Graph-regularized NMF

Rectal route i.v route i.m route

Insersion in the ward (6hrs post operatively) Insersion under SAB

(immediate post operatively)

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CHAPTER FIVE DISCUSSION:

This study shows that the use of combined intrathecal bupivacaine and pethidine with rectal diclofenac in a multimodal strategy, significantly improves the quality and duration of post Caesarean section analgesia with an acceptable side effect profile.

The time to request for first analgesia was longer in the diclofenac group compared to the control group. The pain scores were significantly lower in the first 4hrs in the diclofenac group and spinal induced maternal hypotension was a common complication observed. However, there was no specific diclofenac induced complication.

Several studies have evaluated the role of intrathecal bupivacaine and pethidine^25,36 with some others evaluating the use of diclofenac alongside other analgesic agents.^22,39 This study explores specific role of diclofenac suppository against a placebo when combined with intrathecal bupivacaine/pethidine. This was necessary considering the resource poor setting like ours where facilities such as PCAs are not readily available, yet there is need to effectively manage post caesarean section pain.

In the face of such inadequacies however, cheaper and more readily available alternatives must be developed, hence this study. At present the main stay for management of post Caesarean section pain in our centre is intramuscular pentazocine given every 4 – 6hrs for the first 48hours. The intramuscular route is not encouraged and the analgesic quality of pentazocine for post Caesarean section pain may be inadequate. It is not surprising therefore, that severe pain was the commonest complication after caesarean section reported by Edomwonyi and colleagues.³ A

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survey of women’s assessment of intra and post partum care in University of Nigeria Teaching Hospital⁴⁰ (UNTH) Enugu, Nigeria revealed poor pain relief and majority of the women were dissatisfied with that aspect of their care. A similar study at the University of Ilorin Teaching Hospital⁴¹ (UITH) Ilorin, Nigeria revealed that 54.6% of patients reported moderate to severe pain on the first day following caesarean section.

The report was not different in the University College Hospital⁴² (UCH) in Ibadan, Nigeria where as much as two-thirds of patients complained of moderate to unbearable pain 24 hrs post operatively. It is evident therefore that post Caesarean section pain remains a significant problem in our environment.^3,40,43

The burden of pain is further magnified by the dramatic increase in the number of caesarean sections performed worldwide over the last two decades.⁴⁴ Caesarean section rates have been rising considerably from between 10 – 15% in the 1980s to rates as high as 24% presently in the United Kingdom.^45,46 In Nigeria there is a similar trend with a progressive rise in Caesarean section rates from about 9.4% in the 1970s up to rates as high as 34.6% presently.⁴⁷ In the University of Benin Teaching Hospital where this study was conducted, a rate of about 22.2% was reported between 1996 and 2000.⁴⁸ Indeed, emerging indications such as maternal request for caesarean section as seen in this study would further increase the caesarean section rate in our environment. This increasing trend in the number of women giving birth by Caesarean section across the world warrants a corresponding increase in research into post-operative pain relief.⁴⁹ In view of the advantages that adequate pain management besets the mother and the newborn,^5,49 development of effective management strategies must be considered a sine qua non to continued obstetric care.

The multimodal strategy employed for management of post Caesarean section pain in this study was found to be effective in improving the duration and quality of post

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Caesarean section analgesia. The concept of multimodal or balanced analgesia advances the use of a potent opioid regimen such as PCA or neuraxial opioid in combination with other classes of analgesics (usually non opioids) with different mechanisms of action.^49,50 Theoretically the use of a combination of analgesic drugs allows for an additive or synergistic effect in pain control while reducing the side effect produced by each class of drug as smaller drug doses are required.^51,52 The different mechanisms of actions of the combined drugs afford the advantage of interrupting the pain pathway at different levels. Typical analgesic combinations include opioids, non opioid analgesics such as paracetamol and NSAIDs with variable addition of local anaesthetics.

The benefit of multimodal analgesia as demonstrated in this study can be further appreciated when the sites of action of the various agents are considered (annex 2).

While the local anaesthetic acts mainly on the dorsal horn of the spinal cord and peripheral nerves, its action is potentiated by the synergistic effect of spinal opioids.

The opioids can act centrally on various parts of the brain, also modulating pain transmission in the spinal cord along the spinothalamic tract with actions on ascending and descending pathways. They are also known to have peripheral action on the norciceptors. The NSAIDs like diclofenac have been traditionally known to act by peripheral inhibition of prostaglandin synthesis. They are presently known to exert their analgesic effects through a variety of other peripheral and central mechanisms. Also, interference with G protein mediated signal transduction by NSAIDs may form the basis of an analgesic mechanism unrelated to prostaglandin synthesis.⁵³ It is apparent that combating pain transmission through so many different mechanisms would offer better pain control.

