Prophylactic Mirtazapine or Clonidine for Post-spinal Anesthesia Shivering
Condition: Shivering
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Mirtazapine; Clonidine; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Each patient received 30 mg mirtazapine tablet and a placebo tablet for clonidine orally with sips of water 2 h preoperatively.; Each patient received 150 µg clonidine tablet and a placebo tablet for mirtazapine orally with sips of water 2 h preoperatively.; Each patient received two placebo tablets for mirtazapine and clonidine orally with sips of water 2 h preoperatively.
Other intervention name(s): Remeron; Catapress
Intervention MeSH terms: Clonidine; Mirtazapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention