Journal of Clinical Anesthesia (2013) 25, 275280

Original Contribution

Prophylactic ketamine to prevent shivering in parturients undergoing Cesarean delivery during spinal anesthesia
E.A. Kose MD (Assistant Professor)a,b,, M. Honca MD (Staff Anesthesiologist) c , D. Dal MD (Professor) d , S.B. Akinci MD (Professor)e , U. Aypar MD (Professor)e
Department of Anesthesiology and Reanimation, Kirikkale University, School of Medicine, Kirikkale, Turkey Department of Anesthesiology and Reanimation, Etlik Zubeyde Hanim Women's Health Education and Research Hospital, Ankara, Turkey c Department of Anesthesiology and Reanimation, Kecioren Teaching and Medical Research Hospital, Ankara, Turkey d Department of Anesthesiology and Reanimation, Marmara University, School of Medicine, Istanbul, Turkey e Department of Anesthesiology and Reanimation, Hacettepe University, School of Medicine, Ankara, Turkey
b a

Received 27 July 2012; revised 12 November 2012; accepted 21 November 2012

Keywords:
Anesthesia, obstetric; Cesarean section; Ketamine; Shivering, spinal anesthesia

Abstract Study Objective: To compare the efficacy and safety of ketamine 0.25 mg/kg with ketamine 0.5 mg/kg to prevent shivering in patients undergoing Cesarean delivery. Design: Prospective, randomized, double-blinded, placebo-controlled study. Setting: Operating rooms and postoperative recovery rooms. Patients: 120 ASA physical status 1 and 2 pregnant women scheduled for Cesarean delivery during spinal anesthesia. Measurements: Patient characteristics, anesthetic and surgical details, Apgar scores at 1 and 5 minutes, and side effects of the study drugs were recorded. Heart rate, mean arterial pressure, oxygen saturation via pulse oximetry, tympanic temperature, severity of shivering, and degree of sedation were recorded before intrathecal injection and thereafter every 5 minutes. Patients were randomized to three groups: saline (Group C, n=30), intravenous (IV) ketamine 0.25 mg/kg (Group K-0.25, n=30), or IV ketamine 0.5 mg/kg (Group K-0.5, n=30). Grade 3 or 4 shivering was treated with IV meperidine 25 mg and the prophylaxis was regarded as ineffective. Main Results: The number of shivering patients was significantly less in Group K-0.25 and in Group K-0.5 than in Group C (P = 0.001, P = 0.001, respectively). The tympanic temperature values of Group C were lower at all times of the study than in either ketamine group. Median sedation scores of Group K-0.5 were significantly higher than in Group K-0.25 or Group C at 10, 20, 30, and 40 minutes after spinal anesthesia. Conclusions: Prophylactic IV ketamine 0.25 mg/kg was as effective as IV ketamine 0.5 mg/kg in preventing shivering in patients undergoing Cesarean section during spinal anesthesia. 2013 Elsevier Inc. All rights reserved.

Correspondence: Emine Arzu Kose, MD, Kirikkale University, School of Medicine, Department of Anesthesiology and Reanimation, 71100-Kirikkale, Turkey. Tel.: + 90 318 225 2485/2263; fax: + 90 318 225 28 19. E-mail address: arzuhct@hotmail.com (E.A. Kose). 0952-8180/$ see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jclinane.2012.11.014

1. Introduction
Shivering is defined as a detectable fasciculation or tremor of the face, jaw, head, trunk, or extremities lasting longer than 15 seconds [1]. The incidence of shivering has been reported

276 to be about 36% to 85% after spinal anesthesia [2-4]. In a recent meta-analysis, the average incidence of shivering was 52% [2]. Spinal anesthesia impairs the thermoregulation system by inhibiting tonic vasoconstriction, which plays a role in temperature regulation [5]. Although the exact mechanism of shivering during spinal anesthesia is not known, hypotheses have been formed to explain the phenomenon [6-8]. Heat is internally redistributed from the core to the peripheral compartment. The loss of thermoregulatory vasoconstriction below the blockage results in increased heat loss from body surfaces in excess of metabolic heat production. There is altered thermoregulation characterized by a 0.5 C decrease in vasoconstriction and a slight increase in the sweating threshold. Shivering is the most disconcerting part of the birth experience to patients [9]. Ketamine may decrease core-to-peripheral redistribution of heat by direct central sympathetic stimulation and inhibition of norepinephrine uptake into postganglionic sympathetic nerve endings [10]. Intravenous (IV) ketamine 0.5 mg/kg was effective in the treatment and prevention of shivering after regional anesthesia, but patients experienced hallucinations [11-13]. The aim of this study was to compare the efficacy and safety of ketamine 0.25 mg/kg ketamine with ketamine 0.5 mg/kg as a prophylactic agent in the prevention of shivering in patients undergoing Cesarean section during spinal anesthesia.

