Effects of equiosmolar 3% hypertonic saline, 8.4% sodium bicarbonate & 20% mannitol on intracranial pressure and metabolic changes in patients undergoing supratentorial craniotomy and tumors excision: a prospective, randomized controlled study

INTRODUCTION:

Increasedintracranial pressure (ICP) is a common complication in patients coming forsurgical treatments with intracranial space-occupying lesions. In order toobtain an acceptable operating condition, ICP must be lowered by physiologicaland pharmacological procedures. Mannitol is the most commonly usedpharmacological medication to reduce intraoperative ICP [1]. An importantanaesthetic objective is to create an intraoperatively relaxed brain withminimal effects on intracranial hemodynamics in order to ease tumor removal andenhance neurological prognosis. Physical and pharmacological treatments areused to manage perioperatively, increase in intracranial pressure (ICP) resultingfrom tumor mass. The administration of hyperosmolar therapeutic agent is anintegral part of perioperative patient care. The ’gold standard’ for reducingICP is 20% mannitol, however 3% hypertonic saline (HTS) and 8.4% sodiumbicarbonate 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 thebrain parenchyma to the intravascular compartment. By rheological impact, theymay also improve micro-vascular circulation [4].

Mannitolgenerates 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 20and 60 minutes, and lasts for four to six hours [5, 6]. Rapid administration ofmannitol increases the risk of hypotension [7].

Hypertonicsaline is available in 3%, 5%, 7.5%, and 23% concentrations. HTS does notpenetrate the Blood Brain Barrier, produces an osmotic gradient, and enhancessystemic hemodynamic. Weed and McKibben [8] initially advocated the clinicaluse of HTS for cerebral oedema. It developed as a resuscitation agent inpatients with hemorrhagic shock and neurotrauma due to its early start,recognized end point of therapy (Na+145-155 mEq/l), intravascular volumerestoration, decrease in intracranial pressure, and anti-inflammatory effect[9, 10].

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

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

AIMAND OBJECTIVES

Aim:

·       To compare the effect of equimolar 3% Hypertonic Saline, 8.4 % Sodium bicarbonate and 20% Mannitol on Intracranial Pressure and metabolic changes inpatient 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).

 SecondaryObjectives:

To compare the following parametersbetween the groups:

·        Cerebral perfusion pressure (CPP)

·        Brain relaxation

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

·        Hemodynamicparameters Heart Rate (HR), Systolic Blood Pressure (SBP), DiastolicBlood Pressure (DBP), Mean Arterial Pressure (MAP), Central Venous Pressure (CVP).

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

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

  MATERIALAND METHODS

 Study Setting:

•     The study will be conducted inDepartment of Anaesthesiology, King George’s Medical University, Lucknow incollaboration with Department of Neurosurgery, KGMU, Lucknow after gettingclearance from the Institutional ethical committee, KGMU, Lucknow.

Study Design:

•      A ProspectiveRandomized Controlled Study.

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

                        n=

n= Sample size

σ = Standard Deviation

∆ = Difference of means

κ= Ratio

Z1-α/2= Two-sided Zvalue

Z1-β= Power

       

Confidence Interval (2-sided)

95%

|Power

80%

  | |ICP decrease percentage between

the T0 and T45 value.

(Ali A al., 2018)[15]

MANNITOL

 HYPERTONIC SALINE

Difference*

|Mean

27.35

 33.1

 -5.75

|Standard deviation

6.5

 7.2

  |Variance

42.25

 51.84

  |

---

|Sample size

46

    |

---

|Attrition bias (10%)                                                  4

|Total Sample size                                         75 (25 in each group)

 â€¢      InclusionCriteria:

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

o  ASA Grade I and II

o  Elective SupratentorialCraniotomy

 â€¢      Exclusion Criteria

o   Patientrefusal

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

o   Pregnancy

o  Cardiac dysfunction withdysrhythmia

o  Renal dysfunction

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

o   Active psychiatric or neurological disorders

 Methodology:

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

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

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

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

All the patients will be reviewed night beforesurgery, and kept nil per oral night before surgery for at least eight hoursfor solid food and two hours for plain water before the planned surgery.Patients will be shifted to operation room (OR) and standard ASA monitoringlike 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 intubatedafter adequate muscle relaxation with vecuronium 0.08-0.1 mg/kg withappropriately sized cuffed endotracheal tube. Maintenance of anesthesia will bedone with 60% air with 40% oxygen, 1.5–2.0% sevoflurane with desired MAC up to0.8-1.0 along with continuous infusion of vecuronium @ 0.03 mg/kg/hourintravenously, supplemented with intravenous fentanyl 1.0 mcg/kg/hr. Patientswill be ventilated with volume-controlled mode and end tidal carbon dioxide(ETCO2) will be maintained between 30 to 35 mm Hg. Two large bore intravenouscatheter will be placed for fluid resuscitation, arterial catheter and CVCunder USG guidance will be placed with standard technique and institutionalprotocol.

