Cerebral oedema is a common cause of unconsciousness and various manifestation in Cerebrovascular accident, head injury, convulsive disorder and encephalitis either due to infection or toxin due to failure of energy dependant Sodium Potassium ATPase pump resulting accumulation of sodium and water in addition 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 oedema of varied origin.

Material & method: In this study 1171 patients of cerebral oedema of various aetiology attending Medical Emergency of RA Hospital & Research Centre, Warisaliganj (Nawada) Bihar been selected for comparative evaluation of Mannitol (10%) with Glycerol (10%) versus Mannitol (20%) intravenously to adjudge the clinical efficacy and safety profile.

Result: Patients of Group A taking Mannitol (10%) with Glycerol (10%) had grade I clinical response in % 9584/586) without any adversity, residual neurological deficit or mortality and morbidity while patients of Group B on Mannitol (20%) only % (108/585) with 92 mortality and morbidity in 279 cases.

Keywords: cerebral oedema, cerebrovascular accident, sodium potassium ATPase pump, free radicals, proteases, mortality, morbidity

Cerebral oedema is a common sequel of cerebro vascular accident (CVA), Head injury, convulsive disorder and infective or toxic involvement of brain. Cerebral oedema pathogenesis at cellular level is complex as - damaged cells swell, injured blood vessels leak and blocked absorption pathways force fluid to enter brain tissues. Cellular and blood vessel damage activate an injury cascade i.e.-release of glutamate into the extracellular space opens Calcium and sodium entry channels on cell membranes. Membrane ATPase pumps releases one calcium ion in exchange for 3 sodium ions which create an osmotic gradient promoting increase water entry to cells and causes dysfunction but not necessarily permanent damage. Ultimately hypoxia depletes the cells’ energy stores and disables the sodium – potassium ATPase reducing calcium exchange.^1­–3

Failure of the energy-dependent sodium pump in the cellular membrane causes accumulation of Sodium and water to the intracellular space to maintain osmotic gradient while accumulation of Calcium inside the cell activate intracellular cytotoxic processes. Formation of genes like c-foc and c-jun and cytokines and other intermediary substances initiate inflammatory response. Activation of Microglial cells releases free radicals and proteases attacks on cell membranes and capillaries which results in the cells recovery impossible.^4–7

In addition negligent and lack of proper restriction, investigation and health care counselling and education, people suffer with dreaded sequel of hypertension i.e.- Cerebrovascular accident results in unconscious, convulsion, paralysis and coma which modify the outcome of the disease and increases the mortality. To overcome the brain oedema, the commonly prescribed urgent measure remains intravenous mannitol and oxygen inhalation. Usually Oral glycerol remains the choice to relieve brain oedema. Considering the clinical effect of oral glycerol and availability of Mannitol 10% with Glycerol 10%, a clinical study was conducted to evaluate the clinical effect and safety profile of 10% glycerol with 10% mannitol versus Mannitol 20% in management of cerebral oedema of either origin.

To adjudge the clinical efficacy of Mannitol 10% with Glycerol 10% versus Mannitol 20% in management of cerebral oedema of varied origin.

Comparative clinical study.

Material

Patients of cerebral oedema of either origin attending at RA. Hospital & Research Centre Emergency were selected for evaluation of Mannitol (10%) with Glycerol (10%) versus conventional Mannitol 20% therapy.

Methods

Parent or attendants of the admitted patients were thoroughly interrogated for the presenting feature onset, its duration, treatment taken and their outcome, any history of such attacks in past. All the patients were examined for their blood pressure, temperature, any marks of injury over the head, blood sugar, and sample collected for other vital parameters assessment. Patients were classified in to two groups comprising equal number of patients i.e.-

 All the patients irrespective of their cause of unconsciousness Or cerebral oedema were advocated

1. Oxygen inhalation.
2. Specific treatment (Anti hypertensive measure for hypertension, anti diabetic measure for diabetes mellitus,)
3. IV nutrition.
4. IV chemoprophylaxis.
5. Other desired measures as per need (anti convulsant for convulsion).
6. Diazepam administration is duly restricted.

While group a patients were given Mannitol 10% and glycerol 10% (Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism. In doses of 0.25‐2.0g/kg glycerol) Intravenous and group B Mannitol 20%. (Mannitol in a dose of 1.5g/kg body weight was infused over a period of 15minutes, followed by 0.5g/kg body weight every 8hours until the patient regained consciousness or for a maximum period of 72hours.)

Patients were assessed as per following index of assessment i.e.

