.1%) hyponatremic and normonatremic patients, respectively (P < 0.05). The serum ANP levels on day 0 after SAH were higher in Hunt and Kosnik grades 3-4 than in 1-2 and in Fisher groups 3-4 than in 1-2 (P < 0.05).. Increasing serum ANP concentrations were independently associated with hyponatremia resulting in DIND. Early treatment of hyponatremia might prevent DIND in patients after SAH.

Topics: Aged; Atrial Natriuretic Factor; Biomarkers; Early Diagnosis; Female; Humans; Hyponatremia; Male; Natriuresis; Predictive Value of Tests; Sensitivity and Specificity; Subarachnoid Hemorrhage; Water-Electrolyte Balance

Daily changes in serum concentrations of natriuretic peptides and various cardiopulmonary parameters were measured after the onset of subarachnoid hemorrhage (SAH) to investigate the pathogenesis of the cardiac and pulmonary consequences in 15 patients with acute phase SAH, divided into the control group (n = 5) with consciousness continuously preserved from SAH onset to admission, and the consciousness disturbance group (n = 10). Daily changes in serum A-type and B-type natriuretic peptides (ANP and BNP, respectively) were measured for 10 days, and intrathoracic blood volume index and extravascular lung water index (EVLWI) were measured for 5 days by the single transpulmonary thermodilution method. Natriuretic peptides in the consciousness disturbance group showed significantly higher values during the 10-day period, with ANP 119.2 +/- 12.4 pg/ml (mean +/- standard error of the mean, p = 0.005) on day 2 and BNP 354.1 +/- 80.3 pg/ml (p = 0.009) on day 1. EVLWI showed higher values in the consciousness disturbance group compared to the control group throughout the 5-day period. The increases in natriuretic peptide levels and increase in pulmonary extravascular water content found in SAH patients with consciousness disturbance show that load on the left ventricle or atrium as well as pulmonary capillary pressure are increased immediately after onset, supporting the contention that excessive release of catecholamines occurs at this time.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Volume; Catecholamines; Extravascular Lung Water; Female; Humans; Hyponatremia; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Edema; Sodium; Subarachnoid Hemorrhage; Thermodilution; Unconsciousness

Adrenomedullin (AM), a vasorelaxant peptide, is secreted into the cerebrospinal fluid (CSF) from the choroid plexus and can exert natriuretic effects in the kidney. CSF AM concentration is elevated 7-10 days after the onset of aneurysmal subarachnoid hemorrhage (SAH). The aim of the present study was to determine whether CSF AM concentrations correlate with hyponatremia and delayed ischemic neurological deficits (DIND) after SAH.. CSF and plasma concentrations of AM, brain natriuretic peptide, and atrial natriuretic peptide concentrations were measured in 32 patients with SAH who underwent aneurysmal clipping within 48 h of onset. CSF and blood samples were obtained from these patients during the early period (days 1-3, day 0 being regarded as the day of SAH onset) and the late period (days 8-10).. In all patients, AM concentration during the early and late periods was significantly higher in the CSF than in the plasma (p = 0.0028 and p < 0.0001). In addition, CSF AM concentration was significantly higher during the late period than during the early period (p < 0.0001). Hyponatremia (plasma sodium <135 mmol/l) was present in 11 patients (34.4%) during the late period, and DIND developed in 6 patients (19%) between day 5 and day 13. Logistic regression analysis demonstrated that late-period CSF AM concentration correlated with hyponatremia and DIND (95% CI: 1.003-1.069, p = 0.0074 and 95% CI: 1.003-1.052, p = 0.0108).. The present study demonstrated that CSF AM during the late period following SAH correlates with hyponatremia and DIND.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Brain Ischemia; Case-Control Studies; Cohort Studies; Female; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Natriuretic Peptide, Brain; Subarachnoid Hemorrhage; Time Factors

Symptoms of hyponatremia and diuresis due to cerebral salt wasting syndrome (CSWS) are often observed after aneurysmal subarachnoid hemorrhage (SAH). Inadequately treated CSWS is known to work as a trigger of symptomatic vasospasm in SAH patients. Therefore, it is indispensable to detect and treat CSWS as early as possible in ICU. A 36-year-old man with SAH was admitted to our ICU. His urine volume increased excessively 3 days after ICU admission, and it reached a peak (39,250 ml x day(-1)) on the 6th day in ICU. Since infusion volume was controlled with regard to daily urinary output, hyponatremia was not noticeable and excessive urine volume stood out conspicuously. Though vasopressin and desmopressin were administered, the symptoms of natriuresis and hyponatremia were aggravated, associated with hyper secretion of natriuretic peptides (ANP 160 pg x dl(-1), BNP 172 pg x dl(-1)). Recent studies revealed that hyponatremia and hypovolemia following SAH might be caused by exaggerated secretion of natriuretic peptides. Experimental studies showed that the administration of vasopressin and desmopressin cause excessive secretion of natriuretic peptides under the circumstance of volume expansion in rats. We infer that the administration of vasopressin and desmopressin to our patient deterionated natriuresis in CSWS as in the previous experimental findings.

