Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

Characteristics and Outcomes of Prolonged Venoarterial Extracorporeal Membrane Oxygenation After Cardiac Surgery: The Post-Cardiotomy Extracorporeal Life Support (PELS-1) Cohort Study.

OBJECTIVES: Most post-cardiotomy (PC) extracorporeal membrane oxygenation (ECMO) runs last less than 7 days. Studies on the outcomes of longer runs have provided conflicting results. This study investigates patient characteristics and short- and long-term outcomes in relation to PC ECMO duration, with a focus on prolonged (> 7 d) ECMO. DESIGN: Retrospective observational cohort study. SETTING: Thirty-four centers from 16 countries between January 2000 and December 2020. PATIENTS: Adults requiring post PC ECMO between 2000 and 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characteristics, in-hospital, and post-discharge outcomes were compared among patients categorized by ECMO duration. Survivors and nonsurvivors were compared in the subgroup of patients with ECMO duration greater than 7 days. The primary outcome was in-hospital mortality. Two thousand twenty-one patients were included who required PC ECMO for 0-3 days (n = 649 [32.1%]), 4-7 days (n = 776 [38.3%]), 8-10 days (n = 263 [13.0%]), and greater than 10 days (n = 333 [16.5%]). There were no major differences in the investigated preoperative and procedural characteristics among ECMO duration groups. However, the longer ECMO duration category was associated with multiple complications including bleeding, acute kidney injury, arrhythmias, and sepsis. Hospital mortality followed a U-shape curve, with lowest mortality in patients with ECMO duration of 4-7 days (n = 394, 50.8%) and highest in patients with greater than 10 days ECMO support (n = 242, 72.7%). There was no significant difference in post-discharge survival between ECMO duration groups. In patients with ECMO duration greater than 7 days, age, comorbidities, valvular diseases, and complex procedures were associated with nonsurvival. CONCLUSIONS: Nearly 30% of PC ECMO patients were supported for greater than 7 days. In-hospital mortality increased after 7 days of support, especially in patients undergoing valvular and complex surgery, or who had complications, although the long-term post-discharge prognosis was comparable to PC ECMO patients with shorter support duration.

Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest in Australia: a narrative review.

Extracorporeal cardiopulmonary resuscitation (ECPR) in patients with prolonged or refractory out-of-hospital cardiac arrest (OHCA) is likely to be beneficial when used as part of a well developed emergency service system. ECPR is technically challenging to initiate and resource-intensive, but it has been found to be cost-effective in hospital-based ECPR programs. ECPR expansion within Australia has thus far been reactive and does not provide broad coverage or equity of access for patients. Newer delivery strategies that improve access to ECPR for patients with OHCA are being trialled, including networked hospital-based ECPR and pre-hospital ECPR programs. The efficacy, scalability, sustainability and cost-effectiveness of these programs need to be assessed. There is a need for national collaboration to determine the most cost-effective delivery strategies for ECPR provision along with its place in the OHCA survival chain.

Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation.

Rationale: Data suggest that altered antimicrobial concentrations are likely during extracorporeal membrane oxygenation (ECMO). Objectives: The primary aim of this analysis was to describe the pharmacokinetics (PKs) of antimicrobials in critically ill adult patients receiving ECMO. Our secondary aim was to determine whether current antimicrobial dosing regimens achieve effective and safe exposure. Methods: This study was a prospective, open-labeled, PK study in six ICUs in Australia, New Zealand, South Korea, and Switzerland. Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Adequacy of antimicrobial dosing regimens were evaluated using predefined concentration exposures associated with maximal clinical outcomes and minimal toxicity risks. Measurements and Main Results: We included 993 blood samples from 85 patients. The mean age was 44.7 ± 14.4 years, and 61.2% were male. Thirty-eight patients (44.7%) were receiving renal replacement therapy during the first PK sampling. Large variations (coefficient of variation of ⩾30%) in antimicrobial concentrations were seen leading to more than fivefold variations in all PK parameters across all study antimicrobials. Overall, 70 (56.5%) concentration profiles achieved the predefined target concentration and exposure range. Target attainment rates were not significantly different between modes of ECMO and renal replacement therapy. Poor target attainment was observed across the most frequently used antimicrobials for ECMO recipients, including for oseltamivir (33.3%), piperacillin (44.4%), and vancomycin (27.3%). Conclusions: Antimicrobial PKs were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000559819).

