Balancing quality and quaternary care imperative using a high-risk case review committee in adults.

OBJECTIVES: Quaternary care centres have an imperative to serve as hospitals of last resort and must also meet professional quality targets. We developed a high-risk committee (HRC) to evaluate cases meeting pre-defined predicted risk cut-offs as a part of an overall quality improvement drive. METHODS: We describe the structure, outcomes and effects of the Penn HRC. Using propensity-matching, we investigated whether the committee modifies or screens risk. We used multivariable analysis to examine the impact of unmeasured variables on clinical outcomes in this cohort. RESULTS: Institutional predicted and observed mortality had already been in decline prior to HRC institution in 2017, due to a multi-faceted quality improvement initiative. Between 2017 and 2020, the HRC discussed 205 patients with a median predicted risk of mortality of 10.6% (range 0.4-66%). Coronary artery bypass grafting was the most commonly presented operation. A total of 155 patients underwent operation (risk 10.3%), 12 had surgery deferred for optimization (risk 6%), 50 had surgery declined (risk 11.7%) and 12 patients had a deferred decision for further investigation. Overall 30-day survival was 86% for the entire cohort and 89% for operated patients. A matched analysis of similar patients prior to and following the HRC showed that the HRC did not directly modify outcomes. Most patients had better than expected survival (observed:expected mortality < 1). Predicted risk did not predict 30-day mortality among this high-risk cohort. CONCLUSIONS: HRCs serve as an important element in quality improvement by encouraging a thoughtful approach and channelling the collective experience of a group of senior surgeons. It may improve patient selection by identifying a cohort with extremely poor survival, while allowing safe operation with acceptable outcomes among a group with very high operative risk.

Proposal for a trial of early left ventricular venting during venoarterial extracorporeal membrane oxygenation for cardiogenic shock.

Objective: Patients with profound cardiogenic shock may require venoarterial (VA) extracorporeal membrane oxygenation (ECMO) for circulatory support most commonly via the femoral vessels. The rate of cardiac recovery in this population remains low, possibly because peripheral VA-ECMO increases ventricular afterload. Whether direct ventricular unloading in peripheral VA-ECMO enhances cardiac recovery is unknown, but is being more frequently utilized. A randomized trial is warranted to evaluate the clinical effectiveness of percutaneous left ventricle venting to enhance cardiac recovery in the setting of VA-ECMO. Methods: We describe the rationale, design, and initial testing of a randomized controlled trial of VA-ECMO with and without percutaneous left ventricle venting using a percutaneous micro-axial ventricular assist device. Results: This is an ongoing prospective randomized controlled trial in adult patients with primary cardiac failure presenting in cardiogenic shock requiring peripheral VA-ECMO, designed to test the safety and effectiveness of percutaneous left ventricle venting in improving the rate of cardiac recovery. Conclusions: The results of this nonindustry-sponsored trial will provide critical information on whether left ventricle unloading in peripheral VA-ECMO is safe and effective.

Arginine transport in catabolic disease states.

Arginine appears to be a semiessential amino acid in humans during critical illness. Catabolic disease states such as sepsis, injury, and cancer cause an increase in arginine utilization, which exceeds body production, leading to arginine depletion. This is aggravated by the reduced nutrient intake that is associated with critical illness. Arginine depletion may have negative consequences on tissue function under these circumstances. Nutritional regimens containing arginine have been shown to improve nitrogen balance and lymphocyte function, and stimulate arginine transport in the liver. We have studied the effects of stress mediators on arginine transport in vascular endothelium, liver, and gut epithelium. In vascular endothelium, endotoxin stimulates arginine uptake, an effect that is mediated by the cytokine tumor necrosis factor-alpha (TNF-alpha) and by the cyclo-oxygenase pathway. This TNF-alpha stimulation involves the activation of intracellular protein kinase C (PKC). A significant increase in hepatic arginine transport activity also occurs following burn injury and in rats with progressive malignant disease. Surgical removal of the growing tumor results in a normalization of the accelerated hepatic arginine transport within days. Chronic metabolic acidosis and sepsis individually augment intestinal arginine transport in rats and Caco-2 cell culture. PKC and mitogen-activated protein kinases are involved in mediating the sepsis/acidosis stimulation of arginine transport. Understanding the regulation of plasma membrane arginine transport will enhance our knowledge of nutrition and metabolism in seriously ill patients and may lead to the design of improved nutritional support formulas.

