Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage

Clinical article

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Object

Mannitol, an osmotic agent used to decrease intracranial pressure, can cause acute kidney injury (AKI). The objectives of this study were to assess the impact of mannitol on the incidence and severity of AKI and to identify risk factors and outcome for AKI in patients with intracranial hemorrhage (ICH).

Methods

The authors retrospectively evaluated 153 adult patients who received mannitol infusion after ICH between January 2005 and December 2009 in the neurosurgical intensive care unit. Multivariate analysis was used to evaluate the risk factors for AKI after ICH. Based on the odds ratio, weighted scores were assigned to predictors of AKI.

Results

The overall incidence of AKI among study participants was 10.5% (n = 16). Acute kidney injury occurred more frequently in patients who received mannitol infusion at a rate ≥ 1.34 g/kg/day than it did in patients who received mannitol infusion at a rate < 1.34 g/kg/day. A higher mannitol infusion rate was associated with more severe AKI. Independent risk factors for AKI were mannitol infusion rate ≥ 1.34 g/kg/day, age ≥ 70 years, diastolic blood pressure (DBP) ≥ 110 mm Hg, and glomerular filtration rate < 60 ml/min/1.73 m2. The authors developed a risk model for AKI, wherein patients with a higher risk score showed a graded association with a higher incidence of AKI.

Conclusions

The incidence of AKI following mannitol infusion in patients with ICH was 10.5%. A higher mannitol infusion rate was associated with more frequent and more severe AKI. Additionally, age ≥ 70 years, DBP ≥ 110 mm Hg, and established renal dysfunction before starting mannitol therapy were associated with development of AKI.

Abbreviations used in this paper:AKI = acute kidney injury; AKIN = Acute Kidney Injury Network; AUC = area under the curve; DBP = diastolic blood pressure; GFR = glomerular filtration rate; ICH = intracranial hemorrhage; ICP = intracranial pressure; IQR = interquartile range; ROC = receiver operating characteristic; SBP = systolic blood pressure.

Abstract

Object

Mannitol, an osmotic agent used to decrease intracranial pressure, can cause acute kidney injury (AKI). The objectives of this study were to assess the impact of mannitol on the incidence and severity of AKI and to identify risk factors and outcome for AKI in patients with intracranial hemorrhage (ICH).

Methods

The authors retrospectively evaluated 153 adult patients who received mannitol infusion after ICH between January 2005 and December 2009 in the neurosurgical intensive care unit. Multivariate analysis was used to evaluate the risk factors for AKI after ICH. Based on the odds ratio, weighted scores were assigned to predictors of AKI.

Results

The overall incidence of AKI among study participants was 10.5% (n = 16). Acute kidney injury occurred more frequently in patients who received mannitol infusion at a rate ≥ 1.34 g/kg/day than it did in patients who received mannitol infusion at a rate < 1.34 g/kg/day. A higher mannitol infusion rate was associated with more severe AKI. Independent risk factors for AKI were mannitol infusion rate ≥ 1.34 g/kg/day, age ≥ 70 years, diastolic blood pressure (DBP) ≥ 110 mm Hg, and glomerular filtration rate < 60 ml/min/1.73 m2. The authors developed a risk model for AKI, wherein patients with a higher risk score showed a graded association with a higher incidence of AKI.

Conclusions

The incidence of AKI following mannitol infusion in patients with ICH was 10.5%. A higher mannitol infusion rate was associated with more frequent and more severe AKI. Additionally, age ≥ 70 years, DBP ≥ 110 mm Hg, and established renal dysfunction before starting mannitol therapy were associated with development of AKI.

Intracranial hemorrhage (ICH) is a severe disease with a mortality rate approaching 50% and nearly 50% of survivors left with cognitive deficits or motor dysfunction.4,10,29,34,38,41 Patients with ICH suffer from additional brain injury caused by increased intracranial pressure (ICP), which requires prompt intervention to prevent devastating neurological outcomes.

Mannitol, a hyperosmolar agent that causes osmotic diuresis, is considered useful in the treatment of increased ICP.33 The effect of mannitol therapy is dose dependent, with higher doses providing a longer-lasting reduction in ICP.37,40 However, marked hyperosmolality may cause acute kidney injury (AKI).3,13 Previous studies have shown that extracerebral organ system dysfunctions are related to unfavorable neurological outcomes and high mortality rates in patients with brain injury and hemorrhage.16,36 In particular, AKI is associated with worse outcome in patients with brain injury.22,42 However, there is little information published regarding the incidence, risk factors, and outcome of mannitol-induced AKI.

In previous case reports, AKI occurred at even small (< 400 g) doses of mannitol.2,13,35,39 Pérez-Pérez et al. concluded that AKI is related to the rate of infusion rather than the total dose of mannitol.32 These results suggest that AKI may be associated with the infusion rate of mannitol rather than the dosage.

The Acute Kidney Injury Network (AKIN) proposed a modified diagnostic staging system for AKI that focuses on small changes in serum creatinine.28 The AKIN classification has been validated in intensive care units and has been found to predict in-hospital mortality, the need for renal replacement therapy, and prolonged hospital stay.1

Thus, the present study was undertaken to evaluate the incidence of and associated risk factors for AKI resulting from mannitol therapy in patients treated for ICH and to determine if the infusion rate is associated with AKI, as defined by the AKIN classification.

