Research Spotlight

Roe, C. R. and H. Brunengraber (2015). “Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years experience.” Mol Genet Metab 116(4): 260-268.

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BACKGROUND: The treatment of long-chain mitochondrial beta-oxidation disorders (LC-FOD) with a low fat-high carbohydrate diet, a diet rich in medium-even-chain triglycerides (MCT), or a combination of both has been associated with high morbidity and mortality for decades. The pathological tableau appears to be caused by energy deficiency resulting from reduced availability of citric acid cycle (CAC) intermediates required for optimal oxidation of acetyl-CoA. This hypothesis was investigated by diet therapy with carnitine and anaplerotic triheptanoin (TH). METHODS: Fifty-two documented LC-FOD patients were studied in this investigation (age range: birth to 51years). Safety monitoring included serial quantitative measurements of routine blood chemistries, blood levels of carnitine and acylcarnitines, and urinary organic acids. RESULTS: The average frequency of serious clinical complications were reduced from ~60% with conventional diet therapy to 10% with TH and carnitine treatment and mortality decreased from ~65% with conventional diet therapy to 3.8%. Carnitine supplementation was uncomplicated. CONCLUSION: The energy deficiency in LC-FOD patients was corrected safely and more effectively with the triheptanoin diet and carnitine supplement than with conventional diet therapy. Safe intervention in neonates and infants will permit earlier intervention following pre-natal diagnosis or diagnosis by expanded newborn screening.

Modrykamien, A. M., L. Killian and R. W. Walters (2016). “Liberal Manipulation of Ventilator Settings and Its Impact on Tracheostomy Rate and Ventilator-Free Days.” Respiratory Care 61(1): 30-35.

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BACKGROUND: The utilization of checklists, bundles, and protocols attempts to provide standardization in the delivery of patient care. Despite important progress obtained in the prevention of hospital-acquired infections, the daily management of mechanical ventilation is still prone to heterogeneity, depending on the number of providers manipulating the ventilator. Whether the number of changes made on ventilator parameters impacts clinical outcomes remains unknown. METHODS: A quality improvement project was designed to assess whether liberal manipulations of ventilator settings affect the rate of tracheostomy and 28 ventilator-free days. Over the course of 7 d, respiratory therapists recorded all ventilator changes in newly ventilated subjects. Ventilator changes were considered as major changes if manipulations included changes in the mode of ventilation. Minor changes included manipulations of settings within the same mode of ventilation. We evaluated whether the number of total and major changes affected clinical outcomes. Logistic regression was used for multivariate analysis. RESULTS: One-hundred seventeen ventilator manipulations were recorded among 54 subjects. Of those 117 ventilator changes, 35% were major manipulations. For every major ventilator manipulation, the odds of requiring tracheostomy increased 4.95 times. Furthermore, for every major ventilator change, there was an 18.6% decrease in 28 ventilator-free days. These associations were found after adjustments by APACHE (Acute Physiology and Chronic Health Evaluation) II score, body mass index, and type of ICU. The total number of changes was not associated with either primary outcome measure. CONCLUSIONS: The number of major ventilator manipulations is associated with rate of tracheostomy and stay on the ventilator.

Chiruvolu, A., V. N. Tolia, H. Qin, G. L. Stone, D. Rich, R. J. Conant and R. W. Inzer (2015). “Effect of delayed cord clamping on very preterm infants.” American Journal of Obstetrics and Gynecology 213(5).

