Comparison of the onset and offset times of two available formulations of rocuronium bromide in an animal model.

Rocuronium bromide is a neuromuscular blocker in widespread use in anaesthesia, emergency and intensive care. Reports of reduced efficacy of a new different formulation of rocuronium bromide were submitted to Medsafe, the New Zealand Medicines and Medical Devices Safety Authority, in 2020. Given the requirement for rapid and predictable paralysis for patient safety the efficacy of the two available formulations of rocuronium bromide was investigated in an animal model. After ethics committee approval, 19 rats were anaesthetised and paralysis, defined as loss of tibialis anterior flexion on direct electrical stimulation of the sciatic nerve, was assessed by mechanomyography in response to ED90 doses of rocuronium.Paralysis was observed at a median of 12 seconds for the new different formulation: A, Hameln Pharma (interquartile range (IQR) 6-106 seconds) and 28 seconds for formulation B: Pfizer (IQR 12-68 seconds) P = 0.48. Offset of paralysis was observed after 293 seconds for formulation A (IQR 250-372 seconds) and 241 seconds for formulation B (IQR 220-263 seconds). While the differences observed were substantial, they were not statistically significant. Moreover, the direction of observed difference was towards a shorter median onset and longer offset for the newer formulation, a finding in the opposite direction to the initial clinical concern.Relevance to the clinical situation is indeterminate given the study was stopped at low numbers for futility and limitations around the clinical applicability of animal pharmacokinetics and dynamics. Nevertheless our findings provide some reassurance that the newly available different formulation of this critical use medication does not exhibit a substantial increase in time to onset.

Premorbid beta blockade in sepsis is associated with a lower risk of a lactate concentration above the lactate threshold, a retrospective cohort study.

Sepsis and septic shock represent a significant worldwide mortality burden. A lactate greater than 4 mmol/L is associated with increased mortality in septic patients. This is the concentration at the "lactate threshold" where serum lactate concentrations rise markedly with increased workload in exercise. Hyperlactatemia in both sepsis and exercise is contributed to by adrenergic agonism which stimulates aerobic glycolysis, increasing lactate production and decreasing lactate clearance. Our hypothesis is that in patients with sepsis, treatment with beta blockers in the community will be associated with a lower probability of initial lactate ≥ 4 mmol/L. This was single centre retrospective cohort study. We used an in-house SQL Database for all admissions to ICU/HDU for the 2017-2020 calendar years. The dataset was filtered for an APACHE III Diagnosis of sepsis. T-tests were used for continuous data, Chi squared and Fisher's exact test were used as appropriate to compare proportions. Logistic regression was used to investigate covariate effects. Of the 160 patient records analysed, 49 were prescribed beta blockers. A greater proportion of patients not prescribed beta blockers in the community had a first lactate ≥ 4 mmol/L (p = 0.049). This was robust to regression analysis. There was no difference in the proportion of patients with lactate ≥ 2 mmol/L (p = 0.52). In our cohort patients previously prescribed beta blockers were less likely to have a lactate of ≥ 4 mmol/mL. This supports the proposed mechanism that treatment with beta blockers increases the lactate threshold in sepsis. Further study is warranted.

pH Gradient Liposomes Extract Protein Bound Amitriptyline in Peritoneal Dialysis-Exploratory Work.

Poisoning is a significant cause of injury-related death worldwide. Dialysis is usually ineffective in removing the toxin once it has been absorbed because of drug protein binding and high volumes of distribution. In this work, we explore whether the addition of liposomes to peritoneal dialysate could extract protein bound amitriptyline. Liposomes were prepared using the thin film hydration method. In the in vitro experiment, 3 mL of 20% albumin with a concentration of 6000 nmol/L amitriptyline in a proprietary dialysis cartridge was dialysed against 125 mL of phosphate-buffered saline with and without 80 mg 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) liposomes. In the in vivo arm, peritoneal dialysis was undertaken in 6 rats with pH gradient liposome augmented dialysate after intravenous amitriptyline injection. Peritoneal blood flow was estimated by CO2 extraction. Total amitriptyline extracted was compared to freely dissolved (non-protein bound) and total amitriptyline perfusing the membrane during the peritoneal dwell. Mean liposome size for DOPG and acidic centre pH gradient liposomes was 119 nm and 430 nm, respectively. In the in vitro experiment, more amitriptyline was extracted into the liposome containing dialysate than the control dialysate (40 +/- 2 nmol/L vs. 27 +/- 1 nmol/L). In the in vivo experiment, the total amitriptyline in dialysate was 5240 +/- 2750 nmol. Mean total free amitriptyline perfusing the peritoneal membrane was 93 +/- 46 nmol. Mean total blood amitriptyline perfusing the peritoneal membrane was 23,920 +/- 6920 nmol. Two of the six animals were excluded due to overestimation of peritoneal blood flow. This exploratory work suggests the addition of liposome nanoparticles to peritoneal dialysate extracted protein bound amitriptyline from blood.

