A dose-escalation clinical trial of intranasal ketamine for uncontrolled cancer-related pain.

STUDY OBJECTIVE: The objective of our study was to determine safety and pharmacology (pharmacokinetics and preliminary efficacy) of intranasal (IN) ketamine for uncontrolled cancer-related pain. DESIGN: Dose escalation clinical trial. SETTING: Outpatient. PATIENTS: Ten adult patients with uncontrolled cancer-related pain. INTERVENTION: Each patient received escalating doses of ketamine over four visits, each 2-5 days apart: 10 mg IN at visit 1, 10 mg intravenous (IV) at visit 2, 30 mg IN at visit 3, and 50 mg IN at visit 4. MEASUREMENTS: Pain was measured before and after drug administration for up to 4 h using the 11 point (0-10) Numerical Pain Rating Scale (NPRS). MAIN RESULTS: All subjects had advanced cancer, with intractable pain, despite being on moderate dosage of opioids. There was a statistically significant reduction in median NPRS by 1.5 (1-4), 3 (2-3), and 4 (3-5) points at 60 min after receiving the medication and remained decreased by 1.5 (1-2), 2 (1-2) and 1 (1-4) points at the end of the study visit (240 min) with the 10 mg, 30 mg and 50 mg IN dosage, respectively. The median percentage of maximal pain relief being 22.5 (16.6-71.5), 65.5 (40-100), and 69.25 (50-100) for 10 mg, 30 mg and 50 mg IN dosage, respectively and 100 (75-100) with 10 mg IV dose. All side effects (nausea and feeling of unreality) resolved by the end of each study visit. No severe adverse events occurred. CONCLUSION: In this single-institution study, all dosages of IN ketamine administered in the study (10, 30, and 50 mg) provided significant pain relief for intractable cancer-related pain and were well tolerated. The 50 mg dose provided maximal pain relief without major side effects. Further study focused on repeated administration efficacy and safety for cancer-related pain is warranted.

Lumbar Spondylolisthesis Progression: What is the Effect of Lumbar Medial Branch Nerve Radiofrequency Ablation on Lumbar Spondylolisthesis Progression? A Single-Center, Observational Study.

BACKGROUND: Radiofrequency ablation (RFA) is a denervation therapy commonly performed for pain of facet etiology. Degenerative spondylolisthesis, a malalignment of the spinal vertebrae, may be a co-existing condition contributing to pain; yet the effect of RFA on advancing listhesis is unknown. To the extent that denervating RFA may weaken paraspinal muscles that provide stability to the spine, the therapy can potentially contribute to progressive spinal instability. METHODS: Single-center, prospective, observational pilot study in an interventional pain practice to test the hypothesis that RFA of painful facets in the setting of spondylolisthesis may contribute to advancement of further degenerative spondylolisthesis. Fifteen participants with pre-existing degenerative Grade I or Grade II spondylolisthesis and coexisting axial lumbar pain underwent lumbar RFA encompassing spondylolisthesis level and followed with post-RFA imaging at 12 months and beyond to measure percent change in spondylolisthesis. RESULTS: The primary outcome was the percent advancement of spondylolisthesis per year measured on post-RFA lateral lumbar spine imaging compared with non-intervention inferred baseline advancement of 2% per very limited observational studies. Among the 15 participants enrolled, 14 completed the study (median age 66; 64.3% women; median BMI 33.5; mean follow-up time 23.9 months). The mean advancement of spondylolisthesis per year after RFA was 1.30% (95% CI -0.14 to 2.78%), with 9/14 below 1.25%. CONCLUSION: Among patients with lumbar pain originating from facets in the setting of degenerative spondylolisthesis who underwent lumbar RFA, the observed advancement of spondylolisthesis is clinically similar to the estimated maximum baseline of 2% per year change. The study findings did not find a destabilizing effect of lumbar RFA in advancing spondylolisthesis in this patient population.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 µg/mL; difference, 7.94 µg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Safety of Intranasal Ketamine for Reducing Uncontrolled Cancer-Related Pain: Protocol of a Phase I/II Clinical Trial.

