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Intrapericardial administration of anti-arrhythmic medications in patients with electrical storm
Journal Pre-proofs Intrapericardial Administration of Anti-arrhythmic Medications in Patients with Electrical Storm Ali Yousif, Sardar Ijaz, Benjamin J. Scherlag PII: DOI: Reference:
S0306-9877(19)31291-5 https://doi.org/10.1016/j.mehy.2020.109640 YMEHY 109640
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
2 January 2020 19 February 2020 20 February 2020
Please cite this article as: A. Yousif, S. Ijaz, B.J. Scherlag, Intrapericardial Administration of Anti-arrhythmic Medications in Patients with Electrical Storm, Medical Hypotheses (2020), doi: https://doi.org/10.1016/j.mehy. 2020.109640
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1
Intrapericardial Administration of Anti-arrhythmic Medications in Patients with Electrical
2
Storm
3
Ali Yousif, MD
4
Sardar Ijaz, MD
5
Benjamin J. Scherlag, PhD
6
Section of Cardiovascular Diseases, Department of Internal Medicine
7
University of Oklahoma Health Sciences Center
8
Running Title: Intrapericardial Anti-arrhythmics in Electrical Storm
9 10
Word Count: 2,177, References not included; Abstract: 183
11 12
Corresponding Author:
13
Benjamin J. Scherlag, PhD
14
Oklahoma University Health Sciences Center
15
Cardiovascular Services, Suite 5400
16
800 Stanton L Young Blvd
17
Oklahoma City, OK
18
E-mail: [email protected].
19 20
No source of funding used for preparation of this manuscript.
21 22 23
1
1
Abstract
2
Introduction: Electrical storm (ES) is cardiac electrical instability characterized by
3
recurrent episodes of ventricular tachyarrhythmias. ES is associated with increased
4
mortality and morbidity, hence requires prompt intervention. Treatment of underlying
5
etiology is of prime importance in termination of ES. Anti-arrhythmic medications serve
6
as an adjunctive therapy in suppression of ES by reducing myocardial excitability. The
7
anti-arrhythmic conventionally employed is amiodarone in combination with non-
8
selective beta-blockers to reduce the adrenergic input to myocardium. However, anti-
9
arrhythmics at increased concentrations can lead to adverse system effects including
10
hemodynamic instability.
11
Hypothesis: We hypothesize 1. The use of intravenous or oral anti-arrhythmic therapy
12
for patients in electrical storm is limited by their toxicities and blood pressure lowering
13
effect. Corollary 1. Injection of anti-arrhythmic medications into the pericardial space, an
14
extra-vascular structure encasing the heart, provides an option for use of higher
15
concentration of anti-arrhythmic while limiting systemic absorption. Corollary 2. The
16
pericardial space has direct communication to the epicardium, the outer most layer of
17
cardiac muscle, spatial proximity may allow for effective therapeutic options in electrical
18
storm. We present experimental and clinical evidence in support of these hypothesis.
19 20
INTRODUCTION
21
Electrical storm (ES), also referred to as ventricular tachycardia (VT) storm or
22
arrhythmic storm, is a potentially fatal electrical instability characterized by multiple
23
repetitive episodes of ventricular arrhythmias occurring during a brief period of time. The
2
1
spectrum of ventricular arrhythmias includes monomorphic VT, polymorphic VT and
2
ventricular fibrillation (VF) (1). The reported incidence of electrical storm varies and mostly
3
from data on patients with implantable cardiac defibrillator (ICD). The aggregate reported
4
incidence in patients with ICD is 2-25 % per year (2). The effect on immediate mortality
5
is debatable; however, long-term mortality can reach 80 % due to cardiac
6
decompensation resulting in worsening heart failure (1). VT storm also results in
7
significant morbidity: multiple device shocks, frequent hospitalizations, psychological
8
stress, and impaired quality of life (1, 2). One of the mainstay therapies for electrical storm
9
is intravenous (IV) or oral anti-arrhythmic therapy. Although IV or oral anti-arrhythmic
10
therapy can suppress ventricular arrhythmias, sometimes they can be ineffective in
11
terminating arrhythmia and its use may cause unintended hemodynamic instability.
12
We present a hypothesis to explain that intra-pericardial (IP) administration of anti-
13
arrhythmic therapy is an option in electrical storm patients in conjunction with IV/oral anti-
14
arrhythmic therapy or instead of IV/oral therapy in patients intolerant or unresponsive to
15
IV/oral anti-arrhythmic administration.
16 17
BACKGROUND
18
The treatment of patients in electrical storm is complex and often requires a
19
combination of multiple invasive and non-invasive approaches. Initial treatment depends
20
on the hemodynamic status. Hemodynamically unstable patients should be cardioverted
21
as per advanced cardiac life support (ACLS) protocol (3). In hemodynamically stable
22
patients, the underlying etiology should be elucidated. For example, if there is a suspicion
23
of ischemia, coronary angiography should be performed with goal for complete
3
1
revascularization of the culprit coronary lesion. However, oftentimes a precipitant cause
2
for ES is not easily identified and if found the cause may be irreversible, hence treatment
3
is focused on suppressing adrenergic surge and sympathetic overdrive that occurs in
4
electrical storm. With advancement of technology, new invasive approaches such as
5
radiofrequency catheter ablation and neuraxial modulation procedures have grown in
6
popularity and became widely accepted in current clinical practice and management of
7
ES patients (3,4). Nevertheless, administration of anti-arrhythmic medications is used
8
early in the course of ES and has an adjunctive yet important role in this patient
9
population.
