Effect of wound infiltration with bupivacaine or lower dose bupivacaine/magnesium versus placebo for postoperative analgesia after cesarean section.

AIM: The authors examined the analgesic effect of wound infiltration with bupivacaine or lower dose bupivacaine and magnesium versus normal saline for postoperative analgesia after cesarean section.
MATERIALS AND METHODS: A total of 120 patients, American Society of Anesthesiologists (ASA) I-II were prepared for elective cesarean section. At the end of the surgery, the wound was continuously infiltrated at a rate of 5 ml/h for 24 h post-operatively by one of the following solutions: 0.25% bupivacaine, a mixture of 0.125% bupivacaine and 5% magnesium sulphate or normal saline (0.9%). Total opioid consumption, Visual Analogue Scale (VAS) at rest and movement, incidence of opioid side-effects and signs of wound inflammation were assessed during the period of the study (24 h post-operatively). Three months later, residual pain, surgical wound infection, need for extra-antibiotic therapy and wound healing impairment were assessed.
RESULTS: Post-operative pain scores at rest were statistically significant higher in the control group than those in the both wound infiltration groups from 4(th) h and onwards (P < 0.0001). Meanwhile, post-operative pain was higher in bupivacaine group versus magnesium group (P < 0.0001, P < 0.0001, 0.0012, respectively). There was statistically significant increase in VAS during movement in the control group versus others at 2, 4, 12, 24 h post-operatively (P < 0.0001). However, patients received magnesium plus bupivacaine wound infiltration showed a significant decrease in post-operative pain scores than whom received bupivacaine from 4(th) h and onward (P < 0.0001, 0.0054, 0.0001, respectively). Morphine consumption was significantly reduced in the magnesium group, (P < 0.0001). Incidence of residual pain was comparable in the three groups. The incidence of sedation and urine retention were noted to be significantly higher in the control group in comparison to other groups, (P <0.0001). The incidence of post-operative nausea and vomiting was reduced in patients received magnesium plus bupivacaine block versus others (P < 0.0001).
CONCLUSION: Continuous wound infiltration with a mixture of bupivacaine and magnesium sulphate after cesarean section showed an effective analgesia and reduced post-operative Patient Controlled Analgesia (PCA) requirements as compared to continuous wound infiltration with local anesthetic only or placebo with fewer incidences of opioid adverse effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

The ideal post-operative analgesic regimen should provide effective analgesia, be minimally invasive, not expensive, without side-effects.[1] The usage of continuous wound infusion with local anesthetics as a part of multi-model analgesia after surgical procedure depends on the recognition of the role of parietal nociceptive afferent nerves in eliciting pain induced by surgery.[23]

Cesarean delivery is one of the most common surgical procedures, and it is associated with an intense post-operative pain. Opioid-based analgesia is the first choice of cesarean delivery analgesia, but it has a number of side effects.[45]

Magnesium has anti-nociceptive effects in animal and human models of pain. These effects are primarily based on physiological Ca antagonism. Magnesium is a non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist. Intravenous magnesium sulphate reduces intra and post-operative analgesic requirements,[67] and prolongs neuromuscular blockade.[89]

In this study, the authors hypothesized the continuous wound infusion after cesarean section with a mixture of bupivacaine, and magnesium sulphate would be associated with reduction of post-operative opioid consumption for analgesia compared with continuous wound infusion with bupivacaine only.

MATERIALS AND METHODS

After approval of institutional ethical committee and written informed consent were obtained from the patients. One hundred twenty female patients, American Society of Anesthesiologists (ASA) I-II were prepared for elective cesarean section with pfannenstiel incision were included in this randomized, prospective, double blinded controlled study. Patients aged between 18 years and 40 years and gestational age 37-42 weeks.

Exclusion criteria included: Refusal of the patient, known allergy to local anesthetics or magnesium sulphate, patients with a history of clinically significant cardiovascular, pulmonary, hepatic, renal, neurologic, psychiatric, metabolic disease were excluded from the study. Patients had any contraindication to spinal anesthesia or chronic use of any types of analgesics or sedatives were excluded.

Patients were instructed how to use the pump of patient controlled analgesia. Visual analogue scale of pain (0-10, the 0-presumably no pain and 10: Worst pain) was explained to patients before surgery. Patients were pre-loaded with 10 ml/kg Ringer's lactate before spinal anesthesia. Intrathecal injection of 2 ml 0.5% hyperbaric bupivacaine (10 mg) in a sitting position with a pencil point 25 gauge spinal needle at level of L3-L4 inter-space. At the end of the surgery, the surgeon inserted percutaneously a multi-hole 20 gauge catheter deep to fascia approximately 1 cm away from the incision. Immediately after, the skin was sutured, the wound was continuously infiltrated at a rate of 5 ml/h through the multi-hole catheter for 24 h post-operatively by one of the following solutions:

Group I (BG, bupivacaine group): With 0.25% bupivacaine

Group II (MG, magnesium sulphate group): A mixture of 0.125% bupivacaine and 5% magnesium sulphate.

