Comparison of Pharmacological Treatments for Agitated Delirium in the Last Days of Life.

CONTEXT: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. OBJECTIVES: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days. METHODS: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3. RESULTS: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics. CONCLUSION: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.

Do Types of Opioids Matter for Terminal Cancer Dyspnea? A Preliminary Multicenter Cohort Study.

CONTEXT: Dyspnea is among the most distressing symptoms in the last weeks to days of life (terminal dyspnea). While physicians frequently use parenteral opioids other than morphine for terminal dyspnea, little is known about their effects in cancer patients. OBJECTIVES: To explore the effectiveness and safety of parenteral morphine, oxycodone, and hydromorphone for cancer patients with terminal dyspnea. METHODS: This was a secondary analysis of a multicenter cohort study that consecutively enrolled advanced cancer patients with moderate/severe terminal dyspnea. Participating palliative care physicians initiated parenteral opioids (morphine/oxycodone/hydromorphone), utilizing a standardized treatment algorithm. We examined the dyspnea intensity (Integrated Palliative care Outcome Scale [IPOS]) at 24 and 48 hours. RESULTS: Of 108 patients (mean age = 72), 66 (61%), 34 (32%), and 8 (7.4%) received morphine, oxycodone, and hydromorphone, respectively. At 24 hours, mean dyspnea IPOS scores significantly decreased from 3.0 (standard error (SE) = 0.1) at the baseline to 1.6 (0.1), 2.9 (0.1) to 2.0 (0.2), and 3.5 (0.2) to 1.2 (0.4) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.011) groups, respectively. At 48 hours, the IPOS scores significantly reduced from 2.9 (0.1) at the baseline to 1.4 (0.1), 2.9 (0.1) to 1.6 (0.2), and 3.5 (0.2) to 1.2 (0.2) in the morphine (P < 0.001), oxycodone (P < 0.001), and hydromorphone (P = 0.004) groups, respectively. No significant differences in mean scores were found among the three groups at 24 (P = 0.080) and 48 hours (P = 0.322). Adverse events were rare. CONCLUSION: Parenteral morphine, oxycodone, and hydromorphone may be similarly effective and safe for cancer patients with terminal dyspnea.

Current Management Options for Dyspnea in Cancer Patients.

OPINION STATEMENT: Dyspnea is one of the most frequent and distressing symptoms in patients with advanced cancer. As dyspnea deteriorates patients' quality of life markedly and tends to worsen as the disease progresses, comprehensive assessment and timely treatment of the underlying etiologies are essential. International guidelines recommend various non-pharmacological and pharmacological management options. However, there is a scarcity of confirmatory clinical trials on cancer dyspnea, and the overall level of evidence is weak. Recently, observational and survey studies indicated a wide range of practice patterns of palliative care specialists, providing important insight into the real-world management of dyspnea. In this paper, we summarize current management options for dyspnea in cancer patients, highlight major controversies in the literature, and propose future research directions toward quality care for patients with dyspnea and their families.

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life.

CONTEXT: How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care. OBJECTIVES: To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety. METHODS: A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death. RESULTS: A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to -0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three. CONCLUSION: The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

Systemic Opioids for Dyspnea in Cancer Patients: A Real-world Observational Study.

CONTEXT: Although Systemic opioids are recommended as a pharmacological treatment for cancer-related dyspnea, their effectiveness and safety needs to be investigated in a real-world context OBJECTIVES: To evaluate the effectiveness and safety of systemic regular opioids for dyspnea in cancer patients, in the real-world palliative care practice. METHODS: This was a multicenter prospective observational study. We consecutively enrolled adult cancer patients starting regular opioids (morphine, oxycodone, hydromorphone, or fentanyl) for dyspnea from 12 palliative care services across Japan. We evaluated dyspnea intensity using the Numerical Rating Scale (NRS) and Integrated Palliative Outcome Scale (IPOS) every 24 hours until 72 hours after starting opioids (T1-T3). We also evaluated common opioid-related adverse events (AEs) and other severe AEs. RESULTS: We enrolled 402 cancer patients. The proportion of responders was 68.8% (95%confidence intervals (CI): 0.63-0.74) at T1, 75.7% (95%CI: 0.70-0.81) at T2, and 82.1% (95%CI: 0.76-0.87) at T3. The mean differences in dyspnea NRS from baseline were 1.73 (95%CI: 1.46-1.99) at T1, 1.99 (95%CI: 1.71-2.28) at T2, and 2.47 (95%CI:2.13-2.82) at T3. The most common treatment-emergent AE was somnolence with an incidence of the severe form of approximately 10% throughout the study period. In the multivariate analysis, baseline dyspnea NRS ≥6 had a positive correlation with dyspnea relief by systemic regular opioids, while liver metastasis, clinician-predicted survival days, and opioid tolerance had a negative correlation. CONCLUSION: Regular systemic opioids were effective for dyspnea in real-world cancer patients.

