Clinical features of organophosphate poisoning: A review of different classification systems and approaches

Abstract

Purpose:

The typical toxidrome in organophosphate (OP) poisoning comprises of the Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms. However, several other manifestations are described. We review the spectrum of symptoms and signs in OP poisoning as well as the different approaches to clinical features in these patients.

Materials and Methods:

Articles were obtained by electronic search of PubMed^® between 1966 and April 2014 using the search terms organophosphorus compounds or phosphoric acid esters AND poison or poisoning AND manifestations.

Results:

Of the 5026 articles on OP poisoning, 2584 articles pertained to human poisoning; 452 articles focusing on clinical manifestations in human OP poisoning were retrieved for detailed evaluation. In addition to the traditional approach of symptoms and signs of OP poisoning as peripheral (muscarinic, nicotinic) and central nervous system receptor stimulation, symptoms were alternatively approached using a time-based classification. In this, symptom onset was categorized as acute (within 24-h), delayed (24-h to 2-week) or late (beyond 2-week). Although most symptoms occur with minutes or hours following acute exposure, delayed onset symptoms occurring after a period of minimal or mild symptoms, may impact treatment and timing of the discharge following acute exposure. Symptoms and signs were also viewed as an organ specific as cardiovascular, respiratory or neurological manifestations. An organ specific approach enables focused management of individual organ dysfunction that may vary with different OP compounds.

Conclusions:

Different approaches to the symptoms and signs in OP poisoning may better our understanding of the underlying mechanism that in turn may assist with the management of acutely poisoned patients.

Introduction

Organophosphate (OP) poisoning continues to be a frequent reason for admission to hospitals and Intensive Care Units in developing countries.[1,2,3] The traditional approach to clinical features in acute OP poisoning has centered on receptor specific effects on muscarinic, nicotinic and central nervous system (CNS) receptors that result in diverse symptoms and signs.[4,5] This conventional classification of clinical features is useful given that muscarinic effects are reversed by atropine whilst nicotinic neuromuscular effects are not.[6] It is also known that drugs that cross the blood-brain barrier (e.g. atropine) are more likely to reverse CNS symptoms and signs than drugs that do not cross the blood-brain barrier.[7] An alternate approach to clinical features may be in terms of the time of onset of symptoms. In general, following OP exposure, Salivation, Lacrimation, Urination, Defecation, Gastric cramps, Emesis (SLUDGE) symptoms occur acutely within minutes to hours. However, some patients develop delayed effects either after an initial period of intense cholinergic symptoms and signs or after a period of minimal or no clinical features. Further symptoms and signs may occur as a continuum, wherein patients with acute symptoms involving one neuronal sub-system (e.g. neuromuscular weakness) may progress to develop delayed symptoms and signs of other neuronal sub-systems (e.g. extra-pyramidal). The third approach, an organ specific approach, have focused on neurologic,[8,9] respiratory[10,11] or cardiovascular[12,13,14] effects of OP. This review was thus undertaken to detail different classifications of the clinical features of OP poisoning and discuss mechanisms for the occurrence of these manifestations.

Materials and Methods

We performed a literature search (1966 to April 2014) using PubMed^® with the search terms organophosphorus compounds or phosphoric acid esters medical subject heading (MESH) AND poison or poisoning (MESH) AND manifestations or symptoms that included neuromuscular or neurobehavioral or neurologic manifestations or tremor or skin or oral or eye manifestations or chorea or muscle weakness or fasciculation or dystonia or shock or respiratory failure [Table 1]. We also reviewed our personal files and records as well as references from other studies to identify additional articles. The focus was to provide different classifications of all symptoms and signs reported in OP poisoning.

Table 1.

Search strategy used for identifying articles on manifestations in organophosphate poisoning

The clinical features were classified (a) as receptor specific manifestations, (b) based on time of occurrence and (c) nature of organ system involvement. Mechanisms for the occurrence of specific manifestations, as well as the time of symptom onset, were explored from published literature.