Insulin-like growth factor-2 activation of intestinal glutamine transport is mediated by mitogen-activated protein kinases.

Insulin-like growth factor-2 (IGF-2) plays a pivotal role in regulating intestinal epithelial metabolism, growth, and proliferation, but its regulatory effects on mucosal cell amino acid transport have not been well studied. The purpose of this in vitro study was to investigate the regulatory mechanisms and intracellular signaling pathways involved in the regulation of IGF-2 on glutamine transport in cultured intestinal cells. Continuous incubation with IGF-2 stimulated glutamine transport activity in cultured IEC-6 cells in a dose- and time-dependent fashion. Prolonged incubation (up to 48 hours) resulted in a 50% increase in transport activity (0.81+/-0.21 nmole/mg protein/min in IGF-2 cells vs. 0.57+/-0.15 nmole/mg protein/min in control cells) and a threefold increase in glutamine transporter ATB(0) mRNA levels. IGF-2 stimulated transport activity by increasing transport maximal capacity (V(max) 4.31+/-0.36 nmole/mg protein/min in IGF-2 cells vs. 2.51+/-0.23 nmole/mg protein/min in control cells) without affecting the transport affinity (K(m) 0.31+/-0.03 mmol/L glutamine in IGF-2 cells vs. 0.28+/-0.03 mmol/L glutamine in control cells). This IGF-2-induced glutamine transport activity was attenuated by actinomycin-D or cycloheximide. The levels of mitogen-activated protein kinases p42/44, MEK1/2, and p38 as well as protein kinase C levels were elevated in IGF-2-treated cells and inhibitors of mitogen-activated protein kinase MEK1 (PD 98059), mitogen-activated protein kinase p38, and protein kinase C (chelerythrine chloride) individually attenuated the IGF-2-induced glutamine transport. These data suggest that IGF-2 stimulates intestinal glutamine uptake in cultured rat intestinal epithelial cells via a mechanism that involves transcription and translation of the transporter. Activation of mitogen-activated protein kinases and protein kinase C cascades are involved in the regulation. This increase in glutamine uptake may occur to support intestinal cell growth and proliferation.

Metabolic acidosis stimulates intestinal glutamine absorption.

Glutamine is an essential nutrient for cell integrity during acidotic states such as shock, but the effect of extracellular pH on intestinal mucosal cell glutamine uptake is poorly understood. The purpose of this in vitro study was to investigate the intracellular signaling pathways involved in controlling intestinal glutamine transport during acidosis. Lowering the pH in the cell culture medium resulted in an increase in glutamine transport activity in a time- and pH-dependent fashion. Chronic acidosis (pH 6.6 for 48 hours) resulted in a twofold increase in glutamine transport activity (1.63+/-0.25 nmole/mg protein/minute in acidosis vs. 0.78+/-0.11 nmole/mg protein/minute in control) and a threefold increase in glutamine transport gene ATB(0) messenger RNA levels. This acidosis-induced increase in glutamine transport activity was due to a stimulation of transporter maximal transport capacity (V(max) 13.6+/-0.73 nmole/mg protein/minute in acidosis vs. 6.3+/-0.46 nmole/mg protein/minute in control) rather than a change in transporter affinity (K(m)=0.23+/-0.02 mmol/L glutamine in acidosis vs. 0.19+/-0.02 mmol/L glutamine in control). This acidosis-stimulated glutamine transport activity was blocked by actinomycin-D or cycloheximide. Cellular mitogen-activated protein kinase (MAPK) MEK1/2 and p42/44 levels were elevated in acidotic cells, and the acidosis-induced glutamine transport activity was blocked by the MAPK MEK 1 inhibitor PD 98059. Acidosis stimulates glutamine transport in Caco-2 cells via signaling pathways that lead to transcription of the glutamine transporter gene and translation of functional transporters. Mitogen-activated protein kinases are key intracellular regulators involved in this signal transduction cascade. An increased availability of glutamine to cells subjected to redox stress may help in maintaining cellular integrity.