Gremlin 1 depletion in vivo causes severe enteropathy and bone marrow failure.

The intestinal epithelium is perpetually renewed from a stem cell niche in the base of crypts to maintain a healthy bowel mucosa. Exit from this niche and maturation of epithelial cells requires tightly controlled gradients in BMP signalling, progressing from low BMP signalling at the crypt base to high signalling at the luminal surface. The BMP antagonist gremlin 1 (Grem1) is highly expressed by subepithelial myofibroblasts adjacent to the intestinal crypts but its role in regulating the stem cell niche and epithelial renewal in vivo has not been explored. To explore the effects of Grem1 loss in adulthood following normal growth and development, we bred mice (ROSA26CreER-Grem1 flx/flx ) in which Grem1 could be deleted by tamoxifen administration. While Grem1 remained intact, these mice were healthy, grew normally, and reproduced successfully. Following Grem1 depletion, the mice became unwell and were euthanised (at 7-13 days). Post-mortem examination revealed extensive mucosal abnormalities throughout the small and large intestines with failure of epithelial cell replication and maturation, villous atrophy, and features of malabsorption. Bone marrow hypoplasia was also observed with associated early haematopoietic failure. These results demonstrate an essential homeostatic role for gremlin 1 in maintaining normal bowel epithelial function in adulthood, suggesting that abnormalities in gremlin 1 expression can contribute to enteropathies. We also identified a previously unsuspected requirement for gremlin 1 in normal haematopoiesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair.

OBJECTIVE: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. DESIGN: Prospective, randomized double-blinded control trial. SETTING: Tertiary referral hospital. PARTICIPANTS: Sixty-two patients undergoing elective open AAA repair. INTERVENTION: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). MEASUREMENTS: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. CONCLUSION: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice.

Pulmonary vascular dysfunction in ARDS.

Acute respiratory distress syndrome (ARDS) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (PH). Multiple factors may contribute to the development of PH in this setting. In this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ARDS and reported on mortality in the period 1977 to 2010. There were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. In order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. We consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ARDS, including the important effects of mechanical ventilation. Pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (TPG) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. The great variability in management strategies within and between studies means that no unified analysis of these papers was possible. Uniquely, Bull et al. (Am J Respir Crit Care Med 182:1123-1128, 2010) have recently reported that elevated pulmonary vascular resistance (PVR) and TPG were independently associated with increased mortality in ARDS, in a large trial with protocol-defined management strategies and using lung-protective ventilation. We then considered the existing literature to determine whether the relationship between PVR/TPG and outcome might be causal. Although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. Nonetheless, abnormally elevated PVR/TPG may provide a useful index of disease severity and progression. Further studies are required to understand the role and importance of pulmonary vascular dysfunction in ARDS in the era of lung-protective ventilation.

Are autopsy findings still relevant to the management of critically ill patients in the modern era?

OBJECTIVES: The purpose of this study was to determine the accuracy of clinical diagnoses compared to autopsy findings in critically ill patients in the current medical era. DESIGN: We conducted a retrospective, blinded review of matched medical records and postmortem findings in patients who died between June 2006 and June 2011. SETTING: An ICU of a major university teaching hospital in Dublin, Ireland. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A modification of the Goldman criteria was used to classify diagnostic error. There were 629 ICU deaths during the study period. Two hundred and seven patients underwent autopsy and 204 records were available for review. The mean age was 59 ± 18.1 years, 62% were male, 70% were postoperative patients, and median length of ICU stay was 3 days. Admission diagnosis, admission source, and admission specialty were similar between autopsy and nonautopsy patients. Five patients (2.4%; CI, 0.8-5.6%) had a class I discrepancy and 11 patients (5.4%; CI, 2.4-9.7%) had a class II discrepancy. Minor missed diagnoses were present in 31 patients (15.2%; CI, 4.5-12.4%). There was complete concordance between clinical and postmortem findings (class V) in 161 patients (79%; CI, 72.7-84.3%). In more than half the cases of discrepancy, it was not possible for physicians to make the diagnosis antemortem in the time available, despite appropriate investigations. CONCLUSIONS: We detected a lower rate of clinicopathological discrepancy in critically ill patients than previously reported. Potential reasons for such findings include advances in diagnostic techniques and the use of a more robust definition to classify diagnostic discrepancies. Autopsy can still identify discrepancies in diagnosis even in patients who have undergone appropriate investigations. Prospective research is required to accurately define discrepancy rates in the critically ill population and to identify the patient subgroups in whom autopsy will continue to yield valuable information.

The α and Δ isoforms of CREB1 are required to maintain normal pulmonary vascular resistance.

Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of α and Δ isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the ß isoform intact (CREB(αΔ) mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREB(αΔ) mice. CREB(αΔ) mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREB(αΔ) and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREB(αΔ). CREB(αΔ) mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that α and Δ isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of α and Δ isoforms of CREB1 warrant further investigation in hypoxic lung diseases.

Acute respiratory distress syndrome: underrecognition by clinicians.

