Volume responsiveness revisited: an observational multicenter study of continuous versus binary outcomes combining echocardiography and venous return physiology.

Echocardiography can assess cardiac preload when fluid administration is used to treat acute circulatory failure. Changes in stroke volume (SV) are inherently a continuous phenomenon relating to the pressure gradient for venous return (VRdP). However, most clinical studies have applied a binary definition based on a fractional change in SV. This study tested the hypothesis that calculating the analog mean systemic filling pressure (Pmsa) and VRdP would enhance echocardiography to describe SV responses to a preload challenge. We investigated 540 (379 males) patients during a standardized passive leg raising (PLR) maneuver. Patients were further categorized by the presence of impaired right ventricular function (impRV) or increased intra-abdominal hypertension (IAH). Multivariable linear regression identified VRdP (partial r = -0.26, P < 0.001), ventilatory-induced variations in superior vena cava diameter (partial r = 0.43, P < 0.001), and left ventricular outflow tract maximum-Doppler velocity (partial r = 0.13, P < 0.001) as independent variables associated with SV changes. The model explained 38% (P < 0.001) of the SV change in the whole cohort and 64% (P < 0.001) when excluding patients with impRV or IAH. The correlation between Pmsa or VRdP and SV changes lost statistical significance with increasing impRV or IAH. A binary definition of volume responsiveness (>10% increase in SV) generated an area under the curve of 0.79 (P < 0.001) in logistic regression but failed to identify Pmsa or VRdP as independent variables and overlooked the confounding influence of impRV and IAH. In conclusion, venous return physiology may enhance echocardiographic assessments of volume responsiveness, which should be based on continuous changes in stroke volume.NEW & NOTEWORTHY The analog mean systemic filling pressure and the pressure gradient for venous return combined with echocardiography predict continuous changes in stroke volume following a passive leg raising maneuver. The confounding effects of impaired right ventricular function and increased intra-abdominal pressure can be identified. Using a binary cutoff for the fractional change in stroke volume, common in previous clinical research, fails to identify the importance of variables relevant to venous return physiology and confounding conditions.

ßeta blocker interruption after uncomplicated myocardial infarction: rationale and design of the randomized ABYSS trial.

BACKGROUND: The long-term use of ß-blocker after myocardial infarction (MI) when global left ventricular ejection fraction (LVEF) is preserved has not been studied in the era of modern myocardial reperfusion and secondary prevention therapies. It is unknown whether ß-blockers are useful in stable post-MI patients without reduced LVEF and without heart failure. METHODS: The Assessment of ß-blocker interruption 1 Year after an uncomplicated myocardial infarction on Safety and Symptomatic cardiac events requiring hospitalization (ABYSS) Trial enrolled in 49 centers in France, 3,700 patients with a prior (>6 months) history of MI and a LVEF >40%, chronically treated with a ß-blocker and without any major cardiovascular event (MACE) in the past 6 months. These patients were randomized to interruption or continuation of their ß-blocker therapy. The primary objective is to demonstrate the noninferiority of interruption vs continuation of the ß-blocker therapy on the primary composite endpoint of all-cause death, stroke, MI, hospitalization for any cardiovascular reason at the end of follow-up (accrual follow-up) with a one-year minimum follow-up for the last randomized patient. Secondary objectives will focus on patient reported outcomes with the evaluation of the quality of life before and after randomization with the EQ5D-5L questionnaire. Enrolment has been completed. CONCLUSION: The ABYSS trial evaluates the cardiovascular safety of ß-blocker interruption in stabilized post-MI patients without heart failure nor reduced LVEF. ABYSS trial is a reappraisal of ß-blockers life-long therapy in stable post-MI patients without reduced LVEF. CLINICAL TRIAL REGISTRATION: NCT03498066 (clinicaltrials.gov).

Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers.

BACKGROUND: Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. METHODS: We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy. RESULTS: We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%). CONCLUSIONS: Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

Respiratory effects of lung recruitment maneuvers depend on the recruitment-to-inflation ratio in patients with COVID-19-related acute respiratory distress syndrome.

