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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 355-360

Incidence and determinants of acute kidney injury following Mannitol therapy


Department of Medicine, Government Medical College, Thrissur, 680596, Kerala, India

Date of Submission02-Jul-2021
Date of Acceptance28-Sep-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. Mary Grace
Department of Medicine, Government Medical College, Thrissur, 680596, Kerala.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_46_21

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  Abstract 

Background: Mannitol is a commonly used drug in general medicine and neuro medicine wards. Mannitol reduces intracerebral pressure by redistributing water from the brain parenchyma. Renal failure is cited as one of the most common side effects and concern over this often limits the use of Mannitol. This study is intended to find out whether the use of Mannitol, in the doses commonly used in our setting, is associated with derangement of renal function and if so what are its determinants. Materials and Methods: We did a prospective observational study on 151 consecutive patients. The duration of the study was for one year from January to December 2020. Mannitol was used in the usual dose of 100 ml of 20% solution 8 hourly. Acute kidney injury was diagnosed based on the KDIGO criteria. Results: The study population included 103 males (68%) and 48 females (32%). The age group ranged from 14 years to 98 years. A total of 42 patients (27.8%) developed acute kidney injury of which 26 were males (62%) and 16 were females (38%). By multiple regression analysis, age more than 65 years and diastolic blood pressure more than 100 mm of Hg were the two significant predictors for the occurrence of acute kidney injury. Conclusion: Mannitol is a safe drug that can be used to reduce intracerebral pressure, provided the dose of the drug is carefully monitored, especially in those with risk factors such as advanced age and high diastolic blood pressure. An equally important aspect is the early recognition of the renal impairment because stopping the drug will in most situations reverse the damage. Since any renal impairment, however small and short-lasting, can have adverse long-term effects, such insults must be avoided as far as possible.

Keywords: Acute kidney injury, cerebral edema, Mannitol


How to cite this article:
Grace M, Paul GA, Aravindan V, Afzal CM, Joy BA, Ajmal NM. Incidence and determinants of acute kidney injury following Mannitol therapy. MGM J Med Sci 2021;8:355-60

How to cite this URL:
Grace M, Paul GA, Aravindan V, Afzal CM, Joy BA, Ajmal NM. Incidence and determinants of acute kidney injury following Mannitol therapy. MGM J Med Sci [serial online] 2021 [cited 2022 Jan 18];8:355-60. Available from: http://www.mgmjms.com/text.asp?2021/8/4/355/333317




  Background Top


Mannitol is a polyol, occurring naturally as sugar in fruits and vegetables. Being pharmacologically inert, when it is given in large quantities it raises the osmolarity of the plasma. Mannitol is used as a 20% solution. The t½ of Mannitol is.5-1.5 hours. But this prolonged to more than 36 hours in the presence of renal impairment.[1],[2] By increasing the osmotic gradient between blood and brain parenchyma, Mannitol promotes the transfer of water from the brain tissue to the circulatory system. Because it is freely filtered at the glomerulus and there is minimal reabsorption in the tubules,[1] it behaves as an osmotic diuretic. Brain edema is one of the most devastating complications in patients with acute brain injury. Mannitol reduces intracerebral pressure by redistributing water from the brain parenchyma.[3],[4] Being an osmotic diuretic it may also be used to promote the excretion of toxic substances. Some of the situations where Mannitol is used are rhabdomyolysis and as a renoprotective agent during surgical procedures. The mechanism of action of Mannitol in providing renoprotection, is by the release of prostaglandins in the kidney, thereby facilitating vasodilatation and increase in urine flow. But the renoprotective effect is not well established. During episodes of ischemia followed by reperfusion, the oxygen free radicals which are generated are harmful to the body.

In this circumstance Mannitol, by its property of free radical scavenger, plays a protective role. The most established indication for Mannitol is the reduction of intracerebral pressure. The side effects of Mannitol include acute kidney injury, electrolyte disturbances like hyponatremia, hypokalemia increase in serum osmolality, pulmonary edema and rebound cerebral edema.[4] Mannitol can cause both fluid overload as well as volume depletion. Some of the other complications include anaphylaxis, thrombophlebitis, and necrosis of the skin in case of extravasation. Renal failure is cited as one of the most common side effects and concern over this often limits the use of Mannitol. The mechanism for renal impairment includes renal vasoconstriction, osmotic diuresis, and osmotic nephropathy (swelling of the tubular cells).[1],[2],[5] The rapid improvement in renal function following the withdrawal of the drug, argues that the mechanism of renal impairment is more likely to be the functional cause rather than structural damage. In low doses, Mannitol causes renal vasodilation, through the action of prostaglandins. But very high doses are associated with constriction of the renal vasculature. This occurs when the serum level of Mannitol is more than 1000 mg/dl. The safe level would be much lower in patients with deranged renal function, because of the accumulation of Mannitol in the body. The serum level of Mannitol can be estimated if the osmolal gap is known. The osmolal gap is the difference between the measured and calculated osmolality.

