Marita Thompson

Cardiac Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-α

BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-alpha secretion is, at least in part, cardiac myocytes. METHODS AND RESULTS To determine the consequences of TNF-alpha production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-alpha coding sequence was driven by the murine alpha-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis. CONCLUSIONS This is the first report detailing the effects of tissue-specific production of TNF-alpha by cardiac myocytes in vivo. These findings indicate that production of TNF-alpha by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.

Outcomes among neonates, infants, and children after extracorporeal cardiopulmonary resuscitation for refractory inhospital pediatric cardiac arrest: a report from the National Registry of Cardiopulmonary Resuscitation.

Objectives: Describe the use of extracorporeal cardiopulmonary resuscitation as rescue therapy in pediatric patients who experience cardiopulmonary arrest refractory to conventional resuscitation. We report on outcomes and factors associated with survival in children treated with extracorporeal cardiopulmonary resuscitation during cardiopulmonary arrest from the American Heart Association National Registry of CardioPulmonary Resuscitation. Design: Multicentered, national registry of in-hospital cardiopulmonary resuscitation. Setting: Two hundred eighty-five hospitals reporting to the registry from January 2000 to December 2007. Patients: Pediatric patients <18 yrs of age who received extracorporeal membrane oxygenation during cardiopulmonary resuscitation for in-hospital cardiopulmonary arrest. Interventions: None. Measurements and Outcomes: Prearrest and arrest variables were collected. The primary outcome variable was survival to hospital discharge. The secondary outcome was neurologic status after extracorporeal cardiopulmonary resuscitation at hospital discharge. Favorable neurologic outcome was defined as Pediatric Cerebral Performance Categories 1, 2, 3, or no change from admission Pediatric Cerebral Performance Category. Results: Of 6288 pediatric cardiopulmonary arrest events reported, 199 (3.2%) index extracorporeal cardiopulmonary resuscitation events were identified; 87 (43.7%) survived to hospital discharge. Fifty-nine survivors had Pediatric Cerebral Performance Category outcomes recorded, and of those, 56 (94.9%) had favorable outcomes. In a multivariable model, the prearrest factor of renal insufficiency and arrest factors of metabolic or electrolyte abnormality and the pharmacologic intervention of sodium bicarbonate/tromethamine were associated with decreased survival. After adjusting for confounding factors, cardiac illness category was associated with an increased survival to hospital discharge. Conclusions: Forty-four percent of pediatric patients who failed conventional cardiopulmonary resuscitation from in-hospital cardiopulmonary arrest and who were reported to the National Registry of CardioPulmonary Resuscitation database as treated with extracorporeal cardiopulmonary resuscitation survived to hospital discharge. The majority of survivors with recorded neurologic outcomes were favorable. Patients with cardiac illness category were more likely to survive to hospital discharge after treatment with extracorporeal cardiopulmonary resuscitation. Extracorporeal cardiopulmonary resuscitation should be considered for select pediatric patients refractory to conventional in-hospital resuscitation measures.

A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions

Objectives: To compare the efficacy of a low-dose methadone tapering schedule to a high-dose methadone tapering schedule in pediatric intensive care unit patients exposed to infusions of fentanyl, with or without infusions of midazolam, for ≥5 days. Design: Prospective, double-blind, randomized trial. Setting: Pediatric intensive care unit in a tertiary care childrens hospital. Patients: Seventy-eight patients, 74 of whom had been receiving infusions of both fentanyl and midazolam, were randomized. Forty-one patients were randomized to the low-dose methadone group and 37 were randomized to the high-dose methadone group. Sixty patients successfully completed the trial, 34 were in the low-dose methadone group, and 26 were in the high-dose methadone group. Interventions: Patients were randomized to receive methadone either at a starting dose of 0.1 mg/kg/dose (low-dose methadone group) or at a starting dose based on both the patients weight and the most recent fentanyl infusion rate (high-dose methadone group). In each group, methadone was administered every 6 hrs for the first 24 hrs and then every 12 hrs for the second 24 hrs. The methadone was then decreased to once daily and tapered off over the next 10 days. Patients were monitored for withdrawal symptoms using the Modified Narcotic Withdrawal Score. Measurements and Main Results: The percentage of patients who successfully completed the 10-day methadone taper was the same in the low-dose methadone group as in the high-dose methadone group (56% vs. 62%; p = .79). Patients that failed to complete the assigned methadone taper had a greater total fentanyl dose and longer pediatric intensive care unit length of stay compared to patients who completed the assigned methadone taper. Conclusions: Patients who received infusions of fentanyl for at least 5 days were just as likely to complete a low-dose methadone taper as a high-dose methadone taper. Because of the risks of both withdrawal and oversedation with any fixed methadone schedule, the methadone dose must be adjusted according to each patients response.

Extracorporeal membrane oxygenation (ECMO) initiation without intubation in two children with mediastinal malignancy

We report the cases of two children presenting with severe airway compromise secondary to a mediastinal malignancy managed with extracorporeal membrane oxygenation without intubation. Results are presented on the use of ECMO as a primary means of stabilizing a pediatric patient with a critical mediastinal mass, thus providing another management strategy for this difficult situation. Pediatr Blood Cancer 2007;49:751–754.

The use of extracorporeal life support in adolescent amlodipine overdose

Calcium channel blocker (CCB) toxicity is associated with refractory hypotension and can be fatal. A 13 year old young woman presented to the emergency department(ED) six hours after an intentional overdose of amlodipine, barbiturates, and alcohol. She remained extremely hypotensive despite the administration of normal saline and calcium chloride and despite infusions of norepinephrine, epinephrine, insulin, and dextrose. Due to increasing evidence of end organ dysfunction, Extracorporeal Life Support (ECLS) was initiated 9 hours after presentation to the ED. The patients blood pressure and end organ function immediately improved after cannulation. She was successfully decannulated after 57 hours of ECLS and was neurologically intact. Patients with calcium channel blocker overdose who are resistant to medical interventions may respond favorably to early ECLS.

The Effects of Cytokines on Intracellular Calcium in Isolated, Adult Guinea Pig Myocytes. |[dagger]| 197

The Effects of Cytokines on Intracellular Calcium in Isolated, Adult Guinea Pig Myocytes. † 197