|Year : 2019 | Volume
| Issue : 2 | Page : 88-93
Sub-anaesthetic bolus dose of intravenous ketamine for postoperative pain following caesarean section
Anil Kumar Bhiwal, Vartika Sharma, Karuna Sharma, Anuj Tripathi, Sunanda Gupta
Department of Anaesthesiology, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India
|Date of Submission||27-Apr-2019|
|Date of Acceptance||06-Jun-2019|
|Date of Web Publication||06-Sep-2019|
Dr. Anil Kumar Bhiwal
B-2/S-4 Doctor Quarter, Geetanjali Medical College and Hospital, Udaipur - 313 001, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Effective postoperative analgesia following Caesarean Section is important because parturients are at a higher risk for thromboembolic events due to immobility, increased likelihood of developing postpartum depression (PPD) following inadequate pain control which also can interrupt breastfeeding. Ketamine at sub anesthetic doses has been considered to reduce postoperative pain and analgesic consumption following caesarean section. Aims: The aim of this study was to evaluate the efficacy of sub anesthetic doses of ketamine on post caesarean analgesia. Material and Methods: This randomized double blind, placebo controlled study was conducted on 108 parturients, divided into three groups (36 in each group);Group C- received 2 ml of 0.9% normal saline; Group Ka- received 0.15 mg/kg of ketamine (2 ml) and Group Kb- 0.3 mg/kg of ketamine (2 ml) after 5 min of delivery. Postoperatively VAS score, consumption of rescue analgesic in 24 h and adverse effects were recorded. Statistical analysis was done with Analysis of variance (ANOVA) for continuous variables and Chi-square test for categorical scale. P values less than 0.05 were considered significant. Results: Postoperative VAS scores were significantly higher in control group while the time to the first analgesic requirement was significantly prolonged in Ka group (5.44 ± 1.45 h) and Kb group (6.18 ± 1.61 h) as compared to the control group (4.97 ± 1.48 h). The total number of doses and total dose of rescue analgesic (tramadol) required in 24 hours was significantly less in the Ka group (194.44 ± 53.15 mg) and Kb group (152.78 ± 50.63 mg) as compared to group C (136.11 ± 48.71 mg. Conclusion: Administration of sub-anesthetic doses (0.15 mg/kg and 0.3 mg/kg) of intravenous ketamine enhanced postoperative analgesia and reduced the total rescue analgesic consumption in first 24 h following CS. Ketamine 0.3 mg/kg also increased the time to first postoperative rescue analgesic request.
Keywords: Caesarean section, ketamine, postoperative analgesia, spinal anesthesia
|How to cite this article:|
Bhiwal AK, Sharma V, Sharma K, Tripathi A, Gupta S. Sub-anaesthetic bolus dose of intravenous ketamine for postoperative pain following caesarean section. J Obstet Anaesth Crit Care 2019;9:88-93
|How to cite this URL:|
Bhiwal AK, Sharma V, Sharma K, Tripathi A, Gupta S. Sub-anaesthetic bolus dose of intravenous ketamine for postoperative pain following caesarean section. J Obstet Anaesth Crit Care [serial online] 2019 [cited 2020 Jan 28];9:88-93. Available from: http://www.joacc.com/text.asp?2019/9/2/88/266141
| Introduction|| |
Effective postoperative analgesia following Caesarian Section (CS) is important because parturients are at a higher risk for thromboembolic events due to immobility following inadequate pain control. The presence of severe pain during 36 hours after CS has been associated with an increased likelihood of developing postpartum depression (PPD) and reduces the ability for effective breastfeeding.,,
The analgesic of choice requires minimal transfer in the breast milk to reduce the effects on neonate, the analgesic should have least maternal side effects including bradycardia, respiratory depression, arterial hypotension, vomiting and pruritus and minimal or no interference with caring for newborn or discharge from hospital.,
Multimodal therapy for postoperative analgesia blocks multiple pain pathways while minimizing side effects of each individual pain medication. Various drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, opioids, tramadol, local anesthetics and α-2 receptor agonists have been used to control the postoperative pain following CS. Use of opioid-free analgesia should be preferred in the perioperative period to reduce adverse effects like nausea, vomiting, pruritus, and respiratory depression.,
There is growing evidence that Ketamine which is an N-methyl-D-aspartate (NMDA) receptor antagonist is efficacious when used as an adjuvant for postoperative pain control. Ketamine binds noncompetitively to the phencyclidine binding site of NMDA receptors, modifies them via allosteric mechanisms and inhibits the NMDA receptor-mediated pain facilitation. Its prolonged analgesic effect despite its short half-life and its use in subanesthetic doses is theorized to be due to blockade of spinal cord central sensitization. Ketamine also inhibits the opioid receptor internalization and activates monoaminoergic descending inhibitory pathways at supraspinal sites resulting in antinociception and prevents opioid-induced hyperalgesia and acute tolerance. When used at sub-anesthetic doses (<0.3 mg/kg), it provides analgesia with less pronounced psychoactive side effects.
