Background: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium.
Methods: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486.
Findings: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [–4·4 to -2·2]), and combination group (n=10, -3·0 [–4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths.
Interpretation: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group.
Funding: National Institute of Nursing Research.
Delirium is a frequent condition in patients in a palliative care situation and most often associated with substantial burden or even danger for the persons concerned as well as caregivers and health-care-professionals. Despite the lack of randomized-controlled-trials (RCTs) benzodiazepines and neuroleptic agents are used extensively in palliative care for the pharmacological management of delirium. A focused review for RCTs assessing pharmacotherapy with benzodiazepines and neuroleptics for the treatment of delirium in patients treated in a palliative care or hospice setting published in 2017 was performed in PubMed. A narrative summary of the findings of the RCTs and practical recommendation are presented. Of 42 publications, two RCTs could be included. One trial assessed the use of lorazepam (in addition to haloperidol) in case of agitation, the other placebo or risperidone or haloperidol in delirious palliative care patients. Neither risperidone nor haloperidol were superior compared to placebo, but were associated with higher mortality and morbidity. Lorazepam (along with haloperidol) reduced agitation in patients with delirium compared to placebo (along with haloperidol), but was unable to reduce the severity and incidence of delirium. It is of importance to note that psychopharmacotherapy with antipsychotics is mainly indicated for the hyperactive form of delirium and psychotic symptoms (e.g., delusions or hallucinations) in the hyper- and hypoactive delirium. Severe agitation and aggressivity can be an indication for neuroleptics, when non-pharmacological interventions fail, whereas the use of benzodiazepines has to be limited to critical situations where neuroleptics cannot be applied and cases of delirium due to alcohol withdrawal. Both substances can aggravate, precipitate or mask delirium, result adverse events with substantial distress or unfavorable survival outcomes for the patients. Thus, they should only be used in severely symptomatic patients and the duration of the medication has to be limited in time. When delirium symptoms decay the psychopharmacotherapy has to be tapered. More important than psychopharmacotherapy, the thorough investigation and treatment of potentially reversible causes of delirium (e.g., pharmacotherapy, infection) and the routine identification of patients at risk for delirium along with prophylactic measures are essential. The recently published landmarks RCTs provide moderate evidence to adopt recommendations from other medical specialties (i.e., intensive care, geriatrics) to the field of palliative care.
Antipsychotics are frequently used for treatment of delirium, although little evidence exists that they improve delirium outcomes. Our objective was to evaluate haloperidol (HAL) compared to non-haloperidol antipsychotics (NHAP) or no pharmacologic treatment (NP) in the management of delirium in older adults under the care of a palliative care consult service across a large, integrated health care system.
A retrospective chart review examined data from September 2014-September 2015. All hospitalized patients =65 years old with a diagnosis of delirium during palliative care consultation were included (n = 304). Primary outcome was length of stay after delirium diagnosis. Secondary outcomes included delirium symptom length, sedation, and QTc prolongation. Univariate statistical tests, analysis of covariance, and multiple regression methods were used to compare groups.
Post-delirium length of stay in the HAL, NHAP, and NP groups were 8.5, 7.0, and 6.8 days, respectively (p = 0.19). Delirium duration in the HAL, NHAP, and NP groups were 6.7, 6.0, and 4.9 days, respectively (p = 0.05). Safety outcomes were statistically different than the reference group (NHAP).
Congruent with existing literature in other generalized patient populations, no significant difference in post-delirium length of stay existed in geriatric, palliative care population.
Background: Opioids, antipsychotics and hypnotics are recommended for comfort care in dying. We studied their prescription during the last 3 days in residents deceased in the long-term care facility (LTCF).
Methods: In a retrospective, cross-sectional survey in Belgium, England, Finland, Italy, the Netherlands and Poland, LTCFs, selected by proportional stratified random sampling, reported all deaths over the previous 3 months. The nurse most involved in the residents' care reviewed the chart for opioid, antipsychotic and hypnotic prescription, cause of death and comorbidities. Multivariable logistic regression was performed to adjust for resident characteristics.
