Clinical trial NCT03679052: Prophylactic Mirtazapine or Clonidine for Post-spinal Anesthesia Shivering
Official title: Prophylactic Mirtazapine or Clonidine for Post-spinal Anesthesia Shivering in Patients Undergoing Urological Surgeries: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Shivering
Lead sponsor: Ain Shams University
Sponsor class: OTHER
First posted: 2018-09-20
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study was conducted to study the effect of a prophylactic dose of oral mirtazapine on shivering compared with a prophylactic dose of oral clonidine in patients undergoing urological surgeries under spinal anesthesia.

Detailed description: Enrollment After approval by the institute ethics committee, this study was conducted at Ain-Shams university hospitals, from the1st of March 2018 till the 31st of August 2018, on 300 patients aged 18-60 years and body weight 60-100 Kg of the American Society of Anesthesiologists (ASA) physical status I or II who underwent urological surgeries under spinal anesthesia. A written informed consent will be obtained from all patients to participate in the study.

Patient's refusal, duration of surgery more than 120 min, obesity with body mass index (BMI) \>35 kg/m2, generalized infection or localized infection at level of blockade, neurologic disease, coagulation disorder, patients with hypo- or hyperthyroidism, cardiopulmonary disease, psychological disorders, a need for blood transfusion during surgery, an initial body temperature \>38.0C or \<36.0C, a known history of alcohol or substance abuse, or receiving vasodilators, or medications likely to alter thermoregulation excluded the patient from the study Randomization and Blinding This study was designed to be a randomized, placebo-controlled, double-blinded parallel study. Following enrollment, patients were randomized into 3 equal groups;

1. Group I (Mirtazapine group): (n=100) each patient received 30 mg mirtazapine tablet and a placebo tablet for clonidine orally with sips of water 2 h preoperatively.
2. Group II (Clonidine group): (n=100) each patient received 150 µg clonidine tablet and a placebo tablet for mirtazapine orally with sips of water 2 h preoperatively.
3. Group III (Control group): (n=100) each patient received two placebo tablets for mirtazapine and clonidine orally with sips of water 2 h preoperatively.

Randomization was done using computer-generated table of random numbers in a 1:1 ratio in opaque and sealed envelope (SNOSE). The assigned treatment was written on a card and sealed in opaque envelopes consecutively numbered. These envelopes were opened just immediately before infusing the medication in the patient's room. The study drugs were prepared by the hospital pharmacy and follow-up of patients were conducted by anesthesia residents not involved in any other part of the study.

Study Protocol On arrival in the operating theatre, all patients had an inserted venous cannula. I.V. fluids were preheated to 37oC. No other warming device was used. Lactated Ringer's solution was warmed to 37 oC and was infused at 10 ml/kg over 30 min before spinal anesthesia. The infusion rate was reduced to 6 ml/ kg.

Subarachnoid anesthesia was instituted at either L3/4 or L4/5 interspaces. Hyperbaric bupivacaine, 5 mg /ml, 15 mg was injected using a 25 G Quincke spinal needle, Supplemental oxygen (5 liter/ min) was delivered via a facemask during the operation. All patients were covered with one layer of surgical drapes over the chest, thighs, and calves during the operation and one cotton blanket over the entire body after operation. The operating and recovery rooms temperatures were maintained at 23-25°C with approximately 60% humidity.

Assessment parameters Heart rate, mean arterial pressure (MAP), and peripheral oxygen saturation were recorded using standard noninvasive monitors before intrathecal injection and thereafter at 5, 10, 15, 20 minutes then every 10 minutes to complete 90 minutes from the intrathecal injection.

Sensory levels were assessed by pinprick to determine the peak sensory level and time to two segment regression in minutes. Motor block was assessed by using Modified Bromage scale(14) (0 = no block 1 = hip block, 2 = hip and knee block, 3 = hip, knee, and ankle block) to determine the time to reach complete motor block and duration of motor blockade (minutes).

Sedation score was assessed with a four-point scale as per Filos et al.(15): 1: Awake and alert. 2: Somnolent, but responsive to verbal stimuli. 3: Somnolent, arousable to physical stimuli. 4: Unarousable.

Body temperature (axillary temperature) was recorded with an axillary thermometer. The ambient temperature was measured by a wall thermometer. The ambient temperature was maintained at 25oC with constant humidity.

