Practice Style Variation in Medicaid and Non-Medicaid Children With Complex Chronic Conditions Undergoing Surgery.

OBJECTIVES: With differential payment between Medicaid and Non-Medicaid services, we asked whether style-of-practice differs between similar Medicaid and Non-Medicaid children with complex chronic conditions (CCCs) undergoing surgery. SUMMARY OF BACKGROUND DATA: Surgery in children with CCCs accounts for a disproportionately large percentage of resource utilization at major children's hospitals. METHODS: A matched cohort design, studying 23,582 pairs of children with CCCs undergoing surgery (Medicaid matched to Non-Medicaid within the same hospital) from 2009 to 2013 in 41 Children's Hospitals. Patients were matched on age, sex, principal procedure, CCCs, and other characteristics. RESULTS: Median cost in Medicaid patients was $21,547 versus $20,527 in Non-Medicaid patients (5.0% higher, P < 0.001). Median paired difference in cost (Medicaid minus Non-Medicaid) was $320 [95% confidence interval (CI): $208, $445], (1.6% higher, P < 0.001). 90th percentile costs were $133,640 versus $127,523, (4.8% higher, P < 0.001). Mean paired difference in length of stay (LOS) was 0.50 days (95% CI: 0.36, 0.65), (P < 0.001). ICU utilization was 2.8% higher (36.7% vs 35.7%, P < 0.001). Finally, in-hospital mortality pooled across all pairs was higher in Medicaid patients (0.38% vs 0.22%, P = 0.002). After adjusting for multiple testing, no individual hospital displayed significant differences in cost between groups, only 1 hospital displayed significant differences in LOS and 1 in ICU utilization. CONCLUSIONS: Treatment style differences between Medicaid and Non-Medicaid children were small, suggesting little disparity with in-hospital surgical care for patients with CCCs operated on within Children's Hospitals. However, in-hospital mortality, although rare, was slightly higher in Medicaid patients and merits further investigation.

Outcomes, ICU Use, and Length of Stay in Chronically Ill Black and White Children on Medicaid and Hospitalized for Surgery.

BACKGROUND: With increasing Medicaid coverage, it has become especially important to determine whether racial differences exist within the Medicaid system. We asked whether disparities exist in hospital practice and patient outcomes between matched black and white Medicaid children with chronic conditions undergoing surgery. STUDY DESIGN: We conducted a matched cohort study, matching 6,398 pairs within states on detailed patient characteristics using data from 25 states contributing adequate Medicaid Analytic eXtract claims for admissions of children with chronic conditions undergoing the same surgical procedures between January 1, 2009 and November 30, 2010 for ages 1 to 18 years. RESULTS: The black patient 30-day revisit rate was 19.3% vs 19.8% in matched white patients (p = 0.61), 30-day readmission rates were 7.0% vs 6.9% (p = 0.43), and 30-day mortality rates were 0.38% vs 0.19% (p = 0.06), respectively. A higher percentage of black patients exceeded their own state's individual median length of stay (44.0% vs 39.6%; p < 0.001) and median ICU length of stay (25.9% vs 23.8%; p < 0.001). Intensive care unit use was higher in black patients (25.9% vs 23.8%; p < 0.001). After adjusting for multiple testing, only 2 states were found to differ significantly by race (New York for length of stay and New Jersey for ICU use). CONCLUSIONS: We did not observe disparities in 30-day revisits and readmissions for chronically ill children in Medicaid undergoing surgery, and only slight differences in length of stay, ICU length of stay, and use of the ICU, where blacks displayed somewhat elevated rates compared with white controls.

A pilot and feasibility study of the plasma and tissue pharmacokinetics of cefazolin in an immature porcine model of pediatric cardiac surgery.

