The Cerebrospinal Fluid Proteomic Response to Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study.

BACKGROUND: Quantitative analysis of ventricular cerebrospinal fluid (vCSF) proteins following acute brain injury (ABI) may help identify pathophysiological pathways and potential biomarkers that can predict unfavorable outcome. METHODS: In this prospective proteomic analysis study, consecutive patients with severe ABI expected to require intraventricular catheterization for intracranial pressure (ICP) monitoring for at least 5 days and patients without ABI admitted for elective clipping of an unruptured cerebral aneurysm were included. vCSF samples were collected within the first 24 h after ABI and ventriculostomy insertion and then every 24 h for 5 days. In patients without ABI, a single vCSF sample was collected at the time of elective clipping. Data-independent acquisition and sequential window acquisition of all theoretical spectra (SWATH) mass spectrometry were used to compare differences in protein expression in patients with ABI and patients without ABI and in patients with traumatic and nontraumatic ABI. Differences in protein expression according to different ICP values, intensive care unit outcome, subarachnoid hemorrhage (SAH) versus traumatic brain injury (TBI), and good versus poor 3-month functional status (assessed by using the Glasgow Outcome Scale) were also evaluated. vCSF proteins with significant differences between groups were compared by using linear models and selected for gene ontology analysis using R Language and the Panther database. RESULTS: We included 50 patients with ABI (SAH n = 23, TBI n = 15, intracranial hemorrhage n = 6, ischemic stroke n = 3, others n = 3) and 12 patients without ABI. There were significant differences in the expression of 255 proteins between patients with and without ABI (p < 0.01). There were intraday and interday differences in expression of seven proteins related to increased inflammation, apoptosis, oxidative stress, and cellular response to hypoxia and injury. Among these, glial fibrillary acidic protein expression was higher in patients with ABI with severe intracranial hypertension (ICH) (ICP ≥ 30 mm Hg) or death compared to those without (log 2 fold change: + 2.4; p < 0.001), suggesting extensive primary astroglial injury or death. There were differences in the expression of 96 proteins between patients with traumatic and nontraumatic ABI (p < 0.05); intraday and interday differences were observed for six proteins related to structural damage, complement activation, and cholesterol metabolism. Thirty-nine vCSF proteins were associated with an increased risk of severe ICH (ICP ≥ 30 mm Hg) in patients with traumatic compared with nontraumatic ABI (p < 0.05). No significant differences were found in protein expression between patients with SAH versus TBI or between those with good versus poor 3-month Glasgow Outcome Scale score. CONCLUSIONS: Dysregulated vCSF protein expression after ABI may be associated with an increased risk of severe ICH and death.

Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients.

OBJECTIVES: To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice. DESIGN: Prospective observational study. SETTING: Single-center, mixed medical-surgical ICU in Europe. PATIENTS: Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin. INTERVENTIONS: Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison. MEASUREMENTS AND MAIN RESULTS: One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = -0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = -0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (-32 ± 26 µU/timepoint vs +92 ± 57 µU/timepoint p = 0.03; mean ± SEM), but not for lactate (-0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17). CONCLUSIONS: In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

Near-Continuous Glucose Monitoring Makes Glycemic Control Safer in ICU Patients.

