Comparision of Dexmedetomidine and Propofol in Patients Undergoing Laparoscopic Cholecystectomy Under Spinal Anesthesia.

BACKGROUND: Spinal anesthesia (SA) with sedation is considered to be an alternative to general anesthesia for laparoscopic cholecystectomy (LC) in high-risk patients. Ketamine in analgesic dose with propofol or dexmedetomidine infusion provides titratable sedation, hemodynamic stability, and minimum respiratory depression without psychomimetic effects. AIM: To compare the efficacy of ketamine-dexmedetomidine and ketamine-propofol combination in relation to sedation, analgesia, hemodynamic effects, and perioperative side effects. SETTINGS AND
DESIGN: This was a prospective, randomized single-blind comparative study comprising 100 American Society of Anesthesiologists I, II, and III patients posted for LC.
MATERIALS AND METHODS: Patients were randomized into two groups of 50 patients each. Group KP (ketamine + propofol) received intravenous (i.v.) bolus of injection ketamine 0.5 mg.kg -1 and propofol infusion at 3 mg.kg -1.h -1. Group KD (ketamine + dexmedetomidine) received i.v. bolus of injection ketamine 0.5 mg.kg -1 and dexmedetomidine infusion at 0.4 μg.kg -1.h -1. Parameters observed were vitals, perioperative side effects, time to first rescue analgesia, and return of consciousness. STATISTICAL ANALYSIS: Student's independent t-test was employed for comparing continuous variables. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables.
RESULTS: Duration of analgesia was longer in KD Group (191.2 vs. 173.5 min), and time to regain consciousness was faster in KP Group (14.9 vs. 20.4 min).
CONCLUSION: Both the techniques of sedation are feasible, safe, and comparable, except the duration of analgesia and time to regain consciousness which was longer in KD Group. Copyright:

INTRODUCTION

Laparoscopic surgeries are normally performed under general anesthesia (GA) with endotracheal intubation to prevent aspiration and respiratory embarrassment secondary to induction of pneumoperitoneum and also to prevent discomfort and shoulder pain due to stretching of the diaphragm in patients who are awake during the procedure. The main advantages of spinal anesthesia (SA) are awake, spontaneously breathing patient, prevention of airway manipulation, less incidence of postoperative nausea and vomiting (PONV), and provision of effective postoperative analgesia with shorter recovery time.[123]

One major problem associated with laparoscopic cholecystectomy (LC) under SA is shoulder tip pain, which is the most common reason for the conversion of these patients to GA.[456] Many studies have used various measures to reduce shoulder tip pain such as position changes, abdominal massage, passive drainage and subhepatic suction of residual gas, spraying bupivacaine on the peritoneum over diaphragm, painting the diaphragm with a gauze soaked in bupivacaine, and adding various adjuvants to intrathecal local anesthetics.[2789] However, PONV, pruritus, and hemodynamic instability have been the limiting factors.

SA with sedation is a recognized technique for many surgical procedures. However, during laparoscopic surgery, sedation should not deteriorate the hemodynamics and respiratory drive of the patient. Addition of ketamine as a part of the sedation technique in the present study is expected to have little effect on the respiratory variables monitored. Ketamine also has other advantages as it increases the heart rate (HR) and arterial blood pressure by activating the sympathetic nervous system and reduces the incidence of SA-induced hypotension. However, the occurrence of hallucinations, confusion, and other emergence phenomena has tended to limit its widespread use. Atashkhoyi et al. reported that low-dose ketamine is associated with less pain during propofol injection, lower incidence of hemodynamic changes, lower total dose of propofol, improved postoperative analgesia, and fewer emergence phenomenon.[10]

Dexmedetomidine is a selective α2-adrenergic receptor agonist known to produce sedation and analgesia with sympatholytic and hemodynamic stabilizing properties without significant respiratory depression.[11] In addition, intravenous (i.v.) dexmedetomidine administration for SA prolongs the effects of the sensory and motor block and provides a sedative effect.[12]

The increasing demand of LC under SA led to the surge in search for pharmacological agents that may help in reducing discomfort of pneumoperitoneum with the lower incidence of hemodynamic and respiratory changes. The purpose of this study was to compare the feasibility and safety of SA with sedation with ketamine in analgesic dose with propofol or dexmedetomidine infusion as the sole anesthesia technique for conduct of LC.

