Psychotherapy for Ketamine's Enhanced Durability in Chronic Neuropathic Pain: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Chronic pain affects approximately 8 million Canadians (~20%), impacting their physical and mental health while burdening the health care system with costs of upwards of US $60 billion a year. Indeed, patients are often trialed on numerous medications over several years without reductions to their symptoms. Therefore, there is an urgent need to identify new therapies for chronic pain to improve patients' quality of life, increase the availability of treatment options, and reduce the burden on the health care system. OBJECTIVE: The primary objective of this study is to examine the feasibility of a parallel 3-arm pilot randomized controlled trial whereby patients are randomized to either intravenous ketamine alone, cognitive behavioral therapy (CBT) and mindfulness meditation (MM) training (CBT/MM), or the combination of intravenous ketamine and CBT/MM. The secondary outcome is to assess the durability and efficacy of combination intravenous ketamine and CBT/MM for treatment of chronic pain as compared to CBT/MM or intravenous ketamine alone (assessed at week 20 of the study). METHODS: This is a single-center, 16-week, 3-arm pilot study that will take place at the Chronic Pain Clinic at St. Michael's Hospital, Toronto, Ontario, which receives 1000 referrals per year. Patients will be enrolled in the study for a total of 20 weeks. Participants who are allocated CBT/MM therapy will receive remote weekly psychotherapy from week 1 to week 16, inclusive of health coaching administered through the NexJ Health Inc (NexJ Health) platform. Patients who are allocated ketamine-infusion therapy will receive monthly ketamine infusion treatments on weeks 2, 7, and 12. Patients who are allocated ketamine+CBT/MM will receive weekly psychotherapy from weeks 1 to 16, inclusive, as well as ketamine infusion treatments on weeks 2, 7, and 12. We will be assessing recruitment rates, consent rates, withdrawal rates, adherence, missing data, and adverse events as pilot outcome measures. Secondary clinical outcomes include changes relative to baseline in pain intensity and pain interference. RESULTS: As of November 1, 2023, the recruitment process has not been initiated. Given the recruitment, consent, and intervention target of 30 participants for this feasibility study, with each patient undergoing monitoring and treatments for a course of 20 weeks, we expect to complete the study by December 2025. CONCLUSIONS: This study assesses the feasibility of conducting a 3-arm randomized controlled trial to examine the effects of ketamine administration with the concurrent use of CBT/MM in a population with chronic neuropathic pain. The results of this pilot randomized controlled trial will inform the development of a larger-scale randomized controlled trial. Future studies will be aimed at including a sufficiently powered sample that will inform decisions about optimal treatment calibration and treatment effect duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT05639322; https://classic.clinicaltrials.gov/ct2/show/NCT05639322. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/54406.

Sustained Mood Improvement with Laughing Gas Exposure (SMILE): Study protocol for a randomized placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression.

BACKGROUND: Nitrous oxide has shown potentially as an efficacious intervention for treatment-resistant depression, yet there remains insufficient evidence pertaining to repeated administration of nitrous oxide over time and active placebo-controlled studies with optimal blinding. Thus, we aim to examine the feasibility and preliminary efficacy of a six-week follow up study examining the effects of a 4 week course of weekly administered nitrous oxide as compared to the active placebo, midazolam. METHODS: In this randomized, active placebo-controlled, pilot trial, 40 participants with treatment-resistant depression will receive either inhaled nitrous oxide (1 hour at 50% concentration) plus intravenous saline (100mL) or inhaled oxygen (1 hour at 50% concentration) plus intravenous midazolam (0.02 mg/kg in 100mL, up to 2mg) once per week, for 4 consecutive weeks. Participants will be followed up for 6 weeks starting from the first treatment visit. Primary feasibility outcomes include recruitment rate, withdrawal rate, adherence, missing data, and adverse events. The primary exploratory clinical outcome is change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at day 42 of the study. Other exploratory clinical outcomes include remission (defined as MADRS score <10), response (defined as ≥ 50% reduction in MADRS score), and adverse side effects. DISCUSSION: This pilot study will provide valuable information regarding the feasibility and preliminary efficacy of repeated nitrous oxide administration over time for treatment-resistant depression. If feasible, this study will inform the design of a future definitive trial of nitrous oxide as an efficacious and fast-acting treatment for treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT04957368. Registered on July 12, 2021.

Peri-Operative Wearables in Elder Recover after Surgery (POWERS) study: a protocol for a multicentre, prospective cohort study to evaluate perioperative activity with postoperative disability in older adults after non-cardiac surgery.

