Comparative study between intrathecal dexmedetomidine and intrathecal magnesium sulfate in prevention of post spinal shivering in uroscopic surgery. (RCT)

Background: Hypothermia and shivering are associated common complications after spinal anesthesia especially in uroscopic procedures when large amounts of cold intraluminal irrigating fluids are used. Among all adjuvants that have been used in literatures for shivering management, magnesium sulphate and dexmedetomidine were the most effective with least side effects. Our aim of the study is to compare the effect of intrathecal dexmedetomidine versus intrathecal magnesium sulfate in prevention of post spinal shivering. Methods: This prospective randomized, double-blinded controlled study was conducted at Kasr El-Aini Hospital from September 2017 till April 2018, on 105 patients scheduled for uroscopic surgeries. 105 patients were randomly allocated into three groups using computerized generated random tables, Group C (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5 mg) +0.5 ml normal saline, Group M (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5 mg) +25 mg magnesium sulfate and Group D (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5mg) + 5 μg dexmedetomidine in 0.5 ml saline. Primary outcomes were the incidence and intensity of shivering. Secondary outcomes were incidence of hypothermia (Temp < 36° C), sedation, the use of pethidine to control shivering and complications as hypotension, bradycardia, nausea and vomiting. Results: C group showed statistically significant higher number of total patients who developed shivering (21), patients who developed grade IV shivering (20) and patients who needed pethidine (21) to treat shivering than M group (8,5,5) and D group (5,3,6) which were comparable to each other. Time needed to give pethidine after giving the block was similar in the three groups. Hypothermia didn’t occur in any patient in the three groups. The three groups comparable & M and score

were both effective in reducing the incidence of post spinal shivering. So, we encourage the use of magnesium sulphate being more physiological, readily available in most operating theatres and much cheaper than dexmedetomidine.

Clinical trial registration ID: PACTR201801003001727
Background For short procedures like uroscopic surgeries, spinal anesthesia (SA) is a very reliable and convenient technique especially procedures in which patient consciousness is important to detect intraoperative complications such as TURP syndrome (1). However, hypothermia and shivering are associated common complications after SA especially in such procedures if large amounts of cold intraluminal irrigating fluids are used (2). SA impairs thermoregulation, inhibits the tonic vasoconstriction, and causes redistribution of core heat from the trunk to the peripheral tissue (3). Shivering interferes with proper monitoring and it is associated with several adverse effects as it increases circulating catecholamine, heart rate, cardiac output, minute ventilation, patient's oxygen consumption, metabolic CO2 production, lactic acid level, intraocular and intra cranial pressure, postoperative pain from surgical incision stretching (4).
Various opioid and non-opioid agents have been used for shivering prevention like meperidine, ketamine, tramadol, clonidine but they have many side effects or their results were not conclusive (5).
Magnesium sulfate (Mg SO4) which is an inorganic salt has been shown to suppress postoperative shivering suggesting that the agent reduces the shivering threshold (16). It has a good safety profile as there are no side effects related to the intrathecal use of the drug with no significant changes in hemodynamic parameter (17). Mg SO4 has been effectively exaimened in many trials intravenously (2,(18)(19)(20) and in few trials intrathecally (3) to control shivering.
Our aim of the study is to evaluate and to compare the effect of intrathecal dexmedetomidine versus intrathecal magnesium sulfate in prevention of post spinal shivering.
Primary outcomes were incidence and intensity of shivering. Secondary outcomes were incidence of pethidine use, hemodynamics and incidence of complications i.e hypotension, bradycardia and sedation.

