Fomepizole dosing during continuous renal replacement therapy - an observational study.

BACKGROUND: Fomepizole is the preferred antidote for treatment of methanol and ethylene glycol poisoning, acting by inhibiting the formation of the toxic metabolites. Although very effective, the price is high and the availability is limited. Its availability is further challenged in situations with mass poisonings. Therefore, a 50% reduced maintenance dose for fomepizole during continuous renal replacement therapy (CRRT) was suggested in 2016, based on pharmacokinetic data only. Our aim was to study whether this new dosing for fomepizole during CRRT gave plasma concentrations above the required 10 µmol/L. Secondly, we wanted to study the elimination kinetics of fomepizole during CRRT, which has never been studied before. METHODS: Prospective observational study of adult patients treated with fomepizole and CRRT. We collected samples from arterial line (pre-filter) = plasma concentration, post-filter and dialysate for fomepizole measurements. Fomepizole was measured using high-pressure liquid chromatography with a reverse phase column. RESULTS: Ten patients were included in the study. Seven were treated with continuous veno-venous hemodialysis (CVVHD) and three with continuous veno-venous hemodiafiltration (CVVHDF). Ninety-eight percent of the plasma samples were above the minimum plasma concentration of 10 µmol/L. Fomepizole was removed during CRRT with a median saturation/sieving coefficient of 0.85 and dialysis clearance of 28 mL/min. CONCLUSION: Fomepizole was eliminated during CCRT. The new dosing recommendations for fomepizole and CRRT appeared safe, by maintaining the plasma concentration above the minimum value of 10 µmol/L. Based on these data, the fomepizole maintenance dose during CRRT could be reduced to half as compared to intermittent hemodialysis.

Adaptation of trustworthy guidelines developed using the GRADE methodology: a novel five-step process.

BACKGROUND: Adaptation of guidelines for use at the national or local level can facilitate their implementation. We developed and evaluated an adaptation process in adherence with standards for trustworthy guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, aiming for efficiency and transparency. This article is the first in a series describing our adaptation of Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for a Norwegian setting. METHODS: Informed by the ADAPTE framework, we developed a five-step adaptation process customized to guidelines developed using GRADE: (1) planning, (2) initial assessment of the recommendations, (3) modification, (4) publication, and (5) evaluation. We developed a taxonomy for describing how and why recommendations from the parent guideline were modified and applied a mixed-methods case study design for evaluation of the process. RESULTS: We published the adapted guideline in November 2013 in a novel multilayered format. The taxonomy for adaptation facilitated transparency of the modification process for both the guideline developers and the end users. We excluded 30 and modified 131 of the 333 original recommendations according to the taxonomy and developed eight new recommendations. Unforeseen obstacles related to acquiring a licensing agreement and procuring a publisher resulted in a 9-month delay. We propose modifications of the adaptation process to overcome these obstacles in the future. CONCLUSIONS: This case study demonstrates the feasibility of a novel guideline adaptation process. Replication is needed to further validate the usefulness of the process in increasing the organizational and methodologic efficiency of guideline adaptation.

Identification of viable myocardium in acute anterior infarction using duration of systolic lengthening by tissue Doppler strain: a preliminary study.

BACKGROUND: The aim of this study was to investigate whether strain Doppler echocardiography before reperfusion therapy could quantify ischemic dysfunction and predict viable myocardium in acute myocardial infarction as determined by magnetic resonance imaging. METHODS: Twenty-six patients (mean age, 60 ± 12 years; seven women) with acute myocardial infarctions who underwent acute percutaneous coronary intervention were examined using strain Doppler echocardiography immediately before the procedure. Percutaneous coronary intervention was performed 296 ± 122 min after the onset of pain. Peak left ventricular systolic longitudinal strain and the duration of systolic lengthening were analyzed. Magnetic resonance imaging was performed 11 ± 5 months after therapy. Scarring exceeding 50% of the segment area was considered nonviable. RESULTS: Peak systolic strain fell gradually (becoming less negative) from normal segments to segments with transmural infarction (P < .0001), and the duration of systolic lengthening increased (P < .0001). Myocardial scarring was closely correlated with peak systolic strain (R = 0.76, P < .00001) and the duration of systolic lengthening (R = 0.88, P < .00001). There was a significant correlation between the degree of scarring and time to percutaneous coronary intervention (R = 0.40, P = .045). In segments with systolic lengthening, the improvement in strain after remodeling was significantly higher (5.5 ± 5.1%) than in segments with duration of systolic lengthening > 67% of systole (2.2 ± 3.7%) (P < .001). Receiver operating characteristic curve analyses showed that duration of systolic lengthening > 67.3% could identify nonviable myocardium (sensitivity, 90%; specificity, 94%). CONCLUSIONS: In patients with acute myocardial infarctions in the anterior wall, strain measurements can identify myocardium with nontransmural scarring. The duration of systolic lengthening is a novel, easily implemented variable that may identify ischemic but viable myocardium. Myocardial infarctions in other left ventricular regions should be investigated in future studies.

Comparison of left ventricular ejection fraction and left ventricular global strain as determinants of infarct size in patients with acute myocardial infarction.

BACKGROUND: The aim was to compare left ventricular ejection fraction (LVEF) and left ventricular (LV) global strain by speckle tracking as predictors of final infarct size. METHODS: LV global strain and LVEF by echocardiography were assessed in the acute phase and after revascularization in 39 patients with ST-elevation myocardial infarction treated with thrombolysis. RESULTS: After revascularization, global strain and LVEF correlated well with infarct size measured by contrast-enhanced cardiac magnetic resonance. A cutoff value of -15.0% for global strain had a sensitivity of 90% and a specificity of 86% to identify myocardial infarcts larger than 20%. Interobserver variability, expressed by intraclass correlation coefficients, for global strain and LVEF was 0.91 and 0.72, respectively. CONCLUSIONS: LV global strain is a more precise diagnostic predictor of large infarcts compared with LVEF and is more reproducible. Global strain measured after revascularization demonstrates advantages over LVEF in the evaluation of LV injury in patients with ST-elevation myocardial infarction.

Left ventricle longitudinal deformation assessment by mitral annulus displacement or global longitudinal strain in chronic ischemic heart disease: are they interchangeable?

BACKGROUND: Increasing infarct mass is associated with impaired prognosis in chronic ischemic heart disease. Global strain by echocardiographic assessment relates closely to infarct mass assessed by delayed enhancement magnetic resonance imaging but requires deformation analysis in a 16-segment model of the left ventricular. Mitral annular (MA) displacement reflects longitudinal left ventricular deformation and could provide similar information. METHODS: Global longitudinal strain and MA displacement by Doppler tissue imaging were assessed in 61 patients 9 months after first myocardial infarctions and compared with global myocardial infarct mass assessed using contrast-enhanced magnetic resonance imaging. RESULTS: Both indices significantly separated medium-sized infarcts from small or large infarcts (P < .05) and correlated significantly with global infarct mass (P < .01 for both). There was a good correlation between global strain and MA displacement (r = 0.65, P < .01). The sensitivities and specificities to identify myocardial infarcts differed only slightly among the indices, but global longitudinal strain tended to be the best. CONCLUSIONS: Longitudinal deformation by global strain or MA displacement correlated well with myocardial infarct mass and could discriminate between different extents of myocardial infarctions. Global longitudinal strain tended to be better, especially for the identification of the smallest infarcts.

Determinants of left ventricular early-diastolic lengthening velocity: independent contributions from left ventricular relaxation, restoring forces, and lengthening load.

BACKGROUND: Peak early-diastolic mitral annulus velocity (e') by tissue Doppler imaging has been introduced as a clinical marker of diastolic function. This study investigates whether lengthening load (early-diastolic load) and restoring forces are determinants of e' in addition to rate of left ventricular (LV) relaxation. METHODS AND RESULTS: In 10 anesthetized dogs, we measured e' by sonomicrometry and tissue Doppler imaging during baseline, volume loading, caval constriction, dobutamine infusion, and occlusion of the left anterior descending coronary artery. Relaxation was measured as the time constant (tau) of LV pressure decay by micromanometer. Lengthening load was measured as LV transmural pressure at mitral valve opening (LVP(MVO)). Restoring forces were quantified by 2 different indices: (1) As the difference between minimum and unstressed LV diameter (Lmin-L0) and (2) as the estimated fully relaxed LV transmural pressure (FRP(Est)) at minimum diameter. In the overall analysis, a strong association was observed between e' and LVP(MVO) (beta=0.49; P<0.001), which indicates an independent effect of lengthening load, as well as between e' and Lmin-L0 (beta=-0.38; P<0.002) and between e' and FRP(Est) (beta=-0.31; P<0.002), consistent with an independent contribution of restoring forces. A direct effect of rate of relaxation on e' was observed in a separate analysis of baseline, dobutamine, and ischemia when postextrasystolic beats were included (beta=-0.06, P<0.01). CONCLUSIONS: The present study indicates that in the nonfailing ventricle, in addition to LV relaxation, restoring forces and lengthening load are important determinants of early-diastolic lengthening velocity.

