Comparison of levobupivacaine versus ketamine and levobupivacaine for ultrasound-guided adductor canal block in patients undergoing unilateral total knee replacement: A randomized, double-blinded study

Abstract

Background and Aims:

Ultrasound-guided adductor canal block (ACB) has been increasingly used for postoperative analgesia in total knee replacement (TKR) surgery patients. We hypothesized that the addition of ketamine to levobupivacaine in ultrasonograsonography (USG)-guided ACB would result in prolonged and better postoperative analgesia in patients undergoing TKR.

Material and Methods:

This randomized prospective study was conducted on 90 patients undergoing unilateral TKR. In Group LK (n = 45), levobupivacaine 0.25% plus ketamine 1 mg/kg (total volume 20 ml) was given, and in Group L (n = 45), 20 ml of 0.25% levobupivacaine was given. The primary objective was to compare the pain-free interval, i.e. the time until the first dose of rescue analgesia, between Group LK and Group L. The secondary objectives were to assess the amount of rescue analgesic, pain scores, and complications.

Results:

We observed that the time to the first dose of rescue analgesia in Group LK (9.33 h ± 2.17) was significantly longer than in Group L. (5.02 h ± 1.63) (P value = 0.001; Cohen’s d = 2.243). The total dose of rescue analgesic was significantly lower in Group LK (188.89 mg ± 48.72) compared to Group L (271.11 mg ± 50.55) (P value = 0.001). Patients in Group L had significantly higher numerical rating scale compared to Group LK at rest at 4, 6, and 12 h and on movement at 2, 4, 6, and 12 h postoperatively.

Conclusions:

The addition of ketamine to levobupivacaine in ACB resulted in prolongation of the pain-free interval, decreased requirement for rescue analgesia, and better pain control during rest and movement.

Introduction

Total knee replacement (TKR) is one of the most commonly performed orthopaedic surgeries in elderly patients, with approximately 27000 cases performed in India in 2019.[1] The procedure causes intense postoperative pain, the management of which is a major task for anaesthesiologists.[2] Multimodal analgesic regimens are available for postoperative analgesia, comprising systemic opioids, local anaesthetic (LA) infiltration, epidural blocks, and peripheral nerve blocks (PNB).[3] However, each modality has its associated side effects. The use of opioids can cause adverse effects such as nausea, sedation, vomiting, pruritus, and reduced respiratory drive.[3] Epidural analgesia may cause hypotension and urinary retention, and it may be challenging to perform in elderly patients because of spine abnormalities. A femoral nerve block can cause extreme quadriceps muscle weakness.[4] These effects delay early ambulation and, hence, the discharge of patients from the hospital.

The ultrasound-guided adductor canal block (ACB) involves injecting LA deep into the sartorius muscle inside the adductor canal and is a reliable and easy method to block the saphenous nerve.[5] As blocking the saphenous nerve only blocks sensory supply to the limb, quadriceps muscle strength is better preserved than with the femoral nerve block, thus facilitating early postoperative mobilisation of the limb.[6] Performing ACB under ultrasound guidance helps to enhance the quality of the block by allowing accurate positioning of the tip of the needle while injecting at a more precise location.[7] The role of ACB for postoperative pain relief in patients who have undergone TKR surgeries has been proven in various studies.[2,8]

Levobupivacaine, an amide LA, is the S (−) stereoisomer of dextro-bupivacaine. It is less cardiotoxic compared to bupivacaine.[9] However, levobupivacaine has a limited period of analgesia.[7] This warrants the need to add adjuvants to increase the duration of the block.

Ketamine, an N-methyl-D-aspartate receptor antagonist, has central, local, and regional anaesthetic as well as analgesic properties.[7] Ketamine has been used as an adjuvant with LA by various routes in studies and has been found to provide better postoperative analgesia and enhance the effect of LA drugs.[7,10,11]

To the best of our knowledge, there are no studies comparing the usage of levobupivacaine with ketamine in ACB in the available literature. We hypothesise that the addition of levobupivacaine with ketamine in ultrasonography (USG) guided ACB would result in prolonged and better postoperative analgesia in patients undergoing TKR surgery. The primary objective of our study was to compare the pain-free interval, i.e. the time until the first dose of rescue analgesia, between levobupivacaine and levobupivacaine plus ketamine in ACB in unilateral TKR patients. Our secondary objective was to assess the amount of rescue analgesia required after using levobupivacaine versus levobupivacaine plus ketamine in ACB in unilateral TKR patients.

