The risk of delirium after sedation with propofol or midazolam in intensive care unit patients.

AIM: Knowledge of risk factors may provide strategies to reduce the high burden of delirium in intensive care unit (ICU) patients. We aimed to compare the risk of delirium after deep sedation with propofol versus midazolam in ICU patients. METHODS: In this prospective cohort study, ICU patients who were in an unarousable state for ≥24 h due to continuous sedation with propofol and/or midazolam were included. Patients admitted ≤24 h, those with an acute neurological disorder and those receiving palliative sedation were excluded. ICU patients were assessed daily for delirium during the 7 days following an unarousable state due to continuous sedation. RESULTS: Among 950 included patients, 605 (64%) subjects were delirious during the 7 days after awaking. The proportion of subsequent delirium was higher after midazolam sedation (152/207 [73%] patients) and after both propofol and midazolam sedation (257/377 [68%] patients), compared to propofol sedation only (196/366 [54%] patients). Midazolam sedation (adjusted cause-specific hazard ratio [adj. cause-specific HR] 1.32, 95% confidence interval [CI] 1.05-1.66) and propofol and midazolam sedation (adj. cause-specific HR 1.29, 95% CI 1.06-1.56) were associated with a higher risk of subsequent delirium compared to propofol sedation only. CONCLUSION: This study among sedated ICU patients suggests that, compared to propofol sedation, midazolam sedation is associated with a higher risk of subsequent delirium. This risk seems more apparent in patients with high cumulative midazolam intravenous doses. Our findings underpin the recommendations of the Society of Critical Care Medicine Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (disruption) guidelines to use propofol over benzodiazepines for sedation in ICU patients.

Opioid Use Increases the Risk of Delirium in Critically Ill Adults Independently of Pain.

Rationale: It is unclear whether opioid use increases the risk of ICU delirium. Prior studies have not accounted for confounding, including daily severity of illness, pain, and competing events that may preclude delirium detection.Objectives: To evaluate the association between ICU opioid exposure, opioid dose, and delirium occurrence.Methods: In consecutive adults admitted for more than 24 hours to the ICU, daily mental status was classified as awake without delirium, delirium, or unarousable. A first-order Markov model with multinomial logistic regression analysis considered four possible next-day outcomes (i.e., awake without delirium, delirium, unarousable, and ICU discharge or death) and 11 delirium-related covariables (baseline: admission type, age, sex, Acute Physiology and Chronic Health Evaluation IV score, and Charlson comorbidity score; daily: ICU day, modified Sequential Organ Failure Assessment, ventilation use, benzodiazepine use, and severe pain). This model was used to quantify the association between opioid use, opioid dose, and delirium occurrence the next day.Measurements and Main Results: The 4,075 adults had 26,250 ICU days; an opioid was administered on 57.0% (n = 14,975), severe pain occurred on 7.0% (n = 1,829), and delirium occurred on 23.5% (n = 6,176). Severe pain was inversely associated with a transition to delirium (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.53-0.97). Any opioid administration in awake patients without delirium was associated with an increased risk for delirium the next day [OR, 1.45; 95% CI, 1.24-1.69]. Each daily 10-mg intravenous morphine-equivalent dose was associated with a 2.4% increased risk for delirium the next day.Conclusions: The receipt of an opioid in the ICU increases the odds of transitioning to delirium in a dose-dependent fashion.

Haloperidol, clonidine and resolution of delirium in critically ill patients: a prospective cohort study.

PURPOSE: Haloperidol and clonidine are commonly used to treat agitation in delirious intensive care unit (ICU) patients, but it is unclear whether these agents may shorten the duration of delirium. The objective of this study was to determine whether haloperidol, clonidine, or their combined administration to delirious ICU patients results in delirium resolution. METHODS: This was a cohort study on a mixed ICU, excluding patients with a primary neurological disorder. The main outcome was the probability of delirium resolution, using propensity score matching and Markov multinomial logistic regression models for daily transitions. Secondary outcomes were delirium duration, number of delirium days, ventilation days, length of stay in the ICU and hospital, and ICU mortality. RESULTS: A total of 3614 patients were included (1165 delirious [32%]; 2449 non-delirious [68%]). Delirium occurred on 4708 (18.9%) of 24,906 days. The probability of delirium resolution was lower in delirious patients who received haloperidol (OR 0.47, 95% CI 0.39-0.57), clonidine (OR 0.78, 95% CI 0.63-0.97), or both (OR 0.45, 95% CI 0.36-0.56) compared to untreated delirious patients. Delirious patients who received haloperidol, clonidine, or both had generally longer delirium duration, more delirium and ventilation days, and spent more time in the ICU and in hospital than untreated delirious patients. These agents had no effect on ICU mortality. CONCLUSION: Haloperidol and clonidine use in delirious ICU patients may be associated with reduced probability of delirium resolution. This finding, however, merits further investigation given inherent limitations of this observational analysis.

