William R. Lynch

Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients

The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use. Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely. This position paper represents the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO. The aim of this paper is to provide physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients. Importantly, this will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions. Given the need for further evidence, we encourage restraint in the widespread use of ECMO until we have a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.

Effect of rate and inspiratory flow on ventilator-induced lung injury.

BACKGROUND We examined the effects of decreasing respiratory rate (RR) at variable inspiratory times (It) and reducing inspiratory flow on the development of ventilator-induced lung injury. METHODS Forty sheep weighing 24.6+/-3.2 kg were ventilated for 6 hours with one of five strategies (FIO2 = 1.0, positive end-expiratory pressure = 5 cm H2O): (1) pressure-controlled ventilation (PCV), RR = 15 breaths/min, peak inspiratory pressure (PIP) = 25 cm H2O, n = 8; (2) PCV, RR = 15 breaths/min, PIP = 50 cm H2O, n = 8; (3) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 6 seconds, n = 8; (4) PCV, RR = 5 breaths/min, PIP = 50 cm H2O, It = 2 seconds, n = 8; and (5) limited inspiratory flow volume-controlled ventilation, RR = 5 breaths/min, pressure-limit = 50 cm H2O, flow = 15 L/min, n = 8. RESULTS Decreasing RR at conventional flows did not reduce injury. However, limiting inspiratory flow rate (LIFR) maintained compliance and resulted in lower Qs/Qt (HiPIP = 38+/-18%, LIFR = 19+/-6%, p < 0.001), reduced histologic injury (HiPIP = 14+/-0.9, LIFR = 2.2+/-0.9, p < 0.05), decreased intra-alveolar neutrophils (HiPIP = 90+/-49, LIFR = 7.6+/-3.8,p = 0.001), and reduced wet-dry lung weight (HiPIP = 87.3+/-8.5%, LIFR = 40.8+/-17.4%,p < 0.001). CONCLUSIONS High-pressure ventilation for 6 hours using conventional flow patterns produces severe lung injury, irrespective of RR or It. Reduction of inspiratory flow at similar PIP provides pulmonary protection.

Hemodynamic effect of a low-resistance artificial lung in series with the native lungs of sheep

BACKGROUND An artificial lung with 1 to 6 month work life could act as a bridge to transplantation. A pumpless artificial lung has been developed. METHODS The artificial lung was placed in series with the native lungs of adult sheep. Hemodynamics were observed, as the right ventricle generated flow through the device. Through a left thoracotomy, two 20-mm grafts were anastomosed in an end-to-side fashion to the pulmonary artery. The grafts were externalized, and directed flow through the chest wall, to the extracorporeal lung. The animals were recovered, weaned from the ventilator, and when standing, flow was diverted through the device. RESULTS Five of 7 animals survived 24 hours with 75% to 100% of the cardiac output diverted through the device. All animals were active, with interest in food and water, and able to stand. CONCLUSIONS The right ventricle perfused the artificial lung with 75% to 100% of the cardiac output for 24 hours. This device demonstrates the feasibility of a pumpless pulmonary assist device relying on the right ventricle for perfusion.

Outcome of Adult Respiratory Failure Patients Receiving Prolonged (≥14 Days) ECMO.

