Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial

Introduction

Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF.

Methods

We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann’s solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality.

Results

The infusion of half-molar sodium lactate increased (mean ± SD) CO from 4.05 ± 1.37 L/min to 5.49 ± 1.9 L/min (P < 0.01) and TAPSE from 14.7 ± 5.5 mm to 18.3 ± 7 mm (P = 0.02). Plasma sodium and pH increased (136 ± 4 to 146 ± 6 and 7.40 ± 0.06 to 7.53 ± 0.03, respectively; both P < 0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality.

Conclusions

Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01981655","term_id":"NCT01981655"}}NCT01981655. Registered 13 August 2013.     

Role of calcium desensitization in the treatment of myocardial dysfunction after deep hypothermic circulatory arrest

Introduction

Rewarming from deep hypothermic circulatory arrest (DHCA) produces calcium desensitization by troponin I (cTnI) phosphorylation which results in myocardial dysfunction. This study investigated the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan, a calcium sensitizer, on myocardial function after rewarming from DHCA.

Methods

Forty male Wistar rats (400 to 500 g) underwent cardiopulmonary bypass (CPB) through central cannulation and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After DHCA (20 minutes) and CPB-assisted rewarming (60 minutes) rats were randomly assigned to 60 minute intravenous infusion with levosimendan (0.2 μg/kg/min; n = 15), epinephrine (0.1 μg/kg/min; n = 15) or saline (control; n = 10). Systolic and diastolic functions were evaluated at different preloads with a conductance catheter.

Results

The slope of left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) recovered significantly better with levosimendan compared to epinephrine (Ees: 85 ± 9% vs 51 ± 11%, P<0.003 and PRSW: 78 ± 5% vs 48 ± 8%, P<0.005; baseline: 100%). Levosimendan but not epinephrine reduced left ventricular stiffness shown by the end-diastolic pressure-volume relationship and improved ventricular relaxation (Tau). Levosimendan preserved ATP myocardial content as well as energy charge and reduced plasma lactate concentrations. In normothermia experiments epinephrine in contrast to Levosimendan increased cTnI phosphorylation 3.5-fold. After rewarming from DHCA, cTnI phosphorylation increased 4.5-fold in the saline and epinephrine group compared to normothermia but remained unchanged with levosimendan.

Conclusions

Levosimendan due to prevention of calcium desensitization by cTnI phosphorylation is more effective than epinephrine for treatment of myocardial dysfunction after rewarming from DHCA.     

Heart–lung interactions during neurally adjusted ventilatory assist

Introduction

Assist in unison to the patient’s inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function.

Methods

Heart–lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each.

Results

NAVAal was 3.1 ± 1.1cmH₂O/μV and PSVal was 17 ± 2 cmH₂0. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level.

Conclusions

Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level.

Trial registration

Clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00647361","term_id":"NCT00647361"}}NCT00647361, registered 19 March 2008

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0499-8) contains supplementary material, which is available to authorized users.     

Plasma glutamine concentration after intensive care unit discharge: an observational study

Introduction

Low plasma glutamine concentration at ICU admission is associated with unfavorable outcomes. The prediction of plasma glutamine concentration after ICU discharge on outcomes has not been characterized. In the recent Scandinavian Glutamine Trial, a survival advantage was seen with glutamine supplementation as long as patients stayed in the ICU. It was therefore hypothesized that the glutamine level may drop at ICU discharge, indicative of a sustained glutamine deficiency, which may be related to outcome.

Methods

Fully fed ICU patients intravenously supplemented with glutamine for >3 days were studied at ICU discharge and post ICU. In study A, plasma glutamine level was followed every 5 to 7 days post ICU of the remaining hospital stay and compared to the level on the day of ICU discharge (n = 63). In study B, plasma glutamine level 24 to 72 hours after ICU discharge was related to 12-month all-cause mortality (n = 100).

Results

Post-ICU plasma glutamine levels were within normal range and were not found to be predictive for mortality outcome. Plasma glutamine level at discharge, on the other hand, was within normal limits but higher in nonsurvivors. In addition, it was adding prediction value to discharge SOFA scores for post-ICU mortality.