INTRODUCTION: The ageing population has led to an increasing proportion of surgical patients with greater frailty and comorbidity. Complications and mortality within 30 days of a surgical procedure are often used to evaluate success in the perioperative period however these measures can potentially underestimate a substantial level of morbidity associated with surgery. Personal wearable technologies are now readily available and can offer detailed information on activity intensity, sedentary behaviour and sleeping patterns. These devices may provide important information perioperatively by acting as a non-invasive, and cost-efficient means to risk stratify patients. METHODS AND ANALYSIS: The Peri-Operative Wearables in Elder Recover After Surgery (POWERS) study is a multicentre observational study of 200 older adults (≥65 years) having major elective non-cardiac surgery. The objectives are to characterise the association between preoperative and postoperative activity monitor measurements with postoperative disability and recovery, as well as characterise trajectories of activity and sleep in the perioperative period. Activity will be monitored with the ActiGraph GT3X device and measured for 7-day increments, preoperatively, and at 1 week, 1 month and 3 months postoperatively. Disability will be assessed using the WHO Disability Assessment Schedule 2.0 assessed at 1 week, 1 month and 3 months postoperatively. ETHICS AND DISSEMINATION: The POWERS study received research ethics board approval at all participating sites on 1 August 2019 (REB # 19-121 (CTO 1849)). Renewal was granted on 19 May 2022.

Local Injection for Treating Mood Disorders (LIFT-MOOD): A Pilot Feasibility RCT of Stellate Ganglion Block for Treatment-Resistant Depression.

Background: With nearly one-third of patients with major depressive disorder being resistant to available antidepressants, there is a need to develop new treatments for this population. Stellate ganglion block (SGB) is a procedure used to block sympathetic input to the central autonomic system; it has been administered to treat several conditions, including pain. Recently, indications for SGB have extended and the potential benefits for psychiatric disorders are under investigation. Methods: The Local Injection For Treating Mood Disorders (LIFT-MOOD) study investigated the feasibility of a trial of 2 right-sided injections of bupivacaine 0.5% (7 mL) at the stellate ganglion in participants with treatment-resistant depression (TRD) using a randomized, placebo-controlled, pilot trial. Ten participants were randomized in a 1:1 allocation to receive active treatment or placebo (saline). Primary feasibility outcomes included recruitment rate, withdrawal, adherence, missing data, and adverse events. As a secondary, exploratory objective, we explored the efficacy of SGB in improving symptoms of depression by calculating the change in scores from baseline to follow-up on day 42 for each treatment group. Results: The recruitment rate was reasonable and sufficient, retention and adherence were high, missing data were low, and adverse events were mild and temporary. Both treatment groups demonstrated decreases in Montgomery-Åsberg Depression Rating Scale scores, compared to baseline, by the end of the study. Conclusion: This study supports the feasibility of a confirmatory trial of SGB in participants with TRD. Conclusions regarding efficacy cannot be made based on this preliminary study due to the small number of participants who completed active treatment. Larger-scale randomized controlled trials with long-term follow-ups and alternate sham procedures are needed to assess the efficacy and duration of symptom improvement with the use of SGB in TRD.

Prospective preference assessment for the Comparison of Analgesic Regimen Effectiveness and Safety in Surgery (CARES) trial.

BACKGROUND: Clinical trials face major barriers such as under-enrollment and selective enrollment, which threaten study completion and undermine validity and generalizability. Thus, we conducted a prospective preference assessment (PPA) prior to commencing the Comparison of Analgesic Regimen Effectiveness and Safety in Surgery (CARES) trial-a randomized controlled study comparing the outcomes of managing acute postoperative pain between opioid-sparing and opioid-based therapies. This PPA aimed to (1) determine the patients' willingness to participate in the CARES trial, (2) identify the areas for improvement, and (3) assess the differences between willing and unwilling patients. METHODS: Patients undergoing elective laparoscopic cholecystectomy were recruited between August 2019 and February 2020 from two academic hospitals. A survey was administered to each patient consisting of (1) a vignette describing the trial, (2) an assessment of the patients' understanding of the trial, (3) open-ended questions assessing the attitudes towards the trial, and (4) patient-completed questionnaires. Data were analyzed qualitatively with thematic analysis and quantitatively with the Wilcoxon signed-rank and chi-square tests. RESULTS: Forty-two patients were enrolled and grouped based on the 6-point Likert scale into willing (4-6, 71%) and not willing (1-3, 29%) to participate in the CARES trial. There were no significant differences with respect to all variables: age, education, sex, visible minority status, previous research, previous surgery, regular use of pain medications, surgical concerns, previous discussions on pain management, significant pain within the past 3 months, and significant use of pain medication within the past month. Factors that motivated participation were contributing to scientific research (45%), altruism (29%), and improving personal pain (24%). Common discouraging factors were negative perceptions of opioids (29%), side effects (21%), being blinded to the study medication (21%), and poor pain management (19%). CONCLUSIONS: This PPA revealed that two key discouraging factors for patients were being blinded to the type of pain medication being taken and the potential for poor pain management as a consequence of participation. Modifications to improve patient acceptance of the CARES trial include ensuring sufficient rescue medicine and follow-up visits consistent with current standards of care for all patients, as well as patient education surrounding safe administration and side effects of the study medications.

