Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective,randomized, placebo-controlled,double-blinded trial

Introduction

Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting.

Methods

In this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).

Results

A total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint.

Conclusions

Early treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01867645","term_id":"NCT01867645"}}NCT01867645     

Nutrition intervention for migraine: a randomized crossover trial

Background

Limited evidence suggests that dietary interventions may offer a promising approach for migraine. The purpose of this study was to determine the effects of a low-fat plant-based diet intervention on migraine severity and frequency.

Methods

Forty-two adult migraine sufferers were recruited from the general community in Washington, DC, and divided randomly into two groups. This 36-week crossover study included two treatments: dietary instruction and placebo supplement. Each treatment period was 16 weeks, with a 4-week washout between. During the diet period, a low-fat vegan diet was prescribed for 4 weeks, after which an elimination diet was used. Participants were assessed at the beginning, midpoint, and end of each period. Significance was determined using student’s t-tests.

Results

Worst headache pain in last 2 weeks, as measured by visual analog scale, was initially 6.4/10 cm (SD 2.1 cm), and declined 2.1 cm during the diet period and 0.7 cm during the supplement period (p=0.03). Average headache intensity (0–10 scale) was initially 4.2 (SD 1.4) per week, and this declined by 1.0 during the diet period and by 0.5 during the supplement period (p=0.20). Average headache frequency was initially 2.3 (SD 1.8) per week, and this declined by 0.3 during the diet period and by 0.4 during the supplement period (p=0.61). The Patient’s Global Impression of Change showed greater improvement in pain during the diet period (p<0.001).

Conclusions

These results suggest that a nutritional approach may be a useful part of migraine treatment, but that methodologic issues necessitate further research.

Trial registration

Clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT01699009","term_id":"NCT01699009"}}NCT01699009 and {"type":"clinical-trial","attrs":{"text":"NCT01547494","term_id":"NCT01547494"}}NCT01547494.     

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     

High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy - a prospective randomised trial

Introduction

Critically ill patients with respiratory failure undergoing bronchoscopy have an increased risk of hypoxaemia-related complications. Previous studies have shown that in awake, hypoxaemic patients non-invasive ventilation (NIV) is helpful in preventing gas exchange deterioration during bronchoscopy. An alternative and increasingly used means of oxygen delivery is its application via high-flow nasal cannula (HFNC). This study was conducted to compare HFNC with NIV in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy.

Methods

Prospective randomised trial randomising 40 critically ill patients with hypoxaemic respiratory failure to receive either NIV or HFNC during bronchoscopy in the intensive care unit.

Results

After the initiation of NIV and HFNC, oxygen levels were significantly higher in the NIV group compared to the HFNC group. Two patients were unable to proceed to bronchoscopy after the institution of HFNC due to progressive hypoxaemia. During bronchoscopy, one patient on HFNC deteriorated due to intravenous sedation requiring non-invasive ventilatory support. Bronchoscopy was well tolerated in all other patients. There were no significant differences between the two groups regarding heart rate, mean arterial pressure and respiratory rate. Three patients in the NIV group and one patient in the HFNC group were intubated within 24 hours after the end of bronchoscopy (P = 0.29).

Conclusions

The application of NIV was superior to HFNC with regard to oxygenation before, during and after bronchoscopy in patients with moderate to severe hypoxaemia. In patients with stable oxygenation under HFNC, subsequent bronchoscopy was well tolerated.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01870765","term_id":"NCT01870765"}}NCT01870765. Registered 30 May 2013.     

Long-term outcome in early survivors of cardiogenic shock at the acute stage of myocardial infarction: a landmark analysis from the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) Registry

Introduction

There are little data about patients with cardiogenic shock (CS) who survive the early phase of acute myocardial infarction (AMI). The aim of this study was to assess long-term (5-year) mortality among early survivors of AMI, according to the presence of CS at the acute stage.

Methods

We analyzed 5-year follow-up data from the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2005 registry, a nationwide French survey including consecutive patients admitted for ST or non-ST-elevation AMI at the end of 2005 in 223 institutions.

