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Hyponatremia Following Mild/Moderate Subarachnoid Hemorrhage Is Due To SIAD and Glucocorticoid Deficiency and not Cerebral Salt Wasting

Hyponatremia Following Mild/Moderate Subarachnoid Hemorrhage Is Due To SIAD and Glucocorticoid... Context: Hyponatremia is common after acute subarachnoid hemorrhage (SAH) but the etiology is unclear and there is a paucity of prospective data in the field. The cause of hyponatremia is variously attributed to the syndrome of inappropriate antidiuresis (SIAD), acute glucocorticoid insufficiency, and the cerebral salt wasting syndrome (CSWS). Objective: The objective was to prospectively determine the etiology of hyponatremia after SAH using sequential clinical examination and biochemical measurement of plasma cortisol, arginine vasopressin (AVP), and brain natriuretic peptide (BNP). Design: This was a prospective cohort study. Setting: The setting was the National Neurosurgery Centre in a tertiary referral centre in Dublin, Ireland. Patients: One hundred patients with acute nontraumatic aneurysmal SAH were recruited on presentation. Interventions: Clinical examination and basic biochemical evaluation were performed daily. Plasma cortisol at 0900 hours, AVP, and BNP concentrations were measured on days 1, 2, 3, 4, 6, 8, 10, and 12 following SAH. Those with 0900 hours plasma cortisol <300 nmol/L were empirically treated with iv hydrocortisone. Main Outcome Measures: Plasma sodium concentration was recorded daily along with a variety of clinical and biochemical criteria. The cause of hyponatremia was determined clinically. Later measurement of plasma AVP and BNP concentrations enabled a firm biochemical diagnosis of the cause of hyponatremia to be made. Results: Forty-nine of 100 developed hyponatremia <135 mmol/L, including 14/100 <130 mmol/L. The cause of hyponatremia, and determined by both clinical examination and biochemical hormone measurement, was SIAD in 36/49 (71.4%), acute glucocorticoid insufficiency in 4/49 (8.2%), incorrect iv fluids in 5/49 (10.2%), and hypovolemia in 5/49 (10.2%). There were no cases of CSWS. Conclusions: The most common cause of hyponatremia after acute nontraumatic aneurysmal SAH is SIAD. Acute glucocorticoid insufficiency accounts for a small but significant number of cases. We found no cases of CSWS. Hyponatremia is the commonest electrolyte abnormality to occur after subarachnoid hemorrhage (SAH) (1). Our own data, derived from a large retrospective study, showed that 56% of patients admitted with SAH develop hyponatremia (2). Hospital admission was longer in patients who developed hyponatremia, which suggests that appropriate treatment of hyponatremia could reduce duration of admission, as well as diminish the likelihood of associated morbidity and mortality. The etiology of hyponatremia after SAH is diverse (1) and includes syndrome of inappropriate antidiuresis (SIAD), cerebral salt wasting, acute ACTH/glucocorticoid deficiency, excess iv fluids, and diuretic therapy, and appropriate therapy must be targeted to the correct etiology to restore eunatremia. However, there is considerable dispute as to which of these diverse etiologies most commonly cause hyponatremia after SAH. A number of small studies have suggested that cerebral salt wasting syndrome (CSWS) is the most common cause (3–6), due to the finding that plasma atrial natriuretic peptide (ANP) (3, 5) and brain natriuretic peptic (BNP) concentrations (7) both rise after SAH. However, these studies were all small and underpowered. In contrast, recent data have suggested that the presence of elevated plasma BNP concentrations could not be regarded as a reliable predictor of either blood volume status or the development of hyponatremia (8). Elevated plasma BNP concentrations may therefore not necessarily mediate the development of hyponatremia. Our own retrospective studies (2, 9) have failed to substantiate cerebral salt wasting as a cause for anything more than a minority of cases of hyponatremia after SAH and strongly support SIAD as the predominant cause of hyponatremia. Our findings are at variance with those derived from a recent retrospective study of similar size, where only 35.4% of severe hyponatremia (<130 mmol/L) was considered to be due to SIAD, with a substantial proportion, 22.9%, considered to be secondary to CSWS (10). However, the patient cohort had more severe SAH than in our study and only those patients with plasma Na <130 mmol/L were analyzed in detail. Most patients in this study also developed hyponatremia more than 7 days after SAH, which is later than the natural history of hyponatremia in our experience, such that the two largest studies to date are not comparable due to fundamental differences in cohort and methodology. One weakness of our own retrospective data is that the study analyzed a time period when data on ACTH/cortisol dynamics were not routine, and we were unable to comment therefore on how many patients with apparent SIAD had their electrolyte abnormalities as a manifestation of glucocorticoid deficiency. It is now apparent that acute ACTH deficiency is more common than previously recognized after neurosurgical insult (11), and data in patients who have sustained traumatic brain injury (TBI) have reported life-threatening hyponatremia (12) and hypotension requiring pressor support (13). Recent studies by Klose et al (14) and Parenti et al (15) found that between 7.1% and 12% were cortisol deficient immediately after SAH. Both of these studies were prospective but small, with analysis of cortisol dynamics taking place at a single time point after SAH. It has been shown that plasma cortisol levels fluctuate significantly after other intracerebral insults such as TBI (16), so transient cortisol deficiency may have been missed, leading to an underestimation of the true frequency of acute cortisol deficiency. It is likely that at least some of those who develop hyponatremia after SAH are suffering from acute ACTH deficiency due to pituitary injury. Given the conflicting and retrospective nature of the above data, we performed a prospective study of patients with SAH attending our unit. Our aims were as follows: 1.  To test whether our retrospective data showing SIAD is the commonest cause of hyponatremia (2) could be confirmed with prospective, sequential data analyzing the prevalence, incidence, and severity of hyponatremia after SAH. 2.  To determine the correct cause of hyponatremia after SAH, using prospective clinical data and sequential direct measurement of plasma arginine vasopressin (AVP) and plasma BNP after SAH. 3.  To prospectively determine the contribution of acute cortisol deficiency to the development of hyponatremia after SAH. Materials and Methods We recruited 100 patients on admission to our center with nontraumatic aneurysmal SAH. Our center is the national referral center for neurosurgical disease in Ireland, with a catchment area of 3.5 million people. Those patients aged less than 18, pregnant and lactating females, those hyponatremic on admission, those with a history of arteriovenous malformation, previous intracerebral insult or endocrinopathy, and those on corticosteroids were excluded. Aneurysmal SAH was confirmed by computed tomographic angiography or invasive angiography. Blood was drawn at 0900 hours on days 1 to 12 after SAH to measure serum sodium, urea, and creatinine levels. Urinary sodium was also measured daily. On days 1, 2, 3, 4, 6, 8, 10, and 12, plasma total cortisol at 0900 hours was measured. On the same days, samples were taken and stored for later measurement of AVP and BNP. Patients were also examined daily and fluid balance and other key clinical and radiological parameters such as Glasgow Coma Scale (GCS), mean arterial pressure, pressor requirements, sedation requirements, computed