Prognostication and Prediction of Outcomes in Patients with Organophosphorus and Carbamate Poisoning: A Prospective Cohort Study

HIGHLIGHTS

This study utilized a handheld device to assess E-AChE (erythrocyte acetylcholinesterase) levels and established a robust link with poisoning severity. Plasma BChE (butyrylcholinesterase) levels showed no such correlation. The findings underscore the necessity for customized treatment based on poisoning severity and emphasize the importance of careful atropine administration. Our study reports a lower mortality rate attributed to well-equipped healthcare facilities.

INTRODUCTION

Organophosphorus (OP) and carbamate poisoning pose a significant public health challenge, particularly in countries like India where agriculture is one of the largest economic sectors.^1–3 These instances of poisoning constitute a significant share, approximately estimated to range from 1 to 2%, among cases presenting to the emergency room (ER).^4–6 In our institution, OP and carbamate poisoning frequently necessitate admissions to the high dependency unit (HDU) and intensive care unit (ICU), mirroring the situation in other healthcare facilities.^7,8 The toxicity of OP and carbamate poisoning stems from their capacity to deactivate the enzyme acetylcholinesterase, leading to the accumulation of acetylcholine and subsequent overstimulation of receptors.^9–11 Serious clinical manifestations of both OP and carbamate poisoning share similarities. Delayed or inadequate treatment can result in severe consequences such as muscle paralysis, cardiac brady-asystole, secretory gland hypersecretion, respiratory failure, coma, and even fatality. Timely administration of antidotes significantly reduces the clinical severity of poisoning and eliminates symptoms.^2,6,10–12

The OP compounds not only have a high affinity for synaptic acetylcholinesterase (S-AChE) but also lead to the inhibition of various other cholinesterases, including red blood cell or erythrocyte cholinesterase (E-AChE) and butyl cholinesterase (BChE) (also known as pseudo-cholinesterase). Direct measurement of S-AChE is not feasible; thus, we depend on surrogate markers such as E-AChE or pseudocholinesterase levels.^9,11 Notably, many OP substances exhibit stronger inhibitory effects on BChE compared to AChE, resulting in lower-than-expected BChE levels in clinical settings.¹³ Several laboratory methods, including the most popular Ellman et al.’s method, have been developed to assess E-AChE levels.^14–16 Field-testing kits, such as the Test-mate ChE system and Lovibond Cholinesterase AF 267 test kit, are available for E-AChE or BChE testing using the Ellman method.^17–20 While BChE levels are commonly used in diagnosing OP poisoning, their correlation with clinical severity remains limited.^2,11,13,14 Conversely, E-AChE, although not routinely utilized, may exhibit a stronger correlation due to its structural similarity to the synaptic cholinesterase enzyme.

In this study, we used the ChE check mobile, a cholinesterase rapid test in vitro diagnostic (IVD) device, that works through Ellman’s colorimetric principle to estimate E-AChE levels and evaluate its correlation with poisoning severity, atropine requirements, and prognosis.

MATERIALS AND METHODS

PARTICIPANTS

RESULTS

A total of 60 patients meeting the predefined inclusion criteria were enrolled in the study. The mean age of the study population was 30.6 (SD: 13.7) years, with a predominance of male patients (n = 43; 71.7%). The vital signs and symptoms observed at the presentation are provided in Table 1. The severity of poisoning was assessed using the peradeniya organophosphorus poisoning (POP) scale, a validated scale for assessing the severity of OP poisoning, and the results are presented in Table 1.^25–27

Monocrotophos (n = 10; 20.4%) and Carbofuran (n = 4; 8.1%) were the most commonly ingested OP and carbamate compounds, respectively. Out of the 49 cases analyzed, compounds were detected in 25 (51.0%) cases belonging to WHO class I, 23 (46.9%) cases in class II, and 1 (2.1%) case in class III. Additional details regarding the toxicants ingested and the toxidrome observed at the presentation can be found in Table 2. It is worth noting that two patients had also consumed drugs (Alprazolam and Imidacloprid) alongside the toxic substances. Most patients (n = 50, 83.3%) had received primary medical care from another facility before presenting to our center. The care received included gastric lavage (n = 43; 71.7%), a bolus dose of injection atropine (n = 36; 60.0%), induced emesis using salt (n = 12; 20.0%), administration of oximes (n = 6; 10.0%), intubation and mechanical ventilation (n = 4; 6.7%).

The details of the ER and ICU management, complications, and outcomes are summarized in Table 3. The study findings revealed that the median E-AChE level was 4 (IQR: 1.3, 18.8) units/gram hemoglobin, and the median plasma BChE was 175 (IQR: 96, 2013) units per liter. The initial median dose of atropine required for atropinization was 10 mg (IQR: 0, 61.5), and the median total atropine dose administered was 116 (IQR: 32, 320) mg. On average, patients required atropine treatment for 2.7 (SD: 1.7) days. The E-AChE level showed a significant negative correlation with both the initial atropinization dose (Spearman’s rho or ρ: –0.653, p-value < 0.001) and the total atropine requirement (ρ: –0.659, p-value < 0.001) during admission, serving as a predictor of various measures of severity, as outlined in Table 4. However, the concurrently measured plasma BChE did not demonstrate any significant correlation with atropine requirements (p-value: 0.12), ICU admission (p-value: 0.07), or severity of poisoning based on POP (p-value: 0.056). Both E-AChE and plasma BChE were found to predict in-hospital mortality (p-value: 0.002). Approximately, one-third of the patients (n = 22; 33.6%) developed atropine delirium and required restraint measures. Patients with delirium had a significantly higher median total atropine dose [72 (IQR: 32, 325.5) mg] compared to those without atropine-related adverse effects [28 (IQR: 0, 121) mg] (p-value: 0.038).

