JCDR - Register at Journal of Clinical and Diagnostic Research
Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X
Internal Medicine Section DOI : 10.7860/JCDR/2020/44376.13839
Year : 2020 | Month : Jul | Volume : 14 | Issue : 07 Full Version Page : OC05 - OC08

Complications Associated with Osmotic Therapy in Acute Stroke Patients- A Prospective Longitudinal Observational Study

Sudhan Rackimuthu1, Pawan Raj Pulu Ishwara2, Sucharitha Suresh3

1 Undergraduate Student, Department of Neurology, Father Muller Medical College, Mangalore, Karnataka, India.
2 Associate Professor, Department of Neurology, Father Muller Medical College, Mangalore, Karnataka, India.
3 Assistant Professor, Department of Hospital Administration, Father Muller Medical College, Mangalore, Karnataka, India.


NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR: Pawan Raj Pulu Ishwara, Soorya House, NSC Bose Road, Chandrika Extension, Bejai, Mangalore, Karnataka, India.
E-mail: drpawanraj88@gmail.com
Abstract

Introduction

Mannitol is one of the most frequently used drugs to treat cerebral oedema resulting from ischemic and haemorrhagic strokes. Mannitol administration is associated with complications such as Acute Kidney Injury (AKI) and electrolyte imbalance.

Aim

To study effect of mannitol therapy on electrolyte levels and renal function in acute stroke patients.

Materials and Methods

The present prospective longitudinal observational study was carried out from January 2019 till September 2019 in Father Muller Medical College, Mangalore, India. After taking informed consent, patients with acute stroke who received mannitol were recruited into the study. Nature of the stroke, presence of comorbidities and dosage of mannitol given were recorded. Serum electrolytes, Serum urea and creatinine were recorded at admission and on fifth day. Serum urea was measured by enzymatic photometric method using urease and glutamate dehydrogenase and serum creatinine was measured by Jaffe’s kinetic method. Comparison of data among different groups was performed using student t-test, ANOVA test, Mann-whitney test and Pearson test. The p-values <0.05 were taken as statistically significant.

Results

Total of 72 patients were included in the study. Mean age was 57.7±14.6 years and male: female ratio was 2.27:1. Of the total study subjects, 16 suffered from diabetes (22.22%), 40 from hypertension (55.55%). Ischemic stroke was seen in 41.66% patients and haemorrhagic stroke was seen in 58.33% of the patients. The dose of mannitol administered to all the patients was less than 1 gram/kg/day (low dose mannitol). Cumulative dose of mannitol was 180±177.3 grams. Serum sodium levels were significantly lower on fifth day compared to admission (p-value 0.030) whereas serum potassium and chloride levels were not significantly changed during therapy. There was statistically significant elevation in serum urea levels from admission to fifth day (p-value <0.001) whereas creatinine levels were not significantly altered. Total cumulative dose was compared to serum electrolyte levels and urea and creatinine at admission and fifth day and no significant changes were found. On analysing comorbidities, electrolyte fluctuations were more common in diabetics and Chronic Kidney Disease (CKD) patients whereas renal function parameters were abnormal in diabetics, CKD and hypertensive patients. None of the patients needed any corrective measures to treat the dyselectrolytemias or altered renal function.

Conclusion

Low dose mannitol therapy does not produce any significant electrolyte or renal function abnormality in patients with acute stroke. Careful monitoring may be required while treating patients with additional comorbidities.

Keywords

Introduction

The World Health Organisation (WHO) defines stroke as ‘rapidly developed clinical signs of focal or global disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin’ [1]. Stroke is a leading cause of mortality and long-term disability globally [2,3]. The incidence of stroke in low and middle-income countries has more than doubled and the prevalence of stroke and stroke related deaths have increased in absolute numbers, particularly in the elderly [4,5].

Cerebral oedema is a well-described stroke complication and is associated with poor outcome [6-10]. Current guidelines (American Stroke Association) mention that osmotic therapy is reasonable in patients with clinical deterioration from cerebral oedema resulting from cerebral infarction [11]. Drugs such as mannitol, hypertonic saline, glycerol, corticosteroids, barbiturates and diuretics have been commonly used to treat cerebral-oedema [12,13]. Mannitol is administered intravenously as a 20% solution and dosage is adjusted according to the body weight and severity of brain oedema. Various studies have described low dose mannitol therapy as dosage of 1 g/kg/day and high dose mannitol therapy as greater than 1 g/kg/day [14].