10 11
Intravenous and Oral Anti-Arrhythmic Therapies
12
There are several available anti-arrhythmic therapies albeit with variable
13
effectiveness in ES. The choice of an anti-arrhythmic depends on underlying cardiac
14
disease, presence of heart failure symptoms, and potential for medication induced side
15
effects. Beta-blockers are Class II anti-arrhythmic agents per Vaughan-Williams
16
Classification. Beta-blockers play an important role in suppressing ventricular arrhythmias
17
in ES due to their anti-adrenergic properties. In MADIT II study, ICD patients on maximally
18
tolerated dose of oral beta-blockers had a 52% relative risk reduction of recurrent VT/VF
19
requiring ICD therapy (5). But not all beta-blockers are equally effective. In a recent
20
double-blinded randomized study of ICD patients admitted with ES, the incidence of
21
ventricular arrhythmic events, time to arrhythmia termination, length of stay, and rate of
22
ICD discharges were significantly reduced in those randomized to an oral non-selective
23
beta blocker propranolol compared to oral beta-1 selective metoprolol (6). Despite
4
1
benefits seen with beta-blockers, their use is limited to patients with non-labile
2
hemodynamics. In patients with labile hemodynamic status, short-acting intravenous
3
esmolol infusion can be used, but may not be tolerated for a longer duration.
4
The most commonly used anti-arrhythmic medication in ES is Amiodarone.
5
Amiodarone is a predominately class III agent with Class I, II, and IV properties. Initial
6
randomized trials showed superiority of amiodarone to placebo in suppressing ventricular
7
arrhythmias when 1-gm total dose of amiodarone as an infusion was completed within
8
24-hours (7). In patients with an ICD, combining amiodarone with beta-blockers
9
significantly reduces the risk of recurrent ICD shocks when compared to beta-blockers
10
alone or sotalol alone (8). In a small retrospective study of ES patients, those previously
11
on amiodarone or who received amiodarone at the time of ventricular storm, had
12
significantly less electrical storm recurrence compared to those not treated with
13
amiodarone (9). Unfortunately, amiodarone is known to cause long-term side effects such
14
as hepatoxicity, hypo- and hyperthyroidism, skin toxicity, and pulmonary fibrosis (10).
15
Additionally, amiodarone administration is associated with bradycardia, hypotension,
16
acute liver failure, nausea or phlebitis in the acute setting (10, 11). Hypotension is
17
especially common with IV amiodarone administration and since low systemic blood
18
pressure is common in ES patients, the use of intravenous amiodarone is occasionally
19
not tolerated in acute setting. Amiodarone has been reported to cause fatal fulminant
20
hepatic failure within 48-hours of administration in case reports of patients with atrial
21
fibrillation (11, 12). Although, this has been reported in atrial fibrillation patients without
22
prior history of liver disease, many patients in ES and acute decompensated heart failure
5
1
concurrently have elevation in liver enzymes that may worsen by parenteral or oral
2
amiodarone administration.
3
Mexilitine and lidocaine are class IB agents that can be administered orally or
4
intravenously respectively. These agents are used as add-on therapy to amiodarone in
5
ES patients especially in the setting of ischemia (4). Although mexilitine has been shown
6
to reduce the frequency of ventricular arrhythmia burden in ICD patients (13), it has
7
significant central nervous system side effects that are dose dependent. Symptoms
8
include tremors, hallucinations, dizziness, and seizures, which may limit up titration and
9
prolonged use of these agents (4).
10 11
Intra-pericardial Administration of Anti-arrhythmic Drugs
12
Due to the increased side effects and limitations of parenteral and oral anti-
13
arrhythmic therapies, an alternative method to deliver these agents is warranted.
14
Administration of anti-arrhythmic medications into the pericardium has been described in
15
both animal and human studies in atrial fibrillation (14-18). The pericardium is a double-
16
layered fibro-serous sac surrounding the heart. Access to the pericardium is done
17
routinely through percutaneous access for purpose of catheter ablation to treat cardiac
18
arrhythmias that arise from the epicardium, the outermost layer of the heart (Figure 1)
19
(19). Unfortunately there is limited published data on human subjects with electrical storm.
20
Administration of anti-arrhythmics into the pericardial space allows for higher myocardium
21
concentration of the drug compared to intravenously administered anti-arrhythmics. In a
22
rat model, IP administration of sotalol or atenolol had 3.8 and 4.7 times higher overall left
23
ventricle tissue concentration compared to IV B-blockers (Table 1) (20). Furthermore, IP
6
1
administration has lower plasma level concentration when compared to IV administered
2
anti-arrhythmic medications (15). In adult sheep, even when higher levels of anti-
3
arrhythmics were infused IP continuously at 50mg/hour, no systemic effects such as
4
thyroid dysfunction, hepatic toxicity and interstitial pneumonitis were observed (16). Also,
5
IP administration of anti-arrhythmics was not associated with localized effects on
6
pericardium thru inflammation or fibrosis (16). The ability to achieve higher intra-
7
pericardial concentration while reducing plasma levels concentration has important
8
implications, as lower plasma levels will likely lead to low systemic and extra-cardiac side
9
effects.