Determinants of 90-day case fatality among older patients admitted to intensive care units: A retrospective cohort study.

BACKGROUND: A recent systematic review identified highly variable case-fatality rates among studies of older patients admitted to intensive care units (ICUs). However, structural and process determinants including patient resident status, tertiary ICU status, and treatment limitations were unavailable. OBJECTIVE: The objective of this study was to evaluate the role of determinants such as resident status, tertiary ICU, and treatment limitations on 90-day case fatality among older ICU patients. METHODS: A retrospective cohort of all Queensland residents aged 75 years and older admitted to four ICUs within the Metro North Hospital and Health Service was included. The impact of Metro North Hospital and Health Service resident status, tertiary ICU, treatment limitations, and other known determinants on 90-day all-cause case fatality (case-fatality) was assessed. RESULTS: Of the 2144 eligible first admissions included, 1365 were residents, and 893 were nonelective admissions. The case-fatality rates were higher in residents (21% vs 12%, p < 0.001), nonelective admissions (32% vs 7%, p < 0.001), and non-tertiary ICU admissions (27% vs 16%, p < 0.001). The case fatality increased progressively with age, being highest (29.6%) in the >90 years age-group. Multivariable mixedeffects logistic regression modelling demonstrated that presence of treatment limitations was strongly associated with case fatality, but neither resident status nor the tertiary ICU was associated. CONCLUSION: The presence of treatment limitations should be considered when evaluating variations in case fatality among cohorts of older ICU patients, in addition to variables with well-established association with case fatality such as comorbidities and illness severity.

90-day Case-Fatality in Critically ill Patients with Chronic Liver Disease Influenced by Presence of Portal Hypertension, Results from a Multicentre Retrospective Cohort Study.

BACKGROUND: Critical illness in patients with chronic liver disease (CLD) is increasing in occurrence, and by virtue of its adverse effect on prognosis, its presence may influence the decision to offer admission to intensive care units (ICU). Our objective was to examine the determinants and outcome of patients with CLD admitted to ICU. METHODS: A retrospective cohort of patients admitted to four adult ICUs in Queensland, Australia from 2017 to 2019. Patients with mild or moderate-severe CLD were defined by the absence and presence of portal hypertension, respectively, and were was determined using granular ICU and state-wide administrative databases. The primary outcome was 90-day all cause case-fatality. RESULTS: We included 3836 patients in the analysis, of which, 60 (2%) had mild liver disease and 132 (3%) had moderate-severe liver disease . Patients with CLD had higher incidence of other co-morbidities with the median adjusted-Charlson co-morbidity index (CCI) was 1 (interquartile range; IQR 0-3) for no CLD, 2 (IQR 1.5-4) for mild CLD, and 3 (IQR 2-5) for moderate-severe CLD. Case-fatality rates at 90 days was 17% for no CLD, 25% for mild CLD, and 41% for moderate-severe CLD. Among those with mild and moderate-severe CLD, an increased co-morbidity burden as measured by an adjusted CCI score of low (0-3), medium (4-5), high (6-7) and very high (>7) resulted in increasing case-fatality rates of 24-40%, 11-28.5%, 33-62%, and 50% respectively. Moderate-severe CLD, but not mild CLD, was independently associated with increased case-fatality at 90 days (Odds Ratio 1.58; 95% confidence interval 1.01-2.48; p = 0.004) after adjusting for medical co-morbidities and severity of illness using logistic regression analysis. CONCLUSIONS: Although patients with moderate-severe CLD have an increased risk for 90-day case-fatality, patients with mild CLD are not at higher risk for death following ICU admission.

Heterogeneity in Clinical Practices for Post-Cardiotomy Extracorporeal Life Support: a Pilot Survey from the PELS-1 Multicenter Study.