BACKGROUND: Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. AIM: The purposes of this study were to determine the plasma and tissue concentrations with standard of care, perioperative cefazolin dosing in an immature porcine model of pediatric cardiac surgery, and to determine the feasibility of this model. METHODS: Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB + DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of the skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, noncompartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. RESULTS: Following the first intravenous dose, maximal cefazolin concentrations in the subcutaneous tissue and skeletal muscle were similar between groups with peak tissue concentrations 15-30 min after administration. After the second cefazolin dose given with the initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle- and subcutaneous-unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed subcutaneous and skeletal muscle concentrations of cefazolin >16 µg·ml(-1) while this percentage was 78-79% for the CPB + DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP + DHCA (P = 0.03). CONCLUSIONS: The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of the cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.

Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet.

Ischemic brain injury continues to be of major concern in patients undergoing cardiopulmonary bypass (CPB) surgery for congenital heart disease. Striatum and hippocampus are particularly vulnerable to injury during these processes. Our hypothesis is that the neuronal injury resulting from CPB and the associated circulatory arrest can be at least partly ameliorated by pre-treatment with granulocyte colony stimulating factor (G-CSF). Fourteen male newborn piglets were assigned to three groups: deep hypothermic circulatory arrest (DHCA), DHCA with G-CSF, and sham-operated. The first two groups were placed on CPB, cooled to 18 °C, subjected to 60 min of DHCA, re-warmed and recovered for 8-9 h. At the end of experiment, the brains were perfused, fixed and cut into 10 µm transverse sections. Apoptotic cells were visualized by in situ DNA fragmentation assay (TUNEL), with the density of injured cells expressed as a mean number ± SD per mm(2). The number of injured cells in the striatum and CA1 and CA3 regions of the hippocampus increased significantly following DHCA. In the striatum, the increase was from 0.46 ± 0.37 to 3.67 ± 1.57 (p = 0.002); in the CA1, from 0.11 ± 0.19 to 5.16 ± 1.57 (p = 0.001), and in the CA3, from 0.28 ± 0.25 to 2.98 ± 1.82 (p = 0.040). Injection of G-CSF prior to bypass significantly reduced the number of injured cells in the striatum and CA1 region, by 51 and 37 %, respectively. In the CA3 region, injured cell density did not differ between the G-CSF and control group. In a model of hypoxic brain insult associated with CPB, G-CSF significantly reduces neuronal injury in brain regions important for cognitive functions, suggesting it can significantly improve neurological outcomes from procedures requiring DHCA.

Effect of granulocyte-colony stimulating factor on expression of selected proteins involved in regulation of apoptosis in the brain of newborn piglets after cardiopulmonary bypass and deep hypothermic circulatory arrest.

OBJECTIVE: The study objective was to investigate the effect of granulocyte-colony stimulating factor on the expression of proteins that regulate apoptosis in newborn piglet brain after cardiopulmonary bypass and deep hypothermic circulatory arrest. METHODS: The newborn piglets were assigned to 3 groups: (1) deep hypothermic circulatory arrest (30 minutes of deep hypothermic circulatory arrest, 1 hour of low-flow cardiopulmonary bypass); (2) deep hypothermic circulatory arrest with prior injection of granulocyte-colony stimulating factor (17 µg/kg 2 hours before cardiopulmonary bypass); and (3) sham-operated. After 2 hours of post-bypass recovery, the frontal cortex, striatum, and hippocampus were dissected. The expression of proteins was measured by gel electrophoresis or protein arrays. Data are presented in arbitrary units. Statistical analysis was performed using 1-way analysis of variance. RESULTS: In the frontal cortex, only Fas ligand expression was significantly lower in the granulocyte-colony stimulating factor group when compared with the deep hypothermic circulatory arrest group. In the hippocampus, granulocyte-colony stimulating factor increased Bcl-2 (54.3 ± 6.4 vs 32.3 ± 2.2, P = .001) and serine/threonine-specific protein kinase (141.4 ± 19 vs 95.9 ± 21.1, P = .047) when compared with deep hypothermic circulatory arrest group. Caspase-3, Bax, Fas, Fas ligand, death receptor 6, and Janus protein tyrosine kinase 2 levels were unchanged. The Bcl-2/Bax ratio was 0.33 for deep hypothermic circulatory arrest group and 0.93 for the granulocyte-colony stimulating factor group (P = .02). In the striatum, when compared with the deep hypothermic circulatory arrest group, the granulocyte-colony stimulating factor group had higher levels of Bcl-2 (50.3 ± 7.4 vs 31.8 ± 3.8, P = .01), serine/threonine-specific protein kinase (132.7 ± 12.3 vs 14 ± 1.34, P = 2.3 × 10(6)), and Janus protein tyrosine kinase 2 (126 ± 17.4 vs 77.9 ± 13.6, P = .011), and lower levels of caspase-3 (12.8 ± 5.0 vs 32.2 ± 11.5, P = .033), Fas (390 ± 31 vs 581 ± 74, P = .038), Fas ligand (20.5 ± 11.5 vs 57.8 ± 15.6, P = .04), and death receptor 6 (57.4 ± 4.4 vs 108.8 ± 13.4, P = .007). The Bcl-2/Bax ratio was 0.25 for deep hypothermic circulatory arrest and 0.44 for the granulocyte-colony stimulating factor groups (P = .046). CONCLUSIONS: In the piglet model of hypoxic brain injury, granulocyte-colony stimulating factor decreases proapoptotic signaling, particularly in the striatum.

