The paradigm shift from polycythemia to anemia in COPD: the critical role of the renin-angiotensin system inhibitors.

INTRODUCTION: Although polycythemia has been considered a common adverse event in COPD, anemia is reported more often and has gained more importance than polycythemia over the last thirty years. AREAS COVERED: Factors considered to be associated with the development of anemia in COPD have included: Aging and kidney dysfunction with erythropoietin deficiency and bone marrow suppression due to uremic toxins; heart failure (HF), often encountered in COPD and accompanied by anemia in one-third of the cases; Low-grade chronic inflammation, directly suppressing bone marrow and diminishing iron absorption and utilization via increased hepcidin levels; long-term oxygen therapy (LTOT), ameliorating chronic hypoxia, and most important, RAS inhibitors, which are widely used for the comorbidities associated with COPD (hypertension, HF, CKD, diabetes) and have previously been shown to lower hematocrit values or cause anemia in various clinical conditions. EXPERT OPINION: Introduction of LTOT in COPD and especially the established use of RAS inhibitors form the basis for the shift from polycythemia to anemia in COPD. Interestingly, when the SGLT2 inhibitors are introduced for cardiorenal protection in COPD, one could anticipate correction of anemia or even reemergence of polycythemia, since this new class of drugs can augment erythropoietin secretion and increase hematocrit values.

Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers on Acute Kidney Injury in Emergency Medical Admissions.

BACKGROUND: Acute kidney injury (AKI) has been observed in up to 20% of adult hospital admissions. Sepsis, diarrhea and heart failure, all causing reduced effective volume, are considered risk factors for AKI, especially among patients treated with medications that block the Renin-Angiotensin System (RAS), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). We aimed to determine the incidence of acute kidney injury (AKI) in emergency medical admissions in relation to the use and dosage of ACEi/ARB. METHODS: A single-center observational study conducted in 577 consecutive medical admissions via the Emergency Room (ER) at a University General Hospital in Athens, Greece, between June and July 2018. Patients with incomplete medical records, discharged within 24 h, maintained on chronic renal replacement therapy, admitted to the Cardiology Department or the ICU were excluded. Thus, a total of 309 patients were finally included in this analysis. RESULTS: We compared 86 (28%) patients who presented in the ER with AKI (AKIGroup) with 223 (72%) patients without AKI (non-AKI Group) at the time of admission. Patients in the AKI Group were more frequently male (58% vs. 46%, p = 0.06), with a higher frequency of diarrhea (16% vs. 6%, p = 0.006), edema (15% vs. 6%, p = 0.014) and lower systolic blood pressure (120 (107-135) vs. 126 (113-140), p = 0.007) at presentation, despite higher prevalence of hypertension (64% vs. 47%, p = 0.006). Overall, ACEi/ARB were more likely to have been prescribed in the AKI Group than in the non-AKI Group (49% vs. 28%, p = 0.001). Interestingly, AKI was more frequently observed in patients treated with the target or above target dosage of ACEi/ARB, but not in those receiving lower than the recommended dosage. CONCLUSION: The risk of AKI in emergency medical admissions is higher among users of ACEIs/ARB at target or above target dosages. Physicians should adjust RAS blockade according to estimated Glomerular Filtration Rate (eGFR) and advise their patients to withhold ACEi/ARB in cases of acute illness.

Hyperferritinemia in patients with COVID-19: An opportunity for iron chelation?

Studies from China on COVID-19 revealed that nonsurvivors had cytokine storm with high IL-6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free radical production and amplify lipid peroxidation causing membrane dysfunction and multiorgan failure. Consequently, iron chelators have been successfully utilized in various experimental and clinical models of cytokine storm and multiorgan damage, such as in ischemia-reperfusion injury, sepsis, and infections. Since viral replication may be influenced by iron accumulation, iron chelation has been proven beneficial in a variety of viral infections, such as HIV-1, hepatitis B virus, Mengovirus, Marburg hemorrhagic fever, Enterovirus 71, and West Nile virus. In this commentary, we elaborate on the idea of considering iron chelation as a therapeutic modality in patients with severe COVID-19 infection. For critically ill patients in the ICU, intravenous deferoxamine would provide sufficient and rapid iron chelation to ameliorate cytokine storm, whereas in less severe cases an oral chelator could prevent the development of excessive inflammatory response.