Trending peripheral venous PCO2 in patients with respiratory failure using mathematically arterialised venous blood gas samples.

BACKGROUND: Trending venous blood gases (VBGs) has been suggested as an alternative to arterial blood gases (ABGs) in patients with respiratory failure, but there are limits to its utility. The aim of this study was to compare the trending of venous carbon dioxide partial pressure (pCO2) (pCO2v) with mathematically arterialised pCO2 (pCO2ca) and to further evaluate whether pCO2ca follows change in arterial pCO2 (pCO2a) more accurately. METHODS: We analysed two data sets. The first was a retrospective study of patients with respiratory failure admitted to the intensive care unit. Venous samples were mathematically arterialised using the vTAC method. The change in pCO2 between two consecutive samples (ΔpCO2) for pCO2v was compared with the change in calculated pCO2ca values. In the second data set taken from previously published work, we analysed 82 trend points (difference between consecutive samples) for change in pCO2. There were pCO2v, pCO2a and pCO2ca values for each trend point. The primary outcome measures were the 95% limits of agreement (LOAs) between different sampling methods for ΔpCO2. RESULTS: In the first data set, 46 patients had 203 VBG results giving 157 trend points for ΔpCO2 analysis. The 95% LOAs for ΔpCO2ca and ΔpCO2v were -9.28 to 11.12 mm Hg.In the second data set, 95% LOAs for ΔpCO2 were -9.46 to 9.48 mm Hg for ΔpCO2a and ΔpCO2v, -8.94 to 8.58 mm Hg for ΔpCO2ca and ΔpCO2v, and -4.54 to 4.91 mm Hg for ΔpCO2a and ΔpCO2ca. CONCLUSION: This study suggests that trending pCO2v is not an accurate way to trend pCO2a in patients with respiratory failure. ΔpCO2ca via vTAC trended differently to ΔpCO2v. Our data suggest pCO2ca more accurately trends pCO2a.

Liposomes to Augment Dialysis in Preclinical Models: A Structured Review.

In recent years, a number of groups have been investigating the use of "empty" liposomes with no drug loaded as scavengers both for exogenous intoxicants and endogenous toxic molecules. Preclinical trials have demonstrated that repurposing liposomes to sequester such compounds may prove clinically useful. The use of such "empty" liposomes in the dialysate during dialysis avoids recognition by complement surveillance, allowing high doses of liposomes to be used. The "reach" of dialysis may also be increased to molecules that are not traditionally dialysable. We aim to review the current literature in this area with the aims of increasing awareness and informing further research. A structured literature search identified thirteen papers which met the inclusion criteria. Augmenting the extraction of ammonia in hepatic failure with pH-gradient liposomes with acidic centres in peritoneal dialysis is the most studied area, with work progressing toward phase one trials. Liposomes used to augment the removal of exogenous intoxicants and protein-bound uraemic and hepatic toxins that accumulate in these organ failures and liposome-supported enzymatic dialysis have also been studied. It is conceivable that liposomes will be repurposed from the role of pharmaceutical vectors to gain further indications as clinically useful nanomedical antidotes/treatments within the next decade.

How Much PEEP Does High Flow Deliver via Tracheostomy? A Literature Review and Benchtop Experiment.