tomography results, and medications were recorded daily by a single researcher (M.J.H.). If the patient was transferred from another center, their clinical and laboratory findings from that center were recorded, including fluid balance, fluid prescriptions, serum sodium, urea, and creatinine. For logistical reasons, samples for measurement of plasma total cortisol, AVP, and BNP were only taken after patient transfer to our center. SIAD was defined by the well-established diagnostic criteria of Janicic and Verbalis (17). The patient was required to have euvolemic hyponatremia, with inappropriate urine concentration, low urine volume, and natriuresis, with the exclusion of hypocortisolemia and hypothyroidism. By contrast, CSWS was defined as hypovolemic hyponatremia with diuresis and natriuresis (18, 19). Fluid iv administration was considered incorrect where there was clinical evidence of fluid overload, or if hypotonic solution, such as dextrose, 0.45% NaCl, or compound sodium lactate solution, had caused hyponatremia. The parameters used for the differential diagnosis of hyponatremia are shown in Supplemental Tables 1 and 2, published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org. If plasma sodium was abnormally high, urine osmolality was measured. Cranial diabetes insipidus (CDI) was diagnosed using the Seckl and Dunger criteria (20) and treated with oral or subcutaneous desmopressin, in line with local protocols. Those diagnosed with CDI were initially treated with as-needed doses of desmopressin due to the often transient nature of CDI in these patients. Those with persistent CDI were maintained on oral desmopressin after discharge. We thought that it would be ethically inappropriate not to treat patients with acute hypocortisolemia with steroids. Therefore, patients with 0900 hours plasma cortisol less than 300 nmol/L were empirically treated with hydrocortisone 50 mg iv four times daily. If a patient that we had started on hydrocortisone needed to have their plasma cortisol measured as part of the study protocol, their hydrocortisone was held for two doses preceding the blood draw, meaning that they would not have received any hydrocortisone for 15 hours preceding venesection (21). Patients who were commenced on hydrocortisone whose plasma cortisol did not recover to >300 nmol/L before discharge remained on hydrocortisone after discharge, at an oral maintenance dose of 10 mg twice daily, until dynamic testing. Ethics The study was approved by the ethics section of Beaumont Hospital Medical Research Committee. The purpose of the study was explained carefully to patients and relatives, who were provided with written information on the background to the study. Due to the severity of most patients' illnesses, written consent was usually given by the next of kin. Analytical methods Plasma cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter Unicell DXI 800 with intra-assay coefficients of variation (CV) of 8.3%, 5%, and 4.6% at plasma cortisol concentrations of 76, 438, and 865 nmol/L, respectively. Plasma AVP was measured using a two-step RIA as previously described (22). Intra-assay CV was 12%, 16%, and 16% at plasma AVP concentrations of 3.82 pmol/L, 8.78 pmol/L, and 27.02 pmol/L, respectively. Interassay CV was 8.7% and 10.1% at plasma AVP concentrations of 2.37 pmol/L and 4.93 pmol/L, respectively. Plasma BNP was measured using a two-site immunoenzymatic sandwich assay. Intra-assay CV was 2.9%, 2.3%, and 1.9% at plasma BNP concentrations of 79.5 pg/mL, 384.7 pg/mL, and 1975.8 pg/mL, respectively. Interassay CV was not available for this methodology. Statistical analysis Statistical analysis was performed using GraphPad Prism 5 statistical software (Graphpad Software). Data are nonparametric and expressed as median (range) unless otherwise stated. Continuous variables were compared using the Mann-Whitney test. Categorical variables were analyzed using the χ2 test. Results One hundred patients (61% female) with nontraumatic aneurysmal SAH were recruited. The median age was 53 years (range 16–82). Seventy-two percent were transferred to our center from other hospitals, all within 3 days of SAH. The spectrum of SAH was mild to moderate, with a median Hunt and Hess scale (23) of 2/5 and a median Fisher grade (24) of 3/4. Acute mortality, occurring in the first 2 weeks after SAH, was 11%. Overall median length of stay was 15.5 days (range 5–232 days). The policy of the neurosurgical unit is to use early iv isotonic saline to prevent cerebral vasopspasm. Most patients were maintained on iv 0.9% sodium chloride for the early part of their admission, at a rate of 125–250 mL/h. No patient received hypertonic saline. Eleven patients received compound sodium lactate or 0.45% saline. Incidence and time course of hyponatremia Forty-nine of 100 patients developed hyponatremia (plasma sodium <135 mmol/L), including 14 who developed clinically significantly hyponatremia (plasma sodium <130 mmol/L). Of the hyponatremic patients, 36/49 (73.4%) developed hyponatremia between days 1 and 3 post SAH, 6/49 (12.2%) developed hyponatremia between 4 and 7 days after SAH, and 7/49 (14.3%) developed hyponatremia more than 7 days after SAH. The median duration of hyponatremia was 3 days (range 1 to 10 days) and was transient in all cases, with resolution of hyponatremia during hospital admission. Of the patients who developed hyponatremia, 45/49 (91.8%) were treated with either operative clipping, endovascular coiling, or both. Twenty-one of 49 (42.9%) developed hyponatremia at a median time of 3 days after intervention (range 1–9 days). Eight of 21 (38.1%) developed hyponatremia more than 3 days after their intervention. There was no correlation between the severity of SAH, measured by either Hunt and Hess scale or Fisher grade, and the development of hyponatremia (P = .86 and .36, respectively). There was no significant difference in length of stay between those who developed hyponatremia (median 17 days, range 6–232) and those who did not (median 13 days, range 5–62) (P = .15 between groups). Effect of position and treatment of aneurysm on hyponatremia Fifty-seven percent of patients had an anterior circulation aneurysm; 24% had a posterior circulation aneurysm, and 6% had both. Thirteen percent had aneurysms in other locations. There was no difference in the incidence of hyponatremia according to defined anatomical territory. There was no significant difference in the incidence of hyponatremia between those patients who had an intervention and those who did not (44/83 vs 5/17, P = .11). There was also no difference in the incidence of hyponatremia between those patients who had craniotomy and clipping performed and those who had endovascular coiling performed (7/16 vs 34/63, P = .23). Causes of hyponatremia Using the clinical assessment protocols described above, 35/49 (71.4%) hyponatremic patients were found to have SIAD; 5/49 (10.2%) were found to have hyponatremia from incorrect or injudicious iv fluids (ie, the administration of 0.45% saline), 5/49 (10.2%) were found to have hyponatremia from volume depletion, and 4/49 (8.2%) were found to have hyponatremia from acute cortisol deficiency, which resolved after administration of parenteral hydrocortisone. All patients had normal thyroid function tests. Patients with hyponatremia due to SIAD were generally in positive fluid balance (Figure 1, A and B). None were hypotensive and there was no significant difference between mean arterial pressure in those with SIAD and eunatremic patients. Median 0900 hours plasma cortisol in patients with SIAD was 607 nmol/L (range 310–1513 nmol/L). In each patient who developed hyponatremia, AVP was significantly higher before and during the episode of hyponatremia compared with AVP levels measured once the hyponatremia had resolved (P = .03) (Figure 2). There was no difference in BNP when levels were compared before, during, and after the episode of hyponatremia (P = .37). Patients with SIAD had loss of the osmotic link between plasma sodium and AVP release (R = −0.02, P = .92), whereas those with normal sodium levels maintained this physiological association (R = .51, P = .04) (Figure 3). Figure 3. Open in new tabDownload slide Relationship between plasma sodium and AVP secretion. The association between plasma sodium and AVP release is maintained in those patients with normonatremia (R = 0.51, P = .04), but lost in those with SIAD (R = −0.02, P = .93). Figure 3. Open in new tabDownload slide Relationship between plasma sodium and AVP secretion. The association between plasma sodium and AVP release is maintained in those patients with normonatremia (R = 0.51, P = .04), but lost in those with SIAD (R = −0.02, P = .93). Figure 2. Open in new tabDownload slide Comparison of AVP levels before development of hyponatremia, during hyponatremic episode, and after resolution of hyponatremia, in patients with SIAD. AVP levels are significantly higher before and during episode of hyponatremia when compared with after resolution of hyponatremia (P = .03). Figure 2. Open in new tabDownload slide Comparison of AVP levels before development of hyponatremia, during hyponatremic episode, and after resolution of hyponatremia, in patients with SIAD. AVP levels are significantly higher before and during episode of hyponatremia when compared with after resolution of hyponatremia (P = .03). Figure 1. Open in new tabDownload slide (A) Fluid balance in patients with SIAD. points, median; bars, range; Day, day post-SAH. (B) Fluid balance in all patients. points, median; Day, day post-SAH. Figure 1. Open in new tabDownload slide (A) Fluid balance in patients with SIAD. points, median; bars, range; Day, day post-SAH. (B) Fluid balance in all patients. points, median; Day, day post-SAH. Overall, 14 patients developed acute cortisol deficiency, at a median of day 4 (range 2–6 days). Nine of 14 patients developed acute cortisol deficiency without hyponatremia, with a median cortisol nadir of 130 nmol/L (range 83–225 nmol/L). Four of 14 developed acute cortisol deficiency causing hyponatremia, with a median nadir cortisol of 141 nmol/L (range 57–251 nmol/L). All four were treated with iv hydrocortisone as per protocol, with rapid normalization of plasma sodium. The final patient had a transient drop in plasma cortisol to 93 nmol/L, which recovered within 2 days; after normalization of cortisol, the patient then developed hyponatremia, which was thought to be due to SIAD rather than cortisol deficiency. None of the 14 hypocortisolemic patients developed hypoglycemia or hypotension. Cortisol deficiency did not resolve in 6/14, which necessitated hydrocortisone treatment after discharge. Five patients developed hyponatremia due to the use of incorrect, hypotonic iv fluids, such as compound sodium lactate or 0.45% sodium chloride. These patients were clinically euvolemic and generally had low AVP levels (Figure 4); none were fluid overloaded. Hyponatremia in this group uniformly resolved with alteration of the patients' iv fluid prescriptions. Five patients developed hyponatremia due to inadequate fluid replacement, resulting in hypovolemia. All five patients had low urine output (<1.5 L/24 h) rather than the diuresis and natriuresis typical of CSWS. There were no cases of hypovolemia due to diuretics. All cases of hypovolemic hyponatremia resolved with appropriate fluid repletion. Figure 4. Open in new tabDownload slide Comparison of AVP levels between different patient groups. Each point represents an individual AVP measurement. *, P = .01; ***, P < .0001. Figure 4. Open in new tabDownload slide Comparison of AVP levels between different patient groups. Each point represents an individual AVP measurement. *, P = .01; ***, P < .0001. Plasma AVP concentrations were higher in SIAD than in any other hyponatremic group (Figure 4). In contrast, there was no difference in plasma BNP concentrations between any hyponatremic group (Figure 5) and no difference between plasma BNP concentrations in the eunatremic and hyponatremic groups. Figure 5. Open in new tabDownload slide Comparison of BNP levels between different patient groups. Each point represents an individual BNP measurement. All comparisons between groups were nonsignificant (P > .05). Figure 5. Open in new tabDownload slide Comparison of BNP levels between different patient groups. Each point represents an individual BNP measurement. All comparisons between groups were nonsignificant (P > .05). Discussion In this article, which documents a prospective biochemical and clinical examination of a large cohort of SAH patients, by a single experienced observer, we have confirmed the findings from our retrospective study. Hyponatremia occurred in 50% of SAH patients, and the commonest cause of hyponatremia was SIAD. In addition, we have shown that 14% of SAH patients develop acute ACTH deficiency and that some of these patients develop steroid-remedial hyponatremia. Finally, we were unable to demonstrate any case of hyponatremia that fitted clinical criteria for the diagnosis of cerebral salt wasting; the pattern of changes in plasma AVP and BNP concentrations was typical of SIAD. Incidence of hyponatremia Our results correspond with previous retrospective data from our group (2) and others (10), indicating that hyponatremia occurs in approximately half of all patients after nontraumatic aneurysmal SAH, usually occurring in the first 3 days after SAH. Most hyponatremic patients maintained their plasma sodium above 130 mmol/L for the duration of their inpatient stay, but in our cohort 14% developed clinically significant hyponatremia. The clinical or radiological severity of SAH was less in this study than in our retrospective study, due to a change in referral patterns, and the lower proportion of patients with severe hyponatremia in this study, compared with the retrospective study, may reflect the milder spectrum of disease. Causation of hyponatremia Our data demonstrate that most cases of hyponatremia after SAH are due to SIAD. We diagnosed 71.4% of our hyponatremic cohort with SIAD based on well-defined clinical diagnostic criteria (Supplemental Tables 1 and 2). Plasma AVP and BNP were not available (although cortisol levels were) until after study completion, when the batched plasma samples were assayed as a cohort. This was a conscious decision, as we wanted our approach to be clinically relevant to practicing clinicians, and so clinical definitions were used to define SIAD and CSWS. Very few patients had central venous pressure evaluation, such that assessment of patients' volume status was primarily based on clinical judgment by clinicians experienced in evaluating hyponatremia. Although it can be difficult to evaluate volume status clinically, particularly when endeavoring to separate mild hypovolemia from eunatremia, cerebral salt wasting is usually characterized by profound natriuresis, diuresis, and marked volume depletion. However, the subsequent analysis of stored plasma verified the accuracy of clinical diagnostic criteria. In the group determined on clinical grounds to have SIAD, plasma AVP concentrations rose before development of hyponatremia, remained elevated during hyponatremia, and fell after recovery from hyponatremia. Moreover, urine volumes fell as plasma AVP concentrations rose in this group. This qualitative pattern strongly suggests a primary causative role for AVP in the development of hyponatremia and supports the diagnosis of SIAD. In contrast, plasma AVP levels remained unchanged throughout the development and progression of hyponatremia in patients whose hyponatremia developed due to a cause other than SIAD. SIAD in this