Methods

We retrospectively studied 537 consecutive adult patients who received mannitol infusion after ICH between January 2005 and December 2009 in the neurosurgical intensive care unit. We excluded 384 patients with tumors (n = 32); renal failure requiring dialysis (n = 3); no measurement of serum creatinine before, during, and after mannitol therapy (n = 179); an administration interval of mannitol more than 2 days (n = 93); AKI (an increase in serum creatinine 0.3 mg/dl from baseline) on admission (n = 14); and patients transferred from outside hospitals during therapy (n = 63). The remaining 153 patients were included in the study.

Patient data were collected from electronic medical records and databases. The demographic data and clinical data collected were age, sex, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and status at time of admission for all of the following conditions: diabetes mellitus, hypertension, liver disease, cerebrovascular accident, ischemic heart disease, Glasgow Coma Scale score, and type of ICH. Administration of mannitol, either alone or concurrently with other drugs (specifically furosemide, nonsteroidal antiinflammatory drugs, osmotic agents, and potentially nephrotoxic antibiotics), radiocontrast agents, inotropic agents, barbiturates, decompressive craniectomy, and adverse events such as myocardial infarction and infection were also investigated.

We examined the laboratory results for serum hemoglobin, glucose, urea, creatinine, sodium, osmolality, and glomerular filtration rate (GFR). The GFR was estimated using the 4-variable Modification in Diet and Renal Disease equation.21 The study was approved by our institutional review board.

The primary outcome was the occurrence of AKI, defined as a ≥ 0.3-mg/dl increase in serum creatinine level above baseline or a change of ≥ 50%, according to the AKIN classification. The severity of AKI was classified according to the AKIN system as follows: Stage 1 (increase in serum creatinine level by ≥ 50% or ≥ 0.3 mg/dl), Stage 2 (increase in serum creatinine level by > 100%), and Stage 3 (increase in serum creatinine level by > 200% or by ≥ 0.5 mg/dl with serum creatinine level of ≥ 4.0 mg/dl).28

Mannitol was administered intravenously by bolus in a relatively consistent manner. Serum electrolytes and osmolality were measured before each dose of mannitol, at least once to several times a day as needed. If serum osmolality exceeded 285 mOsm/kg, 100 ml of normal saline was infused. If serum osmolality exceeded 315 mOsm/kg, 100 ml of 0.45% normal saline was infused. The infusion rate was calculated as follows: total dose of mannitol (g)/body weight (kg)/day.

A receiver operating characteristic (ROC) curve was applied to determine the cutoff mannitol infusion rate required to predict AKI. The ROC curve analysis resulted in a cutoff of 1.34 g/kg/day for AKI probability. Using this cutoff, the prediction rule showed a 75.0% sensitivity, a 65.7% specificity, and an area under the curve (AUC) of 0.71 (p = 0.007, 95% CI 0.58–0.84).

Statistical Analysis

Continuous variables are expressed as the median with the interquartile range (IQR) or as the mean ± SD. Categorical variables are expressed as counts (percentages). Between-group comparisons of body weight, serum osmolality, and creatinine were made using the Student t-test or the Mann-Whitney U-test, as appropriate. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for the development of AKI in patients with ICH. Variables with a p value < 0.05 by univariate analysis were entered into multivariate analysis. Odds ratios and 95% CIs were calculated, and, based on the odds ratio, weighted scores were assigned to each of the AKI predictors. We then evaluated the incidence of AKI according to the score value. The evaluation of each AKI predictor produced an ROC curve; we used the AUC to assess the power of discrimination between patients with and without AKI. All analyses were performed using SPSS version 12.0 (SPSS, Inc.), and p values < 0.05 were considered significant.

Results

Patient characteristics are summarized in Tables 1 and 2. The mean age of patients was 55 ± 14 years, and 77 patients (50.3%) were male (Table 1). Of the 16 patients (10.5%) in whom AKI developed, 1 (6.3%) received a total of 3 hemodialysis sessions. Complete recovery (return to baseline serum creatinine level) was observed in 11 of 16 patients, including the patient who underwent hemodialysis, a median of 4 days after hospitalization (IQR 2.5–10.5 days). The mortality rate was approximately 3.5 times higher in patients with AKI than in those without (12.5% vs 3.6%, p = 0.133).

TABLE 1:

Baseline characteristics of patients on admission*

VariableValue
no. of patients153
mean age in yrs55 ± 14
no. of males77 (50.3%)
mean body weight in kg62.4 ± 10.1
mean SBP in mm Hg151 ± 33
mean DBP in mm Hg86 ± 18
median Glasgow Coma Scale score14 (9–15)
medical history
 hypertension64 (42.1%)
 diabetes mellitus11 (7.2%)
 ischemic heart disease7 (4.6%)
 cerebrovascular accident16 (10.5%)
 type of ICH
  intracerebral hemorrhage57 (36.3%)
  subarachnoid hemorrhage71 (45.2%)
  intracerebral & subarachnoid hemorrhage5 (3.2%)
  subdural or epidural hemorrhage20 (12.7%)
laboratory data
 mean hemoglobin in g/dl13.7 ± 1.7
 mean GFR in ml/min/1.73 m295.0 ± 22.9
 median serum sodium in mmol/L139 (138–141)
 median serum osmolality in mOsm/kg297 (292–304)

Continuous variables are expressed as the median (IQR) or as the mean ± SD. Categorical variables are expressed as counts (%).

