INTRODUCTION:

Increased intracranial pressure (ICP) is a common complication in patients coming for surgical treatments with intracranial space-occupying lesions. In order to obtain an acceptable operating condition, ICP must be lowered by physiological and pharmacological procedures. Mannitol is the most commonly used pharmacological medication to reduce intraoperative ICP [1]. An important anaesthetic objective is to create an intraoperatively relaxed brain with minimal effects on intracranial hemodynamics in order to ease tumor removal and enhance neurological prognosis. Physical and pharmacological treatments are used to manage perioperatively, increase in intracranial pressure (ICP) resulting from tumor mass. The administration of hyperosmolar therapeutic agent is an integral part of perioperative patient care. The ’gold standard’ for reducing ICP is 20% mannitol, however 3% hypertonic saline (HTS) and 8.4% sodium bicarbonate have proven to be efficacious with little systemic adverse effects [2, 3]. The creation of an osmotic gradient across the blood-brain barrier (BBB) by hyperosmolar treatment facilitates the transfer of fluid from the brain parenchyma to the intravascular compartment. By rheological impact, they may also improve micro-vascular circulation [4].

Mannitol generates a dose-dependent (0.25- 1 g/kg) drop in intracranial pressure (ICP) that is evident between 10 to 20 minutes of administration, peaks between 20 and 60 minutes, and lasts for four to six hours [5, 6]. Rapid administration of mannitol increases the risk of hypotension [7].

Hypertonic saline is available in 3%, 5%, 7.5%, and 23% concentrations. HTS does not penetrate the Blood Brain Barrier, produces an osmotic gradient, and enhances systemic hemodynamic. Weed and McKibben [8] initially advocated the clinical use of HTS for cerebral oedema. It developed as a resuscitation agent in patients with hemorrhagic shock and neurotrauma due to its early start, recognized end point of therapy (Na+145-155 mEq/l), intravascular volume restoration, decrease in intracranial pressure, and anti-inflammatory effect [9, 10].

Eight-point four percent sodium bicarbonate is used to treat acute metabolic acidosis and certain poisonings largely as an electrolyte replenisher and systemic alkalizer. [10] Unknown is the method of action of 8.4% sodium bicarbonate; however it functions via the same process of osmotic gradient formation across the BBB. Recent research has demonstrated sodium bicarbonate potential for reducing ICP in patients with traumatic brain injury (TBI). [11-13]

The primary objective of the present study is to compare the efficacy of 20% mannitol, 3% HS and 8.4% Sodium bicarbonate.

AIM AND OBJECTIVES

Aim:

·        To compare the effect of equimolar 3% Hypertonic Saline, 8.4 % Sodium bicarbonate and 20% Mannitol on Intracranial Pressure and metabolic changes in patient undergoing craniotomy for supratentorial tumor /mass excision.

Primary Objectives:

·        To compare the effect of equimolar 3% Hypertonic Saline, 8.4 % Sodium Bicarbonate and 20% mannitol on intracranial pressure (ICP).

Secondary Objectives:

To compare the following parameters between the groups:

·         Cerebral perfusion pressure (CPP)

·         Brain relaxation

·         Metabolic changes (ABG, Serum Osmolarity) and electrolytes
(Na⁺, K⁺, HCO₃, Cl^-)

·         Hemodynamic parameters Heart Rate (HR), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP), Central Venous Pressure (CVP).

·        The neurological outcome at the time of discharge of patient from the hospital (Extended Glasgow Outcome Scale (GOS-E).

·        Complications if any like Hypotension, hyponatremia, hypernatremia, hyperkalemia, hypokalaemia, etc.

MATERIAL AND METHODS

Study Setting:

•      The study will be conducted in Department of Anaesthesiology, King George’s Medical University, Lucknow in collaboration with Department of Neurosurgery, KGMU, Lucknow after getting clearance from the Institutional ethical committee, KGMU, Lucknow. 

Study Design: 

•      A Prospective Randomized Controlled Study.

