Effect of intrathecal lipophilic opioids on the incidence of shivering in women undergoing cesarean delivery after spinal anesthesia: a systematic review and bayesian network meta- analysis of randomized controlled trials

Cesarean delivery is one of the most common operations performed. It is routinely carried out under spinal anesthesia using a combination of local anesthetics and opioids. Intrathecal (IT) addition of a lipophilic opioid to local anesthetic reduces the dose of local anesthetic, shortens the onset of block, markedly improves the quality of anesthesia, prolongs the duration of analgesia and also decreases the incidence of shivering [1].

Up to 85% of patients undergoing cesarean delivery may experience shivering after spinal anaesthesia [2, 3]. The etiology of shivering likely involves multiple mechanisms. Pregnant patients have high circulating concentrations of progesterone which may account for decreased shivering thresholds. The sympathetic blockade associated with spinal anesthesia may impair the thermoregulation causing peripheral vasodilatation. This causes the transfer of heat towards the periphery from core and enhances the heat loss through the skin. In addition, at the central nervous system level, there is increased sweating thresholds and decreased vasoconstriction [4]. The oxygen consumption (upto 600%), carbondioxide production and blood pressure may increase with shivering leading to serious hemodynamic effects in patients with compromised cardiopulmonary function. Shivering may also interfere with non-invasive patient monitoring, disrupting care in the perioperative period [2]. Thus, prevention or treatment of shivering is an important clinical goal.

Common treatment regimens for shivering include increasing the body temperature, physical warming, increasing the operating room temperature, and using various medications such as clonidine, meperidine, fentanyl and morphine [5, 6]. Sufentanil, fentanyl and meperidine, in decreasing order of lipid solubility, are used as adjuvants for spinal anesthesia in patients undergoing cesarean delivery. Several randomized controlled studies investigated the effect of these opioids on the incidence of the shivering. However, inconsistencies in the results impeded meaningful conclusions. Therefore, we performed this systematic review and network meta-analysis (SRNMA) to evaluate the effects of the multiple lipophilic neuraxial opioids on the incidence of shivering in women having cesarean delivery under spinal anesthesia.

This meta-analysis was planned in accordance with the PRISMA-NMA guidelines (Preferred Reporting Items for Systematic Reviews for Network Meta-Analysis).

Twenty-one potentially relevant articles were identified from 115 citations. Twenty-one studies consisting of 1433 patients (Control group: 590 patients in twenty-one studies; Fentanyl group:199 patients in seven studies [11‐17]; Sufentanil group: 156 patients in five studies [18‐22]; Meperidine group: 488 patients in ten studies [15, 23‐31]) contained data regarding the effect of IT opioids on shivering (Flow chart: Fig. 1). One included study by Han et al. 2007 investigated the effect of both, fentanyl and meperidine [15]. Tables 1 and 2 summarise the systematic review of the effects of IT fentanyl, sufentanil and meperidine on shivering in women undergoing cesarean delivery. Out of twenty-one studies, ten studies investigated shivering as the primary outcome [14‐16, 21, 24‐26, 28‐30]. Methodological validity scores determined by modified Oxford score ranged from 3 to 7.

In this systematic review evaluating the effects of lipophilic opioids to prevent or reduce shivering in patients having spinal anesthesia for cesarean delivery, fentanyl was found to be more effective than sufentanil and meperidine, however, there was no significant difference between direct or indirect comparison between fentanyl and meperidine. IT fentanyl (7.5–25 mcg) was found to decrease the incidence and severity of shivering as well as to improve the quality of spinal anesthesia in women having CD [32]. Fentanyl is a highly ionized, lipophilic μ-receptor agonist. When it is administered intrathecally, the unionized component is rapidly transferred into the spinal cord. IT fentanyl used with bupivacaine, in doses of 15 microgram has been shown to be effective in prolonging the duration of analgesia, and it also exerts an anti-nausea effect in such small doses. This is probably due to decreased nociceptive stimulation from peritoneal manipulation and uterine exteriorization due to augmented quality of spinal block caused by fentanyl [11]. The reduction of shivering may be attributable to the effect of fentanyl that was added into the subarachnoid space on the thermo-regulator and spinal affect afferent thermal inputs at the spinal cord [33]. It is shown that fentanyl can reduce the intensity and severity of shivering up to 3 h after spinal anesthesia, including the time before delivery of the baby. This reduces the requirement of intravenous medications to treat shivering before delivery, thereby decreasing any harmful effects of medications on the baby [14]. The main detriment of preventing shivering is the fall in body temperature as shivering is a protective autonomic response against hypothermia. However, fentanyl lowered the core temperature for only 2 h, with return to baseline temperature in the third hour, without any harmful effects on the patient [14].

