Cytosolic DNA sensor AIM2 promotes KRAS-driven lung cancer independent of inflammasomes.

Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co-operators of oncogenic KRAS in the lung remains ill-defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent-in-melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS-addicted lung adenocarcinoma (LAC). In genetically defined and experimentally induced (nicotine-derived nitrosamine ketone; NNK) LAC mouse models harboring the KrasG12D driver mutation, AIM2 was highly upregulated compared with other cytosolic DNA sensors and inflammasome-associated PRRs. Genetic ablation of AIM2 in KrasG12D and NNK-induced LAC mouse models significantly reduced tumor growth, coincident with reduced cellular proliferation in the lung. Bone marrow chimeras suggest a requirement for AIM2 in KrasG12D-driven LAC in both hematopoietic (immune) and non-hematopoietic (epithelial) cellular compartments, which is supported by upregulated AIM2 expression in immune and epithelial cells of mutant KRAS lung tissues. Notably, protection against LAC in AIM2-deficient mice is associated with unaltered protein levels of mature Caspase-1 and IL-1ß inflammasome effectors. Moreover, genetic ablation of the key inflammasome adapter, ASC, did not suppress KrasG12D-driven LAC. In support of these in vivo findings, AIM2, but not mature Caspase-1, was upregulated in human LAC patient tumor biopsies. Collectively, our findings reveal that endogenous AIM2 plays a tumor-promoting role, independent of inflammasomes, in mutant KRAS-addicted LAC, and suggest innate immune DNA sensing may provide an avenue to explore new therapeutic strategies in lung cancer.

Dexamethasone for Cardiac Surgery: A Practice Preference-Randomized Consent Comparative Effectiveness Trial.

BACKGROUND: High-dose corticosteroids have been used to attenuate the inflammatory response to cardiac surgery and cardiopulmonary bypass, but patient outcome benefits remain unclear. The primary aim was to determine whether using dexamethasone was superior to not using dexamethasone to increase the number of home days in the first 30 days after cardiac surgery. The secondary aim was to evaluate efficiency, value, and impact of the novel trial design. METHODS: This pragmatic, international trial incorporating a prerandomized consent design favoring local practice enrolled patients undergoing cardiac surgery across seven hospitals in Australia and The Netherlands. Patients were randomly assigned to dexamethasone 1 mg/kg or not (control). The primary outcome was the number of days alive and at home up to 30 days after surgery ("home days"). Secondary outcomes included prolonged mechanical ventilation (more than 48 h), sepsis, renal failure, myocardial infarction, stroke, and death. RESULTS: Of 2,562 patients assessed for eligibility, 1,951 were randomized (median age, 63 yr; 80% male). The median number of home days was 23.0 (interquartile range, 20.1 to 24.1) in the no dexamethasone group and 23.1 (interquartile range, 20.1 to 24.6) in the dexamethasone group (median difference, 0.1; 95% CI, -0.3 to 0.5; P = 0.66). The rates of prolonged mechanical ventilation (risk ratio, 0.72; 95% CI, 0.48 to 1.08), sepsis (risk ratio, 1.02; 95% CI, 0.57 to 1.82), renal failure (risk ratio, 0.94; 95% CI, 0.80 to 1.12), myocardial infarction (risk ratio, 1.20; 95% CI, 0.30 to 4.82), stroke (risk ratio, 1.06; 95% CI, 0.54 to 2.08), and death (risk ratio, 0.72; 95% CI, 0.22 to 2.35) were comparable between groups (all P > 0.10). Dexamethasone reduced intensive care unit stay (median, 29 h; interquartile range, 22 to 50 h vs. median, 43 h; interquartile range, 24 to 72 h; P = 0.004). The authors' novel trial design was highly efficient (89.3% enrollment). CONCLUSIONS: Among patients undergoing cardiac surgery, high-dose dexamethasone decreased intensive care unit stay but did not increase the number of home days after surgery.

Platelet Transfusion in Cardiac Surgery: An Entropy-Balanced, Weighted, Multicenter Analysis.

