Safety of pain control with morphine: new (and old) aspects of morphine pharmacokinetics and pharmacodynamics

Background: A 26-year-old, 59 kg female was administered morphine 10 mg during tonsillectomy, and 5 mg in the recovery room. She died 5 hours after the operation. Hypoxic cerebral injury, arising from morphine side-effects, was pronounced the cause of death, in spite of morphine being undetectable in blood. Recent pharmacokinetic-pharmacodynamic modelling indicates that, after a single intravenous dose, maximum respiratory depression occurs after 1 hour and 40 minutes and persists for hours. Furthermore, respiratory depression is accompanied by airway obstruction, sleep potentiates respiratory depression and airway obstruction, pain stimulates breathing and antagonises respiratory depression, pain relief unmasks respiratory depression, and a slow breathing rate is uncommon.Methods: Pharmacokinetic-pharmacodynamic simulations were used to estimate the time course of morphine effect-site concentrations in an “average” 59 kg female, and to calculate the degree of resulting respiratory depression.Results: Morphine effect-site concentrations approached dangerous levels for respiratory depression andpersisted for hours, while plasma concentrations were undectectably low. Discussion: Court testimony indicates that additional factors contributed to the patient’s demise. Respiratory depression was potentiated by pain relief following quinsy tonsillectomy, and by falling asleep. The airway wasobstructed, as witnessed both by nurses and a fellow patient. In addition, nursing staff failed to recognise that snoring can indicate a dangerously obstructed airway.Conclusions: Dangerous respiratory depression often goes unrecognised in surgical wards. Strategies for improved safety include education of nursing and other staff regarding the following aspects of respiratorydepression: (i) recognition of delayed and prolonged respiratory depression; (ii) noisy breathing indicatesobstructed breathing; (iii) respiratory rate is an unreliable monitor of respiratory depression; (iv) training in airway management should be compulsory; (v) sleeping patients should be administered oxygen, and pulse oximetry monitoring should be done (especially at night); (vi) more local anaesthesia should be administered for postoperative pain; (vii) combination analgesic therapy (NSAIDs, paracetamol, ketamine, dexmedetomidine, gabapentin) should be utilised to reduce morphine requirements; (viii) high risk patients (e.g. elderly, obese, sleep-apnoea syndrome) should be identified; (ix) sedation scores should be recorded to detect obtunded patients. Morphine plasma concentrations do not reflect pharmacological activity. Keywords: morphine; adverse effects; respiratory insufficiency; pharmacokinetics; pharmacodynamic

Editorial: Anaesthetic induction with propofol: How much? How fast? How slow?

No Abstrac

Sevoflurane or halothane with target-controlled sufentanil infusions for coronary artery bypass surgery

Objectives: Comparison of hemodynamics, circulatory efficiency, myocardial ischemia and recall during and after sevoflurane or halothane (0.6 MAC {Minimum Alveolar Concentration} inspired) combined with a target-controlled sufentanil infusion (2 ng.ml-1) for coronary artery bypass grafting. Methods: Prospective randomised non-blinded study in a university teaching hospital of 45 patients undergoing on-pump surgery. Inhalation anesthetic agent was delivered before, during and after cardiopulmonary bypass. Results: Intraoperative hemodynamics were maintained within predetermined limits using vasoactive and cardioactive drugs. Heart rate was unchanged from baseline, however the sevoflurane-sufentanil group required more glycopyrrollate, indicating a tendency towards a slower heart rate. In both groups, similar low incidences of myocardial ischemia were detected. After induction of anesthesia, as well as intraoperatively, oxygen consumption decreased by up to 36.6% compared with the awake values in both groups. Oxygen delivery remained unchanged during all measuring periods. Mixed venous oxygen tensions rose after induction, even in patients with cardiac indices below 2.2 L.min-1.m-2, indicating maintenance of an effective circulation when utilising these techniques. Twelve hours postoperatively, oxygen consumption exceeded awake values by 31%. No explicit recall was reported by any patient on enquiry on the third postoperative day. Conclusions: Low concentrations of sevoflurane or halothane, supplementing target-controlled sufentanil infusions, were both suitable for providing anesthesia for coronary bypass surgery.Keywords: Coronary artery bypass grafting, anesthesia, hemodynamics, sevoflurane, halothane, sufentanil, mixed venous oxygen tension, oxygen consumption, balanced anesthesi

A comparison of induction of anaesthesia using two different propofol preparations