Conclusions

Post-ICU glutamine levels are not indicative of glutamine depletion. The relation between plasma glutamine concentration and glutamine availability during critical illness is not well understood, and needs to be studied further to define the possible role for glutamine supplementation.     

Cardiac-respiratory self-gated cine ultra-short echo time (UTE) cardiovascular magnetic resonance for assessment of functional cardiac parameters at high magnetic fields

Background

To overcome flow and electrocardiogram-trigger artifacts in cardiovascular magnetic resonance (CMR), we have implemented a cardiac and respiratory self-gated cine ultra-short echo time (UTE) sequence. We have assessed its performance in healthy mice by comparing the results with those obtained with a self-gated cine fast low angle shot (FLASH) sequence and with echocardiography.

Methods

2D self-gated cine UTE (TE/TR = 314 μs/6.2 ms, resolution: 129 × 129 μm, scan time per slice: 5 min 5 sec) and self-gated cine FLASH (TE/TR = 3 ms/6.2 ms, resolution: 129 × 129 μm, scan time per slice: 4 min 49 sec) images were acquired at 9.4 T. Volume of the left and right ventricular (LV, RV) myocardium as well as the end-diastolic and -systolic volume was segmented manually in MR images and myocardial mass, stroke volume (SV), ejection fraction (EF) and cardiac output (CO) were determined. Statistical differences were analyzed by using Student t test and Bland-Altman analyses.

Results

Self-gated cine UTE provided high quality images with high contrast-to-noise ratio (CNR) also for the RV myocardium (CNR_{blood-myocardium} = 25.5 ± 7.8). Compared to cine FLASH, susceptibility, motion, and flow artifacts were considerably reduced due to the short TE of 314 μs. The aortic valve was clearly discernible over the entire cardiac cycle. Myocardial mass, SV, EF and CO determined by self-gated UTE were identical to the values measured with self-gated FLASH and showed good agreement to the results obtained by echocardiography.

Conclusions

Self-gated UTE allows for robust measurement of cardiac parameters of diagnostic interest. Image quality is superior to self-gated FLASH, rendering the method a powerful alternative for the assessment of cardiac function at high magnetic fields.     

Early resuscitation of dengue shock syndrome in children with hyperosmolar sodium-lactate: a randomized single-blind clinical trial of efficacy and safety

Introduction

Dengue shock syndrome (DSS) fluid resuscitation by following the World Health Organization (WHO) guideline usually required large volumes of Ringer lactate (RL) that might induce secondary fluid overload. Our objective was to compare the effectiveness of the recommended volume of RL versus a smaller volume of a hypertonic sodium lactate solution (HSL) in children with DSS. The primary end point was to evaluate the effect of HSL on endothelial cell inflammation, assessed by soluble vascular cell adhesion molecule-1 (sVCAM-1) measurements. Secondarily, we considered the effectiveness of HSL in restoring hemodynamic fluid balance, acid–base status, and sodium and chloride balances, as well as in-hospital survival.

Methods

A prospective randomized single-blind clinical trial including 50 DSS children was conducted in the Pediatrics Department of Hasan Sadikin Hospital, Bandung, Indonesia. Only pediatric patients (2 to 14 years old) fulfilling the WHO criteria for DSS and new to resuscitation treatments were eligible. Patients were resuscitated with either HSL (5 ml/kg/BW in 15 minutes followed by 1 ml/kg/BW/h for 12 hours), or RL (20 ml/kg/BW in 15 minutes followed by decreasing doses of 10, 7, 5, and 3 ml/kg BW/h for 12 hours).

Results

In total, 50 patients were randomized and included in outcome and adverse-event analysis; 46 patients (8.2 ± 0.5 years; 24.9 ± 1.9 kg; mean ± SEM) completed the protocol and were fully analyzed (24 and 22 subjects in the HSL and RL groups, respectively). Baseline (prebolus) data were similar in both groups. Hemodynamic recovery, plasma expansion, clinical outcome, and survival rate were not significantly different in the two groups, whereas fluid accumulation was one third lower in the HSL than in the RL group. Moreover, HSL was responsible for a partial recovery from endothelial dysfunction, as indicated by the significant decrease in sVCAM-1.