•      SAMPLE SIZE: The sample size formulae used are as follows: (Bernard, 5th edition) (14)

                             n=

n= Sample size

σ = Standard Deviation

∆ = Difference of means

κ= Ratio

Z_1-α/2= Two-sided Z value

Z_1-β= Power

•      Inclusion Criteria:

o   Patient of either sex, Age group of 18-60 years

o   ASA Grade I and II

o   Elective Supratentorial Craniotomy  

•      Exclusion Criteria 

o   Patient refusal

o   Hyponatremia or Hypernatremia (Serum Na <130 or >150 mEq/L)

o   Pregnancy  

o   Cardiac dysfunction with dysrhythmia

o   Renal dysfunction

o   History of recent craniotomy/Head injury (<1year)

o   Active psychiatric or neurological disorders

Methodology:

After institutional ethics committee approval and informed patient consent, Total 120 patients of ASA I and II patients, of either sex and aged 18 to 60 years undergoing elective supratentorial craniotomy will be included in the study. Patients will be allocated into 3 groups using computer generated table of random number.

Group HS: 3% HTS (5.35 mL/kg)

Group SBC: 8.4% Sodium Bicarbonate (2.7 mL/kg)

Group M: 20% Mannitol (0.5 gm/kg)

All the patients will be reviewed night before surgery, and kept nil per oral night before surgery for at least eight hours for solid food and two hours for plain water before the planned surgery. Patients will be shifted to operation room (OR) and standard ASA monitoring like noninvasive blood pressure (NIBP), electrocardiogram (ECG) and pulse oximetry (SpO2) will be attached. Anesthesia induction will be achieved with intravenous (IV) fentanyl 1-2 µg/kg, and propofol 1.5-2.5 mg/kg, Trachea will be intubated after adequate muscle relaxation with vecuronium 0.08-0.1 mg/kg with appropriately sized cuffed endotracheal tube. Maintenance of anesthesia will be done with 60% air with 40% oxygen, 1.5–2.0% sevoflurane with desired MAC up to 0.8-1.0 along with continuous infusion of vecuronium @ 0.03 mg/kg/hour intravenously, supplemented with intravenous fentanyl 1.0 mcg/kg/hr. Patients will be ventilated with volume-controlled mode and end tidal carbon dioxide (ETCO2) will be maintained between 30 to 35 mm Hg. Two large bore intravenous catheter will be placed for fluid resuscitation, arterial catheter and CVC under USG guidance will be placed with standard technique and institutional protocol.

The patients will receive the study drugs as per group allocation. The infusions will be started at scalp incision and continued over a period of 30 minutes. A double blinding procedure will be followed for the conduct of the study. All the study drugs will be prepared by a person not involve in patient management and data collection. The anesthesiologist, the surgeon and the patient will be unaware of the group allotment. The neurosurgeon will visit the ICP catheter (Codman Microsensor Basic Kit, Johnson & Johnson Co.) through the first burr hole made for craniotomy after rising scalp flap. The catheter will be inserted into the subdural space for measurement of ICP and will be connected to ICP monitor (ICP express Codman, Johnson & Johnson profession inc.). The time of placement of ICP catheter will be marked as T_o and baseline will be noted and after this the ICP will be recorded every 15 minutes till the end of surgery.

Intracranial pressure (ICP) will be measure as per below formulae:

                                          Formula: ICP = ICP vascular + ICP CSF

Cerebral perfusion pressure (CPP) will be measured as per below formulae:

Formula: CPP = MAP – ICP

Where,

MAP = Mean arterial pressure.

ICP = Intra Cranial pressure.

Brain relaxation score will be assessed by the operating surgeon immediately on opening the duramater on a four-point scale (1=adequately relaxed, 2=satisfactorily relaxed, 3=firm brain, 4=bulging brain). If the surgeon will be not satisfied with brain relaxation on dural opening, additional bolus of half of the initial dose of the same study drug will be administered. Heart rate (HR), SBP, DBP, MAP, EtCo2, CVP, will be monitored continuously and recorded at the 15 minutes interval till end of surgery. Fluid intake, urine output and blood loss will be recorded at the interval of 1 hour till the end of surgery. ABG, serum electrolytes and osmolarity will be first recorded at the time of test drug infusion as base line value, and second reading will be noted at 30 minutes after first sample, then after it will be analyzed at the interval of 1 hour till the end of surgery. 

During intraoperative period, patient will be look for any complications like Hypotension, Hyponatremia, Hypernatremia, Hypokalemia, Hyperkalemia and will be treated accordingly.

At the end of surgery further course (extubation/postoperative ventilation) will be decided in consultation with surgeon and clinical status of patients. Patients not fulfilling the criteria for extubation will be shifted to Intensive Care Unit (ICU) for ventilation and delayed extubation, whereas others will be extubated after reversal of neuromuscular blockade with injection neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg) 

The patient will be followed till the discharge from the hospital and neurological outcome with extended Glasgow Outcome Scale will be recorded.