Material and Methods

This double-blinded, prospective, randomised study was conducted on 90 patients who were randomly divided into two groups of 45 patients each (1:1) after approval from the Institutional Ethical Committee [IEC letter no: 267 dated 25.10.2022]. This trial was registered at the Clinical Registry– India (CTRI) with registration number CTRI/2023/05/052456, dated 10/05/2023 [Figure 1]. Written informed consent was obtained from the patients. This manuscript adheres to the applicable EQUATOR guidelines.

Figure 1.

Consort flow diagram. CONSORT = Consolidated Standards of Reporting Trials, n = number of patients, BMI = body mass index

The eligible candidates were patients aged between 18 and 75 years, American Society of Anaesthesiologists (ASA) Class I and II, undergoing unilateral TKR under spinal anaesthesia. During the preanesthesia visit, patients were familiarised with the numerical rating scale (NRS) (0–10, with 0 = no pain, 10 = worst pain ever).[12] Patients with a known history of allergic reaction to lignocaine, levobupivacaine, and ketamine; body mass index (BMI) >35 kg/m²; pre-existing peripheral neuropathy or neurological deficit in the lower extremities; coagulopathy; infection at the site of the block; refusal of consent; psychiatric disorder; prior knee surgery on the same limb or lower limb deformity of the same limb; pregnancy and lactating mothers; or using a regional block for postoperative pain management other than ACB were excluded from study.

Assuming a noninferiority margin of 10%, an allowable difference of 0.16, and a standard deviation of 0.46 from a study by Govil N et al.[13] at 80% power and a 5% level of significance with equal allocation and with a 10% dropout, the sample size (n) was calculated to be 44 in each group.

(S)²: Variance; D: mean difference to be detected; Z_α: Z value for α error (α = 0.05); Zβ: Z value for β error (at β = 0.2).

Patients who satisfied the inclusion criteria were recruited by consecutive sampling. Randomization was performed using a computer-generated table with allotment in a closed envelope into two groups in a 1:1 ratio. Patients were randomly assigned after they arrived in the operating room. A nurse who was not part of the study opened an opaque, sealed envelope, based on which patients were allocated into two groups: one group received 20 ml of levobupivacaine 0.25% plus ketamine 1 mg/kg, and the other group received 20 ml of levobupivacaine 0.25%.

In this prospective randomised study, the patients were enrolled depending on the inclusion and exclusion criteria. All the selected patients for the study were preoperatively assessed and were informed about the study. A detailed patient information sheet was given to the patients. Written informed consent in the vernacular language was obtained from the patients before the study. The study started once the patients came into the preoperative room. The patients were preoperatively explained the NRS for pain assessment (0 = no pain to 10 = worst pain). The patient’s preoperative NRS at rest and during movement were assessed. Intravenous access was obtained before arrival in the operating theatre. Randomization was performed using a computer-generated table with an allotment in a sealed envelope into two groups in a 1:1 ratio. Patients were randomly assigned after they arrived in the operating room.

