Antiadrenergic rescue therapy with amiodarone in children with severe left ventricular dysfunction secondary to scorpion envenomation

Santiago, Justo J.; Dávila, Carmen A. Mazzei de; Davila, Diego F.; Donis, Jose H.; Villaroel, Vanesa

doi:10.1590/S0066-782X2010000100005

Abstracts

BACKGROUND: Children with scorpion envenomation have massive sympathetic activation and variable degrees of left ventricular systolic dysfunction. OBJECTIVE: To evaluate a rescue protocol for children with severe left ventricular dysfunction secondary to scorpion envenomation. METHODS: Four children, after scorpion envenomation, were subjected to a rescue protocol for acute left ventricular dysfunction: Endotracheal intubation and respiratory assistance, electrocardiograms, chest x-Ray, echocardiograms and blood samples for norepinephrine and troponin I serum levels. Samples and echocardiograms were repeated at 12, 24 and 48 hours. Intravenous medications: Dobutamine: 4-6 μg/kg/min. Amiodarone: 3 mg/kg during a 2 hour period. Maintenance: 5 mg/kg/day. Furosemide: 0.5 mg/kg/dose. Diuretics were given when the systemic blood pressure was above percentile fifty. Amiodarone, Dobutamine and Furosemide were administered during the first 48 hours. Beta-adrenergic blockers and angiotensin converting enzyme were given, at 48 hours after admission, once the left ventricular Ejection fraction > 0.35 and the clinical status had improved. RESULTS: On admission, norepinephrine was 1,727.50 ±794.96 pg/ml, troponin I 24.53 ± 14.09 ng/ml and left ventricular ejection fraction 0.20 ± 0.056. At twelve hours, norepinephrine and troponin I serum levels were down to half of the initial values and the ejection fraction increased to 0.32 ± 0.059. During the next 24 and 48 hours, the ejection fraction rose to 0.46 ± 0.045, (p<0.01) and norepinephrine and troponin diminished to 526.75 ± 273.73 (p < 0.02) and 2.20 ± 2.36 (p<0.02) respectively. CONCLUSION: Amiodarone, by acting as a neuromodulator, is very likely responsible for the early and progressive decrease of serum norepinephrine.

Scorpion venoms; norepinephrine; amiodarone; adrenergic beta-agonists

FUNDAMENTO: As crianças picadas por escorpião, pressintam ativação maciça do sistema nervoso simpática com vários graus de disfunção sistólica ventricular esquerda. OBJETIVO: Testar um protocolo de resgate em crianças com grave disfunção ventricular esquerda causada por picada de escorpião. Métodos: Quatro crianças após serem picadas por escorpião foram submetidas a: Encubação endotraqueal e suporte respiratório, eletrocardiograma, radiografia de tórax, ecocardiograma e determinação sérica da norepinefrina e troponina I. As análises foram repetidas após 12, 24 e 48 horas. As seguintes medicações intravenosas foram administradas: dobutamina 4-6 μg/kg/min; amiodarona 3 mg/kg durante duas horas, com dose de manutenção de 5 mg/kg/dia; e furosemida 0,5 mg/kg. Amiodarona, dobutamina e furosemida foram administradas durante as primeiras 48 horas. Bloqueadores beta-adrenérgicos e inibidores da enzima conversora da angiotensina foram administrados até 48 após a internação, uma vez que o estado clínico havia melhorado e a fração de ejeção ventricular esquerda encontrava-se acima de 0,35%. RESULTADOS: Na admissão, a dosagem da norepinefrina foi 1.727,50± 794,96 pg/ml, a de troponina I 24,53 ± 14,09 ng/ml e a fração de ejeção do ventrículo esquerdo foi 0,20 ± 0,056. Após 12 horas, os níveis séricos de norepinefrina e de troponina I diminuíram para a metade dos valores iniciais e a fração de ejeção aumentou para 0,32 ± 0,059. Durante as 24 e 48 horas subseqüentes, a fração de ejeção elevou-se para 0,46 ± 0,045 (p<0,01) e a norepinefrina e de troponina I diminuíram para 526,75 ± 273,73 (p< 0,02) e 2,20 ± 2,36 (p<0,02) respectivamente. CONCLUSÃO: É bem provável que a amiodarona, ao agir como neuromodulador, seja responsável pela redução rápida e progressiva dos níveis séricos de norepinefrina.