However, only a few studies [15-20] have evaluated the effects of mannitol on the clinical parameters of these patients. Mannitol administration is also associated with frequent complications such as Acute Kidney Injury, electrolyte imbalance, volume overload, rebound oedema, thrombophlebitis [21-29] and has thus led to controversies regarding its use in acute stroke care.

Aim of the present study were to look into evaluation of short-term fluctuations in serum electrolytes and renal function in patients with acute stroke receiving mannitol therapy and to correlate the fluctuations if any with comorbidities, in order to help with appropriate monitoring during osmotic therapy.

Materials and Methods

Patients admitted to the Neurology Department of Father Muller Medical College Hospital, Mangalore from January 2019 to September 2019 were included in the study. This study was approved (Approval letter number: FMMCIEC/CCM/122/2019) by the Father Muller Medical College Institutional Ethics Committee. Written informed consent was obtained.

Inclusion criteria: Patients above 18 years of age and clinically diagnosed as Ischemic or Haemorrhagic stroke were included, if patient or their attendants consented to take part in the study.

Exclusion criteria: Patients below the age of 18 years and/or those not willing to give consent, were excluded from the present study.

Data on demographics, risk factors, co-morbidities of the patients were noted and data on mannitol dosage in: 1) grams/kilograms/day; and 2) total cumulative dosage administered to the present study population was obtained. Dosage of mannitol received by patients of study population was adjusted based on weight and severity of cerebrovascular accident. The cumulative dose received by each patient was then calculated and used for further analysis. Dose of mannitol administered to all patients of the study population was 0.2 grams/mL, which was given as 100 mL infusion. Values of Serum electrolytes and Renal function test parameters on admission and on fifth day following mannitol therapy were obtained. Local complications such as thrombophlebitis, Intravenous block and limb swelling [30-33] if any, arising during mannitol therapy in the study population were also recorded.

Electrolytes were measured by Ion Selective Electrodes (ISE) which measured the activity of ions in water which is directly proportional to their concentration. Serum urea was measured by enzymatic photometric method using urease and glutamate dehydrogenase and serum creatinine was measured by Jaffe’s kinetic method. The tests were done by Cobas 6000 automated analyser.

Statistical Analysis

Collected data was tabulated and entered using Microsoft Excel 365 into an excel proforma sheet and analysis was done using SPSS Software Version 21.0. Further evaluation of the data of comparing the means of more than 2 different groups was performed using student t-test, ANOVA test, Mann-whitney test and Pearson test. The p-values <0.05 were taken as statistically significant.

Results

In the present study, 72 stroke patients were recruited with the mean age being 57.72±14.60 with minimum age of 26 and maximum age of 84 years. Among the study population, 50 were males and 22 were females with an M:F ratio of 2.27:1. In the study cohort, 16 suffered from diabetes (22.22%), 40 from hypertension (55.55%), 5 from CKD (6.94%), 3 from ischemic heart disease (4.16%) and one patient each (1.38%) from Pneumonia, Dyslipidemia, Peripheral Artery Occlusive Disease and previous episode of stroke respectively.

Thirty patients (41.66%) were diagnosed as ischemic stroke and 42 (58.33%) patients were diagnosed as haemorrhagic stroke. All 72 patients received Intravenous mannitol as anti-oedema therapy.

The mean cumulative dose of mannitol administered to study population was 180.00±177.39 grams with a minimum dose of 20 grams and maximum dose of 1020 grams. The cumulative dose of mannitol administered to all the patients was less than 1 gram/kg/day and was thus categorised as low dose mannitol [14].

Serum Electrolyte Changes with Mannitol Therapy

Serum sodium, potassium and chloride were measured at admission and on fifth day. On employing ANOVA test, there was a statistically significant reduction in serum sodium levels whereas potassium and chloride levels were not significantly altered [Table/Fig-1]. There was also no statistically significant co-relation of change in sodium, potassium or chloride levels with cumulative dose of mannitol.

Change in electrolyte levels of patients receiving mannitol therapy by applying ANOVA Test (p-values <0.05 were taken as statistically significant).