Results

Of 3670 patients enrolled, shock occurred in 224 (6.1%), and 3411 survived beyond 30 days or hospital discharge, including 99 (2.9%) with shock. Early survivors with CS had a more severe clinical profile, more frequent concomitant in-hospital complications, and were less often managed invasively than those without CS.Five-year survival was 59% in patients with, versus 76% in those without shock (adjusted hazard ratio (HR) = 1.72 [1.24-2.38], P = 0.001). The excess of death associated with CS, however, was observed only during the first year (one-year survival: 77% vs 93%, adjusted HR: 2.87 [1.85 to 4.46] P <0.001), while survival from one to 5 years was similar (76% vs 82%, adjusted HR: 1.06 [0.64 to 1.74]). Propensity score-matched analyses yielded similar results.

Conclusions

In patients surviving the early phase of AMI, CS at the initial stage carries an increased risk of death up to one year after the acute event. Beyond one year, however, mortality is similar to that of patients without shock.

Trial registration

ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00673036","term_id":"NCT00673036"}}NCT00673036, Registered May 5, 2008.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0516-y) contains supplementary material, which is available to authorized users.     

Continuous positive airway pressure and ventilation are more effective with a nasal mask than a full face mask in unconscious subjects: a randomized controlled trial

Introduction

Upper airway obstruction (UAO) is a major problem in unconscious subjects, making full face mask ventilation difficult. The mechanism of UAO in unconscious subjects shares many similarities with that of obstructive sleep apnea (OSA), especially the hypotonic upper airway seen during rapid eye movement sleep. Continuous positive airway pressure (CPAP) via nasal mask is more effective at maintaining airway patency than a full face mask in patients with OSA. We hypothesized that CPAP via nasal mask and ventilation (nCPAP) would be more effective than full face mask CPAP and ventilation (FmCPAP) for unconscious subjects, and we tested our hypothesis during induction of general anesthesia for elective surgery.

Methods

In total, 73 adult subjects requiring general anesthesia were randomly assigned to one of four groups: nCPAP P0, nCPAP P5, FmCPAP P0, and FmCPAP P5, where P0 and P5 represent positive end-expiratory pressure (PEEP) 0 and 5 cm H₂O applied prior to induction. After apnea, ventilation was initiated with pressure control ventilation at a peak inspiratory pressure over PEEP (PIP/PEEP) of 20/0, then 20/5, and finally 20/10 cm H₂O, each applied for 1 min. At each pressure setting, expired tidal volume (Vte) was calculated by using a plethysmograph device.

Results

The rate of effective tidal volume (Vte > estimated anatomical dead space) was higher (87.9% vs. 21.9%; P<0.01) and the median Vte was larger (6.9 vs. 0 mL/kg; P<0.01) with nCPAP than with FmCPAP. Application of CPAP prior to induction of general anesthesia did not affect Vte in either approach (nCPAP pre- vs. post-; 7.9 vs. 5.8 mL/kg, P = 0.07) (FmCPAP pre- vs. post-; 0 vs. 0 mL/kg, P = 0.11).

Conclusions

nCPAP produced more effective tidal volume than FmCPAP in unconscious subjects.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01524614","term_id":"NCT01524614"}}NCT01524614.     

Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: a double blind,randomized clinical trial of efficacy and safety

Introduction

Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery.

Methods

We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively.

Results

Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period.

Conclusions

Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery.

Trial registration

Clinical Trial.gov, {"type":"clinical-trial","attrs":{"text":"NCT01758861","term_id":"NCT01758861"}}NCT01758861     

Methods for a study of Anticipatory and Preventive multidisciplinary Team Care in a family practice

BACKGROUND

T o examine the methodology used to evaluate whether focusing the work of nurse practitioners and a pharmacist on frail and at-risk patients would improve the quality of care for such patients.

DESIGN

Evaluation of methodology of a randomized controlled trial including analysis of quantitative and qualitative data over time and analysis of cost-effectiveness.

SETTING

A single practice in a rural area near Ottawa, Ont.

PARTICIPANTS

A total of 241 frail patients, aged 50 years and older, at risk of experiencing adverse health outcomes.