TABLE 2:

Characteristics of 153 patients during hospitalization*

VariableValue
treatment
 mannitol153 (100%)
  median duration of Tx in days8 (5–11)
  mean maximum dose in g/kg/day1.46 ± 0.37
  mean total dose in g/kg9.41 ± 6.02
  median infusion rate in g/kg/day1.26 (1.07–1.48)
 glycerol49 (32%)
 starch101 (66%)
 furosemide45 (29.4%)
 ACEI/ARB25 (16.3%)
 nephrotoxic antibiotics39 (25.5%)
 NSAIDs111 (72.5%)
 radiocontrast agent118 (77.1%)
 inotropics40 (26.1%)
 barbiturate12 (7.8%)
 decompressive craniectomy17 (11.1%)
 mean operative duration in hrs§3.9 ± 1.1
median peak serum osmolality in mOsm/kg312 (306–320)
myocardial infarction1 (0.6%)
infectious disease27 (17.6%)

Mean values are presented ± SD; median values are presented with the IQR. ACEI/ARB = angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; NSAID = nonsteroidal antiinflammatory drug; Tx = treatment.

Value represents the number (%) of patients.

Aminoglycoside and vancomycin.

Craniotomy or craniectomy.

Particularly events before development of AKI in patients with AKI.

Table 3 lists the variables significantly associated with the development of AKI in patients who received mannitol in univariate analysis. The significant variables associated with AKI were age ≥ 70 years, DBP ≥ 110 mm Hg, GFR < 60 ml/min/1.73 m2, and a rate of mannitol infusion ≥ 1.34 g/kg/day in multivariate analysis (Table 4).

TABLE 3:

Univariate analysis for AKI in patients with intracranial hemorrhage*

VariableNo AKI (n = 137)AKI (n = 16)OR (95% CI)p Value
age ≥70 yrs16 (11.7%)6 (37.5%)4.54 (1.45–14.17)0.009
male6 (48.2%)11 (68.8%)2.37 (0.78–7.17)0.128
SBP ≥180 mm Hg23 (16.8%)6 (37.5%)2.97 (0.98–9.00)0.054
DBP ≥110 mm Hg10 (7.2%)5 (31.3%)5.77 (1.67–19.90)0.005
median Glasgow Coma Scale score14 (10–15)13 (5–14)0.92 (0.80–1.05)0.199
medical history
 hypertension55 (40.4%)9 (56.3%)1.89 (0.67–5.39)0.231
 diabetes mellitus6 (4.4%)5 (31.3%)9.85 (2.59–37.50)0.001
 ischemic heart disease3 (2.2%)4 (25%)14.78 (2.96–73.8)0.001
 cerebrovascular accident14 (10.3%)2 (12.5%)1.25 (0.26–6.05)0.786
ICH1.51 (0.81–2.81)0.198
 intracerebral hemorrhage51 (37.2%)6 (37.5%)
 subarachnoid hemorrhage67 (48.9%)4 (25.0%)
 intracerebral & subarachnoid hemorrhage4 (2.9%)2 (12.5%)
 subdural or epidural hemorrhage39 (28.5%)6 (37.5%)
Tx during hospitalization
 mannitol
  median duration in days8 (6–11)5 (2–11)0.87 (0.75–1.01)0.066
  mean maximum dose in g/kg/day1.46 ± 0.361.40 ± 0.470.63 (0.15–2.57)0.515
  mean total dose in g/kg9.71 ± 6.016.80 ± 5.580.89 (0.79–1.01)0.068
  infusion rate ≥1.34 g/kg/day46 (33.6%)12 (75%)5.94 (1.81–19.43)0.003
 glycerol46 (33.6%)3 (18.8%)0.46 (0.12–1.68)0.239
 starch92 (67.2%)9 (56.3%)0.63 (0.22–1.80)0.387
 furosemide35 (25.5%)10 (62.5%)4.59 (1.65–14.34)0.004
 ACEI/ARB18 (13.1%)6 (18.7%)3.97 (1.29–12.24)0.017
 nephrotoxic antibiotics36 (26.3%)3 (18.8%)0.65 (0.17–2.40)0.516
 NSAIDs102 (74.5%)9 (56.3%)0.44 (0.15–1.27)0.130
 radiocontrast agent106 (77.4%)12 (75%)0.88 (0.26–2.91)0.831
 inotropic agents31 (22.6%)9 (56.3%)4.40 (1.51–12.76)0.006
 barbiturate10 (7.3%)2 (12.5%)1.81 (0.36–9.13)0.470
 decompressive craniectomy15 (11.0%)2 (12.5%)1.16 (0.24–5.62)0.852
mean operative duration in hrs3.9 ± 1.14.1 ± 1.01.22 (0.67–2.22)0.512
laboratory data
 mean hemoglobin in g/dl13.8 ± 1.613.3 ± 2.00.85 (0.63–1.15)0.293
 GFR <60 ml/min/1.73 m22 (1.5%)7 (43.8%)52.50 (9.49–290.33)<0.001
 median serum sodium in mmol/L139 (138–141)140 (137–143)1.02 (0.90–1.16)0.721
 median serum osmolality in mOsm/kg297 (291–304)301 (296–304)1.02 (0.98–1.06)0.288
 peak serum osmolality ≥320 mOsm/kg26 (19.0%)11 (68.8%)12.58 (3.75–42.17)<0.001
myocardial infarction0 (0%)1 (6.3%)1.000
infection22 (16.1%)5 (31.3%)2.38 (0.75–7.51)0.141

Continuous variables are expressed as the median (IQR) or the mean ± SD. Categorical variables are expressed as counts (%).

