Prophecy with Dexmetomitidine will Decrease the Incidence of Pre-Operative Shivering and Enhance Anti-Shivering-Effect of Tramadol during Cesarean Section

Background and Objective: Shivering is often spotted during cesarean sections, which will increase risks and Uncomfortable feelings of pregnant patients. The propose of this study is to observe the effect of low dose Dexmedetomidine pretreatment on the incidence of shivering during cesarean section and to make sure whether it can enhance the anti-shivering effect of tramadol. Methods: Pregnant Women scheduling for term birth by cesarean section under combined spinal-epidural anesthesia were randomly divided into Dexmedetomidine group (Group Dex) and control group (Group Ns). Before anesthesia was performed, 0.2μg/kg Dexmedetomidine or 0.9% saline at the same volume (50ml) was infused intravenously at the speed of 300ml/h by pumping. The incidence of shivering was observed. Tramadol at 30mg was administered as a rescue of shivering over grade II, the efficiency of rescue was observed too. Hear Rates (HR), Mean Arterial Blood Pressure (MAP), Anxiety number score(ANS, ranging from 0 to 10) at different time were recorded. Nausea scoring, the post-operation incidence of vomiting and Apgar score were also recorded. Results: in group Dex was significantly higher than that in Group Ns(8.7% vs 33.3%，P<0.05); And the anxiety score and incidence of nausea after the administrated of tramadol in group Dex were significantly lower than that in Group Ns. There was more stable hemodynamics (HR, MAP) in Group Dex while comparing to that in Group Ns. There was no significant difference in the Apgar score of the baby between the two groups at 2, 5 and 10 min after born. Conclusions: Pretreatment with Dexmedetomidine at the dose of 0.2μg/kg can not only reduce the incidence of shivering during cesarean sections without affecting Apgar scores of infants, and it will also enhance the efficiency of Tramadol in ant-shivering intraoperatively and reduce its side effects. Dexmetomitidine will Decrease the Incidence of Pre-Operative Shivering and Enhance Anti-Shivering-Effect of Tramadol during Cesarean Section.

oxygen demands and puerperants' nervousness, disturbing the perioperative monitoring on an electrocardiograph (ECG) and pulse oxygen saturations, even some unpredictable body movements, which were often complained by Obstetrician and anesthesiologist. In our previous studies, we testified that Nefopam and Tramadol can both prevent perioperative shivering to some degrees [4,5]. Nevertheless, complications of those drugs, such as injection pain relating to nefopam and nausea and vomiting after Tramadol, limited their widely administer in clinical practice [6].
Dexmedetomidine is a highly selective α2 receptor agonist. Its sedative and analgesic effects have been widely recognized, and its anti-shivering effect has also received clinical attention [7,8].
For the delayed sedative effects after intravenous injection, its sedative effect on newborn infants was thought to be very small and could be ignored. Many clinicians have conducted observations and studies on the application of dexmedetomidine in obstetric anesthesia [9,10]. It is believed that different doses of dexmedetomidine have different anti-Shivering effects [11].
And also, a good dose-effective relationship of anti-shivering can be found on Tramadol at a dosage of 0.5mg/kg-1mg/kg [12,13].
This clinical trial was designed to verify the hypothesis that even a small dose of dexmedetomidine could have some capability of antishivering and it could be farm the basement ant-shivering effects which would enhance the effect of anti-shivering of Tramadol.

Patient's Enrollment
This study was approved by the ethics committee of the hospital (N2017061), and all parturient gave written informed consent for anesthesia and relevant intraoperative medication.
The pregnant women who are undergoing cesarean section under combined spinal-epidural anesthesia are included in this study. Inclusion criteria included: Age 20-40 years old, weight 50-80kg, ASA (American Association of Anesthesiologists) grade I to II, 34 to 42 weeks of pregnancy. Exclusion criteria: parturient were complicated with sinus bradycardia, sick sinus syndrome, seconddegree atrioventricular block type II or higher and other serious arrhythmias; patients were diagnosed with dangerous placenta previa and severe pregnancy-induced hypertension syndrome. The preoperative examination showed that patients with body mass index (BMI) > 30 cm / kg2 or laboratory test showed hemoglobin < 90 g / L; Those who experienced unsuccessful puncture of neuraxial anesthesia or puncture longer than 20 min during the procedure, those whose plane of anesthesia was unsatisfactory or whose plane of anesthesia exceeded the thoracic 6-plane, those whose labor course was too long (more than 15 min from starting skin incision to infant retrieval), or those who experienced unexpected massive bleeding during the procedure were excluded.