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The multimodal approach employed in this study has shown a significant extension of intraoperative analgesia into the postoperative period, with a prolonged mean time to request for analgesia compared to the placebo group. This indicates that for a much longer period postoperatively, the lowest range of pain scores are observed thus improving patient comfort and optimising outcome. Although in the early postoperative period generally low pain scores were observed, patients in the diclofenac group had significantly lower pain scores.

This result further confirms the superiority of diclofenac suppository and intrathecal bupivacaine/ pethidine combination in line with shifting trends towards multimodal management strategy.⁵¹ This underscores the need for multimodal therapy as previously canvassed by some authors.^49,50,52 Sole intrathecal pethidine has been employed for Caesarean section^27,54 with analgesia extending into the post operative period but with disturbing side effect profile. Attempts at minimising the side effect of intrathecal opioid by using lower doses in combination with intrathecal bupivacaine^25,36 have also been successful. Yu et al²⁵ added 10mg of pethidine to 2ml of 0.5%

hyperbaric bupivacaine, and obtained a mean duration of analgesia of 234min with an improved side effect profile. The dose of intrathecal pethidine combined with bupivacaine intrathecally was reduced to 7.5mg by Imarengiaye and colleagues³⁶ to further improve the side effect profile, the authors demonstrated a mean duration of effective analgesia of 257min. This multimodal approach in the present study which employed the addition of rectal diclofenac has demonstrated an extension of the duration of effective analgesia to a mean of 347min. The difference in the time to first request for analgesia was further validated by the fact that there was no significant difference in the mean pain score at time of request for analgesia which was 5.0 and 5.2 in the diclofenac and placebo groups respectively.

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The finding of improved post operative analgesia with multimodal approach in this study is in keeping with several previous studies13,21,22,24 Siddik et al¹³ previously demonstrated that in patients receiving I.V PCA morphine, combination of 100mg rectal diclofenac and 2g propacetamol was associated with lower VAS scores and morphine consumption than propacetamol only. Olofsson and colleagues²² also demonstrated that the addition of rectal diclofenac produced enhanced pain control with a concomitant reduction of opioid requirement when compared with a placebo group. Similarly, Cardoso et al²¹ underscored the role of diclofenac in post Caesarean section multimodal analgesia when they showed that intramuscular diclofenac combined with low dose spinal morphine and bupivacaine provides excellent analgesia with minimal side effects. The use of the rectal route for the administration of diclofenac in this study obviates the problems of intramuscular injection thus leading to better acceptance and patient’s comfort without compromising the quality of post operative analgesia.

However, some studies did not detect any significant improvement in pain scores with multimodal approach to pain management.²⁰ Lim and his colleagues⁵⁵ demonstrated a significant opioid sparing effect when100mg rectal diclofenac was combined with Patient Controlled Epidural Analgesia (PCEA) with ropivacaine and fentanyl. The authors, however, did not find significant difference in pain scores or satisfaction scores between those patients who had rectal diclofenac and those who did not.

Similarly, Pavy et al²⁰ demonstrated an opioid sparing effect when intravenous ketorolac was combined with intravenous PCA, but there was no significant improvement in pain scores, maternal satisfaction or side effect profile. These results should be interpreted with caution as type II errors are likely, due to the small sample sizes. Furthermore, Pavy and his colleagues²⁰ reported a change in the dose of

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ketorolac administered in the middle of the study, an inconsistency which may have affected their result.

The quality of analgesia which is a determinant of maternal comfort and satisfaction was appreciable in this study. The numerical rating scores at the various timelines, a direct measure of the severity of pain experienced by the patient and secondarily a measure of the patient’s comfort, reflects the quality of analgesia. Good quality pain control is an absolute necessity in management of post Caesarean section patients, as pain in this period is detrimental to the care of the new born, mother child bonding, early ambulation and discharge.

There were manifestations of complications in the central nervous system, cardiovascular system and gastrointestinal systems. These complications were the commonly reported ones with spinal anaesthesia and administration of intrathecal opioids and included shivering, hypotension, nausea and vomiting.25,27,56,57The commonest side effect was hypotension with an incidence of 41.6%, accounting for 33.1% of all intraoperative side effects and 28.2% of all side effects both in the intra and post operative periods. It was managed with bolus administration of intravenous fluids and or 5mg aliquots of ephedrine with good response in all cases. Nausea and vomiting and shivering were the second and third most common complications observed in this study.

