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.

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.

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.

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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Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study.

BACKGROUND: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. METHODS: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration-response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. RESULTS: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. CONCLUSIONS: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.

The role of voltage-operated and non-voltage-operated calcium channels in endothelin-induced vasoconstriction of rat cerebral arteries.

Endothelin-1 has been identified as a potential mediator in the pathogenesis of ischaemic stroke and cerebral vasospasm. The aim of this study was to analyse the role of voltage-operated calcium channels (VOCC) and non-VOCC in endothelin-1 induced vasoconstriction of rat cerebral arteries. Arterial segments were dissected from different regions of the cerebral circulation and responses assessed using wire myography. Endothelin-1 concentration-contraction curves were constructed in calcium-free medium or in the presence of nifedipine, NNC 55-0396 ((1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride) or SK&F 96365 (1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole) to inhibit the l-type VOCC, T-type VOCC and non-VOCC, respectively. Inhibition of the calcium channels or removal of calcium from the medium variably decreased the maximum effects (Emax) of endothelin-1, however its potency (pEC50) was unaltered. Endothelin-1 caused a small contraction (<22%) in calcium-free solution. Pre-treatment with nifedipine (1µM) did not affect responses to low concentrations of endothelin-1 but decreased Emax, while NNC 55-0396 (1µM) and SK&F 96365 (30-100µM) generally attenuated the endothelin-1-induced contraction. Combination of nifedipine with SK&F 96365 further decreased the Emax. The relaxant effect of the calcium channel antagonists was also assessed in pre-contracted arteries. Only nifedipine and SK&F 96365 relaxed the arteries pre-contracted with endothelin-1. In conclusion, VOCC and non-VOCC calcium channels are involved in different phases of the endothelin-1 contraction in rat cerebral vessels. T-type VOCC may be involved in contraction induced by low concentrations of endothelin-1, while l-type VOCC mediate the maintenance phase of contraction. VOCC and non-VOCC may work in concert in mediating contraction induced by endothelin-1.

Levosimendan preserves the contractile responsiveness of hypoxic human myocardium via mitochondrial K(ATP) channel and potential pERK 1/2 activation.

This study investigated the role of levosimendan, a mitochondrial K(ATP) channel opener, during hypoxia-reoxygenation injury in human isolated tissue. The activation of preconditioning pathways, and the release of mitochondrial cytochrome c were determined. Human right atrial trabeculae were mounted in an organ bath, electrically paced and contractile force measured. Tissue was subjected to hypoxia-reoxygenation, and isoproterenol concentration-response experiments were performed as an index of contractile viability. The intracellular activities of Akt, ERK 1/2, P38, caspase 3, and cytochrome c were assayed by western blot. Following hypoxia-reoxygenation, the maximal contractile response of trabeculae to isoproterenol was significantly increased with levosimendan pretreatment compared to the hypoxia-reoxygenation control (0.88±0.02 versus 0.60±0.01g, P<0.01). This enhanced response was blocked by 5-hydroxydecoanate (0.54±0.09g, P<0.01). A significant increase in both phosphorylated and total ERK 1/2 and P38 occurred at 60min reoxygenation, compared to control tissue. No difference was observed in phosphorylated or total Akt, though there was a trend for increased levels in hypoxic tissue. Cytochrome c was detected at 60min post reoxygenation, in both levosimendan treated and untreated tissue. No increase in cleaved-caspase 3 activity was observed. Our findings suggest that levosimendan preserves the contractile force to isoproterenol after hypoxia-reoxygenation, a response mediated via mK(ATP) channel activation. The significant increase in the activity of prosurvival mediators ERK 1/2 and P38 following hypoxia indicates a potential mechanism of action for levosimendan-induced cardioprotection.

Review article: anatomical considerations for ultrasound guidance for regional anesthesia of the neck and upper limb.

PURPOSE: The purpose of this narrative review is to describe an anatomical approach for residents-in-training and anesthesiologists who are learning techniques of ultrasound-guided regional anesthesia of the neck and upper limb. SOURCES: Relevant articles relating anatomy and anatomical variation to the emerging practice of ultrasound-guided regional anesthesia for the neck and upper limb were sourced via both Medline and PubMed databases. Also, our approach to teaching ultrasound technique has developed from using anatomical resources and cadaveric workshops. This approach emphasizes precise image acquisition, a detailed knowledge of anatomy and anatomical variations, and, importantly, visual interpretation of sonographic landmarks based on pattern recognition when interpreting sonograms. PRINCIPAL FINDINGS: Typical sonographic patterns orient the examiner to nerve position, which is necessary for executing successful regional anesthesia of the neck and upper limb. Only by understanding the typical anatomical arrangement can the examiner then visually interpret any individual anatomical variation that may occur. CONCLUSION: Simple sonographic anatomical patterns can provide a strategy to correctly locate nerves when performing ultrasound-guided cervical and brachial plexus anesthesia.

Cold agglutinins in cardiac surgery: management of myocardial protection and cardiopulmonary bypass.

Cold agglutinins are of unique relevance in cardiac surgery because of the use of hypothermic cardiopulmonary bypass (CPB). Immunoglobulin M autoantibodies to red blood cells, which activate at varying levels of hypothermia, can cause catastrophic hemagglutination, microvascular thrombosis, or hemolysis. Management of CPB and myocardial protection requires individualized planning. We describe a case of aortic valve replacement in a patient with high titre cold agglutinins and a high thermal amplitude for antibody activation. Normothermic CPB and continuous warm blood cardioplegia were successfully used.