A nurse who was not part of the study opened an opaque, sealed envelope, based on which patients were allocated into two groups. One group received 20 ml of levobupivacaine 0.25% plus ketamine 1 mg/kg, and the other group received 20 ml of levobupivacaine 0.25%. The dose of ketamine was decided based on previous studies on other PNB.[14] If a case was excluded, the same random number code was assigned to the subsequent patient to maintain an equal sample size without changing the original random number table. In the operating room, standard ASA monitors were attached—electrocardiogram, pulse oximetry (SpO2), and noninvasive blood pressure—on their arrival in the operation theatre. Subarachnoid block was performed with 15 mg bupivacaine (3 ml of a 0.5% solution) after confirming free flow of cerebrospinal fluid to achieve a sensory block at or above the T10 dermatome. TKR was carried out by the same surgeon in all patients, with more than 10 years of experience performing this surgery. After completion of the surgery, ACB was performed. The drugs were prepared in syringes of the same shape and size for each patient by a nurse not involved in the study. The block was performed by an anesthesiologist experienced in giving ACB blocks (minimum of 25 blocks) and blinded to the treatment groups. The operating surgeon, the anesthesiologist who performed the block, the anesthesiologist who gathered postoperative, and the patients were blinded to the group allocated to them.

The patient was positioned supine, and the knee joint was partially flexed and externally rotated to achieve the frog-leg position. The area was cleaned with 10% povidone-iodine. The anesthesiologist stood on the side of the patient where the block was to be administered, and the ultrasound machine (Fujifilm SonoSite Inc., USA) was placed on the opposite side so that the screen faced the anesthesiologist. A high-frequency linear ultrasound probe (6–15 MHz), covered with a sterile dressing, was placed transversely to the longitudinal axis of the thigh at the junction between the middle and distal third of the thigh. The femur was identified (usually at a depth of 3–5 cm), and then the probe was moved medially to visualize the boat-shaped sartorius muscle.

The femoral artery was then visualized just beneath the sartorius muscle. In case of any difficulty visualizing the femoral artery, color Doppler was used to trace the femoral artery distally from the inguinal crease. After identifying the femoral artery, the probe was moved distally to trace it until it crossed the adductor hiatus to become the popliteal artery. The adductor canal lay deep to the sartorius muscle and was bound medially by the sartorius muscle, anterolaterally by the vastus medialis, and posteriorly by the adductor magnus muscle. The saphenous nerve was located lateral to the femoral artery under the fascia of the sartorius muscle inside the adductor canal. The anesthesiologist used an in-plane approach from lateral to medial, ensuring that the needle tip was always visible. A 20-gauge, 10 cm, short-bevel Stimuplex needle (B. Braun Medical Inc., Melsungen, Germany) was advanced into the adductor canal after traversing the sartorius muscle or vastus medialis muscle. After confirming negative aspiration of blood, a test dose of 1 ml of the LA was administered. The spread of the drug between the femoral artery and sartorius was seen in real time. If the spread of the drug could not be visualized, repositioning of the needle was done. A total of 20 ml of drug volume was given to both groups. The patient was monitored for any local or systemic complications.

A 1 g intravenous paracetamol infusion was given to all patients at 6-hourly intervals. Pain was assessed using NRS scores during rest and movement (active 45-degree flexion) at 0, 2, 4, 6, 8, 12, and 24 h after the end of the surgery. T = 0 was defined as the time of injecting the study medication. Intravenous tramadol 100 mg was given as a rescue analgesic when NRS was ≥4. The pain-free interval, i.e.. the time until the first dose of rescue analgesia requirement, and the total tramadol usage in the first 24 h were noted. Any complications such as nausea, headache, vomiting, lightheadedness, or hypertension were noted.

Statistical analysis

All the analysis was carried out using standard statistical software, IBM statistical package for social sciences (SPSS) version 22.0. Data were checked for normality. Normally distributed continuous parameters such as age, height, weight, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), SPO2, duration of surgery, time to first rescue analgesia, total dose of first rescue analgesia, and NRS (at rest and during movement at different time points) were presented as mean with standard deviation. For skewed parameters, the median and interquartile range were determined. Categorical parameters such as gender, ASA grading, diagnosis, postoperative complications, etc., were expressed as frequency and percentage and were compared using the Chi-square test/Fisher’s exact test. Normally distributed parameters were compared between the LK and L groups using an unpaired t-test. Statistical significance was set at P value < 0.05. Cohen’s d was used as a standardized measure of effect size that quantified the difference between two group means in standard deviation units. It measured the magnitude of differences: small effect (0.2–0.49), moderate effect (0.5– 0.79) and large effect (>/=0.8). Data were presented graphically wherever appropriate for data visualization using histograms, box-and-whisker plots, or column charts for continuous data and bar charts or pie charts for categorical data.

