Palatability of a novel oral formulation of prednisone in healthy young adults.

OBJECTIVES: Prednisone is a widely used anti-inflammatory for a variety of conditions. While oral liquid formulations of prednisone enable weight-based dosing, children frequently find them to be objectionable due to bitter taste. This limitation of prednisone can adversely impact patient acceptance and may result in non-compliance. Efforts to mask flavours often result in poorly controlled, heterogeneous particle distributions and can provide ineffective taste masking. The present work utilized a novel drug delivery technology developed by Orbis Biosciences, Inc., to create an oral taste-masked formulation of prednisone. METHODS: The study examined the palatability of Orbis' microsphere prednisone formulation in healthy young adults (n = 24). Four test articles were used in the study including a reference formulation (Roxanne Laboratories), a control and the test formulation (Orbis) prepared in two different ways. Study participants were randomized in a crossover design. KEY FINDINGS: Results indicated that the test prednisone formulation was indistinguishable from the control, and both were preferable to the reference formulation in every category of palatability assessed using a validated 9-point Hedonic Scale. The data also suggested that preparing the microsphere suspension immediately before administration results in the most ideal palatability properties. CONCLUSIONS: In conclusion, the novel microsphere formulation technology was effective in taste-masking prednisone.

Use of a nursing checklist to facilitate implementation of therapeutic hypothermia after cardiac arrest.

Therapeutic hypothermia has become a widely accepted intervention that is improving neurological outcomes following return of spontaneous circulation after cardiac arrest. This intervention is highly complex but infrequently used, and prompt implementation of the many steps involved, especially achieving the target body temperature, can be difficult. A checklist was introduced to guide nurses in implementing the therapeutic hypothermia protocol during the different phases of the intervention (initiation, maintenance, rewarming, and normothermia) in an intensive care unit. An interprofessional committee began by developing the protocol, a template for an order set, and a shivering algorithm. At first, implementation of the protocol was inconsistent, and a lack of clarity and urgency in managing patients during the different phases of the protocol was apparent. The nursing checklist has provided all of the intensive care nurses with an easy-to-follow reference to facilitate compliance with the required steps in the protocol for therapeutic hypothermia. Observations of practice and feedback from nursing staff in all units confirm the utility of the checklist. Use of the checklist has helped reduce the time from admission to the unit to reaching the target temperature and the time from admission to continuous electroencephalographic monitoring in the cardiac intensive care unit. Evaluation of patients' outcomes as related to compliance with the protocol interventions is ongoing.

Transesophageal Doppler measurement of renal arterial blood flow velocities and indices in children.

BACKGROUND: Doppler-derived renal blood flow indices have been used to assess renal pathologies. However, transesophageal ultrasonography (TEE) has not been previously used to assess these renal variables in pediatric patients. In this study, we (a) assessed whether TEE allows adequate visualization of the renal parenchyma and renal artery, and (b) evaluated the concordance of TEE Doppler-derived renal blood flow measurements/indices compared with a standard transabdominal renal ultrasound (TAU) in children. METHODS: This prospective cohort study enrolled 28 healthy children between the ages of 1 and 17 years without known renal dysfunction who were undergoing atrial septal defect device closure in the cardiac catheterization laboratory. TEE was used to obtain Doppler renal artery blood velocities (peak systolic velocity, end-diastolic velocity, mean diastolic velocity, resistive index, and pulsatility index), and these values were compared with measurements obtained by TAU. Concordance correlation coefficient (CCC) was used to determine clinically significant agreement between the 2 methods. The Bland-Altman plots were used to determine whether these 2 methods agree sufficiently to be used interchangeably. Statistical significance was accepted at P ≤ 0.05. RESULTS: Obtaining 2-dimensional images of kidney parenchyma and Doppler-derived measurements using TEE in children is feasible. There was statistically significant agreement between the 2 methods for all measurements. The CCC between the 2 imaging techniques was 0.91 for the pulsatility index and 0.66 for the resistive index. These coefficients were sensitive to outliers. When the highest and lowest data points were removed from the analysis, the CCC between the 2 imaging techniques was 0.62 for the pulsatility index and 0.50 for the resistive index. The 95% confidence interval (CI) for pulsatility index was 0.35 to 0.98 and for resistive index was 0.21 to 0.89. The Bland-Altman plots indicate good agreement between the 2 methods; for the pulsatility index, the limits of agreement were -0.80 to 0.53. The correlation of the size of the measurement and the mean difference in methods (-0.14; 95% CI = -0.28, 0.01) was not statistically significant (r = 0.31, P = 0.17). For the resistive index, the limits of agreement were -0.22 to 0.12. The correlation of the size of the measurement and the mean difference in methods (-0.05; 95% CI = -0.09, -0.01) was not statistically significant (r = 0.10, P = 0.65). CONCLUSION: This study confirms the feasibility of obtaining 2-dimensional images of kidney parenchyma and Doppler-derived measurements using TEE in children. Angle-independent TEE Doppler-derived indices show significant concordance with those derived by TAU. Further studies are required to assess whether this correlation holds true in the presence of renal pathology. This technique has the potential to help modulate intraoperative interventions based on their impact on renal variables and may prove helpful in the perioperative period for children at risk of acute kidney injury.