Results

Of the 5026 articles on OP poisoning identified by literature search, 2584 articles were in humans; 452 articles pertaining to clinical manifestations of OP poisoning in humans were retrieved for detailed assessment [Table 1]. Articles were categorized based on whether the manifestations were approached as receptor-based or time-based or organ system involved. A descriptive review was undertaken based on the published articles.

Receptor based manifestations were categorized as nicotinic and muscarinic receptor manifestations [Table 2]. Irreversible binding of OP to acetylcholinesterase in the cholinergic synapses in the CNS and peripheral nervous system (PNS) results in high concentrations of acetylcholine in the synaptic clefts that cause initial excessive stimulation and later, blockade of synaptic transmission.[6] The peripheral muscarinic SLUDGE symptoms are due to actions on the relevant glands whilst central muscarinic effects result in symptoms such as confusion, coma and convulsions. Nicotinic effects are motor and sympathetic[5] and result in fasciculations, muscle weakness, tachycardia and hypertension. In a retrospective study of OP poisoning,[15] muscarinic symptoms and signs were the most frequent (84%) followed by CNS (78%) and nicotinic (17%).

Table 2.

Symptoms and signs of organophosphate poisoning based on receptors involved

Using the time-based approach, symptoms are traditionally categorized as acute (minutes to hours) and delayed or late (days to weeks); late and delayed being used interchangeably. Since symptom onset and mechanism of delayed manifestations (e.g. intermediate syndrome, delayed onset coma that typically occur within 2-week) are dissimilar to late manifestations (e.g. organophosphate induced delayed polyneuropathy [OPIDP] that typically occurs after 2-3 weeks), we propose [Table 3] that symptom onset is categorized as acute (within 24-h), delayed (24-h to 2-week) and late (beyond 2-week).

Table 3.

Symptoms and signs of organophosphate poisoning based on time of manifestation

Symptoms and signs were also categorized as organ-specific manifestations as neurologic [Table 4], cardiac [Table 5] and respiratory manifestations and manifestations of other systems.

Table 4.

Neurological manifestations of organophosphate poisoning

Table 5.

Cardiac effects of organophosphate poisoning

Discussion

Receptor specific manifestations

Organophosphate compounds bind irreversibly to acetylcholinesterase in the plasma, red cells and cholinergic synapses [Figure 1] in the CNS and the PNS. Reduced red cell or plasma cholinesterase activity suggests OP exposure. Red cell cholinesterase activity is better correlated with the severity of exposure than plasma cholinesterase activity.[16,17,18]

Figure 1.

The cholinergic system - cholinergic synapses are present in the central nervous system (CNS) and the peripheral nervous system (PNS). Both nicotinic and muscarinic receptors are found in the CNS. The peripheral nicotinic receptors are present in the neuromuscular junction, adrenal medulla and the sympathetic and parasympathetic ganglia of the PNS. Peripheral parasympathetic muscarinic innervation is postganglionic to the heart, exocrine glands and smooth muscle and sympathetic postganglionic fibres innervate the sweat glands

The central nicotinic receptors are of the neuronal subtype (Nn or N2); this subtype is also present in the adrenal medulla and sympathetic and para-sympathetic ganglia of the PNS.[19,20] The peripheral nicotinic receptors (N1 or Nm) are present in the neuromuscular junction.[19] All 5 (M1 to M5) muscarinic receptor subunits[20,21] are present in the CNS [Figure 2]. Peripheral parasympathetic muscarinic innervation is postganglionic to the heart, exocrine glands and smooth muscle, while sympathetic postganglionic fibers innervate the sweat glands.[20,21,22]

Figure 2.