Topics: Adult; Animals; Atrial Natriuretic Factor; Brain Diseases; Contraindications; Humans; Hyponatremia; Hypovolemia; Male; Natriuresis; Rats; Subarachnoid Hemorrhage; Syndrome; Urination Disorders; Vasopressins

Cerebral salt wasting (CSW) frequently occurs concomitantly with aneurysmal subarachnoid hemorrhage (SAH). CSW induces excessive natriuresis and osmotic diuresis, and reduces total blood volume. As a result, the risk of symptomatic cerebral vasospasm may be elevated. Therefore, it is important to determine the mechanism of CSW. The purpose of this study was to evaluate whether the rat SAH model exhibits CSW and to investigate the relationship between CSW and natriuretic peptides. A SAH model was produced in 24 rats by perforating a cerebral artery with a nylon thread up through the common carotid artery. To evaluate CSW, urine was cumulatively collected from SAH onset to 12 hours and sodium (Na) excretion was analyzed. Body weight and hematocrit were analyzed before and after SAH onset. Concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in plasma were also analyzed. Urine volume and total Na excretion of SAH rats were significantly higher than those of sham rats (p<0.05). Body weight of SAH rats significantly decreased and hematocrit significantly increased (p < 0.05). ANP concentration was significantly decreased in SAH rats (p<0.05). However, BNP concentrations did not change. This study demonstrated for the first time that a rat SAH model exhibited CSW. It was suggested that the cause of CSW was neither ANP nor BNP. In addition, this rat SAH model will be useful for study of CSW after SAH.

Topics: Animals; Atrial Natriuretic Factor; Carotid Artery, Common; Cerebral Arteries; Disease Models, Animal; Emaciation; Hematocrit; Male; Natriuretic Peptide, Brain; Rats; Rats, Wistar; Sodium Chloride; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Wasting Syndrome

The present study was designed to assess the relationship between the presence of focal brain aedema and serum concentrations of atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) in patients with subarachnoid haemorrhage (SAH). Serum levels of ANP and BNP were measured at six different time periods (Day 1, 2, 3, 4 to 7, 8 to 14, and 15 to 25) in 61 SAH-patients. Focal brain aedema, which was caused by an intracerebral haematoma associated with SAH or surgical complications, was found in eight SAH-patients by means of consecutive CT scans. The mean serum ANP and BNP levels in patients with focal brain aedema were significantly higher than those in patients without focal brain aedema between Days 4 and 14. These findings suggest that focal brain aedema may have some role in the pathogenesis of an excessive secretion of ANP and BNP during the subacute phase of SAH.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Brain Edema; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Retrospective Studies; Statistics, Nonparametric; Subarachnoid Hemorrhage; Time Factors

Hyponatremia and hypovolemia following aneurysmal subarachnoid hemorrhage (SAH) might be speculated by exaggerated secretion of natriuretic peptides and resulted ischemic sequela caused by cerebral vasospasm. We measured serum concentration of natriuretic peptides and investigated their influence on post-SAH hyponatremia. Among 49 patients of SAH, their plasma concentration of the natriuretic peptides (atrial natriuretic peptide: ANP and brain natriuretic peptide: BNP) were measured at the day of ictus and 7th day of SAH. The correlation between concentration of natriuretic peptides and location of aneurysm, severity of SAH, incidence of hyponatremia and symptomatic vasospasm were elucidated. The plasma concentration of ANP did not alter on admission and 7th day post SAH, whereas that of BNP increased in the patients with moribund SAH and those with ruptured A-com aneurysm. The initial increase of BNP following SAH could be attributed to direct damage of SAH on the hypothalamus. Hyponatremia and symptomatic vasospasm tended to occur in the patients who had persistent increase of plasma BNP concentration during one week post SAH. Therapeutic intervention to maintain normonatremia by fluid-management decreased occurrence of symptomatic vasospasm, even though patients with increased plasma BNP concentration. It might be concluded that increased secretion of BNP following SAH is caused by direct effect to the hypothalamus and prolonged hyper secretion of BNP resulted hyponatremia, hypovolemia and exaggerated symptomatic vasospasm.

Topics: Aneurysm, Ruptured; Atrial Natriuretic Factor; Female; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptides; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Central salt wasting syndrome may be caused by pathological increases in serum natriuretic peptides after subarachnoid hemorrhage (SAH). However, it is unclear as to why the serum concentration of atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) increases in the subacute phase of SAH. The present study was designed to assess the correlation between focal brain edema and serum concentration of ANP or BNP in patients with SAH. Focal brain edema was found in 8 SAH-patients and peaked between days 4 and 7 of SAH. The mean serum ANP and BNP levels in patients with focal brain edema were significantly higher than those in patients without focal brain edema between days 4 and 14 of SAH. These results suggest that focal brain edema might correlate with increased levels of ANP and BNP in the subacute phase of SAH.

Topics: Atrial Natriuretic Factor; Brain Edema; Humans; Natriuretic Peptide, Brain; Retrospective Studies; Subarachnoid Hemorrhage; Tomography, X-Ray Computed; Vasopressins

Whereas cardiac hormones increase after subarachnoid haemorrhage (SAH), and may contribute to sodium wastage and hyponatraemia, there is controversy concerning the relative roles of atrial natriuretic peptide (ANP) vs. brain natriuretic peptide (BNP) and the factors initiating their secretion. Noting previous work linking stress hormone responses with cardiac injury after SAH, we have studied responses in stress hormones, markers of cardiac injury and the temporal changes in ANP and BNP and related them to changes in sodium status post ictus and during recovery from acute SAH.. Eighteen patients with verified SAH of variable severity were studied in a single unit for a 14-day period post ictus under controlled conditions of sodium and fluid intake. All received a standardized protocol of daily dexamethasone and nimodipine throughout the study. Severity was graded using criteria of Hess and Hunt at admission. Stress hormones (AVP, catecholamines and admission plasma cortisol), markers of cardiac injury (ECG and daily plasma troponin T) and cardiac hormones (ANP and BNP) were measured daily and related to severity, plasma sodium and renin-aldosterone activity. Hormone levels (ANP, BNP and endothelin) in cerebrospinal fluid (CSF) were also measured in nine patients.. Intense neurohormonal activation (AVP, cortisol and catecholamines) at admission was associated with increased levels of both plasma ANP and BNP whereas levels in CSF were unaffected. In individual patients plasma levels of ANP and BNP were strongly correlated (P < 0.001). Cardiac events (abnormal ECG and/or elevated troponin) occurred in six of seven patients graded severe but neither stress hormones nor cardiac peptides differed significantly in patients with mild (n = 11) vs. severe (n = 7) SAH. During the course of a progressive fall in plasma sodium concentration (P = 0.001), there was a delayed activation of renin-aldosterone which was inversely correlated with declining levels of plasma ANP/BNP (P < 0.002).. Excessive secretion of both ANP and BNP occurs in all patients after acute subarachnoid haemorrhage and is unrelated to severity, stress hormone activation or markers of cardiac injury. Inhibition of renin-aldosterone by cardiac hormones may impair renal sodium conservation and contribute to developing hyponatraemia. In the absence of evidence for activation of natriuretic peptides within the brain, the prompt and consistent increase in both ANP and BNP strongly supports the view that the heart is the source of increased natriuretic peptide secretion after acute subarachnoid haemorrhage.

