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.
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.
The majority of patients with ATTRv may have now access to a DMT. Criteria for early diagnosis are available.
Assessment of fluid responsiveness relies on dynamic echocardiographic parameters that have not yet been compared in large cohorts.
To determine the diagnostic accuracy of dynamic parameters used to ...predict fluid responsiveness in ventilated patients with a circulatory failure of any cause.
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.
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).
∆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.
Over the past two decades, ultrasound (US) has become widely accepted to guide safe and accurate insertion of vascular devices in critically ill patients. We emphasize central venous catheter ...insertion, given its broad application in critically ill patients, but also review the use of US for accessing peripheral veins, arteries, the medullary canal, and vessels for institution of extracorporeal life support. To ensure procedural safety and high cannulation success rates we recommend using a systematic protocolized approach for US-guided vascular access in elective clinical situations. A standardized approach minimizes variability in clinical practice, provides a framework for education and training, facilitates implementation, and enables quality analysis. This review will address the state of US-guided vascular access, including current practice and future directions.
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.
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).
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.
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 .).
Cardiac output (CO) monitoring is a valuable tool for the diagnosis and management of critically ill patients. In the critical care setting, few studies have evaluated the level of agreement between ...CO estimated by transthoracic echocardiography (CO-TTE) and that measured by the reference method, pulmonary artery catheter (CO-PAC). The objective of the present study was to evaluate the precision and accuracy of CO-TTE relative to CO-PAC and the ability of transthoracic echocardiography to track variations in CO, in critically ill mechanically ventilated patients.
Thirty-eight mechanically ventilated patients fitted with a PAC were included in a prospective observational study performed in a 16-bed university hospital ICU. CO-PAC was measured via intermittent thermodilution. Simultaneously, a second investigator used standard-view TTE to estimate CO-TTE as the product of stroke volume and the heart rate obtained during the measurement of the subaortic velocity time integral.
Sixty-four pairs of CO-PAC and CO-TTE measurements were compared. The two measurements were significantly correlated (r = 0.95; p < 0.0001). The median bias was 0.2 L/min, the limits of agreement (LOAs) were -1.3 and 1.8 L/min, and the percentage error was 25%. The precision was 8% for CO-PAC and 9% for CO-TTE. Twenty-six pairs of ΔCO measurements were compared. There was a significant correlation between ΔCO-PAC and ΔCO-TTE (r = 0.92; p < 0.0001). The median bias was -0.1 L/min and the LOAs were -1.3 and +1.2 L/min. With a 15% exclusion zone, the four-quadrant plot had a concordance rate of 94%. With a 0.5 L/min exclusion zone, the polar plot had a mean polar angle of 1.0° and a percentage error LOAs of -26.8 to 28.8°. The concordance rate was 100% between 30 and -30°. When using CO-TTE to detect an increase in ΔCO-PAC of more than 10%, the area under the receiving operating characteristic curve (95% CI) was 0.82 (0.62-0.94) (p < 0.001). A ΔCO-TTE of more than 8% yielded a sensitivity of 88% and specificity of 66% for detecting a ΔCO-PAC of more than 10%.
In critically ill mechanically ventilated patients, CO-TTE is an accurate and precise method for estimating CO. Furthermore, CO-TTE can accurately track variations in CO.
We have almost no information concerning the value of inferior vena cava (IVC) respiratory variations in spontaneously breathing ICU patients (SBP) to predict fluid responsiveness.
SBP with clinical ...fluid need were included prospectively in the study. Echocardiography and Doppler ultrasound were used to record the aortic velocity-time integral (VTI), stroke volume (SV), cardiac output (CO) and IVC collapsibility index (cIVC) ((maximum diameter (IVCmax)- minimum diameter (IVCmin))/ IVCmax) at baseline, after a passive leg-raising maneuver (PLR) and after 500 ml of saline infusion.
Fifty-nine patients (30 males and 29 females; 57 ± 18 years-old) were included in the study. Of these, 29 (49 %) were considered to be responders (≥10 % increase in CO after fluid infusion). There were no significant differences between responders and nonresponders at baseline, except for a higher aortic VTI in nonresponders (16 cm vs. 19 cm, p = 0.03). Responders had a lower baseline IVCmin than nonresponders (11 ± 5 mm vs. 14 ± 5 mm, p = 0.04) and more marked IVC variations (cIVC: 35 ± 16 vs. 27 ± 10 %, p = 0.04). Prediction of fluid-responsiveness using cIVC and IVCmax was low (area under the curve for cIVC at baseline 0.62 ± 0.07; 95 %, CI 0.49-0.74 and for IVCmax at baseline 0.62 ± 0.07; 95 % CI 0.49-0.75). In contrast, IVC respiratory variations >42 % in SBP demonstrated a high specificity (97 %) and a positive predictive value (90 %) to predict an increase in CO after fluid infusion.
In SBP with suspected hypovolemia, vena cava size and respiratory variability do not predict fluid responsiveness. In contrast, a cIVC >42 % may predict an increase in CO after fluid infusion.
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