Venenos de escorpião; norepinefrina; amiodarona; betaagonistas

FUNDAMENTO: Los niños con picaduras de escorpión sufren activación masiva del sistema nervioso simpático con varios grados de disfunción sistólica ventricular izquierda. OBJETIVO: Probar un protocolo de rescate en niños con disfunción ventricular severa izquierda ocasionada por picadura de escorpión. MÉTODOS: Cuatro niños tras un escorpión picarlas se sometieron a: incubación endotraqueal y soporte respiratorio, electrocardiograma, radiografía de tórax, ecocardiograma y determinación sérica de la norepinefrina y troponina I. Los análisis se repitieron tras 12, 24 y 48 horas. Las siguientes medicaciones intravenosas se administraron: dobutamina 4-6 mcg/kg/min; amiodarona 3 mg/kg durante dos horas, con dosis de mantenimiento de 5 mg/kg/día; y furosemida 0.5 mg/kg. Amiodarona, dobutamina y furosemida se administraron durante las primeras 48 horas. Bloqueante betaadrenergicos e inhibidores de la enzima convertidora de la angiotensina se administraron hasta 48 tras la internación, una vez que el estado clínico había mejorado y la fracción de eyección ventricular izquierda se hallaba superior a un 0,35%. RESULTADOS: Al ingreso, la dosificación de la norepinefrina fue 1727,50± 794,96 pg/ml, la de troponina I 24,53 ± 14,09 ng/ml y la fracción de eyección del ventrículo izquierdo fue 0,20 ± 0,056. Tras 12 horas, los niveles séricos de norepinefrina y de troponina I disminuyeron para la mitad de los valores iniciales y la fracción de eyección aumentó para 0,32 ± 0,059. Durante las 24 y 48 horas subsiguientes, la fracción de eyección se elevó para 0,46 ± 0,045 (p<0,01) y la norepinefrina y de troponina I se redujeron para 526,75 ± 273,73 (p< 0,02) y 2,20 ± 2,36 (p<0,02) respectivamente. CONCLUSIÓN: Es bien probable que la amiodarona, al actuar como neuromodulador, sea responsable de la reducción rápida y progresiva de los niveles séricos de norepinefrina.

Venenos de escorpión; norepinefrina; amiodarona; betaagonistas

ORIGINAL ARTICLE

^IInstituto de Investigaciones Cardiovasculares de la Universidad de los Andes

^IIHospital Universitario de los Andes

^IIIUniversidad de los Andes, Mérida - Venezuela

Mailing address

ABSTRACT

BACKGROUND: Children with scorpion envenomation have massive sympathetic activation and variable degrees of left ventricular systolic dysfunction.

OBJECTIVE: To evaluate a rescue protocol for children with severe left ventricular dysfunction secondary to scorpion envenomation.

METHODS: Four children, after scorpion envenomation, were subjected to a rescue protocol for acute left ventricular dysfunction: Endotracheal intubation and respiratory assistance, electrocardiograms, chest x-Ray, echocardiograms and blood samples for norepinephrine and troponin I serum levels. Samples and echocardiograms were repeated at 12, 24 and 48 hours. Intravenous medications: Dobutamine: 4-6 mcg/kg/min. Amiodarone: 3 mg/kg during a 2 hour period. Maintenance: 5 mg/kg/day. Furosemide: 0.5 mg/kg/dose. Diuretics were given when the systemic blood pressure was above percentile fifty. Amiodarone, Dobutamine and Furosemide were administered during the first 48 hours. Beta-adrenergic blockers and angiotensin converting enzyme were given, at 48 hours after admission, once the left ventricular Ejection fraction > 0.35 and the clinical status had improved.

RESULTS: On admission, norepinephrine was 1727.50 ± 794.96 pg/ml, troponin I 24.53 ± 14.09 ng/ml and left ventricular ejection fraction 0.20 ± 0,056. At twelve hours, norepinephrine and troponin I serum levels were down to half of the initial values and the ejection fraction increased to 0.32 ± 0.059. During the next 24 and 48 hours, the ejection fraction rose to 0.46 ± 0.045, (p<0.01) and norepinephrine and troponin diminished to 526.75 ± 273.73 (p < 0.02) and 2.20 < 2.36 (p<0.02) respectively.

CONCLUSION: : Amiodarone, by acting as a neuromodulator, is very likely responsible for the early and progressive decrease of serum norepinephrine.

Key Words: Scorpion venoms; norepinephrine; amiodarone; adrenergic beta-agonists.