BACKGROUND: Platelet transfusion is common in cardiac surgery, but some studies have suggested an association with harm. Accordingly, we investigated the association of perioperative platelet transfusion with morbidity and mortality. METHODS: We conducted a retrospective analysis of prospectively collected data from the Australian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. We included consecutive adults from 2005 to 2018 across 40 centers. We used inverse probability of treatment weighting via entropy balancing to investigate the association of perioperative platelet transfusion with our 2 primary outcomes, operative mortality (composite of both 30-day and in-hospital mortality) and 90-day mortality, as well as multiple other clinically relevant secondary outcomes. RESULTS: Among 119,132 eligible patients, 25,373 received perioperative platelets and 93,759 were considered controls. After entropy balancing, platelet transfusion was associated with reduced operative mortality (odds ratio [OR], 0.63; 99% confidence interval [CI], 0.47-0.84; P < .0001) and 90-day mortality (OR, 0.66; 99% CI, 0.51-0.85; P < .0001). Moreover, it was associated with reduced odds of deep sternal wound infection (OR, 0.57; 99% CI, 0.36-0.89; P = .0012), acute kidney injury (OR, 0.84; 99% CI, 0.71-0.99; P = .0055), and postoperative renal replacement therapy (OR, 0.71; 99% CI, 0.54-0.93; P = .0013). These positive associations were observed despite an association with increased odds of return to theatre for bleeding (OR, 1.55; 99% CI, 1.16-2.09; P < .0001), pneumonia (OR, 1.26; 99% CI, 1.11-1.44; P < .0001), intubation for longer than 24 hours postoperatively (OR, 1.13; 99% CI, 1.03-1.24; P = .0012), inotrope use for >4 hours postoperatively (OR, 1.14; 99% CI, 1.11-1.17; P < .0001), readmission to hospital within 30 days of surgery (OR, 1.22; 99% CI, 1.11-1.34; P < .0001), as well as increased drain tube output (adjusted mean difference, 89.2 mL; 99% CI, 77.0 mL-101.4 mL; P < .0001). CONCLUSIONS: In cardiac surgery patients, perioperative platelet transfusion was associated with reduced operative and 90-day mortality. Until randomized controlled trials either confirm or refute these findings, platelet transfusion should not be deliberately avoided when considering odds of death.

Association of perioperative transfusion of fresh frozen plasma and outcomes after cardiac surgery.

BACKGROUND: Fresh frozen plasma (FFP) transfusion is used to manage coagulopathy and bleeding in cardiac surgery patients despite uncertainty about its safety and effectiveness. METHODS: We performed a propensity score matched analysis of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database including patients from 39 centres from 2005 to 2018. We investigated the association of perioperative FFP transfusion with mortality and other clinical outcomes. RESULTS: Of 119,138 eligible patients, we successfully matched 13,131 FFP recipients with 13,131 controls. FFP transfusion was associated with 30-day mortality (odds ratio (OR), 1.41; 99% CI, 1.17-1.71; p < .0001), but not with long-term mortality (hazard ratio (HR), 0.92; 99% CI, 0.85-1.00; p = .007, Holm-Bonferroni α = 0.0004). FFP was also associated with return to theatre for bleeding (OR, 1.97; 99% CI, 1.66-2.34; p < .0001), prolonged intubation (OR, 1.15; 99% CI, 1.05-1.26; p < .0001) and increased chest tube drainage (Mean difference (MD) in mL, 131; 99% CI, 120-141; p < .0001). It was also associated with reduced postoperative creatinine levels (MD in g/L, -6.33; 99% CI, -10.28 to -2.38; p < .0001). CONCLUSION: In a multicentre, propensity score matched analysis, perioperative FFP transfusion was associated with increased 30-day mortality and had variable associations with secondary clinical outcomes.

A national study of infective endocarditis models of care in Australia.

