Time-Limited Trials for Patients With Critical Illness: A Review of the Literature.

TOPIC IMPORTANCE: Since the 1990s, time-limited trials have been described as an approach to navigate uncertain benefits and limits of life-sustaining therapies in patients with critical illness. In this review, we aim to synthesize the evidence on time-limited trials in critical care, establish what is known, and highlight important knowledge gaps. REVIEW FINDINGS: We identified 18 empirical studies and 15 ethical analyses about time-limited trials in patients with critical illness. Observational studies suggest time-limited trials are part of current practice in ICUs in the United States, but their use varies according to unit and physician factors. Some ICU physicians are familiar with, endorse, and have participated in time-limited trials, and some older adults appear to favor time-limited trial strategies over indefinite life-sustaining therapy or care immediately focused on comfort. When time-limited trials are used, they are often implemented incompletely and challenged by systematic barriers (eg, continually rotating ICU staff). Predictive modeling studies support prevailing clinical wisdom that prognostic uncertainty decreases over time in the ICU for some patients. One study prospectively comparing usual ICU care with an intervention designed to support time-limited trials yielded promising preliminary results. Ethical analyses describe time-limited trials as a pragmatic approach within the longstanding discussion about withholding and withdrawing life-sustaining therapies. SUMMARY: Time-limited trials are endorsed by physicians, align with the priorities of some older adults, and are part of current practice. Substantial efforts are needed to test their impact on patient-centered outcomes, improve their implementation, and maximize their potential benefit.

Single-Center Experience With Lung Transplant Evaluation Referrals of Acute Respiratory Distress Syndrome Patients During the COVID-19 Pandemic: How Do You Make Up For Lost Time?

Transfer of select, medically refractory acute respiratory distress syndrome patients to lung transplant centers requires extensive resources. Here, we report 270 consecutive lung transplant patient referrals to our center for medically refractory ARDS from June 2021 to April 2022, following the implementation of clinical care pathways for intake of these patients. Eighty-seven of 270 patients (32.2%) met screening criteria and were evaluated for transfer within a median of 12 days, during which 38 of 87 patients (43.7%) died and 12 of 87 patients (13.8%) transferred elsewhere. Thirty-seven of 87 patients (42.5%) were accepted for transfer of which 16 of 37 patients (43.2%) successfully transferred to our center with a median transfer waiting period of 12 days. Because of resource constraints, 21 of 37 accepted patients (56.8%) could not be transferred of which 9 of 21 patients (42.9%) died while waiting. Nine of 16 transferred patients (56.2%) eventually underwent lung transplantation with over 80% 6-month survival. ARDS patients referred for transplantation have high risk of mortality and, therefore, require well-described pathways for evaluation and transfer.

Self-Assessment of Research Skills and Barriers to Research Careers among Pulmonary and Critical Care Fellows.

BACKGROUND: Recruitment and retention of Pulmonary and Critical Care Medicine (PCCM) trainees into academic research positions remain difficult. Factors influencing graduates, like salary and personal circumstances, remain unchangeable. However, some program-level factors, like research skill acquisition and mentorship, may be modifiable to encourage matriculation into academic research positions. OBJECTIVE: We aim to identify proficiency in research-specific skills in PCCM trainees and barriers to careers as research-focused academic faculty. METHODS: We surveyed PCCM fellows in a nationwide cross-sectional analysis including demographics, research intent, research skills self-assessment, and academic career barriers. The Association of Pulmonary and Critical Care Medicine Program Directors approved and disseminated the survey. Data were collected and stored using the REDCap database. Descriptive statistics were used to assess survey items. RESULTS: 612 fellows received the primary survey with 112 completing the survey for a response rate of 18.3%. A majority were male (56.2%) and training at university-based medical centers (89.2%). Early fellowship trainees (first-/second-year fellows) comprised 66.9% of respondents with 33.1% being late fellowship trainees (third-/fourth-year fellows). Most early trainees (63.2%) indicated they intended to incorporate research into their careers. A chi-square testing of independence was performed to examine the relationship between training level and perceived proficiency. Significant relationships in perceived proficiency were identified between early and late fellowship trainees with an absolute difference of 25.3% (manuscript writing), 18.7% (grant writing), 21.6% (study design), and 19.5% (quantitative/qualitative methodology). The most prevalent barriers were unfamiliarity with grant writing (59.5%) and research funding uncertainty (56.8%). CONCLUSION: With an ongoing need for academic research faculty, this study identifies self-perceived gaps in research skills including grant writing, data analytics, and study conception and design. These skills map to fellow-identified barriers to careers in academics. Mentorship and innovative curriculum focusing on the development of key research skills may enhance academic research faculty recruitment.

