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Anesthesiology Feb 2023Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a...
Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87-95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.
Topics: Animals; Dogs; Succinylcholine; Fasciculation; Anesthesia; Halothane; Muscles
PubMed: 36629464
DOI: 10.1097/ALN.0000000000004437 -
BMC Anesthesiology Oct 2016Using electronic health record data, we hypothesized that larger reversal doses are used for patients with deeper levels of neuromuscular blockade (NMB) as evidenced by... (Observational Study)
Observational Study
BACKGROUND
Using electronic health record data, we hypothesized that larger reversal doses are used for patients with deeper levels of neuromuscular blockade (NMB) as evidenced by the last recorded TOF measurement. We also examined if dosing regimens reflect current practice guidelines of using ideal body weight (IBW) for NMB agents and total body weight (TBW) for neostigmine.
METHODS
This is a retrospective observational study of adult, ASA 1-4 patients who underwent general anaesthesia and received non-depolarizing NMB agents between 01/01/2004 and 12/31/2013. For the primary outcome, percentages of cases receiving neostigmine and median doses administered for each subjective train-of-four (TOF) category were calculated. Secondary analyses evaluated associations between NMB dosing and neostigmine administration based on Body Mass Index (BMI) categories.
RESULTS
A total of 135,633 cases met inclusion criteria for the study. There was no clinically significant difference in median neostigmine dosing based on last TOF count prior to reversal administration: 37.5 mcg/kg for TOF of 4/4 vs. 37.9 mcg/kg for TOF of 0/4 for the total neostigmine dose. Significantly higher number of patients with lower TOF counts received additional neostigmine administration: 5.7 % for 0/4 vs. 1.5 % for 4/4 TOF counts. The median times to extubation following neostigmine administration were clinically similar across TOF count categories. The median doses for neostigmine based on TBW decreased with higher BMI categories and were significantly different between the lowest and highest categories: 42.8 mcg/kg vs 30.8 mcg/kg for total doses (p < .0001) respectively. The percentages of cases requiring reversal in addition to the initial dose increased with increasing BMI categories and were 2.1 % for BMI < 18 vs. 3.3 % for BMI ≥ 40. The total median dose of NMB agents in ED95 equivalents per IBW increased from 2.9 in the Underweight category to 4.2 in the Class III Obese category. The majority of patients in the pancuronium subgroup received very low ED95 equivalent dose of 0.1 and did not require reversal. Patients receiving cisatracurium were given significantly higher median ED95 equivalent dose of 5.6 vs 2.8-3.9 compared to other intermediate acting NMB agents, while receiving clinically similar doses of neostigmine.
CONCLUSIONS
Neither neostigmine dosing nor times to extubation were affected by the depth of the neuromuscular blockade prior to reversal. The need for additional reversal, or rescue, correlated strongly with the depth of NMB. There was significant variability in neostigmine dosing across the BMI categories. Underweight patients received relatively lower NMB doses while simultaneously receiving relatively higher reversal doses, and the opposite was true for patients with BMI >40.
Topics: Airway Extubation; Body Weight; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Female; Guideline Adherence; Humans; Male; Middle Aged; Neostigmine; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Retrospective Studies; Time Factors
PubMed: 27770778
DOI: 10.1186/s12871-016-0266-2 -
Archiwum Medycyny Sadowej I Kryminologii 2017Pancuronium is a typical non-depolarizing, curare-mimetic, very potent muscle relaxant. Besides application in anesthesiology and intensive care, it is used in execution...
Pancuronium is a typical non-depolarizing, curare-mimetic, very potent muscle relaxant. Besides application in anesthesiology and intensive care, it is used in execution as a part of lethal injection. In medico-legal practice, there are cases of using this substance in order to commit suicide or to deprive other people of their lives. Accidental pancuronium intoxications are very rare. The authors present such case ended in sudden death of hospitalized woman after mistakenly injection of the drug. 57-year-old female alcoholic was admitted to the Acute Poisoning Centre after ethylene glycol ingestion. During the fifth day of treatment the nurse by mistake, instead of furosemide, intravenously administered her pancuronium. Sudden respiratory and circulatory arrest occurred, so she was intubated and resuscitation with artificial ventilation were undertaken, however within 1 hour and 45 minutes the patient died. Due to the vague background of a sudden deterioration in the patient's condition, the case was brought for prosecution. The autopsy and histopathological studies did not reveal the cause of death, but undertaken chemico-toxicological examinations identified the presence of pancuronium in blood, liver and kidney (190 ng/ml, 70 ng/g and 125 ng/g, respectively). Chemico-toxicological analysis proved that the cause of death of the 57-year-old hospitalized woman was pancuronium intoxication due to evident medical error during drug administration. In our case the concentration of pancuronium in blood was in therapeutic range (200-600 ng/ml). However, even a therapeutic pancuronium dose administered to patient the breath of whom is not supported and monitored can be a threat to his life.
Topics: Critical Care; Fatal Outcome; Female; Humans; Medical Errors; Middle Aged; Pancuronium; Respiratory Insufficiency
PubMed: 29663745
DOI: 10.5114/amsik.2017.75056 -
The Journal of Pain Mar 2019Translational correlates to pain with activities after deep tissue injury have been rarely studied. We hypothesized that deep tissue incision causes greater activation...
Translational correlates to pain with activities after deep tissue injury have been rarely studied. We hypothesized that deep tissue incision causes greater activation of nociception-transmitting neurons evoked by muscle contraction. In vivo neuronal activity was recorded in 203 dorsal horn neurons (DHNs) from 97 rats after sham, skin-only, or skin + deep muscle incision. We evaluated DHN responses to static, isometric muscle contractions induced by direct electrical stimulation of the muscle. The effect of pancuronium on DHN response to contractions was also examined. Approximately 50% of DHNs with receptive fields in the hindpaw were excited during muscle contraction. One-second .5- and 1.0-g muscle contractions produced greater DHN activity after skin + deep muscle incision (median [interquartile range], 32 [5-39] impulses, P = .021; and 36 [26-46] impulses, P = .006, respectively) than after sham (6 [0-21] and 15 [8-32] impulses, respectively). Neuromuscular blockade with pancuronium inhibited the muscle contractions and DHN activation during electrical stimulation, demonstrating contraction-induced activation. The greater response of spinal DHNs to static muscle contraction after skin + deep muscle incision may model and inform mechanisms of dynamic pain after surgery. PERSPECTIVE: Completion of various activities is an important milestone for recovery and hospital discharge after surgery. Skin + deep muscle incision caused greater activation of nociception-transmitting DHNs evoked by muscle contraction compared with skin-only incision. This result suggests an important contribution of deep muscle injury to activity-evoked hyperalgesia after surgery.
Topics: Animals; Disease Models, Animal; Electric Stimulation; Isometric Contraction; Male; Neuromuscular Nondepolarizing Agents; Nociceptors; Pain, Postoperative; Pancuronium; Posterior Horn Cells; Rats; Rats, Sprague-Dawley
PubMed: 30296612
DOI: 10.1016/j.jpain.2018.09.012 -
International Journal of Molecular... Sep 2021Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired...
Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.
Topics: Antineoplastic Agents; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Survival; Drug Repositioning; Flow Cytometry; Humans; Leukemia, Myeloid, Acute; Mutation
PubMed: 34576326
DOI: 10.3390/ijms221810163 -
Immunity, Inflammation and Disease Dec 2017Perioperative anaphylactic reactions due to drugs and substances associated with general anesthesia can potentially be life-threatening. The objective of this study was...
INTRODUCTION
Perioperative anaphylactic reactions due to drugs and substances associated with general anesthesia can potentially be life-threatening. The objective of this study was to investigate the significance of the basophil activation test (BAT) for allergy diagnosis work up.
METHODS
A total of 14 patients (5 men, 9 women; mean age: 57.8 years) with clinical records of anaphylactic reactions under general anesthesia were studied by means of anesthesia records, skin and serological tests. Eleven healthy subjects without any history of allergic sensitization to anaesthetic drugs served as controls. BATs based on stimulation of whole blood cells measuring CD63 activation of basophils and using CCR3 as basophil marker by flow cytometry (Flow CAST®, BÜHLMANN Laboratories AG, Schönenbuch, Switzerland) were performed with the following substances (in dependence on the history and the skin tests of the patient): analgesics (acetylsalicylic acid, celecoxib, diclofenac, ibuprofen, indometacin, metamizole, paracetamol, propyphenazone, tramadol), antibiotics (PPL (benzylpenicilloyl polylysine), MDM (minor determinant mixture), amoxicillin, cefuroxime, ciprofloxacin, doxycycline, erythromycin, roxithromycin, sulfamethoxazole, trimethoprim), local anesthetics (articaine, bupivacaine, lidocaine, prilocaine, procaine, methyl-4-hydroxybenzoate), narcotics and NMBA (atracurium, cisatracurium, etomidate, neostigmine, midazolam, mivacurium, pancuronium, propofol, pyridostigmine, succinylcholine, sufentanil, thiopental, vecuronium), and other individual substances.
