Discordance Between Respiratory Drive and Sedation Depth in Critically Ill Patients Receiving Mechanical Ventilation.

OBJECTIVES: In mechanically ventilated patients, deep sedation is often assumed to induce "respirolysis," that is, lyse spontaneous respiratory effort, whereas light sedation is often assumed to preserve spontaneous effort. This study was conducted to determine validity of these common assumptions, evaluating the association of respiratory drive with sedation depth and ventilator-free days in acute respiratory failure. DESIGN: Prospective cohort study. SETTING: Patients were enrolled during 2 month-long periods in 2016-2017 from five ICUs representing medical, surgical, and cardiac specialties at a U.S. academic hospital. PATIENTS: Eligible patients were critically ill adults receiving invasive ventilation initiated no more than 36 hours before enrollment. Patients with neuromuscular disease compromising respiratory function or expiratory flow limitation were excluded. INTERVENTIONS: Respiratory drive was measured via P0.1, the change in airway pressure during a 0.1-second airway occlusion at initiation of patient inspiratory effort, every 12 ± 3 hours for 3 days. Sedation depth was evaluated via the Richmond Agitation-Sedation Scale. Analyses evaluated the association of P0.1 with Richmond Agitation-Sedation Scale (primary outcome) and ventilator-free days. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients undergoing 197 bedside evaluations across five ICUs were included. P0.1 ranged between 0 and 13.3 cm H2O (median [interquartile range], 0.1 cm H2O [0.0-1.3 cm H2O]). P0.1 was not significantly correlated with the Richmond Agitation-Sedation Scale (RSpearman, 0.02; 95% CI, -0.12 to 0.16; p = 0.80). Considering P0.1 terciles (range less than 0.2, 0.2-1.0, and greater than 1.0 cm H2O), patients in the middle tercile had significantly more ventilator-free days than the lowest tercile (incidence rate ratio, 0.78; 95% CI, 0.65-0.93; p < 0.01) or highest tercile (incidence rate ratio, 0.58; 95% CI, 0.48-0.70; p < 0.01). CONCLUSIONS: Sedation depth is not a reliable marker of respiratory drive during critical illness. Respiratory drive can be low, moderate, or high across the range of routinely targeted sedation depth.

Negative drift of sedation depth in critically ill patients receiving constant minimum alveolar concentration of isoflurane, sevoflurane, or desflurane: a randomized controlled trial.

BACKGROUND: Intensive care unit (ICU) physicians have extended the minimum alveolar concentration (MAC) to deliver and monitor long-term volatile sedation in critically ill patients. There is limited evidence of MAC's reliability in controlling sedation depth in this setting. We hypothesized that sedation depth, measured by the electroencephalography (EEG)-derived Narcotrend-Index (burst-suppression N_Index 0-awake N_Index 100), might drift downward over time despite constant MAC values. METHODS: This prospective single-centre randomized clinical study was conducted at a University Hospital Surgical Intensive Care Unit and included consecutive, postoperative ICU patients fulfilling the inclusion criteria. Patients were randomly assigned to receive uninterrupted inhalational sedation with isoflurane, sevoflurane, or desflurane. The end-expiratory concentration of the anaesthetics and the EEG-derived index were measured continuously in time-stamped pairs. Sedation depth was also monitored using Richmond-Agitation-Sedation-Scale (RASS). The paired t-test and linear models (bootstrapped or multilevel) have been employed to analyze MAC, N_Index and RASS across the three groups. RESULTS: Thirty patients were recruited (female/male: 10/20, age 64 ± 11, Simplified Acute Physiology Score II 30 ± 10). In the first 24 h, 21.208 pairs of data points (N_Index and MAC) were recorded. The median MAC of 0.58 ± 0.06 remained stable over the sedation time in all three groups. The t-test indicated in the isoflurane and sevoflurane groups a significant drop in RASS and EEG-derived N_Index in the first versus last two sedation hours. We applied a multilevel linear model on the entire longitudinal data, nested per patient, which produced the formula N_Index = 43 - 0.7·h (R2 = 0.76), showing a strong negative correlation between sedation's duration and the N_Index. Bootstrapped linear models applied for each sedation group produced: N_Index of 43-0.9, 45-0.8, and 43-0.4·h for isoflurane, sevoflurane, and desflurane, respectively. The regression coefficient for desflurane was almost half of those for isoflurane and sevoflurane, indicating a less pronounced time-effect in this group. CONCLUSIONS: Maintaining constant MAC does not guarantee stable sedation depth. Thus, the patients necessitate frequent clinical assessments or, when unfeasible, continuous EEG monitoring. The differences across different volatile anaesthetics regarding their time-dependent negative drift requires further exploration. TRIAL REGISTRATION: NCT03860129.

Opioid-Induced Sedation and Respiratory Depression: Are Sedation Scales Enough to Prevent Adverse Drug Events Postoperatively?

OBJECTIVES: Nurses who care for hospitalized patients are responsible for ensuring adequate pain management is provided in a safe manner. The clinical challenge is balancing the effective control of the patient's pain with the side effects of administering opioids. The aim of this literature review is to explore the evidence on how nurses assess for opioid-induced sedation and advancing respiratory depression and how they integrate those data in their critical thinking skills when deciding to administer opioids for pain. DESIGN: A matrix method was used to guide the review and synthesis of the evidence. Tables with column headings (citation, purpose of study, design/measurements, outcomes, and results) were constructed to record data extracted from each study. DATA SOURCES: Primary source research articles were examined using the MESH terms sedation, sedation scale, respiratory depression, opioid, pain, pain assessment, adverse events, naloxone and postoperative. REVIEW/ANALYSIS METHODS: Original studies such as retrospective case-control studies and descriptive studies were included. The final studies that met the inclusion criteria and were independently reviewed by the authors. The two main areas of interest were the evidence for how nurses assess for advancing sedation and excessive respiratory depression and how nurses integrate their assessment data in their critical thinking skills when deciding to administer opioids for pain. RESULTS: Results indicated a lack of evidence examining the relationships among sedation, respiratory depression, and adverse events and the overall impact of managing these variables on patients' pain. CONCLUSIONS: This review revealed a lack of evidence between how nurses assess for opioid induced advancing sedation and excessive respiratory depression, and the impact, including the adverse events associate with acute pain management.

A Novel Research Method for Determining Sedative Exposure in Critically Ill Patients.

BACKGROUND: Although potent sedative and opioid drugs are some of the most commonly used medications to manage pain, anxiety, and discomfort in critically ill patients, conducting clinical trials where sedative and opioid medications are outcome variables within a longitudinal research design can be a methodological challenge. OBJECTIVES: The purpose of this article is to provide in detail a conceptual discussion of the concept and analysis of sedative exposure: A novel research analysis method for aggregating sedative and opioid medication doses from disparate drug classes commonly administered to critically ill patients and used by our team in several clinical research studies. METHODS: Comparing the dose of each sedative and opioid administered to an individual patient (within a defined time interval) to all other patients in a research study receiving the same medications allows for ranking of dosages for each medication by quartiles. Rank values for all sedatives and opioids received can be summed to a single value resulting in a Sedation Intensity Score. In addition, a simple count of how many hours at least one dose of a sedative or opioid medication has been administered can determine sedation frequency. RESULTS: This method can allow for comparison of sedative exposure with medications from disparate drug classes and for analysis of estimates of change in medication use over time. DISCUSSION: This novel research analysis method can overcome the challenges and limitations of determining changes in sedative and opioid medication regimens in cohort and clinical trial study designs.

Screening for delirium with the Intensive Care Delirium Screening Checklist (ICDSC): Symptom profile and utility of individual items in the identification of delirium dependent on the level of sedation.

OBJECTIVE: The importance of the proper identification of delirium, with its high incidence and adversities in the intensive care setting, has been widely recognized. One common screening instrument is the Intensive Care Delirium Screening Checklist (ICDSC); however, the symptom profile and key features of delirium dependent on the level of sedation have not yet been evaluated. METHOD: In this prospective cohort study, the ICDSC was evaluated versus the Diagnostic and Statistical Manual, 4th edition, text revision, diagnosis of delirium set as standard with respect to the symptom profile, and correct identification of delirium. The aim of this study was to identify key features of delirium in the intensive care setting dependent on the Richmond Agitation and Sedation Scale levels of sedation: drowsiness versus alert and calmness.ResultThe 88 delirious patients of 225 were older, had more severe disease, and prolonged hospitalization. Irrespective of the level of sedation, delirium was correctly classified by items related to inattention, disorientation, psychomotor alterations, inappropriate speech or mood, and symptom fluctuation. In the drowsy patients, inattention reached substantial sensitivity and specificity, whereas psychomotor alterations and sleep-wake cycle disturbances were sensitive lacked specificity. The positive prediction was substantial across items, whereas the negative prediction was only moderate. In the alert and calm patient, the sensitivities were substantial for psychomotor alterations, sleep-wake cycle disturbances, and symptom fluctuations; however, these fluctuations were not specific. The positive prediction was moderate and the negative prediction substantial. Between the nondelirious drowsy and alert, the symptom profile was similar; however, drowsiness was associated with alterations in consciousness.Significance of resultsIn the clinical routine, irrespective of the level of sedation, delirium was characterized by the ICDSC items for inattention, disorientation, psychomotor alterations, inappropriate speech or mood and symptom fluctuation. Further, drowsiness caused altered levels of consciousness.

Long-term benzodiazepine and Z-drugs use in England: a survey of general practice [corrected].

BACKGROUND: Current British National Formulary (BNF) guidelines state that benzodiazepines and zolpidem, zopiclone, and zaleplon, commonly known as Z-drugs (BZD), be prescribed for no more than 4 weeks, although anecdotal data suggest that many patients are prescribed BZDs for much longer. As there are no recent, evidence-based estimates of long-term (>12 months) BZD use in the UK, the scale of this potential problem is unknown. AIM: To produce the first reliable, evidence-based estimate of long-term BZD use in the UK. DESIGN AND SETTING: Estimates of UK long-term BZD use were projected from data obtained from a survey conducted in 2014-2015 by the Bridge Project, a prescribed-drug withdrawal support charity in the North of England (Bradford). METHOD: Percentages of long-term users of BZD were derived from the survey, by sampling primary care GP surgeries with around 100 000 registered patients, and these were applied to UK-wide NHS patient numbers. The data were filtered to exclude the very young and old, and those with other health issues. RESULTS: The mean percentage of registered patients prescribed BZDs for more than a year in the survey sample is 0.69% (95% confidence interval [CI] = 0.54 to 0.84). Applying this value to national patient numbers yields a mean projection of 296 929 (95% CI = 232 553 to 361 305) long-term users of BZD in the UK. The data also suggest that as many as 119 165 of these patients may be willing to accept prescribed drug dependency withdrawal services. CONCLUSION: More than a quarter of a million people in the UK are likely to be taking highly dependency-forming hypnotic medication far beyond the recommended time scales. As there is evidence that long-term use of BZDs causes adverse physiological and neurological effects, and protracted withdrawal (with associated complications), this represents a serious public health problem.

Deprescribing anticholinergic and sedative medicines: protocol for a Feasibility Trial (DEFEAT-polypharmacy) in residential aged care facilities.

