Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19.

ECMO management of severe ARDS patients with COVID-19, who are not responding to lung protective ventilation and salvage strategies like prone positioning or inhaled nitric oxide, is safe if performed in a dedicated referral centre. https://bit.ly/3p5HOEN.

Predicting risk of intensive care unit admission after resection for non-small cell lung cancer: a validation study.

A model for predicting the risk of emergency, unplanned intensive care unit (ICU) admission after lung resection for lung cancer has been reported. However, it has not been validated outside of the derivation cohort, and the aim of our study was to undertake external validation at our institution. We reviewed a series of consecutive patients who underwent major lung resection for non-small cell lung cancer over a 6-year period. Test performance was evaluated by area under the receiver operator characteristic (ROC) curve. Between 2003 and 2008, 425 patients underwent major lung resections for lung cancer. The mean age (SD) was 65 (10) years and 241 (57%) were men. A total of 77 (18%) patients were admitted to ICU, 47 for elective admission and 30 (7%) for treatment of post-procedure complications. Of the 30 patients admitted for complications, the median length of ICU (interquartile range) stay was 3 days (1-15 days). The mortality rate among these patients was 17%. The area under the ROC curve was 0.66 (95% CI 0.53-0.79). The Brunelli scoring system had moderate discriminating ability to predict the risk of ICU admission after lung resection in our institution.

Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1).

CONTEXT: Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic. OBJECTIVE: To compare the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO. DESIGN, SETTING, AND PATIENTS: A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009-2010. The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1. Detailed demographic, physiological, and comorbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching). MAIN OUTCOME MEASURE: Survival to hospital discharge analyzed according to the intention-to-treat principle. RESULTS: Of 80 ECMO-referred patients, 69 received ECMO (86.3%) and 22 died (27.5%) prior to discharge from the hospital. From a pool of 1756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. CONCLUSION: For patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

Evaluating glycemic control algorithms by computer simulations.

BACKGROUND: Numerous guidelines and algorithms exist to achieve glycemic control. Their strengths and weaknesses are difficult to assess without head-to-head comparison in time-consuming clinical trials. We hypothesized that computer simulations may be useful. METHODS: Two open-label randomized clinical trials were replicated using computer simulations. One study compared performance of the enhanced model predictive control (eMPC) algorithm at two intensive care units in the United Kingdom and Belgium. The other study compared three glucose control algorithms-eMPC, Matias (the absolute glucose protocol), and Bath (the relative glucose change protocol)-in a single intensive care unit. Computer simulations utilized a virtual population of 56 critically ill subjects derived from routine data collected at four European surgical and medical intensive care units. RESULTS: In agreement with the first clinical study, computer simulations reproduced the main finding and discriminated between the two intensive care units in terms of the sampling interval (1.3 h vs. 1.8 h, United Kingdom vs. Belgium; P < 0.01). Other glucose control metrics were comparable between simulations and clinical results. The principal outcome of the second study was also reproduced. The eMPC demonstrated better performance compared with the Matias and Bath algorithms as assessed by the time when plasma glucose was in the target range between 4.4 and 6.1 mmol/L (65% vs. 43% vs. 42% [P < 0.001], eMPC vs. Matias vs. Bath) without increasing the risk of severe hypoglycemia. CONCLUSIONS: Computer simulations may provide resource-efficient means for preclinical evaluation of algorithms for glycemic control in the critically ill.

A modified technique for insertion of dual lumen bicaval cannulae for venovenous extracorporeal membrane oxygenation.

PURPOSE: Venovenous extracorporeal membrane oxygenation is used increasingly in adults with severe acute reversible respiratory failure. Cannulation is associated with a risk of vascular damage or cardiac perforation. METHODS AND RESULTS: This report describes a modified technique of insertion for dual lumen bicaval cannulae. We have adopted the technique on 25 occasions and had no incidence of vascular damage or cardiac perforation. CONCLUSION: We suggest that the technique may mitigate the risk of guidewire looping during insertion of the dilators/cannula and thereby reduce the risk of perforation of the right ventricle.

A case of spontaneous intestinal perforation in osteogenesis imperfecta.

