Early Inhibition of Natriuresis Suppresses Symptomatic Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid HemorrhageNakagawa I. · Hironaka Y. · Nishimura F. · Takeshima Y. · Matsuda R. · Yamada S. · Motoyama Y. · Park Y.-S. · Nakase H.
Department of Neurosurgery, Nara Medical University, Kashihara, Japan Corresponding Author
Ichiro Nakagawa, MD, PhD
Department of Neurosurgery
Nara Medical University
840 Shijo-cho, Kashihara, Nara 634-8522 (Japan)
Background: Hyponatremia is a common complication occurring in one third of patients after subarachnoid hemorrhage (SAH). One mechanism that likely mediates the development of hyponatremia in SAH is cerebral salt wasting syndrome (CSWS), which induces natriuresis and reduces total blood volume, resulting in a risk of symptomatic vasospasm (SVS). The mineral corticoid fludrocortisone acetate enhances sodium reabsorption in the renal distal tubules and may help prevent post-SAH hyponatremia. However, management with fludrocortisone acetate is ineffective if hyponatremia is advanced, because CSWS and subsequent SVS develop rapidly. Therefore, an additional earlier marker is required to predict the development of hyponatremia for the initiation of immediate treatment in select patients. However, no conclusive evidence exists showing that hyponatremia influences the risk of SVS, and no standard treatment protocol exists for treating hyponatremia in patients with SAH. This study was undertaken to evaluate whether selective early treatment of hyponatremia prevents SVS in patients with increased urinary sodium excretion in the early phase following SAH. Methods: A total of 103 patients with aneurysmal SAH were managed for a postoperative electrolyte disorder after aneurysmal clipping or coil embolization. Between 2004 and 2007 (period 1), 54 patients started treatment to correct the electrolyte disorder after hyponatremia had occurred. Between 2007 and 2011 (period 2), 49 patients were prospectively subjected to sodium replacement treatment according to their daily sodium balance, and inhibition of natriuresis with fludrocortisone acetate was initiated just after an increase in urinary sodium excretion >300 mEq/day. The occurrence of hyponatremia, SVS, and outcomes were compared between the two periods. Results: Hyponatremia was observed in 14 patients (26%) in period 1 and 7 patients (14%) in period 2. The incidence of fludrocortisone acetate administration was significantly higher, and initiation of electrolyte correction was significantly earlier, in period 2 patients. We observed a significant difference in the frequency of SVS, which occurred in 10 patients (18.5%) in period 1 and 3 patients (6.1%) in period 2. Both urinary sodium excretion and urine volume at day 7 were significantly different between the two periods. However, no significant difference was observed in overall outcome between the two periods. Conclusions: Early inhibition of natriuresis with fludrocortisone acetate before the occurrence of hyponatremia prevented SVS after aneurysmal SAH. Increased urinary sodium excretion in the early phase of SAH is a good indicator for the initiation of electrolyte correction with fludrocortisone acetate.
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Hyponatremia is a common electrolyte imbalance after subarachnoid hemorrhage (SAH). It occurs in as many as 30% of patients with SAH and is associated with extracellular volume depletion and cerebral ischemia . Peters et al.  introduced the term cerebral salt wasting syndrome (CSWS), which is defined as the renal loss of sodium during intracranial disease, leading to hyponatremia and a decrease in extracellular fluid volume. Although several studies have recently indicated that rapidly increasing levels of natriuretic peptides may be the cause of natriuresis, hyponatremia, and CSWS in patients with SAH [3,4,5,6], the precise mechanism of CSWS is still unknown.
Patients with asymptomatic cerebral vasospasm reportedly become symptomatic when CSWS occurs [7,8], and symptomatic vasospasm (SVS) is reported to be closely related to hyponatremia in CSWS [9,10]. Furthermore, CSWS after SAH is associated with an increased rate of cerebral ischemia [8,11]. However, there are no standard reference tests or treatment protocols for hyponatremia in patients with SAH. Therefore, early diagnosis and development of an effective treatment for hyponatremia are critical for prehyponatremic patients with aneurysmal SAH.
