Yaron Finkelstein

Colchicine for Prevention of Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation: The COPPS-2 Randomized Clinical Trial

IMPORTANCE Postpericardiotomy syndrome, postoperative atrial fibrillation (AF), and postoperative effusions may be responsible for increased morbidity and health care costs after cardiac surgery. Postoperative use of colchicine prevented these complications in a single trial. OBJECTIVE To determine the efficacy and safety of perioperative use of oral colchicine in reducing postpericardiotomy syndrome, postoperative AF, and postoperative pericardial or pleural effusions. DESIGN, SETTING, AND PARTICIPANTS Investigator-initiated, double-blind, placebo-controlled, randomized clinical trial among 360 consecutive candidates for cardiac surgery enrolled in 11 Italian centers between March 2012 and March 2014. At enrollment, mean age of the trial participants was 67.5 years (SD, 10.6 years), 69% were men, and 36% had planned valvular surgery. Main exclusion criteria were absence of sinus rhythm at enrollment, cardiac transplantation, and contraindications to colchicine. INTERVENTIONS Patients were randomized to receive placebo (n=180) or colchicine (0.5 mg twice daily in patients ≥70 kg or 0.5 mg once daily in patients <70 kg; n=180) starting between 48 and 72 hours before surgery and continued for 1 month after surgery. MAIN OUTCOMES AND MEASURES Occurrence of postpericardiotomy syndrome within 3 months; main secondary study end points were postoperative AF and pericardial or pleural effusion. RESULTS The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%-18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, -2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, -8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%-24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%-15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed. CONCLUSIONS AND RELEVANCE Among patients undergoing cardiac surgery, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01552187.

Recurrence and Outcomes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children

OBJECTIVES: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Childrens Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes. RESULTS: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes. CONCLUSIONS: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis.

Background:  Approximately one‐third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug‐transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.

Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children

Pollock‐BarZiv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL, Solomon M, McCrindle BW, Grant D. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children.
Pediatr Transplantation 2010: 14:968–975.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Significance This paper provides unique insights into mechanism-based therapeutics for Rett syndrome (RTT), a devastating neurodevelopmental disorder. This clinical trial was based on pioneer preclinical work from the laboratory of M.S. Outcome measures include clinical instruments, standardized behavioral measures, and biomarkers, the latter being not only objective but also applicable to experimental studies. We believe this work will a have major impact on the understanding and treatment of RTT, as well as other neurodevelopmental disorders. Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Invasive Kingella kingae Infections in Children: Clinical and Laboratory Characteristics

OBJECTIVE. Kingella kingae, a Gram-negative coccobacillus, is being increasingly recognized as an invasive pathogen in children, causing mainly bacteremia and arthritis; however, there have been only a few studies on K kingae infections to date, mostly small-scale series. The aim of this study was to report our experience with invasive K kingae infections in children who were hospitalized at a major tertiary medical center in Israel. METHODS. The medical charts of 62 children with proven invasive K kingae infections were reviewed: 42 with positive blood culture results and 20 with positive synovial fluid culture results. RESULTS. Most infections occurred among previously healthy children aged 5 to 22 months. Eighty percent had a mild concurrent illness of the respiratory or gastrointestinal tract. A chronic underlying disease was documented in 19% of the 1- to 15-year-old children with bacteremia. Three patients had persistent bacteremia, identified by 2 positive blood cultures drawn 1 to 4 days apart. Four (10%) patients from the bacteremia group had endocarditis, and 2 required emergency cardiac surgery. Only a mild-to-moderate elevation of serum inflammatory markers was noted except for patients with endocarditis or a prolonged course of arthritis. Patients with bacteremia received a diagnosis significantly later than those with arthritis, with no other between-group differences in age, month of disease onset, and inflammatory marker levels. All K kingae isolates were resistant to vancomycin and clindamycin. CONCLUSIONS. Our large series indicates that invasive K kingae infections occur in previously healthy children, mostly during the first 2 years of life; affected older children usually have an underlying medical condition. The infection generally elicits only a mild inflammatory response unless accompanied by endocarditis. Despite its low virulence, K kingae might cause a life-threatening heart disease that requires emergent, aggressive treatment.

Risk of suicide following deliberate self-poisoning

IMPORTANCE Suicide is the tenth leading cause of death in the United States, and its rate has risen by 16% in the past decade. Deliberate self-poisoning is the leading method of attempted suicide. Unlike more violent methods, which are almost universally fatal, survival following self-poisoning is common, providing an opportunity for secondary prevention. However, the long-term risk of suicide following a first episode of self-poisoning is unknown. OBJECTIVE To determine the risk of suicide and mortality from other causes following a first self-poisoning episode. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using multiple linked health care databases. We identified all individuals with a first self-poisoning episode in Ontario, Canada, from April 1, 2002, through December 31, 2010, and followed up all surviving participants until December 31, 2011, or death, whichever occurred first. For each individual with a deliberate self-poisoning episode, we randomly selected 1 control from the same population with no such history, matched for age (within 3 months), sex, and calendar year. MAIN OUTCOMES AND MEASURES The primary analysis examined the risk of suicide following discharge after self-poisoning. The secondary analyses explored factors associated with suicide and examined the risk of death caused by accidents or any other cause. RESULTS We identified 65 784 patients (18 482 [28.1%] younger than 20 years) who were discharged after a first self-poisoning episode. During a median follow-up of 5.3 years (interquartile range, 3.1-7.6 years), 4176 died, including 976 (23.4%) by suicide. The risk of suicide following self-poisoning was markedly increased relative to controls (hazard ratio, 41.96; 95% CI, 27.75-63.44), corresponding to a suicide rate of 278 vs 7 per 100 000 person-years, respectively. The median time from hospital discharge to completed suicide was 585 days (interquartile range, 147-1301 days). Older age, male sex, multiple intervening self-poisoning episodes, higher socioeconomic status, depression, and recent psychiatric care were strongly associated with suicide. Patients with a self-poisoning episode were also more likely to die because of accidents (hazard ratio, 10.45; 95% CI, 8.10-13.47) and all causes combined (hazard ratio, 5.55; 95% CI, 5.12-6.02). CONCLUSIONS AND RELEVANCE A first self-poisoning episode is a strong predictor of subsequent suicide and premature death. Most suicides occur long after the index poisoning, emphasizing the importance of longitudinal, sustained secondary prevention initiatives.

