By Bar-Meir, Eran; Schein, Ophir; Eisenkraft, Arik; Rubinshtein, Ronen; Et al
Organophosphate poisoning may precipitate complex ventricular arrhythmias, a frequently overlooked and potentially lethal aspect of this condition. Acute effects consist of electrocardiographic ST- T segment changes and AV conduction disturbances of varying degrees, while long-lasting cardiac changes include QT prolongation, polymorphic tachycardia (“Torsades de Pointes”), and sudden cardiac death. Cardiac monitoring of Organophosphate intoxicated patients for relatively long periods after the poisoning and early aggressive treatment of arrhythmias may be the clue to better survival. We present here a review of the literature with a focus on late cardiac arrhythmias (mainly “Torsades de pointes”), possible mechanisms, and treatment modalities, with special emphasis on postpoisoning monitoring for development of arrhythmias.
Keywords Arrhythmia, Insecticides, Medical Treatment, Organophosphorous Compounds, Torsades De Pointes
INTRODUCTION
Organophosphates (OP) may be divided into two major groups: agricultural pesticides and chemical warfare agents (CWA). The wide use of OPs as agricultural pesticides increases the likelihood of poisoning with these compounds. Indeed, 25 million episodes of pesticide poisoning are reported annually.14,15 During the last decade of the 20th century, the annual estimate was 3 million severe poisonings, out of which 2 millions were suicide attempts and 1 million due to accidental exposures. 200,000 of these cases ended in death, mostly in developing countries.32,40 The threat of exposure to CWA has been traditionally considered a military issue. Several recent events, however, have demonstrated that civilians may also be exposed to these agents.29,37
Cardiac complications often accompany poisoning with these compounds, which may be serious and often fatal. These complications are potentially preventable if they are recognized early and treated adequately. The current knowledge of OPs cardiac effects largely consists of limited publications, studies and case reports.33 Therefore many physicians may not be fully aware of these complications.
NONCARDIAC CLINICAL PRESENTATION OF OP POISONING
The clinical presentation of OP poisoning involves excessive cholinergic activation. The cholinergic synapses are present in both the central nervous system (CNS) and the peripheral nervous system (PNS). The neurotransmitter in the cholinergic system is acetylcholine (ACh). OPs are potent inhibitors of the enzyme acetylcholinesterase (AChE), resulting in accumulation of acetylcholine and over-stimulation of cholinergic synapses. There are two types of receptors-muscarinic and nicotinic. Muscarinic receptor activates sweat glands and smooth muscle, resulting in sweating, salivation, lacrimation, nausea, vomiting, diarrhea, abdominal cramps, increased bronchial secretion, and dyspnea, as well as bradycardia and urinary and fecal incontinence (SLUDGE* syndrome).
Miosis is a common sign following vapor exposure, usually resulting in blurred vision. Although common, it should not be considered a definitive sign of intoxication because it may not be seen following ingestion or dermal exposure.38
Nicotinic receptors activate the neuromuscular junction, resulting in twitching, fasciculations, muscle weakness, and in severe cases flaccid paralysis. Central nervous sustem (CNS) effects include anxiety, restlessness, tremor, confusion, convulsion, and coma.36 Without proper treatment, the victim may die shortly after exposure, mainly because of respiratory failure.
Antidotal treatment of OP poisoning is emergent and consists of atropine, oxime, and anticonvulsive therapy, preferably by intravenous route. In Israel, it is common to use also centrally acting anticholinergics (scopolamine) in cases with CNS involvement.21,31 Severe respiratory compromise requires ventilatory support. The treatment protocol is found in detail elsewhere.9,38
CARDIAC MANIFESTATIONS OF OP POISONING
There are several cardiac manifestations of OP poisoning. According to Ludomirsky et al.,23 three phases of cardiac toxicity can be described:
1. A brief initial period of hypertension and sinus tachycardia. These are considered nicotinic effects and may be due to a pheochromocytoma-like pattern caused by the excessive release of catecholamines from the adrenal medulla, which is under sympathotonic control and activated by acetylcholine.30
2. A prolonged phase characterized by sinus bradycardia and hypotension. These effects are thought to be due to extreme parasympathetic overflow, usually accompanied by electrocardiographic ST-T segment changes and AV conduction disturbances of varying degrees. The clinical significance of these findings is usually related to the severity of the intoxication.