The most common management strategy for hyponatremia underlying CSWS after SAH is water and salt supplementation. However, hypervolemic therapy and increasing sodium intake cannot be safely undertaken because urinary sodium excretion may be enhanced, which would eventually accelerate water loss. Consequently, hyponatremia is not readily corrected by intravenous infusion alone. Inhibition of natriuresis by reducing sodium excretion would be an ideal treatment for preventing hyponatremia and maintaining the intravascular volume required for preventing cerebral vasospasm in patients with SAH. The mineral corticoid fludrocortisone acetate is a known alternative that enhances sodium reabsorption in the renal distal tubules and supports efficient hypervolemic therapy under appropriate serum sodium levels and plasma osmolarity, and it may help prevent post-SAH hyponatremia [12,13]. However, management with fludrocortisone acetate is ineffective if hyponatremia is advanced, because CSWS and subsequent SVS develop rapidly . Therefore, an additional earlier marker is required to predict the development of hyponatremia for the initiation of immediate treatment in select patients. Increased urinary sodium excretion in the early phase of SAH precedes serum hyponatremia . However, whether early prediction of hyponatremia and initiation of inhibition of natriuresis can prevent SVS is unknown. In the present study, we focused on the increase in daily urinary sodium excretion and evaluated whether early inhibition of natriuresis prevented SVS in patients with increased urinary sodium excretion in the early phase following SAH.
The patients included in this study were recruited from all patients with aneurysmal SAH who were admitted to our institution between July 2004 and May 2011. The clinical condition of the patients was graded upon admission according to the classification of Hunt and Kosnik (H-K) , and the severity of SAH was classified based on the initial appearance on computed tomographic (CT) scans according to Fisher et al. . Diagnostic cerebral angiography or CT angiography was performed during the first 12 h after admission. Ruptured aneurysms were treated with either surgical clip application or endovascular coil embolization within 24 h of SAH. The main factors for selecting endovascular coil embolization were the difficulty of clip application and an aneurysm located in the posterior circulation. The treatment modality was selected based on a consensus reached between the neurosurgical and the endovascular team. Patients with any of the following conditions were excluded: H-K grade V, head trauma, known endocrinological disturbances, renal disease, and congestive heart failure.
All patients remained normovolemic and normotensive after SAH. Their water balance was calculated every 12 h from the difference between the total amount of water intake and water loss, and water was replaced to maintain the balance. All patients were administered fasudil hydrochloride hydrate (Eril; Asahi Kasei Co.) at a dose of 90 mg/day and diltiazem hydrochloride (Herbesser; Mitsubishi Tanabe Co.) at a dose of 5 µg/kg/min to prevent vasospasm from the day after treatment of SAH to day 14. All patients were equipped with cisternal or spinal drainage to remove subarachnoid clots and control intracranial pressure from the day after the onset of SAH to day 14. We used transcranial Doppler ultrasonography as a screening tool for the presence of cerebral vasospasm, and when elevated mean flow velocities suggested cerebral vasospasm, diagnostic confirmation was typically done with angiography. When cerebral vasospasm developed, hemodynamic augmentation therapy with crystalloids, colloids, and inotropic agents (dopamine or dobutamine) was initiated. Furthermore, percutaneous angioplasty was performed, and fasudil hydrochloride hydrate was transarterially injected. A ventriculoperitoneal shunt was positioned when normal pressure hydrocephalus progressed.
Blood parameters including serum sodium, potassium, protein, and glucose were measured at 24-hour intervals. Daily urine volume, sodium and potassium excretion, and osmotic pressure were also determined from stored urine samples every 24 h.
The patients were divided into two groups. The period 1 group consisted of 54 patients with SAH who were admitted to our institution from July 2004 to September 2007. These patients were treated with fludrocortisone acetate (Florinef; Bristol-Myers Co.) at a dose of 0.2–0.4 mg/day from the day after hyponatremia occurred until the serum sodium level normalized. The period 2 group consisted of 49 patients with SAH treated from October 2007 to May 2011. We prospectively subjected these patients to the protocol of management of hyponatremia after SAH. Sodium balance was calculated every 24 h from the difference between the total amount of sodium intake and urinary sodium excretion. Sodium replacement was performed to restore the balance. We started fludrocortisone acetate treatment just after observing an increase in urinary sodium excretion >300 mEq/day, before hyponatremia occurred, and continued the treatment until the urine sodium excretion level normalized . Hyponatremia was defined as an absolute value of <135 mEq/l occurring at any time during the first 14 days of hospitalization. All patients signed a written authorization allowing access to their medical records for research purposes, and our institutional review board approved the research protocol.
