Cardiogenic shock in pregnancy.

Cardiac disease complicates 1%-4% of pregnancies globally, with a predominance in low and middle-income countries (LMICs). Increasing maternal age, rates of obesity, cardiovascular comorbidities, pre-eclampsia and gestational diabetes all contribute to acquired cardiovascular disease in pregnancy. Additionally, improved survival in congenital heart disease (CHD) has led to increasing numbers of women with CHD undergoing pregnancy. Implementation of individualised care plans formulated through pre-conception counselling and based on national and international guidance have contributed to improved clinical outcomes. However, there remains a significant proportion of women of reproductive age with no apparent comorbidities or risk factors that develop heart disease during pregnancy, with no indication for pre-conception counselling. The most extreme manifestation of cardiac disease is cardiogenic shock (CS), where the primary cardiac pathology results in inadequate cardiac output and hypoperfusion, and is associated with significant mortality and morbidity. Key to management is early recognition, intervention to treat any potentially reversible underlying pathology and supportive measures, up to and including mechanical circulatory support (MCS). In this narrative review we discuss recent developments in the classification of CS, and how these may be adapted to improve outcomes of pregnant women with, or at risk of developing, this potentially lethal condition.

Safety of tracheostomy during extracorporeal membrane oxygenation support: A single-center experience.

BACKGROUND: Some patients on extracorporeal membrane oxygenation (ECMO) require prolonged mechanical ventilation. An early tracheostomy strategy while on ECMO has appeared to be beneficial for these patients. This study aims to explore the safety of tracheostomy in ECMO patients. METHODS: This is a retrospective observational single-center study. RESULTS: Hundred and nine patients underwent tracheostomy (76 percutaneous and 33 surgical) during V-V ECMO support over an 8-year period. Patients with a percutaneous tracheostomy showed a significantly shorter ECMO duration [25.5 (17.3-40.1) vs 37.2 (26.5-53.2) days, p = 0.013] and a shorter ECMO-to-tracheostomy time [13.3 (8.5-19.7) vs 27.8 (16.3-36.9) days, p < 0.001] compared to those who underwent a surgical approach. There was no difference between the two strategies regarding both major and minor/no bleeding (p = 0.756). There was no difference in survival rate between patients who underwent percutaneous or surgical tracheostomy (p = 0.173). Patients who underwent an early tracheostomy (within 10 days from ECMO insertion) showed a significantly shorter hospital stay (p < 0.001) and a shorter duration of V-V ECMO support (p < 0.001). Our series includes 24 patients affected by COVID-19, who did not show significantly higher rates of major bleeding when compared to non-COVID-19 patients (p = 0.297). Within the COVID-19 subgroup, there was no difference in major bleeding rates between surgical and percutaneous approach (p = 1.0). CONCLUSIONS: Percutaneous and surgical tracheostomy during ECMO have a similar safety profile in terms of bleeding risk and mortality. Percutaneous tracheostomy may favor a shorter duration of ECMO support and hospital stay and can be considered a safe alternative to surgical tracheostomy, even in COVID-19 patients, if relevant clinical expertise is available.

High-flow nasal cannula oxygen in patients with haematological malignancy: a retrospective observational study.

Patients with haematological malignancies (HM) face high rates of intensive care unit (ICU) admission and mortality. High-flow nasal cannula oxygen (HFNCO) is increasingly used to support HM patients in ward settings, but there is limited evidence on the safety and efficacy of HFNCO in this group. We retrospectively reviewed all HM patients receiving ward-based HFNCO, supervised by a critical care outreach service (CCOS), from January 2014 to January 2019. We included 130 consecutive patients. Forty-three (33.1%) were weaned off HFNCO without ICU admission. Eighty-seven (66.9%) were admitted to ICU, 20 (23.3%) required non-invasive and 34 (39.5%) invasive mechanical ventilation. ICU and hospital mortality were 42% and 55% respectively. Initial FiO2 < 0.4 (OR 0.27, 95% CI 0.09-0.81, p = 0.019) and HFNCO use on the ward > 1 day (OR 0.16, 95% CI 0.04, 0.59, p = 0.006) were associated with reduced likelihood for ICU admission. Invasive ventilation was associated with reduced survival (OR 0.27, 95%CI 0.1-0.7, p = 0.007). No significant adverse events were reported. HM patients receiving ward-based HFNCO have higher rates of ICU admission, but comparable hospital mortality to those requiring CCOS review without respiratory support. Results should be interpreted cautiously, as the model proposed depends on the existence of CCOS.

The role of a critical care outreach service in the management of patients with haematological malignancy.