BACKGROUND: In the context of acute respiratory distress syndrome (ARDS), the response to lung recruitment maneuvers (LRMs) varies considerably from one patient to another and so is difficult to predict. The aim of the study was to determine whether or not the recruitment-to-inflation (R/I) ratio could differentiate between patients according to the change in lung mechanics during the LRM. METHODS: We evaluated the changes in gas exchange and respiratory mechanics induced by a stepwise LRM at a constant driving pressure of 15 cmH2O during pressure-controlled ventilation. We assessed lung recruitability by measuring the R/I ratio. Patients were dichotomized with regard to the median R/I ratio. RESULTS: We included 30 patients with moderate-to-severe ARDS and a median [interquartile range] R/I ratio of 0.62 [0.42-0.83]. After the LRM, patients with high recruitability (R/I ratio ≥ 0.62) presented an improvement in the PaO2/FiO2 ratio, due to significant increase in respiratory system compliance (33 [27-42] vs. 42 [35-60] mL/cmH2O; p < 0.001). In low recruitability patients (R/I < 0.62), the increase in PaO2/FiO2 ratio was associated with a significant decrease in pulse pressure as a surrogate of cardiac output (70 [55-85] vs. 50 [51-67] mmHg; p = 0.01) but not with a significant change in respiratory system compliance (33 [24-47] vs. 35 [25-47] mL/cmH2O; p = 0.74). CONCLUSION: After the LRM, patients with high recruitability presented a significant increase in respiratory system compliance (indicating a gain in ventilated area), while those with low recruitability presented a decrease in pulse pressure suggesting a drop in cardiac output and therefore in intrapulmonary shunt.

The Endothelium and COVID-19: An Increasingly Clear Link Brief Title: Endotheliopathy in COVID-19.

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells-leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Doppler Echocardiographic Indices Are Specific But Not Sensitive to Predict Pulmonary Artery Occlusion Pressure in Critically Ill Patients Under Mechanical Ventilation.

OBJECTIVES: The objective of this study was to prospectively evaluate the ability of transthoracic echocardiography to assess pulmonary artery occlusion pressure in mechanically ventilated critically ill patients. DESIGN: In a prospective observational study. SETTING: Amiens University Hospital Medical ICU. PATIENTS: Fifty-three mechanically ventilated patients in sinus rhythm admitted to our ICU. INTERVENTION: Transthoracic echocardiography was performed simultaneously to pulmonary artery catheter. MEASUREMENTS AND MAIN RESULTS: Transmitral early velocity wave recorded using pulsed wave Doppler (E), late transmitral velocity wave recorded using pulsed wave Doppler (A), and deceleration time of E wave were recorded using pulsed Doppler as well as early mitral annulus velocity wave recorded using tissue Doppler imaging (E'). Pulmonary artery occlusion pressure was measured simultaneously using pulmonary artery catheter. There was a significant correlation between pulmonary artery occlusion pressure and lateral ratio between E wave and E' (E/E' ratio) (r = 0.35; p < 0.01), ratio between E wave and A wave (E/A ratio) (r = 0.41; p < 0.002), and deceleration time of E wave (r = -0.34; p < 0.02). E/E' greater than 15 was predictive of pulmonary artery occlusion pressure greater than or equal to 18 mm Hg with a sensitivity of 25% and a specificity of 95%, whereas E/E' less than 7 was predictive of pulmonary artery occlusion pressure less than 18 mm Hg with a sensitivity of 32% and a specificity of 81%. E/A greater than 1.8 yielded a sensitivity of 44% and a specificity of 95% to predict pulmonary artery occlusion pressure greater than or equal to 18 mm Hg, whereas E/A less than 0.7 was predictive of pulmonary artery occlusion pressure less than 18 mm Hg with a sensitivity of 19% and a specificity of 94%. A similar predictive capacity was observed when the analysis was confined to patients with EF less than 50%. A large proportion of E/E' measurements 32 (60%) were situated between the two cut-off values obtained by the receiver operating characteristic curves: E/E' greater than 15 and E/E' less than 7. CONCLUSIONS: In mechanically ventilated critically ill patients, Doppler transthoracic echocardiography indices are highly specific but not sensitive to estimate pulmonary artery occlusion pressure.

