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.
IMPORTANCE: Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care.
OBJECTIVE: To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care.
DESIGN, SETTING, AND PARTICIPANTS: A double-blind, parallel-arm, dose-titrated randomized clinical trial was conducted at 11 Australian inpatient hospice or hospital palliative care services between August 13, 2008, and April 2, 2014, among participants with life-limiting illness, delirium, and a delirium symptoms score (sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items) of 1 or more.
INTERVENTIONS: Age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution were administered every 12 hours for 72 hours, based on symptoms of delirium. Patients also received supportive care, individualized treatment of delirium precipitants, and subcutaneous midazolam hydrochloride as required for severe distress or safety.
MAIN OUTCOME AND MEASURES: Improvement in mean group difference of delirium symptom score (severity range, 0-6) between baseline and day 3. Five a priori secondary outcomes: delirium severity, midazolam use, extrapyramidal effects, sedation, and survival.
RESULTS: Two hundred forty-seven participants (mean [SD] age, 74.9 [9.8] years; 85 women [34.4%]; 218 with cancer [88.3%]) were included in intention-to-treat analysis (82 receiving risperidone, 81 receiving haloperidol, and 84 receiving placebo). In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09-0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06-0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09-1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17-1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20-2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91-1.84; P = .14).
CONCLUSIONS AND RELEVANCE: In patients receiving palliative care, individualized management of delirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added.
TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12607000562471.
AIM: To evaluate the effectiveness of quetiapine and haloperidol in patients of delirium referred to psychiatry consultation liaison services.
METHODS: The study followed a single blind randomised controlled trial design. Thirty-two patients in the haloperidol group and 31 patients in the quetiapine group were assessed at the baseline and 6 consecutive days. Flexible dosing regimen (haloperidol: 0.25-1.25 mg; quetiapine 12.5-75 mg/d) was used. Delirium Rating Scale-Revised-98 (DRS-R-98) and mini mental status examination (MMSE) were the primary and secondary efficacy measures respectively.
RESULTS: Baseline DRS-R-98 severity score and MMSE scores did not differ between the 2 study groups. From baseline to day 6, there was significant reduction in the total DRS-R-98 scores, DRS-R-98 cognitive domain scores, DRS-R-98 non-cognitive domain scores and significant increase in the MMSE scores in both the groups. Both the groups did not differ on any of the assessments in terms of DRS-R98 and MMSE scores. The effectiveness of both the medications was similar in adult and elderly (≥ 60 years) patients. At the end of the trial, 68.75% and 67.74% of subjects in the haloperidol and quetiapine group respectively had mean DRS-R-98 scores below 10. By 6(th) day, 12 (37.5%) patients in haloperidol group and 9 (29.03%) patients in the quetiapine group had DRS-R98 score of "0" with no significant difference between the two groups (P = 0.47).
CONCLUSION: Quetiapine is as effective as haloperidol in the management of delirium.
BACKGROUND: Cardiopulmonary bypass initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. We aimed to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass.
METHODS: The Steroids In caRdiac Surgery (SIRS) study is a double-blind, randomised, controlled trial. We used a central computerised phone or interactive web system to randomly assign (1:1) patients at high risk of morbidity and mortality from 80 hospital or cardiac surgery centres in 18 countries undergoing cardiac surgery with the use of cardiopulmonary bypass to receive either methylprednisolone (250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients were assigned with block randomisation with random block sizes of 2, 4, or 6 and stratified by centre. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation of at least 6. Patients were excluded if they were taking or expected to receive systemic steroids in the immediate postoperative period or had a history of bacterial or fungal infection in the preceding 30 days. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcomes were 30-day mortality and a composite of death and major morbidity (ie, myocardial injury, stroke, renal failure, or respiratory failure) within 30 days, both analysed by intention to treat. Safety outcomes were also analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00427388.
FINDINGS: Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752). Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0·87, 95% CI 0·70-1·07, p=0·19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1·03, 95% CI 0·95-1·11, p=0·52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%]).
INTERPRETATION: Methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass. The SIRS trial does not support the routine use of methylprednisolone for patients undergoing cardiopulmonary bypass.
FUNDING: Canadian Institutes of Health Research.