MATERIALS AND METHODS

This prospective, randomized, comparative, single-blinded study was conducted in the department of anesthesia and surgery from July 2018 to March 2020. After the approval from institutional ethical committee and informed written consent, 100 patients of American Society of Anesthesiologist (ASA) Grade I, II, and III aged 18–60 years scheduled for LC under SA were studied. The following eligibility criteria were followed.

Inclusion criteria

Written informed consent by the patient

ASA I, II, and III

Patient aged 18–60 years of either sex

Patients scheduled for elective LC under SA.

Exclusion criteria

Patient refusal

Patients with a history of allergic reaction to propofol, ketamine, or dexmedetomidine

Patients with significant central nervous system disease

Patients with ejection fraction below 45% and/or peak expiratory flow rate and forced vital capacity of <65% of predicted values

Bleeding diathesis

Local spinal deformity which precluded safe SA

Body mass index >35

Pregnancy

Known contraindication to SA.

Using GPOWER software version 3.0.10(Heinrich Heine University Dusseldorf, Germany), it was estimated that the least number of patients required in each group with 80% power and 5% significance level is 50. Since we have to compare two groups in our study, thus, we have included 100 patients in our study.

After detailed preanesthetic evaluation, all selected patients under study were randomly divided into two groups: Group KP (ketamine + propofol) and Group KD (ketamine + dexmedetomidine) using computer-generated randomization.

Group KP received i.v. bolus of injection ketamine 0.5 mg.kg −1 and propofol infusion at 3 mg.kg −1.h −1.

Group KD received i.v. bolus of injection ketamine 0.5 mg.kg −1 and dexmedetomidine 0.4 μg.kg −1.h −1.

The patient was not aware as to which treatment he/she is getting, making the study single blinded. The same surgical and anesthesiology team performed all LC cases.

All patients were premedicated with i.v. injection midazolam (0.05 mg.kg −1), glycopyrrolate (0.004 mg.kg −1), and ondansetron (0.15 mg.kg −1). On arrival to the anesthesia induction room, standard monitoring was applied to the patient. 18G venous cannula was inserted under local anesthesia, and all patients received adequate preloading with 10 ml.kg −1 of Ringers lactate solution i.v. over 15 min. Baseline measurements, including hemodynamic parameters such as HR and mean arterial pressure (MAP), respiratory rate (RR), and arterial blood gases were recorded before the administration of SA, preinsufflation (after stabilization of SA), postinsufflation (before the start of surgical manipulation), after complete desufflation, and every 10 min after arrival to the recovery room.

Patients were positioned in the lateral position for SA. A 27G Quincke spinal needle was introduced in the subarachnoid space at L3–L4 interspace under all aseptic precautions; after confirming free flow of the cerebrospinal fluid, 0.3 mg.kg −1 of hyperbaric bupivacaine 0.5% was injected intrathecally in the cephalad direction at a velocity of 0.1 ml.s −1; then, after keeping the patient in 15° Trendelenburg position for 5 min, the patient was again made to lie in a supine position. A segmental sensory block up to T4 dermatome was obtained without any respiratory distress. Dexmedetomidine and propofol were prepared in infusion syringes at 10 μg.ml-1 and 10 mg.ml-1, respectively, to be started before insufflation.

The level of sedation was recorded every 5 min, and subsequent infusion rates were titrated to achieve a predetermined level of 3 on a 6-point Ramsay sedation scale (arousal to command). Oxygen was administered by face mask at a flow of 4-6 L.min −1 to keep oxygen saturation above 95%. Fluid and vasopressor were given i.v. to minimize the MAP fluctuation to <20% of the baseline. Sedative infusion was stopped if the RR was ≤10 breaths per minute and finally discontinued at the end of the surgical procedure.

Rescue analgesia was given with i.v. injection of ketamine 0.3 mg.kg −1. Indication for rescue sedation or analgesia was coughing, bucking, lacrimation, sudden movement, or variation in hemodynamic parameters by >20% from baseline.

All patients were closely observed for evidence of hallucinations or other emergence phenomenon. Patients remained in the recovery room until motor function had returned to the lower limbs, the autonomic effects of SA had resolved, and standard discharge criteria had been met (stable vital signs, awake and oriented, controlled pain, and absent nausea and vomiting).

Statistical methods

The recorded data were compiled and entered in a spreadsheet (Microsoft Excel) and then exported to the data editor of SPSS Version 20.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were expressed as mean ± SD, and categorical variables were summarized as frequencies and percentages. Graphically, the data were presented by bar diagrams and line diagrams. The normality of data was assessed by Kolmogorov–Smirnov test. Student's independent t-test was employed for comparing continuous variables, when the data showed normality; otherwise, Mann–Whitney U-test was used. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables. A P < 0.05 was considered statistically significant. All Pvalues were two tailed.

