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).

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.

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.

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.

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.

The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review.

BACKGROUND: Palliative sedation is the intentional lowering of consciousness of a patient in the last phase of life to relieve suffering from refractory symptoms such as pain, delirium and dyspnoea. AIM: In this systematic review, we evaluated the use of monitoring scales to assess the degree of control of refractory symptoms and/or the depth of the sedation. DESIGN: A database search of PubMed and Embase was performed up to January 2010 using the search terms 'palliative sedation' OR 'terminal sedation'. DATA SOURCES: Retro- and prospective studies as well as reviews and guidelines containing information about monitoring of palliative sedation, written in the English, German or Dutch language were included. RESULTS: The search yielded 264 articles of which 30 were considered relevant. Most studies focused on monitoring refractory symptoms (pain, fatigue or delirium) or the level of awareness to control the level of sedation. Four prospective and one retrospective study used scales validated in other settings: the Numeric Pain Rating Scale, the Visual Analogue Scale, the Memorial Delirium Assessment Scale, the Communication Capacity Scale and Agitation Distress Scale. Only the Community Capacity Scale was partially validated for use in a palliative sedation setting. One guideline described the use of a scale validated in another setting. CONCLUSIONS: A minority of studies reported the use of observational scales to monitor the effect of palliative sedation. Future studies should be focused on establishing proper instruments, most adequate frequency and timing of assessment, and interdisciplinary evaluation of sedation depth and symptom control for palliative sedation.

Palliative sedation: reliability and validity of sedation scales.

CONTEXT: Observer-based sedation scales have been used to provide a measurable estimate of the comfort of nonalert patients in palliative sedation. However, their usefulness and appropriateness in this setting has not been demonstrated. OBJECTIVES: To study the reliability and validity of observer-based sedation scales in palliative sedation. METHODS: A prospective evaluation of 54 patients under intermittent or continuous sedation with four sedation scales was performed by 52 nurses. Included scales were the Minnesota Sedation Assessment Tool (MSAT), Richmond Agitation-Sedation Scale (RASS), Vancouver Interaction and Calmness Scale (VICS), and a sedation score proposed in the Guideline for Palliative Sedation of the Royal Dutch Medical Association (KNMG). Inter-rater reliability was tested with the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient. Correlations between the scales using Spearman's rho tested concurrent validity. We also examined construct, discriminative, and evaluative validity. In addition, nurses completed a user-friendliness survey. RESULTS: Overall moderate to high inter-rater reliability was found for the VICS interaction subscale (ICC = 0.85), RASS (ICC = 0.73), and KNMG (ICC = 0.71). The largest correlation between scales was found for the RASS and KNMG (rho = 0.836). All scales showed discriminative and evaluative validity, except for the MSAT motor subscale and VICS calmness subscale. Finally, the RASS was less time consuming, clearer, and easier to use than the MSAT and VICS. CONCLUSION: The RASS and KNMG scales stand as the most reliable and valid among the evaluated scales. In addition, the RASS was less time consuming, clearer, and easier to use than the MSAT and VICS. Further research is needed to evaluate the impact of the scales on better symptom control and patient comfort.

Pressure during decision making of continuous sedation in end-of-life situations in Dutch general practice.

BACKGROUND: Little is known about pressure from patients or relatives on physician's decision making of continuous palliative sedation. We aim to describe experienced pressure by general practitioners (GPs) in cases of continuous sedation after the introduction of the Dutch practice guideline, using a questionnaire survey. METHODS: A sample of 918 Dutch GPs were invited to fill out a questionnaire about their last patient under continuous sedation. Cases in which GPs experienced pressure from the patient, relatives or other persons were compared to those without pressure. RESULTS: 399 of 918 invite GPs (43%) returned the questionnaire and 250 provided detailed information about their most recent case of continuous sedation. Forty-one GPs (16%) indicated to have experienced pressure from the patient, relatives or colleagues. In GPs younger than 50, guideline knowledge was not related to experienced pressure, whereas in older GPs, 15% with and 36% without guideline knowledge reported pressure. GPs experienced pressure more often when patients had psychological symptoms (compared to physical symptoms only) and when patients had a longer estimated life expectancy. A euthanasia request of the patient coincided with a higher prevalence of pressure for GPs without, but not for GPs with previous experience with euthanasia. GPs who experienced pressure had consulted a palliative consultation team more often than GPs who did not experience pressure. CONCLUSION: One in six GPs felt pressure from patients or relatives to start sedation. This pressure was related to guideline knowledge, especially in older GPs, longer life expectancy and the presence of a euthanasia request, especially for GPs without previous experience of euthanasia.