BACKGROUND: High-quality evidence for post-cardiotomy extracorporeal life support (PC-ECLS) management is lacking. This study investigated the real-world PC-ECLS clinical practices. METHODS: This cross-sectional, multi-institutional, international pilot survey explored center organization, anticoagulation management, left ventricular unloading, distal limb perfusion, PC-ECLS monitoring and transfusions practices. Twenty-nine questions were distributed among 34 hospitals participating in the Post-cardiotomy Extra-Corporeal Life Support Study. RESULTS: Of the 32 centers [16 low-volume (50%); 16 high-volume (50%)] that responded, 16 (50%) had dedicated ECLS specialists. Twenty-six centers (81.3%) reported using additional mechanical circulatory supports. Anticoagulation practices were highly heterogeneous: 24 hospitals (75%) reported using patient's bleeding status as a guide, without a specific threshold in 54.2% of cases. Transfusion targets ranged 7-10 g/dL. Most centers used cardiac venting on a case-by-case basis (78.1%) and regular distal limb perfusion (84.4%). Nineteen (54.9%) centers reported dedicated monitoring protocols including daily echocardiography (87.5%), Swan-Ganz catheterization (40.6%), cerebral near-infrared spectroscopy (53.1%) and multimodal assessment of limb ischemia. Inspection of the circuit (71.9%), oxygenator pressure drop (68.8%), plasma free hemoglobin (75%), d-dimer (59.4%), lactate dehydrogenase (56.3%) and fibrinogen (46.9%) are used to diagnose hemolysis and thrombosis. CONCLUSIONS: This study shows remarkable heterogeneity in clinical practices for PC-ECLS management. More standardized protocols and better implementation of available evidence are recommended.

Excess burden of critical illness related to inflammatory bowel disease.

BACKGROUND: Although inflammatory bowel disease (IBD) is associated with major morbidity and mortality, few studies have evaluated its associated burden of critical illness. AIMS: To examine the epidemiology and outcome of intensive care unit (ICU) admission among patients with IBD in North Brisbane, Australia. METHODS: A population-based cohort design was used. All admissions to ICU serving the Metro North Hospital and Health Service among adult residents during 2017-2019 were included. Data were obtained from ICU clinical information systems with linkages to statewide admissions and death registries. RESULTS: Among 9011 ICU admissions, 101 (1.1%) were among patients with IBD, of which 57 (0.6%) and 44 (0.5%) had ulcerative colitis (UC) and Crohn disease (CD) respectively. The incidence of ICU admission was 379, 1336, 1514 and 1429 per 100 000 annually among those without IBD, CD, UC and IBD respectively. Patients with IBD were at excess risk for admission across all age groups, with women aged <50 years at highest risk and men thereafter. The all-cause 90-day case-fatality rates following ICU admission were not significantly different among patient groups and were 18%, 12%, 15% and 12% for CD, UC, IBD and non-IBD respectively. However, as compared with non-IBD patients, those with CD (151.8 vs 39.4 per 100 000; relative risk (RR) 3.85; 95% confidence interval (CI) 1.25-9.02; P = 0.013), UC (159.4 vs 39.4 per 100 000; RR 4.05; 95% CI 1.48-8.84; P = 0.005) and IBD (155.6 vs 39.4 per 100 000; RR 3.95; 95% CI 1.96-7.10; P = 0.002) were at significantly higher risk for mortality. CONCLUSIONS: Patients with IBD suffer a major burden of critical illness.

Venovenous extracorporeal CO2 removal to support ultraprotective ventilation in moderate-severe acute respiratory distress syndrome: A systematic review and meta-analysis of the literature.

BACKGROUND: A strategy that limits tidal volumes and inspiratory pressures, improves outcomes in patients with the acute respiratory distress syndrome (ARDS). Extracorporeal carbon dioxide removal (ECCO2R) may facilitate ultra-protective ventilation. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of venovenous ECCO2R in supporting ultra-protective ventilation in moderate-to-severe ARDS. METHODS: MEDLINE and EMBASE were interrogated for studies (2000-2021) reporting venovenous ECCO2R use in patients with moderate-to-severe ARDS. Studies reporting ≥10 adult patients in English language journals were included. Ventilatory parameters after 24 h of initiating ECCO2R, device characteristics, and safety outcomes were collected. The primary outcome measure was the change in driving pressure at 24 h of ECCO2R therapy in relation to baseline. Secondary outcomes included change in tidal volume, gas exchange, and safety data. RESULTS: Ten studies reporting 421 patients (PaO2:FiO2 141.03 mmHg) were included. Extracorporeal blood flow rates ranged from 0.35-1.5 L/min. Random effects modelling indicated a 3.56 cmH2O reduction (95%-CI: 3.22-3.91) in driving pressure from baseline (p < .001) and a 1.89 mL/kg (95%-CI: 1.75-2.02, p < .001) reduction in tidal volume. Oxygenation, respiratory rate and PEEP remained unchanged. No significant interactions between driving pressure reduction and baseline driving pressure, partial pressure of arterial carbon dioxide or PaO2:FiO2 ratio were identified in metaregression analysis. Bleeding and haemolysis were the commonest complications of therapy. CONCLUSIONS: Venovenous ECCO2R permitted significant reductions in ∆P in patients with moderate-to-severe ARDS. Heterogeneity amongst studies and devices, a paucity of randomised controlled trials, and variable safety reporting calls for standardisation of outcome reporting. Prospective evaluation of optimal device operation and anticoagulation in high quality studies is required before further recommendations can be made.