The effect of hypothermia on neuronal viability following cardiopulmonary bypass and circulatory arrest in newborn piglets.

OBJECTIVE: To determine the effect of recovery with mild hypothermia after cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on the activity of selected key proteins involved in initiation (Bax, Caspase-3) or inhibition of apoptotic injury (Bcl-2, increased ratio Bcl-2/Bax) in the brain of newborn piglets. METHODS: The piglets were placed on CPB, cooled with pH-stat management to 18 degrees C, subjected to 30 min of DHCA followed by 1h of low flow at 20 ml/kg/min, rewarmed to 37 degrees C (normothermia) or to 33 degrees C (hypothermia), separated from CPB, and monitored for 6h. Expression of above proteins was measured in striatum, hippocampus and frontal cortex by Western blots. The results are mean for six experiments+/-SEM. RESULTS: There were no significant differences in Bcl-2 level between normothermic and hypothermic groups. The Bax levels in normothermic group in cortex, hippocampus and striatum were 94+/-9, 136+/-22 and 125+/-34 and decreased in the hypothermic group to 59+/-17 (p=0.028), 70+/-6 (p=0.002) and 48+/-8 (p=0.01). In cortex, hippocampus and striatum Bcl-2/Bax ratio increased from 1.23, 0.79 and 0.88 in normothermia to 1.96, 1.28 and 2.92 in hypothermia. Expression of Caspase-3 was 245+/-39, 202+/-74 and 244+/-31 in cortex, hippocampus and striatum in the normothermic group and this decreased to 146+/-24 (p=0.018), 44+/-16 (p=7 x 10(-7)) and 81+/-16 (p=0.01) in the hypothermic group. CONCLUSION: In neonatal piglet model of cardiopulmonary bypass with circulatory arrest, mild hypothermia during post bypass recovery provides significant protection from cellular apoptosis, as indicated by lower expression of Bax and Caspase-3 and an increased Bcl-2/Bax ratio. The biggest protection was observed in striatum probably by decreasing of neurotoxicity of striatal dopamine.

Resuscitation with 100%, compared with 21%, oxygen following brief, repeated periods of apnea can protect vulnerable neonatal brain regions from apoptotic injury.

