Risk factors for the development of complications in Organophosphate and Carbamate poisoning

 

Teny Grace Skaria¹, B Shrikar Reddy¹, Ryali Valli Sri Vidya¹, Siddhanth Mahesh Shetty¹, Rutuja Rajendra Pagnis¹, Vijayanarayana K¹, Sudha Vidyasagar², Viji P C¹, Girish Thunga^1*

¹Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India, 576104

²Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India, 576104

 

ABSTRACT:

Organophosphate and carbamate (OPC) poisoning is a major concern in developing countries and is associated with increased risk of complications and mortality. The study aims to analyze the prevalence, clinical outcomes and identify the risk factors for complication development in patients with OPC poisoning. A total of 488 patients’ records with OPC poisoning admitted to Kasturba Hospital, Manipal from January 2013 and December 2017 were retrospectively analysed with respect to the complications developed. Demographics, clinical characteristics and risk factors were assessed to determine their association with the development of complications. Complications were developed in 37.9% of the patients with OPC poisoning. Aspiration pneumonia was predominant complication 13.9%. Sepsis (Odds ratio [OR]: 12.033), aspiration pneumonia (OR: 3.621), acute renal injury (OR: 20.032), cardiac arrest (OR: 139.921) and hypoxic ischemic encephalopathy (HIE) (OR: 13.508) were significantly associated with mortality (p<0.001). The age group 31-50 (OR: 1.974; 95% confidence interval [CI]: 1.253-3.110), older age >50 (OR: 3.851; CI: 2.309-6.423), prehospitalization period >24 hours (OR: 2.691; CI: 1.729-4.188) and pseudocholinesterase levels< 1400 IU/L (OR: 2.389; CI: 1.032-5.531) were predictive factors for the development of complications in OPC poisoning. OPC poisoning if unattended can lead to progressively severe adverse outcomes. Therefore, it is vital to rapidly initiate effective treatment and alert the healthcare professionals to carefully monitor the high-risk groups with older age, delayed admission and lower pseudocholinesterase levels that are susceptible to developing complications.

 

 

INTRODUCTION:

India is predominantly an agrarian country with 70% of the population predominantly depending on agriculture as a source of income. Over the last few decades, the use of pesticides has increased dramatically to control agricultural pests. The lack of appropriate control measures and information regarding the harmful effects of these substances has led to an increased burden of self-harm¹.

 

Approximately 1-5 million pesticide poisoning cases are estimated annually among farm workers. In 2012, Kenya reported 1479 pesticide poisoning cases with 579 fatalities and Uganda reported around 87 fatalities. The incidence rate of pesticide poisoning in Central America is 35 per 100,000, Belize is 17 per 100,000 and Thailand is 17.8 per 100,000. As per UN report 2017, about 200,000 people die from the pesticide poisoning per year globally². Organophosphate and carbamate (OPC) compounds are among the highly consumed poisons in India¹.The number of OPC intoxications in India is estimated to be 7-10 million resulting in 10000 fatalities each year³.

 

In OPC poisoning, the targeted enzymes under attack are acetylcholinesterase and pseudocholinesterase. These cholinesterases are inhibited by OPC compounds leading to accumulation of acetylcholine at the synapses exhibiting muscarinic, nicotinic and CNS symptoms⁴. Muscarinic symptoms that are exhibited by the parasympathetic fibers include vomiting, diarrhoea, miosis, shortness of breath and salivation⁵ while diaphoresis is by the muscarinic receptors at sympathetic fibers⁴. Nicotinic symptoms such as fasciculation, tachycardia and muscle weakness occur due sympathetic and motor effects³. Excessive acetylcholine at the synapses in the central nervous system results in symptoms such as seizures,coma and altered sensorium⁶. Pseudocholinesterase levels are used as a potential diagnostic tool in the determination of OPC poisoning.

 

The further stimulation of muscarinic acetylcholine receptors is competitively inhibited by atropine, while pralidoxime relieves both muscarinic and nicotinic symptoms by the reactivation of acetylcholinesterase⁵. An individual study by Faiz et al. reported a 16.66% rise in mortality due to complications⁷. The undesirable effects of OPC compounds potentially leading to poor outcome are tissue hypoxia, central apnea, paralysis, muscle weakness or respiratory failure and ischemia instigating multiple organ dysfunction syndrome^8,9. The health care professionals are not fully cognizant of the various complications that occur in organophosphate poisoning leading to delayed recovery and mortality. Hence the present study analyzes the prevalence, outcome and the risk factors associated with the development of complications in patients with OPC poisoning at a tertiary care hospital in India.