Results

The demographic variables, ASA grading, primary diagnosis, duration of surgery, and preoperative NRS were comparable between the two groups [Table 1].

Table 1.

Comparison of demographics, clinical profile, and preoperative parameters of patients who underwent unilateral total knee replacement surgery between the levobupivacaine with ketamine (LK) group and the levobupivacaine group (L)

Variables	Group LK (n=45) Mean±SD/f (%)	Group L (n=45) Mean±SD/f (%)	P
Age in years	61.04±7.97	59.76±7.07	0.420
Sex
Male	14 (31.1)	14 (31.1)
Female	31 (68.9)	31 (68.9)	1.00
Height in cm	164.51±6.65	165.7±5.81	0.370
Weight in Kg	73.83±9.27	72.28±9.95	0.447
BMI (kg/m2)	28.04±3.19	27.03±3.92	0.183
ASA Grading
1	8 (17.8)	9 (20.0)	0.788
2	37 (82.2)	36 (80.0)
Diagnosis
Left OA knee	23 (51.1)	21 (46.7)	0.673
Right OA knee	22 (48.9)	24 (53.3)
Duration of surgery (Minutes)	65.00±7.61	63.33±6.66	0.272
Preop NRS at rest	5.60±2.90	5.40±3.14	0.755
Preop NRS at movement	8.87±1.44	8.44±2.82	0.297
Heart rate (Beats/min)	75.29±9.81	76.84±8.61	0.426
SBP (mmHg)	132.31±6.77	131.42±9.28	0.605
DBP (mmHg)	80.82±6.11	79.69±6.78	0.407
SpO2 (%)	99.56±0.69	99.56±0.66	1.000

Data expressed as mean (SD) or frequency and percentage=f (%). BMI=body mass index, ASA=American Society of Anaesthesiologists, OA=osteoarthritis, NRS=numerical rating scale, SBP=systolic blood pressure, DBP=diastolic blood pressure, n=number of patients. A P<0.05 is considered statistically significant

Group LK had a mean pain-free interval of 9.33 h (standard deviation [SD] = 2.17; 95% confidence interval, 8.698 to 9.969 h) before the first dose of rescue analgesia was required after the ACB. The median time was 8.000 h (95% confidence interval, 7.469 to 8.531 h). In contrast, Group L had a mean pain-free interval of 5.02 h (SD = 1.63; 95% confidence interval, 4.546 to 5.499 h) (P value = 0.001). The median time was 6.000 h (95% confidence interval, 5.584 to 6.416 h). The Cohen’s d value was 2.243, indicating a very large effect size. The mean total dose of tramadol used postoperatively in Group LK was 188.89 mg (SD = 48.72), while in Group L, it was 271.11 mg (SD = 50.55) (P value = 0.001). The effect size was large, with a Cohen’s d value of 1.656. [Table 2] [Supplement Figure 1 ^{(57.8KB, tif)} ]

Table 2.

Comparison of rescue analgesia parameters of patients who underwent unilateral total knee replacement surgery between the levobupivacaine group with ketamine (LK) and the levobupivacaine (L) group after ultrasound-guided adductor canal block

Variables	Group LK (n=45) Mean±SD	Group L (n=45) Mean±SD	P	Effect Size
Time of first dose of rescue analgesia after block (hours)	9.33±2.17	5.02±1.63	0.001*	2.243
Total dose of tramadol used post-op (mg)	188.89±48.72	271.11±50.55	0.001*	1.656

Data expressed as mean (SD). n=number of patients, SD=Standard deviation. A P<0.05 is considered statistically significant. Cohen’s d is used as a standardized measure of effect size: small effect (0.2–0.49), moderate effect (0.5–0.79), and large effect (≥0.8)

Patients in Group L had significantly higher NRS at rest than those in Group LK at 4, 6, and 12 h postoperatively. Patients in Group L had significantly higher NRS during movement than those in Group LK at 2, 4, 6, and 12 h postoperatively. On the contrary, we found significantly higher mean NRS at 8 h of movement in Group LK (4.47 ± 2.82) compared to the mean NRS in Group L (2.78 ± 1.90) (P value = 0.001; Cohen’s d = 0.702) [Table 3 and Figure 2].