Shivering if occurred was graded using a scale similar to that validated by Badjatia et al (16):

1. None: no shivering noted on palpation of the masseter, neck, or chest wall
2. Mild: shivering localized to the neck and/or thorax only
3. Moderate: shivering involved gross movement of the upper extremities (in addition to neck and thorax)
4. Severe: shivering involved gross movements of the trunk and upper and lower extremities.

Shivering was assessed immediately before the block and every 10 minutes till the end of surgery and for another 20 min in the recovery room. Grade 3 or 4 of shivering score was regarded failure of prophylaxis, meperidine 25 mg IV was administered and no assessment of shivering was done.

Side-effects, including hypotension (defined as a decrease in MAP of more than 20% from baseline or a decrease of arterial blood pressure below 90 mmHg and baseline MAP was calculated from three measurements taken on the ward before surgery) was treated by crystalloid infusion and if necessary ephedrine 5 mg IV was administered. The amount of ephedrine given in each group was recorded. Bradycardia was considered if the heart rate \<50 beats/min and was treated with IV atropine (0.01mg/kg). If there was respiratory depression (RR \< 12 bpm) and a decrease in arterial SpO2 (\<90%), it was treated with oxygen through a transparent face mask. Incidence of nausea and vomiting during early 2 hours postoperatively were recorded. IV granisetron (1 mg) was given in case of vomiting or after 2 successive episodes of nausea.

Patient's satisfaction was done by asking the patient to answer the question, "How would you rate your experience after the surgery?" using a 7-point Likert verbal rating scale(17): \[Figure 1\] and acceptable satisfaction score of the patient being 5-7.

Likert scale:

1 2 3 4 5 6 7 Extremely dissatisfied Dissatisfied Somewhat dissatisfied Undecided Somewhat satisfied Satisfied Extremely satisfied Figure 1: A 7-point Likert-like verbal rating scale for assessment of patients' satisfaction(17).

Endpoint: The study end point was 20 minutes after the end of the procedure (in the recovery room)

Primary Outcome Measure:

Total participants received pethidine for treatment of post-spinal shivering in the three groups till 20 minutes after the end of the procedure (in the recovery room)

Secondary Outcome Measures:

* Incidence, onset, severity and duration of post-spinal shivering.
* Time to first analgesic request, from the end of surgery up to approximately six hours after surgery
* Incidence of hypotension.
* Incidence of bradycardia.
* Incidence of nausea and vomiting during early 2 hours postoperatively.
* Patient' satisfaction towards shivering prophylaxis was assessed 24 hours after the procedure.

  3-Analysis of Data:

Depending on Shah et al., 2016 who found that shivering was 17.5% and 40.0% in Ondansetron and control respectively(18) and on Bagle et al., 2016 who found that shivering was 10.0% and 40.0% in clonidine and control respectively(6) and assuming the power= 0.80 and α=0.05, and by using PASS 11th release the minimal sample size for an equal controlled study to detect a significant statistical difference between ondansetron \& clonidine and control is 80 women in each group. We recruited 100 women in each group for possible attrition(19).

The collected data were coded, tabulated, and statistically analyzed using IBM SPSS statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp., Chicago, USA, 2013.

Eligibility criteria: Inclusion Criteria:

* • on 300 patients aged 18-60 years

  * of the American Society of Anesthesiologists (ASA) physical status I or II
  * underwent urological surgeries under spinal anesthesia. A written informed consent was obtained from all patients to participate in the study.

Exclusion Criteria:

* • Patient's refusal,

  * duration of surgery more than 120 min,
  * obesity with body mass index (BMI) \>35 kg/m2,
  * generalized infection or localized infection at level of blockade,
  * neurologic disease,
  * coagulation disorder,
  * patients with hypo- or hyperthyroidism,
  * cardiopulmonary disease,
  * psychological disorders,
  * a need for blood transfusion during surgery,
  * an initial body temperature \>38.0C or \<36.0C,
  * a known history of alcohol or substance abuse,
  * or receiving vasodilators, or medications likely to alter thermoregulation

Primary outcomes:
measure: Total participants received pethidine for treatment of post-spinal shivering in the three groups till 20 minutes after the end of the procedure (in the recovery room)
timeFrame: till 20 minutes after the end of the procedure (in the recovery room)
Secondary outcomes:
Other outcomes:
Locations:
city: Heliopolis
country: Egypt
facility: Ibrahim Mamdouh Esmat
state: Cairo
Study officials:
References: