Baden Prevention and Reduction of Incidence of Postoperative Delirium Trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium

BACKGROUND: Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10 to 80% (Schonauer et al., J Pept Sci. 2017). Delirium was first described more than half a century ago in the cardiac surgery population (Blachy and Starr, Am J Psychiatry 121:371-5, 1964), where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population (Sessler et al., Am J Respir Crit Care Med 166:1338-44, 2002). This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies (Nishio et al., Crit Care Med 5:953-7, 1997; Ehlenbach et al., JAMA 303:763-70, 2010; Jahangir et al., World J Cardiol 3:383-7, 2011; Abegunde et al., Lancet 370:1929-1938, 2007; Darmon et al., Intensive Care Med 43:829-840, 2017; Marino et al., J Nephrol 28:717-24, 2015; Ng LL et al., J Am Coll Cardiol 69:56-69, 2017; Sezen et al., J Pharmacol Exp Ther 287:238-45, 1998; Kim et al., Ann Lab Med 37:388-97, 2017). Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100β will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery. METHODS/DESIGN: The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo. DISCUSSION: There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015

Additional file 1: of Baden Prevention and Reduction of Incidence of Postoperative Delirium Trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium

SPIRIT checklist. (DOC 115 kb

A preoperative single dose of methadone for moderate-to-severely painful surgery reduces postoperative morphine consumption

BACKGROUND Data from patient questionnaires reveal that the intensity of postoperative pain is widely underestimated. Insufficient pain control may contribute to impaired short- and long-term outcome. Preoperative administration of methadone might potentially improve postoperative pain control due to its long pharmacological half-life. METHODS The aim of this study was to evaluate the effect of a single dose of methadone administered at anesthesia induction on postoperative analgesic requirements in ASA I-III patients after moderate-to-severely painful surgery scheduled for ≥90 minutes. Patients were randomized to receive either a single dose of methadone (0.2 mg/kg) or fentanyl (standard, 0.003 mg/kg) intravenously (IV) at anesthesia induction. For postoperative pain control, all study patients were accommodated with morphine on the basis of patient-controlled analgesia (PCA). RESULTS Per-protocol analysis revealed that the median cumulative morphine consumption was significantly lower in patients receiving a single dose of methadone, in the Postanesthesia Care Unit (0 mg vs. 7 mg of morphine, P<0.01) and during the first 72 hours after surgery (19 mg vs. 35 mg of morphine, P<0.05 for all days). Fentanyl consumption during surgery (0.25 mg [0.1-0.425 mg] in the study group vs. 0.3 mg [0.15-0.45 mg] in the control group, P=0.4499) was comparable among groups. Median pain scores at rest and in motion, and patient satisfaction were also similar in both groups (95.7% vs. 89.3% of patients were satisfied in the study and control group, respectively) during follow-up on postoperative days 1-3. CONCLUSIONS A single dose of methadone administered at anesthesia induction prior to moderate-to-severely painful surgery is a possible strategy to reduce postoperative morphine consumption

The determinants of low-intensity intergroup violence: the case of Northern Ireland

Includes supplementary materials: online appendix; replication fileWhat accounts for low-intensity intergroup violence? This article explores the determinants of low-intensity sectarian violence in Northern Ireland, which has marked the post-1998 peace agreement period. Low-intensity violence comprises a variety of events from riots to attacks against other civilians as well as against homes and symbolic buildings such as churches. We argue that this violence is more likely and prevalent in interface areas where similarly sized rival communities are geographically in contact with each other. Parity and contact spur intergroup competition and threat perception, and they increase the viability of violence. We use original cross-sectional time-series violence data for the 2005–12 period at a disaggregated subnational level, the ward, and a wide variety of social and economic indicators to test our hypotheses. In particular, we assess the impact of within-ward ethnic composition, on the one hand, and the ethnic composition of neighboring wards, on the other. We find that the number of intergroup violent events peaks in wards where there is parity between groups, and in predominantly Catholic (Protestant) wards that border predominantly Protestant (Catholic) wards. The article makes two main contributions: it shows that micro-level dynamics of violence can expand beyond local territorial units, and it suggests that ethnic segregation is unlikely to prevent intergroup violence

Sex determination of baleen whale artefacts:Implications for ancient DNA use in zooarchaeology

Methods to determine the sex from tissue samples of mammals include the amplification of Y chromosome specific regions, which should only amplify from males, or amplification of homologous regions of the X and Y chromosome containing XY specific SNPs. A disadvantage of the first approach is that PCR failure can be misinterpreted as the identification of a female. The latter approach is proposed to identify PCR failure through non-amplification of the X homologue, which should be present in both sexes. This method is therefore potentially more suitable for molecular sexing of degraded DNA with a high probability of PCR failure, such as for example, ancient DNA samples. Here, we investigate the validity of this assumption regarding the use of XY homologue PCR assays for molecular sexing of ancient DNA. We tested a primer set targeting the ZFX/ZFY alleles using ancient DNA extracts from 100 to 4500 years old bowhead whale samples, and for comparison on dilution series from modern bowhead whales of known sex. DNA sequencing of PCR products obtained from the ancient material confirmed a higher proportion of successful PCR amplifications of the X homologue over the Y homologue. This potentially biased sex determination was further assessed by testing highly diluted DNA extracts of modern samples, for which a consistently higher success rate of PCR amplification and lower PCR cycle threshold was found for the X homologue from females than either homologue from males. This is most likely due to the higher copy number of the X homologue in females, although other yet unknown attributes of the protocol may also cause the observed bias. The current case study provides a valuable example of a potential pitfall in molecular sex determination of ancient mammal DNA in zooarchaeology. High-throughput sequencing methods, in which sufficiently large numbers of reads can be unambiguously mapped to X and Y regions, should overcome such biases and be the most robust approach for molecular sex determination using degraded DNA