Group III (CG, control group): With normal saline (0.9%).

The medication sets were prepared at the pharmacy by a blind pharmacist. Each set contained a syringe of 120 ml for wound infiltration; the component of the syringe differed according to group allocation. In Group I (BG), contained 60 ml of bupivacaine 0.5% plus 60 ml of 0.9% saline while in Group II (MG), contained 6000 mg of magnesium sulphate in 60 ml + 30 ml of bupivacaine 0.5% plus 30 ml of 0.9% saline versus 120 ml of 0.9% saline in Group III (CG).

Patient, anesthetist, investigator starting post-operative infusion and investigator making post-operative observations and recordings were blinded to the group assignment.

All groups received ketorolac (30 mg) intravenously/8 h for post-operative analgesia. Acetaminophen through slow intravenous route at a dose of 500 mg with a maximum dose of 4 g/day for the 1st day after surgery as a rescue analgesia.

At the end of the operation, an intravenous patient controlled analgesia device was begun (2 mg morphine per demand with 10 min lockout time and a maximum allowed dose 10 mg/h).

Randomization was performed using a computer based random number generator in permutated blocks of varying sizes and the assignment entered in sealed envelopes that were not opened until informed consent was obtained.

During the operation monitoring of the patient included, heart rate, non-invasive blood pressure, electrocardiogram, and oxygen saturation SaO2.

The following measurements were assessed during the period of the study (24 h post-operatively):

Total opioid consumption

Visual Analogue Scale was measured at 2, 4, 12, 24 h post-operatively at rest and movement (sitting from lying down position). If VAS > 3 at any time 500 mg of Paracetamol was infused intravenously

Incidence of nausea and vomiting (if occurring ondansetron 4 mg intravenous was given)

Sedation (according to Ramsay'scale).

Incidence of retention of urine (urinary catheter was removed at the end of surgery and retention was defined as the need for catheter during 1st 24 h post-operatively.

Hypotension: Defined as mean arterial pressure <20% of the pre-spinal value.

Respiratory depression (respiratory rate ≤10 and SaO2 ≤ 85).

The wound was observed for 24 h for signs of inflammation.

Three months after surgery, the patients were followed by phone call to ask about:

Residual pain (pain, itching, burning sensation, local sensitivity loss, and requirements for analgesics), surgical wound infection, need for extra-antibiotic therapy and wound healing impairment (e.g. keloid formation).

Statistical analysis

Thirty four patients were needed per group to have an 80% chance of detecting a 35% reduction in 24-h morphine consumption at a 5% significance level, using a Mann-Whitney test with a 0.05 2-sided significance level. To enable detection of differences in the side-effects between the 2 groups, we expected that somewhat larger groups would be required, and 40 patients per group included.

Data were analyzed using the SPSS 15.0 software, with Fisher exact test, unpaired t-test, and Mann-Whitney test, as appropriate; P < 0.05 was considered to be statistically significant.

RESULTS

One hundred twenty patients, scheduled for cesarean section were enrolled in the study [Table 1]. There was no significant difference between groups as regards to age, weight and duration of surgeries, [Table 1].

Table 1

Demographic data and duration of surgeries

The total morphine consumption in the first 24 h was significantly reduced in the magnesium groupn (mean ± SD), (25 ± 7.3, 10 ± 4.5, 40 ± 12.3) in the three groups respectively (P < 0.0001). However, patients received wound infiltration with bupivacaine showed a significant decrease in analgesic requirement than control one (P < 0.0001).

Time to first patient controlled analgesic requirement (mean ± SD) was 119 ± 28, 175 ± 36, 100 ± 24 min in the three studied groups respectively (P < 0.0001 between Group I and II, 0.0017 between Group II and III, <0.0001 between Group II and III).

No usage of rescue analgesia in Group I and Group II versus 845 ± 123 mg of acetaminophine in Group III.