We found that addition of IT fentanyl was associated with lowest incidence of intraoperative discomfort due to increase in the quality of analgesia. The incidence of pruritus with the administration of opioid into the subarachnoid space was reported to be 67% for fentanyl, and 80% for sufentanil [34]. But, several studies have shown that there was no increase in the incidence of pruritus with IT fentanyl doses less than 50 microgram [35‐37]. Also, the pruritus associated with IT fentanyl and sufentanil is transient and resolves rapidly, usually without any need for treatment [11, 21]. The results of our study are supported by similar findings, which compared nine different neuroaxial adjuvants and found fentanyl to be the optimal choice [38].

Sufentanil is highly lipophilic with a higher affinity to opioid receptors, with a less cephalad spread and a much higher analgesic potency when compared with fentanyl or morphine [39‐41]. It is well accepted for use in spinal anesthesia together with local anesthetics for caesarean delivery [20]. The combination of hyperbaric ropivacaine 10 mg with sufentanil 5 μg produced effective spinal anaesthesia for caesarean delivery with significantly less hypotension, vomiting and shivering, shorter duration of motor blockade and longer lasting analgesia than hyperbaric ropivacaine15 mg [19]. Our results show, however, that IT sufentanil was not effective in decreasing and severity of shivering in patients undergoing CD. While this finding could be due to the fact that this meta-analysis was limited by the small number of available studies evaluating this outcome, a previous meta-analysis on IT and epidural sufentanil had similar findings, and the authors postulated that the low dose range of IT and epidural sufentanil used (1.5–20 μg) may not be effective in decreasing shivering [42, 43].

Meperidine is an opioid with intermediate lipid solubility and is unique in having local anesthetic properties [44]. It has been used as a sole agent for spinal anesthesia for cesarean delivery [45‐47]. It prolongs postoperative analgesia for up to 4 h, which is considerably lower compared to IT morphine, which can provide analgesic effect for up to 24 h [48‐50]. An incidence of pruritus of 10.7–32% has been reported with the use of ≥50 mg of IT meperidine, which is much lower than IT morphine [33, 47, 51]. Meperidine is shown to be effective against shivering. While the mechanism of action is not fully understood, the anti-shivering effect of intravenous meperidine is due to its effect on the kappa opioid receptor and decreases the threshold of shivering [26, 52‐55]. Possible suggested mechanisms for the anti-shivering effect of meperidine include k-opioid receptor activity, anticholinergic action, biogenic monoamine reuptake inhibition, NMDA receptor antagonism, or stimulation of alpha 2–adrenoceptors, and possibly modulating the heat loss caused by vasodilatation after spinal anesthesia [54, 56‐58]. Meperidine slightly increases the threshold for sweating, significantly decreases the threshold for vasoconstriction, and reduces the threshold for shivering [59]. We found that IT meperidine was associated with nausea and vomiting, which limits its clinical efficacy.

IT fentanyl significantly decreased the incidence and severity of shivering in women undergoing cesarean delivery under spinal anesthesia without increasing maternal adverse events, indicating that its routine use in this patient population should be considered. IT sufentanil did not decrease the incidence or severity of shivering. IT meperidine also decreased the incidence and severity of shivering, but it was associated with significant nausea and vomiting.