Tag Archives: CHF


Potential new therapy for acute heart failure

Interesting new drug to know about: Serelaxin, recombinant human relaxin-2. It’s hard to assess the clinical significance of the statistically significant findings. Let’s see if a benefit is replicated in future studies. It’s hard to imagine a normotensive patient that can’t be fixed with existing therapies though.

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.

Lancet. 2013 Jan 5;381(9860):29-39


BACKGROUND: Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

METHODS: RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.

FINDINGS: 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019).

INTERPRETATION: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality

COPD and heart disease interactions

Ischaemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) often affect the same patient; in fact, more than one-third of patients with angiography-proven IHD also have COPD on spirometry(1).
A recent study suggests COPD exacerbations in patients with IHD were associated with longer (5 more days) recovery times and suffered more severe breathlessness between exacerbations(2).

An accompanying editorial highlights some important points:

  • Patients admitted with COPD exacerbations are more susceptible to myocardial infarction during the admission.
  • Infective COPD exacerbations may contribute to heart failure through systemic inflammation, autonomic activation, and increased fluid in the lung. Lung infection can increase ventilation/perfusion mismatch and increased work of breathing, further straining the heart.
  • Heart failure can be very difficult to diagnose during a COPD exacerbation because cough, dyspnoea and wheeze are common to both disorders. Physical examination may not be discriminatory, and chest radiography is insensitive to milder degrees of heart failure.

The authors recommed a high index of suspicion combined with consideration of biomarkers (BNP or pro-BNP) and imaging such as echocardiography or even nuclear medicine scans, cardiac MRI, and cardiac catheterisation.

So, next time you’re managing a COPD exacerbation, ask yourself:

  • Could there be concomitant heart failure contributing to symptoms?
  • If not, is the patient at risk of cardiac events during this admission, for which we need to be vigilant?
  • Do I need to consider additional laboratory (BNP) or imaging (echo) investigations? Remember BNP may be elevated in pneumonia and other non-cardiac critical illness, although a normal BNP rules out heart failure.
  • Should I add empiric anti-failure therapy to the acute treatment regimen?
  • If there is combined COPD exacerbation and heart failure, are there any conflicting priorities in therapy (eg. the pros and cons of beta-agonists, anticholinergics, and steroids)?

1. The complex relationship between ischemic heart disease and COPD exacerbations
Chest. 2012 Apr;141(4):837-8

2. The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD
Chest. 2012 Apr;141(4):851-7


BACKGROUND: Comorbid ischemic heart disease (IHD) is a common and important cause of morbidity and mortality in patients with COPD. The impact of IHD on COPD in terms of a patient’s health status, exercise capacity, and symptoms is not well understood.

METHODS: We analyzed stable-state data of 386 patients from the London COPD cohort between 1995 and 2009 and prospectively collected exacerbation data in those who had completed symptom diaries for ≥ 1 year.

RESULTS: Sixty-four patients (16.6%) with IHD had significantly worse health status as measured by the St. George Respiratory Questionnaire (56.9 ± 18.5 vs 49.1 ± 19.0, P = .003), and a larger proportion of this group reported more severe breathlessness in the stable state, with a Medical Research Council dyspnea score of ≥ 4 (50.9% vs 35.1%, P = .029). In subsets of the sample, stable patients with COPD with IHD had a higher median (interquartile range [IQR]) serum N-terminal pro-brain natriuretic peptide concentration than those without IHD (38 [15, 107] pg/mL vs 12 [6, 21] pg/mL, P = .004) and a lower exercise capacity (6-min walk distance, 225 ± 89 m vs 317 ± 85 m; P = .002). COPD exacerbations were not more frequent in patients with IHD (median, 1.95 [IQR, 1.20, 3.12] vs 1.86 (IQR, 0.75, 3.96) per year; P = .294), but the median symptom recovery time was 5 days longer (17.0 [IQR, 9.8, 24.2] vs 12.0 [IQR, 8.0, 18.0]; P = .009), resulting in significantly more days per year reporting exacerbation symptoms (median, 35.4 [IQR, 13.4, 60.7] vs 22.2 [IQR, 5.7, 42.6]; P = .028). These findings were replicated in multivariate analyses allowing for age, sex, FEV(1), and exacerbation frequency where applicable.

CONCLUSIONS: Comorbid IHD is associated with worse health status, lower exercise capacity, and more dyspnea in stable patients with COPD as well as with longer exacerbations but not with an increased exacerbation frequency.