BACKGROUND: Approximately 12 million Americans are affected with cancer. Of these, 53% experience pain at all stages of cancer. Pain may remain uncontrolled despite high-dose opioid therapy, and opioids have many well-documented harmful side effects. Intranasal ketamine has been shown to be effective in controlling breakthrough noncancer pain in a double-blind randomized control trial (DBRCT) by Carr et al in 2003 as well as to help with depression in a DBRCT by Lapidus et al in 2014. We seek to obtain preliminary data on the safety, feasibility, and utility of this novel technique for the treatment of uncontrolled cancer pain. OBJECTIVE: This study aimed to obtain preliminary data via a clinical trial addressing the safety, feasibility, pharmacokinetics, and pharmacodynamics of intranasal ketamine. These initial findings will be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients and to address the compelling need to identify new, successful management therapies for cancer pain. METHODS: This is an institutional review board- and investigational new drug-approved, prospective phase I/II trial to investigate the safety and use of intranasal ketamine in patients with uncontrolled pain related to cancer or cancer treatment. Informed consent will be obtained prior to all study procedures. All patients will be assigned to the same investigational treatment arm. After patient selection via inclusion/exclusion criteria, patients will be seen over 5 visits, with each visit conducted 2-7 days apart. Patients will be administered ketamine on visits 1-4 and monitored for 240 minutes with continuous pulse oximetry and regular blood pressure checks. Blood samples as well as patient-reported outcomes will be collected at set time points at baseline and after drug delivery. Patients will receive 10 mg intranasal ketamine on visit 1, 10 mg intravenous ketamine on visit 2, 30 mg intranasal ketamine on visit 3, and 50 mg intranasal ketamine on visit 4. On visit 5, an addition blood sample will be drawn. RESULTS: As of March 2019, enrollment is in progress, and a total of 7 subjects have completed the study. Enrollment is expected to be completed by April 2019. Final data analysis will commence soon after, and the results are expected to be submitted for publication in 2019. CONCLUSIONS: If intranasal ketamine can be utilized for pain control in cancer patients, it could provide superior analgesia and better quality of life, without the risk of significant respiratory depression and constipation associated with opioid medications. These findings will be an important initial step toward testing the effectiveness of intranasal ketamine as a nonopioid medication for cancer pain and as potential maintenance outpatient therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03146806; https://clinicaltrials.gov/ct2/show/NCT03146806. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12125.

Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional transfusion.

BACKGROUND: Platelet (PLT) and plasma transfusion remain the mainstay hemostatic therapy for perioperative bleeding. Several studies have indicated that acquired fibrinogen (FIB) deficiency can be the primary cause of bleeding after cardiac surgery. The aim of this study was to compare hematologic and transfusion profiles between the first-line FIB replacement and PLT transfusion in post-cardiac surgical bleeding. STUDY DESIGN AND METHODS: In this prospective, randomized, open-label study, 20 adult patients who underwent valve replacement or repair and fulfilled preset visual bleeding scale were randomized to 4 g of FIB or 1 unit of apheresis PLTs. Primary endpoints included hemostatic condition in the surgical field and 24-hour hemostatic product usage. Hematologic data, clinical outcome, and safety data were collected up to the 28th day postoperative visit. RESULTS: In patients who received the first-line FIB concentrate (n = 10), the visual bleeding scale improved after intervention, and the incidence of PLT transfusion and total plasma donor exposure were lower compared to the PLT group (n = 10). Postintervention FIB level was statistically higher (209 mg/dL vs. 165 mg/dL) in the FIB group than in the PLT group, but PLT count and prothrombin were lower. There were no statistical differences in the postoperative blood loss and red blood cell transfusion between two groups. CONCLUSIONS: Our preliminary data indicate that the primary FIB replacement may potentially reduce the incidence of PLT transfusion and the number of donor exposures. Plasma FIB level of 200 mg/dL is attainable with a single dose of 4 g, and this level seems to mitigate bleeding despite moderately decreased thrombin generation.