Population Pharmacokinetics of Vancomycin in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation (an ASAP ECMO Study).

Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on Pmetrics. The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC0-24) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (Vc). The mean vancomycin renal clearance and Vc were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).

Impact of frailty on clinical outcomes in patients with and without COVID-19 pneumonitis admitted to intensive care units in Australia and New Zealand: a retrospective registry data analysis.

BACKGROUND: It is unclear if the impact of frailty on mortality differs between patients with viral pneumonitis due to COVID-19 or other causes. We aimed to determine if a difference exists between patients with and without COVID-19 pneumonitis. METHODS: This multicentre, retrospective, cohort study using the Australian and New Zealand Intensive Care Society Adult Patient Database included patients aged ≥ 16 years admitted to 153 ICUs between 01/012020 and 12/31/2021 with admission diagnostic codes for viral pneumonia or acute respiratory distress syndrome, and Clinical Frailty Scale (CFS). The primary outcome was hospital mortality. RESULTS: A total of 4620 patients were studied, and 3077 (66.6%) had COVID-19. The patients with COVID-19 were younger (median [IQR] 57.0 [44.7-68.3] vs. 66.1 [52.0-76.2]; p < 0.001) and less frail (median [IQR] CFS 3 [2-4] vs. 4 [3-5]; p < 0.001) than non-COVID-19 patients. The overall hospital mortality was similar between the patients with and without COVID-19 (14.7% vs. 14.9%; p = 0.82). Frailty alone as a predictor of mortality showed only moderate discrimination in differentiating survivors from those who died but was similar between patients with and without COVID-19 (AUROC 0.68 vs. 0.66; p = 0.42). Increasing frailty scores were associated with hospital mortality, after adjusting for Australian and New Zealand Risk of Death score and sex. However, the effect of frailty was similar in patients with and without COVID-19 (OR = 1.29; 95% CI: 1.19-1.41 vs. OR = 1.24; 95% CI: 1.11-1.37). CONCLUSION: The presence of frailty was an independent risk factor for mortality. However, the impact of frailty on outcomes was similar in COVID-19 patients compared to other causes of viral pneumonitis.

Evolving outcomes of extracorporeal membrane oxygenation during the first 2 years of the COVID-19 pandemic: a systematic review and meta-analysis.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used extensively for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). Reports early in the pandemic suggested that mortality in patients with COVID-19 receiving ECMO was comparable to non-COVID-19-related ARDS. However, subsequent reports suggested that mortality appeared to be increasing over time. Therefore, we conducted an updated systematic review and meta-analysis, to characterise changes in mortality over time and elucidate risk factors for poor outcomes. METHODS: We conducted a meta-analysis (CRD42021271202), searching MEDLINE, Embase, Cochrane, and Scopus databases, from 1 December 2019 to 26 January 2022, for studies reporting on mortality among adults with COVID-19 receiving ECMO. We also captured hospital and intensive care unit lengths of stay, duration of mechanical ventilation and ECMO, as well as complications of ECMO. We conducted random-effects meta-analyses, assessed risk of bias of included studies using the Joanna Briggs Institute checklist and evaluated certainty of pooled estimates using GRADE methodology. RESULTS: Of 4522 citations, we included 52 studies comprising 18,211 patients in the meta-analysis. The pooled mortality rate among patients with COVID-19 requiring ECMO was 48.8% (95% confidence interval 44.8-52.9%, high certainty). Mortality was higher among studies which enrolled patients later in the pandemic as opposed to earlier (1st half 2020: 41.2%, 2nd half 2020: 46.4%, 1st half 2021: 62.0%, 2nd half 2021: 46.5%, interaction p value = 0.0014). Predictors of increased mortality included age, the time of final patient enrolment from 1 January 2020, and the proportion of patients receiving corticosteroids, and reduced duration of ECMO run. CONCLUSIONS: The mortality rate for patients receiving ECMO for COVID-19-related ARDS has increased as the pandemic has progressed. The reasons for this are likely multifactorial; however, as outcomes for these patients evolve, the decision to initiate ECMO should include the best contextual estimate of mortality at the time of ECMO initiation.

