2 Minute Medicine Rewind July 23, 2018

A Phase 3 Trial of L-Glutamine in Sickle Cell Disease

Sickle cell disease is characterized by increased oxidative stress in red blood cells. L-glutamine is required for the synthesis of nicotinamide adenine dinucleotide (NAD), which contributes to an increased redox ratio, thereby decreasing oxidative stress. A phase 2 trial showed that treatment with L-glutamine resulted in lower mean numbers of pain crises and hospitalizations than placebo in patients with sickle cell disease, prompting a phase 3 trial to confirm these results. In this phase 3 randomized controlled trial, 230 patients with sickle cell anemia or sickle β⁰-thalassemia and a history of two or more pain crises during the previous year were assigned 2:1 to receive either L-glutamine or placebo to study the efficacy of L-glutamine in reducing the incidence of pain crises in this patient population. Secondary end points included the number of hospitalizations for sickle-cell related pain, the number of emergency department (ED) visits, and changes in hematologic measures from baseline during the 48-week trial period. The rate of hydroxyurea use was similar in both trial arms (L-glutamine 66.4%, placebo 66.7%). Researchers found that fewer pain crises occurred in the L-glutamine group (median 3.0) than in the placebo group (median 4.0), for a difference of 25% (p=0.005). In addition, the L-glutamine group experienced fewer hospitalizations (median 2.0) than the placebo group (median 3.0), for a difference of 33% (p=0.005). These differences were observed regardless of hydroxyurea treatment. In addition, while the number of ED visits did not differ significantly between the two groups (p=0.09), fewer patients from the intervention group were hospitalized (p=0.005). This study therefore shows that L-glutamine may be a highly effective treatment modality for the management of pain crises in sickle cell anemia.

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest

In patients with cardiac arrest, epinephrine may increase the chance of a return to spontaneous circulation through augmentation of coronary blood flow. However, concerns exist regarding potentially harmful effects of – and -adrenergic stimulation, including dysrhythmias and platelet activation promoting thrombosis and cerebral ischemia. In this randomized controlled trial, 8014 patients with out-of-hospital cardiac arrests with unsuccessful initial resuscitation attempts were administered standard care and either parenteral epinephrine or saline placebo to determine the rate of survival at 30 days. The main secondary outcome was rate of survival until hospital discharge with favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale. Researchers found that at day 30, more patients in the epinephrine group were alive than in the placebo group (3.2% vs. 2.4%, respectively, OR 1.39, 95% CI 1.06 to 1.82, p=0.02). The number needed to treat with epinephrine to prevent one death at 30 days was 112 (95% CI 63 to 500). There was no significant difference between the two groups in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (2.2% in the epinephrine group vs. 1.9% in the placebo group, OR 1.18, 95% CI 0.86 to 1.61). However, severe neurologic impairment was more common among survivors in the epinephrine group (31.0%) than in the placebo group (17.8%). Overall, results from this study suggest that, while epinephrine may increase survivorship at 30 days in patients with cardiac arrest, survivors are more likely to experience poor neurologic outcomes.

Association of Digital Media Use With Subsequent Symptoms of Attention-Deficit/Hyperactivity Disorder Among Adolescents