BACKGROUND: Previous reports suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is underdiagnosed in both adult and pediatric clinical practice. Underrecognition of this condition may be a barrier to instituting a low tidal volume ventilation strategy. This study aimed to determine the accuracy of clinical diagnoses of ARDS in daily practice using the American European Consensus Conference (AECC) criteria as a criterion standard and to investigate whether clinical recognition of ARDS altered ventilator management. METHODS: This retrospective study included intensive care unit (ICU) patients who died and underwent postmortem examination. Two independent reviewers assigned each patient to those with ALI/ARDS or no ALI. For those who met AECC criteria for ARDS, all patient records were reviewed for the presence of a documented diagnosis of the condition. The accuracy of the clinicians in diagnosing ALI/ARDS was determined, and ventilator settings between the clinically "diagnosed" and "non-diagnosed" groups were compared. The diagnostic accuracy in predetermined subgroups (those with diffuse alveolar damage, with ≥3 affected chest x-ray quadrants, with diagnosis≥3 days, with pulmonary vs extrapulmonary cause) was also examined. RESULTS: Of 98 consecutive ICU patients who died and underwent autopsy, 51 met the inclusion criteria. Sixteen of 51 patients (31.3%) who had ALI/ARDS according to the AECC criteria had this recorded in their clinical notes. Those with histologic evidence of ALI/ARDS (diffuse alveolar damage) and with a more severe chest x-ray pattern or who satisfied the criteria for a number of consecutive days were no more likely to have a clinical diagnosis of ALI/ARDS recorded. However, those with a pulmonary cause of ALI/ARDS were more likely to have a diagnosis recorded. Tidal volumes, positive end-expiratory pressure, and mean airway pressure were higher in those with a clinical diagnosis of ARDS. CONCLUSIONS: Acute respiratory distress syndrome is underrecognized by clinicians in ICU, and recognition does not result in lower tidal volume ventilation. Significant barriers remain to the recognition of ALI/ARDS and application of an evidence-based ventilator strategy.

Hypoxia-induced inflammation in the lung: a potential therapeutic target in acute lung injury?

Acute lung injury (ALI) is a severe form of hypoxic lung disease responsible for a large number of deaths worldwide. Despite recent advances in supportive care, no reduction in mortality has been evident since the introduction of a standard consensus definition almost two decades ago. New strategies are urgently required to help design effective therapies for this condition. A key pathological feature of ALI involves regional alveolar hypoxia. Because alveolar hypoxia in isolation, such as that encountered at high altitude, causes an inflammatory pulmonary phenotype in the absence of any other pathogenic stimuli, these regions may not be passive bystanders but may actually contribute to the pathogenesis and progression of lung injury. Unique transcriptional responses to hypoxia in the lung apparently allow it to express an inflammatory phenotype at levels of hypoxia that would not produce such a response in other organs. We will review recent advances in our understanding of these unique transcriptional responses to moderate levels of alveolar hypoxia, which may provide new insights into the pathogenesis of ALI.

Discrepancies between clinical and autopsy diagnosis in liver transplant recipients - a case series.

The utility of the autopsy in patients who have undergone prior orthotopic liver transplantation (OLT) has not previously been defined. We sought to investigate the role of the autopsy in liver transplantation by comparing the clinically derived cause of death with the autopsy cause of death in a cohort of liver transplant recipients at our institution. This study was undertaken in the setting of declining autopsy rates worldwide. Between 2006 and 2011 twenty-nine patients died who had previously undergone OLT, of on whom 19 postmortem examinations were performed. We retrospectively reviewed all post mortem findings, and separately we examined the corresponding medical records to determine the clinical impression of the cause of death. Discrepancies between the post mortem and clinical findings were categorised according to a modification of Goldman's criteria. Our case series demonstrated a discrepancy between the clinical and post mortem examination (PME) findings in 54% of patients. Two patients had major diagnoses (Goldman Class 1) not detected clinically and in seven patients the PME revealed additional undetected minor diagnoses. This case series demonstrates that, even in the modern era of advanced diagnostic imaging techniques, the post mortem examination continues to be a valuable tool in confirming diagnostic accuracy and improving standards in the care of liver transplant recipients.

Use of 2-hour creatinine clearance to guide cessation of continuous renal replacement therapy.

PURPOSE: A simple test that could guide successful cessation of continuous renal replacement therapy (CRRT) in critically ill patients would be clinically useful. This study aimed to investigate whether a 2-hour creatinine clearance (2h-CrCl) measurement could more accurately predict successful cessation of CRRT than serum creatinine or urine output alone. MATERIALS AND METHODS: This retrospective study identified all patients admitted to a university teaching hospital intensive care unit who received CRRT and had a 2h-CrCl measurement performed in the 12 hours preceding CRRT cessation. The ability of 2h-CrCl to predict successful discontinuation of CRRT was compared to other renal indices. RESULTS: Of 85 patients who had 2h-CrCl performed prior to CRRT cessation 53 (62.4%)(success group) remained dialysis free 7 days after CRRT cessation. 2h-CrCl was a better predictor of remaining CRRT free at day 7 (OR, 1.108 [1.05-1.17] per 1 mL/min increase in 2 hours CrCl, P < .001) than urine output, serum creatinine or age. A 2h-CrCl value of 23 mL/min had a sensitivity, specificity and positive predictive value for remaining CRRT free at day 7 of 75.5%, 84.4%, and 88.8%, respectively. CONCLUSION: 2h-CrCl may be a useful measurement to help guide discontinuation from CRRT.

Use of extracorporeal membrane lung assist device (Novalung) in H1N1 patients.

We present three patients with severe respiratory failure secondary to H1N1 influenza type A pneumonitis, in whom hypercapnia and respiratory acidosis were not controlled by the conventional mechanical lung ventilation or high-frequency oscillatory ventilation. Use of a pumpless arteriovenous extracorporeal carbon dioxide removal device (Novalung™, Inspiration Healthcare Ltd, Leicester, UK) resulted in reduced carbon dioxide levels, improved pH, and a reduction in inspiratory pressures, allowing for a less-harmful ventilator strategy. These cases demonstrate that the Novalung is a safe and effective device to use in patients with H1N1 pneumonitis refractory to the conventional therapy and may be an alternative to extracorporeal membrane oxygenation (ECMO) in selected cases.