Neuropsychiatric outcome in subgroups of Intensive Care Unit survivors: Implications for after-care.

PURPOSE: Poor neuropsychiatric outcomes are common in survivors of critical illness but it is unclear what patient groups to target for interventions to improve mental health. We compared anxiety, depression, and post-traumatic stress disorder (PTSD) symptoms and health-related quality of life (HrQoL) across different subgroups of Intensive Care Unit (ICU) survivors. MATERIALS AND METHODS: A single-center cohort study was conducted in a mixed-ICU in the Netherlands among survivors of an ICU admission ≥48 h (n = 1730). Survivors received a survey one year after discharge, containing the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES/IES-R), and EQ-5D (response rate of 67%). Neuropsychiatric symptoms and quality of life were evaluated in a priori defined subgroups, by chi-square tests and Mann-Whitney U tests. RESULTS: Symptoms of anxiety (HADS anxiety ≥8), depression (HADS depression ≥8), and PTSD (IES ≥35; IES-R ≥ 1.6) were reported by 34%, 33%, and 19% of ICU survivors, with a median HrQoL utility score of 0.81 (IQR:0.65-1.00). These figures were similar for survivors of ARDS, sepsis, severe multiple organ failure (SOFA>11), or ICU stay ≥7 days. CONCLUSIONS: This underlines the importance of prevention and treatment for neuropsychiatric symptoms in ICU survivors in general, not only in specific patient groups.

Supported self-help to prevent relapse or recurrence of depression: Who benefits most?

BACKGROUND: This study aimed to identify subgroups for whom supported self-help preventive cognitive therapy (S-PCT) is more (cost)effective than treatment as usual (TAU) in preventing relapse and recurrence of major depression. METHODS: We conducted a randomized controlled trial in which 248 remitted, recurrently depressed participants were randomized to S-PCT (n = 124) or TAU (n = 124). Clinical outcome was relapse or recurrence of major depressive disorder (SCID-I). We tested the moderating effects on relapse or recurrence of age, gender, education level, residual depressive symptoms, number of previous episodes, age of onset, antidepressant medication, somatization, and self-efficacy with logistic regression analyses adjusted for baseline values of depressive symptoms. We examined moderating effects on costs using linear regression analyses adjusted for baseline costs. A stratified cost-effectiveness analysis was performed to tease out differences in cost-effectiveness between subgroups. RESULTS: We found no moderating effect on relapse or recurrence for any of the potential moderators. For costs, the number of previous depressive episodes was identified as a moderator. At a willingness-to-pay of 16,000€, the probability that S-PCT was cost-effective compared to TAU was 95% for participants with 2-3 episodes and 11% for participants with ≥4 episodes. LIMITATIONS: Participants and counselors were not blinded. The study was primarily designed to assess the (cost)effectiveness of S-PCT and not to conduct moderation analyses. CONCLUSIONS: S-PCT was effective in preventing relapse or recurrence of depressive disorders in a broad range of participants, but is more likely to be cost-effective in participants with 2-3 episodes than ≥4 episodes. This indicates that S-PCT can best be offered to participants with fewer previous depressive episodes.

A supported self-help for recurrent depression in primary care; An economic evaluation alongside a multi-center randomised controlled trial.