Conclusion

Similar hemodynamic shock recovery and plasma expansion were achieved in both groups despite much lower fluid intake and fluid accumulation in the HSL group.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00966628","term_id":"NCT00966628"}}NCT00966628. Registered 26 August 2009.     

In vivo contrast free chronic myocardial infarction characterization using diffusion-weighted cardiovascular magnetic resonance

Background

Despite the established role of late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in characterizing chronic myocardial infarction (MI), a significant portion of chronic MI patients are contraindicative for the use of contrast agents. One promising alternative contrast free technique is diffusion weighted CMR (dwCMR), which has been shown ex vivo to be sensitive to myocardial fibrosis. We used a recently developed in vivo dwCMR in chronic MI pigs to compare apparent diffusion coefficient (ADC) maps with LGE imaging for infarct characterization.

Methods

In eleven mini pigs, chronic MI was induced by complete occlusion of the left anterior descending artery for 150 minutes. LGE, cine, and dwCMR imaging was performed 8 weeks post MI. ADC maps were derived from three orthogonal diffusion directions (b = 400 s/mm²) and one non-diffusion weighted image. Two semi-automatic infarct classification methods, threshold and full width half max (FWHM), were performed in both LGE and ADC maps. Regional wall motion (RWM) analysis was performed and compared to ADC maps to determine if any observed ADC change was significantly influenced by bulk motion.

Results

ADC of chronic MI territories was significantly increased (threshold: 2.4 ± 0.3 μm²/ms, FWHM: 2.4 ± 0.2 μm²/ms) compared to remote myocardium (1.4 ± 0.3 μm²/ms). RWM was significantly reduced (threshold: 1.0 ± 0.4 mm, FWHM: 0.9 ± 0.4 mm) in infarcted regions delineated by ADC compared to remote myocardium (8.3 ± 0.1 mm). ADC-derived infarct volume and location had excellent agreement with LGE. Both LGE and ADC were in complete agreement when identifying transmural infarcts. Additionally, ADC was able to detect LGE-delineated infarcted segments with high sensitivity, specificity, PPV, and NPV. (threshold: 0.88, 0.93, 0.87, and 0.94, FWHM: 0.98, 0.97, 0.93, and 0.99, respectively).

Conclusions

In vivo diffusion weighted CMR has potential as a contrast free alternative for LGE in characterizing chronic MI.     

EVIDENCE FOR ISOKINETIC KNEE TORQUE ASYMMETRIES IN MALE LONG DISTANCE‐TRAINED RUNNERS

Purpose/Background

Strength asymmetries are related to knee injuries and such injuries are frequently observed among runners. The purpose of this study was to examine whether long‐distance runners have symmetric performance during knee isokinetic testing at two angular velocities.

Methods

Twenty‐three healthy and well‐trained male long‐distance runners performed open‐chain isokinetic trials for assessment of concentric quadriceps and hamstrings contractions at velocities of 60 °·s^‐1 and 240 °·s^‐1. Data were compared between the lower limbs at different velocities.

Results

Peak torque and total work were similar between the limbs. Asymmetry was observed for knee flexor power at 240 °·s^‐1 (237 ± 45 W and 205 ± 53 W, in the preferred and non‐preferred limb, respectively). Asymmetry indexes for flexor power were different between the velocities tested (13.1% and 2.21% for 240 °·s^‐1 and 60 °·s^‐1, respectively).

Conclusion

A limb asymmetry was observed among runners for knee flexor power, mainly at higher angular velocities (240 °·s^‐1). In addition, H/Q ratios were observed to be contraction velocity dependent.

Level of Evidence

3     

Body temperature affects cerebral hemodynamics in acutely brain injured patients: an observational transcranial color-coded duplex sonography study

Introduction

Temperature changes are common in patients in a neurosurgical intensive care unit (NICU): fever is frequent among severe cases and hypothermia is used after cardiac arrest and is currently being tested in clinical trials to lower intracranial pressure (ICP). This study investigated cerebral hemodynamics when body temperature varies in acute brain injured patients.