UNLABELLED: A 51-year-old male with known osteogenesis imperfecta (OI) (type 1) presented with symptoms and signs of infective endocarditis. Transthoracic echocardiography showed chordal rupture and free mitral regurgitation, resulting in an emergency mitral valve repair. The surgical procedure was largely uneventful but subsequent clinical course on the intensive care unit was complicated by bowel perforation requiring two laparatomies for a colonic resection and loop ileostomy formation. Histology of the excised tissue demonstrated absent musculature with no evidence of ischemia. Spontaneous non-ischemic bowel perforation as a complication of osteogenesis imperfecta is to date unreported. Our case highlights the need for a high index of suspicion of non-ischemic bowel perforation in patients with connective tissue disorders. KEYWORDS: Osteogenesis imperfecta; Bowel perforation; Collagen; Non-ischemic; Connective tissue disorders; Pathogenesis; Collagen vascular disorder; Acute abdomen.

A quick and easy method of measuring the hypercapnic ventilatory response in patients with COPD.

BACKGROUND: Hypercapnic ventilatory response (HCVR) techniques have not previously been adequately validated in patients with chronic obstructive pulmonary disease (COPD). We have tested the hypothesis that end-tidal PCO(2) may be used to test the HCVR in COPD during non-steady-state rebreathing, despite the fact that large (arterial-end-tidal) PCO(2) differences (P(a-et)CO(2)) exist during air breathing. METHODS: Eight patients and 11 healthy volunteers underwent steady-state HCVR testing and non-steady-state rebreathing HCVR testing, using Pa and PetCO(2). RESULTS: In COPD patients, PetCO(2) was lower than PaCO(2) by a constant amount throughout steady-state HCVR, but equalised with PaCO(2) during non-steady-state HCVR. Consequently there were no differences in HCVR slope using either method (steady-state p=0.91; rebreathing p=0.73), or HCVR intercept in rebreathing (p=0.68) whether PaCO(2) or PetCO(2) was used. The steady-state HCVR intercept using PetCO(2) was greater than that using PaCO(2) (p=0.02). In healthy volunteers PetCO(2) equalised with PaCO(2) during steady-state HCVR, but was progressively greater than PaCO(2) during non-steady-state. Consequently, there was no difference in HCVR slope (p=0.21) or intercept (p=0.46) whether PaCO(2) or PetCO(2) was used. During non-steady-state there was a P(a-et)CO(2) difference in slope (p=0.03) and intercept (p=0.04). CONCLUSIONS: In COPD patients non-steady-state HCVR using PetCO(2) is well tolerated, which is as accurate as PaCO(2). HCVR slope may be derived using PetCO(2) during steady-state testing, though there may be errors in intercept compared to use of PaCO(2). In healthy volunteers PetCO(2) may be used to estimate PaCO(2) during steady-state but not rebreathing HCVR.

Intensive insulin therapy: enhanced Model Predictive Control algorithm versus standard care.

OBJECTIVE: To investigate the effectiveness of an enhanced software Model Predictive Control (eMPC) algorithm for intravenous insulin infusion, targeted at tight glucose control in critically ill patients, over 72 h, in two intensive care units with different management protocols. DESIGN: Comparison with standard care in a two center open randomized clinical trial. SETTING: Two adult intensive care units in University Hospitals. PATIENTS AND PARTICIPANTS: Thirty-four critically ill patients with hyperglycaemia (glucose >120 mg/dL) or already receiving insulin infusion. INTERVENTIONS: Patients were randomized, within each ICU, to intravenous insulin infusion advised by eMPC algorithm or the ICU's standard insulin infusion administration regimen. MEASUREMENTS AND RESULTS: Arterial glucose concentration was measured at study entry and when advised by eMPC or measured as part of standard care. Time-weighted average glucose concentrations in patients receiving eMPC advised insulin infusions were similar [104 mg/dL (5.8 mmol/L)] in both ICUs. eMPC advised glucose measurement interval was significantly different between ICUs (1.1 vs. 1.8 h, P < 0.01). The standard care insulin algorithms resulted in significantly different time-weighted average glucose concentrations between ICUs [128 vs. 99 mg/dL (7.1 vs. 5.5 mmol/L), P < 0.01]. CONCLUSIONS: In this feasibility study the eMPC algorithm provided similar, effective and safe tight glucose control over 72 h in critically ill patients in two different ICUs. Further development is required to reduce glucose sampling interval while maintaining a low risk of hypoglycaemia.

