Surgical Oncologists and the COVID-19 Pandemic: Guiding Cancer Patients Effectively through Turbulence and Change.

BACKGROUND: The COVID-19 pandemic has posed extraordinary demands from patients, providers, and health care systems. Despite this, surgical oncologists must maintain focus on providing high-quality, empathetic care for the almost 2 million patients nationally who will be diagnosed with operable cancer this year. The focus of hospitals is transitioning from initial COVID-19 preparedness activities to a more sustained approach to cancer care. METHODS: Editorial Board members provided observations of the implications of the pandemic on providing care to surgical oncology patients. RESULTS: Strategies are presented that have allowed institutions to successfully prepare for cancer care during COVID-19, as well as other strategies that will help hospitals and surgical oncologists manage anticipated challenges in the near term. Perspectives are provided on: (1) maintaining a safe environment for surgical oncology care; (2) redirecting the multidisciplinary model to guide surgical decisions; (3) harnessing telemedicine to accommodate requisite physical distancing; (4) understanding interactions between SARS CoV-2 and cancer therapy; (5) considering the ethical impact of professional guidelines for surgery prioritization; and (6) advocating for our patients who require oncologic surgery in the midst of the COVID-19 pandemic. CONCLUSIONS: Until an effective vaccine becomes available for widespread use, it is imperative that surgical oncologists remain focused on providing optimal care for our cancer patients while managing the demands that the COVID-19 pandemic will continue to impose on all of us.

Inhaled Epoprostenol Through Noninvasive Routes of Ventilator Support Systems.

BACKGROUND: The administration of inhaled epoprostenol (iEPO) through noninvasive routes of ventilator support systems has never been previously evaluated. OBJECTIVE: Describe the use of iEPO when administered through noninvasive routes of ventilator support systems. METHODS: Critically ill patients admitted to the intensive care unit who received iEPO through noninvasive routes were analyzed. Improvements in respiratory status and hemodynamic parameters were evaluated. Safety end points assessed included hypotension, rebound hypoxemia, significant bleeding, and thrombocytopenia. RESULTS: A total of 36 patients received iEPO through noninvasive routes: high-flow oxygen therapy through nasal cannula, n = 29 (81%) and noninvasive positive-pressure ventilation, n = 7 (19%). Sixteen patients had improvement in their respiratory status: mean decrease in fraction of inspired oxygen (FiO2), 20% ± 13%; mean increase in partial pressure of arterial oxygen to FiO2 (PaO2/FiO2) ratio, 60 ± 50 mm Hg; and mean decrease in HFNC oxygen flow rate, 6 ± 3 liters per minute (LPM). Eight patients had declines in their respiratory status (mean increase in FiO2, 30% ± 20%; mean decrease in PaO2/FiO2 ratio, 38 ± 20 mm Hg; and mean increase in HFNC oxygen flow rate, 15 ± 10 LPM), and 12 patients had no change in their respiratory status. Conclusion and Relevance: This represents the first evaluation of the administration of iEPO through noninvasive routes of ventilator support systems and demonstrates that in critically ill patients, iEPO could be administered through a noninvasive route. Further evaluation is needed to determine the extent of benefit with this route of administration.

Noninferiority of Inhaled Epoprostenol to Inhaled Nitric Oxide for the Treatment of ARDS.

BACKGROUND: Inhaled nitric oxide and inhaled epoprostenol have been evaluated for the management of hypoxemia in acute respiratory distress syndrome, with clinical trials demonstrating comparable improvements in oxygenation. However, these trials have several limitations, making it difficult to draw definitive conclusions regarding clinical outcomes. OBJECTIVE: The aim of this study was to evaluate the noninferiority and safety of inhaled epoprostenol compared with inhaled nitric oxide in mechanically ventilated acute respiratory distress syndrome (ARDS) patients with a primary outcome of ventilator-free days from day 1 to day 28. METHODS: This was a retrospective, noninterventional, propensity-matched, noninferiority cohort study. Propensity score for receipt of inhaled nitric oxide was developed and patients were matched accordingly using a prespecified algorithm. Secondary objectives included evaluating day 28 intensive care unit-free days, changes in PaO2/FiO2 ratio after inhalation therapy initiation, and hospital mortality. Safety endpoints assessed included hypotension, methemoglobinemia, renal dysfunction, rebound hypoxemia, significant bleeding, and thrombocytopenia. RESULTS: Ninety-four patients were included, with 47 patients in each group. Patients were well-matched with similar baseline characteristics, except patients in inhaled nitric oxide group had lower PaO2/FiO2 ratio. Management of ARDS was similar between groups. Mean difference in ventilator-free days between inhaled epoprostenol and inhaled nitric oxide was 2.16 days (95% confidence interval = -0.61 to 4.9), with lower limit of 95% confidence interval greater than the prespecified margin, hence satisfying noninferiority. There were no differences in any secondary or safety outcomes. CONCLUSIONS: Inhaled epoprostenol was noninferior to inhaled nitric oxide with regard to ventilator-free days from day 1 to day 28 in ARDS patients.