Introduction

In Mérida-Venezuela, we have identified distinct geographical areas in which scorpion envenomation is potentially lethal^1,2. Our initial findings indicated that the clinical manifestations were predominantly cardiovascular (i.e. pulmonary edema and cardiogenic shock). In a second clinical investigation, we performed two-dimensional echocardiograms and measured norepinephrine serum levels, to simultaneously assess cardiac function and sympathetic activation³. Our results demonstrated that, in children with scorpion envenomation, pulmonary edema and cardiogenic shock were accompanied by massive sympathetic activation and variable degrees of reversible left ventricular systolic dysfunction.

The mechanisms by which scorpion envenomation causes myocardial damage and systolic dysfunction are still the subject of intense controversy^4-9. Sympathetic nervous system activation^9,10 and direct effects of the venom on the myocardium^11-12 are thought to be responsible for myocardial damage and systolic dysfunction. Histopathological findings in fatal human scorpion envenomation have shown unequivocal evidence of coagulative myocytolysis^5,7,13. These lesions, known as myocardial contraction bands, are considered the hallmark of catecholamine cardiotoxicity¹⁴. Moreover, cardiac troponin, a biological marker of myocardial necrosis, increases from admission to 24-36 hours after the sting^15,16.

Children with pulmonary edema and cardiogenic shock secondary to scorpion envenomation are usually in critical conditions and hemodynamically unstable^4,17. Medical management is aimed at providing cardiorespiratory assistance to improve tissue perfusion and oxygenation¹⁸. Ideally, cardioprotection from catecholamine cardiotoxicity should be based on beta-adrenergic antagonists^19,20. However, the presence of acutely depressed left ventricular systolic function precludes the administration of these extremely useful drugs^3,17,21,22. Therefore, we have used the sympatholytic actions of intravenous and oral amiodarone as a rescue therapy for children with severe left ventricular dysfunction secondary to scorpion envenomation²³.

Methods

Children referred to the Pediatric Emergency of the Hospital Universitario de Los Andes, between November 2003 and November 2004, with clinical diagnosis of scorpion envenomation and who were in pulmonary edema or cardiogenic shock were managed according to the following rescue protocol for severe left ventricular systolic dysfunction. On admission and after informed consent was obtained from the child´s parent, all patients were assessed by the same physicians and found to be hemodynamically unstable. Endotracheal intubation and respiratory support were instituted when necessary. They all were subjected to the following noninvasive tests: electrocardiograms, chest x-Ray, two-dimensional echocardiograms and blood tests. The latter included special samples for norepinephrine determination by high-pressure liquid chromatography¹⁹ and troponin I by enzyme immunoassay (Immulite Automated Analyser, USA). Normal values for troponin I with this method are <1 ng/ml. Blood samples and two-dimensional echocardiograms were repeated at 12, 24 and 48 hours after admission and analyzed in a blind manner. The investigator responsible for this part of the protocol had no knowledge of the clinical status of the patient. This protocol was approved by the Human Research Committee of the Instituto de Investigaciones Cardiovasculares de la Universidad de Los Andes.

Based on the clinical and echocardiographic findings of shock and severely depressed left ventricular systolic function (Table 1: Ejection fraction 0.20 ± 0.056), the following rescue protocol was performed:

Thumbnail

1) Intravenous Dobutamine: 4-6 mcg/kg/min.

2) Intravenous Amiodarone: 3 mg/kg to be administered in a 2 hour period. Maintenance. 5 mg/Kg/day²⁴

3) Furosemide: 0.5 mg/kg/dose.

4) Digitalis: 10 mcg/kg/day

Diuretics were given when systemic blood pressure was above the 50^th percentile²⁵. Amiodarone, dobutamine and furosemide were administered during the first 48 hours. Beta-adrenergic blockers (carvedilol: 0.04 mg/kg/dose, at a 12-hour interval) and angiotensin converting enzyme (captopril: 0.01 mg/kg/dose at an 8-hour interval)²⁶ were given up to 48 hours after admission, since left ventricular function (ejection fraction > 0.35) and clinical status had improved. Simultaneously, dobutamine, amiodarone and furosemide were progressively down titrated and discontinued.

Results are expressed as mean ± SD. Statistical analyses of echocardiographic, neurohormonal and biochemical findings were performed by repeated-measures analysis of variance, linear regression, and correlation analysis. Statistical significance was set at p < 0.05.

