A Consensus-Driven Revision of the Accreditation Council for Graduate Medical Education Case Log System: Pediatric Anesthesiology Fellowship Education.

BACKGROUND: Clinical experiences, quantified by case logs, are an integral part of pediatric anesthesiology fellowship programs. Accreditation of pediatric anesthesiology fellowships by the Accreditation Council of Graduate Medical Education (ACGME) and establishment of case log reporting occurred in 1997 and 2009, respectively. The specialty has evolved since then, but the case log system remains largely unchanged. The Pediatric Anesthesiology Program Directors Association (PAPDA) embarked on the development of an evidence-based case log proposal through the efforts of a case log task force (CLTF). This proposal was part of a larger consensus-building process of the Society for Pediatric Anesthesia (SPA) Task Force for Pediatric Anesthesiology Graduate Medical Education. The primary aim of case log revision was to propose an evidence-based, consensus-driven update to the pediatric anesthesiology case log system. METHODS: This study was executed in 2 phases. The CLTF, composed of 10 program directors representing diverse pediatric anesthesiology fellowship programs across the country, utilized evidence-based literature to develop proposed new categories. After an approval vote by PAPDA membership, this proposal was included in the nationally representative, stakeholder-based Delphi process executed by the SPA Task Force on Graduate Medical Education. Thirty-seven participants engaged in this Delphi process, during which iterative rounds of surveys were used to select elements of the old and newly proposed case logs to create a final revision of categories and minimums for updated case logs. The Delphi methodology was used, with a two-thirds agreement as the threshold for inclusion. RESULTS: Participation in the Delphi process was robust, and consensus was almost completely achieved by round 2 of 3 survey rounds. Participants suggested that total case minimums should increase from 240 to 300 (300-370). Participants agreed (75.86%) that the current case logs targeted the right types of cases, but requirements were too low (82.75%). They also agreed (85.19%) that the case log system and minimums deserved an update, and that this should be used as part of a competency-based assessment in pediatric anesthesia fellowships (96%). Participants supported new categories and provided recommended minimum numbers. CONCLUSIONS: The pediatric anesthesiology case log system continues to have a place in the assessment of fellowship programs, but it requires an update. This Delphi process established broad support for new categories and benchmarked minimums to ensure the robustness of fellowship programs and to better prepare the pediatric anesthesiology workforce of the future for independent clinical practice.

A Consensus-Driven Approach to Redesigning Graduate Medical Education: The Pediatric Anesthesiology Delphi Study.

BACKGROUND: Pediatric anesthesiology fellowship education has necessarily evolved since Accreditation Council for Graduate Medical Education (ACGME) accreditation in 1997. Advancements in perioperative and surgical practices, emerging roles in leadership, increasing mandates by accreditation and certification bodies, and progression toward competency-based education-among other things-have created pressure to enrich the current pediatric anesthesiology training system. The Society for Pediatric Anesthesia (SPA) formed a Task Force for Pediatric Anesthesiology Graduate Medical Education that included key leaders and subject matter experts from the society. A key element of the Task Force's charge was to identify curricular and evaluative enhancements for the fellowship program of the future. METHODS: The Task Force executed a nationally representative, stakeholder-based Delphi process centered around a fundamental theme: "What makes a pediatric anesthesiologist?" to build consensus among a demographically varied and broad group of anesthesiologists within the pediatric anesthesiology community. A total of 37 demographically and geographically varied pediatric anesthesiologists participated in iterative rounds of open- and close-ended survey work between August 2020 and July 2021 to build consensus on the current state, known deficiencies, anticipated needs, and strategies for enhancing national educational offerings and program requirements. RESULTS: Participation was robust, and consensus was almost completely achieved by round 2. This work generated a compelling Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis that suggests more strengths and opportunities in the current Pediatric Anesthesiology Graduate Medical Education program than weaknesses or threats. Stakeholders agreed that while fellows matriculate with some clinical knowledge and procedural gaps, a few clinical gaps exist upon graduation. Stakeholders agreed on 8 nonclinical domains and specific fundamental and foundational knowledge or skills that should be taught to all pediatric anesthesiology fellows regardless of career plans. These domains include (1) patient safety, (2) quality improvement, (3) communication skills, (4) supervision skills, (5) leadership, (6) medical education, (7) research basics, and (8) practice management. They also agreed that a new case log system should be created to better reflect modern pediatric anesthesia practice. Stakeholders further identified the need for the development of standardized and validated formative and summative assessment tools as part of a competency-based system. Finally, stakeholders noted that significant departmental, institutional, and national organizational support will be necessary to implement the specific recommendations. CONCLUSIONS: A Delphi process achieved robust consensus in assessing current training and recommending future directions for pediatric anesthesiology graduate medical education.