Direct oral anticoagulants in atrial fibrillation following cardiac surgery: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) have been increasingly used as anticoagulation therapy in the postoperative period. However, their effectiveness in post-cardiac surgical atrial fibrillation is yet to be determined. METHODS: We conducted a meta-analysis, searching three international databases from 1 January 2003 to 26 January 2022 for studies reporting on DOACs in at least 10 adult patients (>18 yr of age) with post-cardiac surgical atrial fibrillation. The primary outcomes were major neurological events and bleeding; secondary outcomes were mortality, hospital and ICU length of stay, cost, and other complications from therapy. We included studies of any design, including RCTs, cohort studies with and without propensity score matching methods, and single-armed case series. RESULTS: Twelve studies (8587 DOACs; 8315 warfarin) were included in this meta-analysis. The incidences of postoperative bleeding and major neurological events with DOACs were 7.3% (95% confidence interval [CI]: 3.4-14.7%) and 2.2% (95% CI: 0.9-4.9%), respectively. The incidence of major neurological events was lower in high-risk patients, including those with hypertension and higher CHA2DS2-VASc score, whereas patients with prior transient ischaemic attack or stroke had higher incidence of bleeding. Trial sequential analysis revealed that the cumulative Z-curve crossed the conventional boundary of benefit. Compared with warfarin, DOACs reduced the risk of bleeding (relative risk [RR] 0.74; 95% CI: 0.62-0.89; P=0.0011) and major neurological events (RR 0.63; 95% CI: 0.48-0.83; P=0.0012) but not mortality (RR 1.02; 95% CI: 0.77-1.35; P=0.090). CONCLUSIONS: DOACs reduced bleeding and major neurological events in patients with post-cardiac surgical atrial fibrillation, appearing safer than warfarin in this context. However, which specific DOAC provides the most effective anticoagulation in this patient population needs further investigation. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42021282777.

Frailty and mortality associations in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Observational data during the pandemic have demonstrated mixed associations between frailty and mortality. AIM: To examine associations between frailty and short-term mortality in patients hospitalised with coronavirus disease 2019 (COVID-19). METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase and the COVID-19 living systematic review from 1 December 2019 to 15 July 2021. Studies reporting mortality and frailty scores in hospitalised patients with COVID-19 (age ≥18 years) were included. Data on patient demographics, short-term mortality (in hospital or within 30 days), intensive care unit (ICU) admission and need for invasive mechanical ventilation (IMV) were extracted. The quality of studies was assessed using the Newcastle-Ottawa Scale. RESULTS: Twenty-five studies reporting 34 628 patients were included. Overall, 26.2% (n = 9061) died. Patients who died were older (76.7 ± 9.6 vs 69.2 ± 13.4), more likely male (risk ratio (RR) = 1.08; 95% confidence interval (CI): 1.06-1.11) and had more comorbidities. Fifty-eight percent of patients were frail. Adjusting for age, there was no difference in short-term mortality between frail and non-frail patients (RR = 1.04; 95% CI: 0.84-1.28). The non-frail patients were commonly admitted to ICU (27.2% (4256/15639) vs 29.1% (3567/12274); P = 0.011) and had a higher mortality risk (RR = 1.63; 95% CI: 1.30-2.03) than frail patients. Among patients receiving IMV, there was no difference in mortality between frail and non-frail (RR = 1.62; 95% CI 0.93-2.77). CONCLUSION: This systematic review did not demonstrate an independent association between frailty status and short-term mortality in patients with COVID-19. Patients with frailty were less commonly admitted to ICU and non-frail patients were more likely to receive IMV and had higher mortality risk. This finding may be related to allocation decisions for patients with frailty amidst the pandemic.

Outcomes of Prolonged ICU Stay for Patients Undergoing Cardiac Surgery in Australia and New Zealand.

