Continuous Low-Intensity Ultrasound Improves Cartilage Repair in Rabbit Model of Subchondral Injury.

Subchondral drilling (SD), a bone marrow stimulation technique, is used to repair cartilage lesions that lack regenerative potential. Cartilage repair outcomes upon SD are typically fibrocartilaginous in nature with inferior functionality. The lack of cues to foster the chondrogenic differentiation of egressed mesenchymal stromal cells upon SD can be attributed for the poor outcomes. Continuous low-intensity ultrasound (cLIUS) at 3.8 MHz is proposed as a treatment modality for improving cartilage repair outcomes upon marrow stimulation. Bilateral defects were created by SD on the femoral medial condyle of female New Zealand white rabbits (n = 12), and the left joint received cLIUS treatment (3.8 MHz, 3.5 Vpp, 8 min/application/day) and the contralateral right joint served as the control. On day 7 postsurgery, synovial fluid was aspirated, and the cytokine levels were assessed by Quantibody™ assay. Rabbits were euthanized at 8 weeks and outcomes were assessed macroscopically and histologically. Defect areas in the right joints exhibited boundaries, incomplete fill, irregular cartilage surfaces, loss of glycosaminoglycan (GAG), and absence of chondrocytes. In contrast, the repaired defect area in the joints that received cLIUS showed complete fill, positive staining for GAG with rounded chondrocyte morphology, COL2A1 staining, and columnar organization. Synovial fluid collected from cLIUS-treated left knee joints had lower levels of IL1, TNFα, and IFNγ when compared to untreated right knee joints, alluding to the potential of cLIUS to mitigate early inflammation. Further at 8 weeks, left knee joints (n = 12) consistently scored higher on the O'Driscoll scale, with a higher percent hyaline cartilage score. No adverse impact on bone or change in the joint space was noted. Upon a single exposure of cLIUS to TNFα-treated cells, nuclear localization of pNFκB and SOX9 was visualized by double immunofluorescence and the expression of markers associated with the NFκB pathway was assayed by quantitative real-time polymerase chain reaction. cLIUS extends its chondroprotective effects by titrating pNFκB levels, preventing its nuclear translocation, while maintaining the expression of SOX9, the collagen II transcription factor. Our combined results demonstrate that healing of chondral defects treated with marrow stimulation by SD can be accelerated by employing cLIUS regimen that possesses chondroinductive and chondroprotective properties. Impact statement Repair of cartilage represents an unsolved biomedical burden. In vitro, continuous low-intensity ultrasound (cLIUS) has been demonstrated to possess chondroinductive and chondroprotective potential. To our best knowledge, the use of cLIUS to improve cartilage repair outcomes upon marrow stimulation, in vivo, has not been reported and our work reported here fills that gap. Our results demonstrated enhanced cartilage repair outcomes under cLIUS (3.8 MHz) in a rabbit model of subchondral injury by subchondral drilling. Enhanced repair stemmed from mesenchymal stem cell differentiation in vivo and the subsequent synthesis of articular cartilage-specific matrix.

Theoretically proposed optimal frequency for ultrasound induced cartilage restoration.

BACKGROUND: Matching the frequency of the driving force to that of the system's natural frequency of vibration results in greater amplitude response. Thus we hypothesize that applying ultrasound at the chondrocyte's resonant frequency will result in greater deformation than applying similar ultrasound power at a frequency outside of the resonant bandwidth. Based on this resonant hypothesis, our group previously confirmed theoretically and experimentally that ultrasound stimulation of suspended chondrocytes at resonance (5 MHz) maximized gene expression of load inducible genes. However, this study was based on suspended chondrocytes. The resonant frequency of a chondrocyte does not only depend on the cell mass and intracellular stiffness, but also on the mechanical properties of the surrounding medium. An in vivo chondrocyte's environment differs whether it be a blood clot (following microfracture), a hydrogel or the pericellular and extracellular matrices of the natural cartilage. All have distinct structures and compositions leading to different resonant frequencies. In this study, we present two theoretical models, the first model to understand the effects of the resonant frequency on the cellular deformation and the second to identify the optimal frequency range for clinical applications of ultrasound to enhance cartilage restoration. RESULTS: We showed that applying low-intensity ultrasound at the resonant frequency induced deformation equivalent to that experimentally calculated in previous studies at higher intensities and a 1 MHz frequency. Additionally, the resonant frequency of an in vivo chondrocyte in healthy conditions, osteoarthritic conditions, embedded in a blood clot and embedded in fibrin ranges from 3.5 - 4.8 MHz. CONCLUSION: The main finding of this study is the theoretically proposed optimal frequency for clinical applications of therapeutic ultrasound induced cartilage restoration is 3.5 - 4.8 MHz (the resonant frequencies of in vivo chondrocytes). Application of ultrasound in this frequency range will maximize desired bioeffects.