Clinical assessment of left ventricular rotation and strain: a novel approach for quantification of function in infarcted myocardium and its border zones.

Left ventricular (LV) circumferential strain and rotation have been introduced as clinical markers of myocardial function. This study investigates how regional LV apical rotation and strain can be used in combination to assess function in the infarcted ventricle. In healthy subjects (n = 15) and patients with myocardial infarction (n = 23), LV apical segmental rotation and strain were measured from apical short-axis recordings by speckle tracking echocardiography (STE) and MRI tagging. Infarct extent was determined by late gadolinium enhancement MRI. To investigate mechanisms of changes in strain and rotation, we used a mathematical finite element simulation model of the LV. Mean apical rotation and strain by STE were lower in patients than in healthy subjects (9.0 +/- 4.9 vs. 12.9 +/- 3.5 degrees and -13.9 +/- 10.7 vs. -23.8 +/- 2.3%, respectively, P < 0.05). In patients, regional strain was reduced in proportion to segmental infarct extent (r = 0.80, P < 0.0001). Regional rotation, however, was similar in the center of the infarct and in remote viable myocardium. Minimum and maximum rotations were found at the infarct borders: minimum rotation at the border zone opposite to the direction of apical rotation, and maximum rotation at the border zone in the direction of rotation. The simulation model reproduced the clinical findings and indicated that the dissociation between rotation and strain was caused by mechanical interactions between infarcted and viable myocardium. Systolic strain reflects regional myocardial function and infarct extent, whereas systolic rotation defines infarct borders in the LV apical region. Regional rotation, however, has limited ability to quantify regional myocardial dysfunction.

A novel echocardiographic marker of end systole in the ischemic left ventricle: "tug of war" sign.

The present study introduces a new clinical method to define left ventricular (LV) end systole (ES) during tissue Doppler imaging (TDI). Preliminary experiments showed a sharp inflection point in strain traces (S(IP)) from ischemic borderzones, which coincided with onset of a postsystolic shortening wave (V(PS)) in the velocity trace. In a single-vessel disease model, we investigated whether S(IP) and V(PS) may serve as markers of global ES and their mechanism. In six anesthetized dogs we measured LV pressure and myocardial long-axis function by using TDI and sonomicrometry. Ischemia was induced by left anterior descending coronary artery occlusion. ES was defined by the minimum first derivative of LV pressure. TDI and sonomicrometry demonstrated a sharp S(IP) and V(PS) at ES in the ischemic borderzone (defined as moderately ischemic myocardium by pressure-dimension loop analysis). Time differences relative to ES ( +/- SD) were -0.1 +/- 2.3 (intraclass correlation coefficient R(IC) = 0.996) and 6.8 +/- 10.7 ms (R(IC) = 0.89) for S(IP) as shown by sonomicrometry and TDI, respectively. There was a strong inverse relationship between postsystolic shortening in the borderzone and simultaneous lengthening of nonischemic myocardium. In 30 patients with acute myocardial infarction, S(IP) and V(PS) evaluated by TDI were compared with ES defined by aortic valve closure. Time differences were -4 +/- 14 (R(IC) = 0.94) and -2 +/- 11 ms (R(IC) = 0.96), respectively. In the ischemic borderzone, S(IP) and V(PS) identified global ES with high accuracy. The force balance or "tug of war" between borderzone and nonischemic myocardium is a likely underlying mechanism for these markers. The method may be used as an "all in one heart beat" approach for TDI analysis in acute myocardial ischemia.