Consensus guidelines on the use of intravenous ketamine for acute pain management from the American Society of Regional Anaesthesia and Pain Medicine, the American Academy of Pain Medicine and the American Society of Anaesthesiologists 2018 supports the use of sub-anesthetic bolus dose of ketamine up to 0.35 mg/kg and infusions up to 1 mg/kg/hour for acute pain as adjuncts to opioids for perioperative analgesia. We hypothesized that low dose intravenous ketamine if added to multimodal analgesic regimen would provide adequate post caesarean analgesia. This study was designed to assess the efficacy of subanesthetic doses of ketamine on post caesarean analgesia.
| Material and Methods|| |
After obtaining approval from the Institutional Research Ethics Board and written informed consent this study was conducted on 108 parturient aged 18–45 years, at term (≥37-week gestation), American Society of Anaesthesiologists (ASA) physical status 1 or 11, undergoing Caesarian Section under spinal anesthesia. Parturient with known allergy to ketamine, contraindications to spinal anesthesia, any associated comorbid conditions, long-term opioid use and history of chronic pain were excluded from the study.
Study design and group allocation
A total of 108 parturients were randomized into three groups (36 in each group) using computer generated random number table and allocation concealment was done by envelope method. The operating theatre technician who was not involved in care of the parturient prepared the drug solution. The parturient and the anesthesiologist involved in the anesthetic management were unaware of contents of the solution administered. The study drugs were administered intravenously 5 minutes after delivery of the baby as per the following protocol: Group C- received 2 ml of 0.9% normal saline; Group Ka- received 0.15 mg/kg of ketamine (2 ml) and Group Kb- 0.3 mg/kg of ketamine (2 ml).
Procedure and conduct of the study
Parturients were preloaded with lactated Ringer's solution at 10 ml/kg after securing an IV access with 18 G cannula and pre-medicated with ranitidine 50 mg and metoclopramide 10 mg IV half an hour before spinal anesthesia. In the operating room baseline values of blood pressure (BP), heart rate, and oxygen saturation were recorded.
The spinal anesthesia was performed with 12.5 mg of 0.5% bupivacaine heavy using 25-gauge pencil point needle at L3-L4/L4-L5 interspace in sitting position. Immediately after the SAB, patients were repositioned supine with a 15° wedge below the right buttock to achieve left uterine tilt. Sensory block was assessed by pinprick method in mid clavicular line bilaterally at 1-minute interval and surgery were allowed when the block height was achieved at T6 level. Motor block was assessed by the Modified Bromage Score at 1-minute interval. Oxygen was administered through simple face mask at 4 L/min. Hemodynamic variables like heart rate (HR), systolic BP, diastolic BP, mean arterial Pressure (MAP), and peripheral oxygen saturation were monitored at 2, 4, 6, 8, 10, 15, and 20 minutes following spinal anesthesia. Hypotension was defined as a fall in MAP greater than 20% below the pre-anesthetic baseline value and was treated with 100 ml IV fluid bolus and ephedrine 5 mg. Bradycardia was defined as HR <50 beats per minute and treated with atropine 0.6 mg IV The study drug was administered intravenously 5 minutes after delivery of the baby based on group allocation. The APGAR score was recorded for all the neonates at 1 and 5 min. Every patient received diclofenac Na suppository 100 mg after completion of surgery.
