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1.  Spinal muscular atrophy type 1: Are proactive respiratory interventions associated with longer survival? 
Context
Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood.
Objective
To determine whether the early initiation of noninvasive respiratory interventions is associated with longer survival.
Design
Single-institution retrospective cohort study identified children with spinal muscular atrophy type 1 from January 1, 2002 to May 1, 2009 who were followed for 2.3 mean yrs.
Setting
Tertiary care children’s hospital and outpatient clinics in a vertically integrated healthcare system.
Patients or Other Participants
Forty-nine children with spinal muscular atrophy type 1 were grouped according to the level of respiratory support their caregivers chose within the first 3 months after diagnosis: proactive respiratory care (n = 26) and supportive care (n = 23).
Interventions
Proactive respiratory care included bilevel non-invasive ventilation during sleep and twice a day cough assist while supportive respiratory care included suctioning, with or without supplemental oxygen.
Measurements and Main Results
Kaplan–Meier survival curves were assessed based on intention to treat. Children treated with early proactive respiratory support had statistically longer survival compared to supportive care (log rank 0.047); however, the adjusted hazard ratio for survival was not statistically different (2.44 [95% confidence interval 0.84–7.1]). Children in the proactive group were more likely to be hospitalized for respiratory insufficiency (83% vs. 46%) and had shortened time after diagnosis until first hospital admission for respiratory insufficiency (median 118 vs. 979 days).
Conclusion
Longer survival time with spinal muscular atrophy type 1 is associated with early, noninvasive respiratory care interventions after diagnosis.
doi:10.1097/PCC.0b013e3182388ad1
PMCID: PMC4334579  PMID: 22198810
noninvasive ventilation; respiratory failure; spinal muscular atrophy; survival analysis
2.  Sildenafil Exposure and Hemodynamic Effect after Fontan Surgery 
Objective
Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery.
Design
Prospective, dose-escalation trial.
Setting
Single-center, pediatric catheterization laboratory.
Patients
9 children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: Median (range) age and weight: 5.2 years (2.5–9.4) and 16.3 kg (9.5–28.1). Five children (55%) were male, and 6/9 (67%) had a systemic right ventricle.
Interventions
Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 minutes).
Measurements
Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography.
Main Results
Maximum sildenafil concentrations ranged from 124–646 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 8/9 children and 90% inhibition in 7/7 of children with doses ≥0.35 mg/kg. Sildenafil improved stroke volume (+22%, p=0.05) and cardiac output (+10%, p=0.01) with no significant change in heart rate in 8/9 children. Sildenafil also lowered systemic (-16%, p=0.01) and pulmonary vascular resistance index (PVRI) in all 9 children (median baseline PVRI 2.4 [range: 1.3, 3.7]; decreased to 1.9 [0.8, 2.7] WU x m2; p=0.01) with no dose-response effect. Pulmonary arterial pressures decreased (−10%, p=0.02) and pulmonary blood flow increased (9%, p=0.02). There was no change in myocardial performance index and no adverse events.
Conclusions
After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.
doi:10.1097/PCC.0000000000000007
PMCID: PMC3887448  PMID: 24201857
single ventricle; sildenafil; Fontan; pulmonary hypertension; pulmonary vascular resistance; pharmacokinetics
3.  The Temporal Kinetics of Circulating Angiopoietin Levels in Children with Sepsis 
Objective
Capillary integrity continues to challenge critical care physicians worldwide when treating children with sepsis. Vascular growth factors, specifically angiopoietin (angpt)-1 and angpt-2, play opposing roles in capillary stabilization in septic patients, respectively. We aim to determine whether pediatric patients with severe sepsis/shock have persistently high angpt-2/1 ratios when compared to non-septic pediatric intensive care unit (PICU) patients over a 7-day period.
Design
Prospective, observational study. Patients were classified within 24h of admission into: non-systemic inflammatory response syndrome (non-SIRS), SIRS/sepsis, or severe sepsis/shock. Plasma levels of angpt-1 and angpt-2 were measured via ELISA. The angpt-2/1 ratio was graphically plotted and determined whether patients fell into ‘constant’ or ‘variable’ patterns.
Setting
Tertiary care center PICU.
Patients
Critically ill pediatric patients with varying sepsis severity.
Interventions
None
Measurements and Main Results
Forty five patients were enrolled (n=9 non-SIRS, n=19 SIRS/sepsis, and n=17 severe sepsis/shock). Gender, age, weight, comorbidities and PICU length of stay were not significantly different between the groups. Admission pediatric risk stratification scores and net fluid ins/outs were significantly elevated in the severe sepsis/shock group when compared (all p<0.05). Admission angpt-2 levels and angpt-2/1 ratios were significantly different in the severe sepsis/shock group when all groups were compared (both p<0.05). Additionally, the latter were significantly elevated in the severe sepsis/shock group at multiple time points (all p≤0.05) with the peak occurring on day 2 of illness. In a separate analysis, 32% of SIRS/sepsis and 82% of severe sepsis/shock had ‘variable’ angpt-2/1 ratio patterns compared to none in the control group (p<0.001).
Conclusions
Pediatric patients with severe sepsis and septic shock possess significantly elevated angpt-2/1 ratios during their first 3 days of illness which peak at day 2 of illness. A subset of these patients demonstrated ‘variable’ angpt-2/1 ratio patterns.
doi:10.1097/PCC.0b013e3182a553bb
PMCID: PMC3947338  PMID: 24141659
Pediatric; capillary leak; shock; intensive care
4.  pRIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease) score identifies Acute Kidney Injury and predicts mortality in critically ill children : a prospective study 
Objectives
1) To determine whether pRIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease) criteria serves to characterize the pattern of Acute Kidney Injury (AKI) in critically ill pediatric patients; and 2) to identify if pRIFLE score will predict morbidity and mortality in our patient´s cohort.
