CLINICAL STUDY Indian Journal of Clinical Practice, Vol. 30, No. 5, October 2019 Clinical Efficacy of Mannitol 10% with Glycerol 10% versus Mannitol 20% in Cerebral Edema
AVINASH SHANKAR*, SHUBHAM†, AMRESH SHANKAR‡, ANURADHA SHANKAR#
Abstract Introduction: Cerebral edema is a common cause of unconsciousness and a manifestation in cerebrovascular accident, head injury, convulsive disorder and encephalitis, either due to infection or toxin. Failure of energy-dependent sodium-potassium ATPase pump, results in accumulation of sodium and water. The release of free radicals and proteases due to activation of microglial cells disrupts cell membrane and capillaries. Objective of the study: Comparative assessment of clinical efficacy of mannitol 10% with glycerol 10% versus mannitol 20% in cerebral edema of varied origin. Material and methods: In this study, 1171 patients of cerebral edema of various etiology attending Medical Emergency of RA Hospital & Research Centre, Warisaliganj (Nawada), Bihar, were selected for comparative evaluation of mannitol 10% with glycerol 10% versus mannitol 20% intravenously to adjudge the clinical efficacy and safety profile. Results: Patients of Group A taking mannitol 10% with glycerol 10% had Grade I clinical response in 584/586 without any adversity, residual neurological deficit or mortality and morbidity while among patients of Group B on mannitol 20%, only 108/585 had Grade I clinical response with mortality in 92 cases and morbidity in 279 cases. Keywords: Cerebral edema, cerebrovascular accident, sodium potassium ATPase pump, free radicals, proteases, mortality, morbidity
erebral edema is a common sequel of causes dysfunction but not necessarily permanent cerebrovascular accident (CVA), head injury, damage. Ultimately, hypoxia depletes the cells’ energy Cconvulsive disorder and infective or toxic stores and disables the sodium-potassium ATPase, involvement of brain. Cerebral edema pathogenesis reducing calcium exchange. at cellular level is complex as - damaged cells swell, Failure of the energy-dependent sodium pump in the injured blood vessels leak and blocked absorption cellular membrane causes accumulation of sodium and pathways force fluid to enter brain tissues. Cellular water into the intracellular space to maintain osmotic and blood vessel damage follows an injury cascade, i.e., gradient while accumulation of calcium inside the cell release of glutamate into the extracellular space opens activates intracellular cytotoxic processes. Formation calcium and sodium entry channels on cell membranes. of genes like c-foc and c-jun and cytokines and other Membrane ATPase pump releases one calcium ion in intermediary substances initiate inflammatory response. exchange for 3 sodium ions which creates an osmotic gradient promoting increased water entry to cells and Activation of microglial cells releases free radicals and proteases that attack cell membranes and capillaries, which results in the cell recovery impossible. In addition, due to negligent and lack of proper *Chairman, National Institute of Health & Research restrictions, investigations and health care counseling Institute of Applied Endocrinology and education, people suffer from dreaded sequel of Warisaliganj (Nawada), Bihar †Consultant Pediatrician, Delhi hypertension, i.e., CVA resulting in unconsciousness, ‡Hon Director, Aarogyam Punarjeevan, Patna, Bihar convulsion, paralysis and coma, which modify the #Senior Research Fellow Regional Institute of Ayurveda, Itanagar, Arunachal Pradesh outcome of the disease and increase the mortality. Address for correspondence Dr Avinash Shankar To overcome brain edema, the commonly prescribed Chairman, National Institute of Health & Research urgent measure remains intravenous mannitol and Institute of Applied Endocrinology Warisaliganj (Nawada), Bihar - 805 130 oxygen inhalation. Usually oral glycerol is also the E-mail: [email protected] choice to relieve brain edema.