The feasibility and effects of a pharmacological treatment algorithm for cancer patients with terminal dyspnea: A multicenter cohort study.

BACKGROUND: How clinicians treat patients with terminal dyspnea widely varies, which could hamper quality care. We visualized comprehensive pharmacological treatment delivered by palliative care physicians. AIM: To examine adherence to a comprehensive pharmacological treatment algorithm for patients with terminal dyspnea, and to explore its outcomes during 48 h. DESIGN: A multicenter cohort study at five sites (February 2020 to June 2021). SETTING/PARTICIPANTS: We prospectively enrolled consecutive patients with advanced cancer, Eastern Cooperative Oncology Group performance status 3-4, and moderate/severe dyspnea. Participating palliative care physicians initiated algorithm-based treatment. The primary outcome was the proportion of adherence to the treatment algorithm over 24 h (predefined goal, 70%). We evaluated the adherence, goal achievement, and dyspnea level with a numerical rating scale (NRS), as well as adverse events over 48 h. RESULTS: All 108 patients received algorithm-based pharmacological treatment. Among 96 and 87 patients who were alive at 24 and 48 h, respectively, 96 (100%; 95% confidence interval [CI] = 96%-100%) and 82 (94%; 95%CI = 87%-98%) continued to receive the algorithm treatment, respectively, and 66 (69%; 95%CI = 59%-77%) and 64 (74%; 95%CI = 63%-82%) achieved the treatment goals, respectively. Using a complete case analysis with paired t-tests, mean dyspnea NRS scores significantly reduced from 7.3 (standard error, 0.2) at the baseline to 4.9 (0.3) at 24 h (n = 72; p < 0.001), and 7.2 (0.3) at the baseline to 4.6 (0.4) at 48 h (n = 55; p < 0.001). Most adverse events were mild to moderate. CONCLUSIONS: The comprehensive pharmacological treatment algorithm was feasible, and the study data supports its preliminary efficacy and safety. The use of this algorithm may help clinicians improve care for patients with terminal dyspnea.

Morphine May Contribute to Improving Respiratory Failure in Severe COVID-19: A Case Report.

At present, the world is undergoing successive waves of the COVID-19 pandemic. When COVID-19 becomes severe, it causes respiratory failure and symptoms of dyspnoea. The patient's dyspnoea worsens to the IPOS of 3. One COVID-19 patient admitted to our medical institution developed severe illness characterised by hypoxaemia and dyspnoea. In addition to disease-modifying treatments such as remdesivir and dexamethasone, we administered morphine to relieve his dyspnoea. Surprisingly, we observed an improvement in both hypoxaemia and dyspnoea.

Feasibility of a fast-track randomized controlled trial of cell-free and concentrated ascites reinfusion therapy for patients with refractory malignant ascites.

BACKGROUND: Malignant ascites often causes discomfort in advanced cancer patients. Paracentesis is the most common treatment modality, but it requires frequently repeated treatment. Cell-free and concentrated ascites reinfusion therapy (CART) may prolong the paracentesis interval, but controlled trials are lacking. We assessed the feasibility of a randomized controlled trial of CART vs. paracentesis alone for patients with refractory malignant ascites. METHODS: This study was an open-label, fast-track, randomized controlled, feasibility trial. Patients admitted to four designated cancer hospitals who received no further anticancer treatments were eligible. Patients were randomly assigned 1:1 to a CART arm or control (simple paracentesis) arm. The feasibility endpoint was the percentage of patients who completed the study intervention. Secondary endpoints included paracentesis-free survival, patient's request on the questionnaire for paracentesis (PRO-paracentesis)-free survival (the period until the patients first reported that they would want paracentesis if indicated), and adverse events. RESULTS: We screened 953 patients for eligibility. Of 61 patients with refractory malignant ascites, 21 patients were determined as eligible. Finally, 20 patients consented and were allocated; 18 patients (90%, 95% CI: 68.3-98.8) completed the study intervention. All patients had an ECOG performance status of 3 or 4. The median drained ascites volume was 3,200 mL in the CART arm and 2,500 mL in the control arm. In the CART arm, the median reinfused albumin volume was 12.6 g. Median paracentesis-free survivals were 5 days (95% CI: 2-6) in the CART arm, and 6 days (3-9) in the control arm. Median PRO-paracentesis-free survivals were 4 days (2-5) and 5 days (1-9), respectively. A total of 73% of patients received paracentesis within 2 days from their first request for the next paracentesis. One patient in the CART arm developed Grade 1 fever. CONCLUSIONS: A fast-track randomized controlled trial of CART for patients with malignant ascites is feasible. The efficacy and safety of CART should be assessed in future trials. PRO-paracentesis-free survival may be a complementary outcome measure with paracentesis-free survival in future trials. TRIAL REGISTRATION: Registered at University Hospital Medical Information Network Clinical Trial Registry as UMIN000031029 . Registered on 28/01/2018.