ParameterDay of measurementMeanStandard deviationp-value
Serum Cl {mEq/L (milliequivalents per litre)}Admission96.999.460.904
Fifth day97.176.17
Serum K {mmol/L (millimole per litre)}Admission3.890.660.225
Fifth day4.020.49
Serum Na {mEq/L (milliequivalents per litre)}Admission136.676.830.030
Fifth day135.536.36

Renal Function Changes with Mannitol Therapy

There was an increasing trend in serum urea levels from admission to fifth day, which was statistically significant when employing Friedman test while serum creatinine was not significantly altered [Table/Fig-2]. On using Pearson’s coefficient analysis, there was no statistically significant co-relation of cumulative dose of mannitol with change in serum urea or creatinine levels [Table/Fig-3].

Change in renal function parameters of patients receiving mannitol therapy by applying Friedman Test.

ParameterDay of measurementMeanStandard deviationp-value
Serum creatinine (mg/dL)Admission1.301.220.217
Fifth day1.361.38
Serum urea (mg/dL)Admission34.6124.23<0.001
Fifth day39.4230.98

Correlation between cumulative dose of mannitol with changes in electrolyte levels and renal function parameters.

Values measured on admission and fifth dayPearson correlationp-value
Serum Cl changes {mEq/L (meq/ltr)} with cumulative dose-0.0170.885
Serum K changes {mmol/L (mmole/ltr)} with cumulative dose0.0120.919
Serum Na changes {mEq/L (meq/ltr)} with cumulative dose-0.0070.951
Serum Creatinine changes {mg/dL (mg/dL)} with cumulative dose-0.1190.318
Serum Urea changes {mg/dL (mg/dL)} with cumulative dose-0.1060.375

Cumulative Dose of Mannitol and Electrolyte Changes and Renal Function Parameters in Patients with Comorbidities

Serum sodium changes were statistically significant in diabetic patients. Serum potassium changes were significant in patients with CKD and diabetics. There was no significant change in chloride levels with respect to comorbidities [Table/Fig-4].

Correlation between cumulative dose of mannitol with changes in electrolyte levels in patients with comorbidities.

ParameterCo-morbidityMeanStandard deviationp-value
Serum Cl {mEq/L (milliequivalents per litre)}DMNo96.75.420.235
Yes98.798.29
HTNNo97.417.140.772
Yes96.985.35
IHDNo97.336.150.292
Yes93.476.44
CKDNo97.055.930.558
Yes98.749.62
Serum K {mmol/L (millimole per litre)}DMNo3.950.400.029
Yes4.250.68
HTNNo3.930.410.155
Yes4.090.53
IHDNo4.030.480.589
Yes3.870.72
CKDNo3.970.44<0.001
Yes4.740.57
Serum Na {mEq/L (milliequivalents per litre)}DMNo134.736.020.046
Yes138.316.93
HTNNo135.345.990.828
Yes135.686.71
IHDNo135.556.410.884
Yes135.006.08
CKDNo135.496.410.865
Yes136.006.28

DM: Diabetes mellitus; HTN: Hypertension; IHD: Ischemic heart disease; CKD: Chronic kidney disease


Serum creatinine level changes were significant in patients with CKD and serum urea level changes were statistically significantly in patients with CKD, diabetes and hypertension [Table/Fig-5].

Correlation between cumulative dose of mannitol with changes in renal function parameters in patients with comorbidities. The p-values <0.05 were taken as statistically significant.

ParameterCo-morbidityMeanStandard deviationp-value
Serum creatinine {mg/dL (milligram per dL)}DMNo1.251.260.220
Yes1.741.74
HTNNo1.020.910.061
Yes1.631.63
IHDNo1.321.340.257
Yes2.252.35
CKDNo1.090.92<0.001
Yes4.991.55
Serum urea {mg/dL (milligram per dL)}DMNo34.4121.150.009
Yes56.9449.83
HTNNo30.2518.380.024
Yes46.7536.81
IHDNo38.6530.420.319
Yes57.0046.03
CKDNo33.3419.78<0.001
Yes120.8041.06

DM: Diabetes mellitus; HTN: Hypertension; IHD: Ischemic heart disease; CKD: Chronic kidney disease


However, none of the patients had any clinical complications due to change in electrolytes or renal parameters. None of the patients needed any corrective measures to treat the dyselectrolytemias or altered renal function.