RESULTS

A total of 100 patients with cholelithiasis were consented to undergo LC under SA with sedation. The two groups were comparable regarding age, sex, weight, duration of surgery, and ASA status of patients [Table 1] (P > 0.05).

Table 1

Comparison of baseline characteristics between group ketamine + dexmedetomidine and ketamine + propofol (n=50)

Parameter	Group KD	Group KP	P
Age (years)	43.7±9.87	45.1±10.73	0.498
Gender (male:female)	19:31	21:29	0.683
Weight (kg)	70.3±6.72	69.5±5.83	0.526
Duration of surgery (min)	54.8±6.67	52.9±7.94	0.198
ASA status, n (%)
ASA I	37 (74)	38 (76)	0.683
ASA II	11 (22)	9 (18)
ASA III	2 (4)	3 (6)

The data are presented as mean±SD and analyzed using unpaired t-test or as n (%) and analyzed using Chi-square test. ASA=American Society of Anesthesiologist, Group KD=Ketamine and dexmedetomidine, Group KP=Ketamine and propofol, SD=Standard deviation

The baseline HR [Figure 1] and MAP [Figure 2] were comparable in two groups. HR in patients in Group KD was lower than in Group KP at all time intervals, and it was statistically significant up to 20 min of dexmedetomidine infusion [Figure 1]. HR was comparable in both the groups after stopping sedation in PACU [Figure 1]. In Group KD, 6 (12%) patients had bradycardia, and in Group KP, only 2 (4%) had bradycardia which required pharmacological intervention and was statistically insignificant [Table 2]. MBP was lower in Group KD at all time intervals, but it was statistically insignificant [Figure 2]. MBP was lower after SA in both the groups and persisted after pneumoperitoneum, which increased again after desufflation and in PACU [Figure 2].

Figure 1

Graphical representation of HR (beats/min) at different time intervals in the group KD and KP. HR = Heart rate, Group KD = Ketamine and dexmedetomidine, Group KP = Ketamine and propofol

Figure 2

Graphical representation of MAP (mm hg) at different time intervals in the group KD and KP. MAP = Mean arterial pressure, Group KD = Ketamine and dexmedetomidine, Group KP = Ketamine and propofol

Table 2

Comparison based on side effects in two groups

Side effects	Group KD (n=50), n (%)	Group KP (n=50), n (%)	P
Shoulder tip pain	0 (0)	2 (4)	0.495
Bradycardia	6 (12)	2 (4)	0.267
Hypotension	4 (8)	1 (2)	0.362
PONV	3 (6)	1 (2)	0.617
Headache	1 (2)	2 (4)	1.000
Respiratory depression	3 (6)	0 (0)	0.242
Airway obstruction	2 (4)	0 (0)	0.495

The data are presented as n (%) and analyzed using Chi-square test. PONV=Postoperative nausea and vomiting, Group KD=Ketamine and dexmedetomidine, Group KP=Ketamine and propofol, SD=Standard deviation

Regarding perioperative side effects, shoulder tip pain was noticed in only 2 (4%) patients in KP Group which was relieved with top up of injection ketamine [Table 2]. Only 3 (6%) patients in KD Group had PONV in comparison to 1 (2%) patient in KP Group which was statistically insignificant [Table 2]. None of the patients in KP Group had respiratory depression, but 3 (6%) patients had in KD Group, which required titration of sedation and was statistically insignificant [Table 2]. Only 2 (4%) patients in KD Group had airway obstruction which was managed by jaw thrust maneuver [Table 2]. One patient, i.e., 2% of patients in Group KD, and 2 (4%) patients in Group KP complained of headache which was insignificant [Table 2].

As far as postoperative parameters are concerned, patients in Group KD took more time to regain consciousness in comparison to patients in Group KP (20.4 vs. 14.9 min), which was statistically significant (P < 0.001) [Table 3]. Time to demand first rescue analgesia was significantly longer in Group KD than Group KP (191.2 vs. 173.5 min) (P < 0.001) [Table 3]. PaCO2, RR, and SpO2 were comparable in both the groups.