Mannitol (mg/dl) = Osmolal gap (mOsmol/kg) × 18.2

Molecular weight of Mannitol is 182

Thus monitoring of the osmolal gap should be encouraged while using Mannitol. An osmolal gap of more than 60–75 mOsmol/kg is associated with renal damage. It is ideal to maintain a gap of less than 55 mOsmol/kg.

The outcome of Mannitol-induced renal injury is usually good. Recovery is usually complete within 10 days unless other exacerbating events are added. The treatment of Mannitol-induced AKI includes the withdrawal of the agent. The recovery will be hastened by hemodialysis. Any deterioration in renal functions, irrespective of the magnitude of change and duration of damage, is associated with adverse outcome.[6],[7] Hence physicians using Mannitol must be aware of this complication and be on the lookout for it.

Mannitol is a commonly used drug in general medicine and neuro medicine wards. The common conditions for which Mannitol is used in our setting are cerebrovascular disease, subarachnoid hemorrhage, meningoencephalitis, and intracranial space-occupying lesion. In these situations, Mannitol acts by reducing the raised intracranial tension. Similarly, Mannitol is utilized in the post-trauma and post-surgery cases in the neurosurgical wards.

This study is intended to find out whether the use of Mannitol, in the medical and neuro medicine wards, in the doses commonly used in our setting, is associated with derangement of renal function and if so what are its determinants.

Aim and objectives

  • 1 To estimate the incidence of Mannitol induced renal injury


  • 2 To identify the risk factors associated with the development of Mannitol induced renal injury



  Materials and methods Top


We did a longitudinal study on 151 consecutive patients who were admitted in the general medicine and neurology wards and for whom Mannitol was given as part of their treatment protocol. The study duration was a period of one year, starting from January 2020 to December 2020.

Inclusion criteria

  1. Those patients above the age of 18 years admitted to general medicine wards and medicine ICU


  2. Those receiving Mannitol infusion as part of their treatment protocol.


  3. Those patients receiving Mannitol for whom repeat laboratory investigations were done as part of follow up


Exclusion criteria

  1. Those patients who were admitted with the diagnosis of traumatic brain injury.


  2. Those patients diagnosed with chronic kidney disease.


  3. Those patients who developed acute kidney injury before starting Mannitol infusion.


  4. Those patients receiving drugs that could interfere with renal function tests.


Mannitol is used in doses of 100 ml of 20% solution 8 hourly. It is usually given for 5–7 days. Only those patients who consented were included in the study. We aimed to study the incidence and determinants of acute kidney injury following Mannitol therapy. The following parameters were followed up clinical status, urine output, blood pressure, blood urea and serum creatinine, serum electrolytes.

Blood pressure was recorded at the time of admission, before starting Mannitol infusion, and daily thereafter. The blood investigations were sent on the day of admission and days 3,5 and end of treatment with Mannitol.

An increase in systolic blood pressure of more than 20 mm of Hg and diastolic blood pressure of more than 10 mm of Hg from the baseline after starting Mannitol was taken as accelerated hypertension. Acute kidney injury was diagnosed based on the KDIGO criteria.[8] KDIGO defines AKI as any of the following:

Increase in serum creatinine by 0.3 mg/dL or more within 48 hours or increase in serum creatinine to 1.5 times baseline or more within the last 7 days or urine output less than 0.5 mL/kg/h for 6 hours.

Statistical analysis

All data were entered into the proforma and then into Microsoft Excel 2007 spreadsheet. The data were analyzed using SPSS software. Continuous variables were expressed as the appropriate means and standard deviations or medians and interquartile ranges. Categorical variables were summarized as the counts and percentages in each category. All continuous variables were analyzed using the unpaired ‘t’ test for normally distributed data and the Mann-Whitney U test for skewed data. Categorical variables were analyzed using the Chi-square test. The risk factors for the development of acute kidney injury were determined by univariate and multivariate regression analysis. A p-value of less than 0.05 was taken as significant.

