Effect of Gelfoam Soaked Epidural Dexmedetomidine or Bupivacaine for Postoperative Analgesia in Lumbar Laminectomy: A Prospective Randomized Clinical Study.

BACKGROUND AND AIMS: Postoperative pain is spine surgery can last for an average of two to three days. Epidural catheter management are difficult in spine surgery for postoperative pain. Still, there have been not much studies on epidural administered gelfoam soaked dexmedetomidine or bupivacaine, to enhance postoperative analgesia.
METHODS: Ninety six adult patients were randomized into three groups. Gelfoam soaked in 0.1 mg dexmedetomidine (0.02 mg. mL-1) in group D, 0.25% isobaric bupivacaine (5 mL) in group B and gelfoam soaked in 0.9% normal saline (5 mL) in group C. The Primary outcome was to compare the total amount of rescue analgesic consumption till 48 hours. The Secondary outcome was to compare time to first dose of rescue analgesia (duration of analgesia), the visual analogue scale and side effects up to 48 hours. Chi-square test, independent t test and analysis of variance test were used, and P < 0.05 was considered significant.
RESULTS: Ninety patients completed the study. Total dose of rescue analgesic consumed in 48 hours was significantly higher in control group (paracetamol 4.17 ± 0.75 gm with tramadol 205 ± 37.94 mg). Bupivacaine soaked gelfoam group (paracetamol 3.04±0.71 gm with tramadol 151.85 ± 35.31 mg) had more rescue analgesic consumption than dexmedetomidine soaked gelfoam group (paracetamol 1.72 ± 0.57 gm with tramadol 86.11 ± 28.73 mg). Time for first rescue analgesic requirement with dexmedetomidine soaked gelfoam group was significantly longer (14.67 ± 7.76 hours) than in bupivacaine soaked gelfoam group (11.33 ± 6.08 hours) and control group (6.40 ± 2.77 hours). Postoperative mean VAS scores were lower in group D and group B compared with group C along with no significant adverse effects.
CONCLUSION: Patients undergoing lumbar laminectomy with gelfoam soaked epidural dexmedetomidine or bupivacaine decreases rescue analgesic consumption, prolongs the duration of analgesia and decreases mean VAS score postoperatively. Copyright:

INTRODUCTION

Postoperative pain in spine surgery can last for an average of 2–3 days.[1] Inadequate postoperative pain relief may lead to increased morbidity and mortality and may delay recovery.[2] Nonsteroidal anti-inflammatory drugs or opioids are commonly used for postoperative pain in spine surgeries but are associated with side effects and wide variations in their clinical effects. Epidural analgesia is an effective and safe method in spine surgeries to avoids unwanted side effects.[3]

Regional anesthesia with local anesthetic agents, parenteral and epidural opioids or adjuvants such as clonidine, patient-controlled opioid therapy, and nonsteroidal anti-inflammatory agents are main modalities.[4] Postoperative analgesia should provide continuous pain relief, so that patient can be mobilized early.[5]

Epidural opioids as a single dose at the time of the surgery or through an epidural catheter are common for postoperative analgesia.[6] Epidural catheter management is difficult in spine surgery for postoperative pain and can spread infection to the site of surgery, restricting its application in spine surgeries.[78]

Parental opioids may lead to oversedation, respiratory depression, urinary retention, constipation, and opioid-induced hyperalgesia.[9] Although the use of dexmedetomidine has been extensively studied for postoperative epidural analgesia with epidural catheter in situ.[210] Still, there have been no studies on epidural administered gelfoam soaked dexmedetomidine to enhance postoperative analgesia. Thus, this study was to evaluate the effectiveness of drugs such as dexmedetomidine or bupivacaine in the form of soaked gelfoam placed over epidural space for postoperative analgesia.

MATERIALS AND METHODS

This prospective randomized double-blinded clinical study was conducted in patients posted for lumbar laminectomy surgery. Our clinical research was standardized following ethical principles of medical research involving human subjects according to the Declaration of Helsinki 2013. After getting approval from the ethical committee (IEC no. 60/18/RMLIMS/2019) and obtaining written and informed consent from all patients, the study was done over a period of 18 months (March 2019–August 2020). A total of 90 patients of either sex between the age group of 18 and 60 years belonging to the American Society of Anesthesiologists (ASA) physical status Classes I or II posted for elective one segment laminectomy were included in this study. Patients with body mass index (BMI) ≥30 kg.m−2, history of previous lumbar spinal surgery, neurological deficits, prior neuromuscular disease, history of preoperative opioid or steroid use, history of substance abuse, history of allergic reactions to study drugs, patients with excessive bleeding requiring placement of drain, and cerebrospinal fluid leak (dural tear) were excluded from this study.