PURPOSE: To determine the effect of repeated intermittent apnea and resuscitation with 100% vs. 21% oxygen enriched gas on levels of key regulatory proteins contributing to cell death (Bax, Caspase-3) or protecting neurons from hypoxic/ischemic injury (Bcl-2, p-Akt, p-CREB). METHODS: The anaesthetized, mechanically ventilated newborn piglets underwent 10 episodes of apnea with resuscitation either with 100% or with 21% oxygen. Following 6h recovery the animals were sacrificed painlessly, the brain dissected out and used to determine levels of Bcl-2, Bax, Caspase-3, p-Akt and p-CREB in the striatum, frontal cortex, midbrain and hippocampus were studied. RESULTS: In hippocampus and striatum, Bcl-2 expression was higher with 100% vs. 21% group (173+/-29% vs. 121+/-31%, p<0.05 and 189+/-10% vs. 117+/-47%, p<0.01, respectively) whereas the Bax expression was lower (88+/-3% vs. 100+/-9%, p<0.05 and 117+/-5% vs. 133+/-10%, p<0.05, respectively). Expression of Caspase-3 in the striatum, was lower with 100% vs. 21% group (197+/-35% vs. 263+/-33%, p<0.05, respectively) but not different in the hippocampus. p-Akt expression was higher with 100% vs. 21% oxygen in the hippocampus and striatum (225+/-44% vs. 108+/-35%, p<0.01 and 215+/-12% vs. 164+/-16%, p<0.01, respectively). The p-CREB expression was higher with 100% vs. 21% oxygen resuscitation in the hippocampus (217+/-41% vs. 132+/-30%, p<0.01) with no changes in striatum. Much smaller or insignificant differences between 100% vs. 21% oxygen groups were observed in the frontal cortex and midbrain, respectively. CONCLUSION: In neonatal piglet model of intermittent apnea, selectively vulnerable regions of brain (striatum and hippocampus) are better protected from apoptotic injury when resuscitation was conducted with 100%, rather than 21%, oxygen.

Response of brain oxygenation and metabolism to deep hypothermic circulatory arrest in newborn piglets: comparison of pH-stat and alpha-stat strategies.

BACKGROUND: To determine the effect of pH-stat as compared with alpha-stat management on brain oxygenation, level of striatal extracellular dopamine, phosphorylation, and levels of protein kinase B (Akt) and cyclic adenosine 3', 5'-monophosphate response element-binding protein (CREB), and levels of extracellular signal-regulated kinase (ERK)1/2, Bcl-2, and Bax in a piglet model of deep hypothermic circulatory arrest (DHCA). METHODS: The piglets were placed on cardiopulmonary bypass (CPB), cooled with pH-stat or alpha-stat to 18 degrees C, subjected to 90 minutes of DHCA, rewarmed, weaned from CPB, and maintained for two hours recovery. The cortical oxygen was measured by: quenching of phosphorescence; dopamine by microdialysis; phosphorylation of CREB (p-CREB), ERK (p-ERK) 1/2, Akt (p-Akt), and level of Bcl-2, Bax by Western blots. RESULTS: Oxygen pressure histograms for the microvasculature of the cortex show substantially higher oxygen levels during cooling and during the oxygen depletion period after cardiac arrest (up to 15 minutes) when using pH-stat compared with alpha-stat management. Significant increases in dopamine occurred at 45 minutes and 60 minutes of DHCA in the alpha-stat and pH-stat groups, respectively. The p-CREB and p-Akt in the pH-stat group were significantly higher than in the alpha-stat group (140 +/- 9%, p < 0.05 and 125 +/- 6%, p < 0.05, respectively). There was no significant difference in p-ERK1/2 and Bax. The Bcl-2 increased in the pH-stat group to 121 +/- 4% (p < 0.05) compared with the alpha-stat group. The ratio Bcl-2:Bax increased in the pH-stat group compared with the alpha-stat group. CONCLUSIONS: The increase in p-CREB, p-Akt, Bcl-2, Bcl-2/Bax, and delay in increase of dopamine indicated that pH-stat, in the piglet model, prolongs "safe" time of DHCA and provides some brain protection against ischemic injury.

Brain oxygen and metabolism is dependent on the rate of low-flow cardiopulmonary bypass following circulatory arrest in newborn piglets.