Postoperative pain was evaluated by VAS score (0 = no pain; 10 = worst pain imaginable) at 2, 6, 10, 12, 24 h and tramadol 100 mg intravenously was given as rescue analgesic when VAS ≥4. The time interval from the intrathecal injection of anesthetic solution to the first request of analgesic drug, the total number of doses and the total dose of analgesic required in 24 h were recorded. Postoperative sedation was recorded at different time intervals (after completion of surgery, 2 h, 4 h, and 6 h) using the Ramsey Sedation Score (1 = cooperative, oriented, 2 = responds to commands only, 3 = brisk response to light glabellar tap or loud noise, 4 = sluggish response to light glabellar tap or loud noise, 5 = no response).
Postoperative nausea and vomiting (PONV) and pruritus in the first 24 hours following CS was recorded and was treated with ondansetron 4 mg and dexamethasone 8 mg, respectively.
Postoperative complaints of disturbing dreams were recorded until 72 hours following CS and was treated with midazolam 1 mg IV. Satisfaction score by the patient was recorded after 24 hours as excellent/satisfactory/non satisfactory.
Sample size calculation
With the assumption of alpha error to be 5% and beta error to be 20% i.e., 95% confidence level and 80% power of study, assumption of exposed group was taken to be 95% with 10% margin of error. Therefore, sample of 36 patients were taken for each group with a minimum number of 108 patients.
Statistical analysis was done using SPSS software (version 17, SPSS, Chicago, IL). Data was presented as mean, standard deviation, median (range), or percentage, as appropriate. Analysis of variance (ANOVA) was used to find the significance between three groups of parturients for continuous variables and paired t-test was used for intergroup comparison. Chi-square test was used to find the significance of study parameters on categorical scale. P values less than 0.05 were considered significant.
| Results|| |
One hundred and eight parturients were enrolled in the study. There were no significant difference between the three groups regarding demographic data like age, weight, height, and gestation week, the spinal to incision time and duration of surgery. (P > 0.05) APGAR score at 1 and 5 minutes was also comparable between the three groups (P > 0.05) as ketamine was administered intravenously 5 minutes after the delivery of the baby [Table 1].
We observed no significant difference in mean arterial pressure (MAP), HR intraoperatively at different time intervals between the three groups. The incidence of hypotension and requirement of ephedrine was also found to be statistically non-significant.
Postoperative VAS score was found to be highly statistically significant between the three groups after 2 h (P < 0.001) and statistically significant after 10 h and 12 h (P < 0.05) but there was no significant difference in VAS score at 6 h and 24 h among the three groups (P > 0.05) [Figure 1].
|Figure 1: Comparison of VAS score at different time intervals after surgery among the groups|
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The time to the first analgesic requirement (hours) was prolonged in Ka group (5.44 ± 1.45) and Kb group (6.18 ± 1.61) as compared to the control group (4.97 ± 1.48) and was found to be statistically significant (P < 0.05) [Figure 2]. The total number of doses and total dose of rescue analgesic required in 24 hours was less in the Ka group and Kb group as compared to the group C which was found to be highly statistically significant (P < 0.001). However, when Ka and Kb group was compared the significant difference was found only in time to first analgesic request (P = 0.045) [Table 2].
|Figure 2: Comparison of time to the first analgesic request (hours) in different groups|
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|Table 2: Comparison of postoperative rescue analgesic (tramadol) requirement (Data represented as mean±SD)|
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The incidence of nausea, vomiting was greater in the control group (75%) as compared to the Ka (66%) and Kb (52.17%) groups which was found to be non-significant (P = 0.14). The incidence of pruritus was significantly greater in group C (25%) when compared to group Ka (2.7%) and Kb(8.3%) (P = 0.01). Only two patients in group Kb reported disturbing dreams in 24 h [Table 3].
|Table 3: Comparison of postoperative side effects, satisfaction score, sedation score|
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Satisfaction score after 24 h was found to be excellent in 2 patients (5.5%) in group Ka and 7 patients (19.4%) in group Kb. All patients (100%) in group C reported a satisfactory score while it was reported by 34 patients (94.4%) in group Ka and 29 patients (80.5%) in group Kb. None of the patients in the three groups reported non-satisfactory score [Table 3].