Machine Learning Models Versus the National Early Warning Score System for Predicting Deterioration: Retrospective Cohort Study in the United Arab Emirates.

BACKGROUND: Early warning score systems are widely used for identifying patients who are at the highest risk of deterioration to assist clinical decision-making. This could facilitate early intervention and consequently improve patient outcomes; for example, the National Early Warning Score (NEWS) system, which is recommended by the Royal College of Physicians in the United Kingdom, uses predefined alerting thresholds to assign scores to patients based on their vital signs. However, there is limited evidence of the reliability of such scores across patient cohorts in the United Arab Emirates. OBJECTIVE: Our aim in this study was to propose a data-driven model that accurately predicts in-hospital deterioration in an inpatient cohort in the United Arab Emirates. METHODS: We conducted a retrospective cohort study using a real-world data set that consisted of 16,901 unique patients associated with 26,073 inpatient emergency encounters and 951,591 observation sets collected between April 2015 and August 2021 at a large multispecialty hospital in Abu Dhabi, United Arab Emirates. The observation sets included routine measurements of heart rate, respiratory rate, systolic blood pressure, level of consciousness, temperature, and oxygen saturation, as well as whether the patient was receiving supplementary oxygen. We divided the data set of 16,901 unique patients into training, validation, and test sets consisting of 11,830 (70%; 18,319/26,073, 70.26% emergency encounters), 3397 (20.1%; 5206/26,073, 19.97% emergency encounters), and 1674 (9.9%; 2548/26,073, 9.77% emergency encounters) patients, respectively. We defined an adverse event as the occurrence of admission to the intensive care unit, mortality, or both if the patient was admitted to the intensive care unit first. On the basis of 7 routine vital signs measurements, we assessed the performance of the NEWS system in detecting deterioration within 24 hours using the area under the receiver operating characteristic curve (AUROC). We also developed and evaluated several machine learning models, including logistic regression, a gradient-boosting model, and a feed-forward neural network. RESULTS: In a holdout test set of 2548 encounters with 95,755 observation sets, the NEWS system achieved an overall AUROC value of 0.682 (95% CI 0.673-0.690). In comparison, the best-performing machine learning models, which were the gradient-boosting model and the neural network, achieved AUROC values of 0.778 (95% CI 0.770-0.785) and 0.756 (95% CI 0.749-0.764), respectively. Our interpretability results highlight the importance of temperature and respiratory rate in predicting patient deterioration. CONCLUSIONS: Although traditional early warning score systems are the dominant form of deterioration prediction models in clinical practice today, we strongly recommend the development and use of cohort-specific machine learning models as an alternative. This is especially important in external patient cohorts that were unseen during model development.

Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts.

Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91(phox)-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91(phox)-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91(phox). Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase-dependent ROS generation.

The effect of metformin and thiazolidinedione use on lung cancer in diabetics.

BACKGROUND: Metformin and the thiazolidinediones (TZDs) may have a protective effect against the development of lung cancer. METHODS: Patients with diabetes mellitus (DM) were identified from the electronic medical records of the Cleveland Clinic. Diabetics with lung cancer were identified then verified by direct review of their records. Control subjects were matched with cancer subjects 1:1 by date of birth, sex, and smoking history. The frequency and duration of diabetic medication use was compared between the groups. The cancer characteristics were compared between those with lung cancer who had and had not been using metformin and/or a TZD. RESULTS: 93,939 patients were identified as having DM. 522 lung cancers in 507 patients were confirmed. The matched control group was more likely to have used metformin and/or a TZD (61.0% vs. 41.2%, p < 0.001 for any use; 55.5% vs. 24.6%, p < 0.001 for >24 months vs. 0-12 months). In the group with lung cancer, those who had used metformin alone had a different histology distribution than those who received neither metformin nor a TZD, were more likely to present with metastatic disease (40.8% vs. 28.2%, p = 0.013), and had a shorter survival from the time of diagnosis (HR 1.47, p < 0.005). CONCLUSIONS: The use of metformin and/or the TZDs is associated with a lower likelihood of developing lung cancer in diabetic patients. Diabetics who develop lung cancer while receiving metformin may have a more aggressive cancer phenotype.