Apical rotation by speckle tracking echocardiography: a simplified bedside index of left ventricular twist.

OBJECTIVE: The study objective was to determine whether left ventricular (LV) apical rotation by speckle tracking echocardiography (STE) may serve as a clinically feasible index of LV twist. LV twist has been proposed as a sensitive marker of LV function, but clinical implementation has not been feasible because of the complexity and limitations of present methodologies. METHODS: The relationship between apical rotation and LV twist was investigated in anesthetized dogs (n = 9) and a clinical study that included healthy controls (n = 18) and patients (n = 27) with previous myocardial infarction. Rotation by STE was compared with twist measured by magnetic resonance imaging and sonomicrometry in humans and dogs, respectively. RESULTS: In dogs, apical rotation by STE correlated well with LV twist over a wide range of loading conditions and inotropic states, and during myocardial ischemia (R = 0.94, P < .01). Similarly, in humans there was a strong correlation between apical rotation and twist (R = 0.88, P < .01) but only a weak correlation between basal rotation and twist (R = 0.53, P < .01). Apical rotation accounted for 72% +/- 14% and 73% +/- 15% of the twisting deformation by magnetic resonance imaging in controls and patients, respectively. In dogs, apical rotation and twist decreased during myocardial ischemia (P < .05). In patients, LV twist and apical rotation were reduced (P < .05) only when LV ejection fraction was less than 50%. CONCLUSION: Apical rotation represents the dominant contribution to LV twist, and apical rotation by STE reflects LV twist over a wide range of hemodynamic conditions. These findings suggest that apical rotation by STE may serve as a simple and feasible clinical index of LV twist.

Mechanisms of preejection and postejection velocity spikes in left ventricular myocardium: interaction between wall deformation and valve events.

BACKGROUND: Normal left ventricular myocardium demonstrates distinct spikes in the velocity trace before and after left ventricular ejection. We tested the hypothesis that the preejection and postejection velocity spikes reflect early systolic shortening and late systolic lengthening that are interrupted by mitral and aortic valve closure, respectively. METHODS AND RESULTS: In 11 anesthetized dogs, timing of valve closure was determined by pressure variables; left ventricular dimensions were determined by sonomicrometry. Myocardial shortening started 20+/-10 ms (mean+/-SD; P<0.001) before mitral valve closure and was interrupted at the time of mitral valve closure (time difference, 4+/-7 ms). Similarly, myocardial lengthening started 31+/-15 ms (P<0.001) before aortic valve closure and was interrupted at the time of aortic valve closure (time difference, 0+/-3 ms). Prevention of mitral (n=4) and aortic (n=4) valve closure by stenting the valves abolished the preejection and postejection velocity spikes, respectively. Echocardiographic measurements of patients (n=15) with severe mitral regurgitation showed that the preejection velocity spike was reduced after prosthetic valve replacement (43+/-25 versus 32+/-15 mm/s; P=0.036), indicating that preejection shortening was larger with a leaking valve. Similarly, late systolic lengthening was reduced in patients (n=15) with severe aortic regurgitation after prosthetic valve replacement; minimum postejection velocity spike was increased from -32+/-11 to -17+/-11 mm/s; P=0.0003). Asynchronous onset of contraction/relaxation and atrioventricular interaction were investigated as alternative mechanisms of the velocity spikes in dogs and patient groups but were found implausible. CONCLUSIONS: This study supports the hypothesis that normal left ventricular preejection and postejection velocity spikes are attributed to valve closures that interrupt early systolic shortening and late systolic lengthening, respectively.

Noninvasive separation of large, medium, and small myocardial infarcts in survivors of reperfused ST-elevation myocardial infarction: a comprehensive tissue Doppler and speckle-tracking echocardiography study.

