The effect of endotracheal suction on regional tidal ventilation and end-expiratory lung volume

Purpose: To examine the impact of different endotracheal tube (ETT) suction techniques on regional end-expiratory lung volume (EELV) and tidal volume (VT) in an animal model of surfactant-deficient lung injury. Methods: Six 2-week old piglets were intubated (4.0 mm ETT), muscle-relaxed and ventilated, and lung injury was induced with repeated saline lavage. In each animal, open suction (OS) and two methods of closed suction (CS) were performed in random order using both 5 and 8 French gauge (FG) catheters. The pre-suction volume state of the lung was standardised on the inflation limb of the pressure-volume relationship. Regional EELV and VT expressed as a proportion of the impedance change at vital capacity (%ZVCroi) within the anterior and posterior halves of the chest were measured during and for 60 s after suction using electrical impedance tomography. Results: During suction, 5 FG CS resulted in preservation of EELV in the anterior (nondependent) and posterior(dependent) lung compared to the other permutations, but these only reached significance in the anterior regions (p\0.001 repeated-measures ANOVA). VT within the anterior, but not posterior lung was significantly greater during 5FG CS compared to 8 FG CS; the mean difference was 15.1 [95% CI 5.1, 25.1]%ZVCroi. Neither catheter size nor suction technique influenced post-suction regional EELV or VT compared to pre-suction values (repeated-measures ANOVA). Conclusions: ETT suction causes transient loss of EELV and VT throughout the lung. Catheter size exerts a greater influence than suction method, with CS only protecting against derecruitment when a small catheter is used, especially in the non-dependent lung.

A Bayesian approach to assess interaction between known risk factors: The risk of lung cancer from exposure to asbestos and smoking

We review the literature on the combined effect of asbestos exposure and smoking on lung cancer, and explore a Bayesian approach to assess evidence of interaction. Previous approaches have focussed on separate tests for an additive or multiplicative relation. We extend these approaches by exploring the strength of evidence for either relation using approaches which allow the data to choose between both models. We then compare the different approaches.

Oxygen delivery through high-flow nasal cannulae increase end-expiratory lung volume and reduce respiratory rate in post-cardiac surgical patients

Background: High-flow nasal cannulae (HFNC) create positive oropharyngeal airway pressure but it is unclear how their use affects lung volume. Electrical impedance tomography (EIT) allows assessment of changes in lung volume by measuring changes in lung impedance. Primary objectives were to investigate the effects of HFNC on airway pressure (Paw) and end-expiratory lung volume (EELV), and to identify any correlation between the two. Secondary objectives were to investigate the effects of HFNC on respiratory rate (RR), dyspnoea, tidal volume and oxygenation; and the interaction between body mass index (BMI) and EELV. Methods: Twenty patients prescribed HFNC post-cardiac surgery were investigated. Impedance measures, Paw, PaO2/FiO2 ratio, RR and modified Borg scores were recorded first on low flow oxygen (nasal cannula or Hudson face mask) and then on HFNC. Results: A strong and significant correlation existed between Paw and end-expiratory lung impedance (EELI) (r=0.7, p<0.001). Compared with low flow oxygen, HFNC significantly increased EELI by 25.6% (95% CI 24.3, 26.9) and Paw by 3.0 cmH2O (95% CI 2.4, 3.7). RR reduced by 3.4 breaths per minute (95% CI 1.7, 5.2) with HFNC use, tidal impedance variation increased by 10.5% (95% CI 6.1, 18.3) and PaO2/FiO2 ratio improved by 30.6 mmHg (95% CI 17.9, 43.3). HFNC improved subjective dyspnoea scoring (p=0.023). Increases in EELI were significantly influenced by BMI, with larger increases associated with higher BMIs (p<0.001). Conclusions: This study suggests that HFNC improve dyspnoea and oxygenation by increasing both EELV and tidal volume, and are most beneficial in patients with higher BMIs.

Non-pharmacological interventions for breathlessness management in patients with lung cancer : A systematic review

The aim is to review the published scientific literature for studies evaluating nonpharmacological interventions for breathlessness management in patients with lung cancer. The following selection criteria were used to systematically search the literature: studies were to be published research or systematic reviews; they were to be published in English and from 1990 to 2007; the targeted populations were adult patients with dyspnoea/breathlessness associated with lung cancer; and the study reported on the outcomes from use of non-pharmacological strategies for breathlessness. This review retrieved five studies that met all inclusion criteria. All the studies reported the benefits of non-pharmacological interventions in improving breathlessness regardless of differences in clinical contexts, components of programmes and methods for delivery. Analysis of the available evidence suggests that tailored instructions delivered by nurses with sufficient training and supervision may have some benefits over other delivery approaches. Based on the results, non-pharmacological interventions are recommended as effective adjunctive strategies in managing breathlessness for patients with lung cancer. In order to refine such interventions, future research should seek to explore the core components of such approaches that are critical to achieving optimal outcomes, the contexts in which the interventions are most effective, and to evaluate the relative benefits of different methods for delivering such interventions.

PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Age of blood and recipient factors determine the severity of transfusion-related acute lung injury (TRALI)

Introduction Critical care patients frequently receive blood transfusions. Some reports show an association between aged or stored blood and increased morbidity and mortality, including the development of transfusion-related acute lung injury (TRALI). However, the existence of conflicting data endorses the need for research to either reject this association, or to confirm it and elucidate the underlying mechanisms. Methods Twenty-eight sheep were randomised into two groups, receiving saline or lipopolysaccharide (LPS). Sheep were further randomised to also receive transfusion of pooled and heat-inactivated supernatant from fresh (Day 1) or stored (Day 42) non-leucoreduced human packed red blood cells (PRBC) or an infusion of saline. TRALI was defined by hypoxaemia during or within two hours of transfusion and histological evidence of pulmonary oedema. Regression modelling compared physiology between groups, and to a previous study, using stored platelet concentrates (PLT). Samples of the transfused blood products also underwent cytokine array and biochemical analyses, and their neutrophil priming ability was measured in vitro. Results TRALI did not develop in sheep that first received saline-infusion. In contrast, 80% of sheep that first received LPS-infusion developed TRALI following transfusion with "stored PRBC." The decreased mean arterial pressure and cardiac output as well as increased central venous pressure and body temperature were more severe for TRALI induced by "stored PRBC" than by "stored PLT." Storage-related accumulation of several factors was demonstrated in both "stored PRBC" and "stored PLT", and was associated with increased in vitro neutrophil priming. Concentrations of several factors were higher in the "stored PRBC" than in the "stored PLT," however, there was no difference to neutrophil priming in vitro. Conclusions In this in vivo ovine model, both recipient and blood product factors contributed to the development of TRALI. Sick (LPS infused) sheep rather than healthy (saline infused) sheep predominantly developed TRALI when transfused with supernatant from stored but not fresh PRBC. "Stored PRBC" induced a more severe injury than "stored PLT" and had a different storage lesion profile, suggesting that these outcomes may be associated with storage lesion factors unique to each blood product type. Therefore, the transfusion of fresh rather than stored PRBC may minimise the risk of TRALI.

End-expiratory lung volume recovers more slowly after closed endotracheal suctioning than after open suctioning : a randomized crossover study

Purpose Endotracheal suctioning causes significant lung derecruitment. Closed suction (CS) minimizes lung volume loss during suction, and therefore, volumes are presumed to recover more quickly postsuctioning. Conflicting evidence exists regarding this. We examined the effects of open suction (OS) and CS on lung volume loss during suctioning, and recovery of end-expiratory lung volume (EELV) up to 30 minutes postsuction. Material and Methods Randomized crossover study examining 20 patients postcardiac surgery. CS and OS were performed in random order, 30 minutes apart. Lung impedance was measured during suction, and end-expiratory lung impedance was measured at baseline and postsuctioning using electrical impedance tomography. Oximetry, partial pressure of oxygen in the alveoli/fraction of inspired oxygen ratio and compliance were collected. Results Reductions in lung impedance during suctioning were less for CS than for OS (mean difference, − 905 impedance units; 95% confidence interval [CI], − 1234 to –587; P < .001). However, at all points postsuctioning, EELV recovered more slowly after CS than after OS. There were no statistically significant differences in the other respiratory parameters. Conclusions Closed suctioning minimized lung volume loss during suctioning but, counterintuitively, resulted in slower recovery of EELV postsuction compared with OS. Therefore, the use of CS cannot be assumed to be protective of lung volumes postsuctioning. Consideration should be given to restoring EELV after either suction method via a recruitment maneuver.

Generation and characterisation of Cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature

Introduction: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. Methods: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Results: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Conclusion: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer. © 2013 Barr et al.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

Why we need a population-based approach to clinical indicators for cancer: a case study using microscopic confirmation of lung cancer in Queensland

An important function of clinical cancer registries is to provide feedback to clinicians on various performance measures. To date, most clinical cancer registries in Australia are located in tertiary academic hospitals, where adherence to guidelines is probably already high. Microscopic confirmation is an important process measure for lung cancer care. We found that the proportion of patients with lung cancer without microscopic confirmation was much higher in regional public hospitals (27.1%) than in tertiary hospitals (7.5%), and this disparity remained after adjusting for age, sex and comorbidities. The percentage was also higher in the private than in the public sector. This case study shows that we need a population-based approach to measuring clinical indicators that includes regional public hospitals as a matter of priority and should ideally include the private sector.