Comprehensive Review of the Mechanistic Approach and Related Therapies to Cardiovascular Effects of Aluminum Phosphide

INTRODUCTION

Aluminum Phosphide (AlP) is used as a fumigant insecticide and rodenticide in protection of grains during the storage and transportation process (Mehrpour and Singh, 2010). This agent is widely used in developing countries for several reasons such as being highly potent and cost benefit, having no effect on seed viability and leaving little residue on food grains (Bumbrah et al., 2012; Mostafalou et al., 2013; Birnbaum et al., 1997). Poisoning with this compound can occur through ingestion of salts or inhalation of phosphine gas. Phosphine is generated from AlP after exposure to the water or an acidic media such as the acidic contents of the stomach (Proudfoot, 2009). Due to lack of a specific antidote, the mortality rate is more than 70% of the intoxicated cases (Anand et al., 2011; Singh et al., 1989; Singh et al., 1991). Typical features of AlP poisoning are gastrointestinal disorders, refractory hypotension and cardiogenic shock (Mehrpour et al., 2012). Left ventricle and septum hypokinesia, ejection fractions reduction (Bhasin et al., 1991), raised systemic venous pressure, normal pulmonary artery wedge pressure, inadequate systemic vasoconstriction and electrocardiographic (ECG) abnormalities (Kalra et al., 1991; Hosseinian et al., 2011) are cardiovascular features of phosphine poisoning. This agent can cause a multi organ failure such as heart failure that is the main cause of death within 12-24 h after acute exposure (Chugh et al., 1991; Bogle et al., 2006; Mostafazadeh and Farzaneh, 2012; Moghadamnia, 2012; Singh et al., 1991). Thus, it is essential to focus on cardiovascular complications of phosphine poisoning to find an effective and appropriate therapeutic strategy because if cardiac dysfunction and arrhythmias improve, most likely the patients will survive from acute phosphine poisoning through supportive cares. In this study we reviewed all the studies related to cardiovascular toxicity of AlP. Since the exact underlying mechanism of cardiotoxicity and peripheral circulatory failure caused by phosphine is still unknown, this study can reveal the direction of future studies.

METHOD

The keywords “aluminum phosphide”, “phosphine”, “heart failure”, “cardiovascular toxicity”, “cardiac dysfunction”, arrhythmias” and “hypotension” were searched in bibliographic databases including PubMed, Web of Science, Google Scholar and Scopus between years 1980 and 2014. The title and abstracts of all paper were scrutinized and read initially and those that obviously did not meet inclusion criteria were excluded.

RESULTS AND DISCUSSION

Electrocardiography findings and refractory hypotension: AlP poisoning is known to be associated with various ECG abnormalities, ranging from acute myocardial infarction, to atrial fibrillation, premature supraventricular or ventricular contractions, ST segment elevation/depression, bundle branch blocks, PR and QRS interval prolongation and sinoatrial block (Udriste et al., 2013; Khosla et al., 1988; Gurjar et al., 2011; Moghadamnia, 2012). The incidence of ECG and ECG abnormalities reported in various studies are 45% (Shadnia et al., 2010; Soltaninejad et al., 2012), 65% (Shadnia et al., 2009), 80% (Gupta et al., 1995) and 50% (Chugh et al., 1991) in phosphine poisoned patients that summarized in the Table 1. ECG changes are mostly non-specific indicator for phosphide poisoning (Chugh et al., 1991; Anand et al., 2011) but evaluations of ECG parameters can predict the severity and usefulness of therapeutic strategies in the poisoned patients. Soltaninejad et al. (2012) found that there was a significant correlation between ECG abnormalities and mortality and subsequently, anti-arrhythmic agents can be used as prophylactic treatment in acute AlP intoxication. In the survey by Shadnia et al. (2009, 2010) the ECG abnormalities were observed in 65.6% of cases who did not survive and most of them had ST segment depression and sinus tachycardia and there was a significant difference between survival and non-survival cases according to ECG abnormality. On the other hand, Chugh et al. (1991) reported no relationship between the ECG abnormalities and mortality. In another study, the ECG abnormalities were noted in 28 cases (58.7%) at the time of admission and was considered as prognostic factor along with other factors such as shock, low Glasgow coma scale for AlP poisoning (Louriz et al., 2009). In Kaushik’s case report, ECG abnormalities along with T-wave abnormalities were observed which is attributed to subendocardial infarction rather than toxic myocarditis alone, because subendocardium which is the well-perfused zone of myocardium, is most vulnerable to any reduction in coronary flow and cellular hypoxia (Kaushik et al., 2007). In another case report, broad QRS complex, ST-T changes along with raised CK-mb were observed which indicates severe myocardial injury (Shah et al., 2009). In three other cases, Brugada type pattern in combination with various ECG abnormalities were observed in AlP poisoning (Mahajan et al., 2012; Udriste et al., 2013; Nayyar and Nair, 2009). Brugada syndrome is a disorder presenting with ST segment elevation, right bundle branch block, susceptibility to ventricular tachycardia and structurally normal heart (Mahajan et al., 2012). It is most probably due to hypomagnesaemia caused by direct toxic effect of phosphine on cardiac tissue (Mahajan et al., 2012). Khosla et al. (1988) reported that ECG abnormalities were detected in 6 of their 11 patients and there was metabolic acidosis in all 6. ECG changes completely associate with acid-base disturbances.