Methods
After approval of the Ethics Committee (clinical trial registration ID: PACTR201801003001727) and obtaining informed written consent from each patient, this prospective randomized, double-blinded controlled study was conducted at Kasr El-Aini Hospital from September 2017 till April 2018, on 105 patients scheduled for uroscopic surgeries. Included patients were those aged between 20-60 years old and classified by the American Society of Anesthesiologist (ASA) physical status as class I or class II. Exclusion criteria were patient's refusal, coagulopathy, history of allergic reactions to local anesthetics and severe cardiac, respiratory, hepatic or renal disease.
In the operating room, after the skin was infiltrated with 2% Lidocaine; venous access was done with a 18 gauge cannula and a preload of 500 ml lactated ringer solution was infused and no premedication was given. Monitoring by five lead ECG, pulse oximetry and non-invasive arterial blood pressure (NABP) was done. Baseline systolic and diastolic arterial blood pressure (SBP and DBP), heart rate (HR) and arterial oxygen saturation (PSO2) were recorded. Spinal block was done while the patient was sitting and leaning forward at L4-L5 interspace or L3-L4 with a 22-gauge spinal needle after sterilization by povidone iodine and infiltration of the skin at the site of lumbar puncture with 2 cm of lidocaine 1%.
Patients were randomly allocated into three groups using computerized generated random tables, Group C (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5 mg) +0.5 ml normal saline, Group M (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5 mg) +25 mg magnesium sulfate and Group D (n=35) received 2.5 ml hyperbaric bupivacaine 0.5% (12.5mg) + 5 μg dexmedetomidine in 0.5 ml saline. The specific intrathecal injections were prepared and injected by a non-involved anesthesiologist. Onsets and duration of motor and sensory block were assessed by Bromage scale and pinprick test respectively.
One layer of surgical drapes was placed over the patient, the room temperature was kept at 24° C and all irrigating and IV fluids were pre-warmed. No warming device was used. The incidence and intensity of shivering were assessed by a blinded observer immediately after block, every 5 minutes for the first 15 minutes, then every 10 minutes for two hours after the block using Crossley and Mahajan scale (21) (0= no shivering, 1= piloerection or peripheral vasoconstriction but no visible shivering, 2= muscular activity in only one muscle group, 3= muscular activity in more than one muscle group but not generalized shivering, 4=shivering involve the whole body). 25 mg of IV meperdine was given on reaching grade 3 shivering. Core temperature was monitored using a tympanic probe before block, immediately after block and every 15 minutes for two hours after the block. Hypothermia and active warming were considered if core temperature reached 36° C. HR, BP and SPO2 were recorded every 5 minutes for the first 15 minutes, then every 10 minutes for two hours after the block.
Sedation was observed and recorded every 30 minutes for two hours or till giving IV pethidine using the Ramsay sedation scale (22), in which 1 = patient was anxious, agitated or restless; 2 = patient was co-operative, oriented, and tranquil; 3 = patient responded to commands only; 4 = patient exhibited a brisk response to light glabellar tap or loud auditory stimulus; 5 = patient exhibited a sluggish response to light glabellar tap or loud auditory stimulus; and 6 = patient exhibited no response.
Patients were monitored for complications. Hypotension (20 % decreases in SBP from the baseline) was treated by increments of 3 mg of ephedrine and 200 ml of lactated ringer, bradycardia (HR < 50) was treated by a bolus of 0.01-0.02mg/kg of atropine. Nausea and vomiting treated with 10 mg metoclopramide.
Postoperatively, patients were transferred to PACU, monitored and covered with one layer of cotton sheet. PACU temperature was kept at 25° C.
Primary outcomes were the incidence and intensity of shivering. Secondary outcomes were incidence of hypothermia, sedation, the use of pethidine to control shivering and complications as hypotension, bradycardia, nausea and vomiting.

Method of analysis:
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp) Qualitative data were described using number and percent. The Kolmogorov-Smirnov test was used to verify the normality of distribution Quantitative data were described using mean, standard deviation. Significance of the obtained results was judged at the 5% level. Chi-square test was used for categorical variables, to compare between different groups. F-test (ANOVA) was used for normally distributed quantitative variables, to compare between more than two groups, and Post Hoc test (Tukey) for pairwise comparisons.

Results
One hundred and eighteen patients scheduled for uroscopic surgeries were enrolled in this study, 8 patients didn't meet inclusion criteria and 5 patients were excluded from the study due to failure to achieve block within 15 min. Types of the performed surgeries were 41cystoscopy, 17 TURP, 28 ureteroscopy and 19 urethroscopy and theses surgeries were comparable between the three groups.
All patients were comparable regarding demographic data including age, weight, height, sex, duration of surgery and ASA classification (table 1).
All patients in the three group were comparable regarding SBP and DBP (figure 2), HR and SpO2 C group showed statistically significant higher number of total patients who developed shivering, patients who developed grade IV shivering and patients who needed pethidine to treat shivering than M group and D group which were comparable to each other (table 2,3).
Time needed to give pethidine after giving the block was similar in the three groups.
The three groups were comparable regarding occurrence of nausea, vomiting, bradycardia & hypotension. All patients of C group, 32 patients in M group and 33 patients in D group had sedation score of 2. 3 patients in M group and 2 patients in D group had a sedation score of 3 (table 4).