patient cohort was managed expectantly; the vaptan class of aquaretic agents was not available during the timeline of this study and neurosurgical practice, to prevent cerebral vasospasm, dictated that fluid restriction was generally only possible to a minimum of 2.5 to 3 L per day. Despite the absence of active management of hyponatremia in the SIAD group, our data concurred with that of previous studies, which reported that hyponatremia due to SIAD is transient after SAH (2, 10). As expected from published data on the pathophysiology of SIAD, the relationship between plasma AVP concentrations and plasma osmolality was lost in patients with SIAD (25, 26), whereas the well-published linear relationship between these parameters was preserved in eunatremic patients (25, 27) (Figure 3). Our clinical identification of patients who had dilutional hyponatremia due to incorrect iv fluids was verified by the subsequent plasma AVP measurements, which were mostly suppressed. Plasma AVP concentrations were also higher in the SIAD group than in the ACTH-deficient group and the volume-depleted group (Figure 4). No previous studies have sequentially measured plasma AVP concentrations and correlated them to the development of hyponatremia. Our AVP data verified the accuracy of a clinical approach to the differential diagnosis of hyponatremia developing after SAH, with maintenance of the relationship between plasma AVP and plasma osmolality in eunatremic patients, elevated plasma AVP concentrations, which preceded hyponatremia, in the SIAD group, and suppression of plasma AVP in the fluid-overloaded group. The only finding that is not consistent is that of reduced AVP levels in the volume depleted group. However, none of this group, which was clinically thought to be hypovolemic, was severely hypotensive, which may somewhat explain this observation. It is also possible that some of these patients were misclassified and were actually suffering from SIAD. Only a minority of patients was found to be volume depleted, and none of these patients had convincing evidence of a profound diuresis or natriuresis, which could have been attributed to cerebral salt wasting. Although in the hypovolemic group we did demonstrate a sequential rise in plasma BNP concentrations after SAH, plasma BNP concentrations rose in all groups irrespective of etiology, and rose also in the eunatremic cohort, with no significant difference in BNP levels between any group (Figure 5). As a result, we could not find a consistent role for BNP in the development of hyponatremia after SAH. Our interpretation is that although we have verified the findings of a number of groups by showing that plasma BNP concentrations increase after SAH (28, 29), this rise seems to be universal, unrelated to the subsequent development of hyponatremia, and of no causal significance in terms of development of hyponatremia. We therefore cannot support the contention that cerebral salt wasting contributes significantly to hyponatremia after SAH. We do not contend the existence of cerebral salt wasting, as some authorities do (3–6). We have previously published data from a single patient who demonstrated a marked rise in both plasma ANP and plasma BNP concentrations in the early phase after SAH, with the subsequent development of profound natriuresis, diuresis, blood volume contraction, and hypovolemic hyponatremia (1); plasma AVP concentrations only rose in response to hypovolemia in this patient. We were unable to reproduce this hormonal or hemodynamic sequence of events in any patient in this study. The overwhelmingly predominant sequence was a rise in plasma AVP concentration, with a subsequent euvolemic hyponatremia, typical of SIAD. Previous, smaller studies have shown that the natriuretic peptides rise in acute SAH, which appears to be independent of SAH severity or catecholamine levels (29). Both human (3–5, 7, 8, 30–33) and animal (34) studies have suggested a role for BNP in the development of cerebral vasospasm and possibly CSWS with consequent hyponatremia. However, the human studies were small in size, did not measure plasma sodium and BNP sequentially (4, 30, 31), or only selected the subgroup that developed hypovolemic hyponatremia for analysis (8). In those studies that did examine plasma sodium, AVP, and BNP sequentially, both appeared to rise, with the rise in AVP lasting only a few days immediately after SAH and the rise in BNP being more sustained. Given that most patients in our study developed hyponatremia in the first 3 days after SAH, we would argue that an early AVP peak with the development of hyponatremia is suggestive of SIAD rather than BNP-related CSWS. It should also be stated that many earlier studies were underpowered and contained patients with much more severe SAH than our cohort. Interestingly, recent animal studies of SAH in rats have cast doubt on the putative causative role of ANP and BNP in CSWS (34). Prevalence of acute ACTH/cortisol deficiency post-SAH There is good evidence that acute cortisol deficiency occurs in at least 15% to 20% of patients with moderate/severe TBI (11) causing hyponatremia (12) and hypotension requiring pressor support (13). The evidence for acute hypocortisolemia after SAH is less robust (14, 15), with published data showing conflicting results. Parenti et al (15) showed that 7% of patients had subnormal plasma cortisol concentrations during SAH and Klose et al (14) found that 3/26 (11.5%) had 0900 hour plasma cortisol <276 nmol/L, at a median of 7 days after SAH (14). These studies did not present data on hyponatremia resulting from cortisol deficiency. Our data show a comparable rate of acute hypocortisolemia but also report the causative relationship between acute hypocortisolemia and hyponatremia. The plasma cortisol concentration that we defined as a normal cutoff was based on our previous data in acutely unwell patients after vascular surgery, whereby 0900 hours plasma cortisol concentrations were >300 nmol/L at all times during their admission. This is very comparable to the cutoff defined by Klose's group (14). Plasma total cortisol is a good surrogate marker of plasma-free cortisol level in neurosurgical patients (16), and as all of our cohort had serum albumin >30 g/L during their hospital admission, we felt confident that 0900 hour plasma cortisol concentrations <300 nmol/L represented inappropriate hypocortisolemia after SAH. Four patients presented with biochemical findings typical of SIAD, together with inappropriately low plasma cortisol concentrations for an acutely unwell patient. Treatment with iv hydrocortisone rapidly returned plasma sodium concentration to normal. This was suggestive of a causal relationship between cortisol deficiency and hyponatremia, although we cannot be absolutely certain in the absence of a control group of untreated patients that the return to eunatremia would have occurred anyway. However, in the clinical context of an unwell patient, clinical ethics dictated that we should intervene. Of those patients who presented biochemically as SIAD, 10% had acute ACTH/cortisol deficiency. Interestingly, most patients who developed acute hypocortisolemia did not develop hyponatremia, so hyponatremia was not a sensitive marker for the identification of acute ACTH deficiency. Our data do raise questions about the consideration of acute cortisol deficiency as a consequence of SAH. In conclusion, hyponatremia is common after acute nontraumatic aneursymal SAH and is predominantly due to SIAD as determined by both prospective clinical assessment and sequential measurement of AVP and BNP levels. 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Google Scholar Crossref Search ADS PubMed WorldCat Copyright © 2014 by The Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Hyponatremia Following Mild/Moderate Subarachnoid Hemorrhage Is Due To SIAD and Glucocorticoid Deficiency and not Cerebral Salt Wasting

