Palliative clinical trials in advanced chronic liver disease: Challenges and opportunities.

Patients with advanced chronic liver disease have a complex symptom burden and many are not candidates for curative therapy. Despite this, provision of palliative interventions remains woefully inadequate, with an insufficient evidence base being a contributory factor. Designing and conducting palliative interventional trials in advanced chronic liver disease remains challenging for a multitude of reasons. In this manuscript we review past and ongoing palliative interventional trials. We identify barriers and facilitators and offer guidance on addressing these challenges. We hope that this will reduce the inequity in palliative care provision in advanced chronic liver disease.

Association of Frailty and the Expanded Operative Stress Score with Preoperative Acute Serious Conditions, Complications, and Mortality in Males Compared to Females: A Retrospective Observational Study.

OBJECTIVE: The aim of this study was to expand Operative Stress Score (OSS) increasing procedural coverage and assessing OSS and frailty association with Preoperative Acute Serious Conditions (PASC), complications and mortality in females versus males. SUMMARY BACKGROUND DATA: Veterans Affairs male-dominated study showed high mortality in frail veterans even after very low stress surgeries (OSS1). METHODS: Retrospective cohort using NSQIP data (2013-2019) merged with 180-day postoperative mortality from multiple hospitals to evaluate PASC, 30-day complications and 30-, 90-, and 180-day mortality. RESULTS: OSS expansion resulted in 98.2% case coverage versus 87.0% using the original. Of 82,269 patients (43.8% male), 7.9% were frail/very frail. Males had higher odds of PASC [adjusted odds ratio (aOR) = 1.31, 95% confidence interval (CI) = 1.21-1.41, P < 0.001] and severe/life-threatening Clavien-Dindo IV (CDIV) complications (aOR = 1.18, 95% CI = 1.09-1.28, P < 0.001). Although mortality rates were higher (all time-points, P < 0.001) in males versus females, mortality was similar after adjusting for frailty, OSS, and case status primarily due to increased male frailty scores. Additional adjustments for PASC and CDIV resulted in a lower odds of mortality in males (30-day, aOR = 0.81, 95% CI = 0.71-0.92, P = 0.002) that was most pronounced for males with PASC compared to females with PASC (30-day, aOR = 0.75, 95% CI = 0.56-0.99, P = 0.04). CONCLUSIONS: Similar to the male-dominated Veteran population, private sector, frail patients have high likelihood of postoperative mortality, even after low-stress surgeries. Preoperative frailty screening should be performed regardless of magnitude of the procedure. Despite males experiencing higher adjusted odds of PASC and CDIV complications, females with PASC had higher odds of mortality compared to males, suggesting differences in the aggressiveness of care provided to men and women.

Patient Perspectives on Perioperative Supportive Care Needs Surrounding Major Abdominal Operations for Cancer.

PURPOSE: The development of supportive care interventions delivered by surgeons for their patients is a major research priority. Designing such interventions requires understanding patients' supportive care needs for major operations. This qualitative analysis aimed to determine the supportive care needs of patients undergoing major abdominal operations for cancer. METHODS: We conducted semi-structured interviews with a subset of participants in a randomized, controlled trial of a specialist palliative care intervention for patients undergoing abdominal resections for cancer (NCT03436290). Sampling was designed to balance the population by sex, age (older vs. younger than 65 years), and treatment group assignment (intervention vs. control). The interview guide was developed to elicit patient perceptions of their supportive care needs from diagnosis to the time of interview, about 1 month after their operation. Two coders used an iterative, inductive method to identify recurring themes in the interviews. RESULTS: Analysis of interview transcripts revealed five primary themes: preoperative preparation, postoperative recovery, expectation setting, coordination of care, and provider characteristics. Cutting across these themes were patients' focus on time, timeliness, and timelines, as well as their desires for information both from their surgeons and other sources. Surgeons inspired trust through the quality of their communication and their responsiveness to questions. Patients were sensitive to perceived deviations from their expectations and spoke of the need to develop patience and to expect the unexpected. CONCLUSIONS: Patients expressed several needs for supportive care that surgical teams can potentially address to improve the experience of major cancer surgery.

Sex-Related Differences in Acuity and Postoperative Complications, Mortality and Failure to Rescue.