The data on post-operative pain at rest and movement are shown in Table 2. Post-operative pain scores at rest were statistically significant higher in the control group than those in the both wound infiltration groups from 4th h and onwards (P < 0.0001). Meanwhile, post-operative pain was higher in bupivacaine group versus magnesium group (P < 0.0001, P < 0.0001, 0.0012, respectively). Regarding post-operative pain at movement, there was statistically significant increase in VAS in the control group versus others at 2, 4, 12, 24 h post-operatively (P < 0.0001). However, patients received magnesium plus bupivacaine wound infiltration showed a significant decrease in post-operative pain scores than whom received bupivacaine from 4th h and onward (P value were 0.0782, <0.0001, 0.0054, 0.0001, respectively).

Table 2

Visual analogue scale on rest and movement

The incidence of sedation (sedation score > 0) and urine retention, [Table 3] were noted to be significantly higher in the control group in comparison to other groups, (P <0.0001).

Table 3

Opioid complications, signs of wound inflammation and results of follow-up after 3 months

The incidence of post-operative nausea and vomiting [Table 3], was substantially reduced in patients received magnesium plus bupivacaine block versus others (P < 0.0001). However, the incidence of postoperative nausea and vomiting PONV was comparable in the control group versus whom received bupivacaine continuous wound infiltration (P = 0.318).

Regarding the incidence of residual pain [Table 3], incidence of pain was comparable in the three groups (P value was 0.355, 0.215 respectively) when comparing a control group with local infiltration groups. Incidence of keloid or wound infection was comparable among the three groups.

DISCUSSION

After cesarean section, continuous wound infusion with local anesthesia alone reduced opioid needs by about 37%. Meanwhile, continuous wound infusion with a mixture of local anesthesia and magnesium sulphate reduced opioid needs by about 75% as compared with placebo. Opioid sparing effect reduced post-operative nausea and vomiting, sedation, and urine retention.

Chronic pain represents a significant problem in 6-12% of the patients after cesarean section.[10] Morphine is often used via PCA devices, but large doses required can lead to fatigue nausea and vomiting as well as drowsiness.[11]

Another different techniques have been used to reduce post-operative pain including local anesthetic infiltration, non-steroidal anti-inflammatory drugs and positive suggestion.[121314]

There are several studies investigating wound infiltration with local anesthetic:[15161718192021] One demonstrated no difference in VAS from wound infiltration with local anesthetic (bupivacaine) versus placebo, but a decrease in opioid requirements.[16] Other demonstrated better analgesia and reduced rescue requirements.[20] One demonstrated when given with nonsteroidal anti-inflammatory drugs (NSAIDS) there is no added benefit to local infiltration.[17] One investigated changes in inflammatory and nociceptor mediators with the continuous local anesthetic instillation. It found no difference in post-operative pain or analgesic consumption, intrathecal fentanyl, and morphine were given.[21]

Other substances infiltrated post-cesarean: Pethidine,[22] ketamine,[23] diclofenac[19] were more effective than the combination of local infiltration and systemic NSAIDS. Magnesium used as a co-analgesic subcutaneously. One study found wound infiltration with ropivacaine and magnesium was more effective than ropivacaine infiltration and intravenous magnesium for radical prostatectomy. Patients had general anesthesia and systemic opioids were given intraoperatively. Outcome was post-operative tramadol usage.[24]

Magnesium used as a co-analgesic for peripheral blocks: Two studies demonstrated prolongation of peripheral nerve blocks in axillary plexus block[25] and interscalene block.[26]

To our knowledge this is the first study investigating subcutaneous magnesium infiltration post-cesarean.

Continuous wound infiltration of local anesthesia can provide analgesia through different mechanisms. It directly blocks transmission of pain from the nociceptive afferents of the wound surface. In addition, it can inhibit local inflammatory response to injury, which contributes to pain and hyperalgesia. This may reduce the release of inflammatory mediators which reduce the formation of free oxygen radicals and decrease edema formation.[2728]

Opioid sparing effect of continuous wound infiltration contribute to decrease the incidence of nausea and vomiting, which ranges from 30% to 80% with other regimens of post-operative analgesia depending mainly on opioids.[29] PONV can result in major post-operative discomfort, increased economic cost and delayed hospital discharge.[29]

There is no technical failure or local anesthetic toxicity with continuous wound infusion. Furthermore, wound infection rate was comparable.

The limitation of the present study includes that: Parity and number of previous cesarean sections are not stated. These are an important omission as parturients may compare pain to their previous experience of delivery or may have altered sensation/pain from previous cesareans. The other source of bias is the fear of using medication as many women do not want to take medication as they feel it might affect their baby and so would not push the button even though a VAS may measure 4 or 5.

In conclusion, the use of continuous wound infiltration with a mixture of bupivacaine and magnesium sulphate after cesarean section showed an effective analgesia and reduced post-operative PCA requirements as compared to continuous wound infiltration with local anesthetic only or placebo with fewer incidences of opioid adverse effects.