David Sturgess

Activation of μ-opioid receptor and Toll-like receptor 4 by plasma from morphine-treated mice

In this study, we quantified the ability of opioids present in biological samples to activate the μ-opioid receptor and TLR4 using cell-based assays. Each assay was standardised, in the presence of plasma, using morphine, its μ receptor-active metabolite morphine-6 glucuronide (M6G) and its μ receptor-inactive, but TLR4-active metabolite morphine-3 glucuronide (M3G). Specificity was verified using antagonists. Morphine- and M6G-spiked plasma samples exhibited μ receptor activation, which M3G-spiked plasma lacked. In contrast, M3G showed moderate but consistent activation of TLR-4. Plasma samples were collected at a number of time points from mice administered morphine (1 or 10mg/kg every 12h for 3days) or saline. Morphine administration led to intermittent μ receptor activation, reversed by μ receptor antagonists, and to TRL4 activation at time points where M3G is measured in plasma. Interestingly, this protocol of morphine administration also led to TLR4-independent NF-κB activation, at time points where M3G was not detected, presumably via elevation of circulating cytokines including, but not limited to, TNFα. Circulating TNFα was increased after three days of morphine administration, and TNFα mRNA elevated in the spleen of morphine-treated mice.

Tracheal extubation of the adult intensive care patient with a predicted difficult airway - a narrative review

Management of the difficult airway is an important, but as yet poorly‐studied, component of intensive care management. Although there has been a strong emphasis on prediction and intubation of the difficult airway, safe extubation of the patient with a potentially difficult airway has not received the same attention. Extubation is a particularly vulnerable time for the critically ill patient and, because of the risks involved and the consequences of failure, it warrants specific consideration. The Royal College of Anaesthetists 4th National Audit Project highlighted differences in the incidence and consequences of major complications during airway management between the operating room and the critical care environment. The findings in the section on Intensive Care and Emergency Medicine reinforce the importance of good airway management in the critical care environment and, in particular, the need for appropriate guidelines to improve patient safety. This narrative review focuses on strategies for safe extubation of the trachea for patients with potentially difficult upper airway problems in the intensive care unit.

Diastolic (dys)function in sepsis

Sepsis is a clinical syndrome that results from the systemic response of the body to infection [1]. It is a serious clinical problem, accounting for substantial morbidity and mortality. The majority of these patients die of refractory hypotension and of cardiovascular collapse [2].

Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion.

Opioids modulate the tumor microenvironment with potential functional consequences for tumor growth and metastasis. We evaluated the effects of morphine administration on the circulating proteolytic profile of tumor‐free mice. Serum from morphine‐treated (1 or 10 mg/kg, i.p. every 12 h) or saline‐treated mice was collected at different time points and tested ex vivo in endothelial, lymphatic endothelial, and breast cancer cell migration assays. Serum from mice that were treated with 10 mg/kg morphine for 3 d displayed reduced chemotactic potential for endothelial and breast cancer cells, and elicited reduced cancer cell invasion through reconstituted basement membrane compared with serum from saline controls. This was associated with decreased circulating matrix metalloproteinase 9 (MMP‐9) and increased circulating tissue inhibitor of metalloproteinase 1 (TIMP‐1) and TIMP‐3/4 as assessed by zymography and reverse zymography. By using quantitative RT‐PCR, we confirmed morphine‐induced alterations in MMP‐9 and TIMP expression and identified organs, including the liver and spleen, in which these changes originated. Pharmacologic inhibition of MMP‐9 abrogated the difference in chemotactic attraction between serum from saline‐treated and morphine‐treated mice, which indicated that reduced proteolytic ability mediated the decreased migration toward serum from morphine‐treated mice. This novel mechanism may enable morphine administration to promote an environment that is less conducive to tumor growth, invasion, and metastasis.—Xie, N., Khabbazi, S., Nassar, Z. D., Gregory, K., Vithanage, T., Anand‐Apte, B., Cabot, P. J., Sturgess, D., Shaw, P. N., Parat, M.‐O. Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion. FASEB J. 31, 5208–5216 (2017). www.fasebj.org

Preoperative Warming Versus no Preoperative Warming for Maintenance of Normothermia in Women Receiving Intrathecal Morphine for Cesarean Delivery: A Single-blinded, Randomized Controlled Trial