 

METHODS:

Study setting and data sources:

A retrospective observational study was conducted in a tertiary care center with approval from the Institutional ethics committee of Kasturba Medical College (IEC 590/2017) affiliated to Manipal Academy of Higher Education, Manipal from January 2013 – December 2017.

 

The diagnosis of OPC poisoning was made on the history of poison consumed and clinical features of the patients at the time of admission. Pseudocholinesterase levels were used as a potential diagnostic tool in the determination of OPC poisoning. The clinical features of the patients were further classified into muscarinic, nicotinic and CNS symptoms. Demographic details such as age, gender, occupation, the intention of poisoning, pre-hospitalization period, and quantity of poison ingested were recorded. The toxicity of poison was further categorized according to the WHO GHS classification and Labelling of Chemicals¹⁰. Information regarding the presence of complications namely intermediate syndrome, sepsis, aspiration pneumonia, ventilator associated pneumonia, acute renal injury, cardiac arrest and hypoxic-ischemic encephalopathy due to OPC poisoning among the study population was collected and assessed with respect to the clinical outcomes.

 

Study population:

A total of 664 patient records with the diagnosis of OPC poisoning presented to the emergency ward were reviewed in the study. Patients below the age of 18 years, patients with mixed poisoning and those discharged against medical advice were excluded from the study. The records of 488 patients were in accordance with the eligibility criteria and analyzed.

 

Outcomes:

Outcomes were evaluated in terms of recovery or expiry and also in terms of the development of complications. The complications were analyzed in terms of days of mechanical ventilation, ICU days, days of hospitalization, and clinical status which were evaluated at the time of discharge.

 

Statistical Analysis:

Summary of the patients’ categorical characteristics and parameters were described as frequency and percentages whereas, continuous variables are expressed as mean with standard deviation. Univariate analysis was performed to predict the influence of various complications on mortality.

 

Multivariate analysis following a univariate analysis was preformed to identify the variables associated with complications development. The variables exhibiting significance in univariate analysis were further considered for multivariate analysis. Data entry and statistical analysis was preformed using IBM SPSS version 20.0 (IBM Corp. IBM SPSS Statistics for Windows, Armonk, NY) and the p value < 0.05 were considered statistically significant.

 

RESULTS:

Demographic data of patients:

During the study period, a total of 488 eligible patients were admitted to the Emergency Ward of Kasturba Hospital with a history of OPC poisoning. The age of the study population was found to be 37.25 ± 15.12 years. A considerable variation between the male and female population in the study was observed, with males being 339 (69.5%) and females 149 (30.5%). Majority of the cases were referred admissions from local hospitals (Table 1). OPC compounds consumed were classified according to the WHO Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Among the study population Category 3 was found to be most common with 207 (42.4%) patients (Table 1).

 

Table 1: Demographic Characteristics of OPC Poisoning Patients

Total number of patients	N = 488 (%)
Patient Demographics
Mean Age ± SD in years	37.25 ± 15.12
Male	339 (69.5%)
Female	149 (30.5%)
Intention of poisoning
Suicidal	479 (98.2%)
Accidental	7 (1.4%)
Homicidal	2 (0.4%)
Type of admission
Direct Admission Referred Admission	144 (29.5%) 342 (70.1%)
Type of pesticide (WHO-GHS)
Category 1	36 (7.4%)
Category 2	68 (13.9%)
Category 3	207 (42.4%)
Category 4	20 (4.1%)
Category 5	6 (1.2%)
Unknown	151 (30.9%)

 

Table 2: Clinical Presentation of OPC poisoning patients

Clinical presentation	N (%)
Muscarinic symptoms
Miosis	17 (3.5%)
Increased Secretions	97 (19.9%)
Vomiting	105 (21.5%)
Diarrhea	32 (6.6%)
Sialorrhea	34 (7.0%)
Lacrimation	22 (4.5%)
Bradycardia	31 (6.4%)
Shortness of breath	50 (10.2%)
Diaphoresis	44 (9.0%)
Nicotinic Symptoms
Mydriasis	358 (73.4%)
Fasciculation	103 (21.1%)
Tachycardia	85 (17.4%)
CNS Symptoms
Seizure	30 (6.1%)
Coma	17 (3.5%)
Restlessness	254 (52.0%)
Altered Sensorium	101 (20.7%)

Values are presented as frequency (%)

 

Clinical Presentation:

The clinical presentation of patients admitted with organophosphate poisoning was an amalgam of muscarinic, nicotinic and CNS effects. Vomiting 105 (21.5%), increased secretions 97 (19.9%) and shortness of breath 50 (10.2%) were the most prevalent muscarinic symptoms. Nicotinic features comprised of mydriasis 358 (73.4%), fasciculation 103 (21.1%) and tachycardia 85(17.4%). Further, 30 (6.1%) patients were found to have seizures, and 17 (3.5%) were found to be in the coma state (Table 2). These symptoms could have been varied following previous treatment as 70.1% of cases were referred from local hospitals (Table 1).