INTRODUCTION: Targeted deprescribing of anticholinergic and sedative medicines can lead to positive health outcomes in older people; as they have been associated with cognitive and physical functioning decline. This study will examine whether the proposed intervention is feasible at reducing the prescription of anticholinergic and sedative medicines in older people. METHODS AND ANALYSIS: The Standard Protocol Items: Recommendations for Interventional trials (SPIRIT checklist) was used to develop and report the protocol. Single group (precomparison and postcomparison) feasibility study design. STUDY POPULATION: 3 residential care homes have been recruited. INTERVENTION: This will involve a New Zealand registered pharmacist using peer-reviewed deprescribing guidelines, to recommend to general practitioners (GPs), sedative and anticholinergic medicines that can be deprescribed. The cumulative use of anticholinergic and sedative medicines for each participant will be quantified, using the Drug Burden Index (DBI). OUTCOMES: The primary outcome will be the change in the participants' DBI total and DBI PRN 3 and 6 months after implementing the deprescribing intervention. Secondary outcomes will include the number of recommendations taken up by the GP, participants' cognitive functioning, depression, quality of life, activities of daily living and number of falls. DATA COLLECTION POINTS: Participants' demographic and clinical data will be collected at the time of enrolment, along with the DBI. Outcome measures will be collected at the time of enrolment, 3 and 6 months' postenrolment. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Human Disability and Ethics Committee. Ethical approval number (16/NTA/61). TRIAL REGISTRATION NUMBER: Pre-results; ACTRN12616000721404.

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat.

In this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.

Implication of general anaesthetic and sedation techniques in temporomandibular joint disorders - a systematic review.

The purpose of this study was to conduct a systematic review of the literature on temporomandibular joint damage directly related to general anaesthesia and sedation. We searched MEDLINE, SCOPUS and the COCHRANE Library for titles and abstracts containing terms related to the subject. The search delimiters were analytical and descriptive studies with abstracts in Spanish, German, English or French, with no time limit. The search was updated in January 2015. Of the 398 articles found, 89 were duplicates and only 28 were of interest. Of these, 23 (82.14%) were case and case series reports, 4 (14.28%) were longitudinal studies and 1 (3.57%) was a cross-sectional study. General anaesthesia and sedation are risk factors for temporomandibular joint damage because of the drop in muscle tone caused by the drugs employed and because of airway management manoeuvres involving the joint. Joint complications have been described with spontaneous ventilation as well as with ventilation assisted by a face or laryngeal mask and with intubation. They are more frequent in women and/or patients with previous temporomandibular problems. Proper assessment is required both before and after anaesthesia or sedation in order to foresee and avoid or minimize temporomandibular complications. The data should be treated with caution, as the evidence of case and case series reports is not of a high standard and the small number of analytical studies is not entirely comparable. General anaesthesia and sedation techniques can influence the onset of temporomandibular joint disorders. More studies are needed to provide better clinical evidence.

Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review.

Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders.

[Austrian expenditures on psychopharmaceutical drugs between 2006 and 2013]. / Analyse der Ausgaben für Psychopharmaka in Österreich von 2006 bis 2013.

OBJECTIVES: Health costs, which are increasing at a yearly rate of 4 %, represent 11% and thus a large share of Austria's gross domestic product (GDP). High expenditures derive frommental health care costs, including medication. In this article we investigate whether the costs and usage of psychopharmaceutic products in Austria are rising. METHOD: We did a descriptive analysis of the sales figures and number for packaging units of pharmaceutical products of ATC-classes N05 and N06 in all Austrian hospitals, pharmacies and medicine chests for the years 2006-2013. All data were provided free of charge by IMSHealth. RESULTS: The sales volume and number of prescribed packaging units of pharmaceuticals of ATC-classes N05 and N06 increased over the time period in question. In 2013, about 25% more packaging units were being sold than in 2006. Among the two ATC-classes, however, the indication subgroups developed differently. Expenditures increased a total of about 31%within the period of consideration. CONCLUSIONS: The increase in psycho-pharmaceutical sales exceeds the expansion rates of other health expenditures (17.8 %). During the 9 years of observation, 25% more psychopharmaceutical products were sold. This may result from increased prevalence of mental disorders, higher usage or an increment in prescriptions.