SWEAT ICU-An Observational Study of Physician Workload and the Association of Physician Outcomes in Academic ICUs.

The optimal staffing model for physicians in the ICU is unknown. Patient-to-intensivist ratios may offer a simple measure of workload and be associated with patient mortality and physician burnout. To evaluate the association of physician workload, as measured by the patient-to-intensivist ratio, with physician burnout and patient mortality. DESIGN: Cross-sectional observational study. SETTING: Fourteen academic centers in the United States from August 2020 to July 2021. SUBJECTS: We enrolled ICU physicians and collected data on adult ICU patients under the physician's care on the single physician-selected study day for each physician. MEASUREMENTS and MAIN RESULTS: The primary exposure was workload (self-reported number of patients' physician was responsible for) modeled as high (>14 patients) and low (≤14 patients). The primary outcome was burnout, measured by the Well-Being Index. The secondary outcome measure was 28-day patient mortality. We calculated odds ratio for burnout and patient outcomes using a multivariable logistic regression model and a binomial mixed effects model, respectively. We enrolled 122 physicians from 62 ICUs. The median patient-to-intensivist ratio was 12 (interquartile range, 10-14), and the overall prevalence of burnout was 26.4% (n = 32). Intensivist workload was not independently associated with burnout (adjusted odds ratio, 0.74; 95% CI, 0.24-2.23). Of 1,322 patients, 679 (52%) were discharged alive from the hospital, 257 (19%) remained hospitalized, and 347 (26%) were deceased by day 28; 28-day outcomes were unknown for 39 of patients (3%). Intensivist workload was not independently associated with 28-day patient mortality (adjusted odds ratio, 1.33; 95% CI, 0.92-1.91). CONCLUSIONS: In our cohort, approximately one in four physicians experienced burnout on the study day. There was no relationship be- tween workload as measured by patient-to-intensivist ratio and burnout. Factors other than the number of patients may be important drivers of burnout among ICU physicians.

Evolution of Investigating Informed Assent Discussions about CPR in Seriously Ill Patients.

CONTEXT: Outcomes after cardiopulmonary resuscitation (CPR) remain poor. We have spent 10 years investigating an "informed assent" (IA) approach to discussing CPR with chronically ill patients/families. IA is a discussion framework whereby patients extremely unlikely to benefit from CPR are informed that unless they disagree, CPR will not be performed because it will not help achieve their goals, thus removing the burden of decision-making from the patient/family, while they retain an opportunity to disagree. OBJECTIVES: Determine the acceptability and efficacy of IA discussions about CPR with older chronically ill patients/families. METHODS: This multi-site research occurred in three stages. Stage I determined acceptability of the intervention through focus groups of patients with advanced COPD or malignancy, family members, and physicians. Stage II was an ambulatory pilot randomized controlled trial (RCT) of the IA discussion. Stage III is an ongoing phase 2 RCT of IA versus attention control in in patients with advanced chronic illness. RESULTS: Our qualitative work found the IA approach was acceptable to most patients, families, and physicians. The pilot RCT demonstrated feasibility and showed an increase in participants in the intervention group changing from "full code" to "do not resuscitate" within two weeks after the intervention. However, Stages I and II found that IA is best suited to inpatients. Our phase 2 RCT in older hospitalized seriously ill patients is ongoing; results are pending. CONCLUSIONS: IA is a feasible and reasonable approach to CPR discussions in selected patient populations.

Clinician attitudes and concordance with self-assessed and actual intravenous fluid prescribing patterns: A single-institution evaluation of survey and electronic prescribing data.

BACKGROUND: Recent studies suggest that balanced fluids improve inpatient outcomes compared to normal saline. The objective of this study was to obtain insights into clinicians' knowledge, attitudes and perceived prescribing practices concerning IV isotonic fluids and to analyze perceived prescribing in the context of actual prescribing. METHODS: This study, conducted at a single center (Medical University of South Carolina), included 1) a cross-sectional survey of physicians and advanced practice providers (APPs) (7/2019-8/2019) and 2) review electronic health record (EHR) claims data (2/2018-1/2019) to quantify the prescribing patterns of isotonic fluids. RESULTS: Clinicians perceived ordering equivalent amounts of normal saline and balanced fluids although normal saline ordering predominated (59.7%). There was significant variation in perceived and actual ordering across specialties, with internal medicine/subspecialty and emergency medicine clinicians reporting preferential use of normal saline and surgical/subspecialty and anesthesia clinicians reporting preferential use of balanced fluids (p < 0.0001). Clinicians who self-reported providing care in an intensive care unit (ICU) reported more frequent use of balanced fluids than non-ICU clinicians (p = 0.03). Actual prescribing data mirrored these differences. Clinicians' self-reported use of continuous infusions (p = 0.0006) and beliefs regarding the volume of fluid required to cause harm (p = 0.003) were also associated with self-reported differences in fluid prescribing. Clinician experience, most clinical considerations (e.g., indications, contraindications, barriers to using a specific fluid), and fluid cost were not associated with differential prescribing. CONCLUSIONS: Persistent normal saline utilization is associated with certain specialties, care locations, and the rate and volume of fluid administered, but not with other clinical considerations or cost. These findings can guide interventions to improve evidence-based fluid prescribing.

