Olanzapine Versus Haloperidol for Treatment of Delirium in Patients with Advanced Cancer: A Phase III Randomized Clinical Trial.

BACKGROUND: Treatment of delirium often includes haloperidol. Second-generation antipsychotics like olanzapine have emerged as an alternative with possibly fewer side effects. The aim of this multicenter, phase III, randomized clinical trial was to compare the efficacy and tolerability of olanzapine with haloperidol for the treatment of delirium in hospitalized patients with advanced cancer. MATERIALS AND METHODS: Eligible adult patients (≥18 years) with advanced cancer and delirium (Delirium Rating Scale-Revised-98 [DRS-R-98] total score ≥17.75) were randomized 1:1 to receive either haloperidol or olanzapine (age-adjusted, titratable doses). Primary endpoint was delirium response rate (DRR), defined as number of patients with DRS-R-98 severity score <15.25 and ≥4.5 points reduction. Secondary endpoints included time to response (TTR), tolerability, and delirium-related distress. RESULTS: Between January 2011 and June 2016, 98 patients were included in the intention-to-treat analysis. DRR was 45% (95% confidence interval [CI], 31-59) for olanzapine and 57% (95% CI, 43-71) for haloperidol (Δ DRR -12%; odds ratio [OR], 0.61; 95% CI, 0.2-1.4; p = .23). Mean TTR was 4.5 days (95% CI, 3.2-5.9 days) for olanzapine and 2.8 days (95% CI, 1.9-3.7 days; p = .18) for haloperidol. Grade ≥3 treatment-related adverse events occurred in 5 patients (10.2%) and 10 patients (20.4%) in the olanzapine and haloperidol arm, respectively. Distress rates were similar in both groups. The study was terminated early because of futility. CONCLUSION: Delirium treatment with olanzapine in hospitalized patients with advanced cancer did not result in improvement of DRR or TTR compared with haloperidol. Clinical trial identification number. NCT01539733. Dutch Trial Register. NTR2559. IMPLICATIONS FOR PRACTICE: Guidelines recommend that pharmacological interventions for delirium treatment in adults with cancer should be limited to patients who have distressing delirium symptoms. It was suggested that atypical antipsychotics, such as olanzapine, outperform haloperidol in efficacy and safety. However, collective data comparing the efficacy and safety of typical versus atypical antipsychotics in patients with cancer are limited. If targeted and judicious use of antipsychotics is considered for the treatment of delirium in patients with advanced cancer, this study demonstrated that there was no statistically significant difference in response to haloperidol or olanzapine. Olanzapine showed an overall better safety profile compared with haloperidol, although this difference was not statistically significant.

Accuracy of the Delirium Observational Screening Scale (DOS) as a screening tool for delirium in patients with advanced cancer.

BACKGROUND: The Delirium Observation Screening Scale (DOS) was developed to facilitate early recognition of delirium by nurses during routine clinical care. It has shown good validity in a variety of patient populations, but has not yet been validated in hospitalized patients with advanced cancer, although the DOS is commonly used in this setting in daily practice. The aim of this study was to evaluate the accuracy of the DOS in hospitalized patients with advanced cancer using the revised version of the Delirium Rating Scale (DRS-R- 98) as the gold standard. METHODS: Patients with advanced cancer admitted to the medical oncology ward were screened for delirium with the DOS and DRS-R-98. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of the DOS were calculated, using a DOS score ≥ 3 as a cut-off for delirium. RESULTS: Ninety-five DOS negative and 98 DOS positive patients were identified. Sensitivity of the DOS, was > 99.9% (95%-CI, 95.8-100.0%), specificity was 99.5% (95%-CI 95.5-99.96%), PPV was 94.6% (95% CI 88.0-97.7), and NPV was > 99.9% (95% CI 96.1-100.0). CONCLUSIONS: The DOS is an accurate screening tool for delirium in patients with advanced cancer. Since it has the benefit of being easily implicated in daily practice, we recommend to educate caregivers to screen patients with advanced cancer by DOS analysis. By early recognition and adequate treatment of this distressing delirium syndrome the quality of life of patients with advanced cancer can be improved. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01539733 (Feb 27, 2012 - retrospectively registered), Netherlands Trial Register NTR2559 (Oct 7, 2010).

