Effect of intrathecal midazolam-bupivacaine combination on post-operative analgesia

 

 

Abstract               Background and Aim: Post-operative analgesia is an important aspect of perioperative patient care in elective, emergency as well as day care surgeries due to various advantages. Use of intrathecal adjuvants is increasing to achieve good perioperative care and outcome.  Methods: A prospective randomized double-blind study was carried out on 50 patients of ASA grade I/II, aged 16-60 years, scheduled for elective lower abdominal and lower limb surgeries. Patients were randomly allocated in two groups. Group A received 3ml 0.5% bupivacaine heavy (15mg) + 0.2 ml of 0.9% saline intrathecally. Group B received 3 ml 0.5% bupivacaine heavy (15 mg) + 0.2 ml preservative free midazolam (1mg). Patients were closely monitored for hemodynamic, sedation or any perioperative complications. ‘Effective analgesia’ was taken as time from S2 segment regression to administration of first rescue analgesic in minutes (T3 = T2 –T1). Results: Statistically significant difference was found with regards to S2 segment regression time between the two groups (p < 0.05) (217 min in group A v/s 240 min in group B). In our study, mean time to first rescue analgesic drug (T2) (diclofenac sodium 1mg/kg intramuscularly at VAS score ≥ 40 mm) was significantly prolonged in group B (p<0.001) (418±42.6 min in group B v/s 262.2±26.53 min in group A). Effective analgesia time (T3) was also prolonged. (179 min in group B v/s 45 min group A). Two groups did not defer as regards to type/duration of surgery, Time to onset of sensory block and time to achieve maximum sensory block. Conclusion: Intrathecal combination of midazolam and Bupivacaine provides longer duration of post-operative analgesia along with prolonged sensory regression time with hemodynamic stability and no significant adverse effects.

Key Word: Intrathecal Midazolam, Post-operative Analgesia, Bupivacaine

 

 

INTRODUCTION

Concept of post-operative analgesia is gaining importance in elective, emergency and day care surgeries due to number of advantages such as:

• Minimal psychological stress
• Improved hemodynamic stability and respiration
• Relief of sympathetic overactivity and prevention of peripheral or central sensitization.
• Greater flexibility about timing of surgery
• Reduced postoperative complication
• Early return to routine activities

Intrathecal adjuvants drugs like fentanyl, clonidine⁷, ketamine¹⁹ etc. have been used by various investigators. Side effects of intrathecal opioids²⁷ like respiratory depression, nausea, vomiting, pruritus limit their use. Likewise, intrathecal administration of clonidine can lead to hemodynamic changes. As there are reports of presence of Benzodiazepine/GABA receptor complex in spinal cord and only few studies on intrathecal midazolam in humans, we decided to asses intrathecal midazolam-Bupivacaine combination with primary aim to study its postoperative analgesic effect and co-relate it with sensory dermatomal regression time.

 

METHODS

A prospective randomized double-blind study was carried out on 50 patients of ASA grade I/II, aged 16-60 years, scheduled for elective lower abdominal and lower limb surgeries. All the patients were evaluated preoperatively and those having history of allergy to any drug or having any contraindications to spinal anaesthesia were excluded from the study. Patients using any drug that modifies pain perception were excluded from the study. Fasting for minimum 6 hours was advised prior to scheduled time of surgery. Procedure was explained to all patients and informed consent was taken.