Topics: Acute Disease; Adult; Aged; Aldosterone; Arginine Vasopressin; Atrial Natriuretic Factor; Creatine; Electrocardiography; Endothelins; Epinephrine; Female; Humans; Hydrocortisone; Male; Middle Aged; Natriuretic Peptide, Brain; Norepinephrine; Sodium; Subarachnoid Hemorrhage; Time Factors; Troponin T

Several authors described elevated natriuretic peptides, atrial natriuretic peptide(ANP) and brain natriuretic peptide (BNP), in patients with subarachnoid hemorrhage(SAH), which were account for inappropriate antidiuretic hormone(SIADH) or cerebral salt wasting syndrome(CSW). Although the secretion of natriuretic peptide depends on the total blood volume, central venous pressure, and cardiac output volume, the volume of fluid intake in patients with SAH had not been taken in consideration in previous report. We here examined the relationship between fluid intake and the natriuretic peptides in two cases without cardiac failure. ANP elevated 2 or 3 days after SAH and remained in normal range for 2 weeks. BNP elevated when the volume of fluid intake was increased, and BNP did not elevate during the periods with lower fluid intake. Several authors proposed the possibility of iatrogenic factor in natriuresis after SAH and these results supported this opinion.

Topics: Adult; Atrial Natriuretic Factor; Female; Fluid Therapy; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Subarachnoid Hemorrhage

The natriuretic peptide system consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The system is implicated in the control of body fluid homeostasis, causes natriuresis and diuresis (ANP and BNP), and regulates vascular tone (CNP). A reciprocal relationship between ANP and endothelin (ET) has been suggested, and earlier studies have documented a possible role of ET in cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The authors studied plasma ANP, BNP, CNP, and ET for 6 consecutive days in 13 patients with SAH by using radioimmunoassay. The median admission values for ANP were 31.5 pg/ml (range 16.8-323 pg/ml [normal 15 +/- 7 pg/ml]); for BNP, 45.3 pg/ml (range 2.2-80.2 pg/ml [normal 12 +/- 9 pg/ml]); for CNP, 7.7 pg/ml (range < 2-20 pg/ml [normal 5.2 +/- 3 pg/ml]); and for ET, 11 pg/ml (range 6.5-25.1 pg/ml [normal 7.2 +/- 4 pg/ml]). Additional increases (defined as > 100% increase on two consecutive measurements) were noted in ANP (11 patients), BNP (10 patients), and CNP (three patients), and resulted in a negative fluid balance in 10 of the 13 patients. The CNP increased in three of four patients with cerebral vasospasm and in one of nine patients without cerebral vasospasm (Fisher's exact test, p = 0.2). No major fluctuations in plasma ET were noted. In seven patients, the plasma ET level did not increase beyond 10 pg/ml during the days of measurement. In six patients, only an occasional sample showed an increase to a maximum of 25 pg/ml. Changes in BNP, ANP, and CNP were independent of each other. The authors conclude that both plasma ANP and BNP increase after SAH and often result in a negative fluid balance. Plasma ANP and BNP seem differentially regulated in the presence of SAH but not by the level of the plasma ET. The possible role of CNP as a regulatory response to cerebral vasospasm needs further exploration.

Topics: Adult; Aged; Atrial Natriuretic Factor; Endothelium; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Radioimmunoassay; Subarachnoid Hemorrhage

Hyponatremia following subarachnoid hemorrhage (SAH) occurs due to the inappropriate secretion of antidiuretic hormone (SIADH). However, this condition is also sometimes associated with certain dehydration states.. To clarify the pathogenesis, daily values of urine volume, water balance, and sodium balance (Na Bal) were correlated with plasma levels of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), and plasma renin activity (PRA) in 31 cases of SAH.. Na Bal was markedly negative on days 2 and 3. Cumulative Na Bal showed continuous negative values until day 10 following SAH. ANP values showed a consistent elevation, while ADH showed only an initial surge. PRA, as the gross indicator of circulatory volume, showed a lack of suppression, indicating no increase in the circulatory volume.. Hyponatremia following SAH therefore appears to be the result of increased natriuresis, due to the inappropriate elevation of ANP rather than SIADH. In this situation, water restriction should not be recommended, since the circulatory volume is decreased.