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OBJECTIVE: Despite significant proposed benefits, delayed umbilical cord clamping (DCC) is not practiced widely in preterm infants largely because of the question of feasibility of the procedure and uncertainty regarding the magnitude of the reported benefits, especially intraventricular hemorrhage (IVH) vs the adverse consequences of delaying the neonatal resuscitation. The objective of this study was to determine whether implementation of the protocol-driven DCC process in our institution would reduce the incidence of IVH in very preterm infants without adverse consequences. STUDY DESIGN: We implemented a quality improvement process for DCC the started in August 2013 in infants born at <= 32 weeks’ gestational age. Eligible infants were left attached to the placenta for 45 seconds after birth. Neonatal process and outcome data were collected until discharge. We compared infants who received DCC who were born between August 2013 and August 2014 with a historic cohort of infants who were born between August 2012 and August 2013, who were eligible to receive DCC, but whose cord was clamped immediately after birth, because they were born before the protocol implementation. RESULTS: DCC was performed on all the 60 eligible infants; 88 infants were identified as historic control subjects. Gestational age, birthweight, and other demographic variables were similar between both groups. There were no differences in Apgar scores or admission temperature, but significantly fewer infants in the DCC cohort were intubated in delivery room, had respiratory distress syndrome, or received red blood cell transfusions in the first week of life compared with the historic cohort. A significant reduction was noted in the incidence of IVH in the DCC cohort compared with the historic control group (18.3% vs 35.2%). After adjustment for gestational age, an association was found between the incidence of IVH and DCC with IVH was significantly lower in the DCC cohort compared with the historic cohort; an odds ratio of 0.36 (95% confidence interval, 0.15-0.84; P < .05). There were no significant differences in deaths and other major morbidities. CONCLUSION: DCC, as performed in our institution, was associated with significant reduction in IVH and early red blood cell transfusions. DCC in very preterm infants appears to be safe, feasible, and effective with no adverse consequences.

Campa, M., B. Mansouri, R. Warren and A. Menter (2015). “A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis.” Dermatol Ther (Heidelb) 2015 Dec 29. [Epub ahead of print].

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The development of several highly effective biologic drugs in the past decade has revolutionized the treatment of moderate-to-severe plaque psoriasis. With increased understanding of the immunopathogenesis of psoriasis, the emphasis has turned toward more specific targets for psoriasis drugs. Although the complex immunological pathway of psoriasis is not yet completely understood, current models emphasize the significant importance of interleukin (IL)-23 and IL-17. Several biologic drugs targeting these cytokines are now in various stages of drug development. Drugs targeting IL-23 include BI-655066, briakinumab, guselkumab, tildrakizumab, and ustekinumab. Drugs targeting IL-17 include brodalumab, ixekizumab, and secukinumab. While many of these have shown safety and good efficacy in clinical trials of moderate-to-severe plaque psoriasis, long-term safety is still to be established.

Brinkman, W. T., J. J. Squiers, G. Filardo, M. Arsalan, R. L. Smith, D. Moore, M. J. Mack and J. M. DiMaio (2015). “Perioperative Outcomes, Transfusion Requirements, and Inflammatory Response After Coronary Artery Bypass Grafting With Off-Pump, Mini-Extracorporeal,and On-Pump Circulation Techniques.” Journal of Investigative Medicine 63(8): 916-920.

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Objectives Mini-extracorporeal circulation (MECC) units were developed to reduce postoperative morbidity, transfusion requirements, and inflammation associated with conventional on-pump coronary artery bypass (ONCAB) surgery without the technical demands of the off-pump (OPCAB) technique. We compared perioperative outcomes and inflammatory mediation among OPCAB, MECC, and ONCAB techniques. Methods We prospectively enrolled 102 patients undergoing elective isolated coronary bypass grafting. Perfusion methods were OPCAB (n = 34), MECC (n = 34), and ONCAB (n = 34). Serial blood samples were collected to measure serum inflammatory markers. Results There were no operative deaths or strokes. Total red blood cell (RBC) products used in OPCAB, MECC, and ONCAB patients were 0.676, 1.000, and 1.235 units, respectively. Adjusted (by splined Society of Thoracic Surgeons operative risk score) analysis showed no statistically significant differences in mean RBC product use among the different operative systems (OPCAB vs MECC, P = 0.580; OPCAB vs ONCAB, P = 0.311; MECC vs ONCAB, P = 0.633). Adjusted (by Society of Thoracic Surgeons risk score and baseline level) mean plasma level differences (24 hours postoperative – baseline) of C-reactive protein for OPCAB (117.89; 95% confidence interval [95% CI], 106.23-129.54) and for MECC (124.88; 95% CI, 113.45-136.32) were significantly higher than for ONCAB (98.82; 95% CI, 86.40-111.24). No significant adjusted differences (P = 0.304) in interleukin-6 level changes were observed. Conclusions Off-pump coronary artery bypass and MECC did not significantly reduce mean total RBC transfusion requirements. Off-pump coronary artery bypass and MECC were associated with greater C-reactive protein elevation than ONCAB, suggestive of an increased inflammatory response to each of these techniques.