The primary outcome measure was the occurrence of SVS. Angiographic vasospasm was considered to be present when narrowing of the lumen of the artery was seen on angiograms. SVS was defined as documented arterial vasospasm that was consistent with new neurological deficits that presented between 4 and 14 days after the onset of SAH and could not be explained by other causes of neurological deterioration, rebleeding, hydrocephalus, electrolyte disturbance, hypoxia, or seizures. SVS was clinically categorized as absent, moderate, or severe. Moderate SVS was defined as the presence of an incomplete focal deficit or an impaired level of consciousness without coma (Glasgow coma scale score lower than 8). Severe SVS was defined as complete focal deficit or the presence of coma.
We diagnosed SVS only in the absence of other causes and when supported by cerebral angiography. Outcomes were evaluated using the modified Rankin scale at 30 days after onset.
All data are presented as means ± standard deviation. Differences between the two periods were assessed using Fisher’s exact test. Patient age and the initiation date of fludrocortisone acetate were compared between the two periods using Student’s t test. Other data were analyzed using the general mixed-model analysis of variance. Statistical significance was considered at p < 0.05.
A total of 103 patients participated in the study (34 males, 69 females; mean age, 63 years). In period 1 (54 patients), the mean age of the patients was 67 years (range, 27–89 years). Sixty-three percent of the patients were women. In period 2 (49 patients), the mean age of the patients was 65 years (range, 36–88 years). Sixty-nine percent of the patients were women. The distribution of H-K grading at admission and Fisher grouping are shown in table 1. The ruptured aneurysm was located in the anterior circulation in 45 patients (83%) in period 1 and in 41 patients (84%) in period 2. Craniotomy and clip application was performed in 45 patients (83%) in period 1 and in 46 patients (94%) in period 2. Endovascular treatment was performed in 9 patients (17%) in period 1 and in 3 patients (6.1%) in period 2. A ventriculoperitoneal shunt was positioned in 11 patients (20%) in period 1 and in 8 patients (16.3%) in period 2. No significant differences were noted in age, gender, H-K grade, Fisher classification on initial CT, location of aneurysms, or therapeutic modality between the two periods (table 1).
Hyponatremia was observed in 14 patients (26%) in period 1 and in 7 patients (14%, a lower tendency) in period 2 after SAH. An increase in urinary sodium excretion >300 mEq/day was observed in 37 patients (68.5%) in period 1 and in 25 patients (51.0%) in period 2. Of those with excess sodium excretion, 8 patients (21.6%) in period 1 and 3 (12%) in period 2 developed SVS. Furthermore, 8 of 37 (21.6%) patients with excess sodium excretion and 2 of 17 (11.8%) patients without excess sodium excretion developed SVS in period 1. Three of 25 (12.0%) patients with excess sodium excretion and 0 of 24 (0%) without excess sodium excretion developed SVS in period 2. These results indicate that SVS occurred more frequently in patients with excess sodium excretion. Twenty-six percent of the patients in period 1 and 51% of the patients in period 2 were medicated with fludrocortisone acetate; the day of initiation of medication was day 7.1 ± 2.1 in period 1 and day 4.7 ± 2.2 in period 2 after onset of SAH. There were significant differences between the groups (table 2). No major adverse effects of mineral corticoids, including pulmonary edema or prolonged hypokalemia, developed in any of the patients. At day 7, both urinary sodium excretion and urine volume were significantly different between the two periods.
There was a significant difference in the occurrence of SVS, which was seen in 10 patients (18.5%) in period 1 and in 3 patients (6.1%) in period 2 (table 3). No patients were clinically categorized with severe SVS in either period. The patients in period 2 were more likely to have a good outcome at 30 days (table 3).