INTRODUCTION: Yentl syndrome describing sex-related disparities has been extensively studied in medical conditions but not after surgery. This retrospective cohort study assessed the association of sex, frailty, presenting with preoperative acute serious conditions (PASC), and the expanded Operative Stress Score (OSS) with postoperative complications, mortality, and failure-to-rescue. METHODS: The National Surgical Quality Improvement Program from 2015 to 2019 evaluating 30-d complications, mortality, and failure-to-rescue. RESULTS: Of 4,860,308 cases (43% were male; mean [standard deviation] age of 56 [17] y), 6.0 and 0.8% were frail and very frail, respectively. Frailty score distribution was higher in men versus women (P < 0.001). Most cases were low-stress OSS2 (44.9%) or moderate-stress OSS3 (44.5%) surgeries. While unadjusted 30-d mortality rates were higher (P < 0.001) in males (1.1%) versus females (0.8%), males had lower odds of mortality (adjusted odds ratio (aOR) = 0.92, 95% confidence interval [CI] = 0.90-0.94, P < 0.001) after adjusting for frailty, OSS, case status, PASC, and Clavien-Dindo IV (CDIV) complications. Males have higher odds of PASC (aOR = 1.33, CI = 1.31-1.35, P < 0.001) and CDIV complications (aOR = 1.13, CI = 1.12-1.15, P < 0.001). Male-PASC (aOR = 0.76, CI = 0.72-0.80, P < 0.001) and male-CDIV (aOR = 0.87, CI = 0.83-0.91, P < 0.001) interaction terms demonstrated that the increased odds of mortality associated with PASC or CDIV complications/failure-to-rescue were lower in males versus females. CONCLUSIONS: Our study provides a comprehensive analysis of sex-related surgical outcomes across a wide range of procedures and health care systems. Females presenting with PASC or experiencing CDIV complications had higher odds of mortality/failure to rescue suggesting sex-related care differences. Yentl syndrome may be present in surgical patients; possibly related to differences in presenting symptoms, patient care preferences, or less aggressive care in female patients and deserves further study.

Interpreting the risk analysis index of frailty in the context of surgical oncology.

BACKGROUND AND OBJECTIVES: The Risk Analysis Index (RAI) accurately predicts adverse postoperative outcomes but the inclusion of cancer status in the RAI has raised two key concerns about its suitability for use in surgical oncology: (1) the potential over classification of cancer patients as frail, and (2) the potential overestimation of postoperative mortality for patients with surgically curable cancers. METHODS: We performed a retrospective cohort analysis to assess the RAI's power to appropriately identify frailty and predict postoperative mortality in cancer patients. We assessed discrimination for mortality and calibration across five RAI models-the complete RAI and four variants that removed different cancer-related variables. RESULTS: We found that the presence of disseminated cancer was a key variable driving the RAI's power to predict postoperative mortality. The model including only this variable [RAI (disseminated cancer)] was similar to the complete RAI in the overall sample (c = 0.842 vs. 0.840) and outperformed the complete RAI in the cancer subgroup (c = 0.736 vs 0.704, respectively, p < 0.0001, Max R2 = 19.3% vs. 15.1%, respectively). CONCLUSION: The RAI demonstrates somewhat less discrimination when applied exclusively to cancer patients, but remains a strong predictor of postoperative mortality, especially in the setting of disseminated cancer.

Integrating Specialist Palliative Care in the Liver Transplantation Evaluation Process: A Qualitative Analysis of Hepatologist and Palliative Care Provider Views.

Patients undergoing evaluation for liver transplantation face heavy burdens of symptoms, health care use, and mortality. In other similarly ill populations, specialist palliative care has been shown to benefit patients, but specialist palliative care is infrequently used for liver transplantation patients. This project aims to describe the potential benefits of and barriers to specialist palliative care integration in the liver transplantation process. We performed qualitative analysis of transcripts from provider focus groups followed by a community engagement studio of patients and caregivers. Focus groups consisted of 14 palliative care specialists and 10 hepatologists from 11 institutions across the United States and Canada. The community engagement studio comprised patients and caregivers of patients either currently on the liver transplantation waiting list or recently after transplant. The focus groups identified 19 elements of specialist palliative care that could benefit this patient population, including exploring patients' illness understanding and expectations; assessing physical symptoms comprehensively; discussing patient values; and providing caregiver support, a safe space to discuss noncurative options, and anticipatory guidance about likely next steps. Identified barriers included role boundaries, differences in clinical cultures, limitations of time and staff, competing goals and priorities, misconceptions about palliative care, limited resources, changes in transplant status, and patient complexity. Community studio participants identified many of the same opportunities and barriers. This study found that hepatologists, palliative care specialists, patients, and caregivers identified areas of care for liver transplantation patients that specialist palliative care can improve and address.

The Correlation Between Case Total Work Relative Value Unit, Operative Stress, and Patient Frailty: Retrospective Cohort Study.