Results: Response rate was 81.6%. We included 1079 deceased residents in 322 LCTFs. Opioid prescription ranged from 18.5% (95% CI: 13.0-25.8) of residents in Poland to 77.9% (95% CI: 69.5-84.5) in the Netherlands, antipsychotic prescription from 4.8% (95% CI: 2.4-9.1) in Finland to 22.4% (95% CI: 14.7-32.4) in Italy, hypnotic prescription from 7.8% (95% CI: 4.6-12.8) in Finland to 47.9% (95% CI: 38.5-57.3) in the Netherlands. Differences in opioid, antipsychotic and hypnotic prescription between countries remained significant (P < 0.001) when controlling for age, gender, length of stay, cognitive status, cause of death in multilevel, multivariable analyses. Dying from cancer showed higher odds for receiving opioids (OR 3.51; P < 0.001) and hypnotics (OR 2.10; P = 0.010).
Conclusions: Opioid, antipsychotic and hypnotic prescription in the dying phase differed significantly between six European countries. Further research should determine the appropriateness of their prescription and refine guidelines especially for LTCF residents dying of non-cancer diseases.
The need for controlled trials evaluating the efficacy of antipsychotics in the management of delirium has been recognised since the Practice Guidelines for the treatment of patients with delirium were introduced in 1999. Since then, only few relevant studies have been published. In contrast to the Practice Guidelines, which favoured psychopharmacological management, the National Institute for Health and Care Excellence Guidelines solely recommend psychopharmacological management for distress. To date, it has not yet been clearly defined what the distressing symptoms of delirium are. Considering this controversy and the necessity of further studies in this
domain, the most beneficial approach for delirious patients remains unclear.
In the absence of suitable oral or intravenous access for medication administration and when the intramuscular medications are undesirable, alternative routes for drug delivery may be considered. Antipsychotics administered via an inhaled, intranasal, rectal, or topical route have been described in the literature. Topically administered antipsychotics have been previously reported to produce negligible systemic absorption despite being used in clinical practice for nausea and behavioral symptoms associated with dementia. Additionally, the American Academy of Hospice and Palliative Medicine recommends against the use of topical medications that lack supporting literature. Three studies have assessed the systemic absorption of different antipsychotics after administration of only a single, topically applied dose. To evaluate whether the repeated administration of a topically applied antipsychotic may result in detectable serum levels in an accumulating fashion, a pharmacokinetic study was conducted. Five healthy, adult participants consented to receive extemporaneously prepared topical quetiapine in Lipoderm every 4 hours for a total of 5 doses. Blood samples were drawn at baseline and hours 2, 4, 8, 12, 16, and 24, and serum quetiapine concentrations were measured using high-performance liquid chromatography. Quetiapine was undetectable in every sample from 3 participants. Two participants had minimally detectable serum quetiapine levels no sooner than hour 12 of the study period. Extemporaneously prepared quetiapine in Lipoderm resulted in nonexistent or minimal serum level following repeated topical administration. The use of topically applied quetiapine should still be questioned.
BACKGROUND: Palliative sedation (PS) is an intervention to treat refractory symptoms and to relieve suffering at the end of life. Its prevalence and practice patterns vary widely worldwide. The aim of our study was to evaluate the frequency, clinical indications and outcomes of PS in advanced cancer patients admitted to our tertiary comprehensive cancer center.
METHODS: We retrospectively studied the use of PS in advanced cancer patients who died between March 1st, 2012 and December 31st, 2014. PS was defined as the use of continuous infusion of midazolam or neuroleptics for refractory symptoms in the end of life. This study was approved by the Research Ethics Committee of our institution (project number 2481-15).
