Prevention of post-spinal anesthesia shivering: Low dose ketamine vs tramadol

INTRODUCTION

Shivering is described as an involuntary, spontaneous, and repetitive muscular movement.  It is one of the frequent problems throughout and following subarachnoid anesthesia due to vasodilation, which could promote fast heat loss and cause a peripheral redistribution of body heat, in the end, hypothermia will be the result that lowers the shivering threshold.^1-2

Shivering is not a fatal event, even, it may create severe dilemmas in patients with a history of cardiac or pulmonary diseases, such as raised oxygen consumption that leads to hypoxemia, lactic acidosis, and increased carbon dioxide production. Furthermore, it increases intraocular and intracerebral pressure, can be annoying for patients, worsens wound pain and impedes ECG monitoring, pulse oximetry, and blood pressure, which may discompose a patient safety issue. ^3-4

Some non-pharmacological methods such as blankets, radiant heat, forced air warmers and increasing the operating theater ambient temperature inhibit shivering through the preservation of the body temperature through reducing heat loss. However, these techniques are costly and tardy to use.⁵ Regarding pharmacologic agents, there are five agents including N-methyl d-aspartate receptor antagonists, opioids, magnesium sulfate, dexmedetomidine, biogenic amines (serotonin 5-HT3 receptor antagonist), and cholinomimetics have been used for restriction of post-spinal anesthesia shivering. ⁶

Ketamine, a competing receptor antagonist of (NMDA) N-methyl D-aspartate has been revealed to prevent postoperative shivering in many articles.

⁷On the other hand, a centrally acting analgesic medicine, Tramadol, with µ-opioid agonist outcomes with least effects at kappa (k) and delta (δ) receptors, is efficient in the inhibition of post-spinal anesthesia shivering. The mechanism of action is purposed to work within the modulatory influence on central monoaminergic pathways, preventing the neuronal uptake of serotonin and norepinephrine in the spinal cord and increasing hydroxytryptamine secretion, and hence resets the body temperature regulation center. ⁸

This is a prospective, randomized, double-blind, placebo-controlled study that was invented to compare the effectiveness of low-dose intravenous ketamine (0.2 mg/kg) with that of (0.5 mg/kg) intravenous tramadol for the inhibition of post-spinal anesthesia shivering in patients who underwent elective surgeries. The primary outcome was the prevention of shivering, and the secondary outcome was the effect of study medicines on hemodynamics and level of sedation.

PATIENT AND METHODS

This is a prospective, randomized, double-blind, placebo-controlled study that was approved by the Mustasharak Hospital Ethical Review Committee, KSA. Written informed consent was received from 150 patients American Society of Anesthesiologist (ASA) I and II aged 21–60 years, who were prepared for surgery under subarachnoid anesthesia from March 2017 to December 2018. Patients with history of diseases involving cardiovascular system or thyroid disease, patients have hypersensitivity to bupivacaine, tramadol, or ketamine, patients have psychogenic disorders, initial temperatureoC or >38^oC, history of alcohol abuse, those patients who needed blood transfusion during surgery or who received medications possible to alter thermoregulation, subarachnoid anesthesia with mixture of subarachnoid fentanyl, subarachnoid anesthesia with sedation, such as propofol, or ketamine, or failed subarachnoid anesthesia that turned to general anesthesia were omitted from this study.

Before subarachnoid anesthesia, an 18-gauge intravenous cannula was inserted and 10 mL/kg of normal saline was started. Conventional monitoring including electrocardiogram (ECG), heart rate (HR), noninvasive blood pressure (NIBP) and pulse oximetry (SPO2) was fastened. Hemodynamic readings (MAP, HR, and SPO2), tympanic membrane, core, and room temperatures were recorded before subarachnoid anesthesia. Room temperature was fixed at 25°C±1 for all patients. Preoperatively, no premedication was given to patients. Subarachnoid anesthesia was established at either L3–L4 or L4–L5 in the sitting position by an anesthetist who was blind to the study by using 22–25 gauge Quincke spinal needles (NniEVER CE 0120, made in Nishikata, Koshigaya, Sait Ama, Japan) and 2.8 mL (14 mg) of heavy bupivacaine 0.5% was injected (Sunnypivacaine, batch no. 170518, Cairo-Egypt). The subarachnoid anesthesia block was assessed using the Bromage scale and pinprick for the desired motor and sensory block, which was Bromage scale 3 and T6, respectively. Oxygen at 4 L/minute was conducted via a nasal prong, and patients were covered with drapes but without active warming. Just after subarachnoid anesthesia, patients were randomized using the open envelope technique to one of the following three groups: (K) group = ketamine (ketamine hydrochloride, 50 mg/ml, ROTEXMEDICA GmbH, Germany) (0.2 mg/kg intravenously), (T) group = Tramadol (Tramadol Hydrochloride 50 mg/ml, Measham, DE12 7DT, England) (0.5 mg/kg intravenously) and (S) group = Normal saline (5 mL normal saline). The study medicines were given just after subarachnoid anesthesia administration as coded syringes by the anesthetist who was not included in the patient management. Furthermore, the study medicines and normal saline were prepared in coded 5 mL syringes and conferred to the responsible anesthetists who were blinded to study group allocations and were given as an intravenous bolus.

Tympanic membrane temperature ( Weich Allyn Braun Thermoscan® PRO 6000) and core temperatures (Nasopharyngeal thermometer) were observed and documented every 5 minutes until the end of the surgery. Shivering scores were reported every 5 minutes and every 10 minutes postoperatively for 60 minutes. Shivering was ranked using a scale similar to that validated by Tsai and Chu⁹ (Table 1).