In the present study, we prospectively introduced a standardized postoperative management protocol for hyponatremia, including early electrolyte correction with fludrocortisone acetate after clip application or coil embolization to prevent postoperative hyponatremia aggravation and to suppress the onset of SVS. We demonstrated for the first time that early inhibition of natriuresis using fludrocortisone acetate in prehyponatremic patients with increased urinary sodium excretion suppressed SVS in patients with aneurysmal SAH. The increased urinary sodium excretion in the early phase of SAH served as a good indicator for the initiation of electrolyte correction with fludrocortisone acetate.
Hyponatremia occurs in up to 30% of patients after aneurysmal SAH and is associated with CSWS [11,17], which involves renal salt loss leading to a negative sodium balance, hyponatremia, natriuresis, and intravascular volume depletion . Since cerebral blood flow and volume plays an important role in SVS, this intravascular volume contraction leading to hypovolemia has been implicated as a risk factor for the development of SVS and poor clinical outcome. Igarashi et al.  reported that SVS is closely related to severe natriuresis and osmotic diuresis induced by CSWS. However, they emphasized that strict observation is required, because CSWS and subsequent SVS develop rapidly. Therefore, appropriate diagnosis is critical for good patient outcomes, and an additional earlier marker is required to predict the development of CSWS and the initiation of immediate treatment. Elevated serum atrial natriuretic peptide levels that precede the onset of hyponatremia predict which patients will develop SVS. [5,18]. Elevation of atrial natriuretic peptide values cannot be directly linked to hyponatremia after SAH [19,20], suggesting that it participates in the initiation of hyponatremia and that another factor is responsible for CSWS . Brain natriuretic peptide has also been shown to correlate with hyponatremia after SAH . However, natriuretic peptides are not always associated with hyponatremia and SVS. Another study showed that cerebrospinal fluid adrenomedullin concentrations are significantly increased in hyponatremic patients and in patients in whom delayed ischemic neurological deficits developed .
Recent studies show that hyponatremic SAH patients demonstrate a negative sodium balance due to increased sodium excretion as a consequence of natriuresis that is greater than sodium intake [12,23]. In a previous study, we showed that increased urinary sodium excretion precedes serum hyponatremia in the early phase of SAH and suggested that increased urinary sodium excretion would serve as a predictive factor for CSWS after SAH . The in-out balance of sodium may also be a reliable marker, but calculating these values each time in a busy clinical practice is impractical. However, evaluation of daily urinary sodium excretion is simple, quick, and repeatable. In the present prospective study, we focused on urinary sodium excretion in the early phase of SAH and the prophylactic treatment for hyponatremia using fludrocortisone acetate in prehyponatremic patients who may develop hyponatremia during cerebral vasospasm progression. In period 2, fludrocortisone acetate administration was initiated significantly earlier than in patients in period 1, and twice as many patients received fludrocortisone acetate compared with patients in period 1.
In SAH patients, hyponatremia is associated with increased morbidity and mortality . Some reports have demonstrated that hyponatremia is associated with increased rates of cerebral ischemia [8,11]. Patients with asymptomatic cerebral vasospasm reportedly become symptomatic when CSWS occurs [7,8]. Igarashi et al.  demonstrated that delayed ischemic neurological deficit is closely related to CSWS, which is supported by our present results. In a large cohort of patients with ruptured aneurysms, Morinaga et al.  showed that clinical manifestations of vasospasm developed in 16 of 19 patients with hyponatremia. Katayama et al.  showed a slightly lower trend for the development of SVS following prevention of hyponatremia. However, Qureshi et al.  concluded that the presence of hyponatremia was not associated with increased risk of delayed ischemic neurological deficit. Furthermore, Mori et al.  and Moro et al.  reported no differences in SVS and outcomes following the prevention of hyponatremia and hypovolemia. Therefore, there is no conclusive evidence that hyponatremia influences the onset of SVS or prognosis in patients with SAH. In the present study, we showed that strict electrolyte correction with fludrocortisone acetate in addition to a recent multidisciplinary approach for the prevention of SVS suppressed the onset of SVS after SAH. Although there was no significant difference in the incidence of hyponatremia in patients between the two periods, our results showed that selective prophylactic management of natriuresis suppressed aggravation and prolongation of hyponatremia.Indeed, the incidence of fludrocortisone acetate administration was significantly greater, and initiation of electrolyte correction was significantly earlier in patients in period 2. Regardless of the difference in the onset of SVS between the two periods, we observed only trends, and no significant differences in overall outcome were observed. No patients developed severe SVS, and the patients who developed moderate SVS were appropriately treated with hemodynamic augmentation and endovascular treatment in both periods, which may have influenced the similar overall outcome between the two periods in the present study.