Parenteral glucose and glucose control in the critically ill: a kinetic appraisal.

BACKGROUND: We investigated the influence of parenteral glucose infusion on insulin-driven tight glucose control (4.4-6.1 mmol/liter) in the critically ill by appraising kinetic characteristics of the glucoregulatory system. METHODS: Turnover characteristics of the glucoregulatory system associated with constant 0, 1.2, and 2.4 mg/kg/min parenteral glucose infusion were obtained by literature review and mass-balance calculations. RESULTS: Without parenteral glucose infusion, the achievement of tight glucose control is hampered by long time delays with an anticipated glucose equilibration half-time (T((1/2))) of 185 min. The constant parenteral glucose infusions of 1.2 and 2.4 mg/kg/min reduce T((1/2)) to 80 and 40 min, respectively. This follows on from the accelerated glucose turnover brought about by the insulin-modulated glucose uptake, which increases in response to increasing exogenous insulin required to achieve tight glucose control. However, large variations exist among glucose turnover characteristics in the critically ill. CONCLUSIONS: The constant parenteral glucose infusion greater or equal to 2.4 mg/kg/min is expected to simplify the achievement of tight glucose control by reducing system delays and may facilitate the development of more intuitive, efficacious, and safer insulin-titration guidelines.

Glycaemic control in critically ill patients with cardiovascular disease.

PURPOSE OF REVIEW: The role of hyperglycaemia in the pathogenesis of myocardial damage during cardiac surgery or patients with acute coronary syndromes has been the subject of increasing interest over the past few years. Several further trials and meta-analyses investigating the role of insulin treatment, either aimed at tight control of blood glucose concentration or as part of a regimen including glucose and potassium, have been reported recently and are the subject of this review. RECENT FINDINGS: Good control of blood glucose has been demonstrated to improve outcomes for diabetic patients undergoing cardiac surgery and following acute myocardial infarction. In surgical intensive care patients, tight glucose control improved mortality--a finding that is awaiting confirmation in multicentre studies. The use of glucose-insulin-potassium regimens does not improve outcomes in patients with acute myocardial infarction who have undergone reperfusion therapy, but may be beneficial during cardiac surgery. SUMMARY: Tight control of blood glucose has been shown to be beneficial in several patient groups. The optimal target glucose concentration and glucose and insulin regimens remain to be confirmed or determined in each clinical situation.

Incidence, duration and causes of intensive care unit admission following pulmonary resection for malignancy.

BACKGROUND: We assessed the overall incidence and duration of ICU admission following pulmonary resection and attempted to identify patients requiring prolonged ICU stay. METHODS: Analysis of prospectively collected data on all patients undergoing pulmonary resection for suspected malignant disease that subsequently required ICU admission between March 2002 and October 2003. RESULTS: Of 170 patients 52 (30%) needed intensive care post-operatively: 21 (12%) for less than 24 h and 31 (18%) for more, for which group the average length of stay was 11.3 days. There was no significant difference between the patient groups at ICU admission in terms of median APACHE II scores (12 vs. 14), gas exchange (PaO2/FIO2, 441 vs. 364 mmHg), estimated post-operative absolute FEV1 (1.62 vs. 1.31 l) or predicted percentage FEV1 (61.8% vs. 44.3%). Mean ICU cost was 1,838 sterling pounds vs. 25,974 sterling pounds per admission, respectively. CONCLUSIONS: Following pulmonary resection some 18% of patients need a protracted ICU stay at considerable cost. Neither severity of illness scoring, indices of gas exchange at ICU admission, nor predicted post-operative FEV1 identifies such patients.

Multicentric, randomized, controlled trial to evaluate blood glucose control by the model predictive control algorithm versus routine glucose management protocols in intensive care unit patients.