Design
Prospective Cohort.
Setting
Multidisciplinary, tertiary care, 10- bed PICU.
Patients
266 patients admitted to PICU from November 2009 to November 2010.
Interventions
None.
Measurements and Main Results
The incidence of AKI in the PICU was 27.4%, of which 83.5% presented within 72hrs of admission to the PICU. Patients with AKI were younger, weighed less, were more likely to be on in fluid overload ≥10%, and were more likely to be on inotropic support, diuretics or amino glycosides. No difference in gender, use of other nephrotoxins, or mechanical ventilation was observed. Fluid overload ≥10% was an independent predictor of morbidity and mortality.
In multivariate analysis, AKI-Injury and Failure categories, as defined by pRIFLE, predicted mortality, hospital length of stay, and PICU length of stay.
Conclusions
In this cohort of critically ill pediatric patients, AKI identified by pRIFLE and fluid overload ≥ 10% predicted increased morbidity and mortality. Implementation of pRIFLE scoring and close monitoring of fluid overload upon admission may help develop early interventions to prevent and treat AKI in critically ill children.
doi:10.1097/PCC.0b013e3182745675
PMCID: PMC4238883  PMID: 23439463
Acute kidney injury; pRIFLE, children; fluid overload; outcome
5.  Pediatric Severe Sepsis in US Children’s Hospitals 
Objective
To compare the prevalence, resource utilization, and mortality for pediatric severe sepsis identified using two established identification strategies.
Design
Observational cohort study from 2004–2012.
Setting
Forty-four pediatric hospitals contributing data to the Pediatric Health Information Systems database.
Patients
Children ≤18 years of age.
Measurements and Main Results
We identified patients with severe sepsis or septic shock by using two International Classification of Diseases, 9th edition-Clinical Modification (ICD9-CM) based coding strategies: 1) combinations of ICD9-CM codes for infection plus organ dysfunction (combination code cohort); 2) ICD9-CM codes for severe sepsis and septic shock (sepsis code cohort). Outcomes included prevalence of severe sepsis, as well as hospital and intensive care unit (ICU) length of stay (LOS), and mortality. Outcomes were compared between the two cohorts examining aggregate differences over the study period and trends over time. The combination code cohort identified, 176,124 hospitalizations (3.1% of all hospitalizations), while the sepsis code cohort identified 25,236 hospitalizations (0.45%), a 7-fold difference. Between 2004 and 2012, the prevalence of sepsis increased from 3.7% to 4.4% using the combination code cohort and from 0.4% to 0.7% using the sepsis code cohort (p<0.001 for trend in each cohort). LOS (hospital and ICU) and costs decreased in both cohorts over the study period (p<0.001). Overall hospital mortality was higher in the sepsis code cohort than the combination code cohort (21.2%, (95% CI: 20.7–21.8 vs. 8.2%,(95% CI: 8.0–8.3). Over the 9 year study period, there was an absolute reduction in mortality of 10.9% (p<0.001) in the sepsis code cohort and 3.8% (p<0.001) in the combination code cohort.
Conclusions
Prevalence of pediatric severe sepsis increased in the studied US children’s hospitals over the past 9 years, though resource utilization and mortality decreased. Epidemiologic estimates of pediatric severe sepsis varied up to 7-fold depending on the strategy used for case ascertainment.
doi:10.1097/PCC.0000000000000225
PMCID: PMC4221502  PMID: 25162514
Pediatrics; Sepsis; Critical Care; Epidemiology
6.  Opioid use after cardiac surgery in children with Down syndrome 
OBJECTIVES
To determine the cumulative opioid doses administered to patients with Down syndrome (DS) after cardiac surgery and compare them to patients without DS.
DESIGN
Retrospective, observational, comparative study.
SETTING
PICU in a university-affiliated, freestanding pediatric teaching hospital.
PATIENTS
Infants and children who presented to our institution for heart surgery after July 1, 2008, and met the following criteria: 1) no opioid medications for 48 hours prior to surgery, 2) sternotomy approach with primary closure, 3) no additional operative procedures in the 5 days after surgery. All patients with DS were included, and patients without DS with similar age, type of cardiac lesion, and length of surgical procedure were selected in a ~2:1 ratio, blinded to opioid exposure.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Clinical and demographic data were extracted from electronic medical record data. Univariate analyses and mulitvariate linear regression modeling were performed to determine the influence of DS, patient characteristics, and clinical covariates on weight-adjusted opioid dose. The differences in median cumulative opioid doses between those with DS (n=44) and those without (n=77) were not significant in the first 24 hours [+0.39 mg/kg (95% CI −0.45 to +1.39 mg/kg)] or 96 hours [+0.54 mg/kg (−0.59 to +2.07 mg/kg)] after surgery. Age, cardiac bypass time, benzodiazepines, and neuromuscular blocking agents were significantly correlated with opioid dose, but DS, gender, pain score, creatinine, acetaminophen, NSAIDs, and steroid medications were not. Patients with DS had longer hospital stays; in multivariate analysis, higher opioid exposures in the first 96 hours after surgery and higher peak serum creatinine values correlated with longer hospitalization.