Sedation score between the three groups was found to be statistically non-significant (P > 0.05) at different time intervals [Table 3].
| Discussion|| |
Ketamine exerts its analgesic property in acute pain through reversible antagonism of N-methyl D-aspartate receptors and its effect on μ opioid receptors, muscarinic receptors, monoaminergic receptors and γ-aminobutyric receptors and possesses least psychomimetic effects., Various studies have reported that low dose of IV ketamine (≤0.3 mg/kg) are effective in reducing the analgesic requirements in first 24 h after surgery.,,
In our study, group C patients experienced more postoperative pain with significantly higher VAS scores at 2 h, 10 h, and 12 h following surgery (P < 0.05). The lower VAS scores in ketamine groups have been reported to have the advantages of early maternal-child bonding and early initiation of breastfeeding. Similarly, Rahmanian M et al. showed higher postoperative VAS scores at 1 h, 2 h, 6 h and 12 h in the control group, Menkiti ID et al. found higher postoperative VAS scores until 150 min in the control group, Sen S et al. also showed higher VAS score at 90 min, 150 min, 180 min in control group. In contrast to our study, Bauchat JR et al. did not show any significant differences in the NRS scores between both groups in the first 24 h following surgery which could be attributed to the use of a multimodal analgesic regimen in their study by adding fentanyl 15 μg and morphine 150 μg intrathecal to 12 mg hyperbaric bupivacaine during spinal anesthesia and by providing standard postoperative analgesic regimen with scheduled IV ketorolac 30 mg IV every 6 h for 24 h in all patients. Similarly, Han SY et al. and Suppa E et al. did not show any significant differences in postoperative VAS scores which could be explained by the use of opioid as rescue analgesic by PCA device at regular intervals in both the groups.
The time to first request for rescue analgesic drug postoperatively was found to be significantly longer in the Kb group (6.18 ± 1.61 h) than the Ka group (5.44 ± 1.45 h) and control group (4.97 ± 1.48 h) P < 0.05. In our study, the postoperative total rescue analgesic consumption in 24 h (tramadol 100 mg) was significantly lower in both Kb group (136.11 ± 0.49 mg) and Ka group (152.78 ± 50.63 mg) as compared to the control group (194.44 ± 53.15 mg) P < 0.001. Similarly, Menkiti ID et al. found that the mean time of first postoperative analgesic administration was longer with a mean difference of 44 min and postoperative diclofenac and pentazocine consumption was lower in ketamine group. Sen S et al. showed that the time to first request for postoperative analgesia was greater in ketamine group with a mean difference of 30 min and reduced 24 h intramuscular diclofenac requirements. Rahmanian et al. also reported a delayed time to first request of analgesia by 80 minutes in ketamine group. This markedly prolonged duration of analgesia may be accounted for by the additive effect of intraoperative ketamine on postsynaptic NMDA blockade (reducing wind-up and central sensitization) and use of morphine responsible for the presynaptic opioid inhibition (reducing afferent transmission) in their postoperative analgesic regimen. In contrast, Bauchat et al. did not show any significant difference in the time to first rescue analgesic request and total dose of rescue analgesic between both groups as ketamine was given after delivery of fetus and NMDA receptors may have been sensitized before ketamine administration. The larger analgesic requirements due to patient group differences in terms of threshold of pain in our western counter parts and the use of a multimodal analgesic regimen in their study which may have masked the small analgesic benefit of low-dose ketamine. Han SY et al. also did not find significant difference in requirement of postoperative analgesia. This could be explained as fentanyl was used for PCA in all patients till 48 h postoperatively in their study.