 

Incidence of complications in OPC poisoning:

The incidence of complications was about 37.9% in the study population as a whole, and the details are depicted in Table 3. Aspiration pneumonia was the predominant complication in 68 patients followed by cardiac arrest in 60 patients. Ventilator associated pneumonia (VAP) in 51, intermediate syndrome in 39, sepsis in 37, hypoxic-ischemic encephalopathy (HIE) in 15 and acute kidney injury in 12 patients were later developed during the hospital stay. There was a need for tracheostomy in 52 (10.7%) of the patients. The mortality rate was higher in the patients developing cardiac arrest, acute renal injury, HIE, and sepsis.

 

Univariate analysis of various complications was carried out to identify a possible association with mortality in the study population. Sepsis (OR: 12.033; CI: 5.856-24.725), aspiration pneumonia (OR: 3.621; CI: 2.009 - 6.526), acute renal injury (OR: 20.032; CI: 5.279 - 76.018), cardiac arrest (OR: 139.921; CI: 58.328-335.654) and HIE (OR: 13.508; CI: 4.467 - 40.853) were associated with mortality of the patients (Table 4). However, complications such as intermediate syndrome and VAP were not statistically associated with mortality.

Table 3: Incidence of complications in OPC poisoning with relation to outcome, mechanical ventilation, ICU and hospitalization

Complications	Total 488 N (%)	Recovered n (% of N)	Expired n (% of N)	Days of mechanical ventilation	Days in ICU	Days of hospitalization
Intermediate Syndrome	39 (7.99)	35(89.74%)	4(10.26%)	13.10 ± 8.23	15.70 ± 9.81	20.15 ± 13.77
Sepsis	37 (7.58)	15(40.54%)	22(59.46%)	10.36 ± 6.88	13.27 ± 7.94	15.38 ± 9.76
Aspiration Pneumonia	68 (13.93)	46(67.65%)	22(32.35%)	9.34 ± 6.00	11.44 ± 7.48	14.6 ± 10.06
VAP	51 (10.45)	39(76.47%)	12(23.53%)	14.29 ± 7.05	17.61 ± 7.00	21.92 ± 11.22
Acute Renal Injury	12 (2.46)	3(25.00%)	9 (75.00%)	8.82 ± 7.15	11.17 ± 7.17	12.33 ± 9.432
Cardiac Arrest	60 (12.30)	8(13.33%)	52(86.67%)	7.24 ± 5.92	8.54 ± 7.01	8.77 ± 13.37
HIE	15 (3.07)	5(33.33%)	10(66.66%)	10.33 ± 4.85	13.2 ± 6.56	17.24 ± 10.77

Values are presented as mean ± SD or frequency (%).   VAP = ventilator associated pneumonia; HIE = Hypoxic ischemic encephalopathy

 

Table 4: Univariate analysis of the complications associated with mortality in patients with OPC poisoning.

OR = Odds ratio; CI = Confidence interval; VAP = ventilator associated pneumonia; HIE = Hypoxic ischemic encephalopathy

Table 5: Factors affecting the development of complications in OPC poisoning

SD = Standard deviation; IU/L = International units per litre; ^a = details of the quantity of poison consumed unavailable; ^b = details of poison unavailable; WHO GHS = World Health Organization Globally Harmonized System.

 

Risk Factors for the development of complications in OPC poisoning:

Factors affecting the development of complications in OPC poisoning are categorized and represented as mean ± standard deviation (Table 5).

 

Univariate and multivariate regression analysis was performed to identify the risk factors for the development of complications as shown in Table 6. Although the quantity of poison consumed had an odds ratio >1, the results were not statistically significant (Table 6).