Tidal volume variability during airway pressure release ventilation: case summary and theoretical analysis.

Airway pressure-release ventilation (APRV) is used in the management of patients with severe or refractory respiratory failure. In addition to reversal of inspiratory-expiratory ratios, this pressure control mode also allows unrestricted spontaneous breathing. The spontaneous tidal volume (V(T)), as well as the V(T) resulting from transition between the high and low airway pressures, is uncontrolled. There are limited data on the within-patient variation of actual V(T) and the safety of these modes. The authors present a patient with severe ARDS who was managed with biphasic modes (APRV and bi-level positive airway pressure). Serial V(T) measurements showed that V(T) ranged from 4 to 12 mL/kg predicted body weight. Computed tomography scan images and chest radiographs obtained before and following APRV showed lung parenchyma changes that may be related to ventilator-induced lung injury. We also present a mathematical model that is useful for simulating APRV and demonstrating the issues related to volume delivery for mandatory breaths during the transition between the 2 pressure levels. A key finding of this analysis is the interdependence of release volume, autoPEEP, and the T(low) time setting. Furthermore, it is virtually impossible to target a specific P(aCO(2)) with a desired level V(T) and autoPEEP in a passive model, emphasizing the importance of spontaneous breathing with this mode. This case report suggests caution when using these modes, and that end-inspiratory lung volumes and V(T) should be limited to avoid lung injury. The important point of this case study and model analysis is that the application of APRV is more complex than it appears to be. It requires a lot more knowledge and skill than may be apparent from descriptions in the literature.

Team-building and change management in respiratory care: description of a process and outcomes.

BACKGROUND: Teamwork promotes enhanced outcomes in various business sectors but can be hampered when there are organizational "silos." This study describes an intervention that fostered teamwork among 4 separate respiratory therapy (RT) departments within a single hospital. METHODS: An initial retreat of leaders of the 4 RT groups indicated a common goal of developing a scorecard by which RT outcomes could be followed and improved. Developing this scorecard involved a business review process that comprised 7 facilitated meetings, in which the 4 RT groups developed metrics and targets for RT outcomes in 4 categories: quality/innovation; service; productivity; and employee engagement. RESULTS: The process of developing the scorecard prompted improvements in the quality of RT care (eg, enhanced cross-staffing, low respiratory therapist turnover). A welcome impact of the business review process was enhanced collaboration and teamwork among the 4 RT groups, as manifested by sharing of educational resources, developing a cross-departmental float pool, and forming a process and group to standardize RT care across all groups. CONCLUSIONS: The results of this business review process show that teamwork among 4 separate RT departments improved and that enhanced outcomes were achieved. Based on this experience, we recommend consideration of this business review process as a team-building activity that can confer demonstrable clinical benefits.

Non-invasive positive pressure ventilation in lung transplant recipients with acute respiratory failure: Beyond the perioperative period.

PURPOSE: The purpose of this study is to evaluate outcomes in MICU lung transplant recipients with acute respiratory failure treated with non-invasive positive pressure ventilation (NPPV) and identify factors associated with NPPV failure (need for intubation). METHODS: Retrospective chart review of all lung transplant recipients who were admitted with acute respiratory failure to the MICU from January 2009-August 2016 was completed. Logistic regression analysis was performed to determine which factors were independently associated with NPPV failure. RESULTS: Of 156 patients included in the study, 125 (80.1%) were tried on NPPV. Sixty-eight (54.4%) were managed successfully with NPPV with a hospital survival rate of 94.1%. Subjects who failed NPPV had higher hospital mortality, similar to those intubated from the outset (15 [48.3%]; 22 [38.6%], p = .37). In multivariate analyses, APACHE III scores >78 (9.717 [3.346, 28.22]) and PaO2/FiO2 ≤ 151 (4.54 [1.72, 11.99]) were associated with greater likelihood of NPPV failure. There was no difference in NPPV failure based on the presence of BOS. In patients with high severity of illness, there was no difference in mortality between initial IMV and NPPV failure when stratified on the basis of hypoxemia (PaO2/FiO2 > 151, p-value 0.34; PaO2/FiO2 ≤ 151, p-value 0.99). CONCLUSIONS: NPPV is a viable option for lung transplant recipients with acute respiratory failure. Extreme caution should be exercised when used in patients with high severity of illness (APACHE III >78) and/or severe hypoxemia (PaO2/FiO2 ≤ 151).