CONCLUSIONS
This cohort did not provide evidence for opioid resistance in patients with DS. Younger age, longer cardiac bypass time, exposure to benzodiazepines, and neuromuscular blockade did correlate with increased opioid doses after cardiac surgery.
doi:10.1097/PCC.0b013e31829f5d9d
PMCID: PMC3830692  PMID: 23962833
Opioid; Narcotic Analgesics; Pain; Postoperative; Analgesia; Thoracic Surgical Procedures; Down Syndrome
7.  EXTRACORPOREAL MEMBRANE OXYGENATION vs. COUNTERPULSATILE, PULSATILE, AND CONTINUOUS LEFT VENTRICULAR UNLOADING FOR PEDIATRIC MECHANICAL CIRCULATORY SUPPORT 
OBJECTIVE
Despite progress with adult ventricular assist devices (VADs), limited options exist to support pediatric patients with life-threatening heart disease. Extracorporeal membrane oxygenation (ECMO) remains the clinical standard. To characterize (patho)physiologic responses to different modes of mechanical unloading of the failing pediatric heart, ECMO was compared to either intraaortic balloon pump (IABP), pulsatile-flow (PF)VAD, or continuous-flow (CF)VAD support in a pediatric heart failure model.
DESIGN
Experimental.
SETTING
Large animal laboratory operating room.
SUBJECTS
Yorkshire piglets (n=47, 11.7±2.6 kg).
INTERVENTIONS
In piglets with coronary ligation-induced cardiac dysfunction, mechanical circulatory support devices were implanted and studied during maximum support.
MEASUREMENTS and MAIN RESULTS
Left ventricular, right ventricular, coronary, carotid, systemic arterial, and pulmonary arterial hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption and total-body oxygen consumption (VO2) were calculated from arterial, venous, and coronary sinus blood sampling. Blood flow was measured in 17 organs with microspheres. Paired student t-tests compared baseline and heart failure conditions. One-way repeated-measures ANOVA compared heart failure, device support mode(s), and ECMO. Statistically significant (p<0.05) findings included: 1) improved left ventricular blood supply/demand ratio during PFVAD, CFVAD, and ECMO but not IABP support, 2) improved global myocardial blood supply/demand ratio during PFVAD, and CFVAD but not IABP or ECMO support, and 3) diminished pulsatility during ECMO and CFVAD but not IABP and PFVAD support. A profile of systems-based responses was established for each type of support.
CONCLUSIONS
Each type of pediatric VAD provided hemodynamic support by unloading the heart with a different mechanism that created a unique profile of physiological changes. These data contribute novel, clinically relevant insight into pediatric mechanical circulatory support and establish an important resource for pediatric device development and patient selection.
doi:10.1097/PCC.0b013e3182a551b0
PMCID: PMC3913264  PMID: 24108116
pediatric heart failure; ventricular assist device; mechanical circulatory support; extracorporeal membrane oxygenation; intra-aortic balloon pump; counterpulsation; continuous flow; pulsatile flow
9.  Functional Outcomes in Pediatric Severe Sepsis; Further Analysis of the RESOLVE Trial 
Objective
Evaluate risk factors for poor functional outcome in 28 day survivors after an episode of severe sepsis.
Design
Retrospective cohort study examining data from the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE, F1K-MC-EVBP) trial.
Setting
104 pediatric centers in 18 countries.
Subjects
Children with severe sepsis who required both vasoactive-inotropic infusions and mechanical ventilation and who survived to 28 days (n=384).
Interventions
None.
Measurements and Main Results
Poor functional outcome was defined as a Pediatric Overall Performance Category (POPC) score ≥3 and an increase from baseline when measured 28 days after trial enrollment. Median(IQR) POPC at enrollment was 1 (1–2). Median(IQR) POPC at 28 days was 2 (1–4).
34% of survivors had decline in their functional status at 28 days, and 18% were determined to have a “poor” functional outcome. Hispanic ethnicity was associated with poor functional outcome compared to the white referent group [RR= 1.9 (95% CI 1.0, 3.0)]. Clinical factors associated with increased risk of poor outcome included: central nervous system and intra-abdominal infection sources compared to the lung infection referent category [RR= 3.3 (95%CI 1.4, 5.6) and 2.4 (95%CI 1.0, 4.5) respectively]; a history of recent trauma [RR=3.9 (95%CI 1.4, 5.4)]; receipt of cardiopulmonary resuscitation prior to enrollment [RR=5.1 (95% CI 2.9, 5.7)]; and baseline Pediatric Risk of Mortality III (PRISM) score of 20 – 29 [RR=2.8 (95%CI 1.2, 5.2)] and PRISM ≥30 [RR=4.5 (95%CI 1.6, 8.0)] compared to the referent group with PRISM scores of 0 – 9.
Conclusions
In this sample of 28 day survivors of pediatric severe sepsis diminished functional status was common. This analysis provides evidence that particular patient characteristics and aspects of an individual’s clinical course are associated with poor functional outcome 28 days after onset of severe sepsis. These characteristics may provide opportunity for intervention in order to improve functional outcome in pediatric patients with severe sepsis. Decline in functional status 28 days after onset of severe sepsis is a frequent and potentially clinically meaningful event. Further consideration should be given to functional status as the primary outcome that future trials of novel or unproven therapies are designed to affect.
doi:10.1097/PCC.0b013e3182a551c8
PMCID: PMC4080839  PMID: 24108117
sepsis; septic shock; severe sepsis; outcome assessment; mechanical ventilation; multiple organ failure; functional status; Pediatric Overall Performance Category
10.  Changes in Transfusion Practice Over Time in the Pediatric Intensive Care Unit 
Objective
Recent randomized clinical trials have shown the efficacy of a restrictive transfusion strategy in critically ill children. The impact of these trials on pediatric transfusion practice is unknown. Additionally, long-term trends in pediatric transfusion practice in the intensive care unit have not been described. We assessed transfusion practice over time, including the effect of clinical trial publication.