Table 3.

Comparison of NRS at rest and NRS on movement of patients who underwent unilateral total knee replacement surgery between the levobupivacaine with ketamine group (LK) and levobupivacaine group (L) after ultrasound-guided adductor canal block

Variables	Group LK (n=45) Mean±SD	Group L (n=45) Mean±SD	P	Effect Size
NRS at Rest
NRS at 0 h	0.00±0.00	0.22±1.49	0.320	0.220
NRS at 2 h	0.09±0.47	0.61±1.79	0.061	0.402
NRS at 4 h	0.16±0.47	1.53±2.16	0.001	0.881
NRS at 6 h	0.82±1.23	2.13±1.96	0.001	0.801
NRS at 8 h	2.40±2.26	0.96±1.26	0.001	0.789
NRS at 12 h	2.13±2.18	3.13±2.16	0.031	0.461
NRS at 24 h	3.96±2.52	4.78±1.54	0.065	0.394
NRS at Movement
NRS at 0 h	0.00±0.00	0.22±1.49	0.320	0.220
NRS at 2 h	0.16±0.56	1.18±2.45	0.008	0.575
NRS at 4 h	0.76±1.07	3.07±2.38	0.001	1.254
NRS at 6 h	2.27±1.63	4.09±2.36	0.001	0.898
NRS at 8 h	4.47±2.82	2.78±1.90	0.001	0.702
NRS at 12 h	4.33±2.53	5.73±2.66	0.012	0.539
NRS at 24 h	6.44±2.63	7.09±1.97	0.192	0.277

Data expressed as mean (SD). NRS=numerical rating scale, SD=standard deviation. A P<0.05 is considered statistically significant. Cohen’s d is used as a standardized measure of effect size: small effect (0.2– 0.49), moderate effect (0.5–0.79), and large effect (≥0.8)

Figure 2.

Comparison of NRS score at rest and on movement in patients who underwent unilateral total knee replacement surgery between the levobupivacaine with ketamine group (LK) and the levobupivacaine group (L) after ultrasound-guided ACB

The postoperative parameters assessed in both groups showed no statistically significant differences across heart rate, SBP, DBP, and oxygen saturation, indicating that both groups were similar in these vital signs following surgery. There were no statistically significant differences in the incidence of postoperative complications (headache, nausea, transient hypertension, and vomiting) between Group LK and Group L. However, there was a trend suggesting that light-headedness may be more prevalent in Group LK, although this difference did not reach statistical significance [Table 4].

Table 4.

Comparison of postoperative vital parameters and complications in patients who underwent unilateral total knee replacement surgery between the levobupivacaine with ketamine group (LK) and the levobupivacaine group (L)

Variables	Group LK (n=45) Mean±SD	Group L (n=45) Mean±SD	P
Heart rate (Beats/min)	76.24±9.04	78.24±7.68	0.261
SBP (mmHg)	129.87±7.74	130.31±9.41	0.807
DBP (mmHg)	79.64±5.97	79.82±6.41	0.892
SpO2 (%)	99.40±0.94	99.02±0.99	0.066
Postoperative Complications
Headache	2 (4.4)	4 (8.9)	0.677
Light-headedness	5 (11.1)	0 (0)	0.06
Nausea	5 (11.1)	8 (17.8)	0.368
Transient Hypertension (MAP >20% baseline)	3 (6.7)	0	0.242
Vomiting	3 (6.7)	2 (4.4)	1.000
Nystagmus	1 (2.2)	0	1.000

Data expressed as mean (SD). SBP=systolic blood pressure, DBP=diastolic blood pressure, MAP=mean arterial pressure, n=number of patients. A P<0.05 is considered statistically significant