OBJECTIVE: To determine the optimum rate of low-flow hypothermic cardiopulmonary bypass (LF), following circulatory arrest (DHCA) on brain oxygenation (bO(2)), extracellular dopamine (DA), phosphorylation of select neuroregulatory proteins responsible for neuronal injury, and survival following ischemic brain injury: CREB, Erk1/2, Akt, Bcl-2, and Bax. METHODS: The piglets were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. They were then subjected to 30 min of DHCA followed by 1h of LF at 20, 50, or 80 ml/(kg/min), rewarmed, separated from CPB, and maintained for 2h. The bO(2) was measured by quenching of phosphorescence; DA by microdialysis; phosphorylation of CREB, ERK1/2, Akt, Bcl-2, and Bax by Western blots. The results are means+/-SD for seven experiments. RESULTS: Pre-bypass bO(2) was 47.4+/-4.2 mmHg and decreased to 1.9+/-0.8 mmHg during DHCA. At the end of LF at 20, 50, and 80 ml/(kg/min), bO(2) was 11.8+/-1.6, 26+/-1.8, and 33.9+/-2.6 mmHg, respectively. The DA increased 510-fold relative to control (p<0.001) by 15 min of LF-20 with maximum increase occurring at 45 min. With LF-50, increase in DA was not statistically significant and no increase was observed when LF-80 was used. Bcl-2 immunoreactivity increased after LF-50 and LF-80 (140+/-14.5%, p<0.05 and 202+/-34%, p<0.05, respectively). Neither flow increased Bax immunoreactivity. The ratio of Bcl-2/Bax, pCREB, pAkt, pErk increased significantly with increasing the flow rate of LF. CONCLUSIONS: The protective effect of LF following DHCA on brain metabolism is dependent on the flow rate. Flow-dependent increase in pCREB, pErk1/2, pAkt, increase in Bcl-2/Bax, and decrease in DA indicated that to minimize DHCA-dependent neuronal injury, LF flow should be above 50 ml/(kg/min).

Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction.

We performed a blinded, randomized pharmacokinetic study of milrinone in 16 neonates with hypoplastic left heart undergoing stage I reconstruction to determine the impact of cardiopulmonary bypass and modified ultrafiltration on drug disposition and to define the drug exposure during a continuous IV infusion of drug postoperatively. Neonates received an initial dose of either a 100 or 250 microg/kg of milrinone into the cardiopulmonary bypass circuit at the start of rewarming. Postoperatively, milrinone was infused to clinical needs. A mixed-effect modeling approach was used to characterize milrinone pharmacokinetics during cardiopulmonary bypass, modified ultrafiltration, and postoperatively using the NONMEM algorithm. All patients in this study demonstrated a modified ultrafiltration concentrating effect that occurred despite a modified ultrafiltration drug clearance of 3.3 mL x kg(-1) x min(-1). The infants in this study demonstrated an impaired renal clearance during the immediate postoperative period. A constant infusion of 0.5 microg x kg(-1) x min(-1) resulted in drug accumulation during the initial 12 h of drug administration. Postoperatively, milrinone clearance was significantly impaired (0.4 mL x kg(-1) x min(-1)), improved by the 12th postoperative hour, and approached steady-state clearance (2.6 mL x kg(-1) x min(-1)) by postoperative day 4. In the postoperative setting of markedly impaired renal function, an infusion rate of 0.2 microg x kg(-1) x min(-1) should be considered.

Hyperkalemic cardiac arrest after cardiopulmonary bypass in a child with unsuspected duchenne muscular dystrophy.

Adverse reactions to volatile anesthetics and depolarizing muscle relaxants can occur in patients with Duchenne muscular dystrophy (DMD) resulting in acute rhabdomyolysis and hyperkalemia. We report a case of hyperkalemic cardiac arrest after cardiac surgery using cardiopulmonary bypass in a child with unsuspected DMD. Early diagnosis and management of hyperkalemia resulted in a successful outcome. Genetic testing confirmed the diagnosis of DMD. We recommend a thorough preoperative investigation, including creatine kinase estimation, in children with a history of unexplained motor delay.