INTERVENTION

At-risk patients were randomly assigned to receive Anticipatory and Preventive Team Care (from their family physicians, 1 of 3 nurse practitioners, and a pharmacist) or usual care.

MAIN OUTCOME MEASURES

The principal outcome for the study was the quality of care for chronic disease management. Secondary outcomes included other quality of care measures and evaluation of the program process and its cost-effectiveness. This article examines the effectiveness of the methodology used. Quantitative data from surveys, administrative databases, and medical records were supplemented with qualitative information from interviews, focus groups, work logs, and study notes.

CONCLUSION

Three factors limit our ability to fully demonstrate the potential effects of this team structure. For reasons outside our control, the intervention duration was shorter than intended; the practice’s physical layout did not facilitate interactions between the care providers; and contamination of the intervention effect into the control arm cannot be excluded. The study used a randomized design, relied on a multifaceted approach to evaluating its effects, and used several sources of data.

TRIAL REGISTRATION NUMBER

{"type":"clinical-trial","attrs":{"text":"NCT00238836","term_id":"NCT00238836"}}NCT00238836 (CONSORT).     

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.     

Calorie intake and patient outcomes in severe acute kidney injury: findings from The Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial

Introduction

Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes.

Methods

We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models.

Results

Overall, mean DCI during treatment in ICU was low at only 10.9 ± 9 Kcal/kg/day for non-survivors and 11 ± 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90-days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling.

Conclusions

In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes.

Trial registration

ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00221013","term_id":"NCT00221013"}}NCT00221013     

Mechanism of decreased sensitivity of dobutamine associated left ventricular wall motion analyses for appreciating inducible ischemia in older adults

Background

Dobutamine associated left ventricular (LV) wall motion analyses exhibit reduced sensitivity for detecting inducible ischemia in individuals with increased LV wall thickness. This study was performed to better understand the mechanism of this reduced sensitivity in the elderly who often manifest increased LV wall thickness and risk factors for coronary artery disease.

Methods

During dobutamine cardiovascular magnetic resonance (DCMR) stress testing, we assessed rate pressure product (RPP), aortic pulse wave velocity (PWV), LV myocardial oxygen demand (pressure volume area, PVA, mass, volumes, concentricity, and the presence of wall motion abnormalities (WMA) and first pass gadolinium enhanced perfusion defects (PDs) indicative of ischemia in 278 consecutively recruited individuals aged 69 ± 8 years with pre-existing or known risk factors for coronary artery disease. Each variable was assessed independently by personnel blinded to participant identifiers and analyses of other DCMR or hemodynamic variables.

Results

Participants were 80% white, 90% hypertensive, 43% diabetic and 55% men. With dobutamine, 60% of the participants who exhibited PDs had no inducible WMA. Among these participants, myocardial oxygen demand was lower than that observed in those who had both wall motion and perfusion abnormalities suggestive of ischemia (p = 0.03). Relative to those with PDs and inducible WMAs, myocardial oxygen demand remained different in these individuals with PDs without an inducible WMA after accounting for LV afterload and contractility (p = 0.02 and 0.03 respectively), but not after accounting for either LV stress related end diastolic volume index (LV preload) or resting concentricity (p = 0.31-0.71).

Conclusions

During dobutamine stress testing, elderly patients experience increased LV concentricity and declines in LV preload and myocardial oxygen demand, all of which are associated with an absence of inducible LV WMAs indicative of myocardial ischemia. These findings provide insight as to why dobutamine associated wall motion analyses exhibit reduced sensitivity for identifying inducible ischemia in elderly.

Trial registration

This study was registered with Clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00542503","term_id":"NCT00542503"}}NCT00542503).     

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     

Effect of ischemic preconditioning in skeletal muscle measured by functional magnetic resonance imaging and spectroscopy: a randomized crossover trial

Background

Nuclear magnetic resonance (NMR) imaging and spectroscopy have been applied to assess skeletal muscle oxidative metabolism. Therefore, in-vivo NMR may enable the characterization of ischemia-reperfusion injury. The goal of this study was to evaluate whether NMR could detect the effects of ischemic preconditioning (IPC) in healthy subjects.