Results

Four children with scorpion envenomation were referred to the emergency department of the Hospital Universitario de Los Andes in Mérida, Venezuela. They came from rural areas of southwestern Venezuela and had received antivenin at the site of the accident (Antiscorpion serum, Centro de Biotecnología, Universidad Central, Caracas, Venezuela).

Clinical, epidemiologic, electrocardiographic and echocardiographic characteristics

As can be seen in table 1, two patients were male and two female. Ages ranged from 3 to 14 years. The time interval between the accident and antivenin administration was 7.0 ± 4.54 hours. Heart and respiratory rates were markedly increased, and systemic blood pressure was below the third percentile. The electrocardiogram was abnormal in all four patients (Figure 1), and the ejection fraction was severely depressed (0.20 ± 0.056).

Echocardiographic, neurohormonal and biochemical changes during the administration of the rescue protocol for left ventricular systolic dysfunction

On admission, serum norepinephrine (1727.50 ± 794.96 ng/ml) and troponin I (24.53 ± 14.09) were markedly elevated and left ventricular ejection fraction was severely depressed (0.20 ± 0.056) (Table 2, Figure 1A). Twelve hours after initiation of the rescue protocol, mean norepinephrine (p < 0.02) and troponin I serum levels were down to half of baseline values and the ejection fraction had increased from 0.20 ± 0.056 to 0,32 ± 0,059. During the next 48 hours, the ejection fraction returned to values close to normal (0.46 ± 0.045, p < 0.01) and biochemical markers of sympathetic activation (p < 0.02) and myocardial necrosis (p < 0.002) were also significantly diminished (Table 2).

Thumbnail

Figure 2 illustrates the dramatic improvement in septal wall motion and left ventricular function. Norepinephrine (r = - 0.76, p < 0.004) and troponin I ( r = - 0.60, p < 0.01) serum levels correlated inversely and significantly with ejection fraction. On the contrary, norepinephrine and troponin T correlated directly and significantly with one another (r = 0.60, p< 0.01) (Figure 3).

Discussion

Acutely depressed left ventricular function has been consistently demonstrated by two-dimensional echocardiograms and hemodynamic measurements in children with scorpion envonomation^17,4. Although histopathological and biochemical studies have documented the presence of cathecolamine cardiotoxicity^4,14,6 and myocardial necrosis^5,7, current clinical management of the cardiovascular manifestations of scorpion envenomation is mainly based on mechanical ventilation and positive inotropic support^17,18. Moreover, clinical and experimental studies clearly indicated that beta-adrenergic agonists drugs might enhance the deleterious effects of massive sympathetic activation on the myocardium^27,28.

Children with acute left ventricular systolic dysfunction secondary to scorpion envenomation clearly need the positive inotropic support provided by endogenous catecholamines and exogenous beta-adrenergic agonists¹⁸. In an attempt to modulate the massive sympathetic activation caused by scorpion envenomation and minimize the need for positive inotropic support with beta-adrenergic agonists, we have followed an antiadrenergic rescue protocol for acutely depressed left ventricular systolic function. This rescue protocol is based on the favorable effects of intravenous amiodarone on critically ill children²³. Intravenus administration of amiodarone has acute sympatholytic and vagotonic actions²⁹. Furthermore, amiodarone selectively decreases sympathetic efferent traffic to the heart and improves left ventricular function^30-33.

Upon admission, our patients with acutely depressed left ventricular function had biochemical evidence of massive sympathetic activation and of myocardial necrosis. Norepinephrine and troponin I serum levels were markedly elevated. Serial echocardiograms and determinations of troponin I and of norepinephrine showed a dramatic improvement in left ventricular function and a decrease in the extent of sympathetic activation and of myocardial necrosis, within twelve hours of having initiated the antiadrenergic rescue protocol for left ventricular systolic dysfunction. During this period, patients received diuretics, beta-adrenergic agonists and amiodarone. The former two drugs are known to increase sympathetic activation and mortality in the presence of left ventricular dysfunction^34,35, whereas amiodarone has opposite effects on sympathetic activation and mortality^22,36. Therefore, the very favorable effects of our antiadrenergic rescue protocol are very likely secondary to the sympatholytic and vagotonic actions of amiodarone^29-31.