10
In
addition,
IP
administration
of
anti-arrhythmic
medications
causes
11
electrophysiologic changes and an increase in transmural concentration gradients within
12
the myocytes (14-15). In a goat model with sustained atrial fibrillation, Van Brakel et. al
13
demonstrated IP administration of sotalol and flecainide significantly increased atrial
14
effective refractive period (ERP) when compared to IV infusion (14). Although the study
15
did not show significant improvement in conversion rates to normal sinus rhythm with IP
16
administration, it did demonstrate that electrophysiologic properties of cardiac myocytes
17
are markedly affected by IP administration of anti-arrhythmics. Also, in a goat animal
18
model, Bolderman et al. showed IP administration of amiodarone and sotalol had a
19
significant reduction in the ability to induce atrial fibrillation compared to IV administration
20
of amiodarone and sotalol (15). Furthermore, Garcia et al. demonstrated the feasibility of
21
a unique concept of implanting a biomaterial hydrogel platform containing amiodarone
22
into the pericardial space directly adjacent to atrial epicardium (21). Access to the
23
pericardial space was done via subxiphoid approach and delivery of the hydrogel was
7
1
done through a specially designed device (22). In a porcine model with atrial fibrillation
2
(AF), amiodarone-containing hydrogel significantly reduced duration of sustained AF
3
episodes and inducibility of AF at 3 weeks and 1 month (21). Although, the concept of
4
implanting a platform to continuously release anti-arrhythmic medications in the
5
pericardium is intriguing, further studies are needed in humans. The effects on atrial
6
refractoriness were more prominent in the group that received IP administration of
7
amiodarone. As shown in these studies IP administration of anti-arrhythmics affects
8
electrophysiological properties of myocytes and inducibility of atrial fibrillation.
9
In patients undergoing coronary artery bypass graft surgery, 100 patients
10
randomized to amiodarone hydrogel over the epicardium had significantly decreased
11
incidence of postoperative atrial fibrillation compared to placebo (18). The plasma
12
amiodarone level was not detectable during the 14-days follow-up and there was no
13
intracardiac or systemic adverse effects. In addition, the atrial concentration of
14
amiodarone was significantly higher than concentrations in extracardiac tissues. The
15
author’s concluded that the IP administration route is an effective, safe, and preventative
16
treatment strategy of post-operative atrial fibrillation when compared to systemic
17
administration of amiodarone (18). Alternative anti-arrhythmics have also been infused
18
into the pericardium. Ujhelyi et al. showed in a swine model randomized to sequential
19
procainamide doses delivered intravenously or into the pericardial space (23). Despite
20
administering lower cumulative procainamide IP doses, atrial refractoriness prolongation
21
and increase of atrial fibrillation thresholds was similar between intravenous and IP
22
groups (23). However, IP procainamide administration did not have an effect on
23
ventricular electrophysiological properties. The effectiveness of IP administration can be
8
1
explained by the fact that IP administration allows for higher and localized concentration
2
of antiarrhythmic with close proximity to cardiac myocytes and longer drug-tissue contact
3
when compared to systemic administration of anti-arrhythmics (17).
4
Since the animal models did report the effect of amiodarone on ventricular and
5
atrial ERP, we suggest that this effect of IP administration of amiodarone would show the
6
same efficacy in patients with ventricular arrhythmias and ES.
7
administration allows for high concentration of drugs in pericardium with low plasma level
8
concentrations of anti-arrhythmics with limited systemic side effects making it an attractive
9
option in ES patients who are more likely to have liver dysfunction and renal failure. For
10
example, in a porcine model with induced acute myocardial infarction, Xiao et al. showed
11
IP administration of omega-3 polyunsaturated fatty acids significantly reduced ventricular
12
arrhythmia burden and infarction size compared to controls (24). In addition, the effect of
13
the pericardial dose was achieved with only 5% of a systemic dose (24). Although Xiao
14
et al. study was not performed in electrical storm, it demonstrated IP administration of
15
anti-arrhythmics can influence ventricular myocardium and reduce arrhythmia burden
16
while doing so with a significantly reduced dose. Also, the epicardium can be a substrate
17
for ventricular arrhythmias in non-ischemic cardiomyopathy patients (25). Thus
18
administering anti-arrhythmics within the pericardium in non-ischemic cardiomyopathy
19
patients who are deemed to have an epicardial substrate based on cardiac imaging may
20
be effective in terminating ventricular arrhythmias. We propose that IP administration of
21
anti-arrhythmics should be considered in selected patients with electrical storm: (1)
22
patients with known history of toxicity to anti-arrhythmics (2) those with unstable
23
hemodynamic status in whom addition of systemic anti-arrhythmic medications likely will
Moreover, IP
9
1
further worsen hemodynamics (3) patients who continue to be in electrical storm and thus
2
considered refractory to systemic anti-arrhythmic medications and (4) patients
3
undergoing catheter ablation for ventricular arrhythmia in whom an ablation target is not
4
identified. The IP administration of anti-arrhythmic drugs can be combined with other
5
treatment modalities such as intravenous anti-arrhythmic, sympathetic denervation, and
6
catheter ablation to treat ES via multiple approaches. Further studies are needed in ES
7
patients to determine efficacy of the IP approach in this patient population.
8 9 10 11 12
HYPOTHESIS On the basis of these experimental and clinical reports, we hypothesize: 1. Intravenous antiarrhythmic drug administration for electrical storm patients is limited by increased toxicity and adverse events limiting its use in some patients.
13
2. IP administration of antiarrhythmic drug allows the use of higher concentrations
14
of anti-arrhythmic drugs with limited systemic absorption as an effective therapeutic
15
option in patients with electrical storm.
16 17
Conflict of interest: None
18 19 20 21
References:
10
1
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et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular
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Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American
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College of Cardiology/American Heart Association Task Force on Clinical Practice
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Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72(14):e91-e220.