OBJECTIVE: Assess the relationships between case total work relative value units (wRVU), patient frailty, and the physiologic stress of surgical interventions. SUMMARY OF BACKGROUND DATA: Surgeon reimbursement is frequently apportioned by wRVU. These subjective, procedure-specific valuations generated by physician survey estimate the intensity and time for typical patient care services. We hypothesized wRVU would not adequately account for patient-specific factors, such as frailty, that modify the required physician work, regardless of procedural complexity. METHODS: Using National and Veterans Affairs Surgical Quality Improvement Programs (2015-2018), we evaluated the correlation between case total wRVU, patient frailty (risk analysis index) and physiologic surgical stress (operative stress score). RESULTS: Of 4,111,371 (86%) cases, the correlation between total wRVU and operative stress was moderate [ρs = 0.587 (95% confidence interval, 0.586-0.587)], but negligible with frailty ρ = 0.177 (95% confidence interval, 0.176-0.178)]. Very high operative stress procedures [n = 34,047 (1%)] generated a mean total wRVU of 55.1 (standard deviation, 12.9), comprising 7%, 2%, and 1% of thoracic, vascular, and general surgical cases, respectively. Very frail patients [n = 152,535 (4%)] accounted for 9% of thoracic, 9% of vascular, 4% of general, 5% of urologic, and 4% of neurologic surgical cases, generating 21.0 (standard deviation, 12.4) mean total wRVU. Some nonfrail patients undergoing low operative stress procedures [n = 60,128 (2%)] nonetheless generated the highest quintile wRVU; these comprised >15% of plastic, gynecologic, and urologic surgical cases. CONCLUSIONS: Surgeon reimbursement correlates with operative stress but not patient frailty. The total wRVU does not adequately reflect patient-specific factors that increase the physician workload required to render optimal care to complex patients.

Worse Than Death: Survey of Public Perceptions of Disability Outcomes After Hypothetical Traumatic Brain Injury.

OBJECTIVE: The aim of this study was to determine the health utility states of the most commonly used traumatic brain injury (TBI) clinical trial endpoint, the Extended Glasgow Outcome Scale (GOSE). SUMMARY BACKGROUND DATA: Health utilities represent the strength of one's preferences under conditions of uncertainty. There are insufficient data to indicate how an individual would value levels of disability after a TBI. METHODS: This was a cross-sectional web-based online convenience sampling adaptive survey. Using a standard gamble approach, participants evaluated their preferences for GOSE health states 1 year after a hypothetical TBI. The categorical GOSE was studied from vegetative state (GOSE2) to upper good recovery (GOSE8). Median (25th percentile, 75th percentile) health utility values for different GOSE states after TBI, ranging from -1 (worse than death) to 1 (full health), with 0 as reference (death). RESULTS: Of 3508 eligible participants, 3235 (92.22%) completed the survey. Participants rated lower GOSE states as having lower utility, with some states rated as worse than death, though the relationship was nonlinear and intervals were unequal between health states. Over 75% of participants rated a vegetative state (GOSE2, absence of awareness and bedridden) and about 50% rated lower severe disability (GOSE3, housebound needing all-day assistance) as conditions worse than death. CONCLUSIONS: In the largest investigation of public perceptions about post-TBI disability, we demonstrate unequally rated health states, with some states perceived as worse than death. Although limited by selection bias, these results may guide future comparative-effectiveness research and shared medical decision-making after neurologic injury.

Using the Unified Medical Language System to Expand the Operative Stress Score - First Use Case.

BACKGROUND: The Unified Medical Language System (UMLS) maps relationships between and within >100 biomedical vocabularies, including Current Procedural Terminology (CPT) codes, creating a powerful knowledge resource which can accelerate clinical research. METHODS: We used synonymy and concepts relating hierarchical structure of CPT codes within the UMLS, (1) guiding surgical experts in expanding the Operative Stress Score (OSS) from 565 originally rated CPT codes to additional, 1,853 related procedures; (2) establishing validity of the association between the added OSS ratings and 30-day outcomes in VASQIP (2015-2018). RESULTS: The UMLS Metathesaurus and Semantic Network was converted into an interactive graph database (https://github.com/dbmi-pitt/UMLS-Graph) delineating ontology relatedness. From this UMLS-graph, the CPT hierarchy was queried obtaining all paths from each code to the hierarchical apex. Of 1,853 added ratings, 43% and 76% were siblings and cousins of original OSS CPT codes. Of 857,577 VASQIP cases (mean age, 64±11years; 91% male; 75% white), 786,122 (92%) and 71,455 (8%) were rated in the original and added OSS. Compared to original, added OSS cases included more females (14% versus 9%) and frail patients (25% versus 19%) undergoing high stress procedures (11% versus 8%; all P <.001). Postoperative mortality consistently increased with OSS. Very low stress procedures had <0.5% (original, 0.4% [95%CI, 0.4%-0.5%] versus added, 0.9% [95%CI, 0.6%-1.2%]) and very high 3.8% (original, 3.5% [95%CI, 3.0%-4.0%] versus added, 5.8% [95%CI, 4.6-7.3%]) mortality rates. CONCLUSIONS: The synonymy and concepts relating biomedical data within the UMLS can be abstracted and efficiently used to expand the utility of existing clinical research tools.