OBJECTIVES: Tight glycemic control using intermittent blood glucose measurements is associated with a risk of hypoglycemia. Glucose concentrations can now be measured near continuously (every 5-15 min). We assessed the quality and safety of glycemic control guided by a near-continuous glucose monitoring system in ICU patients. DESIGN: Prospective, cluster-randomized, crossover study. SETTING: Thirty-five-bed medico-surgical department of intensive care with four separate ICUs. PATIENTS: Adult patients admitted to the department and expected to stay for at least 3 days were considered for inclusion if they had persistent hyperglycemia (blood glucose > 150 mg/dL) up to 6 hours after admission and/or were receiving insulin therapy. INTERVENTIONS: A peripheral venous catheter was inserted in all patients and connected to a continuous glucose monitoring sensor (GlucoClear; Edwards Lifesciences, Irvine, CA). The four ICUs were randomized in pairs in a crossover design to glycemic control using unblinded or blinded continuous glucose monitoring monitors. The insulin infusion rate was adjusted to keep blood glucose between 90 and 150 mg/dL using the blood glucose values displayed on the continuous glucose monitor (continuous glucose monitoring group-unblinded units) or according to intermittent blood glucose readings (intermittent glucose monitoring group-blinded units). MEASUREMENTS AND MAIN RESULTS: The quality and safety of glycemic control were assessed using the proportion of time in range, the frequency of blood glucose less than 70 mg/dL, and the time spent with blood glucose less than 70 mg/dL (TB70), using blood glucose values measured by the continuous glucose monitoring device. Seventy-seven patients were enrolled: 39 in the continuous glucose monitoring group and 38 in the intermittent glucose monitoring group. A total of 43,107 blood glucose values were recorded. The time in range was similar in the two groups. The incidence of hypoglycemia (8/39 [20.5%] vs 15/38 [39.5%]) and the TB70 (0.4% ± 0.9% vs 1.6% ± 3.4%; p < 0.05) was lower in the continuous glucose monitoring than in the intermittent glucose monitoring group. CONCLUSIONS: Use of a continuous glucose monitoring-based strategy decreased the incidence and severity of hypoglycemia, thus improving the safety of glycemic control.

Prolonged overcirculation-induced pulmonary arterial hypertension as a cause of right ventricular failure.

AIMS: Three-month chronic systemic-to-pulmonary shunting in growing piglets has been reported as an early pulmonary arterial hypertension (PAH) model with preserved right ventricular (RV) function. We sought to determine whether prolonged shunting might be associated with more severe PAH and RV failure. METHODS AND RESULTS: Fourteen growing piglets were randomized to a sham operation or the anastomosis of the left innominate artery to the pulmonary arterial trunk. Six months later, the shunt was closed and the animals underwent haemodynamic evaluation followed by tissue sampling for pathobiological assessment. Prolonged shunting had resulted in increased mean pulmonary artery pressure (22 ± 2 versus 17 ± 1 mmHg) and pulmonary arteriolar medial thickness, while cardiac output was decreased. However, RV-arterial coupling was markedly deteriorated, with a ~50% decrease in the ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Lung tissue expressions of endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor-2 were similarly altered compared with previously observed after 3-month shunting. At the RV tissue level, pro-apoptotic ratio of Bax-to-Bcl-2 expressions and caspase-3 activation were increased, along with an increase in cardiomyocyte size, while expressions in voltage-gated potassium channels (Kv1.5 and Kv2.1) and angiogenic factors (angiopoietin-2 and vascular endothelial growth factor) were decreased. Right ventricular expressions of pro-inflammatory cytokines [interleukin (IL)-1α, IL-1ß, tumour necrosis factor-α (TNF-α)] and natriuretic peptide precursors (NPPA and NPPB) were increased. There was an inverse correlation between RV Ees/Ea and pro-apoptotic Bax/Bcl-2 ratios. CONCLUSIONS: Prolonged left-to-right shunting in piglets does not further aggravate pulmonary vasculopathy, but is a cause of RV failure, which appears related to an activation of apoptosis and inflammation.

vCSF Danger-associated Molecular Patterns After Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study.

BACKGROUND: Danger-associated molecular patterns (DAMPs) may be implicated in the pathophysiological pathways associated with an unfavorable outcome after acute brain injury (ABI). METHODS: We collected samples of ventricular cerebrospinal fluid (vCSF) for 5 days in 50 consecutive patients at risk of intracranial hypertension after traumatic and nontraumatic ABI. Differences in vCSF protein expression over time were evaluated using linear models and selected for functional network analysis using the PANTHER and STRING databases. The primary exposure of interest was the type of brain injury (traumatic vs. nontraumatic), and the primary outcome was the vCSF expression of DAMPs. Secondary exposures of interest included the occurrence of intracranial pressure ≥20 or ≥ 30 mm Hg during the 5 days post-ABI, intensive care unit (ICU) mortality, and neurological outcome (assessed using the Glasgow Outcome Score) at 3 months post-ICU discharge. Secondary outcomes included associations of these exposures with the vCSF expression of DAMPs. RESULTS: A network of 6 DAMPs (DAMP_trauma; protein-protein interaction [PPI] P=0.04) was differentially expressed in patients with ABI of traumatic origin compared with those with nontraumatic ABI. ABI patients with intracranial pressure ≥30 mm Hg differentially expressed a set of 38 DAMPS (DAMP_ICP30; PPI P< 0.001). Proteins in DAMP_ICP30 are involved in cellular proteolysis, complement pathway activation, and post-translational modifications. There were no relationships between DAMP expression and ICU mortality or unfavorable versus favorable outcomes. CONCLUSIONS: Specific patterns of vCSF DAMP expression differentiated between traumatic and nontraumatic types of ABI and were associated with increased episodes of severe intracranial hypertension.