Informed consent from the patients and clearance from the Institutional Ethical Committee was obtained.


  Results Top


We studied 151 consecutive patients who were given Mannitol infusion. The study population included 103 males (68%) and 48 females (32%). The age group ranged from 14 years to 98 years. The average age was 59 years. The majority were less than 65 years of age (62%). The major category of clinical diagnosis was intracerebral bleed, followed by an ischemic stroke. The rest of the cohort was made up of space-occupying lesions, meningoencephalitis, post-seizure, subarachnoid hemorrhage [Table 1].
Table 1: Epidemiology and Clinical diagnosis of Study Cohort

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Among the patients with hypertension, the majority had systolic BP of more than 180 mm Hg and /or diastolic BP of more than 100 mm of Hg.

A total of 42 patients (27.8%) developed acute kidney injury of which 26 were males (62%) and 16 were females. (38%) [Table 2].
Table 2: Blood pressure data of the study cohort

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By univariate regression, the factors which were predictive of the development of AKI (with statistical significance, were age more than 65 years, systolic blood pressure more than 160 mm of Hg, diastolic blood pressure more than 90 mm of Hg, and accelerated hypertension at the time of admission. On multivariate regression, the significant factors were age more than 65 years and diastolic blood pressure more than 100 mm of Hg [Table 3][Table 4][Table 5].
Table 3: Univariate analysis for development of AKI-epidemiological data and clinical diagnosis

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Table 4: Univariate Analysis for Development of AKI -Blood Pressure

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Table 5: Regression analysis of factors for development of AKI

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  Discussion Top


In this study 42 patients (28%) developed acute kidney injury. This incidence is higher than some of the previous studies. Lin et al. observed acute kidney in 6.5% of the study cohort.[9] The incidence has ranged from 10.5% to 20.3%, among different patient cohorts.[10]

In the study by de Assis in a heterogeneous population the incidence was 11.6%.[11],[12] But in the study by Dziedzic T et al, the incidence reported was much higher than the above studies. They reported an incidence of 76%.[13]

The dose of Mannitol advocated in the literature ranges from 0.25-1g/kg body weight. The infusion is given over 20–30 minutes. However, the dose-response curve is not well established. One view that is held is that Mannitol should be given in high doses and the mode of delivery should be rapid bolus infusion. Only then can we expect a sustained reduction in the intracerebral pressure.[3],[14] The peak effect of lowering the raised intracerebral pressure occurs in 30–45 minutes and the effect is expected to last for 6 hours. Equally important is the duration of therapy with Mannitol. Due care should be given, both to starting and ending Mannitol therapy. Mannitol should be given only in those cases with features of raised intracerebral pressure, taking care to avoid the drug routinely in all cases of cerebrovascular disease. Since the onset of cerebral edema following a cerebrovascular event is expected to be after around 2–5 days, the start of therapy should also be planned accordingly. The stopping of Mannitol infusion also should be carefully followed up, making sure the duration of therapy is not unnecessarily prolonged. The serum osmolality should be ideally kept at less than 320 mOsmol/l.

Mannitol-induced AKI has been described, generally after treatment with >200 g/day and cumulative doses of 750-1000g.[5],[15] This cumulative dose may be reduced by 33% in patients with CKD.[5] According to older case reports acute kidney injury has occurred even with doses less than 400 g/day.[16],[17]

Kim M Y et al. opined that a total dose of >1.34 g/kg/day is associated with increased risk.[10] Kim and Marshall have independently observed that a bolus dose of Mannitol of 0.25 g/kg/day, reduces the intracranial pressure as much as larger doses.[10],[18] Thus Mannitol in lower doses may be both effective as well as safe. According to Kim, a bolus of 0.25 g/kg is allowable, a maximum of 6 times a day. In the view of Dorman, a higher infusion rate is a risk factor for renal damage.[2] Perez-Perez et al. noted that the safe upper limit of the rate of infusion is.25g/kg/hour.[5] According to Marshall et al. bolus infusion of Mannitol at the dose of.25g/kg is effective in reducing the raised intracerebral pressure.[18] According to Perez and Kim M Y et al, the infusion rate is a more important determinant for the development of AKI than the daily or total quantification of the dose.[5],[10] Rate of infusion >0.25 g/kg/hour for 58 + 28 hours may be detrimental.