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Management of Electrical Storm. Heart, Lung, and Circulation. 2019; 28(1):123-133.
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Papadopoulou E, et al. Propranolol Versus Metoprolol for Treatment of Electrical Storm
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et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening
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Comparison of Beta-blockers, amiodarone plus Beta blockers, or sotalol for prevention
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of shocks from implantable cardioverter defibrillators – The OPTIC study: a randomized
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trial. J Am Med Assoc, 295 (2006), 165-171.
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strom in ICD patients the sign of a dying heart? Outcome of patients with clusters of
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ventricular tachyarrhythmias. Europace, 2(2000), 263-269.
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Examining the safety of amiodarone. Expert Opin Drug Safety. 2012; 11(2):191-214.
Santangeli P, Di Biase L, Burkhardt JD, Bai R, Mohanty P, Pump A, Natale A.
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D, Demetria M. Acute liver failure with amiodarone infusion: A case report and systemic
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reviw. J Clin Pharm Ther. 2018; 43(1):129-133.
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J.2009;54:58‐58.
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Golovchiner G, Aves T, and Pinter A. Mexilitine as an adjunctive therapy to amiodarone
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reduces the frequency of ventricular tachyarrhythmia events. J cardiovascular Pharm.
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2013. 62(2): 199-204.
Gao, D, Van Herendael H, Alshengeiti L, Dorian P, Mangat I, Korley V, Ahmad K,
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Effects of intrapericardial sotalol and flecainide on transmural atrial electrophysiology
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and atrial fibrillation. Journal of cardiovascular electrophysiology. 2009;20(2):207-15.
Van Brakel TJ, Hermans JJ, Accord RE, Schotten U, Smits JF, Allessie MA, et al.
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15.
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Veen FH, et al. Intrapericardial delivery of amiodarone and sotalol: atrial transmural
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drug distribution and electrophysiological effects. J Cardiovasc Pharmacol.
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2009;54(4):355-63.
Bolderman RW, Hermans JJ, Rademakers LM, Jansen TS, Verheule S, van der
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Intrapericardial delivery of amiodarone rapidly achieves therapeutic levels in the atrium.
22
Heart Surg Forum. 2013;16(5):E279-86.
Marcano J, Campos K, Rodriguez V, Handy K, Brewer MA, Cohn WE.
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Postoperative Atrial Fibrillation. J Card Surg. 2016;31(4):253-8.
Habbab LM, Chu FV. Intrapericardial Amiodarone for the Prevention of
3 4
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application of amiodarone-releasing adhesive hydrogel to prevent postoperative atrial
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fibrillation. J Thorac Cardiovasc Surg. 2014;148(3):939-43.
Feng XD, Wang XN, Yuan XH, Wang W. Effectiveness of biatrial epicardial
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access for the treatment of cardiac arrhythmias. EP Europace. 2012;14(2):ii13-ii18.
Andre d’Avila, Jacob S. Koruth, Srinivas Dukkipati, Vivek Y. Reddy. Epicardial
10 11
20.
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Maessen JG. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J
13
Cardiovasc Pharmacol. 2004;44(1):50-6.
Van Brakel TJ, Hermans JJ, Janssen BJ, Van Essen H, Botterhuis N, Smits SF,
14 15
25.
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cardiomyopathy. J Arrhythm. 2018; 34(4):336-346.
Chung FP, Lin CY, Lin YJ, et al. Ventricular arrhythmias in non-ischemic
17 18
24.
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novel approach to reducing myocardial infarct sizes and arrhythmias. Am J Physiol
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Heart Circ Physiol. 2008; 294: H2212-H2218.
Xiao Y, Sigg DY, Ujhelyi MR, et al. Pericardial delivery of omega-3 fatty acid: a
21
14
1
21.
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Encapsulated Amiodarone to the Epicardium Reduces Atrial Fibrillation. Circ Arrhythm
3
Electrophysiol. 2018; 11(5): e006408.
Garcia JR, Campbell PF, Kumar G, et al. Minimally invasive delivery of Hydrogel-
4 5
22. Garcia JR, Campbell PF, Kumar G, et. al. A Minimally Invasive, Translational
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Method to Deliver Hydrogels to the Heart Through the Pericardial Space. JACC: Basic
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to Translational Science. 2017; 2(5): 601-609.
8 9
23.
Ujhelyi MR, Hadsall KZ, Euler DE et al. Intrapericardial therapeutics: A
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pharmacodynamic and Pharmocokinetic Comparison Between Pericardial and
11
Intravenous Procainamide Delivery. J Cardiovasc Electrophysio. 2002; 13(6): 605-11.
12 13
Figure 1. Sagittal cross section of the human heart showing the two layers of the
14
pericardium surrounding the pericardial cavity. Anti-arrhythmic medications can directly
15
be injected into the pericardial cavity through a percutaneous subxiphoid approach
16
(arrow).
17 18
Table 1. Drug concentrations in pericardial fluid (PF), plasma, and cardiac tissue after 7
19
days of intrapericardial (IP) or intravenous (IV) sotalol or atenolol infusion. n.d. = not
20
detectable. Data represent mean +/- SEM. *P < 0.05 and **P < 0.01 compared to IV
21
delivery. Table obtained from Van Brakel TJ, et al. Intrapericardial delivery enhances
22
cardiac effects of sotalol and atenolol. J Cardiovasc Pharmacol. 2004;44(1):50-6.
