Background Many patients requiring pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach. Methods We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation). Results The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. Conclusions As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long-Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137 .).

Intravenous methylprednisolone (IVMP) infusions have been associated with adverse cardiovascular effects. Inconsistent monitoring practices in a pediatric hospital led to questions about patient safety and allocation of nursing resources. This study describes vital sign changes in children and monitoring practices related to IVMP.This retrospective chart review received Institutional Review Board approval. Children aged 5 to 17 years receiving IVMP from January 2006 to January 2009 were included. Seventy-four patients with 94 hospital admissions were evaluated. Data collected included systolic blood pressure, diastolic blood pressure, and heart rate, as well as the time and dosage of IVMP. Frequency of vital sign monitoring as ordered and as performed was described. Interrater reliability was calculated, and descriptive statistics were used in the data analysis.At baseline, about half of the patients had vital signs out of normal range for age. After the first dose, vital signs fluctuated, with a majority having greater than 10% changes from baseline as increases, decreases, or both. Time of initial 10% change in vital signs ranged from immediately after the dose to 135.5 hours later. Increased vital sign changes were seen in the older patients and in patients receiving higher doses. Monitoring of vital signs occurred more frequently than was ordered. Only 1 patient had a specific order for monitoring with IVMP.The patients included in this study experienced documented fluctuations in vital signs. A prospective study to evaluate the relationship of IVMP and patient safety will assist in standardizing vital sign monitoring guidelines.

Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.ClinicalTrials.gov NCT00349622.

Abstract In recent years, there has been an increase in pediatric clinical trials as the result of an identified need for greater research with this population. Given the potential risks, and the vulnerability of the population, there has also been an identified need for greater safety elicitation and monitoring in pediatric psychopharmacology trials, for example, through the use of a data and safety monitoring board (DSMB). However, research indicates that pediatric trials and psychiatric trials are less likely to use a DSMB. The rationale for the current study was to determine what safety methodologies have been reported in pediatric psychopharmacology trials over the past 10 years. A literature review was conducted of all pediatric psychopharmacology trials published since 2001. Results indicated that the most common elicitation method was collecting laboratory information and vital signs. Six percent of trials solely relied on spontaneous reporting of adverse events, and only 11.8% reported using a DSMB. These results suggest that elicitation methods and use of DSMBs are still low. Practical considerations, affected stakeholders, and barriers are discussed. Recommendations for moving forward include the use of multiple elicitation methods and automatic requirement of a DSMB for pediatric psychopharmacology trials, required completion of a standardized safety reporting form, and engaging multiple interested parties in these processes.

To provide recommendations for optimized anticoagulant therapy in the inpatient setting and outline broad elements that need to be in place for effective management of anticoagulant therapy in hospitalized patients; the guidelines are designed to promote optimization of patient clinical outcomes while minimizing the risks for potential anticoagulation-related errors and adverse events.The medical literature was reviewed using MEDLINE (1946-January 2013), EMBASE (1980-January 2013), and PubMed (1947-January 2013) for topics and key words including, but not limited to, standards of practice, national guidelines, patient safety initiatives, and regulatory requirements pertaining to anticoagulant use in the inpatient setting. Non-English-language publications were excluded. Specific MeSH terms used include algorithms, anticoagulants/administration and dosage/adverse effects/therapeutic use, clinical protocols/standards, decision support systems, drug monitoring/methods, humans, inpatients, efficiency/ organizational, outcome and process assessment (health care), patient care team/organization and administration, program development/standards, quality improvement/organization and administration, thrombosis/ drug therapy, thrombosis/prevention and control, risk assessment/standards, patient safety/standards, and risk management/methods.Because of this document's scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors and are endorsed by the Board of Directors of the Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The board is composed of physicians, pharmacists, and nurses with demonstrated expertise and experience in the management of patients receiving anticoagulation therapy.Recommendations for delivering optimized inpatient anticoagulation therapy were developed collaboratively by the authors and are summarized in 8 key areas: (1) process, (2) accountability, (3) integration, (4) standards of practice, (5) provider education and competency, (6) patient education, (7) care transitions, and (8) outcomes. Recommendations are intended to inform the development of coordinated care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized inpatient anticoagulation therapy are intended to apply to all clinicians involved in the care of hospitalized patients receiving anticoagulation therapy.Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients. Several national organizations have introduced initiatives to reduce the likelihood of patient harm associated with the use of anticoagulants. Health care organizations are under increasing pressure to develop systems to ensure the safe and effective use of anticoagulants in the inpatient setting. This document provides consensus guidelines for anticoagulant therapy in the inpatient setting and serves as a companion document to prior guidelines relevant for outpatients.

Object Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). Methods Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. Results Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. Conclusions NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. Clinical trial registration no.: NCT00747253 ( ClinicalTrials.gov ).

PURPOSE:

To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS).

