Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

Job satisfaction and symptoms of depression, anxiety, stress, and burnout: A survey of Australian and New Zealand intensive care research coordinators.

INTRODUCTION: Intensive care unit clinical research is often implemented by specialised research coordinators (RCs). Clinical research activity within Australian and New Zealand intensive care units has escalated, particularly during the COVID-19 pandemic. Growth of the intensive care RC workforce to match research demand is poorly understood. AIM: The aim of this study was to repeat an Intensive Care Research Coordinator Interest Group workforce survey conducted in 2004 and 2009 to describe the current workforce and role satisfaction and also to determine reported symptoms of depression, anxiety, stress, and burnout in Australian and New Zealand intensive care RCs. METHODS: In April 2021, an online anonymised survey was distributed to intensive care RCs to complete demographic and workforce questions, the McCloskey/Mueller Satisfaction Scale, the Depression Anxiety Stress Scales-21, and the Maslach Burnout Inventory-Human Services Survey for Medical Personnel. RESULTS: Of 128 Intensive Care Research Coordinator Interest Group eligible members, 98 (77%) completed the survey. Respondents were mainly women (91%), the median age was 47 years, 37% have a postgraduate qualification, and a third have over 10 years of RCC experience (31%). Half do not have permanent employment (52%). The mean Depression Anxiety Stress Scales-21 scores were within the normal range, and respondents reported symptoms of depression (21 [21%]), anxiety (23 [23%]), and stress (26 [27%]). Nearly half of the respondents (44%) exhibited an early symptom of burnout by reporting problematic experiences of work. The overall role satisfaction score was 3.5/5 (neutral; neither satisfied nor dissatisfied). CONCLUSIONS: Intensive care RCs are an experienced group of professionals with limited satisfaction in the role. One-fifth of the ICU RCs experienced depression, anxiety, or stress symptoms, with close to half reporting signs of burnout. These results highlight the need to address areas of concern to ensure retention of this specialised intensive care workforce.

Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain. Objective: To determine whether SDD reduces in-hospital mortality in critically ill adults. Design, Setting, and Participants: A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021. Interventions: ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care. Main Outcomes and Measures: The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs. Results: Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively. Conclusions and Relevance: Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT02389036.

Protocol summary and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU) crossover, cluster randomised controlled trial.

Background: It is unclear whether the use of selective decontamination of the digestive tract (SDD) improves outcomes in ventilated patients in intensive care units (ICUs) and whether SDD is associated with the development of antibiotic resistance. Objective: To describe the study protocol and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Unit Patients (SuDDICU) trial. Design, setting, participants and intervention: SuDDICU is an international, crossover, cluster randomised controlled trial of mechanically ventilated patients in ICUs using two 12-month trial periods. For each period, participating ICUs will implement SDD plus standard care or standard care alone. The SuDDICU drug intervention is an oral paste and gastric suspension of three antibiotics combined with a 4-day course of intravenous antibiotics. Observational ecological assessments will be conducted during five surveillance periods. The trial will be conducted in 19 ICUs in Australia and ten ICUs in Canada and the United Kingdom, and will recruit 15 000-17 000 patients. Recruitment commenced in Australia in 2017. Main outcome measures: The primary outcome is all-cause hospital mortality. Secondary outcomes include: duration of ventilation, ICU stay and hospital stay; incidence of new antibiotic-resistant organisms during the index ICU admission; changes in antibiotic-resistant organism rates; incidence of new Clostridioides difficile infections; and total use of antibiotics. Results and conclusions: SuDDICU will determine whether the use of SDD plus standard care is associated with a reduction in hospital mortality in ventilated ICU patients compared with standard care alone. It will also quantify the impact of the use of SDD on the development of antibiotic resistance. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12615000411549) and ClinicalTrials.gov (NCT02389036).

Prophylactic Intra-Aortic Balloon Counterpulsation in High Risk Cardiac Surgery: The PINBALL Pilot Multicentre, Registry-Linked, Randomised, Controlled Feasibility Trial.

BACKGROUND: Prophylactic intra-aortic balloon counterpulsation (IABC) is commonly used in selected patients undergoing coronary artery bypass graft (CABG) surgery, but definitive evidence is lacking. The aim of the multicentre PINBALL Pilot randomised controlled trial (RCT) was to assess the feasibility of performing a definitive trial to address this question. METHODS: Patients listed for CABG surgery with impaired left ventricular function and at least one additional risk factor for postoperative low cardiac output syndrome were eligible for inclusion if the treating surgical team was uncertain as to the benefit of prophylactic IABC. The primary outcome of feasibility was based on exceeding a pre-specified recruitment rate, protocol compliance and follow-up. RESULTS: The recruitment rate of 0.5 participants per site per month did not meet the feasibility threshold of two participants per site per month and the study was stopped early after enrolment of 24 out of the planned sample size of 40 participants. For 20/24 (83%) participants, preoperative IABC use occurred according to study assignment. Six (6)-month follow-up was available for all enrolled participants, [IABC 1 death (8%) vs. control 1 death (9%), p = 0.95]. CONCLUSION: The PINBALL Pilot recruitment rate was insufficient to demonstrate feasibility of a multicentre RCT of prophylactic IABC in high risk patients undergoing CABG surgery.

The accuracy of a point of care measurement of activated partial thromboplastin time in intensive care patients.

Point of care (POC) devices are increasingly being used in intensive care units to obtain faster results. Data are limited on the performance of these devices in critically ill patients, especially those on heparin infusion. The objective of this study was to assess the agreement between POC activated partial thromboplastin time (APTT) and laboratory APTT results in patients on heparin infusion and to determine its impact on the clinical decisions regarding heparin dosage. We screened all patients admitted to the intensive care unit (ICU) at St George Hospital, Sydney, over a 7-month period and enrolled those who were receiving intravenous heparin infusion. We measured APTT by two methods: bedside POC test (Hemochron Junior Signature Plus) and central laboratory method (STA analyser). We used the Bland-Altman method to test the statistical agreement between the two measurements and Cohen's kappa statistic to test the clinical agreement regarding heparin dosing decision. A total of 176 paired samples from 44 patients (mean age 63 years, 64% males, mean APACHE 18) were analysed. The mean turnaround time for the point of care APTT result was significantly shorter than the central laboratory result (5.0±0.2 min vs 64.6±2.7 min, p<0.0001). Despite the statistically significant correlation, the overall agreement tested by the Bland-Altman method was poor. The 95% limits of agreement were widest (-27.266 to 64.791) and mean percentage bias was highest (24%) for the comparison between POC APTT using citrated blood and laboratory APTT. When POC APTT results of less than 90 seconds using whole blood were compared to laboratory APTT results, the limits of the agreement became narrower (-23.243 to 28.419), and the mean percentage bias decreased to 5%. The agreement between clinical decisions regarding heparin dosage based on the two methods was poor for plain and citrated blood (kappa 0.35 and 0.11, respectively). The POC APTT results were not sufficiently accurate for use in patients on heparin infusion compared to laboratory APTT assay.