Depolarization-activated outward K + currents in isolated adult rat ventricular myocytes were characterized using the whole-cell variation of the patch-clamp recording technique. During brief depolarizations to potentials positive to -40 mV, Ca2+-independent outward K ÷ currents in these cells rise to a transient peak, followed by a slower decay to an apparent plateau. The analyses completed here reveal that the observed outward current waveforms result from the activation of two kinetically distinct voltage-dependent K + currents: one that activates and inactivates rapidly, and one that activates and inactivates slowly, on membrane depolarization. These currents are referred to here as/to (transient outward) and I s (delayed rectifier), respectively, because their properties are similar (although not identical) to these K ÷ current types in other cells. Although the voltage dependences of Ito and I s activation are similar, /to activates = 10-fold and inactivates ~30-fold more rapidly than I s at all test potentials. In the composite current waveforms measured during brief depolarizations, therefore, the peak current predominantly reflects Ito, whereas I s is the primary determinant of the plateau. There are also marked differences in the voltage dependences of steady-state inactivation of these two K ÷ currents: I s undergoes steady-state inactivation at all potentials positive to -120 mV, and is 50% inactivated at -69 mV; I~o, in contrast, is insensitive to steady-state inactivation at membrane potentials negative to -50 mV. In addition, Ito recovers from steady-state inactivation faster than Is: at -90 mV, for example, = 70% recovery from the inactivation produced at -20 mV is observed within 20 ms for/to; Is recovers = 25-fold more slowly. The pharmacological properties of/to and I s are also distinct: 4-aminopyridine preferentially attenuates Ito, and tetraethylammonium suppresses predominantly I s. The voltage-and time-dependent properties of these currents are interpreted here in terms of a model in which Ito underlies the initial, rapid repolarization phase of the action potential (AP), and I s is responsible for the slower phase ofAP repolarization back to the resting membrane potential, in adult rat ventricular myocytes.Address reprint requests to Dr. Jeanne M.

Objective In-hospital cardiac arrest is an important public health problem. High-quality resuscitation improves survival but is difficult to achieve. Our objective is to evaluate the effectiveness of a novel, interdisciplinary, postevent quantitative debriefing program to improve survival outcomes after in-hospital pediatric chest compression events. Design, Setting, and Patients Single-center prospective interventional study of children who received chest compressions between December 2008 and June 2012 in the ICU. Interventions Structured, quantitative, audiovisual, interdisciplinary debriefing of chest compression events with front-line providers. Measurements and Main Results Primary outcome was survival to hospital discharge. Secondary outcomes included survival of event (return of spontaneous circulation for ≥ 20 min) and favorable neurologic outcome. Primary resuscitation quality outcome was a composite variable, termed “excellent cardiopulmonary resuscitation,” prospectively defined as a chest compression depth ≥ 38 mm, rate ≥ 100/min, ≤ 10% of chest compressions with leaning, and a chest compression fraction > 90% during a given 30-second epoch. Quantitative data were available only for patients who are 8 years old or older. There were 119 chest compression events (60 control and 59 interventional). The intervention was associated with a trend toward improved survival to hospital discharge on both univariate analysis (52% vs 33%, p = 0.054) and after controlling for confounders (adjusted odds ratio, 2.5; 95% CI, 0.91–6.8; p = 0.075), and it significantly increased survival with favorable neurologic outcome on both univariate (50% vs 29%, p = 0.036) and multivariable analyses (adjusted odds ratio, 2.75; 95% CI, 1.01–7.5; p = 0.047). Cardiopulmonary resuscitation epochs for patients who are 8 years old or older during the debriefing period were 5.6 times more likely to meet targets of excellent cardiopulmonary resuscitation (95% CI, 2.9–10.6; p < 0.01). Conclusion Implementation of an interdisciplinary, postevent quantitative debriefing program was significantly associated with improved cardiopulmonary resuscitation quality and survival with favorable neurologic outcome. (Crit Care Med 2014; XX:00–00)