Considerations of physicians about the depth of palliative sedation at the end of life.

BACKGROUND: Although guidelines advise titration of palliative sedation at the end of life, in practice the depth of sedation can range from mild to deep. We investigated physicians' considerations about the depth of continuous sedation. METHODS: We performed a qualitative study in which 54 physicians underwent semistructured interviewing about the last patient for whom they had been responsible for providing continuous palliative sedation. We also asked about their practices and general attitudes toward sedation. RESULTS: We found two approaches toward the depth of continuous sedation: starting with mild sedation and only increasing the depth if necessary, and deep sedation right from the start. Physicians described similar determinants for both approaches, including titration of sedatives to the relief of refractory symptoms, patient preferences, wishes of relatives, expert advice and esthetic consequences of the sedation. However, physicians who preferred starting with mild sedation emphasized being guided by the patient's condition and response, and physicians who preferred starting with deep sedation emphasized ensuring that relief of suffering would be maintained. Physicians who preferred each approach also expressed different perspectives about whether patient communication was important and whether waking up after sedation is started was problematic. INTERPRETATION: Physicians who choose either mild or deep sedation appear to be guided by the same objective of delivering sedation in proportion to the relief of refractory symptoms, as well as other needs of patients and their families. This suggests that proportionality should be seen as a multidimensional notion that can result in different approaches toward the depth of sedation.

Continuous palliative sedation for cancer and noncancer patients.

CONTEXT: Palliative care is often focused on cancer patients. Palliative sedation at the end of life is an intervention to address severe suffering in the last stage of life. OBJECTIVES: To study the practice of continuous palliative sedation for both cancer and noncancer patients. METHODS: In 2008, a structured questionnaire was sent to 1580 physicians regarding their last patient receiving continuous sedation until death. RESULTS: A total of 606 physicians (38%) filled out the questionnaire, of whom 370 (61%) reported on their last case of continuous sedation (cancer patients: n=282 [76%] and noncancer patients: n=88 [24%]). More often, noncancer patients were older, female, and not fully competent. Dyspnea (odds ratio [OR]=2.13; 95% confidence interval [CI]: 1.22, 3.72) and psychological exhaustion (OR=2.64; 95% CI: 1.26, 5.55) were more often a decisive indication for continuous sedation for these patients. A palliative care team was consulted less often for noncancer patients (OR=0.45; 95% CI: 0.21, 0.96). Also, preceding sedation, euthanasia was discussed less often with noncancer patients (OR=0.42; 95% CI: 0.24, 0.73), whereas their relatives more often initiated discussion about euthanasia than relatives of cancer patients (OR=3.75; 95% CI: 1.26, 11.20). CONCLUSION: The practice of continuous palliative sedation in patients dying of cancer differs from patients dying of other diseases. These differences seem to be related to the less predictable course of noncancer diseases, which may reduce physicians' awareness of the imminence of death. Increased attention to noncancer diseases in palliative care practice and research is, therefore, crucial as is more attention to the potential benefits of palliative care consultation.

Palliative sedation at home in the Netherlands: a nationwide survey among nurses.

