A study of the pharmacokinetics and pharmacodynamics of oxytocin at elective caesarean delivery.

Oxytocin is widely used to prevent atonic postpartum haemorrhage after caesarean delivery. Initial treatment failure rates are high and inadequate dosing may contribute. Excessive doses, however, are associated with serious adverse effects. The pharmacokinetic data from this context are sparse and there is a lack of data in the immediate postpartum minutes after an initiating bolus. The pharmacodynamic data from this context are exclusively from dose-effect studies, with some suggesting that higher doses of oxytocin are required to provide adequate uterine tone in obese compared with non-obese women. We aimed to perform a pharmacokinetic and pharmacodynamic study that would facilitate more precise weight-based oxytocin dosing. We measured arterial oxytocin concentration, uterine tone and haemodynamic parameters in 25 women in the first 40 min after exogenous oxytocin administration at elective caesarean delivery. Serum oxytocin concentrations varied considerably between individuals. We constructed a one-compartment pharmacokinetic model of exogenous oxytocin deposition, after its administration with an initiating bolus and a maintenance infusion, at elective caesarean delivery. Body weight was evaluated as a potential covariate but was not included in the model due to lack of statistically significant reduction in the objective function. We calculated the volume of distribution and clearance (mean [coefficient of variation]) as 156.1 l [18%] and 83 ml.s-1 [32%] but found no within-individual correlation between serum oxytocin concentration and uterine tone or haemodynamic parameters. In conclusion, we observed a large variation in serum oxytocin concentrations between individuals receiving similar doses of oxytocin and were unable to establish weight-based dosing of exogenous oxytocin at caesarean delivery. Our findings suggest that future studies on oxytocin pharmacokinetics would need large sample sizes. In the absence of such data, oxytocin dosing should continue to be guided by uterine tone assessments and adjusted according to a strategy based on the best evidence from dose-effect studies.

Oxytocin: at birth and beyond. A systematic review of the long-term effects of peripartum oxytocin.

Oxytocin is one of the most commonly used medications during labour and delivery. Recent insights from basic neuroscience research suggest that the uterotonic effects of oxytocin may arguably be trivial when compared with its profound effects on higher-order human behaviour. The purpose of this review is to highlight the potential consequences of manipulating oxytocinergic signalling during the peripartum period and its long-term impact on the maternal-infant dyad. We identified four domains where modulation of oxytocinergic signalling might be consequential: postpartum depression; breastfeeding; neurodevelopment; and chronic pain, and performed a literature search to address the impact of peripartum oxytocin administration. We have shown modest, but inconsistent, evidence linking peripartum oxytocin administration with postpartum depression. Breastfeeding success appeared to be negatively correlated with peripartum oxytocin exposure, perhaps secondary to impaired primitive neonatal reflexes and maternal-infant bonding. The association between perinatal oxytocin exposure and subsequent development of neurodevelopmental disorders such as autism in the offspring was weak, but these studies were limited by the lack of information on the cumulative dose. Finally, we identified substantial evidence for analgesic and anti-hypersensitivity effects of oxytocin which might partly explain the low incidence of chronic pain after caesarean birth. Although most data presented here are observational, our review points to a compelling need for robust clinical studies to better dissect the impact of peripartum oxytocin administration, and as stewards of its use, increase the precision with which we administer oxytocin to prevent overuse of the drug.

The association between post-dural puncture headache and needle type during spinal anaesthesia: a systematic review and network meta-analysis.