Subtypes of muscarinic and nicotinic receptors - the peripheral nicotinic receptors at the neuromuscular junction are of the N1 or Nm type and the central nicotinic receptors are of the neuronal nicotinic acetylcholinesterase subtype (Nn or N2). All five (M1 to M5) muscarinic receptor subunits are present in the central nervous system. The peripheral muscarinic receptors are predominantly of the M3 subunit although the M2 subunit is also represented in the heart and exocrine glands

Most symptoms and signs in OP poisoning are the result of excessive muscarinic receptor stimulation. Features such as tachycardia and high blood pressure, which are sometimes observed in acute poisoning and not readily explained is postulated to be due to overwhelming cholinergic effects on the CNS, sympathetic ganglionic synapses or the adrenal medulla.[6]

The traditional approach offers insight on the possible site(s) of action of the OP compound in patients with muscle weakness. Wadia et al. reported that in the so-called Type I paralysis, weakness appeared within 24-h and some responded to atropine.[5] In contrast, in Type II paralysis, weakness appeared after 24-h with concomitant atropine being administered in large doses, usually, 30-mg or more.[5] Recent electrophysiological studies have suggested possible reasons for this differential effect. Patients with early respiratory failure had normal repetitive nerve stimulation studies suggesting a predominant central muscarinic mechanism, highlighting the importance of rapid atropinization while patients with late respiratory failure had evidence of neuromuscular dysfunction.[23] Patients with moderate muscle weakness had an initial decrement-increment pattern on electrophysiology at high rates of stimulation progressing to decrement-increment patterns at intermediate-and low-frequency situations. Further progression was characterized by decrement-increment and repetitive fade patterns.[24] These electrophysiological abnormalities may thus help in the continued assessment and treatment (e.g. atropine, oximes) of neuromuscular weakness in poisoned patients.

Overstimulation of central receptors may contribute to early death. In animal models, OP causes excitatory electroencephalographic changes in the respiratory control regions of the brain.[25,26] In addition, focal respiratory center seizures result initially in an increase in phrenic nerve output followed by sudden cessation of activity.[26,27] Pretreatment of animals with centrally acting agents such as atropine or diazepam, dramatically increases 24-h survival of rats administered dichlorvos, while peripherally acting drugs such as ipratropium or glycopyrrolate did not impact outcome.[28] These results further support the hypothesis that early paralysis in OP poisoning may be centrally mediated.

Possible therapeutic implications of a receptor based approach

The choice of anticholinergic depends on the targeted receptor – central, peripheral or both. While atropine is the logical choice, as it acts on central and peripheral cholinergic receptors, adverse effects or allergic reactions may preclude its use.[7] In such situations glycopyrrolate or scopolamine are advocated.[7] Atropine and glycopyrrolate appear to be equally effective.[29] However, as glycopyrrolate does not cross the blood-brain barrier, a benzodiazepine or a specific antimuscarinic drug with good CNS penetration such as scopolamine may be needed to counter central effects.[7] In a case report, rapid reversal of severe extra-pyramidal signs was seen with intravenous scopolamine in chlorpyrifos poisoning.[30] However given the selective action, scopolamine is considered inferior to atropine and caramiphen.[31,32]

Given the irreversible binding of OP to acetylcholinesterase, the choice of muscle relaxant in OP poisoning is also important. Several studies[33,34,35,36] have reported prolonged neuromuscular blockade and apnea in the setting of acute or chronic exposure to OP due to reduced succinylcholine metabolism as a result of cholinesterase inhibition by the insecticide.[33]

In some patients with mega-dose OP intoxication, refractoriness to high dose atropine therapy (100-mg/h) with an inadequate heart rate response may be observed. In such situations, the addition of small doses of an adrenergic agent (e.g. adrenaline 1-2 mcg/min) improves heart rate with a dramatic reduction in atropine requirements (personal observations). The lack of response to atropine may be explained by sympathetic ganglionic dysfunction or blockade with inadequate adrenergic output at the postganglionic neuronal level or by inhibition of the sympathetic fibers of the adrenal gland.