Design
Single-center, retrospective observational study.
Setting
A 10-bed pediatric intensive care unit (PICU) in an urban academic medical center.
Patients
Critically ill, non-bleeding children between the ages of 3 days and 14 years old, admitted to the University of Maryland Medical Center PICU between January 1, 1998 and December 31, 2009, excluding those with congenital heart disease, hemolytic anemia, and hemoglobinopathies.
Interventions
None.
Measurements and Main Results
During the time period studied, 5327 patients met inclusion criteria. Of these, 335 received at least one red cell transfusion while in the PICU. The overall proportion transfused declined from 10.5% in 1998 to 6.8% in 2009 (p = 0.007). Adjusted for acuity, the likelihood of transfusion decreased by calendar year of admission. In transfused patients, the pre-transfusion hemoglobin level declined, from 10.5 g/dL to 9.3 g/dL, though these changes failed to meet statistical significance (p=0.09). Neonatal age, respiratory failure, shock, multi-organ dysfunction, and acidosis were associated with an increased likelihood of transfusion in both univariate and multivariable models.
Conclusions
The overall proportion of patients transfused between 1998 and 2009 decreased significantly. The magnitude of the decrease varied over time, and no additional change in transfusion practice occurred after the publication of a major pediatric clinical trial in 2007. Greater illness acuity and younger patient age were associated with an increased likelihood of transfusion.
doi:10.1097/PCC.0b013e31829b1bce
PMCID: PMC4178535  PMID: 23962831
pediatrics; pediatric intensive care units; physicians practice patterns; erythrocyte transfusion; blood component transfusion; evidence-based practice
11.  Hospitalizations of children with neurological disorders in the United States 
Objective
Although neurologic disorders are among the most serious acute pediatric illnesses, epidemiologic data are scarce. We sought to determine the scope and outcomes of children with these disorders in the US.
Design
Retrospective cohort study
Setting
All non-federal hospitals in 11 states encompassing 38% of the US pediatric population.
Patients
Children 29 days-19 years old hospitalized in 2005
Interventions
None
Measurements and Main Results
Using ICD-9-CM codes, we identified admissions with neurological diagnoses, analyzed patient and hospitalization characteristics, and generated age- and sex-adjusted national estimates. Of 960,020 admissions in the 11 states, 10.7% (103,140) included a neurological diagnosis, which yields a national estimate of 273,900 admissions of children with neurological diagnoses. The most common were seizures (53.9%) and traumatic brain injury (17.3%). Children with neurological diagnoses had nearly 3 times greater intensive care unit (ICU) use than other hospitalized children (30.6% vs. 10.6%, p<0.001). Neurological diagnoses were associated with nearly half of deaths (46.2%, n=1,790). Among ICU patients, children with neurological diagnoses had more than 3 times the mortality of other patients (4.8% vs.1.5%, p<.001). Children with neurological diagnoses had a significantly longer median hospital LOS than other children (3 days [1, 5] vs. 2 days [2,4], p<.001) and greater median hospital costs ($4,630 [$2,380, $9,730] vs. $2,840 [$1,520, $5,550], p<.001).
Conclusions
Children with neurological diagnoses account for a disproportionate amount of ICU stays and deaths compared to children hospitalized for other reasons.
doi:10.1097/PCC.0b013e31828aa71f
PMCID: PMC3795828  PMID: 23842588
epidemiology; neurological outcome; pediatric; intensive care; pediatric neurocritical care; hospitalization
12.  Chilled to the marrow: Neonatal brain injury, hypothermia and the immune system 
doi:10.1097/PCC.0b013e31829b1e94
PMCID: PMC3839943  PMID: 24096690
Hypothermia; brain injury; immune system; hypoxic ischemic encephalopathy; neonatal brain injury
13.  Energy imbalance and the risk of overfeeding in critically ill children* 
Objective
To examine the role of targeted indirect calorimetry in detecting the adequacy of energy intake and the risk of cumulative energy imbalance in a subgroup of critically ill children suspected to have alterations in resting energy expenditure. We examined the accuracy of standard equations used for estimating resting energy expenditure in relation to measured resting energy expenditure in relation to measured resting energy expenditure and cumulative energy balance over 1 week in this cohort.
Design
A prospective cohort study.
Setting
Pediatric intensive care unit in a tertiary academic center.
Interventions
A subgroup of critically ill children in the pediatric intensive care unit was selected using a set of criteria for targeted indirect calorimetry.
Measurements
Measured resting energy expenditure from indirect calorimetry and estimated resting energy expenditure from standard equations were obtained. The metabolic state of each patient was assigned as hypermetabolic (measured resting energy expenditure/estimated resting energy expenditure >110%), hypometabolic (measured resting energy expenditure/estimated resting energy expenditure <90%), or normal (measured resting energy expenditure/estimated resting energy expenditure = 90– 110%). Clinical variables associated with metabolic state and factors influencing the adequacy of energy intake were examined.
Main Results
Children identified by criteria for targeted indirect calorimetry, had a median length of stay of 44 days, a high incidence (72%) of metabolic instability and alterations in resting energy expenditure with a predominance of hypometabolism in those admitted to the medical service. Physicians failed to accurately predict the true metabolic state in a majority (62%) of patients. Standard equations overestimated the energy expenditure and a high incidence of overfeeding (83%) with cumulative energy excess of up to 8000 kcal/week was observed, especially in children <1 yr of age. We did not find a correlation between energy balance and respiratory quotient (RQ) in our study.