E.A. Kose et al. recorded. Heart rate (HR), mean arterial pressure (MAP), and oxygen saturation via pulse oximetry (SpO2) were recorded before intrathecal injection and every 5 minutes thereafter during the perioperative period. Before intrathecal injection and at 10-minute intervals during the perioperative period, tympanic temperatures as measured by a Fist Temp Genius Model 3000 A aural canal thermometer (Sherwood Medical Co., St. Louis, MO, USA) were also recorded. Tympanic temperature recording and shivering assessment were continued two hours postoperatively. All patients were covered with one blanket over the chest, thighs, and calves during the operation, then one cotton blanket over the entire body postoperatively. All patients were actively warmed by forced-warm air (Warming Unit-Model 505 Bair Hugger; Arizant, Inc., Eden Prairie, MN, USA). Before receiving spinal anesthesia, each patient received 10 mL/kg/ hr of lactated Ringers solution. The infusion rates were then reduced to 6 mL/kg/hr. Spinal anesthesia was instituted at either the L3-L4 or L4-L5 interspaces with patients placed in sitting position. A 3 mL volume of hyperbaric bupivacaine (Marcaine spinal heavy 0.5%; AstraZeneca, Istanbul, Turkey) was injected using a 25gauge Quincke spinal needle (Becton Dickinson, Franklin Lakes, NJ, USA). Patients were randomized to three groups by sequentially numbered envelopes, to receive saline (Group C, n=30), ketamine 0.25 mg/kg (Group K-0.25, n=30), or ketamine 0.5 mg/kg (Group K-0.5, n=30). After intrathecal injection, drugs diluted to a volume of 3 mL in coded syringes were given as an IV bolus by an anesthesiologist who was blinded to study group allocation. Supplemental oxygen (5 L/ min) was delivered by facemask during the operation. Sensory block was assessed by pinprick test and the presence of shivering was assessed by a blinded observer. Shivering was graded on a scale similar to that which was validated by Tsai and Chu [14]: 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, 4 = shivering involving the whole body. The severity of shivering was recorded at 5minute intervals during the operation and in the recovery room. If Grade 3 or 4 shivering was noted after spinal anesthesia, IV meperidine 25 mg was administered. Side effects such as hypotension, bradycardia, nausea and vomiting, nystagmus, and hallucinations were recorded. If the patients HR decreased below 50 beats per minute (bpm), IV atropine 0.5 mg was administered. Hypotension was defined as a decrease in MAP of more than 20% from baseline and treated with a crystalloid infusion and, if necessary, IV ephedrine 5 mg. The amount of ephedrine given in each group was recorded. If patients developed nausea and vomiting, IV metoclopramide 10 mg was administered. Hallucination was defined as a false sensory experience in which the patient reported that she saw, heard, smelled, tasted, or felt something that was nonexistent. After administration of the study drugs, degree of sedation was assessed by a 5-point scale at 10-minute intervals during the

2. Materials and methods

After obtaining Ethics Committee approval from Etlik Zubeyde Hanim Women's Health Education and Research Hospital and written, informed consent, 120 healthy ASA physical status 1 and 2 pregnant women between the ages of 18 and 45 years, who presented for scheduled Cesarean delivery during spinal anesthesia, were enrolled in this randomized, placebo-controlled study. Patients with placenta previa, preeclampsia, Raynauds syndrome, hypothyroidism or hyperthyroidism, cardiopulmonary disease, psychological disorders, history of allergy to the study medications, initial body temperature N 38.0 C or b 36 C, known history of alcohol or substance abuse, and those who needed blood transfusion during surgery or who received medications likely to alter thermoregulation were excluded from the study. Operating room (OR) temperature was maintained at 23 C. Intravenous fluids were preheated to 37 C in a warmed cabinet and administered without inline warming. Patients did not receive premedication. Patients characteristics and other anesthetic and surgical data including age, ASA physical status, body mass index (BMI), gestation, parity, indication for Cesarean section, height of block, amount of fluid given intraoperatively, time from spinal anesthesia to incision, time from spinal anesthesia to wound dressing, total estimated blood loss (EBL), and Apgar scores at 1 and 5 minutes were