Table 1:	Cardiac electrophysiology disorders and evidences of hypotension in associated with AlP poisoning

BP: Blood pressure, SBP: Systolic blood pressure (mmHg), DBP: Diastolic blood pressure (mmHg), BBB: Bundle branch block, LVEF: Left ventricle ejection fraction

Metabolic acidosis which is probably caused by blockage of oxidative phosphorylation and cellular hypoxia (Mehrpour et al., 2008), should be treated by administering sodium bicarbonate (Bumbrah et al., 2012; Gurjar et al., 2011; Mehrpour et al., 2008).

Refractory hypotension and shock which have been increasingly seen, are other fatal cardiovascular complications following acute AlP poisoning (Khosla et al., 1988). Death after 24 h occurs usually owing to shock, cardiac dysrhythmia, metabolic acidosis and acute respiratory distress syndrome (Moghadamnia, 2012). Non-survivors have more refractory hypotension and acidosis than the survivors (Moghadamnia, 2012). The exact mechanism of refractory hypotension and intractable shock is not clear; however, they possibly occur due to arrhythmia, conduction disturbance and myocardial damage and myocardial depression. Moreover, the peripheral circulatory failure owing to capillary dysfunction or widespread small vessel damage can lead to peripheral vasodilatation, resulting in refractory hypotension and shock (Anand et al., 2011). Refractory hypotension and shock are usually unresponsive to conventional treatment; however, managing AlP poisoning, especially resuscitation of shock and institution of supportive measures should be started as soon as the patient’s arrival. All acute AlP poisoned patients require continuous invasive hemodynamic monitoring and early resuscitation with fluid and vasoactive agents. Norepinephrine or phenylephrine, dopamine, dobutamine and anti-arrhythmic agents can be used to treat refractory hypotension and shock.

Several studies which have been published about the beneficial effect of magnesium, show that treatment of hypomagnesaemia by magnesium sulphate can decrease AlP cardiac toxicity (Katira et al., 1990; Gupta and Ahlawat, 1995; Chugh et al., 1994b) and reduce the mortality rate from 90-50% of poisoned patients (Jadhav et al., 2012; Anand et al., 2011; Chugh et al., 1994a; Chugh et al., 1997; Singh et al., 1990; Siwach et al., 1994). Baeeri et al. (2013) reported that ²⁵Mg²⁺-carrying nanoparticle significantly elevates blood pressure and heart rate of rats poisoned with AlP (Baeeri et al., 2013). There is only one study in 1994 that claimed supplemental magnesium cannot improve the survival rate of AlP poisoned patients (Siwach et al., 1994). Also, Jadhav et al. (2012) reported that in addition to magnesium sulfate and electrocardioversion, amiodarone has beneficial role in treatment of ventricular tachycardia caused by AlP poisoning (Jadhav et al., 2012). In another study, Mehrpour et al. reported that digoxin by elevation of myocardial contractility and blood pressure is useful in management of cardiogenic shock (Mehrpour et al., 2011, 2012). Although the use of digoxin does not seem to be logical, it can be considered as an alternative treatment of the cardiogenic shock induced by AlP poisoning. Another approach in management of acute AlP poisoning is administration of high doses of glucagon (Arefi and Tabrizchi, 2012; Torabi, 2013). Glucagon is usually used as cardiac inotropic agent in the treatment of shock caused by beta-blockers and calcium channel blockers poisoning (Arefi and Tabrizchi, 2012). Inotropic action of glucagon is mediated by elevation of intracellular cAMP and calcium (Arefi and Tabrizchi, 2012). At the end, there is an interesting study about the beneficial effect of Intra-aortic Balloon Pump (IABP) as a cardiocirculatory assist device for treatment of cardiogenic shock following AlP poisoning (Siddaiah et al., 2009). IABP can mechanically support the heart, decrease the afterload and improve perfusion to the vital organs and coronary arteries (Siddaiah et al., 2009; Elabbassi et al., 2013; David et al., 2000). Intravascular hydroxyethyl starch solution (a colloid volume expander) is another route for treatment of severe hypotension that decrease the extravascular leakage of albumin and fluids (Marashi et al., 2011).