452 IJCP Sutra: "Patients with pulmonary TB should be monitored by follow-up sputum microscopy at defined intervals." Indian Journal of Clinical Practice, Vol. 30, No. 5, October 2019 Clinical Study
Considering the clinical effect of oral glycerol and ÂÂ Specific treatment (antihypertensive measure for availability of mannitol 10% with glycerol 10%, a clinical hypertension, antidiabetic measure for diabetes study was conducted to evaluate the clinical effect and mellitus) safety profile of 10% glycerol with 10% mannitol versus ÂÂ IV nutrition mannitol 20% in the management of cerebral edema of ÂÂ IV chemoprophylaxis varied origin. ÂÂ Other desired measures as per need Objective of the Study (anticonvulsant for convulsion)
To adjudge the clinical efficacy of mannitol 10% with ÂÂ Diazepam administration was duly restricted. glycerol 10% versus mannitol 20% in the management While Group A patients were given mannitol 10% and of cerebral edema of varied origin. glycerol 10% (Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism in Study Design doses of 0.25‐2.0 g/kg glycerol) intravenous, Group B received mannitol 20%. Mannitol in a dose of 1.5 g/kg This was a comparative clinical study. body weight was infused over a period of 15 minutes, Material and Methods followed by 0.5 g/kg body weight every 8 hours until the patient regained consciousness or for a maximum Material period of 72 hours. Patients were assessed as per following index of Overall, 1171 patients of cerebral edema of varied origin assessment: attending RA Hospital & Research Centre Emergency were selected for evaluation of mannitol 10% with ÂÂ Recovery time from unconsciousness glycerol 10% versus conventional mannitol 20% therapy. ÂÂ Status of paralysis Methods ÂÂ Neural recovery zz Status of alertness Parents or attendants of the admitted patients were thoroughly interrogated for the presenting feature zz Status of speech onset, its duration, treatment taken and its outcome, zz Mental capability any history of such attacks in past. All the patients were zz Motor power and tone examined for their blood pressure, temperature, any marks of injury over the head, blood sugar and samples ÂÂ Effect on various bio-parameters were collected for other vital parameters assessment. ÂÂ Post-therapy sequel: Patients were classified into two groups comprising zz Polyuria equal number of patients (Table 1). zz Polydipsia All the patients, irrespective of their cause of zz Irritability unconsciousness or cerebral edema, were advocated: zz Pulmonary congestion ÂÂ Oxygen inhalation zz Fluid and electrolyte imbalance
Table 1. Distribution of Patients on the basis of Clinical zz Acidosis Status zz Electrolyte loss Clinical status Group A Group B zz Dryness of mouth, thirst Head injury 54 54 zz Marked diuresis Cerebrovascular accident 315 315 zz Urinary retention z Toxemia 5 5 z Edema zz Headache Febrile convulsion 5 5 zz Blurred vision Convulsive disorder 181 180 zz Convulsions Encephalitis 26 26 zz Nausea
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zz Vomiting Table 2. Number of Patients of Cerebral Edema zz Hypotension Age group Number of patients zz Tachycardia (years) Male Female Total To assess the safety profile of the administered drug, the basic bio-parameters, i.e., hematological, hepatic 10-15 09 05 14 and renal profile, were repeated. 15-20 11 07 18 On the basis of clinical achievement, clinical response 20-25 28 13 41 was graded as: 25-30 64 34 98 Grade I: Complete recovery from unconsciousness 30-35 58 26 84 within 6 hours. No convulsion, Recovery from paralysis (motor power and tone) without any adversity and 35-40 87 29 116 residual neuropsychiatric presentation or change in bio- 40-45 54 24 78 parameters. 45-50 58 30 88 Grade II: Complete recovery from unconsciousness within 12 hours. No convulsion, Recovery from 50-55 110 54 164 paralysis (motor power and tone) without any adversity 55-60 130 70 200 and residual neuropsychiatric presentation or change in bio-parameters >60 188 82 270 Grade III: Improvement in unconsciousness, complete Total 797 (68%) 374 (32%) 1,171 recovery in >48 hours. Occasional convulsion, improvement in power and tone, presence of adversity like polyuria, polydipsia, hypotension, tachycardia, Male Female blurred vision, post-therapy urinary retention, marked change in bio-parameters.