Topics: Adult; Aged; Aneurysm, Ruptured; Atrial Natriuretic Factor; Body Water; Dehydration; Female; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Natriuresis; Renin; Subarachnoid Hemorrhage; Vasopressins

Atrial natriuretic peptide (ANP) is released excessively in spontaneously hypertensive rats (SHR), and vasodepression is its main effect on the blood vessels. The aim of the study was to investigate the changes in ANP secretion in the cerebral vasospasm following subarachnoid hemorrhage (SAH) in SHRs. The SAH was induced by the injection of 100 microliters of unheparinized, autologous blood into the cerebrospinal fluid (CSF), via a canule formerly inserted into the cisterna magna (CM). In the sham SAH group the SAH was imitated with 0.9% saline injection. The concentrations of ANP in the blood samples obtained in the acute and chronic stages of vasospasm were radioimmunoassayed with commercial RIA kits (Peninsula RIK 9103). It was found that both SAH and sham SAH induced a significant increase in plasma ANP in the chronic phase of vasospasm. No such changes were observed in the acute phase. This shows that the chronic cerebral vasospasm following SAH considerably enhances the ANP secretion in SHRs, probably through the increased endothelin release. These compensatory and regulatory mechanisms help prevent the development of brain oedema and the progression of vasopasm through secondary vasodilation.

Topics: Animals; Atrial Natriuretic Factor; Brain Edema; Hypoxia; Ischemic Attack, Transient; Male; Rats; Rats, Inbred SHR; Subarachnoid Hemorrhage

The effects of centrally administered atrial natriuretic peptide (ANP) on the brain water and electrolyte contents were investigated in a rodent subarachnoid haemorrhage (SAH) model. SAH caused statistically significant increases in the brain sodium and water contents, while the potassium content did not change significantly, indicating that the brain oedema could be classified as having a primarily vasogenic component. Two micrograms or 5 micrograms of rat ANP administered into the lateral ventricle at the time of SAH induction statistically significantly decreased the water and sodium accumulation measured 90 minutes following SAH. The same treatment did not inhibit development of brain oedema measured 3 hours following SAH. However, when 5 micrograms of ANP was administered intraventricularly at the time of SAH induction and also 90 minutes later, the brain oedema 3 hours following SAH was again reduced statistically significantly. These effects of ANP were found not to be mediated by primary changes in serum osmolality and electrolyte concentrations. The present results confirm that centrally administered ANP may act directly on the central nervous system to inhibit brain water and sodium accumulation in SAH-induced brain oedema. The potentials of influencing the central neuro-endocrine system as a novel way of the treatment of brain oedema are discussed.

Topics: Animals; Atrial Natriuretic Factor; Blood-Brain Barrier; Brain Edema; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Injections, Intraventricular; Male; Rats; Rats, Wistar; Subarachnoid Hemorrhage; Water-Electrolyte Balance

Hyponatremia is a common complication after subarachnoid hemorrhage. In this study we investigated the relations among hyponatremia, plasma natriuretic peptides, and antidiuretic hormone concentrations after subarachnoid hemorrhage.. Blood samples for radioimmunoassay measurement of plasma brain natriuretic peptide-like immunoreactivity, atrial natriuretic peptide-like immunoreactivity, and antidiuretic hormone were obtained every 2 to 4 days until day 14 after subarachnoid hemorrhage.. Eleven of 20 patients with verified subarachnoid hemorrhage demonstrated mild hyponatremia (126 mEq/L < serum sodium < 135 mEq/L) during their clinical course. Atrial natriuretic peptide and antidiuretic hormone concentrations were significantly elevated on days 0 to 2 after onset of subarachnoid hemorrhage. Atrial natriuretic peptide concentrations remained high in patients who developed mild hyponatremia on days 6 to 14 after onset of subarachnoid hemorrhage. In contrast, antidiuretic hormone concentrations became significantly lower during the second week in these patients.. Mild hyponatremia after subarachnoid hemorrhage may be attributable not to the syndrome of inappropriate secretion of antidiuretic hormone but to cerebral salt-wasting syndrome. Atrial natriuretic peptide may be a causal natriuretic factor in cerebral salt-wasting syndrome.

Topics: Adult; Aged; Atrial Natriuretic Factor; Body Water; Female; Humans; Male; Middle Aged; Natriuretic Agents; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Osmolar Concentration; Sodium; Subarachnoid Hemorrhage; Vasopressins

The relationship between plasma atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) both of which show high values after subarachnoid hemorrhage and cerebral vasospasm was studied. The subjects were 23 patients who were admitted because of aneurysmal subarachnoid hemorrhage during three years from March, 1989 to March, 1992 and in whom plasma ANP and ADH levels could be determined over time. Cerebral vasospasm was evaluated by the finding of cerebral angiography, clinical symptoms, and presence or not of low density areas on CT. Hyponatremia was defined as the serum sodium level of 130 mEq/l or less for two days or more. Angiographical vasospasm was found in 17 patients (85%), symptomatic vasospasm in 15 patients (65.2%), low density areas on CT in 9 patients (40.9%) and hyponatremia in 8 patients (34.8%). Symptomatic vasospasm was noted in 7 of the 8 patients (87.5%) with hyponatremia, low density areas on CT in 4 patients (50%), the detection rate being high. The plasma ANP and ADH levels were 76.7 +/- 32.1 pg/ml and 2.2 +/- 0.7 pg/ml respectively in the patients with symptomatic vasospasm against 38.3 +/- 21.3 pg/ml and 2.4 +/- 0.6 pg/ml respectively without symptomatic vasospasm, the plasma ANP level being significantly high in the patients with symptomatic vasospasm (p < 0.01). The plasma ANP and ADH were 71.2 +/- 33.8 pg/ml and 2.0 +/- 1.1 pg/ml respectively in the patients with low density areas on CT against 51.2 +/- 31.3 pg/ml and 1.8 +/- 0.5 pg/ml respectively without low density areas on CT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Humans; Hyponatremia; Intracranial Aneurysm; Ischemic Attack, Transient; Rupture, Spontaneous; Subarachnoid Hemorrhage; Vasopressins