OBJECTIVE: To evaluate a fully automated algorithm for the establishment of tight glycemic control in critically ill patients and to compare the results with different routine glucose management protocols of three intensive care units (ICUs) across Europe (Graz, Prague, and London). RESEARCH DESIGN AND METHODS: Sixty patients undergoing cardiac surgery (age 67 +/- 9 years, BMI 27.7 +/- 4.9 kg/m2, 17 women) with postsurgery blood glucose levels >120 mg/dl (6.7 mmol/l) were investigated in three different ICUs (20 per center). Patients were randomized to either blood glucose management (target range 80-110 mg/dl [4.4-6.1 mmol/l]) by the fully automated model predictive control (MPC) algorithm (n = 30, 10 per center) or implemented routine glucose management protocols (n = 30, 10 per center). In all patients, arterial glucose was measured hourly to describe the glucose profile until the end of the ICU stay but for a maximum period of 48 h. RESULTS: Compared with routine protocols, MPC treatment resulted in a significantly higher percentage of time within the target glycemic range (% median [min-max]: 52 [17-92] vs. 19 [0-71]) over 0-24 h (P < 0.01). Improved glycemic control with MPC treatment was confirmed in patients remaining in the ICU for 48 h (0-24 h: 50 [17-71] vs. 21 [4-67], P < 0.05, and 24-48 h: 65 [38-96] vs. 25 [8-79], P < 0.05, for MPC [n = 16] vs. routine protocol [n = 13], respectively). Two hypoglycemic events (<54 mg/dl [3.0 mmol/l]) were observed with routine protocol treatment. No hypoglycemic event occurred with MPC. CONCLUSIONS: The data suggest that the MPC algorithm is safe and effective in controlling glycemia in critically ill postsurgery patients.

Ventilation is unstable during drowsiness before sleep onset.

Ventilation is unstable during drowsiness before sleep onset. We have studied the effects of transitory changes in cerebral state during drowsiness on breath duration and lung volume in eight healthy subjects in the absence of changes in airway resistance and fluctuations of ventilation and CO2 tension, characteristic of the onset of non-rapid eye movement sleep. A volume-cycled ventilator in the assist control mode was used to maintain CO2 tension close to that when awake. Changes in cerebral state were determined by the EEG on a breath-by-breath basis and classified as alpha or theta breaths. Breath duration and the pause in gas flow between the end of expiratory airflow and the next breath were computed for two alpha breaths which preceded a theta breath and for the theta breath itself. The group mean (SD) results for this alpha-to-theta transition was associated with a prolongation in breath duration from 5.2 (SD 1.3) to 13.0 s (SD 2.1) and expiratory pause from 0.7 (SD 0.4) to 7.5 s (SD 2.2). Because the changes in arterial CO2 tension (PaCO2) are unknown during the theta breaths, we made in two subjects a continuous record of PaCO2 in the radial artery. PaCO2 remained constant from the alpha breaths through to the expiratory period of the theta breath by which time the duration of breath was already prolonged, representing an immediate and altered ventilatory response to the prevailing PaCO2. In the eight subjects, the CO2 tension awake was 39.6 Torr (SD 2.3) and on assisted ventilation 38.0 Torr (1.4). We conclude that the ventilatory instability recorded in the present experiments is due to the apneic threshold for CO2 being at or just below that when awake.

Depression of diaphragm contractility by nitrous oxide in humans.

UNLABELLED: Nitrous oxide is widely used in anesthesia and critical care medicine. The effect of nitrous oxide on diaphragm contractility in humans is unknown. We evaluated the effect of a 50% nitrous oxide-50% oxygen mixture on diaphragm contractility in healthy adult volunteers. The sniff transdiaphragmatic pressure (Sn Pdi) and the twitch transdiaphragmatic pressure (Tw Pdi) elicited by bilateral supramaximal phrenic nerve stimulation were measured before during and after inhalation of a mixture of 50% nitrous oxide and 50% oxygen. Sn Pdi decreased by 15.4% during nitrous oxide inhalation, with a value of 136 +/- 21 cm H(2)O before nitrous oxide and a value of 115 +/- 27 cm H(2)O during nitrous oxide inhalation (P = 0.03). Similarly, Tw Pdi decreased from 21.2 +/- 1.8 cm H(2)O before nitrous oxide inhalation to 16.9 +/- 4.1 cm H(2)O during nitrous oxide inhalation (P = 0.03). The effect of nitrous oxide was totally abolished 20 min after its discontinuation. Nitrous oxide has a short-acting suppressant effect on the pressure generating capacity of the diaphragm in healthy humans. IMPLICATIONS: We investigated whether nitrous oxide (a common component of gas anesthesia) reduces diaphragm strength in humans. Diaphragm strength is reduced by nitrous oxide but the effect wears off within 20 min of administration. Caution is advised when using nitrous oxide without anesthesiologist supervision in patients at risk of ventilatory failure