Invasive Tracheobronchial Aspergillosis in Critically Ill Patients with Severe Influenza. A Clinical Trial.

Rationale: Invasive tracheobronchial aspergillosis (ITBA) is an uncommon but severe clinical form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree.Objectives: To analyze the diagnostic and prognostic differences between tracheobronchial aspergillosis and pulmonary aspergillosis without tracheobronchial lesions among patients admitted to the ICU with severe influenza.Methods: This retrospective, observational study included critically ill patients with influenza associated with pulmonary aspergillosis from three hospital ICUs between 2010 and 2019. Patient characteristics and clinical and mycologic data at admission and during ICU stay were collected in a database to evaluate variables in the two groups.Measurements and Main Results: Thirty-five patients admitted to the ICU with severe influenza and pulmonary aspergillosis were included. Ten patients were included in the group with ITBA (n = 10 of 35; 28.6%), and 25 patients were included in the group without ITBA. The group with ITBA comprised more patients with active smoking, diabetes mellitus, and higher severity scores (Simplified Acute Physiology Score II). Ninety-day mortality rates in the groups with and without ITBA were 90% and 44%, respectively (P = 0.02). Moreover, significantly higher serum 1,3-ß-d-glucan and galactomannan and BAL fluid galactomannan concentrations were observed in the group with ITBA compared with the group without ITBA (P < 0.0001, P = 0.003, and P = 0.008, respectively).Conclusions: ITBA was associated with higher severity scores, mortality, and serum and BAL fluid galactomannan and 1,3-ß-d-glucan concentrations than invasive pulmonary aspergillosis without tracheobronchial lesions. ITBA should be systematically researched by bronchoscopic examination in ICU patients with concomitant pulmonary aspergillosis and influenza.Clinical trial registered with www.clinicaltrials.gov (NCT04077697).

Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. METHODS: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. RESULTS: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01). CONCLUSIONS: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

Hereditary transthyretin amyloidosis: current treatment.

PURPOSE OF REVIEW: Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant, life-threatening disease. Until recently only early stages of ATTRv-PN (polyneuropathy) had access to disease-modifying therapy (DMT), whereas there was no specific treatment for ATTRv-CM (cardiomyopathy). This review updates our knowledge about results of three phase 3 clinical trials, expert's consensus for early diagnosis and emerging biomarkers. RECENT FINDINGS: Two phase 3 studies using RNAi and antisense oligonucleotides (ASO) were successful. Primary endpoints were progression of neuropathic score mNIS +7 and quality of Life (QOL) in a population of ATTRv-PN at different levels of severity. They knock downed circulating amyloidogenic mutant and wild-type TTR. Safety concerned ASO with a risk of thrombocytopenia. RNAi showed possible reversibility of the disease. Phase 3 ATTRACT trial-tested tafamidis versus placebo in patients with ATTRv-CM and ATTRwt-CM and showed a significant reduction of all-cause mortality and rates of cardiovascular-related hospitalizations. All three drugs obtained marketing authorization by European Medicines Agency (EMA) and Food and drug administration (FDA). Early diagnosis criteria for ATTRv-PN and ATTRv-CM are available. Ongoing clinical trials for ATTRv are presented. New biomarkers are plasma neurofilament light chain, intraepidermal nerve fiber density. SUMMARY: The majority of patients with ATTRv may have now access to a DMT. Criteria for early diagnosis are available.

Estimation of Pulmonary Artery Occlusion Pressure Using Doppler Echocardiography in Mechanically Ventilated Patients.