REVIEW OF LITERATURE

Rozet, I., et al., 2007 [16] conducted a prospective, randomized, double-blind study in which patients with American Society of Anesthesiologists physical status II–IV who were scheduled to undergo craniotomy for a variety of brain pathologies were enrolled. Patients were administered 5 ml/kg of 20% mannitol (n=20) or 3% HS (n = 20). There was no difference in brain relaxation (mannitol = 2, HS = 2 points; P = 0.8) or cerebral arteriovenous oxygen and lactate between the two groups. Compared to HS, mannitol increased urine output (P < 0.03) and was related with an increase in blood lactate (P < 0.001) over time. At 6 h, the osmolality of the cerebrospinal fluid increased in both groups (P < 0.05 versus baseline) HS increased the concentration of sodium in cerebrospinal fluid over time (P < 0.001) when compared to mannitol. They concluded that Mannitol and HS both cause an increase in cerebrospinal fluid osmolality and are linked with identical brain re-laxation scores as well as arteriovenous oxygen and lactate differences during craniotomy.

Hernández-Palazón et al 2016 [17] conducted a randomized, prospective, double-blind study, in which 60 patients undergoing elective supratentorial craniotomy were randomly assigned to receive either 3 ml/kg of 20% mannitol or 3% HS at a ratio of 1:1. There was no difference in brain relaxation [mannitol, 1(1–3) versus HS, 1(1.4) points; p 1⁄4 0.55]. Patients with brain midline shift had a poorer reaction to hyperosmolar solutions than those without midline shift: 37% versus 8%, respectively; odds ratio = 1⁄4 6.6 (95% CI= 1.54–28.3); p 1⁄4 0.006. During the 6-hour study period, plasma osmolality increased in both groups (p50.05 compared with baseline). There were no significant differences between the groups in terms of postoperative complications or length of ICU and hospital stay. Single doses of 3 ml/kg of 20% mannitol and 3% HS are safe and effective for intraoperative brain debulking during elective supratentorial craniotomy. However, these dosages are less successful in patients with preexisting mass effect and midline shift.

Sokhal, N et al., 2017 [18] conducted a study to compared the changes in ICP and systemic hemodynamics in patients having craniotomy for supratentorial tumours following infusion of equimolar solutions of both drugs in which forty adults were administered a normal anaesthetics induction. From time zero (T0) to one and a half hours (T90), arterial blood gas (ABG) was analyzed every 30 minutes and numerous data were recorded. Statistical techniques were utilised to analyses the data. Both mannitol and HS greatly decreased the ICP, and the levels were frequently comparable between the two groups. In both groups, brain relaxation scores were comparable. Using mannitol greatly increased urine production. In both groups, perioperative complications, total hospital stay, and Glasgow outcome score at discharge were comparable. They concluded that the effects of mannitol and hypertonic saline at equiosmolar concentrations on ICP reduction, cerebral relaxation, and systemic hemodynamics were comparable.

Ali, A., et al., 2018 [15] conducted a prospective, randomized, double-blind trial in which the patients scheduled to undergo supratentorial craniotomy were enrolled. The patients were observed for routine hemodynamic indicators, depth of anaesthesia, and intracranial pressure (ICP). They were given a 15-minute infusion of either 5 mL/kg of 20% mannitol (n=20) or 3% HS (n=19). The basal (before hypertonic infusion, ICPT0) and final (30 min after hypertonic infusion ended, ICPT45) ICP values for the M group were 13.7±3.0 and 9.5±1.9mmHg, respectively, compared to 14.2±2.8 and 8.7±1.1mmHg for the HS group (P>0.05). The median decrease in ICP from T0 to T45 was 4 (1 to 7) mmHg for group M and 5 (1 to 9) mmHg for group HS (P=0.035). Central venous pressure, pulse pressure variation, and serum sodium and lactate values were comparable between groups at baseline; however, the last recorded pulse pressure variation and lactate value were lower in group HS, and the sodium value was greater in group HS (P < 0.05). The length of hospital stays and stays in intensive care units were comparable between groups. During supratentorial brain tumour surgery, they concluded that 3% HS reduced ICP more effectively than 20% mannitol.