Post-dural puncture headache is one of the most undesirable complications of spinal anaesthesia. Previous pairwise meta-analyses have either compared groups of needles or ranked individual needles based on the pooled incidence of post-dural puncture headache. These analyses have suggested both the gauge and needle tip design as risk-factors, but failed to provide an unbiased comparison of individual needles. This network meta-analysis compared the odds of post-dural puncture headache with needles of varying gauge and tip design. We searched randomised controlled trials in medical databases. The primary outcome measure of the network meta-analysis was the incidence of post-dural puncture headache. Secondary outcomes were procedural failure, backache and non-specific headache. Overall, we compared 11 different needles in 61 randomised controlled trials including a total of 14,961 participants. The probability of post-dural puncture headache and procedural failure was lowest with 26-G atraumatic needles. The 29-G cutting needle was more likely than three atraumatic needles to have the lowest odds of post-dural puncture headache, although with increased risk of procedural failure. The probability rankings were: 26 atraumatic > 27 atraumatic > 29 cutting > 24 atraumatic > 22 atraumatic > 25 atraumatic > 23 cutting > 22 cutting > 25 cutting > 27 cutting = 26 cutting for post-dural puncture headache; and 26 atraumatic > 25 cutting > 22 cutting > 24 atraumatic > 22 atraumatic > 25 atraumatic > 26 cutting > 29 cutting > 27 atraumatic = 27 cutting for procedural success. Meta-regression by type of surgical population (obstetric/non-obstetric) and participant position (sitting/lateral) did not alter these rank orders. This analysis provides an unbiased comparison of individual needles that does not support the use of simple rules when selecting the optimal needle. The 26-G atraumatic needle is most likely to enable successful insertion while avoiding post-dural puncture headache but, where this is not available, our probability rankings can help clinicians select the best of available options.

Choice of local anaesthetic for epidural caesarean section: a Bayesian network meta-analysis.

Rapid-onset epidural local anaesthesia can avoid general anaesthesia for caesarean delivery. We performed a Bayesian network meta-analysis of direct and indirect comparisons to rank speed of onset of the six local anaesthetics most often used epidurally for surgical anaesthesia for caesarean delivery. We searched Google Scholar, PubMed, EMBASE, Ovid, CINAHL and CENTRAL to June 2019. We analysed 24 randomised controlled trials with 1280 women. The mean (95%CrI) onset after bupivacaine 0.5% was 19.8 (17.3-22.4) min, compared with which the mean (95%CrI) speed of onset after lidocaine 2% with bicarbonate, 2-chloroprocaine 3% and lidocaine 2% was 6.4 (3.3-9.6) min faster, 5.7 (3.0-8.3) min faster and 3.9 (1.8-6.0) min faster, respectively. Speed of onset was similar to bupivacaine 0.5% after ropivacaine 0.75% and l-bupivacaine 0.5%: 1.6 (-1.4 to 4.8) min faster and 0.4 (-2.2 to 3.0) min faster, respectively. The rate (95%CrI) of intra-operative hypotension was least after l-bupivacaine 0.5%, 315 (236-407) per 1000, and highest after 2-chloroprocaine 3%, 516 (438-594) per 1000. The rate (CrI) of intra-operative supplementation of analgesia was least after ropivacaine 0.75% 48 (19-118) per 1000 and highest after 2-chloroprocaine 3%, 250 (112-569) per 1000.

Carbetocin reduces the need for additional uterotonics in elective caesarean delivery: a systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.

BACKGROUND: Carbetocin has been found to be superior to oxytocin in terms of need for additional uterotonics and prevention of postpartum haemorrhage at caesarean delivery. However, this is based on combined data from labouring and non-labouring parturients and it remains unclear how effective carbetocin is in the purely elective setting. The aim of this review was to compare carbetocin to oxytocin in elective caesarean delivery. METHODS: Medline, Embase, CINAHL, Web of Science, and the Cochrane databases were searched for randomised controlled trials in any language. The primary outcome was need for additional uterotonics. Secondary outcomes were mean blood loss, need for blood transfusion and incidence of postpartum haemorrhage >1000 mL. RESULTS: Nine studies with a total of 1962 patients were included. Trial sequential analysis confirmed that the information size (n=1692) had surpassed that required (n=1166) in order to demonstrate a statistically significant reduction in the use of additional uterotonics. Need for additional uterotonics was reduced by 53% with carbetocin compared to oxytocin (OR 0.47, 95% CI 0.34 to 0.64; P <0.001, I2=63.5). The number needed-to-treat was 11. The risk of bias, data heterogeneity and inconsistency in reporting bleeding outcomes made it difficult to reach definite conclusions about prevention of PPH. CONCLUSIONS: Carbetocin is associated with a reduced need for additional uterotonics when compared with oxytocin at elective caesarean delivery. Standardisation of bleeding-related outcomes in studies is necessary to facilitate synthesis of data in future analyses.