Haloperidol versus placebo for delirium prevention in acutely hospitalised older at risk patients: a multi-centre double-blind randomised controlled clinical trial.

Background: because the few randomised placebo-controlled trials investigating the potential role for prophylactic haloperidol in delirium prevention have focused on specific surgical populations, we investigated its efficacy and safety in acutely hospitalised older patients. Methods: this multi-centre, double-blind, stratified, block randomised, placebo-controlled trial was conducted at six Dutch hospitals. Patients age ≥70 years, acutely admitted through the emergency department for general medicine or surgical specialties and at risk for delirium were randomised (n = 245) to haloperidol or placebo 1 mg orally twice-daily (maximum of 14 doses) on top of standard nonpharmacological prevention strategies. The primary outcome was delirium incidence. Other endpoints included delirium severity and duration, drug safety and clinical outcomes. Results: intention-to-treat analysis included 242 participants (calculated sample size n = 390, statistical power of current sample 59%) allocated to haloperidol (n = 118) or placebo (n = 124). In the haloperidol and placebo group, delirium incidence was 19.5 versus 14.5% (OR 1.43, 95% CI 0.72 to 2.78); median (IQR) delirium duration 4 (2, 5) versus 3 (1, 6) days (P = 0.366); maximum DRS-R-98 score 16 (9.8, 19.5) versus 10 (5.5, 22.5) (P = 0.549; 53.7% missing data); hospital LOS 7 (4, 10.3) versus 7 (5, 11.8) days (P = 0.343); 3-month mortality 9.9 versus 12.5% (OR 0.77, 95% CI 0.34 to 1.75), respectively. No treatment-limiting side effects were noted. Conclusions: prophylactic low-dose oral haloperidol did not reduce delirium incidence in acutely hospitalised older patients. Therefore, prophylactic use of haloperidol in this population is not recommended.

Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Delirium is associated with substantial morbidity and mortality rates in elderly hospitalised patients, and a growing problem due to increase in life expectancy. Implementation of standardised non-pharmacological delirium prevention strategies is challenging and adherence remains low. Pharmacological delirium prevention with haloperidol, currently the drug of choice for delirium, seems promising. However, the generalisability of randomised controlled trial results is questionable since studies have only been performed in selected postoperative hip-surgery and intensive care unit patient populations. We therefore present the design of the multicenter, randomised, double-blind, placebo-controlled clinical trial on early pharmacological intervention to prevent delirium: haloperidol prophylaxis in older emergency department patients (The HARPOON study). METHODS/DESIGN: In six Dutch hospitals, at-risk patients aged 70 years or older acutely admitted through the emergency department for general medicine and surgical specialties are randomised (n = 390) for treatment with prophylactic haloperidol 1 mg or placebo twice daily for a maximum of seven consecutive days. Primary outcome measure is the incidence of in-hospital delirium within seven days of start of the study intervention, diagnosed with the Confusion Assessment Method, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for delirium. Secondary outcome measures include delirium severity and duration assessed with the Delirium Rating Scale Revised 98; number of delirium-free days; adverse events; hospital length-of-stay; all-cause mortality; new institutionalisation; (Instrumental) Activities of Daily Living assessed with the Katz Index of ADL, and Lawton IADL scale; cognitive function assessed with the Six-item Cognitive Impairment Test, and the Dutch short form Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be contacted by telephone three and six months post-discharge to collect data on cognitive- and physical function, home residency, all-cause hospital admissions, and all-cause mortality. DISCUSSION: The HARPOON study will provide relevant information on the efficacy and safety of prophylactic haloperidol treatment for in-hospital delirium and its effects on relevant clinical outcomes in elderly at-risk medical and surgical patients. TRIAL REGISTRATION: EudraCT Number: 201100476215; ClinicalTrials.gov Identifier: NCT01530308; Dutch Clinical Trial Registry: NTR3207.

Nivolumab-Induced Exocrine Pancreatic Insufficiency.