Discussion
Besides its well-known advantages, SA has an additional one in uroscopic surgeries especially procedures that need lumnal fluids irrigation such as TURP, as it allows early detection of complications as TURP syndrome in conscious patients (1). However, SA is not a complication free technique; Shivering is one of the common complications of spinal anesthesia with an incidence reach 40-60% of patients undergoing spinal anesthesia (5). SA impairs thermoregulation and inhibits the tonic vasoconstriction which plays a significant role in temperature regulation. SA also causes redistribution of core heat from the trunk (below the block level) to the peripheral tissue (3). Irrigation by cold fluid during uroscopic surgeries is an added important contributor to hypothermia and shivering in such procedures (2).
Though, shivering is a protective mechanism to preserve body heat but it causes patient discomfort and pain and it may be dangerous in patients with impaired cardiovascular reserve or a limited respiratory capacity as shivering increases circulating catecholamine, heart rate, cardiac output, minute ventilation, patient's oxygen consumption, metabolic CO2 production and lactic acid level. It also increases intraocular and intra cranial pressure, postoperative pain from surgical incision stretching. Shivering also may interfere with the monitoring of patients by causing artifacts of the ECG, blood pressure, and pulse oximetry (4). Also shivering in high grades -III & IV-may cause some difficulties to the surgeon and increase the operative time.
Hypothermia is a major risk for shivering, but there is no definite linear relationship between body temperature and appearance of shivering. Other major risk factors include aging, level of sensory block, and temperatures of the operating room and intravenous solutions (23).
The neurotransmitter pathways of shivering are complex and different receptors are involved like opioids, α-2 adrenergic, serotonergic, and anti-cholinergic receptors. Different drugs that act on these receptors have been examined in different trials for the prevention or treatment of shivering that occurs after SA (4). These drugs include meperidine, fentanyl, clonidine, ketamine, and tramadol, and they have resulted in different degrees of efficacy and many associated side effects like hemodynamic instability, respiratory depression, nausea and vomiting (24).
Dexmedetomidine is a highly selective α2 adrenoreceptor agonist with about ten times higher affinity for α2adrenoreceptor than clonidine (25). The response to activation of this alpha-2-receptors includes decrease sympathetic tone resulting in decrease in blood pressure and heart rate.
Dexmedetomidine has been effectively examined in several studies for prevention and treatment of shivering following general or spinal anesthesia in a dose that doesn't cause major sedation or hemodynamic instability., no respiratory depression, less nausia and vomiting (11). The exact mechanism of dexmedetomidine in shivering control is not clear. One possible mechanism is that dexmedetomidine and other α-2 agonists control shivering, by their action on α-2b receptors in the hypothalamic thermoregulatory center of the brain increasing the level of the shivering threshold.
Other possible mechanism is that dexmedetomidine avoids vasoconstriction which has an important role in temperature regulation (26).

Magnesium (Mg+2) is a naturally occurring non-competitive antagonist of N-methyl-Daspartate
(NMDA) receptors with a good safety profile (27) and has been reported to reduce shivering threshold centrally (16). Being a calcium antagonist, magnesium has a mild muscle relaxant effect which may reduce the gain of shivering (incremental shivering intensity with progressing hypothermia) (2).
Magnesium also causes peripheral vasodilation that increases the cutaneous circulation leading to decreasing the incidence of shivering (28). Similar to our study using the same intrathecal dexmedetomidine dose (5 μg), Ellakany et al (15) concluded that both intrathecal dexmedetomidine and meperidine effectively lowered the incidence of  Gozdemir et al. (2) found that following spinal anesthesia, iv infusion of 80/kg mg Mg So4 over 30 minutes, followed by iv infusion at a rate of 2g/hr till the end of surgery is significantly effective in prevention of postspinal anesthesia shivering in patients undergoing TURP.
In Sachidananda et al study (20), prophylactic iv infusion of MgSO4 and tramadol effectively reduced shivering incidence during cesarean section under SA with a reduced shivering intensity with MgSO4 There is no difference between the three groups in intraoperative hemodynamics. Regarding onset of sensory and motor block, D group had the fastest onset of sensory and motor block while M group had a delayed onset of sensory and motor block than D and M groups. This may be due to change in ph and baricity of bupivacaine due to addition of magnesium sulfate. Similar results were observed in two studies (31,32) which compared the intrathecal effect 10 μg dexmedetomidine and 50 mg Mg SO4 when added to bupivacaine targeting the characteristics of spinal block as primary out comes.

Conclusion
We concluded that intrathecal injection of dexmedetomidine and magnesium sulfate with bupivacaine in spinal anesthesia were both effective in reducing the incidence of post spinal shivering. So, we encourage the use of magnesium sulphate being more physiological, readily available in most operating theatres and much cheaper than dexmedetomidine.

Limitations and recommendations:
The limitation was that we didn't estimate the mean volume of the irrigating fluids in each group. different doses.

Declarations
Ethics approval and consent to participate: ethics approval from Cairo university hospitals research committee-department of anesthesia was obtained (N-12015006). Written informed consents were obtained from participants before inclusion. Consent for publication: not applicable.
Availability of data and material: The data that support the findings of this study are available from Cairo university hospitals; however, they are not publicly available. Data are however available from the authors upon reasonable request after permission of Cairo University.
Competing interests: The authors declare that they have no competing interests.     Comparison between the three studied groups according to Systolic blood pressure and diastolic blood pressure (mmHg) Figure 3 Comparison between the three studied groups according to Heart Rate (Beat/min.) and SPO2 (%) Figure 4 Comparison between the three studied groups according to temperature (° C).

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