Table 3

Postoperative parameters in two groups

	Mean±SD		P
	Group KD (n=50)	Group KP (n=50)
Time to regain consciousness (min)	20.4±5.17	14.9±4.32	<0.001*
Time to first rescue analgesia (min)	191.2±14.83	173.5±11.25	<0.001*

The data are presented as mean±SD (SD) and analyzed using unpaired t-test. *Highly statistically significant difference (P<0.001). Group KD=Ketamine and dexmedetomidine, Group KP=Ketamine and propofol, SD=Standard deviation

DISCUSSION

Performing laparoscopic surgery under SA carries many advantages, which are accomplished through two aspects: first, the laparoscopic technique itself reduces the degree of tissue trauma and consequently the injury response, and second, the SA itself provides the reduction in surgical stress response with blockade of various humoral mediator cascade systems.[2]

Combination of SA with effective sedation technique helps in achieving adequate level of sensory and motor blockade, management of pneumoperitoneum and shoulder tip pain, provision of postoperative pain relief adequate to prevent deterioration of respiratory mechanics, and early ambulation.[3]

In our study, there was significant decrease in both HR and MAP in both the groups after insufflations and positioning for LC, which were corrected by fluids and vasopressor drugs as confirmed in a study by Lau et al.[13] In addition, ketamine used in the present study played a role in supporting the blood pressure as explained by Atashkhoyi et al.[10] Dexmedetomidine has been used intravenously in doses ranging from 0.1 to 10 μg.kg − 1.h − 1, but the higher doses have been associated with a significant incidence of bradycardia and hypotension.[14]

Greater increase in PaCO2 after CO2 pneumoperitoneum was when the patient was under GA, as compared to when the patient was breathing spontaneously.[15] None of the patients in our study had any significant variation of PaO2 or PaCO2 during the surgery under SA as reported by Sinha et al.,[4] Hamad et al.,[16] and Yousef and Lasheen.[17] Respiratory depression was noted in three patients in KD Group only which was statistically insignificant in comparison to KP Group.[18]

Effective sedation was achieved in both the groups with no significant respiratory or hemodynamic compromise. Compared with KD group, arousal from sedation was faster in KP Group as studied by Janardhana et al.[19] and Ok et al.[20] Time to first analgesic request was significantly longer in KD Group patients, similar to the finding of the study by Koruk et al.[21]

Shoulder tip pain is a very common and quite troublesome problem during laparoscopic surgeries. This is a referred pain due to the stretching of diaphragm by insufflating CO2 as diaphragm is supplied by cervical roots which are spared during regional anesthesia (RA). Overall, the reported rate of conversion from RA to GA due to intolerable shoulder pain has been 7%–43% for LC.[452223] However, in our study, shoulder tip occurred in 2 (4%) of patients in KP Group only which was managed with titration of sedation and was statistically insignificant. None of our patient was converted to GA.

Another advantage of RA is reduced incidence of PONV. Adequate hydration, reduced systemic use of opioids, and preoperative prophylaxis by ondansetron resulted in reduced incidence. In our study, the incidence of PONV in KP Group was 2%, which is comparable to the studies done by Imbelloni et al.[1] and Sinha et al.,[4] but the incidence of PONV was slightly more in KD Group, although statistically insignificant. PONV can delay discharge of the patients from the hospital.[15]

The limitations of our study include: first, our study was single-blind study; due to practical logistics, double blind was not feasible. Second, we did not evaluate the effects of various maintenance doses of dexmedetomidine (0.2–0.7 μg.kg−1.h−1). Thus, the optimal maintenance dose of dexmedetomidine for LC remains unknown. Third, we excluded obese patients (body mass index >35 kg.m−2). RA may be more suitable than GA in these patients because obese patients often have comorbidities, such as ischemic heart disease, hypoventilation syndrome, and metabolic disorders.[24] Obese patients have a higher incidence of gastroesophageal reflux disease which can be aggravated by increased intra-abdominal pressure, so excluded from our study.[25]

This study did not include a cost analysis, but other studies indicate that LC under SA is more cost-effective than under GA.[26]

CONCLUSION

Intravenous (i.v.) sedation with ketamine in analgesic dose (0.5 mg.kg-1) with propofol (3 mg.kg−1.h−1) or dexmedetomidine (0.4 μg.kg−1.h−1) as the sole anesthesia technique for conduct of LC under SA is safe, feasible, more cost-effective, provides good postoperative pain relief and patient satisfaction, and is an attractive option as the anesthesia of choice, especially in developing countries. Both the techniques of sedation are comparable except duration of analgesia which was longer in KD Group and time to regain consciousness which was early in KP Group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.