The trial design was a prospective, double-blinded, randomized, parallel three arm groups, and placebo-controlled study. The local ethical committee approval was obtained from Fayoum University Hospitals (R 64) and the study protocol was registered in Pan African Clinical Trial Registry (PACTR) under trial number (PACTR201710002706318). Each participant was informed about the study protocol in details and complete written informed consents were signed before enrollment in the study. One hundred twenty patients of both genders aged 18–60-years ASA physical status I&II, undergoing elective surgical procedures in the lower half of the body (orthopedic, general or gynecological surgeries) were included in this trial. Surgical procedures included hernioplasty, appendicectomy, vaginal hysterectomy, abdominal hysterectomy, or open reduction and internal fixation of lower limbs. Patients excluded were those with thyroid disorders, patients with a history of convulsions, multiple allergies, severe cardiopulmonary diseases, pregnancy, uncooperative patients, patients requiring blood transfusion, and patients with severe hepatic or renal diseases. The selected patients were randomly allocated using computer generated method and opaque sealed envelopes into 3 groups containing 40 patients each according to the study drug; Placebo or Saline group (Group S), Ondansetron group (8 mg) (Group O), and dexmedetomidine group (1 μg/kg) (Group D). Preoperatively, demographic characteristics as age, sex, height, and weight were recorded.
After admission to the OR, routine standard monitoring was used in all patients in the form of non-invasive blood pressure (NIBP), pulse oximetry and ECG. The temperature of the operating room was maintained at 24 °C–26 °C by adjusting the temperature setting of air conditioners. Before intrathecal block, each patient was preloaded with 15 ml/kg of Ringer Lactate solution. The block was introduced at either L3/4 or L4/5 interspace with 3 ml of 0.5% hyperbaric bupivacaine (15 mg) by attending anesthesiologists who were not participating in this trial. After completion of intrathecal blocks, the patient lied supine and oxygen was administered via a nasal cannula (2 L/min) till the end of the procedure. Tympanic membrane temperature was monitored with Braun® thermoscan thermometer every 5 min for 45 min after the intrathecal block. The intravenous fluids were kept at room temperature (24 °C- 26 °C) and all the patients were covered with a standard single blanket. Just after the intrathecal injection, one of the study drugs was given slowly by IV route over five minutes. The study drugs were prepared, diluted to a volume of 5 ml and presented as coded syringes by an anesthetist who was not involved in the management of the patients or data acquisition.
During and shortly after completion of the surgical procedures, the data of non-invasive blood pressure, heart rate, oxygen saturation, core body temperature, duration of surgical procedures, type of surgical procedures and the level of intrathecal blocks were recorded.
The primary outcome was the incidence of shivering in the early 45 min after intrathecal blocks as defined by a shivering score ≥ 3 at any time of the predefined assessment points (highest score). Shivering score, sedation score, incidence of hypotension, incidence of bradycardia, incidence of hypoxemia, and incidence of nausea, and vomiting were secondary outcomes. The shivering score were assessed at 5 min interval for 45 min after intrathecal block and graded using a scale like that validated by Tsai and Chu [15] (Grade 0: no shivering, Grade 1: piloerection or peripheral vasoconstriction but no visible shivering, Grade 2: muscular activity in only one muscle group, Grade 3: muscular activity in more than one muscle group but not generalized and Grade 4: shivering involving the whole body). Continuous shivering ≥ grade 3 for 15 min was considered significant side effect of intrathecal block despite prophylactic IV administration of study drugs and a rescue dose of 0.5 mg / kg of pethidine was administered to control this unpleasant prolonged shivering. Sedation scores (highest score) were assessed on 5-point scale (1: fully awake and oriented patient, 2: drowsy, 3: eyes closed, arousable on command, 4: eyes closed, arousable to physical stimuli, 5: eyes closed and patient unarousable to physical stimuli). Over-sedation was defined as sedation score ≥ 4 with hypoxemia (oxygen saturation < 92%), necessitate conscious level monitoring, or require postoperative intensive care admission and its incidence was recorded. Hypotension (systolic blood pressure < 90 mmHg) was controlled by IV ephedrine administration 5 mg increments and by IV fluid boluses to keep systolic blood pressure ≥ 90 mmHg upon the discretion of the attending anesthesiologists. Bradycardia (heart rate < 60 beats/ minute) was treated by IV atropine sulphate 10 μg/kg upon the judgment and preferences of the attending anesthesiologist. Nausea and vomiting incidences were recorded and managed according to the attending anesthesiologist discretion. The investigators who were responsible for data collection and analysis were blinded to the groups’ allocation and all patients and care givers were unaware of the administered IV study drugs nature. The current study adheres to CONSORT guidelines.
Statistical analysis of data
A pilot study was performed prior to patient recruitment to estimate an appropriate sample size. The pilot study encompassed 45 subjects (15 in each arm). The incidence of shivering (the primary outcome) in placebo S group was 40% (6 subjects), in group O was 13% (2 subjects), and in the group, D was 20% (3 subjects). A sample size of 33 participants was determined per group by using a Z test family, assuming two tail α = 0.05, 80% power (β = 0.2), and an allocation ratio = 1. Recruitment of 40 participants per group was done to account for possible protocol violation or data loss. Sample size calculation was estimated by using G*Power software version 3.1.9.2 (Institute of Experimental Psychology, Heinrich Heine University, Dusseldorf, Germany).
Continuous parametric data were presented as mean ± standard deviation (SD), ordinal non-parametric data were presented as median (interquartile range) (IQR), and categorical data were presented as number of patients and proportions. Shapiro Wilk test was used to test the normality of data distributions, P < 0.05. Continuous variables including hemodynamic data and temperature values were analyzed using repeated measures analysis of variance followed by Bonferroni’s post-hoc testing to determine intragroup, within groups, and groups by time differences. Shivering and sedation scores between three groups were compared using the Kruskal–Wallis test and post hoc test was done by implementation of the Dunn’s test. Nominal data were analyzed and compared using the Chi-square test or Fisher exact test when appropriate.
Adjusted P values for multiple post-hoc comparisons between every 2 group were calculated by using the Bonferroni correction method to account for the problem of multiple testing (type I error inflation). The P-value of 0.05 was divided by the number of comparisons i.e. 3 (0.05/3). Thus, test result with P values < 0.017 were considered statistically significant difference for multiple post-hoc comparisons between every 2 groups otherwise, P-values of < 0.05 were considered statistically significant. Statistical analysis was performed using the SPSS version 17 (Inc., Chicago, IL, USA).