Local Complications with Mannitol Therapy

The complications observed, following the mannitol therapy in the study population were-Intravenous block (2.8%), Thrombophlebitis (1.4%) and limb swelling (5.6%).

Intravenous block and limb swelling were treated with Glycerin-Magnesium sulfate dressing, followed by changing of Cannula site. Thrombophlebitis was treated with analgesics and local application of Benzyl nicotinate and Heparin ointment.

Discussion

The present study tried to correlate cumulative mannitol dose with short term fluctuations in serum electrolytes and renal parameters in patients suffering from acute stroke. All the patients received cumulative mannitol dose of equal to or less than 1 gm/kg/day.

The present study found that serum sodium levels were statistically significantly lower from admission to fifth day on mannitol therapy, however clinically there was no significant hyponatremic episodes needing correction. The reduction in sodium may occur due to mannitol being an osmotic diuretic, which increases urinary excretion of sodium. Reduction in sodium levels on mannitol therapy has also been observed in multiple other studies [16,17,29]. There was no significant change seen in other serum electrolyte levels on mannitol therapy and there was also no significant correlation between cumulative dose of mannitol and electrolyte changes. Hence, low dose mannitol therapy does not produce clinically significant electrolyte changes during acute stroke treatment.

The present study found a significant correlation between fluctuation of serum sodium levels with cumulative mannitol dose in patients with Diabetes. Serum sodium levels in patients with diabetes receiving mannitol therapy tended to be slightly higher than that of other patients. Hypernatremia is described as a complication associated with diabetes [34]. However, a literature search did not reveal any study correlating mannitol therapy in diabetics to hypernatremia.

The present study also showed an increase in serum potassium levels with cumulative mannitol dose in patients with diabetes and CKD. A study done by Nicolis GL et al., also shows significant correlation of change in potassium levels in diabetes patients causing glucose-induced hyperkalemia [35]. Hyperkalemia in CKD patients is likely due to insufficient clearance of mannitol from circulation leading to increased tubular reabsorption of potassium [14]. The present study shows that although electrolyte fluctuations tend to occur during mannitol therapy especially in diabetics and CKD patients, low dose mannitol therapy appears to be relatively safe.

Although serum urea and creatinine levels were higher in CKD patients and diabetics along with serum urea levels being higher in diabetic patients after receiving mannitol, it did not translate to clinically significant renal dysfunction. Mannitol is found to have both renal damaging [17] and renal protective [18] properties in literature. With regards to renal functions, the present study showed low dose mannitol therapy did not affect renal parameters in the short term.

The present study also shows that complications arising due to Intravenous mannitol therapy are relatively uncommon with limb swelling, Intravenous block and thrombophlebitis being encountered during the present study.

Limitation(s)

Due to the time bound nature, this study was conducted only on a small sample size of the population. Treatment with mannitol therapy was not standardised and hence uniformity in administration of dosage was not maintained. Other co-morbidities such as infections, systemic illnesses, nephrotoxic drugs and administration of other drugs were not taken into consideration. The interval of measurement of electrolytes was not strictly standardised.

Conclusion(s)

The present study findings showed that low dose mannitol therapy of less than 1 gm/kg/day is relatively safe and does not produce clinically significant electrolyte disturbance or renal dysfunction in acute stroke patients. However, monitoring of serum sodium, potassium and renal function may be useful in patients with comorbidities such as diabetes and CKD.

Further studies with a larger study population with standardised administration of dosage of mannitol and interval of measurement of electrolytes, urea and creatinine would be needed to further elucidate the relationship.

Declaration: Part of this study was presented as an E-poster titled “Complications of mannitol therapy in patients with acute stroke-A prospective observational study” in European Academy of Neurology Virtual Congress held on 23-27th May 2020.

References

[1]Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T, Cerebrovascular disease in the community: Results of a WHO collaborative study Bull World Health Organ 1980 58(1):113-130.  [Google Scholar]

[2]Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the Global Burden of Disease Study 2015 The lancet 2016 388(10053):1459-544.10.1016/S0140-6736(16)31012-1  [Google Scholar]  [CrossRef]

[3]Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Disability-Adjusted Life Years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010 The lancet 2012 380(9859):2197-223.10.1016/S0140-6736(12)61689-4  [Google Scholar]  [CrossRef]