The Impact of Timing on Clinical and Economic Outcomes During Inter-ICU Transfer of Acute Respiratory Failure Patients: Time and Tide Wait for No One.

Approximately one in 30 patients with acute respiratory failure (ARF) undergoes an inter-ICU transfer. Our objectives are to describe inter-ICU transfer patterns and evaluate the impact of timing of transfer on patient-centered outcomes. DESIGN: Retrospective, quasi-experimental study. SETTING: We used the Healthcare Cost and Utilization Project State Inpatient Databases in five states (Florida, Maryland, Mississippi, New York, and Washington) during 2015-2017. PARTICIPANTS: We selected patients with International Classification of Diseases, 9th and 10th Revision codes of respiratory failure and mechanical ventilation who underwent an inter-ICU transfer (n = 6,718), grouping as early (≤ 2 d) and later transfers (3+ d). To control for potential selection bias, we propensity score matched patients (1:1) to model propensity for early transfer using a priori defined patient demographic, clinical, and hospital variables. MAIN OUTCOMES: Inhospital mortality, hospital length of stay (HLOS), and cumulative charges related to inter-ICU transfer. RESULTS: Six-thousand seven-hundred eighteen patients with ARF underwent inter-ICU transfer, 68% of whom (n = 4,552) were transferred early (≤ 2 d). Propensity score matching yielded 3,774 well-matched patients for this study. Unadjusted outcomes were all superior in the early versus later transfer cohort: inhospital mortality (24.4% vs 36.1%; p < 0.0001), length of stay (8 vs 22 d; p < 0.0001), and cumulative charges ($118,686 vs $308,977; p < 0.0001). Through doubly robust multivariable modeling with random effects at the state level, we found patients who were transferred early had a 55.8% reduction in risk of inhospital mortality than those whose transfer was later (relative risk, 0.442; 95% CI, 0.403-0.497). Additionally, the early transfer cohort had lower HLOS (20.7 fewer days [13.0 vs 33.7; p < 0.0001]), and lower cumulative charges ($66,201 less [$192,182 vs $258,383; p < 0.0001]). CONCLUSIONS AND RELEVANCE: Our study is the first to use a large, multistate sample to evaluate the practice of inter-ICU transfers in ARF and also define early and later transfers. Our findings of favorable outcomes with early transfer are vital in designing future prospective studies evaluating evidence-based transfer procedures and policies.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. CLINICAL TRIALS REGISTRATION: NCT04363736.

Development and implementation of a clinical decision support-based initiative to drive intravenous fluid prescribing.

OBJECTIVE: Studies suggest superior outcomes with use of intravenous (IV) balanced fluids compared to normal saline (NS). However, significant fluid prescribing variability persists, highlighting the knowledge-to-practice gap. We sought to identify contributors to prescribing variation and utilize a clinical decision support system (CDSS) to increase institutional balanced fluid prescribing. MATERIALS AND METHODS: This single-center informatics-enabled quality improvement initiative for patients hospitalized or treated in the emergency department included stepwise interventions of 1) identification of design factors within the computerized provider order entry (CPOE) of our electronic health record (EHR) that contribute to preferential NS ordering, 2) clinician education, 3) fluid stocking modifications, 4) re-design and implementation of a CDSS-integrated IV fluid ordering panel, and 5) comparison of fluid prescribing before and after the intervention. EHR-derived prescribing data was analyzed via single interrupted time series. RESULTS: Pre-intervention (3/2019-9/2019), balanced fluids comprised 33% of isotonic fluid orders, with gradual uptake (1.4%/month) of balanced fluid prescribing. Clinician education (10/2019-2/2020) yielded a modest (4.4%/month, 95% CI 1.6-7.2, p = 0.01) proportional increase in balanced fluid prescribing, while CPOE redesign (3/2020) yielded an immediate (20.7%, 95% CI 17.7-23.6, p < 0.0001) and sustained increase (72% of fluid orders in 12/2020). The intervention proved most effective among those with lower baseline balanced fluids utilization, including emergency medicine (57% increase, 95% CI 0.7-1.8, p < 0.0001) and internal medicine/subspecialties (18% increase, 95% CI 14.4-21.3, p < 0.0001) clinicians and substantially reduced institutional prescribing variation. CONCLUSION: Integration of CDSS into an EHR yielded a robust and sustained increase in balanced fluid prescribing. This impact far exceeded that of clinician education highlighting the importance of CDSS.

