Dilip Patel

Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis

With advancing liver disease and the development of portal hypertension, there are major alterations in somatic and visceral blood flow. Using phase‐contrast magnetic resonance angiography, we characterised alterations in blood flow within the hepatic, splanchnic and extra‐splanchnic circulations of patients with established liver cirrhosis.

A Randomized Controlled Trial of Peripheral Blood Mononuclear Cell Depletion in Experimental Human Lung Inflammation

RATIONALE Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial

Background Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. Methods and findings To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population. Conclusions Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. Trial registration ClinicalTrials.gov NCT01640964

Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography

A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49 ± 0.98 versus 3.82 ± 0.86 L/min, P = 0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).

The BRICS (Bronchiectasis Radiologically Indexed CT Score): A Multicenter Study Score for Use in Idiopathic and Postinfective Bronchiectasis

Objectives The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis. Methods The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients. Results A total of 184 high‐resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV1, sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating‐characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV1, 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging. Conclusions A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis.

016 Patient preference in myocardial perfusion imaging - comparison between computed tomography, magnetic resonance imaging, invasive coronary angiography with fractional flow reserve, and positron emission tomography

Introduction Myocardial perfusion can be assessed using a variety of imaging modalities, but little is known regarding patient preference or acceptability. This study assessed patient experience of myocardial perfusion imaging using computed tomography (CT), magnetic resonance imaging (MRI), invasive coronary angiography (ICA) +/− fractional flow reserve and oxygen-15 positron emission tomography (PET/CT). Methods 31 patients underwent CT as part of a research study and completed questionnaires. Of these 28 underwent ICA, 26 MRI and 14 PET/CT. Patients rated concern, comfort and satisfaction on a 5 point Likert scale. Pain during/after investigations were assessed and overall preferences and comments were recorded. Results Prior to CT 71% had no concern, compared to 69% for PET/CT, 50% for MRI and 39% for ICA. The main reasons cited for concern were claustrophobia for MRI and potential side-effects for ICA. Patients reported similar comfort and overall satisfaction for all modalities. Pain during the investigation was slightly lower for ICA compared to MRI or CT, but this difference was not statistically significant. However, pain after the investigation was significantly higher for ICA compared to MRI or CT (P < 0.001). CT was the preferred modality for 42%, compared to ICA for 31%, MRI for 12% and PET/CT for 4%. All patients would be willing to undergo CT or PET/CT again compared to 96% for MRI and 79% for ICA. Conclusion Although overall satisfaction and comfort were similar for all imaging modalities, ICA was associated with more discomfort after the procedure and MRI with more concern regarding claustrophobia.

Reply: The alveolar macrophage and acute respiratory distress syndrome: a silent actor?

We are grateful to Dr. Mokart and colleagues for their interest in our article (1) and for their stimulating comments. We entirely agree that the pathogenesis of acute lung injury (ALI) is complex and that many cell types are likely to be involved. In many respects, our purpose was to stimulate the process of taking a systematic experimental approach from in vivo models to the more relevant human situation. In this setting, and at this very early stage, experimental considerations led us to try to change as few variables as possible (in this case attempting to target circulating monocytes by mononuclear cell leukapheresis). Equally, ethical considerations clearly impacted which cell types we could deplete, and a comprehensive assessment of the role of alveolar macrophages in the human situation was always going to be beyond the scope of our study. Having said this, and in keeping with findings elsewhere (2, 3), our in vivo work showed that prior depletion of alveolar macrophages (with preservation of blood monocytes) did not influence the progression of ALI (4). In contrast, depletion of monocytes after the delivery of intratracheal LPS significantly reduced lung inflammation, despite the preservation of alveolar macrophages (4). The correspondents also make interesting points in relation to the setting of neutropenia. We completely agree that ALI occurs in this context. However, our specific intention was to study the influence of monocytes in a neutrophil-dependent model of lung inflammation. As the authors imply, the pathogenesis of ALI associated with neutropenia is likely to be quite different from “usual” ALI. The authors correctly point out that we depleted monocytes after administration of LPS. However, we have performed similar in vivo experiments in which monocytes were depleted before LPS administration (Dhaliwal and colleagues, unpublished data). Prior monocyte depletion also significantly reduced acute lung inflammation. In our human study, we chose to deplete monocytes after LPS inhalation because physicians are far more commonly faced with established ALI than with the opportunity to prevent it. We accept that “prophylactic” monocyte depletion might potentially have yielded a different outcome from the one we observed in our human study, and this deserves further exploration. We also accept that our model of human inflammation attempts to mimic “subclinical” ALI— monocytes undoubtedly play a role in established ALI. Furthermore, our in vivo model had an endpoint at 48 hours, with optimal monocyte depletion at 18 hours, which was sustained to the end of the study period. This is different from our human model, in which we temporally depleted mononuclear cells within 2 hours of LPS, with a recrudescence before 24 hours. It was not our intention to draw conclusions about “the role of monocytes in ARDS pathophysiology.” In keeping with logistical and ethical constraints, our intention was to evaluate the potential influence of circulating mononuclear cells on subclinical LPS-induced (i.e., neutrophil-dependent) acute lung inflammation in humans. Ultimately, we believe our study highlights the feasibility of evaluating the pathophysiology of (and new interventions for) acute lung inflammation in humans. However, it simultaneously emphasizes difficulties in attempting to replicate experimental conditions and responses between rodents and humans, and the challenges inherent in influencing leukocyte populations in human studies. As Mokart and colleagues imply, experimental and interventional studies of human acute lung inflammation are at an early stage and have a long way to go. n