Prophylactic ketamine for shivering in parturients perioperative period [15]: 1 = fully awake and oriented, 2 = drowsy, 3 = eyes closed and rousable to command, 4 = eyes closed but rousable to mild physical stimulation, and 5 = eyes closed but unrousable to mild physical stimulation.
Table 1

277
Patient characteristics, anesthetic and surgical details Group C (n=30) Age (yrs) ASA physical status (1/2) Body mass index (kg/m2) Gestation (wks) Parity 0 1 2 Indication for Cesarean section previous Cesarean section maternal request other Sensory block cold touch Amount of intraoperative fluid (L) Time from spinal anesthesia to incision (min) Time from spinal anesthesia to wound dressing (min) Estimated blood loss (L) Apgar scores at 1st min Apgar scores at 5th min Group K-0.25 Group K-0.5 (n=30) (n=30) 28.2 (18-43) 25/5 26.9 5.9 38.6 1.0 6 15 9

2.1. Statistical analysis

Previous studies have found an incidence of 57% for shivering during regional anesthesia. We anticipated an incidence of 55% in the control group and regarded as clinically meaningful a difference of 40% in the frequency of shivering between the control and treatment groups. Twentyfour patients were required in each group in order to have a power of 80% for a type I error of 0.05 and type II error of 0.2. Statistical analysis was performed using the SPSS statistical package (version 11.5; SPSS, Inc., Chicago, IL, USA). Continuous variables, including hemodynamic data and temperature values over time within the groups, were analyzed using repeated-measures analysis of variance (ANOVA) followed by Bonferronis post hoc testing. Statistical comparisons among the groups were performed using one-way ANOVA, followed by Tukeys post hoc testing. Shivering scores and sedation scores were compared using the Kruskal-Wallis test, and the Mann-Whitney U test was used for two-group comparisons by Bonferroni correction if needed. Chi-square test was used to analyze the difference between ASA physical status, number of shivering patients, presence of nausea and vomiting, and hallucinations. Fishers Exact test was used when fewer than 5 patients were expected. Results are shown as medians (ranges) and means ( SD), and exact numbers of proportions are expressed as percentages. A P-value b 0.05 was considered statistically significant.

27.3 (18-43) 26.8 (20-45) 25/5 27/3 27.8 6.8 38.3 0.7 8 15 7 26.3 6.1 38.5 0.6 5 17 8

20 (66%) 7 (23%) 3 (11%)

17 (63%) 9 (30%) 4 (7%)

22 (71%) 7 (23%) 1 (6%) T3 (T2-T4) T4 (T4-T5) 1.8 0.4

T3 (T2-T4) T3 (T2-T4) T4 (T3-T5) T4 (T3-T4) 1.8 0.3 2.0 04

14 2.3

13 3.4

15 3.5

65 7

71 5

68 6

0.7 (0.5-0.7) 0.6 (0.5-0.8) 8 (6-9) 9 (8-9) 8 (7-9) 9 (8-9)

0.7 (0.5-0.7) 8 (7-9) 9 (8-9)

3. Results
One hundred twenty-three patients were approached for the study. Two patients were excluded due to psychological disorders and one patient due to hyperthermia. Patient characteristics and other anesthetic and surgical data, including age, ASA physical status, BMI, gestation, parity, indication for Cesarean section, height of block, amount of fluid given intraoperatively, time from spinal anesthesia to incision, time from spinal anesthesia to wound dressing, total EBL, and Apgar scores at 1 and 5 minutes were similar among the groups [Table 1]. Throughout the study, HR and SpO2 values were similar among the groups. However, differences were noted within the groups regarding MAP when compared with baseline values (P b 0.001). In addition, MAP values in Group C were the lowest of the three groups [Fig. 1]. The number of shivering patients differed significantly among groups at 15 minutes after spinal anesthesia (P b 0.001) [Table 2]. When posthoc comparisons were made, it

Data are means SD, medians (ranges), or numbers (proportions). Group C received saline (control group), Group K-0.25 received intravenous (IV) ketamine 0.25 mg/kg, and Group K-0.5 received IV 0.5 mg/kg.

was observed that the number of shivering patients was significantly less in Group K-0.25 and Group K-0.5 than Group C (P = 0.001, P = 0.001, respectively). There was no difference between Group K-0.25 and Group K-0.5 (P = 0.313). In Group C, 10 patients experienced shivering at Grade 3 and two patients at Grade 4. After treatment with IV meperidine 25 mg, shivering ceased in all patients. No patients in Group K-0.25 or Group K-0.5 required treatment for shivering. Shivering that required treatment ( Grade 3) was not observed in any of the patients during the postoperative period. There were statistically significant differences within the groups regarding tympanic temperature values when compared with baseline values (P b 0.001). In addition, while tympanic temperature values in Group K-0.25 and of Group K-0.5 were

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E.A. Kose et al.