Sonographic muscle mass assessment in patients after cardiac surgery.

BACKGROUND: Patients undergoing cardiac surgery particularly those with comorbidities and frailty, experience frequently higher rates of post-operative morbidity, mortality and prolonged hospital length of stay. Muscle mass wasting seems to play important role in prolonged mechanical ventilation (MV) and consequently in intensive care unit (ICU) and hospital stay. AIM: To investigate the clinical value of skeletal muscle mass assessed by ultrasound early after cardiac surgery in terms of duration of MV and ICU length of stay. METHODS: In this observational study, we enrolled consecutively all patients, following their admission in the Cardiac Surgery ICU within 24 h of cardiac surgery. Bedside ultrasound scans, for the assessment of quadriceps muscle thickness, were performed at baseline and every 48 h for seven days or until ICU discharge. Muscle strength was also evaluated in parallel, using the Medical Research Council (MRC) scale. RESULTS: Of the total 221 patients enrolled, ultrasound scans and muscle strength assessment were finally performed in 165 patients (patients excluded if ICU stay < 24 h). The muscle thickness of rectus femoris (RF), was slightly decreased by 2.2% [(95% confidence interval (CI): - 0.21 to 0.15), n = 9; P = 0.729] and the combined muscle thickness of the vastus intermedius (VI) and RF decreased by 3.5% [(95%CI: - 0.4 to 0.22), n = 9; P = 0.530]. Patients whose combined VI and RF muscle thickness was below the recorded median values (2.5 cm) on day 1 (n = 80), stayed longer in the ICU (47 ± 74 h vs 28 ± 45 h, P = 0.02) and remained mechanically ventilated more (17 ± 9 h vs 14 ± 9 h, P = 0.05). Moreover, patients with MRC score ≤ 48 on day 3 (n = 7), required prolonged MV support compared to patients with MRC score ≥ 49 (n = 33), (44 ± 14 h vs 19 ± 9 h, P = 0.006) and had a longer duration of extracorporeal circulation was (159 ± 91 min vs 112 ± 71 min, P = 0.025). CONCLUSION: Skeletal quadriceps muscle thickness assessed by ultrasound shows a trend to a decrease in patients after cardiac surgery post-ICU admission and is associated with prolonged duration of MV and ICU length of stay.

Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes.

BACKGROUND: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. SUMMARY: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Inhibition of the renin-angiotensin system in the cardiorenal syndrome with anaemia: a double-edged sword.

: The term 'cardiorenal syndrome' (CRS) was introduced to describe problems related to the simultaneous existence of heart and renal insufficiency. The prevalence of anaemia in CRS is high and increases the risk of hospitalizations and death. Renin-angiotensin system (RAS) inhibition is the cornerstone therapy in cardiovascular and renal medicine. As angiotensin II regulates both glomerular filtration rate (GFR) and erythropoiesis, RAS inhibition can further deteriorate renal function and lower hematocrit or cause anaemia in patients with heart failure. The aim of this review is to explore the relationship among CRS, anemia and administration of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and summarize the evidence suggesting that RAS inhibition may be considered an iatrogenic cause of deterioration of CRS with anemia. It should be emphasized however, that RAS inhibition reduces mortality in both groups with and without worsening of renal function, and therefore, no patient with CRS should be denied an ACEi or ARB trial without careful evaluation.

Determinants of prolonged intensive care unit stay in patients after cardiac surgery: a prospective observational study.

BACKGROUND: Prolonged intensive care unit (ICU) stay of patients after cardiac surgery has a major impact on overall cost and resource utilization. The aim of this study was to identify perioperative factors which prolong stay in ICU. METHODS: All adult patients from a single, specialized cardiac center who were admitted to the ICU after cardiac surgery during a 2-month period were included. Demographic and clinical characteristics, comorbidities, preoperative use of drugs, intraoperative variables, and postoperative course were recorded. Hemodynamic and blood gas measurements were recorded at four time intervals during the first 24 postoperative hours. Routine hematologic and biochemical laboratory results were recorded preoperatively and in the first postoperative hours. RESULTS: During the study period 145 adult patients underwent cardiac surgery: 65 (45%) underwent coronary artery bypass graft surgery, 38 (26%) valve surgery, 26 (18%) combined surgery and 16 (11%) other types of cardiac operation. Seventy nine (54%) patients had an ICU stay of less than 24 hours. Random forests analysis identified four variables that had a major impact on the length of stay (LOS) in ICU; these variables were subsequently entered in a logistic regression model: preoperative hemoglobin [odds ratio (OR) =0.68], duration of aortic clamping (OR =1.01) and ratio of arterial oxygen partial pressure to inspired oxygen fraction (PaO2/FiO2) (OR =0.99) and blood glucose during the first four postoperative hours (OR =1.02). ROC curve analysis showed an AUC =0.79, P<0.001, 95% CI: 0.71-0.86. CONCLUSIONS: Low preoperative hemoglobin, prolonged aortic clamping time and low PaO2/FiO2 ratio and blood glucose measured within the first postoperative hours, were strongly related with prolonged LOS in ICU.

Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin-induced thrombocytopenia-reactive antibodies or with true HIT (HIT-reactive antibodies plus thrombocytopenia): An 11-year experience.

Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three-point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to ≤5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached ≤5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT.

Factors influencing arrival of patients with acute myocardial infarction at emergency departments: implications for community nursing interventions.

AIM: This paper identifies the characteristics of Greek patients with acute myocardial infarction who have long prehospital delays and identifies the factors that are specifically associated with these delays. BACKGROUND: The time between the first appearance of symptoms until the hospitalization of the patient with myocardial infarction correlates statistically significantly with in-hospital and long-term mortality. METHODS: The study took place in two Greek coronary care units from 1 June 2007 to 31 July 2008. From 232 consecutive patients with myocardial infarction, 160 were enrolled. Data were collected by a trained hospital staff nurse, who interviewed all patients within 48 hours of hospital admission. RESULTS: Smokers arrived statistically significantly sooner at the hospital than non-smokers [smokers' prehospital time delay: 78.9 (sd = 3.2) minutes vs. non-smokers' prehospital time delay: 98.2 (sd = 4.1) minutes, Mann-Whitney U-test, Z = -2.5, P < 0.05]. Patients with hyperlipidaemia arrived with a mean delay of 13 minutes less than normolipidaemic patients. Those with inferior ST segment elevation myocardial infarction exhibited statistically significantly shorter delay times than those with anterior or lateral (inferior vs. anterior, P = 0.003, inferior vs. lateral, P = 0.024, anova with Bonferroni-Holm post hoc test, F = 7.5, P = 0.001). CONCLUSION: Community nurses should educate all patients about myocardial infarction, not only those at high risk but also those without known risk factors for ischaemic heart disease.

The role of the renin-angiotensin system in the regulation of erythropoiesis.

The renin-angiotensin system is the major regulator of blood pressure by virtue of controlling vascular resistance and plasma volume. Much less recognition exists for the role of the renin-angiotensin system in regulating erythropoiesis, a biological function critical for oxygen delivery to tissues. In this review, we present evidence that angiotensin II (Ang II) is a physiologically important regulator of erythropoiesis with 2 key actions. First, Ang II is a growth factor of erythroid progenitors and, in cooperation with erythropoietin, increases red blood cell mass. Second, Ang II acts as an erythropoietin secretagogue to maintain increased erythropoietin levels despite increments in hematocrit. Among a multitude of physiologic and pathophysiologic implications, these lines of evidence provide an explanation for the effect of angiotensin-converting enzyme inhibitors and Ang II type 1 receptor blockers to decrease hematocrit or cause anemia in various clinical conditions.

Nurses are more efficient than doctors in teaching basic life support and automated external defibrillator in nurses.

BACKGROUND: Cardiac arrest (CA) is a leading cause of death worldwide. The European Resuscitation Council (ERC) has developed basic life support/automated external defibrillation (BLS/AED) courses for uniform training in out-of-hospital CA. OBJECTIVE: The present study compares the resuscitation skills of two groups of nursing staff, one taught by newly trained ERC nurse-instructors and the other by newly trained doctor-instructors. METHOD: Eighteen doctors and 18 nurses were asked to teach a total of 108 nurses in a (BLS/AED) course. One month after its completion, all 108 nurses were asked to be re-evaluated, with the use of the objective structured clinical examination. CONCLUSIONS: No statistical significant difference between the two groups was noted in the written test, in contrast with data collected from the practice skills check-list. Nurses in group A could easily identify the patient in cardiac arrest but had difficulties concerning chest compressions and handling the AED. Nurses in group B were more focused during the performances, used AED more accurately and continued cardiopulmonary resuscitation with no delays. Nurses prove to be more efficient in training nurses.