 

Table 6: Univariate and multivariate analysis of factors affecting development of complications

Factor	Univariate		Multivariate
	OR (95% CI)	p value	AOR (95% CI)	p value
Quantity of poison consumed
Known	1.003 (1.000-1.005)	0.059	-	-
WHO GHS poison category
Category 1	0.714 (0.126-4.037)	0.703	-	-
Category 2	0.744 (0.140-3.954)	0.728	-	-
Category 3	0.448 (0.088-2.278)	0.333	-	-
Category 4	0.176 (0.023-1.326)	0.092	-	-
Category 5	-	-	-	-
Age
18-30	-	-	-	-
31-50	1.940 (1.255-2.997)	0.003	1.974 (1.253-3.110)	0.003
>50	3.511 (2.151-5.729)	<0.001	3.851 (2.309-6.423)	<0.001
Gender
Female	-	-	-	-
Male	1.579 (1.044-2.388)	0.030	1.450 (0.935-2.249)	0.097
Pre-hospitalization period (hours)
<24	-	-	-	-
>24	2.424 (1.602-3.668)	<0.001	2.691 (1.729-4.188)	<0.001
Pseudocholinesterase (IU/L)
<700	1.605 (1.053-2.448)	0.028	1.748 (1.117-2.737)	0.015
701-1400	2.488 (1.143-5.418)	0.022	2.389 (1.032-5.531)	0.042
>1401	-	-	-	-

OR = Odds ratio; AOR = Adjusted odds ratio; CI= Confidence interval

 

 

 

Multivariate analysis revealed that patients of age group 31-50 (OR: 1.974; CI: 1.253-3.110), age >50 (OR: 3.851; CI: 2.309-6.423), admission time >24hours post consumption to hospital (OR: 2.691; CI: 1.729-4.188), pseudocholinesterase levels 701 -1400 units (OR: 2.389: CI: 1.032-5.531) < 700 units (OR: 1.748; CI: 1.117- 2.737), were independently associated with complications. Although gender was found to be significant in univariate analysis, it rendered to be insignificant in the multivariate analysis.

 

DISCUSSION:

Organophosphate poisoning is a major global health hazard with a mortality rate of about 3-25% worldwide¹¹. Male preponderance (69.5%) was observed in our study with a mean age of 37.25±15.12 comparable to a study by Coskun et al.⁶ WHO GHS Category 3 pesticides were found to be greatly consumed in our study.

 

The building up of acetylcholine at the synapses presents the muscarinic, nicotinic and CNS effects. The predominant muscarinic symptoms in our study were vomiting (21.5%), increased secretions (19.9%) and shortness of breath (10.2%) unlike the study by Rajyalakshmi et al. where miosis (65%), sweating (58%) and vomiting (51%) were the common muscarinic features¹². Majority of the subjects presented with dilated pupils and very few with miosis as most of the cases were referred admissions following initiation of atropine at local hospitals. This result was in congruence with a study by Unnikrishnan et al. in the same hospital¹³. Fasciculation (21%) was the most frequent nicotinic symptom, useful for the diagnosis of OPC poisoning¹⁴. Seizures occur as a result of hyperactivity of the cholinergic system and were observed in 30 (6.1%) patients. If uncontrolled, seizures can lead to brain damage in OPC poisoning¹⁵.

 

Nearly most of the pulmonary complications of OPC poisoning arise due to decreased consciousness, aspiration, prolonged ventilation due to delayed neuromuscular junction (NMJ) dysfunction, loss of airway protection, excessive bronchial secretions and respiratory failure^8,16.

 

Aspiration pneumonia (13.9%) was the predominant complication in our study, comparable to a retrospective study by Tripathy et al. (15%)¹⁷. The mortality rate of aspiration pneumonia (32.40%) corresponded to that seen in a retrospective study conducted by Shah et al. on Indian population (33.33%)¹⁸. A retrospective study conducted in South Indian population reported that patients suffering from OPC poisoning are very vulnerable to VAP with 10.8% of the observed population developed VAP, a resonating pattern was observed in our study with 51(10.4%) developing VAP at a similar hospital setting¹⁹. However, in the present study, VAP was not statistically associated with mortality, similar to a prospective observational study by Velayudhan et al²⁰. Tracheostomy is usually performed at our hospital when prolonged ventilation is anticipated as reported in the literature^21,13.

 

Intermediate syndrome is a consequence of overstimulation of nicotinic receptors at the NMJ and is usually manifested 24-96 hours after poisoning^22,23. The clinical features are muscle weakness in the neck, proximal limb, ocular, cranial nerves and respiratory muscles²⁴. Our study observed about 39 patients (8%) developing intermediate syndrome. Reports suggest that the incidence of intermediate syndrome varies between 8-84% in India^25-27. Complete recovery from post-acute muscle paralysis in patients with intermediate syndrome is usually 4-18 days with the support of mechanical ventilation^{24, 16}. This justifies the longer duration of ventilation (13.10 ± 8.23) and hospitalization (20.15 ± 13.77 days) in patients with intermediate syndrome, a similar result was reported by Dandapani et al.²⁷.

