Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E-2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin-mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra-arterial co-administration of lactic acid and E-2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E-2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin-1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid-mediated reflex increase in arterial pressure that is MOR stimulation-independent and APETx2-sensitive.

Background We hypothesized that preconditioning with a short exposure to isoflurane (ISO) would reduce neurodegeneration induced by prolonged exposure to ISO in neonatal rats, as previously shown in neuronal cell culture. Methods We randomly divided 7-day-old Sprague-Dawley rats into 3 groups: control, 1.5% ISO, and preconditioning (PC) + 1.5% ISO. The control group was exposed to carrier gas (30% oxygen balanced in nitrogen) for 30 min and then carrier gas again for 6 h the following day. The 1.5% ISO group was exposed to carrier gas for 30 min and then 1.5% ISO for 6 h the following day. The PC + 1.5% ISO group was preconditioned with a 30 min 1.5% ISO exposure and then exposed to 1.5% ISO for 6 h the following day. Blood and brain samples were collected 2 h after the exposures for determination of neurodegenerative biomarkers, including caspase-3, S100β, caspase-12, and an autophagy biomarker Beclin-1. Results Prolonged exposure to ISO significantly increased cleaved caspase-3 expression in the cerebral cortex of 7-day old rats compared to the group preconditioned with ISO and the controls using Western blot assays. However, significant differences were not detected for other markers of neuronal injury. Conclusion The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by preconditioning with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury.

ObjectivePediatric liver transplantation presents a number of anesthetic challenges, especially in providing adequate perioperative analgesia. In an effort to reduce opioid consumption and improve functional outcomes following pediatric liver transplantation, we have instituted a novel analgesia protocol centered on the provision of continuous regional analgesia with erector spinae plane (ESP) blockade.CasesWe describe preincisional bilateral ESP catheter placement in two pediatric patients undergoing orthotopic liver transplantation. The first case was a 12-year-old boy with maple syrup urine disease undergoing initial transplantation and the second case was an 8-year-old boy who underwent an 11 hours complex redo liver transplant in the setting of glycogen storage disease type 1A requiring initial liver transplant in 2014. The 8-year-old boy presented to the operating suite with acute Budd-Chiari syndrome with comorbid ascites and a large right pleural effusion. In both cases, ESP blockade resulted in good analgesia, markedly reduced intraoperative and postoperative opioid consumption as compared with institutional data and published rates of consumption and was associated with rapid return of bowel function.ConclusionsThese early experiences suggest a role for continuous ESP blockade to improve analgesia and potentially change the paradigm of treatment in this fragile patient population. The technique should be considered in similar interventions. Further study will be undertaken to validate our observation.

Protein kinase signal transduction pathways play critical roles in regulating nociception. Here we show that c-kit, a tyrosine kinase receptor, is expressed in lamina I and II layer of the dorsal horn. Moreover, the superficial c-kit+ fibers originate from the DRG, and c-kit in lamina II inner layer comes from the intrinsic expression of the spinal cord. KitW-v mice, which contain a hypomorphic mutation, exhibited normal acute pain in most pain behavior tests. In formalin test, the first phase was not affected, whereas the second phase pain response of KitW-v mice was significantly reduced relative to wild-type littermates. KitW-v mice also showed abnormal neuropathic pain, notably in the contralateral side of nerve injury. The expression and release of CGRP and substance P was not altered by the c-kit mutation. Together, these results implicate c-kit-mediated signaling transduction in the development of persistent pain.

Volatile anesthetics can cause neuronal and glial toxicity in the developing mammalian brain, as well as long-term defects in learning and memory. The goals of this study were to compare anesthetics using a clinically relevant exposure paradigm, and to assess the anesthetic effects on hippocampal development and behavior. Our hypothesis was that volatile anesthetics disrupt hippocampal development, causing neurobehavioral defects later in life. Bromodeoxyuridine (BrdU) was administered to rats on postnatal day (P)1, and the rats were exposed to volatile anesthetics (isoflurane, sevoflurane, or desflurane) for 2 h on P2. On days P7 and P14, the BrdU-labeled cells were quantified in the hippocampal dentate gyrus using immunohistochemical assays and fluorescent microscopy. Caspase-3 positive cells were quantified on P2 to evaluate apoptosis. The remaining animals underwent behavioral testing at ages 6 weeks and 6 months, using the Morris Water Maze. Significantly fewer BrdU-positive cells were detected in the hippocampal dentate gyrus in both isoflurane and desflurane-treated animals compared with controls at P7, but there were no changes in cell numbers after sevoflurane exposure. Cell counts for all three anesthetics compared with controls were equivalent at P14. Isoflurane or desflurane exposure yielded slight differences in the behavioral tests at 6 weeks, but no differences at 6 months post-exposure. We conclude that a single 2-h exposure at P2 to either isoflurane or desflurane causes a transient disruption of hippocampal neuronal development with no significant detectable long-term effects on learning and memory, whereas the same exposure to sevoflurane has no effects.