Antenatal Use of Selective Serotonin-Reuptake Inhibitors and QT Interval Prolongation in Newborns

OBJECTIVES. Prolongation of the QT interval is a risk factor for sudden death. Selective serotonin-reuptake inhibitor antidepressants can prolong the QT interval and are widely used by pregnant women. Whether antenatal exposure to selective serotonin-reuptake inhibitor causes QT prolongation in offspring is unknown. The aim of this study was to determine the effect of maternal use of selective serotonin-reuptake inhibitor antidepressants during pregnancy on the QTc interval of the offspring. METHODS. Between January 2000 and December 2005, we collected data on all of the newborns born at a single tertiary care hospital. Electrocardiograms of infants exposed to selective serotonin-reuptake inhibitor antidepressants in utero were compared with those of healthy control newborns matched on gestational age. The tracings were interpreted by a pediatric cardiologist who was unaware of the drug exposure. RESULTS. We identified 52 newborns exposed to selective serotonin-reuptake inhibitor antidepressants in the immediate antepartum period and 52 matched control subjects. The mean QTc was significantly longer in the group of newborns exposed to antidepressants as compared with control subjects (409 ± 42 vs 392 ± 29 milliseconds). Five (10%) newborns exposed to selective serotonin-reuptake inhibitor antidepressants had a markedly prolonged QTc interval (>460 milliseconds) compared with none of the unexposed newborns. The longest QTc interval observed among exposed newborns was 543 milliseconds. All of the drug-associated repolarization abnormalities normalized in subsequent electrocardiographic tracings. CONCLUSIONS. Antepartum use of selective serotonin-reuptake inhibitor antidepressants is associated with QTc interval prolongation in exposed neonates. Additional research using a standardized protocol is needed to determine whether exposure to selective serotonin-reuptake inhibitor antidepressants in late pregnancy is also associated with arrhythmias.

Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic

OBJECTIVE The objective of this study was to report the outcomes of intrauterine pregnancies misdiagnosed as ectopic and exposed to methotrexate, a major teratogen. STUDY DESIGN We report the outcomes of all subjects who sought consultation after exposure to high-dose methotrexate to induce abortion in presumed ectopic pregnancies, which were later identified as viable intrauterine pregnancies by 3 North American Teratology Information Services between 2002 and 2010. RESULTS Eight women with normal, desired pregnancies were administered high-dose methotrexate in the first trimester because of presumed, misdiagnosed ectopic pregnancies. All pregnancies resulted in catastrophic outcomes. Two pregnancies resulted in severely malformed newborns with methotrexate embryopathy; 3 women miscarried shortly after exposure, and in 3 the erroneous diagnosis led the physicians to advise and perform surgical termination. CONCLUSION Erroneous diagnosis of intrauterine pregnancies as ectopic with subsequent first-trimester exposure to methotrexate may result in the birth of severely malformed babies or fetal demise.

Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti‐factor Xa levels

Summary.  Background: Unfractionated heparin (UFH) is a widely used anticoagulant. Current American College of Chest Physicians guidelines for infants extrapolated from adults recommend 28 U kg−1 h−1 of UFH to achieve an anti‐factor Xa level of 0.35–0.7 IU mL−1. Objective: To assess the profile of anti‐FXa‐based UFH dosing guidelines in infants. Patients/Methods: We included all infants aged < 6 months treated with per‐protocol intravenous UFH at the Hospital for Sick Children, Toronto, over a 3.5‐year period. Results: Of 100 infants, 11% achieved sustained therapeutic anti‐FXa levels with current dose recommendations. Only 15% achieved target anti‐FXa levels within 24 h with per‐protocol dose escalations. Seventeen per cent of patients never achieved therapeutic anti‐FXa levels, despite up to 60 days of therapy and triple the recommended dose. The median dose needed to achieve therapeutic anti‐FXa levels in the remaining 83 infants was 33 U kg−1 h−1 (interquartile range, 30–36). Two in three infants had decreased thrombus size at completion of therapy and no thrombus progression/recurrence, and 11/100 infants suffered major bleeding. Without exclusion of extracorporeal membrane oxygenation patients, an activated partial thromboplastin time (APTT) of > 180 s was detected as a risk factor for major bleeding. Conclusions: UFH monitoring is challenging in infants. Despite their delay in reaching therapeutic anti‐FXa levels, infants monitored with the adult‐based anti‐FXa range have a high thrombus resolution rate, no thrombus progression, but a relatively high bleeding rate. Extreme APTT elevation may contribute to this bleeding risk, particularly in critically ill patients. Current UFH guidelines for young infants may still be inadequate, and laboratory methods with age‐appropriate ranges may be required to further improve clinical outcomes within this population.