AIM: This paper is a report of a nationwide study conducted to assess experiences of nurses involved in palliative sedation at home after introduction of a physicians' guideline for palliative sedation. BACKGROUND: Most studies investigating the practice of palliative sedation focus on physicians' practices and attitudes. However, little is known about experiences and attitudes of nurses. METHODS: A web-based structured questionnaire was offered to 387 nurses providing medical technical care in 2007, assessing their experiences concerning decision-making, treatment policy and communication, focussing on the last patient receiving palliative sedation. RESULTS: The questionnaire was filled out by 201 nurses (response rate 52%). The majority of respondents agreed with the indication for palliative sedation. However, 21% reported to have refused carrying out a palliative sedation in the preceding year. The general practitioner was not present at the start of palliative sedation in a third of the cases, but was available when needed. The sedation was considered insufficiently effective by 42% of the respondents. According to a third of the respondents, the level of sedation was not related to the required level of symptom relief nor were changes in dosage based on the severity of symptoms. CONCLUSION: Although the guideline for palliative sedation appears to be followed adequately in the majority of cases with respect to indication for palliative sedation and reportage. The survey findings revealed shortcomings in medication policy, communication, medical control over the start and continued monitoring of palliative sedation.

[Palliative sedation largely in accordance with Dutch national guideline]. / Palliatieve sedatie na introductie KNMG-richtlijn.

OBJECTIVE: To evaluate the practice of continuous palliative sedation after the introduction of a national guideline. DESIGN: Investigation by questionnaire. METHOD: In 2008, 1580 physicians were asked to fill out a questionnaire regarding the last patient for whom they had prescribed continuous sedation until death. RESULTS: The response was 38% (n = 606). Eighty-two percent of the respondents were aware of the national guideline. Dyspnoea, pain and physical exhaustion were most often mentioned as the decisive indications for continuous sedation. The decision to use sedation was discussed with all mentally competent patients; in 18% of these cases, the patients had only been informed of the decision. Life expectancy at the start of continuous sedation was estimated to be less than 2 weeks in 97% of the cases. In 14% of the cases, the physicians felt pressured to start the sedation, predominantly by patients and relatives. Physicians were present at the start of sedation in 81% of the cases. Midazolam was used to induce sedation in 92%, and 41% of the physicians estimated that continuous sedation had hastened death to some extent. Most physicians believed that their patients' symptoms had been adequately relieved by continuous sedation, that the relatives were satisfied and that the quality of dying had been good. CONCLUSION: Continuous sedation practice in the Netherlands largely reflects the recommendations of the national guideline. Issues needing further attention are the pressure felt by physicians to start continuous sedation, as well as the possible life-shortening effect of continuous sedation as perceived by some of the physicians.

Hemodynamic changes during a combined psoas compartment-sciatic nerve block for elective orthopedic surgery.

BACKGROUND: Hemodynamic variables can theoretically be influenced by a combined psoas compartment-sciatic nerve block (CPCSNB) owing to a relatively high systemic absorption of local anesthetics and extended vasodilatation in the anesthetized limb (hemisympatectomy). In this study we assessed and documented hemodynamic changes during CPCSNB for elective orthopedic surgery. METHODS: Twenty consecutive patients scheduled for a total hip arthroplasty revision surgery were subjected to a CPCSNB with 150 mg bupivacaine (with epinephrine 1:200.000) 90 minutes before surgery (2 separate single-injection blocks: 30 mg bupivacaine for the sciatic nerve block and 120 mg bupivacaine for the psoas compartment block). Cardiac index, invasive arterial blood pressure, and heart rate were measured at baseline and 60 minutes after puncture using a minimally invasive cardiac output monitoring device (FloTrac/Vigileo™ system (Edwards Lifesciences, Irvine, CA)). RESULTS: Cardiac index did not change after a CPCSNB (preblock cardiac index 2.98 ± 0.54 l · min(-1) · m(-2) versus postblock cardiac index 2.99 ± 0.60 l · min(-1) · m(-2)). There was a significant reduction in mean arterial blood pressure (108 ± 16 mm|Hg vs. 99 ± 16 mm|Hg (P < 0.001)) and diastolic blood pressure (75 ± 9 mm|Hg vs. 68 ± 10 mm|Hg (P = 0.001)). Heart rate increased significantly (68 ± 9 beats · min(-1) vs. 73 ± 10 beats · min(-1) (P = 0.001)). CONCLUSION: CPCSNB did not affect cardiac index. Changes in arterial blood pressure and heart rate, although statistically significant, remained within an acceptable clinical range (<10% variation). CPCSNB does not appear to induce clinically significant hemodynamic changes in this group of patients.

