Rodenticide Poisoning: Critical Appraisal of Patients at a Tertiary Care Center

INTRODUCTION

Pesticide abuse for self-harm is a global concern, more so in developing nations. In India, rodenticide poisoning is a common occurrence, though the exact incidence is yet to be ascertained. Rodenticides as a group encompass divergent compounds ranging from yellow phosphorus to superwarfarins.¹ Among the various congeners of this group, yellow phosphorus stands high in mortality hierarchy as it can cause hepatocellular necrosis and fulminant hepatic failure.² Previous research work in the area revealed that yellow phosphorus is the commonest rodenticide used for intentional self-harm, causing 30% fatalities.³ Preliminary observation at our institute revealed a high case burden and compelling mortality indices of rodenticide poisoning. This study was designed to critically appraise the clinical characteristics of these patients and possibly identify prognostic determinants.

MATERIALS and METHODS

A prospective observational study was designed to recruit a sample size of 100 inpatients with rodenticide poison exposure. The eligibility was decided based on the predefined criteria (Table 1). A total of 115 patients fulfilled the eligibility standards. After attrition, there were 99 patients whose data were consolidated (Fig. 1). Preliminary information, such as age, sex, demographics, etc., were documented. The case presentation and the time scale of development of signs/symptoms were recorded chronologically as also the laboratory parameters. The variables were charted and analyzed for significance related to frequency and mortality. Statistical analysis was carried out using the SPSS version 20.0 software. For frequency distribution and descriptive statistics Fisher’s exact test of association was used, whereas binary logistic regression model applied for mortality determinants. Significance was defined as a p value of %3C;0.05.

RESULT

The sex distribution was 51 male and 48 female patients. The study population’s age ranged between 19 and 46 years. In all, 90.91% consumed paste formulation of rodenticide in which the active constituent was yellow phosphorus (67.68% of patients) and yellow phosphorus + zinc phosphide (23.23%). The remaining 9 patients’ choice of rodenticide included brodifacoum cake (2), aluminum phosphide pellets (2), 2% zinc phosphide granules (2), bromadiolone cake (2) and locally manufactured dried strychnine powder (1). The amount consumed could not be ascertained due to obvious reasons and hence was an unreliable predictor of outcome. In general, those who consumed more than 5 g of paste stood more vulnerable to death, though the association was not statistically significant (Table 2). Hitherto, the body mass index, nutritional status, and sex differences did not have any influence on the outcome. The time to resuscitation, however, showed a significant relationship to death. Our institute being a referral center, only 47 patients presented early after rodenticide consumption among whom 46 survived. Survival rate among patients instituted gastric decontamination (activated charcoal) within 2 hours of exposure (97.87%) was significantly higher than those who were not (84.62%; p = 0.033).

The clinical picture revealed conspicuous absence of signs and symptoms on day 1 of exposure. Only 13.13% (n = 13) of patients showed symptoms of gastrointestinal (GI) intolerance such as nausea, vomit, and abdominal pain in the initial 24 hours following rodenticide intake. Majority of patients (72.73%) manifested with toxidrome after a lag period of 24–36 hours (range 18–72 hours). A small segment (14.14%) remained asymptomatic through the entire course of inpatient observation. During the hospital stay, 52.53% (n = 52) of patients manifested abdominal pain, 22.21% (n = 22) developed jaundice, 15.15% (n = 15) suffered bleeding manifestations, 10.10% (n = 10) had altered mentation, 10.10 (n = 10) experienced symptomatic hypotension, 7.08% (n = 7) developed oliguric acute kidney injury (AKI), and 17.17% (n = 17) had features of multi-organ dysfunction. Baseline laboratory parameters such as liver function test, blood glucose, blood urea level, serum creatinine, arterial blood gas analysis, and coagulation parameters were essentially within the normal limits. Further follow-up investigations showed elevated aspartate transaminase (AST; 48.47%), alanine transaminase (ALT; 49.50%), bilirubin levels (22.21%), metabolic acidosis (10.12%), serum creatinine (7.08%), prothrombin time/international normalised ratio (PT/INR) prolongation (15.15%), and activated partial thromboplastin time (aPTT; 3.30%) (Table 2). The treatment rendered included N-acetylcysteine (NAC) in various formulations, vitamin K supplements, and supportive care. The mortality was 9.1% (n = 9) of which 77.78% (n = 7) died of fulminant hepatic failure. The mean time for death was 4.22 days since exposure (range 2–8 days).