DESIGN:

Analysis done on pooled safety data (N = 2615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension >5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies).

PARTICIPANTS:

Patients aged 18 to 55 years (18-60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or macular edema (ME) at screening were excluded.

INTERVENTION:

Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA).

MAIN OUTCOME MEASURES:

Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board.

RESULTS:

Among 2615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3%; 1.25 mg: n = 15, 1.2%). Most patients (n = 13, 68%) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68%); 2 patients had late onset (>12 months) ME. Of the 19 patients with ME, 5 (26%), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1%) in the all studies group. In most cases (n = 16, 84%), ME resolved after discontinuing the study drug. Eleven patients required topical anti-inflammatory medications. No patient had further vision deterioration.

CONCLUSIONS:

Fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Heart failure is one of the key causes of morbidity and mortality world-wide. The recent findings that regeneration is possible in the heart have made stem cell therapeutics the Holy Grail of modern cardiovascular medicine. The success of cardiac regenerative therapies hinges on the combination of an effective allogeneic "off the shelf" cell product with a practical delivery system. In 2007 Medistem discovered the Endometrial Regenerative Cell (ERC), a new mesenchymal-like stem cell. Medistem and subsequently independent groups have demonstrated that ERC are superior to bone marrow mesenchymal stem cells (MSC), the most widely used stem cell source in development. ERC possess robust expansion capability (one donor can generate 20,000 patients doses), key growth factor production and high levels of angiogenic activity. ERC have been published in the peer reviewed literature to be significantly more effect at treating animal models of heart failure (Hida et al. Stem Cells 2008).Current methods of delivering stem cells into the heart suffer several limitations in addition to poor delivery efficiency. Surgical methods are highly invasive, and the classical catheter based techniques are limited by need for sophisticated cardiac mapping systems and risk of myocardial perforation. Medistem together with Dr. Amit Patel Director of Clinical Regenerative Medicine at University of Utah have developed a novel minimally invasive delivery method that has been demonstrated safe and effective for delivery of stem cells (Tuma et al. J Transl Med 2012). Medistem is evaluating the combination of ERC, together with our retrograde delivery procedure in a 60 heart failure patient, double blind, placebo controlled phase II trial. To date 17 patients have been dosed and preliminary analysis by the Data Safety Monitoring Board has allowed for trial continuation.The combined use of a novel "off the shelf" cell together with a minimally invasive 30 minute delivery method provides a potentially paradigm-shifting approach to cardiac regenerative therapy.

BACKGROUND:

Continuous pulse oximetry monitoring is recommended to improve safety during postoperative opioid use, however concerns with monitoring on general care units remain, given potential system barriers to alarm transmission, recognition, and nursing response.

METHODS:

This prospective, observational study evaluated unit and hospital-level factors affecting nurses' response to monitor desaturation alarms in postoperative patients on a general postoperative unit. With exemption and waiver of consent granted from the Institutional Review Board, monitoring data were downloaded from bedside monitors of postoperative patients. Alarm notification data and response times were recorded from the continuous capture of institutional surveillance data. Paging notifications were coded as clinically relevant (i.e., true oxygen desaturation with SpO2<89 for >15s) or irrelevant (i.e., artifact, inappropriate alarm threshold, or failure to delay page). Linear mixed models, and correlation coefficients were used to examine the relationships between unit staffing, shift, paging burden and response time. Means and [95% confidence intervals] are presented.

RESULTS:

1616 monitoring hours in 103 patients yielded 342 desaturation events (duration 23.6s [20.99, 26.1]) and 710 notification pages, 36% of which were for clinically relevant desaturation. Nursing response time was 52.1s [46.4, 57.7], which was longer at night (63.8 [51.2, 76.35]; p=0.035), but not related to unit staffing. Missed alarm events (i.e., no notification page transmitted) occurred for 26% of the clinically relevant events, and were associated with higher paging burden (p=0.04), lower SpO2 values (81.8 [80.5, 83.0] vs. 83.2 [82.6, 83.8]; p=0.026), and higher odds of intervention (OR 3.5 [1.38, 8.9]). 65% of patients with desaturation events received interventions which correlated with the number of pages (rho=0.422; p<0.01) and events (rho=0.57; p<0.01), desaturation duration (rho=0.505; p<0.01), and SpO2 (rho=-0.324; p<0.01).

CONCLUSIONS:

One-third of pulse oximetry alarm notifications were for clinically relevant oxygen desaturation, facilitating timely nursing response and intervention for most patients. Unit staffing and false alarm frequency were not associated with response time, suggesting a high level of attention on this unit. The nature and degree of missed alarm events suggests patient safety concerns posed by hospital-level transmission systems warranting further strategies to ensure monitoring safety.

OBJECTIVES:

: Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials.

DESIGN:

: Case study, narrative review.

METHODS::

The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.

FINDINGS:

: The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility.

CONCLUSIONS::

The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.