Tidal volume measurement error in pressure control modes of mechanical ventilation: A model study.

UNLABELLED: Tidal volume (VT) measurement during pressure control (PC) ventilation with preset inspiratory time may produce errors due to patient inspiratory effort. We evaluated VT error in 3 common ICU ventilators. METHODS: Simulated patient: 60kg adult with ARDS using IngMar Medical ASL 5000 having moderate inspiratory effort. Ventilators evaluated: Covidien PB 840, Maquet Servo-i, and Dräger Evita XL, PC breaths at preset inspiratory time (TI) 0.6-1.4s. VT error was defined as ventilator displayed VT minus the simulator displayed VT (mL/kg or % of true). RESULTS: Relaxation of inspiratory effort caused flow reversal (exhalation) during TI, which led to VT error. For the PB 840, VT error was proportional to TI (maximum -2.0mL/kg, -19%). For the Servo-i, VT error was not related to TI (maximum error -0.2mL/kg or -1.2%). Volume error for Evita XL was not related to TI (maximum error was -0.7mL/kg or -6%). CONCLUSIONS: Calculation of VT as the integral of flow over the preset inspiratory time rather than the period between zero crossings of flow may result in underestimation of both inhaled and exhaled volumes. The size of VT error can be large enough to potentially affect patient outcomes on some ventilators.

Accuracy of the Electronic Health Record: Patient Height.

BACKGROUND: Protective lung ventilation requires calculating predicted body weight (BW) from height. Thus, inaccuracy of height data in the electronic health record (EHR) is a risk factor for ventilator-induced lung injury. Charted height data often have uncertain accuracy. Study purposes were (1) to evaluate the difference between patient height charted in the EHR and predicted height (PH) from ulnar length and (2) to determine how the height data source affects predicted BW and the resulting values for protective tidal volume (V(T)). METHODS: Subject height data from the EHR were collected from several ICUs. Simultaneous ulnar data were collected by measuring ulnar length (cm): male PH (cm) = 79.2 ± 3.60 × ulnar length; female PH = 95.6 ± 2.77 × ulnar length. For each subject, BW (kg) was calculated from height charted in EHR and from predicted height: male BW = 50 ± 0.91 × (height - 152.4); female BW = 45.5 ± 0.91 × (height - 152.4). Then V(T) was calculated as 8 mL/kg BW. Bland-Altman analysis of height and V(T) differences (charted - predicted) determined the limits of agreement. RESULTS: For white males (n = 27) the mean (SD) height from EHR was 177 (7.5); predicted height was 178 (6.9). The limits of agreement for height in males were -18.5 and 17.8 cm. The limits of agreement for females were -23.1 and 21.3 cm. The limits of agreement for V(T) in males were -1.8 and 1.8 mL/kg. The limits of agreement for V(T) in females were -3.0 and 2.9 mL/kg. CONCLUSIONS: For overall populations, mean height calculated from values charted in the EHR is similar to that estimated from ulnar length. However, for individuals, differences in height between the 2 sources can be large, leading to large differences in predicted BW and resultant V(T) set in terms of mL/kg.

Characteristics and outcomes of patients with lung transplantation requiring admission to the medical ICU.

BACKGROUND: There are few data on characteristics and outcomes among patients with lung transplantation (LT) requiring admission to the medical ICU (MICU) beyond the perioperative period. METHODS: We interrogated the registry database of all admissions to the MICU at Cleveland Clinic (a 53-bed closed unit) to identify patients with history of LT done > 30 days ago (n = 101; mean age, 55.4 ± 12.6 years; 53 men, 48 women). We collected data regarding demographics, history of bronchiolitis obliterans syndrome, preadmission FEV1, clinical and laboratory variables at admission, MICU course, length of stay, hospital survival, and 6-month survival. RESULTS: The most common indication for MICU admission was acute respiratory failure (n = 51, 50.5%). Infections were most frequently responsible for respiratory failure, whereas acute rejection (cellular or humoral) was less likely (16%). Nearly one-fourth of the patients required hemodialysis (24.1%), and more than one-half required invasive mechanical ventilation (53.5%). Despite excellent hospital survival (88 of 101), 6-month survival was modest (56.4%). APACHE (Acute Physiology and Chronic Health Evaluation) III score at admission and single LT were independent predictors of hospital survival but did not predict outcome at 6 months. Functional status at discharge was the only independent predictor of 6-month survival (adjusted OR, 5.1; 95% CI, 1.1-22.7; P = .035). CONCLUSIONS: Acute rejection is an infrequent cause of decompensation among patients with LT requiring MICU admission. For patients admitted to the MICU, 6-month survival is modest. Functional status at the time of discharge is an independent predictor of survival at 6 months.

