Preventing pain on injection of propofol: A comparison between lignocaine pre-treatment and lignocaine added to propofol

Publisher's copy made available with the permission of the publisherA randomized double-blind study compared two methods of preventing the pain from injection of propofol, lignocaine pre-treatment followed by propofol and lignocaine added to propofol. One hundred patients received a 4 ml solution intravenously with a venous tourniquet for 1 minute, followed by propofol mixed with 2 ml of solution. Patients were divided into two treatment groups of 50 patients each: 4 ml 1% lignocaine pre-treatment followed by propofol and 2 ml saline, or 4 ml saline followed by propofol and 2 ml 2% lignocaine. Pain was assessed with a 100 mm visual analogue scale after induction and in recovery. The incidence of injection pain was 8% in the propofol mixed with lignocaine group, and 28% in the lignocaine pre-treatment group. This difference is statistically significant (P=0.017). For those patients who had pain, the mean pain score was 26.5 on induction for the propofol with lignocaine group (n=4), while the mean score was 44.4 for the pre-treatment group (n=13). The difference was not statistically significant (P=0.25). None of the propofol mixed with lignocaine group recalled pain, while 13 of the pre-treatment group did so. Lignocaine pre-treatment does not improve the immediate or the recalled comfort of patients during propofol induction when compared to lignocaine added to propofol. It is recommended that lignocaine should be added to propofol for induction rather than given before induction.P. Lee, W. J. Russellhttp://www.aaic.net.au/Article.asp?D=200339

Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 μM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation. © 2018 Yang et al

A comparative study of different induction techniques (Propofol-Placebo, Propofol-Ephedrine and Propofol- Placebo-Crystalloid) on intubating conditions after rocuronium administration

This was a prospective randomized double blind controlled study to compare intubating conditions at 60 seconds with rocuronium 0.6 mg/kg by using three different induction techniques: propofol-placebo (PP), propofol-ephedrine (PE) and propofol-placebocrystalloid (PC). Ninety patients were included and randomly allocated to receive one of the three combinations. The patients were induced using fentanyl 2 μg/kg, followed by propofol 2.5 mg/kg with normal saline as placebo (Group PP and Group PC) or ephedrine 70 μg/kg (Group PE) given over 30 seconds. Subsequently, rocuronium 0.6 mg/kg was given over five seconds and endotracheal intubations were performed 60 seconds later. Intubating conditions were clinically acceptable in all patients except in four patients in PP group, who had poor intubating conditions. The proportion of excellent intubating conditions was significantly highest in Group PE (94%) followed by Group PC (81%) and lowest in Group PP (50%). In conclusion, induction with propofol-ephedrine and propofol-placebo-crystalloid combinations provided significantly better intubating conditions than propofol alone, when rocuronium 0.6 mg/kg was used for intubation at 60 second

Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.

Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by 19F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4-S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on NaV channels. © 2018 Wang et al

Determination of propofol by GC/MS and fast GC/MS-TOF in two cases of poisoning

Two cases of suspected acute and lethal intoxication caused by propofol were delivered by the judicial authority to the Department of Sciences for Health Promotion and Mother-Child Care in Palermo, Sicily. In the first case a female nurse was found in a hotel room, where she lived with her mother; four 10 mg/mL vials and two 20 mg/mL vials of propofol were found near the decedent along with syringes and needles. In the second case a male nurse was found in the operating room of a hospital, along with a used syringe. In both cases a preliminary systematic and toxicological analysis indicated the presence of propofol in the blood and urine. As a result, a method for the quantitative determination of propofol in biological fluids was optimized and validated using a liquid-liquid extraction protocol followed by GC/MS and fast GC/MS-TOF. In the first case, the concentration of propofol in blood was determined to be 8.1 \u3bcg/mL while the concentration of propofol in the second case was calculated at 1.2 \u3bcg/mL. Additionally, the tissue distribution of propofol was determined for both cases. Brain and liver concentrations of propofol were, respectively, 31.1 and 52.2 \u3bcg/g in Case 1 and 4.7 and 49.1 \u3bcg/g in Case 2. Data emerging from the autopsy findings, histopathological exams as well as the toxicological results aided in establishing that the deaths were due to poisoning, however, the manner of death in each were different: homicide in Case 1 and suicide in Case 2

Safety and efficacy of a propofol and ketamine based procedural sedation protocol in children with cerebral palsy undergoing botulinum toxin A injections.

