Filippo Annoni

Angiotensin II in Refractory Septic Shock

ABSTRACT Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin–angiotensin–aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

No relationship between red blood cell distribution width and microcirculatory alterations in septic patients

BACKGROUND Increased red cell distribution width (RDW), a quantitative measure of erythrocyte size variability, has been associated with increased mortality in critically ill patients. METHODS In this post-hoc analysis of prospectively collected data, we studied 122 septic patients with and without shock who had undergone sublingual microcirculatory assessment using Sidestream Dark Field (SDF) videomicroscopy. Patient demographics, comorbidities, the Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission and the Sequential Organ Failure Assessment (SOFA) score on the day of the microcirculatory assessment were collected. The RDW was retrospectively collected on the day of the microcirculatory evaluation from the routine daily blood count analysis. RESULTS Median patient age was 68[55-77] years, and median APACHE II and SOFA scores were 22[17-28] and 10[8-12], respectively; ICU mortality was 43%. On the day of the microcirculatory analysis, the median RDW was 13.8[12.8-15.5]% and was elevated (>13.4%) in 74 (61%) patients. There was no correlation between RDW and microcirculatory parameters (functional capillary density, r2 = 0.12; proportion of small perfused vessels, r2 = 0.17; mean flow index, r2 = 0.14). RDW was not related to disease severity, the presence of shock or survival. CONCLUSIONS RDW is not associated with microcirculatory alterations or prognosis in septic patients.

Early Effects of Enteral Urea on Intracranial Pressure in Patients With Acute Brain Injury and Hyponatremia

Background: Hyponatremia occurs commonly after acute brain injury and is often due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Urea administration is 1 therapeutic option. Methods: In our Department, enteral urea is routinely administered to patients with acute brain injury who develop hyponatremia consistent with SIADH and do not respond to an initial sodium load. We reviewed the records of all patients over a 2-year period, who had acute brain injury, received enteral urea because of hyponatremia, and had intracranial pressure (ICP) monitoring using an intraventricular catheter. We recorded demographic, biological, and clinical data; mean ICP values during the 6 hours before and after the first dose of urea were also recorded. Results: We included 40 patients (23 subarachnoid hemorrhage, 8 traumatic brain injury, 6 intracranial hemorrhage, 2 postbrain tumor surgery, and 1 ischemic stroke); median age was 54 years (IQRs, 44 to 63 y) and median admission APACHE II score was 19 (13 to 19); 6-month survival was 63%. Median baseline sodium was 133 mEq/L (131 to 135 mEq/L). No patients received additional therapy to decrease ICP during the 6 hours following urea initiation. After the first urea dose (15 g), ICP decreased from 14 (13 to 18 mm Hg) to 11 mm Hg (8 to 13 mm Hg) (P<0.001). Changes in ICP were not correlated to changes in sodium (r2=0.02). The reduction in ICP was larger in patients with ICP≥15 mm Hg (n=22) than in the others (−8 mm Hg [−14 to −3 mm Hg] vs. −2 mm Hg [−3 to 0 mm Hg], P=0.001). Conclusions: Enteral urea administration in patients with acute brain injury and hyponatremia is associated with a significant reduction in ICP independent of changes in sodium levels.

Red Cell Distribution Width After Subarachnoid Hemorrhage

Background: High red cell distribution width (RDW) values have been associated with increased hospital mortality in critically ill patients, but few data are available for subarachnoid hemorrhage (SAH). Methods: We analyzed an institutional database of adult (>18 y) patients admitted to the Department of Intensive Care after nontraumatic SAH between January 2011 and May 2016. RDW (normal value, 10.9% to 13.4%) was obtained daily from admission for a maximum of 7 days, from routine blood analysis. We recorded the occurrence of delayed cerebral ischemia (DCI), and neurological outcome (assessed using the Glasgow Outcome Scale [GOS]) at 3 months. Results: A total of 270 patients were included (median age 54 y—121/270 male [45%]), of whom 96 (36%) developed DCI and 109 (40%) had an unfavorable neurological outcome (GOS, 1 to 3). The median RDW on admission was 13.8 [13.3 to 14.5]% and the highest value during the intensive care unit (ICU) stay 14.2 [13.6 to 14.8]%. The RDW was high (>13.4%) in 177 patients (66%) on admission and in 217 (80%) at any time during the ICU stay. Patients with a high RDW on admission were more likely to have an unfavorable neurological outcome. In multivariable regression analysis, older age, a high WFNS grade on admission, presence of DCI or intracranial hypertension, previous neurological disease, vasopressor therapy and a high RDW (OR, 1.1618 [95% CI, 1.213-2.158]; P=0.001) during the ICU stay were independent predictors of unfavorable neurological outcome. Conclusions: High RDW values were more likely to result in an unfavorable outcome after SAH. This information could help in the stratification of SAH patients already on ICU admission.