Craniotomy or craniectomy.

TABLE 4:

Multivariate analysis of AKI

CovariateOR95% CIp Value
age ≥70 yrs14.6521.397–153.6340.025
DBP ≥110 mm Hg53.3072.812–1010.6200.008
diabetes mellitus2.2780.154–33.6210.549
ischemic heart disease13.0410.278–610.8220.191
GFR <60 ml/min/1.73 m2129.7863.864–4359.8580.007
ACEI/ARB4.8840.363–65.6280.232
inotropic agents6.0930.650–57.0860.113
furosemide4.5620.386–53.9620.229
rate of mannitol infusion ≥1.34 g/kg/day67.6272.903–1575.3100.009
peak serum osmolality ≥320 mOsm/kg2.7280.251–29.6970.410

More patients who received a mannitol infusion rate of ≥ 1.34 g/kg/day developed AKI and presented predominantly with severe AKI than those who received a lower rate (trend, p = 0.002, Fig. 1).

Fig. 1.
Fig. 1.

Proportion of patients with AKI based on mannitol infusion rate. Values beneath the graph represent numbers of patients with the respective AKIN stage or no AKI.

Figure 2 shows the changes in body weight, serum osmolality, and serum creatinine level during hospitalization in patients with and without AKI. The body weight of patients with AKI tended to increase until 2 days after stopping mannitol and, on discharge, tended to be lower in comparison with that of patients without AKI. However, the difference between groups was not statistically significant. There was a significant difference in serum osmolality and creatinine level between patients with AKI and those without AKI.

Fig. 2.
Fig. 2.

Changes in mean body weight (A), median serum osmolality (B), and mean serum creatinine level (C) in patients with and without AKI. Day 1 = day after stopping mannitol infusion; Day 2 = 2 days after stopping mannitol infusion. Dots indicate the no-AKI group; diamonds, the AKI group. Between-groups comparison for each time point: *p < 0.01; **p < 0.05; ^p = 0.054.

A risk model was constructed using the predictors of AKI (Table 5). In the present study, risk score levels ranged between 0 and 4 points. The relationship between risk score and AKI incidence is graded: the higher the score, the stronger the association with AKI (Fig. 3). Scores were applied to predict risk for AKI after ICH. The area under the ROC curve was 0.917 (95% CI 0.851–0.983, Fig. 4). In case of a risk score of 3, positive and negative predictive values were greater than 90% (Table 6).

TABLE 5:

Risk indices for the prediction of AKI*

CovariatePointsAUC for Single VariableSESPPPVNPV
age ≥70 yrs10.6290.380.880.270.92
DBP ≥110 mm Hg10.6200.310.930.330.92
GFR <60 ml/min/1.73 m220.7110.440.990.770.94
rate of mannitol infusion ≥1.34 g/kg/day10.7070.750.660.210.96

NPV = negative predictive value; PPV = positive predictive value; SE = sensitivity; SP = specificity.

Fig. 3.
Fig. 3.

Incidence of AKI by risk score. Values beneath the graph represent numbers of patients with the respective risk score.

Fig. 4.
Fig. 4.

Receiver operating characteristic curve for prediction of AKI.

TABLE 6:

Sensitivity, specificity, and positive and negative predictive values for different levels of the risk score predicting AKI

ScoreSESPPPVNPV
0.510.530.201.00
1.50.750.920.520.97
2.50.440.990.880.94
3.50.131.001.000.91
501.000.90

Discussion

In this study, we evaluated the incidence of and risk factors for AKI in patients treated with mannitol for ICH. Of 153 patients, 16 (10.5%) developed AKI. Risk factors for AKI were identified as age ≥ 70 years, DBP ≥ 110 mm Hg, GFR < 60 ml/min/1.73 m2, and a rate of mannitol infusion ≥ 1.34 g/kg/day. The incidence of AKI increased in patients with a higher risk score.

In our study, the incidence of AKI was 10.5%, which is consistent with a previous report of 11.6%,9 although Dziedzic et al. reported an incidence of 76%.14 Zacharia et al.42 and Li et al.22 reported an incidence of AKI of 23.1% and 23%, respectively, in patients with aneurysmal subarachnoid hemorrhage and traumatic brain injury, regardless of administration of mannitol, using the RIFLE and AKIN classification systems. In the present study, data from 43 patients who did not receive mannitol were reanalyzed. Of 43 patients, 38 (88.4%) were excluded. The proportion of patients on dialysis was higher in patients not treated with mannitol than those treated with it (15.8% vs 7.8%). Five patients who did not receive mannitol treatment tended to have a lower severity of illness and did not develop AKI (data not shown). The incidence of AKI was 10.1% in 158 patients with ICH, regardless of administration of mannitol. The difference in the rate of AKI between these studies and ours may be due to different patient cohorts, comorbidities, or treatments affecting renal function. Clearly, larger studies are warranted to clarify the incidence of AKI in patients receiving mannitol infusion for increased ICP.

