MYH7 variants cause complex congenital heart disease.

MYH7, encoding the myosin heavy chain sarcomeric ß-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7-related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7-related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias.

IV Versus Subcutaneous Enoxaparin in Critically Ill Infants and Children: Comparison of Dosing, Anticoagulation Quality, Efficacy, and Safety Outcomes.

OBJECTIVE: Subcutaneous enoxaparin is the mainstay anticoagulant in critically ill pediatric patients although it poses several challenges in this patient population. Enoxaparin infused IV over 30 minutes represents an attractive alternative, but there is limited experience with this route of administration in children. In this study, we assess dosing, anticoagulation quality, safety, and clinical efficacy of IV enoxaparin compared to subcutaneous enoxaparin in critically ill infants and children. DESIGN: Retrospective single-center study comparing dosing, anticoagulation quality, safety, and clinical efficacy of two different routes of enoxaparin administration (IV vs subcutaneous) in critically ill infants and children. Key outcome measures included dose needed to achieve target antifactor Xa levels, time required to achieve target antifactor Xa levels, proportion of patients achieving target anticoagulation levels on initial dosing, number of dose adjustments, duration spent in the target antifactor Xa range, anticoagulation-related bleeding complications, anticoagulation failure, and radiologic response to anticoagulation. SETTING: Tertiary care pediatric hospital. PATIENTS: All children admitted to the cardiac ICU, PICU, or neonatal ICU who were prescribed enoxaparin between January 2014 and March 2016 were studied. INTERVENTIONS: One hundred ten patients were identified who had received IV or subcutaneous enoxaparin and had at least one postadministration peak antifactor Xa level documented. MEASUREMENTS AND MAIN RESULTS: Of the 139 courses of enoxaparin administered, 96 were therapeutic dose courses (40 IV and 56 subcutaneous) and 43 were prophylactic dose courses (20 IV and 23 subcutaneous). Dosing, anticoagulation quality measurements, safety, and clinical efficacy were not significantly different between the two groups. CONCLUSIONS: Our study suggests that anticoagulation with IV enoxaparin infused over 30 minutes is a safe and an equally effective alternative to subcutaneous enoxaparin in critically ill infants and children.

Implementation of an extracorporeal cardiopulmonary resuscitation simulation program reduces extracorporeal cardiopulmonary resuscitation times in real patients.

OBJECTIVE: To determine if development of an extracorporeal cardiopulmonary resuscitation simulation program reduced extracorporeal cardiopulmonary resuscitation times in real patients DESIGN: : Before-after study. SETTING: Twenty-six bed pediatric cardiac ICU in a tertiary urban hospital. PATIENTS: Forty-three cardiac patients (aged 1 d to 16 yr) who received extracorporeal cardiopulmonary resuscitation. INTERVENTIONS: An interdisciplinary team collaborated to define the roles and clarify responsibilities of each individual involved in extracorporeal cardiopulmonary resuscitation. An "ideal rapid deployment" was defined and tested using simulation sessions. This included a task analysis, role creation, and multidisciplinary simulations, including structured debriefings and video review and the creation of a master checklist. MEASUREMENTS AND MAIN RESULTS: There were a total of 43 episodes of extracorporeal cardiopulmonary resuscitation during the study period, 16 (37%) of which occurred during the preintervention time period (from February 2009 to March 2010) and 27 (63%) during the postintervention time period (April 2010 to March 2013). The median deployment time in the preintervention time period was 51 minutes (interquartile range, 43-62 min), whereas the median deployment time in the postintervention time period was 40 minutes (interquartile range, 23-52 min) (p = 0.018). CONCLUSIONS: There are no standard guidelines of how a team should coordinate the efforts of nursing, physicians, extracorporeal membrane oxygenation specialists, surgeons, respiratory therapists, patient care technicians, and unit clerks to emergently execute this complex procedure. Because time is of the essence, it is essential to develop a highly functioning and well-coordinated team with a standardized method of the procedure, its documentation, and communication. Simulation accomplished this for our program. Following these simulation exercises, not only was there a subjectively observed improved coordination and smoother deployment of extracorporeal membrane oxygenation in real-life extracorporeal cardiopulmonary resuscitation, but we have also demonstrated a significantly faster deployment of extracorporeal membrane oxygenation as compared with the presimulation era.

