An interesting case report by Dr Heidlebaugh and colleagues from the Department of Emergency Medicine at the William Beaumont Hospital describes a 72 year old marathon runner who arrested during cardiac catheterisation. It suggests a possible novel alternative to ECMO for cardiac arrest.
The patient became bradycardic then asystolic during catheterisation of his right coronary artery. High quality CPR was initiated and an Impella LV assist device was placed. This restored cardiac output which was followed by episodes of venticular fibrillation and then ROSC. His initial low ejection fraction of 15% recovered after targeted temperature management on ICU to 50% and he fully recovered neurologically.
This patient already had femoral arterial access for introduction of the Impella, since he was in a cath lab. He also had immediate CPR on arresting, and was an abnormally fit 72 year old. It remains to be seen whether this procedure can be applied to other patients in cardiac arrest. The authors state:
“..until ECLS is readily available, poor survival and neurological outcome after cardiac arrest might be avoided in many patients by the use of pLVAD to offload the LV and enhance perfusion. Furthermore, there may be a subset of patients, in whom the support that pLVAD offers is sufficient to optimize hemodynamic parameters and bridge to ROSC, thus reducing the need for ECLS.”
This video by Dr. I-Wen Wang from the Barnes-Jewish Hospital explains how the Impella is inserted and how it works.
Sudden cardiac arrest is associated with high early mortality, which is largely related to postcardiac arrest syndrome characterized by an acute but often transient decrease in left ventricular (LV) function. The stunned LV provides poor cardiac output, which compounds the initial global insult from hypoperfusion. If employed early, an LV assist device (LVAD) may improve survival and neurologic outcome; however, traditional methods of augmenting LV function have significant drawbacks, limiting their usefulness in the periarrest period. Full cardiac support with cardiopulmonary bypass is not always readily available but is increasingly being studied as a tool to intensify resuscitation. There have been no controlled trials studying the early use of percutaneous LVADs (pLVADs) in pericardiac arrest patients or intra-arrest as a bridge to return of spontaneous circulation. This article presents a case study and discussion of a patient who arrested while undergoing an elective coronary angioplasty and suffered prolonged cardiopulmonary resuscitation. During resuscitation, treatment included placement of a pLVAD and initiation of therapeutic hypothermia. The patient made a rapid and full recovery.
Image is of M. Joshua Morris, a happy LVAD recipient (not the patient in the described study) who kindly alerted me to this article. Used with permission.
An editorial1 reviewing options for circulatory support in patients with cardiogenic shock argues that traditional inotrope therapy may be replaced by newer alternatives that have a less detrimental effect on myocardial oxygen demand.
Newer inotropic agents include levosimendan, istaroxime, and omecamtiv mecarbil. Mechanical therapies include intra-aortic balloon pumps (IABP), ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO).
Levosimendan is an inodilator, with the following characteristics:
stabilises the myocardial calcium-troponin C complex
activates adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle and cardiac mitochondria,
acts as a traditional phosphodiesterase inhibitor at higher doses
improved cardiac output and a reduction in filling pressures compared with dobutamine
may also improve diastolic function by increasing relaxation rate
modulates the neuroendocrine response to heart failure by reducing brain natriuretic peptide levels
has anti-apoptotic and anti-inflammatory effects
renal function may also improve
is associated with a similar risk of ventricular arrhythmias to dobutamine
increases risk of new onset atrial fibrillation
has conflicting literature surrounding mortality
has shown a lack of consistent outcome benefits in studies
may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively2.
Istaroxime, a novel inotrope with positive lusitropic (cardiac relaxant) effects3:
is an inhibitor of the sodium-potassium-ATPase (resulting, like digoxin, in elevated intracellular calcium) with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA)
provides a dose-dependant increase in cardiac output without significant change in heart rate or arrhythmia
in one study reducesd pulmonary capillary wedge pressure, increased systolic blood pressure, and reduced heart rate and left ventricular end-diastolic volume
requires further clinical evaluation.
Omecamtiv mecarbil is a cardiac myosin activator. This new drug:
improves myocardial contraction by increasing the hydrolysis of ATP by myosin ATPase
this produces the power stroke between actin and myosin and subsequent shortening of sarcomere length
in phase-2a studies in patients with systolic heart failure it demonstrated improved stroke volume without an increase in heart rate, although cardiac ischaemia emerged at high plasma concentrations4,5.
PURPOSE OF REVIEW: ICU patients frequently develop low output syndromes due to cardiac dysfunction, myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be useful in restoring hemodynamic parameters and improving peripheral organ perfusion, but can increase short-term and long-term mortality in these patients. Novel inotropes may be promising in the management of ICU patients, having no serious adverse effects. This review summarizes all the current knowledge about the use of conventional and new inotropic agents in various clinical entities of critically ill patients.
RECENT FINDINGS: In recent European Society of Cardiology guidelines, inotropic agents are administered in patients with low output syndrome due to impaired cardiac contractility, and signs and symptoms of congestion. The most recommended inotropes in this condition are levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B). Recent data indicate that levosimendan may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan can be effectively used for weaning of mechanical ventilation in postcardiac surgery patients and has also cardioprotective effect as expressed by the absence of troponin release in this patient population. Finally, new agents, such as istaroxime and cardiac myosin activators may be safe and improve central hemodynamics in experimental models of heart failure and heart failure patients in phase II clinical trials; however, large-scale randomized clinical trials are required.
SUMMARY: In an acute cardiac care setting, short-term use of inotropic agents is crucial for the restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning of cardiosurgery. New promising agents should be tested in randomized clinical trials.
Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that impaired Ca2+ cycling may contribute to myocardial dysfunction. Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na-K ATPase inhibition may increase contractility (inotropy) and facilitate active relaxation (lusitropy), improving both systolic and diastolic functions. Istaroxime, a novel luso-inotrope that activates SERCA2a and inhibits the Na-K ATPase, is currently in phase II clinical development and has been shown to improve systolic and diastolic functions and central hemodynamics, increase systolic but not diastolic blood pressure, and decrease substantially heart rate. Irrespective of its clinical utility, the development of istaroxime has evolved our understanding of the clinical importance of inhibiting the Na-K ATPase in order to obtain a clinically significant effect from SERCA2a activation in the setting of myocardial failure.
BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings.
METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223.
FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15  mL), fractional shortening (8% ), and ejection fraction (7% ; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.
INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure.
FUNDING: Cytokinetics Inc.
5. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial Lancet. 2011 Aug 20;378(9792):676-83 Abstract
BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure.
METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442.
FINDINGS: T45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged.
INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent.
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.
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.
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.