3. Third phase: QT prolongation, polymorphic tachycardia (“Torsades de Pointes,” TdP),[dagger] and sudden cardiac death are characteristics of this phase. The third phase can appear a few hours after the intoxication, but sometimes it may occur unheralded 1 to 15 days following exposure to the OP, when the signs of clinical intoxication have already subsided. It is possible that with nerve agents, this period is even longer.13,38 Late arrhythmias are imminent even if the treatment in the acute phase is efficient.
Many patients with OP poisoning demonstrate various other ECG changes. Chharba et al. have described these other ECG changes, which included intraventricular conduction delays during the acute phase of the intoxication, and prolonged (>2 months) ST-T changes, which correlated in several fatal cases with histological signs of diffuse myocardial damage.6[double dagger] Intraventricular conduction delays and atrioventricular block were described in 10 out of 183 patients in a Russian series of severe OP poisoning.24 ECG changes were reported in the majority of 168 patients in another series in correlation with the severity of the intoxication. Thirteen of them demonstrated significant conduction disturbances or bradycardia. In patients who died, there was evidence of focal necrosis and regeneration.19
In animal studies with Vx, a highly toxic CWA, a decrease in Left Ventricular function was described during the intoxication.13 These findings are in accordance with the histological findings of diffuse myocardial damage following OP poisonings in animals.1,39
In this review we focus on the late arrhythmias that characterize the third phase of intoxication.
QT PROLONGATION AND RELATED ARRHYTHMIAS IN OP POISONING
Ludomirsky et al.23 were the first to associate cardiac arrhythmias and late sudden death with OP intoxications. They summarized their experience with 15 patients. Fourteen patients had prolonged QTc, of which six developed TdP. After processing the data, the authors found that a patient with a QTc > 0.58 s is in a high-risk group for a fatal arrhythmia, whereas all patients with a QTc >0.60 s suffered from potentially fatal arrhythmias. It is worth mentioning that recent data show that more than 90% of cases of drug- induced TdP occur with QTc values of more than 0.50s.18
Overall, the frequency of QT prolongation in several series of severe OP poisoning may range from 20 to 80% depending on the severity of the intoxication and the type of the offending agent.5,19,20,24 These changes usually start not before the second to third day after the intoxication, and may appear even later. These changes may last up to two weeks following intoxication with agricultural OPs.19,20,24 There is no information on duration and incidence of QT prolongation with CWA in humans, but animal studies demonstrated these changes to persist much longer: up to 1 month following exposure in primates13 and up to 15 weeks in rats.1
Ventricular bigeminy creates a typical “long-short” sequence, which might trigger TdP. The emergence of ventricular bigeminy in a patient with QT prolongation should be diagnosed as “impending Torsades” and treated accordingly.43 In contrast to this, in adrenergic-dependent (tachycardia-dependent) TdP, the ventricular arrhythmias follow sinus tachycardia, generally during stressful circumstances. This type of arrhythmia is usually seen only in severe forms of congenital LQT.43 Allon et al.3 have recently shown a decrease in epinephrine-induced arrhythmias (EPIA) threshold in rats exposed to sarin vapor lasting up to 6 months after exposure. This increase in vulnerability to developing arrhythmias long after OP intoxication, especially under challenging conditions such as stress or intensive physical exercise, may explain the delayed mortality observed following OP exposure.