The use of oximes in OP poisoning that has been extensively reviewed in other publications, merit mention for completion. Oximes are nucleophilic agents that cleave covalently bound OP off the OP-acetylcholinesterase conjugate thereby releasing the acetylcholinesterase.[37] Oxime therapy in OP poisoning has been the subject of numerous trials and meta-analysis. Although there is a pharmacological basis of use of oximes in OP poisoning, recent systematic reviews suggest that the current evidence is insufficient to indicate if oximes are beneficial.[38,39]

Symptoms based on time of occurrence

The time of occurrence of symptoms and signs depend on the route of exposure, poison load and chemical nature and solubility characteristics of the compound. Traditionally, symptoms are categorized as acute (minutes to hours) and delayed or late (days to weeks).[40,41,42] The time of onset and mechanism of delayed manifestations such as intermediate syndrome,[43] delayed onset coma[44] and extrapyramidal manifestation[45] are different to that of late manifestations such as organophosphate induced delayed polyneuropathy (OPIDP) that typically occurs after 2-3 weeks[46] and up to 4-week post exposure.[42] Thus, we propose [Table 3] that symptom onset is categorized as acute (within 24-h), delayed (24-h to 2-week) and late (beyond 2-week).

Acute onset symptoms

The acute symptoms and signs are due to muscarinic, nicotinic and central receptor effects. Muscarinic symptoms of salivation and bronchorrhea that dominate initially may cause drowsy patients to drown in their secretions. Acute muscarinic effects on the heart (bradycardia, hypotension) can be life-threatening. Nicotinic effects of muscle weakness contribute to respiratory distress whilst the acute central effects of restlessness, agitation, confusion and sometimes convulsions further compromise airway and breathing and increase aspiration risk and hypoxia. Since many of these effects are reversed by atropine, early and appropriate medical attention is vital. In developing countries, where OP poisoning is common, quick access to medical care is more problematic than early recognition.

Implications of route of exposure on onset of symptoms

The route of exposure determines the rapidity of symptom onset. Common routes of exposure are inhalational, skin and ingestional. The inhalational route has the fastest onset, generally within a few minutes of exposure. In the terrorist attacks in Japan with the nerve gas agent Sarin,[47] instantaneous death by respiratory arrest was suggested in 4 victims.[48] In farmers, inhalation exposure resulting in rapid symptom onset may occur with a sudden change in the wind direction during insecticide spraying.

In skin exposure, the volume of exposure, intactness of the skin and solubility characteristics of the OP determines lag-time. In one report, nausea, abdominal cramping, arm and leg weakness occurred within 30-min of dermal exposure of chlorpyrifos, a lipid soluble OP.[49] Although leg weakness improved, weakness of muscles at the site of skin exposure persisted beyond 2-week. In another report, symptom onset occurred at 3-h following the exposure to water soluble OP, monocrotophos, through a skin laceration.[50] Symptoms of poisoning have also occurred after 4-h and 24-h after application of a home-made shampoo contaminated with an OP.[51] In a rare situation of subcutaneous chlorpyrifos self-injection,[52] delayed cholinergic phase, prolonged coma and severe permanent neurologic injury were observed. Delayed and prolonged effects were attributed to the adipose and muscle tissue acting as reservoirs.[52]

In ingestional poisoning, symptom onset would depend on the poison load and absorption characteristics. In general, symptoms occur within a few minutes to hours. However, the first symptom in parathion poisoning may be delayed by up to 24-h as parathion must first be converted from the thion to the oxon form to be physiologically active. Many organothiophosphates readily undergo conversion from thions to oxons. This conversion occurs due to the substitution of oxygen for sulfur in the environment under the influence of oxygen and light, and in the body chiefly by the action of liver microsomes.[53] Oxons are generally more toxic than thions, but oxons break down more readily.

Delayed onset symptoms

With adequate atropinization,[54] the acute cholinergic symptoms abate within a few hours, but some patients develop delayed effects. Several recent publications [Figure 3] strengthen the case for its recognition as a distinct clinical entity.

Figure 3.