Background Pediatric patients with cerebral palsy (CP) often undergo intramuscular botulinum toxin (BoNT‐A) injections. These injections can be painful and may require procedural sedation. An ideal sedation protocol has yet to be elucidated. Objective To investigate the safety and efficacy of a propofol and ketamine based sedation protocol in pediatric patients with cerebral palsy requiring BoNT‐A injections. Design This is a retrospective chart review of children with CP undergoing propofol and ketamine based sedation for injections with botulinum toxin A. Setting The sedations took place in a procedural sedation suite at a tertiary children’s hospital from Feb 2013 through Sept 2017. Patients 164 patients with diagnoses of cerebral palsy were included in this study. Methods An initial bolus of 0.5 mg/kg ketamine followed by a 2 mg/kg bolus of propofol was administered with supplemental boluses of propofol as needed to achieve deep sedation during the intramuscular BoNT‐A injections. Main Outcome Measurements Propofol dosages, adverse events, serious adverse events, and sedation time parameters were reviewed. Results 345 sedations were successfully performed on 164 patients. The median total dose of propofol was 4.7 mg/kg (IQR 3.5, 6.3). Adverse events were encountered in 10.1% of procedures including hypoxemia responsive to supplemental oxygen (9.6%) and transient apnea (1.4%). The mean procedure time, recovery time and total sedation time were 10, 11 and 33 minutes, respectively. With regard to patient variables, including age, weight, dose of propofol, sedation time, and Gross Motor Function Classification System classification, there was no association with increased incidence of adverse events. Conclusion Our sedation protocol of propofol and ketamine is safe and effective in children with cerebral palsy undergoing procedural sedation for intramuscular injections with BoNT‐A. The adverse events encountered appeared to be related to airway and respiratory complications secondary to musculoskeletal deformities, emphasizing the importance of airway monitoring and management in these patients

The cerebrovascular effects of adrenaline, noradrenaline and dopamine infusions under propofol and isoflurane anaesthesia in sheep

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsInfusions of catecholamines are frequently administered to patients receiving propofol or isoflurane anaesthesia. Interactions between these drugs may affect regional circulations, such as the brain. The aim of this animal (sheep) study was to determine the effects of ramped infusions of adrenaline, noradrenaline (10, 20, 40 µg/min) and dopamine (10, 20, 40 µg/kg/min) on cerebral blood flow (CBF), intracranial pressure (ICP), cerebrovascular resistance (CVR) and cerebral metabolic rate for oxygen (CMRO₂). These measurements were made under awake physiological conditions, and during continuous propofol (15 mg/min) or 2% isoflurane anaesthesia. All three catecholamines significantly and equivalently increased mean arterial pressure from baseline in a dose-dependent manner in the three cohorts (P0.05). Under propofol (n=6) and isoflurane (n=6), all three catecholamines significantly increased CBF (P<0.001). Dopamine caused the greatest increase in CBF, and was associated with significant increases in ICP (awake: P<0.001; propofol P<0.05; isoflurane P<0.001) and CVR (isoflurane P<0.05). No significant changes in CMRO₂ were demonstrated. Under propofol and isoflurane anaesthesia, the cerebrovascular effects of catecholamines were significantly different from the awake, physiological state, with dopamine demonstrating the most pronounced effects, particularly under propofol. Dopamine-induced hyperaemia was associated with other cerebrovascular changes. In the presence of an equivalent effect on mean arterial pressure, the exaggerated cerebrovascular effects under anaesthesia appear to be centrally mediated, possibly induced by propofol- or isoflurane-dependent changes in blood-brain barrier permeability, thereby causing a direct influence on the cerebral vasculature.http://www.aaic.net.au/Article.asp?D=200205

Excitable neurons, firing threshold manifolds and canards

We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674-1697, 2012). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model

Propofol and children--what we know and what we do not know.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps

Propofol-Based Procedural Sedation with or without Low-Dose Ketamine in Children

Objective Examine comparative dosing, efficacy, and safety of propofol alone or with an initial, subdissociative dose of ketamine approach for deep sedation. Background Propofol is a sedative-hypnotic agent used increasingly in children for deep sedation. As a nonanalgesic agent, use in procedures (e.g., bone marrow biopsies/aspirations, renal biopsies) is debated. Our intensivist procedural sedation team sedates using one of two protocols: propofol-only (P-O) approach or age-adjusted dose of 0.25 or 0.5 mg/kg intravenous ketamine (K + P) prior to propofol. With either approach, an initial induction dose of 1 mg/kg propofol is recommended and then intermittent dosing throughout the procedure to achieve adequate sedation to safely and effectively perform the procedure. Approach: Retrospective evaluation of 754 patients receiving either the P-O or K + P approach to sedation. Results A total of 372 P-O group patients and 382 K + P group. Mean age (7.3 ± 5.5 years for P-O; 7.3 ± 5.4 years for K + P) and weight (30.09 ± 23.18 kg for P-O; 30.14 ± 24.45 kg for K + P) were similar in both groups (p = NS). All patients successfully completed procedures with a 16% combined incidence of hypoxia (SPO2 < 90%). Procedure time was 3 minutes longer for K + P group than P-O group (18.68 ± 15.13 minutes for K + P; 15.11 ± 12.77 minutes for P-O; p < 0.01), yet recovery times were 5 minutes shorter (17.04 ± 9.36 minutes for K + P; 22.17 ± 12.84 minutes for P-O; p < 0.01). Mean total dose of propofol was significantly greater in P-O than in K + P group (0.28 ± 0.20 mg/kg/min for K + P; 0.40 ± 0.26 mg/kg/min for P-O; p < 0.0001), and might explain the shorter recovery time. Conclusion Both sedation approaches proved to be well tolerated and equally effective. Addition of ketamine was associated with reduction in the recovery time, probably explained by the statistically significant decrease in the propofol dose