Another important clinical issue is the difficulty in diagnosing TdP. TdPs’ twisting morphology may not be apparent when only short bursts occur or when the monitoring consists of single lead recording. Moreover, extrasystoles (caused by early afterdepolarizations, EADs) can arise from the terminal part of the QTU segment and may lead to underestimation of the QT interval. The diagnosis of TdP should be considered whenever ventricular tachycardia seems to be “pause dependent.”43
In severe cases of OP intoxication, the incidence of cardiac arrhythmias is high, yet there is only partial correlation between the total incidence of ventricular arrhythmias and the degree of the cholinergic syndrome or A\ChE inhibition.9 On the other hand, a stronger relationship was found between the OP exposure dose and the cardiac effect, thus raising the possibility of a direct toxic effect of the OP beyond ChE inhibition, as previously discussed.4 QT prolongation and arrhythmias are more common in cases of clinically severe poisoning, and in fact in our review of large clinical series of OP poisoning listed later, we didn’t find cases of arrhythmias in cases of mild intoxications.19,23,24 Chuang et al.7 showed that in severe OP poisonings (serum cholinesterase activity of less than 300 mU/ml), there is a higher incidence of QTc prolongation on ECG, and that among severely poisoned patients who presented with QTc prolongation the mortality rate is significantly higher than in cases with milder presentation.
Factors predisposing to QT prolongation and to high risk of TdP (and therefore deserving attention if found even in mildly OP- intoxicated patients) include older age, female gender, low left ventricular ejection fraction, left ventricular hypertrophy, ischemia, and electrolyte abnormalities, including hypokalemia and hypomagnesemia.2
THE PURPORTED ETIOLOGY OF QT PROLONGATION IN OP POISONING
The exact mechanisms of QT prolongation in OP intoxication are not fully understood. Most congenital long QT syndromes (LQTS) involve abnormal function of ion channels, either Na+ or (in the majority) K+, which impair ventricular repolarization. Similar changes, mostly mediated by inhibition of potassium outward channels, may be caused by acquired factors such as metabolic abnormalities (hypokalemia, hypocalcemia, or hypomagnesemia), or by various drugs including OPs, although the exact ion channel malfunction in OP intoxication is still unknown. The ensuing intracellular surplus of positive ions delays ventricular repolarization (thus prolonging the QT interval) and may trigger EADs. These EADs, which appear on the ECG as pathological tall U waves, may reach threshold amplitude and trigger ventricular arrhythmias.18,44
Several theories have been proposed to explain the phenomenon of OP-induced QT prolongation:
1. Vagal overstimulation due to incomplete reactivation of the AChE, as sometimes happens in cases of severe intoxication. Persistent cholinergic overstimulation can prolong the QT interval and induce ventricular arrhythmias. This vagal-induced QT prolongation is sometimes seen with the Valsalva maneuver, or with other cholinergic drugs such as Cisapride.8,45 Bradyarrhythmias per se (as seen in the second phase of OP intoxication) may lengthen the QT interval and trigger TdP episodes.43 In addition to its effect on QT and arrhythmogenesis, vagal stimulation exerts a direct toxic effect on the myocardium, as evidenced by Manning and by Hall.12,25
2. Some researchers claim that the muscarinic receptor is involved in the ACh-induced QT prolongation and TdP. Although the precise mechanisms remain to be elucidated, an abnormal regulation of potassium channels by the muscarinic receptor and its signal transduction were suggested in congenital long QT syndrome.10 Its relevance to OP poisoning remains to be established.
3. Central/peripheral nervous system effect. OP intoxication involves both systems, and there is a strong clinical correlation between cardiotoxicity and neurotoxicity.26 It is well established that QT prolongation may accompany various CNS pathologies such as thalamic hematoma or subarachnoid hemorrhage.11 The central injury following exposure to OPs may therefore set the stage for QT prolongation and arrhythmias.
4. Direct effect on cardiac autonomie innervation. OPs are known to affect both central and peripheral neurons. The more common manifestations of this mechanism are central effects as well as late peripheral neuropathy. It is conceivable that local damage to autonomie innervation of the heart may create autonomie imbalance that may result in QT prolongation and proarrhythmia.
5. Excessive cholinergic stimulation may result in coronary constriction, especially in patients with atherosclerotic changes and endothelial dysfunction.22 Derangements of myocardial perfusion may explain some of the myocardial injury in OP intoxication.