OBJECTIVE: To determine the effect of intensive care unit (ICU) length of stay (LOS) on hospital mortality and non-home discharge for patients undergoing cardiac surgery over a 16-year period in Australia and New Zealand. DESIGN: A retrospective, multicenter cohort study covering the period January 1, 2004 to December 31, 2019. SETTING: One hundred one hospitals in Australia and New Zealand that submitted data to the Australia New Zealand Intensive Care Society Adult Patient Database. PARTICIPANTS: Adult patients (aged >18) who underwent coronary artery bypass grafting, valve surgery, or combined valve + coronary artery surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors analyzed 252,948 cardiac surgical patients from 101 hospitals, with a median age of 68.3 years (IQR 60-75.5), of whom 74.2% (187,632 of 252,948) were male patients. A U-shaped relationship was observed between ICU LOS and hospital mortality, with significantly elevated mortality at short (<20 hours) and long (>5 days) ICU LOS, which persisted after adjustment for illness severity and across clinically important subgroups (odds ratio for mortality with ICU LOS >5 days = 3.21, 95% CI 2.88-3.58, p < 0.001). CONCLUSIONS: Prolonged duration of ICU LOS after cardiac surgery is associated with increased hospital mortality in a U-shaped relationship. An ICU LOS >5 days should be considered a meaningful definition for prolonged ICU stay after cardiac surgery.

Personal protective equipment preparedness in intensive care units during the coronavirus disease 2019 pandemic: An Asia-Pacific follow-up survey.

BACKGROUND: Personal-protective equipment (PPE)-preparedness, defined as adherence to guidelines, healthcare worker (HCW) training, procuring PPE stocks and responding appropriately to suspected cases, is crucial to prevent HCW-infections. OBJECTIVES: To perform a follow-up survey to assess changes in PPE-preparedness across six Asia-Pacific countries during the COVID-19 pandemic. METHODS: A prospective follow-up cross-sectional, web-based survey was conducted between 10/08/2020 to 01/09/ 2020, five months after the initial Phase 1 survey. The survey was sent to the same 231 intensivists across the six Asia-Pacific countries (Australia, Hong Kong, India, New Zealand, Philippines, and Singapore) that participated in Phase 1. The main outcome measure was to identify any changes in PPE-preparedness between Phases 1 and 2. FINDINGS: Phase 2 had responses from 132 ICUs (57%). Compared to Phase 1 respondents reported increased use of PPE-based practices such as powered air-purifying respirator (40.2% vs. 6.1%), N95-masks at all times (86.4% vs. 53.7%) and double-gloving (87.9% vs. 42.9%). The reported awareness of PPE stocks (85.6% vs. 51.9%), mandatory showering policies following PPE-breach (31.1% vs. 6.9%) and safety perception amongst HCWs (60.6% vs. 28.4%) improved significantly during Phase 2. Despite reported statistically similar adoption rate of the buddy system in both phases (42.4% vs. 37.2%), there was a reported reduction in donning/doffing training in Phase 2 (44.3% vs. 60.2%). There were no reported differences HCW training in other areas, such as tracheal intubation, intra-hospital transport and safe waste disposal, between the 2 phases. CONCLUSIONS: Overall reported PPE-preparedness improved between the two survey periods, particularly in PPE use, PPE inventory and HCW perceptions of safety. However, the uptake of HCW training and implementation of low-cost safety measures continued to be low and the awareness of PPE breach management policies were suboptimal. Therefore, the key areas for improvement should focus on regular HCW training, implementing low-cost buddy-system and increasing awareness of PPE-breach management protocols.

Development and validation of a tool to appraise guidelines on SARS-CoV-2 infection control strategies in healthcare workers.