Blood extent and localization visible in CCT predicts complications and prognosis in patients suffering from subarachnoid haemorrhage (SAH). Plasma renin activity (PRA) elevation is one of the hormonal parameters of autonomic disorders after SAH and its prognostic relevance could be confirmed by this study, too. But the correlation of PRA with blood amount and distribution was the main target of this study. Large amounts of blood are connected with higher PRA-levels and more PRA-rises. Even a linear correlation between the amount of blood defined by a CCT-score and PRA in ng ml h-2 could be established. A significant correlation was found between intraventricular, suprasellar blood, ventricular enlargement of the third/lateral ventricles and PRA-elevations. Disorders of hypothalamic and/or medullary centres of sympathetic control are thought to be the underlying cause and to depend on blood extent and distribution.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Volume; Enzyme Activation; Female; Humans; Male; Middle Aged; Renin; Subarachnoid Hemorrhage; Tomography, X-Ray Computed

The cause of hyponatremia following subarachnoid hemorrhage (SAH) has been understood as an inappropriate secretion of antidiuretic hormone (SIADH). Whereas, water restriction for the management of this condition sometimes induces a severe dehydration, resulting in vasospasm. To clarify the pathogenesis of hyponatremia following SAH, we measured the daily sodium and water balance with the plasma concentration of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), and plasma renin activity (PRA) in seventeen cases after subarachnoid hemorrhage. Although the patients received an adequate amount of fluid (more than 4080ml/day; daily average in seventeen cases) and sodium (more than 277 mEq/day; daily average in seventeen cases), eight out of the seventeen cases showed transient hyponatremia of a slight degree beginning on 8.8 days after SAH. ANP values were elevated markedly in fifteen out of the seventeen cases, remaining high during the first two weeks following SAH. ADH values were elevated remarkably in eight out of the seventeen cases. However, these values declined immediately to a normal range within two days following SAH. PRA were increased or came within the normal range, suggesting the lack of water retention. Overall sodium balance and water balance did not differ significantly between hyponatremia cases and normonatremia ones, whereas, sodium balance in acute phase was significantly negative, associated with marked natriuresis in patients with hyponatremia. These correlations suggested that hyponatremia after SAH is the result of natriuresis by an increased ANP rather than ADH. In conclusion, a greater replenishment of water and sodium is required to avoid hyponatremia with dehydration. This technique may be helpful for the prevention of vasospasms following SAH.

Topics: Acute Disease; Adult; Aged; Atrial Natriuretic Factor; Female; Fluid Therapy; Humans; Hyponatremia; Male; Middle Aged; Natriuresis; Sodium; Subarachnoid Hemorrhage

Hyponatremia is common following subarachnoid hemorrhage and has alternatively been attributed to either the inappropriate secretion of antidiuretic hormone or natriuresis causing intravascular volume contraction. We prospectively studied body sodium and intravascular volume regulation in 19 patients, beginning within 3 days after acute aneurysmal subarachnoid hemorrhage occurred, in order to determine the impact of hypervolemic therapy on both hyponatremia and volume contraction and to ascertain whether humoral factors account for hyponatremia. Serial measurements of plasma arginine vasopressin, atrial natriuretic factor, renin activity, aldosterone, and catecholamines were correlated with body sodium and fluid balance, change in blood volume, serum sodium concentration, and osmolality. Six patients (32%) developed hyponatremia, but only 2 had a negative sodium balance. In most patients, levels of atrial natriuretic factor were elevated, while plasma renin activity and aldosterone concentrations were generally suppressed. Plasma arginine vasopressin levels were not suppressed during hypo-osmolality and did not correlate with serum osmolality in hyponatremic patients. Only 1 patient had a decrease in blood volume, which was associated with marked rises in aldosterone and plasma renin activity, but normal serum sodium and plasma atrial natriuretic factor levels. We conclude that following subarachnoid hemorrhage: (1) Hypervolemic therapy prevents volume contraction but not hyponatremia, (2) humoral factors may favor both sodium loss and water retention, and (3) arginine vasopressin regulation is disturbed and may contribute to hyponatremia.

Topics: Adult; Aged; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Volume; Female; Fluid Therapy; Humans; Hyponatremia; Male; Middle Aged; Renin; Subarachnoid Hemorrhage

Following subarachnoid hemorrhage, the plasma concentration of atrial natriuretic factor is elevated and appears to be independent of atrial stretch. While the hypothalamus and circumventricular organs contribute to sodium and intravascular volume regulation, their influence on atrial natriuretic factor is not known. We tested the hypothesis that, following subarachnoid hemorrhage, suprasellar cisternal blood, intraventricular blood, or ventricular enlargement would be associated with elevated plasma levels of atrial natriuretic factor. Computed tomograms of 26 patients performed less than or equal to 3 days after hemorrhage were analyzed to determine the presence of suprasellar or intraventricular blood and enlargement of the third or lateral ventricle. These results were correlated with the plasma atrial natriuretic factor and serum sodium concentrations. The initial atrial natriuretic factor concentration was elevated and was higher in patients with suprasellar or intraventricular blood than in those without (suprasellar: 131 +/- 20 and 54 +/- 10 pg/ml, respectively; intraventricular: 137 +/- 25 and 84 +/- 31 pg/ml, respectively). The atrial natriuretic factor concentration remained higher over the week following hemorrhage in patients with suprasellar blood than in those without (127 +/- 16 and 68 +/- 12 pg/ml, respectively). The atrial natriuretic factor concentration was not correlated with hyponatremia (125-134 meq/l) or age-corrected ventricular size. Hyponatremia did not correlate with the presence of intraventricular or suprasellar blood. Our data suggest that suprasellar and intraventricular blood disturb hypothalamic function, resulting in an elevated plasma atrial natriuretic factor concentration. The presence of a direct relation between atrial natriuretic factor and hyponatremia remains unclear.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cerebral Ventricles; Female; Humans; Hyponatremia; Male; Middle Aged; Sella Turcica; Subarachnoid Hemorrhage