ARRHYTHMIAS IN LARGE CLINICAL SERIES OF OP POISONINGS
Russian investigators were the first to draw attention to the life-threatening late-occurring arrhythmias in the recovery period of acute OP intoxication. In 1975, Lyzhnikov et al.24 reported on 183 cases of severe OP intoxication treated in the institute of intensive care in Moscow. In 34 patients (18.5%) the QT interval was prolonged (79 16% above average), correlating with the severity of the intoxication and with the decrease of AChE activity. Twenty- nine of the 34 patients with prolonged QT died within 6 days of admission due to cardiac arrest, most of which following ventricular fibrillation. Treatment with potassium supplements for suppression of arrhythmias has failed. Importantly, this series does not enable to differentiate between arrhythmias that were part of the generalized critical condition of the patient and arrhythmias that were purely due to the arrhythmogenic effect of OPs. However, all arrhythmias in this series occurred after the second day of the poisoning.
Another large series reported by Kiss and Fazekas19 included 168 patients with OP intoxication. Suicide attempts were the main causes of exposure and were reported in 122 patients, 50 of whom eventually died. Prolongation of QT was observed in 134 patients (80%) 1-12 days postexposure. QT prolongation correlated with the severity of the intoxication. Fifty-six patients had cardiac arrhythmias; seven of these were ventricular tachycardia and six were ventricular fibrillation. Atropine treatment failed to suppress these arrhythmias.
Finkelstein et al.9 described 53 cases of OP intoxication that needed artificial ventilation, ICU monitoring and treatment. They have reported on 22 of their patients (41.5%) who presented with cardiac arrhythmias: 27% of them had asymptomatic prolonged Q-T interval while 37% had ventricular tachycardia and/or TdP. Half of the last group eventually died. In the other half, arrhythmias were controlled by a temporary pacemaker. Cardiac arrhythmias were found in all of the patients who were treated with high doses of both atropine and obidoxime. In the 47 patients receiving relatively low doses of obidoxime (a cumulative dose of less than 5 g) the frequency of cardiac arrhythmias was proportional to the dose of atropine.9
Importantly, late arrhythmias have not been reported in the two Japanese terrorist attacks in the 1990s, involving the use of the nerve agent Sarin with thousands of persons injured. There were no reported cases of late sudden death, and among 155 patients examined 3 weeks following the intoxication no cardiac abnormalities were found.27 In a late follow-up of 85 patients 2 years after the event there were no OP-related cardiac abnormalities.35 It is conceivable that the rarity of cardiac phenomena may be related to the high proportion of mild injuries among the patients in these series.
MANAGEMENT OF LQTS AND “TORSADES DE POINTES” RESULTING FROM OP POISONING
Treatment of ventricular arrhythmias associated with QT prolongation is aimed toward shortening of the QT interval and reducing the QT dispersion.
Immediate cardioversion should be performed in situations where TdP does not terminate spontaneously and results in hemodynamic compromise.
The short-term treatment, which is intended to cease and prevent the recurrences of TdP, is well established in the medical literature and includes pharmacologie treatment aimed to reduce the OP effects, correction of underlying electrolyte abnormalities, and the administration of magnesium, potassium, temporary transvenous cardiac pacing, and rarely intravenous (iv) isoproterenol (see Table 1).
Nevertheless, none of those treatments have been specifically studied for TdP in the preset of organophosphate poisoning.
Animal studies have shown that rapid IV administration of atropine in hypoxic poisoned animals may cause ventricular fibrillation. Although this complication has not been reported in humans, atropine should ideally be given intravenously only after hypoxia has been at least partially corrected.38
It is worth mentioning that despite reports of successful termination of TdP following prolonged QT using lidocaine, the efficacy of this drug in OP intoxication is limited, and might even aggravate the arrhythmia.20
Long-term treatment is generally not required in cases of OP intoxication because the QT interval often becomes normal by treating the underlying cause. The long-term treatment of acquired LQT following an OP intoxication is limited to permanent pacemaker implantation in patients with sick sinus syndrome or AV block in whom a pause or bradycardia is a precipitating event for Torsades.