Discussion

TKR is associated with postoperative pain, which is mainly due to extensive bone cutting and inflammation caused by surgical trauma during the procedure. ACB is a trusted procedure to manage postoperative pain after TKR, allowing patients to mobilise the limb early.[2,8,13,14] Performing ACB under ultrasound guidance helps enable accurate positioning of the tip of the needle while decreasing the rate of complications associated with the block.[7]

We recruited 90 ASA 1 and 2 patients who were undergoing unilateral TKR under spinal anaesthesia. Group LK (n = 45) received 20 ml of 0.25% levobupivacaine plus ketamine 1 mg/kg, and Group L (n = 45) received 20 ml of 0.25% levobupivacaine [Figure 1].

The demographic characteristics, such as age, gender, height, weight, BMI, and the clinical profiles of patients, including ASA grading, diagnosis, duration of surgery, and preoperative NRS score at rest and during movement in both groups, were similar [Table 1].

In our study, we found that Group LK had a significantly longer pain-free interval of 9.33 h (SD = 2.17) (P value = 0.001), with a Cohen’s d value of 2.243, indicating a very large effect size and suggesting that the addition of ketamine to levobupivacaine significantly prolonged pain relief compared to Group L [Table 2].

A study conducted by Lashgarinia M et al.,[10] in 60 patients who underwent upper limb surgeries with USG-guided supraclavicular brachial plexus block found a significantly longer time to rescue analgesia in the ketamine and lidocaine group (377.6 ± 106.3 min) compared to the lidocaine group (207.5 ± 73.6 min) (P value < 0.001). Another study by Othman AH et al.[14] in patients undergoing radical mastectomy under ultrasound-guided modified pectoral block found that the average time to the first dose of analgesia was 18.25 ± 1.98 h in the bupivacaine with ketamine group compared to 12.56 ± 2.64 h in the bupivacaine group. (P value < 0.001). A study by Mansour RF et al.[7] found that the time for requirement of the first rescue analgesia was significantly longer in the levobupivacaine with ketamine group (18.7 ± 4.8 h) compared to the levobupivacaine group (6.5 ± 2.4 h) postoperatively in transversus abdominis plane (TAP) block in patients who underwent abdominoplasty (P value < 0.001).

Our results concur with a double-blind study by Moharam SA et al.,[15] in which sixty patients undergoing open thoracotomy received a paravertebral block. They found that the ketamine and levobupivacaine group had a significantly longer pain-free interval (15.83 ± 4.23 h) compared to the levobupivacaine group (4.97 ± 0.96 h) (P value < 0.001).

In our study, the patients in Group LK required a significantly lower mean total dose of tramadol postoperatively (188.89 ± 48.72 mg) (P value = 0.001) with Cohen’s d value of 1.656 indicating a large effect size, which suggested that the addition of ketamine to levobupivacaine significantly decreased the requirement for rescue analgesia tramadol compared to Group L, (271.11 ± 50.55 mg) (P value = 0.001) [Table 2]. Lashgarinia et al.,[10] in their study, found that lidocaine with ketamine resulted in a significantly lower total amount of rescue pethidine (109.8 ± 39.6 mg) compared to the lidocaine group (169 mg ± 44.8). (P value < 0.001). A study by Othman et al.[14] also found that the bupivacaine with ketamine group required significantly higher doses of morphine compared to the bupivacaine group after surgery (P value = 0.016). Mansour RF et al. found that the levobupivacaine with ketamine group used significantly less rescue morphine than the levobupivacaine group in TAP block after abdominoplasty (P value < 0.001).[7] Moharam SA et al.,[15] found that the total amount of rescue morphine was significantly lower in the levobupivacaine with ketamine group (3.9 ± 1.4 mg) in the 24 h postoperatively compared to the levobupivacaine group (7.9 ± 1.67 mg). (P value < 0.001).