DISCUSSION

Previous research on rodenticide poisoning highlights that yellow phosphorus is the most culprit agent.³ Probable reasons motivating this choice include easy availability, low cost, and high toxicity profile.³ The compound is manufactured predominantly in paste formulation either alone or in combination with zinc phosphide under various commercial nomenclatures (RATOL, RATNIL, RATOUT, etc.). The estimated killing dosage of around 8–12 mg/kg is not very accurate, with deaths reported on either side of the reference value.^4,5 The toxicity is due to phosphoric acid liberated via an exothermic reaction upon exposure of yellow phosphorus to the gastric milieu. Phosphoric acid acts like a general protoplasmic poison, causing direct cellular lysis by inhibition of ribosomal function.⁶

The clinical picture is falsely reassuring in the first few hours wherein minimal, if any, symptoms occur. The term “toxic time bomb” used to denote this phenomenon is well founded. Absence of reliable clinical or biochemical markers to identify the ongoing systemic toxicity in this early phase is the stumbling stone for intensive care physicians working in this field. The initial phase lasting for 18–36 hours is punctuated by GI symptoms such as nausea, vomit, and abdominal pain in a few patients.⁷ Following this phase is the stormy onset of features related to acute hepatic failure, encephalopathy, myocardial dysfunction, AKI, and or multi-organ failure.^4,7 This phase lasts between 36 hours and 96 hours and is followed by either death or clinical resolution over the next few days. The mean time for recovery was estimated at 8.8 days in previous reports.⁸ In our study, we observed that 72.73% of patients manifested after 24 hours of poison exposure. The predominant features included abdominal pain (52.53%), jaundice (22.21%), bleeding manifestations (15.15%), encephalopathy (10.10%), shock (10.10%), AKI (7.08%) and multi-organ dysfunction (17.17%). In our case series, we identified hepatic encephalopathy, jaundice, and shock as reliable forerunners of death (Table 2). Clinical manifestations and outcome vary in different reports. In an earlier analysis, 87% patients had some hepatic derangement and 27% died of fulminant hepatic failure.² Similarly, mortality in a second case series was 28%.³ The mortality in our series was 9.1% (n = 9) which is far less than the regional estimates (30%). This was probably attributed to the intake of sublethal amounts of xenobiotic. Since there is no foolproof quantitative assessment method to ascertain the amount of poison consumed, its effect on mortality could not be deciphered in our study. The main mode of death was fulminant hepatic failure in 77.78% (n = 7) with the remaining two dying of refractory shock and multi-organ failure (Figs 2 and 3).

The laboratory picture was dominated by liver function abnormalities such as AST (48.47%/n = 48) and ALT 49.50%/n = 49) elevation. We could not plot the mean area under AST/ALT curve because of the huge variation between survivors and nonsurvivors. The mean value of liver enzymes for survivors vs nonsurvivors was AST (123.50 ± 57.24 vs 1035 ± 314 IU/L) and ALT (147.61 ± 65.12 vs 1153 ± 245 IU/L), respectively. The difference was statistically significant (p < 0.01). The PT/INR was prolonged in 53 patients (53.54%), but no statistically significant difference was found between survivors and the dead (mean 28 ± 15 seconds). Metabolic acidosis was documented in seven patients all of whom died, thereby showing statistical importance (p < 0.01). Literature search revealed that AST/ALT elevations >10 times the normal value, derangements in PT/INR, metabolic acidosis, and hypoglycemia were important portenders of death.² Nalabothu et al., in his cross-sectional case series, identified model for end stage liver disease (MELD) score as a prognostic tool for yellow phosphorus poisoning.³ Akin to previous research work, our study also observed significant relationship of elevated liver enzymes and metabolic acidosis to death (Table 2).