Long-term treatment with β-adrenergic blockers has been shown to result in a significant reduction in the incidence of cardiac events only in patients with congenital LQT and are therefore not recommended as adjuvant therapy for an acquired OP intoxication LQT.17
The role and efficacy of other potential long-term medications such as sodium channel blockers (Mexiletine, FIecainide, Pentisomide), potassium channel activators (Nicorandil, pinacidil, cromakalim), alpha-adrenergic receptor blockers, calcium channel blockers, and protein kinase inhibitors in treating long QT and Torsades de pointes especially due to OP poisoning are still to be studied.18
TABLE 1
Short-term treatment of TdP
MONITORING, AND PREDISCHARGE AND POSTDISCHARGE EVALUATION
Our recommendations for monitoring and predischarge and postdischarge evaluation of OP-intoxicated patients are based on the following assumptions:
1. The vast majority if not all TdP cases occur in moderate to severe OP poisonings.
2. There is a direct correlation between the amount of QT prolonga\tion and the likelihood of developing TdP.
3. The time frame for this problem is up to 2 weeks in agricultural OPs and may be up to 1 month in CW injuries.
4. QT changes usually appear within several days following the poisoning.
Recommendations:
1. A baseline ECG should be performed in all OP intoxicated patients with special attention to QT measurement. In cases of moderate to severe intoxication,** daily ECG should be performed to evaluate QT until discharge and patients should be monitored if possible.
2. Patients should not be discharged before QT normalization.
3. A Holler test is recommended prior to discharge of patients who had QT prolongation.
4. The role of provocative tests such as exercise test and epinephrine infusion remains to be determined.
5. In cases of mass casualty where technical factors prevent the application of the recommendations, special attention should be given to patients with severe intoxication, and to those who had arrhythmias or markedly prolonged QT.
* SLUDGE syndrome: salivation, lacrimation, urination, defecation, GI (gastrointestinal) distress, and emesis.
[dagger] Torsades de pointes refers to Ventricular Fibrillation characterized by polymorphic QRS complexes that change in amplitude and cycle length, giving the appearance of oscillations around the baseline. The electrocardiographic hallmark is polymorphic Ventricular Tachycardia preceded by marked QT prolongation. The clinical picture is characterized by recurrent syncope that may develop to Ventricular Fibrillation and sudden cardiac death.16
[double dagger] ST-T changes in the ECG are seen in cases of myocardial ischemia and necrosis.
The Valsalva maneuver is mainly used to assess autonomie reflex control of cardiovascular function. It is performed by having the subject conduct a maximal, forced expiration against a closed glottis for 15 s.
** The Israeli hospital deployment plan for the management of chemical casualties characterizes intoxication severity: The mildly intoxicated patient is ambulatory (able to walk). Moderate casualties are nonambulatory (unable to walk), whereas casualties in need of immediate intubation (respiratory insufficiency) are regarded as suffering from severe intoxication. This division is accepted by others as well.28,41
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Eran Bar-Meir
CBRN Medical Branch, Medical Corps, Israel Defense Forces, and Department of Plastic Surgery, Sheba
Medical Center and Tel-Aviv University, Tel-Hashomer, Israel
Ophir Schein and Arik Eisenkraft
CBRN Medical Branch, Medical Corps, Israel Defense Forces, Tel- Hashomer, Israel
Ronen Rubinshtein
Department of Cardiology, Lady Davis Carmel Medical Center, Haifa, Israel
Ahuva Grubstein
CBRN Medical Branch, Medical Corps, Israel Defense Forces, Tel- Hashomer, Israel
Arie Militianu
Department of Cardiology, Lady Davis Carmel Medical Center, and The Bruce Rappaport School
of Medicine, Technion, Haifa, Israel
Michael Glikson
Electrophysiology Unit, Heart Institute, Sheba Medical Center, and Tel Aviv University,
Tel-Hashomer, Israel
The first two authors have contributed equally to this work.
Address correspondence to Dr. Ophir Schein, 33 Hatavor St, 65255 Tel-Aviv, Israel. E-mail: [email protected]
Copyright Taylor & Francis Ltd. Mar 2007
(c) 2007 Critical Reviews in Toxicology. Provided by ProQuest Information and Learning. All rights Reserved.
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