A comprehensive review of rFVIIa use in a tertiary care pediatric center.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is a hemostatic agent developed for the treatment of bleeds in patients with hemophilia and inhibitors. Case reports/series document its growing use in patients without hemophilia. Such reports however do not accurately describe the proportion of rFVIIa used for various indications. We sought to document the complete use of rFVIIa at our institution over a 6-year period (2000-2005). PROCEDURE: Using a computerized registry documenting all rFVIIa use in our institution a complete list of patients receiving rFVIIa was generated. Clinical data on these patients was obtained through chart review. RESULTS: 111 patients received 7,016,400 microg of rFVIIa over the 6 years: 23 patients had congenital bleeding disorders (10 patients with hemophilia and inhibitors; 7 with congenital FVII deficiency; 6 with platelet function disorders). These 23 patients (21% of all patients receiving rFVIIa) accounted for 79.9% of all rFVIIa used; patients with hemophilia alone accounted for 68.6%. The 88 patients without a congenital bleeding disorder (79% of all patients using rFVIIa) accounted for 20.1% of rFVIIa used. However their annual use of rFVIIa increased 10-fold during the 6 years. CONCLUSIONS: Patients with hemophilia use massive amounts of rFVIIa repeatedly while patients without hemophilia use rFVIIa infrequently and at smaller doses. The use of rFVIIa in patients without congenital bleeding disorders (all "off-label" use) is rapidly growing in both number of patients and in total use and has likely significant clinical and economic ramifications.

Children in side-impact motor vehicle crashes: seating positions and injury mechanisms.

BACKGROUND: This study aimed to describe the injury mechanisms of children involved in side-impact car crashes, particularly as these relate to seating position, and to estimate the danger of the near-side seating position. METHODS: A prospective two-center study of children involved in severe car crashes in Canada was conducted as well as a retrospective cohort study of children involved in crashes reported in the Fatality Analysis Reporting System (FARS) and the National Automotive Sampling System: Crashworthiness Data System (NASS CDS). RESULTS: Children sitting at the side the car was struck (near-side position) sustained severe head, trunk, and limb injuries. Many of these injuries were attributable to direct intrusion, but some occurred without direct damage to the occupant compartment. Center-seat and far-side occupants had severe injuries only when unrestrained. Injury severity scores were higher for children seated on the near side, and this was statistically significant (p = 0.024) The analysis of Fatality Analysis Reporting System data showed that the risk of fatality was higher for children seated in the near-side position than for those in the center-seat position. The fatality risk ratio was 2.53 (95% confidence interval [CI], 2.08-3.07) for restrained children and 1.84 (95% CI, 1.57-2.17) for unrestrained children. Analysis of the NASS-CDS data showed that for restrained children, severe injury (ISS > or = 16) was more common among those on the near side (7 per 1,000 children) than among those in the center seat (2 per 1,000) or on the far-side seat (1 per 1,000) (p < 0.001). CONCLUSIONS: Severe injuries to near-side occupants occurred in both the presence and absence of compartment intrusion. A typical pattern of head, chest, and extremity injury similar to that seen among child pedestrians was observed among near-side child occupants in side-impact crashes. The center seat was statistically safer than the near-side seat, particularly for restrained child occupants. Scene information may be useful to trauma teams for the prediction of injury type and location. Avoiding intrusion and preventing the occupant from striking the vehicle wall are both important to side-impact protection for children. Improvement of the vehicle safety cage may protect against intrusion injuries. Seating two child occupants in inboard seating positions may provide additional protection against intrusion injuries, and also may protect against nonintrusion injuries.