Frequency sensitive mechanism in low-intensity ultrasound enhanced bioeffects.

This study presents two novel theoretical models to elucidate frequency sensitive nuclear mechanisms in low-intensity ultrasound enhanced bioeffects. In contrast to the typical 1.5 MHz pulsed ultrasound regime, our group previously experimentally confirmed that ultrasound stimulation of anchored chondrocytes at resonant frequency maximized gene expression of load inducible genes which are regulatory markers for cellular response to external stimuli. However, ERK phosphorylation displayed no frequency dependency, suggesting that the biochemical mechanisms involved in enhanced gene expression is downstream of ERK phosphorylation. To elucidate such underlying mechanisms, this study presents a theoretical model of an anchored cell, representing an in vitro chondrocyte, in an ultrasound field. The model results showed that the mechanical energy storage is maximized at the chondrocyte's resonant frequency and the energy density in the nucleus is almost twice as high as in the cytoplasm. Next, a mechanochemical model was developed to link the mechanical stimulation of ultrasound and the increased mechanical energy density in the nucleus to the downstream targets of the ERK pathway. This study showed for the first time that ultrasound stimulation induces frequency dependent gene expression as a result of altered rates of transcription factors binding to chromatin.

Extended-release mesalamine granules for ulcerative colitis.

OBJECTIVE: To evaluate the efficacy and safety of extended-release mesalamine granules in the maintenance of remission in ulcerative colitis (UC). DATA SOURCES: Literature was obtained through searches of MEDLINE (1990-June 2012) using the terms mesalamine granules, ulcerative colitis, Apriso, and Salofalk. Bibliographies from retrieved articles were searched for additional citations. STUDY SELECTION AND DATA EXTRACTION: All English-language articles reporting on use of extended-release mesalamine granules in humans identified through the search were evaluated and included. DATA SYNTHESIS: The preferred initial treatment for induction and maintenance of remission in mild to moderate UC is agents from the 5-aminosalicylate class (balsalazide, mesalamine, olsalazine, sulfasalazine). Mesalamine granules are available as an encapsulated product in the US and as a nonencapsulated formulation in Europe. Data evaluating encapsulated mesalamine granules for induction of remission are lacking; however, the European mesalamine granule formulation has been evaluated for induction of remission. Patients receiving mesalamine granules for induction achieved clinical and endoscopic remission more frequently than those receiving placebo. Two pivotal, randomized, double-blind, placebo-controlled, multicenter studies have evaluated encapsulated mesalamine granules for maintenance in 562 adults in remission from UC. In both studies, the proportion of patients who remained relapse-free at 6 months was higher for those receiving encapsulated mesalamine granules than placebo. Mesalamine granules are well tolerated, with headache, nausea, and upper respiratory infections being the most frequently reported adverse effects. CONCLUSIONS: Current evidence supports the use of extended-release mesalamine granules for maintenance of remission in mild to moderate UC. Further studies are necessary to examine the ideal dose and regimen of encapsulated mesalamine granules for induction of remission in UC.

Assessing pharmacy residents' knowledge of biostatistics and research study design.