Evidence has shown that the postoperative pain is caused by both peripheral and central sensitization. Following the stimulation of free nerve endings by surgical incision, cutting and traction, chemical mediators of pain like bradykinin and prostaglandin maintains the pain for a longer time with resultant primary hyperalgesia. The development of secondary hyperalgesia is induced by peripheral sensitization when facilitation of A-α and A-β nerve fibers occurs. Since chemical mediators continue to be released following the initial insult, their effects must be prevented for a longer time than the duration of action of single dose of analgesia administered. Clinical trials using low-dose ketamine have suggested a number of mechanisms for its analgesic effect which includes activation of monoaminergic descending inhibitory pathways at supraspinal sites, prevention of acute opioid tolerance and suppression of central sensitization, a phenomenon by which dorsal root neurons increase their spontaneous discharge rate and responsiveness and enlarge their receptive field in response to repeated painful stimulus. Low dose IV ketamine used in our study may have reduced pain and delayed the onset of central sensitization. Although this effect of ketamine may be due to antagonism of spinal NMDA receptor sites, it can also act on several opioidergic and cholinergic receptor types.
All patients in the control group had a Ramsey sedation score of one after completion of surgery, 2 h, 4 h, and 6 h postoperatively while only one patient (2.7%) in group Ka and two patients (5.5%) in group Kb reported mild sedation (Ramsey sedation score 2) at the completion of surgery and none of the patients scored more than two in both ketamine groups at other time intervals. Similarly, mild sedation was reported by Menkiti ID et al. in 3 (9%) patients, Sen et al. observed mild sedation in only two patients (6.6%), Ebong EJ et al. reported a maximum Ramsey sedation score of two in ketamine group probably caused by the CNS depressant effect of ketamine. Bauchat et al. assessed sedation using Richmond agitation-sedation scale at 5 min following study drug infusion and reported restlessness and drowsiness significantly more in the ketamine group as compared to saline group (P = 0.03) while 35% patients in ketamine group complaint of light-headedness, dizziness, and double vision compared to 8% in saline group which occurred only during infusion and had no lasting effects, postoperatively.
In our study, the incidence of postoperative nausea and vomiting (PONV) was found higher in control group (38%) than the Ka (25%) and Kb (19.4%) group, but the difference was statistically nonsignificant (P = 0.14) while the total dose of IV ondansetron required for PONV in the first 24 h following surgery was found significantly less in the ketamine groups (P < 0.05) which could be explained by less requirement of rescue analgesic (tramadol 100 mg IV) in the Kb group as compared to the Ka and control group. Similarly, Rahmanian M et al., Reza et al., Haliloglu M et al., Bauchat et al. reported no significant difference in the occurrence of nausea and vomiting between the ketamine group and control group.
In our study, pruritus was significantly more common in the control group (25%) as compared to Ka (8.3%) and Kb(2.7%) groups and similar results was found by Rahmanian M et al.
In our study the lower incidence of disturbing dreams could be explained by the use of subanesthetic doses of ketamine. Similarly, Bilgen S et al. found that there was only one patient who reported postoperative hallucination in the ketamine group while Menkiti ID et al. and Haliloglu M et al. found that no patient in either group exhibited psychomimetic phenomenon. Rahmanian M et al. showed a greater prevalence of hallucination in the ketamine group. The differences in the type of anesthesia, sample size, dose of ketamine and the time of administration of ketamine might have contributed to the different findings.
There are some limitations in our study. We could not assess the efficacy of subanesthetic doses of ketamine for preemptive analgesia. We did not measure central sensitization as we recorded pain scores only in the immediate postoperative period up to 24 h following surgery. We did not find out how ketamine might affect different components of pain as global pain scores. We did not study antidepressant effects in the postpartum period. Mood-altering effect of ketamine and its effect on chronic post CS pain can also be studied in future.
In conclusion, administration of two different subanesthetic doses (0.15 mg/kg and 0.3 mg/kg) of intravenous ketamine in our study enhanced postoperative analgesia in women undergoing CS under spinal anesthesia without any significant side effects and reduced the total rescue analgesic consumption in first 24 h following CS, with an additional benefit offered by 0.3 mg/kg IV ketamine in increasing the time to first postoperative rescue analgesic request.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Yost NP, Bloom SL, Sibley MK, Lo JY, McIntire DD, Leveno KJ. A hospital-sponsored quality improvement study of pain management after caesarean delivery. Am J Obstet Gynecol 2004;190:1341-6.