There is no known antidote for yellow phosphorus poisoning. That said, management of this condition hovers around meticulous monitoring and intensive supportive care. The NAC has received quite some attention in the recent past for its beneficial effects in such cases. The logical theory backing its utility is that it replenishes glutathione stores that neutralize the free radical-induced cytotoxicity of yellow phosphorus.⁹ Administering NAC early in the course of the disease could possibly have a lifesaving effect as proven by previous reports.¹⁰ Ironically many of the yellow phosphorus-poisoned patients remain asymptomatic during the initial few hours. Whether every patient with a history of yellow phosphorus poisoning should be instituted NAC irrespective of his or her clinical status is a matter of speculation. Multiple other efforts that evaluated the validity of NAC in the treatment of yellow phosphorus overdosage have yielded conflicting results.^6,11,12 Given the excellent therapeutic window of NAC, early administration of this agent for all yellow phosphorus-poisoned patients would definitely outweigh the risk. NAC at our institute was administered without scientific rationale at widely variable dosages and formulations. Furthermore, our study was not designed to evaluate the efficacy of NAC in rodenticide poisoning and hence its impact on the outcome could not be assessed.

CONCLUSION

Phosphorus-based rodenticides claim many human lives. Given the fact that there is no specific antidote, constant vigil and timely resuscitation could be the only factors to tilt the balance favorably. Stringent legislative measures to restrict the indiscriminate and over-the-counter sales of yellow phosphorus are much needed in our country. In this study, we identified delayed resuscitation, jaundice, hepatic encephalopathy, elevation of AST and ALT to >1000 IU/L, metabolic acidosis, and refractory shock as the significant predictors of bad outcome in this patient population. The common mode of death was fulminant hepatic failure.

LIMITATION

Our research study was not designed to be conducted in a controlled environment and hence the management was at the discretion of the treating physician. Although the study team could gain access into time-bound investigation of the patients, they were not part of the decision-making committee. This being an observational study, no particular institutional or evidence-based protocol was followed in administering NAC and hence its benefits/shortfall could not be assessed.

ETHICS APPROVAL

The study was approved by the institutional ethics committee.

REFERENCES

1. Suneetha DK, Inbanathan J, Kannoth S, Reshma PK, Shashank MS. Profile of rat killer poisoning cases in a tertiary care hospital at Mysore. Int J Sci Study 2016;3(12):264–267.

2. Fernandez OU, Canizares LL. Acute hepatotoxicity from ingestion of yellow phosphorus-containing fireworks. J Clin Gastroenterol 1995;21(2):139–142. DOI: 10.1097/00004836-199509000-00015.

3. Nalabothu M, Monigari N, Acharya R. Clinical profile and outcomes of rodenticide poisoning in tertiary care hospital. Int J Sci Res Publ 2015;5(8):1–12. Available from: http://www.ijsrp.org/research-paper-0815/ijsrp-p4442.pdf.

4. Karanth S, Nayyar V. Rodenticide-induced hepatotoxicity. J Assoc Physicians India 2003;51:816–817.

5. Fletcher GF, Galambos JT. Phosphorus poisoning in humans. Arch Intern Med 1963;112:846–852. DOI: 10.1001/archinte.1963.03860060084008.

6. Mishra AK, Devakiruba NS, Jasmine S, Sathyendra S, Zachariah A, Iyadurai R. Clinical spectrum of yellow phosphorous poisoning in a tertiary care centre in South India: A case series. Trop Doct 2016;47(3):245–249. DOI: 10.1177/0049475516668986.

7. Mauskar A, Mehta K, Nagotkar L, Shanbag P. Acute hepatic failure due to yellow phosphorus ingestion. Indian J Pharmacol 2011;43:355–356. DOI: 10.4103/0253-7613.81500.

8. Radhika V, Narayanasamy K, Chezhian A, Senthil Kumar R, Jasmine JJ. Rat killer poisoning vs. liver damage: a view in south indian patients of tertiary care center. J Gastroint Dig Syst 2018;8(3):569.

9. Clinical Practice Guidelines: Paracetamol Poisoning. Available from: http://www.rch.org.au/clinicalguide/guideline_index/paracetamol_ poisoning/.

10. Kharkongore MA, Mishrae AK, Ninane KF, Iyaduraie R. N-Acetylcysteine in yellow phosphorus poisoning. Curr Med Issues 2017;15(2):136–138. DOI: 10.4103/0973-4651.206530.

11. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137(3):856–864. DOI: 10.1053/j.gastro.2009.06.006 ,864.e1.

12. Hu J, Zhang Q, Ren X, Sun Z, Quan Q. Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure: a meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol 2015;39(5):594–599. DOI: 10.1016/j.clinre.2015.01.003.