The present study is a monocentric comparative prospective randomized and interventional study conducted in our tertiary care hospital and research center. After taking approval from the institutional ethical committee (IEC No. 16/16), we completed the study in 1 year, starting from August 2017 to July 2018. In this study, ethical principles for medical research were strictly followed according to the Helsinki Declaration of 2013.
The study’s primary objective is to compare hemodynamic changes like HR, CVP, SV (stroke volume), CO (cardiac output), and cardiac index (CI) between 2 doses of mannitol using a Flotrac monitor.
The study’s secondary objective is to compare brain relaxation and side effects between 2 doses of mannitol. In our study, we have included the patients of ASA I and II, between the age 20 and 60 years, posted for supratentorial surgery having a GCS of more than 10. Exclusion criteria for our study were patient refusal, patients ASA III or higher, Glasgow coma score <10, known history of hypersensitivity to mannitol, history of drug abuse or alcohol intake, and uncontrolled medical conditions such as hypertension, diabetes mellitus or bronchial asthma, seizure disorder, plasma sodium <130 meq L-1 or >150 meq L-1, creatinine clearance <30 mL kg-1, and any heart disease. The recruited 60 patients were randomly allocated to one of the following two groups (30 each), irrespective of age or gender. Randomization was achieved by block randomization with variable block design using a computer-generated randomization sequence. Allocation was double blinded using SNOPES.
Group A: Dose of 0.7 gm kg-1 20% mannitol infused over 20 min.
Group B: Dose of 1.4 gm kg-1 20% mannitol infused over 20 min. (Quentin et al., 2013)
After preoperative evaluation, consent and premedication of tablet Alprazolam 0.25 mg and tablet Ranitidine 150 mg on the night before the surgery, patients were transferred to the operation theatre. In the operation theatre, we have attached basic monitors like non-invasive blood pressure (NIBP), pulse oximetry (SpO2), and electrocardiogram (ECG), and 18 gauge intravenous access was taken. Patients were premedicated with inj. Midazolam 0.05 mg kg-1 and inj. Fentanyl 2 μg kg-1 intravenously. General anesthesia was induced with inj. propofol 2-3 mg kg-1 and inj. vecuronium 0.1mg kg-1. Ventilatory parameters were set to maintain EtCO2 around 30 ± 5 mmHg. Under the aseptic conditions, a 7fr triple lumen central venous catheter was inserted in the internal jugular vein via the seldinger technique and intra-arterial cannulation was performed in the radial artery using a 22G cannula. The FloTrac transducer was then connected to the indwelling intra-arterial line, and the pressure transducer was connected to the central venous catheter and both to the Vigileo TM System. The patient’s age, weight, height, and gender were entered. Baseline readings of heart rate (HR), mean arterial pressure (MAP), and cardiac function parameters like central venous pressure (CVP), stroke volume (SV), cardiac output (CO), and cardiac index (CI) were noted. We monitored temperature by the nasopharyngeal probe, and urine output monitoring was done hourly. Anesthesia was maintained using 50%O2+50% air and inhaled isoflurane to keep the MAC between 0.8 and 1.2 with intermittent boluses of inj. Vecuronium (0.001–0.002 mg kg-1) and fentanyl 50 ug. Target EtCO2 was kept between 28 and 32 and was monitored continuously. We maintained core body temperature between 36 and 37.4°C. Starting with skin incision, patients received inj. Mannitol (20%) in doses of 0.7gm kg-1 and 1.4gm kg-1 in Groups A and B over 20 min via central line.
The attending neurosurgeon, who was kept blind to study groups, assessed the condition of the brain after dural opening on a 4-point scale: 1-Perfectly relaxed, 2-Satisfactory relaxed, 3-Firm brain, and 4-Bulging brain (Quentin et al., 2013). Hemodynamic parameters like heart rate (HR), mean arterial pressure (MAP), and cardiac function parameters like central venous pressure (CVP), stroke volume (SV), cardiac output (CO), and cardiac index (CI) were recorded at baseline, 10 and 20 min after the start of mannitol infusion. These indices were again recorded at 5, 10, 15, 30, 45, 60, 90, and 120 min after termination of 20% mannitol infusion.
When we get hypertension that is MAP >20% above baseline value and /or tachycardia that is HR >20% above baseline value, we used inj. fentanyl 0.5–1 ug kg-1 bolus or had increased the inspired isoflurane concentration to a maximum of 1.2 MAC or had infused propofol 0.5 mg kg-1. If all this failed, we used labetalol in 5 mg increments. Hypotension dropping MAP to <20% below the baseline value was treated by escalating isoflurane to the minimum level of 0.8 MAC and intravenous fluids in bolus. We had used inj. Mephentermine 6 mg boluses for decreased blood pressure if the above strategies did not work. Inj Atropine 0.6 mg bolus was given for bradycardia, a heart rate less than 40. All patients were given inj Paracetamol 15 mg kg-1 30 min before completion of surgery. We had started tapering isoflurane at the time of skin suturing. We had reversed patients using inj. Neostigmine 0.05 mg kg-1 and inj. Glycopyrrolate 0.01 mg kg-1. We assessed for complications like tachycardia, excessive bleeding, excessive diuresis, and the requirement of postoperative ventilation. We had defined excessive bleeding by calculation of more than allowable blood loss. We have taken excessive diuresis as urine output of more than 4 ml kg-1 h-1.
All patients were shifted to the postoperative ward with good analgesia and standard postoperative care.
Sample size calculation
We had calculated sample size by below mentioned formula (Charan and Biswas, 2013). (Jaykaran & Tamoghna, 2013)
n=Z1-α/2 2 X SD2/d2
Z1-α/2=Power of the study
SD= Standard deviation
D= Absolute error (difference in the means).
In a study (Quentin, et al) (Quentin et al., 2013), the mean heart rate was 72±14 in patients of low dose (0.7 gm kg-1) of Mannitol and 70±13 in patients of high dose (1.4 gm kg-1) of Mannitol. We had taken power as 80%, significance level as 5% with 95% confidence interval and absolute error of 2. We had taken SD as 5 and found total sample size of 24 in each group after calculation.
N= (1.96*1.96)*(5*5)/(2*2) =24
The data of results were recorded in percentages, frequencies, and mean±SD. We used chi-square for the comparison of categorical variables between the groups. For the comparison of continuous variables between the groups, an unpaired t test was used. The repeated measures of analysis of variance were used to find the effect of time and time to group interaction in the change in various continuous variables. The p value<0.05 was considered significant. We did all statistical analysis using SPSS 16.0 version (Chicago, Inc., USA).