COVID-19 Drug Treatments Are Prone to Sequestration in Extracorporeal Membrane Oxygenation Circuits: An Ex Vivo Extracorporeal Membrane Oxygenation Study.

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO.

Delayed Tracheoesophageal Fistula and Refractory Respiratory Failure Caused by Inhalation Burns and Emergency Venovenous ECMO to Facilitate Its Management: A Case Report.

Acquired tracheoesophageal fistulae are uncommon in burn patients but can occur as a complication of inhalation injury. We report a case of a 30-yr-old male patient presenting after suffering from inhalation and 25% total body surface area burns. On postburns day 14, he developed a massive tracheoesophageal fistula causing refractory acute respiratory failure. Veno-venous extracorporeal membrane (VV ECMO) oxygenation was initiated without systemic anticoagulation via bi-femoral cannulation under transthoracic echocardiography guidance. He underwent successful 5-hr apnoeic ventilation-assisted surgical repair of the fistula via a right posterolateral thoracotomy. ECMO was discontinued after 36 hr, and he was discharged to the ward after 33 d in the intensive care unit. Inhalation burn injury can cause a delayed life-threatening tracheoesophageal fistula. Surgical repair can be successfully performed for this condition. VV- ECMO can be used to facilitate prolonged apnoeic surgery and to manage refractory respiratory failure due to this condition.

Determinants of research productivity during postgraduate medical education: a structured review.

BACKGROUND: Although formal participation in research is an integral and often mandatory component of clinical training programs, resulting productivity is highly variable. The objective of this review was to identify determinants of successful research performance among graduate medical education trainees. METHODS: A structured review of the published literature was performed by searching PubMed, CINAHL, and EMBASE from inception through to 7 April, 2021. Articles examining graduate medical education trainee research productivity evidenced by publications in peer-reviewed journals were included. RESULTS: Eighty-five articles were included of which most (66; 78%) were reported from the USA or Canada (10; 12%). A wide range of disciplines were represented with the most common being general surgery, internal medicine, orthopedic surgery, and pediatrics. Themes (number of reports) included trainee characteristics (n = 24), project characteristics (n = 8), mentoring/supervision (n = 11), and programmatic aspects (n = 57). Although variable results were observed, research productivity tended to be higher with prior research experience, later years of training, male gender, and pursuit of a postgraduate degree. Few project related aspects of success were identified. Trainee publication was associated with mentors with higher rank, publication productivity, and supportive academic environments. Training programs with organised programs/curricula including protection of time for research were associated with increased productivity as were provision of incentives or rewards but not mandatory requirements. CONCLUSION: This review identifies several trainee characteristics, project and mentor aspects, and programmatic aspects associated with increased productivity that may serve as a useful resource for trainees and graduate medical education training programs.

Octreotide for resuscitation of cardiac arrest due to carcinoid crisis precipitated by novel peptide receptor radionuclide therapy (PRRT): A case report.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic carcinoid tumours but can precipitate a carcinoid crisis through release of stored bioamines. Cardiac arrest is an uncommon manifestation of carcinoid crisis and has never been reported as a complication of PRRT. We report a case of a 58-year old female who suffered from cardiac arrest following PRRT for metastatic carcinoid tumour. She was successfully resuscitated using intravenous octreotide following 22 min of failure to resuscitate with a standard advanced cardiac life support protocol. Following resuscitation, severe carcinoid heart disease was diagnosed, and the patient subsequently underwent successful surgical valve replacement. Although there is no trial evidence, considering pharmacological rationale and successful outcome in this case, we suggest early administration of intravenous octreotide during resuscitation of patients suffering cardiac arrest post PRRT for carcinoid disease and recommend preventive strategies.

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report.

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.

Short- and long-term outcomes of neutropenic cancer patients in intensive care according to requirement for invasive ventilation.