Medication Use in the Last Days of Life in Hospital, Hospice, and Home Settings in the Netherlands.

BACKGROUND: The purpose of medication management in the last days of life is to optimize patient's comfort. Little is known about the medication use in the days before death and how this relates to the care setting. OBJECTIVE: To describe medication use in the last week of life for patients dying in hospital, hospice, and home settings in the Netherlands. DESIGN: Retrospective chart review study. SETTING: A convenience sample of patient records from the three settings in three different regions in the Netherlands that cover more than half the country. MEASUREMENTS: Information about medication use in the last week of life of patients who ultimately died an expected death was registered, including type of medication, start and if applicable stop dates, administration routes, and doses. RESULTS: One hundred seventy-nine records were analyzed. Medications most frequently used in the last week of life were analgesics (n = 168, 94.1%) and psycholeptics (n = 150, 84.7%), in particular by hospice patients. The mean number of medications used per patient was nine during day 7 before death and six on the day of dying. On the day of death, 48 (26.8%) patients used a preventive medication. This percentage was highest for patients dying in the hospital or at home. CONCLUSIONS: Patients who die an expected death receive many medications in the last week of life, part of which are preventive medications. Medication management in patients' final days of life can be improved, especially in the hospital and home setting.

Predictors of Persistent Neuropathic Pain--A Systematic Review.

BACKGROUND: Characterization of the prognostic variables for persistent neuropathic pain (PNP) remains incomplete despite multiple articles addressing this topic. To provide more insight into the recovery and prognosis of neuropathic pain, high-quality data are required that provide information about the predictors that contribute to the development of PNP. OBJECTIVE: To determine the methodological quality of studies about predictors for PNP and to summarize findings of predictors found in high-quality studies. STUDY DESIGN: A systematic review. SETTING: VU University Medical Center, Amsterdam, The Netherlands. METHODS: Studies were identified by searching the electronic databases PubMed, Embase, and Cochrane Library. Methodological quality of each article was independently assessed by 2 reviewers. RESULTS: Forty-six relevant studies were identified, classified into 4 different neuropathic pain (NP)-syndromes: postherpetic neuralgia (n = 35), radicular pain and sciatica (n = 3), postsurgical pain (n = 6), and other types of NP (n = 2). Seven studies were of high quality. The 3 high-quality studies found for PHN reported male gender, older age, smoking, trauma at the site of lesion, missed antiviral prescriptions, higher acute pain severity, higher rash severity, more neuropathic characteristics, shorter rash duration, and a lower health status as predictors for PNP. For persistence of radicular pain one high-quality study reported negative outcome expectancies, pain-related fear of movement, and passive pain coping as predictors for PNP. Psychological distress, acute pain, breast cancer surgery, higher body mass index, area of secondary hyperalgesia, neuropathic characteristics, hypoesthesia, and hyperesthesia were found to be predictive for postsurgical pain in 3 high-quality studies. LIMITATIONS: Some publications may have been missed during literature search. The low-quality of the studies could be the result of an incomplete description of their methods. CONCLUSIONS: High-quality studies mainly assessed factors related to disease functions and structures. Due to shortcomings in methodological quality and limited areas of predictor selection, there is a need for high-quality studies focusing on predictor measurement, statistical analysis and the use of a standardized set of predictors.

Pain in dementia: prevalence and associated factors: protocol of a multidisciplinary study.