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Publisher
Oxford University Press
Copyright
Copyright © 2014 by The Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
DOI
10.1210/jc.2013-3032
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See Article on Publisher Site

Abstract

Context: Hyponatremia is common after acute subarachnoid hemorrhage (SAH) but the etiology is unclear and there is a paucity of prospective data in the field. The cause of hyponatremia is variously attributed to the syndrome of inappropriate antidiuresis (SIAD), acute glucocorticoid insufficiency, and the cerebral salt wasting syndrome (CSWS). Objective: The objective was to prospectively determine the etiology of hyponatremia after SAH using sequential clinical examination and biochemical measurement of plasma cortisol, arginine vasopressin (AVP), and brain natriuretic peptide (BNP). Design: This was a prospective cohort study. Setting: The setting was the National Neurosurgery Centre in a tertiary referral centre in Dublin, Ireland. Patients: One hundred patients with acute nontraumatic aneurysmal SAH were recruited on presentation. Interventions: Clinical examination and basic biochemical evaluation were performed daily. Plasma cortisol at 0900 hours, AVP, and BNP concentrations were measured on days 1, 2, 3, 4, 6, 8, 10, and 12 following SAH. Those with 0900 hours plasma cortisol <300 nmol/L were empirically treated with iv hydrocortisone. Main Outcome Measures: Plasma sodium concentration was recorded daily along with a variety of clinical and biochemical criteria. The cause of hyponatremia was determined clinically. Later measurement of plasma AVP and BNP concentrations enabled a firm biochemical diagnosis of the cause of hyponatremia to be made. Results: Forty-nine of 100 developed hyponatremia <135 mmol/L, including 14/100 <130 mmol/L. The cause of hyponatremia, and determined by both clinical examination and biochemical hormone measurement, was SIAD in 36/49 (71.4%), acute glucocorticoid insufficiency in 4/49 (8.2%), incorrect iv fluids in 5/49 (10.2%), and hypovolemia in 5/49 (10.2%). There were no cases of CSWS. Conclusions: The most common cause of hyponatremia after acute nontraumatic aneurysmal SAH is SIAD. Acute glucocorticoid insufficiency accounts for a small but significant number of cases. We found no cases of CSWS. Hyponatremia is the commonest electrolyte abnormality to occur after subarachnoid hemorrhage (SAH) (1). Our own data, derived from a large retrospective study, showed that 56% of patients admitted with SAH develop hyponatremia (2). Hospital admission was longer in patients who developed hyponatremia, which suggests that appropriate treatment of hyponatremia could reduce duration of admission, as well as diminish the likelihood of associated morbidity and mortality. The etiology of hyponatremia after SAH is diverse (1) and includes syndrome of inappropriate antidiuresis (SIAD), cerebral salt wasting, acute ACTH/glucocorticoid deficiency, excess iv fluids, and diuretic therapy, and appropriate therapy must be targeted to the correct etiology to restore eunatremia. However, there is considerable dispute as to which of these diverse etiologies most commonly cause hyponatremia after SAH. A number of small studies have suggested that cerebral salt wasting syndrome (CSWS) is the most common cause (3–6), due to the finding that plasma atrial natriuretic peptide (ANP) (3, 5) and brain natriuretic peptic (BNP) concentrations (7) both rise after SAH. However, these studies were all small and underpowered. In contrast, recent data have suggested that the presence of elevated plasma BNP concentrations could not be regarded as a reliable predictor of either blood volume status or the development of hyponatremia (8). Elevated plasma BNP concentrations may therefore not necessarily mediate the development of hyponatremia. Our own retrospective studies (2, 9) have failed to substantiate cerebral salt wasting as a cause for anything more than a minority of cases of hyponatremia after SAH and strongly support SIAD as the predominant cause of hyponatremia. Our findings are at variance with those derived from a recent retrospective study of similar size, where only 35.4% of severe hyponatremia (<130 mmol/L) was considered to be due to SIAD, with a substantial proportion, 22.9%, considered to be secondary to CSWS (10). However, the patient cohort had more severe SAH than in our study and only those patients with plasma Na <130 mmol/L were analyzed in detail. Most patients in this study also developed hyponatremia more than 7 days after SAH, which is later than the natural history of hyponatremia in our experience, such that the two largest studies to date are not comparable due to fundamental differences in cohort and methodology. One weakness of our own retrospective data is that the study analyzed a time period when data on ACTH/cortisol dynamics were not routine, and we were unable to comment therefore on how many patients with apparent SIAD had their electrolyte abnormalities as a manifestation of glucocorticoid deficiency. It is now apparent that acute ACTH deficiency is more common than previously recognized after neurosurgical insult (11), and data in patients who have sustained traumatic brain injury (TBI) have reported life-threatening hyponatremia (12) and hypotension requiring pressor support (13). Recent studies by Klose et al (14) and Parenti et al (15) found that between 7.1% and 12% were cortisol deficient immediately after SAH. Both of these studies were prospective but small, with analysis of cortisol dynamics taking place at a single time point after SAH. It has been shown that plasma cortisol levels fluctuate significantly after other intracerebral insults such as TBI (16), so transient cortisol deficiency may have been missed, leading to an underestimation of the true frequency of acute cortisol deficiency. It is likely that at least some of those who develop hyponatremia after SAH are suffering from acute ACTH deficiency due to pituitary injury. Given the conflicting and retrospective nature of the above data, we performed a prospective study of patients with SAH attending our unit. Our aims were as follows: 1.  To test whether our retrospective data showing SIAD is the commonest cause of hyponatremia (2) could be confirmed with prospective, sequential data analyzing the prevalence, incidence, and severity of hyponatremia after SAH. 2.  To determine the correct cause of hyponatremia after SAH, using prospective clinical data and sequential direct measurement of plasma arginine vasopressin (AVP) and plasma BNP after SAH. 3.  