In our study, we found that patients in Group LK reported statistically significantly lower pain levels at rest compared to those in Group L at various postoperative time points, particularly at 4 h (P value = 0.001), 6 h (P value = 0.001, and 12 h (P value = 0.031) [Table 3]. The Cohen’s d value at 4 h and 6 h at rest was 0.881 and 0.801, respectively, indicating a large effect size and suggesting a strong clinical benefit. The Cohen’s d value at 12 h at rest was 0.461, indicating a small effect size [Table 3].

Patients in Group LK reported lower pain levels during movement (active 45-degree flexion) compared to those in Group L at various postoperative time points, particularly at 2 h (P value = 0.008), 4 h (P value = 0.001), 6 h (P value = 0.001), and 12 h (P value = 0.012) [Table 3]. The Cohen’s d value at 2 h during movement was 0.575, indicating a moderate effect size. The Cohen’s d value at 4 h during movement was 1.254, indicating a large effect size and suggesting significant pain relief in the LK group. The Cohen’s d value at 6 h during movement was 0.898, indicating a large effect size and a strong clinical benefit. The Cohen’s d value at 12 h during movement was 0.539, indicating a moderate effect size.

A study conducted by Lashgarinia et al.[10] found that at all-time points in the first 24 h postoperatively, patients who received lidocaine with ketamine had a lesser visual analogue scale (VAS) value than patients who received lidocaine only (P value < 0.05). Similarly, Mansour RF et al.[7] reported that the addition of ketamine to levobupivacaine in TAP block led to a significant reduction in VAS in the levobupivacaine with ketamine group at rest at 6, 12, and 16 h postoperatively, in contrast to the levobupivacaine group. VAS was significantly lower during movement at 4, 6, 8, 12, 16, and 24 h postoperatively in the levobupivacaine with ketamine group compared to the levobupivacaine group. Moharam SA et al.[15] found that NRS was significantly lower at rest in the levobupivacaine with ketamine group at 0, 1, 2, 18, 24, 36, and 48 h, as well as significantly lower during deep breathing at 0, 1, 2, 36, and 48 h postoperatively compared to the levobupivacaine group.

We found a significantly higher mean NRS at 8 h on movement in Group LK (4.47 ± 2.82) compared to the mean NRS in Group L (2.78 ± 1.90) (P = 0.001; Cohen’s d = 0.702). This may be because the mean time to the first dose of rescue analgesic in Group L was 5.022 h (95% confidence interval: 4.546–5.499 h). Hence, the patients in Group L received the rescue analgesic injection tramadol, which resulted in a lower NRS (2.78 ± 1.90) at 8 h. [Supplement Figure 1]

The addition of ketamine to LA in PNB has been found to increase the duration of the pain-free interval by (377.6 ± 106.3 min) in the supraclavicular brachial plexus block, (18.25 ± 1.98 h) in the modified pectoral block, and (18.7 ± 4.8 h) in the TAP block.[7,10,14] This duration is variable and depends on the dose of ketamine, the site of administration, and the dose and concentration of LA used. In our study, the mean time to the first dose of rescue analgesia was 9.33 h (95% confidence interval of 8.69 to 9.97 h), which was well within the range in the above-mentioned studies. The mean NRS of (4.47 ± 2.82) at 8 h on movement might be due to the weaning off of the effect of ketamine when our patients were assessed at 8 h.

Our study showed no statistically significant differences in the incidence of postoperative complications (headache, nausea, transient hypertension, nystagmus, and vomiting) between Group LK and Group L [Table 4].

The limitation of this study was that we did not measure serum ketamine levels to determine if its effects were local or systemic.

Conclusions

We conclude that in ACB, the addition of ketamine 1 mg/kg to 0.25% levobupivacaine decreased the requirement of rescue analgesia, and patients experienced better pain control at rest at 4, 6, and 12 h and on movement at 2, 4, 6, and 12 h in the postoperative period in patients undergoing unilateral TKR without significant adverse effects.

Conflicts of interest

There are no conflicts of interest.

Supplement Figure 1

Kaplan–Meier curve comparing the time to first dose of rescue analgesia after block (hours) between the two groups. Group LK= Levobupivacaine and ketamine, Group L= Levobupivacaine

Funding Statement

Nil.