BACKGROUND: Historically, clinicians have demonstrated a lack of confidence and poor aptitude for biostatistics as a tool for medical literature interpretation. Evaluation of pharmacy residents' ability to interpret biostatistics commonly used in peer-reviewed literature has not been previously conducted. OBJECTIVE: To evaluate the level of understanding and perception of biostatistics concepts among pharmacy residents. METHODS: A survey of postgraduate year 1 (PGY1) residents in American Society of Health-System Pharmacists-accredited residency programs was conducted in May 2009. The survey instrument consisted of 27 items, including 10 knowledge-based questions, and was distributed to residency programs for anonymous reporting via SurveyMonkey. The primary outcome of interest was biostatistics knowledge, defined as the percent total score of correct knowledge items. Statistical attitude and confidence questions were rated on a 5-point Likert-type scale (1 = strongly disagree, 5 = strongly agree). The t-test or 1-way analysis of variance was conducted, as appropriate, to assess for differences in mean biostatistics knowledge scores by respondent characteristics. Forward stepwise regression was used to identify which characteristics were independently associated with biostatistics knowledge. RESULTS: A total of 214 PGY1 residents responded to the online survey assessment, and a subset of respondents (n = 166) answered 1 or more of the biostatistics knowledge questions. Of those who responded to at least 1 knowledge assessment, the overall mean (SD) biostatistics knowledge score was 47.3% (18.50%; range 0-90). Overall, respondents were predominantly female (74%) and younger than 30 years (81%). Residents scored highest in the recognition of the purpose of a double-blind study (92.6%; 95% CI 88.52 to 96.67), interpretation of relative risk (75.8%; 95% CI 69.02 to 82.57), and identification of the appropriate analytic method for a nominal variable (69.4%; 95% CI 62.16 to 76.59). Bivariate analyses showed that there were statistically significant mean differences in knowledge scores by attitude (p = 0.001) and confidence (p < 0.001). The multivariate model showed that above-average confidence ratings were associated with an absolute increase of 7.6% in biostatistics knowledge score (p < 0.019) compared to those whose confidence rating was at or below average. CONCLUSIONS: Overall, pharmacy residents' perception and understanding of biostatistics were poor in this assessment, which correlates with previous reports. Enhanced training in biostatistics and literature evaluation of both mentors and trainees should be incorporated in PharmD programs and residency training sites.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium difficile infection.

Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy.

An evidence-based medicine elective course to improve student performance in advanced pharmacy practice experiences.

OBJECTIVE: To implement and evaluate the impact of an elective evidence-based medicine (EBM) course on student performance during advanced pharmacy practice experiences (APPEs). DESIGN: A 2-hour elective course was implemented using active-learning techniques including case studies and problem-based learning, journal club simulations, and student-driven wiki pages. The small class size (15 students) encouraged independent student learning, allowing students to serve as the instructors and guest faculty members from a variety of disciplines to facilitate discussions. ASSESSMENT: Pre- and posttests found that students improved on 83% of the core evidence-based medicine concepts evaluated. Fifty-four APPE preceptors were surveyed to compare the performance of students who had completed the EBM course prior to starting their APPEs with students who had not. Of the 38 (70%) who responded, the majority (86.9%) agreed that students who had completed the course had stronger skills in applying evidence-based medicine to patient care than other students. The 14 students who completed the elective also were surveyed after completing their APPEs and the 11 who responded agreed the class had improved their skills and provided confidence in using the medical literature. CONCLUSIONS: The skill set acquired from this EBM course improved students' performance in APPEs. Evidence-based medicine and literature search skills should receive more emphasis in the pharmacy curriculum.

Epileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations.

Antimicrobials are the most frequently implicated class of drugs in drug-induced seizure, with ß-lactams being the class of antimicrobials most often implicated. The seizure-inducing potential of the carbapenem subclass may be directly related to their ß-lactam ring structure. Data on individual carbapenems and seizure activity are scarce. To evaluate the available evidence on the association between carbapenem agents and seizure activity, we conducted a literature search of the MEDLINE (1966-May 2010), EMBASE (1974-May 2010), and International Pharmaceutical Abstracts (1970-May 2010) databases. Reference citations from the retrieved articles were also reviewed. Mechanistically, seizure propensity of the ß-lactams is related to their binding to γ-aminobutyric acid (GABA) receptors. There are numerous reports of seizure activity associated with imipenem-cilastatin, with seizure rates ranging from 3-33%. For meropenem, doripenem, and ertapenem, the seizure rate for each agent is reported as less than 1%. However, as their use increases and expands into new patient populations, the rate of seizures with these agents may increase. High-dose therapy, especially in patients with renal dysfunction, preexisting central nervous system abnormalities, or a seizure history increases the likelihood of seizure activity. Although specific studies have not been conducted, data indicate that carbapenem-associated seizure is best managed with benzodiazepines, followed by other agents that enhance GABA transmission. Due to the drug interaction between carbapenems and valproic acid, resulting in clinically significant declines in valproic acid serum concentrations, the combination should be avoided whenever possible. Clinicians should be vigilant regarding the possibility of carbapenem-induced seizures when selecting and dosing antimicrobial therapy.

Topiramate: safety and efficacy of its use in the prevention and treatment of migraine.

Migraine headaches are typically episodic in nature and may affect nearly 10% of the population. In addition to treatment, prevention of subsequent episodes or progression to a chronic migraine state is an important therapeutic area. Topiramate is a centrally acting medication approved for both the prevention of seizures and migraine headache. At this time, the exact mechanism of how topiramate assists in migraine prevention is unknown. Several large randomized, controlled trials have aided in establishing topiramate's role in migraine prevention. Despite a favorable pharmacokinetic and adverse effect profile established in clinical trials, several additional studies, case reports and toxicology reports have demonstrated topiramate as a cause of cognitive and behavioural changes. The use of topiramate in migraine prevention can improve a patient's quality of life and is a cost-effective option for migraine prevention.