BACKGROUND: Neutropenic fever is a frequently encountered complication when caring for cancer patients and can lead to intensive care admission, with high mortality rates in those patients who require invasive mechanical ventilation (IMV). Although hospital survival in this population has improved, long-term outcomes of critically ill neutropenic cancer patients have not been well defined. AIMS: To evaluate short- and long-term outcomes of neutropenic cancer patients admitted to intensive care, according to requirement for invasive ventilation. Additionally, we aimed to determine predictors of poor clinical outcomes in this group. METHODS: A retrospective cohort study of neutropenic cancer patients admitted to our intensive care unit (ICU) from 2008 to 2016. RESULTS: We included 192 cancer patients of whom 100 (52.1%) required IMV. Overall ICU mortality was 29.7% and 12-month post-ICU mortality was 61.5%. Patients requiring IMV had significantly higher short- and long-term mortality (P < 0.001). Multivariate analysis determined three variables to be predictors of mortality at ICU discharge in the whole cohort: IMV (OR 13.52), renal replacement therapy (RRT, OR 2.37) and higher APACHE II scores (OR 1.1 for each unit increase). These variables were identical in the subgroup requiring invasive ventilation, with RRT (OR 2.76) and APACHE II scores (OR 1.1 for each unit increase) predicting short-term mortality. CONCLUSION: Neutropenic cancer patients admitted to ICU have lower short-term mortality than previously reported in cohort studies, however their mortality rises significantly following discharge from ICU. Those patients who require IMV are at significantly increased risk of both short- and long-term mortality.

A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models.

BACKGROUND: Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. METHODS: In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg with planar nuclear medicine imaging was used in a mechanically ventilated ovine model. To measure tobramycin concentrations by intravenous and nebulised tobramycin 400 mg (4 ml, 100 mg/ml) administration in the lung interstitial space (ISF) fluid and blood of mechanically ventilated sheep, the microdialysis technique was used over an 8-h duration. RESULTS: Tobramycin 100 mg/ml achieved a higher lung dose (121.3 mg) compared to 40 mg/ml (41.3 mg) solution. The imaging study with labelled tobramycin indicated that nebulised tobramycin distributed more extensively into each lung zone of the mechanically ventilated sheep than intravenous administration. A higher lung ISF peak concentration of tobramycin was observed with nebulised tobramycin (40.8 mg/l) compared to intravenous route (19.0 mg/l). CONCLUSIONS: The research methods appear promising to describe lung pharmacokinetics for formulations intended for nebulisation during mechanical ventilation. These methods need further validation in an experimental pneumonia model to be able to contribute toward optimising dosing regimens to inform clinical trials and/or clinical use.

Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients. METHODS: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded. RESULTS: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens. CONCLUSIONS: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.

Effect of preoperative renal function on long-term survival after cardiac surgery.

OBJECTIVES: The study objective was to investigate the effect of renal failure on intermediate-term survival in cardiac surgery patients. METHODS: All patients aged 18 years or older undergoing coronary artery bypass grafting, valvular surgery, thoracic aortic surgery, or a combination of these from January 1, 2002 to December 1, 2005 were included. Data were obtained from the cardiac surgery and intensive care databases. Using a matching algorithm, the date of death was obtained from the National Death Index. The simplified Medical Diet for Renal Disease formula was used to calculate the estimated glomerular filtration rate, and the patients were stratified accordingly. An estimation of the effect of the preoperative renal function on the interval to death was determined using Cox regression analysis with and without cubic splines and polynomial regression. The long-term survival was described using the Kaplan-Meier product limit method. RESULTS: A total of 5297 patients were included in the present study. The vital status of all patients was obtained at a mean of 2.9 years (range, 1-5) postoperatively. The actuarial 1-year survival rate was 96% ± 1%, and the 3-year survival rate was 92% ± 1%. The greatest early mortality occurred in the severe renal dysfunction group; however, the dialysis-dependent renal failure group showed increased mortality over time compared with the other groups. The lowest risk of death (longest interval to death) occurred with an estimated glomerular filtration rate of approximately 90 mL/min/1.73 m(2). CONCLUSIONS: The results of our study have shown that preoperative renal dysfunction is an independent predictor of long-term mortality in cardiac surgery patients.