BACKGROUND: High flow tracheostomy (HFT) is a commonly used weaning and humidification strategy for tracheostomised patients, but little is known as to how much PEEP or mechanical benefit it offers. Patient anatomy and device characteristics differentiate it from high flow nasal cannula and the physiological effects observed. OBJECTIVES: (1) To review the available literature on the effects of HFT on airway pressure and indices of gas exchange. (2) To quantify PEEP generated by a HFT circuit. METHODS: A randomised benchtop experiment was conducted, with a size 8 uncuffed Portex tracheostomy connected to an Optiflow™ with Airvo 2™ humidifier system. The tracheostomy tube was partially immersed in water to give rise to a column of water within the inner surface of the tube. An air fluid interface was generated with flows of 40 L/min, 50 L/min, and 60 L/min. The amount of potential PEEP (pPEEP) generated was determined by the distance the water column was pushed downward by the flow delivered. Findings. Overall 40 L/min, 50 L/min, and 60 L/min provided pPEEP of approximately 0.3 cmH2O, 0.5 cmH2O, and 0.9 cmH2O, respectively. There was a statistically significant change in pPEEP with change in flows from 40-60 L/min with an average change in pPEEP of 0.25-0.35 cmH2O per 10 L/min flow (p value <0.01). Interpretation. HFT can generate measurable and variable PEEP despite the open system used. The pPEEP generated with HFT is minimal despite statistically significant change with increasing flows. This pPEEP is unlikely to provide mechanical benefit in weaning patients off ventilatory support.

Is lactate lower in septic patients who are prescribed beta blockers? Retrospective cohort study of an intensive care population.

OBJECTIVE: Elevated serum lactate has long been considered an important marker of sepsis severity. Increasing evidence supports catecholamine-stimulated aerobic glycolysis being a major contributor to the hyperlactataemia seen in sepsis. Beta-blockade may blunt such catecholamine mediated rise in lactate analogous to the way it can mask tachycardia. This could impact the way we evaluate sepsis severity and adequacy of initial treatment. The objective of this study is to investigate whether septic patients who were on beta-blocker treatment at presentation have lower serum lactate level. METHODS: Using a retrospective cohort design we gathered data on patients admitted to our base hospital intensive care unit with APACHE III diagnosis of sepsis and septic shock during the 2017 calendar year. Serum lactate, current medications, presenting vital signs, illness severity scores, laboratory data and mortality outcome were extracted from patients' medical record and the unit's clinical database. RESULTS: Of 189 records analysed, 49 patients were concurrently prescribed beta-blockers. More beta-blocked patients were male, beta-blocked patients were older, and a greater proportion of beta blocked patients had their first lactate measured as an inpatient. After regression to correct for identified significant covariates mean serum lactate was 0.87 (95% confidence interval 0.05-1.69) mmol/L lower in those prescribed beta blockers. CONCLUSIONS: In our cohort pre-existing beta blocker treatment was associated with lower serum lactate measurements in patients presenting with sepsis. Pre-existing beta blocker treatment may reduce serum lactate at presentation in patients with sepsis.

Liposome supported peritoneal dialysis in rat amitriptyline exposure with and without intravenous lipid emulsion.

Liposome supported peritoneal dialysis is a recently described technique which may eventually be applicable in the clinical scenario of the intoxicated patient. We evaluated the hypothesis that intravenous injection of lipid emulsion (ILE) would augment acidic pH gradient liposome supported peritoneal dialysis (LSPD). Orogastrically amitriptyline dosed rats were treated with either Sodium bicarbonate (NaHCO3) intravenously and standard intraperitoneal dialysate (Group A); NaHCO3 intravenously and LSPD (Group B); or ILE and LSPD (Group C). The primary endpoint was dialysate amitriptyline concentration after a 60 min dwell. Secondary analysis included an estimate of extraction ratio for peritoneal blood flow (ERs). There were significantly higher intraperitoneal concentrations of amitriptyline and ERs in the two groups treated with LSPD (Group B, p = 0.02, Group C, p < 0.01 vs. Group A). There was no observed effect for ILE on intraperitoneal amitriptyline concentration or ERs (p > 0.20). LSPD increased the amitriptyline concentration in peritoneal dialysate. No further increase was demonstrated with ILE. This may be either because such an effect is absent, or type II error. Exploratory analysis suggests LSPD may be driven by total rather than free drug concentrations.

Magnetic extraction of toxin binding liposomes; a method to ameliorate drug toxicity? Preliminary in vitro/ in vivo study.

AIM: Removal of a toxin from the body once absorbed is usually not possible. We describe the use of magnetite containing pH gradient 'MagnepH' liposomes to overcome limitations preventing removal. METHODS: MagnepH liposomes were added to albumin solution containing amitriptyline and dosed intravenously in rats prior to amitriptyline injection. Albumin solution or drawn blood was exposed to a magnet and sampled. RESULTS: One third of amitriptyline was extracted in vitro. In vivo amitriptyline concentrations were 1830 nmol/l (controls) and 10870 nmol/l (MagnepH; n = 2). Amitriptyline extraction increased from 0.6% (control) to 10.4% (MagnepH; 95% CI for difference 2.0-17.6%). CONCLUSION: MagnepH liposomes sequestered amitriptyline and could then be extracted. This method has potential to ameliorate limitations to extracorporeal removal of toxins in poisoning.