We determined serum atrial natriuretic peptide (ANP) and anti-diuretic hormone (ADH) on a time course basis in cases of subarachnoid hemorrhage and studied their influence on the development of hyponatremia. Twenty six cases of subarachnoid hemorrhage were admitted to our hospital in the past 1 year, and by the site of ruptured aneurysms, there were Acom 6 cases, ICA 6 cases, MCA 5 cases and VA BA 4 cases. Serum ANP and ADH levels were determined in the acute phase on Day 1-4, in the hyponatremia phase on Day 5-14 and in the chronic phase on Day 15 downward. Levels of not more than 130 mEq/l were regarded as hyponatremia. Cases showing other evident causes such as heart failure and renal insufficiency were excluded. In the normal control group (n = 20) which was admitted to this hospital for a close check-up, serum ANP was 26.5 +/- 11.6 pg/ml (10-50); levels of more than 50 pg/ml were regarded as being abnormally high. 1) Hyponatremia was observed in 7 cases (26-9%); the day of onset was 11.9 hospital day. The duration was 5.0 days and the minimum serum Na level was 126.4 mEq/l. 2) The serum ADH level was high regardless of whether or not there was the development of hyponatremia in the acute phase but tended to decrease gradually and became normal in the hyponatremia phase. 3) The serum ANP level in the cases of hyponatremia was 40.7 +/- 9.1 pg/ml in the acute phase, 69.0 +/- 25.7 pg/ml in the hyponatremia phase and 40.2 +/- 21.5 pg/ml in the chronic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Humans; Hyponatremia; Subarachnoid Hemorrhage; Vasopressins

The causes of volume depletion and hyponatremia after subarachnoid hemorrhage are not fully understood but may be in part due to natriuresis or "cerebral salt wasting." Because previous studies using infrequent hormone sampling have given inconsistent results, we determined if elevations in atrial natriuretic factor concentrations preceded negative sodium and fluid balances.. We measured diurnal atrial natriuretic factor and vasopressin concentrations and sodium balance for 5 days in 14 consecutive patients after aneurysmal subarachnoid hemorrhage.. Plasma concentrations of atrial natriuretic factor on admission were elevated in subarachnoid hemorrhage patients (mean +/- SD 106 +/- 59 pg/ml) compared with acutely ill controls (39 +/- 30 pg/ml). In eight patients, high peak concentrations of atrial natriuretic factor, greater than 300 pg/ml or a twofold increase above baseline, were followed by natriuresis and a negative sodium balance. Three patients, two of whom became hyponatremic, developed cerebral infarcts after natriuresis. Vasopressin concentrations were slightly elevated just after hemorrhage but subsequently declined to normal values.. A markedly increased atrial natriuretic factor concentration precedes natriuresis in some patients and, with other abnormalities of water handling possibly including a relatively diminished vasopressin concentration, may cause volume depletion. Patients with natriuresis appear to be at increased risk for delayed cerebral infarction after subarachnoid hemorrhage.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Volume; Humans; Hyponatremia; Intracranial Aneurysm; Middle Aged; Natriuresis; Prospective Studies; Rupture, Spontaneous; Sodium; Subarachnoid Hemorrhage

Topics: Atrial Natriuretic Factor; Humans; Subarachnoid Hemorrhage

We tested the hypothesis that the concentration of atrial natriuretic factor in the cerebrospinal fluid is an indicator of brain injury in patients with intracranial disease. Atrial natriuretic factor concentration was measured in 72 samples of cerebrospinal fluid from 28 patients with intraventricular drains and in nine samples from outpatient controls undergoing diagnostic lumbar puncture. Levels were correlated with diagnosis; systemic fluid administration; concentration of atrial natriuretic factor in the plasma; intracranial pressure; sodium, glucose, and protein concentrations, osmolality, and cell count in the cerebrospinal fluid; sodium concentration in the serum; and hemodynamics. Atrial natriuretic factor concentration was highest in cerebrospinal fluid from patients with intracerebral hematoma, followed by those with obstructive hydrocephalus and subarachnoid hemorrhage (19 +/- 2, 13 +/- 3, and 8 +/- 2 pg/ml, respectively); atrial natriuretic factor concentration was less than 4 pg/ml in the controls. Patients treated with fluid restriction had significantly higher atrial natriuretic factor levels than those receiving maintenance or high-volume fluids (16 +/- 3, 8 +/- 2, 10 +/- 1 pg/ml, respectively). The concentration of atrial natriuretic factor in the plasma was significantly elevated in patients with intracerebral hematoma and subarachnoid hemorrhage (155 +/- 38 and 92 +/- 20 pg/ml, respectively) and did not correlate with fluid administration or the concentration of atrial natriuretic factor in the cerebrospinal fluid. Neither cerebrospinal fluid nor plasma concentrations of atrial natriuretic factor correlated with intracranial pressure; cerebrospinal fluid sodium, glucose, or protein concentrations, osmolality, or cell count; serum sodium concentration; or hemodynamics. We conclude that the concentration of atrial natriuretic factor in the cerebrospinal fluid is a nonspecific indicator of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Brain Diseases; Fluid Therapy; Glucose; Hematoma; Hemodynamics; Humans; Hydrocephalus; Intracranial Pressure; Osmolar Concentration; Proteins; Spinal Puncture; Subarachnoid Hemorrhage