Spectrum of delayed manifestations in organophosphate poisoning - delayed onset cholinergic symptoms are reported to occur 40-48 h following poisoning (a). Intermediate syndrome (b) typically occurs 24-96 h following poisoning although it may be delayed up to 114-h (c). Delayed onset coma or encephalopathy (d) occurs about 4-day after poisoning, generally after a period of normal conscious state. Cerebellar ataxia (e) has been reported to occur 8-day after poisoning and extrapyramidal manifestations (f) after 5-15 days (reproduced with permission)

Although acute cholinergic manifestations typically occur within 24-h of exposure, late onset cholinergic symptoms and signs have been observed 40-48 h after dichlofenthion poisoning.[55]

Intermediate syndrome, the best described delayed manifestation, is characterized by paralysis of proximal limb muscles, neck flexors, motor cranial nerves and respiratory muscles 24-96 h after poisoning, after the cholinergic phase had settled down, with weakness lasting for up to 18-day.[56] A neuromuscular junctional defect has been demonstrated in electromyography studies.[57] Delayed onset intermediate syndrome has been reported 114-h after methamidophos poisoning.[58] Since methamidophos is highly lipophilic and persists in fat stores, re-distribution and re-inhibition of cholinesterase may have delayed symptom onset.[58]

Although intermediate syndrome involves muscle groups, focal weakness has also been reported; in particular, laryngeal paralysis,[59,60,61,62] either acute[61] or delayed by 4-14 days[59,60] presenting as “failed extubation.” Laryngeal electromyography was consistent with bilateral laryngeal paralysis although standard needle electromyography was normal.[60] Severe and prolonged diaphragmatic paralysis has also been reported with Malathion poisoning.[63]

Coma is seen in 17-29% of patients and can last for hours to days.[16,64] OP poisoning may also present as brainstem stroke.[65] However, some patients manifest altered consciousness or coma days after poisoning, particular after a period of “normal” consciousness. This clinical entity termed delayed organophosphate encephalopathy (DOPE) or “CNS intermediate” is probably akin to type II paralysis. Coma with absent brainstem reflexes or encephalopathy has been reported after 4-day of normal consciousness and spontaneously resolved after another 4-day.[44,66] The clinical distinguishing feature between “brain death” and this “mimic” was “small miosed pupils” in patients with DOPE. The delay in coma onset was attributed to the slow release and re-distribution of the lipid soluble OP compounds with saturation of the CNS receptors over time rather than immediately. Since OP compounds cause irreversible binding, if the rate of regeneration of acetylcholinesterase receptors was slower than that of inhibition, then symptoms could persist or worsen over time. This hypothesis is supported by the persistently low pseudocholinesterase levels and increasing atropine requirements during coma.[44] The electroencephalogram in patients with late-onset coma showed features consistent with encephalopathy. Mitochondrial dysfunction, reported with chronic exposure to dichlorvos[67] may also play a role in delayed coma. Delayed onset extrapyramidal signs are not uncommon. In the earliest report[68] six patients manifested dystonia, rest tremor, cog-wheel rigidity and choreo-athetosis, 4-40 days after poisoning and disappeared spontaneously in 1-4 weeks. More recently,[45] similar features were described in 4 patients between 5 and 15-day, with complete recovery. Cerebellar ataxia has also been described as a delayed presentation.[69]

Late onset symptoms

The classical late onset neuropathy in OP poisoning, OPIDP is characterized by distal weakness that occurs 2-4 weeks after OP exposure. In a retrospective patient cohort, OPIDP developed in 34.2% between the 14^th and 22^nd-day following poisoning and was characterized by cramping pain and paresthesias of the extremities followed by weakness of the distal limb muscles, especially in the legs.[70] The molecular target for OPIDP is considered to be the neuropathy target esterase which is inhibited by OPs.[46,71] Electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities.[71] Nerve biopsy may show features of axonal degeneration with secondary demyelination.[71] Recovery is, usually, complete, particularly in the young. However, mild weakness with increase in vibration threshold may persist for 2-year following acute poisoning.[72] Other late onset features reported include cerebellar ataxia, developing about 5-week after acute exposure to an OP[73] and extrapyramidal symptoms at 40-day.[68]

Organ specific manifestations

An organ specific approach enables focused attention and support of specific organ dysfunction. Given that OP compounds are neurotoxic insecticides, the dominant organ involved in acute and chronic exposure is the nervous system. The spectrum of neurological manifestations is summarized in Table 4.