Radio-frequency tracking of respiratory equipment: rationale and early experience at the Cleveland Clinic.

BACKGROUND: When respiratory therapists (RTs) seek respiratory care equipment, finding it quickly is desirable, both to expedite patient care and to avert RTs wasting time. To optimize RTs' ability to quickly locate ventilators, we developed and implemented a radio-frequency identification (RFID) tagging system called eTrak. METHODS: The Clinical Engineering and Information Technology groups at Cleveland Clinic collaboratively developed a Wi-Fi-based RFID program that used active RFID tags. Altogether, 218 ventilators, 82 noninvasive ventilators, and various non-respiratory equipment were tagged, beginning in March 2010. We calculated the difference in time required to locate equipment before versus after implementation. RESULTS: The eTrak system had a mean 145 log-ons per week over the first year of use, and was associated with a decreased time required for RTs to locate ventilators: median 18 min (range 1-45 min) versus 3 min (range 1-6 min) (P < .001). Surveys of RTs regarding whether equipment was hard to find before versus after implementing eTrak showed a non-significant trend toward improvement. CONCLUSIONS: An RFID tracking system for respiratory equipment shortened the time to locate ventilators and non-significantly improved RT satisfaction with finding equipment. RFID tagging of equipment warrants further investigation.

Exhaled breath analysis with a colorimetric sensor array for the identification and characterization of lung cancer.

INTRODUCTION: The pattern of exhaled breath volatile organic compounds represents a metabolic biosignature with the potential to identify and characterize lung cancer. Breath biosignature-based classification of homogeneous subgroups of lung cancer may be more accurate than a global breath signature. Combining breath biosignatures with clinical risk factors may improve the accuracy of the signature. OBJECTIVES: To develop an exhaled breath biosignature of lung cancer using a colorimetric sensor array and to determine the accuracy of breath biosignatures of lung cancer characteristics with and without the inclusion of clinical risk factors. METHODS: The exhaled breath of 229 study subjects, 92 with lung cancer and 137 controls, was drawn across a colorimetric sensor array. Logistic prediction models were developed and statistically validated based on the color changes of the sensor. Age, sex, smoking history, and chronic obstructive pulmonary disease were incorporated in the prediction models. RESULTS: The validated prediction model of the combined breath and clinical biosignature was moderately accurate at distinguishing lung cancer from control subjects (C-statistic 0.811). The accuracy improved when the model focused on only one histology (C-statistic 0.825-0.890). Individuals with different histologies could be accurately distinguished from one another (C-statistic 0.864 for adenocarcinoma versus squamous cell carcinoma). Moderate accuracies were noted for validated breath biosignatures of stage and survival (C-statistic 0.785 and 0.693, respectively). CONCLUSIONS: A colorimetric sensor array is capable of identifying exhaled breath biosignatures of lung cancer. The accuracy of breath biosignatures can be optimized by evaluating specific histologies and incorporating clinical risk factors.

Caring for VIPs: nine principles.

Caring for very important persons (VIPs), including celebrities and royalty, presents medical, organizational, and administrative challenges, often referred to collectively as the "VIP syndrome." The situation often pressures the health care team to bend the rules by which they usually practice medicine. Caring for VIP patients requires innovative solutions so that their VIP status does not adversely affect the care they receive. We offer nine guiding principles in caring for VIP patients.

Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase mediate hyperoxia-induced cell death in lung epithelium.

Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat patients with respiratory failure. However, hyperoxia may exacerbate the development of acute lung injury, perhaps by increasing lung epithelial cell death. Therefore, interrupting lung epithelial cell death is an important protective and therapeutic strategy. In the present study, hyperoxia (95% O(2)) results in murine lung epithelium cell death by DNA-laddering, terminal deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V-fluorescein isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide production, as assessed by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity and flow cytometric assay, and increases phospho-extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These processes are inhibited by a reactive oxygen species inhibitor, diphenylene iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, which can all be suppressed by DPI and PD98059. However, the broad caspase inhibitor z-VAD-FMK protects cells from death without affecting superoxide generation and ERK1/2 activation. Taken together, our data suggest that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK activation, and functions upstream of caspase activation in lung epithelial cells.