Advances in Extracorporeal Support Technologies in Critically Ill Children.

The field of pediatric heart failure is evolving, and the patient population is growing as survival after complex congenital heart surgeries is improving. Mechanical circulatory support and extracorporeal respiratory support in critically ill children has progressed to a mainstay rescue modality in pediatric intensive care medicine. The need for mechanical circulatory support is growing, since the number of organ donors does not meet the necessity. This article aims to review the current state of available mechanical circulatory and respiratory support systems in acute care pediatrics, with an emphasis on the literature discussing the challenges associated with these complex support modalities.

Insulin glargine supplementation during early management phase of diabetic ketoacidosis in children.

OBJECTIVE: To study the effect of subcutaneous administration of insulin glargine on the rate of resolution of acidosis and intravenous insulin infusion requirement in children with moderate and severe diabetic ketoacidosis (DKA). STUDY DESIGN: Retrospective cohort study. SETTING: Pediatric intensive care unit of a university-based children's hospital. PATIENTS: Children with moderate to severe DKA admitted between March 2001 and February 2003. RESULTS: The outcomes of children who received 0.3 units/kg of subcutaneous insulin glargine in the first 6 h of management in addition to the standard treatment (n=12) were compared with those of children who received standard treatment alone (n=59). Measured outcomes included dose of intravenous insulin required, duration of insulin infusion and acidosis correction time. The two groups were similar in demographics and severity of illness. The mean time for acidosis correction (venous pH>or=7.3) in the insulin glargine group was shorter than the standard therapy group (12.4+/-2.9 h and 17.1+/-6.2 h respectively, p<0.001). The insulin infusion time was shorter in the insulin glargine group (14.8+/-6.0 h vs 24.4+/-9.0 h, p<0.001). There was a trend towards shorter total hospital stay in the glargine group (3.2+/-1.0 days vs 3.72+/-1.06 days). CONCLUSIONS: In our small series of children with moderate and severe DKA, supplementing with subcutaneous insulin glargine led to a faster resolution of acidosis without any adverse effects. This could potentially lead to a shorter need for insulin infusion and a shorter ICU length of stay.

Patency of common carotid artery and internal jugular vein after a simple vessel sparing cannulation for extracorporeal membrane oxygenation support.

BACKGROUND: Common carotid artery and internal jugular vein are commonly cannulated for establishment of peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) support. We present our results of a vessel sparing cannulation technique for neck vessels, which helps maintain vessel patency after decannulation. METHODS: All patients who underwent ECMO, between January 2004 and January 2013 at a single center, were retrospectively reviewed. Follow up data for the patency of common carotid artery (CCA) and internal jugular vein (IJV) after decannulation were recorded. RESULTS: Twenty-four consecutive patients who were successfully decannulated after VA ECMO support who underwent vessel sparing cannulation were retrospectively reviewed. Follow up data were unavailable in 4 and 1 patient did not survive. Amongst the remaining 19 patients the median duration of ECMO support in the remaining was 7 (IQR; 4-10) days. Follow up studies documenting vessel patency were available for IJV in 18 patients and CCA in 14 patients. At a median follow up of 137days (IQR; 35-7240) 15 (78%) patients had patent IJVs and 14 (100%) patients had patent CCAs. CONCLUSION: The simple vessel sparing technique is effective in allowing restoration of the patency of the neck vessels after ECMO decannulation. LEVEL OF EVIDENCE: Case series with no comparison group (Level IV).

Isoflurane therapy for severe refractory status asthmaticus in children.