OBJECTIVES: Evaluation of left atrial pressure is frequently required for mechanically ventilated critically ill patients. The objective of the present study was to evaluate the 2016 American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines for assessment of the pulmonary artery occlusion pressure (a frequent surrogate of left atrial pressure) in this population. DESIGN: A pooled analysis of three prospective cohorts of patients simultaneously assessed with a pulmonary artery catheter and echocardiography. SETTINGS: Medical-surgical intensive care department of two university hospitals in France. PATIENTS: Mechanically ventilated critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 98 included patients (males: 67%; mean ± SD age: 59 ± 16; and mean Simplified Acute Physiology Score 2: 54 ± 20), 53 (54%) experienced septic shock. Using the 2016 American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines, the predicted pulmonary artery occlusion pressure was indeterminate in 48 of the 98 patients (49%). Of the 24 patients with an elevated predicted left atrial pressure (grade II/III diastolic dysfunction), only 17 (71%) had a pulmonary artery occlusion pressure greater than or equal to 18 mm Hg. Similarly, 20 of the 26 patients (77%) with a normal predicted left atrial pressure (grade I diastolic dysfunction) had a measured pulmonary artery occlusion pressure less than 18 mm Hg. The sensitivity and specificity of American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines for predicting elevated pulmonary artery occlusion pressure were both 74%. The agreement between echocardiography and the pulmonary artery catheter was moderate (Cohen's Kappa, 0.48; 95% CI, 0.39-0.70). In a proposed alternative algorithm, the best echocardiographic predictors of a normal pulmonary artery occlusion pressure were a lateral e'-wave greater than 8 (for a left ventricular ejection fraction ≥ 45%) or an E/A ratio less than or equal to 1.5 (for a left ventricular ejection fraction < 45%). CONCLUSIONS: The American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines do not accurately assess pulmonary artery occlusion pressure in ventilated critically ill patients. Simple Doppler measurements gave a similar level of diagnostic performance with less uncertainly.

Reassessment of the Accuracy of Cardiac Doppler Pulmonary Artery Pressure Measurements in Ventilated ICU Patients: A Simultaneous Doppler-Catheterization Study.

OBJECTIVES: Doppler echocardiography is a well-recognized technique for the noninvasive evaluation of pulmonary artery pressure; however, little information is available concerning patients receiving mechanical ventilation. Furthermore, recent studies have debatable results regarding the relevance of this technique to assess pulmonary artery pressure. The aim of our study was to reassess the accuracy of Doppler echocardiography to evaluate pulmonary artery pressure and to predict pulmonary hypertension. DESIGN: Prospective observational study. SETTING: Amiens ICU, France. PATIENTS: ICU patients receiving mechanical ventilation. INTERVENTIONS: In 40 patients, we simultaneously recorded Doppler echocardiography variables (including tricuspid regurgitation and pulmonary regurgitation) and invasive central venous pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, and mean pulmonary artery pressure. MEASUREMENTS AND MAIN RESULTS: Systolic pulmonary artery pressure assessed from the tricuspid regurgitation derived maximal pressure gradient added to the central venous pressure demonstrated the best correlation with the invasive systolic pulmonary artery pressure (r = 0.87) with a small bias (-3 mm Hg) and a precision of 9 mm Hg. A Doppler echocardiography systolic pulmonary artery pressure greater than 39 mm Hg predicted pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg) with 100% sensitivity and specificity. Tricuspid regurgitation maximal velocity greater than 2.82 m/s as well as tricuspid regurgitation pressure gradient greater than 32 mm Hg predicted the presence of pulmonary hypertension. Pulmonary regurgitation was recorded in 10 patients (25%). No correlation was found between pulmonary regurgitation velocities and either mean pulmonary artery pressure or diastolic pulmonary artery pressure. Pulmonary acceleration time less than 57 ms and isovolumic relaxation time less than 40 ms respectively predicted pulmonary hypertension 100% of the time and had a 100% negative predictive value. CONCLUSIONS: Tricuspid regurgitation maximal velocity pressure gradient added to invasive central venous pressure accurately estimates systolic pulmonary artery pressure and mean pulmonary artery pressure in ICU patients receiving mechanical ventilation and may predict pulmonary hypertension.

Feasibility of myocardial perfusion assessment with contrast echocardiography: can it improve recognition of significant coronary artery disease in the ICU?