Many studies have shown that risk for AKI increases with age.19,23 Aging kidneys with reduced renal reserve are more vulnerable to acute stress and are more likely to develop AKI.6 The authors of a case report described an elderly patient in whom AKI developed with approximately half of the dose of mannitol that would be required to cause AKI in a young patient.24 Other reports have concluded that elderly patients have a higher rate of mannitol-induced AKI than younger patients.5,32 Our results confirmed age as a risk factor for the development of AKI in patients treated with mannitol. Along with age, high blood pressure leads to injury of the vascular walls of the arterioles and capillaries, which in turn occlude the vascular lumen and can cause organ damage. Kidney involvement is particularly common in patients with high blood pressure.21 We found that a DBP of ≥ 110 mm Hg was a significant risk factor for AKI in patients who received mannitol for ICH. In 2007, the European Society of Hypertension and the European Society of Cardiology published guidelines for the diagnosis of hypertension, in which patients with SBP of ≥ 180 mm Hg or DBP of ≥ 110 mm Hg are classified as having Grade 3 hypertension and are at high or very high risk for cardiovascular disease.26 Although SBP of ≥ 180 mm Hg did not show significance in our study, high DBP was significantly associated with AKI. Renal dysfunction is a known risk factor for the development of AKI. Some reports have suggested that the development of AKI after mannitol infusion may be related to a preexisting renal impairment.13,32 However, the relationship between AKI and preexisting renal impairment has not been explored among patients treated with mannitol.9,15 Our results demonstrate that patients with preexisting renal dysfunction showed a significant chance of developing AKI. With normal renal function, the half-life of mannitol is approximately 70 minutes, increasing to as long as 36 hours in patients with uremia.2,30 Accordingly, the usual dose of mannitol may have accumulated and aggravated renal insufficiency in patients with underlying renal impairment. It has been recommended that serum osmolality be kept below 320 mOsm/kg due to the risk of renal injury.3 In our study, a peak serum osmolality of ≥ 320 mOsm/kg was not a significant risk factor for AKI, although the proportions of patients with peak serum osmolality ≥ 320 mOsm/kg were 19.3% and 68.8% in the non-AKI and AKI group, respectively. However, due to the small sample size of our study, this association might not have been significant.

In the treatment of increased ICP, administration of < 200 g/day, or an accumulated dosage of 1100 g of mannitol, is recommended, which corresponds to an osmolar gap of 60 mOsm/kg.12 In our study, the total dose and daily maximum dose of mannitol were 480 g (IQR 320–800 g) and 80 g/day (IQR 80–120 g/day), respectively (data not shown). These doses were considerably less than the maximum recommended doses, which may be insufficient to evaluate the impact of mannitol dose on the development of AKI. When we evaluated the total dose (g/kg) and daily maximum dose (g/kg/day) of mannitol, divided by body weight, between those who developed AKI and those who did not, there was no significant intergroup difference.

Dorman et al. have suggested that the rate of mannitol infusion is responsible for AKI in a study in which AKI developed after a daily mannitol dose of 189 ± 64 g and a total dose of 626 ± 270 g over 3.5 ± 1.5 days.13 These doses were less than those previously associated with AKI, namely 200 g/day and a cumulative dose of 1000 g.13 In addition, the authors of other reports have described small doses of mannitol resulting in AKI: 360 g over 2 days,35 236 g over 4 days,39 200–390 g over 1–2 days in 2 patients,13 and 310 ± 182.8 g over 1–3 days in 8 patients.2 Pérez-Pérez et al. reported on 4 patients in whom AKI developed after they received mannitol infusion at a rate of 0.25 g/kg/hr.32 As previously stated, the elimination half-life of mannitol is approximately 70 minutes in patients with normal renal function. Mannitol injections should be repeated at 4- to 6-hour intervals under the assumption that the majority of the prior dose has been excreted. When the rate of infusion exceeds the rate of renal excretion, mannitol could accumulate in the extracellular space and cause high local renal osmolality, potentially resulting in renal vasoconstriction and deterioration of GFR. There is an inverse relationship between body weight and peak osmolality and excretion half-life;30 the mannitol dose should be adjusted accordingly to minimize the risk of renal injury. Also, Marshall et al. have suggested that a mannitol bolus of 0.25g/kg reduces ICP as much as larger doses of mannitol.27 Based on the results reported by Marshall et al. and those of the present study, a mannitol bolus of 0.25 g/kg is allowable a maximum of 6 times per day. This management is used in clinical practice. Our results reinforce and extend previous findings regarding the optimal method of mannitol administration.

It has been reported previously that patients with renal injury recovered after discontinuation of mannitol therapy and after renal replacement therapy.13,24,39 However, even mild renal impairment has been associated with short- and long-term adverse outcomes in patients.7,8 Acute kidney injury, even after complete renal recovery, is still associated with adverse outcomes.18,25 The ability to assess the risk of AKI is important in patient management decisions. Our model warrants prospective validation in a larger population.