A liberalized fasting guideline for formula-fed infants does not increase average gastric fluid volume before elective surgery.

UNLABELLED: Recommended preoperative fasting intervals for infant formula vary from 4 to 8 h. We conducted a prospective, randomized, observer-blinded trial of 97 ASA physical status I and II infants scheduled for elective surgery to determine whether average gastric fluid volume (GFV) recovered from infants formula-fasted for 4 h (liberalized fast, Group L) differed from that recovered from infants allowed clear liquids up until 2 h, but fasted 8 h for formula and solids (traditional fast, Group T). In Group L, 31 of 39 subjects followed protocol and ingested formula 4-6 h before surgery. In Group T, 36 of 58 subjects followed protocol, taking clear liquids 2-5 h before the induction of anesthesia. Thirty subjects had prolonged fasts and were included only in a secondary intent-to-treat analysis. Respective mean age (5.7 +/- 2.3 versus 6.4 +/- 2.4 mo; range, 0.7-10.5 mo), weight (7.5 +/- 1.8 versus 7.5 +/- 1.1 kg), and volume of last feed (4.9 +/- 2.2 versus 4.0 +/- 2.3 oz.) did not vary between Groups L and T. GFV (L: 0.19 +/- 0.38 versus T: 0.16 +/- 0.30 mL/kg) and gastric fluid pH (L: 2.5 +/- 0.5 versus T: 2.9 +/- 1.3) did not vary. For all subjects, GFV (mL/kg) increased with age (Spearman correlation coefficient = +0.23, P = 0.03). Infant irritability and hunger and parent satisfaction were similar between groups. We conclude that average GFV after either a 4- to 6-h fast for infant formula or 2-h fast after clear liquids is small and not significantly different between groups. On the basis of these findings, clinicians may consider liberalizing formula feedings to 4 h before surgery in selected infants. IMPLICATIONS: Healthy infants aged < or =10.5 mo may drink formula up to 4 h before surgery without increasing gastric fluid volume compared with infants allowed clear liquids up to 2 h and formula 8 h before surgery.

Effect of perfusion flow rate on tissue oxygenation in newborn piglets during cardiopulmonary bypass.

BACKGROUND: Our knowledge of the best perfusion flow rate to use during cardiopulmonary bypass (CPB) in order to maintain tissue oxygenation remains incomplete. The present study examined the effects of perfusion flow rate and patent ductus arteriosus (PDA) during normothermic CPB on oxygenation in several organ tissues of newborn piglets. METHODS: The experiments were performed on 12 newborn piglets: 6 with PDA ligation (PDA-L), and 6 without PDA ligation (PDA-NL). CPB was performed through the chest at 37 degrees C. During CPB, the flow rate was changed at 15-minute intervals, ranging from 100 to 250 ml/kg/min. Tissue oxygenation was measured by quenching of phosphorescence. RESULTS: For the PDA-L group, oxygen in the brain did not change significantly with changes in flow rate. In contrast, for the PDA-NL group, oxygen was dependent upon the flow rate. Statistically significant decreases in cortical oxygen were observed with flow rates below 175 ml/kg/min. Within the myocardium, liver, and intestine, there were no significant differences in the oxygen levels between the PDA-L and PDA-NL groups. In these tissues, the oxygen decreased significantly as the flow rate decreased below 150 ml/kg/min, 125 ml/kg/min, and 175 ml/kg/min, respectively. Oxygen pressure in skeletal muscle was not dependent on either PDA ligation or flow rate. CONCLUSIONS: In newborn piglets undergoing CPB, the presence of a PDA results in reduced tissue oxygenation to the brain but not to other organs. In general, perfusion flow rates of 175 ml/kg/min or greater are required in order to maintain normal oxygenation of all organs except muscle.