[4]Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Global and regional burden of stroke during 1990-2010: Findings from the Global Burden of Disease Study 2010 The Lancet 2014 383(9913):245-55.10.1016/S0140-6736(13)61953-4  [Google Scholar]  [CrossRef]

[5]Strong K, Mathers C, Bonita R, Preventing stroke: Saving lives around the world Lancet Neurol 2007 6(2):182-87.10.1016/S1474-4422(07)70031-5  [Google Scholar]  [CrossRef]

[6]Dostovic Z, Dostovic E, Smajlovic D, Ibrahimagic OC, Avdic L, Brain edema after ischaemic stroke Med Arch 2016 70(5):339-41.10.5455/medarh.2016.70.339-34127994292  [Google Scholar]  [CrossRef]  [PubMed]

[7]Battey TW, Karki M, Singhal AB, Wu O, Sadaghiani S, Campbell BC, Brain edema predicts outcome after nonlacunar ischemic stroke Stroke 2014 45(12):3643-48.10.1161/STROKEAHA.114.00688425336512  [Google Scholar]  [CrossRef]  [PubMed]

[8]Kasner SE, Demchuk AM, Berrouschot J, Schmutzhard E, Harms L, Verro P, Predictors of fatal brain edema in massive hemispheric ischemic stroke Stroke 2001 32(9):2117-23.10.1161/hs0901.09571911546905  [Google Scholar]  [CrossRef]  [PubMed]

[9]Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R, ‘Malignant’ middle cerebral artery territory infarction: Clinical course and prognostic signs Arch Neurol 1996 53(4):309-15.10.1001/archneur.1996.005500400370128929152  [Google Scholar]  [CrossRef]  [PubMed]

[10]Pollay M, Blood-Brain Barrier, Cerebral Edema. In: Wilkins RH, Rengachary SS, editors Neurosurgery 1996 2nd edNew YorkMcGraw Hill Book Co:335-44.  [Google Scholar]

[11]Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner SE, Kimberly WT, Recommendations for the management of cerebral and cerebellar infarction with swelling: A statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2014 45(4):1222-38.10.1161/01.str.0000441965.15164.d624481970  [Google Scholar]  [CrossRef]  [PubMed]

[12]Michinaga S, Koyama Y, Pathogenesis of brain edema and investigation into anti-edema drugs International Journal of Molecular Sciences 2015 16(5):9949-75.10.3390/ijms1605994925941935  [Google Scholar]  [CrossRef]  [PubMed]

[13]Bardutzky J, Schwab S, Antiedema therapy in ischemic stroke Stroke 2007 38(11):3084-94.10.1161/STROKEAHA.107.49019317901384  [Google Scholar]  [CrossRef]  [PubMed]

[14]Manninen PH, Lam AM, Gelb AW, Brown SC, The effect of high-dose mannitol on serum and urine electrolytes and osmolality in neurosurgical patients Can J Anaesth 1987 34(5):442-46.10.1007/BF030143453117392  [Google Scholar]  [CrossRef]  [PubMed]

[15]Hemphill JC, Beal MF, Gress DR, Critical care in neurology. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors Harrison’s Principles of Internal Medicine 2001 15th edNew YorkMcGraw Hill:2491-98.  [Google Scholar]

[16]Rautaray SS, Sarkar PD, Agrawal BK, Study of the effect of mannitol on serum electrolytes before and after three days in stroke patients Biomedical Research 2008 19(3):177-80.  [Google Scholar]

[17]Hinson HE, Stein D, Sheth KN, Hypertonic saline and mannitol therapy in critical care neurology Journal of Intensive Care Medicine 2013 28(1):03-11.10.1177/088506661140068821436162  [Google Scholar]  [CrossRef]  [PubMed]

[18]Shawkat H, Westwood MM, Mortimer A, Mannitol: A review of its clinical uses Continuing Education in Anaesthesia, Critical Care & Pain 2012 12(2):82-85.10.1093/bjaceaccp/mkr063  [Google Scholar]  [CrossRef]

[19]Pradhan B, Majhi C, Panigrahi SK, Clinical profiles, electrolytes status in acute strokes and their outcome Int J Adv Med 2018 5(3):492-97.10.18203/2349-3933.ijam20181446  [Google Scholar]  [CrossRef]

[20]Kumar BP, Scandashree K, Udaykumar P, Study of drugs used in cerebral edema in patients with stroke at a tertiary care center Natl J Physiol Pharm Pharmacol 2017 7(2):151-54.10.5455/njppp.2017.7.0824619082016  [Google Scholar]  [CrossRef]