Background: Sedatives and analgesics are often administered to achieve conscious sedation for diagnostic and therapeutic procedures. Appropriate concerns have been raised regarding post procedure delirium related to peri-procedural medication in the elderly. The objective of this study was to investigate the effect of premedication on new onset delirium and procedural care in elderly patients. Methods: Patients ≥ 70 years old and scheduled for elective cardiac catheterization were randomly assigned to receive either oral diphenhydramine and diazepam (25 mg/5 mg) or no premedication. All patients underwent a mini mental state exam and delirium assessment using confusion assessment method prior to the procedure and repeated at 4 h after the procedure and prior to discharge. Patients' cooperation during the procedure and ease of post-procedure were measured using Visual Analog Scale (VAS). The degree of alertness was assessed immediately on arrival to the floor, and twice hourly afterwards using Observer's Assessment of Alertness/Sedation Scale (OAA/S). Results: A total of 93 patients were enrolled. The mean age was 77 years, and 47 patients received premedication prior to the procedure. None of the patients in either group developed delirium. Patients' cooperation and the ease of procedure was greater and pain medication requirement less both during and after the procedure in the pre-medicated group (P < 0.05 for both). Nurses reported an improvement with patient management in the pre-medicated group (P = 0.08). Conclusions: In conclusion, premedication did not cause delirium in elderly patients undergoing cardiac catheterization. The reduced pain medication requirement, perceived procedural ease and post procedure management favors premedication in elderly patients undergoing cardiac catheterization.
IMPORTANCIA: No hay intervenciones altamente eficaces para prevenir el delirio han sido identificados.
OBJETIVO: Para examinar si ramelteon, un agonista de la melatonina, es eficaz para la prevención del delirio.
DISEÑO, lugar y participantes: Estudio multicéntrico, evaluador cegado-ensayo aleatorio controlado con placebo se realizó en unidades de cuidados intensivos y salas de agudos regulares de 4 hospitales universitarios y 1 hospital general. Los pacientes elegibles tenían 65 y 89 años de edad, recién admitido debido a problemas médicos graves, y capaz de tomar medicamentos por vía oral. Los pacientes fueron excluidos del estudio si tenían una estancia o esperanza de vida esperado de menos de 48 horas.
INTERVENCIONES: Sesenta y siete pacientes fueron asignados al azar por el método de sobre cerrado para recibir ramelteon (8 mg / d; 33 pacientes) o placebo (34 pacientes) cada noche durante 7 días.
PRINCIPALES RESULTADOS Y MEDIDAS: La incidencia de delirio, como se define por el Manual Diagnóstico y Estadístico de los Trastornos Mentales (cuarta edición).
RESULTADOS: ramelteón se asoció con un menor riesgo de delirio (3% vs 32%, p = 0,003), con un riesgo relativo de 0,09 (IC del 95%, desde 0,01 hasta 0,69). Incluso después de que se controlaron los factores de riesgo para, ramelteón seguía asociado con una menor incidencia de delirio (P = 0,01; odds ratio [IC del 95%, ,008-0,54] 0,07). Las estimaciones de Kaplan-Meier de tiempo hasta la aparición de delirio fueron 6,94 (IC 95%, 6,82-7,06) días para ramelteon y 5,74 (5,05-6,42) días para el placebo. Comparación de log-rank test mostró que la frecuencia de delirio fue significativamente menor en los pacientes que toman ramelteón que en los que recibieron placebo (χ (2) = 9,83, p = 0,002).
Conclusiones y relevancia: ramelteón administran todas las noches para los pacientes ancianos ingresados para atención aguda puede proporcionar protección contra el delirio. Este hallazgo apoya un posible papel patogénico de la neurotransmisión melatonina en el delirio.
REGISTRO DE PRUEBA: Red de Información Médica Hospital Universitario Identificador Registros de Ensayos Clínicos: UMIN000005591.
OBJECTIVE: This study aims to investigate the role of fast-track surgery in preventing the development of postoperative delirium and other complications in elderly patients with colorectal carcinoma.
METHODS: A total of 240 elderly patients with colorectal carcinoma (aged ≥70 years) undergoing open colorectal surgery was randomly assigned into two groups, in which the patients were managed perioperatively either with traditional or fast-track approaches. The length of hospital stay (LOS) and time to pass flatus were compared. The incidence of postoperative delirium and other complications were evaluated. Serum interleukin-6 (IL-6) levels were determined before and after surgery.
RESULTS: The LOS was significantly shorter in the fast-track surgery (FTS) group than that in the traditional group. The recovery of bowel movement (as indicated by the time to pass flatus) was faster in the FTS group. The postoperative complications including pulmonary infection, urinary infection and heart failure were significantly less frequent in the FTS group. Notably, the incidence of postoperative delirium was significantly lower in patients with the fast track therapy (4/117, 3.4 %) than with the traditional therapy (15/116, 12.9 %; p = 0.008). The serum IL-6 levels on postoperative days 1, 2, and 3 in patients with the fast-track therapy were significantly lower than those with the traditional therapy (p < 0.001).