Among the entire sample, 55% (n = 33) of the patients necessitated mechanical ventilation and were subsequently admitted to the medical ICU. The main reasons for intubation in the ER were primarily attributed to low sensorium and respiratory failure, accounting for 23.3% (n = 14) of cases. Additionally, 15 patients had to be intubated after their admission to the hospital. Among patients experiencing acute cholinergic crises, ventilatory support could be discontinued within 5 days. However, prolonged ventilatory support was needed for patients who developed hospital-acquired infections or intermediate syndrome. In the ICU, three patients succumbed to their illness, one due to acute cholinergic crises, while the others were infection-related (Table 3). The E-AChE levels in the three fatal cases were recorded as 0, 2.4, and 2 U/g Hb, contrasting with a median (IQR) of 4.1 (1.3–4.1) U/g Hb in other cases. During hospitalisation, 23 patients (38.3%) acquired infections. Among these, there were 21 cases of ventilator-associated pneumonia, 2 cases of urinary tract infection, and 5 cases of blood culture-proven bacteremia.

When studying atropine requirements for initial treatment and outcomes in various severity levels of OP poisoning using the POP scale, significant differences were found in the median (range) of initial atropinization doses: mild group: 0 (0–64) mg, moderate group: 31.5 (0–256) mg, and severe group: 81 (60–222) mg. The severity of OP poisoning was directly linked to ventilation needs. All patients in the severe group required ventilation, while a significantly higher proportion of patients in the moderate group (90.9%) needed respiratory support compared to the mild group (28.6%). ICU admission rates followed a similar pattern, further emphasizing the importance of early patient classification and referral at smaller healthcare centers.

A receiver operating characteristic (ROC) curve was plotted to determine the optimal cut-off value for E-AChE in predicting moderate to severe poisoning according to the POP scale (Fig. 2). On the other hand, the institutional lower limit of pseudocholinesterase or BChE at 5320 U/L had a higher sensitivity of 92% but a poor specificity of 20.6% for predicting moderate to severe poisoning according to the POP scale. In addition, a ROC curve was plotted for the optimal cut-off of plasma BChE (Fig. 3).

DISCUSSION

The ingestion of OP and carbamate poisons is a common method of intentional self-harm observed in our ER.^6,8 The current gold standard for diagnosing anticholinesterase poisoning in most medical centers involves measuring pseudo-cholinesterase levels.^2,16 However, the literature review revealed a minimal correlation between BChE levels and clinical severity or patient outcomes.^15–17 In contrast, a study by Thiermann et al. demonstrated that RBC cholinesterase or E-AChE correlated with neuromuscular weakness.²⁸ Building upon this knowledge, our study measured E-AChE using a handheld cholinesterase check device at admission and examined the link between severity and outcomes. In resource-limited settings in India and other developing countries, where laboratory support for evaluating E-AChE or BChE levels may be lacking in most Government and Rural Health Centers, this handheld device offers a practical solution.

We found a significant association between admission E-AChE levels and moderate to severe toxicity, as determined by the POP severity score. Additionally, higher initial doses of atropine were required for patients with lower blood E-AChE levels. In contrast, admission plasma BChE levels lacked correlations in predicting severity, atropine requirements, and intermediate syndrome. This reveals the need to move from BChE-based screening to E-AChE-based protocol for OP and carbamate poisonings. More than half of our patients needed mechanical ventilation and ICU admission which may be due to referral bias. A tracheostomy was needed for prolonged ventilation, mainly due to intermediate syndrome or ventilator-associated pneumonia. We diagnosed intermediate syndrome in 30% of cases, emphasizing its significant occurrence in cases of OP poisoning. These varying requirements of atropine doses, the requirement for mechanical intubation and ICU admissions in different severity of poisoning as per the POP scale, underscores the importance of tailoring treatment plans based on the severity of OP poisoning, providing valuable insights for optimizing treatment strategies and patient management.

About one-third of individuals exhibited delirium, necessitating the use of restraints. The relatively high incidence of these symptoms raises concerns about the potential overuse of atropine and prompts further investigation into determining the optimal method of atropinization and when to stop atropine infusion. However, no severe toxicity related to atropine was observed in our patients, and the delirium resolved upon adjusting the infusion rate or discontinuing the drug. These findings highlight the importance of closely monitoring and adjusting atropine administration to minimize adverse effects while ensuring effective treatment. There were a total of three (5%) deaths during hospitalisation indicating a comparatively lower mortality rate for OP and carbamate poisoning than previously reported in the literature.^29,30 This positive outcome can be attributed to the presence of a well-equipped ICU and the provision of high-quality care within our healthcare setting.

CONCLUSION

The utilization of the handheld check ChE mobile device can be a valuable tool for rapid prognostication of patients with OP and carbamate poisoning, facilitating the early referral of potentially critically ill patients. Our study revealed a moderate negative correlation between E-AChE levels and the atropine requirements. Low E-AChE levels were also associated with an increased likelihood of complications, including the need for ventilation and ICU admission. Furthermore, our findings indicate that admission pseudo cholinesterase levels do not correlate with disease severity, atropine requirements, and ICU admission. Additionally, we observed a strong correlation between the POP severity score and the need for ICU admission, ventilation, and atropine requirements. Therefore, integrating the POP severity score into the assessment of patients presenting to the ER of a Tertiary Care Center can aid in determining the severity of the disease.

ORCID

Avanish Jha https://orcid.org/0000-0002-3495-0827

Darpanarayan Hazra https://orcid.org/0000-0002-5941-0587

Bijesh Yadav https://orcid.org/0000-0002-5764-1373

Anand Zachariah https://orcid.org/0000-0002-9039-364X

Reginald Alex https://orcid.org/0000-0002-0767-8602

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