Conclusions
We detected a high incidence of overfeeding in a subgroup of critically ill children using targeted indirect calorimetry The predominance of hypometabolism, failure of physicians to correctly predict metabolic state, use of stress factors, and inaccuracy of standard equations all contributed to overfeeding in this cohort. Critically ill children, especially those with a longer stay in the PICU, are at a risk of unintended overfeeding with cumulative energy excess.
doi:10.1097/PCC.0b013e3181fe279c
PMCID: PMC4151116  PMID: 20975614
pediatric; critical care; nutrition; overfeeding; metabolism
15.  Hypothermia Decreases Cerebrospinal Fluid Asymmetric Dimethylarginine Levels in Traumatic Brain Injury Children 
Objectives
Pathological increases in asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, have been implicated in endothelial dysfunction and vascular diseases. Reduced NO early after traumatic brain injury (TBI) may contribute to hypoperfusion. Currently, methods to quantify ADMA in the cerebrospinal fluid (CSF) have not been fully explored. We aimed to develop and validate a method to determine ADMA in the CSF of a pediatric TBI population and to use this method to assess the effects of (i) TBI and (ii) therapeutic hypothermia (TH) on this mediator.
Design, Setting, Patients
An ancillary study to a prospective, phase II randomized clinical trial (RCT) of early hypothermia in a tertiary care pediatric intensive care unit for children with TBI admitted to Children's Hospital of Pittsburgh.
Interventions
None
Measurements and Main Results
A UPLC-MS/MS method was developed and validated to quantitate ADMA. A total of 56 samples collected over 3 days starting with injury onset were analyzed from the CSF of consented therapeutic hypothermia (n=9) and normothermia (n=10) children. Children undergoing diagnostic lumbar puncture (n=5) were controls. ADMA was present at a quantifiable level in all samples. Mean ADMA levels were significantly increased in normothermic TBI children compared to control (0.19± 0.08 μmol/L and 0.11± 0.02μmol/L respectively, p=0.01), and hypothermic children had significantly reduced mean ADMA levels (0.11 ± 0.05 μmol/L) vs. normothermic (p=0.03) measured on day 3. Patient demographics including age, gender, and NO levels (measured as nitrite and nitrate using liquid chromatography coupled with Griess reaction) did not significantly differ between normothermia and hypothermia groups. Also, NO levels did not correlate with ADMA concentrations.
Conclusions
ADMA levels were significantly increased in the CSF of TBI children. Early hypothermia attenuated this increase. The implications of attenuated ADMA on NOS activity and regional cerebral blood flow after TBI by TH deserve future attention.
doi:10.1097/PCC.0b013e31827212c0
PMCID: PMC4134918  PMID: 23439461
traumatic brain injury; nitric oxide synthase; cerebrospinal fluid; asymmetric dimethyl arginine; therapeutic hypothermia; neuroprotection
16.  Efficacy and safety of lung recruitment in pediatric patients with acute lung injury 
Objective
To assess the safety and efficacy of a recruitment maneuver, the Open Lung Tool, in pediatric patients with acute lung injury and acute respiratory distress syndrome.
Design
Prospective cohort study using a repeated-measures design.
Setting
Pediatric intensive care unit at an urban tertiary children's hospital.
Patients
Twenty-one ventilated pediatric patients with acute lung injury.
Intervention
Recruitment maneuver using incremental positive end-expiratory pressure.
Measurements and Main Results
The ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (PaO2/FIO2 ratio) increased 53% immediately after the recruitment maneuver. The median PaO2/FIO2 ratio increased from 111 (interquartile range, 73–266) prerecruitment maneuver to 170 (interquartile range, 102–341) immediately postrecruitment maneuver (p < .01). Improvement in PaO2/FIO2 ratio persisted with an increase of 80% over the baseline at 4 hrs and 40% at 12 hrs after the recruitment maneuver. The median PaO2/FIO2 ratio was 200 (interquartile range, 116–257) 4 hrs postrecruitment maneuver (p < .05) and 156 (interquartile range, 127–236) 12 hrs postrecruitment maneuver (p < .01). Compared with prerecruitment maneuver, the partial pressure of arterial carbon dioxide (PaCO2) was significantly decreased at 4 hrs postrecruitment maneuver but not immediately after the recruitment maneuver. The median PaCO2 was 49 torr (interquartile range, 44–60) prerecruitment maneuver compared with 48 torr (interquartile range, 43–50) immediately postrecruitment maneuver (p = .69), 45 torr (interquartile range, 41–50) at 4 hrs postrecruitment maneuver (p < .01), and 43 torr (interquartile range, 38–51) at 12 hrs postrecruitment maneuver. Recruitment maneuvers were well tolerated except for significant increase in PaCO2 in three patients. There were no serious adverse events related to the recruitment maneuver.
Conclusions
Using the modified open lung tool recruitment maneuver, pediatric patients with acute lung injury may safely achieve improved oxygenation and ventilation with these benefits potentially lasting up to 12 hrs postrecruitment maneuver.
doi:10.1097/PCC.0b013e3181fe329d
PMCID: PMC4127306  PMID: 21057351
ARDS; respiratory distress syndrome; adult; ALI; acute lung injury; positive end-expiratory pressure; pulmonary gas exchange
17.  Using acupuncture for acute pain in hospitalized children 
Objective
Clinical study to determine the acceptability and feasibility of acupuncture for acute postoperative pain control in hospitalized children.