Family experience of palliative sedation therapy: proportional vs. continuous deep sedation.

PURPOSE: Some patients experience intense symptoms refractory to intensive palliative care, and palliative sedation is sometimes used. Palliative sedation may be classified into proportional and continuous deep sedation (CDS). The primary aim of this study was to compare family experience between families of patients who received proportional or CDS. METHODS: A multicenter questionnaire survey was conducted involving bereaved families of cancer patients who received proportional or CDS based on a sedation protocol. Overall evaluation of sedation (satisfaction, family-perceived distress, appropriateness of timing, and patient distress) and 13-item family concerns, good death, satisfaction with care, depression, quality of care, unfinished business, and balance between symptom relief and maintaining communication were measured. RESULTS: Among the 2120 patients who died, 222 patients received a continuous infusion of midazolam. A sedation protocol was used in 147 patients, and questionnaires were sent to 124 families. A total of 78 responses were finally returned (proportional, 58 vs. CDS, 20). There were no significant differences in the overall evaluation, family concerns, total score of good death, satisfaction, depression, or balance between symptom relief and maintaining communication. On the other hand, some quality of care items, i.e., relationship with medical staff (P < 0.01), physical care by nurses (P = 0.04), and coordination and consistency (P = 0.04), were significantly better in the CDS group than in the proportional sedation group. Family-reported unfinished business was also better in the CDS group, with marginal significance. CONCLUSIONS: Family experience of CDS was not less favorable than proportional sedation, and actually rated more favorably for some elements of quality of care and unfinished business.

The Possibility of Conducting a Clinical Trial on Palliative Care: A Survey of Whether a Clinical Study on Cancer Dyspnea Is Acceptable to Cancer Patients and Their Relatives.

CONTEXT: Conducting randomized controlled trials on palliative care is difficult owing to barriers like fragility of the patients' health status and health care providers' concerns for patients. However, quality randomized controlled trials are required for care improvement. OBJECTIVES: To investigate the willingness of cancer patients and their relatives to participate in a clinical study on cancer dyspnea and identify feasible clinical study designs for this condition. METHODS: A nationwide, cross-sectional, web-based survey was conducted with 206 cancer patients and 206 relatives of cancer patients. Their willingness to participate in clinical studies on cancer dyspnea and factors influencing this willingness were assessed in two scenarios: outpatients receiving anticancer treatment and terminally ill inpatients. RESULTS: About 23% patients and 23% relatives were willing to participate in clinical trials while 40% and 32%, respectively, were unwilling. Factors related to patient participation were quick and easy trials (outpatient 57%, terminally ill 53%) and oral medication with minimal potential side effects (outpatient 48%). Factors related to unwillingness to participate were placebo-controlled trials (outpatient 51%, terminally ill 50%), disagreements about participation between patients and families (outpatient 49%, terminally ill 49%), and continuous injections (outpatient 61%, terminally ill 47%). Compared to patients, relatives responded more reluctantly, especially for patients in terminal care. Conversely, patients were less reluctant in the terminal setting than the outpatient setting. CONCLUSION: Some patients and relatives were reluctant to participate in clinical trials on cancer dyspnea. Thus, trials need to be minimally invasive, quick, and fully explained to and understood by patients and families.

Chronic pulmonary aspergillosis may cause eosinophilic granulomatosis with polyangiitis via allergic bronchopulmonary aspergillosis.

An 84-year-old man visited our hospital with a prolonged productive cough. Chest computed tomography showed a thick wall cavity and bilateral consolidations. Laboratory findings revealed peripheral blood eosinophilia, increased total IgE and elevated myeloperoxidase anti-neutrophil cytoplasmic antibody. Specific IgE and IgG antibodies and an immediate skin reaction against Aspergillus showed positive results. The histological findings of the lung parenchyma were compatible with eosinophilic pneumonia and bronchial biopsy showed eosinophilic vasculitis. Bronchoalveolar lavage fluid culture yielded Aspergillus fumigatus. These results met the diagnosis criteria for both allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatosis with polyangiitis (EGPA). This case thus suggests that A. fumigatus might be a pathogen common to both diseases, and prolonged exposure to A. fumigatus in some patients with ABPA may promote progression to EGPA.