This study adhered to CONSORT guidelines (http://www.consort-statement.org). Patients were randomly allocated into three groups (30 patients each) by computer-generated sequence of random number group. The drugs were prepared by an anesthesia resident who did not participate in the study and handed over to the surgeon. This study was conducted in a random double-blinded manner, neither the administrator of the drugs nor the patients know about the study drug. Amount of drug volume was equal in all three groups to avoid any study bias. All the patients were explained and counseled about the visual analog scale (VAS)[11] the day before surgery, and written and informed consent was taken.

All the patients were premedicated with alprazolam 0.25 mg and ranitidine 150 mg orally, the night before surgery. Patients were taken in operation theater after 8 h fasting period and intravenous (i.v.) access established using an 18 gauge cannula in preoperative area. Midazolam 0.03 mg.kg−1, glycopyrrolate 0.2 mg, and ringer lactate 500 mL given intravenously before induction. Standard monitoring, i.e. electrocardiogram, pulse oximetry (SpO2), noninvasive arterial pressure measurement, end-tidal CO2 (EtCO2), body temperature was monitored and baseline parameters were recorded. All the patients were preoxygenated for 3–5 min with 100% oxygen. Induction and tracheal intubation were done with fentanyl (0.002 mg.kg−1), propofol (2–2.5 mg.kg−1), and vecuronium (0.1 mg.kg−1). The position of the tube was verified with auscultation and capnography. Once the position was confirmed, intermittent positive pressure ventilation was started, then patients were turned prone and again tube position and air entry were confirmed. Padding at all bony prominences was done. Anesthesia was maintained with air and O2 (50%:50%) along with isoflurane 0.5%–1%, fentanyl (0.0005–0.001 mg.kg−1.h−1), and intermittent vecuronium bolus (0.02 mg.kg−1) every 20–30 min. Ventilation parameters were a tidal volume of 6–8 mL.kg−1, respiratory rate of 10–12 breath.min−1, and peak inspiratory pressure of <30 cmH2O. Ventilation was adjusted to maintain EtCO2 between 30 and 35 mmHg. Any adverse effects of drug or allergic reactions were also observed closely during the intraoperative period. A standard-sized gelfoam, i.e., 5 cm × 1 cm soaked with the respective study drug was placed in epidural space of all patients before closure. The three groups were divided as followings:

Group D: 5 cm × 1 cm gelfoam soaked in 0.1 mg dexmedetomidine (0.02 mg.mL− 1)

Group B: 5 cm × 1 cm gelfoam soaked in 0.25% isobaric bupivacaine (5 mL)

Group C: 5 cm × 1 cm gelfoam soaked in 0.9% normal saline (5 mL).

At the end of surgery, all the patients were turned supine and the neuromuscular blockade was reversed with injection of neostigmine 0.05 mg.kg−1 and injection of glycopyrrolate 0.01 mg.kg−1. One gram i.v. paracetamol was given for analgesia in all patients at the end of surgery. Patients were extubated after the return of spontaneous respiration with clinically adequate tidal volume. Postoperative pulse rate, blood pressure, and oxygen saturation were recorded and patients were shifted to postanesthesia care unit (PACU) where continuous monitoring was carried out.

In PACU, all patients were given supplemental oxygen at 2 l.min−1 for the first 2 h. After this period, oxygen was administered only if patient has saturation below 92%. Heart rate <50 beats.min−1 was considered as bradycardia, and injection atropine 0.4–0.6 mg was given. Mean arterial pressure <65 mmHg treated as hypotension and injection 6 mg ephedrine was given as i.v. bolus. Patients were already explained with VAS preoperatively. In the postoperative period, they were asked about subjective pain on a scale of 0–10 with 0 representing no pain and 10 as the worst experienced pain. Patients were administered supplemental rescue analgesia with injection 1 g paracetamol and 50 mg tramadol i.v. bolus if VAS >3. We used both paracetamol and tramadol as strong rescue analgesia instead of either diclofenac or tramadol because of using newer adjuvant drug dexmedetomidine first time as gelfoam soaked. This could be repeated after 4–6 h if the patient still complained of pain. No other analgesic except injection paracetamol and tramadol were permitted for the first 48 h postoperatively. After 48 h, alternate opioid therapies were permitted at the investigator's discretion. The duration of pain relief was defined as the time from the end of the operation until the patient requests for the first supplementation of rescue analgesic drugs. Time of first demand of analgesic and total analgesic consumption for initial 48 h were recorded. Patients were encouraged to ambulate 6 h after surgery if they feel comfortable. Time of ambulation was counted from the time at which patients were shifted to the PACU until the time patients could be ambulated, later patients were discharged from PACU to ward if modified Aldrete's score[12] is ≥9. Time of discharge was noted and pulse oximetry monitoring continued in ward for 48 h. Level of sedation was assessed by Ramsay Sedation Scale,[13] and episode of nausea was recorded by the nausea score[14] (0 – no nausea, 1 – mild, 2 – moderate, and 3 – severe). Nausea was recorded any time the patient complains of nausea or notice to have vomited postoperatively. All the parameters were recorded on 2 h, 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, and 48 h by the resident anesthesiologist, who was unaware of the group allocation.