Nitrate bolus in acute heart failure

Despite intravenous nitrate boluses being used in original studies demonstrating benefit in acute heart failure1,2, I regularly meet reluctance from both physicians and nurses in the emergency department to give them.

Their resistance seems to be based on a concern for inducing hypotension, and they prefer to ‘titrate up’ an infusion.

iv nitrate options include nitroglycerin (GTN), and isosorbide dinitrate (ISDN). Studies have used ISDN 4mg every 4 mins, ISDN 3mg every 5 mins, and GTN 2mg every 3 mins3.

There are a number of reasons to avoid starting with a low rate infusion in a sick heart failure patient.

Matthew Reed highlighted cannula size as an important factor4:



If a GTN infusion is commenced at a rate of 1 ml/h, a critically unwell patient with a large cannula—for example, a grey cannula (16G) — will have to wait over 6 min for the drug to enter the body. This compares with 1.5 min for a pink cannula (20G) at the same infusion rate. If a large-diameter cannula is chosen for these patients, then a fast initial infusion rate should also be chosen to ensure that the GTN begins to act quickly.


Alistair Steel subsequently pointed out further reasons to avoid slow infusions5:



(1) mechanical slack within an infusion device may mean an infusion set at 1 ml/h will take many minutes for the driver to contact and advance the syringe plunger. For this reason, infusions should be purged before patient connection.


(2) the pharmacokinetics of the drug should be considered. At low infusion rates it will take significant time for a steady state to be achieved (a drug such as GTN, with a half-life of 2 min, would require 10 min to achieve steady state). For clinical effects to be seen quickly, a bolus should be given before commencing infusions.


(3) the use of 1 ml/h infusions (8 µg/min using a 0.5% solution) may be excessively cautious – the British National Formulary recommends a therapeutic dose range from 10 to 200 µg/min. Furthermore, there is emerging evidence that, when used for decompensated heart failure, higher doses of GTN are associated with more favourable outcomes.


(4) at low infusion rates any obstruction in the intravenous system will take a proportionally longer time to become apparent, as it will take longer for the pressure to build up and trigger the syringe pump’s high pressure alarm.
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Now a recent study confirms such a regimen can be used safely in the elderly. ISDN 3mg bolus treatment was not associated with higher rates of hypotension in the elderly population treated for heart failure in the emergency department. Despite a small study and a retrospective design, this lends support to the practice of iv bolus nitrate therapy for acute heart failure, even in the elderly.

1. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
Lancet. 1998 Feb 7;351(9100):389-93

2. High-doses intravenous isosorbide dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema
J Am Coll Cardiol. 2000 Sep;36(3):832-7 Free Full Text

3. Managing acute pulmonary oedema with high or standard dose nitrate
Emerg Med J. 2009 May;26(5):357-8

4. Administering a glyceryl trinitrate infusion: big is not always best
Emerg Med J 2007;24:423-424

5. Administering a glyceryl trinitrate infusion: faster is better than slower
Emerg Med J. 2008 Jan;25(1):60

6. Isosorbide dinitrate bolus for heart failure in elderly emergency patients: a retrospective study
Eur J Emerg Med. 2011 Oct;18(5):272-5

Dobutamine for severe heart failure – more harm than good?

A systematic review and meta-analysis of randomised controlled trials showed dobutamine is not associated with improved mortality in heart failure patients and in the case of severe heart failure there is some suggestion of increased mortality, although this did not reach statistical significance.

The authors do point out that the quality of the reports of the trials reviewed was suboptimal. However, they state:
It should be noted that the results of this study are in accord with large observational studies that have also suggested harm associated with use of dobutamine in patients with severe heart failure. Taken together, this evidence should cause clinicians to reconsider their use of dobutamine in patients with heart failure, particularly those most at risk of the adverse effects, those with underlying ischaemic heart disease.

PURPOSE: Dobutamine is recommended for patients with severe heart failure; however uncertainty exists as to its effect on mortality. This study aims to critically review the literature to evaluate whether dobutamine, compared with placebo or standard care, is associated with lower mortality and a range of secondary outcomes, in patients with severe heart failure.