Methods

We enrolled 26 patients, 14 with acute brain injury who developed fever and were given antipyretic therapy (defervescence group) and 12 who underwent an intracranial neurosurgical procedure and developed hypothermia in the operating room; once admitted to the NICU, still under anesthesia, they were re-warmed before waking (re-warming group). We measured cerebral blood flow velocity (CBF-V) and pulsatility index (PI) at the middle cerebral artery using transcranial color-coded duplex sonography (TCCDS).

Results

In the defervescence group mean CBF-V decreased from 75 ± 26 (95% CI 65 to 85) to 70 ± 22 cm/s (95% CI 61 to 79) (P = 0.04); the PI also fell, from 1.36 ± 0.33 (95% CI 1.23 to 1.50) to 1.16 ± 0.26 (95% CI 1.05 to 1.26) (P = 0.0005). In the subset of patients with ICP monitoring, ICP dropped from 16 ± 8 to 12 ± 6 mmHg (P = 0.003). In the re-warming group mean CBF-V increased from 36 ± 10 (95% CI 31 to 41) to 39 ± 13 (95% CI 33 to 45) cm/s (P = 0.04); the PI rose from 0.98 ± 0.14 (95% CI 0.91 to 1.04) to 1.09 ± 0.22 (95% CI 0.98 to 1.19) (P = 0.02).

Conclusions

Body temperature affects cerebral hemodynamics as evaluated by TCCDS; when temperature rises, CBF-V increases in parallel, and viceversa when temperature decreases. When cerebral compliance is reduced and compensation mechanisms are exhausted, even modest temperature changes can greatly affect ICP.     

Serotonin,glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles – a microdialysis study

Background

Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline-induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect.

Methods

Healthy participants, 15 men and 15 aged-matched women (25.7 ± 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections.

Results

The median (IQR) peak pain intensity (0–100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05).

Conclusions

5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations.     

Continuous versus bolus intermittent loop diuretic infusion in acutely decompensated heart failure: a prospective randomized trial

Introduction

Intravenous loop diuretics are a cornerstone of therapy in acutely decompensated heart failure (ADHF). We sought to determine if there are any differences in clinical outcomes between intravenous bolus and continuous infusion of loop diuretics.

Methods

Subjects with ADHF within 12 hours of hospital admission were randomly assigned to continuous infusion or twice daily bolus therapy with furosemide. There were three co-primary endpoints assessed from admission to discharge: the mean paired changes in serum creatinine, estimated glomerular filtration rate (eGFR), and reduction in B-type natriuretic peptide (BNP). Secondary endpoints included the rate of acute kidney injury (AKI), change in body weight and six months follow-up evaluation after discharge.

Results

A total of 43 received a continuous infusion and 39 were assigned to bolus treatment. At discharge, the mean change in serum creatinine was higher (+0.8 ± 0.4 versus -0.8 ± 0.3 mg/dl P <0.01), and eGFR was lower (-9 ± 7 versus +5 ± 6 ml/min/1.73 m²P <0.05) in the continuous arm. There was no significant difference in the degree of weight loss (-4.1 ± 1.9 versus -3.5 ± 2.4 kg P = 0.23). The continuous infusion arm had a greater reduction in BNP over the hospital course, (-576 ± 655 versus -181 ± 527 pg/ml P = 0.02). The rates of AKI were comparable (22% and 15% P = 0.3) between the two groups. There was more frequent use of hypertonic saline solutions for hyponatremia (33% versus 18% P <0.01), intravenous dopamine infusions (35% versus 23% P = 0.02), and the hospital length of stay was longer in the continuous infusion group (14. 3 ± 5 versus 11.5 ± 4 days, P <0.03). At 6 months there were higher rates of re-admission or death in the continuous infusion group, 58% versus 23%, (P = 0.001) and this mode of treatment independently associated with this outcome after adjusting for baseline and intermediate variables (adjusted hazard ratio = 2.57, 95% confidence interval, 1.01 to 6.58 P = 0.04).

Conclusions

In the setting of ADHF, continuous infusion of loop diuretics resulted in greater reductions in BNP from admission to discharge. However, this appeared to occur at the consequence of worsened renal filtration function, use of additional treatment, and higher rates of rehospitalization or death at six months.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01441245","term_id":"NCT01441245"}}NCT01441245. Registered 23 September 2011.     

