Rebecca Ichord

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. METHODS The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). CONCLUSIONS The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.

Prospective Trial of a Pediatric Ventricular Assist Device

BACKGROUND Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

ELECTROENCEPHALOGRAPHIC MONITORING DURING HYPOTHERMIA AFTER PEDIATRIC CARDIAC ARREST

Background: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA. Methods: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12–24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner. Results: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen. Conclusions: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening. BS = burst suppression; CA = cardiac arrest; CPR = cardiopulmonary resuscitation; DD = developmental delay; FEN = fentanyl; FOS = fosphenytoin; HIE = hypoxic ischemic encephalopathy; LEV = levetiracetam; LZP = lorazepam; MDZ = midazolam; NCS = nonconvulsive seizures; NCSE = nonconvulsive status epilepticus; NPV = negative predictive value; PB = phenobarbital; PED = periodic epileptiform discharge; PICU = pediatric intensive care unit; PPV = positive predictive value; SE = status epilepticus; SIDS = sudden infant death syndrome; sz = seizures; TH = therapeutic hypothermia; VEC = vecuronium; VPA = valproic acid; VT = ventricular tachycardia.

Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.

Mimics of Childhood Stroke: Characteristics of a Prospective Cohort

BACKGROUND. Little is known about the clinical features and spectrum of diagnoses in children with “stroke mimics,” those with acute neurologic deficits but without cerebrovascular diseases. OBJECTIVES. Our goal was to describe patients with stroke mimics and to determine if clinical features predict benign diagnoses. METHODS. Our stroke consult team registered a prospective consecutive cohort of 143 patients with acute presentations suspicious for cerebrovascular disease from November 2003 to November 2004. Cases in which stroke was ruled out (stroke mimics) were reviewed for clinical features and diagnostic test results and were classified “benign” if there was no structural brain lesion and there was an expectation of complete recovery. RESULTS. Of the 143 cases evaluated for suspected stroke, 30 (21%) had stroke mimics. Presenting signs included seizure (n = 11), headache (n = 9), mental status change (n = 6), focal weakness (n = 14), and focal sensory change (n = 7). Eleven patients had “benign” diagnoses (3 migraine, 3 psychogenic diagnoses, 3 musculoskeletal abnormalities, 1 delirium, and 1 episodic vital sign changes). Nineteen patients had “not-benign” diagnoses (3 reversible posterior leukoencephalopathy syndrome, 3 neonatal seizures, 2 vascular anomalies, 2 inflammatory disease, 2 intracranial infection, 2 epilepsy, 2 metabolic stroke, 1 tumor, 1 drug toxicity, and 1 idiopathic intracranial hypertension). Except for the presence of seizures, there were no significant differences in presentation or risk factors between benign and not-benign cases. CONCLUSIONS. Many disorders mimic childhood stroke. History and clinical presentation often do not distinguish the one third of patients with benign disorders from the two thirds with more serious problems, necessitating timely comprehensive investigations, especially brain MRI.

Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury.

We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p<0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease A Scientific Statement From the American Heart Association

Thrombosis has long been recognized as a potentially life-threatening complication in children with congenital heart disease (CHD), children with acquired heart disease, and in adults with CHD. High-risk groups include patients with shunt- dependent single ventricles (shunt thrombosis, 8%–12%; 4%

Electrographic Neonatal Seizures after Infant Heart Surgery

Summary:  Purpose: Neonatal seizures are relatively common and an important early sign of acute encephalopathy in those who survive infant heart surgery. The contemporary occurrence of seizures in this setting is not fully known, and their electrographic characteristics are incompletely described. This study describes the characteristics of electrographic neonatal seizures (ENSs) in contemporary infants with congenital heart disease (CHD) surgically repaired by using cardiopulmonary bypass, with or without deep hypothermic circulatory arrest.

Transcranial Doppler Ultrasonography and Prophylactic Transfusion Program Is Effective in Preventing Overt Stroke in Children with Sickle Cell Disease

OBJECTIVE To assess the impact of our transcranial Doppler ultrasonography (TCD) program on the incidence of first stroke and the rate of transfusion for stroke prevention in children with sickle cell disease. STUDY DESIGN In this single-institution, retrospective study, we compared the incidence of stroke and of transfusion for stroke prevention in 475 patients observed in the 8-year period before instituting TCD screening with the rate in 530 children in the 8-year period after. RESULTS The incidence of overt stroke in the pre-TCD period was 0.67 per 100 patient-years, compared with 0.06 per 100 patient-years in the post-TCD period (P<.0001). Of the 2 strokes in the post-TCD period, 1 occurred in a child too young for the screening protocol, and 1 occurred in a child with high velocities solely in the anterior cerebral arteries. The rate of transfusion therapy for stroke prevention increased from 0.67 per 100 patient-years to 1.12 per 100 patient-years since instituting our program (P=.008). CONCLUSIONS Our program has been successful in reducing the rate of first overt stroke, but with increased use of transfusion. Additional modifications to screening might further reduce the risk of first stroke, and studies of alternative treatments may be beneficial.