Risk Factors for Increased Hospital Resource Utilization and In-Hospital Mortality in Adults With Single Ventricle Congenital Heart Disease.

Most patients with single ventricle congenital heart disease are now expected to survive to adulthood. Co-morbid medical conditions (CMCs) are common. We sought to identify risk factors for increased hospital resource utilization and in-hospital mortality in adults with single ventricle. We analyzed data from the 2001 to 2011 Nationwide Inpatient Sample database in patients aged ≥18 years admitted to nonteaching general hospitals (NTGHs), TGHs, and pediatric hospitals (PHs) with either hypoplastic left heart syndrome, tricuspid atresia or common ventricle. National estimates of hospitalizations were calculated. Elixhauser CMCs were identified. Length of stay (LOS), total hospital costs, and effect of CMCs were determined. Age was greater in NTGH (41.5 ± 1.3 years) than in TGH (32.8 ± 0.5) and PH (25.0 ± 0.6; p <0.0001). Adjusted LOS was shorter in NTGH (5.6 days) than in PH (9.7 days; p <0.0001). Adjusted costs were higher in PH ($56,671) than in TGH ($31,934) and NTGH ($18,255; p <0.0001). CMCs are associated with increased LOS (p <0.0001) and costs (p <0.0001). Risk factors for in-hospital mortality included increasing age (odds ratio [OR] 5.250, CI 2.825 to 9.758 for 45- to 64-year old vs 18- to 30-year old), male gender (OR 2.72, CI 1.804 to 4.103]), and the presence of CMC (OR 4.55, CI 2.193 to 9.436) for 2 vs none). No differences in mortality were found among NTGH, TGH, and PH. Cardiovascular procedures were more common in PH hospitalizations and were associated with higher costs and LOS. CMCs increase costs and mortality. In-hospital mortality is increased with age, male gender, and the presence of hypoplastic left heart syndrome.

Influence of inhalation injury on energy expenditure in severely burned children.

OBJECTIVE: Determine the effect of inhalation injury on burn-induced hypermetabolism in children. DESIGN: Prospective study comparing hypermetabolism (i.e., resting energy expenditure and oxygen consumption) in burned children with and without inhalation injury during acute hospitalization. SETTING: Single pediatric burn center. PATIENTS: Eighty-six children (1-18 years) with ≥40% total body surface area burns were stratified to two groups: no inhalation injury and inhalation injury. INTERVENTIONS: None. MAIN MEASUREMENTS AND RESULTS: Inhalation injury was diagnosed based on bronchoscopic evaluation. At admission, PaO2:FiO2 ratios (an index of respiratory distress) were significantly higher in patients with no inhalation injury than in patients with inhalation injury. No differences were detected in resting energy expenditure or percent of the predicted basal metabolic rate between groups. Additionally, oxygen consumption did not significantly differ between groups. CONCLUSIONS: Inhalation injury does not augment the burn-induced hypermetabolic stress response in children, as reflected by resting energy expenditure and oxygen consumption.

Hospital utilization in adults with single ventricle congenital heart disease and cardiac arrhythmias.

OBJECTIVES: The study sought to identify the impact of cardiac arrhythmias on hospitalizations in adults with single ventricle (SV) congenital heart disease (CHD). BACKGROUND: Surgical advances have dramatically improved survival in patients with CHD. Cardiac arrhythmias and sudden cardiac death are common in adults with CHD. METHODS AND RESULTS: Data from 43 pediatric hospitals in the 2004 to 2011 Pediatric Health Information System database were used to identify patients ≥18 years of age admitted with International Classification of Diseases-9th Revision codes for a diagnosis of either hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA) or common ventricle (CV), and a cardiac arrhythmia. Primary and secondary diagnoses, length of stay (LOS), hospital charges, and interventional procedures were determined. Multilevel models were used to evaluate differences in demographics, diagnoses, and clinical outcomes among the 3 subgroups (HLHS, TA, and CV). Interactions of charges with arrhythmia and admission year were examined using ANOVA. There were 642 admissions in 424 patients with SV CHD and an arrhythmia diagnosis. A single arrhythmia diagnosis was present in 454 admissions (71%). Total hospital charges were $80.7 million with mean charge per admission of $127,296 ± 243,094. The mean charge per hospital day was $16,653 ± 17,516 and increased across the study period (P < 0.01). Arrhythmia distributions were impacted by SV anatomic subtype (P < 0.001). Hospital resource utilization was significantly different among arrhythmia groups (P < 0.001). CONCLUSIONS: In adults with SV CHD, arrhythmias are affected by SV anatomic subtype and impact adversely upon hospital resource utilization.

Impact of anatomical subtype and medical comorbidities on hospitalizations in adults with single ventricle congenital heart disease.