Recently, Rahman and Friedman  reviewed the evaluation and management of hyponatremia in neurosurgical patients. They developed several recommendations regarding the treatment of hyponatremia in patients with SAH in particular. However, their review relied heavily on expert opinion because of a paucity of convincing literature showing evidence about hyponatremia. The mechanisms that likely mediate the development of hyponatremia after SAH are CSWS and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). These two processes are difficult to discriminate in clinical practice. Fluid restriction, as usually recommended in cases of pure SIADH, is dangerous in patients with SAH and vasospasm, because CSWS and SIADH may coexist in the same patient. Careful replenishment of lost volume and assessment of circulating volume are necessary in SAH patients. In the previous report, patients with SAH and SVS who do not show early clinical improvement in response to volume or pressor therapy are at high risk for death or disability [27,28]. Hypertonic saline and albumin may be used to treat hyponatremia and vasospasm, but it is unclear whether this treatment is helpful for preventing or improving SVS [29,30]. Consequently, our postoperative management was performed under normotensive and normovolemic management. Although some randomized studies have demonstrated that hydrocortisone prevents hyponatremia, there were no differences in SVS and outcome [23,25]. Hydrocortisone, which is widely used because of its glucocorticoid effects, also efficiently inhibits hyponatremia and hypovolemia, and its effects are easily controllable because of its shorter elimination half-life . However, hydrocortisone also has a potential risk of side effects such as hyperglycemia, immunosuppression, and gastrointestinal hemorrhage .
Fludrocortisone acetate, a mineral corticoid that enhances sodium reabsorption in the renal distal tubules and supports efficient hypervolemic therapy under appropriate serum sodium levels and plasma osmolarity, can help prevent post-SAH hyponatremia. Morinaga et al.  treated patients with hyponatremia with fludrocortisone acetate and reported a decrease in natriuresis and recovery from hyponatremia within 5 days. Here, we also administered fludrocortisone acetate to patients with hyponatremia and reconfirmed its effect . Hypokalemia and pulmonary edema are side effects of fludrocortisone acetate [11,32] that can be easily controlled as long as patients with impaired cardiopulmonary function are not given the drug. However, we emphasized the selection of patients who may need to be treated with mineral corticoid and excluded those with a potential risk of side effects, including pulmonary edema and congestive heart failure. We suggest that natriuresis must be inhibited using mineral corticoids before hyponatremia develops to prevent SVS in patients with SAH.
The present study has several limitations. This study design was nonrandomized in nature, and the small sample size (limited power) may have introduced biases regarding patient and data collection. Nevertheless, the fact that multidisciplinary standard SAH patient protocols, except for the treatment of hyponatremia, were not changed during the study period provides reassurance that the results represent a possible beneficial effect of early treatment of hyponatremia for preventing SVS.
We demonstrated the importance of high daily urinary sodium excretion as an early marker for predicting the development of hyponatremia and initiating immediate treatment. High daily urinary sodium excretion in the early phase of SAH could be a factor that predicts hyponatremia and subsequent SVS. We believe that it is important to start sodium and fluid restoration and inhibition of natriuresis with fludrocortisone acetate before the occurrence of hyponatremia for the prevention of SVS.
Ichiro Nakagawa, MD, PhD
Department of Neurosurgery
Nara Medical University
840 Shijo-cho, Kashihara, Nara 634-8522 (Japan)
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