Observation and Results
Among the admitted 1,171 patients of cerebral edema, 374 797 (68%) and 374 (32%) were male and female, respectively. Majority of the patients were of age >50 years, though 14 cases were in the age group of 10‑15 years (Table 2 and Fig. 1). Out of all, majority had CVA (630 [53.8%]), 361 (30.8%) 797 had convulsive disorder while 108 (9.2%) had head injury (Table 3). Among the selected patients, 77.2% were hypertensive, out of which 9.3% had malignant hypertension (average >160) (Table 4); 75.5% were diabetic, out of which 10.7% had random blood sugar >400 mg% Figure 1. Pie diagram showing sex-wise distribution of (Table 5). patients. All admitted cases were unconscious, 36.9% presented Among the selected patients, 183 were addicted to all with convulsion and 53.8% with hemiplegia (Table 6). types of narcotics while 355 were having no history of In all, 67.3% patients had been admitted within any personal habits (Table 8); 865 were pure vegetarian 24 hours of incident while the rest after 24 hours while rest were nonvegetarian (Fig. 3). (Fig. 2). Of all the patients, 704 known hypertensives Patients of Group A had complete recovery from and 590 known diabetics were not taking any drug unconsciousness by 4 hours while Group B patients while no history had been elucidated in 287 cases took >12 hours and 92 patients failed to revive and (Table 7). succumbed.
454 IJCP Sutra: "Antiretroviral therapy (ART) must be offered to all patients with HIV and TB at the earliest." Indian Journal of Clinical Practice, Vol. 30, No. 5, October 2019 Clinical Study
Table 3. Distribution of Patients as per Causes of Table 6. Distribution of Patients as per Clinical Cerebral Edema Presentation
Causative factors Number of patients Clinical presentation Number of patients Percent (%) Head injury 108 Unconscious 1171 100 Cerebrovascular accident 630 Hemiplegia 630 53.8 Toxemia 10 Right side 139 22.06 Febrile convulsion 10 Left side 491 77.94 Convulsion 433 36.9 Convulsive disorder 361 Encephalitis 52 900 789 800 Table 4. Distribution of Patients as per Average Blood Pressure Recorded on Admission 700 600 Average blood Number of patients 500 pressure (mmHg) 382 Male Female Total 400
<120 152 115 267 patients of No. 300 130-135 74 46 120 200 100 135-140 74 39 113 0 140-145 91 38 129 <24 hours >24 hours 145-150 95 40 135 Lag period (hours)
150-155 101 57 158 Figure 2. Bar diagram showing lag period. 155-160 100 40 140 Table 7. Distribution of Patients as per Previous >160 80 29 109 History of Illness
Total 767 404 1171 History of previous illness Number of patients Hypertensive taking antihypertensive 296 Table 5. Distribution of Patients as per Random Blood Hypertensive never taken any drug 704 Sugar Status Known diabetic taking drugs 294 Random blood Number of patients sugar (mg%) Known diabetic not taking any drug 590 Male Female Total Unknown 287 <200 200 87 287 200-250 54 40 94 Table 8. Distribution of Patients Based on Their 250-300 166 84 250 Personal Habits 300-350 89 45 124 Personal habits Number of patients Alcoholic 302 350-400 223 68 291 Smoker 254 >400 75 50 125 Tobacco chewer 567 Cannabis smoker 165 All 586 patients of Group A achieved normal central Gutka 214 nervous system (CNS) function without any residual All types of narcotics 183 paralysis, improved general condition and normal life status with Grade I response in 584 without any No addictions 355
IJCP Sutra: "People living with HIV should be screened for TB." 455 Clinical Study Indian Journal of Clinical Practice, Vol. 30, No. 5, October 2019