INTRODUCTION: Although improvement in survival from haematological malignancies has been reported, a substantial number of these patients develop life threatening complications. Critical care outreach services (CCOS) aim to avert inappropriate ICU admissions, while ensuring timely patient review. METHODS: We retrospectively analysed patients with haematological malignancy reviewed by an outreach service between January 2014 and December 2015 at a single institution. The aim of our study was to describe the patient population assessed by a well-established outreach team, identify predictors of ICU admission, as well as ICU and hospital mortality. RESULTS: Sixty of 126 patients reviewed (47.6%) were admitted to ICU. ICU and hospital mortality were 25.3% and 45.2%, respectively. The odds of being admitted to ICU was 13 times higher (p = 0.013) if the patient was referred for hypoxia, 20 times higher (p = 0.006) if they were referred for sepsis or 14 times higher (p = 0.027) if they were referred to CCOS for hypotension, compared to when the team was automatically alerted. The odds of not surviving hospital admission increased 1.27 times for every extra day of CCOS review (p = 0.02). When a patient was referred having a refractory or progressive haematological condition, the odds of not surviving to hospital discharge increased by four or 12 times, respectively, compared to when the referred patient was in remission. Receiving high flow nasal cannula oxygen (HFNCO) was associated with a reduction in ICU admission (p = 0.03), irrespective of the underlying diagnosis, performance status or location of delivery. The CCOS participated in end-of-life discussions in 29% patients. CONCLUSIONS: ICU and hospital mortality of patients with haemato-oncological malignancy continue to improve. CCOS are heavily involved in the recognition and management of these patients, as well as in the facilitation of end-of-life discussions. Sepsis was associated with increased risk of ICU admission and mortality. Initiation of HFNCO outside ICU appears to be feasible and safe and was not associated with increasing risk in this single centre study.

Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine's role in PDA through studying its effect on OPN. Nicotine significantly (p < 0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved. Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA.

Expression and regulation of osteopontin in type 1 diabetes.

Osteopontin (OPN) is a secreted acidic phosphoprotein that is involved in many inflammatory and immune-modulating disorders. We previously demonstrated that OPN is a novel islet protein and a pro survival factor that may serve as an intrinsic feedback regulator of nitric oxide signaling in ß-cells. Here, we investigated the endogenous expression of pancreatic OPN in non obese diabetic (NOD) mice and explored its regulation in the islets and b-cells. High levels of pancreatic OPN mRNA and protein were seen in the prediabetic NOD mice pancreata. The temporal pattern of OPN expression inversely correlated with progression of insulitis and ß-cell destruction. Immunostaining of pancreatic serial sections showed co localization of OPN with most of the islet hormones. Next we investigated the regulation of OPN in the islets and ß-cells. Naturally occurring early upregulation of OPN transcription was seen after exposure of native normoglycemic NOD islets and ß-cells to a high-dose combination of IL-1ß, TNF-α and IFN-γ. To distinguish between the effect of cytokines and high glucose on OPN transcription, RINm5F cells were transfected with luciferase-labeled rat OPN promoter and treated with cytokines or glucose. Cytokines induced upregulation of OPN promoter activity within one hour, while glucose induced a dose-dependent upregulation of OPN promoter activity after 24 hrs. Long-term exposures to cytokines or glucose reduced OPN expression and promoter activity. Our data provide the first observations into the presence of a positive intrinsic mechanism that regulates pancreatic OPN expression. Based upon previous studies that support a protective role of OPN in the islets, our data suggest that exhaustion of this local OPN system is implicated in the associated loss of endogenous islet protection and progression of the destructive insulitis and diabetes severity in the NOD mouse model.

Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling.

Vascular endothelial growth factor (VEGF) is a crucial pro-angiogenic component in pancreatic ductal adenocarcinoma (PDA), and its high expression levels have been correlated with poor prognosis and early postoperative recurrence. We have recently shown that high levels of angiotensin II (AngII) type 1 receptor (AT1R) correlate and colocalize with VEGF in invasive PDA and that AngII induces VEGF expression in PDA cell lines. In this study, we explored the signaling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1R and VEGF expression in noninvasive precursor lesions. An AT1R antagonist significantly (p<0.05) inhibited the AngII-mediated induction of VEGF messenger RNA and protein in all PDA cell lines. AngII-VEGF induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a mitogen-activated protein kinase signaling mechanism. AngII activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced VEGF synthesis. Immunohistochemical analysis of precursor lesions showed increased expression of AT1R in most ductal cells undergoing metaplasia. Pancreatic intraepithelial neoplasms showed more intense AT1R staining when compared to intraductal papillary mucinous neoplasms, which showed heterogeneous immunoreactivity. VEGF followed the same distribution pattern of AT1R in both lesions. AT1R expression in the premalignant pancreatic lesions suggests its involvement in tumor progression and angiogenesis. Our mechanistic findings provide the first insight into an AngII-initiated signaling pathway that regulates PDA angiogenesis. An AT1R-mediated VEGF induction suggests the possibility of AT1R blockade as a novel therapeutic strategy to control angiogenesis in PDA.