Responding to Those Who Hope for a Miracle: Practices for Clinical Bioethicists.

Significant challenges arise for clinical care teams when a patient or surrogate decision-maker hopes a miracle will occur. This article answers the question, "How should clinical bioethicists respond when a medical decision-maker uses the hope for a miracle to orient her medical decisions?" We argue the ethicist must first understand the complexity of the miracle-invocation. To this end, we provide a taxonomy of miracle-invocations that assist the ethicist in analyzing the invocator's conceptions of God, community, and self. After the ethicist appreciates how these concepts influence the invocator's worldview, she can begin responding to this hope with specific practices. We discuss these practices in detail and offer concrete recommendations for a justified response to the hope for a miracle.

Effect of Religion on End-of-Life Care Among Trauma Patients.

Evidence suggests that religiousness is associated with more aggressive end-of-life (EOL) care among terminally ill patients. The effect of religion on care in more acutely life-threatening diseases is not well studied. This study examines the association of religious affiliation and request for chaplain visit with aggressive EOL care among critically injured trauma patients. We conducted a retrospective review of all trauma patients surviving at least 2 days but dying within 30 days of injury over a 3-year period at a major academic trauma center. Time until death was used as a proxy for intensity of life-prolonging therapy. Controlling for social factors, severity of injury, and medical comorbidities, religious affiliation was associated with a 43 % increase in days until death. Controlling for these same variables, chaplain request was associated with a 24 % decrease in time until death. These results suggest that religious patients receive more aggressive, and ultimately futile, EOL care and that pastoral care may reduce the amount of futile care consumed.

Religiously affiliated intensive care unit patients receive more aggressive end-of-life care.

BACKGROUND: Previous studies among cancer patients have demonstrated that religious patients receive more aggressive end-of-life (EOL) care. We sought to examine the effect of religious affiliation on EOL care in the intensive care unit (ICU) setting. MATERIALS AND METHODS: We conducted a retrospective review of all patients admitted to any adult ICU at a tertiary academic center in 2010 requiring at least 2 d of mechanical ventilation. EOL patients were those who died within 30 d of admission. Hospital charges, ventilator days, hospital days, and days until death were used as proxies for intensity of care among the EOL patients. Multivariate analysis using multiple linear regression, zero-truncated negative binomial regression, and Cox proportional hazard model were used. RESULTS: A total of 2013 patients met inclusion criteria; of which, 1355 (67%) affirmed a religious affiliation. The EOL group had 334 patients, with 235 (70%) affirming a religious affiliation. The affiliated and nonaffiliated patients had similar levels of acuity. Controlling for demographic and medical confounders, religiously affiliated patients in the EOL group incurred 23% (P = 0.030) more hospital charges, 25% (P = 0.035) more ventilator days, 23% (P = 0.045) more hospital days, and 30% (P = 0.036) longer time until death than their nonaffiliated counterparts. Among all included patients, survival did not differ significantly among affiliated and nonaffiliated patients (log-rank test P = 0.317), neither was religious affiliation associated with a difference in survival on multivariate analysis (hazard ratio of death for religious versus nonreligious patients 0.95, P = 0.542). CONCLUSIONS: Compared with nonaffiliated patients, religiously affiliated patients receive more aggressive EOL care in the ICU. However, this high-intensity care does not translate into any significant difference in survival.

Pheochromocytoma in Neurofibromatosis Type 1: When Should it Be Suspected?