Design
Nonrandomized clinical trial.
Setting
A single, tertiary referral pediatric intensive care unit.
Patients
A total of 20 patients aged 7 months to 18 years. Eleven of the patients had posterior spinal fusion surgery and the remaining nine patients had other surgical diagnoses.
Interventions
Two 10- to 15-minute sessions of acupuncture 24–48 hours apart.
Outcome Measures and Results
The treatment was highly accepted (27 patients were approached and 4 patients refused; of the 23 patients enrolled, 20 patients completed the study). Acupuncture was well tolerated by patients without adverse events related to treatment. In follow-up interviews, 70% of both parents and patients believed acupuncture helped the child's pain. Eighty-five percent of the parents said they would pay out of pocket for acupuncture if not covered by insurance. The pain scores, vital signs, and narcotic usage were recorded before and several times after acupuncture. In posterior spinal fusion patients, the mean pain scores (0–10) immediately before and 4 and 24 hours after acupuncture were: 3.7, 1.7, and 3.1, respectively, after the first acupuncture session and 3.7, 2.2, and 3.1, respectively, after the second session. In the other surgical cohort, the mean pain scores immediately before and 4 and 24 hours after the first session of acupuncture were 2.5, 0.3, and 1.6, respectively.
Conclusions
Our results support that acupuncture is highly accepted and feasible in critically ill, postoperative pediatric patients with acute pain. Our findings suggest that acupuncture may be a potentially useful adjunctive tool for acute pediatric postoperative pain management. A randomized, controlled clinical trial is warranted to confirm these findings.
doi:10.1097/PCC.0b013e318198afd6
PMCID: PMC4127308  PMID: 19307808
pain; postoperative pain; acupuncture; child; complementary therapies; pediatric intensive care unit
18.  Improved Oxygenation 24 Hours After Transition to Airway Pressure Release Ventilation or High-Frequency Oscillatory Ventilation Accurately Discriminates Survival in Immunocompromised Pediatric Patients With Acute Respiratory Distress Syndrome* 
Objectives
Children with an immunocompromised condition and requiring invasive mechanical ventilation have high risk of death. Such patients are commonly transitioned to rescue modes of non-conventional ventilation, including airway pressure release ventilation and high-frequency oscillatory ventilation, for acute respiratory distress syndrome refractory to conventional ventilation. Our aim was to describe our experience with airway pressure release ventilation and high-frequency oscillatory ventilation in children with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation and to identify factors associated with survival.
Design
Retrospective cohort study.
Setting
Tertiary care, university-affiliated PICU.
Patients
Sixty pediatric patients with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation.
Interventions
None.
Measurements and Main Results
Demographic data, ventilator settings, arterial blood gases, oxygenation index, and Pao2/Fio2 were recorded before transition to either mode of nonconventional ventilation and at predetermined intervals after transition for up to 5 days. Mortality in the entire cohort was 63% and did not differ between patients transitioned to airway pressure release ventilation and high-frequency oscillatory ventilation. For both airway pressure release ventilation and high-frequency oscillatory ventilation, improvements in oxygenation index and Pao2/Fio2 at 24 hours expressed as a fraction of pretransition values (oxygenation index24/oxygenation indexpre and Pao2/Fio224/Pao2/FIO2pre) reliably discriminated nonsurvivors from survivors, with receiver operating characteristic areas under the curves between 0.89 and 0.95 (p for all curves < 0.001). Sensitivity-specificity analysis suggested that less than 15% reduction in oxygenation index (90% sensitive, 75% specific) or less than 90% increase in Pao2/Fio2 (80% sensitive, 94% specific) 24 hours after transition to airway pressure release ventilation were the optimal cutoffs to identify nonsurvivors. The comparable values 24 hours after transition to high-frequency oscillatory ventilation were less than 5% reduction in oxygenation index (100% sensitive, 83% specific) or less than 80% increase in Pao2/Fio2 (91% sensitive, 89% specific) to identify nonsurvivors.
Conclusions
In this single-center retrospective study of pediatric patients with an immunocompromised condition and acute respiratory distress syndrome failing conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation, improved oxygenation at 24 hours expressed as Pao2/Fio224/Pao2/Fio2pre or oxygenation index24/oxygenation indexpre reliably discriminates nonsurvivors from survivors. These findings should be prospectively verified.
doi:10.1097/PCC.0000000000000069
PMCID: PMC4114308  PMID: 24413319
acute lung injury; acute respiratory distress syndrome; airway pressure release ventilation; high-frequency oscillatory ventilation; mechanical ventilation; pediatric
19.  Are Pediatric Critical Care Medicine Fellowships Teaching and Evaluating Communication and Professionalism? 
Objective
To describe the teaching and evaluation modalities utilized by pediatric critical care medicine (PCCM) training programs in the areas of professionalism and communication.
Design
Cross sectional national survey.
Setting
PCCM fellowship programs.
Subjects
PCCM program directors.
Interventions
None.
Measurements and Main Results
Survey response rate was 67% of program directors in the United States, representing educators for 73% of current PCCM fellows. Respondents had a median of 4 years experience, with a median of 7 fellows and 12 teaching faculty in his/her program. Faculty role modeling or direct observation with feedback were the most common modalities used to teach communication. However, 6 of the 8 (75%) required elements of communication evaluated were not specifically taught by all programs. Faculty role modeling was the most commonly utilized technique to teach professionalism in 44% of the content areas evaluated, and didactics were the technique utilized in 44% of other professionalism content areas. Thirteen of the 16 required elements of professionalism (81%) were not taught by all programs. Evaluations by members of the healthcare team were used for assessment for both competencies. The use of a specific teaching technique was not related to program size, program director experience, or training in medical education.