15
16
Table 1. Drug concentration in left ventricle (LV), plasma, and pericardial fluid (PF) after 7-days of intrapericardial (IP) or intravenous (IV) drug administration
Drug
Concentration (ng/g wet tissue or ng/ml) LV Plasma PF
Dose Route N Bodyweight (mg/kg.h) (g) Sotalol 0.03 IP 6 310 +/- 11 576 +/- 118* 24 +/-5 2332 +/- 480** Sotalol 0.03 IV 6 304 +/- 7 153 +/- 59 40 +/- 21 n.d. Atenolol 0.03 IP 5 317 +/- 14 312 +/- 96* 39 +/- 4 5323 +/- 818** Atenolol 0.03 IV 6 320 +/- 17 66 +/- 9 30 +/- 7 n.d. Table 1. Drug concentrations in pericardial fluid (PF), plasma, and cardiac tissue after 7 days of intrapericardial (IP) or intravenous (IV) sotalol or atenolol infusion. n.d. = not detectable. Data represent mean +/- SEM. *P < 0.05 and **P < 0.01 compared to IV delivery. Table obtained from Van Brakel TJ, et al. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J Cardiovasc Pharmacol. 2004;44(1):50-6.
Conflict of Interest: None declared
17
S0306-9877(19)31291-5 https://doi.org/10.1016/j.mehy.2020.109640 YMEHY 109640
To appear in:
Medical Hypotheses
Received Date: Revised Date: Accepted Date:
2 January 2020 19 February 2020 20 February 2020
Please cite this article as: A. Yousif, S. Ijaz, B.J. Scherlag, Intrapericardial Administration of Anti-arrhythmic Medications in Patients with Electrical Storm, Medical Hypotheses (2020), doi: https://doi.org/10.1016/j.mehy. 2020.109640
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.
1
Intrapericardial Administration of Anti-arrhythmic Medications in Patients with Electrical
2
Storm
3
Ali Yousif, MD
4
Sardar Ijaz, MD
5
Benjamin J. Scherlag, PhD
6
Section of Cardiovascular Diseases, Department of Internal Medicine
7
University of Oklahoma Health Sciences Center
8
Running Title: Intrapericardial Anti-arrhythmics in Electrical Storm
9 10
Word Count: 2,177, References not included; Abstract: 183
11 12
Corresponding Author:
13
Benjamin J. Scherlag, PhD
14
Oklahoma University Health Sciences Center
15
Cardiovascular Services, Suite 5400
16
800 Stanton L Young Blvd
17
Oklahoma City, OK
18
E-mail: [email protected].
19 20
No source of funding used for preparation of this manuscript.
21 22 23
1
1
Abstract
2
Introduction: Electrical storm (ES) is cardiac electrical instability characterized by
3
recurrent episodes of ventricular tachyarrhythmias. ES is associated with increased
4
mortality and morbidity, hence requires prompt intervention. Treatment of underlying
5
etiology is of prime importance in termination of ES. Anti-arrhythmic medications serve
6
as an adjunctive therapy in suppression of ES by reducing myocardial excitability. The
7
anti-arrhythmic conventionally employed is amiodarone in combination with non-
8
selective beta-blockers to reduce the adrenergic input to myocardium. However, anti-
9
arrhythmics at increased concentrations can lead to adverse system effects including
10
hemodynamic instability.
11
Hypothesis: We hypothesize 1. The use of intravenous or oral anti-arrhythmic therapy
12
for patients in electrical storm is limited by their toxicities and blood pressure lowering
13
effect. Corollary 1. Injection of anti-arrhythmic medications into the pericardial space, an
14
extra-vascular structure encasing the heart, provides an option for use of higher
15
concentration of anti-arrhythmic while limiting systemic absorption. Corollary 2. The
16
pericardial space has direct communication to the epicardium, the outer most layer of
17
cardiac muscle, spatial proximity may allow for effective therapeutic options in electrical
18
storm. We present experimental and clinical evidence in support of these hypothesis.
19 20
INTRODUCTION
21
Electrical storm (ES), also referred to as ventricular tachycardia (VT) storm or
22
arrhythmic storm, is a potentially fatal electrical instability characterized by multiple
23
repetitive episodes of ventricular arrhythmias occurring during a brief period of time. The
2
1
spectrum of ventricular arrhythmias includes monomorphic VT, polymorphic VT and
2
ventricular fibrillation (VF) (1). The reported incidence of electrical storm varies and mostly
3
from data on patients with implantable cardiac defibrillator (ICD). The aggregate reported
4
incidence in patients with ICD is 2-25 % per year (2). The effect on immediate mortality
5
is debatable; however, long-term mortality can reach 80 % due to cardiac
6
decompensation resulting in worsening heart failure (1). VT storm also results in
7
significant morbidity: multiple device shocks, frequent hospitalizations, psychological
8
stress, and impaired quality of life (1, 2). One of the mainstay therapies for electrical storm
9
is intravenous (IV) or oral anti-arrhythmic therapy. Although IV or oral anti-arrhythmic
10
therapy can suppress ventricular arrhythmias, sometimes they can be ineffective in
11
terminating arrhythmia and its use may cause unintended hemodynamic instability.
12
We present a hypothesis to explain that intra-pericardial (IP) administration of anti-
13
arrhythmic therapy is an option in electrical storm patients in conjunction with IV/oral anti-
14
arrhythmic therapy or instead of IV/oral therapy in patients intolerant or unresponsive to
15
IV/oral anti-arrhythmic administration.