Lipid emulsion in local anesthetic toxicity.

PURPOSE OF REVIEW: Enthusiasm for regional anesthesia has been driven by multimodal benefits to patient outcomes. Despite widespread awareness and improved techniques (including the increasing use of ultrasound guidance for block placement), intravascular sequestration and the attendant risk of local anesthetic systemic toxicity (LAST) remains. Intravenous lipid emulsion (ILE) for the treatment of LAST has been endorsed by anesthetic regulatory societies on the basis of animal study and human case report data. The accumulated mass of reporting now permits objective interrogation of published literature. RECENT FINDINGS: Although incompletely elucidated the mechanism of action for ILE in LAST seemingly involves beneficial effects on initial drug distribution (i.e., pharmacokinetic effects) and positive cardiotonic and vasoactive effects (i.e., pharmacokinetic effects) acting in concert. Recent systematic review by collaborating international toxicologic societies have provided reserved endorsement for ILE in bupivacaine-induced toxicity, weak support for ILE use in toxicity from other local anesthetics, and largely neutral recommendation for all other drug poisonings. Work since publication of these recommendations has concluded that there is a positive effect on survival for ILE when animal models of LAST are meta-analyzed and evidence of a positive pharmacokinetic effect for lipid in human models of LAST. SUMMARY: Lipid emulsion remains first-line therapy (in conjunction with standard resuscitative measures) in LAST. Increasing conjecture as to the clinical efficacy of ILE in LAST, however, calls for high-quality human data to refine clinical recommendations.

Reversal of lipophilic weak bases using pH gradient acidic centre liposomes: demonstration of effect in dabigatran-induced anticoagulation.

INTRODUCTION: Liposomes have recently emerged as rational vehicles for drug detoxification. Modification of the core pH may further enhance the ability of liposomes to sequester lipophilic toxins that are weak bases. Dabigatran, a reversible inhibitor of thrombin, has been widely promoted as a novel oral anticoagulant. As a lipophilic weak-base, it provides a rational target for reversal with acidic-centred liposomal preparations. The present study tests the hypothesis that acidic centre liposomes will reverse dabigatran induced anticoagulation. METHOD: Following enteric dabigatran dosing in vitro assessment of thrombin clotting times (TCT) was undertaken in rabbit plasma spiked with incremental liposome concentrations. Tail vein bleeding was assessed following intravenous liposome injection in rats after enteric dabigatran administration. RESULTS: Liposomes achieved reversal of TCT to baseline at low levels of thrombin inhibition, and partial reversal of TCT at higher levels. Liposomes completely reversed the effects of dabigatran on rat tail vein bleeding time (134.0 (6.7) s liposomes vs. 410 (37.8) s control; p < 0.01). CONCLUSION: Dabigatran-induced coagulopathy was reversed in vitro and in vivo by acidic-centred liposomes. pH-modified liposomes are a promising investigational entity in the antidotal treatment of pharmacologic weak bases that are lipid soluble at physiologic pH.

Co-administration of phospholipid emulsion with first dose bacteriocidal antibiotic may retard progression of the sepsis response in gram negative septicaemia.

Endotoxic lipopolysaccharide (LPS) is a major constituent of the outer membrane of the gram-negative bacillus, and its' release a potent pro-inflammatory stimulus. Unchecked the cytokine cascades unleashed by blood borne LPS leads to clinical manifestations of severe sepsis and septic shock. Experimentally exogenous administration of cell-wall specific bacteriocidal drugs are known to precipitate endotoxin release and contribute to development of the sepsis syndrome. Mitigation of the inflammatory septic response with intravenous infusion of phospholipid emulsion has been demonstrated in vivo, with phospholipid credited with binding and neutralizing circulating endotoxin. We therefore propose co-administration of phospholipid emulsion preparations in conjunction with potent cell wall specific antibacterial agents in gram-negative sepsis - hypothesizing that released LPS may be immediately sequestered by phospholipid thereby blunting the severity of the developing septic response.