BACKGROUND: The objective of the study was to evaluate the ability of established and new parameters of global systolic left ventricle function to estimate myocardial infarct size. Increasing infarct extent is associated with impaired prognosis in chronic ischemic heart disease. Systolic myocardial deformation is a complex 3D process that is mainly influenced by the amount and transmural distribution of viable myocardium. Speckle-tracking echocardiography (2D-STE) enables deformation assessment along the 3 main cardiac axes independent of insonation angle. METHODS AND RESULTS: Global longitudinal, circumferential, and radial strain and left ventricle twist by 2D-STE, global longitudinal strain rate and strain by tissue Doppler imaging, and left ventricle ejection fraction and wall motion score index were assessed in 40 patients 8.5+/-5.4 months after a first myocardial infarct and compared with global myocardial infarct mass assessed by contrast-enhanced MRI. Longitudinal and circumferential strain by 2D-STE and longitudinal strain and strain rate by tissue Doppler imaging significantly separated medium-sized infarcts from small or large infarcts at the global level (P<0.05). All deformation indices correlated significantly with global infarct mass (P<0.01). Circumferential and longitudinal strains by 2D-STE demonstrated the best ability to identify medium-sized global myocardial infarcts. CONCLUSIONS: Circumferential and longitudinal strains by 2D-STE correlate with myocardial infarct mass and significantly differentiate among large, medium, and small myocardial infarcts.

Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease.

2D-STE (two-dimensional speckle tracking echocardiography) is a novel echocardiographic modality that enables angle-independent assessment of myocardial deformation indices. In the present study, we tested whether peak systolic epsilon(parallel) (longitudinal strain) values measured by 2D-STE could identify areas of MI (myocardial infarction) as determined by CE MRI (contrast-enhanced magnetic resonance imaging). Conventional echocardiographic apical long-axis recordings were performed in 38 patients, 9 months after a first MI. Peak systolic epsilon(parallel) measured by 2D-STE in 16 left ventricle segments was compared with segmental infarct mass and transmurality assessed by CE MRI. Segmental values were averaged to global and territorial values for assessment of global function and myocardial function in the coronary distribution areas. CE MRI identified transmural infarction in 27 patients, and a mean infarct size of 36+/-25 g. Peak systolic epsilon( parallel) correlated with the infarct mass at the global level (r=0.84, P<0.001). A strain value of -15% identified infarction with 83% sensitivity and 93% specificity at the global level and 76% and 95% at the territorial level, and a strain value of -13% identified transmural infarction with 80% sensitivity and 83% specificity at the segmental level. Global infarct mass correlates with the wall motion score index (r=0.70, P<0.001), and left ventricular ejection fraction measured by MRI or echocardiography (r=-0.71 and -0.58, both P<0.001). In chronic infarction, peak systolic epsilon(parallel) measured by 2D-STE correlates with the infarct mass assessed by CE MRI at a global level, and separates infarcted from non-infarcted tissue. Global strain is an excellent predictor of myocardial infarct size in chronic ischaemic heart disease.

Early prediction of infarct size by strain Doppler echocardiography after coronary reperfusion.

OBJECTIVES: The objective of this study was to investigate whether strain Doppler echocardiography performed immediately after revascularization by percutaneous coronary intervention could predict the extent of myocardial scar, determined by contrast-enhanced magnetic resonance imaging (MRI). BACKGROUND: There is considerable variability in survival rate after percutaneous coronary intervention, and accurate early risk stratification is therefore of major clinical importance. METHODS: Thirty individuals with acute anterior myocardial infarction were examined with longitudinal strain by Doppler 1.5 h after revascularization. The extent of scarring 9 months later was analyzed by MRI in 16 corresponding myocardial segments. Strain in all left ventricular segments was averaged to obtain a global value. Infarct size was estimated by clinical parameters and cardiac markers. RESULTS: A good correlation was found between the global strain and total infarct size (R = 0.77, p < 0.00001). A multivariate regression analysis showed that global peak strain and serum glutamic oxaloacetic transaminase correlated with the infarct size measured by MRI (p = 0.0001 and p = 0.001, respectively). Furthermore, a clear inverse relationship was found between the segmental strain and the transmural extent of infarction in each segment (R = 0.67, p < 0.0001). CONCLUSIONS: This study demonstrates that assessment of regional and global strain at 1.5 h after reperfusion therapy correlates with size and transmural extent of myocardial infarction as determined by contrast-enhanced MRI. The novel global strain parameter is a valuable predictor of the total extent of myocardial infarction and may therefore be an important clinical tool for risk stratification in the acute phase of myocardial infarction.

Grading of myocardial dysfunction by tissue Doppler echocardiography: a comparison between velocity, displacement, and strain imaging in acute ischemia.