In the AKIN classification, renal impairment is evaluated by changes in serum creatinine level and urine output.28 Haase et al. demonstrated that serum creatinine level is a stronger predictor of mortality than urine output.17 Furthermore, serum creatinine level is easily measured in clinical practice, whereas accurate measurement of urine output is difficult and is influenced by hydration status and use of diuretics.29 In particular, urine output may be maintained in a substantial portion of patients with AKI.11 Thus, the prognostic significance and ease of measurement favor the use of serum creatinine level over urine output in AKI.

Mannitol therapy is the cornerstone of treating increased ICP and cerebral edema. Although concerns about renal injury limit its use, there is little known about mannitol-induced AKI. This study evaluated the incidence, risk factors, and outcome of mannitol-induced AKI. Previous studies have found that advanced age, high blood pressure, renal dysfunction, and mannitol dose are associated with the development of AKI in patients with ICH.13,22,31,32 This study supports the relationship between these risk factors and AKI and proposes a risk model to predict AKI, which may be useful in its prevention.

This study has several limitations. First, it was retrospective in design, which restricts our ability to identify and evaluate all potential confounders, including disease severity, with such measures as the Sequential Organ Failure Assessment (SOFA) or the Acute Physiology And Chronic Health Evaluation (APACHE). Second, this study excluded substantial numbers of patients because of strict criteria. These numbers may mitigate the value of the results in our study. However, it may be valuable that our study reconfirmed the risk factors for AKI in patients treated with mannitol. Third, we limited AKIN criteria to changes in serum creatinine level and disregarded urine output. However, serum creatinine is easily measurable and more valuable than urine output.17 Fourth, the study was performed at a single center, and it might not be appropriate to extrapolate our results to other institutions. However, our incidence of AKI is consistent with that described in previous reports.9 Finally, the present risk model needs to be validated in other populations to establish its broad applicability.

Conclusions

We have determined the incidence of and risk factors for AKI in patients treated with mannitol for ICH. We also developed a model for evaluating AKI risk in these patients. On the basis of our findings, AKI following mannitol infusion in patients with ICH was common. A higher infusion rate of mannitol was associated with more frequent and more severe AKI. Additionally, advanced age, high DBP, and preexisting renal dysfunction were associated with the development of AKI. Our risk model may help clinicians manage reversible factors, communicate AKI risk to patients, and more efficiently treat high-risk patients. Further research is required to improve the outcomes of patients with ICH.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Jang, MY Kim, Oh. Acquisition of data: MY Kim, Park. Analysis and interpretation of data: MY Kim. Drafting the article: MY Kim. Critically revising the article: MY Kim, Jang. Reviewed submitted version of manuscript: Jang. Statistical analysis: MY Kim. Administrative/technical/material support: Jang, Hong, JS Kim, Oh. Study supervision: Kang, Lee, Huh, YG Kim, DJ Kim, Oh.

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  • 8

    Coca SGYusuf BShlipak MGGarg AXParikh CR: Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 53:9619732009

  • 9

    de Assis Aquino Gondim FAiyagari VShackleford ADiringer MN: Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 103:4444472005

  • 10

    Dennis MS: Outcome after brain haemorrhage. Cerebrovasc Dis 16:Suppl 19132003

  • 11

    Diamond JRYoburn DC: Nonoliguric acute renal failure. Arch Intern Med 142:188218841982

  • 12

    Dickenmann MOettl TMihatsch MJ: Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 51:4915032008

  • 13

    Dorman HRSondheimer JHCadnapaphornchai P: Mannitol-induced acute renal failure. Medicine (Baltimore) 69:1531591990

  • 14

    Dziedzic TSzczudlik AKlimkowicz ARog TMSlowik A: Is mannitol safe for patients with intracerebral hemorrhages? Renal considerations. Clin Neurol Neurosurg 105:87892003

  • 15

    Fang LYou HChen BXu ZGao LLiu J: Mannitol is an independent risk factor of acute kidney injury after cerebral trauma: a case-control study. Ren Fail 32:6736792010

  • 16

    Gruber AReinprecht AIllievich UMFitzgerald RDietrich WCzech T: Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 27:5055141999

  • 17

    Haase MBellomo RMatalanis GCalzavacca PDragun DHaase-Fielitz A: A comparison of the RIFLE and Acute Kidney Injury Network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study. J Thorac Cardiovasc Surg 138:137013762009

  • 18

    Hobson CEYavas SSegal MSSchold JDTribble CGLayon AJ: Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 119:244424532009

  • 19

    Hsu CYMcCulloch CEFan DOrdoñez JDChertow GMGo AS: Community-based incidence of acute renal failure. Kidney Int 72:2082122007

  • 20

    Kitiyakara CGuzman NJ: Malignant hypertension and hypertensive emergencies. J Am Soc Nephrol 9:1331421998

  • 21

    Levey ASCoresh JGreene TStevens LAZhang YLHendriksen S: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:2472542006

  • 22

    Li NZhao WGZhang WF: Acute kidney injury in patients with severe traumatic brain injury: implementation of the acute kidney injury network stage system. Neurocrit Care 14:3773812011