[21]Lin SY, Tang SC, Tsai LK, Yeh SJ, Shen LJ, Wu FL, Incidence and risk factors for acute kidney injury following mannitol infusion in patients with acute stroke: A retrospective cohort study Medicine 2015 94(47):e203210.1097/MD.000000000000203226632702  [Google Scholar]  [CrossRef]  [PubMed]

[22]Fiaccadori E, Delsante M, Fani F, Regolisti G, Acute kidney injury and stroke: Unresolved issues Internal and Emergency Medicine 2018 13(1):13-15.10.1007/s11739-017-1742-528864910  [Google Scholar]  [CrossRef]  [PubMed]

[23]Visweswaran P, Massin EK, Dubose TD, Mannitol-induced acute renal failure J Am Soc Nephrol 1997 8(6):1028-33.  [Google Scholar]

[24]Rimal J, Pisklakov SV, Boules H, Patel A, Acute hyperkalemia and hyponatremia following intraoperative mannitol administration J Anesth Clin Res 2013 4(3):294https://doi.org/10.4172/2155-6148.100029410.4172/2155-6148.1000294  [Google Scholar]  [CrossRef]

[25]Ong CJ, Keyrouz SG, Diringer MN, The role of osmotic therapy in hemispheric stroke Neurocrit Care 2015 23(2):285-91.10.1007/s12028-015-0173-226130406  [Google Scholar]  [CrossRef]  [PubMed]

[26]Cancer G, Gipstein RM, Boyle JD, Hypernatremia complicating prolonged mannitol diuresis N Engl J Med 1965 272(21):1116-17.10.1056/NEJM19650527272210914281557  [Google Scholar]  [CrossRef]  [PubMed]

[27]Oster JR, Singer I, Hyponatremia, hyposmolality, and hypotonicity: Tables and fables Arch Intern Med 1999 159(4):333-36.10.1001/archinte.159.4.33310030305  [Google Scholar]  [CrossRef]  [PubMed]

[28]Diringer MN, Scalfani MT, Zazulia AR, Videen TO, Dhar R, Cerebral hemodynamic and metabolic effects of equi-osmolar doses mannitol and 23.4% saline in patients with edema following large ischemic stroke Neurocrit Care 2011 14(1):11-17.10.1007/s12028-010-9465-821042881  [Google Scholar]  [CrossRef]  [PubMed]

[29]Keyrouz SG, Dhar R, Diringer MN, Variation in osmotic response to sustained mannitol administration Neurocrit Care 2008 9(2):204-09.10.1007/s12028-008-9118-318563637  [Google Scholar]  [CrossRef]  [PubMed]

[30]Hong LI, Chen L, Chen J, Study on the effects of two different routes of intravenous administration on mannitol induced phlebitis Chinese Journal of Biochemical Pharmaceutics 2017 37(8):202-03.  [Google Scholar]

[31]Erickson BA, Yap RL, Pazona JF, Hartigan BJ, Smith ND, Mannitol extravasation during partial nephrectomy leading to forearm compartment syndrome Int Braz J Urol 2007 33(1):68-71.10.1590/S1677-5538200700010001017335600  [Google Scholar]  [CrossRef]  [PubMed]

[32]Edwards JJ, Samuels D, Fu ES, Forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia Anesth Analg 2003 96(1):245-46.10.1213/00000539-200301000-00049  [Google Scholar]  [CrossRef]

[33]Torre-Healy A, Marko NF, Weil RJ, Hyperosmolar therapy for intracranial hypertension Neurocritical Care 2012 17(1):117-30.10.1007/s12028-011-9649-x22090171  [Google Scholar]  [CrossRef]  [PubMed]

[34]Blas-Macedo J, Blas-Soto V, Hypernatremia in hyperosmolar hyperglycemic syndrome Revista Médica del Instituto Mexicano del Seguro Social 2011 49(3):335-37.  [Google Scholar]

[35]Nicolis GL, Kahn T, Sanchez A, Gabrilove JL, Glucose-induced hyperkalemia in diabetic subjects Arch Intern Med 1981 141(1):49-53.10.1001/archinte.1981.003400100450127447584  [Google Scholar]  [CrossRef]  [PubMed]