Table 9. Outcome of the Study 1000 900 865 Particulars Number of patients 800 Group A Group B 700 600 Consciousness recovery time 4 hrs >12 hrs 500 Regain in power and tone All 212 400 306 No. of patients of No. 300 Improved general condition All 108 200 Quality-of-life 100 0 Normal 586 112 Vegetarian Nonvegetarian Mortality None 92 Dietary status CNS function Figure 3. Bar diagram showing dietary status. Normal 586 214 adversity or alteration in bio-parameters while in Altered None 132 Group B only 212 patients regained power and tone, Residual paralysis None 147 improved general condition was noted in 108, normal Safety profile life status was achieved in 112, altered CNS function Renal profile was noted in 132 with residual paralysis in 147, with Grade I clinical response in only 108 with altered Blood urea bio-parameters in 24 cases (Table 9 and Fig. 4). <26 mg 586 472 In all, 584 of the 586 patients of cerebral edema on >26 mg - 21 mannitol 10% with glycerol 10% intravenously had Serum creatinine early regain of consciousness and recovery of power, <1.5 mg 586 473 tone, memory and IQ without any adversity or residual >1.5 mg - 20 neurodeficit as compared to mannitol 20%, which led to Urine albumin Grade I clinical response in only 108/585, morbidity in 279/585 and mortality in 92/585 with altered neurological Positive None 24 function. Urine RBC Present None 20 Discussion Hepatic profile On injury or ischemia of CNS, mediators like glutamate, Serum bilirubin free fatty acid or high extracellular potassium compounds are released or activated, resulting in swelling and <1 mg 586 493 damage of nerve cells. In addition, substances like SGOT histamine, arachidonic acid and free radicals, including <35 IU 586 493 nitrous oxide, are also known mediators causing SGPT cerebral edema. Bradykinin may be involved after cold <35 IU 586 493 lesion, concussive brain injury, traumatic spinal cord and ischemic brain injury. Clinical grade In stroke, cerebral ischemia causes loss of membrane Grade I 584 108 ionic pumps and cell swelling while irreversible cell Grade II 02 106 membrane damage is caused by generation of free Grade III - 279 radicals and proteases. As per Monro-Kellie hypothesis, change in the volume and blood 150 mL - changes the volume of other. of any of the three content of skull (inside the skull) - Conversely, primary blood flow disturbances also lead i.e., brain 1400 mL, cerebral spinal fluid (CSF) 150 mL to brain edema.
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Thus, a combination of mannitol and glycerol decreases Enrolled (1,171) the dose of mannitol. Therefore, its side effects like diuresis and asthenia are reduced. In addition, glycerol helps in neural recovery and sustained resolution of CVA (630) Head Injury (108) Others (433) cerebral edema, thus ensuring prompt recovery of CNS function without alteration in mental capability and IQ or residual paresis. Mannitol (10%) + Glycerol (10%) (586) Conclusion
Mannitol 10% with glycerol 10% proves better than Survived (586) Dead (Nil) mannitol 20% as it spares dose of mannitol and protects from mannitol overdose adversity with better CNS bioregulation without any residual neurodeficit. Gr I Gr II Gr III (584) (02) (None) Suggested reading
1. Rosenberg GA. Brain edema and disorders of Mannitol (20%) (585) cerebrospinal fluid circulation. In: Bradley WG, Daroff RB, Ferichel GM, Marsden CD (Eds.). Neurology in Clinical Practice. Vol. 2, 3rd Edition, Boston: Butterworth-Heinemann; 2000. pp. 1545-59. Survived (493) Dead (92) 2. Hemphill JC, Beal MF, Gress DR. Critical care in neurology. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL (Eds.). Harrison's Gr I Gr II Gr III Principles of Internal Medicine. 15th Edition, New (108) (106) (279) York: McGraw‑Hill; 2001. pp. 2491-8. 3. Schilling L, Wahl M. Mediators of cerebral edema. Adv Figure 4. Schematic presentation of study outcomes. Exp Med Biol. 1999;474:123-41. Significant supremacy of mannitol 10% with glycerol 4. Rosenberg GA. Ischemic brain edema. Prog Cardiovasc 10% as compared to mannitol 20% can be explained as Dis. 1999;42(3):209-16. follows: 5. Murr R, Berger S, Schürer L, Kempski O, Staub F, Baethmann A. Relationship of cerebral blood flow Mannitol is an isomer of sorbitol. When administered disturbances with brain oedema formation. Acta intravenously confined to the extracellular space, it is Neurochir Suppl (Wien). 1993;59:11-7. only slightly metabolized and rapidly excreted by the 6. Biller J, Bruno A. Acute ischaemic stroke. In: Johnson kidney. Approximately 80% of a 100 g dose appears RT, Griffin JW (Eds.). Current Therapy in Neurologic in the urine in 3 hours. The drug is freely filtered by Disease. 