BACKGROUND: Pain is a common problem in people with dementia, however the exact prevalence of pain in dementia subtypes, e.g. Alzheimer's Disease (AD), Vascular Dementia (VaD), Frontotemporal Dementia (FTD) and dementia with Lewy Bodies (DLB), is unknown, as is the relation between pain and the different subtypes of dementia. In this study, the prevalence of pain in people with dementia will be investigated per dementia subtype and the relationship between the various subtypes of dementia and the presence of specific types of pain (i.e. musculoskeletal pain, neuropathic pain and orofacial pain) will be examined. Secondly, associations between various types of pain, cognitive functioning, neuropsychiatric symptoms and quality of life in people with dementia will be examined. A third purpose is to study the value of the assessment of autonomic responses in assessing pain in people with dementia. Finally, the effect of feedback to the attending physician on the presence of pain, based on examination by investigators with backgrounds in neuropsychology, geriatric dentistry and elderly care medicine, will be evaluated. METHODS/DESIGN: A cross-sectional, partially longitudinal observational study in 400 participants with dementia, aged 60 years and older. Participants will be recruited from an outpatient memory clinic and dementia special care units. All participants will be examined by an elderly care medicine trainee, a dentist with experience in geriatric dentistry, and a neuropsychologist. The primary outcome is presence of pain. Secondary outcomes will include oral health, autonomic responses to pain stimulus, vital sensibility and gnostic sensibility, musculoskeletal examination, cognitive functioning, neuropsychiatric symptoms, and quality of life. DISCUSSION: This study will help to enhance our knowledge regarding the prevalence of different types of pain in different dementia subtypes i.e. AD, VaD, FTD and DLB. This study also aims to contribute to a better understanding of oral health status in people with dementia, the use of autonomic responses in the assessment of pain in people with dementia and the relationships between pain and cognitive symptoms, neuropsychiatric symptoms and quality of life in people with various dementia subtypes and in different stages of the disease.

The palliative performance scale applied in high-care residential hospice: a retrospective study.

BACKGROUND: The Palliative Performance Scale (PPS) is a tool that is widely used to predict end of life. In Ontario, Canada, the PPS is used to mark the terminal phase of life and eligibility for terminal care. OBJECTIVE: The aim of this retrospective study was to confirm that a PPS level of 40% can be used as a marker for the terminal phase of life. METHOD: PPS levels from 78 patients were calculated based on the intake reports made at admission to an inpatient hospice. RESULTS: Although 77 patients passed away within a period of 3 months, PPS levels at admission varied from 10% to 70%. Fifty-six percent of all patients had a PPS level of 40% or less. Regarding survival, three significant PPS profiles, consisting of two or more PPS levels could be distinguished.

A favorable course of palliative sedation: searching for indicators using caregivers' perspectives.

OBJECTIVE: Comparing characteristics of a favorable sedation course during palliative sedation to a less favorable course based on the reports Dutch physicians and nurses. RESULTS: Cases identified as having a favorable sedation course less often concerned a male patient (P = .019 nurses' cases), reached the intended sedation depth significantly quicker (P < .05 both nurses and physicians' cases), reached a deeper level of sedation (P = .015 physicians' cases), and had a shorter total duration of sedation compared (P < .001 physicians' cases) to patients with a less favorable sedation course. CONCLUSIONS: A favorable course during palliative sedation seems more probable when health care professionals report on a (relatively) shorter time to reach the required depth of sedation and when a deeper level of sedation can be obtained.

Continuous palliative sedation: not only a response to physical suffering.

BACKGROUND: Palliative sedation is a medical intervention aimed at relieving symptoms that can no longer be controlled by conventional treatment. Ample knowledge is available regarding the nature of such symptoms, but there is no in-depth information regarding how health care workers decide about palliative sedation. OBJECTIVE: The study objective was to investigate considerations concerning the indications for continuous palliative sedation (CPS) and issues that influence these considerations. DESIGN: The study consisted of qualitative interviews regarding patients who had recently received CPS. SETTING/SUBJECTS: The study involved physicians and nurses working in general practice, nursing homes, and hospitals. MEASUREMENT: Analyses by a multidisciplinary research team used the constant comparative method. RESULTS: Together with physical symptoms, psychological and existential suffering may combine to produce a refractory state for which other treatment options than CPS were not available or considered inappropriate. A limited life expectancy was by many considered crucial (e.g., to avoid hastening death) and by some less important (e.g., because the patient's suffering was considered to be key). Issues influencing the decision to use CPS related to patient preferences (e.g., dignity, not wanting to experience further suffering) or family issues (impact of suffering on family, family requesting CPS). CONCLUSIONS: The indication for CPS typically originates from physical symptoms and nonphysical problems producing a refractory state in which a patient suffers unbearably. In such states, preferences of patients and families and the life expectancy criterion are weighed against the severity of refractory symptoms. Therefore the use of CPS is not only a response to the physical suffering of patients in the dying phase.