Psychological Outcomes in Family Members of Patients With Acute Respiratory Failure: Does Inter-ICU Transfer Play a Role?

BACKGROUND: Family members of patients admitted to the ICU experience a constellation of sequelae described as postintensive care syndrome-family. The influence that an inter-ICU transfer has on psychological outcomes is unknown. RESEARCH QUESTION: Is inter-ICU transfer associated with poor psychological outcomes in families of patients with acute respiratory failure? STUDY DESIGN AND METHODS: Cross-sectional observational study of 82 families of patients admitted to adult ICUs (tertiary hospital). Data included demographics, admission source, and outcomes. Admission source was classified as inter-ICU transfer (n = 39) for patients admitted to the ICU from other hospitals and direct admit (n = 43) for patients admitted from the ED or the operating room of the same hospital. We used quantitative surveys to evaluate psychological distress (Hospital Anxiety and Depression Scale [HADS]) and posttraumatic stress (Post-Traumatic Stress Scale; PTSS) and examined clinical, family, and satisfaction factors associated with psychological outcomes. RESULTS: Families of transferred patients travelled longer distances (mean ± SD, 109 ± 106 miles) compared with those of patients directly admitted (mean ± SD, 65 ± 156 miles; P ≤ .0001). Transferred patients predominantly were admitted to the neuro-ICU (64%), had a longer length of stay (direct admits: mean ± SD, 12.7 ± 9.3 days; transferred patients: mean ± SD, 17.6 ± 9.3 days; P < .01), and a higher number of ventilator days (direct admits: mean ± SD, 6.9 ± 8.6 days; transferred: mean ± SD, 10.6 ± 9.0 days; P < .01). Additionally, they were less likely to be discharged home (direct admits, 63%; transferred, 33%; P = .08). In a fully adjusted model of psychological distress and posttraumatic stress, family members of transferred patients were found to have a 1.74-point (95% CI, -1.08 to 5.29; P = .30) higher HADS score and a 5.19-point (95% CI, 0.35-10.03; P = .03) higher PTSS score than those of directly admitted family members. INTERPRETATION: In this exploratory study, posttraumatic stress measured by the PTSS was higher in the transferred families, but these findings will need to be replicated to infer clinical significance.

Inter-ICU transfer of patients with ventilator dependent respiratory failure: Qualitative analysis of family and physician perspectives.

OBJECTIVES: Ventilator dependent respiratory failure (VDRF) patients are seriously ill and often transferred between ICUs. Our objective was to obtain multi-stakeholder insights into the experiences of families during inter-ICU transfer. METHODS: We conducted a qualitative study using semi-structured interviews with family members of VDRF patients as well as clinicians that have received or transferred VDRF patients to our hospital. Interviews were transcribed and template analysis was used to identify themes within/across stakeholder groups. RESULTS: Patient, family, clinician and systems-level factors were identified as key themes during inter-ICU transfer. The main findings highlight that family members were rarely engaged in the decision to transfer as well as a lack of standardized communication between clinicians during care transitions. Family members were reassured with the care after transfer in spite of practical and financial challenges. Clinicians acknowledged the lack of a systematic approach for meeting the needs of families and suggested various resources. CONCLUSIONS: This is one of the first qualitative studies to gather a multi-stakeholder perspective and identify problems faced by families during inter-ICU transfer of VDRF patients. PRACTICE IMPLICATIONS: Our results provide a starting point for the development of family-centered support interventions which will need to be tested in future studies.

Patient and Hospital Characteristics Associated with Interhospital Transfer for Adults with Ventilator-Dependent Respiratory Failure.