Inside the operation theatre, ECG, NIBP monitor and pulse oximeter were applied to all patients and baseline pulse, blood pressure, oxygen saturation and respiratory rate were recorded. Patients were preloaded with 10-15 ml/kg of intravenous Ringer’s lactate solution after securing 18 Gauge intravenous line. Patients were randomly allocated in two groups. Group A received 3ml 0.5% bupivacaine heavy (15mg) + 0.2 ml of 0.9% saline intrathecally. Group B received 3 ml 0.5% bupivacaine heavy (15 mg) + 0.2 ml preservative free midazolam (1mg-from 5mg/ml ampoule). Subarachnoid block was performed under all aseptic precautions in sitting/lateral decubitus position(figure-4) with 23 Gauge Quincke^’s spinal needle in L₂-L₃ or L₃-L₄ space via midline/paramedian approach. Patients were immediately made supine and time to subarachnoid injection was noted. Sensory block was assessed by the loss of sensation to pinprick. Time to onset of sensory block, maximum level of sensory block achieved and time to achieve maximum sensory block were noted in minutes. A dermatomal sensory loss from T₁₀-S₄ level was considered satisfactory according to type of surgery. Pulse rate, arterial blood pressure, SpO₂ and respiratory rate were recorded every five minutes till first half an hour and then every fifteen minutes intraoperatively. Intravenous fluids were continued throughout the surgery. Any intraoperative complications like nausea/vomiting (NV), pruritus(P), shivering(S) and respiratory depression(Rd) were looked for. Sedation levels were assessed using the Observer’s Assessment of Alertness/Sedation scale (OAA/S) as used by Chernik et al³

Responds readily to name spoken in normal tone                                             5(Alert)

Lethargic response to name spoken in normal tone                                         4

Responds only after name is called loudly and / or repeatedly    3             

Responds only after mild prodding or shaking                                     2

Does not respond to mild prodding or shaking                                    1(Asleep)

intraoperatively every 30 mins and every hourly for six hours following arrival in PACU. Hypotension (defined as 30% fall in systolic BP from the baseline BP) was treated with intravenous fluids and inj. mephenteramine 6mg i.v. Bradycardia (defined as pulse rate <60 beats per min) was treated with inj. atropine sulphate 0.6 mg i. v. Shivering was treated with 100% O_2, warm fluids and adequate patient covering. No other sedative or analgesic drug was given to the patients intra operatively. Respiratory depression (defined as RR<12/min or SpO₂<90%) was treated with 100% O₂. Duration of surgery for each case was noted. Postoperatively, time to regression of sensory block to second sacral dermatome (S₂) was assessed by pinprick and recorded in minutes (T₁). Pain was assessed postoperatively using Visual Analogue Scale (VAS). The scale consisting of a 100 mm line with 0 = no pain and 100 = worst possible pain was explained to all patients. All patients were followed up postoperatively till patients complained of pain as per VAS and vitals were monitored at 30 min intervals postoperatively up to 6 hours following arrival in PACU. When VAS score was ≥ 40 mm, the patients were given inj. diclofenac sodium 1mg/kg i.m. and this time was noted. Time from subarachnoid injection to administration of first rescue analgesic was taken as ‘Time to first rescue analgesic’ and recorded in minutes (T₂). ‘Effective analgesia’ was taken as time from S₂ segment regression to administration of first rescue analgesic in minutes (T₃ = T₂ –T₁). Patients were also observed for any post-operative complications like nausea, vomiting, shivering, respiratory depression, amnesia, pruritus or urinary retention.

 

Statistical Analysis: Data were presented as mean value, mean ± SD and percentage as appropriate. Two groups were compared by unpaired t-test and p value < 0.05 was considered statistically significant while p value < 0.001 was considered highly significant.

RESULTS                                      

Demographic and surgical variables were comparable in both groups (P>0.05). (Table: 1)

Table 1: Types and Duration of surgery

No statistically significant difference was found with regards to – time to onset of sensory block, maximum sensory level achieved and time to achieve maximum block height as judged by pinprick method. (Table 2).

 

Table 2: Characteristic of sensory blockade

Level of sedation was assessed using Observer’s Assessment of Alertness/Sedation (OAA/S) scale and the scale was comparable in both the groups. (Table 3)

 

Table 3: Intraoperative sedation by OAA/S scale

Time for regression of sensory block to S2 segment was 217 min in group A v/s 240 min in group B (p < 0.05). Time to first rescue analgesic was prolonged significantly in group B as compared to group A (p < 0.001) (262 min in group A v/s 418 min in group B) (Table 4) and patients’ subjective response to analgesia was definitely better in group B.(Table 5)

 

Table 4: Duration of analgesia

 

Table 5: Subjective response to analgesia

No significant difference was observed in vital parameters during intraoperative monitoring between the two groups.