16 17
BACKGROUND
18
The treatment of patients in electrical storm is complex and often requires a
19
combination of multiple invasive and non-invasive approaches. Initial treatment depends
20
on the hemodynamic status. Hemodynamically unstable patients should be cardioverted
21
as per advanced cardiac life support (ACLS) protocol (3). In hemodynamically stable
22
patients, the underlying etiology should be elucidated. For example, if there is a suspicion
23
of ischemia, coronary angiography should be performed with goal for complete
3
1
revascularization of the culprit coronary lesion. However, oftentimes a precipitant cause
2
for ES is not easily identified and if found the cause may be irreversible, hence treatment
3
is focused on suppressing adrenergic surge and sympathetic overdrive that occurs in
4
electrical storm. With advancement of technology, new invasive approaches such as
5
radiofrequency catheter ablation and neuraxial modulation procedures have grown in
6
popularity and became widely accepted in current clinical practice and management of
7
ES patients (3,4). Nevertheless, administration of anti-arrhythmic medications is used
8
early in the course of ES and has an adjunctive yet important role in this patient
9
population.
10 11
Intravenous and Oral Anti-Arrhythmic Therapies
12
There are several available anti-arrhythmic therapies albeit with variable
13
effectiveness in ES. The choice of an anti-arrhythmic depends on underlying cardiac
14
disease, presence of heart failure symptoms, and potential for medication induced side
15
effects. Beta-blockers are Class II anti-arrhythmic agents per Vaughan-Williams
16
Classification. Beta-blockers play an important role in suppressing ventricular arrhythmias
17
in ES due to their anti-adrenergic properties. In MADIT II study, ICD patients on maximally
18
tolerated dose of oral beta-blockers had a 52% relative risk reduction of recurrent VT/VF
19
requiring ICD therapy (5). But not all beta-blockers are equally effective. In a recent
20
double-blinded randomized study of ICD patients admitted with ES, the incidence of
21
ventricular arrhythmic events, time to arrhythmia termination, length of stay, and rate of
22
ICD discharges were significantly reduced in those randomized to an oral non-selective
23
beta blocker propranolol compared to oral beta-1 selective metoprolol (6). Despite
4
1
benefits seen with beta-blockers, their use is limited to patients with non-labile
2
hemodynamics. In patients with labile hemodynamic status, short-acting intravenous
3
esmolol infusion can be used, but may not be tolerated for a longer duration.
4
The most commonly used anti-arrhythmic medication in ES is Amiodarone.
5
Amiodarone is a predominately class III agent with Class I, II, and IV properties. Initial
6
randomized trials showed superiority of amiodarone to placebo in suppressing ventricular
7
arrhythmias when 1-gm total dose of amiodarone as an infusion was completed within
8
24-hours (7). In patients with an ICD, combining amiodarone with beta-blockers
9
significantly reduces the risk of recurrent ICD shocks when compared to beta-blockers
10
alone or sotalol alone (8). In a small retrospective study of ES patients, those previously
11
on amiodarone or who received amiodarone at the time of ventricular storm, had
12
significantly less electrical storm recurrence compared to those not treated with
13
amiodarone (9). Unfortunately, amiodarone is known to cause long-term side effects such
14
as hepatoxicity, hypo- and hyperthyroidism, skin toxicity, and pulmonary fibrosis (10).
15
Additionally, amiodarone administration is associated with bradycardia, hypotension,
16
acute liver failure, nausea or phlebitis in the acute setting (10, 11). Hypotension is
17
especially common with IV amiodarone administration and since low systemic blood
18
pressure is common in ES patients, the use of intravenous amiodarone is occasionally
19
not tolerated in acute setting. Amiodarone has been reported to cause fatal fulminant
20
hepatic failure within 48-hours of administration in case reports of patients with atrial
21
fibrillation (11, 12). Although, this has been reported in atrial fibrillation patients without
22
prior history of liver disease, many patients in ES and acute decompensated heart failure
5
1
concurrently have elevation in liver enzymes that may worsen by parenteral or oral
2
amiodarone administration.
3
Mexilitine and lidocaine are class IB agents that can be administered orally or
4
intravenously respectively. These agents are used as add-on therapy to amiodarone in
5
ES patients especially in the setting of ischemia (4). Although mexilitine has been shown
6
to reduce the frequency of ventricular arrhythmia burden in ICD patients (13), it has
7
significant central nervous system side effects that are dose dependent. Symptoms
8
include tremors, hallucinations, dizziness, and seizures, which may limit up titration and
9
prolonged use of these agents (4).
10 11
Intra-pericardial Administration of Anti-arrhythmic Drugs
12
Due to the increased side effects and limitations of parenteral and oral anti-
13
arrhythmic therapies, an alternative method to deliver these agents is warranted.
14
Administration of anti-arrhythmic medications into the pericardium has been described in
15
both animal and human studies in atrial fibrillation (14-18). The pericardium is a double-
16
layered fibro-serous sac surrounding the heart. Access to the pericardium is done
17
routinely through percutaneous access for purpose of catheter ablation to treat cardiac
18
arrhythmias that arise from the epicardium, the outermost layer of the heart (Figure 1)
19
(19). Unfortunately there is limited published data on human subjects with electrical storm.