Considerations when measuring myocardial perfusion reserve by cardiovascular magnetic resonance using regadenoson

Background

Adenosine cardiovascular magnetic resonance (CMR) can accurately quantify myocardial perfusion reserve. While regadenoson is increasingly employed due to ease of use, imaging protocols have not been standardized. We sought to determine the optimal regadenoson CMR protocol for quantifying myocardial perfusion reserve index (MPRi) – more specifically, whether regadenoson stress imaging should be performed before or after rest imaging.

Methods

Twenty healthy subjects underwent CMR perfusion imaging during resting conditions, during regadenoson-induced hyperemia (0.4 mg), and after 15 min of recovery. In 10/20 subjects, recovery was facilitated with aminophylline (125 mg). Myocardial time-intensity curves were used to obtain left ventricular cavity-normalized myocardial up-slopes. MPRi was calculated in two different ways: as the up-slope ratio of stress to rest (MPRi-rest), and the up-slope ratio of stress to recovery (MPRi-recov).

Results

In all 20 subjects, MPRi-rest was 1.78 ± 0.60. Recovery up-slope did not return to resting levels, regardless of aminophylline use. Among patients not receiving aminophylline, MPRi-recov was 36 ± 16% lower than MPRi-rest (1.13 ± 0.38 vs. 1.82 ± 0.73, P = 0.001). In the 10 patients whose recovery was facilitated with aminophylline, MPRi-recov was 20 ± 24% lower than MPRi-rest (1.40 ± 0.35 vs. 1.73 ± 0.43, P = 0.04), indicating incomplete reversal. In 3 subjects not receiving aminophylline and 4 subjects receiving aminophylline, up-slope at recovery was greater than at stress, suggesting delayed maximal hyperemia.

Conclusions

MPRi measurements from regadenoson CMR are underestimated if recovery perfusion is used as a substitute for resting perfusion, even when recovery is facilitated with aminophylline. True resting images should be used to allow accurate MPRi quantification. The delayed maximal hyperemia observed in some subjects deserves further study.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00871260","term_id":"NCT00871260"}}NCT00871260     

Short-term effects of noisy pressure support ventilation in patients with acute hypoxemic respiratory failure

Introduction

This study aims at comparing the very short-term effects of conventional and noisy (variable) pressure support ventilation (PSV) in mechanically ventilated patients with acute hypoxemic respiratory failure.

Methods

Thirteen mechanically ventilated patients with acute hypoxemic respiratory failure were enrolled in this monocentric, randomized crossover study. Patients were mechanically ventilated with conventional and noisy PSV, for one hour each, in random sequence. Pressure support was titrated to reach tidal volumes approximately 8 mL/kg in both modes. The level of positive end-expiratory pressure and fraction of inspired oxygen were kept unchanged in both modes. The coefficient of variation of pressure support during noisy PSV was set at 30%. Gas exchange, hemodynamics, lung functional parameters, distribution of ventilation by electrical impedance tomography, breathing patterns and patient-ventilator synchrony were analyzed.

Results

Noisy PSV was not associated with any adverse event, and was well tolerated by all patients. Gas exchange, hemodynamics, respiratory mechanics and spatial distribution of ventilation did not differ significantly between conventional and noisy PSV. Noisy PSV increased the variability of tidal volume (24.4 ± 7.8% vs. 13.7 ± 9.1%, P <0.05) and was associated with a reduced number of asynchrony events compared to conventional PSV (5 (0 to 15)/30 min vs. 10 (1 to 37)/30 min, P <0.05).

Conclusions

In the very short term, noisy PSV proved safe and feasible in patients with acute hypoxemic respiratory failure. Compared to conventional PSV, noisy PSV increased the variability of tidal volumes, and was associated with improved patient-ventilator synchrony, at comparable levels of gas exchange.

Trial registration

ClinicialTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00786292","term_id":"NCT00786292"}}NCT00786292     

Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model

Introduction

New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.

Methods

Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.

Results

Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.

Conclusion

In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.     

Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction

Background

In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis.

Methods

T2* cardiovascular magnetic resonance (CMR) was performed in 167 TM patients receiving standard subcutaneous deferoxamine monotherapy, and 22 had severe myocardial siderosis (T2* < 8 ms) with impaired left ventricular (LV) function. Fifteen of these patients received combination therapy with subcutaneous deferoxamine and oral deferiprone with CMR follow-up.