CONCLUSIONS: Compared to traditional perioperative management, fast-track surgery decreases the LOS, facilitates the recovery of bowel movement, and reduces occurrence of postoperative delirium and other complications in elderly patients with colorectal carcinoma. The lower incidence of delirium is at least partly attributable to the reduced systemic inflammatory response mediated by IL-6.
BACKGROUND: Delirium is a common complication in patients with hip fractures and is associated with an increased risk of subsequent dementia. The aim of this trial was to evaluate the effect of a pre- and postoperative orthogeriatric service on the prevention of delirium and longer-term cognitive decline.
METHODS: This was a single-center, prospective, randomized controlled trial in which patients with hip fracture were randomized to treatment in an acute geriatric ward or standard orthopedic ward. Inclusion and randomization took place in the Emergency Department at Oslo University hospital. The key intervention in the acute geriatric ward was Comprehensive Geriatric Assessment including daily interdisciplinary meetings. Primary outcome was cognitive function four months after surgery measured using a composite outcome incorporating the Clinical Dementia Rating Scale (CDR) and the 10 words learning and recalls tasks from the Consortium to Establish a Registry for Alzheimer's Disease battery (CERAD). Secondary outcomes were pre- and postoperative delirium, delirium severity and duration, mortality and mobility (measured by the Short Physical Performance Battery (SPPB)). Patients were assessed four and twelve months after surgery by evaluators blind to allocation.
RESULTS: A total of 329 patients were included. There was no significant difference in cognitive function four months after surgery between patients treated in the acute geriatric and the orthopedic wards (mean 54.7 versus 52.9, 95% confidence interval for the difference -5.9 to 9.5; P = 0.65). There was also no significant difference in delirium rates (49% versus 53%, P = 0.51) or four month mortality (17% versus 15%, P = 0.50) between the intervention and the control group. In a pre-planned sub-group analysis, participants living in their own home at baseline who were randomized to orthogeriatric care had better mobility four months after surgery compared with patients randomized to the orthopedic ward, measured with SPPB (median 6 versus 4, 95% confidence interval for the median difference 0 to 2; P = 0.04).
CONCLUSIONS: Pre- and postoperative orthogeriatric care given in an acute geriatric ward was not effective in reducing delirium or long-term cognitive impairment in patients with hip fracture. The intervention had, however, a positive effect on mobility in patients not admitted from nursing homes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01009268 Registered November 5, 2009.
PURPOSE: Postoperative delirium is the most common postoperative complication in the elderly. The purpose of this study was to evaluate the safety and effectiveness of the preventive administration of low-dose haloperidol on the development of postoperative delirium after abdominal or orthopedic surgery in elderly patients.
SUBJECTS: A total of 119 patients aged 75 years or older who underwent elective surgery for digestive or orthopedic disease were included in this study.
METHODS: Patients were divided into those who did (intervention group, n = 59) and did not (control group, n = 60) receive 2.5 mg of haloperidol at 18:00 daily for 3 days after surgery; a randomized, open-label prospective study was performed on these groups. The primary endpoint was the incidence of postoperative delirium during the first 7 days after the operation.
RESULTS: The incidence of postoperative delirium in all patients was 37.8%. No side effects involving haloperidol were noted; however, the incidences of postoperative delirium were 42.4 and 33.3% in the intervention and control groups, respectively, which were not significantly different (p = 0.309). No significant effect of the treatment was observed on the severity or persistence of postoperative delirium.
CONCLUSIONS: The preventive administration of low-dose haloperidol did not induce any adverse events, but also did not significantly decrease the incidence or severity of postoperative delirium or shorten its persistence.
Low intraoperative Bispectral Index (BIS) values may be associated with increased mortality. In a previously reported trial to prevent delirium, we randomized patients undergoing hip fracture repair under spinal anesthesia to light (BIS >80) or deep (BIS approximately 50) sedation. We analyzed survival of patients in the original trial. Among all patients, mortality was equivalent across sedation groups. However, among patients with serious comorbidities (Charlson score >4), 1-year mortality was reduced in the light (22.2%) vs deep (43.6%) sedation group (hazard ratio [HR], 0.43; 95% confidence interval, 0.19-0.97; P = 0.04) during spinal anesthesia. Similarly, among patients with Charlson score >6, 1-year mortality was reduced in the light (28.6%) vs deep (52.6%) sedation group (HR 0.33; 95% confidence interval, 0.12-0.94; P = 0.04) during spinal anesthesia. Further research on reduced mortality after light sedation during spinal anesthesia is needed.
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.