 

Association of OPC poisoning with various cardiac complications has been previously reported in the literature²⁸. The fatality rate due to cardiac arrest in our cohort (87%) was significantly high. This rate was not much different to a prospective study by Shah et al. where the fatality rate due to cardiac complications was 75%¹⁸. A case report documented cardiac arrest induced by OPC poisoning wherein the treatment was delayed due to the absence of an early diagnosis of intoxication. This corroborates the significance of the early diagnosis of OPC poisoning, and timely initiation of treatment is essential to reduce the occurrence of cardiac complications²⁹.

 

Acute kidney injury (AKI) (2.5%) is a rare complication in OPC poisoning with a significant high risk of fatality in our study. A retrospective study by Lee et al. determined that OPC poisoning was associated with 6.17 fold higher risk of developing acute renal injury. Evidence suggests that renal injury due to OPC compounds can be due to direct injury, secondary to hemodynamic instability, or seizure-induced rhabdomyolysis³⁰. According to literature, mechanical ventilation is considered to be a risk factor for acute kidney injury due to the underlying acute lung injury in critically ill patients^30-32. Zafar et al. described a 23 year-old man who developed AKI due to OPC intoxication and was successfully treated using atropine, pralidoxime, and hemodialysis, suggesting their importance to prevent grave clinical course³³.

 

Development of complications such as sepsis and HIE were observed in 8% and 3% of our study population respectively, similar results were reported in a cross-sectional observational study by Mundhae et al. wherein sepsis and HIE were found in 6.51% and 7.74% of their study population³⁴. HIE occurs within one to three weeks after anoxic damage, where the patients become apathetic, confused, irritable with extrapyramidal features involving muscle stiffness and involuntary motor movements^35,36. Early stabilization with symptomatic treatment is essential to prevent the patient from coma or death in HIE³⁶. Sepsis is a rare complication in OPC poisoning, and there has been a paucity of literature with relation to its occurrence. However, sepsis may develop in the patients of OPC poisoning owing to their prolonged ventilation³⁷.

 

The independent risk factors associated with the development of complications in OPC poisoning were increasing age, pseudocholinesterase levels <1400mg/dl and pre-hospitalization period >24 hours.

 

With increasing age, there is a decrease in respiratory muscle strength, reduced thoracic chest wall compliance, and decreased ventilator response to hypoxia leading to pulmonary and cardiac complications³⁸. An increased risk of infections is associated with increasing age due to the overall decline in immune system function. The inability of liver and kidneys to detoxify and remove pesticides from the body has led to an increased threat of renal and hepatic failure in older adults³⁹.

 

Pseudocholinesterase is synthesized in the liver and is usually found in smooth muscle, adipose tissue, and plasma⁴⁰. Pseudocholinesterase levels are reduced to a greater extent since OPC compounds are more potent inhibitors of pseudocholinesterase than acetylcholinesterase⁵. About 62.7% of our study population presented with complications had pseudocholinesterase <700mg/dL which was higher in comparison to a prospective study by Rajyalakshmi et al. where 34% developed complications with low levels of pseudocholinesterase¹².

 

Delay in admission>24hrs can be a risk factor for the development of late complications (delayed muscle weakness, aspiration, anoxic brain damage) that occur 24-96 hours later⁴¹. Furthermore, delay in initiation of oxime therapy to prevent aging of the enzyme or time delay from reaching a tertiary center can lead to poor outcome in patients presenting to the hospital^{16, 42}. Henceforth, early hospitalization followed by rapid decontamination with the right choice of antidote is crucial for survival in patients presented with OPC poisoning.

 

The information on pre-hospitalization period, treatments given at local hospital, plasma acetylcholinesterase level and pseudocholinesterase changes were not available as it was a retrospective study. These were the limitations of the study.

 

KEY POINTS:

·       Our study focused on 7 complications occurring in OPC poisoning of which aspiration pneumonia, cardiac arrest, ventilator associated pneumonia, and intermediate syndrome were the prevalent complications.

·       Cardiac arrest, sepsis, aspiration pneumonia, acute kidney injury, and hypoxic ischemic encephalopathy were significantly associated with mortality.

·       The presence of these complications leads to increased days of ventilation, ICU with consequent longer days of hospitalization.

·       The risk factors identified with the development of complications in OPC poisoning are increasing age, delayed admission and pseudocholinesterase levels <1400 units.

 

ACKNOWLEDGMENTS:

The authors would like to thank the Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Medical Records Department, Department of Medicine of Kasturba Medical College, Centre for Toxicovigilance and Drug Safety and Manipal Academy of Higher Education for their support during the study.

 

CONFLICT OF INTEREST:

Authors report no potential conflict of interest.

 

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Received on 21.06.2019           Modified on 23.07.2019

Accepted on 18.08.2019         © RJPT All right reserved