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.

Efficacy of regional blocks or local anaesthetic infiltration for analgesia after caesarean delivery: a network meta-analysis of randomised controlled trials.

Caesarean delivery is common and can cause severe postoperative pain but injection of local anaesthetic at various sites for regional blocks or local anaesthetic infiltration may reduce this. We aimed to compare and rank these sites. We searched PubMed, Google Scholar, EMBASE and CENTRAL to June 2021 for randomised controlled trials and performed a random-effects Bayesian model network meta-analysis. The primary outcome was dose of parenteral morphine equivalents in the first 24 postoperative hours. We used surface under cumulative ranking probabilities to order techniques. We analysed 114 trials (8730 participants). The ordered mean (95% credible interval) reduction in morphine equivalents, from 34 mg with placebo, were as follows: ilio-inguinal 15 (1-32) mg; ilio-inguinal-iliohypogastric 13 (6-19) mg; transversalis fascia 11 (4-26) mg; erector spinae 11 (10-32); transverse abdominis 9 (4-13) mg; wound catheter infusion 8 (2-15) mg; quadratus lumborum 8 (1-15) mg; wound infiltration 8 (2-13) mg; and no intervention -4 (-10 to 2) mg. Ordered efficacies for injection sites were different for other relevant outcomes, including pain (to 4-6 h and to 24 h) and time to rescue analgesia: there was no single preferred route of injection. The ordered mean (95% credible interval) reduction in dynamic pain scores (0-10 scale) at 24 h compared with placebo were as follows: wound infusion 1.2 (0.2-2.1); erector spinae 1.3 (-0.5 to 3.1); quadratus lumborum 1.0 (0.1-1.8); ilio-inguinal-iliohypogastric 0.6 (-0.5 to 1.8); transverse abdominis 0.6 (-0.1 to 1.2); wound infiltration 0.5 (-0.3 to 1.3); transversalis fascia -0.8 (-3.4 to 1.9); ilio-inguinal -0.9 (-3.6 to 1.7); and no intervention -0.8 (-1.8 to 0.2). We categorised our confidence in effect sizes as low or very low.

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.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.

Is crystalloid co-loading necessary to prevent spinal hypotension during elective cesarean delivery? A randomized double-blind trial.

BACKGROUND: Hypotension is common during spinal anesthesia for cesarean delivery. Preventive strategies include fluid loading and phenylephrine. We hypothesized that if prophylactic phenylephrine infusion is used, omission of fluid loading would be non-inferior to fluid co-loading in maintaining cardiac output. We assumed that if there was a difference, the increase in cardiac output would be greater in the no-loading than in the co-loading group. METHODS: Term pregnant women scheduled for elective cesarean delivery were randomized to receive 1 L crystalloid co-loading or maintenance fluids only. Phenylephrine was titrated to maintain blood pressure. Changes in cardiac output following spinal anesthesia were the primary outcome. The study was powered as a non-inferiority trial, allowing the no-loading arm to have a 50% greater change in cardiac output. Heart rate, dose of phenylephrine, occurrence of nausea and vomiting, Apgar scores and neonatal acid base status were secondary outcomes. RESULTS: Data from 63 women were analyzed. In contrast to our hypothesis, there was 33% less increase in cardiac output with no loading (ratio 0.67, 95% CI 0.15 to 1.36), and 60% greater reduction of cardiac output with no loading (ratio 1.6, 95% CI 1.0 to 2.7). Total dose of phenylephrine was higher in the no-loading group. There may be a less favorable neonatal acid base status without volume loading. CONCLUSION: Omission of crystalloid co-loading leads to a decrease in cardiac output which has a potentially unfavorable impact on neonatal acid base status. We conclude that crystalloid co-loading may be useful in the presence of phenylephrine infusion.

Association of apolipoprotein E ε4 allele with cognitive impairment in patients with epilepsy and interaction with phenytoin monotherapy.

Cognitive impairment implicates many factors beyond phenytoin monotherapy in patients with epilepsy. Apolipoprotein E ε4 allele has been reported to play a role in severe memory impairment that ultimately progresses to Alzheimer's disease (AD); however, knowledge about its role in cognitive impairment in patients with epilepsy is lacking. Our study proposes the possible involvement of the APOE ε4 allele in cognitive impairment in patients with epilepsy which is further worsened by phenytoin monotherapy. Assessment of the APOE ε4 allele in a population with epilepsy will help to identify the patients vulnerable to cognitive impairment and, therefore, the corrective therapy that needs to be addressed.

Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro.

BACKGROUND: More than half of the cells in the brain are glia and yet the impact of general anaesthetics on these cells is largely unexamined. We hypothesized that astroglia, which are strongly implicated in neuronal well-being and synapse formation and function, are vulnerable to adverse effects of isoflurane. METHODS: Cultured rat astrocytes were treated with 1.4% isoflurane in air or air alone for 4 h. Viability, proliferation, and cytoskeleton were assessed by colorimetric assay, immunocytochemistry, or a migration assay at the end of treatment or 2 days later. Also, primary rat cortical neurones were treated for 4 days with conditioned medium from control [astrocyte-conditioned media (ACM)], or isoflurane-exposed astrocytes (Iso-ACM) and synaptic puncta were assessed by synapsin 1 and PSD-95 immunostaining. RESULTS: By several measures, isoflurane did not kill astrocytes. Nor, based on incorporation of a thymidine analogue, did it inhibit proliferation. Isoflurane had no effect on F-actin but reduced expression of α-tubulin and glial fibrillary acidic protein both during exposure (P<0.05 and P<0.001, respectively) and 2 days later (P<0.01), but did not impair astrocyte motility. ACM increased formation of PSD-95 but not synapsin 1 positive puncta in neuronal cultures, and Iso-ACM was equally effective. CONCLUSIONS: Isoflurane decreased expression of microtubule and intermediate filament proteins in astrocytes in vitro, but did not affect their viability, proliferation, motility, and ability to support synapses.

Role of cosyntropin in the prevention of post-dural puncture headache: a propensity-matched retrospective analysis.

BACKGROUND: Post-dural puncture headache (PDPH) is a well-documented complication of accidental dural puncture in obstetric patients. Reports have shown successful treatment with adrenocorticotropic hormone (ACTH) but evidence remains low and limited. In this retrospective analysis, we assessed whether prophylactic administration of cosyntropin, a synthetic derivative of ACTH, reduced the incidence of PDPH after accidental dural puncture in parturients. METHOD: The study population included 132 women with an accidental dural puncture over a three-year period (June 1, 2018 to Oct 31, 2021) at a large tertiary-care center. Patient electronic medical records were reviewed for patient characteristics, prophylactic administration of cosyntropin, PDPH diagnosis, and need for epidural blood patch. Typically, 1 mg of cosyntropin was administered as an intravenous bolus or infusion post-delivery. The propensity score was calculated based on the following factors: age, body mass index, and placement of an intrathecal catheter. Patients were matched allowing 10% variation in scores to reduce potential treatment assignment bias. RESULTS: A total of 115 patients were included in the final analysis. Intravenous cosyntropin was administered to 65 patients (55.6%). Among those who received cosyntropin, 37 (56.9%) developed PDPH compared with 29 patients (58%) in the no-cosyntropin group (P = 0.08). Epidural blood patch was performed in 21 patients (56.8%) who received cosyntropin and 13 patients (61.7%) who did not (P = 0.70). CONCLUSION: Prophylactic administration of cosyntropin is not associated with a reduced incidence of PDPH.

Combining ALT/AST Values with Surgical APGAR Score Improves Prediction of Major Complications after Hepatectomy.

Hepatectomy is a complex procedure with high morbidity and mortality. Early prediction/prevention of major complications is highly valuable for patient care. Surgical APGAR score (SAS) has been validated to predict post-surgical complications (PCs). We aimed to define a simple complications classification following hepatectomy based on a therapy-oriented severity Clavien-Dindo classification (CDC). 119 patients undergoing liver resection were included. PCs were determined at follow-up based on CDC. Clinicopathological factors were used to calculate SAS. A receiver-operator characteristic (ROC) curve analysis estimated the predictive value of SAS for PCs. Circulating markers levels of liver injury were analyzed as critical elements on PCs. SAS (P=0.008), estimated blood-loss (P=0.018) and operation time (P=0.0008) were associated with PCs. SAS was reduced in patients with (+) compared to those without (-) complications (6.64±1.84 vs 5.70±1.79, P=0.0079). The area-under-the-curve was 0.646 by ROC, indicating an acceptable discrimination with 65% possibility to distinguish (-) and (+) groups (P=0.004). Best cutoff value for SAS was ≤6/≥7, at which sensitivity and specificity were maximal. ALT/ASL levels were significantly different within the group with 9-10 SAS points (P=0.01 and 0.02). In conclusion, SAS provides accurate risk stratification for major PCs after hepatectomy, and might help improving the overall patient outcome.