Grouping, Randomizing and Blinding
Enrolled parturients were divided into two groups using a random number table, dexmedetomidine (Henrui,Jiansu,china)DEX group, n = 145) and saline (NS group, n = 126), and dexmedetomidine 0.2 μ g / kg (diluted to 50 ml with saline) (DEX group) or saline 50 ml (NS group) was pumped intravenously at 300 ml / h over 10 min with a pumper, respectively. The drugs for observation were formulated by an anaesthetic nurse. The anesthesiologists involved in the anesthesia management and effect assessment were blinded to the grouping of the medication.

Anesthetic Surgical Procedure and Data Collection
All enrolled parturients were required to abstain from lumpy according to the method of the previous study [4]. 0: no shivering at all;1, controllable shivering; 2 uncontrollable shiverings which disturbing SpO2 wave and can speak normally; 3, uncontrollable shivering with hands shaking sharply and could not speak normally.
Shivering score at 2 were treated with Tramadol(Grantai, Germany) at 30mg intravenously after the baby delivery, the effect of tramadol anti-shivering was accessed 5min after injection and the SpO2 wave return to normal was regarded as an effective treatment. Nausea cases related to Tramadol were noted. Apgar scores were assessed 2min,5min, 10min after the infant was delivered, respectively. Fluid transfused, surgery duration (from skin incision to skin closed) were recorded too. Postoperative analgesia was treated with a patient-controlled intravenous pump. The primary outcome of the observation including a shivering score and the efficiency of tramadol in the 2nd degree of shivering. Secondary outcomes including HR, MAP, ANS, Apgar score, Vomiting cases etc.

Statistical analysis
Sample size counting in the previous study, we got a 40% incidence of shivering in the controlled group and a 20% incidence

Secondary Outcomes
Hemodynamic Fluctuation, including HR and MAP in Group Dex, was significantly less than that in Group Ns.
ANS in Group Dex was significantly lower than that in Group Ns.

Discussion
The main outcomes in this trial showed that the incidence of intraoperative shivering decreased dramatically after preoperative infuse of Dexmedetomidine at a dosage of 0.2ug/kg, which is notably lower than the recommended dosage for bolus dosage for sedation and anti-shivering [10,14]. There still some cases that showed intraoperative shivering in Group Dex, which could result from the low dosage of Dexmetedetomidine, and also might cause by inadequate heat keeping, such as we did not apply the infusing fluid warmer and the air warmer during operation, which showed an effective anti-Shivering effect intraoperatively [15,16]. Tramadol could deal with intraoperative shivering effectively and it was recommended by many clinical practitioners [13,17]. After the rescue of tramadol, 75.8% of patients stop their shivering, which verified the anti-shivering effect of tramadol. However, data in this trial showed that the anti-shivering effect Tramadol was enhanced by Dexmetedomidine. Data in this trial showed a significantly lower ANS in the patient who treated with Dexmetedomidine, which implied that the advantage of Dexmedetomidine preoperative administering [18,19]. Intraoperative shivering in the cesarean section under spinal anesthesia is one of the most frequent surgical procedures in current clinical practices [9,20,21].
Research focusing on intraoperative Shivering of cesarean section had observed many drugs [20,22] and methods [23,24]. The Subarachnoid injection with small dose of Anti-shivering medicine was tried by some Clinical practitioner [23,24]. It took about 10-15 min for Dexmetedomidine to show its effect of sedation, and also a rapid injection of Dexmedetomidine was suggested to avoid, for its adverse result in severe hypertension and bradycardia [25,26].
Meanwhile, according to our clinical experiences, intraoperative shivering occurs mostly 0-5min after infants delivered.
Dexmedetomidine administering in C-section would show a not in time treatment. In this trail, Low dose of Dexmetedomidine at 0.2ug/kg infusing intravenously before surgery in this trial showed an effective anti-shivering capability, and it did not have an obvious effect on the Apgar score of the newborn infants.
Intraoperative hemodynamic stability was one of the outmost goals of intraoperative management. More and more evidence showed that this goal can be achieved by the appropriate administering of Dexmedetomidine [27,28]. A certain dosage of Dexmedetomidine infused slowing with pumper will often result in a stable heart rate and arterial blood pressure [29]. In this trial, a relatively small dose of Dexmedetomidine infusion gained a significant stable Heart rate and MAP in Group Dex. Limitation of this clinical trial: Though the temperature in the operating setting was fixed to 22-23 ℃, there were not air warmer and warmer blanket was applied in this trail. A body temperature monitor, such as core temperature, was not performed in this trail. A perfect perioperative temperature protection strategy will decrease the incidence of intraoperative shivering and also decrease the medicine requirement. In conclusion, for those puerperants who plan for cesarean section under the spinal block, preoperative infusion of Dexmetedomidine at 0.2ug/kg in 10 min could significantly decrease the incidence of intraoperative shivering. It could also enhance the anti-shivering effect of tramadol and bring more stable hemodynamic circulation [29].