Background: Investigators have reported inter-patient variability with regard to propofol dosage for induction of anesthesia, since early dose finding studies. With the arrival of generic formulations of propofol, questions have arisen regarding further variability in dose requirements. Various studies have confirmed that generic propofol preparations are pharmacokinetically and pharmacodynamically equivalent to Diprivan®. Nevertheless a number of practitioners are under the impression that certain generic propofol preparations require greater doses for induction of anaesthesia than does Diprivan®.Methods: 20 female patients of ASA status I-II, between the ages of 18-55 years, scheduled for routine surgery were randomly allocated to two groups to undergo induction of anaesthesia using two different propofol formulations; Diprivan® and Propofol 1% Fresenius®. Either preparation was administered using a target-controlled infusion of propofol (STEL-TCI) targeting the plasma (central) compartment at a concentration of 6 μg.ml-1, employing the pharmacokinetic parameters of Marsh et al. A processed EEG (bispectral index) was continuously recorded. Loss of consciousness (LOC) was regarded as the moment at which the patient could not keep her eyes open and was confirmed by the absence of an eyelash reflex. At this point propofol administration was discontinued and data were recorded for a further two minutes, before administering an appropriate opioid and/or nitrous oxide/volatile agent and/or muscle relaxant to maintain anaesthesia. Time to LOC after start of propofol administration, and the dose of propofol administered during induction were annotated. Results: There were no demographic differences between the groups. There were no differences between the groups with regard to the mean dose for LOC, time to LOC and to the mean BIS values obtained at the following stages: awake, at LOC, at 1 and 2 minutes after LOC as well as the lowest recorded value.Conclusions: Our results confirm that the two propofol formulations that we studied, are pharmacologically equivalent with regard to induction of anaesthesia. Other mechanisms can explain the variability in clinical response to bolus administration of propofol. The most important is the recirculatory or “front-end” kinetics of propofol in which cardiac output plays a major role, as well as the rate of drug administration. Emulsion degradation can also influence dose-response and in this regard it should be noted that the addition of foreign substances such as lignocaine, can result in rapid deterioration of the soyabean emulsion

Effects of sodium salicylate on productivity of postpartum dairy cows

Inflammation has been proposed as a contributor to metabolic disorders in transition dairy cows. The purpose of this experiment was to determine whether a non-steroidal anti-inflammatory drug, sodium salicylate (SS), benefits transition cows. At calving, 78 cows (primiparous, n = 39; second lactation, n = 28; ≥3 lactations, n = 11) were assigned alternately to either a control (CON) or SS treatment for 7 days and remained on study until 21 days postpartum. Treatment was administered via individual water bowls at a concentration of 2.5 g/L, delivering a mean of 183 ± 8.5 g/day SS during the 7 days of treatment. Milk yields were collected daily and milk samples were collected twice weekly. Data were analyzed using mixed models with repeated measures over time. No treatment effects were detected for daily feed or water intake. Milk yield for third or greater lactation cows tended to increase (P \u3c 0.10) with SS at the end of the trial (days 19 to 20). Milk protein content increased (P \u3c 0.05) with SS in first- and second-lactation cows during week 1 and milk urea nitrogen (MUN) decreased (P \u3c 0.01) with SS. Milk fat content increased (P \u3c 0.05) with SS in weeks 2 and 3 postpartum. A 10% increase (P \u3c 0.05) in energy-corrected milk (ECM) was observed for SS cows during week 3. Metritis incidence increased (P \u3c 0.01) with SS in third or greater lactation cows, but no other effects on disease incidence were detected. In contrast to our hypothesis that SS treatment would decrease transition disorder incidences, SS treatment seemed to promote increased milk fat content and milk energy output during early lactation with no effect on total disorder incidence.; Dairy Day, 2011, Kansas State University, Manhattan, KS, 2011; Dairy Research, 2011 is known as Dairy Day, 201

Editorial: Is the HPCSA requirement for a research dissertation for specialist registration the best option?

No Abstrac

Impact of oral meloxicam and long-distance transport on cell-mediated and humoral immune responses in feedlot steers receiving modified live BVDV booster vaccination on arrival