Methods

Twenty-three participants were included in two randomized crossover protocols in which the effects of IPC were measured by NMR and muscle force assessments. Leg ischemia was administered for 20 minutes with or without a subsequent impaired reperfusion for 5 minutes (stenosis model). IPC was administered 4 or 48 hours prior to ischemia. Changes in ³¹phosphate NMR spectroscopy and blood oxygen level-dependent (BOLD) signals were recorded. 3-Tesla NMR data were compared to those obtained for isometric muscular strength.

Results

The phosphocreatine (PCr) signal decreased robustly during ischemia and recovered rapidly during reperfusion. In contrast to PCr, the recovery of muscular strength was slow. During post-ischemic stenosis, PCr increased only slightly. The BOLD signal intensity decreased during ischemia, ischemic exercise and post-ischemic stenosis but increased during hyperemic reperfusion. IPC 4 hours prior to ischemia significantly increased the maximal PCr reperfusion signal and mitigated the peak BOLD signal during reperfusion.

Conclusions

Ischemic preconditioning positively influenced muscle metabolism during reperfusion; this resulted in an increase in PCr production and higher oxygen consumption, thereby mitigating the peak BOLD signal. In addition, an impairment of energy replenishment during the low-flow reperfusion was detected in this model. Thus, functional NMR is capable of characterizing changes in reperfusion and in therapeutic interventions in vivo.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00883467","term_id":"NCT00883467"}}NCT00883467     

Design and rationale of the MR-INFORM study: stress perfusion cardiovascular magnetic resonance imaging to guide the management of patients with stable coronary artery disease

Background

In patients with stable coronary artery disease (CAD), decisions regarding revascularisation are primarily driven by the severity and extent of coronary luminal stenoses as determined by invasive coronary angiography. More recently, revascularisation decisions based on invasive fractional flow reserve (FFR) have shown improved event free survival. Cardiovascular magnetic resonance (CMR) perfusion imaging has been shown to be non-inferior to nuclear perfusion imaging in a multi-centre setting and superior in a single centre trial. In addition, it is similar to invasively determined FFR and therefore has the potential to become the non-invasive test of choice to determine need for revascularisation.

Trial design

The MR-INFORM study is a prospective, multi-centre, randomised controlled non-inferiority, outcome trial. The objective is to compare the efficacy of two investigative strategies for the management of patients with suspected CAD. Patients presenting with stable angina are randomised into two groups: 1) The FFR-INFORMED group has subsequent management decisions guided by coronary angiography and fractional flow reserve measurements. 2) The MR-INFORMED group has decisions guided by stress perfusion CMR. The primary end-point will be the occurrence of major adverse cardiac events (death, myocardial infarction and repeat revascularisation) at one year. Clinical trials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01236807","term_id":"NCT01236807"}}NCT01236807.

Conclusion

MR INFORM will assess whether an initial strategy of CMR perfusion is non-inferior to invasive angiography supplemented by FFR measurements to guide the management of patients with stable coronary artery disease. Non-inferiority of CMR perfusion imaging to the current invasive reference standard (FFR) would establish CMR perfusion imaging as an attractive non-invasive alternative to current diagnostic pathways.     

PINOT NOIR: Pulmonic INsufficiency imprOvemenT with Nitric Oxide Inhalational Response

Background

Tetralogy of Fallot (TOF) repair and pulmonary valvotomy for pulmonary stenosis (PS) lead to progressive pulmonary insufficiency (PI), right ventricular enlargement and dysfunction. This study assessed whether pulmonary regurgitant fraction measured by cardiovascular magnetic resonance (CMR) could be reduced with inhaled nitric oxide (iNO).

Methods

Patients with at least moderate PI by echocardiography undergoing clinically indicated CMR were prospectively enrolled. Patients with residual hemodynamic lesions were excluded. Ventricular volume and blood flow sequences were obtained at baseline and during administration of 40 ppm iNO.