METHODS: A systematic review and meta-analysis of randomised controlled trials was performed. PubMed, EMBASE, the Cochrane Central Trials Registry, the metaRegister of Controlled Trials and bibliographies of retrieved articles were searched. Randomised trials comparing dobutamine with placebo or standard care, in human, adult patients with severe heart failure, were included if they reported at least one outcome of interest. Data regarding trial validity, methodological processes and clinical outcomes were extracted, and a meta-analysis was performed.

RESULTS: Fourteen studies, with 673 participants, met the inclusion criteria and were included; 13 studies reported mortality. There was minimal heterogeneity (I (2) = 4.5%). The estimate of the odds ratio for mortality for patients with severe heart failure treated with dobutamine compared with standard care or placebo was 1.47 (95% confidence interval 0.98-2.21, p = 0.06).

CONCLUSIONS: This meta-analysis showed that dobutamine is not associated with improved mortality in patients with heart failure, and there is a suggestion of increased mortality associated with its use, although this did not reach the conventional level of statistical significance. Further research to define the role of dobutamine in treatment of severe heart failure should be a priority.

Dobutamine for patients with severe heart failure- a systematic review and meta-analysis of randomised controlled trials
Intensive Care Med. 2012 Mar;38(3):359-67

Furosemide infusion in acute decompensated heart failure

A randomised controlled trial of 308 patients with acute decompensated heart failure compared continuous furosemide infusion with ‘low’ dose (equal to their total daily oral loop diuretic dose in furosemide equivalents) or high dose furosemide boluses. There was no outcome difference between infusion and bolus, although the high dose (2.5 times previous oral diuretic dose 12 hourly for 48 hours) improved patients’ symptoms while causing transient elevations in serum creatinine. Editorialist Dr G Fonarow states:

‘..these findings should change current practice. Since a high-dose regimen may relieve dyspnea more quickly without adverse effects on renal function, that regimen is preferable to a low-dose regimen. Administration of boluses may be more convenient than continuous infusion and equally effective.’

 

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.

METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients’ global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.

RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients’ global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.

CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Diuretic strategies in patients with acute decompensated heart failure
N Engl J Med. 2011 Mar 3;364(9):797-805

In V.Fib and talking to you!

Some patients with severe refractory heart failure are kept alive thanks to implantable pumps such as the left ventricular assist device (LVAD). Many emergency physicians are likely to be unfamiliar with these but could encounter patients who have them. One particular peculiarity is that latter generation devices maintain non-pulsatile flow and provide or assist cardiac output independent of cardiac rhythm. In extreme situations patients can have life-sustaining cardiac outputs without palpable pulses or even audible heart sounds.

Click on image for Wikipedia article

A great example of how weird this can get is provided by a case of a 66 year male with an LVAD (HeartMate II (Thoratec Corporation)) who presented due to spontaneous discharge of his internal cardioverter-defibrillator (ICD). He was alert but had no pulses, and no detectable blood pressure using both a manual sphygmomanometer and an automated non-invasive blood pressure device. His 12 lead showed ventricular fibrillation. An invasive blood pressure showed a mean arterial pressure (mAP) of 80 mmHg. Several hours later his VF was successfully terminated and his mAP remained 80 mmHg

Some interesting points made by the authors include:

  • CPR was unnecessary in this guy but in cases of severe RV dysfunction it might need to be done to provide flow into the LV.
  • A danger of CPR in patients with an LVAD is the risk of damage to the device or ventricular rupture

LVAD use is significantly increasing so we can expect to encounter more episodes of previously impossible presentations to our emergency departments.

ABSTRACT
Optimal medical treatment, cardiac resynchronization, and the use of an implantable cardioverter defibrillator are established therapies of severe congestive heart failure. In refractory cases, left ventricular assist devices are more and more used not only as bridging to cardiac transplantation but also as destination therapy. Ventricular arrhythmias may represent a life-threatening condition and often result in clinical deterioration in patients with congestive heart failure. We report a case of asymptomatic sustained ventricular fibrillation with preserved hemodynamics caused by a nonpulsatile left ventricular assist device. Consecutive adequate but unsuccessful discharges of the implantable cardioverter defibrillator were the only sign of the usually fatal arrhythmia, prompting the patient to consult emergency services. Electrolyte supplementation and initiation of therapy with amiodarone followed by external defibrillation resulted in successful restoration of a stable cardiac rhythm after 3.5 hours.

Asymptomatic Sustained Ventricular Fibrillation in a Patient With Left Ventricular Assist Device
Ann Emerg Med. 2011 Jan;57(1):25-8.