The objective of this study was to investigate the impact of oral meloxicam (MEL) and long-distance transportation on cell-mediated immunity (CMI) in preconditioned steers receiving a booster vaccination on arrival. We hypothesized that steers treated with MEL at 1 mg/kg body weight, 6 h before night-time transport, would be less immunocompromised on arrival (day 0) and after 7 days, and that CMI following vaccination with a modified live bovine viral diarrhea virus (BVDV) recall antigen would be increased. Brahman crossbreed steers, 13–17 months of age (n = 87), were randomly assigned to one of four treatment groups: MEL, transported (MTR) (n = 22), MEL, non-transported (MNT) (n = 22), lactose placebo, transported (CTR) (n = 21), and lactose placebo, non-transported (CNT) (n = 22). MTR and CTR steers were transported for approximately 16 h non-stop on a truck from Mississippi to Iowa (approximately 1300 km), whereas steers in the MNT and CNT groups remained in Mississippi as non-transported controls. Body weight was measured and jugular blood was collected at −1, 0, and 7 days from all steers at the same time, regardless of location. Multi-parameter flow cytometry (MP-FCM) was used to identify T-cell subsets and detect the expression of three activation markers (CD25 [interleukin (IL)-2 receptor], intracellular interferon-gamma [IFNγ], and IL-4) after in vitro stimulation with BVDV recall antigen. Plasma cortisol concentration was measured on day −1, 0, and 7 as a marker of transport-associated stress. Serum antibody titer to BVDV was assessed on day −1 and day 7 post-booster vaccination. Whole-blood samples were analyzed using MP-FCM on days 0 and 7. Results were log transformed and analyzed using repeated measures of analysis of variance. Compared with non-transported controls, transport led to an increase in BVDV-induced expression of CD25, IFNγ, and IL-4 in CD4+, CD8+, and γδ+ T-cell subsets (P 0.10). A treatment*transport interaction was noted for the increase in IL-4 expression by CD8+ T cells after transport, with a significant difference between the CTR and MTR groups at day 7. In conclusion, the use of oral MEL prior to transport appears to have inhibitory or homeostatic effects, but further research is needed to validate the effect of MEL treatment on specific T-cell subsets in transported cattle.This is a manuscript of the article Published as Van Engen, N. K., R. Platt, J. A. Roth, M. L. Stock, T. Engelken, R. C. Vann, L. W. Wulf et al. "Impact of oral meloxicam and long-distance transport on cell-mediated and humoral immune responses in feedlot steers receiving modified live BVDV booster vaccination on arrival." Veterinary Immunology and Immunopathology 175 (2016): 42-50. doi: https://doi.org/10.1016/j.vetimm.2016.05.006. © 2016 Elsevier. This manuscript is made available under the Elsevier user license (https://www.elsevier.com/open-access/userlicense/1.0/)

Standardization of European eel (Anguilla anguilla) sperm motility evaluation by CASA software

[EN] The development of powerful computer-assisted sperm analysis software has made kinetic studies of spermatozoa possible. This system has been used and validated for several species, but some technical questions have emerged regarding fish sample evaluations (i.e., frame rate, sperm dilution, chamber model, time of analysis, magnification lens, etc.). In the present study, we have evaluated the effects of different procedural and biological settings with the aim to correctly measure sperm quality parameters of the European eel. The use of different chambers did not affect the sperm motility parameters. However, regarding lens magnification, 10x was the most accurate lens, showing the least variation in the acquired data. Similarly, the frame rate setting resulted in a dramatic effect in some sperm kinetic parameters, primarily in terms of curvilinear velocity; we therefore recommend using the camera's highest available frame rate setting. Finally, the reduction in sperm motility over postactivation times suggests that sperm analysis should be performed within the first 60 seconds after activation of the European eel sperm. In conclusion, some protocol variables of sperm analysis by computer-assisted sperm analysis software can affect the measurement of eel sperm quality parameters, and should be considered before directly comparing results obtained by different laboratories. Moreover, because marine fish species show relatively similar features of sperm kinetic parameters, these results could be considered in the evaluation of the motility of sperm from other fish species. (C) 2013 Elsevier Inc. All rights reserved.This study was funded from the European Community's 7th Framework Programme under the Theme 2 "Food, Agriculture and Fisheries, and Biotechnology," grant agreement 245257 (Pro-Eel), and Generalitat Valenciana (ACOMP/2011/229). D.S.P. and P.C.F.C. have postdoctoral grants from UPV (CE-01-10) and PAC-EMBRAPA, respectively. I.M. and V.G. have predoctoral grants from Generalitat Valenciana and Spanish MICINN, respectively. The authors thank the Proiser R&D, S.L. team, who performed the task of fractioning the original sequences for the experiment described in section 3.2.Gallego Albiach, V.; Carneiro, PCF.; Mazzeo, I.; Vilchez Olivencia, MC.; Peñaranda, D.; Soler, C.; Pérez Igualada, LM.... (2013). Standardization of European eel (Anguilla anguilla) sperm motility evaluation by CASA software. Theriogenology. 79(7):1034-1040. https://doi.org/10.1016/j.theriogenology.2013.01.019S1034104079

Simulacral, genealogical, auratic and representational failure: Bushman authenticity as methodological collapse

This article engages with the concept of authenticity as deployed in anthropology. The first section critiques authenticity as a simple reference to cultural purity, a traditional isomorphism or historical verisimilitude or as an ‘ethnographic authenticity’. Demarcation of authenticity must take into account philosophical literature that argues that authenticity is an existential question of the ‘modern’ era. Thus, authenticity is offered to us as individuals as a remedy for the maladies of modernity: alienation, anomie and alterity. Authenticity is then discussed as a question of value within an economy of cultural politics that often draws on simulacra, creating cultural relics of dubious origin. The final section discusses various methodological failures and problematiques that are highlighted by the concern for, and scrutiny of, authenticity. The first is the simulacral failure. The subjects of anthropology are mostly real flesh-and-blood people-on-the-ground with real needs. In contrast is the simulacral subject, the brand, the tourist image, the media image or the ever-familiar hyper-real bushmen. Lastly, the article considers what Spivak calls ‘withholding’ – a resistance to authentic representation by the Other. Resistance suggests a need for a radically altered engagement with the Other that includes both a deepening, and an awareness, of anthropology as a process of common ontological unfolding