Effect of intravenous magnesium on post-operative pain following Latarjet shoulder reconstruction.

Background: Single injection ropivacaine interscalene anesthesia (ISA) is frequently used in Latarjet reconstruction to enhance post-operative analgesia. A potential limitation is the occurrence of severe rebound pain on block resolution. We investigated the effect of intravenous magnesium on post-operative pain, particularly at the transition of block resolution to multimodal analgesia. Methods: Elective patients (n = 40) having Latarjet open shoulder reconstruction were randomised to receive either intravenous magnesium sulphate 50 mg/kg (M) or normal saline (S) before induction. Post-operatively, a standardised analgesic regimen was used, and post-operative pain was recorded using a verbal numerical rating assessment (VNRA) score. Requirement for injected opioid analgesia was recorded. Results: ISA provided longstanding analgesia in all patients with block duration slightly prolonged in the magnesium group (16.7(1.0) (S), 17.8(1.3) h (M), p = 0.049). Magnesium resulted in less rebound pain following ISA resolution (VNRA 4.0 (0.6) M, 6.2 (0.8) S, p = 0.03) and lower pain intensity at 24 h. Four patients had nausea and two required rescue opioid injection. Conclusion: Magnesium before Latarjet surgery results in less rebound pain following ropivacaine block and improves post-operative analgesia. Magnesium may be indicated in major upper limb surgery, where significant pain intensity is anticipated. Level of evidence: Treatment study; Randomised blinded; Level 2.

Antibody or Anybody? Considering the Role of MRGPRX2 in Acute Drug-Induced Anaphylaxis and as a Therapeutic Target.

Acute anaphylaxis to small molecule drugs is largely considered to be antibody-mediated with immunogloblin E (IgE) and mast cell activation being key. More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil activation has also been suggested, at least in reactions to neuromuscular blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been highlighted as a possible triggering mechanism in acute anaphylaxis to many clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon the presence of drug-recognising antibody. Given the reasonable assumption that MRGPRX2 is expressed in all individuals, the corollary of this is that in theory, anybody could respond detrimentally to triggering drugs (recently suggested to be around 20% of a drug-like compound library). But this clearly is not the case, as the incidence of acute drug-induced anaphylaxis is very low. In this mini-review we consider antibody-dependent and -independent mechanisms of mast cell activation by small molecule drugs with a focus on the MRGPRX2 pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider how increased understanding of the role of MRGPRX2 in anaphylaxis is important for future drug development and can complement exploration of this receptor as a drug target in broader clinical settings.

MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex.

BACKGROUND: Neuromuscular-blocking agents (NMBAs) can cause both IgE-dependent and IgE-independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE: We further characterize the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE-dependent anaphylaxis. METHODS: The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS: All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 min following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE: We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly, however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.

Evaluation of right heart function in a rat model using modified echocardiographic views.

Echocardiography plays a major role in assessing cardiac function in animal models. We investigated use of a modified parasternal mid right-ventricular (MRV) and right ventricle (RV) outflow (RVOT) view, in assessing RV size and function, and the suitability of advanced 2D-strain analysis. 15 WKY rats were examined using transthoracic echocardiography. The left heart was assessed using standard short and long axis views. For the right ventricle a MRV and RVOT view were used to measure RV chamber and free wall area. 2D-strain analysis was applied to both ventricles using off-line analysis. RV chamber volume was determined by injection of 2% agarose gel, and RV free wall dissected and weighed. Echocardiography measurement was correlated with necropsy findings. The RV mid-ventricular dimension (R1) was 0.42±0.07cm and the right ventricular outflow tract dimension (R2) was 0.34±0.06cm, chamber end-diastolic area measurements were 0.38±0.09cm2 and 0.29±0.08cm2 for MRV and RVOT views respectively. RVOT and MRV chamber area correlated with gel mass. Doppler RV stroke volume was 0.32±0.08ml, cardiac output (CO) 110±27 ml.min-1 and RV free wall contractility assessed using 2D-strain analysis was demonstrated. We have shown that modified MRV and RVOT views can provide detailed assessment of the RV in rodents, with 2D-strain analysis of the RV free wall potentially feasible.

Sensory Distribution of the Lateral Cutaneous Nerve of Forearm After Ultrasound-Guided Block: Potential Implications for Thumb-Base Surgery.

Surgery of the wrist and hand commonly involves regional anesthesia of the median nerve and superficial radial nerve within the forearm. In this sonographic study, the contribution of the lateral cutaneous nerve of forearm (LCNF) to thumb cutaneous sensation was studied. Patients scheduled for thumb suspension arthroplasty (n = 35) were examined by ultrasound, with LCNF, median nerve, and superficial radial nerve identified. A single nerve was then injected with local anesthetic, and the area of cutaneous sensory loss mapped at 15 minutes. The remaining 2 nerves were then blocked for progression to theater. In 15 patients, the LCNF was blocked first at the antecubital fossa, where it was located posterior to the cephalic vein 9.1 (1.6) mm distal to the interepicondylar line. Bifurcation occurred further distally, 18 (2.6) mm from the interepicondylar line. In 14 of 15 cases, LCNF sensory distribution extended to the thumb base, 8.3 (7.8) mm distal to the radiocarpal joint. This study has demonstrated the LCNF to innervate the thumb base, indicating neural blockade of this nerve may be required for surgery of the basal thumb joint.

Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro.

BACKGROUND: Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: bosentan, pulmonary artery 6.28±0.13 and radial artery 6.04±0.10; macitentan, pulmonary artery 8.02±0.13 and radial artery 7.49±0.08; and ambrisentan, pulmonary artery 7.38±0.13 and radial artery 6.96±0.10. CONCLUSIONS: Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.

Is cerebral desaturation during beachchair anaesthesia really an indicator of cerebral injury? / ¿Es la desaturación cerebral durante la anestesia semisentada un indicador fiable de una lesión cerebral?

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