The treatment protocol that is generally followed in our center is 100 ml of 20% solution of Mannitol, given every 8 hours for a usual period of 5–7 days. This would mean around 60 g/day and the cumulative dose is less than 500 g if used for one week. Considering the elimination time for Mannitol to be around one hour, repeat dosing can be done in 4–6 hourly intervals. Taking into consideration, the safe limits of the total dose and infusion rate determined by previous studies,[10] if we give Mannitol 20% solution, 25 g/kg over one-hour boluses, 5 times daily, the chances of renal impairment can be minimized.

Thus as per the above data, the bolus doses we are giving are above the safe limit, especially for women. That may be one of the reasons for the slightly higher incidence of acute kidney injury in our cohort.

In this study, 35% of patients with intracerebral bleed developed acute kidney injury, while it was 22% among other causes.

Just like the overall incidence, the incidence of acute kidney injury among the patients with intracerebral bleed was much higher than in some of the other studies. In previous studies of patients with intracerebral bleed, the incidence of Mannitol-induced AKI was 10.5%.[10],[13] In the study by Lin SY et al. there was no difference between ischemic and hemorrhagic stroke in the development of acute kidney injury.[9] We also did not notice any significant difference in the development of acute kidney injury based on the indication for which it was given.

In the study by Kim et al. the variables which were significant in causing acute kidney injury were age >70 years, diastolic blood pressure >110 mm of Hg and dose >1.34g/kg/day.[9]

In other studies, the risk factors postulated were advanced age, diabetes mellitus, high blood pressure, pre-existing renal dysfunction, concomitant use of nephrotoxic drugs, dose, and rate of mannitol infusion.[2],[18] Pre-existing renal impairment is a significant risk factor for renal damage following Mannitol. The half-life of Mannitol is 1–2 hours in people with normal renal function. This is prolonged to 36 hours in patients with uremia,[19] (and reduced to 6 hours after dialysis for 6 hours).[10] The usual dose of Mannitol will accumulate and aggravate renal injury. We did not include patients with pre-existing renal impairment for evaluation.

Many have observed advanced age to be a predictor of acute kidney injury following the use of Mannitol.[5],[20],[21] We also confirmed this by our observation of a significant increase in acute kidney injury among patients more than 65 years of age. The reason for this could be the reduced renal reserve as age advances.[22] Like advanced age, higher blood pressure levels can also influence the renal reserve adversely by causing injury to the vascular walls.[10]

According to Kim diastolic blood pressure >110 mm of Hg was a significant risk factor for Mannitol induced acute kidney injury in intracerebral bleed.[10] In our view, diastolic blood pressure greater than 100 mm Hg itself has an adverse influence. Like our study, Kim et al. also did not observe any relation between systolic blood pressure and the development of acute kidney injury.[10]

By doing univariate analysis, systolic blood pressure more than 160 mm Hg and accelerated hypertension, were found to be significant factors in predicting kidney damage.

After doing multiple regression analysis, the two factors which stood out significantly were age above 65 years and diastolic blood pressure more than 100 mm of Hg.


  Conclusion Top


Mannitol is a safe drug that can be used to reduce intracerebral pressure, provided the dose of the drug is carefully monitored, especially in those with risk factors such as advanced age and high diastolic blood pressure. An equally important aspect is the early recognition of the renal impairment because stopping the drug will in most situations reverse the damage. Since any renal impairment, however small and short-lasting, can have adverse long-term effects, such insults must be avoided as far as possible. Previously it was believed that acute kidney injury is a self-limited condition and it does not carry with it any long-term effects. But it is well established that acute kidney injury is associated with recurrent acute kidney injury and also with chronic kidney disease. Besides its influence on the renal prognosis, acute kidney injury also has a role in the mortality and morbidity of other comorbidities such as malignancy and cardiovascular and cerebrovascular disease. Thus avoiding the development of acute kidney injury should be given prime importance in the management of all patients and especially those with multiple comorbidities. Thus frequent monitoring of the patients is essential while using Mannitol. Equally important is to avoid using it in patients with multiple risk factors.

Study limitations

One limitation of the study is the small sample size. Another limitation is the lack of measurement of serum osmolarity to get an idea about the level of Mannitol.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest.

Ethical consideration

The ethical approval for undertaking the proposed study has been obtained from Institutional Ethics Committee vide their letter no. IEC/GMCTSR/078/2020 dated 05 December 2020.