Antimicrobial prophylaxis in open lower extremity fractures.

CLINICAL QUESTION: Based on the grade of open fracture, which antibiotic should be selected for antimicrobial prophylaxis, and what is the optimal timing and duration of administration? RESULTS: For Grade I and II open fractures, a first-generation cephalosporin (eg, cefazolin) should be administered within 3 hours of initial injury and be continued for 24 hours after initial injury. Grade III open fractures require coverage with an aminoglycoside in addition to a first-generation cephalosporin within 3 hours of initial injury, and antibiotics should be continued for 48-72 hours after initial injury but no more than 24 hours after wound closure. If a fracture is at risk of contamination with clostridium species, such as a farm-related injury, penicillin should be added to the antibiotic regimen. IMPLEMENTATION: Pitfalls to avoid when using antibiotics for infection prophylaxis in open fractures include utilizing cultures immediately postinjury to direct choice of agent for antimicrobial prophylaxis, because infecting pathogens do not typically correlate to pathogens initially cultured after injury; failure to consider patients' medication allergy history or reconcile allergy records; and failure to obtain a thorough history to determine injury exposure (eg, farm, water).

Nighttime and weekend medication error rates in an inpatient pediatric population.

BACKGROUND: Nighttime and weekend admission has been associated with increased morbidity and mortality and has been linked to a variety of factors. Medication errors in hospitalized patients occur frequently, but the association between error rates and time of day and day of week (weekday vs weekend) has not been extensively studied. OBJECTIVE: To compare reported medication error rates over a 1-year period between daytime versus nighttime shifts and weekday versus weekend in a children's hospital and to characterize the types of errors that occurred. METHODS: One hundred forty errors reported between January and December 2008 were retrospectively reviewed and classified by error type and severity according to established standards. Two investigators independently classified errors, and a third investigator with pediatric pharmacy expertise resolved discrepancies. Data on doses dispensed were collected from pharmacy records. RESULTS: Over the study period, the reported error rate during daytime nursing shifts was 1.17 errors per 1000 doses dispensed versus 2.12 errors per 1000 doses dispensed for nighttime nursing shifts (p = 0.005). The error rates during pharmacy shifts (1st, 2nd, and 3rd) were 1.01, 2.24, and 1.88 per 1000 doses dispensed, respectively (p = 0.0019). Reported errors for weekday versus weekend were 1.9 errors per 1000 weekday doses versus 2.55 errors per 1000 doses, respectively (p = 0.181), and error rate for weekend shifts relative to first shift on weekdays was greater (p = 0.0004). Errors in medication administration, followed by dispensing errors, occurred most frequently. CONCLUSIONS: There was an increase in medication error rate during evening and nighttime shifts relative to day shift and during weekends relative to weekdays at this institution. Additional studies to validate this finding are needed; however, error prevention efforts should be instituted now for evening, nighttime, and weekend medication dispensing and administration.

Intravenous lipid emulsion for treatment of local anesthetic toxicity.

CLINICAL QUESTION: Is intravenous lipid emulsion a safe and effective therapy for the reversal and treatment of local anesthetic toxicity? RESULTS: Systematic reviews, human case reports, and experimental animal studies have demonstrated the efficacy of intravenous lipid emulsion therapy in successfully reversing cardiac arrhythmias, cardiac arrest, and cardiac collapse seen with severe systemic local anesthetic toxicity. There are fewer data to support treatment of neurologic toxicities associated with local anesthetics. IMPLEMENTATION: Intravenous lipid emulsion 20% should be available whenever patients receive large doses of local anesthetics in operating rooms and emergency departments. Various dosing protocols have been published in the medical literature. Although the dosing protocols are based on low-level evidence, a lack of major adverse events makes lipid emulsion an appropriate therapy for treating cardiotoxic symptoms induced by local anesthetics.

Topiramate-induced myoclonus and psychosis during migraine prophylaxis.

