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Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.
Dixon, B, Smith, RJ, Campbell, DJ, Moran, JL, Doig, GS, Rechnitzer, T, MacIsaac, CM, Simpson, N, van Haren, FMP, Ghosh, AN, et al
The Lancet. Respiratory medicine. 2021;(4):360-372
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Abstract
BACKGROUND Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.
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TICACOS international: A multi-center, randomized, prospective controlled study comparing tight calorie control versus Liberal calorie administration study.
Singer, P, De Waele, E, Sanchez, C, Ruiz Santana, S, Montejo, JC, Laterre, PF, Soroksky, A, Moscovici, E, Kagan, I
Clinical nutrition (Edinburgh, Scotland). 2021;(2):380-387
Abstract
UNLABELLED Since the first TICACOS study, 3 additional studies have been published comparing a medical nutrition therapy guided by indirect calorimetry to a regimen prescribed on the basis of predictive equations. A recent guidelines document included a meta-analysis including these 4 papers and found a trend for improvement (OR 0.98-1.48) in favor of medical nutrition therapy guided by indirect calorimetry in terms of survival. The aim of our study was to perform a multicenter prospective, randomized, controlled non blinded study in critically patients to assess the added value for measuring daily resting energy expenditure as a guide for nutritional support. The primary objective was to decrease infectious rate of these critically ill patients. MATERIAL AND METHODS This phase III, multi-center, randomized, controlled non blinded study was planned to include 580 newly-admitted, adult ventilated ICU patients that were planned to stay more than 48 h in the ICU departments. The nutritional support was aimed to meet 80-100% of energy requirement measured by indirect calorimetry. The calorie needs were determined by IC in the Study group and by an equation (20-25 kcal/kg ideal body weight/day) in the Control Group. The ICU staff was trained to strive to supply 80-100% of a patient's energy requirements through artificial nutrition, preferably enteral feeding. Primary endpoint was infection rate and secondary endpoints included other morbidities and mortality during ICU, at 90 and 180 days. Comparison between the study and the control group was performed using T test for equality of means (independent samples test). Correlations were performed using the Pearson correlation test. A p level of 0.05 or below was considered as significant. Cross tabs procedure used Chi-square test for testing differences in complication rates, length of stay and length of ventilation. Correlations between energy balances and complications was also be tested using one way analysis as well as ANOVA analysis between groups and within groups. Kaplan Meir curves assessed the proportion of surviving patients in the 2 groups. RESULTS Seven centers with a calorimeter available participated to the study. Due to slow inclusion rate, the study was stopped after 6 years and after inclusion of 417 patients only. From the 417 intended to treat patients, 339 followed the protocol. There was no differences between control and study groups in terms of age, sex BMI, SOFA (7.1 ± 3.1 vs 7.4 ± 3.3) and APACHE II scores (22.4 ± 7.9 vs 22.2 ± 7.4). The rate of infection (40 vs 31), including pneumonia rate, need for surgery, dialysis requirement, length of ventilation, ICU length of stay, and hospital length of stay were not different between groups. Mortality (30 in the control vs 21 in the study group) was not significantly different between groups. The decreased mortality observed in the study group when added to previous studies may have a positive effect on the meta-analysis previously published. CONCLUSION Tight Calorie Control guided by indirect calorimetry decreased the rate of infection and mortality but not significantly. This may be explained by the not relatively small sample size. There results together with the previous 4 prospective randomized studies, may improve the results of the meta-analysis exploring the effects of IC guided nutrition on mortality.
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Role of heat shock protein and cytokine expression as markers of clinical outcomes with glutamine-supplemented parenteral nutrition in surgical ICU patients.
Wischmeyer, PE, Mintz-Cole, RA, Baird, CH, Easley, KA, May, AK, Sax, HC, Kudsk, KA, Hao, L, Tran, PH, Jones, DP, et al
Clinical nutrition (Edinburgh, Scotland). 2020;(2):563-573
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BACKGROUND Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. OBJECTIVE Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. METHODS Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. RESULTS eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. CONCLUSION Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70.
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Feasibility of Blood Glucose Management Using Intra-Arterial Glucose Monitoring in Combination with an Automated Insulin Titration Algorithm in Critically Ill Patients.
Mader, JK, Motschnig, M, Theiler-Schwetz, V, Eibel-Reisz, K, Reisinger, AC, Lackner, B, Augustin, T, Eller, P, Mirth, C
Diabetes technology & therapeutics. 2019;(10):581-588
Abstract
Background: This two-center pilot study combined for the first time an intra-arterial glucose sensor with a decision support system for insulin dosing (SGCplus system) in critically ill patients with hyperglycemia. Methods: Twenty-two patients who were equipped with an arterial line and required iv insulin therapy were managed by the SGCplus system during their medical treatment at the intensive care unit. Results: Time to target was 111 ± 195 min (80-150 mg/dL) and 135 ± 267 min (100-160 mg/dL) in the lower and higher glucose target group. Mean blood glucose (BG) was 142 ± 32 mg/dL with seven BG values <70 mg/dL. Mean daily insulin dose was 62 ± 38 U and mean daily carbohydrate intake 148 ± 50 g/day (enteral nutrition) and 102 ± 58 g/day (parenteral nutrition). Acceptance of SGCplus suggestions was high (93%). Conclusions: The SGCplus system can be safely applied in critically ill patients with hyperglycemia and enables good glycemic control.