Rowemarry HJ, Fisher JRW. Baby friendly hospital practices; Caesarean section is a persistent barrier to early initiation of breast feeding. Birth 2002;29:124-30.
Eisenach JC, Pan PH, Smiles R. Persistent pain after caesarean section and vaginal birth: A cohort study. Int J Obstet Anesth 2010;19:4-9.
Bar-Oz B, Bulkowstein M, Benyamini L. Use of antibiotic and analgesic drugs during lactation. Drug Saf 2003;26:925-35.
Wittels B, Glosten B, Faure EA. Postcaesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: Neurobehavioural outcomes among nursing neonates. Anesth Analg 1997;85:600-6.
Weinbroum AA. Non-opioid IV adjuvants in the perioperative period: Pharmacological and clinical aspects of ketamine and gabapentinoids. Pharmacol Res 2012;65:411-29.
Cassuto J, Wallin G, Högström S, Faxén A, Rimbäck G. Inhibition of postoperative pain by continuous low-dose intravenous infusion of lidocaine. Anesth Analg 1985;64:971-4.
Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl D-Aspartate (NMDA) receptors in pain: A review. Anesth Analg 2003;97:1108-16.
Woolf CJ, Chong MS. Preemptive analgesia- treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362-79.
Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006:CD004603.
Laskowi K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011;58:911-23.
Elia N, Tramer MR. Ketamine and postoperative pain- A quantitative systematic review of randomized trials. Pain 2009;113:61-70.
Menkiti ID, Kushimo DOT. Low-dose intravenous ketamine improves postoperative analgesia after caesarean delivery with spinal bupivacaine in African parturients. Int J Obstet Anesth 2012;21:217-21.
Sen S, Ozmert G, Aydin ON, Baran N, Cahskan E. The persisting analgesic effect of low-dose intravenous ketamine after spinal anaesthesia for caesarean section. Eur J Anaesthesiol 2005;22:518-23.
Ebong EJ, Mato CN, Fyneface-Ogan S. Pre-incisional intravenous low-dose ketamine does not cause pre-emptive analgesic effect following Caesarean Section under Spinal anaesthesia. J Anaesth Clin Res 2011;2:138.
Rahmanian M, Leysi M, Hemmati AA, Mirmohammadkhani M. The effect of low-dose intravenous ketamine on postoperative pain following caesarian section with spinal anaesthesia: A randomized clinical trial. Oman Med J 2015;30:11-6.
Bauchat JR, Higgins N, Wojciechowski KG, McCarthy RJ, Toledo P, Wong CA. Low-dose ketamine with multimodal postcesarean delivery analgesia: A randomized controlled trial. Int J Obstet Anesth 2011;20:3-9.
Han Yeup S, Jin Cheol H, Yang Dae W, Lee HJ, Cho HB, Chae SW, et al
. The effect of low-dose ketamine on post-caesarian delivery analgesia after spinal anaesthesia. Korean J Pain 2013;26:270-6.
Suppa E, Valente A, Catarci S, Zanfini A, Draisci G. A study of low-dose S-ketamine infusion as “preventive” pain treatment for caesarean section with spinal anesthesia: Benefits and side-effects. Minerva Anesthesiol 2012;78:774-81.
Ghazi K, Hajipour A. Effects of pre-emptive ketamine on post-caesarean analgesic requirement. Acta Med Iranica 2002;40:100-3.
Rowlingson JC. Advances in acute pain management. IARS Rev Course Lectures 2000;65-72.
Haliloglu M, Ozdemir M, Uzture N, Cenksoy PO, Bakan N. Perioperative low-dose ketamine improves postoperative analgesia following caesarean delivery with general anaesthesia. J Matern Fetal Neonatal Med 2016;29:962-6.
Bilgen S, Koner O, Ture H, Menda F, Ficicioglu C, Aykac B. Effect of three different doses of ketamine on postoperative pain following caesarean delivery: A prospective randomized study. Minerva Anesthesiol 2012;78:442-9.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]