RESULTS: During the study period, 552 cancer patients died at the institution and 374 met the inclusion criteria for this study. Main reason for exclusion was death in the Intensive Care Unit. Among all included patients, 54.2% (n = 203) received PS. Patients who received PS as compared to those not sedated were younger (67.8 vs. 76.4 years-old, p < 0.001) and more likely to have a diagnosis of lung cancer (23% vs. 14%, p = 0.028). The most common indications for sedation were dyspnea (55%) and delirium (19.7%) and the most common drugs used were midazolam (52.7%) or midazolam and a neuroleptic (39.4%). Median initial midazolam infusion rate was 0.75 mg/h (interquartile range – IQR - 0.6-1.5) and final rate was 1.5 mg/h (IQR 0.9–3.0). Patient survival (length of hospital stay from admission to death) of those who had PS was more than the double of those who did not (33.6 days vs 16 days, p < 0.001). The palliative care team was involved in the care of 12% (n = 25) of sedated patients.
CONCLUSIONS: PS is a relatively common practice in the end-of-life of cancer patients at our hospital and it is not associated with shortening of hospital stay. Involvement of a dedicated palliative care team is strongly recommended if this procedure is being considered. Further research is needed to identify factors that may affect the frequency and outcomes associated with PS.
Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics, and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients. To analyze the relationship of a combination of opioids, anxiolytics, and antipsychotics on survival and the change of night-time death percentage. A retrospective study of 765 consecutive patients admitted to hospice in Croatia over the period of four years (2013–2017). The main outcome was the total length of survival of hospice patients regarding different drug combination, along with night-time death percentage. Different combinations of opioids, anxiolytics, and antipsychotics were associated with longer survival in hospice compared with patients using no such drugs. When we included different parameters which affected overall survival into a multivariate analysis, only the patients who had the combination of both opioids, anxiolytics, and antipsychotics in their regular therapy were associated with longer survival in hospice (11 vs. five days, hazard ratio 0.54, P < 0.001). No combination of opioids, anxiolytics, and antipsychotics significantly changed the night-time death percentage. This research supports the safety of opioids, anxiolytics, and antipsychotics in the hospice setting when used both individually as well as in combination.
Importance The use of benzodiazepines to control agitation in delirium in the last days of life is controversial.
Objective To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer.
Design, Setting, and Participants Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016.
Interventions Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode.
Main Outcomes and Measures The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival.
Results Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]).
Conclusions and Relevance In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects.
Trial Registration clinicaltrials.gov Identifier: NCT01949662
BACKGROUND: Haloperidol is widely prescribed as an antiemetic in patients receiving palliative care, but there is limited evidence to support and refine its use.
OBJECTIVE: To explore the immediate and short-term net clinical effects of haloperidol when treating nausea and/or vomiting in palliative care patients.
DESIGN: A prospective, multicenter, consecutive case series.
SETTING/SUBJECTS: Twenty-two sites, five countries: consultative, ambulatory, and inpatient services.
MEASUREMENTS: When haloperidol was started in routine care as an antiemetic, data were collected at three time points: baseline; 48 hours (benefits); day seven (harms). Clinical effects were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE).
RESULTS: Data were collected (May 2014–March 2016) from 150 patients: 61% male; 86% with cancer; mean age 72 (standard deviation 11) years and median Australian-modified Karnofsky Performance Scale 50 (range 10–90). At baseline, nausea was moderate (88; 62%) or severe (11; 8%); 145 patients reported vomiting, with a baseline NCI CTCAE vomiting score of 1.0. The median (range) dose of haloperidol was 1.5 mg/24 hours (0.5–5 mg/24 hours) given orally or parenterally. Five patients (3%) died before further data collection. At 48 hours, 114 patients (79%) had complete resolution of their nausea and vomiting, with greater benefit seen in the resolution of nausea than vomiting. At day seven, 37 (26%) patients had a total of 62 mild/moderate harms including constipation 25 (40%); dry mouth 13 (21%); and somnolence 12 (19%).
CONCLUSIONS: Haloperidol as an antiemetic provided rapid net clinical benefit with low-grade, short-term harms.