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Optimized calorie and high protein intake versus recommended caloric-protein intake in critically ill patients: a prospective, randomized, controlled phase II clinical trial.
Azevedo, JRA, Lima, HCM, Montenegro, WS, Souza, SCC, Nogueira, IROM, Silva, MM, Muniz, NA
Revista Brasileira de terapia intensiva. 2019;(2):171-179
Abstract
OBJECTIVE To evaluate differences in outcomes for an optimized calorie and high protein nutrition therapy versus standard nutrition care in critically ill adult patients. METHODS We randomized patients expected to stay in the intensive care unit for at least 3 days. In the optimized calorie and high protein nutrition group, caloric intake was determined by indirect calorimetry, and protein intake was established at 2.0 to 2.2g/kg/day. The control group received 25kcal/kg/day of calories and 1.4 to 1.5g/kg/day protein. The primary outcome was the physical component summary score obtained at 3 and 6 months. Secondary outcomes included handgrip strength at intensive care unit discharge, duration of mechanical ventilation and hospital mortality. RESULTS In total, 120 patients were included in the analysis. There was no significant difference between the two groups in calories received. However, the amount of protein received by the optimized calorie and high protein nutrition group was significantly higher compared with the control group. The physical component summary score at 3 and 6 months did not differ between the two groups nor did secondary outcomes. However, after adjusting for covariates, a negative delta protein (protein received minus predetermined protein requirement) was associated with a lower physical component summary score at 3 and 6 months postrandomization. CONCLUSION In this study optimized calorie and high protein strategy did not appear to improve physical quality of life compared with standard nutrition care. However, after adjusting for covariates, a negative delta protein was associated with a lower physical component summary score at 3 and 6 months postrandomization. This association exists independently of the method of calculation of protein target.
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Safety and Efficacy of Electromagnetic-Guided Bedside Placement of Nasoenteral Feeding Tubes versus Standard Placement.
Shadid, H, Keckeisen, M, Zarrinpar, A
The American surgeon. 2017;(10):1184-1187
Abstract
Although enteral feeding in critically ill patients has been shown to be beneficial, reliable postpyloric placement of feeding tubes remains a challenge. The standard of care involves blind placement, frequently requiring multiple attempts, and radiographs. To evaluate the effect of electromagnetic-guided bedside placement in reducing time to establishment of feeding, lung placement, use of radiography, and cost, we initiated a prospective trial using electromagnetic-guided bedside placement and compared them to a retrospective cohort. Fifty-three consecutive placements of nasoenteral feeding tubes were made using electromagnetic-guidance on patients requiring enteral nutrition in a surgical intensive care unit at a tertiary care center. Sixty-three placement attempts in the preceding seven months served as controls. There were no significant differences between the two groups in terms of age, sex, weight, body mass index, hiatal or ventral hernias, or previous esophageal/gastric operations. The number of radiographs needed per patient, need for fluoroscopy, radiology charge per patient for the tube placement, and time from first attempt at placement to confirmation of postpyloric location were lower for the electromagnetic-guided group. Use of electromagnetic guidance allows reliable and cost-effective postpyloric enteral feeding tube placement compared with blind insertion.
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Space GlucoseControl system for blood glucose control in intensive care patients--a European multicentre observational study.
Blaha, J, Barteczko-Grajek, B, Berezowicz, P, Charvat, J, Chvojka, J, Grau, T, Holmgren, J, Jaschinski, U, Kopecky, P, Manak, J, et al
BMC anesthesiology. 2016;:8
Abstract
BACKGROUND Glycaemia control (GC) remains an important therapeutic goal in critically ill patients. The enhanced Model Predictive Control (eMPC) algorithm, which models the behaviour of blood glucose (BG) and insulin sensitivity in individual ICU patients with variable blood samples, is an effective, clinically proven computer based protocol successfully tested at multiple institutions on medical and surgical patients with different nutritional protocols. eMPC has been integrated into the B.Braun Space GlucoseControl system (SGC), which allows direct data communication between pumps and microprocessor. The present study was undertaken to assess the clinical performance and safety of the SGC for glycaemia control in critically ill patients under routine conditions in different ICU settings and with various nutritional protocols. METHODS The study endpoints were the percentage of time the BG was within the target range 4.4 - 8.3 mmol.l(-1), the frequency of hypoglycaemic episodes, adherence to the advice of the SGC and BG measurement intervals. BG was monitored, and insulin was given as a continuous infusion according to the advice of the SGC. Nutritional management (enteral, parenteral or both) was carried out at the discretion of each centre. RESULTS 17 centres from 9 European countries included a total of 508 patients, the median study time was 2.9 (1.9-6.1) days. The median (IQR) time-in-target was 83.0 (68.7-93.1) % of time with the mean proposed measurement interval 2.0 ± 0.5 hours. 99.6% of the SGC advices on insulin infusion rate were accepted by the user. Only 4 episodes (0.01% of all BG measurements) of severe hypoglycaemia <2.2 mmol.l(-1) in 4 patients occurred (0.8%; 95% CI 0.02-1.6%). CONCLUSION Under routine conditions and under different nutritional protocols the Space GlucoseControl system with integrated eMPC algorithm has exhibited its suitability for glycaemia control in critically ill patients. TRIAL REGISTRATION ClinicalTrials.gov NCT01523665.