BACKGROUND: Multidisciplinary endocarditis team (MDET) management is supported by current evidence and recommended in international society guidelines. The extent to which this recommendation has been implemented in Australian centres and the attitudes, barriers and facilitators of this model are unclear. AIM: To describe current infective endocarditis (IE) models of care in Australian specialist referral centres and evaluate facilitators, barriers and attitudes towards MDET implementation. METHODS: Aims were addressed using two online surveys. Survey 1 audited IE models of care and was distributed to infectious disease physicians at specialist referral centres. Survey 2 assessed barriers, facilitators and attitudes towards MDETs and was distributed via societal email listings. RESULTS: From 56 identified cardiac surgery centres, survey 1 received 47 responses (84%). A total of 28% (13/47) of participating institutions had an existing MDET. A total of 85% (11/13) of MDETs were in public hospitals and 85% (11/13) were in high IE volume centres. Survey 2 had 109 respondents from seven specialties. Attitudes towards MDET implementation were generally favourable. Identified barriers to MDET implementation included a lack of funding, resources, expertise, time and collaboration. Facilitators included strong leadership, engagement from key stakeholders and tangible benefits. CONCLUSIONS: Even though it is recommended in international guidelines, the MDET model is used by less than one-third of Australian specialist referral centres. Stakeholders in IE care have generally favourable attitudes towards MDET implementation but cite a lack of resources, funding, collaboration and time as barriers to this. Dedication of financial and administrative support and leadership from key stakeholders are required to increase MDET utilisation.

Sex Differences in Opioid Administration After Cardiac Surgery.

OBJECTIVES: To assess whether there are sex-based differences in the administration of opioid analgesic drugs among inpatients after cardiac surgery. DESIGN: A retrospective cohort study. SETTING: At a tertiary academic referral center. PARTICIPANTS: Adult patients who underwent cardiac surgery from 2014 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the cumulative oral morphine equivalent dose (OMED) for the postoperative admission. Secondary outcomes were the daily difference in OMED and the administration of nonopioid analgesics. The authors developed multivariate regression models controlling for known confounders, including weight and length of stay. A total of 3,822 patients (1,032 women and 2,790 men) were included. The mean cumulative OMED was 139 mg for women and 180 mg for men, and this difference remained significant after adjustment for confounders (adjusted mean difference [aMD], -33.21 mg; 95% CI, -47.05 to -19.36 mg; p < 0.001). The cumulative OMED was significantly lower in female patients on postoperative days 1 to 5, with the greatest disparity observed on day 5 (aMD, -89.83 mg; 95% CI, -155.9 to -23.80 mg; p = 0.009). By contrast, women were more likely to receive a gabapentinoid (odds ratio, 1.91; 95% CI, 1.42-2.58; p < 0.001). The authors found no association between patient sex and the administration of other nonopioid analgesics or specific types of opioid analgesics. The authors found no association between patient sex and pain scores recorded within the first 48 hours after extubation, or the number of opioids administered in close proximity to pain assessments. CONCLUSIONS: Female sex was associated with significantly lower amounts of opioids administered after cardiac surgery.

Prolonged Non-Steroidal Anti-Inflammatory Drug Exposure After Pleurodesis Increases Pneumothorax Recurrence: A Retrospective Cohort Study.

INTRODUCTION: The use of non-steroidal anti-inflammatory drugs (NSAID) in patients undergoing pleurodesis remains controversial. Although many surgeons are comfortable prescribing NSAIDs post-operatively, some oppose this practice due to concerns of suppressing the inflammatory response and quality of pleurodesis. Only a small body of inconsistent publications exists with respect to guiding therapy in this common clinical scenario. METHODS: A retrospective cohort study was undertaken assessing effect of NSAID exposure on pleurodesis outcomes. An institutional thoracic surgery database was reviewed yielding 147 patients who underwent pleurodesis for pneumothorax between 2010 and 2018. Medical records and imaging were reviewed for patient characteristics, NSAID exposure, recurrent pneumothorax and other adverse events. RESULTS: There was no overall difference between rates of recurrence and procedural failure of pleurodesis (Relative Risk [RR] 1.67 [95% CI 0.74-3.77]). However, NSAID exposure of >48 hours was associated with increased risk of recurrent pneumothorax (RR 2.16 [95% CI 1.05-4.45]). There was no increased rate of other adverse events related to NSAID usage. CONCLUSIONS: NSAID exposure does not increase failure rates or other adverse events following pleurodesis for pneumothorax. However, prolonged NSAID exposure post-pleurodesis may increase procedural failure rates. Further large volume randomised control trials are required.

Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

BACKGROUND: Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. METHODS: In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. RESULTS: A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management. CONCLUSIONS: Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

Development of a short form of the Cardiac Distress Inventory.

BACKGROUND: Cardiac distress may be viewed as a persistent negative emotional state that spans multiple psychosocial domains and challenges a patient's capacity to cope with living with their heart condition. The Cardiac Distress Inventory (CDI) is a disease-specific clinical assessment tool that captures the complexity of this distress. In busy settings such as primary care, cardiac rehabilitation, and counselling services, however, there is a need to administer briefer tools to aid in identification and screening. The aim of the present study was to develop a short, valid screening version of the CDI. METHODS: A total of 405 participants reporting an acute coronary event in the previous 12 months was recruited from three hospitals, through social media and by direct enrolment on the study website. Participants completed an online survey which included the full version of the CDI and general distress measures including the Kessler K6, Patient Health Questionnaire-4, and Emotion Thermometers. Relationship of the CDI with these instruments, Rasch analysis model fit and clinical expertise were all used to select items for the short form (CDI-SF). Construct validity and receiver operating characteristics in relation to the Kessler K6 were examined. RESULTS: The final 12 item CDI-SF exhibited excellent internal consistency indicative of unidimensionality and good convergent and discriminant validity in comparison to clinical status measures, all indicative of good construct validity. Using the K6 validated cutoff of ≥ 18 as the reference variable, the CDI-SF had a very high Area Under the Curve (AUC) (AUC = 0.913 (95% CI: 0.88 to 0.94). A CDI-SF score of ≥ 13 was found to indicate general cardiac distress which may warrant further investigation using the original CDI. CONCLUSION: The psychometric findings detailed here indicate that the CDI-SF provides a brief psychometrically sound screening measure indicative of general cardiac distress, that can be used in both clinical and research settings.

Intraoperative hemodynamics and risk of cardiac surgery-associated acute kidney injury: An observation study and a feasibility clinical trial.

Targeting greater pump flow and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) could potentially alleviate renal hypoxia and reduce the risk of postoperative acute kidney injury (AKI). Therefore, in an observational study of 93 patients undergoing on-pump cardiac surgery, we tested whether intraoperative hemodynamic management differed between patients who did and did not develop AKI. Then, in 20 patients, we assessed the feasibility of a larger-scale trial in which patients would be randomized to greater than normal target pump flow and MAP, or usual care, during CPB. In the observational cohort, MAP during hypothermic CPB averaged 68.8 ± 8.0 mmHg (mean ± SD) in the 36 patients who developed AKI and 68.9 ± 6.3 mmHg in the 57 patients who did not (p = 0.98). Pump flow averaged 2.4 ± 0.2 L/min/m2 in both groups. In the feasibility clinical trial, compared with usual care, those randomized to increased target pump flow and MAP had greater mean pump flow (2.70 ± 0.23 vs. 2.42 ± 0.09 L/min/m2 during the period before rewarming) and systemic oxygen delivery (363 ± 60 vs. 281 ± 45 mL/min/m2 ). Target MAP ≥80 mmHg was achieved in 66.6% of patients in the intervention group but in only 27.3% of patients in the usual care group. Nevertheless, MAP during CPB did not differ significantly between the two groups. We conclude that little insight was gained from our observational study regarding the impact of variations in pump flow and MAP on the risk of AKI. However, a clinical trial to assess the effects of greater target pump flow and MAP on the risk of AKI appears feasible.

The Prognostic Significance of Red Cell Distribution Width in Cardiac Surgery: A Systematic Review and Meta-Analysis.