The impact of diastolic blood pressure values on the neurological outcome of cardiac arrest patients

AIM Which haemodynamic variable is the best predictor of neurological outcome remains unclear. We investigated the association of several haemodynamic variables with neurological outcome in CA patients. METHODS Retrospective analysis of adult comatose survivors of CA admitted to the intensive care unit (ICU) of a University Hospital. Exclusion criteria were early death due to withdrawal of care, missing haemodynamic data and use of intra-aortic balloon pump or extracorporeal membrane oxygenation. We retrieved CA characteristics; lactate concentration and cardiovascular sequential organ failure assessment (cSOFA) score on admission; systolic (SAP), diastolic (DAP), mean arterial pressure (MAP), and the use of vasopressors and inotropic agents during the first 6 h of ICU stay. Unfavourable neurological outcome (UO) was defined as a 3-month cerebral performance category score of 3-5. RESULTS Among the 170 patients (median age 63 years, 67% male, 60% out-of-hospital CA), 106 (63%) had UO. Admission lactate was higher in patients with UO than in those with favourable neurological outcome (4.0[2.4-7.3] vs. 2.5[1.4-6.0] mEq/L; p = 0.003) as was the cSOFA (3 [1-4] vs. 2[0-3]; p = 0.007). The lowest DAP during the first 6 h after ICU admission was significantly lower in patients with unfavourable neurological outcome, notably in patients with high cSOFA scores. In multivariable analysis, high adrenaline doses and the lowest value of DAP during the first 6 h after ICU admission was significantly associated with unfavourable neurological outcome. CONCLUSIONS In CA patients admitted to the ICU, low DAP during the first 6 h is an independent predictor of unfavourable neurological outcome at 3 months.

243: NONINVASIVE CCE IS NOT CORRELATED WITH ECHOCARDIOGRAPHIC SINGLE-BEAT VENTRICULOARTERIAL COUPLING

Learning Objectives: Ventriculo-arterial coupling (VA-C), defined as the ratio between the arterial elastance (Ea) and the end-systolic ventricular elastance (Ees), is one of the most accurate methods to evaluate the mechanical and energetic efficiency of the cardiovascular system. It can be estimated at the bedside by a single-beat echocardiographic measure combined with systolic and diastolic arterial pressures. Minimally invasive pulse contour method analysis (MostCare, Vygon, Ecouen, France) provides the Cardiac Cycle Efficiency (CCE), which describes the ratio between the hemodynamic performance and the energy expenditure. No data are available about the correlation between CCE and VA-C. The objective of the study was to evaluate the correlation between CCE and VA-C Methods: In critically ill patients with a good quality transthoracic echocardiographic window, the estimation of Ees and Ea was derived from echocardiographic measures according to the formula proposed by Chen et al1. We ensured a good quality arterial pressure curve. VA-C was calculated as Ea/Ees. From the MostCare device, CCE, dP/dT and EaMC were collected concomitantly; Three measures from each technique were collected and averaged Data were analyzed by linear regression analysis. Results: We studied 17 patients (median age: 58 years; 12/17 male) 2 [1-3] days after ICU admission. Median ejection fraction on echocardiography was 61 [56-64]%. Median Ea and Ees on echocardiography were 2.03 [1.68-2.21] and 2.94 [2.12-3.25], respectively, which resulted in VA-C of 0.81 [0.57-0.92]. Median CCE, dP/dT and EaMC values were 0.17 [-0.02 to 0.23] U, 1.33 [1.15-1.6] mmHg/ms and 1.06 [0.91.25] mmHg/mL. There was a significant correlation between stroke volume (r=0.77; p=0.002) and Ea (r=0.53; p=0.02) measured by the two techniques, but not between VA-C and CCE (r=-0.05; p=0.83) or CCE/EaMC (r=-0.09; p=0.71) or dP/dT (r=-0.27; p=0.28). Conclusions: CCE is no substitute for VA-C determined by echocardiography. 244