Objective:To examine the outcomes of prolonged (≥14 days) extracorporeal membrane oxygenation (P-ECMO) for adult severe respiratory failure and to assess characteristics associated with survival. Background:The use of ECMO for treatment of severe respiratory adult patients is associated with overall survival rates of 50% to 70% with median ECMO duration of 10 days. No prior multi-institutional studies have examined outcomes of P-ECMO for severe respiratory failure. Methods:Data on all adult (≥18 years) patients who required P-ECMO for severe respiratory failure from 1989 to 2013 were extracted from the Extracorporeal Life Support Organization international multi-institutional registry. We examined outcomes over 23 years and compared the 2 more recent time periods of 1989 to 2006 versus 2007 to 2013. Results:Up to 974 patients, mean age 40.2 (18–83) years, had ECMO duration of mean 25.2 days/median 21.0 days (range: 14–208 days). Venovenous ECMO support was most common (venovenous: 79.5%, venoarterial: 9.9%). Reason for ECMO discontinuation included native lung recovery (54%), organ failure (23.7%), family request (6.7%), hemorrhage (2.7%), and diagnosis incompatible with life (5.6%). Forty patients (4.1%) underwent lung transplant with 50% postoperative in-hospital mortality. Increased prevalence of P-ECMO was noted with 72% (701/974) of all cases reported since 2008. Survival to hospital discharge was 45.4% (443/974) and did not vary with ECMO duration. Multivariate logistic regression analysis confirmed that P-ECMO patients 2007 to 2013 had a lower risk of death [odds ratio (OR): 0.650; 95% confidence interval (CI), 0.454–0.929; P = 0.010] compared with 1989 to 2006. Factors independently associated with survival were younger age (OR: 0.983; 95% CI, 0.974–0.993; P < 0.001) and lower PaCO2 (OR, 0.991; 95% CI, 0.986–0.996; P < 0.001). Conclusions:Prolonged ECMO use for adult respiratory failure was associated with a lower (45.4%) hospital survival rate, compared with prior reported survival rates of short duration ECMO. Prolonged ECMO survival significantly increased in recent years, and increasing ECMO duration did not alter the survival fraction in the 1989 to 2013 study cohort. Although P-ECMO survival rates are less than short ECMO runs, P-ECMO support is justified.

Prolonged duration ECMO for ARDS: Futility, native lung recovery, or transplantation?

Extracorporeal membrane oxygenation (ECMO) is recommended as a treatment modality for severe acute respiratory distress syndrome (PaO2/FiO2 ⩽ 100 mm Hg with positive end-expiratory pressure ≥ 5 cm H2O) as defined by the Berlin definition. The reported usual duration of ECMO in these patients is 7–10 days. However, increasing reports of prolonged duration ECMO (>14 days) for respiratory failure document survival rates of 50–70% with native lung recovery, and ECMO bridge to lung transplantation has been performed at many centers. At present, there are no established national criteria for when to consider futility or lung transplantation in adult patients requiring ECMO for acute respiratory failure. We report a case of prolonged duration venovenous-ECMO (1,347 hours, 56.13 days), with native lung recovery and discuss treatment strategies to optimize native lung recovery in ECMO patients. The lung may have unexpected regenerative capacity with native lung recovery after prolonged mechanical support, similar to acute kidney injury and native renal recovery. We recommend redefining irreversible lung injury and futility in ECMO.

Roller and centrifugal pumps: A retrospective comparison of bleeding complications in extracorporeal membrane oxygenation

Centrifugal pumps are increasingly used for extracorporeal membrane oxygenation (ECMO) rather than roller pumps. However, shear forces induced by these types of continuousflow pumps are associated with acquired von Willebrand factor deficiency and bleeding complications. This study was undertaken to compare adverse bleeding complications with the use of centrifugal and roller pumps in patients on prolonged ECMO support. The records of all adult ECMO patients from June 2002 to 2013 were retrospectively reviewed using the University of Michigan Health System database and the Extracorporeal Life Support Organization registry, focusing on patients supported for at least 5 days. Ninety-five ECMO patients met criteria for inclusion (48 roller vs. 47 centrifugal pump). Indications included pulmonary (79%), cardiac (15%), and extracorporeal cardiopulmonary resuscitation (6%), without significant difference between the two groups. Despite lower heparin anticoagulation (10.9 vs. 13.7 IU/kg/hr) with centrifugal pumps, there was a higher incidence of nonsurgical bleeding (gastrointestinal, pulmonary, and neurological) in centrifugal pump patients (26.1 vs. 9.0 events/1,000 patient-days, p = 0.024). In conclusion, in our historical comparison, despite reduced anticoagulation, ECMO support using centrifugal pumps was associated with a higher incidence of nonsurgical bleeding. The mechanisms behind this are multifactorial and require further investigation

Partial liquid ventilation and positive end-expiratory pressure reduce ventilator-induced lung injury in an ovine model of acute respiratory failure