5th Edition, St Louis: Mosby; 1997. pp. 191-7. the glomeruli with <10% tubular reabsorption; it is 7. Cerebrovascular diseases. Victor M, Ropper AH (Eds.) not secreted by tubular cells and induces diuresis by Principles of Neurology. 7th Edition, New York: elevating the osmolarity of the glomerular filtrate. McGraw-Hill; 2001. pp. 821-924. Mannitol is used to reduce acutely raised intracranial 8. Davis M, Lucatorto M. Mannitol revisited. J Neurosci pressure (ICP) until more definitive treatment can be Nurs. 1994;26(3):170-4. applied, e.g., after head trauma. 9. North B, Reilly P. Raised Intracranial Pressure - A Clinical Guide. 1st Edition, Oxford: Heinemann Such solutions are effective not only in lowering the Medical Books; 1990. pp. 71-85. ICP, but also in improving the cerebral blood flow and metabolism. 10. de los Reyes RA, Ausman JI, Diaz FG. Agents for cerebral edema. Clin Neurosurg. 1981;28:98-107. Glycerol is a potent osmotic dehydrating agent with 11. Richling B. Current status of treatment of the cerebral additional effects on brain metabolism. In doses of edema. Anaesthesist. 1987;36(5):191-6. 0.25‐2.0 g/kg, glycerol decreases ICP in various disease 12. Berger J, Levy RM. Infection of the nervous system. states; however, intravenous doses of 1-2 g/kg every In: Grotta JC (Eds.). Management of Acutely Ill 2 hour can be administered safely in severe cases of Neurological Patient. New York: Churchill Livingstone; elevated ICP. 1993. pp. 135-53.
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13. Bennett JE. Cryptococcosis. In: Braunwald E, Fauci AS, 18. Meyer JS, Charney JZ, Rivera VM, Mathew NT. Treatment Kasper DL, Hauser SL, Longo DL, Jameson JL (Eds.). with glycerol of cerebral oedema due to acute cerebral Harrison's Principles of Internal Medicine. 15th Edition, infarction. Lancet. 1971;2(7732):993-7. New York: McGraw-Hill; 2001. pp. 1174-5. 19. Newkirk TA, Tourtellotte WW, Reinglass JL. Prolonged 14. Meyer JS, Fukuuchi Y, Shimazu K, Ouchi T, Ericsson AD. control of increased intracranial pressure with glycerin. Effect of intravenous infusion of glycerol on hemispheric Arch Neurol. 1972;27(1):95-6. blood flow and metabolism in patients with acute cerebral infarction. Stroke. 1972;3(2):168-80. 20. Mathew NT, Rivera VM, Meyer JS, Charney JZ, Hartmann A. Double-blind evaluation of glycerol 15. Meyer JS, Itoh Y, Okamoto S, Welch KM, Mathew NT, therapy in acute cerebral infarction. Lancet. 1972;2(7791): Ott EO, et al. Circulatory and metabolic effects of glycerol infusion in patients with recent cerebral infarction. 1327-9. Circulation. 1975;51(4):701-12. 21. Reinglass JL. Dose response curve of intravenous glycerol 16. Cantore G, Guidetti B, Virno M. Oral glycerol for in the treatment of cerebral edema due to trauma. A case the reduction of intracranial pressure. J Neurosurg. report. Neurology. 1974;24(8):743-7. 1964;21:278-83. 22. Frithz G, Werner I. The effect of glycerol infusion in 17. Buckell M, Walsh L. Effect of glycerol by mouth on raised acute cerebral infarction. Acta Med Scand. 1975;198(4): intracranial pressure in man. Lancet. 1964;2(7370):1151-2. 287-9.
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Vast Progress in Reducing Rubella, but 3 in 10 Children Still Unprotected Against the Disease For the first time, more than half of all the world’s infants are protected against the debilitating rubella virus, according to a new study by the WHO and the US CDC. Worldwide, more than 80 countries have eliminated the disease. This progress has been achieved through broadening access to the safe and highly effective rubella vaccine – especially across lower-income countries. While there has been significant progress, 26 countries are yet to introduce the rubella vaccine, leaving 3 in 10 children globally without access. The greatest gaps persist in Africa… (WHO)
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458 IJCP Sutra: "Less than 6 years contacts of TB patients, should get INH for 6 months, after excluding active TB."