  The patients will receive the study drugs as pergroup allocation. The infusions will be started at scalp incision and continuedover a period of 30 minutes. A double blinding procedure will be followed forthe conduct of the study. All the study drugs will be prepared by a person notinvolve in patient management and data collection. The anesthesiologist, thesurgeon and the patient will be unaware of the group allotment. Theneurosurgeon will visit the ICP catheter (Codman Microsensor Basic Kit, Johnson& Johnson Co.) through the first burr hole made for craniotomy after risingscalp flap. The catheter will be inserted into the subdural space formeasurement of ICP and will be connected to ICP monitor (ICP express Codman,Johnson & Johnson profession inc.). The time of placement of ICP catheterwill be marked as To and baseline will be noted and after this theICP will be recorded every 15 minutes till the end of surgery.

Intracranial pressure (ICP) will be measure as perbelow formulae:

Formula: ICP = ICP vascular + ICP CSF

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

Formula: CPP = MAP – ICP

Where,

MAP = Mean arterial pressure.

ICP = Intra Cranial pressure.

 Brain relaxation score will be assessed by theoperating surgeon immediately on opening the duramater on a four-point scale(1=adequately relaxed, 2=satisfactorily relaxed, 3=firm brain, 4=bulgingbrain). If the surgeon will be not satisfied with brain relaxation on duralopening, additional bolus of half of the initial dose of the same study drugwill be administered. Heart rate (HR), SBP, DBP, MAP, EtCo2, CVP, will bemonitored continuously and recorded at the 15 minutes interval till end ofsurgery. Fluid intake, urine output and blood loss will be recorded at theinterval of 1 hour till the end of surgery. ABG, serum electrolytes andosmolarity will be first recorded at the time of test drug infusion as baseline 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 ofsurgery.

During intraoperative period, patient will be lookfor 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 withsurgeon and clinical status of patients. Patients not fulfilling the criteriafor extubation will be shifted to Intensive Care Unit (ICU) for ventilation anddelayed extubation, whereas others will be extubated after reversal ofneuromuscular blockade with injection neostigmine (0.05 mg/kg) andglycopyrrolate (0.01 mg/kg)

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

REVIEW OF LITERATURE

Rozet, I., et al., 2007 [16] conducted a prospective, randomized, double-blindstudy in which patients with American Society of Anesthesiologists physicalstatus II–IV who were scheduled to undergo craniotomy for a variety of brainpathologies 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 lactatebetween 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 fluidincreased in both groups (P < 0.05 versus baseline) HS increased theconcentration of sodium in cerebrospinal fluid over time (P < 0.001)when compared to mannitol. They concluded that Mannitol and HS both cause anincrease in cerebrospinal fluid osmolality and are linked with identical brainre-laxation scores as well as arteriovenous oxygen and lactate differencesduring craniotomy.

**Hernández-Palazón et al 2016 [17]**conducted a randomized, prospective, double-blind study, in which 60 patientsundergoing elective supratentorial craniotomy were randomly assigned to receiveeither 3 ml/kg of 20% mannitol or 3% HS at a ratio of 1:1. There was nodifference in brain relaxation [mannitol, 1(1–3) versus HS, 1(1.4)points; p 1â„4 0.55]. Patients with brain midline shift had a poorerreaction to hyperosmolar solutions than those without midline shift: 37% versus8%, respectively; odds ratio = 1â„4 6.6 (95% CI= 1.54–28.3); p1â„4 0.006. During the 6-hour study period, plasma osmolality increased inboth groups (p50.05 compared with baseline). There were no significantdifferences between the groups in terms of postoperative complications orlength 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 electivesupratentorial craniotomy. However, these dosages are less successful in patientswith 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 patientshaving craniotomy for supratentorial tumours following infusion of equimolarsolutions of both drugs in which forty adults were administered a normal anaestheticsinduction. From time zero (T0) to one and a half hours (T90), arterial bloodgas (ABG) was analyzed every 30 minutes and numerous data were recorded.Statistical techniques were utilised to analyses the data. Both mannitol and HSgreatly decreased the ICP, and the levels were frequently comparable betweenthe two groups. In both groups, brain relaxation scores were comparable. Usingmannitol greatly increased urine production. In both groups, perioperativecomplications, total hospital stay, and Glasgow outcome score at discharge werecomparable. They concluded that the effects of mannitol and hypertonic salineat equiosmolar concentrations on ICP reduction, cerebral relaxation, and systemichemodynamics were comparable.