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[The optimal blood glucose target in critically ill patient: comparison of two intensive insulin therapy protocols].
Raurell Torredà, M, del Llano Serrano, C, Almirall Solsona, D, Catalan Ibars, RM, Nicolás Arfelis, JM
Medicina clinica. 2014;(5):192-9
Abstract
BACKGROUND AND OBJECTIVE Recent studies in critically ill patients receiving insulin intravenous therapy (IIT) have shown an increased incidence of severe hypoglycemia, while intermittent subcutaneous insulin «sliding scales» (conventional insulin therapy [CIT]) is associated with hyperglycemia. The objective of this study is to assess whether glycemic control range IIT can affect glucose levels and their variability and to compare it with CIT. PATIENTS AND METHOD Prospective comparative cohort study in intensive care unit, with 2 study periods: Period 1, IIT with glycemic target range 110-140 mg/dL, and Period 2, IIT of 140-180 mg/dL. In both periods CIT glycemic target was 110-180 mg/dL. We assessed severe hypoglycemia (< 50 mg/dL), moderate hypoglycemia (51-79 mg/dL), hyperglycemia (> 216 mg/L) and the variability of blood glucose. RESULTS We studied 221 patients with 12.825 blood glucose determinations. Twenty-six and 17% of patients required IIT for glycemic control in Period 1 and 2, respectively. Hypoglycemia was associated with a discontinuous nutritional intake, glycemic target 110-140 mg/dL and low body mass index (BMI) (P = .002). Hyperglycemia was exclusively associated with a history of diabetes mellitus (OR 2.6 [95% CI 1.6 to 4.5]). Glycemic variability was associated with a discontinuous nutritional intake, low BMI, CIT insulinization, diabetes mellitus, elderly and high APACHE II (P < .001). CONCLUSIONS The use of IIT is useful to reduce the variability of blood glucose. Although the 140-180 mg/dL range would be more secure as to presenting greater variability and hyperglycemia, the 110-140 mg/dL range is most suitable.
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High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods.
Yeatts, SD, Palesch, YY, Moy, CS, Selim, M
Neurocritical care. 2013;(2):257-66
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Abstract
BACKGROUND Hemoglobin degradation products, in particular iron, have been implicated in secondary neuronal injury following intracerebral hemorrhage (ICH). The iron chelator Deferoxamine Mesylate (DFO) exerts diverse neuroprotective effects, reduces perihematoma edema (PHE) and neuronal damage, and improves functional recovery after experimental ICH. We hypothesize that treatment with DFO could minimize neuronal injury and improve outcome in ICH patients. As a prelude to test this hypothesis, we conducted a Phase I, open-label study to determine the tolerability, safety, and maximum tolerated dose (MTD) of DFO in patients with ICH. Intravenous infusions of DFO in doses up to 62 mg/kg/day (up to a maximum of 6000 mg/day) were well-tolerated and did not seem to increase serious adverse events (SAEs) or mortality. We have initiated a multi-center, double-blind, randomized, placebo-controlled, Phase II clinical trial (High Dose Deferoxamine [HI-DEF] in Intracerebral Hemorrhage) to determine if it is futile to move DFO forward to Phase III efficacy evaluation. METHODS We will randomize 324 subjects with spontaneous ICH to either DFO at 62 mg/kg/day (up to a maximum daily dose of 6000 mg/day) or saline placebo, given by intravenous infusion for 5 consecutive days. Treatment will be initiated within 24 hours after ICH symptom onset. All subjects will be followed for 3 months and will receive standard of care therapy while participating in the study. At 3 months, the proportion of DFO-treated subjects with a good clinical outcome, assessed by modified Rankin Scale, will be compared to the placebo proportion in a futility analysis. CONCLUSIONS The Hi-Def trial is expected to advance our understanding of the pathopgysiology of secondary neuronal injury in ICH and will provide a crucial "Go/No Go" signal as to whether a Phase III trial to investigate the efficacy of DFO is warranted.
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[Correction of metabolic hypoxia in patients with severe burn injury and septic toxemia].
Kozinets, GP, Osadchaia, OI, Tsygankov, VP, Isaenko, NP, Zhernov, AA, Boiarskaia, AM
Klinichna khirurhiia. 2012;(12):38-42
Abstract
The clinical efficacy of the preparation reamberin in correction of metabolic hypoxia in patients with severe thermal burn injury under septicotoxemia was studied. It was established high efficacy of the preparation in the correction of the antioxidant defense system, its considerable antitoxic activity. Established role of reamberin in maintaining the functioning of the humoral detoxication systems, and antimicrobial resistance in patients with severe thermal injury.