OBJECTIVE: To describe the use of inhaled isoflurane in a series of children with life-threatening asthma. DESIGN: Retrospective case series. SETTING: Pediatric intensive care unit of a tertiary-care children's hospital. Ten children ranging in age from 1 to 16 years with 11 episodes of severe asthma requiring invasive mechanical ventilation in the pediatric intensive care unit over a 5-year period. RESULTS: Isoflurane resulted in an improvement in arterial pH and a reduction in partial pressure of arterial carbon dioxide (PaCO(2)) in all the 11 instances. This effect was sustained in 10 cases and led to clinical improvement and rapid weaning from mechanical ventilation. One child failed to show sustained response and was placed on veno-venous extracorporeal membrane oxygenation. One child died secondary to anoxic brain injury sustained prior to hospitalization. Hypotension was the major side effect, and occurred in 8 children necessitating vasopressor support. CONCLUSIONS: Isoflurane improves arterial pH and reduces partial pressure of arterial carbon dioxide in mechanically ventilated children with life-threatening status asthmaticus who are not responsive to conventional management.

Late presentation of alveolar capillary dysplasia in an infant.

OBJECTIVE: To report a case of late presentation of alveolar capillary dysplasia and misalignment of pulmonary veins. DESIGN: Descriptive case report. SETTING: Pediatric intensive care unit of a tertiary care children's hospital. PATIENT: Seven-week-old female infant with severe hypoxemic respiratory failure. CONCLUSION: Alveolar capillary dysplasia with misalignment of pulmonary veins is a cause of primary pulmonary hypertension in newborns that can rarely present past the newborn period. Early lung biopsy can be helpful in establishing the diagnosis and avoiding ineffective, futile, and expensive therapeutic interventions.

Transcatheter Treatment of Thrombosis in the Single Ventricle Pathway: An Institutional Experience.

BACKGROUND: Shunt or conduit thrombosis in a single ventricle circuit is a life-threatening complication that requires prompt treatment to rapidly restore shunt/conduit patency. Transcatheter interventions represent an attractive alternative to systemic thrombolysis or open surgical procedures. We report our center's experience with catheter-based approaches in patients with palliated single ventricle who present with shunt/conduit thrombosis. METHODS: A retrospective review was performed of all patients with palliated single ventricle physiology who were diagnosed over a 5-year period with shunt/conduit thrombosis and received catheter-based interventions. Patients were followed up to hospital discharge. RESULTS: Thirteen patients were identified that were diagnosed with thrombosis of a modified Blalock-Taussig shunt (five patients), bidirectional cavopulmonary shunt (one patient), and total cavopulmonary pathway (seven patients). Shunt/conduit thrombosis occurred both early and late after palliation surgery. Catheter-based interventions included balloon angioplasty (one patient), stent implantation (12 patients), and mechanical thrombectomy (one patient). Thrombophilia was identified in seven patients. Technical and clinical success with restoration of normal shunt flow and improvement in clinical status was achieved in 12 patients. Reversible procedure-related complications occurred in three patients with no significant sequelae. CONCLUSIONS: Our experience suggests that percutaneous catheter-based interventions are safe and effective in managing shunt/conduit thrombosis in infants and children with palliated single ventricle circulation.

Perceptions of Bedside Cardiac Critical Care Registered Nurses on 24 Hour Attending Intensivist Coverage.

OBJECTIVE: To elicit the perceptions of bedside critical care nurses toward continual in-house attending coverage and its effect on patient safety, communication, and nursing education. DESIGN: A 5-point Likert-type questionnaire was designed to evaluate the perception of bedside nurses in the pediatric cardiac intensive care unit (PCICU) toward the presence of a 24 hour in-house attending physician. SETTING: Single tertiary referral PCICU in Washington, DC SUBJECTS: The 46 PCICU nurses who participated in the study were separated into two groups based on exposure to the recent implementation of continual in-house attending coverage at our institution. Group one consisted of 14 nurses with only exposure to the new 24/7 in-house coverage while group two encompassed 32 nurses who had experienced both the new and old system (off-site on-demand attending physician). MEASUREMENTS AND MAIN RESULTS: Surveys demonstrated that both groups found that the new system has a positive impact on nursing education (median score of 5) as well as a positive impact on the communication between multidisciplinary teams and between care team and families (median score of 5). Nurses who experienced only the new system scored one point lower (median score of 4) regarding the effect of this staffing model on patient outcomes than nurses who had experienced both systems (median score of 5, P = .016). Between 83% and 98% of all 46 nurses who participated indicated they agree or strongly agree with each of the questions regarding the benefit of 24 hour in-house attending coverage. CONCLUSION: Our study suggests that regardless of differences in experience, pediatric cardiac nurses believe the presence of an on-site intensivist to be beneficial to both nursing and patients.

