CHAPTER FOUR DISCUSSION AND CONCLUSION
4.2 ELECTROCARDIOGRAPHICAL CHANGES IN ACUTE HIGH
Electrocardiographic recordings were performed separately in two groups of rats which received different VX dosing regimens: (1) acute single exposure to 1 LD50; (2) chronic daily 0.4 LD50 VX injections for 8 days. Acute 1 LD50 VX exposure investigations produced results that tied in with the current literature on ECG findings in acute nerve agent and organophosphorus insecticide poisoning (Ludomirsky et al., 1982; Robineau, 1987a). Intense increase in parasympathetic tone which manifested as sinus bradycardia, AV conduction disturbances and arrhythmias was revealed in the high dosage VX-challenged animals in this study. Instability in AV conduction pathways presented in the form of first- and second- degree AV blocks were detected as early as 21.7 ± 2.8 min post injection. Series of short-long ECG cycles that occurred in succession to extreme prolongations were detected repeatedly. Malignant torsades de pointes (TdP) ventricular tachycardia followed the cardiac arrhythmias.
Parallel to QTc interval prolongation reported in nerve agent sarin and soman intoxication (Abraham et al., 2001; Allon et al., 2005) and organophosphorus insecticide poisoning (Saadeh et al., 1997; Karki et al., 2004), QTc interval prolongation was discernible in the VX-exposed rats up to 120 min post injection.
Additionally, distinct lengthening of the PR segment was revealed for 120 min
following injection. Impaired conduction through the AV node has been documented as a common cause for PR interval prolongation (Conover, 1996), thus justifying the occurrence of AV blocks in the animals in the present study. First-degree AV blocks had been reported in 1 LD50 VX-challenged beagle dogs which exhibited PR segment lengthening in the ECG traces (Robineau and Guittin, 1987b). It is certain that VX poisoning can produce disturbances in atrioventricular conduction.
Due to technical limitations in ECG devices, ECG investigations in organophosphate compounds intoxication animal studies hitherto either used anesthetised animals or were designed as a one-time measurement where the animals were sacrificed after the procedure. Constraints on follow-up recordings after exposure were present for the latter. In the former case, anaesthetic procedure was speculated to have caused interference in cardiac rhythm as cardiac abnormalities had been described in anesthetised control animals (Robineau, 1987a). The use of ECG implants in this study facilitated the continual monitoring of ECG changes in conscious animals for days after VX challenge. Cardiac arrhythmias including second degree AV blocks, short-long ECG cycles and immense sustained prolongations between ECG waveforms were reproducible up to 14 days post 1 LD50 VX exposure.
Analysis of the ECG traces revealed evident extension of QTc duration for as long as 14 days following intoxication. These results are consistent with reports of accidental human exposure showing QT segment prolongation for a period of duration of 2 to 3 weeks (Chuang et al., 1996; Allon et al., 2005). In addition, Abraham and coworkers
had reported QTc prolongation in rats for up to 3 months post acute 0.9 LD50 sarin or soman exposures (Abraham et al., 2001).
The present study investigated the presence of cardiotoxicity in chronic exposure to low levels of VX, an area of research where not much has been reported so far. Cardiac rhythm disturbances emerged in 50% of the rats by dosing day 2 after administration of the second 0.4 LD50 VX dose. The proportion exhibiting cardiac arrhythmias grew to 100% by the fourth day of injection. Subsequently, the rats exhibited recurrent cardiac rhythm irregularities up till the last day of injection (i.e.
dosing day 8). Cardiac abnormalities observed in the chronically dosed rats included sinus bradycardia, first- and second-degree AV blocks, short-long ECG cycles, extreme pauses between QRS complexes as well as significant QTc and PR interval prolongation. The evidence further corroborated the conclusion drawn from histopathological and clinical observations, that toxic effects of VX are cumulative and that chronic low level VX exposure eventuates in cardiotoxicity. More importantly, occurrence of the cardiac rhythm aberrations arose before appearance of specific symptoms of intoxication (i.e. tonic-clonic convulsions). This is the first report demonstrating cardiac arrhythmias in animals displaying minimal signs of poisoning in the area of nerve agent research as ECG studies of nerve agent have only used convulsive doses of nerve agent i.e. greater than 0.5 LD50 to date (Robineau, 1987a; Robineau, 1987b). This data verified the proposition that cardiotoxicity arising from VX intoxication is independent of convulsive activity and is a disparate entity distinct from neurotoxicity.
Extension of QTc duration and arrhythmias were sustained in the intoxicated rats up till 5 days after the last injection. This demonstrated that akin to acute high dosage VX intoxication, cardiotoxicity arising from repeated low dose VX exposure is long-standing. Consequential adverse repercussions of lengthened repolarisation phase of the ventricular action potential manifested as QTc prolongation is clinically significant as it could generate the development of polymorphic ventricular tachycardia and delayed sudden cardiac death (Ludomirsky et al., 1982; Mancuso et al., 2004). Poor prognosis such as higher respiratory failure incidence, frequency of ventricular premature contraction and mortality rate has also been reported in organophosphate-poisoned patients demonstrating QTc prolongation (Chuang et al., 1996; Grmec et al., 2004). Hence, the incessant QTc lengthening detected post acute and chronic VX challenge in this present study suggests the necessity for continual ECG monitoring in instances of nerve agent exposure in humans.