Intravenous magnesium for chronic complex regional pain syndrome type 1 (CRPS-1).

OBJECTIVE: To assess the effects of intravenous administration of magnesium on complex regional pain syndrome type 1 (CRPS-1), a randomized double-blind placebo-controlled trial was performed. METHODS: Fifty-six patients with CRPS-1 (International Association for the Study of Pain Orlando criteria) received MgSO(4) 70 mg/kg or placebo (NaCl 0.9%) in 4 hours over 5 consecutive days. Pain (BOX-11 and McGill), the level of impairment (Impairment level Sum Score [ISS]), functional limitations (Radboud Skills Questionnaire, Walking Skills Questionnaire/questionnaire rising and sitting down), participation (Impact on Participation and Autonomy [IPA]), and quality of life (Short Form-36, EuroQol, IPA) were evaluated at baseline and at 1, 3, 6, and 12 weeks. RESULTS: No significant differences were found between MgSO(4) and placebo on the BOX-11 and ISS at different time points during the trial on intention-to-treat and per-protocol analysis. A significant improvement on the BOX-11 was found after the first week of the trial in both groups (mean 0.7; standard deviation 1.1). For the MgSO(4) group, a clinically relevant and statistically significant improvement on the ISS at 1 week (median 5, interquartile range [IQR] -1 to 8) and a significant improvement on the McGill up to 6 weeks (median 2 words, IQR 0-4.5) were found compared with baseline, which were not found in the placebo group. Significant improvement in perceived job participation was found for the MgSO(4) group at 12 weeks (median improvement 1.44-1.17; P = 0.01). ISS improved significantly more in patients with a low Hospital Anxiety and Depression Scale (HADS) score (≤10) in the MgSO(4) group (mean 4.4 vs mean -3.1; P = 0.02). CONCLUSION: Administration of the physiological competitive N-methyl-D-aspartate receptor antagonist magnesium in chronic CRPS provides insufficient benefit over placebo. Future research should focus on patients with acute CRPS and early signs and symptoms of central sensitization.

Oxidative stress in Complex Regional Pain Syndrome (CRPS): no systemically elevated levels of malondialdehyde, F2-isoprostanes and 8OHdG in a selected sample of patients.

Exaggerated inflammation and oxidative stress are involved in the pathogenesis of Complex Regional Pain Syndrome (CRPS). However, studies assessing markers for oxidative stress in CRPS patients are limited. In this study, markers for lipid peroxidation (malondialdehyde and F2-isoprostanes) and DNA damage (8-hydroxy-2-deoxyguanosine) were measured in nine patients (mean age 50.1 ± 17.1 years) with short term CRPS-1 (median 3 months) and nine age and sex matched healthy volunteers (mean age 49.3 ± 16.8 years) to assess and compare the level of oxidative stress. No differences were found in plasma between CRPS patients and healthy volunteers for malondialdehyde (5.2 ± 0.9 µmol/L vs. 5.4 ± 0.5 µmol/L) F2-isoprostanes (83.9 ± 18.7 pg/mL vs. 80.5 ± 12.3 pg/mL) and 8-hydroxy-2-deoxyguanosine (92.6 ± 25.5 pmol/L vs. 86.9 ± 19.0 pmol/L). Likewise, in urine, no differences were observed between CRPS patients and healthy volunteers for F2-isoprostanes (117 ng/mmol, IQR 54.5-124.3 vs. 85 ng/mmol, IQR 55.5-110) and 8-hydroxy-2-deoxyguanosine (1.4 ± 0.7 nmol/mmol vs. 1.4 ± 0.5 nmol/mmol). Our data show no elevation of systemic markers of oxidative stress in CRPS patients compared to matched healthy volunteers. Future research should focus on local sampling methods of oxidative stress with adequate patient selection based on CRPS phenotype and lifestyle.