The primary objective was to compare the total amount of rescue analgesic consumption in each group up to 48 h postoperatively, and the secondary objective was to compare time to the first dose of rescue analgesia (duration of analgesia), the VAS, and side effects up to 48 h postoperatively.

Sample size estimation and statistical analysis

We were planning to keep an equal number of participants among three groups. The postoperative analgesia was measured quantitatively by measuring the total consumption of rescue analgesia of paracetamol and tramadol for 48 h. In the previous study,[3] the total tramadol consumption in 24 h for pain relief in patients receiving i.v. tramadol was reported 280 ± 64.5 mg in the control group. We used 1 g injection of paracetamol in combination with 50 mg tramadol, and we were expecting a lower dose of total tramadol requirement in 48 h if the true difference in reduction of tramadol consumption was 50 mg in either of these groups, we required to study 28 patients in each group to be able to reject the null hypothesis that total consumption of rescue analgesic in 48 hours was equal in both groups with the power of study of 0.8 and a significance level of 0.05. Accounting for loss or no consent, we were decided to take 30 in each group.

Broadly, descriptive analysis of quantitative data was expressed as means and standard deviation. Categorical/ordinal data were expressed as a percentage, median, and range. Data were analysed using Statistical Package for the Social Sciences (SPSS, version 23.0), Chicago, Illinois, USA. Continuous data were analyzed using Chi-square test. Intergroup and intragroup comparisons were done using independent test and ANOVA test for numeric data. Association between variables was considered statistically significant if the P < 0.05.

RESULTS

Total 96 patients were randomized after eligibility criteria, but six patients were excluded due to complicated general anesthesia and dural tear. Thus, 30 patients in each group were follow-up and analyzed [Table 1].

Table 1

Consort flow diagram

All three groups were comparable in terms of age, height, weight, BMI, ASA physical status, and duration of surgery [Table 2].

Table 2

Demographic profile of patients

Variable	Mean±SD			P*
	Group D (n=30)	Group B (n=30)	Group C (n=30)
Age (years)	39.57±14.63	42.47±13.23	46.00±11.74	0.177a
Height (cm)	154.0±5.43	151.67±3.89	154.03±3.62	0.062a
Weight (kg)	58.60±6.40	54.20±8.51	56.27±6.43	0.065a
BMI (kg/m2)	24.66±1.84	23.45±2.77	23.69±1.94	0.091a
ASA Grade (1:2)	14/16	17/13	16/14	0.732b
Duration of surgery (min)	126±25.08	118±23.01	122±19.70	0.522a

aANOVA test, bChi-square test. P<0.05 (significant). BMI=Body mass index, ASA=American Society of Anesthesiologist, SD=Standard deviation

Regarding VAS scores, P1 (comparison of P value between Group D and Group B), were comparable up to 36 h postoperatively. Mean VAS scores were increased very slowly in Group D at most of the time intervals up to 36 h, which means patients experienced lesser pain compared to Group B. P2 (comparison of P value between Group D and Group C) was comparable in initial hours only and VAS score was significantly reduced in Group D up to 36 h postoperatively, which means patients in Group D had better pain control than control-Group C (P < 0.05). P3 (P value of comparison between Group B and Group C) was also significant up to 36 h postoperatively, implying that patients of Group B had significantly reduced VAS scores than control Group C (P < 0.05). Thus, we concluded that patients in both Groups D and B were most pain free in comparison to Group C [Table 3].