Immunotherapy is increasingly gaining applicability for several malignancies. While the survival of several malignancies has dramatically improved, immune-related adverse events (irAEs) can occur and can cause severe damage to patients. Side effects such as colitis are well known nowadays; however, with increased use of immunotherapy, less common side effects should also be addressed. In this article, 2 patients that received nivolumab developed exocrine dysfunction of the pancreas. Endocrine dysfunction has been well known, but exocrine dysfunction is less often described. It is important to be aware of this side effect because it is possibly underdiagnosed. Symptoms often mimic symptoms of malignancy, chemotherapy side effects, or immune-related colitis. Although the exact mechanism is yet to be elaborated, dormant CD8+ T cells are likely to be involved. No known therapy is yet been proven to be effective. More knowledge and research about irAEs will lead to possible therapies that will be effective. Currently, high-dose prednisone is recommended based on expert opinion.

Rubidium-82 PET/CT in COVID-19.

A 56-year-old man presented to the emergency department with shortness of breath during the COVID-19 pandemic. Chest computed tomography angiography (CTa) showed bilateral peripheral ground-glass opacifications classified as CO-RADS 5, but no pulmonary embolism. To analyze the possibility of CTa-undetectable pulmonary microthrombi and to rule out cardiac perfusion abnormalities, we decided to perform a rubidium-82 (82Rb) PET/CT. 82Rb PET/CT imaging in this patient yielded uptake in the pulmonary areas of ground-glass opacification and showed corresponding findings between 82Rb PET/CT and CTa imaging without any signs of microthrombi despite the elevated d-dimer. Even in the areas of profound groundglass opacifications, the increased 82Rb uptake indicates that perfusion is adequate to acquire 82Rb uptake in the pulmonary cells. 82Rb PET/CT is a promising imaging technique and might extend the diagnostic potential of conventional nuclear and radiological imaging in detecting pulmonary microthrombi or other minor perfusion defects.

Geriatric screening, fall characteristics and 3- and 12 months adverse outcomes in older patients visiting the emergency department with a fall.

BACKGROUND: Falls in older Emergency Department (ED) patients may indicate underlying frailty. Geriatric follow-up might help improve outcomes in addition to managing the direct cause and consequence of the fall. We aimed to study whether fall characteristics and the result of geriatric screening in the ED are independently related to adverse outcomes in older patients with fall-related ED visits. METHODS: This was a secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study, of which a subset of patients aged ≥70 years with fall-related ED visits were prospectively included in EDs of two Dutch hospitals. Fall characteristics (cause and location) were retrospectively collected. The APOP-screener was used as a geriatric screening tool. The outcome was 3- and 12-months functional decline and mortality. We assessed to what extent fall characteristics and the geriatric screening result were independent predictors of the outcome, using multivariable logistic regression analysis. RESULTS: We included 393 patients (median age 80 (IQR 76-86) years) of whom 23.0% were high risk according to screening. The cause of the fall was extrinsic (49.6%), intrinsic (29.3%), unexplained (6.4%) or missing (14.8%). A high risk geriatric screening result was related to increased risk of adverse outcomes (3-months adjusted odds ratio (AOR) 2.27 (1.29-3.98), 12-months AOR 2.20 (1.25-3.89)). Independent of geriatric screening result, an intrinsic cause of the fall increased the risk of 3-months adverse outcomes (AOR 1.92 (1.13-3.26)) and a fall indoors increased the risk of 3-months (AOR 2.14 (1.22-3.74)) and 12-months adverse outcomes (AOR 1.78 (1.03-3.10)). CONCLUSIONS: A high risk geriatric screening result and fall characteristics were both independently associated with adverse outcomes in older ED patients, suggesting that information on both should be evaluated to guide follow-up geriatric assessment and interventions in clinical care.

Geriatric Screening, Triage Urgency, and 30-Day Mortality in Older Emergency Department Patients.

BACKGROUND: Urgency triage in the emergency department (ED) is important for early identification of potentially lethal conditions and extensive resource utilization. However, in older patients, urgency triage systems could be improved by taking geriatric vulnerability into account. We investigated the association of geriatric vulnerability screening in addition to triage urgency levels with 30-day mortality in older ED patients. DESIGN: Secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study. SETTING: EDs within four Dutch hospitals. PARTICIPANTS: Consecutive patients, aged 70 years or older, who were prospectively included. MEASUREMENTS: Patients were triaged using the Manchester Triage System (MTS). In addition, the APOP screener was used as a geriatric screening tool. The primary outcome was 30-day mortality. Comparison was made between mortality within the geriatric high- and low-risk screened patients in every urgency triage category. We calculated the difference in explained variance of mortality by adding the geriatric screener (APOP) to triage urgency (MTS) by calculating Nagelkerke R2 . RESULTS: We included 2,608 patients with a median age of 79 (interquartile range = 74-84) years, of whom 521 (20.0%) patients were categorized as high risk according to geriatric screening. Patients were triaged on urgency as standard (27.2%), urgent (58.5%), and very urgent (14.3%). In total, 132 (5.1%) patients were deceased within a period of 30 days. Within every urgency triage category, 30-day mortality was threefold higher in geriatric high-risk compared to low-risk patients (overall = 11.7% vs 3.4%; P < .001). The explained variance of 30-day mortality with triage urgency was 1.0% and increased to 6.3% by adding the geriatric screener. CONCLUSION: Combining triage urgency with geriatric screening has the potential to improve triage, which may help clinicians to deliver early appropriate care to older ED patients. J Am Geriatr Soc 68:1755-1762, 2020.