20
Administration of anti-arrhythmics into the pericardial space allows for higher myocardium
21
concentration of the drug compared to intravenously administered anti-arrhythmics. In a
22
rat model, IP administration of sotalol or atenolol had 3.8 and 4.7 times higher overall left
23
ventricle tissue concentration compared to IV B-blockers (Table 1) (20). Furthermore, IP
6
1
administration has lower plasma level concentration when compared to IV administered
2
anti-arrhythmic medications (15). In adult sheep, even when higher levels of anti-
3
arrhythmics were infused IP continuously at 50mg/hour, no systemic effects such as
4
thyroid dysfunction, hepatic toxicity and interstitial pneumonitis were observed (16). Also,
5
IP administration of anti-arrhythmics was not associated with localized effects on
6
pericardium thru inflammation or fibrosis (16). The ability to achieve higher intra-
7
pericardial concentration while reducing plasma levels concentration has important
8
implications, as lower plasma levels will likely lead to low systemic and extra-cardiac side
9
effects.
10
In
addition,
IP
administration
of
anti-arrhythmic
medications
causes
11
electrophysiologic changes and an increase in transmural concentration gradients within
12
the myocytes (14-15). In a goat model with sustained atrial fibrillation, Van Brakel et. al
13
demonstrated IP administration of sotalol and flecainide significantly increased atrial
14
effective refractive period (ERP) when compared to IV infusion (14). Although the study
15
did not show significant improvement in conversion rates to normal sinus rhythm with IP
16
administration, it did demonstrate that electrophysiologic properties of cardiac myocytes
17
are markedly affected by IP administration of anti-arrhythmics. Also, in a goat animal
18
model, Bolderman et al. showed IP administration of amiodarone and sotalol had a
19
significant reduction in the ability to induce atrial fibrillation compared to IV administration
20
of amiodarone and sotalol (15). Furthermore, Garcia et al. demonstrated the feasibility of
21
a unique concept of implanting a biomaterial hydrogel platform containing amiodarone
22
into the pericardial space directly adjacent to atrial epicardium (21). Access to the
23
pericardial space was done via subxiphoid approach and delivery of the hydrogel was
7
1
done through a specially designed device (22). In a porcine model with atrial fibrillation
2
(AF), amiodarone-containing hydrogel significantly reduced duration of sustained AF
3
episodes and inducibility of AF at 3 weeks and 1 month (21). Although, the concept of
4
implanting a platform to continuously release anti-arrhythmic medications in the
5
pericardium is intriguing, further studies are needed in humans. The effects on atrial
6
refractoriness were more prominent in the group that received IP administration of
7
amiodarone. As shown in these studies IP administration of anti-arrhythmics affects
8
electrophysiological properties of myocytes and inducibility of atrial fibrillation.
9
In patients undergoing coronary artery bypass graft surgery, 100 patients
10
randomized to amiodarone hydrogel over the epicardium had significantly decreased
11
incidence of postoperative atrial fibrillation compared to placebo (18). The plasma
12
amiodarone level was not detectable during the 14-days follow-up and there was no
13
intracardiac or systemic adverse effects. In addition, the atrial concentration of
14
amiodarone was significantly higher than concentrations in extracardiac tissues. The
15
author’s concluded that the IP administration route is an effective, safe, and preventative
16
treatment strategy of post-operative atrial fibrillation when compared to systemic
17
administration of amiodarone (18). Alternative anti-arrhythmics have also been infused
18
into the pericardium. Ujhelyi et al. showed in a swine model randomized to sequential
19
procainamide doses delivered intravenously or into the pericardial space (23). Despite
20
administering lower cumulative procainamide IP doses, atrial refractoriness prolongation
21
and increase of atrial fibrillation thresholds was similar between intravenous and IP
22
groups (23). However, IP procainamide administration did not have an effect on
23
ventricular electrophysiological properties. The effectiveness of IP administration can be
8
1
explained by the fact that IP administration allows for higher and localized concentration
2
of antiarrhythmic with close proximity to cardiac myocytes and longer drug-tissue contact
3
when compared to systemic administration of anti-arrhythmics (17).
4
Since the animal models did report the effect of amiodarone on ventricular and
5
atrial ERP, we suggest that this effect of IP administration of amiodarone would show the
6
same efficacy in patients with ventricular arrhythmias and ES.
7
administration allows for high concentration of drugs in pericardium with low plasma level
8
concentrations of anti-arrhythmics with limited systemic side effects making it an attractive
9
option in ES patients who are more likely to have liver dysfunction and renal failure. For
10
example, in a porcine model with induced acute myocardial infarction, Xiao et al. showed
11
IP administration of omega-3 polyunsaturated fatty acids significantly reduced ventricular
12
arrhythmia burden and infarction size compared to controls (24). In addition, the effect of
13
the pericardial dose was achieved with only 5% of a systemic dose (24). Although Xiao
14
et al. study was not performed in electrical storm, it demonstrated IP administration of
15
anti-arrhythmics can influence ventricular myocardium and reduce arrhythmia burden
16
while doing so with a significantly reduced dose. Also, the epicardium can be a substrate
17
for ventricular arrhythmias in non-ischemic cardiomyopathy patients (25). Thus
18
administering anti-arrhythmics within the pericardium in non-ischemic cardiomyopathy
19
patients who are deemed to have an epicardial substrate based on cardiac imaging may
20
be effective in terminating ventricular arrhythmias. We propose that IP administration of
21
anti-arrhythmics should be considered in selected patients with electrical storm: (1)
22
patients with known history of toxicity to anti-arrhythmics (2) those with unstable
23
hemodynamic status in whom addition of systemic anti-arrhythmic medications likely will
Moreover, IP
9
1
further worsen hemodynamics (3) patients who continue to be in electrical storm and thus
2
considered refractory to systemic anti-arrhythmic medications and (4) patients
3
undergoing catheter ablation for ventricular arrhythmia in whom an ablation target is not
4
identified. The IP administration of anti-arrhythmic drugs can be combined with other
5
treatment modalities such as intravenous anti-arrhythmic, sympathetic denervation, and
6
catheter ablation to treat ES via multiple approaches. Further studies are needed in ES
7
patients to determine efficacy of the IP approach in this patient population.