RED CELL DISTRIBUTION WIDTH (RDW) is a routinely available biomarker of likely erythropoietic dysfunction, which may be associated with adverse outcomes after cardiac surgery. This systematic review and meta-analysis aimed to clarify the prognostic value of RDW in patients undergoing cardiac surgery. The authors searched MEDLINE, Embase, and the Cochrane Library from inception to May 10, 2022 for studies investigating the association between elevated RDW (as defined by the authors of included studies) and adverse outcomes after cardiac surgery. Herein, the authors extracted maximally adjusted hazard ratios (HRs) and odds ratios (ORs) with associated CIs, and pooled them using random-effects inverse- variance modeling. The authors explored interstudy heterogeneity using metaregression. The authors included 26 studies involving 48,092 patients who had undergone cardiac surgery. Elevated preoperative RDW was associated with long-term mortality (pooled HR 1.63, 95% CI 1.05-2.52), short-term mortality (pooled OR 2.16, 95% CI 1.21-3.87), acute kidney injury (AKI; pooled OR 1.30, 95% CI 1.19-1.41) and postoperative atrial fibrillation (POAF; pooled OR 1.44, 95% CI 1.05-1.96). Some studies suggested a significant association between preoperative RDW elevation and neurologic complications; however, their number was insufficient for meta-analysis. The postoperative RDW levels were less consistently reported and could not be meta-analyzed. In conclusion, the authors found that elevated preoperative RDW was associated with increased short- and long-term mortality, POAF, and AKI after cardiac surgery. Further research is needed to investigate its role in the risk stratification of patients undergoing cardiac surgery.

Platelet Transfusion After Cardiac Surgery.

OBJECTIVES: To investigate the independent association of platelet transfusion with hospital mortality and key relevant clinical outcomes in cardiac surgery. DESIGN: A single-center, propensity score-matched, retrospective, cohort study. SETTING: At an American tertiary teaching hospital data from the Medical Information Mart for Intensive Care III and IV databases from 2001 to 2019. PARTICIPANTS: Consecutive adults undergoing coronary artery bypass graft and/or cardiac valvular surgery. INTERVENTIONS: Platelet transfusion during perioperative intensive care unit (ICU) admission. MEASUREMENTS AND MAIN RESULTS: Overall, 12,043 adults met the study inclusion criteria. Of these, 1,621 (13.5%) received apheresis-leukoreduced platelets, with a median of 1.19 units per recipient (IQR: 0.93-1.19) at a median of 1.78 hours (IQR: 0.75-4.25) after ICU admission. The platelet count was measured in 1,176 patients (72.5%) before transfusion, with a median count of 120 × 109/L (IQR: 89.0-157.0), and only 53 (3.3%) had platelet counts below 50 × 109/L. After propensity matching of 1,046 platelet recipients with 1,046 controls, perioperative platelet transfusion carried no association with in-hospital mortality (odds ratio [OR]: 1.28; 99% CI: 0.49-3.35; p = 0.4980). However, it was associated with a pattern of decreased odds of suspected infection (eg, respiratory infection, urinary tract infection, septicaemia, or other; OR: 0.70; 99% CI: 0.50-0.97; p = 0.0050), days in the hospital (adjusted mean difference [AMD]: 0.86; 99% CI: -0.27 to 1.98; p = 0.048), or days in intensive care (AMD 0.83; 99% CI: -0.15 to 1.82; p = 0.0290). CONCLUSIONS: Platelet transfusion was not associated with hospital mortality, but it was associated with decreased odds of suspected infection and with shorter ICU and hospital stays.

Association Between Changes in Norepinephrine Infusion Rate and Urinary Oxygen Tension After Cardiac Surgery.