BACKGROUND: Most patients with single ventricle congenital heart disease (SV) are now expected to survive to adulthood. Medical comorbidities are common in SV. METHODS: We used data from 43 pediatric hospitals in the 2004 to 2011 Pediatric Health Information System database to identify patients ≥18 years of age admitted with International Classification of Diseases-9th Revision codes for a diagnosis of either hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA) or common ventricle (CV). Primary (PD) and secondary diagnoses (SD), length of stay (LOS) and hospital charges were determined. Multilevel models were used to evaluate differences in demographics, diagnoses, and admission outcomes among the three subgroups (HLHS, TA, and CV). Interactions of charges with PD and admission year were examined using ANOVA. RESULTS: There were 801 SV patients with 1330 admissions during the study period. Mean age was 24.8±6.2 years (55% male) and mean LOS was 6.8±11.3 days. Total hospital charges were $135 million with mean charge per admission of $101,131±205,808. The mean charge per day was $15,407±16,437. Hospital charges correlated with PD group (p<0.001). Admission rate remained stable (~180/year) from 2006 to 2011. LOS decreased (p=0.0308) and hospital charges per day increased across the study period (p<0.001). PD was non-cardiac in 28% of admissions. Liver-related conditions were more common in patients with HLHS (p<0.001). CONCLUSIONS: Hospitalization costs in adults with SV are significant and are impacted by comorbid medical conditions. Hospitalization rates for adults with SV are not increasing. Gastroenterologic comorbidities including protein-losing enteropathy (PLE) are common in HLHS.

Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay.

Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months postburn. The purpose of this study was to measure insulin sensitivity in severely burned children before discharge when wounds are 95% healed. Twenty-four children, aged 4 to 17 years, with burns > or = 40% TBSA underwent a 2-hour oral glucose tolerance test before discharge from the acute pediatric burn unit. Plasma glucose and insulin levels as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared with published oral glucose tolerance test data from healthy, nonburned children. There was a significant difference between severely burned children and nonburned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53 +/- 1.62 compared with the value in nonburned, healthy children of 1.28 +/- 0.16 (P < .05). Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury.

Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children.

OBJECTIVE: To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. DESIGN: Prospective, randomized study. SETTING: An acute pediatric burn unit in a tertiary teaching hospital. PATIENTS: Children, 4-18 yrs old, with total body surface area burned > or =40% and who arrived within 1 wk after injury were enrolled in the study. INTERVENTIONS: Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose < or =215 mg/dL. MEASUREMENTS AND MAIN RESULTS: Twenty patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 +/- 124 to 1925 +/- 291 kcal/m(2) x day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 +/- 0.8 conventional insulin therapy vs. 6.8 +/- 0.9 mg/kg x min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 +/- 1.3 intensive insulin therapy versus 4.8 +/- 0.6 mg/kg x min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 +/- 0.9 vs. 2.5 +/- 0.6 mg/kg x min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 +/- 0.1 to 1.7 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .004; and 0.7 +/- 0.1 to 1.3 +/- 0.1 microm O(2)/CS/mg protein/min for state 4, p < .002), whereas conventional insulin therapy remained at the same level of activity (0.9 +/- 0.1 to 0.8 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .4; 0.6 +/- 0.03 to 0.7 +/- 0.1 microm O(2)/CS/mg protein/min, p = .6). CONCLUSION: Controlling blood glucose levels < or =120 mg/dL using an intensive insulin therapy protocol improves insulin sensitivity and mitochondrial oxidative capacity while decreasing resting energy expenditure in severely burned children.

Insulin resistance, secretion and breakdown are increased 9 months following severe burn injury.

Insulin resistance in the acute burn period has been well described, however, it is unknown if alterations in glucose metabolism persist beyond discharge from the acute injury. To measure the duration of insulin resistance following recovery from the acute burn injury, we performed a prospective cross-sectional study with a standard 2-h oral glucose tolerance test in 46 severely burned children at 6, 9 or 12 months following initial injury. Glucose uptake and insulin secretion were assessed following the glucose load. Results were compared to those previously published in healthy children. At 6 months after burn, the 2-h glucose concentration was significantly (P<0.001) greater than controls, and the area under the curve (AUC) of glucose was significantly higher compared to 12 months and to healthy children (P=0.027 and P<0.001, respectively). The 9-month AUC glucose was higher than controls (P<0.01). The 6-month 2-h insulin was significantly higher than controls, as was the AUC of insulin in all time points post-burn. The AUC of C-peptide was significantly greater at 6 months after injury compared to 9 and 12 months (P<0.01 for both). Increased 2h and AUC glucose and insulin indicate that glucose metabolism is still affected at 6 and 9 months after injury, and coincides with previously documented defects in bone and muscle metabolism at these time points. Insulin breakdown is also still increased in this population. Further study of this population is warranted to determine if specific treatment is needed.