To prospectively determine the contribution of acute cortisol deficiency to the development of hyponatremia after SAH. Materials and Methods We recruited 100 patients on admission to our center with nontraumatic aneurysmal SAH. Our center is the national referral center for neurosurgical disease in Ireland, with a catchment area of 3.5 million people. Those patients aged less than 18, pregnant and lactating females, those hyponatremic on admission, those with a history of arteriovenous malformation, previous intracerebral insult or endocrinopathy, and those on corticosteroids were excluded. Aneurysmal SAH was confirmed by computed tomographic angiography or invasive angiography. Blood was drawn at 0900 hours on days 1 to 12 after SAH to measure serum sodium, urea, and creatinine levels. Urinary sodium was also measured daily. On days 1, 2, 3, 4, 6, 8, 10, and 12, plasma total cortisol at 0900 hours was measured. On the same days, samples were taken and stored for later measurement of AVP and BNP. Patients were also examined daily and fluid balance and other key clinical and radiological parameters such as Glasgow Coma Scale (GCS), mean arterial pressure, pressor requirements, sedation requirements, computed tomography results, and medications were recorded daily by a single researcher (M.J.H.). If the patient was transferred from another center, their clinical and laboratory findings from that center were recorded, including fluid balance, fluid prescriptions, serum sodium, urea, and creatinine. For logistical reasons, samples for measurement of plasma total cortisol, AVP, and BNP were only taken after patient transfer to our center. SIAD was defined by the well-established diagnostic criteria of Janicic and Verbalis (17). The patient was required to have euvolemic hyponatremia, with inappropriate urine concentration, low urine volume, and natriuresis, with the exclusion of hypocortisolemia and hypothyroidism. By contrast, CSWS was defined as hypovolemic hyponatremia with diuresis and natriuresis (18, 19). Fluid iv administration was considered incorrect where there was clinical evidence of fluid overload, or if hypotonic solution, such as dextrose, 0.45% NaCl, or compound sodium lactate solution, had caused hyponatremia. The parameters used for the differential diagnosis of hyponatremia are shown in Supplemental Tables 1 and 2, published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org. If plasma sodium was abnormally high, urine osmolality was measured. Cranial diabetes insipidus (CDI) was diagnosed using the Seckl and Dunger criteria (20) and treated with oral or subcutaneous desmopressin, in line with local protocols. Those diagnosed with CDI were initially treated with as-needed doses of desmopressin due to the often transient nature of CDI in these patients. Those with persistent CDI were maintained on oral desmopressin after discharge. We thought that it would be ethically inappropriate not to treat patients with acute hypocortisolemia with steroids. Therefore, patients with 0900 hours plasma cortisol less than 300 nmol/L were empirically treated with hydrocortisone 50 mg iv four times daily. If a patient that we had started on hydrocortisone needed to have their plasma cortisol measured as part of the study protocol, their hydrocortisone was held for two doses preceding the blood draw, meaning that they would not have received any hydrocortisone for 15 hours preceding venesection (21). Patients who were commenced on hydrocortisone whose plasma cortisol did not recover to >300 nmol/L before discharge remained on hydrocortisone after discharge, at an oral maintenance dose of 10 mg twice daily, until dynamic testing. Ethics The study was approved by the ethics section of Beaumont Hospital Medical Research Committee. The purpose of the study was explained carefully to patients and relatives, who were provided with written information on the background to the study. Due to the severity of most patients' illnesses, written consent was usually given by the next of kin. Analytical methods Plasma cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter Unicell DXI 800 with intra-assay coefficients of variation (CV) of 8.3%, 5%, and 4.6% at plasma cortisol concentrations of 76, 438, and 865 nmol/L, respectively. Plasma AVP was measured using a two-step RIA as previously described (22). Intra-assay CV was 12%, 16%, and 16% at plasma AVP concentrations of 3.82 pmol/L, 8.78 pmol/L, and 27.02 pmol/L, respectively. Interassay CV was 8.7% and 10.1% at plasma AVP concentrations of 2.37 pmol/L and 4.93 pmol/L, respectively. Plasma BNP was measured using a two-site immunoenzymatic sandwich assay. Intra-assay CV was 2.9%, 2.3%, and 1.9% at plasma BNP concentrations of 79.5 pg/mL, 384.7 pg/mL, and 1975.8 pg/mL, respectively. Interassay CV was not available for this methodology. Statistical analysis Statistical analysis was performed using GraphPad Prism 5 statistical software (Graphpad Software). Data are nonparametric and expressed as median (range) unless otherwise stated. Continuous variables were compared using the Mann-Whitney test. Categorical variables were analyzed using the χ2 test. Results One hundred patients (61% female) with nontraumatic aneurysmal SAH were recruited. The median age was 53 years (range 16–82). Seventy-two percent were transferred to our center from other hospitals, all within 3 days of SAH. The spectrum of SAH was mild to moderate, with a median Hunt and Hess scale (23) of 2/5 and a median Fisher grade (24) of 3/4. Acute mortality, occurring in the first 2 weeks after SAH, was 11%. Overall median length of stay was 15.5 days (range 5–232 days). The policy of the neurosurgical unit is to use early iv isotonic saline to prevent cerebral vasopspasm. Most patients were maintained on iv 0.9% sodium chloride for the early part of their admission, at a rate of 125–250 mL/h. No patient received hypertonic saline. Eleven patients received compound sodium lactate or 0.45% saline. Incidence and time course of hyponatremia Forty-nine of 100 patients developed hyponatremia (plasma sodium <135 mmol/L), including 14 who developed clinically significantly hyponatremia (plasma sodium <130 mmol/L). Of the hyponatremic patients, 36/49 (73.4%) developed hyponatremia between days 1 and 3 post SAH, 6/49 (12.2%) developed hyponatremia between 4 and 7 days after SAH, and 7/49 (14.3%) developed hyponatremia more than 7 days after SAH. The median duration of hyponatremia was 3 days (range 1 to 10 days) and was transient in all cases, with resolution of hyponatremia during hospital admission. Of the patients who developed hyponatremia, 45/49 (91.8%) were treated with either operative clipping, endovascular coiling, or both. Twenty-one of 49 (42.9%) developed hyponatremia at a median time of 3 days after intervention (range 1–9 days). Eight of 21 (38.1%) developed hyponatremia more than 3 days after their intervention. There was no correlation between the severity of SAH, measured by either Hunt and Hess scale or Fisher grade, and the development of hyponatremia (P = .86 and .36, respectively). There was no significant difference in length of stay between those who developed hyponatremia (median 17 days, range 6–232) and those who did not (median 13 days, range 5–62) (P = .15 between groups). Effect of position and treatment of aneurysm on hyponatremia Fifty-seven percent of patients had an anterior circulation aneurysm; 24% had a posterior circulation aneurysm, and 6% had both. Thirteen percent had aneurysms in other locations. There was no difference in the incidence of hyponatremia according to defined anatomical territory. There was no significant difference in the incidence of hyponatremia between those patients who had an intervention and those who did not (44/83 vs 5/17, P = .11). There was also no difference in the incidence of hyponatremia between those patients who had craniotomy and clipping performed and those who had endovascular coiling performed (7/16 vs 34/63, P = .23). Causes of hyponatremia Using the clinical assessment protocols described above, 35/49 (71.4%) hyponatremic patients were found to have SIAD; 5/49 (10.2%) were found to have hyponatremia from incorrect or injudicious iv fluids (ie, the administration of 0.45% saline), 5/49 (10.2%) were found to have hyponatremia from volume depletion, and 4/49 (8.2%) were found to have hyponatremia from acute cortisol deficiency, which resolved after administration of parenteral hydrocortisone. All patients had normal thyroid function tests. Patients with hyponatremia due to SIAD were generally in positive fluid balance (Figure 1, A and B). None were hypotensive and there was no significant difference between mean arterial pressure in those with SIAD and eunatremic patients. Median 0900 hours plasma cortisol in patients with SIAD was 607 nmol/L (range 310–1513 nmol/L). In each patient who developed hyponatremia, AVP was significantly higher before and during the