Spinal induced maternal hypotension remains a major concern for the anaesthetist in the conduct of spinal anaesthesia. Its incidence has been reported to be as high as 50 – 60%.⁵⁸ The high incidence of maternal hypotension reported in this study (41.7%) was similar to the 40% reported by Imarengiaye et al³⁶ who employed similar drug doses. Yu et al,²⁵ however, reported an incidence of 71% associated with 10mg

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intrathecal pethidine. Authors have, however, reported lower incidence of hypotension with intrathecal bupivacaine only.^56,57 The small dose of bupivacaine employed in this study would suggest a lower incidence of hypotension, this was not the observation however. It has been speculated that the addition of opioids to intrathecal bupivacaine makes the solution hypobaric by reducing the baricity. The implication is a tendency to a higher sensory level and a higher block especially in the sitting position.⁵⁹ The ensuing sympathectomy results in marked hypotension. This may have accounted for the rather high incidence of hypotension in this study. Chemical sympathectomy results in a loss of vasomotor tone, reduction in systemic vascular resistance with arterial and venous vasodilatation thus leading to hypotension. With sensory block higher than T4, the cardioacceleratory fibres may be blocked with consequent drop in heart rate and cardiac output.⁶⁰ Uncorrected maternal hypotension may result in foetal morbidity from hypoxaemia and acidosis due to uteroplacental hypoperfusion.⁶¹ Maternal outcome may also be compromised by hypotensive sequelae such as hypoxaemia, acidosis, myocardial or cerebral ischemia.⁶² It is however salutary that the episodes of hypotension noted in this study were mild and easily treatable.

Volume preloading with crystalloid which was the prophylactic measure employed in this study has been previously shown to be important in preventing maternal hypotension.⁶³ Several reports have also indicated otherwise^64,65 significant increases in central venous pressure have also been reported following colloid and crystalloid preloading.⁶⁶ While this raging controversy continues it has also been shown that co-loading of the circulation is better than preco-loading.⁶⁷ Reports have also been made in favour of colloids rather than crystalloids for preloading.⁶⁸ Colloids are expensive and associated with hypersensitivity reactions. The controversy notwithstanding, the attending anaesthetist should be prepared to minimize the occurrence of hypotension

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and manage promptly any significant decrease in maternal blood pressure.⁶⁹ Nevertheless, practice guidelines emphasise the need for preloading prior to the conduct of spinal anaesthesia.⁷

Maternal hypotension remains a problem of spinal anaesthesia despite preloading, necessitating the search for management alternatives bringing to the fore the role of vasopressors. Vasopressors may be used either therapeutically when hypotension is noticed or as a prophylactic measure. Ephedrine which has inherent properties of both alpha and beta activity and preserves uteroplacental circulation is the most widely used and was used in this study. The efficacy of prophylactic ephedrine administered through the intramuscular⁷⁰ or intravenous⁷¹ routes has been studied. Desalu and Kushimo⁷² compared prophylactic ephedrine infusion and volume preloading in African parturients. Their result suggested that standard infusion of ephedrine is superior to crystalloid prehydration in the prevention of spinal induced maternal hypotension. It is plausible that the high incidence of hypotension in this study may have been reduced if ephedrine infusion had been used. The use of ephedrine in this study is due to availability rather than efficacy as evidence abound on the superiority of phenylephrine to ephedrine.⁷³ Phenylephrine which is an alpha adrenoceptor agonist, although with similar effects regarding treatment of hypotension, is associated with a lower incidence of foetal acidosis and maternal nausea and vomiting compared with ephedrine⁷⁴ Intraoperative nausea and vomiting has been reported by several authors with intrathecal pethidine administration.^11,25,75 Indeed reports have indicated that this can occur in as much as 80% of patients.⁷⁶ This study observed nausea in 21.3% with vomiting in 18.1% of the patients. The incidence of nausea and vomiting like most side effects of opioids are dose related and a trend towards lower incidence of nausea/

vomiting with lower doses of opioids has been reported.⁷⁷ Booth et al⁷⁸ reported a

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significant incidence of nausea and vomiting with intrathecal opioid pethidine although he used a dose 2 – 3 times the dose used in this study. The influence of intrathecal pethidine dose was demonstraded again in the finding of Yu et al²⁵ who reported a higher incidence of nausea and vomiting (55%), having added 10mg pethidine to bupivacaine intrathecally.