OBJECTIVES: To determine if the administration of norepinephrine to patients recovering from on-pump cardiac surgery is associated with changes in urinary oxygen tension (PO2), an indirect index of renal medullary oxygenation. DESIGN: Single center, prospective observational study. SETTING: Surgical intensive care unit (ICU). PARTICIPANTS: A nonconsecutive sample of 93 patients recovering from on-pump cardiac surgery. MEASUREMENTS AND MAIN RESULTS: In the ICU, norepinephrine was the most commonly used vasopressor agent (90% of patients, 84/93), with fewer patients receiving epinephrine (48%, 45/93) or vasopressin (4%, 4/93). During the 30-to-60-minute period after increasing the infused dose of norepinephrine (n = 89 instances), urinary PO2 decreased by (least squares mean ± SEM) 1.8 ± 0.5 mmHg from its baseline level of 25.1 ± 1.1 mmHg. Conversely, during the 30-to-60-minute period after the dose of norepinephrine was decreased (n = 134 instances), urinary PO2 increased by 2.6 ± 0.5 mmHg from its baseline level of 22.7 ± 1.2 mmHg. No significant change in urinary PO2 was detected when the dose of epinephrine was decreased (n = 21). There were insufficient observations to assess the effects of increasing the dose of epinephrine (n = 11) or of changing the dose of vasopressin (n <4). CONCLUSIONS: In patients recovering from on-pump cardiac surgery, changes in norepinephrine dose are associated with reciprocal changes in urinary PO2, potentially reflecting an effect of norepinephrine on renal medullary oxygenation.

"The other side of the table ': Early career gynaecological oncologists' transition from trainee to trainer.

BACKGROUND: The transition to consultant practice represents an important transition from the role of trainee to trainer. We used the theoretical framework of Threshold Concepts to better understand this transition by analysing data from a broader qualitative study examining the experience of early career Certified Gynaecological Oncologists (CGOs) in Australia and New Zealand. MATERIALS AND METHODS: Semi-structured interviews were conducted with CGOs of <5 years consultant experience. Transcripts were analysed using reflexive thematic analysis, sensitised by the theoretical framework of Threshold Concepts. RESULTS: Seven early career CGOs were interviewed. Analysis resulted in the construction of five main themes related to the trainer role, each demonstrating characteristics of Threshold Concepts: 'Part of becoming and being a consultant'; 'Managing complex work environments and training responsibilities'; 'Optimising near peer relationships'; 'Recency informing evolution of training'; and "'Being responsible and letting go…' - the next transition." DISCUSSION: The themes offer insights into the areas of the transition to trainer that are troublesome, the impact of negotiating these challenges on professional identity formation, and the strategies used by CGOs to negotiate them. Using the lens of Threshold Concepts, these experiences can be normalised, and supported through efforts to facilitate the development of skills in reflection, feedback, coaching and mentorship.

Fresh frozen plasma transfusion after cardiac surgery.

INTRODUCTION: Fresh frozen plasma (FFP) transfusion in the intensive care unit (ICU) is commonly used to treat coagulopathy and bleeding in cardiac surgery, despite suggestion that it may increase the risk of morbidity and mortality through mechanisms such as fluid overload and infection. METHODS: We retrospectively studied consecutive adults undergoing cardiac surgery from the Medical Information Mart for Intensive Care III and IV databases. We applied propensity score matching to investigate the independent association of within-ICU FFP transfusion with mortality and other key clinical outcomes. RESULTS: Of our 12,043 adults who met inclusion criteria, 1585 (13.2%) received perioperative FFP with a median of 2.48 units per recipient (interquartile range [IQR]: 2.04, 4.33) at a median time of 1.83 h (IQR: 0.75, 3.75) after ICU admission. After propensity matching of 952 FFP recipients to 952 controls, we found no significant association between FFP use and hospital mortality (odds ratio (OR): 1.58; 99% confidence interval (CI): 0.57, 3.71), suspected infection (OR: 0.72; 99% CI: 0.49, 1.08), or acute kidney injury (OR: 1.23; 99% CI: 0.91, 1.67). However, FFP was associated with increased days in hospital (adjusted mean difference (AMD): 1.28; 99% CI: 0.27, 2.41; p = .0050), days in intensive care (AMD: 1.28; 99% CI: 0.27, 2.28; p = .0011), and chest tube output in millilitres up to 8 h after transfusion (AMD: 92.98; 99% CI: 52.22, 133.74; p < .0001). CONCLUSIONS: After propensity matching, FFP transfusion was not associated with increased hospital mortality, but was associated with increased length of stay and no decrease in bleeding in the early post-transfusion period.

Cryoprecipitate Transfusion After Cardiac Surgery.