Establishing a methodology for development and dissemination of nursing evidence-based practice to promote quality care.

Reducing nursing practice variance by standardization of practice guidelines based on supportive literature has demonstrated improvements in the quality of patient care and positive patient outcomes. The challenge is to link the bedside nurse providing nursing care to subject matter experts well-versed in the critical analysis of clinical practice recommendations. This article discusses the restructuring of nursing research departments within Army healthcare facilities to facilitate nursing practice based on supportive evidence and the development of a senior nursing leadership practice council to support dissemination of approved nursing practice guidelines across all Army inpatient medical facilities.

Evaluation of a local ICU sedation guideline on goal-directed administration of sedatives and analgesics.

PURPOSE: Sedatives and analgesics are commonly used in mechanically ventilated patients in the intensive care unit. Sedation guidelines have been shown to improve sedation management as well as various patient outcomes. The main objective was to evaluate adherence to a sedation guideline with both sedative prescribing and documentation of Richmond Agitation-Sedation Scale (RASS) scores. METHODS: In a retrospective chart review, data was collected on 111 medical intensive care unit patients mechanically ventilated via endotracheal tube for 12 hours or greater at Brigham and Women's Hospital. Fifty-seven patients were evaluated pre-guideline implementation and 54 patients were evaluated post-guideline. RESULTS: Significant increases were seen in the post-guideline group in goal-directed sedation with a patient-specific RASS goal in the sedation order: 21.3 vs 85.4% (P < 0.001), and mean number of sedation assessments per 24 hours using the RASS: 4.7 vs 11.4 (P < 0.001). Similarly, this group experienced a higher percentage of RASS scores at their sedation goal: 31.4 vs 44.1% (P < 0.001). No difference was seen in other clinical endpoints. CONCLUSION: Implementation and routine application of a hospital pain and sedation guideline was associated with significantly improved sedation metrics, such as goal-directed sedation, as well as frequency of sedation level assessment and documentation. An increase was observed in the time that post-guideline patients spent at or near their RASS goal.

Implementation of a Hospital-wide Protocol for Induced Hypothermia Following Successfully Resuscitated Cardiac Arrest.

Permanent neurologic impairment following cardiac arrest is often severely debilitating, even after successful resuscitation. Therapeutic hypothermia decreases anoxic brain injury and subsequent cognitive deficits. Current practice guidelines recommend therapeutic hypothermia in comatose survivors of cardiac arrest. To address the multifacets of therapeutic hypothermia, we assembled a multidisciplinary task force including members from various specialties to create an evidence-based guideline with transparency across disciplines and consistency of care. We describe our institutional guidelines for the initiation and management of induced hypothermia in patients successfully resuscitated from a cardiac arrest.

Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase.