episode of hyponatremia compared with AVP levels measured once the hyponatremia had resolved (P = .03) (Figure 2). There was no difference in BNP when levels were compared before, during, and after the episode of hyponatremia (P = .37). Patients with SIAD had loss of the osmotic link between plasma sodium and AVP release (R = −0.02, P = .92), whereas those with normal sodium levels maintained this physiological association (R = .51, P = .04) (Figure 3). Figure 3. Open in new tabDownload slide Relationship between plasma sodium and AVP secretion. The association between plasma sodium and AVP release is maintained in those patients with normonatremia (R = 0.51, P = .04), but lost in those with SIAD (R = −0.02, P = .93). Figure 3. Open in new tabDownload slide Relationship between plasma sodium and AVP secretion. The association between plasma sodium and AVP release is maintained in those patients with normonatremia (R = 0.51, P = .04), but lost in those with SIAD (R = −0.02, P = .93). Figure 2. Open in new tabDownload slide Comparison of AVP levels before development of hyponatremia, during hyponatremic episode, and after resolution of hyponatremia, in patients with SIAD. AVP levels are significantly higher before and during episode of hyponatremia when compared with after resolution of hyponatremia (P = .03). Figure 2. Open in new tabDownload slide Comparison of AVP levels before development of hyponatremia, during hyponatremic episode, and after resolution of hyponatremia, in patients with SIAD. AVP levels are significantly higher before and during episode of hyponatremia when compared with after resolution of hyponatremia (P = .03). Figure 1. Open in new tabDownload slide (A) Fluid balance in patients with SIAD. points, median; bars, range; Day, day post-SAH. (B) Fluid balance in all patients. points, median; Day, day post-SAH. Figure 1. Open in new tabDownload slide (A) Fluid balance in patients with SIAD. points, median; bars, range; Day, day post-SAH. (B) Fluid balance in all patients. points, median; Day, day post-SAH. Overall, 14 patients developed acute cortisol deficiency, at a median of day 4 (range 2–6 days). Nine of 14 patients developed acute cortisol deficiency without hyponatremia, with a median cortisol nadir of 130 nmol/L (range 83–225 nmol/L). Four of 14 developed acute cortisol deficiency causing hyponatremia, with a median nadir cortisol of 141 nmol/L (range 57–251 nmol/L). All four were treated with iv hydrocortisone as per protocol, with rapid normalization of plasma sodium. The final patient had a transient drop in plasma cortisol to 93 nmol/L, which recovered within 2 days; after normalization of cortisol, the patient then developed hyponatremia, which was thought to be due to SIAD rather than cortisol deficiency. None of the 14 hypocortisolemic patients developed hypoglycemia or hypotension. Cortisol deficiency did not resolve in 6/14, which necessitated hydrocortisone treatment after discharge. Five patients developed hyponatremia due to the use of incorrect, hypotonic iv fluids, such as compound sodium lactate or 0.45% sodium chloride. These patients were clinically euvolemic and generally had low AVP levels (Figure 4); none were fluid overloaded. Hyponatremia in this group uniformly resolved with alteration of the patients' iv fluid prescriptions. Five patients developed hyponatremia due to inadequate fluid replacement, resulting in hypovolemia. All five patients had low urine output (<1.5 L/24 h) rather than the diuresis and natriuresis typical of CSWS. There were no cases of hypovolemia due to diuretics. All cases of hypovolemic hyponatremia resolved with appropriate fluid repletion. Figure 4. Open in new tabDownload slide Comparison of AVP levels between different patient groups. Each point represents an individual AVP measurement. *, P = .01; ***, P < .0001. Figure 4. Open in new tabDownload slide Comparison of AVP levels between different patient groups. Each point represents an individual AVP measurement. *, P = .01; ***, P < .0001. Plasma AVP concentrations were higher in SIAD than in any other hyponatremic group (Figure 4). In contrast, there was no difference in plasma BNP concentrations between any hyponatremic group (Figure 5) and no difference between plasma BNP concentrations in the eunatremic and hyponatremic groups. Figure 5. Open in new tabDownload slide Comparison of BNP levels between different patient groups. Each point represents an individual BNP measurement. All comparisons between groups were nonsignificant (P > .05). Figure 5. Open in new tabDownload slide Comparison of BNP levels between different patient groups. Each point represents an individual BNP measurement. All comparisons between groups were nonsignificant (P > .05). Discussion In this article, which documents a prospective biochemical and clinical examination of a large cohort of SAH patients, by a single experienced observer, we have confirmed the findings from our retrospective study. Hyponatremia occurred in 50% of SAH patients, and the commonest cause of hyponatremia was SIAD. In addition, we have shown that 14% of SAH patients develop acute ACTH deficiency and that some of these patients develop steroid-remedial hyponatremia. Finally, we were unable to demonstrate any case of hyponatremia that fitted clinical criteria for the diagnosis of cerebral salt wasting; the pattern of changes in plasma AVP and BNP concentrations was typical of SIAD. Incidence of hyponatremia Our results correspond with previous retrospective data from our group (2) and others (10), indicating that hyponatremia occurs in approximately half of all patients after nontraumatic aneurysmal SAH, usually occurring in the first 3 days after SAH. Most hyponatremic patients maintained their plasma sodium above 130 mmol/L for the duration of their inpatient stay, but in our cohort 14% developed clinically significant hyponatremia. The clinical or radiological severity of SAH was less in this study than in our retrospective study, due to a change in referral patterns, and the lower proportion of patients with severe hyponatremia in this study, compared with the retrospective study, may reflect the milder spectrum of disease. Causation of hyponatremia Our data demonstrate that most cases of hyponatremia after SAH are due to SIAD. We diagnosed 71.4% of our hyponatremic cohort with SIAD based on well-defined clinical diagnostic criteria (Supplemental Tables 1 and 2). Plasma AVP and BNP were not available (although cortisol levels were) until after study completion, when the batched plasma samples were assayed as a cohort. This was a conscious decision, as we wanted our approach to be clinically relevant to practicing clinicians, and so clinical definitions were used to define SIAD and CSWS. Very few patients had central venous pressure evaluation, such that assessment of patients' volume status was primarily based on clinical judgment by clinicians experienced in evaluating hyponatremia. Although it can be difficult to evaluate volume status clinically, particularly when endeavoring to separate mild hypovolemia from eunatremia, cerebral salt wasting is usually characterized by profound natriuresis, diuresis, and marked volume depletion. However, the subsequent analysis of stored plasma verified the accuracy of clinical diagnostic criteria. In the group determined on clinical grounds to have SIAD, plasma AVP concentrations rose before development of hyponatremia, remained elevated during hyponatremia, and fell after recovery from hyponatremia. Moreover, urine volumes fell as plasma AVP concentrations rose in this group. This qualitative pattern strongly suggests a primary causative role for AVP in the development of hyponatremia and supports the diagnosis of SIAD. In contrast, plasma AVP levels remained unchanged throughout the development and progression