BACKGROUND: Diagnosis of significant coronary artery disease (CAD) and acute coronary artery occlusion in ICU can be difficult, and an inappropriate intervention is potentially harmful. Myocardial contrast perfusion echo (MCPE) examines ultrasound contrast intensity replenishment curves in individual myocardial segments measuring peak contrast intensity and slope of return as an index of myocardial blood flow (units = intensity of ultrasound per second [dB/s]). MCPE could possibly serve as a triage tool to invasive angiography by estimating blood flow in the myocardium. We sought to assess feasibility in the critically ill and if MCPE could add incremental value to the clinical acumen in predicting significant CAD. METHODS: This is a single-centre, prospective, observational study. Inclusion criteria were as follows: adult ICU patients with troponin I > 50 ng/L and cardiology referral being made for consideration of inpatient angiography. Exclusion criteria were as follows: poor echo windows (2 patients), known ischaemic heart disease, and contrast contraindications. Seven cardiologists and 6 intensivists blinded to outcome assessed medical history, ECG, troponin, and 2D echo images to estimate likelihood of significant CAD needing intervention (clinical acumen). Clinical acumen, quantitative MCPE, and subjective (visual) MCPE were assessed to predict significant CAD. RESULTS: Forty patients underwent MCPE analysis, 6 (15%) had significant CAD, and median 11 of 16 segments (IQR 8-13) could be imaged (68.8% [IQR 50-81]). No adverse events occurred. A significant difference was found in overall MCPE blood flow estimation between those diagnosed with significant CAD and those without (3.3 vs 2.4 dB/s, p = 0.050). A MCPE value of 2.8 dB/s had 67% sensitivity and 88% specificity in detecting significant CAD. Clinical acumen showed no association in prediction of CAD (OR 0.6, p = 0.09); however, if quantitative or visual MCPE analysis was included, a significant association occurred (OR 17.1, p = 0.01; OR 23.0, p = 0.01 respectively). CONCLUSIONS: MCPE is feasible in the critically ill and shows better association with predicting significant CAD vs clinical acumen alone. MCPE adds incremental value to initial assessment of the presence of significant CAD which may help guide those who require urgent angiography.

Subjective right ventricle assessment by echo qualified intensive care specialists: assessing agreement with objective measures.

BACKGROUND: Right ventricle (RV) size and function assessment by echocardiography (echo) is a standard tool in the ICU. Frequently subjective assessment is performed, and guidelines suggest its utility in adequately trained clinicians. We aimed to compare subjective (visual) assessment of RV size and function by ICU physicians, with advanced qualifications in echocardiography, vs objective measurements. METHODS: ICU specialists with a qualification in advanced echocardiography reviewed 2D echo clips from critically ill patients on mechanical ventilation with PaO2:FiO2 < 300. Subjective assessments of RV size and function were made independently using a three-class categorical scale. Agreement (B-score) and bias (p value) were analysed using objective echo measurements. RV size assessment included RV end-diastolic area (EDA) and diameters. RV function assessment included fractional area change, S', TAPSE and RV free wall strain. Binary and ordinal analysis was performed. RESULTS: Fifty-two clinicians reviewed 2D images from 80 patients. Fair agreement was seen with objective measures vs binary assessment of RV size (RV EDA 0.26 [p < 0.001], RV dimensions 0.29 [p = 0.06]) and function (RV free wall strain 0.27 [p < 0.001], TAPSE 0.27 [p < 0.001], S' 0.29 [p < 0.001], FAC 0.31 [p = 0.16]). However, ordinal data analysis showed poor agreement with RV dimensions (0.11 [p = 0.06]) and RV free wall strain (0.14 [p = 0.16]). If one-step disagreement was allowed, agreement was good (RV dimensions 0.6 [p = 0.06], RV free wall strain 0.6 [p = 0.16]). Significant overestimation of severity of abnormalities was seen with subjective assessment vs RV EDA, TAPSE, S' and fractional area change. CONCLUSION: Subjective (visual) assessment of RV size and function, by ICU specialists trained in advanced echo, can be fairly reliable for the initial exclusion of significant RV pathology. It seems prudent to avoid subjective RV assessment in isolation.

The stop-flow arm equilibrium pressure in preoperative patients: Stressed volume and correlations with echocardiography.