Fig. 1 Change in mean arterial pressure (MAP) with time. Data are means (SD). *Statistically significant difference within groups when compared with baseline values; + statistically significant difference between the ketamine groups and the control group. MAP decreases were statistically significant in all groups when compared with baseline levels (P b 0.001). P b 0.001, Group C vs ketamine groups; P = 0.167, Group K-0.25 vs Group K-0.5.

Fig. 2 Changes in core temperature with time. Data are means (SD). *Statistically significant difference within groups when compared with baseline values; + statistically significant difference between the ketamine groups and the control group. P = 0.026, Group C vs Group K-0.25; P = 0.001, Group C vs Group K-0.5.

similar at all times of the study, tympanic temperature values in Group C were lowest at all times [Fig. 2]. Median sedation scores from Group K-0.5 were significantly higher than those in Group K-0.25 and Group C at 10, 20, 30, and 40 minutes after spinal anesthesia [Table 3]. Median scores from Group K-0.25 and Group C were similar at all study times. Data on hypotensive episodes, amount of administered ephedrine and atropine, and adverse effects are shown in Table 4. The frequency of hypertension, bradycardia, vomiting, and amount of atropine and metoclopramide given were similar among the groups. All hypotensive episodes were treated by crystalloid infusion and, if

necessary, IV ephedrine 5 mg. The frequencies of nausea, hypotension, tachycardia and amount of ephedrine given were higher in Group C than Group K-0.25 or Group K-0.5 (P = 0.020, P b 0.001, P = 0.020, P = 0.001; respectively) [Table 4]. The side effects of ketamine such as nystagmus and hallucinations were more often observed in Group K-0.5 than Group K-0.25 (P b 0.001, P = 0.010; respectively). Amnesia was noted in 9 (30%) Group K-0.5 patients and no Group K-0.25 patient (P = 0.001) [Table 4].

4. Discussion
Spinal anesthesia significantly impairs the thermoregulation system by inhibiting vasoconstriction, which plays a

Table 2 Number of patients with different grades of shivering in the three groups Grade 0/1/2/3/4 Group C (n=30) T0 T5 T10 T15 30/0/0/0/0 22/4/4/0/0 19/3/8/0/0 18/0/0/10/2 Group K-0.25 (n=30) 30/0/0/0/0 30/0/0/0/0 29/1/0/0/0 29/1/0/0/0 Group K-0.5 (n=30) 30/0/0/0/0 30/0/0/0/0 29/1/0/0/0 30/0/0/0/0

Table 3

Sedation scores of the patients in three groups Group C (n=30) Group K-0.25 (n=30) 1 (1-3) 1 (1-3) 1 (1-2) 1 (1-2) Group K-0.5 (n=30) 4 (1-5) 3 (1-4) 2 (1-4) 2 (1-3)

SS 10 SS 20 SS 30 SS 40

1 (1-1) 1 (1-1) 1 (1-2) 1 (1-1)

T0=baseline, T5/10/15=5, 10, 15 minutes. Group C received saline (control group), Group K-0.25 received intravenous (IV) ketamine 0.25 mg/kg, and Group K-0.5 received IV 0.5 mg/kg.

SS=Sedation score; SS10/20/30/40=10, 20, 30, and 40 minutes after spinal anesthesia. Group C received saline (control group), Group K-0.25 received intravenous (IV) ketamine 0.25 mg/kg, and Group K-0.5 received IV 0.5 mg/kg.

Prophylactic ketamine for shivering in parturients

Table 4 Adverse effects and amount of administered drugs for treatment in the three groups Group C Group K-0.25 Group K-0.5 (n=30) (n=30) (n=30) Nausea Vomiting Hypotension Hypertension Bradycardia Tachycardia Nystagmus Hallucination Amnesia Ephedrine (mg) Atropine (mg) Metoclopramide (mg) 13 (43.3) 6 (20.0) 15 (50.0) 0 (0) 2 (6.7) 13 (43.3) 0 (0) 0 (0) 0 (0) 13 (43.3) 2 (6.7) 8 (26.7) 6 4 5 0 1 6 3 0 0 2 1 3 (20.0) (13.3) (16.7) (0) (3.3) (20.0) (10.0) (0) (0) (6.7) (3.3) (10.0) 4 (13.3) 1 (3.3) 2 (6.7) 1 (3.3) 0 (0) 4 (13.3) 16 (53.3) 6 (20.0) 9 (30.0) 4 (13.3) 0 (0) 2 (6.7)

