Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

Dehydration as a Rare Cause of Pulmonary Artery Thrombosis in a 2-Week-Old Term Neonate.

Pulmonary arterial thrombosis is an extremely rare occurrence in the neonatal population. We describe a 2-week-old female neonate who presented in critical condition with severe cyanosis and dehydration and was found to have a large thrombus in the main branches of the pulmonary arteries. She was successfully treated with surgical embolectomy. Pulmonary arterial thrombosis should always be considered in the differential diagnosis of a dehydrated neonate presenting with severe cyanosis and evidence of pulmonary hypertension.

Lobectomy on ECMO as a Life-Saving Procedure following Necrotizing Pneumonia in a Toddler: A Case Study.

Necrotizing pneumonia is a severe form of pneumonia that is mainly treated with conservative treatment, including antibiotics. We report a unique case of necrotizing pneumonia due to group A streptococcus infection in an 18-month-old boy who required extracorporeal membrane oxygenation (ECMO) support. Following surgical lobectomy, the child was weaned off ECMO and recovered uneventfully.

Neonatal Cervical Osteomyelitis With Bilateral Upper Limb Paresis.

Neonatal cervical osteomyelitis is extremely rare, with only a few cases having been reported. We report a neonate with cervical osteomyelitis and extensive inflammation of the surrounded tissues that caused nerve root compression and upper limb paresis.

Cardiac failure in very long chain acyl-CoA dehydrogenase deficiency requiring extracorporeal membrane oxygenation (ECMO) treatment: A case report and review of the literature.

Fatty acid oxidation (FAO) defects often present with multi-system involvement, including several life-threatening cardiac manifestations, such as cardiomyopathy, pericardial effusion and arrhythmias. We report herein a fatal case of cardiac dysfunction and rapid-onset tamponade following an acute illness in a neonate with molecularly proven very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (harboring the known del799_802 mutation), requiring 15 days of extracorporeal membrane oxygenation (ECMO) treatment. As data regarding the use of ECMO in FAO defects in general, and VLCAD in particular, are scarce, we review the literature and discuss insights from in vitro models and several successful reported cases.

Glutaric Aciduria type I and acute renal failure - Coincidence or causality?

Glutaric Aciduria type I (GA-I) is a rare organic acidemia, caused by mutations in the GCDH gene, and characterized by encephalopathic crises with neurological sequelae. We report herein a patient with GA-I who presented with severe acute renal failure requiring dialysis, following an acute diarrheal illness. Histopathological evaluation demonstrated acute tubular necrosis, and molecular diagnosis revealed the patient to be homozygous for a previously unreported mutation, p.E64D. As renal impairment is not part of the clinical spectrum typical to GA-I, possible associations of renal failure and the underlying inborn error of metabolism are discussed, including recent advancements made in the understanding of the renal transport of glutaric acid and its derivatives during metabolic disturbance in GA-I.

Point of care testing in children undergoing cardiopulmonary bypass.

BACKGROUND: Excessive hemorrhage is a major complication after cardiac surgery requiring cardiopulmonary bypass (CPB). The aim of this study was to define the potential role of the cone and platelet analyzer (CPA) and the rotating thromboelastogram (ROTEM) point of care tests in children undergoing CPB. PROCEDURE: We prospectively studied 15 pediatric patients aged 1 month to 10 years. Blood count, blood coagulation tests (prothrombin time [PT], activated partial thromboplastin time, fibrinogen, thrombin time), CPA and ROTEM parameters were measured before and after CPB. Demographic and surgical data were recorded as were those on perioperative blood loss and blood product transfusion. RESULTS: Low body weight, longer duration on CPB and lower core body temperature were associated with an increased bleeding risk. The ROTEM test showed a significant prolongation of clotting time and decreased maximal clot firmness (MCF) postoperatively in children with increased bleeding. The coagulation parameters associated with increased bleeding were: prolonged PT, lower fibrinogen levels, prior to surgery, and lower MCF after surgery. CPA test findings were not associated with postoperative bleeding in our patients. CONCLUSIONS: CPA did not serve as a prognostic tool for predicting bleeding risk in children undergoing CPB. The change in ROTEM's post-CPB results associated with bleeding tendency, and they may predict for poorer clot formation and stability.

Blood lactate levels differ significantly between surviving and nonsurviving patients within the same risk-adjusted Classification for Congenital Heart Surgery (RACHS-1) group after pediatric cardiac surgery.