Determinants of self-rated health in older adults before and 3 months after an emergency department visit: a prospective study.

OBJECTIVES: Self-rated health (SRH) is an important patient-reported outcome, but little is known about SRH after a visit to the emergency department (ED). We investigated the determinants of decline in SRH during 3 months after an ED visit in older patients. DESIGN: This was a multicenter prospective cohort study including acutely presenting older ( ≥ 70 years) patients in the ED (the Netherlands). Patients were asked to self-rate their health between 0 and 10. The main outcome was a decline in SRH defined as a transition of a SRH of at least 6 to a SRH of less than 6, 3 months after the patient's visit to the ED. RESULTS: Three months after the ED visit, 870 (71.4%) patients had a stable SRH and 209 (11.5%) patients declined in SRH. Independent predictors with a decline in SRH were: male gender (OR 1.83) living alone (OR 1.56), living in residential care or nursing home (OR 2.75), number of different medications (OR 1.08), using a walking device (OR 1.70), and the Katz-ADL score (OR 1.22). Patients with functional decline 3 months after an ED visit show a steeper decline in the mean SRH (0.68 points) than patients with no functional decline (0.12 points, P < 0.001). CONCLUSION: Decline in SRH after an ED visit in older patients is at least partly dependent on factors of functional capacity and functional decline. Preventive interventions to maintain functional status may be the solution to maintain SRH, but more research is needed to further improve and firmly establish the clinical usability of these findings.

Vital signs and impaired cognition in older emergency department patients: The APOP study.

BACKGROUND/OBJECTIVES: Cognitive impairment is a frequent problem among older patients attending the Emergency Department (ED) and can be the result of pre-existing cognitive impairment, delirium, or neurologic disorders. Another cause can also be acute disturbance of brain perfusion and oxygenation, which may be reversed by optimal resuscitation. This study aimed to assess the relationship between vital signs, as a measure of acute hemodynamic changes, and cognitive impairment in older ED patients. DESIGN: Prospective cohort study. SETTING: ED's of two tertiary care and two secondary care hospitals in the Netherlands. PARTICIPANTS: 2629 patients aged 70-years and older. MEASUREMENTS: Vital signs were measured at the moment of ED arrival as part of routine clinical care. Cognition was measured using the Six-Item Cognitive Impairment Test (6-CIT). RESULTS: The median age of patients was 78 years (IQR 74-84). Cognitive impairment was present in 738 patients (28.1%). When comparing lowest with highest quartiles, a systolic blood pressure of <129 mmHg (OR 1.30, 95% confidence interval (95%CI) 0.98-1.73)was associated with increased risk of cognitive impairment. A higher respiratory rate (>21/min) was associated with increased risk of impaired cognition (OR 2.16, 95% CI 1.58-2.95) as well as oxygen saturation of <95% (OR 1.64, 95%CI 1.24-2.19). CONCLUSION: Abnormal vital signs associated with decreased brain perfusion and oxygenation are also associated with cognitive impairment in older ED patients. This may partially be explained by the association between disease severity and delirium, but also by acute disturbance of brain perfusion and oxygenation. Future studies should establish whether normalization of vital signs will also acutely improve cognition.

Predictors and Outcomes of Revisits in Older Adults Discharged from the Emergency Department.