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.

Implementation of a pediatric critical care focused bedside ultrasound training program in a large academic PICU.

OBJECTIVES: To determine the feasibility and describe the process of implementing a pediatric critical care bedside ultrasound program in a large academic PICU and to evaluate the impact of bedside ultrasound on clinical management. DESIGN: Retrospective case series, description of program implementation. SETTING: Single-center quaternary noncardiac PICU in a children's hospital. PATIENTS: Consecutive patients from January 22, 2012, to July 22, 2012, with bedside ultrasounds performed and interpreted by pediatric critical care practitioners. INTERVENTIONS: A pediatric critical care bedside ultrasound program consisting of a 2-day immersive course followed by clinical performance with internal quality assurance review was implemented. Studies performed in the PICU following training were documented and reviewed against reference standards including subspecialist-performed ultrasound or clinical response. MEASUREMENTS AND MAIN RESULTS: Seventeen critical care faculties and eight fellows recorded 201 bedside ultrasound studies over 6 months in defined core applications: 57 procedural (28%), 76 hemodynamic (38%), 35 thoracic (17%), and 33 abdominal (16%). A quality assurance review identified 23 studies (16% of all nonprocedural studies) as critical (affected clinical management or gave valuable information). Forty-eight percent of those studies (11/23) were within the hemodynamic core. The proportion of critical studies were not significantly different across the applications (hemodynamic, 11/76 [15%] vs thoracic and abdominal, 12/68 [18%]; p = 0.65). Examples of critical studies include evidence of tamponade secondary to pleural effusions, identification of pulmonary hypertension, hemodynamic assessment before tracheal intubation, recognition of hypovolemia and systemic vascular resistance abnormalities, determination of pneumothorax, location of chest tube and urinary catheter, and differentiation of pleural fluid from pulmonary consolidation. CONCLUSIONS: Implementation of a critical care bedside ultrasound program for critical care providers in a large academic PICU is feasible. Bedside ultrasound evaluation and interpretation by intensivists affected the management of critically ill children.

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.

Effect of deep hypothermic circulatory arrest followed by low-flow cardiopulmonary bypass on brain metabolism in newborn piglets: comparison of pH-stat and α-stat management.

OBJECTIVE: To compare the effects of pH-stat and α-stat management before deep hypothermic circulatory arrest followed by a period of low-flow (two rates) cardiopulmonary bypass on cortical oxygenation and selected regulatory proteins: Bax, Bcl-2, Caspase-3, and phospho-Akt. DESIGN: Piglets were placed on cardiopulmonary bypass, cooled with pH-stat or α-stat management to 18 °C over 30 mins, subjected to 30-min deep hypothermic circulatory arrest and 1-hr low flow at 20 mL/kg/min (LF-20) or 50 mL/kg/min (LF-50), rewarmed to 37 °C, separated from cardiopulmonary bypass, and recovered for 6 hrs. SUBJECTS: Newborn piglets, 2-5 days old, assigned randomly to experimental groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cortical oxygen was measured by oxygen-dependent quenching of phosphorescence; proteins were measured by Western blots. The means from six experiments ± sem are presented as % of α-stat. Significance was determined by Student's t test. For LF-20, cortical oxygenation was similar for α-stat and pH-stat, whereas for LF-50, it was significantly better using pH-stat. For LF-20, the measured proteins were not different except for Bax in the cortex (214 ± 24%, p = .006) and hippocampus (118 ± 6%, p = .024) and Caspase 3 in striatum (126% ± 7%, p = .019). For LF-50, in pH-stat group: In cortex, Bax and Caspase-3 were lower (72 ± 8%, p = .001 and 72 ± 10%, p = .004, respectively) and pAkt was higher (138 ± 12%, p = .049). In hippocampus, Bcl-2 and Bax were not different but pAkt was higher (212 ± 37%, p = .005) and Caspase 3 was lower (84 ± 4%, p = .018). In striatum, Bax and pAkt did not differ, but Bcl-2 increased (146 ± 11%, p = .001) and Caspase-3 decreased (81 ± 11%, p = .042). CONCLUSIONS: In this deep hypothermic circulatory arrest-LF model, when flow was 20 mL/kg/min, there was little difference between α-stat and pH-stat management. However, for LF-50, pH-stat management resulted in better cortical oxygenation during recovery and Bax, Bcl-2, pAk, and Caspase-3 changes were consistent with lesser activation of proapoptotic signaling with pH-stat than with α-stat.

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).

Regulation of brain cell death and survival after cardiopulmonary bypass.