  • 23

    Liangos OWald RO'Bell JWPrice LPereira BJJaber BL: Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 1:43512006

  • 24

    Lin SLHung KYWu FLWei SCWu KD: Mannitol-induced acute renal failure. Nephrol Dial Transplant 10:1201221995

  • 25

    Loef BGEpema AHSmilde TDHenning RHEbels TNavis G: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 16:1952002005

  • 26

    Mancia GDe Backer GDominiczak ACifkova RFagard RGermano G: 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 25:110511872007

  • 27

    Marshall LFSmith RWRauscher LAShapiro HM: Mannitol dose requirements in brain-injured patients. J Neurosurg 48:1691721978

  • 28

    Mehta RLKellum JAShah SVMolitoris BARonco CWarnock DG: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R312007

  • 29

    NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury: Consensus conference. Rehabilitation of persons with traumatic brain injury. JAMA 282:9749831999

  • 30

    Oken DE: Renal and extrarenal considerations in high-dose mannitol therapy. Ren Fail 16:1471591994

  • 31

    Oleinik ARomero JMSchwab KLev MHJhawar NDelgado Almandoz JE: CT angiography for intracerebral hemorrhage does not increase risk of acute nephropathy. Stroke 40:239323972009

  • 32

    Pérez-Pérez AJPazos BSobrado JGonzalez LGándara A: Acute renal failure following massive mannitol infusion. Am J Nephrol 22:5735752002

  • 33

    Rangel-Castilla LGopinath SRobertson CS: Management of intracranial hypertension. Neurol Clin 26:521541x2008

  • 34

    Rost NSSmith EEChang YSnider RWChanderraj RSchwab K: Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. Stroke 39:230423092008

  • 35

    Sakemi TIkeda YOhtsuka NOhtsuka YTomiyoshi YBaba N: Acute renal failure associated with mannitol infusion and reversal with ultrafiltration and hemodialysis. Nephron 73:7337341996

  • 36

    Solenski NJHaley EC JrKassell NFKongable GGermanson TTruskowski L: Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23:100710171995

  • 37

    Sorani MDMorabito DRosenthal GGiacomini KMManley GT: Characterizing the dose-response relationship between mannitol and intracranial pressure in traumatic brain injury patients using a high-frequency physiological data collection system. J Neurotrauma 25:2912982008

  • 38

    Stocchetti NPenny KIDearden MBraakman RCohadon FIannotti F: Intensive care management of head-injured patients in Europe: a survey from the European brain injury consortium. Intensive Care Med 27:4004062001

  • 39

    Visweswaran PMassin EKDubose TD Jr: Mannitol-induced acute renal failure. J Am Soc Nephrol 8:102810331997

  • 40

    Wakai ARoberts ISchierhout G: Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 4CD0010492005

  • 41

    Wong GKWong RMok VWong APoon WS: Natural history and medical treatment of cognitive dysfunction after spontaneous subarachnoid haemorrhage: review of current literature with respect to aneurysm treatment. J Neurol Sci 299:582010

  • 42

    Zacharia BEDucruet AFHickman ZLGrobelny BTFernandez LSchmidt JM: Renal dysfunction as an independent predictor of outcome after aneurysmal subarachnoid hemorrhage: a single-center cohort study. Stroke 40:237523812009

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Article Information

Address correspondence to: Hye Ryoun Jang, M.D., Division of Nephrology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul, 135-710, Republic of Korea. email: hyeryoun.jang@samsung.com.

Please include this information when citing this paper: published online January 31, 2014; DOI: 10.3171/2013.12.JNS13888.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Proportion of patients with AKI based on mannitol infusion rate. Values beneath the graph represent numbers of patients with the respective AKIN stage or no AKI.

  • View in gallery

    Changes in mean body weight (A), median serum osmolality (B), and mean serum creatinine level (C) in patients with and without AKI. Day 1 = day after stopping mannitol infusion; Day 2 = 2 days after stopping mannitol infusion. Dots indicate the no-AKI group; diamonds, the AKI group. Between-groups comparison for each time point: *p < 0.01; **p < 0.05; ^p = 0.054.

  • View in gallery

    Incidence of AKI by risk score. Values beneath the graph represent numbers of patients with the respective risk score.

  • View in gallery

    Receiver operating characteristic curve for prediction of AKI.

References

1

Barrantes FTian JVazquez RAmoateng-Adjepong YManthous CA: Acute kidney injury criteria predict outcomes of critically ill patients. Crit Care Med 36:139714032008

2

Borges HFHocks JKjellstrand CM: Mannitol intoxication in patients with renal failure. Arch Intern Med 142:63661982

3

Brain Trauma Foundation American Association of Neurological Surgeons Joint Section on Neurotrauma and Critical Care: Use of mannitol. J Neurotrauma 17:5215252000

4

Broderick JPBrott TTomsick TMiller RHuster G: Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 78:1881911993

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Chen CFLiu XFMeng XZJia HY: [Comparative study of mannitol-induced acute kidney impairments in patients of different ages suffering from subarachnoid hemorrhage.]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 19:7277302007. (Chinese)

6

Coca SG: Acute kidney injury in elderly persons. Am J Kidney Dis 56:1221312010

7

Coca SGPeixoto AJGarg AXKrumholz HMParikh CR: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. Am J Kidney Dis 50:7127202007