OBJECTIVE: Neurofibromatosis type 1 (NF1) carries an increased risk of pheochromocytoma. Most experts recommend that NF1 patients be screened for pheochromocytoma if hypertension develops. We sought to compare NF1 and non-NF1 patients with pheochromocytoma. METHODS: Retrospective analysis of a prospectively collected database of all patients undergoing pheochromocytoma resection by a single surgeon from 2003-2012. Statistical significance was evaluated using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. RESULTS: Of 56 patients undergoing pheochromocytoma resection, 6 (11%) had NF1. All 6 (100%) NF1 patients had pheochromocytoma diagnosed incidentally during work-up for another condition, whereas 28 of 50 (56%) non-NF1-associated pheochromocytomas were diagnosed incidentally (P = .071). Hypertension was present in 1 (17%) NF1 patient and in 37 (74%) of the non-NF1 patients (P = .011). Tumors were significantly smaller in NF1 patients compared with non-NF1 patients (median tumor dimension, 2.75 cm vs. 5.9 cm, respectively; P = .014). CONCLUSION: Although NF1 patients have a well-known increased risk of developing pheochromocytoma, in the current series, all NF1 patients referred to the surgeon for adrenalectomy had pheochromocytoma diagnosed incidentally. Nevertheless, NF1 patients had significantly smaller tumors and less hypertension than other patients treated for pheochromocytoma, perhaps due to a higher frequency of imaging occasioned by their other neoplasms. The common recommendation to screen for pheochromocytoma when hypertension develops would have failed to spur screening in 83% of these NF1 patients. Routine screening for pheochromocytoma in all NF1 patients may be warranted after evaluating whether this is cost-effective in reducing morbidity and mortality.

Fighting for Dear Life: Christians and Aggressive End-of-Life Care.

Patients or their family members sometimes give religious reasons for requesting life-sustaining technologies that have little hope of restoring health. This poses an ethical challenge for clinicians and a potential strain on limited health-care resources. Among Christians, one explanation for a preference for aggressive, life-prolonging care is the influence of the idea of martyrdom, which became the normative form of dying in early Christianity. The ancient discourse of martyrdom and the modern discourse of aggressive medical care both share a martial orientation and commend an ethos of combat. This paper examines ancient Christian martyrdom discourse to illuminate its affinity with the discourse of aggressive medical care. The ethos of martyrdom has shaped Christian attitudes toward death such that preference for aggressive medical care at the end of life is understandable.

Palliative Care Clinicians' Views on Metrics for Successful Specialist Palliative Care Delivery in the ICU.

CONTEXT: A quarter of palliative care (PC) clinicians' consultations are now requested from the intensive care unit (ICU). Despite this high usage, a standardized set of quality metrics for PC delivery in the ICU does not exist. OBJECTIVES: To explore PC clinicians' views on how to best measure quality of care delivery in their role as a consultant in the ICU setting. METHODS: Secondary analysis of a parent dataset consisting of qualitative data from semi-structured interviews exploring ways to optimize PC clinicians' role in the ICU. Nineteen participants were recruited across five academic medical centers in the US. Participants included PC physicians (n = 14), nurse practitioners (n = 2), and social workers (n = 3). Thematic analysis with an inductive approach was used to generate themes. RESULTS: We identified two central themes: difficulties in measuring PC quality in the ICU (theme 1) and tension between the role of PC and metrics (theme 2). Theme 1 had two subthemes related to logistical challenges in measuring outcomes and PC clinicians' preference for metrics that incorporate subjective feedback from patients, family members, and the primary ICU team. Theme 2 described how PC clinicians often felt a disconnect between the goal of meeting a metric and their goals in delivering high-quality clinical care. CONCLUSION: Our findings provide insight into PC clinician perspectives on quality metrics and identify major barriers that need to be addressed to successfully implement quality measurement in the ICU setting.

Patient Perceptions of Specialist Palliative Care Intervention in Surgical Oncology Care.

INTRODUCTION: Surgical oncology patients have a high symptom burden and increased risk of morbidity. The aim of palliative care is to evaluate and treat the patient in a holistic manner focusing on the unique attributes of each patient. This goal-concordant approach could help surgical patients cope with the stress and uncertainty that often accompany serious illness and surgery, improving overall outcomes. This qualitative analysis sought to explore whether unmet specialist palliative care or end-of-life needs exist in this population. METHODS: Qualitative interviews were completed with a subset of participants in a randomized, controlled trial of a specialist palliative care intervention for patients undergoing abdominal oncologic surgery. The interview guide sought to elicit respondents' perceptions of palliative care and end-of-life needs perioperatively and postoperatively. Recurring themes were identified by two independent coders. RESULTS: Analysis of 47 interview transcripts revealed few serious concerns about end-of-life issues, however appreciation for the supportive presence offered by palliative care was present. Among participants who received specialist palliative care, many found the intervention helpful, but few were able to articulate issues that the intervention improved. CONCLUSION: These findings suggest low levels of unmet palliative care needs among this population, which is consistent with the results of the parent trial. Targeting patients with a higher symptom burden perioperatively may allow for improved symptom management and better adherence to the treatment plan postoperatively, as well as be a more focused use of specialist palliative care clinicians' efforts.