BACKGROUND: This study investigated the effect of low flow cardiopulmonary bypass, circulatory arrest, and selective cerebral perfusion on expression and phosphorylation of selected regulators of cell death and survival in striatum of newborn piglets. METHODS: Animals were assigned to sham operation and three experimental groups. The experimental groups were placed on bypass, cooled to 18 degrees C, and subjected to 90 minutes of deep hypothermic circulatory arrest (DHCA), low-flow cardiopulmonary bypass (LFCPB) at mL/(kg x min), or selective cerebral perfusion (SCP) at 20 mL/(kg x min), followed by rewarming and 2 hours of recovery. The oxygen pressure in the microcirculation of the cortex was measured by quenching of phosphorescence. Levels of phosphorylated and total protein were determined by Western blot analysis. RESULTS: Control oxygen pressure was 55 +/- 9 mm Hg and decreased during DHCA, LFCPB, and SCP to 1.1 +/- 0.6 mm Hg, 9.8 +/- 2.3 mm Hg, and 9.3 +/- 1.9 mm Hg, respectively (p < 0.001). After DHCA, N-terminal of Bcl-2-associated X protein (N-Bax) levels increased (295% +/- 15%, p < 0.01), B-cell leukemia protein (Bcl-2) levels decreased (31% +/- 9%, p < 0.01), and phosphorylation level of protein kinase B (pAkt) and extracellular signal-regulated kinase 1/2 (pERK1/2) did not change. After LFCPB and SCP, N-Bax and Bcl-2 levels were unchanged, pAkt levels increased (367% +/- 122%, p < 0.05 and 337% +/- 47%, p < 0.01, respectively), pERK1 (484% +/- 70% and 501% +/- 255%, respectively; p < 0.01) and pERK2 (569% +/- 128%; p < 0.001 and 494% +/- 162%; p < 0.05, respectively) levels increased, and total ERK2 levels also increased (279% +/- 90% and 153% +/- 44%, respectively, p < 0.05). CONCLUSIONS: Stable levels of Bcl-2 and Bax and the increases in pAkt and pERK1/2 after LFCPB and SCP are likely indicators of improved chances for cell survival.

Brain oxygen and metabolism during circulatory arrest with intermittent brief periods of low-flow cardiopulmonary bypass in newborn piglets.

OBJECTIVE: We performed this study to determine whether brief intermittent periods of low-flow cardiopulmonary bypass during deep hypothermic circulatory arrest would improve cortical metabolic status and prolong the "safe" time of deep hypothermic circulatory arrest. METHODS: After a 2-hour baseline, newborn piglets were placed on cardiopulmonary bypass and cooled to 18 degrees C. The animals were then subjected to 80 minutes of deep hypothermic circulatory arrest interrupted by 5-minute periods of low-flow cardiopulmonary bypass at either 20 mL x kg(-1) x min(-1) (LF-20) or 80 mL x kg(-1) x min(-1) (LF-80) during 20, 40, 60, and 80 minutes of deep hypothermic circulatory arrest. All animals were rewarmed, separated from cardiopulmonary bypass, and maintained for 2 hours (recovery). The oxygen pressure in the cerebral cortex was measured by the quenching of phosphorescence. The extracellular dopamine level in the striatum was determined by microdialysis. Results are means +/- SD. RESULTS: Prebypass oxygen pressure in the cerebral cortex was 65 +/- 7 mm Hg. During the first 20 minutes of deep hypothermic circulatory arrest, cortical oxygen pressure decreased to 1.3 +/- 0.4 mm Hg. Four successive intermittent periods of LF-20 increased cortical oxygen pressure to 6.9 +/- 1.2 mm Hg, 6.6 +/- 1.9 mm Hg, 5.3 +/- 1.6 mm Hg, and 3.1 +/- 1.2 mm Hg. During the intermittent periods of LF-80, cortical oxygen pressure increased to 21.1 +/- 5.3 mm Hg, 20.6 +/- 3.7 mm Hg, 19.5 +/- 3.95 mm Hg, and 20.8 +/- 5.5 mm Hg. A significant increase in extracellular dopamine occurred after 45 minutes of deep hypothermic circulatory arrest alone, whereas in the groups of LF-20 and LF-80, the increase in dopamine did not occur until 52.5 and 60 minutes of deep hypothermic circulatory arrest, respectively. CONCLUSIONS: The protective effect of intermittent periods of low-flow cardiopulmonary bypass during deep hypothermic circulatory arrest is dependent on the flow rate. We observed that a flow rate of 80 mL x kg(-1) x min(-1) improved brain oxygenation and prevented an increase in extracellular dopamine release.