CPAP in LVF again

Another stab at assessing noninvasive ventilation in cardiogenic pulmonary oedema has been made by Italian researchers who compared CPAP with noninvasive pressure support ventilation (nPSV – similar to BiPAP) in a randomised trial of  80 patients. The primary outcome was endotracheal intubation rates. There was no significant difference between the two modalities. This result is in keeping with the much larger 3CPO trial.

Continuous Positive Airway Pressure vs. Pressure Support Ventilation in Acute Cardiogenic Pulmonary Edema: A Randomized Trial
J Emerg Med. 2010 Nov;39(5):676-84

Unilateral pulmonary oedema worse

A few years ago in the Emergency Department I managed a sick hypotensive, hypoxic 20-something year old with a unilateral lung white-out and air bronchograms as pneumonia/septic shock. He died subsequently of refractory pulmonary oedema on the ICU, where the diagnosis of acute pulmonary oedema due to severe aortic stenosis was delayed. Post mortem findings showed pulmonary oedema but no pneumonia. A kind radiologist told me the chest x-ray would certainly have fitted with pneumonia. After this case I learned to echo sick hypotensive patients in the ED.

Circulation reports 869 cardiogenic pulmonary oedema patients, of which 2.1% had unilateral pulmonary oedema (UPE). In patients with UPE, blood pressure was significantly lower (P<=0.01), whereas noninvasive or invasive ventilation and catecholamines were used more frequently (P=0.0004 and P<0.0001, respectively). The prevalence of severe mitral regurgitation in patients with bilateral pulmonary edema and UPE was 6% and 100%, respectively (P<0.0001). In patients with UPE, use of antibiotic therapy and delay in treatment were significantly higher (P<0.0001 and P=0.003, respectively). In-hospital mortality was 9%: 39% for UPE versus 8% for bilateral pulmonary edema (odds ratio, 6.9; 95% confidence interval, 2.6 to 18; P<0.001). In multivariate analysis, unilateral location of pulmonary edema was independently related to death.

Prevalence, Characteristics, and Outcomes of Patients Presenting With Cardiogenic Unilateral Pulmonary Edema
Circulation. 2010 Sep 14;122(11):1109-15

B lines be gone!

Vicki Noble’s Emergency Ultrasound team describe the resolution of Songraphic B lines on the lung ultrasound of a patient with end stage renal disease who presented with dyspnoea due to pumonary oedema which was treated with CPAP.
B-lines are hyperechoic vertical lines that originate at and slide with the pleura and extend radially to the edge of the screen without fading. Isolated B-lines may be seen in normal lungs, but diffuse B-lines in multiple zones indicate interstitial thickening, most commonly seen in congestive heart failure (CHF).

Image from cardiovascularultrasound.com

This case is interesting because it describes real-time resolution of B-lines during therapy in the ED demonstrating that in CHF, B-lines reflect acute rather than chronic changes within lung parenchyma.
Real-time resolution of sonographic B-lines in a patient with pulmonary edema on continuous positive airway pressure
Am J Emerg Med. 2010 May;28(4):541.e5-8

Thoracic electrical bioimpedance in dyspnoea

Thoracic electrical bioimpedance (TEB) was used in ED patients presenting with dyspnoea to differentiate between cardiac and non-cardiac causes.
The fundamental principle behind TEB is based on Ohm’s law. If a constant electrical current is applied to the thorax, changes in impedance (ΔZ) to flow are equal to changes in voltage drop across the circuit. As a current will always seek the path of lowest resistivity, which in the human body is blood, ΔZ of the thorax will primarily reflect the dynamic changes of blood volume in the thoracic aorta. Changes in thoracic electrical impedance are continuously recorded and processed using a computer algorithm to calculate a number of cardiohaemodynamic parameters such as stroke volume, CO, CI, SVR and systemic vascular resistance index (SVRi).

A cardiac index cut-off of 3.2 l/m/m2 had a 86.7% sensitive (95% CI 59.5% to 98.0%) and 88.9% specific (95% CI 73.9% to 96.8%) for cardiac dyspnoea in the 52 patients studies, of which 15 had cardiac-related dyspnoea.

The study has several limitations including small numbers and using the gold standard of discharge diagnosis.

Thoracic electrical bioimpedance: a tool to determine cardiac versus non-cardiac causes of acute dyspnoea in the emergency department
Emerg Med J. 2010 May;27(5):359-63
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