Ce travail a pour objectif d'analyser la place du pharmacien d'officine dans le parcours des patients en soins palliatifs à domicile. Tout d'abord, l'auteur revient sur l'organisation et les définitions des soins palliatifs, puis relate l'histoire de trois patients hospitalisés dans un service de soins palliatifs, afin d'illustrer la réalité de ces soins et permettre de mieux comprendre leurs besoins au moment d'un retour au domicile. Un état des lieux sur les pharmaciens d'officine face aux soins palliatifs est analysé à l'aide d'un questionnaire. Puis l'auteur traite de la mission première du pharmacien qu'est la dispension de médicaments et du matériel médical en abordant leurs spécificités dans le contexte des soins palliatifs.
[Adapté de l'introduction]
Cet article décrit les lignes de conduite mises en place par l’unité de consultation en soins palliatifs du CHU Sainte-Justine concernant la sédation palliative en pédiatrie. Il rappelle les objectifs de la sédation palliative et les critères de son application en pédiatrie. Sont également exposés le choix des médicaments en pédiatrie, les différents types de sédation et l'application de celle-ci à domicile, mais aussi la question de l'accompagnement de la famille.
[D'après résumé auteurs]
La métoclopramide est l'un des anti-émétiques les plus souvent utilisés en soins palliatifs. Mais elle peut avoir des effets secondaires sur le système extrapyramidal, altérant la qualité de vie des patients. Pour autant, ils ne sont pas assez pris en compte par les soignants. Les auteurs insistent sur la vigilance à avoir sur ces effets secondaires.
En soins palliatifs, les nouveaux neuroleptiques atypiques comme l'olanzapine et la rispéridone pour la prise en charge du délirium et des nausées sucite un vif intérêt. Cependant, la supériorité de ces molécules vis à vis des neuroleptiques classiques comme l'haloperidol n'a pas été démontrée. L'objet de cet article consiste donc à établir une justification de l'utilisation de ces nouveaux neuroleptiques atypiques comme agents de premère ligne dans ce contexte en résumant les différents effets secondaires pyramidaux et en identifiant des situations de traitements.
A travers l'étude de cas cliniques, ce document donne des pistes thérapeutiques pour plusieurs symptômes : confusion, anxiété. Il explique également comment peuvent être employés différents types de psychotropes en soins palliatifs.
La lutte contre la douleur de la personne âgée à domicile ou en EMS (Etablissements Médico-Sociaux) reste un combat à mener malgré les nombreux moyens mis en place. Dans cet article, nous suivons la campagne "Vers un milieu de vie sans douleur" lancée par l'association "Ensemble contre la douleur" appliquée à un EMS suisse situé à Lens dans le Valais pendant trois ans (de 2003 à 2006). Cette campagne se base sur une approche clinique de la douleur d'une part et sur la consommation d'autre part d'antalgiques et de neuroleptiques. A la fin de la campagne, une évaluation chiffrée de la douleur est réalisée à travers un questionnaire destiné aux soignants et dont les résultats sont analysés par les médecins afin de réadapter les traitements. La prise en compte des signes cliniques de la douleur par le personnel soignant permet une meilleure prise en charge des résidents.
Les nausées et les vomissements sont des symptômes fréquents chez les patients atteints de cancer. La revue de la littérature montre qu'il est possible d'utiliser certains neuroleptiques tel l'olanpazine comme médicament anti émétique mais des études restent à mener pour confirmer ce rôle.
La lévoprémazine est un neuroleptique qui peut permettre de contrôler chez les patients cancéreux les nausées, la confusion, l'agitation. L'article analyse dans la littérature les effets secondaires indésirables et dans les études la comparaison entre la morphine et la lévomépromazine,
Cette analyse de cas concerne la recherche des causes de survenue du syndrome neurologique malin suite à l'administration associée d'un neuroleptique et d'un opioïde. L'halopéridol a pu être identifié comme le facteur étiologique principal.