Ali, A., et al., 2018 [15] conducted a prospective, randomized,double-blind trial in which the patients scheduled to undergo supratentorialcraniotomy were enrolled. The patients were observed for routine hemodynamicindicators, depth of anaesthesia, and intracranial pressure (ICP). They weregiven 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 afterhypertonic infusion ended, ICPT45) ICP values for the M group were 13.7±3.0 and9.5±1.9mmHg, respectively, compared to 14.2±2.8 and 8.7±1.1mmHg for the HSgroup (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 venouspressure, pulse pressure variation, and serum sodium and lactate values werecomparable between groups at baseline; however, the last recorded pulsepressure variation and lactate value were lower in group HS, and the sodiumvalue was greater in group HS (P < 0.05). The length of hospital staysand stays in intensive care units were comparable between groups. Duringsupratentorial brain tumour surgery, they concluded that 3% HS reduced ICP moreeffectively than 20% mannitol.

**Fang, J., et al., 2018 [19]**conducted this meta-analysis to compared the effectiveness of equimolarhypertonic saline and mannitol on intraoperative brain relaxation in patientshaving craniotomies. Nine RCTs with a total of 665 patients were identified andincluded. Compared to mannitol, there was a larger increase in the likelihoodof intraoperative brain relaxation in the HS group (odds ratio (OR) 2.05, 95%confidence interval (CI) 1.403.01; P = 0.0002) Compared to HS, mannitolslightly decreased the central venous pressure (CVP) (mean difference (MD)1.03, 95% confidence interval (CI) 0.032.03; P = 0.04) and significantlyincreased the diuretic effect regardless of the dosage of HS (standardised meandifference (SMD) 0.86, 95% confidence interval (CI) 1.35~−0.37; P = 0.0006). HSsignificantly increased plasma sodium concentration (MD 7.86, 95% CI2.78 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 osmolalitynor mean arterial pressure showed significant variations (MAP). In patientsrequiring craniotomies, the HS group appeared to provide superior brainrelaxation without a substantial increase in urine output compared to themannitol group.

Tsaousi, G. G et al., 2021 [20] conducteda study on 51 patients undergoing elective supratentorial craniotomy in whichthey receive either 7.5% HTS (2 mL/kg) or 20% mannitol (4.6 mL/kg) at scalpincision. Jugular bulb oxygen saturation and partial pressure of oxygen,arterial-jugular oxygen and carbon dioxide differences, and brain oxygenextraction ratio were positively affected by 7.5% HTS up to 240 minutes postinfusion (P< 0.05), whereas mannitol was associated with only a brief(15-minute) improvement in these indices (P < 0.05). Changes incerebral oxygenation correlated with temporary increases in intravascularvolume and enhanced cardiovascular function. Increases in neuron-specificenolase and S100B at 6 and 12 hours after surgery were comparable betweengroups (P< 0.0001) They concluded that 7.5% HTS has a more positive effecton cerebral oxygenation than an equimolar dosage of 20% mannitol duringsupratentorial craniotomy, but neither solution indicated apparent clinicaladvantage.

**Barik, A. K et al.,2021 [21]**conducted a prospective study, in which 90 patients, of american Societyof Anesthesiologists class I and ΙΙ with supratentorial tumour and scheduledfor surgery were randomized into three groups to receive equimolar 20% mannitol(group 1), 3% hypertonic saline (group 2), and 8.4% sodium bicarbonate (group3) prior to surgery for supratentorial tumour (group 3). The relaxation scoresof groups 3 were substantially higher than those of groups 2 and 1,respectively. Compared to other groups, patients in group 1 had lower mean bloodpressure and central venous pressure, as well as higher urine output and fluidintake. Compared to groups 1 and 2, group 3 patients had significantly higherpH, bicarbonate, partial pressure of carbon dioxide, serum sodium, and serumosmolarity values. Infusion of 8.4% sodium bicarbonate solution was relatedwith superior intraoperative brain relaxation ratings and enhanced haemodynamicstability compared to 3% hypertonic saline solution and 20% mannitol.

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