Norepinephrine serum levels directly correlated with troponin I and inversely with the left ventricular ejection fraction

A possible explanation for these findings is provided by a recent clinical study, which simultaneously assessed myocardial perfusion, left ventricular function and regional wall motion⁶. Reversible myocardial perfusion defects were topographically associated with regional wall motion abnormalities (RWMA). Furthermore, improvement in left ventricular function and RWMA paralleled normalization of myocardial perfusion. In other words, norepinephrine, through its direct effects on the myocardium (i.e. necrosis) and on coronary microcirculation (i.e. vasospasm) is very likely responsible for both myocardial necrosis and left ventricular systolic dysfunction.

Conclusion

Although patients had received antivenin at the site of the accident³⁷, the time interval between the accident and antivenin administration was outside the optimal time window for its beneficial effects¹. This probably explains the progression of the envenomation to the stage of pulmonary edema and shock². We should emphasize that our report is an open and non-randomized study based on a small number of cases. Our encouraging findings provide a therapeutic alternative to a potentially harmful strategy based on high doses and long-term administration of beta-adrenergic agonists. A prospective and randomized rescue protocol, based on the neuromodulatory effects of amiodarone, should be performed.

References

1. Mazzei C, Fuenmayor A, Salgar N, Gonzales Z, Dávila D. Scorpion envenomation in Mérida, Venezuela. Toxicon. 1997; 35: 1459-62.
2. Mazzei C, Dávila D, Gonzales M, Dávila D, Pamoni P. Identificación de especies de escorpiones en el Estado Mérida. [Tesis]. Venezuela: Colegio San Luis de Mérida, Venezuela: 1999.
3. Mazzei de D'Avila CA, D'Avila DF, Donis JH, Bellabarba GA, Villarreal V, Barboza JS. Sympathetic nervous system activation, antivenin administration and cardiovascular manifestations of scorpion envenomation. Toxicon. 2002; 40: 1339-46.
4. Bahloul M, Kallel H, Rekik N, Ben Hamida C, Chelly H, Bouaziz M. Cardiovascular dysfunction following scorpion envenomation: mechanisms and pathophysiology. Press Med. 2005; 34 (2pt1): 115-20.
5. Cupo P, Jurca M, Acedo M, Oliveira J, Hering S. Severe scorpion envenomation in Brazil. Clinical laboratory and anatomopathological aspects. Rev Inst Med Trop Sao Paulo. 1994; 36: 67-76.
6. Cupo P, Figuereido AB, Filho AP, Pintya A,Tavares Jr. G, Caligaris F, et al. Acute lef ventricular dysfunction of severe scorpion envenomation is related to myocardial perfusion disturbance. Int J Cardiol. 2007; 116 (1): 98-106.
7. Daisley H, Alexander D, Pitt P. Acute myocarditis following Tityus trinitatus envenoming: morphological and pathophysiological characteristics. Toxicon. 1999; 37: 159-65.
8. Gueron M, Ilia R, Margulis G. Athropods poisons and the cardiovascular system. Am J Emerg Med. 2000; 18: 708-14.
9. Ismail M. The scorpion envenomin syndrome. Toxicon. 1995; 33: 825-58.
10. Nouira S, Elatrous S, Besbes S, Boukef F, Devaux C, Aubrey N, et al. Neurohormonal activation in severe scorpion envenomation: correlation with hemodynamics and circulating toxin. Toxicol Appl Pharmacol. 2005; 208: 111-6.
11. Ouanes-Besbes L, El Atrous S, Nouira S, Aubrey N, Carayon A, El Ayeb M, et al. Direct vs. mediated effects of scorpion venom: an experimental study of the effects of a second challenge with scorpion venom. Intensive Care Med. 2005; 31: 441-6.
12. Texeira A, Fontoura B, Freire L, Machado C, Camargo E, Texeira M. Evidence for a direct action of Tityus serrulatus scorpion on the cardiac muscle. Toxicon. 2001; 39: 703-9.
13. Benvenuti L, Douetts K, Cardoso J. Myocardial necrosis after envenomation by the scorpion Tityus serrulatus. Trans R Soc Trop Med Hyg. 2002; 96: 275-6.
14. Baroldi G, Mittleman R, Parolini M, Silver M, Fineschi V. Myocardial contraction bands: definitions, quantification and significance in forensic pathology. Int J Legal Med. 2001; 115: 142-51.