BACKGROUND: The distending intravascular pressure at no flow conditions reflects the stressed volume. While this haemodynamic variable is recognised as clinically important, there is a paucity of reports of its range and responsiveness to volume expansion in patients without cardiovascular disease and no reports of correlations to echocardiographic assessments of left ventricular filling. METHODS: Twenty-seven awake (13 male), spontaneously breathing patients without any history of cardiopulmonary, vascular or renal disease were studied prior to induction of anaesthesia. The no-flow equilibrium pressure in the arm following rapid circulatory occlusion (Parm ) was measured via a radial arterial catheter. Transthoracic echocardiography was used to measure left ventricular end diastolic area and volume as well as the diameter of the inferior vena cava. The Parm and echocardiographic variables were measured before and after administration of 500 mL 0.9% NaCl over 10 minutes. Changes were analysed by paired t test, Pearson's correlation and multiple linear regression. RESULTS: Parm increased overall from 22 ± 5 mm Hg to 25 ± 6 mm Hg (mean difference 3.0 ± 4.5 mm Hg, P = 0.002) following the fluid bolus with corresponding increases in arterial pressure and echocardiographic variables. Variability in the direction of the Parm response reflected concomitant changes in vascular compliance. Only weak correlations were observed between changes in Parm and inferior vena cava diameter indexed to body surface area (R2  = 0.29, P = 0.01). CONCLUSION: Preoperative measurements of Parm increased following acute expansion of the intravascular volume. Echocardiography demonstrated poor correlation with Parm .

Moderate and Severe Acute Respiratory Distress Syndrome: Hemodynamic and Cardiac Effects of an Open Lung Strategy With Recruitment Maneuver Analyzed Using Echocardiography.

OBJECTIVES: Open lung ventilation with a recruitment maneuver could be beneficial for acute respiratory distress syndrome patients. However, the increased airway pressures resulting from the recruitment maneuver may induce cardiac dysfunction, limiting the benefit of this maneuver. We analyzed the effect of a recruitment maneuver and decremental positive end-expiratory pressure titration on cardiac function. SETTINGS: Medical ICU Amiens, France. PATIENTS: Twenty patients with moderate to severe acute respiratory distress syndrome INTERVENTIONS:: Patients underwent a stepwise recruitment maneuver with respiratory evaluation and echocardiography assessment of cardiac function including longitudinal strain at baseline, peak positive end-expiratory pressure of recruitment maneuver (positive end-expiratory pressure 40 cm H2O), and at "optimal" positive end-expiratory pressure. The patients were divided into two groups based on change on the PaO2/FIO2 ratio (nonresponders < 50%; responders ≥ 50%). MEASUREMENTS AND MAIN RESULTS: At peak positive end-expiratory pressure during the recruitment maneuver, the arterial pressure, cardiac output, left ventricular size decreased and right ventricular size increased. The left ventricular ejection fraction decreased from 60% ± 13% to 48% ± 18% (p = 0.05). Both left and right ventricular global longitudinal strain were impaired (-15.8% ± 4.5% to -11% ± 4.7% and -19% ± 5% to -14% ± 6% [p = 0.05] respectively). Fifty percent of patients were nonresponders and demonstrated a lower hemodynamic tolerance to the recruitment maneuver than responders. Optimal positive end-expiratory pressure was 14 ± 5 cm H2O (vs 11 ± 4 cm H2O at baseline), and PaO2/FIO2 ratio increased from 111 ± 25 to 197 ± 89 mm Hg (p < 0.0001). All hemodynamic variables returned to their baseline value after the recruitment maneuver despite a higher positive end-expiratory pressure. CONCLUSIONS: An open lung strategy with a stepwise recruitment maneuver permitted a higher positive end-expiratory pressure and improved oxygenation without any cardiac impairment. The recruitment maneuver was associated with mild and transient, cardiac dysfunction, with nonresponders demonstrating poorer tolerance.

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers.

PURPOSE: Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of 99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and 123I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement. METHODS: We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4 h after injection (defined by HM4 ≥ 1.85) or abnormal HM4 < 1.85, and positive DPD uptake (grade ≥ 1 of Perugini classification) or negative DPD uptake. RESULTS: Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e' ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n = 31), MIBG was abnormal in 48% (n = 15) among whom 50% had a normal DPD; all those with a normal MIBG (n = 16) had a normal DPD. CONCLUSIONS: In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value.

Feasibility of biventricular 3D transthoracic echocardiography in the critically ill and comparison with conventional parameters.