BACKGROUND: Major depression is a prevalent mental disorder with a high risk of relapse or recurrence. Only few studies have focused on the cost-effectiveness of interventions aimed at the prevention of relapse or recurrence of depression in primary care. AIM: To evaluate the cost-effectiveness of a supported Self-help Preventive Cognitive Therapy (S-PCT) added to treatment-as-usual (TAU) compared with TAU alone for patients with a history of depression, currently in remission. METHODS: An economic evaluation alongside a multi-center randomised controlled trial was performed (n = 248) over a 12-month follow-up. Outcomes included relapse or recurrence of depression and quality-adjusted-life-years (QALYs) based on the EuroQol-5D. Analyses were performed from both a societal and healthcare perspective. Missing data were imputed using multiple imputations. Uncertainty was estimated using bootstrapping and presented using the cost-effectiveness plane and the Cost-Effectiveness Acceptability Curve (CEAC). Cost estimates were adjusted for baseline costs. RESULTS: S-PCT statistically significantly decreased relapse or recurrence by 15% (95%CI 3;28) compared to TAU. Mean total societal costs were €2,114 higher (95%CI -112;4261). From a societal perspective, the ICER for relapse or recurrence was 13,515. At a Willingness To Pay (WTP) of 22,000 €/recurrence prevented, the probability that S-PCT is cost-effective, in comparison with TAU, is 80%. The ICER for QALYs was 63,051. The CEA curve indicated that at a WTP of 30,000 €/QALY gained, the probability that S-PCT is cost-effective compared to TAU is 21%. CONCLUSIONS: Though ultimately depending on the WTP of decision makers, we expect that for both relapse or recurrence and QALYs, S-PCT cannot be considered cost-effective compared to TAU.

Management of patients with persistent medically unexplained symptoms: a descriptive study.

BACKGROUND: In 2013 the Dutch guideline for management of medically unexplained symptoms (MUS) was published. The aim of this study is to assess medical care for patients with persistent MUS as recorded in their electronic medical records, to investigate if this is in line with the national guideline for persistent MUS and whether there are changes in care over time. METHODS: We conducted an observational study of adult primary care patients with MUS. Routinely recorded health care data were extracted from electronic medical records of patients participating in an ongoing randomised controlled trial in 30 general practices in the Netherlands. Data on general practitioners' (GPs') management strategies during MUS consultations were collected in a 5-year period for each patient prior. Management strategies were categorised according to the options offered in the Dutch guideline. Changes in management over time were analysed. RESULTS: Data were collected from 1035 MUS consultations (77 patients). Beside history-taking, the most frequently used diagnostic strategies were physical examination (24.5%) and additional investigations by the GP (11.1%). Frequently used therapeutic strategies were prescribing medication (24.6%) and providing explanations (11.2%). As MUS symptoms persisted, GPs adjusted medication, discussed progress and scheduled follow-up appointments more frequently. The least frequently used strategies were exploration of all complaint dimensions (i.e. somatic, cognitive, emotional, behavioural and social) (3.5%) and referral to a psychologist (0.5%) or psychiatrist (0.1%). CONCLUSIONS: Management of Dutch GPs is partly in line with the Dutch guideline. Medication was possibly prescribed more frequently than recommended, whereas exploration of all complaint dimensions, shared problem definition and referral to mental health care were used less.

Systematic review of measurement properties of questionnaires measuring somatization in primary care patients.

OBJECTIVE: The aim of this review is to critically appraise the evidence on measurement properties of self-report questionnaires measuring somatization in adult primary care patients and to provide recommendations about which questionnaires are most useful for this purpose. METHODS: We assessed the methodological quality of included studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. To draw overall conclusions about the quality of the questionnaires, we conducted an evidence synthesis using predefined criteria for judging the measurement properties. RESULTS: We found 24 articles on 9 questionnaires. Studies on the Patient Health Questionnaire-15 (PHQ-15) and the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale prevailed and covered the broadest range of measurement properties. These questionnaires had the best internal consistency, test-retest reliability, structural validity, and construct validity. The PHQ-15 also had good criterion validity, whereas the 4DSQ somatization subscale was validated in several languages. The Bodily Distress Syndrome (BDS) checklist had good internal consistency and structural validity. Some evidence was found for good construct validity and criterion validity of the Physical Symptom Checklist (PSC-51) and good construct validity of the Symptom Check-List (SCL-90-R) somatization subscale. However, these three questionnaires were only studied in a small number of primary care studies. CONCLUSION: Based on our findings, we recommend the use of either the PHQ-15 or 4DSQ somatization subscale for somatization in primary care. Other questionnaires, such as the BDS checklist, PSC-51 and the SCL-90-R somatization subscale show promising results but have not been studied extensively in primary care.

Longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders.