PURPOSE: A case of topiramate-induced myoclonus and acute psychosis in a patient taking the recommended dosage of topiramate for migraine prophylaxis is reported. SUMMARY: A 29-year-old Caucasian, wheelchair-bound woman with diplegic cerebral palsy and a history of migraines was admitted to the hospital after developing paranoid thoughts and episodes of myoclonus two weeks after an increase in her topiramate dosage (25 mg twice daily to 50 mg twice daily). Her physical examination upon admission was unremarkable, with the exception of a temperature of 38.2 degrees C. Diagnostic laboratory test values, including those of the cerebrospinal fluid, were within normal limits. During neurologic examination, arm jerking, lip smacking, and finger movements occurred spontaneously and unprovoked, and severe bilateral leg myoclonus with plantar stimulation was observed. The results of an ultrasound of her lower extremities and a computed tomography scan of the brain with and without contrast revealed no abnormalities. An electroencephalogram was taken and showed nothing unusual. After nonpharmacologic etiologies were ruled out, her topiramate dosage was decreased and discontinued over four days. Her mental status and myoclonus drastically improved. She was stable and discharged within 24 hours of topiramate discontinuation. Follow-up at six months revealed that her myoclonus had completely resolved. While she has experienced additional psychotic episodes, these were mild and appear to be related to her depression. Myoclonus has not returned. CONCLUSION: A patient with cerebral palsy experienced myoclonus and acute psychosis after receiving a standard dosage of topiramate for migraine prophylaxis.

Intravenous ibuprofen: the first injectable product for the treatment of pain and fever.

This paper reviews the current data on the use of the first approved intravenous ibuprofen product for the management of post-operative pain and fever in the United States. The management of acute and post-operative pain and fever with nonsteroidal anti-inflammatory agents (NSAIDs) is well documented. A search in Medline and International Pharmaceutical Abstracts of articles until the end of November 2009 and references of all citations were conducted. Available manufacturer data on file were also analyzed for this report. Several randomized controlled studies have demonstrated the opioid-sparing and analgesic effects of 400 and 800 mg doses of intravenous ibuprofen in a series of post-operative patient populations. Two recent studies have also noted the improvement in fever curves in critically ill and burn patients. These data, along with pharmacokinetic and pharmacologic properties, are explored in this review, which addresses the clinical utility of a parenteral NSAID in a hospitalized patient for post-operative pain management and fever reduction. Further data on intravenous ibuprofen are needed to define long-term utilization, management of acute pain, and use in special populations.

Differences in hospital glycemic control and insulin requirements in patients recovering from critical illness and those without prior critical illness.

INTRODUCTION: Hospital patients recovering from critical illness on general floors often receive insulin therapy based on protocols designed for patients admitted directly to general floors. The objective of this study is to compare glycemic control and insulin dosing in patients recovering from critical illness and those without prior critical illness. METHODS: Medical record review of blood glucose measurements and insulin dosing in 25 patients under general ward care while transitioning from the intensive care unit (transition group) and 25 patients admitted directly to the floor (direct floor group). RESULTS: Average blood glucose did not differ significantly between groups (transition group 9.49 mmol/L, direct floor group 9.6 mmol/L; P = 0.83). Significant differences in insulin requirements were observed between groups with average daily doses of 55.9 units in patients transitioning from the intensive care unit (ICU) versus 25.6 units in the direct floor group (P = 0.004). CONCLUSIONS: Patients recovering from critical illness required significantly larger doses of insulin than those patients admitted directly to the floor. Managing insulin therapy in patients transitioning from the ICU may require greater insulin doses.

Interrater variability of a severity-of-illness score in critically ill adults.

BACKGROUND: Critically ill patients often require sedation and analgesia. Scales have been developed to provide clinicians with sedation targets. Daily interruption of continuous infusions of sedatives and sedation protocols improve patients' outcomes. However, perceived instability of a patient's condition can prevent implementation of appropriate sedation targets and daily interruption of sedation. OBJECTIVE: To evaluate the interrater variability of a severity-of-illness score developed to help nurses determine patient-specific sedation targets and identify candidates for daily interruption of sedation. METHODS: The severity-of-illness score was implemented as part of an institutional protocol, and bedside nurses in the medical intensive care unit were taught how to determine and use the score. Bedside nurses recorded the score daily in patients' medical records. For study purposes, a study nurse who made rounds with the medical team and a pulmonary/critical care fellow physician also independently determined the score. RESULTS: A total of 38 assessments of severity-of-illness scores in 10 different patients were made during the study period. For the 24 assessments made by all 3 observers, the kappa coefficient for agreement for the severity-of-illness score was 0.58. CONCLUSIONS: The severity-of-illness score had good interrater variability as a tool for determining sedation targets and identifying candidates for daily interruption of sedation. Future study on how use of the score affects sedative dosing and outcomes is needed.