Objective To examine the isolated and combined effects of positive end-expiratory pressure (PEEP) and partial liquid ventilation (PLV) on the development of ventilator-induced lung injury in an ovine model. Design Prospective controlled animal study. Setting University-based cardiovascular animal physiology laboratory. Subjects Thirty-eight anesthetized supine sheep weighing 22.3 ± 2.2 kg. Interventions Animals were ventilated for 6 hrs (respiratory rate, 15; Fio2, 1.0, inspiratory/expiratory ratio, 1:1) with one of five pressure-controlled strategies, expressed as peak inspiratory pressure (PIP)/PEEP: low-PIP, 25/5 cm H2O (n = 8); high-PIP, 50/5 cm H2O (n = 8); high-PIP-PLV, 50/5 cm H2O-PLV (n = 8); high-PEEP, 50/20 cm H2O (n = 7); and high-PEEP-PLV, 50/20 cm H2O-PLV (n = 7). Measurements and Main Results Compared with the low-PIP control, high-PIP ventilation increased airleak, shunt, histologic evidence of lung injury, neutrophil infiltrates, and wet lung weight. Maintaining PEEP at 20 cm H2O or adding PLV reduced the development of physiologic shunt and dependent histologic injury indexes. Neither higher PEEP nor PLV reduced the high incidence of barotrauma observed in high-PIP animals. Conclusions We conclude that application of PLV or PEEP at 20 cm H2O may improve gas exchange and afford lung protection from ventilator-induced lung injury during high-pressure mechanical ventilation in this model.

Pulmonary venous blood sampling significantly increases the yield of circulating tumor cells in early-stage lung cancer.

OBJECTIVE To identify circulating tumor cells (CTCs) in the blood of patients with early-stage lung cancer and to show that sampling pulmonary vein (PV) blood using microfluidic chip technology will yield significantly more CTCs. Improving early detection of lung cancer is critical to improving lung cancer survival. Reproducible detection of CTCs is limited currently in early stage tumors. METHODS Patients undergoing pulmonary resection had PV blood drawn before resection. Peripheral blood was sampled at preoperative, intraoperative, and postoperative times. Samples were analyzed on microfluidic chips using antibody-based capture. RESULTS A total of 32 patients with primary lung cancer were evaluated. Twenty patients had 1 or more CTCs detected in at least 1 sample (62.5%). The mean number of CTCs from peripheral vein sources at the preoperative, intraoperative, and postoperative time points was 1.3, 1.9, and 0.6 respectively. The average number of CTCs in the PV was 340.0 (range, 0.0-5422.50; P > .01). When PV CTCs were present, the number of CTCs was correlated with pathological tumor size (P = .0236). The number of PV CTCs was not correlated with any other clinical feature (eg, smoking status, preoperative or postoperative stage). Furthermore, the number of PV CTCs was significantly higher when preoperative bronchoscopic biopsy was performed, compared with computed tomography-guided biopsy (P = .0311). Seven patients had evidence of CTC clusters, or microemboli. CONCLUSIONS With a single vein draining the entire tumor basin, lung cancers are unique, allowing the high-yield isolation of CTCs from the PV. This method may facilitate future studies to improve the detection and analysis of early-stage lung CTCs.

Relationship between HER-2 overexpression and brain metastasis in esophageal cancer patients

AIM To study if HER-2 overexpression by locally advanced esophageal cancers increase the chance of brain metastasis following esophagectomy. METHODS We retrospectively reviewed the medical records of esophageal cancer patients who underwent esophagectomy at University of Iowa Hospitals and Clinics between 2000 and 2010. Data analyzed consisted of demographic and clinical variables. The brain metastasis tissue was assayed for HER-2 overexpression utilizing the FDA approved DAKO Hercept Test(®). RESULTS One hundred and forty two patients were reviewed. Median age was 64 years (36-86 years). Eighty eight patients (62%) received neoadjuvant chemoradiotherapy. Pathological complete and partial responses were achieved in 17 (19%) and 71 (81%) patients. Cancer relapsed in 43/142 (30%) patients. The brain was the first site of relapse in 9/43 patients (21%, 95% CI: 10%-36%). HER-2 immunohistochemistry testing of the brain metastasis tissue showed that 5/9 (56%) cases overexpressed HER-2 (3+ staining). CONCLUSION HER-2 overexpression might be associated with increased risk of brain metastasis in esophageal cancer patients following esophagectomy. Further studies will be required to validate this observation.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation

Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E-BP1 pathway was identified as an important driver of collagen I expression in Fib-MCs in experiments utilizing raptor gene silencing and overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states.