Shivering is a known complication of subarachnoid block for caesarean section.⁵⁶ The incidence of shivering observed in this study was 13.8% which is similar to previous report of 15%,²⁵ although a much higher incidence of shivering has also been observed.⁵⁶ The lower incidence of shivering observed in this study compared with that reported by Edomwonyi et al⁵⁶ may be due to the use of intrathecal pethidin in this study. Intrathecal opioids have been shown to be associated with a significant reduction in the incidence of spinal induced shivering.^24,36

The incidence of respiratory depression is controversial, some authors report none^21,27,36 whereas hypoxia has been reported in up to 10% of cases.⁷⁹ There was no case of respiratory depression in this study. All the patients studied had their SpO2

continuously monitored with a multi-parameter monitor without records of hypoxic values (< 92%). This may be explained by the small dose of intrathecal pethidine employed. The patient population studied (young healthy women with high level of endorphins and progesterone) is also known to be resistant to the depressant effects of opioids.⁷⁹

Pruritus has been associated with opioids use of intrathecal opioid, ^21,25 its incidence however seems to be dose related. Studies in which the dose of intrathecal pethidine was 50mg or more revealed an incidence ranging from 10.7 to 32%.^27,80,81 Yu and his colleagues²⁵ conducted a study similar to this one but added 10mg of pethidine to

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bupivacaine inthrathecally, the authors observed mild forms of pruritus post operatively. There was, however, no incidence of pruritus in this study, a finding in keeping with Imarengiaye et al³⁶ who employed a similar dose of intrathecal pethidine.

The absence of pruritus may be accounted for by the small dose of pethidine used.

There was no incidence of side effects related to use of NSAID suggesting that the single dose diclofenac suppository can be safely employed in multimodal approach to post Caesarean section pain management. This finding is in keeping with previous reports that diclofenac can be used for short term therapy(< 1 week) without complications such as gastrointestinal bleeding, bleeding tendency or inflammation at the site of administration⁸² It has also been suggested that the anti-platelet effects associated with the use of NSAIDs are unlikely to cause notable bleeding without co-administration of other drugs known to affect clotting such as heparin.^39,83 Uterine atony which significantly increases the risk of post partum haemorrhage, has not been shown to be associated with NSAID use in women receiving oral or rectal suppositories after Caesarean section.^50,83 Several studies have used simple but clinically relevant assessment of vaginal blood loss or the need for oxytocics either intra or post-operatively and reported no significant effect in patients receiving NSAIDs.^84,85 The tocolytic effect of diclofenac would not be clear as the drug was administered at the end of surgery. However, no increased postoperative blood loss was observed in the patients studied.

Another common concern with analgesic use in the post partum period is the effect on lactation and possible transfer to the newborn. The maternal plasma level of diclofenac was not estimated. This may not really have been necessary considering the single dose employed in the study. However there is a plethora of evidence in the literature indicating the safety of diclofenac in lactating mothers as well as the neonate.^13,86

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While such concerns have been generated by reports of excretion of diclofenac in breast milk, it has been found that the amount excreted is very small and unlikely to be of any untoward consequence.⁸⁷ It has also been reported that diclofenac is not found in colustrum^82,86,88 and the American Academy of Paediatricians has endorsed its use in breast feeding women.⁸⁹

Patients who had known relative contraindications to the use of NSAIDs such as a history of peptic ulceration, bronchial asthma or renal impairment were however excluded from the study. Those with predisposition to impaired renal function such as severe preeclampsia were also excluded in consideration of the potential of NSAIDs to compromise renal function.

It is pertinent to assess the effect of anaesthetic technique on neonatal outcome especially when new drugs or management techniques are evaluated. None of the neonates had low Apgar scores by the fifth minute of life. This is important considering the high incidence of hypotension seen in this study. The cases of hypotension noted were mild and of short duration as the patients responded to additional fluid and/ or rescue medication. Furthermore, the usefulness of the Apgar score as a measure of neonatal well being has been questioned.⁹⁰ This has led to the determination of umbilical artery pH (UApH) and base excess as a better tool or assessment of neonatal outcome.⁹¹ Indeed the determination of UApH was not possible in our centre as at the time this study was done. However, the estimation of UApH may have revealed altered neonatal acid base status in a small number of the neonates since hypotension and ephedrine use have been associated with lower umbilical artery PH compared to other vasopressors.⁹²