Multiple factors may contribute to the development of emergence delirium in a child. We present the case of a healthy 12-year-old girl who received preoperative midazolam with the desired anxiolytic effect, underwent a brief general anesthetic, and then exhibited postoperative delirium, consisting of a transient associative agnosia and expressive aphasia. Administration of flumazenil led to immediate and lasting resolution of her symptoms. We hypothesize that γ-aminobutyric acid type A receptor-mediated effects, most likely related to an atypical offset of midazolam, are an important subset of emergence delirium that is amenable to pharmacologic therapy with flumazenil.

Background: Given the complex nature of liver transplant surgery, adult centers typically use a dedicated liver transplant anesthesia team, which has improved patient outcomes.Aims: Our goal was to determine whether a dedicated pediatric liver transplant anesthesia team was associated with improved patient outcomes. Methods: This retrospective cohort study analyzed patients who underwent liver transplantation from April 2013 to September 2020 at St. Louis Children's Hospital. The general group (April 2013-December 2016) was compared with the liver group (January 2017-September 2020). Outcomes measured included cases per anesthesiologist, early extubation, ventilator days, fluid and blood administration, postoperative events, and intensive care unit and hospital length of stay (LOS).Results: Patients in both groups had similar demographics. The average number of cases/anesthesiologist/year was 2.9 times higher in the liver group (mean (SD) general 0.7 (0.5), liver 2.0 (0.6), and difference in mean [95% CI] 1.3 [0.8, 1.8]). The rate of extubation in the operating room was higher for patients in the liver group (general 56%, liver 80%, and difference in proportion [95% CI] 24.7 [7.0, 42.4]), while the number of ventilator days was lower (mean (SD) general 2.1 (4.4), liver 1.1 (3.6), and difference in proportion [95%CI] −0.9 [−2.6, 0.7]). Colloid administration was higher in the liver group (mean (SD) general 23.9 (14.5) ml/kg, liver 48.4 (37.7) ml/kg, and difference in mean [95% CI] 24. 6 [12.7, 36.4]), while fresh frozen plasma administration was lower in the liver group (mean (SD) general 15.3 (23.9) ml/kg, liver 6.2 (14) ml/kg, and difference in mean [95% CI] −9.0 [−16.8, −1.3]). There were no significant differences between the groups in postoperative events including blood product transfusions, vasopressor use, and thromboses, or in the intensive care unit and hospital LOS. Conclusions:The liver group was associated with increased early extubations, decreased ventilator days, and decreased fresh frozen plasma use.

BackgroundRegional anesthesia allows for opioid‐sparing and enhanced recovery after many major surgeries. Erector spinae blockade, with reduced bleeding risk and the option for continuous infusion, offers an opportunity to promote this principle in pediatric liver transplant patients. Our goal was to evaluate pain scores, opioid use, and return of bowel function following continuous ESP blockade in pediatric liver transplant recipients.MethodsThis retrospective cohort study included extubated patients who received a liver transplant at St. Louis Children's Hospital from July 2016 to July 2021. The control group, which did not meet the criteria for ESP blockade and received standard analgesia regimens, was compared to the group receiving continuous ESP blockade. Measured outcomes included pain scores, opioid consumption through postoperative day two, date of first bowel movement, and length of stay in the ICU and the hospital.ResultsPatient demographics between control and ESP groups showed no significant differences. Pain scores between control and ESP groups also showed no significant differences. Intraoperative and postoperative opioid requirements, studied in oral morphine equivalents per kilogram (OME/kg), were significantly lower for patients with ESP blockade. Time to first bowel movement was also significantly earlier for the ESP group. No significant differences were found in length of ICU or hospital stay. There were no safety concerns or complications related to ESP blockade.ConclusionsUse of continuous ESP blockade resulted in reduced opioid consumption through postoperative day two and earlier return of bowel function.