of hyponatremia in patients whose hyponatremia developed due to a cause other than SIAD. SIAD in this patient cohort was managed expectantly; the vaptan class of aquaretic agents was not available during the timeline of this study and neurosurgical practice, to prevent cerebral vasospasm, dictated that fluid restriction was generally only possible to a minimum of 2.5 to 3 L per day. Despite the absence of active management of hyponatremia in the SIAD group, our data concurred with that of previous studies, which reported that hyponatremia due to SIAD is transient after SAH (2, 10). As expected from published data on the pathophysiology of SIAD, the relationship between plasma AVP concentrations and plasma osmolality was lost in patients with SIAD (25, 26), whereas the well-published linear relationship between these parameters was preserved in eunatremic patients (25, 27) (Figure 3). Our clinical identification of patients who had dilutional hyponatremia due to incorrect iv fluids was verified by the subsequent plasma AVP measurements, which were mostly suppressed. Plasma AVP concentrations were also higher in the SIAD group than in the ACTH-deficient group and the volume-depleted group (Figure 4). No previous studies have sequentially measured plasma AVP concentrations and correlated them to the development of hyponatremia. Our AVP data verified the accuracy of a clinical approach to the differential diagnosis of hyponatremia developing after SAH, with maintenance of the relationship between plasma AVP and plasma osmolality in eunatremic patients, elevated plasma AVP concentrations, which preceded hyponatremia, in the SIAD group, and suppression of plasma AVP in the fluid-overloaded group. The only finding that is not consistent is that of reduced AVP levels in the volume depleted group. However, none of this group, which was clinically thought to be hypovolemic, was severely hypotensive, which may somewhat explain this observation. It is also possible that some of these patients were misclassified and were actually suffering from SIAD. Only a minority of patients was found to be volume depleted, and none of these patients had convincing evidence of a profound diuresis or natriuresis, which could have been attributed to cerebral salt wasting. Although in the hypovolemic group we did demonstrate a sequential rise in plasma BNP concentrations after SAH, plasma BNP concentrations rose in all groups irrespective of etiology, and rose also in the eunatremic cohort, with no significant difference in BNP levels between any group (Figure 5). As a result, we could not find a consistent role for BNP in the development of hyponatremia after SAH. Our interpretation is that although we have verified the findings of a number of groups by showing that plasma BNP concentrations increase after SAH (28, 29), this rise seems to be universal, unrelated to the subsequent development of hyponatremia, and of no causal significance in terms of development of hyponatremia. We therefore cannot support the contention that cerebral salt wasting contributes significantly to hyponatremia after SAH. We do not contend the existence of cerebral salt wasting, as some authorities do (3–6). We have previously published data from a single patient who demonstrated a marked rise in both plasma ANP and plasma BNP concentrations in the early phase after SAH, with the subsequent development of profound natriuresis, diuresis, blood volume contraction, and hypovolemic hyponatremia (1); plasma AVP concentrations only rose in response to hypovolemia in this patient. We were unable to reproduce this hormonal or hemodynamic sequence of events in any patient in this study. The overwhelmingly predominant sequence was a rise in plasma AVP concentration, with a subsequent euvolemic hyponatremia, typical of SIAD. Previous, smaller studies have shown that the natriuretic peptides rise in acute SAH, which appears to be independent of SAH severity or catecholamine levels (29). Both human (3–5, 7, 8, 30–33) and animal (34) studies have suggested a role for BNP in the development of cerebral vasospasm and possibly CSWS with consequent hyponatremia. However, the human studies were small in size, did not measure plasma sodium and BNP sequentially (4, 30, 31), or only selected the subgroup that developed hypovolemic hyponatremia for analysis (8). In those studies that did examine plasma sodium, AVP, and BNP sequentially, both appeared to rise, with the rise in AVP lasting only a few days immediately after SAH and the rise in BNP being more sustained. Given that most patients in our study developed hyponatremia in the first 3 days after SAH, we would argue that an early AVP peak with the development of hyponatremia is suggestive of SIAD rather than BNP-related CSWS. It should also be stated that many earlier studies were underpowered and contained patients with much more severe SAH than our cohort. Interestingly, recent animal studies of SAH in rats have cast doubt on the putative causative role of ANP and BNP in CSWS (34). Prevalence of acute ACTH/cortisol deficiency post-SAH There is good evidence that acute cortisol deficiency occurs in at least 15% to 20% of patients with moderate/severe TBI (11) causing hyponatremia (12) and hypotension requiring pressor support (13). The evidence for acute hypocortisolemia after SAH is less robust (14, 15), with published data showing conflicting results. Parenti et al (15) showed that 7% of patients had subnormal plasma cortisol concentrations during SAH and Klose et al (14) found that 3/26 (11.5%) had 0900 hour plasma cortisol <276 nmol/L, at a median of 7 days after SAH (14). These studies did not present data on hyponatremia resulting from cortisol deficiency. Our data show a comparable rate of acute hypocortisolemia but also report the causative relationship between acute hypocortisolemia and hyponatremia. The plasma cortisol concentration that we defined as a normal cutoff was based on our previous data in acutely unwell patients after vascular surgery, whereby 0900 hours plasma cortisol concentrations were >300 nmol/L at all times during their admission. This is very comparable to the cutoff defined by Klose's group (14). Plasma total cortisol is a good surrogate marker of plasma-free cortisol level in neurosurgical patients (16), and as all of our cohort had serum albumin >30 g/L during their hospital admission, we felt confident that 0900 hour plasma cortisol concentrations <300 nmol/L represented inappropriate hypocortisolemia after SAH. Four patients presented with biochemical findings typical of SIAD, together with inappropriately low plasma cortisol concentrations for an acutely unwell patient. Treatment with iv hydrocortisone rapidly returned plasma sodium concentration to normal. This was suggestive of a causal relationship between cortisol deficiency and hyponatremia, although we cannot be absolutely certain in the absence of a control group of untreated patients that the return to eunatremia would have occurred anyway. However, in the clinical context of an unwell patient, clinical ethics dictated that we should intervene. Of those patients who presented biochemically as SIAD, 10% had acute ACTH/cortisol deficiency. Interestingly, most patients who developed acute hypocortisolemia did not develop hyponatremia, so hyponatremia was not a sensitive marker for the identification of acute ACTH deficiency. Our data do raise questions about the consideration of acute cortisol deficiency as a consequence of SAH. In conclusion, hyponatremia is common after acute nontraumatic aneursymal SAH and is predominantly due to SIAD as determined by both prospective clinical assessment and sequential measurement of AVP and BNP levels. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Jan 1, 2014

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