RESULTS
Three patients showed positive results in the BAT: One to metamizole, one to PPL, and one to pancuronium. BATs with these substances were negative in controls.
CONCLUSIONS
The BAT should be used complementary to skin tests, especially if IgE-mediated mechanisms are presumed and skin tests are inconclusive. A positive reaction in BAT identifies the culprit agent with high probability.
Topics: Adult; Aged; Anaphylaxis; Anesthesia, General; Basophils; Biomarkers; Disease Management; Female; Flow Cytometry; Humans; Immunoglobulin E; Male; Middle Aged; Perioperative Period; Serologic Tests; Skin Tests; Young Adult
PubMed: 28580612
DOI: 10.1002/iid3.175 -
The Journal of Pediatrics Jan 2022To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time.
OBJECTIVE
To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time.
STUDY DESIGN
We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies.
RESULTS
The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin.
CONCLUSION
Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.
Topics: Cohort Studies; Databases, Factual; Drug Utilization; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Pharmaceutical Preparations; United States
PubMed: 34481808
DOI: 10.1016/j.jpeds.2021.08.075 -
Indian Journal of Anaesthesia Nov 2015Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the...
BACKGROUND AND AIMS
Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium.
METHODS
Rats were distributed into three groups (n = 5) according to the drug studied namely, 50% enantiomeric excess bupivacaine mixture (5 μg/mL); pancuronium (2 μg/mL); 50% enantiomeric excess bupivacaine mixture + pancuronium. The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture.
RESULTS
A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture.
CONCLUSION
A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action.
PubMed: 26755834
DOI: 10.4103/0019-5049.170019 -
European Journal of Pharmaceutical... Aug 2023During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking...
Predictive stability, novel HPLC-MS analysis and semi-automatic compounding process for the emergency implementation of a production line of pancuronium in injectable solution.
During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.2 µm) and filled into 10 mL type I glass, manually sealed with bromobutyl rubber stoppers. A novel HPLC-MS stability indicating method for pancuronium quantification and its degradation product was developed and validated. This fast, sensitive and straightforward method was used to study the stability of the formulation using a semi-predictive method, enabling a very fast attribution of a temporary shelf-life, which was confirmed by a classic prospective stability study. The production line and the analytical tools set-up were performed in six weeks and the semi-predictive stability study was conducted in 90 days, allowing us to predict a shelf life, which was successfully confirmed by prospective study. In conclusion, using innovative methods, we were able to rapidly overcome the shortage of a critical drug.
Topics: Humans; Chromatography, High Pressure Liquid; Pancuronium; Prospective Studies; Pandemics; COVID-19; Drug Stability; Drug Compounding
PubMed: 37169099
DOI: 10.1016/j.ejps.2023.106464 -
Chemical Science Aug 2022Supramolecular sequestration and reversal of neuromuscular block (NMB) have great clinical applications. Water-soluble flexible organic frameworks (FOFs) cross-linked by...
Supramolecular sequestration and reversal of neuromuscular block (NMB) have great clinical applications. Water-soluble flexible organic frameworks (FOFs) cross-linked by disulfide bonds are designed and prepared. Different linker lengths are introduced to FOFs to give them varied pore sizes. FOFs are anionic nanoscale polymers and capable of encapsulating cationic neuromuscular blocking agents (NMBAs), including rocuronium (Roc), vecuronium (Vec), pancuronium (Panc) and cisatracurium (Cis). A host-guest study confirms that FOFs bind NMBAs in water. The multivalency interaction between FOFs and NMBAs is able to sequester NMBAs, and prevent them from escaping. These FOFs are non-toxic and biocompatible. Animal studies show that FOFs are effective for the reversal of NMB induced by Roc, Vec and Cis, which shorten the time to a train-of-four ratio of 0.9 by 2.6, 3.8 and 5.7-fold compared to a placebo, respectively.
PubMed: 36093029
DOI: 10.1039/d2sc02456j