OBJECTIVES: The association of cryoprecipitate transfusion with patient outcomes after cardiac surgery is unclear. We aimed to investigate the predictors of, and outcomes associated with, postoperative cryoprecipitate transfusion in cardiac surgery patients. METHODS: We used the Medical Information Mart for Intensive Care III and IV databases. We included adults undergoing cardiac surgery, and propensity score matched cryoprecipitate-treated patients to controls. Using the matched cohort, we investigated the association of cryoprecipitate use with clinical outcomes. The primary outcome was in-hospital mortality. Secondary outcomes were infection, acute kidney injury, intensive care unit length of stay, hospital length of stay, and chest tube output at 2-hour intervals. RESULTS: Of 12,043 eligible patients, 283 (2.35%) patients received cryoprecipitate. The median dose was 5.83 units (IQR 4.17-7.24) given at a median first transfusion time of 1.75 hours (IQR 0.73-4.46) after intensive care unit admission. After propensity scoring, we matched 195 cryoprecipitate recipients to 743 controls. Postoperative cryoprecipitate transfusion was not significantly associated with in-hospital mortality (odds ratio [OR] 1.10; 99% confidence interval [CI] 0.43-2.84; p=0.791), infection (OR 0.77; 99% CI 0.45-1.34; p=0.220), acute kidney injury (OR 1.03; 99% CI 0.65-1.62; p=0.876) or cumulative chest tube output (adjusted mean difference 8 hrs post transfusion, 11 mL; 99% CI -104 to 125; p=0.804). CONCLUSIONS: Although cryoprecipitate was typically given to sicker patients with more bleeding, its administration was not associated with worse outcomes. Large, multicentred studies are warranted to further elucidate cryoprecipitate's safety profile and patterns of use in cardiac surgery.

Incidence and Outcomes of Postoperative Atrial Fibrillation after Coronary Artery Bypass Grafting of a Randomized Controlled Trial: A Blinded End-of-cycle Analysis.

Objective: The objective of this study is to analyse the incidence of postoperative atrial fibrillation (POAF), demography, post-operative outcomes including morbidity and mortality, length of Cardiac Intensive Care Unit (CICU) stay, High Dependency Unit (HDU) stay, and total hospital stay in patients undergoing coronary bypass grafting (CABG) at Institut Jantung Negana (IJN). Methods: We conducted a prospective, randomised, controlled trial. We supplied the treatment group with Tocovid capsules and the control group with placebo containing palm superolein. Results: Since January 2019, we have recruited the target population of 250 patients. However, the result is still blinded as we are still analysing blood samples for tocotrienol levels. 89.2% of patients completed the study with a 3.6% mortality and a 7.6% attrition rate. 35.2% of the patients developed POAF, the mean time being 46.06 ± 26.96 hours post-CABG. We did not observe any statistically significant difference when we compared left atrial size, New York Heart Association (NYHA) functional class, ejection fraction and premorbid history, besides EuroSCORE II (The European System for Cardiac Operative Risk Evaluation II) status except for older age group, right atrial size, and pleural effusion. There was also no difference in bypass time, cross clamp time or number of anastomoses. However, we noted a significant difference in death (p = 0.01) and renal failure requiring dialysis (p = 0.007) among patients with POAF; those patients also had a longer CICU stay (p = 0.005), HDU stay (p = 0.02), and total hospital stay (p = 0.001). Conclusions: POAF is associated with a higher incidence of renal failure and death while it increases CICU, HDU, and total hospital stay. It remains to be seen whether Tocovid reduces POAF and its associated sequelae. Clinical Trial Registration: NCT03807037 (Registered on 16 January 2019).

Economic Evaluation of National Patient Blood Management Clinical Guidelines in Cardiac Surgery.