OBJECTIVE: To examine longitudinal associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. METHODS: Follow-up data of 584 participants with remitted depressive or anxiety disorders were used from the Netherlands Study of Depressive and Anxiety disorders. Multiple physical symptoms were measured at baseline (T1) and two-year follow-up (T2) by the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale. Recurrence of depressive and anxiety disorders was assessed at two-year (T2) and four-year (T4) follow-up with the Composite International Diagnostic Interview. Logistic Generalized Estimating Equations were used to examine associations of multiple physical symptoms with recurrence of depressive and anxiety disorders. Depressive (IDS-SR) and anxiety symptoms (BAI), and other relevant covariates were taken into account. RESULTS: Multiple physical symptoms were significantly associated with recurrence of depression (OR=1.04, 95%CI=1.00-1.08), anxiety (OR=1.07, 95%CI=1.03-1.12), and depressive or anxiety disorders (OR=1.06, 95%CI=1.02-1.10), on average over time. Odds ratios did not change substantially when the IDS-SR mood-cognition and BAI subjective scale were included as covariates. CONCLUSION: The presence of multiple physical symptoms was positively related to recurrence of depressive and anxiety disorders, independent of depressive and anxiety symptoms. Knowledge of risk factors for recurrence of depressive and anxiety disorders, such as the presence of multiple physical symptoms, could provide possibilities for better targeting interventions to prevent recurrence.

Effectiveness of Supported Self-Help in Recurrent Depression: A Randomized Controlled Trial in Primary Care.

BACKGROUND: The burden and economic consequences of depression are high, mostly due to its recurrent nature. Due to current budget and time restraints, a preventive, low- cost, accessible minimal intervention is much needed. In this study, we evaluated the effectiveness of a supported self-help preventive cognitive therapy (S-PCT) added to treatment as usual (TAU) in primary care, compared to TAU alone. METHODS: We conducted a randomized controlled trial among 248 patients with a history of depression, currently in full or partial remission or recovery. Participants were randomized to TAU augmented with S-PCT (n = 124) or TAU alone (n = 124). S-PCT consisted of an 8-week self-help intervention, supported by weekly telephone guidance by a counselor. The intervention included a self-help book that could be read at home. The primary outcome was the incidence of relapse or recurrence and was assessed over the telephone by the Structured Clinical Interview for DSM-IV axis 1 disorders. Participants were observed for 12 months. Secondary outcomes were depressive symptoms, quality of life (EQ-5D and SF-12), comorbid psychopathology, and self-efficacy. These secondary outcomes were assessed by digital questionnaires. RESULTS: In the S-PCT group, 44 participants (35.5%) experienced a relapse or recurrence, compared to 62 participants (50.0%) in the TAU group (incidence rate ratio = 0.71, 95% CI 0.52-0.97; risk difference = 14, 95% CI 2-24, number needed to treat = 7). Compared to the TAU group, the S-PCT group showed a significant reduction in depressive symptoms over 12 months (mean difference -2.18; 95% CI -3.09 to -1.27) and a significant increase in quality of life (EQ-5D) (mean difference 0.04; 95% CI 0.004-0.08). S-PCT had no effect on comorbid psychopathology, self-efficacy, and quality of life based on the SF-12. CONCLUSIONS: A supported self-help preventive cognitive therapy, guided by a counselor in primary care, proved to be effective in reducing the burden of recurrent depression.

Somatisation as a risk factor for incident depression and anxiety.

OBJECTIVE: In this study, we aimed to examine somatisation as a risk factor for the onset of depressive and anxiety disorders. METHODS: 4-year follow-up data from the Netherlands Study of Depression and Anxiety (NESDA), a multisite cohort study of the course of depression and anxiety, was analysed. Participants (18-65 years) without a lifetime depressive or anxiety disorder at baseline were included (n=611). Somatisation was measured at baseline with the somatisation subscale of the 4 Dimensional Symptoms Questionnaire. Onset of depression and anxiety was assessed with the CIDI interview at 2-year and 4-year follow-up. RESULTS: Somatisation was a risk factor for the incidence of depression [Hazard Ratio per unit increase (HR); 95% Confidence Interval (CI): 1.13; 1.09-1.17] and anxiety [HR; 95% CI: 1.14; 1.09-1.18]. Associations attenuated but remained statistically significant after adjusting for socio-demographic characteristics, chronic somatic disorders, and baseline levels of (subclinical) depressive or anxiety symptoms [adjusted HR for depression; 95% CI: 1.06; 1.00-1.12, adjusted HR for anxiety; 95% CI: 1.13; 1.07-1.20]. CONCLUSION: Persons who somatise have an increased risk of becoming depressed or anxious in subsequent years, over and above baseline levels of depressive or anxiety symptoms. They may represent a target group for prevention of depressive and anxiety disorders.