Role of cervical cordotomy and other neurolytic procedures in thoracic cancer pain.

PURPOSE OF REVIEW: Evaluation of the efficacy and safety of the percutaneous cervical cordotomy (PCC) in palliative care medicine in patients suffering from thoracic cancer pain; fluoroscopy-guided versus computed tomographic-guided PCC. Evaluation of recent developments in other neurolytic procedures in thoracic pain. RECENT FINDINGS: Technical progress has provided us with much more accurate means of visualizing the spinal cord and its subunits. Not only do these techniques provide more accuracy in placing the lesion, and thereby increasing safety and efficacy of PCC. There is also no need to use oily contrast media that is incompatible with cerebrospinal fluid and nerve tissue. Recent literature concerning intercostal nerve blocks, selective percutaneous rhizotomy, intrathecal or epidural administration of neurolytic agents is limited. Neurolytic procedures may be improved by ultrasonography-guided procedures. SUMMARY: The results of fluoroscopy-guided PCC are satisfactory with case series reporting complete pain reduction in as much as 82-95% of the patients. For CT-guided PCC initial success rates were reported between 80.5-92.5% patients. However, the complication rates and long-term effects if measured and/or mentioned, varied. Hypothetically this technique may be more accurate and therefore probably safer than fluoroscopic-guided PCC.

Palliative care is not yet a well-defined product within the Dutch healthcare insurance system.

In the Netherlands, the quality and availability of palliative care has improved markedly within the last decade. However, many open questions remain concerning the position of palliative care as an insurable product on the Dutch healthcare market. Therefore, we analysed the policies of all private Dutch healthcare insurance companies as well as the public insurance policy for extraordinary medical costs. We studied how and which parts of palliative care were reimbursed in 2007. We observed a huge variability in costs and reimbursement regulations reflecting a rapid turnover of products for palliative care due to various new developments on this specific field of medical care. We conclude that a better definition of the product 'palliative care' is necessary for patients, health care providers and insurance companies.

Prescribing of pain medication in palliative care. A survey in general practice.

PURPOSE: To examine what pain and adjuvant medication is prescribed in palliative care patients at home in The Netherlands. METHODS: In a nationwide, representative, prospective study in general practice in The Netherlands, prescribed medication was registered in 95 general practices with a listed population of 374 070 patients. The GPs identified those who received palliative care in a retrospective survey of the 2169 patients who died within the 1-year study period. We analysed the analgesics, laxatives and anti-emetics that were prescribed during the last 3 months of life for these patients. RESULTS: The response rate of the survey was 74%. 425 patients received palliative care and 73% of them were prescribed pain medication: 55% a non-opioid analgesic (paracetamol, NSAIDs), 21% a weak opioid (tramadol, codeine), and 51% a strong opioid. Relatively more younger than older patients were prescribed strong opioids, and more cancer than non-cancer patients were prescribed an analgesic. During the last 3 months of life, the proportion of patients prescribed a non-opioid or a weak opioid increased gradually. The proportion of patients prescribed a strong opioid increased considerably nearing the patient's death. About one third of the non-cancer patients were prescribed strong opioids, mostly commencing in the last 2 weeks before death. In 48% of all patients with an opioid prescription, the GP did not prescribe a laxative. CONCLUSIONS: Weak opioids and laxatives are frequently omitted from pain regimens in palliative care at home in The Netherlands.