A rescue drug was given intravenously in the form of Pethidine (25 mg) for patients who developed grade 3 or grade 4 shivering within 15 minutes of subarachnoid anesthesia despite giving a prophylactic dose of one of the study medicines.

Table 1: grades of shivering

Hemodynamic readings in the form of HR, MAP, and SPO2 were reported every 5 minutes intraoperatively and every 10 minutes postoperatively for 60 minutes.

Adverse events in the form of nausea and vomiting, hypotension, hallucinations and sedation were reported. If the patient’s heart rate declined below 50 bpm, atropine 0.5 mg was given intravenously. Also, hypotension was managed with 5 mg of ephedrine intravenously and crystalloids. If the patient exhibited grade 1and more nausea and vomiting, 10 mg of metoclopramide administered intravenously. The level of sedation was assessed according to a five-point range were [1] alert and oriented, [2] somnolent, [3] closed eyes, arousable on a verbal order, [4] closed eyes, arousable to physical stimuli and [5] closed eyes and patient unarousable to physical stimuli.

Sample  size  calculation  and  statistical analysis

The sample size estimated utilizing the conclusions of a former thesis, where the percentage of shivering following the cesarean section under SA after taking tramadol 0.5 mg/kg  was 16% (P =0.16). ¹⁵ The sample size calculated using 0.05% as an alpha value and 90% as a power. Data were analyzed using SPSS version 20 statistical package software.  Chi-square test was used to interpret the difference between ASA physical status, the number of patients developing shivering, the presence of nausea and vomiting, and hallucinations. Results are displayed as medians (interquartile range), and definite numbers of proportions are displayed as percentages. A p-value =0.05 was considered as statistically significant.

RESULTS

A total of 150 patients who underwent surgeries under subarachnoid anesthesia were enrolled in this study. Of these patients, 50 were allocated to the ketamine group (Group K), 50 to the Tramadol group (Group T) and 50 to the Normal saline group/placebo group (Group S).

Regarding demographic characteristics (age, weight, and height), ASA physical status, and duration of surgery, they were comparable and there were no significant differences among the groups (Table 2).

Table 2: Demographic and surgical characteristics. Notes: Data are presented as mean± SD or numbers (proportions).

Regarding recorded baseline hemodynamic data (mean arterial pressure), pulse rate and SPO2, there was no significant difference among all groups as shown in (Table 3). Preoperative tympanic temperatures were also comparable among the groups, and room temperatures were fixed for all patients(Table 3).

Table 3: Preoperative baseline data. Notes: Data are presented as mean±SD.

Regarding intraoperative fluids administered and total blood loss, there was no significant difference among all groups as shown in (table 4).

Table 4 :Intraoperative clinical characteristics Notes: Data are presented as mean±SD.

Regarding the incidence of shivering, shivering was seen in 28 patients (56%) in the tramadol group, 18 patients (36%) in the ketamine group and 35 patients (70%) in the normal saline group, and the overall incidence of shivering was 81/150 (54%; p0.03). Post hoc test showed that there was a significant difference among the groups (tramadol vs placebo and ketamine vs placebo p0.03). However, there was no significant difference between tramadol and ketamine groups (p0.261) as shown in (table 5).

Table 5: Incidence and percentage of shivering severity. Notes: Data are presented as mean±SD, numbers (percentage). *Chi-square test, **ANOVA test. p≤0.05 is significant.

Grade 2 shivering was recorded in 17 (34%) patients in the tramadol group and 11 (22%) patients in the ketamine group, whereas it was recorded in 10 (20%) patients in the normal saline group. The incidence of grade 3 shivering showed a statistically significant difference (p0.03) in the normal saline group (22 [44%]) as compared to the tramadol group (11 [22%]) and the ketamine group (7 [14%]).

The  time taken from the administration of the study drugs to the onset of shivering was statistically different among the groups (p0.001). Patients in the saline group had an earlier onset of shivering, as compared to patients in the tramadol (p0.001) and ketamine (p0.013) groups (Table 5)

In all groups, there was a significant decrease in both tympanic and core temperatures after subarachnoid anesthesia with respect to baseline values. Tympanic and core temperature changes over time in each group were statistically significant (p0.002); however, there were no significant differences among groups (Figure 1) and (Figure 2).

                 Figure (1) Changes in tympanic temperature with time in the intraoperative period among the groups

Figure (2) Changes in core temperature with time in the intraoperative period among the groups.

In the recovery room, the tympanic temperature was recorded every 10 minutes for 1 hour. The mean tympanic temperature increased in all groups with respect to T0 values (Tympanic temperature immediately after arrival in the recovery room), with p0.001. However, there was no significant difference in the temperatures measured at 50 and 60 minutes as shown in (Figure 3).

Figure (3) Changes in tympanic temperature with time in the postoperative period among the groups

Regarding perioperative complications such as hypotension, bradycardia, postoperative nausea and vomiting, and hallucination there were no significant differences among the study groups.

Hypotension was seen in eleven (22%) cases in the tramadol group, nine (18%) cases in the ketamine group and nine (18%) cases in the saline group. All hypotensive episodes were treated with IV crystalloid infusions and 5 mg of IV ephedrine. No patient in any group developed bradycardia.

The sedation score was below 3 in all of the patients. Grade 2 sedation was seen in five cases (10%) in the tramadol group and seventeen cases (34%) in the ketamine group. Hallucinations were not noted in any of the study groups (Table 6).

Nausea and vomiting were seen in seventeen (34%) patients in the tramadol group, eleven (22%) patients in the ketamine group and fourteen cases (28%) in the saline group, and there was no significant difference among the groups regarding the severity of nausea and vomiting (p0.100), as found in (Table 6).

Table (6): Incidence of perioperative complications.

Notes: group K = ketamine, group T = tramadol and group S = saline. * is considered significant.