Possible mechanisms of cardiotoxicity: The exact mechanism of toxicity of phosphine remains still unclear. It seems that main part of its toxicity is done through non-specific mechanisms due to the small size of the phosphine molecule (Nath et al., 2011). However, several mechanisms have been proposed for phosphine toxicity which is discussed in below.

Mitochondrial disorders and energy depletion: As previously mentioned, one of the main target organs of phosphine is heart. The heart needs large amounts of energy to maintain its contractile performance. Adenosine Triphosphate (ATP) works as immediate source of energy, however intracellular ATP is limited. Phosphine has been reported to decrease cardiac energy reserves such as ATP (Anand et al., 2011; Baeeri et al., 2013). Phosphine can cause myocardial energy depletion due to changes in mitochondrial morphology (Anand, 2009; Bumbrah et al., 2012). Ultrastructural changes which were observed in the heart and other tissues, showed mitochondrial injury (Anand et al., 2011), including dysmorphic and swollen mitochondria with enlarged and disrupted cristae (Anand et al., 2011; Bumbrah et al., 2012; Proudfoot, 2009). In view of the fact that oxidative phosphorylation is strictly dependent on the structure and integrity of the inner mitochondrial membrane, even if the activity of mitochondrial complexes is not inhibited directly following phosphine exposure, it can be affected by changes in mitochondrial morphology (Proudfoot, 2009). Numerous studies demonstrated that phosphine can cause myocardial energy depletion due to inhibition of activity of cytochrome c oxidase as an enzyme of the Electron Transport Chain (ETC) (Singh et al., 2006; Bumbrah et al., 2012; Gurjar et al., 2011). Phosphine disturbs the mitochondrial morphology, inhibits complexes I, II, IV of the mitochondrial ETC and reduces the oxidative respiration by 70% leading to severe drop in the mitochondrial membrane potential (Proudfoot, 2009; Bumbrah et al., 2012). Some other agents which are known to protect mitochondrial oxidative phosphorylation such as hydroxycobalamine (Jones, 2008), mitoQ (Tauskela, 2007; Smith and Murphy, 2010) and vitamin C should also be tried (Singh, 1989).

Oxidative stress: Like other kinds of pesticides (Mostafalou et al., 2013; Mostafazadeh and Farzaneh, 2012), there is strong evidence that oxidative stress can be induced by phosphine and the heart is not secure from damaging effects of these reactive radicals that increased through reduction of glutathione level (Chugh et al., 1995; Mehrpour et al., 2012; Kariman et al., 2012). Phosphine induces the production of free radicals not only through inhibition of the antioxidant enzymes (catalase and peroxidase) and reduction of glutathione level, but also via disruption of oxidative phosphorylation (Nath et al., 2011; Anand et al., 2011; Mehrpour et al., 2012). Oxidative stress and especially mitochondrial cytochrome C oxidase inhibition can lead to morphological and functional disorder of heart. The membrane action potential damage caused by AlP is due to lipid peroxidation of cell membrane (Mehrpour et al., 2012) and it seems that probable mechanism of magnesium in improvement of arrhythmias is to stabilize the membrane action potential (Katira et al., 1990; Chugh et al., 1997). Based on these studies, oxidative stress and lipid peroxidation can be considered as a main cause of myocardial injury due to AlP poisoning. There are several studies focused on these pathways for planning new therapeutic strategies; N-acetyl cysteine as an antioxidant and cytoprotective agent (Azad et al., 2001; Hsu et al., 2002) can reduce myocardial oxidative injury and increase survival time (Bogle et al., 2006). Other options for the management of cardiac complication of AlP are antiischemic drugs such as trimetazidine. These agents have protective effects on myocardium through decreasing the production of oxygen-derived free radicals and stimulating the oxidative metabolism of glucose (Moghadamnia, 2012; Duenas et al., 1999). Magnesium nanoparticle in addition to treatment of hypotension and cardiac shock can elevate the intracardiac magnesium levels, reduce lipid peroxidation and improve mitochondrial function (Baeeri et al., 2013).