Fang, J., et al., 2018 [19] conducted this meta-analysis to compared the effectiveness of equimolar hypertonic saline and mannitol on intraoperative brain relaxation in patients having craniotomies. Nine RCTs with a total of 665 patients were identified and included. Compared to mannitol, there was a larger increase in the likelihood of intraoperative brain relaxation in the HS group (odds ratio (OR) 2.05, 95% confidence interval (CI) 1.40~3.01; P = 0.0002) Compared to HS, mannitol slightly decreased the central venous pressure (CVP) (mean difference (MD) 1.03, 95% confidence interval (CI) 0.03~2.03; P = 0.04) and significantly increased the diuretic effect regardless of the dosage of HS (standardised mean difference (SMD) 0.86, 95% confidence interval (CI) 1.35~−0.37; P = 0.0006). HS significantly increased plasma sodium concentration (MD 7.86, 95% CI 2.78 ~12.95, P = 0.002) but decreased intraoperative fluid consumption (SMD −0.56, 95% CI −0.98~−0.15, P = 0.008). However, neither plasma osmolality nor mean arterial pressure showed significant variations (MAP). In patients requiring craniotomies, the HS group appeared to provide superior brain relaxation without a substantial increase in urine output compared to the mannitol group.

Tsaousi, G. G et al., 2021 [20] conducted a study on 51 patients undergoing elective supratentorial craniotomy in which they receive either 7.5% HTS (2 mL/kg) or 20% mannitol (4.6 mL/kg) at scalp incision. Jugular bulb oxygen saturation and partial pressure of oxygen, arterial-jugular oxygen and carbon dioxide differences, and brain oxygen extraction ratio were positively affected by 7.5% HTS up to 240 minutes post infusion (P< 0.05), whereas mannitol was associated with only a brief (15-minute) improvement in these indices (P < 0.05). Changes in cerebral oxygenation correlated with temporary increases in intravascular volume and enhanced cardiovascular function. Increases in neuron-specific enolase and S100B at 6 and 12 hours after surgery were comparable between groups (P< 0.0001) They concluded that 7.5% HTS has a more positive effect on cerebral oxygenation than an equimolar dosage of 20% mannitol during supratentorial craniotomy, but neither solution indicated apparent clinical advantage.

Barik, A. K et al.,2021 [21] conducted a prospective study, in which 90 patients, of american Society of Anesthesiologists class I and ΙΙ with supratentorial tumour and scheduled for surgery were randomized into three groups to receive equimolar 20% mannitol (group 1), 3% hypertonic saline (group 2), and 8.4% sodium bicarbonate (group 3) prior to surgery for supratentorial tumour (group 3). The relaxation scores of groups 3 were substantially higher than those of groups 2 and 1, respectively. Compared to other groups, patients in group 1 had lower mean blood pressure and central venous pressure, as well as higher urine output and fluid intake. Compared to groups 1 and 2, group 3 patients had significantly higher pH, bicarbonate, partial pressure of carbon dioxide, serum sodium, and serum osmolarity values. Infusion of 8.4% sodium bicarbonate solution was related with superior intraoperative brain relaxation ratings and enhanced haemodynamic stability compared to 3% hypertonic saline solution and 20% mannitol.

REFERENCES

1.                  The brain trauma foundation. The american association of neurological surgeons. The joint section on neurotrauma and critical care. initial management. J Neurotrauma 2000;17:463–9.

2.                  VilasBoas WW, MarquesMB, alvesa. Hydroelectrolytic balance and cerebral relaxation with hypertonic isoncotic sa- line versus mannitol (20%) during elective neuroanesthesia. rev Bras anestesiol 2011;61:456–68.

3.                  Zeiler Fa, sader N, West M, gillman lM. sodium Bicarbonate for control of icP: a systematic review. J Neurosurg anesthesiol 2018;30:2–9.

4.                  Sharmas, grover VK, Mathew PJ. Mannitol versus hypertonic saline for intra-operative brain relaxation during aneu- rysm surgery. J Neuroanaesth crit care 2015;2:23.

5.                  eldahab Ha, awad W, Wagh o. should hypertonic saline 3% replace mannitol 20% for reduction of intracranial pres- sure in craniotomy for supratentorial tumors? a comparative study. egypt J anaesth 2009;25:413–28.

6.                  Witherspoon B, ashby Ne. the use of mannitol and hy- pertonic saline therapies in patients with elevated intracranial pressure: a review of the evidence. Nurs clin North am 2017;52:249–60.