Preoperative intravenous hydration confers renoprotection in patients with chronic kidney disease undergoing cardiac surgery.

Patients with chronic kidney disease (CKD) are at risk to develop acute renal failure (ARF) after open heart surgery. This complication is associated with high morbidity, mortality, and cost. Because the ability to concentrate urine is lost early in the progression of CKD, renal patients kept on fluid restriction prior to surgery may develop severe dehydration, a situation consistently found to be one of the most critical risk factors for postoperative ARF. Our goal was to investigate whether intravenous hydration for 12 h prior to cardiac surgery could prevent acute renal injury in patients with CKD. This is a prospective study in a tertiary cardiac surgery center. Forty-five patients admitted for elective open heart surgery with moderate-to-severe CKD, as evidenced by a quantified glomerular filtration rate less than 45 mL/min, were assigned using a 2/1 randomization process, to either receive an intravenous infusion of half-isotonic saline (1 mL/kg/h) for 12 h before the operation (hydration group, n = 30, 29 men, 64 + 1.7 years old), or to be simply kept on fluid restriction (control group, n = 15, 14 men, 64.2 + 2.8 years old). Groups were not different in clinical and intraoperative variables associated with postoperative renal injury. ARF developed in 8 of 15 (53%) patients in the control group, but in only 9 of the 30 (30%) patients in the hydration group. Four patients in the control group (27%), but no one in the hydration group, required dialysis after the operation (P < 0.01). Peak creatinine and blood urea nitrogen values were two to three times higher in the control group than in the hydration group. Preoperative intravenous hydration may ameliorate renal damage in patients with moderate-to-severe renal insufficiency undergoing cardiac surgery.

Posttransplant erythrocytosis.

Posttransplant erythrocytosis (PTE) is defined as a persistently elevated hematocrit to a level greater than 51% after renal transplantation. It occurs in 10% to 15% of graft recipients and usually develops 8 to 24 months after engraftment. Spontaneous remission of established PTE is observed in one fourth of the patients within 2 years from onset, whereas in the remaining three fourths it persists for several years, only to remit after loss of renal function from rejection. Predisposing factors include male gender, retention of native kidneys, smoking, transplant renal artery stenosis, adequate erythropoiesis prior to transplantation, and rejection-free course with well-functioning renal graft. Just as in other forms of erythrocytosis, a substantial number (approximately 60%) of patients with PTE experience malaise, headache, plethora, lethargy, and dizziness. Thromboembolic events occur in 10% to 30% of the cases; 1% to 2% eventually die of associated complications. Posttransplant erythrocytosis results from the combined trophic effect of multiple and interrelated erythropoietic factors. Among them, endogenous erythropoietin appears to play the central role. Persistent erythropoietin secretion from the diseased and chronically ischemic native kidneys does not conform to the normal feedback regulation, thereby establishing a form of "tertiary hypererythropoietinemia." However, erythropoietin levels in most PTE patients still remain within the "normal range," indicating that erythrocytosis finally ensues by the contributory action of additional growth factors on erythroid progenitors, such as angiotensin II, androgens, and insulin-like growth factor 1 (IGF-1). Inactivation of the renin-angiotensin system (RAS) by an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II type 1 AT1 receptor blocker represents the most effective, safe, and well-tolerated therapeutic modality.

Safety and efficacy of off-pump coronary artery bypass grafting in chronic dialysis patients.

Off-pump coronary artery bypass grafting (CABG) has been recently revived, because cardiopulmonary bypass (CPB) appears to worsen the multiple organ dysfunction after conventional CABG. To evaluate the safety and efficacy of the off-pump CABG in chronic dialysis patients, we compared the perioperative morbidity and mortality between 15 dialysis patients who underwent off-pump CABG at our center over the past 8 years with that of a concurrent group of 19 patients who underwent conventional CABG. Patients were selected for off-pump CABG only when complete revascularization was technically feasible. We found that off-pump CABG is as safe and effective as conventional CABG in selected dialysis patients. It might even be beneficial, because it is associated with less hematocrit drop and blood product use, a lower catabolic rate, and fewer dialysis requirements after surgery. However, the impact of off-pump technique on the long-term clinical outcome and resource utilization in renal patients requires further investigation.