Use of intrathecal midazolam did not increase rate of any perioperative complications.

DISCUSSION

Edward M, Serrao et al⁹ (1990) observed that administration of benzodiazepine antagonist flumazenil and GABA_A antagonist bicuculline reversed the analgesic effect of intrathecal midazolam, suggesting that antinociceptive actions are mediated via BZD/GABA_A receptor complex which are abundantly present in lamina II of dorsal horn of spinal cord. Goodchild CS et al¹⁴ (1996) reported that intrathecal midazolam probably causes release of an endogenous opioid at spinal delta receptors as naltrindole, a delta selective opioid antagonist suppressed analgesic action of intrathecal midazolam. Tucker P et al²⁸ (2004) did a cohort study with >1000 subjects investigating safety of intrathecal Midazolam in humans. In contrast with the studies that reported histopathological changes in animals¹⁷, they found no adverse effects with intrathecal Midazolam when assessed by symptoms and long term follow up in humans. This is consistent with administration of a dose of intrathecal midazolam, approximately 0.03 mg/kg, which is less than that associated with both histopathology and behavioural changes in previous animal studies. Kim MH and Lee YM²⁰ (2001) studied the effect of two different doses of intrathecal midazolam (1mg and 2mg) on post op analgesia, while we used 1 mg preservative free intrathecal midazolam. In our study, Sedation scores were comparable in both groups. However, Nishiyama T et al²³ (1992) reported sedation with higher doses of epidural midazolam. In our study, Time taken for regression of sensory block to second sacral dermatome (S₂) was significantly longer in Group B than in Group A (240 ± 26.61 min in Group B v/s 217.4 ± 22.68 min Group A) (p<0.05). Batra et al²and N Bharti, R Madan et al²² , Shadangi et al²⁷ (2011) also found similar results. However, Agrawal N et al¹ (2005) found no statistically significant difference with respect to time for sensory block regression to first sacral dermatome (p>0.05). Mean time to first rescue analgesic drug (T₂) (diclofenac sodium 1mg/kg im at VAS score ≥ 40 mm) was significantly prolonged in group B (p<0.001) (418±42.6 min in group B v/s 262.2±26.53 min in group A). So, total duration of pain relief was increased by about 2 hours in the midazolam group. However, Agrawal N et al¹ (2005) reported that time to first rescue analgesic in bupivacaine – Midazolam group (1 mg) was significantly longer than in bupivacaine group [17.56 ± 8.87 hours v/s 4 ± 3.5 hours]. Effective analgesia time (T₃) was also prolonged by approximately 2 hours (179 min in group B v/s 45 min group A). Thus raising the possibility of another mechanism of action of intrathecal midazolam besides segmental cord level analgesia. Patient’s response to overall analgesia was good in most of the cases of group B as compared to group A. (28% in group A v/s 80% in group B). Characteristics of motor blockade were not studied in detail, as our primary aim was to assess postoperative pain relief. However, onset and duration of motor block as well as surgical relaxation was satisfactory in all the patients perioperatively. In our study, no significant difference was observed in vital parameters during intraoperative monitoring between the two groups. Three patients in midazolam group (group B) developed transient bradycardia(12%) as compared to two patients in control group (group A – 8%) that was treated with inj. atropine 0.6 mg iv. In our study, no statistically significant difference was observed between two groups with regards to rates of hypotension, shivering, nausea vomiting, pruritus or respiratory depression More studies on larger sample of human populations are needed to evaluate the possible mechanism of analgesia of intrathecal midazolam.

 

So, to conclude, Addition of 1 mg (0.2 ml) preservative free midazolam to intrathecal 15 mg (3 ml) hyperbaric 0.5% bupivacaine produces satisfactory  anaesthesia along with prolonged sensory regression times, prolonged post-operative analgesia with better subjective response to analgesia, perioperative hemodynamic stability without any significant adverse effects.

 

REFERENCES