Index of assessment

1. Recovery time from unconsciousness
2. Status of paralysis
3. Neural recovery
4. Status of alertness
5. Status of speech
6. Mental capability
7. Motor power and tone
8. Effect on various bio parameters

Post therapy sequel

9. Polyuria
10. Polydipsia
11. Irritability
12. Pulmonarycongestion
13. Fluid and electrolyteimbalance
14. Acidosis
15. Electrolyte loss
16. Dryness of mouth, thirst
17. Marked diuresis
18. Urinaryretention
19. Oedema,
20. Headache
21. Blurred vision
22. Convulsions 
23. Nausea
24. Vomiting
25. Hypotension
26. Tachycardia

To assess the safety profile of the administered drug the basic bio parameters i.e. haematological, hepatic and renal profile are repeated. On the basis of clinical achievement clinical response was graded as

Grade I: Complete recovery from unconsciousness within 6hrs no convulsion, recovery from paralysis (motor power and Tone) without any adversity and residual neuropsychiatric presentation or change in bio parameters.

Grade II: Complete recovery from unconsciousness within 12hours no convulsion, recovery from paralysis (motor power and tone) without any adversity and residual neuropsychiatric presentation or change in bio parameters.

Grade III: Improvement in unconsciousness, complete recovery in >48hrs, Occasional convulsion, improvement in power and tone, presence of adversity like polyuria, polydipsia, hypotension, tachycardia, blurred vision, post therapy urinary retention,  marked change in bio parameters.

Among the admitted 1171 patients of cerebral oedema 797 (68%) and 374(32%) respectively were of male and female respectively. Majority patients ( ) were of age >50years though 14 cases were of age 10-15years (Table 1 & Figure 1).

Figure 1 Pie diagram showing sex wise composition of patients.

Out of all majority 630 (53.8%) were of CVA, 361 (30.8%) were of convulsive disorder while 108(9.2% were of head injury (Table 2). Among the selected patients 77.2% were hypertensive out of which 9.3% were with malignant hypertension (average >160) (T-3) and 75.5% were diabetic out of which 11.1% were with random blood sugar >400mg% (T-4). All admitted cases were unconscious, 36.9% were presenting with convulsion and 53.8% with hemiplegia (T-5). 67.3% patients been admitted within 24hrs of incident while rest after 24hrs (Figure 2) among the patients 704 known hypertensive and 590 known diabetic were not taking any drug while no history been elucidated in 287 cases (T-6). Among the selected patients 183 were addict to all types of narcotics while 355 were having no history of any personal habits (T-7), 865 were pure vegetarian while rest were non vegetarian (Figure 3).

Figure 2 Bar diagram showing lag period.

Figure 3 Bar diagram showing dietary status.

Patients of group A had complete recovery from unconsciousness by 4hrs while group B patients taken >12hrs and 92 patients fails to revive and succumb. Out of all 536 patients of group A achieved normal CNS function without any residual paralysis, improved general condition and normal life status grade I response in 534 without any adversity or alteration in bio parameters while in group B only 212 patients regained power and tone, improved general condition in 108, normal life status 112, altered CNS function in 132 with residual paralysis in 147grade I clinical response in only 108 with altered bio parameters in 24 cases (Tables 3–8) (Figure 4).

Figure 4 Showing schematic presentation of outcome.

584/586 Patients of Cerebral oedema on Mannitol 10% with Glycerol 10% intravenously had early regain of consciousness and recovery of power, tone, memory and IQ without any adversity or residual neuro deficit than Mannitol 20% which had grade I clinical response in only 108/585 morbidity in 279585 mortality 92/585 with altered neurological function.

On injury or ischemia of Central nervous system CNS mediators like Glutamate, free fatty acid or high extracellular potassium compounds are released or activated resulting in swelling and damage of nerve cells. In addition substances like histamine, arachidonic acid and free radicals including nitrous oxide are also known mediators causing cerbral oedema. Bradykinin may be involved after cold lesion, concussive brain injury, traumatic spinal cord and ischemic brain injury.^8,9

In stroke cerebral ischaemia causes loss of membrane ionic pumps and cell swelling while irreversible cell membrane damage is caused by generation of free radicals and proteases. As per Monro-Kelie hypothesis, change in the volume of any of the three content of skull (inside the skull) i.e. brain – 1400ml, cerebral spinal fluid (CSF) 150 ml and blood 150ml change the volume of other Conversely, primary blood flow disturbances also lead to brain oedema.^10–12

Significant supremacy of Mannitol 0% with Glycerol 10% as compared to Mannitol 20% can be explained as -Mannitol is an isomer of sorbitol, administered intravenously confined to the extracellular space, only slightly metabolized and rapidly excreted by the kidney. Approximately 80% of a 100 g dose appears in the urine in 3hours. The drug is freely filtered by the glomeruli with less than 10% tubular re absorption; it is not secreted by tubular cells and induces diuresis by elevating the osmolarity of the glomerular filtrate.^13–15 Mannitol is used to reduce acutely raised intracranial pressure until more definitive treatment can be applied, e.g., after head trauma.^16,17