Hypertonic saline hydroxyethylstarch restores right ventricular-arterial coupling after normovolemic hemodilution in piglets.

BACKGROUND: Normovolemic hemodilution is known to inhibit hypoxic pulmonary vasoconstriction. How the coupling between the pulmonary arterial (PA) circulation and the right ventricle (RV) is affected by normovolemic hemodilution and by the composition of replacement solutions remains unknown. Therefore, the effects of isotonic and hypertonic saline hydroxyethylstarch solutions on the pulmonary circulation and RV, in control and hypoxic conditions, were compared. METHODS: Anesthetized piglets (n = 14) were equipped with manometer-tipped catheters in the RV and main PA and an ultrasonic flow probe around the main PA. The pulmonary circulation was assessed by pressure-flow relations and vascular impedance, RV afterload by effective arterial elastance (Ea), RV contractility by end-systolic elastance (Ees), and RV-PA coupling by the Ees/Ea ratio. Measurements were done in control (Fio2 0.40) and hypoxic (Fio2 0.12) conditions before and after acute normovolemic hemodilution with either 20 ml/kg isotonic saline hydroxyethylstarch (hydroxyethylstarch 130/0.4 6% in NaCl 0.9%, Voluven, Fresenius-Kabi, Sevres, France) or 5 ml/kg hypertonic saline hydroxyethylstarch (hydroxyethylstarch 200/0.5 6% in NaCl 7.2%, HyperHES, Fresenius-Kabi) solutions. RESULTS: Hypoxic pulmonary vasoconstriction was associated with proportional increases in Ea and Ees and did not affect RV-PA coupling. Hemodilution attenuated the hypoxic response. Hemodilution with isotonic saline hydroxyethylstarch did not affect the RV-PA coupling, whereas hemodilution with hypertonic saline hydroxyethylstarch increased Ees and the Ees/Ea ratio. CONCLUSION: In experimental normovolemic hemodilution, both in control and in hypoxic conditions, RV-PA coupling is unaffected by isotonic saline hydroxyethylstarch but improved by hypertonic saline hydroxyethylstarch, mainly because of an increase in RV contractility.

Use of maximum end-tidal CO(2) values to improve end-tidal CO(2) monitoring accuracy.

BACKGROUND: The arterial partial pressure of CO(2) (P(aCO(2))) can be grossly estimated by the end-tidal partial pressure of CO(2) (P(ETCO(2))). This principle is used in SmartCare (Dräger, Lübeck, Germany), which is an automated closed-loop system that uses P(ETCO(2)) to estimate alveolar ventilation during mechanical ventilation. OBJECTIVE: To assess whether the maximum P(ETCO(2)) value (instead of the averaged P(ETCO(2)) value) over 2-min or 5-min periods improves P(aCO(2)) estimation, and determine the consequences for the SmartCare system. METHODS: We continuously monitored breath-by-breath P(ETCO(2)) during ventilation with SmartCare in 36 patients mechanically ventilated for various disorders, including 14 patients with COPD. Data were collected simultaneously from SmartCare recordings, every 2 min or 5 min, and through a dedicated software that recorded ventilation data every 10 s. We compared the maximum and averaged P(ETCO(2)) values over 2-min and 5-min periods to the P(aCO(2)) measured from 80 arterial blood samples clinically indicated in 26 patients. We also compared SmartCare's classifications of patient ventilatory status based on averaged P(ETCO(2)) values to what the classifications would have been with the maximum P(ETCO(2)) values. RESULTS: Mean P(aCO(2)) was 44 ± 11 mm Hg. P(aCO(2)) was higher than averaged P(ETCO(2)) by 10 ± 6 mm Hg, and this difference was reduced to 6 ± 6 mm Hg with maximum P(ETCO(2)). The results were similar whether patients had COPD or not. Very few aberrant values (< 0.01%) needed to be discarded. Among the 3,137 classifications made by the SmartCare system, 1.6% were changed by using the maximum P(ETCO(2)) value instead of the averaged P(ETCO(2)) value. CONCLUSIONS: Use of maximum P(ETCO(2)) reduces the difference between P(aCO(2)) and P(ETCO(2)) and improves SmartCare's classification of patient ventilatory status.

Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis.

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis. Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation. Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor. Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension.

Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.

Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure.

OBJECTIVE: The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Mongrel dogs. INTERVENTIONS: Fourteen anesthetized dogs were randomized to a transient 90-min pulmonary artery constriction operation to induce persistent right ventricular failure or to a sham operation followed 30 mins later by hemodynamic measurements and sampling of cardiac tissue. MEASUREMENTS AND MAIN RESULTS: We evaluated effective arterial elastance to estimate right ventricular afterload and end-systolic elastance to estimate right ventricular contractility. Transient increase in pulmonary artery pressure persistently increased effective arterial elastance from 0.75 +/- 0.08 to 1.37 +/- 0.18 mm Hg/mL and decreased end-systolic elastance from 1.06 +/- 0.09 to 0.49 +/- 0.09 mm Hg/mL, end-systolic elastance/effective arterial elastance from 1.44 +/- 0.06 to 0.34 +/- 0.03, and cardiac output from 3.78 +/- 0.16 to 1.46 +/- 0.10 L/min, indicating right ventricular failure. At the pathobiologic level, we assessed apoptosis by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. As compared with the sham-operated group, and with the left ventricle in animals with persistent right ventricular failure, there were decreased right ventricular and septal expressions of Bcl-2 with no changes in expressions of Bax, resulting in an increased Bax/Bcl-2 ratio. Right ventricular and septal Bcl-XL, and right ventricular Bcl-w gene expressions were decreased as compared with the sham-operated group, whereas Bak gene expression did not change. There were activations of right ventricular caspases-8 and -9 and of right ventricular and septal caspase-3. Diffuse right ventricular and septal apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. There were also increased right ventricular and septal protein expressions of tumor necrosis factor-alpha. CONCLUSIONS: Acute afterload-induced persistent right ventricular failure appears to be related to an early activation of apoptotic pathways and to a local overexpression of tumor necrosis factor-alpha, a proinflammatory cytokine.

Ventricular-arterial uncoupling in heart failure with preserved ejection fraction after myocardial infarction in dogs - invasive versus echocardiographic evaluation.

BACKGROUND: Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs. METHODS: Echocardiography, levels of neurohormones and conductance catheter measurements of left ventricular pressure-volume relationships were obtained in 17 beagle dogs 2 months after a coronary artery ligation, and in 6 controls. RESULTS: Healed myocardial infarction was associated with preserved echocardiographic left ventricular ejection fraction (0.57 +/- 0.01, mean +/- SEM) and altered Doppler mitral indices of diastolic function. NT-proBNP was increased, aldosterone was decreased, and norepinephrine was unchanged. Invasive measurements showed a markedly decreased end-systolic elastance (2.1 +/- 0.2 vs 6.1 +/- 0.8, mmHg/ml, p < 0.001) and end-systolic elastance to effective arterial elastance ratio (0.6 +/- 0.1 vs 1.4 +/- 0.2, p < 0.001), with altered active relaxation (dP/dtmin -1992 +/- 71 vs -2821 +/- 305, mmHg/s, p < 0.01) but preserved left ventricular capacitance (70 +/- 6 vs 61 +/- 3, ml at 20 mmHg, p = NS) and stiffness constant. Among echocardiographic variables, the wall motion score index was the most reliable indicator of cardiac contractility while E', E/A and E'/A' were correlated to dP/dtmin. CONCLUSIONS: In the canine model of healed myocardial infarction induced by coronary ligation, heart failure is essentially characterized by an altered contractility with left ventricular-arterial uncoupling despite vascular compensation rather than by abnormal diastolic function.