Table 3

Postoperative mean visual analog scale

VAS time interval	Mean±SD			P a
	Group D (n=30)	Group B (n=30)	Group C (n=30)
At 2 h postoperatively	1.07±1.04	1.47±1.2	1.70±1.21	P1=0.174
				P2=0.034
				P3=0.455
At 6 h postoperatively	1.13±1.32	1.60±1.07	4.37±1.47	P1=0.135
				P2=<0.001
				P3=<0.001
At 12 h postoperatively	2.97±1.65	4.03±1.97	5.74±1.74	P1=0.068
				P2<0.001
				P3<0.001
At 18 h postoperatively	2.40±1.20	2.90±1.35	4.07±1.57	P1=0.190
				P2=<0.001
				P3=0.033
At 24 h postoperatively	3.10±1.91	3.53±1.17	4.87±1.80	P1=0.281
				P2=<0.001
				P3=<0.001
At 30 h postoperatively	3.16±1.87	3.82±1.36	5.12±1.96	P1=0.122
				P2<0.001
				P3=0.004
At 36 h postoperatively	3.27±1.53	4.13±0.94	5.50±2.08	P1=0.010
				P2=<0.001
				P3=0.004
At 48 h postoperatively	4.07±1.26	3.63±0.96	4.73±1.23	P1=0.140
				P2=0.042
				P3=0.175

aUnpaired t-test. P1=Group D versus B, P2=Group D versus C, P3=Group B versus C. P<0.05 (significant). SD=Standard deviation, VAS=Visual Analog Scale

Time for the first rescue analgesic requested was significantly prolonged in Group D (14.67 ± 7.76 h) and Group B (11.33 ± 6.08 h) compared to Group C (6.40 ± 2.77 h). Total analgesic consumption in Group C (paracetamol 4.17 ± 0.75 g with tramadol 205 ± 37.94 mg) was significantly more than Group D (paracetamol 1.72 ± 0.57 g with tramadol 86.11 ± 28.73 mg) and Group B (paracetamol 3.04 ± 0.71 g with tramadol 151.85 ± 35.31 mg). Time for ambulation was significant in Group D and Group B in comparison to Group C (P < 0.05). Time for discharge was not significant among all three groups [Table 4].

Table 4

Postoperative analgesic requirement, time of ambulation, and discharge

Parameters	Mean±SD			P a
	Group D (n=30)	Group B (n=30)	Group C (n=30)
Time for 1st dose of rescue analgesic (h)	14.67±7.76	11.33±6.08	6.40±2.77	P1=0.114
				P2=<0.001
				P3=<0.001
Total dose of paracetamol (g)	1.72±0.57	3.04±0.71	4.17±0.75	P1=<0.001
				P2=<0.001
				P3=<0.001
Tramadol (mg)	86.11±28.73	151.85±35.31	205.0±37.94	P1=<0.001
				P2=<0.001
				P3=<0.001
Time of ambulation (h)	5.90±0.71	6.27±1.11	8.07±0.98	P1=0.134
				P2=<0.001
				P3=<0.001
Time of discharge (days)	3.47±0.51	3.57±0.50	3.95±0.507	P1=0.447
				P2=0.613
				P3=0.799

aUnpaired t-test. P1=Group D versus B, P2=Group D versus C, P3=Group B versus C. P<0.05 (significant). SD=Standard deviation

Regarding side effects such as nausea, vomiting, and sedation due to the use of study drugs were comparable in all the groups with statistically no significant difference [Table 5].

Table 5

Distribution of mean side effects

Side effect	Group D (%)	Group B (%)	Group C (%)	P a
Nausea	7 (23.3)	5 (16.7)	7 (23.3)	0.766
Sedation	7 (23.3)	3 (10.0)	3 (10.0)	0.237
Vomiting	3 (10.0)	2 (6.7)	2 (6.7)	0.856

aChi-Square test, P<0.05 (significant). Data are expressed as mean and percentage

DISCUSSION

This study showed that gelfoam soaked in dexmedetomidine or bupivacaine placed in epidural space for lumber laminectomy resulted in better postoperative analgesia in terms of lower requirement of rescue analgesia and less postoperative VAS score. Dexmedetomidine was superior to bupivacaine for prolonged the duration of postoperative analgesia and further reduced the requirement of rescue analgesia and postoperative VAS score.

Gelfoam is a sterile compressed sponge, water-insoluble in nature. It is a hemostatic device capable of absorbing up to 45 times its weight of whole blood.[15] The use of surgical gelfoam placed over nerve root in the epidural space encouraged by many studies to use it as extended-release drug delivery system to prolong the effect of epidural analgesics. Various adjuvant such as morphine, buprenorphine, nalbuphine, ketamine, and steroids used alone in the form of gelfoam soaked to prolong the postoperative analgesia in spine surgery.[1617181920] Easy access to epidural space during spine surgery has led to direct application of drug over the exposed dura mater. Free drug placed in epidural space at the time of the surgery is diluted by blood and tissue fluids, is lost into the disc space, and is absorbed systemically, thus limiting its duration of action,[21] but when soaked in gelfoam will remain for longer time and prolonging their duration of action.