Such solutions are effective not only in lowering the intracranial pressure, but also in improving the cerebral blood flow and metabolism. Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism. In doses of 0.25‐2.0g/kg glycerol decreases intracranial pressure in various disease state however, intravenous doses of 1–2g/kg every 2hr can be administered safely in severe cases of elevated ICP. Thus combination of Mannitol and Glycerol decreases the dose of mannitol thus its side effects like diuresis and asthenia in addition Glycerol helps in neural recovery and sustained resolution of cerebral oedema thus ensure prompt recovery of CNS function without alteration in mental capability and IQ Or residual paresis.^18–22

Mannitol 10% with Glycerol 10% proves better than Mannitol 20% as it spares dose of mannitol and protect from mannitol overdose adversity with better CNS bio regulation without any residual neurodificit.

None.

The authors declare that there are no conflicts of interest.

None.

1. Rosenberg GA. Brain edema and disorders of cerebrospinal fluid circulation. In: Bradley WG, Daroff RB, Ferichel GM, Marsden CD, editors. Neurology in clinical practice. 2^nd Boston, USA: Butterworth Heinmann; 2000. p. 1545–1559
2. 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. 15^th New York: Mc Graw Hill; 200. p. 2491–2498.
3. Schilling L, Wahl M. Mediators of cerebral edema. Adv Exp Med Biol. 1999;474:123–141.
4. Rosenberg GA. Ischemic brain edema. Prog cardiovasc Dis. 1999;42(3):209–216.
5. Murr R, Berger S, Schurer L, et al. Relationship of cerebral blood flow disturbances with brain oedema formation. Acta Neurochir Suppl (Wien). 1993;59:11–17.
6. Biller J, Bruno A. Acute ischaemic stroke. In: Johnson RT, Griffin JW, editors. Current Therapy in Neurologic Disease. 5th edn. St Louis: Mosby; 1997. p. 191–197.
7. Cerebrovascular diseases. In: Victor M, Ropper AH, editor. Principles of Neurology. 7^th New York, USA: Mc Graw Hill; 200. p. 821–924.
8. Davis M, Lucatorto M. Mannitol revisited. J Neurosci Nurs. 1994;26(3):170–174.
9. North B, Reilly P. Raised intracranial pressure – a clinical guide. 1^st USA: Oxford, Heinemann Medical Books; 1990. p. 71–85.
10. de los Reyes RA, Ausman JI, Dias FG. Agents for cerebral edema. Clin Neurosurg. 1981;28:98–107.
11. Richling B. Current status of treatment of cerebral edema. Anaesthesist. 1987;36(5):191–196
12. Berger J, Levy RM. Infection of the nervous system. In: Grotta JC, editor. Management of acutely ill neurological patient. New York, USA: Churchill Livingstone; 1993. p. 135–153.
13. Bennett JE. Cryptococcosis. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s Principles of Internal Medicine. 15^th New York, USA: Mc Graw Hill, 2001. p. 1174–1175.
14. Meyer J S, Fukuuchi Y, Shimazu K, et al. Effect of intravenous infusion of glycerol on hemispheric blood flow and metabolism in patients with acute cerebral infarction. Stroke. 1972;3(2):168–185.
15. Meyer JS, Ito Y, Okamoto N, et al. Circulatory and metabolic effects of glycerol infusion in patients with recent cerebral infarction. Circulation. 1975;51(4):701–712.
16. Cantore G, Guidetti B, Virno M. Oral glycerol for the reduction of in tracranial pressure. J Neurosurg. 1964;21:278–283.
17. Buckell M, Walsh L. Effect of glycerol by mouth on raised intracranialpressure in man. Lancet. 1964;2(7370):1151–1152.
18. Meyer JS, Charney JZ, Rivera VM, et al. Treatment with glycerol of cerebral edema due to acute cerebral infarction. 1971;2(7732):993–997.
19. Newkirk TA, Tourtellotte WW, Reinglass JL. Prolonged control of increased intracranial pressure with glycerin. Arch Neurol. 1972;27(1):95–96.
20. Mathew NT, Rivera VM, Meyer JS, et al. Double–blind evaluation of glycerol therapy in acute cerebral infarction. Lance 1972;2(7791):1327–1329.
21. Reinglass JL. Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. Neurology. 1974;24(8):743–747.
22. Frithz G, Werner I. Effect of glycerol infusion in acute cerebral infarction. Acta Med Scand. 1975;198(4):287–289.