7.                  White H, cook D, Venkatesh B. the use of hypertonic saline for treating intracranial hypertension after traumatic brain injury. anesthanalg 2006;102:1836–46.

8.                  Weed lH, McKibben Ps. experimental alteration of brain bulk. american J Physiology-legacy content 1919;48:531–58.

9.                  Perez ca, Figueroa sa. complication rates of 3% hyper- tonic saline infusion through peripheral intravenous access. J Neurosci Nurs 2017;49:191–5.

10.             Suranis, lockwoodg, MaciasMY, guntupalliB, VaronJ. Hypertonic saline in elevated intracranial pressure: past, present, and future. J intensive care Med 2015;30:8–12.

11.             Mirrakhimov AE, Ayach T, Barbaryan A, Talari G, Chadha R, Gray A. The role of sodium bicarbonate in the management of some toxic ingestions. Int J Nephrol 2017;2017:7831358. PubMed https://doi.org/10.1155/2017/7831358

12.             Wu CT, Chen LC, Kuo CP, Ju DT, Borel CO, Cherng CH, et al. A comparison of 3% hypertonic saline and mannitol for brain relaxation during elective supratentorial brain tumor surgery. Anesth Analg 2010;110:903–7. PubMed https://doi.org/10.1213/ANE.0b013e3181cb3f8b

13.             Bourdeaux C, Brown J. Sodium bicarbonate lowers intracranial pressure after traumatic brain injury. Neurocrit Care 2010;13:24–8. PubMed https://doi.org/10.1007/s12028-010-9368-8.

14.              Bernard Rosner. Fundamentals of Biostatistics (5th edition). (Based on equation 8.27) pg.238

15.              Ali A, Tetik A, Sabanci PA, Altun D, Sivrikoz N, Abdullah T, Aydoseli A, Sencer A, Akinci IO. Comparison of 3% hypertonic saline and 20% mannitol for reducing intracranial pressure in patients undergoing supratentorial brain tumor surgery: a randomized, double-blind clinical trial. Journal of Neurosurgical Anesthesiology. 2018 Apr 1;30(2):171-8.

16.             Rozet, I., Tontisirin, N., Muangman, S., Vavilala, M. S., Souter, M. J., Lee, L. A., ... & Lam, A. M. (2007). Effect of equiosmolar solutions of mannitol versus hypertonic saline on intraoperative brain relaxation and electrolyte balance. The Journal of the American Society of Anesthesiologists, 107(5), 697-704.

17.             Hernández-Palazón, J., Fuentes-García, D., Doménech-Asensi, P., Piqueras-Pérez, C., Falcón-Araña, L., & Burguillos-López, S. (2016). A comparison of equivolume, equiosmolar solutions of hypertonic saline and mannitol for brain relaxation during elective supratentorial craniotomy. British Journal of Neurosurgery, 30(1), 70-75.

18.             Sokhal, N., Rath, G. P., Chaturvedi, A., Singh, M., & Dash, H. H. (2017). Comparison of 20% mannitol and 3% hypertonic saline on intracranial pressure and systemic hemodynamics. Journal of Clinical Neuroscience, 42, 148-154.

19.             Fang, J., Yang, Y., Wang, W., Liu, Y., An, T., Zou, M., & Cheng, G. (2018). Comparison of equiosmolar hypertonic saline and mannitol for brain relaxation during craniotomies: a meta-analysis of randomized controlled trials. Neurosurgical Review, 41(4), 945-956.

20.             Tsaousi, G. G., Pezikoglou, I., Nikopoulou, A., Foroglou, N. G., Poulopoulou, A., Vyzantiadis, T. A., & Vasilakos, D. (2021). Comparison of Equiosmolar Doses of 7.5% Hypertonic Saline and 20% Mannitol on Cerebral Oxygenation Status and Release of Brain Injury Markers During Supratentorial Craniotomy: A Randomized Controlled Trial. Journal of Neurosurgical Anesthesiology.

21.             Barik, A. K., Agrawal, S., Gupta, P., & Kumari, R. (2021). Evaluation of equiosmolar 20% mannitol, 3% hypertonic saline and 8.4% sodium bicarbonate on intraoperative brain relaxation and hemodynamic parameters in patients undergoing craniotomy for supratentorial tumors: a prospective randomized study. Minerva Anesthesiologic, 87(9), 997-1005.