Atrial natriuretic peptide-like immunoreactivity (ANP-LI) was measured in plasma from the external jugular vein (EJV) in the postoperative course of 11 patients with aneurysmal subarachnoid haemorrhage. Samples were taken on day, 1, 2, 3, 5, 7 and 9 after operation and ANP-LI levels were determined using radioimmunoassay. Ten healthy volunteers were investigated with one EJV plasma sample. Comparing the whole group of SAH patients with the control group, no significant differences in ANP-LI levels were found. In one patient very high ANP-LI levels were found together with high mean plasma sodium levels and high urine sodium excretion. This suggests that there is no general correlation between plasma ANP-LI and SAH; in occasional patients such a correlation may be secondary to changes in plasma sodium levels.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Flow Velocity; Brain; Female; Glasgow Coma Scale; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Postoperative Complications; Radioimmunoassay; Subarachnoid Hemorrhage; Water-Electrolyte Balance

One hundred patients affected by S.A.H. have been studied, evaluating the possible correlations between clinical findings and hyponatremia. For a better understanding of hyponatremia during S.A.H., the hematic concentration of A.D.H. and A.N.P. have been determined and correlated with hyponatremia.

Topics: Atrial Natriuretic Factor; Cerebral Arterial Diseases; Female; Humans; Hyponatremia; Male; Prognosis; Spasm; Subarachnoid Hemorrhage; Vasopressins

The authors describe a case of subarachnoid hemorrhage with hyponatremia accompanied by elevation of plasma atrial natriuretic peptide (ANP). The early phase of hyponatremia was classified as the syndrome of inappropriate secretion of antidiuretic hormone (ADH) due to subarachnoid hemorrhage. However, in the later phase, hyponatremia and natriuresis were accompanied by suppression of ADH while plasma ANP remained elevated. The patient was effectively treated with demeclocycline and hypertonic saline. The significance of ANP in the pathophysiology of increased natriuresis is discussed.

Topics: Aged; Atrial Natriuretic Factor; Demeclocycline; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Intracranial Aneurysm; Natriuresis; Saline Solution, Hypertonic; Subarachnoid Hemorrhage; Vasopressins

Measurement of plasma alpha-humanANP (ANP) and antidiuretic hormone (ADH) in 28 cases with aneurysmal subarachnoid haemorrhage (SAH) was carried out, and then compared with control subjects who were infused with hypertonic saline. In cases with hyponatremia (HN), statistical correlation between control subjects and cases without HN was not evident with regards to ANP and plasma osmolality (Posm), excreted fraction of filtrated sodium (FENa) and urinary Na/K. Furthermore, they secreted supernumerarilly in spite of HN. Cases with HN were further subdivided into two groups, they were those cases with negative total sodium balance at the time of appearance of HN, and those cases without total negative sodium balance. In the former, central venous pressure had a tendency to decrease, however, secretion of ANP and ADH was statistically not different in either groups. It appears that ANP regulated urinary sodium excretion against an osmotic or sodium load acts as a maintenance of homeostasis as an osmotic regulator. Cases with HN in which secretion of ADH was physiological, ANP secreted supernumerarilly in spite of hypoosmonaemia and hypovolaemia. Our findings may contribute to a better understanding of the pathophysiological processes leading to hyponatremia in cases with cerebral disorders, and may help to improve the treatment possibilities.

Topics: Adult; Aged; Atrial Natriuretic Factor; Female; Humans; Hyponatremia; Intracranial Aneurysm; Male; Middle Aged; Peptide Fragments; Rupture, Spontaneous; Subarachnoid Hemorrhage; Vasopressins

Atrial natriuretic factor (ANF) is a diuretic natriuretic peptide hormone produced by both the heart and brain which has been postulated to play a role in the hemodynamic and sodium instability that frequently follows subarachnoid hemorrhage (SAH). Levels of ANF were measured in 12 patients with nontraumatic SAH and nine control patients with unruptured cerebral aneurysms. At surgery, the mean plasma ANF level (+/- standard deviation) of the SAH group was significantly higher than that of the control group (158.1 +/- 83.8 vs. 57.8 +/- 45.3 pg/ml, respectively; p = 0.01). There was no significant difference in serum sodium concentration, blood pressure, or central venous pressure between these groups. Nine patients with SAH due to aneurysm rupture had plasma ANF levels similar to those in three patients with SAH due to other causes. Four patients with moderate to severe SAH had significantly higher mean cerebrospinal fluid (CSF) ANF values (17.7 +/- 12.8 pg/ml) than five patients with minimal SAH (0.6 +/- 0.9 pg/ml) or the control group of nine patients (3.7 +/- 1.3 pg/ml) (p less than 0.05). Five patients with moderate to severe SAH had significantly higher plasma ANF values (202.6 +/- 72.2 pg/ml) than five with minimal SAH (86.8 +/- 29.2 pg/ml) or the control group (57.8 +/- 45.3 pg/ml) (p less than 0.05). Plasma ANF values were substantially higher than CSF ANF content in the SAH group (p less than 0.01) and in the control group (p = 0.05). From these data it is concluded that: 1) plasma ANF is elevated significantly after SAH; 2) this rise appears unrelated to the cause of hemorrhage, serum sodium concentration, blood pressure, or central venous pressure, but is related to the extent of the hemorrhage; 3) ANF concentrations in the CSF are significantly lower than in plasma, and are elevated after moderate to severe SAH; and 4) the source of CSF ANF is probably the plasma, and the source of plasma ANF is likely the heart.