OBJECTIVES: The aim of the study was to compare the ability of the tissue Doppler echocardiographic imaging (TDI) modalities velocity, strain, and displacement to quantify systolic myocardial function. BACKGROUND: Several TDI modalities may be used to quantify regional myocardial function, but it is not clear how the different modalities should be applied. METHODS: In 10 anesthetized dogs we measured left ventricular pressure, longitudinal myocardial velocity, strain, and displacement by TDI at baseline and during left anterior descending coronary artery (LAD) stenosis and occlusion. Reference methods were segmental shortening by sonomicrometry and segmental work. In 10 patients with acute anterior wall infarction (LAD occlusion) and 15 control subjects, velocity, strain, and displacement measurements were performed. RESULTS: In the animal study, systolic strain correlated well with segmental shortening (r = 0.96, p < 0.01) and work (r = 0.90, p < 0.01), and differentiated well between non-ischemic (-13.5 +/- 3.2% [mean +/- SD]), moderately ischemic (-6.5 +/- 2.8%), and severely ischemic myocardium (7.1 +/- 13.2%). The ratio post-systolic strain/total strain also differentiated well between levels of ischemia. Displacement and ejection velocity had weaker correlations with segmental shortening (r = 0.92 and r = 0.74, respectively) and regional work (r = 0.85 and r = 0.69), and there was marked overlap between values at baseline and at different levels of ischemia. In the human study, systolic strain differentiated well between infarcted and normal myocardium (1.0 +/- 5.0% vs. -17.8 +/- 3.8%), whereas systolic displacement (-0.3 +/- 1.3 mm vs. -2.3 +/- 0.6 mm) and ejection velocity (0.9 +/- 0.6 cm/s vs. 2.2 +/- 0.6 cm/s) showed overlap. In the infarction group, strain was reduced in segments with infarcted tissue, while systolic velocity and displacement were reduced in all segments and did not reflect the extension of the infarct. CONCLUSIONS: Strain was superior to velocity and displacement for quantification of regional myocardial function. Provided technical limitations can be solved, strain Doppler is the preferred TDI modality for assessing function in ischemic myocardium.

Myocardial strain analysis in acute coronary occlusion: a tool to assess myocardial viability and reperfusion.

BACKGROUND: This study proposes 2 new echocardiographic indices with potential application in acute coronary artery occlusion to differentiate between viable and necrotic myocardium and to identify reperfusion. We investigated whether the ratio between systolic lengthening and combined late and postsystolic shortening (L-S ratio) could identify viable myocardium and whether systolic myocardial compliance, calculated as systolic lengthening divided by systolic pressure rise, could identify necrotic myocardium. METHODS AND RESULTS: In anesthetized dogs, we measured left ventricular (LV) pressure and long-axis strain by Doppler echocardiography (SDE) and sonomicrometry. The left anterior descending coronary artery was occluded for 15 minutes with 3-hour reperfusion (n=6), for 4 hours with 3-hour reperfusion (n=6), or for 4 hours with no reperfusion (n=6). Myocardial work was quantified by pressure-segment length analysis, necrosis by triphenyltetrazolium chloride staining, and edema by water content. L-S ratio and systolic compliance were calculated by SDE. The L-S ratio ranged between 0.00 and 1.00 and was well correlated with regional myocardial work (r=0.77, P<0.0001). In entirely passive myocardium, the L-S ratio approached 1 and was similar in viable (0.88+/-0.02) and necrotic (0.81+/-0.03) myocardium. Compliance, however, was reduced in necrotic myocardium owing to edema (0.07+/-0.01%/mm Hg) but was preserved in viable myocardium (0.15+/-0.01%/mm Hg, P<0.05). Reperfusion of viable myocardium caused a reduction of the L-S ratio after 15 minutes (0.57+/-0.06, P<0.05), reflecting recovery of function. Reperfusion of necrotic myocardium caused no change in the L-S ratio, but compliance was further reduced within 15 minutes (0.03+/-0.01%/mm Hg, P<0.05). CONCLUSIONS: Myocardial L-S ratio and compliance by SDE identified active contraction and necrosis, respectively. These indices should be tested clinically for assessment of myocardial viability and reperfusion.