279 ephedrine given to Group K-0.25 and Group K-0.5 is explained by the same mechanism [Table 4]. The number of shivering patients was significantly lower in Group K-0.25 and Group K-0.5 than Group C (P = 0.005, P = 0.002, respectively). Ten patients experienced shivering at Grade 3 and two patients at Grade 4 in Group C. After treatment with IV meperidine 25 mg, shivering ceased in all patients. No patients in Group K-0.25 or Group K-0.5 required treatment for shivering [Table 2]. Ketamine causes sympathetic stimulation and vasoconstriction in patients at risk of hypothermia. Ketamine, which is a competitive receptor antagonist of N-Methyl-D-aspartic acid (NMDA), plays a role in thermoregulation at various levels. NMDA receptors modulate the noradrenergic and serotonergic neurons in the locus coeruleus and consequently the NMDA receptors in the dorsal horn of the spinal cord [16]. Ketamine has other pharmacological properties such as blocking uptake in the descending inhibitory monoaminergic pain pathways, interacting with muscarinic receptors, having a local anesthetic action, and being a kappa opioid agonist. Ketamine probably controls shivering by nonshivering thermogenesis, either by action on the hypothalamus or by the -adrenergic effect of norepinephrine [13]. The exact mechanism of ketamine is not clear [11-13,16]. The median sedation scores of the Group K-0.5 were greater than Group K-0.25 at 10, 20, 30, and 40 minutes of the study. There were no statistically significant differences between Group K-0.25 and Group C regarding sedation scores at any times [Table 3]. In this study, 9 (30%) of the patients in Group K-0.5 did not remember delivery of their babies because of the heavy sedation and amnestic effect of ketamine. On the other hand, none of the patients in Group K-0.25 had sedation scores greater than 3 or described amnesia [Tables 3, 4]. Nystagmus and hallucination, well-known side effects of ketamine, were more common in Group K-0.5 than Group K0.25 [Table 4]. While Sharma and Thakur [13] reported that two of 20 patients from their study had hallucinations due to the administration of IV 0.5 mg/kg of ketamine, we observed hallucinations in 6 of the 30 patients in Group K-0.5 and no patient of Group K-0.25. Intravenous ketamine 0.25 mg/kg was as effective as IV ketamine 0.5 mg/kg in preventing shivering in patients undergoing Cesarean section during spinal anesthesia and lacked serious adverse effects.

Data are frequencies (percentages). Group C received saline (control group), Group K-0.25 received intravenous (IV) ketamine 0.25 mg/kg, and Group K-0.5 received IV 0.5 mg/kg.

significant role in temperature regulation [5]. A number of factors, including age, level of sensory block, OR temperature, amount of blood loss, and duration of the operation are risk factors for hypothermia in regional anesthesia [3]. In this study, OR temperature was maintained at 23 C, all fluids were preheated to 37 C, and all patients were warmed by a forced air-warming system during the surgery. Other risk factors such as age, level of sensory block, amount of blood loss, and duration of the operation were similar among the groups. The incidence of intraoperative shivering during Cesarean section has been reported to be as high as 60%. Fifteen minutes after spinal anesthesia, shivering was observed in 40% of patients in Group C in the present study. The relatively low incidence of shivering in the control group of our study may be attributable to the additional preventive measures against the development of hypothermia such as warming of all patients by forced air-warming system and warming of all IV fluids to 37 C. The decreases in core temperatures were statistically significant in all groups when compared with baseline values (P b 0.001). In addition, tympanic temperature values of Group C were lower at all times after spinal anesthesia than they were in either ketamine group [Fig. 2]. Although the mean core temperature values of Group K-0.5 were higher than those of Group K-0.25, there was no statistically significant difference between these two groups. Similarly, in the Sagir et al study, the decrease of core temperature seen in the control group was significantly more than the groups given ketamine [11]. Likewise, the mean core temperature values of the control group were lower than in the ketamine groups in the study reported by Honarmand and Safavi [12]. This relative preservation of core temperature in the ketamine groups may be attributed to the sympathetic stimulation and vasoconstrictive effects of the drug. Furthermore, the fewer incidents of hypotensive episodes and the lesser amount of

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