Results

Sixteen patients (11 with repaired TOF and 5 with repaired PS) completed the protocol with adequate data for analysis. The median age [range] was 35 [19–46] years, BMI was 26 ± 5 kg/m² (mean ± SD), 50% were women and 75% were in NYHA class I. Right ventricular end diastolic volume index for the cohort was 157 ± 33 mL/m², end systolic volume index was 93 ± 20 mL/m² and right ventricular ejection fraction was 40 ± 6%. Baseline pulmonary regurgitant volume was 45 ± 25 mL/beat and regurgitant fraction was 35 ± 16%. During administration of iNO, regurgitant volume was reduced by an average of 6 ± 9% (p=0.01) and regurgitant fraction was reduced by an average of 5 ± 8% (p=0.02). No significant changes were observed in ventricular indices for either the left or right ventricle.

Conclusion

iNO was successfully administered during CMR acquisition and appears to reduce regurgitant fraction in patients with at least moderate PI suggesting a potential role for selective pulmonary vasodilator therapy in these patients.

Trials registration

ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00543933","term_id":"NCT00543933"}}NCT00543933     

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     

Early or late parenteral nutrition: ASPEN vs. ESPEN

Citation

Casaer MP, Mesotten D, Hermans G et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365: 506-517.

Background

Controversy exists about the timing of the initiation of parenteral nutrition (PN) in critically ill adults in whom caloric targets cannot be met by enteral nutrition (EN) alone.

Methods

Objective

To compare early-initiation of PN (European guidelines) with late-initiation (American and Canadian guidelines) in adults who are receiving insufficient enteral nutrition in the intensive care unit (ICU).

Design

Prospective, randomized, controlled, parallel-group, multicenter clinical trial.

Setting

Seven multidisciplinary ICUs in Belgium.

Subjects

All adults admitted to participating ICUs with a nutritional risk score of 3 or more who did not meet any exclusion criteria.

Intervention

After enrollment, 2312 patients were randomized to receive PN 48 hours after ICU admission (early-initiation) and 2328 patients were randomized to receive PN on day 8 (late-initiation group). Both groups received early EN using a standardized protocol. PN was continued until EN met 80% of calorific goals, or when oral nutrition was resumed. It was restarted if enteral or oral feeding fell below 50% of calculated calorific needs.

Outcomes

Primary end point was the duration of dependency on intensive care, defined as the number of intensive care days and time to discharge from the ICU.

Results

The median stay in the ICU was one day shorter for the late-initiation group (3 v. 4; p = 0.02). The late-initiation group had a relative increase, of 6.3%, in the likelihood of being discharged earlier, and alive, from the ICU (hazard ratio 1.06; 95% confidence interval [CI] 1.00-1,13; p = 0.04). Rates of death in the ICU and survival at 90 days were similar between the two groups. The late-initiation group, as compared to the early-initiation group, had fewer ICU infections (22.8% v. 26.2%; p = 0.008), less days of renal replacement therapy (7 days (interquartile range [IQR] 3-16) v. 10 days (IQR 5-23); p = 0.008) and fewer patients requiring more than 2 days of mechanical ventilation (36.3% v. 40.2%; p = 0.006).

Conclusions

Late-initiation of PN was associated with faster recovery and fewer complications, when compared with early-initiation.

Trial Registration

{"type":"clinical-trial","attrs":{"text":"NCT00512122","term_id":"NCT00512122"}}NCT00512122     

The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA)

Background

Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T₁ mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis.

Methods

CVD risk scores for 1208 subjects (men, 50.8%) ages 55–94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T₁ times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T₁, 12 and 25 minute post-gadolinium T₁, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001).

Results

25 minute post gadolinium T₁ time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e.g. native T₁ (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index.

Conclusions

Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T₁ times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T₁ time.

Clinical trial registration

http://www.mesa-nhlbi.org/, {"type":"clinical-trial","attrs":{"text":"NCT00005487","term_id":"NCT00005487"}}NCT00005487.     

Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium

Introduction

Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis.

Methods

Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2.

Results

30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035).

Conclusions

AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD.

Trial registration

clinicalTrials.gov ID NCT01029080