Histopathological and biochemical changes: Mild to severe myocyte vacuolation, areas of myocytolysis and degeneration were specially revealed in the left ventricle and interventricular septum following AlP poisoning which are all indicative of myocardial injury (Shah et al., 2009). Other histopathological findings showed varying degrees of congestion in the heart and other organs, similar to those produced by hypoxic injury (Louriz et al., 2009; Bumbrah et al., 2012) and myocardial necrosis (Khosla et al., 1988; Abder-Rahman, 2009). There were some reports regarding inhalation of phosphine gas and cardiovascular findings varying from congestion, focal myocardial infiltration, to small-vessel injury (Chugh et al., 1991; Wilson et al., 1980; Abder-Rahman, 2009). In a study by Abder-Rahman (2009) autopsy findings revealed subendocardial flame hemorrhages in the heart of two sisters and minimal neutrophil inflammatory in the cardiac muscle of the 6-year-old child. Anand et al. (2012) reported myocyte swelling, disarray and interstitial edema in cardiac tissue using electron microscopy and they thought tissue histology findings are non-specific. In Rahbar Taromsari’s study, histopathological findings in myocardium showed congestion (86%), necrosis (7%) and leukocyte infiltration (7%) (Taromsari et al., 2011). Jadhav et al. (2012) disclosed contraction band necrosis, edema, hemorrhage and pyknosis of cardiac myocyte nuclei in the postmortem histological examination of myocardium. It seems there is a direct correlation between heart tissue injury and cellular hypoxia-induced mitochondrial dysfunction. Biochemical findings also confirm myocardial injury following AlP poisoning. Creatine phosphokinase (CPK), CPK-myocardial band (CPK-mb) and troponin-T (TnT) are considered as biochemical markers of cardiac muscle injury (Soltaninejad et al., 2012). Elevation of serum levels of CPK-mb and LDH by many folds has been seen in AlP poisoning and indicates myocardial damage (Anand et al., 2012; Shah et al., 2009; Wilson et al., 1980). However, Duenas et al. (1999) reported that CPK levels were elevated without any changes in CPK-mb fraction. Soltaninejad et al. (2012) revealed that the serum cardiac TnT has a positive relationship to the mortality but increase in CPK or the CPK to CPK-mb ratio does not have such relationship (Soltaninejad et al., 2012). In another case reported by Nayyar and Nair (2009) TnT and CPK levels were normal at admission. Changing in CPK, CPK-mb, TnT levels as a clinical and laboratory indicator of cardiac muscle injury is sometimes observed, but reports are controversial.


Fig. 1:	Cardiotoxicity mechanisms involved in phosphine poisoning and its possible treatment strategies

Because in some case reports which were reported by Nayyar and Nair (2009) Bogle et al. (2006) serum levels of these markers were in normal range following acute AlP poisoning (Bogle et al., 2006; Nayyar and Nair, 2009) but in other reports, their levels were elevated, indicating myocardial damage (Kaushik et al., 2007; Shah et al., 2009; Akkaoui et al., 2007; Singh et al., 2011). On the other hand, some researchers did not discover any evidence about myocardial damage on autopsy in any of their patients (Khosla et al., 1988; Singh, 1989). Thus, it is concluded that elevated levels of these enzymes confirm myocardial injury but their normal levels cannot disprove phosphine cardiotoxicity.

CONCLUSION

Taking collectively, AlP is used as insecticide and rodenticide and is very common in suicide attempts. The heart is the predominantly affected organ and the most of the poisoned patients die due to cardiovascular complications (Bumbrah et al., 2012). Clinical manifestation of cardiac failure varies depending on the dosage and duration of consumption and include peripheral circulatory failure and hypotension (Alter et al., 2001; Bayazit et al., 2000; Ragone et al., 2002), congestion of the heart, separation of myocardial fibres by edema, fragmentation of fibres, non-specifc vacuolation of myocytes, focal necrosis, neutrophil and eosinophil infiltration (Katira et al., 1990; Sinha et al., 2005). The ECG changes have been studied in several studies and include atrial fibrillation, tachycardia, QRS complex and ST-T changes and bundle branch blocks. Although the exact underlying mechanism of cardiotoxicity and peripheral circulatory failure caused by phosphine is still unknown, the possible mechanisms are discussed in this article and summarized in Fig. 1. It seems that the main effect of this poison is disruption of cellular oxygen utilization and hypoxia through refractory hypotension and respiratory system insufficiency. This hypoxia can cause irreparable damages on mitochondria as the main site of oxygen consumption. Therefore, the first priority in treatment of phosphine poisoning is correction of hypotension and improvement of tissue oxygen levels through ventilation support and oxygenation. Extracorporal Membrane Oxygenation (ECMO) is a novel technique for supplying oxygen and it may have a beneficial role in management of AlP poisoning (Elabbassi et al., 2013). On the other hand, direct effects of phosphine on cardiac tissue mediated through inhibition of mitochondrial toxins, induction of oxidative damage and reduction of energy production should be discussed further in the future studies. Focus on the inhibition of oxidative stress and mitochondrial injuries along with the remediation of refractory hypotension can be a useful therapeutic strategy in treatment of AlP poisoned patient.

ACKNOWLEDGMENT

This invited study is the outcome of an in-house financially non-supported study. Authors thank Tehran University of Medical Sciences, National Elite Foundation, Iran National Science Foundation. Authors have no conflict of interest.