Associations of financial strain and income with depressive and anxiety disorders.

BACKGROUND: Previous research has shown socioeconomic inequality in prevalence and onset of depressive disorders. It is not yet clear whether perceived financial strain is associated with depressive and/or anxiety disorders in addition to an objective indicator, such as income. This study examines whether financial strain is associated with the prevalence and onset/recurrence of depressive and/or anxiety disorders, above income. METHODS: Data are from the Netherlands Study of Depression and Anxiety. Associations between financial strain, income and presence of depressive and/or anxiety disorder at baseline were assessed among 2937 participants (18-65 years). Impact of financial strain and income on 4-year onset/recurrence of depressive and/or anxiety disorders were examined among 1250 participants without a depressive or anxiety disorder at baseline. Depressive and anxiety disorders were determined with the Composite-International-Diagnostic-Interview. Financial strain and income were assessed in an interview. RESULTS: Participants with mild or severe financial strain had higher odds of being depressed (OR=1.68, 95% CI 1.35 to 2.09; OR=3.88, 95% CI 2.58 to 5.81) or remitted (OR=1.56, 95% CI 1.24 to 1.96; OR=1.99, 95% CI 1.27 to 3.11) at baseline compared with healthy controls, after adjusting for income. Mild or severe financial strain was not associated with onset/recurrence of depressive and/or anxiety disorders during follow-up (OR=1.08, 95% CI 0.83 to 1.42; OR=1.05, 95% CI 0.64 to 1.73). CONCLUSIONS: Financial strain was associated with having a depressive and/or anxiety disorder, above the effect of income. Healthcare and social services should be alert to this association, even for higher income households. However, financial strain and income were not related with 4-year onset/recurrence of depressive and/or anxiety disorders.

Cost-effectiveness of nurse-led self-help for recurrent depression in the primary care setting: design of a pragmatic randomised controlled trial.

BACKGROUND: Major Depressive Disorder is a leading cause of disability, tends to run a recurrent course and is associated with substantial economic costs due to increased healthcare utilization and productivity losses. Interventions aimed at the prevention of recurrences may reduce patients' suffering and costs. Besides antidepressants, several psychological treatments such as preventive cognitive therapy (PCT) are effective in the prevention of recurrences of depression. Yet, many patients find long-term use of antidepressants unattractive, do not want to engage in therapy sessions and in the primary care setting psychologists are often not available. Therefore, it is important to study whether PCT can be used in a nurse-led self-help format in primary care. This study sets out to test the hypothesis that usual care plus nurse-led self-help for recurrent depression in primary care is feasible, acceptable and cost-effective compared to usual care only. DESIGN: Patients are randomly assigned to 'nurse-led self-help treatment plus usual care' (134 participants) or 'usual care' (134 participants). Randomisation is stratified according to the number of previous episodes (2 or 3 previous episodes versus 4 or more). The primary clinical outcome is the cumulative recurrence rate of depression meeting DSM-IV criteria as assessed by the Structured-Clinical-Interview-for-DSM-IV- disorders at one year after completion of the intervention. Secondary clinical outcomes are quality of life, severity of depressive symptoms, co-morbid psychopathology and self-efficacy. As putative effect-moderators, demographic characteristics, number of previous episodes, type of treatment during previous episodes, age of onset, self-efficacy and symptoms of pain and fatigue are assessed. Cumulative recurrence rate ratios are obtained under a Poisson regression model. Number-needed-to-be-treated is calculated as the inverse of the risk-difference. The economic evaluation is conducted from a societal perspective, both as a cost-effectiveness analysis (costs per depression free survival year) and as a cost-utility analysis (costs per quality adjusted life-year). DISCUSSION: The purpose of this paper is to outline the rationale and design of a nurse-led, cognitive therapy based self-help aimed at preventing recurrence of depression in a primary care setting. Only few studies have focused on psychological self-help interventions aimed at the prevention of recurrences in primary care patients. TRIAL REGISTRATION: NTR3001 (http://www.trialregister.nl).