This study aimed to examine the association between lactate levels in the first hours after surgery for congenital heart defects and the results of Risk-Adjusted Classification for Congenital Heart Surgery (RACHS-1) scoring and to evaluate serial lactate levels over time to determine whether they can serve as a supplementary tool for postoperative assessment within the same RACHS-1 group of patients. A retrospective cohort study was performed using data retrieved from a clinical database of 255 children who had surgery for congenital heart defects between 1999 and 2001 at Sheba Medical Center. Lactate levels were measured postoperatively four times (mg/dL units). The last sample was taken at the end of the surgical procedure, and lactate levels were measured at admission to the pediatrics critical care unit, then 6 and 12 h after admission. The lactate level was measured via arterial blood gases. A total of 27 deaths occurred, yielding a mortality rate of 7.4% when Norwood operations were excluded and 10.16% when they were included. The mean initial postoperative lactate level was significantly lower for survivors (42.2 ± 32.0 mg/dL) than for nonsurvivors (85.4 ± 54.1 mg/dL) (p < 0.01). The serial mean lactate levels decreased progressively for all surviving patients (r (2) = 0.96) compared with nonsurvivors (r (2) = 0.02). The lactate levels correlated with the RACHS-1 subgroups at each time point (r (2) > 0.96 for all). The Pearson correlations between postoperative lactate levels (last lactate measurement taken in the operating room) and cardiopulmonary bypass (CPB) duration (r = 0.549), clamp duration (r = 0.586), and the inotropic score (r = 0.466) (p < 0.001 for all) were significantly positive. The correlations between the maximum lactate levels (during the first 12 postoperative hours) and CPB duration (r = 0.496), clamp duration (r = 0.509), and the inotropic score (r = 0.633) (p < 0.001 for all) were extremely positive. The early elevation of lactate levels in RACHS-1 subgroups 1 to 3 were highly correlated with poor prognosis and death (p < 0.03). In addition, the lactate levels differed significantly between survivors and nonsurvivors within the same RACHS-1 subgroup. The survivors in RACHS-1 subgroups 1 to 3 had lower mean lactate levels than the nonsurvivors in this group (P = 0.011), and this also held true for the survivors and nonsurvivors in RACHS-1 subgroups 4 to 6 (P = 0.026). Lactate levels differed significantly between survivors and nonsurvivors within the same RACHS-1 subgroup. This combination allows the targeting of appropriately intensive interventions and therapies toward the sickest patients.

Terlipressin for children with extremely low cardiac output after open heart surgery.

BACKGROUND: Terlipressin, a long-acting analog of vasopressin, has been used successfully in patients with extremely low cardiac output, but its application in children following open heart surgery is limited. OBJECTIVE: To describe our experience using terlipressin in children with extremely low cardiac output after open heart surgery. METHODS: Records were reviewed of all pediatric patients between January 2003 and December 2005 who had undergone open heart surgery, experienced extremely low cardiac output, and were treated with terlipressin as rescue therapy. Mean arterial blood pressure, heart rate, urine output, and lactate and oxygenation index values were retrieved and analyzed when available. RESULTS: Twenty-nine children who were considered gravely ill despite conventional vasoactive agents received terlipressin as rescue therapy, which rapidly yielded significant improvements in all measured hemodynamic and respiratory indices. Mean +/- SD arterial blood pressure increased significantly, from 49 +/- 17 to 57 +/- 16 mm Hg after 10 minutes (p = 0.004) and to 64 +/- 15 mm Hg 24 hours after treatment onset (p = 0.001). Twenty-four hours following terlipressin administration, urine output increased from 1.5 +/- 2.1 to 3.0 +/- 2.3 mL/kg/h (p = 0.001), the oxygenation index decreased from 16.5 +/- 27.9 to 9.5 +/- 16.7 in the survivors (p = 0.023), and the inotropic score decreased from 41.9 +/- 19.9 to 32.6 +/- 18.8 (p = 0.009). CONCLUSIONS: Terlipressin caused significant improvement in hemodynamic, respiratory, and renal indices in children with extremely low cardiac output after open heart surgery. Further controlled studies are needed to confirm the drug's safety and efficacy in this population.

Beneficial effects of terlipressin in prolonged pediatric cardiopulmonary resuscitation: a case series.