BACKGROUND: Clinical guidelines on infection control strategies in healthcare workers (HCWs) play an important role in protecting them during the severe acute respiratory syndrome coronavirus 2 pandemic. Poorly constructed guidelines that are incomprehensive and/or ambiguous may compromise HCWs' safety. OBJECTIVE: The objective of this study was to develop and validate a tool to appraise guidelines on infection control strategies in HCWs based on the guidelines published early in the coronavirus disease 2019 pandemic. DESIGN, SETTING, AND OUTCOMES: A three-stage, web-based, Delphi consensus-building process among a panel of diverse HCWs and healthcare managers was performed. The tool was validated by appraising 40 international, specialty-specific, and procedure-specific guidelines along with national guidelines from countries with a wide range of gross national income. RESULTS: Overall consensus (≥75%) was reached at the end of three rounds for all six domains included in the tool. The Delphi panel recommended an ideal infection control guideline should encompass six domains: general characteristics (domain 1), engineering recommendations (domain 2), personal protective equipment (PPE) use (domain 3), and administrative aspects (domain 4-6) of infection control. The appraisal tool performed well across the six domains, and the inter-rater agreement was excellent for the 40 guidelines. All included guidelines performed relatively better in domains 1-3 than in domains 4-6, and this was more evident in guidelines originating from lower income countries. CONCLUSION: The guideline appraisal tool was robust and easy to use. Engineering recommendations aspects of infection control, administrative measures that promote optimal PPE use, and HCW wellbeing were generally lacking in assessed guidelines. This tool may enable health systems to adopt high-quality HCW infection control guidelines during the severe acute respiratory syndrome coronavirus 2 pandemic and may also provide a framework for future guideline development.

Colorectal Surgery in Critically Unwell Patients: A Multidisciplinary Approach.

A proportion of patients require critical care support following elective or urgent colorectal procedures. Similarly, critically ill patients in intensive care units may also need colorectal surgery on occasions. This patient population is increasing in some jurisdictions given an aging population and increasing societal expectations. As such, this population often includes elderly, frail patients or patients with significant comorbidities. Careful stratification of operative risks including the need for prolonged intensive care support should be part of the consenting process. In high-risk patients, especially in setting of unplanned surgery, treatment goals should be clearly defined, and appropriate ceiling of care should be established to minimize care that is not in the best interest of the patient. In this article we describe approaches to critically unwell patients requiring colorectal surgery and how a multidisciplinary approach with proactive intensive care involvement can help achieve the best outcomes for these patients.

Population Pharmacokinetics of Piperacillin and Tazobactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation: an ASAP ECMO Study.

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%fT>MIC) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.

Prone Positioning of Nonintubated Patients With Coronavirus Disease 2019-A Systematic Review and Meta-Analysis.

OBJECTIVES: Several studies have reported prone positioning of nonintubated patients with coronavirus diseases 2019-related hypoxemic respiratory failure. This systematic review and meta-analysis evaluated the impact of prone positioning on oxygenation and clinical outcomes. DESIGN AND SETTING: We searched PubMed, Embase, and the coronavirus diseases 2019 living systematic review from December 1, 2019, to November 9, 2020. SUBJECTS AND INTERVENTION: Studies reporting prone positioning in hypoxemic, nonintubated adult patients with coronavirus diseases 2019 were included. MEASUREMENTS AND MAIN RESULTS: Data on prone positioning location (ICU vs non-ICU), prone positioning dose (total minutes/d), frequency (sessions/d), respiratory supports during prone positioning, relative changes in oxygenation variables (peripheral oxygen saturation, Pao2, and ratio of Pao2 to the Fio2), respiratory rate pre and post prone positioning, intubation rate, and mortality were extracted. Twenty-five observational studies reporting prone positioning in 758 patients were included. There was substantial heterogeneity in prone positioning location, dose and frequency, and respiratory supports provided. Significant improvements were seen in ratio of Pao2 to the Fio2 (mean difference, 39; 95% CI, 25-54), Pao2 (mean difference, 20 mm Hg; 95% CI, 14-25), and peripheral oxygen saturation (mean difference, 4.74%; 95% CI, 3-6%). Respiratory rate decreased post prone positioning (mean difference, -3.2 breaths/min; 95% CI, -4.6 to -1.9). Intubation and mortality rates were 24% (95% CI, 17-32%) and 13% (95% CI, 6-19%), respectively. There was no difference in intubation rate in those receiving prone positioning within and outside ICU (32% [69/214] vs 33% [107/320]; p = 0.84). No major adverse events were recorded in small subset of studies that reported them. CONCLUSIONS: Despite the significant variability in frequency and duration of prone positioning and respiratory supports applied, prone positioning was associated with improvement in oxygenation variables without any reported serious adverse events. The results are limited by a lack of controls and adjustments for confounders. Whether this improvement in oxygenation results in meaningful patient-centered outcomes such as reduced intubation or mortality rates requires testing in well-designed randomized clinical trials.