OBJECTIVES: To the best of our knowledge, no published clinical guidelines have ever undergone an economic evaluation to determine whether their implementation represented an efficient allocation of resources. Here, we perform an economic evaluation of national clinical guidelines designed to reduce unnecessary blood transfusions before, during, and after surgery published in 2012 by Australia's sole public blood provider, the National Blood Authority (NBA). METHODS: We performed a cost analysis from the government perspective, comparing the NBA's cost of implementing their perioperative patient blood management guidelines with the estimated resource savings in the years after publication. The impact on blood products, patient outcomes, and medication use were estimated for cardiac surgeries only using a large national registry. We adopted conservative counterfactual positions over a base-case 3-year time horizon with outcomes predicted from an interrupted time-series model controlling for differences in patient characteristics and hospitals. RESULTS: The estimated indexed cost of implementing the guidelines of A$1.5 million (2018-2019 financial year prices) was outweighed by the predicted blood products resource saving alone of A$5.1 million (95% confidence interval A$1.4 million-A$8.8 million) including savings of A$2.4 million, A$1.6 million, and A$1.2 million from reduced red blood cell, platelet, and fresh frozen plasma use, respectively. Estimated differences in patient outcomes were highly uncertain and estimated differences in medication were financially insignificant. CONCLUSIONS: Insofar as they led to a reduction in red blood cell, platelet, and fresh frozen plasma use during cardiac surgery, implementing the perioperative patient blood management guidelines represented an efficient use of the NBA's resources.

Elevated Cardiac Troponin to Detect Acute Cellular Rejection After Cardiac Transplantation: A Systematic Review and Meta-Analysis.

Cardiac troponin is well known as a highly specific marker of cardiomyocyte damage, and has significant diagnostic accuracy in many cardiac conditions. However, the value of elevated recipient troponin in diagnosing adverse outcomes in heart transplant recipients is uncertain. We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library from inception until December 2020. We generated summary sensitivity, specificity, and Bayesian areas under the curve (BAUC) using bivariate Bayesian modelling, and standardised mean differences (SMDs) to quantify the diagnostic relationship of recipient troponin and adverse outcomes following cardiac transplant. We included 27 studies with 1,684 cardiac transplant recipients. Patients with acute rejection had a statistically significant late elevation in standardised troponin measurements taken at least 1 month postoperatively (SMD 0.98, 95% CI 0.33-1.64). However, pooled diagnostic accuracy was poor (sensitivity 0.414, 95% CrI 0.174-0.696; specificity 0.785, 95% CrI 0.567-0.912; BAUC 0.607, 95% CrI 0.469-0.723). In summary, late troponin elevation in heart transplant recipients is associated with acute cellular rejection in adults, but its stand-alone diagnostic accuracy is poor. Further research is needed to assess its performance in predictive modelling of adverse outcomes following cardiac transplant. Systematic Review Registration: identifier CRD42021227861.

Epidemiology of persistent postoperative opioid use after cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: The epidemiology of persistent postoperative opioid use at least 3 months after cardiac surgery is poorly characterised despite its potential public health importance. METHODS: We searched MEDLINE, Embase, and Google Scholar from inception to December 2021 and included studies reporting the rate and risk factors of persistent postoperative opioid use after cardiac surgery in opioid-naive and opioid-exposed patients. We recorded incidence rates and odds ratios (ORs) with 95% confidence intervals (CIs) for risk factors from individual studies and used random-effects inverse variance modelling to generate pooled estimates. RESULTS: From 10 studies involving 112 298 patients, the pooled rate of persistent postoperative opioid use in opioid-naive patients was 5.7% (95% CI: 4.2-7.2%). Risk factors included female sex (OR 1.18; 95% CI: 1.09-1.29), smoking (OR 1.34; 95% CI: 1.06-1.69), alcohol use (OR 1.43; 95% CI: 1.17-1.76), congestive cardiac failure (OR 1.17; 95% CI: 1.08-1.27), diabetes mellitus (OR 1.21; 95% CI: 1.07-1.37), chronic lung disease (OR 1.42; 95% CI: 1.16-1.75), chronic kidney disease (OR 1.35; 95% CI: 1.08-1.68), and length of hospital stay (per day) (OR 1.03; 95% CI: 1.02-1.04). CONCLUSIONS: Persistent postoperative opioid use after cardiac surgery affects at least one in 20 patients. The identification of risk factors, such as female sex, smoking, alcohol use, congestive cardiac failure, diabetes mellitus, chronic lung disease, chronic kidney disease, and length of hospital stay, should help target interventions aimed at decreasing its prevalence.