BACKGROUND: Transthoracic 3D cardiac analysis is enticing in its potential simplicity and wealth of data available. It has been suggested to be accurate vs magnetic resonance imaging in relatively stable patients, but feasibility and agreement with conventional echocardiographic assessment of stroke volume (SV) have not been thoroughly assessed in critically ill patients, who are traditionally harder to image. The objectives of this study were to compare 3D transthoracic volumetric analysis vs Doppler assessment of SV (which is suggested to be accurate in the critically ill) and Simpson's biplane assessment in a cohort typical of the intensive care unit (ICU), where accurate assessment is important: mechanically ventilated patients with a significant ventilation/perfusion (V/Q) mismatch. We hypothesised that it would be feasible but might lack agreement. METHODS: Patients were imaged within 24 hours of admission. Inclusion criteria were adult patients, V/Q mismatch present (defined as a ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300), and mechanically ventilated with Doppler SV assessment possible. Biventricular echocardiographic volumetric analysis was performed using Siemens SC2000 along with standard Simpson's biplane and Doppler SV assessment. 3D images were unacceptable if two segments or more were unable to be seen in two volumetric planes. 3D left ventricular (3DLV) and 3D right ventricular (3DRV) analyses were performed with the Tomtec Imaging and Siemens Acuson platforms, respectively. RESULTS: Ninety-two patients were included (83 in sinus, 9 in atrial fibrillation). 3DLV and 3DRV analyses were feasible in 72% and 55% of patients, respectively; however, they underestimated SV compared with Doppler by 2.6 ml (± 10.4) and 4.1 ml (± 15.4), respectively. Limits of agreement for 2D, 3DLV and 3DRV volumetric analysis techniques were large. CONCLUSIONS: 3DLV and 3DRV volumetric analyses appear feasible (obtainable) in the majority of mechanically ventilated ICU patients. Compared with the Doppler method, 3DLV and 3DRV volumetric analyses underestimate SV. The large limits of agreement between the methods also cast doubt on their comparability. Given the scenarios in which SV analysis is required (e.g., assessment of cardiac performance), our study cautions against the use of 3D SV clinically.

Comparison of Echocardiographic Indices Used to Predict Fluid Responsiveness in Ventilated Patients.

RATIONALE: Assessment of fluid responsiveness relies on dynamic echocardiographic parameters that have not yet been compared in large cohorts. OBJECTIVES: To determine the diagnostic accuracy of dynamic parameters used to predict fluid responsiveness in ventilated patients with a circulatory failure of any cause. METHODS: In this multicenter prospective study, respiratory variations of superior vena cava diameter (∆SVC) measured using transesophageal echocardiography, of inferior vena cava diameter (∆IVC) measured using transthoracic echocardiography, of the maximal Doppler velocity in left ventricular outflow tract (∆VmaxAo) measured using either approach, and pulse pressure variations (∆PP) were recorded with the patient in the semirecumbent position. In each patient, a passive leg raise was performed and an increase of aortic velocity time integral greater than or equal to 10% defined fluid responsiveness. MEASUREMENTS AND MAIN RESULTS: Among 540 patients (379 men; age, 65 ± 13 yr; Simplified Acute Physiological Score II, 59 ± 18; Sequential Organ Failure Assessment, 10 ± 3), 229 exhibited fluid responsiveness (42%). ∆PP, ∆VmaxAo, ∆SVC, and ∆IVC could be measured in 78.5%, 78.0%, 99.6%, and 78.1% of cases, respectively. ∆SVC greater than or equal to 21%, ∆VmaxAo greater than or equal to 10%, and ∆IVC greater than or equal to 8% had a sensitivity of 61% (95% confidence interval, 57-66%), 79% (75-83%), and 55% (50-59%), respectively, and a specificity of 84% (81-87%), 64% (59-69%), and 70% (66-75%), respectively. The area under the receiver operating characteristic curve of ∆SVC was significantly greater than that of ∆IVC (P = 0.02) and ∆PP (P = 0.01). CONCLUSIONS: ∆VmaxAo had the best sensitivity and ∆SVC the best specificity in predicting fluid responsiveness. ∆SVC had a greater diagnostic accuracy than ∆IVC and ∆PP, but its measurement requires transesophageal echocardiography.