Acquired von Willebrand Syndrome: An Under-Recognized Cause of Major Bleeding in the Cardiac Intensive Care Unit.

BACKGROUND: Acquired von Willebrand syndrome (AvWS) in the setting of congenital heart disease is an under-recognized cause of bleeding in the pediatric cardiac critical care unit. METHODS: Fourteen patients diagnosed with AvWS admitted to the cardiac intensive care unit at the Children's National Health System between December 2009 and September 2015 were identified with subsequent chart review and case analysis. RESULTS: Of the 14 patients included in this study, 4 patients were on ventricular-assist devices, 6 patients were on extracorporeal membrane oxygenation, and 4 were patients with congenital heart disease not receiving any mechanical circulatory support. All patients identified manifested persistent severe bleeding, despite appropriate management of anticoagulation and blood product administration based on the established protocols. Detailed hemostatic testing including quantitative von Willebrand factor (vWF) multimer analysis revealed decreased high-molecular-weight multimers (HMWMs) and absent ultra-HMWM, consistent with AvWS in all patients. Eight patients received treatment with vWF concentrate, one patient with desmopressin, and five recovered without specific treatment. Bleeding ceased in all but one patient. CONCLUSIONS: Acquired von Willebrand syndrome is an uncommon but important cause of bleeding in pediatric patients with cardiac disease. A high index of clinical suspicion with knowledge of the characteristic clinical scenario in addition to low levels of vWF multimers is required to manage and diagnose AvWS. Although the optimal management of AvWS in this patient population is unclear, vWF concentrates are available and appear to be efficacious for controlling life-threatening bleeding.

Population pharmacokinetics of piperacillin/tazobactam in critically ill young children.

INTRODUCTION: Piperacillin/tazobactam is a frequently prescribed antibiotic in pediatric intensive care units, but pharmacokinetic data to justify the optimal piperacillin/tazobactam dosing regimen are sparse in critically ill children. METHODS: Blood samples (2-4 per child) were collected from 13 children ages 9 months to 6 years admitted to the pediatric intensive care unit who were receiving standard piperacillin/tazobactam dosing regimens to treat infections. Piperacillin concentrations were measured by a bioassay, and the population pharmacokinetics of the piperacillin component was conducted using nonparametric adaptive grid (BigNPAG) with adaptive γ. Multiple models were tested to determine the best fit of the data. A 5000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for piperacillin/tazobactam 50 mg/kg (of the piperacillin component) every 4 hours, 80 mg/kg every 8 hours and 100 mg/kg every 6 hours as 0.5-, 3- or 4-hour infusions in a population of 1- to 6-year-old male children. Centers for Disease Control and Prevention weight for age charts were used as weight distributions. The percent of the dosing interval of the free drug is above the minimum inhibitory concentration (MIC) (fT>MIC) was calculated over a range of MICs from 0.03 to 128 µg/mL. The bactericidal target attainment was defined as ≥50% fT>MIC for piperacillin/tazobactam. PTA ≥90% at each MIC was defined as optimal. RESULTS: A 2 compartment model fitted piperacillin concentration data the best. Mean (standard deviation) population estimates for clearance, volume of the central compartment (Vc) and intercompartment transfer constants were 0.299 (0.128) L/hr/kg, 0.249 (0.211) L/kg, 6.663 (6.871) hours(-1) and 8.48 (7.74) hours(-1), respectively. This resulted in a mean (standard deviation) elimination half-life of 1.39 (0.62) hours. The bias, precision and r² for the individual predicted versus observed concentrations were -0.055, 0.96 µg/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 µg/mL against Psuedomonas aeruginosa were 100 mg/kg every 6 hours administered as a 3-hour prolonged infusion and 400 mg/kg administered as a 24-hour continuous infusion. These dosing regimens also achieved 77.7% and 74.8% PTA, respectively, at a MIC of 32 µg/mL. CONCLUSION: These are the first pharmacokinetic data of piperacillin/tazobactam (piperacillin component) in critically ill pediatric patients (1-6 years of age). Based on these data, 100 mg/kg q6h as a 3-hour infusion and 400 mg/kg continuous infusion were the only regimens to provide optimal PTA at the Clinical Laboratory Standards Institute breakpoint of 16 µg/mL.