BACKGROUND: Rates of hypothermia for women undergoing spinal anesthesia for cesarean delivery are high and prevention is desirable. This trial compared the effectiveness of preoperative warming versus usual care among women receiving intrathecal morphine, which is thought to exacerbate perioperative heat loss. METHODS: A prospective, single-blinded, randomized controlled trial compared 20 minutes of forced air warming (plus intravenous fluid warming) versus no active preoperative warming (plus intravenous fluid warming) in 50 healthy American Society of Anesthesiologists graded II women receiving intrathecal morphine as part of spinal anesthesia for elective cesarean delivery. The primary outcome of maternal temperature change was assessed via aural canal and bladder temperature measurements at regular intervals. Secondary outcomes included maternal thermal comfort, shivering, mean arterial pressure, agreement between aural temperature, and neonatal outcomes (axillary temperature at birth, Apgar scores, breastfeeding, and skin-to-skin contact). The intention-to-treat population was analyzed with descriptive statistics, general linear model analysis, linear mixed-model analysis, &khgr;2 test of independence, Mann-Whitney, and Bland-Altman analysis. Full ethical approval was obtained, and the study was registered on the Australia and New Zealand Clinical Trials Registry (Trial No: 367160, registered at http://www.ANZCTR.org.au/). RESULTS: Intention-to-treat analysis (n = 50) revealed no significant difference in aural temperature change from baseline to the end of the procedure between groups: F (1, 47) = 1.2, P = .28. There were no other statistically significant differences between groups in any of the secondary outcomes. CONCLUSIONS: A short period of preoperative warming is not effective in preventing intraoperative temperature decline for women receiving intrathecal morphine. A combination of preoperative and intraoperative warming modalities may be required for this population.

Diabetes-Specific Formulae Versus Standard Formulae as Enteral Nutrition to Treat Hyperglycemia in Critically Ill Patients: Protocol for a Randomized Controlled Feasibility Trial

Background During critical illness, hyperglycemia is prevalent and is associated with adverse outcomes. While treating hyperglycemia with insulin reduces morbidity and mortality, it increases glycemic variability and hypoglycemia risk, both of which have been associated with an increase in mortality. Therefore, other interventions which improve glycemic control, without these complications should be explored. Nutrition forms part of standard care, but the carbohydrate load of these formulations has the potential to exacerbate hyperglycemia. Specific diabetic-formulae with a lesser proportion of carbohydrate are available, and these formulae are postulated to limit glycemic excursions and reduce patients’ requirements for exogenous insulin. Objective The primary outcome of this prospective, blinded, single center, randomized controlled trial is to determine whether a diabetes-specific formula reduces exogenous insulin administration. Key secondary outcomes include the feasibility of study processes as well as glycemic variability. Methods Critically ill patients will be eligible if insulin is administered whilst receiving exclusively liquid enteral nutrition. Participants will be randomized to receive a control formula, or a diabetes-specific, low glycemic index, low in carbohydrate study formula. Additionally, a third group of patients will receive a second diabetes-specific, low glycemic index study formula, as part of a sub-study to evaluate its effect on biomarkers. This intervention group (n=12) will form part of recruitment to a nested cohort study with blood and urine samples collected at randomization and 48 hours later for the first 12 participants in each group with a secondary objective of exploring the metabolic implications of a change in nutrition formula. Data on relevant medication and infusions, nutrition provision and glucose control will be collected to a maximum of 48 hours post randomization. Baseline patient characteristics and anthropometric measures will be recorded. A 28-day phone follow-up will explore weight and appetite changes as well as blood glucose control pre and post intensive care unit (ICU) discharge. Results Recruitment commenced in February 2015 with an estimated completion date for data collection by May 2018. Results are expected to be available late 2018. Conclusions This feasibility study of the effect of diabetes-specific formulae on the administration of insulin in critically ill patients and will inform the design of a larger, multi-center trial. Trial Registration Australian New Zealand Clinical Trial Registry (ANZCTR):12614000166673; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12614000166673 (Archived by WebCite at http://www.webcitation.org/6xs0phrVu)

Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile

Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of μ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319–27. ©2018 AACR.

Prolonged echocardiography-guided resuscitation of pulseless electrical activity cardiac arrest due to Prinzmetal angina.

A 43-year-old construction worker was transferred to the intensive care unit (ICU), having been successfully resuscitated from an out-of-hospital pulseless electrical activity (PEA) cardiac arrest. Collateral history disclosed chest discomfort during stressful events and a previous unexplained collapse. The patient arrived to ICU intubated but was able to obey simple commands. An electrocardiogram (ECG) showed no signs of cardiac ischaemia. Several hours later, while extubation was being considered, new ECG observations included ST elevation and sinus bradycardia. Subsequently, first-degree atrioventricular (AV) block deteriorated to complete AV block, then PEA (Fig. 1). Advanced life support was implemented. Transthoracic echocardiography (TTE) was performed intermittently by an attending cardiologist so as to minimise interference with chest compressions. Limited subcostal views were obtained, and conventional twodimensional grey-scale images revealed an absence of ventricular contraction. Continued resuscitation was associated with episodes of torsades de pointes then ventricular fibrillation. In addition to boluses of adrenaline (total 10 mg), atropine (total 3 mg) and an isoprenaline infusion, transvenous cardiac pacing was instituted. Defibrillation was attempted during periods of ventricular fibrillation. After approximately 40 min of continued resuscitation, TTE showed some left ventricle (LV) contractile function had returned, but still insufficient to maintain a cardiac output. This observation encouraged the authors to continue advance life support. By 60 min, there had been progressive improvement with now global hypokinesis, ejection fraction <30%. After 70 min, chest compressions were successfully discontinued because of the return of the patient’s spontaneous circulation. Urgent angiography was performed. Intracoronary glyceryl trinitrate was administered with almost complete resolution of diffuse narrowing. Only residual minor atheroma persisted, consistent with a diagnosis of coronary artery spasm (Prinzmetal variant angina).