OBJECTIVE: Arginine vasopressin was found in experimental and clinical studies to have a beneficial effect in cardiopulmonary resuscitation. The American Heart Association 2000 guidelines recommended its use for adult ventricular fibrillation arrest, and the American Heart Association 2005 guidelines noted that it may replace the first or second epinephrine dose. There is little reported experience with arginine vasopressin in cardiopulmonary resuscitation of children. Terlipressin, a long-acting analog of arginine vasopressin, has recently emerged as a treatment for vasodilatory shock in both adults and in children, but evidence of its effectiveness in the pediatric setting is sparse. The objective of this retrospective study is to describe our experience in adding terlipressin to the conventional protocol in children with cardiac arrest. DESIGN: Retrospective case series study. SETTING: An 18-bed pediatric critical care department at a university-affiliated tertiary care children's hospital. PATIENTS: Seven pediatric patients with asystole, aged 2 months to 5 yrs, who experienced eight episodes of refractory cardiac arrest and did not respond to conventional therapy. INTERVENTIONS: Addition of terlipressin to epinephrine during cardiopulmonary resuscitation of children. MEASUREMENTS AND MAIN RESULTS: Return of spontaneous circulation was monitored and achieved in six out of eight episodes of cardiac arrest. One patient died 12 hrs after return of spontaneous circulation, and four patients survived to discharge with no neurologic sequelae. CONCLUSIONS: The combination of terlipressin to epinephrine during cardiopulmonary resuscitation may have a beneficial effect in children with cardiac arrest. More studies on this drug's safety and efficacy in this setting are mandated.

Terlipressin as rescue therapy for intractable hypotension due to septic shock in children.

Intractable hypotension due to septic shock is associated with high mortality rates in critically ill children worldwide. The use of terlipressin (triglycyl-lysine-vasopressin), an analog of vasopressin with a longer duration of action, recently emerged as a treatment of hypotension not responsive to vasopressors and inotropes. This was a retrospective study set in an 18-bed pediatric critical care department in a tertiary care children's hospital. We reviewed the files of all children with septic shock who were treated with terlipressin between January 2003 and February 2004. Fourteen children (mean age, 5.6 years; range, 4 days to 17.7 years) were treated with terlipressin in 16 septic shock episodes. Significant improvements in respiratory and hemodynamic indices were noted shortly after treatment. Mean arterial blood pressure increased significantly from 54 +/- 3 to 72 +/- 5 mmHg 10 min after terlipressin administration (P = 0.001). Heart rate decreased from 153.0 +/- 6.5 beats/min to 138.0 +/- 7.5 beats/min 12 h after treatment onset (P = 0.003). Epinephrine infusion was decreased or stopped in eight patients after terlipressin administration. Urine output increased from 1.6 +/- 0.5 mL/kg/h to 4.3 +/- 1.2 mL/kg/h 1 h after treatment onset (P = 0.011). PaO2 increased from 95.1 +/- 12.3 mmHg to 110.1 +/- 20.5 mmHg, and the oxygenation index decreased from 10.2 +/- 2.2 to 9.2 +/- 1.7. Terlipressin treatment of hypotension due to septic shock was successful in eight out of 16 episodes. Six of the 14 patients with poor prognosis for survival recovered. We conclude that terlipressin improves hemodynamic indices and renal function in critically ill children. Terlipressin should be considered as a rescue therapy in intractable shock not responsive to catecholamines in children.

Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock.

OBJECTIVE: To report the successful use of terlipressin in an 8-day-old infant for treatment of intractable hypotension caused by septic shock. DESIGN: Descriptive case report. SETTING: An 18-bed pediatric intensive care unit at a tertiary care children's hospital. PATIENT: An 8-day-old child with intractable hypotension due to septic shock after heart surgery. INTERVENTIONS: General supportive intensive care including mechanical ventilatory support, volume replacement, and inotropic support with dopamine 20 microg.kg(-1).min(-1), milrinone 0.75 microg.kg(-1).min(-1), and epinephrine 0.8 microg.kg(-1).min(-1). MEASUREMENTS AND MAIN RESULTS: Terlipressin (7 microg/kg per dose twice daily) was added as rescue therapy because of profound intractable hypotension. Shortly after the beginning of treatment, blood pressure and perfusion dramatically improved. CONCLUSIONS: There is circumstantial evidence that the administration of terlipressin caused the increase in blood pressure. We suggest that terlipressin should be considered as rescue therapy when high-dose catecholamine therapy does not result in sufficient perfusion pressure. Further investigation is needed to prove terlipressin's effectiveness and safety in infants and children.