8 9 10 11 12
HYPOTHESIS On the basis of these experimental and clinical reports, we hypothesize: 1. Intravenous antiarrhythmic drug administration for electrical storm patients is limited by increased toxicity and adverse events limiting its use in some patients.
13
2. IP administration of antiarrhythmic drug allows the use of higher concentrations
14
of anti-arrhythmic drugs with limited systemic absorption as an effective therapeutic
15
option in patients with electrical storm.
16 17
Conflict of interest: None
18 19 20 21
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et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular
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Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72(14):e91-e220.
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Management of Electrical Storm. Heart, Lung, and Circulation. 2019; 28(1):123-133.
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Papadopoulou E, et al. Propranolol Versus Metoprolol for Treatment of Electrical Storm
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and atrial fibrillation. Journal of cardiovascular electrophysiology. 2009;20(2):207-15.
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Veen FH, et al. Intrapericardial delivery of amiodarone and sotalol: atrial transmural
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drug distribution and electrophysiological effects. J Cardiovasc Pharmacol.
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2009;54(4):355-63.
Bolderman RW, Hermans JJ, Rademakers LM, Jansen TS, Verheule S, van der
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Intrapericardial delivery of amiodarone rapidly achieves therapeutic levels in the atrium.
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Heart Surg Forum. 2013;16(5):E279-86.
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Postoperative Atrial Fibrillation. J Card Surg. 2016;31(4):253-8.
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application of amiodarone-releasing adhesive hydrogel to prevent postoperative atrial
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access for the treatment of cardiac arrhythmias. EP Europace. 2012;14(2):ii13-ii18.
Andre d’Avila, Jacob S. Koruth, Srinivas Dukkipati, Vivek Y. Reddy. Epicardial
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Maessen JG. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J
13
Cardiovasc Pharmacol. 2004;44(1):50-6.
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25.
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cardiomyopathy. J Arrhythm. 2018; 34(4):336-346.
Chung FP, Lin CY, Lin YJ, et al. Ventricular arrhythmias in non-ischemic
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24.
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novel approach to reducing myocardial infarct sizes and arrhythmias. Am J Physiol
20
Heart Circ Physiol. 2008; 294: H2212-H2218.
Xiao Y, Sigg DY, Ujhelyi MR, et al. Pericardial delivery of omega-3 fatty acid: a
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14
1
21.
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Encapsulated Amiodarone to the Epicardium Reduces Atrial Fibrillation. Circ Arrhythm
3
Electrophysiol. 2018; 11(5): e006408.
Garcia JR, Campbell PF, Kumar G, et al. Minimally invasive delivery of Hydrogel-
4 5
22. Garcia JR, Campbell PF, Kumar G, et. al. A Minimally Invasive, Translational
6
Method to Deliver Hydrogels to the Heart Through the Pericardial Space. JACC: Basic
7
to Translational Science. 2017; 2(5): 601-609.
8 9
23.
Ujhelyi MR, Hadsall KZ, Euler DE et al. Intrapericardial therapeutics: A
10
pharmacodynamic and Pharmocokinetic Comparison Between Pericardial and
11
Intravenous Procainamide Delivery. J Cardiovasc Electrophysio. 2002; 13(6): 605-11.
12 13
Figure 1. Sagittal cross section of the human heart showing the two layers of the
14
pericardium surrounding the pericardial cavity. Anti-arrhythmic medications can directly
15
be injected into the pericardial cavity through a percutaneous subxiphoid approach
16
(arrow).
17 18
Table 1. Drug concentrations in pericardial fluid (PF), plasma, and cardiac tissue after 7
19
days of intrapericardial (IP) or intravenous (IV) sotalol or atenolol infusion. n.d. = not
20
detectable. Data represent mean +/- SEM. *P < 0.05 and **P < 0.01 compared to IV
21
delivery. Table obtained from Van Brakel TJ, et al. Intrapericardial delivery enhances
22
cardiac effects of sotalol and atenolol. J Cardiovasc Pharmacol. 2004;44(1):50-6.
15
16
Table 1. Drug concentration in left ventricle (LV), plasma, and pericardial fluid (PF) after 7-days of intrapericardial (IP) or intravenous (IV) drug administration
Drug
Concentration (ng/g wet tissue or ng/ml) LV Plasma PF
Dose Route N Bodyweight (mg/kg.h) (g) Sotalol 0.03 IP 6 310 +/- 11 576 +/- 118* 24 +/-5 2332 +/- 480** Sotalol 0.03 IV 6 304 +/- 7 153 +/- 59 40 +/- 21 n.d. Atenolol 0.03 IP 5 317 +/- 14 312 +/- 96* 39 +/- 4 5323 +/- 818** Atenolol 0.03 IV 6 320 +/- 17 66 +/- 9 30 +/- 7 n.d. Table 1. Drug concentrations in pericardial fluid (PF), plasma, and cardiac tissue after 7 days of intrapericardial (IP) or intravenous (IV) sotalol or atenolol infusion. n.d. = not detectable. Data represent mean +/- SEM. *P < 0.05 and **P < 0.01 compared to IV delivery. Table obtained from Van Brakel TJ, et al. Intrapericardial delivery enhances cardiac effects of sotalol and atenolol. J Cardiovasc Pharmacol. 2004;44(1):50-6.
Conflict of Interest: None declared
17