OBJECTIVES: To study predictors of emergency department (ED) revisits and the association between ED revisits and 90-day functional decline or mortality. DESIGN: Multicenter cohort study. SETTING: One academic and two regional Dutch hospitals. PARTICIPANTS: Older adults discharged from the ED (N=1,093). MEASUREMENTS: At baseline, data on demographic characteristics, illness severity, and geriatric parameters (cognition, functional capacity) were collected. All participants were prospectively followed for an unplanned revisit within 30 days and for functional decline and mortality 90 days after the initial visit. RESULTS: The median age was 79 (interquartile range 74-84), and 114 participants (10.4%) had an ED revisit within 30 days of discharge. Age (hazard ratio (HR)=0.96, 95% confidence interval (CI)=0.92-0.99), male sex (HR=1.61, 95% CI=1.05-2.45), polypharmacy (HR=2.06, 95% CI=1.34-3.16), and cognitive impairment (HR=1.71, 95% CI=1.02-2.88) were independent predictors of a 30-day ED revisit. The area under the receiver operating characteristic curve to predict an ED revisit was 0.65 (95% CI=0.60-0.70). In a propensity score-matched analysis, individuals with an ED revisit were at higher risk (odds ratio=1.99 95% CI=1.06-3.71) of functional decline or mortality. CONCLUSION: Age, male sex, polypharmacy, and cognitive impairment were independent predictors of a 30-day ED revisit, but no useful clinical prediction model could be developed. However, an early ED revisit is a strong new predictor of adverse outcomes in older adults.

18F-fluorodeoxyglucose positron emission tomography in elderly patients with an elevated erythrocyte sedimentation rate of unknown origin.

Patients with an elevated erythrocyte sedimentation rate (ESR) and non-specific symptoms often pose a diagnostic dilemma. PET/CT visualises infection, inflammation and malignancy, all of which may cause elevated ESR. The objective of this study was to determine the contribution of 18F-fluorodeoxglucose positron emission tomography (PET/CT) in the diagnostic work-up of referred patients with an elevated ESR, in whom initial routine evaluation did not reveal a diagnosis. We conducted a combined retrospective (A) and prospective (B) study in elderly (>50 years) patients with a significantly elevated ESR of ≥ 50 mm/h and non-specific complaints. In study A, 30 patients were included. Malignancy (8 patients), auto-inflammatory disease (8 patients, including 5 with large-vessel vasculitis) and infection (3 patients) were suggested by PET/CT. Two scans showed non-specific abnormalities and 9 scans were normal. Of the 21 abnormal PET/CT results, 12 diagnoses were independently confirmed and two alternative diagnosis were made. Two diagnoses were established in patients with a normal scan. In study B, 58 patients in whom a prior protocolised work-up was non-diagnostic, were included. Of these, 25 PET/CT-scans showed suspected auto-inflammatory disease, particularly large-vessel vasculitis (14 cases). Infection and malignancy was suspected in 5 and 3 cases, respectively. Seven scans demonstrated non-specific abnormalities, 20 were normal. Of the 40 abnormal PET/CT results, 22 diagnoses were confirmed, 3 alternative diagnoses were established. Only one diagnosis was established in the 20 patients with a normal scan. In both studies, the final diagnosis was based on histology, clinical follow-up, response to therapy or additional imaging. In conclusion, PET/CT may be of potential value in the diagnostic work-up of patients with elevated ESR if routine evaluation reveals no diagnosis. In particular, large-vessel vasculitis appears to be a common finding. A normal PET/CT scan in these patients suggests that it is safe to follow a wait-and-see policy.

[Clinical manifestations and hazards of brucellosis in the Netherlands]. / Klinisch beeld en gevaren van brucellose in Nederland.

Brucellosis, a zoonotic infection characterised by undulant fever, has a low incidence in the Netherlands and is therefore rarely considered. We describe 3 patients aged 26, 47 and 56 years old; each presented with long-standing fever as predominant symptom after having travelled to an endemic area, Iraq or Turkey, 1 week to 4 months prior to manifestation of illness. They had similar symptoms: fever, weight loss, chills, night sweats and dry cough. Blood cultures of all patients became positive for gram-negative rods after 3-4 days of incubation. One patient had imported and consumed sheep-milk cheese from which a genetically indistinguishable Brucella strain was cultured. In another patient, identification of the bacterium proved difficult, resulting in delayed prescription of adequate antibiotic treatment. Serologic testing confirmed the diagnosis in this case. In the laboratory, there is a considerable risk of airborne transmission of the disease necessitating clear notification of the suspicion of brucellosis when material for culturing is submitted.