In this study, serum creatinine, cystatin C, and measurements combining those 2 biomarkers were utilized to calculate eGFR values that were then used to investigate the association between mannitol doses and the risk of in-hospital mortality in patients with ICH. These data demonstrate that patients with abnormal eGFR values (calculated from either serum creatinine, cystatin C, or both combined) receiving mannitol treatment at a dose of above 100 g/day were associated with an increased risk of in-hospital mortality. Moreover, among the entire study population, those exhibiting normal eGFR values calculated from serum creatinine and cystatin C alone and who received mannitol doses above 150 g/day were also independently associated with in-hospital mortality. However, this association was not observed among patients with normal eGFR values derived from combined creatinine and cystatin C measurements. These results provide novel evidence for the dose-dependent association of mannitol and adverse outcomes among those who had abnormal eGFR values.
The exact mechanisms related to large mannitol does and mortality are warranted further investigation. In fact, renal insufficiency is associated with risk factors such as older age, coagulation dysfunction, vascular damage, larger hematomas, and cardiovascular events, including mortality.[2, 21, 37, 39] Patients treated with large mannitol doses experienced induced or exaggerated renal impairment that subsequently lead to increased mortality. It is well recognized that a low-dose mannitol therapy is well tolerated by patients whose renal function and electrolyte profiles are normal.[24] Nevertheless, patients administered large-dose mannitol and experiencing renal insufficiency may have different outcomes.
In part, the present findings are consistent with prior studies, but data from the hemorrhagic stroke population suggest that large doses of mannitol may have adverse outcomes (e.g., serum and urine electrolyte disturbances and osmolality or acute renal failure), including mortality in individuals[7, 10, 19, 24, 25, 30, 34] and animals.[28, 40] Earlier, in the 1980s, Whelan et al. reported a case in which acute oliguric renal failure occurred without a known predisposing factor other than the intravenous infusion of massive quantities of mannitol.[34] At the same time, Goldwasser and Fotino S described 2 patients who suffered reversible acute oliguric renal failure due to a massive mannitol infusion (400–900 g/day) administered as a treatment for intracranial hypertension.[7] These 2 studies, along with later research, showed that large doses of mannitol can be detrimental even in patients with normal renal function.[7, 19, 24, 34]
In the series of studies by Cruz et al., however, patients in the high-dose mannitol group received the agent dose approximately 1.4 g/kg and resulted in good clinical outcomes.[3-5] Furthermore, Helbok et al. found that mannitol (1 g/kg) was effective in reducing ICP and improved brain metabolism. Recently, another study focusing on patients with an acute ICH showed that mannitol seems safe but might not improve outcomes based on data from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).[33] Given these conflicting outcome data, it is important to note that previous studies used various mannitol doses in patient treatment regimens. In the present study, a dose of mannitol above 150 g/day was considered a "high" dose, though it is considerably lower than “high” values in other published studies.[6] Moreover, patients in the present study may receive various osmotic agents like hypertonic saline and glycerin fructose rather than mannitol alone. Nevertheless, mannitol at doses above 150 g/day are still small and we did not create another larger dosage category for analysis. In addition, it may plausible that factors such as the frequency (e.g., interval time between administrations) and duration of mannitol use, individual characteristics (e.g., body mass index, illness severity, and underlying diseases) and clinical scenarios (e.g., comorbid hypertension, diabetes mellitus, or CKD) could also influence the results.
Notably, a considerable proportion of patients presented with an abnormal eGFR after an ICH. Previous studies reported that the prevalence of eGFR values < 60 ml/min/1.73 m2 in patients with ICH ranged from 20–46%,[13, 21, 39] this figure for patients with eGFR values < 90 ml/min/1.73 m2 was 64.8%.[38] In contrast, the percentages of eGFR values < 90 ml/min/1.73 m2 in the present population are 69.2%, 43.5%, and 59.0% based on serum creatinine, cystatin C, and combined creatinine and cystatin C measurements, respectively. These data suggest that renal insufficiency is prevalent in patients with ICH. Accordingly, investigations into the safety and effectiveness of mannitol for ICH patients with normal or abnormal eGFR values offer clinical value.
In this study, the association between mannitol doses and mortality was observed among patients with either normal or abnormal eGFR values based on serum creatinine and cystatin C data. Furthermore, this association was observed among patients with abnormal eGFR values derived from combined creatinine and cystatin C measurements but not for normal eGFR values based on combined measurements. Therefore, these findings suggest that eGFR calculated with a combined creatinine and cystatin C measurement may be superior to either marker alone in discriminating patient risk when using high mannitol doses, the eGFR superiority based on combined measurements is in agreement with previous data.[12, 26] Thus, it may plausible for clinicians to use this index to safely guide mannitol administration in clinical practice.
In this study, the dose and timing of mannitol use for patients with ICH were determined by the clinician's judgment, also, the reason and decision to prescribe mannitol in patients with renal insufficiency is unknown due to the retrospective nature of the study. In the present population, most patients with an abnormal eGFR had mild renal insufficiency and the proportion of patients with moderate-to-severe renal impairment or end-stage renal disease was quite small (17.3% for patients with eGFR values < 60 mL/min/1.73 m2, 3.5% for patients with eGFR values < 30 mL/min/1.73 m2, and 1.5% for patients with eGFR values < 15 mL/min/1.73 m2, based on eGFR values calculated from combination measurements). Hence, eGFR values were only classified as normal or abnormal rather than further categorized according to the guideline.[23] It is possible that, in an emergency situation where patients with severe hemorrhagic stroke presented with episodes of cerebral herniation, mannitol was prescribed as a fast and effective life-saving procedure. Nonetheless, the current results show that administering with mannitol larger than 100 g/day was associated with adverse outcomes among patients with abnormal eGFR values that would preclude clinicians using mannitol without an adequate trade-off or risk–benefit profile. In the cases where mannitol use is contraindicated, other methods can be considered, for example, patients may receive osmotic hypertonic saline, which may be more effective.[14, 35] Other management approaches include elevating the head of the bed to 30°, using mild sedation, and surgical intervention.[36]
This study has several limitations and should be interpreted with caution. First, considering that acute death was more likely to be determined by illness severity, those patients who died within 24 hours were excluded. This may introduce selection bias and could result in underestimating the in-hospital mortality and detrimental mannitol effects. Second, the aim of this study was to investigate the risk of mortality based on eGFR values in patients with ICH receiving hyperosmolar mannitol treatment. Thus, the analysis focused on a safety profile rather than the effectiveness of mannitol. Also, as previously mentioned, this study did not address the issue of the mechanism for the associations observed based on the present data. Third, a single admission measurement of creatinine and cystatin C was used in this study. It is possible that dynamic laboratory parameters may provide more information on renal function. Whether the eGFR value varied between normal and abnormal ranges during the clinical course remains to be seen. Fourth, only hospital discharge outcomes were considered in the present study, long-term outcomes may deserve further investigation. Fifth, this study was limited by its retrospective and single-center design. Furthermore, mannitol seems to be much more frequently used in China than other countries.[33] These features along with the specific population studied may preclude the generalizability of the present results and their extension to other populations.
The strengths of the present study are related to its relatively large sample size and potential clinical implications. Although the present study is observational in nature, these results may be valuable because a clinical trial study regarding this topic may not yet be ethically feasible. Furthermore, the observed associations seem robust due to the relatively large sample. As clinicians consider mannitol use on an individual basis, these findings could provide clinicians with evidence to guide the decision-making process in clinical practice.