Schedules of controlled substances: placement of suvorexant into Schedule IV. Final rule.

With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration (DEA) places the substance [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (suvorexant), including its salts, isomers, and salts of isomers, into schedule IV of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule IV controlled substances on persons who handle (manufacture, distribute, dispense, import, export, engage in research, conduct instructional activities, or possess), or propose to handle suvorexant.

Treatment of resistant insomnia and major depression.

Daily rhythms regulate everiday life and sleep/wake alternation is the best expression of this. Disruptions in biological rhythms is strongly associated with mood disorders, often being the major feature of this, major depressive disorder first of all. Although stabilization of rhythms produced by treatments have important outcome on therapeutic efficacy, insomnia often remains an unresolved symptom when major depression has otherwise been successfully treated with antidepressant. We review scientific literature in order to better clarify how to better approach insomnia as a clinical aspect to investigate and to early treat while treating other psychiatric conditions, major depression in particular. Insomnia is associated with impaired quality of life. It can be resolved with adequate diagnosis and treatment: it should be considered a comorbid condition and should be early identificated and treated in a multidisciplinary way, so that the ideal of treatment for patients with treatment resistant insomnia in major depression is an integration of non-pharmacologic measures, along with judicious use of medication, often used as an adjunctive therapy.

Treatment of insomnia in older adults: re-evaluating the benefits and risks of sedative hypnotic agents.

Insomnia and sleep complaints are common among older adults. Although once considered safer than benzodiazepine drugs, recent data on non-benzodiazepine drugs, such as zolpidem (Ambien(®)), have revealed similar negative effects. This issue, as well as others, has been included in the recent updated 2012 American Geriatrics Society Beers Criteria. This article describes the risks and benefits associated with sedative hypnotic agents in older adults and discusses the conundrum facing practitioners as well as patients.

Comparison and agreement between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in evaluating patients' eligibility for delirium assessment in the ICU.

BACKGROUND: Delirium evaluation in patients in the ICU requires the use of an arousal/sedation assessment tool prior to assessing consciousness. The Richmond Agitation-Sedation Scale (RASS) and the Riker Sedation-Agitation Scale (SAS) are well-validated arousal/sedation tools. We sought to assess the concordance of RASS and SAS assessments in determining eligibility of patients in the ICU for delirium screening using the confusion assessment method for the ICU (CAM-ICU). METHODS: We performed a prospective cohort study in the adult medical, surgical, and progressive (step-down) ICUs of a tertiary care, university-affiliated, urban hospital in Indianapolis, Indiana. The cohort included 975 admissions to the ICU between January and October 2009. RESULTS: The outcome measures of interest were the correlation and agreement between RASS and SAS measurements. In 2,469 RASS and SAS paired screens, the rank correlation using the Spearman correlation coefficient was 0.91, and the agreement between the two screening tools for assessing CAM-ICU eligibility as estimated by the κ coefficient was 0.93. Analysis showed that 70.1% of screens were eligible for CAM-ICU assessment using RASS (7.1% sedated [RASS −3 to −1]; 62.6% calm [0]; and 0.4% restless, agitated [+1 to +3]), compared with 72.1% using SAS (5% sedated [SAS 3]; 66.5% calm [4]; and 0.6% anxious, agitated [5, 6]). In the mechanically ventilated subgroup, RASS identified 19.1% CAM-ICU eligible patients compared with 24.6% by SAS. The correlation coefficient in this subgroup was 0.70 and the agreement was 0.81. CONCLUSION: Both SAS and RASS led to similar rates of delirium assessment using the CAM-ICU.

Pharmacodynamic considerations for moderate and deep sedation.

Moderate and deep sedation can be provided using various classes of drugs, each having unique mechanisms of action. While drugs within a given classification share similar mechanisms and effects, certain classes demonstrate superior efficacy but added concern regarding safety. This continuing education article will highlight essential principles of pharmacodynamics and apply these to drugs commonly used to produce moderate and deep sedation.