An intact animal model for the assessment of coronary blood flow regulation "Coronary blood flow regulation".

Coronary blood flow adapts to metabolic demand ("metabolic regulation") and remains relatively constant over a range of pressure changes ("autoregulation"). Coronary metabolic regulation and autoregulation are usually studied separately. We developed an intact animal experimental model to explore both regulatory mechanisms of coronary blood flow. Coronary pressure and flow-velocities were measured in four anesthetized and closed-chest pigs using an intracoronary Doppler wire. Metabolic regulation was assessed by coronary flow reserve defined as the ratio between the maximally vasodilated and the basal flow, with hyperemia achieved using intracoronary administration of adenosine (90 µg) or bradykinin (10-6  M) as endothelium-independent and -dependent vasodilators respectively. For both vasodilators, we found a healthy coronary flow reserve ≥ 3.0 at baseline, which was maintained at 2.9 ± 0.2 after a 6-hr period. Autoregulation was assessed by the lower breakpoint of coronary pressure-flow relationships, with gradual decrease in coronary pressure through the inflation of an intracoronary balloon. We found a lower limit of autoregulation between 42 and 55 mmHg, which was stable during a 6-hr period. We conclude that this intact animal model is adequate for the study of pharmacological interventions on the coronary circulation in health and disease, and as such suitable for preclinical drug studies.

The Double-Trunk Mask Improves Oxygenation During High-Flow Nasal Cannula Therapy for Acute Hypoxemic Respiratory Failure.

BACKGROUND: High-flow nasal cannula (HFNC) oxygen therapy is used to deliver an FIO2 from 0.21 to 1.0. The double-trunk mask (DTM) is a device designed to increase the FIO2 in patients with a high inspiratory flow demand. The aim of our study was to evaluate the effect of DTM in hypoxemic subjects already receiving HFNC. METHODS: We report a prospective multi-center crossover pilot study including 15 subjects treated with HFNC for acute hypoxemic respiratory failure. Measurements were performed at the end of 30-min periods with HFNC only, with HFNC + DTM, and again with HFNC only. RESULTS: Compared with HFNC alone, HFNC + DTM increased PaO2 from 68 ± 14 mm Hg to 85 ± 22 mm Hg (P < .001) and did not affect PaCO2 (P = .18). In the 11 responders, the PaO2 increased from 63 ± 12 mm Hg to 88 ± 23 mm Hg (P < .001). No complications were reported during DTM use. CONCLUSION: In subjects receiving oxygen via HFNC, the addition of the DTM over the HFNC increased PaO2 without changing the PaCO2 .

Activin-A, transforming growth factor-beta, and myostatin signaling pathway in experimental dilated cardiomyopathy.

BACKGROUND: The pathogenic mechanisms of dilated cardiomyopathy are still uncertain. A number of cytokines and growth factors participate in the remodeling process of the disease. METHODS: We investigated the cardiac myostatin, transforming growth factor (TGF)beta, and activin-A/Smad growth inhibitory signaling pathway in experimental dilated cardiomyopathy. Transvenous endomyocardial biopsies of the interventricular septum were taken weekly in 15 beagle dogs during the development of heart failure (HF) induced by rapid pacing over a period of 7 weeks. Genes involved in the myostatin-TGFbeta-activin-A/Smad signaling pathway and the cardiac hypertrophic process were quantified by real-time quantitative polymerase chain reaction. Left ventricular volume, function, and mass were evaluated by echocardiography. RESULTS: Overpacing was associated with increased left ventricular volumes and decreased ejection fraction, whereas the left ventricular mass remained unchanged. TGFbeta was increased in moderate HF. Activin-A mRNA expression was 4-fold higher in overt congestive HF than at baseline. A 2-fold decrease of activin type II receptors and activin receptor interacting protein 2 gene expressions were observed, as well as a transient decrease of follistatin. Activin type I receptors, activin receptor interacting protein 1, follistatin-related gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HF. Gene expression of the cyclin-dependent kinase inhibitor p21, a direct target gene of the Smad pathway, was 8-fold up-regulated in HF, whereas cyclin D1 was down-regulated. CONCLUSION: We conclude that tachycardia-induced dilated cardiomyopathy is characterized by gene overexpression of the TGFbeta-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy.