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The effects of a1-adrenergic agonists on the waveforms of action potentials and voltage-gated ionic currents were examined in isolated adult rat ventricular myocytes by the whole-cell patch-clamp recording technique. After "puffer" applications of either of two a, agonists, phenylephrine and methoxamine, action-potential durations were increased. In voltage-clamped cells, phenylephrine (5-20 isM) or methoxamine (5-10 #M) reduced the amplitudes of Ca2"-independent voltage-activated outward K+ currents (Io); neither the kinetics nor the voltage-dependent properties of 'out were significantly affected. The effects of phenylephrine or methoxamine on 'out were larger and longer-lasting at higher concentrations and after prolonged or repeated exposures; in all experiments, however, lout recovered completely when puffer applications were discontinued. The suppression of IoUt is attributed to the activation of a1-adrenergic receptors, as neither P-nor r2-adrenergic agonists had measurable effects on IOt; in addition, the effect of phenylephrine was attenuated in the presence of the a antagonist phentolamine (10 ,uM), but not in the presence of the (3 antagonist propranolol (10 ,IM). Voltage-gated Ca2+ currents, in contrast, were not altered measurably by phenylephrine or methoxamine and no currents were activated directly by these agents. Suppression of Iot was also observed during puffer applications ofeither oftwo protein kinase C activators, phorbol 12-myristate 13-acetate (10 nM-1 pM) and 1-oleoyl-2-acetylglycerol (60 ,uM). We conclude that the activation of a1-adrenergic receptors in adult rat ventricular myocytes leads to action-potential prolongation as a result of the specific suppression of 'out and that this effect may be mediated by activation of protein kinase C.Although it seems certain that the major effects of sympathomimetic agents on the mammalian heart are mediated by activation of 8-adrenergic receptors, the presence of aadrenergic receptors, which appear to be predominantly of the a, subtype (1, 2), has also been demonstrated in many preparations, including human atrial (3) and ventricular (4) muscle. In addition to variations among species (2), both the absolute and relative numbers of a,-and /3-adrenergic receptors are altered under some pathological conditions (5, 6). Although stimulation of a receptors results in actionpotential (AP) prolongation and inotropic responses similar (although not identical) to those seen on p-receptor activation (1, 2, 6), the mechanisms involved in mediating these effects are not well understood (1, 6). This contrasts markedly with 13-receptor stimulation, which results in increased cAMP, activation of cAMP-dependent protein kinase, and, presumably, protein phosphorylation (7); at the membrane level, p-receptor agonists increase the amplitude (7) of voltagegated inward Ca2" currents (Ica), by increasing the number and/or the opening probability of functional Ca2" channels (8,9). The effects of a, agonists are apparently not mediated by a similar mechanism, as...

Objective To evaluate the cost-effectiveness of universal neonatal screening for T cell lymphocytopenia in enhancing quality of life and life expectancy for children with severe combined immunodeficiency (SCID). Methods Decision trees were created and analyzed to estimate the cost, life years, and quality adjusted life years (QALYs) across a population when universal screening for lack of T cells is used to detect SCID, as implemented in five states, compared to detection based on recognizing symptoms and signs of disease. Terminal values of each tree limb were derived through Markov models simulating the natural history of three cohorts: unaffected subjects; those-diagnosed with SCID as neonates (early diagnosis); and those diagnosed after becoming symptomatic and arousing clinical suspicion (late diagnosis). Models considered the costs of screening and of care including hematopoietic cell transplantation for affected individuals. Key decision variables were derived from the literature and from a survey of families with children affected by SCID, which was used to describe the clinical history and healthcare utilization for affected subjects. Sensitivity analyses were conducted to explore the influence of these decision variables. Results Over a 70 year time horizon, the average cost per infant was $8.89 without screening and $14.33 with universal screening. The model predicted that universal screening in the U.S. would cost approximately $22.4 million/year with a gain of 880 life years and 802 QALYs. Sensitivity analyses showed that screening test specificity and disease incidence were critical driving forces affecting the incremental cost-effectiveness ratio (ICER). Assuming a SCID incidence of 1/75,000 births and test specificity and sensitivity each at 0.99, screening remained cost-effective up to a maximum cost of $15 per infant screened. Conclusion At our current estimated screening cost of $4.22/infant, universal screening for SCID would be a cost effective means to improve quality and duration of life for children with SCID.

This study provides no strong evidence to support the utility of this decision-support tool, but it demonstrates the value of rigorous evaluation of decision-support information technology.

Objectives: A set of standard processes was developed for delivering continuous drug infusions in order to improve (1) patient safety; (2) efficiency in staff workflow; (3) hemodynamic stability during infusion changes, and (4) efficient use of resources. Failure modes effects analysis (FMEA) was used to examine the impact of process changes on the reliability of delivering drug infusions. Setting: An 11 bed multidisciplinary pediatric ICU in the children's hospital of an academic medical center staffed by board certified pediatric intensivists. The hospital uses computerized physician order entry for all medication orders. Methods: A multidisciplinary team characterized key elements of the drug infusion process. The process was enhanced to increase overall reliability and the original and revised processes were compared using FMEA. Resource consumption was estimated by reviewing purchasing and pharmacy records for the calendar year after full implementation of the revised process. Staff satisfaction was evaluated using an anonymous questionnaire administered to staff nurses in the ICU and pediatric residents who had rotated through the ICU. Results: The original process was characterized by six elements: selecting the drug; selecting a dose; selecting an infusion rate; calculating and ordering the infusion; preparing the infusion; programming the infusion pump and delivering the infusion. The following practice changes were introduced: standardizing formulations for all infusions; developing database driven calculators; extending infusion hang times from 24 to 72 hours; changing from bedside preparation by nurses to pharmacy prepared or premanufactured solutions. FMEA showed that the last three elements of the original process had high risk priority numbers (RPNs) of .225 whereas the revised process had no elements with RPNs .100. The combined effect of prolonging infusion hang times, preparation in the pharmacy, and purchasing premanufactured solutions resulted in 1500 fewer infusions prepared by nurses per year. Nursing staff expressed a significant preference and pediatric residents unanimously expressed a strong preference for the revised process. Conclusions: Standardization of infusion delivery reduced the frequency for completing the most unreliable elements of the process and reduced the riskiness of the individual elements. Both contribute to a safer system.

Electronic and handwritten documentation consumed equal amounts of time. Structured entry, compared to handwriting, may encourage recording of specific or otherwise unincorporated data elements resulting in a more detailed record. This suggests that user interfaces and decision support components may influence both the types and complexity of clinical data recorded by caregivers.