Results

At baseline, deferoxamine was prescribed at 38 ± 10.2 mg/kg for 5.3 days/week, and deferiprone at 73.9 ± 4.0 mg/kg/day. All patients continued both deferiprone and deferoxamine for 12 months. There were no deaths or new cardiovascular complications. The myocardial T2* improved (5.7 ± 0.98 ms to 7.9 ± 2.47 ms; p = 0.010), with concomitant improvement in LV ejection fraction (51.2 ± 10.9% to 65.6 ± 6.7%; p < 0.001). Serum ferritin improved from 2057 (CV 7.6%) to 666 (CV 13.2%) μg/L (p < 0.001), and liver iron improved (liver T2*: 3.7 ± 2.9 ms to 10.8 ± 7.3 ms; p = 0.006).

Conclusion

In patients with severe myocardial siderosis and impaired LV function, combined chelation therapy with subcutaneous deferoxamine and oral deferiprone reduces myocardial iron and improves cardiac function. This treatment is considerably less onerous for the patient than conventional high dose continuous subcutaneous or intravenous deferoxamine monotherapy, and may be considered as an alternative. Very prolonged tailored treatment with iron chelation is necessary to clear myocardial iron, and alterations in chelation must be guided by repeated myocardial T2* scans.

Trial registration

This trial is registered as {"type":"clinical-trial","attrs":{"text":"NCT00103753","term_id":"NCT00103753"}}NCT00103753     

Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study

Introduction

Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown.

Methods

In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standard of care. ATII was started at a dose of 20 ng/kg/min, and titrated for a goal of maintaining a mean arterial pressure (MAP) of 65 mmHg. The infusion (either ATII or placebo) was continued for 6 hours then titrated off. The primary endpoint was the effect of ATII on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg.

Results

ATII resulted in marked reduction in norepinephrine dosing in all patients. The mean hour 1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort (P =0.06). The most common adverse event attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII. 30-day mortality for the ATII cohort and the placebo cohort was similar (50% versus 60%, P =1.00).

Conclusion

Angiotensin II is an effective rescue vasopressor agent in patients with distributive shock requiring multiple vasopressors. The initial dose range of ATII that appears to be appropriate for patients with distributive shock is 2 to 10 ng/kg/min.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01393782","term_id":"NCT01393782"}}NCT01393782. Registered 12 July 2011.     

Safe performance of magnetic resonance of the heart in patients with magnetic resonance conditional pacemaker systems: the safety issue of the ESTIMATE study

Background

No published data exist about the safety of diagnostic magnetic resonance (MR) of the heart performed in a larger series of patients implanted with MR conditional pacemakers (PM). The purpose of our study is to analyse safety and potential alterations of electrical lead parameters in patients implanted with the EnRhythm/Advisa MRI SureScan PM with 5086MRI leads (Medtronic Inc.) during and after MR of the heart at 1.5 Tesla.

Methods

Patients enrolled in this single center pilot study who underwent non-clinically indicated diagnostic MR of the heart were included in this analysis. Heart MR was performed for analyses of potential changes in right and left ventricular functional parameters under right ventricular pacing at 80 and 110 bpm. Atrial/ventricular sensing, atrial/ventricular pacing capture threshold [PCT], and pacing impedances were assessed immediately before, during, and immediately after MR, as well at 3 and 15 months post MR.

Results

Thirty-six patients (mean age 69 ± 13 years; high degree AV block 18 [50%]) underwent MR of the heart. No MR related adverse events occurred during MR or thereafter. Ventricular sensing differed significantly between the FU immediately after MR (10.3 ± 5.3 mV) and the baseline FU (9.8 ± 5.3 mV; p < 0.05). Despite PCT [V/0.4ms] was not significantly different between the FUs (baseline: 0.84 ± 0.27; in-between MR scans: 0.82 ± 0.27; immediately after MR: 0.84 ± 0.24; 3-month: 0.85 ± 0.23; 15-month: 0.90 ± 0.67; p = ns), 7 patients (19%) showed PCT increases by 100% (max. PCT measured: 1.0 V) at the 3-month FU compared to baseline. RV pacing impedance [Ω/5V] differed significantly at the FU in-between MR scans (516 ± 47), and at the 15-month FU (482 ± 58) compared to baseline (508 ± 75).