Hyponatremia in neurological patients: cerebral salt wasting versus inappropriate antidiuretic hormone secretion.

OBJECTIVE: To assess whether hyponatremia in acute neurological patients is associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or with the cerebral salt-wasting syndrome (CSWS). DESIGN: Clinical, controlled, prospective study. SETTING: Department of intensive care of a tertiary care academic hospital. PATIENTS: Forty acute neurological patients with hyponatremia suggesting SIADH or CSWS (20) or with normonatremia (20). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurement of clinical and biological variables. Measurement of blood, plasma, and red blood cell volumes to discriminate SIADH and CSWS. Renal, adrenal and thyroid functions were normal in all patients. Average blood, plasma, and red blood cell volumes were 54, 37 and 17ml/kg in control patients and 54, 37 and 18ml/kg in hyponatremic patients, respectively. CONCLUSIONS: The adequate blood volumes in hyponatremic patients confirm the diagnosis of SIADH and do not support the concept of CSWS.

Impact of a VAP bundle in Belgian intensive care units.

BACKGROUND: In order to decrease the incidence of ventilator-associated pneumonia (VAP) in Belgium, a national campaign for implementing a VAP bundle involving assessment of sedation, cuff pressure control, oral care with chlorhexidine and semirecumbent position, was launched in 2011-2012. This report will document the impact of this campaign. METHODS: On 1 day, once a year from 2010 till 2016, except in 2012, Belgian ICUs were questioned about their ventilated patients. For each of these, data about the application of the bundle and the possible treatment for VAP were recorded. RESULTS: Between 36.6 and 54.8% of the 120 Belgian ICUs participated in the successive surveys. While the characteristics of ventilated patients remained similar throughout the years, the percentage of ventilated patients and especially the duration of ventilation significantly decreased before and after the national VAP bundle campaign. Ventilator care also profoundly changed: Controlling cuff pressure, head positioning above 30° were obtained in more than 90% of cases. Oral care was more frequently performed within a day, using more concentrated solutions of chlorhexidine. Subglottic suctioning also was used but in only 24.7% of the cases in the last years. Regarding the prevalence of VAP, it significantly decreased from 28% of ventilated patients in 2010 to 10.1% in 2016 (p ≤ 0.0001). CONCLUSION: Although a causal relationship cannot be inferred from these data, the successive surveys revealed a potential impact of the VAP bundle campaign on both the respiratory care of ventilated patients and the prevalence of VAP in Belgian ICUs encouraging them to follow the guidelines.

Tissue Doppler imaging evaluation of cardiac adaptation to severe pulmonary hypertension.

Tissue Doppler imaging (TDI) was used to obtain additional insight into the cardiac adaptation to severe pulmonary arterial hypertension. Pulmonary hemodynamics and right and left ventricular function were investigated in 18 untreated patients, 12 with pulmonary arterial hypertension and 6 with chronic thromboembolic pulmonary hypertension. Fourteen age-matched healthy subjects served as controls for TDI measurements. Pulsed TDI was determined using atrioventricular planes and strain and strain rate along the right ventricular free wall, ventricular septum, and left ventricular lateral wall from 4-chamber apical views. Patients had early diastolic dysfunction, with decreased E-wave peak velocity and increased isovolumic relaxation time, both more important in the right than left ventricle. Compared with controls, strain and strain rate decreased along the right ventricular free wall with a midapical predominance (midbasal strain rate 1.7 +/- 0.6 vs 2.2 +/- 0.5; p = 0.02; midapical strain rate 0.9 +/- 0.9 vs 2.3 +/- 0.7; p <0.001), but were preserved along the left ventricular lateral wall. Tricuspid E-wave and isovolumic relaxation time (R = 0.62, p = 0.006), as well as midapical (r = 0.65, p = 0.004), but not midbasal, right ventricular strain and strain rate correlated with mean pulmonary artery pressures. In conclusion, cardiac function was abnormal in patients with severe pulmonary hypertension because of a combination of alterations in both diastolic and systolic right ventricular function and left ventricular diastolic function. Only right ventricular dysfunction correlated with pulmonary artery pressures.

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 (r=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.