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition involving persistent difficulty sustaining attention, hyperactivity, and impulsivity. In previous studies, ADHD has been found to be associated with various environmental risk factors, including digital media. However, the association between the use of modern digital media forms and adolescent ADHD has not been investigated. In this longitudinal cohort study, 2587 adolescents without significant symptoms of ADHD at baseline were surveyed regarding the frequency of their weekly engagement in media activities at baseline, 12 months, and 24 months to assess the association with ADHD symptom occurrence. Data were obtained from the Happiness & Health Study, a longitudinal cohort survey of adolescents in Los Angeles. Self-reported sociodemographic information including age, sex, subsidized lunch eligibility, race/ethnicity, family history of tobacco or alcohol abuse, and baseline behavioral/emotional problems were included as covariates in the ultimate analysis. Researchers found that the most common media activity was checking social media (prevalence of high-frequency use 54.1%). There was a significant covariate-adjusted association between the index of digital media use and ADHD symptoms status (OR 1.10, 95% CI 1.05 to 1.15). Boys and adolescents with more depressive symptoms and delinquent behaviors at baseline had an increased odds of experiencing ADHD symptoms (p<0.001 for both). ADHD symptoms were more prevalent in those who reported a high frequency of digital media activities (9.5% for 7 high-frequency activities, 10.5% for 14 high-frequency activities) than in those who reported no digital media use at baseline (4.6%) (differences 4.9% and 5.9%, 95% CI 2.5% to 7.3% and 2.6% to 9.2%, respectively). This study was limited in that the media use measure has not been validated. Further research is required to determine whether there is a causal relationship between modern digital media use and subsequent ADHD symptoms.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by broad immune dysregulation and cytokine activation. Janus kinases (JAKs) mediate the function of many key cytokines implicated in the pathogenesis of SLE. Baricitinib is an oral selective and reversible inhibitor of JAK1 and JAK2, and has been approved for the treatment of rheumatoid arthritis in many countries. However, its activity in SLE has not been examined. In this randomized controlled trial, 314 patients with SLE were assigned to receive either baricitinib 2 mg, baricitinib 4 mg, or placebo to study the impact on resolution of arthritis or rash as defined by the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) by 24 weeks. Baseline standard of care was balanced across the groups. Researchers found that significantly more patients taking baricitinib 4 mg (67%) experienced resolution of arthritis or rash than those taking placebo (53%) (OR 1.8, 95% CI 1.0 to 3.3, p=0.0414). However, there was no significant difference in resolution of arthritis or rash between the baricitinib 2 mg group (58%) and the placebo group (OR 1.3, 95% CI 0.7 to 2.3, p=0.39). The rates of serious adverse events were higher in the baricitinib 4 mg group (10%) and the baricitinib 2 mg group (10%) than in the placebo group (5%). The rates of deep-vein thrombosis and serious infection were also higher in the baricitinib 4 mg group (1% and 6%, respectively) than in the placebo group (0% and 1%, respectively). Limitations of this study included the relatively short follow-up period of 24 weeks, and the potential for confounding effects due to background therapy, as patients were permitted to continue existing stable background standard of care. This study indicates that a once-daily 4 mg dose of baricitinib may provide clinical benefit to patients with systemic lupus erythematosus.

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection

The overuse of antibiotics in suspected lower respiratory tract infections is a growing public health problem. Procalcitonin levels are typically more elevated in bacterial than in viral infections, and several European trials have shown that use of a procalcitonin assay decreases antibiotic use. However, these results have not been well-replicated in the United States, where prescribing patterns may differ. In this randomized controlled trial, 1656 patients with a suspected lower respiratory tract infection were assigned to the procalcitonin group or the usual-care group to determine total antibiotic exposure, defined as the total number of antibiotic days (days in which any oral or intravenous antibacterial agents were given) within 30 days after enrollment. In the procalcitonin group, physicians were provided with real-time initial and serial procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels. Overall, procalcitonin assay results were obtained for 95.9% of the patients in the procalcitonin group, and for 2.2% of patients in the usual-care group. Researchers found that there was no significant difference in antibiotic exposure between the procalcitonin group (mean antibiotic-days 4.2) and the usual-care group (mean antibiotic-days 4.3) (difference -0.05 days, 95% CI -0.6 days to 0.5 days, p=0.87). There was also no significant difference in the proportion of patients with adverse outcomes (difference -1.5%, 95% CI -4.6% to 1.7%, p<0.001 for noninferiority) during the first 30 days. This study therefore indicates that monitoring procalcitonin levels in patients with suspected lower respiratory infections does not lead to a reduction in antibiotic use.

Image: PD

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