8

Coca SGYusuf BShlipak MGGarg AXParikh CR: Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 53:9619732009

9

de Assis Aquino Gondim FAiyagari VShackleford ADiringer MN: Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 103:4444472005

10

Dennis MS: Outcome after brain haemorrhage. Cerebrovasc Dis 16:Suppl 19132003

11

Diamond JRYoburn DC: Nonoliguric acute renal failure. Arch Intern Med 142:188218841982

12

Dickenmann MOettl TMihatsch MJ: Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 51:4915032008

13

Dorman HRSondheimer JHCadnapaphornchai P: Mannitol-induced acute renal failure. Medicine (Baltimore) 69:1531591990

14

Dziedzic TSzczudlik AKlimkowicz ARog TMSlowik A: Is mannitol safe for patients with intracerebral hemorrhages? Renal considerations. Clin Neurol Neurosurg 105:87892003

15

Fang LYou HChen BXu ZGao LLiu J: Mannitol is an independent risk factor of acute kidney injury after cerebral trauma: a case-control study. Ren Fail 32:6736792010

16

Gruber AReinprecht AIllievich UMFitzgerald RDietrich WCzech T: Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 27:5055141999

17

Haase MBellomo RMatalanis GCalzavacca PDragun DHaase-Fielitz A: A comparison of the RIFLE and Acute Kidney Injury Network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study. J Thorac Cardiovasc Surg 138:137013762009

18

Hobson CEYavas SSegal MSSchold JDTribble CGLayon AJ: Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 119:244424532009

19

Hsu CYMcCulloch CEFan DOrdoñez JDChertow GMGo AS: Community-based incidence of acute renal failure. Kidney Int 72:2082122007

20

Kitiyakara CGuzman NJ: Malignant hypertension and hypertensive emergencies. J Am Soc Nephrol 9:1331421998

21

Levey ASCoresh JGreene TStevens LAZhang YLHendriksen S: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:2472542006

22

Li NZhao WGZhang WF: Acute kidney injury in patients with severe traumatic brain injury: implementation of the acute kidney injury network stage system. Neurocrit Care 14:3773812011

23

Liangos OWald RO'Bell JWPrice LPereira BJJaber BL: Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 1:43512006

24

Lin SLHung KYWu FLWei SCWu KD: Mannitol-induced acute renal failure. Nephrol Dial Transplant 10:1201221995

25

Loef BGEpema AHSmilde TDHenning RHEbels TNavis G: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 16:1952002005

26

Mancia GDe Backer GDominiczak ACifkova RFagard RGermano G: 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 25:110511872007

27

Marshall LFSmith RWRauscher LAShapiro HM: Mannitol dose requirements in brain-injured patients. J Neurosurg 48:1691721978

28

Mehta RLKellum JAShah SVMolitoris BARonco CWarnock DG: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R312007

29

NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury: Consensus conference. Rehabilitation of persons with traumatic brain injury. JAMA 282:9749831999

30

Oken DE: Renal and extrarenal considerations in high-dose mannitol therapy. Ren Fail 16:1471591994

31

Oleinik ARomero JMSchwab KLev MHJhawar NDelgado Almandoz JE: CT angiography for intracerebral hemorrhage does not increase risk of acute nephropathy. Stroke 40:239323972009

32

Pérez-Pérez AJPazos BSobrado JGonzalez LGándara A: Acute renal failure following massive mannitol infusion. Am J Nephrol 22:5735752002

33

Rangel-Castilla LGopinath SRobertson CS: Management of intracranial hypertension. Neurol Clin 26:521541x2008

34

Rost NSSmith EEChang YSnider RWChanderraj RSchwab K: Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. Stroke 39:230423092008

35

Sakemi TIkeda YOhtsuka NOhtsuka YTomiyoshi YBaba N: Acute renal failure associated with mannitol infusion and reversal with ultrafiltration and hemodialysis. Nephron 73:7337341996

36

Solenski NJHaley EC JrKassell NFKongable GGermanson TTruskowski L: Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23:100710171995

37

Sorani MDMorabito DRosenthal GGiacomini KMManley GT: Characterizing the dose-response relationship between mannitol and intracranial pressure in traumatic brain injury patients using a high-frequency physiological data collection system. J Neurotrauma 25:2912982008

38

Stocchetti NPenny KIDearden MBraakman RCohadon FIannotti F: Intensive care management of head-injured patients in Europe: a survey from the European brain injury consortium. Intensive Care Med 27:4004062001

39

Visweswaran PMassin EKDubose TD Jr: Mannitol-induced acute renal failure. J Am Soc Nephrol 8:102810331997

40

Wakai ARoberts ISchierhout G: Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 4CD0010492005

41

Wong GKWong RMok VWong APoon WS: Natural history and medical treatment of cognitive dysfunction after spontaneous subarachnoid haemorrhage: review of current literature with respect to aneurysm treatment. J Neurol Sci 299:582010

42

Zacharia BEDucruet AFHickman ZLGrobelny BTFernandez LSchmidt JM: Renal dysfunction as an independent predictor of outcome after aneurysmal subarachnoid hemorrhage: a single-center cohort study. Stroke 40:237523812009

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