Conclusion

The results of our study suggest MR of the heart to be safe in patients with the MR conditional EnRhythm/Advisa system, albeit although noticeable but clinically irrelevant ventricular PCT changes were observed.     

Characteristic cardiac phenotypes are detected by cardiovascular magnetic resonance in patients with different clinical phenotypes and genotypes of mitochondrial myopathy

Background

Mitochondrial myopathies (MM) are a heterogeneous group of inherited conditions resulting from a primary defect in the mitochondrial respiratory chain with consecutively impaired cellular energy metabolism. Small sized studies using mainly electrocardiography (ECG) and echocardiography have revealed cardiac abnormalities ranging from conduction abnormalities and arrhythmias to hypertrophic or dilated cardiomyopathy in these patients. Recently, characteristic patterns of cardiac involvement were documented by cardiovascular magnetic resonance (CMR) in patients with chronic progressive external ophthalmoplegia (CPEO)/Kearns-Sayre syndrome (KSS) and with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The present study aimed to characterize the prevalence and pattern of cardiac abnormalities and to test the additional diagnostic value of CMR in this patient population. The hypothesis that different neuromuscular MM syndromes present with different cardiac disease phenotypes was evaluated.

Methods

Sixty-four MM patients (50 ± 15 years, 44 % male) and 25 matched controls (52 ± 14 years, 36 % male) prospectively underwent cardiac evaluations including CMR (comprising cine- and late-gadolinium-enhancement (LGE) imaging). Based on the neuromuscular phenotype and genotype, the patients were grouped: a) CPEO/KSS (N = 33); b) MELAS/–like (N = 11); c) myoclonic epilepsy with ragged-red fibers (MERRF) (N = 3) and d) other non-specific MM forms (N = 17).

Results

Among the 64 MM patients, 34 (53 %) had at least one abnormal CMR finding: 18 (28 %) demonstrated an impaired left ventricular ejection-fraction (LV-EF <60 %), 14 (22 %) had unexplained LV hypertrophy and 21 (33 %) were LGE-positive. Compared to controls, MM patients showed significantly higher maximal wall thickness (10 ± 3 vs. 8 ± 2 mm, p = 0.005) and concentricity (LV mass to end-diastolic volume: 0.84 ± 0.27 vs. 0.67 ± 0.11, p < 0.0001) with frequent presence of non-ischemic LGE (30 % vs. 0 %, p = 0.001). CPEO/KSS showed a predominantly intramural pattern of LGE mostly confined to the basal LV inferolateral wall (8/10; 80 %) in addition to a tendency toward concentric remodelling. MELAS/-like patients showed the highest frequency of cardiac disease (in 10/11 (91 %)), a mostly concentric LV hypertrophy (6/9; 67 %) with or without LV systolic dysfunction and a predominantly focal, patchy LGE equally distributed among LV segments (8/11; 73 %). Patients with MERRF and non-specific MM had no particular findings. Pathological CMR findings indicating cardiac involvement were detected significantly more often than pathological ECG results or elevated cardiac serum biomarkers (34 (53 %) vs. 18 (28 %) vs. 21 (33 %); p = 0.008).

Conclusion

Cardiac involvement is a frequent finding in MM patients – and particularly present in KSS/CPEO as well as MELAS/-like patients. Despite a high variability in clinical presentation, CPEO/KSS patients typically show an intramural pattern of LGE in the basal inferolateral wall whereas MELAS patients are characterized by overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE.

Electronic supplementary material

The online version of this article (doi:10.1186/s12968-015-0145-x) contains supplementary material, which is available to authorized users.     

Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects

Background

Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles.

Methods

A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons.

Results

Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after heme arginate compared to placebo (106.2±0.6% at 175±16s vs. 104.5±0.6% at 221±19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak).

Conclusions

A single high dose of heme arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle.

Trial registration

ClinicalTrials: {"type":"clinical-trial","attrs":{"text":"NCT01461512","term_id":"NCT01461512"}}NCT01461512EudraCT: 2008-006967-35