RATIONALE: Patients with ventilator-dependent respiratory failure have improved outcomes at centers with greater expertise; yet, most patients are not treated in such facilities. Efforts to align care for respiratory failure and hospital capability would necessarily require interhospital transfer. OBJECTIVES: To characterize the prevalence and the patient and hospital factors associated with interhospital transfer of adults residing in Florida with ventilator-dependent respiratory failure. METHODS: We performed a retrospective, observational study using Florida Healthcare Cost and Utilization Project data. We selected patients 18 years of age and older with International Classification of Diseases, Ninth Revision, codes of respiratory failure and mechanical ventilation during 2012 and 2013, and we identified cohorts of patients that did and did not undergo interhospital transfer. We obtained patient sociodemographic and clinical variables and categorized hospitals into subtypes on the basis of patient volume and services provided: large, medium (nonprofit or for-profit), and small. RESULTS: Interhospital transfer was our primary outcome measure. Patient sociodemographics, clinical variables, and hospital types were used as covariates. We identified 2,580 patients with ventilator-dependent respiratory failure who underwent interhospital transfer. Overall, transfer was uncommon, with only 2.9% of patients being transferred. In a hierarchical model, age less than 65 years (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.77-2.45) and tracheostomy (OR, 3.19; 95% CI, 2.80-3.65) were associated with higher odds of transfer, whereas having Medicaid was associated with lower odds of transfer than having commercial insurance (OR, 0.65; 95% CI, 0.56-0.75). Additionally, care in medium-sized for-profit hospitals was associated with lower odds of transfer (OR, 1.37 vs. 2.70) than care in medium nonprofit hospitals, despite similar hospital characteristics. CONCLUSIONS: In Florida, interhospital transfer of patients with ventilator-dependent respiratory failure is uncommon and more likely among younger, commercially insured, medically resource-intensive patients. For-profit hospitals are less likely to transfer than nonprofit hospitals. In future studies, researchers should test for geographic variations and examine the clinical implications of selectivity in interhospital transfer of patients with ventilator-dependent respiratory failure.

Where You Live Matters: The Impact of Place of Residence on Severe Sepsis Incidence and Mortality.

BACKGROUND: Medically underserved areas are composed of vulnerable populations with reduced access to ambulatory care services. Our goal was to determine the association between residence in a medically underserved area and severe sepsis incidence and mortality. METHODS: Using administrative data, we identified adults admitted with severe sepsis to nonfederal hospitals in South Carolina. We determined whether each resident lived in a medically underserved area or nonmedically underserved area from US Census and Department of Health and Human Services data. Age-adjusted severe sepsis incidence and mortality rates were calculated and compared between both residential classifications. Multivariate logistic regression measured the association between residence in a medically underserved area and mortality while adjusting for confounders. RESULTS: In 2010, 24,395 adults were admitted with severe sepsis and 1,446,987 (43%) adults lived in a medically underserved area. Residents of medically underserved areas were admitted more frequently with severe sepsis (8.6 vs 6.8 cases/1,000 people, P < .01) and were more likely to die (15.5 vs 11.9 deaths/10,000 people, P < .01), with increased odds of severe sepsis-related death (OR, 1.12) after adjustment for age, race, and severity of illness. ZIP code-based surrogates of socioeconomic status, including median income, proportion below poverty level, and educational attainment, however, had minimal association with sepsis mortality. CONCLUSIONS: Residence in a medically underserved area is associated with higher incidence and mortality rates of severe sepsis and represents a novel method of access-to-care adjustment. Traditional access-to-care surrogates, however, are poorly associated with sepsis mortality.

Variability in structure of university pulmonary/critical care fellowships and retention of fellows in academic medicine.

INTRODUCTION: Individual fellowship programs are challenged to find a format of training that not only meets the Accreditation Council for Graduate Medical Education requirements, but also grooms fellows to be trusted clinicians, and encourages them to enter academic careers. This study was undertaken as part of an internal effort to evaluate and revise the program structure of the pulmonary/critical care medicine fellowship at the Medical University of South Carolina. Our objectives were to characterize variation in the training structure and specifically research opportunities of university pulmonary/critical care medicine fellowship programs, and to identify factors associated with fellow retention in academic medicine and research. METHODS: A 30-item survey was developed through rigorous internal review and was administered via email. Descriptive statistics, Cronbach's alpha, correlations, Wilcoxon sign-rank test, and ANOVA were carried out. RESULTS: We had a response rate of 52%. Program directors reported that, within the past 5 years, 38% of their fellows remained in academic medicine and 20% remained in academics with significant research focus. We found a statistically significant association between obtaining a master's degree and remaining in academics (r = 0.559; P < 0.008). The survey also revealed statistically significant relationships between scholarly requirements (grant proposals, peer-reviewed original research projects) and the percent of fellows who graduated and remained in academics. CONCLUSIONS: This survey offers some insights that may be useful to fellowship program directors. In particular, advanced education in research and maximizing scholarly activities might be associated with increased academic retention among fellowship trainees.