Human mitochondrial oxidative capacity is acutely impaired after burn trauma.

BACKGROUND: Mitochondrial proteins and genes are damaged after burn injury in animals and are assessed in human burn patients in this study. METHODS: The rates of maximal muscle mitochondrial oxidative capacity (adenosine triphosphate production) and uncoupled oxidation (heat production) for both palmitate and pyruvate were measured in muscle biopsies from 40 children sustaining burns on more than 40% of their body surface area and from 13 healthy children controls. RESULTS: Maximal mitochondrial oxidation of pyruvate and palmitate were reduced in burn patients compared with controls (4.0 +/- .2:1.9 +/- .1 micromol O2/citrate synthase activity/mg protein/min pyruvate; control:burn; P < .001 and 3.0 +/- .1: .9 +/- .03 micromol O2/citrate synthase activity/mg protein/min palmityl CoA; control:burn; P = .003). Uncoupled oxidation was the same between groups. CONCLUSIONS: The maximal coupled mitochondrial oxidative capacity is severely impaired after burn injury, although there are no alterations in the rate of uncoupled oxidative capacity. It may be that the ratio of these indicates that a larger portion of energy production in trauma patients is wasted through uncoupling, rather than used for healing.

Insulin sensitivity is related to fat oxidation and protein kinase C activity in children with acute burn injury.

Impaired fatty acid oxidation occurs with type 2 diabetes and is associated with accumulations of intracellular lipids, which may increase diacylglycerol (DAG), stimulate protein kinase C activity, and inactivate insulin signaling. Glucose and fat metabolism are altered in burn patients, but have never been related to intracellular lipids or insulin signaling. Thirty children sustaining >40% total body surface area burns were studied acutely with glucose and palmitate tracer infusions and a hyper-insulinemic euglycemic clamp. Muscle triglyceride, DAG, fatty acyl CoA, and insulin signaling were measured. Liver and muscle triglyceride levels were measured with magnetic resonance spectroscopy. Muscle samples from healthy children were controls for DAG concentrations. Insulin sensitivity was reduced and correlated with whole body palmitate beta-oxidation (P = .004). Muscle insulin signaling was not stimulated by hyper-insulinemia. Tissue triglyceride concentrations and activated protein kinase C-beta were elevated, whereas the concentration of DAG was similar to the controls. Free fatty acid profiles of muscle triglyceride did not match DAG. Insulin resistance following burn injury is accompanied by decreased insulin signaling and increased protein kinase C-beta activation. The best metabolic predictor of insulin resistance in burned patients was palmitate oxidation.

Recovery of labeled CO2 from acetate in severely burned children.

The purpose of this study was to determine the fractional recovery rate of labeled CO(2) in the breath of severely burned children. This information is needed to perform tracer studies of substrate oxidation using carbon-labeled fatty acids. Nine children, ages 4-14 yr with massive burns participated in the study. All experiments were performed 7 days post burn after an overnight fast. A primed (60 micromol/kg), constant (2.0 micromol.kg(-1).min(-1)) infusion of [1,2-(13)C]acetate was given during a 4-h basal period and during a 4-h hyperinsulinemic euglycemic clamp. A priming dose (150 micromol/kg) of NaH(13)CO(3) was given at the beginning of the study. Breath samples were collected every 10 min during the last 40 min of each period. Indirect calorimetry was performed during the last 30 min of each period. The isotopic enrichment of (13)CO(2) was determined by isotope ratio-mass spectrometry, and total CO(2) excretion was measured by indirect calorimetry. The fractional recovery of acetate label was 0.89 +/- 0.05 and 0.88 +/- 0.04 during the basal state and clamp, respectively. We conclude that the fractional recovery of labeled acetate in severely burned children is approximately three times the recovery of a nonburned adult and similar to the value in exercising adults. The high recovery rate reflects the rapid turnover of the TCA cycle in burned children relative to the rate of exchange reactions. Minimal correction of expired CO(2) data is needed in this circumstance to quantify fatty acid oxidation using (13)C-labeled fatty acids.

PPAR-alpha agonism improves whole body and muscle mitochondrial fat oxidation, but does not alter intracellular fat concentrations in burn trauma children in a randomized controlled trial.

BACKGROUND: Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat beta-oxidation. It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma. METHODS: A double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-alpha agonist treatment. RESULTS: Insulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-alpha agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-alpha treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-theta activation during hyper-insulinemia decreased significantly following PPAR-alpha treatment. CONCLUSION: PPAR-alpha agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.