Descending aortic pulsed wave Doppler can predict changes in cardiac output during off-pump coronary artery bypass surgery.

Retraction and stabilization of the heart can induce rapid and large changes in the hemodynamic state during off-pump coronary artery bypass graft surgery (OPCABG). We aimed to determine if Doppler measurement of flow in the descending artery with transesophageal echocardiography (TEE) can provide a beat-to-beat assessment of changes in cardiac output (CO) in 26 OPCABG patients. Simultaneous measurements were performed of CO using thermodilution, and descending aortic flow (FlowDA) with TEE, prior to grafting, and during grafting to the left anterior descending artery (LAD), circumflex (Cx) and right coronary artery (RCA) territories. CO decreased from baseline (SD) values of 6.2 (1.7), to 5.4 (1.8) L/min during grafting to the LAD, 4.4 (1.5) L/min to the Cx territory, and 4.4 (1.4) L/min to the RCA territory (P<0.001). There was poor correlation between CO and FlowDA between individuals. In a subgroup of 16 patients who had grafts to all territories, the changes in Flow(DA), occurred in the same direction and magnitude as changes in CO (P = 0.062, RM-ANOVA for factor*time interaction). Doppler assessment of flow in the descending aorta is able to track changes in CO during OPCABG. (Ann Thorac Cardiovasc Surg 2003; 9: 314-8)

The effect of pericardial restraint, atrial pacing, and increased heart rate on left ventricular systolic and diastolic function in patients undergoing cardiac surgery.

UNLABELLED: Baseline measurements of systolic and diastolic function performed after the induction of anesthesia may be compared with subsequent measurements acquired under different physical conditions such as open pericardium and different heart rate or rhythm. We acquired data from 21 patients undergoing coronary artery surgery. Combined echocardiographic and pulmonary artery catheter measurements were performed before and after pericardial opening, atrial pacing at the native rate, and atrial pacing 30 bpm faster. Indices of systolic function included fractional area change, afterload corrected fractional area change, and myocardial performance index; diastolic function included mitral inflow and pulmonary vein Doppler profiles, color M-Mode Doppler flow propagation velocity, instantaneous end-diastolic stiffness, and isovolumetric relaxation time. Hemodynamic indices included cardiac index, mean arterial, right atrial, and pulmonary capillary wedge pressures, and systemic vascular resistance index. There were no changes in measurements after opening of the pericardium or with institution of atrial pacing. With increased heart rate, there were no changes in systolic function, but instantaneous end-diastolic stiffness increased. Propagation velocity showed a paradoxical improvement with increased heart rate opposite to other trends. Beat fusion occurs with increasing heart rate for mitral inflow Doppler. We recommend that serial measurements are performed at a similar heart rate. IMPLICATIONS: Pericardial restraint or the institution of atrial pacing do not alter left ventricular function, as assessed by pulmonary artery catheter and transesophageal echocardiography measurements. Diastolic (but not systolic) measurements showed inconsistency with increased heart rate.

Prospective randomized trial of high thoracic epidural analgesia for coronary artery bypass surgery.

BACKGROUND: Postoperative pain may be severe after coronary artery bypass surgery. High thoracic epidural analgesia (HTEA) provides intense analgesia. METHODS: Eighty patients were randomized to HTEA or intravenous morphine analgesia (control). Patients received coronary artery bypass surgery (CABG) with cardiopulmonary bypass. Pain was measured by visual analogue scale 0 to 10. Psychologic morbidity, intraoperative hemodynamics, ventricular function, lung function, and physiotherapy cooperation were also assessed. On the third postoperative day HTEA and morphine were ceased and only oral medications were used. Acetaminophen, indomethacin, and tramadol were allowed as supplemental analgesics in both groups. RESULTS: The primary endpoint of pain scores was significantly less with HTEA on postoperative days 1 and 2 at rest, 0.02 +/- 0.2 versus 0.8 +/- 1.8 (p = 0.008) and 0.1 +/- 0.4 versus 1.2 +/- 2.7 (p = 0.022), respectively, and with coughing 1.2 +/- 1.7 versus 4.4 +/- 3.1 (p < 0.001) and 1.5 +/- 2.0 versus 3.6 +/- 3.1 (p = 0.001), respectively. When HTEA and morphine were ceased on day 3, there were no significant differences. The secondary endpoints of postoperative depression (p = 0.033) and posttraumatic stress subscales (p = 0.021) of the Minnesota Multiphasic Personality Inventory were lower with HTEA. Extubation occurred earlier with HTEA, 2.6 versus 5.4 hours (p < 0.001). HTEA showed improved physiotherapy cooperation (p < 0.001), arterial oxygen tension (p = 0.041), and peak expiratory flow rate (p = 0.001). Mean arterial pressure was lower with HTEA (p = 0.036), otherwise there were no differences in intraoperative hemodynamics or ventricular function. CONCLUSIONS: Epidural analgesia reduces pain after coronary operation and is associated with improved physiotherapy cooperation, earlier extubation, and reduced risk of depression and posttraumatic stress.