PROTECTIVE EFFECTS OF HUMANIN-G IN HEMORRHAGIC SHOCK IN FEMALE MICE VIA AMPKα1-INDEPENDENT MECHANISMS.

ABSTRACT: Introduction: Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. We previously showed that the α1 subunit of AMP-activated protein kinase (AMPK), a crucial regulator of mitochondrial function, exerts a protective role in hemorrhagic shock. Humanin is a mitochondrial peptide with cytoprotective properties against cellular stress. Here, we investigated whether AMPKα1 influences systemic levels of endogenous humanin in hemorrhagic shock and whether treatment with the synthetic analog humanin-G affords beneficial effects. Methods: AMPKα1 wild-type (WT) and knockout (KO) female mice were subjected to hemorrhagic shock followed by resuscitation with blood and lactated Ringer's solution. In short-term studies, mice were treated with humanin-G or vehicle and sacrificed at 3 h after resuscitation; in survival studies, mice were treated with PEGylated humanin-G and monitored for 7 days. Results: Compared with the vehicle WT group, KO mice exhibited severe hypotension, cardiac mitochondrial damage, and higher plasma levels of Th17 cytokines but had similar lung injury and similar plasma elevation of endogenous humanin. Treatment with humanin-G improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice, without affecting systemic cytokine or humanin levels. Humanin-G also ameliorated cardiac mitochondrial damage and increased adenosine triphosphate levels in KO mice. Beneficial effects of humanin-G were associated with lung cytoplasmic and nuclear activation of the signal transducer and activator of transcription-3 (STAT3) in AMPKα1-independent manner with marginal or no effects on mitochondrial STAT3 and complex I subunit GRIM-19. Conclusions: Our data indicate that circulating levels of humanin increase during hemorrhagic shock in AMPKα1-independent fashion as a defense mechanism to counteract metabolic derangement and that administration of humanin-G affords beneficial effects through STAT3 activation even in the absence of a functional AMPKα1.

Use of thromboelastography in children on extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) profoundly impacts inflammatory and coagulation pathways, and strict monitoring is essential to guide therapeutic anticoagulation. Thromboelastography (TEG) offers a global evaluation of whole blood hemostatic system components and may be a valuable measurement of hemostatic function in these patients. There is a paucity of data correlating TEG parameters with standard measures of coagulation in heparinized pediatric patients. METHODS: Children on ECMO during a 10-year period were retrospectively reviewed. Standard measures of coagulation were matched to TEGs drawn within 30 min of each other. RESULTS: Out of 296 unique patients with 331 ECMO runs, 74.3% (n = 246) had at least one set of matched laboratory samples for a total of 2502 matched samples. The aPTT correlated with R-time (p<0.001). Platelets and fibrinogen correlated with α-angle (p<0.001). Fibrinogen (p<0.001) and platelets (p<0.001) were each associated with maximum amplitude (MA). 158 (47.7%) patients had at least one bleeding complication, and 100 (30.2%) had at least one thrombotic complication. Interestingly, a decreasing MA was associated with increased thrombotic complications (p<0.001). DISCUSSION: TEG correlated well with traditional measures of hemostasis in pediatric ECMO patients. However, there was not a clear benefit of the TEG over these other measures LEVEL OF EVIDENCE: III.

Effect of intraoperative fluid type on postoperative systemic inflammatory response and end organ dysfunction following total pancreatectomy with islet autotransplantation in children.

PURPOSE: To evaluate the effect of intraoperative fluid type [half normal saline (0.45NS) or lactated Ringer's solution (LR)] on the risk of systemic inflammatory response syndrome (SIRS) and acute kidney injury after total pancreatectomy with islet autotransplantation in children. METHODS: Retrospective review where demographics, operative details, systemic inflammatory response, and evaluation for end organ dysfunction over the first 5 postoperative days was obtained. Mixed effects Poisson regression compared risk of SIRS and acute kidney injury by intraoperative fluid type. RESULTS: Forty three patients were included with no difference in demographic characteristics between groups. SIRS was observed in 95, 77, and 71% over post operative days 1, 3, and 5. Intraoperative fluid type was found to not be associated with postoperative SIRS (RR: 0.91, p = 0.23). However, female sex (RR: 1.30, p < 0.01), increased BMI (RR: 1.08, p < 0.01), and longer operative time (RR: 1.07, p < 0.01) were found to be factors that are associated with increased risk of postoperative SIRS. Intraoperative 0.45NS use was associated with increased acute kidney injury compared to LR on postoperative day 1 (52% vs 0%, p < 0.01), but not on postoperative days 3 or 5. CONCLUSION: Intraoperative fluid type (0.45NS vs LR) does not increase the risk of postoperative SIRS in children after TPIAT. Predictive factors that are associated with an increased risk of eliciting postoperative SIRS includes female sex, increased BMI, and longer operative times. LEVEL OF EVIDENCE: III.

Risk profile of subcutaneous port placement in small children.