Previous studies indicate that noise induced hearing loss (NIHL) involves a decrease in glutathione peroxidase (GPx) activity and a subsequent loss of outer hair cells (OHC). However, the cellular localization of this GPx decrease and the link to OHC loss are still poorly understood. In this report, we examined the cellular localization of GPx (GPx1, GPx 3 and GPx 4) in F-344 rat before and after noise exposure and after oral treatment with ebselen, a small molecule mimic of GPx activity. Results indicate that GPx1 is the major isoform within the cochlea and is highly expressed in cells of the organ of Corti, spiral ganglia, stria vascularis, and spiral ligament. Within 5h of noise exposure (4h at 113 dB, 4-16 kHz), significant OHC loss was already apparent in regions coincident with the 8-16 kHz region of the cochlea. In addition, the stria vascularis exhibited significant edema or swelling and a decrease in GPx1 immunoreactivity or fluorescent intensity. Treatment with ebselen (4 mg/kg p.o.) before and immediately after noise exposure reduced both OHC loss and the swelling of the stria vascularis typically observed within 5h post-noise exposure. Interestingly, GPx1 levels increased in the stria vascularis after noise and ebselen treatment vs noise and vehicle-only treatment, and exceeded baseline no noise control levels. These data indicate that ebselen acts to prevent the acute loss of OHCs and reduces the acute swelling of the stria vascularis by two potential mechanisms: one, as a ROS/RNS scavenger through its intrinsic GPx activity, and two, as a stimulator of GPx1 expression or activity. This latter mechanism may be due to the preservation of endogenous GPx1 from ROS/RNS induced degradation and/or the stimulation of GPx1 expression or activity.

Combined oral delivery of ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumor activity.

The chemoprotective effects of combined ebselen and allopurinol in breast (MTLn3) and ovarian (NuTu-19) cancer models using a repeated cisplatin dosing schedule (6 mg/kg i.p.x3 weeks) were studied. Otoprotection was evaluated using auditory evoked brainstem response (ABR) to determine threshold and latency shifts, and outer hair cell counts. Nephroprotection was analyzed by serological markers [blood urea nitrogen (BUN) and creatinine] and histological evaluation. Myelotoxicity was quantified using cytological counts for platelets and changes in hematocrit. Hepatotoxicity was determined by changes in the serological markers amino alanine transferase (ALT) and aspartate amino transferase. Significant chemoprotective effects were observed for multiple organ systems including oto- (ABR threshold shifts for click and 24-kHz stimuli, p<0.05, 8 and 16 kHz, p<0.01, MTLn3 group; hair cell counts, p<0.05 both groups), nephro- (BUN and creatinine, p<0.01), myelo- (platelet p<0.05, hematocrit p<0.05) and hepatotoxicity (ALT p<0.05) in rats receiving oral ebselen and allopurinol. Importantly, the anti-tumor activity of cisplatin was not compromised. On the contrary, improved mortality, morbidity and outcome were observed in the ovarian cancer model. This combined oral formulation of ebselen and allopurinol is an attractive candidate for clinical evaluation.

Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen.

Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.p.) to analyze allopurinol and ebselen alone and in combination for their ability to reduce cisplatin associated hearing loss and nephrotoxicity. The results from our studies indicate that a combined formulation of ebselen and allopurinol affords significant protection to the cochlea and kidney from cisplatin toxicity. In the cochlea, protection is dependent on the preservation of outer hair cell number, while in the kidney, protection is associated with the preservation of proximal tubular epithelia. Further evaluation of the chemoprotective effects of ebselen and allopurinol on cisplatin side effects in the presence of tumor appears warranted.

Ebselen-mediated protection from single and repeated noise exposure in rat.

OBJECTIVES/HYPOTHESIS: Ebselen, a glutathione peroxidase mimic, is a candidate compound for the prevention of noise-induced hearing loss. STUDY DESIGN: Single-blinded, placebo-controlled study. METHODS: Methods included single and repeated noise exposures on F-344 female rats given oral or injected ebselen or vehicle before and after noise, evoked auditory brainstem responses using click and pure-tone stimuli, light and fluorescence microscopy of cochleae stained with 4',6-Diamidino-2-phenylindole (DAPI) and fluorescein isothiocyanate-phalloidin, and statistical power determined by ANOVA. RESULTS: Auditory brainstem response indicated that ebselen provided significant protection from both temporary and permanent threshold shifts following single and repeated noise exposure. On average, three times more outer hair cells were lost in control versus ebselen-treated animals. CONCLUSION: Ebselen reduces noise-induced hearing loss in rats.