Our results show for the first time that urea is an effective and safe treatment for hyponatremia in patients who develop SIADH and persistent hyponatremia after SAH. Most of the patients in our cohort had a poor radiological score (Fisher III or IV) and half of them had a poor neurological status (WFNS
3) on admission. Importantly, fluid and sodium administration were standardized (only NaCl 0.9% was administered and other potential therapies to reverse hyponatremia were not used), and negative fluid balance, fluid restriction, and diuretic therapy were avoided in all cases. The diagnosis of SIADH was made by using well-established criteria
]. We did not routinely measure blood volume, but none of our patients had clinical or biological signs of hypovolemia or tissue hypoperfusion suggesting a diagnosis of CSWS.
Urea was given after saline solutions failed to prevent or reverse the hyponatremia. In these conditions of persisting hyponatremia, urea restored normal sodium levels within 3 days in half of the patients; 5 patients needed more than 5 days of therapy to restore sodium levels >135 mEq/L, but there were no urea “nonresponders” in the present series. In clinical practice, what represents significant hyponatremia is not clearly defined
]. The lower limit of the normal range is 135 mEq/L, and SAH patients with sodium levels below this threshold have a worse outcome
]; however, mild hyponatremia is rarely associated with symptoms, and treatment often is recommended only when the plasma sodium decreases below 130 mEq/L. We, therefore, defined two therapeutic endpoint values, 130 and 135 mEq/L, which were reached after a median of 1 and 3 days, respectively. The time to correction may seem longer than seen with other therapies
], but the duration of hyponatremia before treatment was approximately 3 days, and the risks of osmotic demyelination would have been significant with quicker correction rates. Although the optimal rate of plasma sodium correction in acute hyponatremia has not been clearly defined, it is generally agreed that increases ≥12 mEq/L during 24 hours must be avoided
]. In the present study, few overcorrections were observed, and none of the patients whose plasma sodium increased ≥12 mEq/L during the first day had long-term neurological impairment. Rates of overcorrection rarely have been reported in previous studies on hyponatremia therapy during SAH; only 1 of 41 patients treated with conivaptan had sodium overcorrection during therapy
]. The progressive increase in plasma sodium levels, in contrast with the sharp increases sometimes reached when other therapies are used, may help to limit clinical complications. Moreover, experimental data suggest the concept that urea has a protective effect against the osmotic demyelination syndrome
Urea increased renal water excretion due to osmotic diuresis and reduced urinary sodium loss. Constant fluid intake was maintained in all patients, and excess water was eliminated without noticeable arterial hypotension. This approach seems to represent a better option than fluid restriction, with potential complications of delayed cerebral infarcts in these patients at high risk of vasospasm. Importantly, there were no adverse effects. Urea is rapidly absorbed from the gastrointestinal tract
] and may cause gastric discomfort
]; however, most patients received the urea though a nasogastric tube, without adverse events. Blood urea levels increased only moderately during therapy, and this is consistent with increased urinary urea excretion, ultimately resulting in effective osmotic water excretion.
This study was not designed to identify the optimal strategy or most appropriate dose of urea therapy. However, the response to urea was not correlated with baseline plasma sodium, suggesting that urea is effective even in mild hyponatremia. In contrast, there was an inverse correlation between baseline urine osmolality and the rate of plasma sodium correction, suggesting that the higher the urine osmolality, the lower the ability of urea at the doses used to induce a rapid osmotic diuresis and to reverse hyponatremia. A similar finding has been reported in other studies and has been attributed to a reduced ability to excrete the excessive water when urine osmolality is high
Alternative therapeutic options for preventing or reversing hyponatremia in neurocritical patients include albumin, fludrocortisone, hypertonic saline, and vasopressin receptor antagonists, such as conivaptan. The effects of albumin in limiting natriuresis have been reported in only one study
], and they remain controversial
]. Fludrocortisone enhances sodium retention through its mineralocorticoid properties, but its ability to correct hyponatremia is limited and it contributes to fluid overload
]. Hypertonic saline solutions can increase plasma sodium concentration efficiently and very rapidly, but they also increase blood volume and the risk of pulmonary edema and heart failure as well as of neurological complications. Their effects are generally transient because the stimuli for water retention and secondary natriuresis remain present
]. Vasopressin receptor antagonists represent a promising option, and conivaptan has been studied in two series of neurointensive care patients. In one study, a single dose of 20 mg of conivaptan increased plasma sodium by at least 4 mEq/L in 13 of 19 hyponatremic patients and maintained the sodium improvement for 3 days in most of the patients
]. In another study, conivaptan increased plasma sodium by at least 6 mEq/L in 19 of 22 euvolemic hyponatremic patients and maintained its effects for an average of 13 hours
]. However, the studies included only 12 patients with SAH, and fludrocortisone or hypertonic saline also were given in some patients. Moreover, conivaptan often was limited to a single bolus, and a third of the patients became hyponatremic when conivaptan was discontinued. Practical limitations to vasopressin receptor antagonists include the costs of the drug and the unpredictability of the response amplitude and duration
]. Diuretics can be used to induce osmotic diuresis; however, they are likely to induce hypovolemia in this setting, with an increased risk of delayed cerebral ischemia
]. Finally, demeclocycline can reverse hyponatremia induced by SIADH, but several adverse events, including nephrotoxicity, have been reported
Our study has some limitations. First, the retrospective nature of the study may have limited the collection of pertinent clinical or biological data, such as adverse events. Second, we did not specifically record the neurological status or intracranial pressure according to plasma sodium values, so that the relationship between sodium changes and clinical changes cannot be evaluated. Also, we did not measure plasma osmolality. Third, no specific protocol was used for urea administration, and regimen changes were at the physician’s discretion, therefore, the optimal dose of urea and its impact on sodium level changes cannot be determined. Fourth, we specifically studied SAH patients, and our findings can be extended to other patients only with caution. Fifth, the purpose of this study was not to evaluate all the different pathophysiological mechanisms that underlie hyponatremia after acute brain injury, and no specific conclusions can be made about the effects of urea in other conditions associated with sodium imbalance in this setting. Sixth, we consider the serum urea levels reached (<80 mg/dL) to be safe, because most of the complications related to uremia occur with urea concentrations >200 mg/dL; however, we cannot exclude that complications may arise at lower urea levels. Finally, the efficacy of urea compared with other available treatments needs to be determined in large, prospective studies.