970: USE OF A BIOMARKER SCORE IN PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) expression in many diseases, though the contribution of miRNAs to the pathophysiology of ALI remains obscure. We hypothesized that in ALI, dysregulated miRNAs modulate gene targets that control endothelial permeability leading to impaired barrier function. Methods: 8-week-old C57BL/6 mice were treated with intratracheal bleomycin or PBS. Lungs were collected at 4 or 7 days. miRNA expression was compared using a qPCR based 56-miRNA array. TargetScan and Enrichr were used to identify predicted gene targets and biological processes of 4 highly down-regulated miRNAs. Expression of 4 predicted miR-26a gene targets, EphA2, VEGFC, KDR and ROCK1 was evaluated by qPCR. EphA2 protein levels were measured by western blot analysis. In situ hybridization was performed to localize lung miR-26a. Human lung microvascular endothelial cells (HMVEC-L) were transfected with miR-26a mimic, inhibitor and negative controls. miR-26a, EphA2 mRNA/protein and cell permeability were measured. Results: Bleomycin decreased 4 miRNAs (miR-1, miR-26a, miR-30b and miR-30c) by greater than 6 fold. Of these miRNAs, miR-26a is predicted to regulate 135 genes involved in cell adhesion and relevant to ALI, including EphA2, VEGFC, KDR and ROCK1. Only lung EphA2 mRNA and protein significantly increased (1.7 fold and 1.5 fold) at 7 days. Transfection of HMEVC-L with miR-26a mimic significantly decreased EphA2 mRNA and protein (0.5 fold) and miR-26a inhibitor significantly increased EphA2 mRNA and protein (1.3 fold). Transfection with miR-26a inhibitor significantly increased HMVEC-L permeability at baseline and with VEGF stimulation, while transfection with miR-26a mimic had no impact. Conclusions: Multiple miRNAs are decreased in bleomycin-induced ALI. miR-26a, a putative regulator of genes involved in cell adhesion, regulated EphA2 expression and endothelial permeability in vitro. Future studies will interrogate targeted delivery systems for miRNA mimics and inhibitors as a novel therapeutic strategy.

Angiotensin converting enzymes in patients with acute respiratory distress syndrome

Angiotensin converting enzymes (ACEs) are important in the control of the cardiovascular function and their inhibition have a primary role in the treatment of hypertension and heart failure. However they have effects beyond the cardiovascular system. Angiotensin 2 production by ACE and stimulation of the angiotensin 1 (AT1) receptor subtype reduces nitric oxide bioavailability, promotes inflammation and fibrosis. The ACE type 2 (ACE2) increases angiotensin 1-7 production and counterbalances ACE effects. Some animal data have shown a beneficial role of the up-regulation of the ACE2 pathway and a detrimental role for the up-regulation of the ACE classic pathway in different ARDS, but there are no data in patients with ARDS.

941: RED CELL DISTRIBUTION WIDTH AND MICROCIRCULATION IN CRITICALLY ILL SEPTIC PATIENTS.

18 hours after sepsis, when compared to baseline values before the CLP procedure (29.9 ± 1.1% and 57.3 ± 1.6%, respectively; P<0.05). In contrast, treatment with AICAR significantly improved both fractional shortening (26.6 ± 3.4%) and ejection fraction (52.4 ± 5.9%) when compared to vehicle treatment (P<0.05). At Western blotting analysis, the beneficial effects of AICAR were associated with increased AMPK phosphorylation, as well as increase of nuclear expression of peroxisome proliferator-activated receptor-Υ co-activator α (PGC-1α), a major regulator of mitochondrial function and biogenesis. Conclusions: Our data indicate that AICAR confers cardioprotective effects during experimental sepsis through activation of AMPK-dependent metabolic repair mechanisms. These findings can potentially lead to a new therapeutic strategy for prevention of cardiac dysfunction in sepsis.