Conclusions
A wide range of techniques are currently utilized within PCCM to teach communication and professionalism, but there are a number of required elements that are not specifically taught by fellowship programs. These areas of deficiency represent opportunities for future investigation and improved education in the important competencies of communication and professionalism.
doi:10.1097/PCC.0b013e31828a746c
PMCID: PMC4112058  PMID: 23867427
communication; professionalism; graduate medical education; fellowship training; evaluation; competency; pediatric
20.  Early Lactate Elevations Following Resuscitation From Pediatric Cardiac Arrest Are Associated With Increased Mortality 
Objective
To describe the association of lactate levels within the first 12 hours after successful resuscitation from pediatric cardiopulmonary arrest with hospital mortality.
Design
Retrospective cohort study.
Setting
Fifteen children’s hospital associated with the Pediatric Emergency Care Applied Research Network.
Patients
Patients between 1 day and 18 years old who had a cardiopulmonary arrest, received chest compressions more than 1 minute, had a return of spontaneous circulation more than 20 minutes, and had lactate measurements within 6 hours of arrest.
Interventions
None.
Measurements and Main Results
Two hundred sixty-four patients had a lactate sampled between 0 and 6 hours (lactate0–6) and were evaluable. Of those, 153 patients had a lactate sampled between 7 and 12 hours (lactate7–12). One hundred thirty-eight patients (52%) died. After controlling for arrest location, total number of epinephrine doses, initial rhythm, and other potential confounders, the odds of death per 1 mmol/L increase in lactate 0–6 was 1.14 (1.08, 1.19) (p < 0.001) and the odds of death per 1 mmol/L increase in lactate7–12 was 1.20 (1.11, 1.30) (p < 0.0001). Area under the curve for in-hospital arrest mortality for lactate0–6 was 0.72 and for lactate7–12 was 0.76. Area under the curve for out-of-hospital arrest mortality for lactate0–6 was 0.8 and for lactate7–12 was 0.75.
Conclusions
Elevated lactate levels in the first 12 hours after successful resuscitation from pediatric cardiac arrest are associated with increased mortality. Lactate levels alone are not able to predict outcomes accurately enough for definitive prognostication but may approximate mortality observed in this large cohort of children’s hospitals.
doi:10.1097/PCC.0b013e3182976402
PMCID: PMC4092112  PMID: 23925146
children; heart arrest; lactate; resuscitation
21.  Effect of Alternative Chest Compression Techniques in Infant and Child on Rescuer Performance 
Objective
Current chest compression(CC) guidelines for an infant recommend a two finger(TF) technique with lone rescuer and a two thumb(TT) with two rescuers, and for a child either a One hand(OH) or Two hand(TH) technique with one or two rescuers. The effect of a 30:2 compression:ventilation ratio(C:V) using these techniques on CC quality and rescuer fatigue is unknown. We hypothesized that during lone rescuer CC, TT in infant and TH in child achieves better compression depth(CD) without additional rescuer fatigue compared with TF and OH respectively.
Design
Randomized observational study.
Setting
University affiliated pediatric hospital.
Subjects
Adult healthcare providers certified in BLS or Pediatric Advanced Life Support.
Interventions
Laerdal™ Baby ALS Trainer and Resusci Junior manikin were modified to digitally record compression depth(CD), compression pressure(CP) and compression rate(CR). Sixteen subjects were randomized to each of the four techniques to perform 5 minutes lone rescuer 30:2 C:V CPR. Rescuer heart rate(HR) and respiratory rate(RR) were recorded continuously and the recovery time(RT) interval for HR/RR to return to baseline was determined. Subjects were blinded to data recording. Groups were compared using two-sample, two-sided t-tests.
Measurements and Main Results
Two-thumb technique generated significantly higher CD and peak CP compared to TF (p<0.001); there was no significant difference between OH vs. TH. TF showed decay of CD and CP over time compared to TT. CR(per minute) and actual compressions delivered were not significantly different between groups. No significant difference of fatigue and recovery time were observed, except TT group had greater increase in the rescuer’s HR(bpm) from baseline compared to TF group, p=0.04.
Conclusions
Two-thumb compression provides higher CD and CP compared to TF without any evidence of decay in quality and additional rescuer fatigue over 5 minutes. There was no significant difference in child CC quality or rescuer fatigue between OH and TH. Two-thumb technique is preferred for infant CC and our data supports the current guidelines for child chest compression.
doi:10.1097/PCC.0b013e31819886ab
PMCID: PMC4088329  PMID: 19307812
Heart massage; Child; Infant; Cardiopulmonary Resuscitation; Fatigue
22.  Nonconvulsive Electrographic Seizures are Common in Children With Abusive Head Trauma* 
Objective
To determine the prevalence of nonconvulsive seizures in children with abusive head trauma.
Design
Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring.
Setting
PICU of a tertiary care hospital.
Subjects
Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team.
Interventions
None.
Measurements and Main Results
Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p = 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p = 0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10).
Conclusions
Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome.
doi:10.1097/PCC.0b013e3182917b83
PMCID: PMC4082326  PMID: 23842589
abusive head trauma; electroencephalographic monitoring; electroencephalography; seizure; traumatic brain injury
23.  Lipoxin A4 and 8-isoprostane in the exhaled breath condensate of children hospitalized for status asthmaticus* 
Objective
To measure levels of 8-isoprostane and Lipoxin A4 in the exhaled breath condensate of children (7–17 yrs old) recovering from status asthmaticus in a pediatric intensive care unit and to compare their respective levels in the exhaled breath condensate collected from age-matched “healthy” children enrolled from an ambulatory pediatric clinic during well-child visits.