15. Cupo P, Hering S. Cardiac troponin I release after severe scorpion envenoming by Tityus serrrulatus. Toxicon. 2002; 40: 823-30.
16. Meki A, Mohamed Z, Mohey H. Significance of assessment of serum cardiac troponin I and interleukin-8 in scorpion envenomed children. Toxicon. 2003; 41: 129-37.
17. Abroug F, Boujdaria R, Belghlith M, Nouira S, Bouchoucha S. Cardiac dysfunction and pulmonary edema following scorpion envenomation. Chest. 1991; 100: 1057-9.
18. Elatrous S, Nouira S, Besbes L, Boussarsar M. Boukef R, Marghli, et al. Dobutamine in severe scorpion envenomation: effects on standard hemodynamics, right ventricular performance, and tissue oxygenation. Chest. 1999; 116: 748-53.
19. Mann D, Kent R, Parsons B, Cooper G. Adrenergic effects on the biology of the human cardiac myocyte. Circulation. 1992; 85: 790-804.
20. Mann D. Basic mechanisms of disease progression in the failing heart: the role of excessive adrenergic drive. Prog Cardiovasc Dis. 1998; 41 (1Suppl 1): 1-8.
21. Simoes M, Maciel B, Marin J. Reversible segmental left ventricular dysfunction caused by accidental administration of sympathomimetic drug in human. Int J Cardiol. 1997; 61: 93-6.
22. Choo D, Huiskes B, Jones J, Fabbri S, Hawkins L, Chatterjee, et al. Amiodarone rescue therapy for severe descompensated heart failure initially unsuitable for beta-blockers. J Cardiovasc Pharmacol Ther. 2003; 8: 187-92.
23. Perry JC, Fenrich AL, Hulse JE, Triedman JK, Friedman RA, Lamberti JJ. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. J Am Coll Cardiol. 1996; 27: 1246-50.
24. Vogel M. Echocardiographic analysis of regional left ventricular wall motion in normal children and neonates. J Am Coll Cardiol. 1990; 15: 1409-12.
25. Karnard D, Deo A, Apte N, Lohe A, Thatte S, Tilve JH. Captopril for correcting diuretic induced hypotension in pulmonary edema after scorpion sting. Br Med J. 1985; 298: 1430-1.
26. Dávila D, Bellabarba G, Hernandez L, Calmon G, Torres A, Barboza J, et al. Plasma norepinephrine, myocardial damage and left ventricular systolic function in Chagas´ heart disease. Int J Cardiol. 1995; 52: 145-51.
27. Mendez-Castellano H, Macias-Tome C. Fundacredesa: Fundación para el Estudio de crecimiento y desarrollo del venezolano. Proyecto Venezuela, Caracas; 1993.
28. Movahed A, Reeves WC, Mehta PM, Gilliland MG, Mozingo SL, Jolly SR. Norepinephrine-induced left ventricular dysfunction in anesthetized and conscious, sedated dogs. Int J Cardiol. 1994; 45: 23-33.
29. Dias V, Ginecchi T, Lavelli B, Bellina V, Manzella D, Porta A, et al. Opposite effects of iv amiodarone on cardiovascular vagal and sympathetic efferent activities in rats. Am J Physiol Regul Integr Comp. 2002; 283: R543-R548.
30. Davila DF, Donis JH, Bellabarba G, Torres A, Casado J, Mazzei de Davila C. Cardiac afferents and neurohormonal activation in congestive heart failure. Med Hypotheses. 2000; 54: 242-53.
31. Davila DF, Nuñez T, Odreman R, Mazzei de Davila C. Mechanisms of neurohormonal activation in chronic congestive heart failure: pathophysiology and therapeutic implications. Int J Cardiol. 2005; 101: 343-6.
32. Du XJ, Esler M, Dart A. Sympatholytic actions of intravenous amiodarone in the rat heart. Circulation. 1995; 91: 462-70.
33. Kaye D, Darta A, Jennings D, Esler M. Antiadrenergic effects of chronic amiodarone therapy in human heart failure. J Am Coll Cardiol. 1990; 15: 1409-12.
34. Abrahm W, Adams K, Fonarow G, Contanzo M, Berowitz R, Lejemtel T, et al. ADHERE Scientific Advisory Committee and Investiators; ADHERE Sstudy Group. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005; 46: 57-64.
35. Francis G, Siegel R, Goldsmith S, Olivari M, Levine T, Cohn J. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure: activation of the neurohumoral axis. Ann Intern Med. 1985; 103: 1-6.
36. Dorian P, Cass D, Schwartz B, Cooper R, Gelasnikas R. Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Eng J Med. 2002; 346: 884-90.
37. Ismail, M. The scorpion envenoming syndrome: the saudi experience with serotherapy. Toxicon. 1994; 32:1019-26.