 
  References Top

1.
Better OS, Rubinstein I, Winaver JM, Knochel JP. Mannitol therapy revisited (1940-1997). Kidney Int 1997;52:886-94.  Back to cited text no. 1
    
2.
Dorman HR, Sondheimer JH, Cadnapaphornchai P. Mannitol-induced acute renal failure. Medicine (Baltimore) 1990;69:153-9.  Back to cited text no. 2
    
3.
Sorani MD, Manley GT. Dose-response relationship of mannitol and intracranial pressure: A metaanalysis. J Neurosurg 2008;108:80-7.  Back to cited text no. 3
    
4.
Fink ME. Osmotherapy for intracranial hypertension: Mannitol versus hypertonic saline. Continuum (Minneap Minn) 2012;18:640-54.  Back to cited text no. 4
    
5.
Pérez-Pérez AJ, Pazos B, Sobrado J, Gonzalez L, Gándara A. Acute renal failure following massive mannitol infusion. Am J Nephrol 2002;22:573-5.  Back to cited text no. 5
    
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Coca SG, Peixoto AJ, Garg AX, Krumholz HM, Parikh 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 2007;50:712-20.  Back to cited text no. 6
    
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Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-term risk of mortality and other adverse outcomes after acute kidney injury: A systematic review and meta-analysis. Am J Kidney Dis 2009;53:961-73.  Back to cited text no. 7
    
8.
Kidney Disease Improving Global Outcomes (KDIGO). Clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2(Suppl 1):1-138.  Back to cited text no. 8
    
9.
Lin SY, Tang SC, Tsai LK, Yeh SJ, Shen LJ, Wu FL, et al. Incidence and risk factors for acute kidney injury following mannitol infusion in patients with acute stroke: A retrospective cohort study. Medicine (Baltimore) 2015;94:e2032.  Back to cited text no. 9
    
10.
Kim MY, Park JH, Kang NR, Jang HR, Lee JE, Huh W, et al. Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage. J Neurosurg 2014;120:1340-8.  Back to cited text no. 10
    
11.
Gondim Fde A, Aiyagari V, Shackleford A, Diringer MN. Osmolality not predictive of mannitol-induced acute renal insufficiency. J Neurosurg 2005;103:444-7.  Back to cited text no. 11
    
12.
Chen CF, Liu XF, Meng XZ, Jia 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 2007;19:727-30.  Back to cited text no. 12
    
13.
Dziedzic T, Szczudlik A, Klimkowicz A, Rog TM, Slowik A. Is mannitol safe for patients with intracerebral hemorrhages? Renal considerations. Clin Neurol Neurosurg 2003;105:87-9.  Back to cited text no. 13
    
14.
Sorani MD, Morabito D, Rosenthal G, Giacomini KM, Manley 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 2008;25:291-8.  Back to cited text no. 14
    
15.
Dickenmann M, Oettl T, Mihatsch MJ. Osmotic nephrosis: Acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 2008;51:491-503.  Back to cited text no. 15
    
16.
Sakemi T, Ikeda Y, Ohtsuka N, Ohtsuka Y, Tomiyoshi Y, Baba N. Acute renal failure associated with mannitol infusion and reversal with ultrafiltration and hemodialysis. Nephron 1996;73:733-4.  Back to cited text no. 16
    
17.
Visweswaran P, Massin EK, Dubose TD Jr. Mannitol-induced acute renal failure. J Am Soc Nephrol 1997;8:1028-33.  Back to cited text no. 17
    
18.
Marshall LF, SMith RW, Rauscher LA, Shapiro HM. Mannitol dose requirements in brain-injured patients. J Neurosurg 1978;48:169-72.  Back to cited text no. 18
    
19.
Oken DE. Renal and extrarenal considerations in high-dose mannitol therapy. Ren Fail 1994;16:147-59.  Back to cited text no. 19
    
20.
Liangos O, Wald R, O’Bell JW, Price L, Pereira BJ, Jaber BL. Epidemiology and outcomes of acute renal failure in hospitalized patients: A national survey. Clin J Am Soc Nephrol 2006;1:43-51.  Back to cited text no. 20
    
21.
Hsu CY, McCulloch CE, Fan D, Ordoñez JD, Chertow GM, Go AS. Community-based incidence of acute renal failure. Kidney Int 2007;72:208-12.  Back to cited text no. 21
    
22.
Coca SG. Acute kidney injury in elderly persons. Am J Kidney Dis 2010;56:122-31.  Back to cited text no. 22
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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