In our study, total dose of rescue analgesic consumed in 48 h was significantly higher in control group (paracetamol 4.17 ± 0.75 g with tramadol 205 ± 37.94 mg). Bupivacaine soaked gelfoam group (paracetamol 3.04 ± 0.71 g with tramadol 151.85 ± 35.31 mg) had more doses of rescue analgesic consumption than dexmedetomidine soaked gelfoam group (paracetamol 1.72 ± 0.57 g with tramadol 86.11 ± 28.73 mg).

Similar results like our study for cumulative rescue analgesic consumption (tramadol) in the first 24 h were significantly lower in group levobupivacaine and dexamethasone soaked gelfoam (88 ± 66.58 mg) and group levobupivacaine soaked gelfoam (120 ± 70.7 mg) as compared with group placebo (280 ± 64.5 mg).[3] Patients with morphine directly instilled over intact epidural space (192 ± 48.7 mg) required higher doses of rescue analgesia (diclofenac sodium) than morphine soaked gelfoam (57 ± 39.2 mg).[18] Kundra et al.[17] studied gelfoam morphine (5 mL of 1 mg.mL− 1 morphine) found reduced rescue analgesic morphine (8.47 ± 3.67 mg)) consumption in 48 h than group control (24.80 ± 6.009 mg). Hence, the use of gelfoam soaked opioids, dexmedetomidine, or bupivacaine was effective to reduce rescue analgesic consumption in postoperative period.

We found that time for the first rescue analgesic requirement with dexmedetomidine soaked gelfoam group (14.67 ± 7.76 h) was significantly longer than in bupivacaine soaked gelfoam (11.33 ± 6.08 h) and control group (6.40 ± 2.77 h). Similar study reported that time for demand of the first rescue analgesia (tramadol) was significantly longer in group levobupivacaine and dexamethasone (10.11 ± 3.10 h), when compared with group levobupivacaine (6.48 ± 2.36 h) and group placebo (1.76 ± 1.13 h).[3] In our study, longer duration for the first rescue analgesic requirement was due to injection paracetamol at the end of surgery and dual rescue analgesic (paracetamol and tramadol) given postoperatively. Buprenorphine soaked absorbable gelatin sponge placed in epidural space had longer duration of analgesia (14.8 ± 0.77 h) than control group (0.66 ± 0.15 h).[16] Various other studies also found that gelfoam soaked epidural morphine in spine surgery can be prolonged duration of analgesia.[1718]

In our study, we observed mean VAS scores at 2, 6, 12, 18, 24, 30, 36 and 48 h. Mean VAS scores were significantly lower in dexmedetomidine and bupivacaine soaked gelfoam group compared to control group. Similar results of less mean VAS pain scores in levobupivacaine soaked gelfoam group compared with group placebo but more than that of group levobupivacaine and dexamethasone soaked gelfoam.[3] Morphine soaked gelfoam in epidural space showed lower mean VAS scores in lumber laminectomy patients.[1718]

Dexmedetomidine or bupivacaine soaked gelfoam group ambulate significantly earlier than control group. Another study in which morphine soaked gelfoam fasten ambulation in postoperative period in spine surgery patients.[18] Kundra et al.[17] reported mean time to ambulation was shorter in gelfoam soaked in morphine as compared to group gelfoam soaked in saline, though this difference was not significant (P > 0.05).

In the present study, side effects such as nausea, vomiting, and sedation were comparable in all three groups with statistically no significant difference. Other studies also did not found any significant difference regarding side effects.[318]

Limitations of the study

Sample size of this study was small, thus masking potential complications with the use of epidural gelfoam such as pressure symptoms, infection, or chronic back pain. We used dexmedetomidine alone in a group to see its individual effect. Future study needed to see the combined effect of dexmedetomidine with bupivacaine to prolong the duration of analgesia and reduced rescue analgesic consumption.

CONCLUSION

Hence, we concluded from the study that gelfoam soaked epidural dexmedetomidine or bupivacaine provided adequate analgesia, reduced rescue analgesic requirement, and devoid of side effects in lumber laminectomy. Dexmedetomidine is slightly better in comparison to bupivacaine for providing early-onset, prolonged postoperative analgesia and less rescue analgesic consumption.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.