Design
Prospective case-controlled study.
Setting
Teaching hospitals and a research laboratory.
Patients
Children recovering from status asthmaticus and age-matched controls.
Interventions
Collection of exhaled breath condensate from patients recovering from status asthmaticus and controls for purpose of measurement of 8-isoprostane and Lipoxin A4.
Measurements and Main Results
There was no difference in age (11.9 ± 3.0 vs. 12.0 ± 3.3 yrs, p = .9) between patients and control subjects. All participants completed the exhaled breath condensate collection without complications. There was no difference in the pulmonary index (3.3 ± 2.2 vs. 3.1 ± 1.9, p = 1.0) after collection of exhaled breath condensate compared with baseline values in patients with status asthmaticus. The level of 8-isoprostane was significantly higher (63 ± 9 vs. 41 ± 13 pg/mL, p < .001), whereas the level of Lipoxin A4 was significantly lower (5.6 ± 2.9 vs. 10.5 ± 3.1 ng/mL, p < .001) in the exhaled breath condensate from children recovering from status asthmaticus compared with control subjects.
Conclusions
8-Isoprostane was elevated and Lipoxin A4 is decreased in the exhaled breath condensate of children recovering from status asthmaticus in a pediatric intensive care unit. These data may provide new insight into the pathophysiology of asthma in children in this clinical setting.
doi:10.1097/PCC.0b013e3182231644
PMCID: PMC4078922  PMID: 21666533
lipoxins; child; asthma
24.  Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery 
Objective
To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery.
Design
Prospective, dose escalation trial.
Setting
Single-center, pediatric catheterization laboratory.
Patients
12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle.
Interventions
Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes).
Measurements
Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance.
Main Results
Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events.
Conclusions
Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.
doi:10.1097/PCC.0b013e31828aa5ee
PMCID: PMC3782306  PMID: 23823195
Single ventricle; sildenafil; bidirectional Glenn anastomosis; pulmonary hypertension; pulmonary vascular resistance; pharmacokinetics
25.  Age-Specific Cerebral Perfusion Pressure Thresholds and Survival in Children and Adolescents With Severe Traumatic Brain Injury 
Objectives
Evidence-based traumatic brain injury guidelines support cerebral perfusion pressure thresholds for adults at a class 2 level, but evidence is lacking in younger patients. The purpose of this study is to identify the impact of age-specific cerebral perfusion pressure thresholds on short-term survival among patients with severe traumatic brain injury.
Design
Institutional review board-approved, prospective, observational cohort study.
Patients
Data on all patients with a postresuscitation Glasgow Coma Score less than 9 were added in the Brain Trauma Foundation prospective New York State TBI-trac database.
Measurements and Main Results
We calculated the survival rates and relative risks of mortality for patients with severe traumatic brain injury based on predefined age-specific cerebral perfusion pressure thresholds. A higher threshold and a lower threshold were defined for each age group: 60 and 50 mm Hg for 12 years old or older, 50 and 35 mm Hg for 6–11 years, and 40 and 30 mm Hg for 0–5 years. Patients were stratified into age groups of 0–11, 12–17, and 18 years old or older. Three exclusive groups of CPP-L (events below low cerebral perfusion pressure threshold), CPP-B (events between high and low cerebral perfusion pressure thresholds), and CPP-H (events above high cerebral perfusion pressure threshold) were defined. As an internal events of hypotension and elevated intracranial pressure. Survival was significantly higher in 0–11 and 18 years old or older age groups for patients with CPP-H events compared with those with CPP-L events. There was a significant decrease in survival with prolonged exposure to CPP-B events for the 0–11 and 18 years old and older age groups when compared with the patients with CPP-H events (p = 0.0001 and p = 0.042, respectively). There was also a significant decrease in survival with prolonged exposure to CPP-L events in all age groups compared with the patients with CPP-H events (p < 0.0001 for 0- to 11-yr olds, p = 0.0240 for 12- to 17-yr olds, and p < 0.0001 for 18-yr old and older age groups). The 12- to 17-year olds had a significantly higher likelihood of survival compared with adults with prolonged exposure to CPP-L events (< 50 mm Hg). CPP-L events were significantly related to systemic hypotension for the 12- to 17-year-old group (p = 0.004) and the 18-year-old and older group (p < 0.0001). CPP-B events were significantly related to systemic hypotension in the 0- to 11-year-old group (p = 0.014). CPP-B and CPP-L events were significantly related to elevated intracranial pressure in all age groups.
Conclusions
Our data provide new evidence that cerebral perfusion pressure targets should be age specific. Furthermore, cerebral perfusion pressure goals above 50 or 60 mm Hg in adults, above 50 mm Hg in 6- to 17-year olds, and above 40 mm Hg in 0- to 5-year olds seem to be appropriate targets for treatment-based studies. Systemic hypotension had an inconsistent relationship to events of low cerebral perfusion pressure, whereas elevated intracranial pressure was significantly related to all low cerebral perfusion pressure events across all age groups. This may impart a clinically important difference in care, highlighting the necessity of controlling intracranial pressure at all times, while targeting SBP in specific instances.
doi:10.1097/PCC.0b013e3182a556ea
PMCID: PMC4077612  PMID: 24196011
cerebral perfusion pressure; head trauma; severe traumatic brain injury; traumatic brain injury management

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