Ethical dilemma: offering short-term extracorporeal membrane oxygenation support for terminally ill children who are not candidates for long-term mechanical circulatory support or heart transplantation.

The use of extracorporeal membrane oxygenation (ECMO) in terminally ill pediatric patients who are not candidates for long-term mechanical circulatory support or heart transplantation requires careful deliberation. We present the case of a 16-year-old female with a relapse of acute lymphoid leukemia and acute-on-chronic cardiomyopathy who received short-term ECMO therapy. In addition, we highlight several ethical considerations that were crucial to this patient's family-centered care and demonstrate that this therapy can be accomplished in a manner that respects patient autonomy and family wishes.

Acquired von Willebrand syndrome in a child following Berlin Heart EXCOR Pediatric Ventricular Assist Device implantation: case report and concise literature review.

The development of acquired von Willebrand syndrome (AVWS) after placement of a pulsatile-flow left ventricular assist device (LVAD) is rare and only recently recognized. We report the case of a young infant who was diagnosed with ventricular assist device (VAD)-related AVWS following implantation of a Berlin Heart EXCOR Pediatric Ventricular Assist Device (Berlin Heart Inc., The Woodlands, Texas, USA) for treatment of severe heart failure. Despite significant bleeding, the patient was successfully managed with von Willebrand factor-containing concentrate until VAD explantation led to definitive resolution of the AVWS. This case demonstrates that the possibility of this diagnosis should be considered in pediatric patients when extensive, nonsurgical bleeding is encountered after pulsatile-flow VAD implantation.

Nephrotoxicity in patients with vancomycin trough concentrations of 15-20 µg/ml in a pediatric intensive care unit.

STUDY OBJECTIVES: To determine if a higher serum vancomycin (Vt) target trough concentration of 15-20 µg/ml or greater is associated with an increased rate of vancomycin-induced nephrotoxicity in children admitted to a pediatric intensive care unit (PICU), and to determine risk factors for developing vancomycin-induced nephrotoxicity. DESIGN: Retrospective cohort study. SETTING: A PICU within a freestanding tertiary care pediatric hospital. PATIENTS: A total of 113 patients received vancomycin for at least 48 hours The high-trough cohort (H group [57 patients]) received vancomycin therapy between November 2008 and June 2009 for pneumonia, bacteremia, or meningitis that was managed by a clinical pharmacist who directed dosage adjustments driven by a novel algorithm to attain a target Vt concentration of 15-20 µg/ml or greater; the control group (C group [56 patients]) received vancomycin therapy during the preceding 10 months (between January and October 2008) for pneumonia or meningitis using standard dosing guidelines with lower target Vt concentrations of 5-15 µg/ml. MEASUREMENTS AND MAIN RESULTS: The highest grade of renal dysfunction according to the Common Terminology Criteria for Adverse Events criteria, v.4.0, was recorded. The mean ± SD Vt was 17.8 ± 3.1 and 8.4 ± 3.1 in the H and C groups, respectively (p<0.001). The rate of grade 1 nephrotoxicity was not significantly different between groups (8.8% in the H group vs 5.4% in the C group; p=0.72). No patient in either group developed a higher grade of renal dysfunction. In the univariable analysis, duration of vancomycin therapy (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.01-1.02, p=0.003), use of extracorporeal membrane oxygenation (OR 1.32, 95% CI 1.13-1.75, p=0.003), and vasopressor use (OR 1.41, 95% CI 1.11-1.37, p<0.001) were associated with nephrotoxicity. In the multivariable analysis, vasopressor use (OR 11.1, 95% CI 1.4-85, p=0.021) and duration of therapy were associated with nephrotoxicity (OR 1.19, 95% CI 1.04-1.37, p=0.011). CONCLUSION: Our observations suggest that maintaining Vt concentrations 15 µg/ml or greater is not associated with an increased rate of nephrotoxicity in a PICU population.