Topics: Adult; Atrial Natriuretic Factor; Female; Humans; Male; Middle Aged; Subarachnoid Hemorrhage; Veins

We investigated the possible relation between neuropeptides and cerebral vasoconstriction in samples of ventricular or cisternal cerebrospinal fluid from 14 patients with subarachnoid hemorrhage. Neuropeptide Y, calcitonin gene-related peptide, atrial natriuretic peptide, and pituitary polypeptide 7B2 were present in the cerebrospinal fluid of these patients. Concentrations of calcitonin gene-related peptide and 7B2 were not significantly different from those in control subjects, but that of atrial natriuretic peptide was significantly lower. Although the mean concentration of neuropeptide Y was not significantly higher than control, consecutive determinations showed an increase 6-11 days after the onset of subarachnoid hemorrhage. An initially high 7B2 concentration decreased gradually, although half the patients showed a second increase greater than 10 days after the onset. Considering the well-recognized vasoconstrictive effect of neuropeptide Y, it is possible that this increase in its concentration in the cerebrospinal fluid plays a role in the pathogenesis of the cerebral vasospasm that is often seen after subarachnoid hemorrhage.

Topics: Aged; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Chromatography, High Pressure Liquid; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Nerve Tissue Proteins; Neuroendocrine Secretory Protein 7B2; Neuropeptide Y; Osmolar Concentration; Pituitary Hormones; Subarachnoid Hemorrhage; Time Factors

We examined the relation between plasma atrial natriuretic peptide (ANP) and the changes of the regulating hormones ADH and renin aldosterone in 20 neurosurgical intensive care patients. All patients suffered from elevated intracranial pressure due to severe head trauma or severe subarachnoidal hemorrhage of the anterior circulation. Under controlled mechanical hyperventilation (CMV) with PEEP, 15 patients without evidence of central dysregulation showed no change in plasma ANP, ADH and aldosterone. In five patients with severe central dysregulation of either electrolytes or blood pressure, increases of plasma ANP of various degrees could be observed together with a decline in serum aldosterone.

Topics: Aldosterone; Atrial Natriuretic Factor; Brain Diseases; Craniocerebral Trauma; Critical Care; Humans; Intracranial Pressure; Reference Values; Renin; Subarachnoid Hemorrhage; Vasopressins; Water-Electrolyte Balance

Hyponatremia is common following aneurysmal subarachnoid hemorrhage and has been linked to the syndrome of inappropriate secretion of antidiuretic hormone. However, the demonstration of volume depletion and natriuresis in some patients has suggested that salt wasting is a more likely etiology. Atrial natriuretic factor appears to play a role in both central and peripheral regulation of sodium homeostasis. To investigate the behavior of circulating atrial natriuretic factor following subarachnoid hemorrhage, we studied 25 patients with intracranial aneurysms: 21 after acute subarachnoid hemorrhage and four without evidence of recent rupture. Atrial natriuretic factor was measured by radioimmunoassay of extracted plasma (normal value, 20.8 +/- 24.6, mean +/- 3 SD). Mean +/- SEM plasma atrial natriuretic factor concentration was elevated to 84 +/- 25 pg/ml on Day 1, rose to 134 +/- 29 pg/ml on Day 3, and fell to 86 +/- 17 pg/ml by Day 7 after subarachnoid hemorrhage (p less than 0.01). In two patients (9.5%) who developed hyponatremia after aneurysm rupture, plasma concentrations were no different from that in the group as a whole; concentrations in patients with no evidence of recent subarachnoid hemorrhage were not elevated. Neither fluid administration nor timing of surgery could account for the elevated concentrations. We conclude that concentrations of circulating atrial natriuretic factor are elevated after subarachnoid hemorrhage but do not solely account for the accompanying hyponatremia.

Topics: Atrial Natriuretic Factor; Humans; Intracranial Aneurysm; Osmolar Concentration; Radioimmunoassay; Rupture; Sodium; Subarachnoid Hemorrhage; Time Factors

Plasma and cerebrospinal fluid (CSF) atrial natriuretic factors/peptides (ANFs/ANPs) were measured in 26 patients with normal or raised intracranial pressure (ICP) by means of an instant radioreceptor assay. All 26 patients were suffering from aneurysmal subarachnoid hemorrhage (SAH), and 11 had also developed raised ICP (ICP greater than 20 mm Hg). In SAH patients with normal ICP, the plasma levels of ANF were 20 to 200 pg/ml (mean +/- SE, 89 +/- 68 pg/ml); in the 11 SAH patients with raised ICP, however, ANF levels were 14 to 262 pg/ml (mean 114 +/- 79 pg/ml). The difference was not statistically significant. The ANF/ANP plasma levels in 6 healthy volunteers were 15 to 167 pg/ml (mean 77 +/- 32 pg/ml). Although the ANF/ANP concentration in the CSF of patients with normal ICP did not reach the lower limit of detectability (i.e., 4 pg/ml) in any case, in those with elevated ICP it was 14 to 120 pg/ml (mean 49 +/- 37 pg/ml). This difference was statistically highly significant. The results of this preliminary study suggest that the ANF/ANP concentration in human CSF is 1 to 2 orders lower than that in the plasma and that there is no significant correlation between ANF/ANP levels in the CSF and the plasma. After SAH in patients with raised ICP, there was an accompanying increase in the ANF/ANP concentration in the CSF, but the ANF/ANP concentration in the plasma was not changed significantly. Accordingly, a central ANF/ANP release might be hypothesized to play a causative or adaptive role in the neuroendocrine regulation of ICP dynamics, although this may simply be an epiphenomenon.

Topics: Adult; Atrial Natriuretic Factor; Female; Humans; Intracranial Aneurysm; Intracranial Pressure; Male; Middle Aged; Subarachnoid Hemorrhage