LIPAEMIC report: results of clinical use of intravenous lipid emulsion in drug toxicity reported to an online lipid registry.

The use of intravenous lipid emulsion (ILE) as an antidote has prompted significant academic and clinical interest. Between August 2009 and August 2012, data from cases of ILE use in intoxicated patients in different hospitals on different continents were voluntarily entered into a registry based on the world wide web (www.lipidregistry.org). Here, we report data from this project. Participating centers were given access to the registry following institutional subscription. Specifically sought were details of the individual patients' presenting condition, indications for ILE use, ILE administration regimen, potential complications, and of clinical outcome. Forty-eight uses of ILE were reported from 61 participating centers. Ten cases of local anesthetic systemic toxicity were reported; all (10/10) survived. Thirty-eight cases of intoxication by other agents were reported [30 decreased conscious state, 8 cardiovascular collapse (3 deaths)]. There was an elevation in GCS (p < 0.0001) and increased systolic blood pressure (p = 0.012) from immediately prior to ILE administration to 30 min after use. One serious and two minor adverse effects of ILE use were recorded in 48 reported cases (one case of bronchospastic reaction, one case of hyperamylasemia and one case of interference with laboratory testing). In this series of cases reported to the registry, improvements were seen for GCS in patients with central nervous system toxicity and in systolic blood pressure in shocked patients over a short time frame after the injection of ILE. Few adverse effects were recorded. Clinical trials and the reporting of drug concentrations after ILE use are necessary to further elucidate the role of ILE in clinical toxicology.

Should we consider the infusion of lipid emulsion in the resuscitation of poisoned patients?

The use of intravenous lipid emulsions (ILEs) as antidote in local anaesthetic systemic toxicity has gained widespread support following convincing data from animal models, and successful case reports in humans. Proposed beneficial mechanisms of action for ILEs include intravascular sequestration of intoxicant and subsequent enhanced redistribution to biologically inert tissues, augmentation of fatty acid utilisation for ATP synthesis in the context of metabolic poisoning, and direct cardiotonic and ion channel effects. The evidence base for use of ILEs in acute drug intoxication is evolving. The present evidence supports use of ILEs only in local anaesthetic systemic toxicity and in lipophilic cardiotoxin intoxication when there is an immediate threat to life, and other therapies have proven ineffective.

Comparison of intravenous lipid emulsion, bicarbonate, and tailored liposomes in rabbit clomipramine toxicity.

OBJECTIVES: Liposome (LIP)-like lipid dispersions have emerged as useful detoxification vehicles in vitro. The authors compare resuscitation with tailored LIPs, 20% intravenous lipid emulsion (ILE), and sodium bicarbonate (BIC), in a rabbit model of clomipramine toxicity. METHODS: Sedated, instrumented New Zealand white rabbits underwent clomipramine infusion at 3.2 mg/kg/min to 50% baseline mean arterial pressure (MAP) and then at 1.6 mg/kg/min for 30 minutes. BIC (3 mL/kg 8.4%), ILE (3 mL/kg 20%), or LIP (24 mg/kg) were infused as rescue treatments at toxicity and were repeated at 10 minutes (n = 5 in each group). RESULTS: Thirty-minute MAP was greatest in ILE-treated animals: 61 mm Hg ILE (interquartile range [IQR] = 49 to 64 mm Hg), 43 mm Hg LIP (IQR = 36.5 to 49 mm Hg), and 10 mm Hg BIC (IQR = 10 to 44 mm Hg; all p = 0.02). Two of the five BIC-treated animals survived to 30 minutes, compared with all five of the ILE-treated animals and all five of the LIP-treated animals (p = 0.044). CONCLUSIONS: Both ILE and LIPs improved hemodynamic recovery compared with bicarbonate in clomipramine-induced cardiotoxicity in rabbits. Greater 30-minute MAP was observed in the ILE group.

Octreotide may attenuate absorption and ameliorate toxicity following enteric drug overdose.

Drug overdose remains a common reason for Emergency Department presentation. Despite aggressive supportive care, and targeted antidotal therapy, deaths from intoxication still occur. For orally ingested toxins, absorption from the gastrointestinal tract is required before clinical evidence of toxin ingestion become manifest. Herein we postulate that octreotide, a synthetic analogue of naturally occurring somatostatin, may retard toxidrome development through an effect on reducing intestinal toxin absorption. Octreotide may therefore represent a useful adjunct to management of enteric self-poisoning.