BACKGROUND/PURPOSE: Long-term central venous access is a safe and common procedure in children. However, complications with devices are a reality. Smaller children are thought to have a higher rate of complication after port placement, and some surgeons avoid placing ports with an arbitrary weight cutoff out of concern for surgical site morbidity. METHODS: We performed a multi-institutional retrospective review of 500 patients less than 5 years of age undergoing port placement at three large volume children's hospitals from 2014 to 2018. Patients were divided by weight greater than or less than 10 kg at the time of insertion. Statistical analysis was performed to evaluate for differences in outcomes between the two groups. RESULTS: The majority of ports were placed for chemotherapy access (71.8%). Other indications included long-term infusions (18.8%) and difficult chronic IV access (9.4%). Of the 500 charts reviewed, 110 (22%) experienced some documented complication (28.9% <10 kg, 20.6% >10 kg, p = 0.096). There were no differences between the two groups in terms of the type or timing of complications. Overall, 16.3% of ports required removal prior to the end of therapy owing to a complication. Complication rate per day with the port in place was not different between the two groups (<10 kg: 0.68 complications/1000 port-days vs >10 kg 0.44 complications/1000 port-days, p = 0.068). CONCLUSION: Weight less than 10 kg was not associated with a significantly higher incidence of any type of port complication in our cohort. This suggests that concern for complications should not exclude children less than 10 kg from port placement. TYPE OF STUDY: Multi-institutional retrospective review. LEVEL OF EVIDENCE: Level III.

Standardizing Preoperative Evaluation for Pediatric Central Venous Access: A Care Algorithm to Improve Safety.

Central vascular access device (CVAD) placement is a common procedure in children. When selecting a CVAD, available evidence and specified indications should be used to choose the device that best supports the patient's treatment and carries the lowest risks. A multidisciplinary team developed a care algorithm to standardize preoperative screening before pediatric CVAD placement, with 3 major parts: CVAD selection, patient risk stratification, and preoperative evaluation. Using a stepwise approach of provider education and incorporation into the electronic health record, the team achieved 82% stratification among inpatients. The team's algorithm integrates the existing literature and recommendations for safe and effective CVAD placement.

Outcomes in the giant omphalocele population: A single center comprehensive experience.

BACKGROUND/PURPOSE: Morbidity and mortality in the giant omphalocele population is complicated by large abdominal wall defects, physiologic aberrancies, and congenital anomalies. We hypothesized different anomalies and treatment types would affect outcomes. METHODS: A 2009-2018 retrospective chart review of giant omphaloceles was performed. Exclusions included cloacal exstrophy, transfer after 3 weeks, surgery prior to transfer, conjoined twins, or not yet achieving fascial closure. Thirty-five patients met criteria and mortality and operative morbidity categorized them into favorable (n = 20) or unfavorable (n = 15) outcomes. Odds ratios analyzed potential predictors. Survivors were stratified into staged (n = 11), delayed (n = 8), and primary closure (n = 6) for subgroup analysis. RESULTS: Unfavorable outcomes were associated with other major congenital anomalies, sac rupture, and major cardiac anomalies, but had significantly lower odds with increasing gestational age (p = 0.03) and birth weight (p < 0.001). In survivors, the primary group was younger at repair (p < 0.001) and had shorter length of stay (hospital p = 0.02, neonatal intensive care unit p = 0.005). There was no significant difference for sepsis, ventilator days, return to the operating room, or ventral hernia. CONCLUSIONS: Predictions of overall outcomes in the giant omphalocele population require analysis of multiple variables. Our findings demonstrated increased odds of unfavorable outcomes in major cardiac anomalies, pulmonary hypertension, genetic diagnosis, other major anomalies, polyhydramnios, postnatal sac rupture, increasing omphalocele sac diameter, lower O/E TLV, lower gestational age at birth, lower birth weight, and repair other than primary. In those surviving to repair, surgical outcomes analyses demonstrated an earlier age of repair and a shorter length of stay for those patients able to be closed primarily; however further research is necessary to determine overall superiority between operative treatment types. LEVEL OF EVIDENCE: Level III.

Withdrawal of Antithrombotic Agents and the Risk of Stroke.

BACKGROUND AND PURPOSE: Antithrombotic medications are effective for ischemic stroke prevention, but stoppage of these medications is associated with an increased risk of thromboembolism. The frequency of antithrombotic withdrawal in the general population is unknown. METHODS: We conducted a random phone sample of 2036 households in the Greater Cincinnati metropolitan area, representative of the stroke population by age, sex, and race, to determine the frequency of antithrombotic medication use and stoppage by physicians for medically indicated procedures. RESULTS: Sixty-two percent of survey respondents reported that they were on an antithrombotic medication. Ten percent of participants reported that they had stopped taking their medication within the past 60 days for a medically indicated intervention. Of those who stopped taking the medication, it was more common for persons taking an anticoagulant to stop their medication (20%) than those taking an antiplatelet agent (9%). Colonoscopies and orthopedic surgeries were the most common reasons for withdrawal of antiplatelet agents, whereas orthopedic and vascular surgeries were the most common reason for withdrawal of anticoagulants. CONCLUSIONS: Recommended discontinuation of antithrombotic medication for surgical or diagnostic procedures is common practice for persons in the community representative of a stroke population. Because stoppage of these medications is associated with an increased risk of thromboembolic stroke, further clinical trials are needed to determine best management practices in this setting.