Neurological manifestations

Three types of paralysis are described. Type I paralysis, characterized by weakness, fasciculations, cramps and twitching, occurs acutely with the cholinergic symptoms. Type II paralysis, seen in 80-49%,[74,75,76] occurs more insidiously 24-96 h following poisoning[56] and has a predilection to proximal, neck and respiratory muscles and cranial nerves with recovery in 1-2 weeks. Type III paralysis characterized by distal weakness occurs 2-3 weeks after poisoning with recovery in weeks to months.[70] Weakness of specific muscle groups at sites of dermal exposure,[49] cranial nerve palsies,[77] supra nuclear gaze palsy,[78] isolated laryngeal paralysis[59,60,61,62] and diaphragmatic paralysis[63] are all reported.

Restlessness, delirium, agitation, convulsions or coma may occur with acute exposure while neuropsychiatric symptoms and signs [Table 4] termed chronic organophosphate induced neuropsychiatric disorder may occur with chronic exposure.[79] Extrapyramidal manifestations,[45,68] ocular signs,[78,80,81,82,83] ototoxicity,[84] presentation as a Guillain-Barre syndrome[85] and sphincter involvement[86] are also described [Table 4].

Cardiovascular manifestations

Cardiac manifestations are observed in about two-thirds of patients with OP poisoning [Table 5].[13,14] Common electrocardiographic findings are QTc prolongation, ST-T segment changes and T wave abnormalities.[13,14,87,88,89,90] Other cardiac manifestations include sinus bradycardia or tachycardia, hypotension or hypertension, supraventricular and ventricular arrhythmias and ventricular premature complexes and noncardiogenic pulmonary edema [Table 5].[91]

Death due to cardiac causes in OP poisoning occurs either due to arrhythmias[13] or severe and refractory hypotension.[92] Although shock is primarily vasodilatory,[92,93,94] circumferential endocardial ischemia with cardiogenic shock and leading to death has also been reported with Malathion poisoning.[95] Necropsy of patients who died following OP poisoning has revealed cardiac discoloration or blotchiness, patchy pericarditis, auricular thrombus and right ventricular hypertrophy and dilatation.[12] Myocardial interstitial edema, vascular congestion, patchy interstitial inflammation, mural thrombus and patchy myocarditis were the histological findings.[12] OP poisoning presenting as cardiac arrest[96] and late onset, prolonged asystole 12-day following poisoning[97] have been described.

Respiratory symptoms

Respiratory symptoms are common in OP poisoning. Muscarinic effects of salivation, rhinorrhea, bronchorrhea and bronchospasm contributed to hypoxemia and increased work of breathing. Nicotinic effects result in muscle weakness and paralysis and predispose to hypercapnic respiratory failure. Central effects of agitation, restlessness and seizures further compromise respiratory function.

In large cohorts, respiratory failure is reported to occur in 24-66% of patients.[3,10,98,99] Severity of poisoning was the primary determinant of respiratory failure.[99] Other factors contributing to respiratory failure include pneumonia,[98,99] cardiovascular collapse,[99] acute pulmonary edema[100] and acute respiratory distress syndrome.[101]

The mechanism of respiratory failure has been explored in experimental models. As described earlier, OP compounds cause excitatory changes in the respiratory control regions with an initial increase in phrenic nerve output and subsequent sudden cessation of activity.[25,26,27] More recently, in a rodent model, exposure to dichlorvos caused a rapid lethal central apnea[102] that was potentiated by hypoxia[103] and protected by vagally mediated feedback signals.[104] In animals sustained with mechanical ventilation, following central apnea, there was progressive pulmonary insufficiency.[102] Brief central apnea and complete acetylcholinesterase inhibition of the brainstem has also been reported with crotylsarin, another OP compound.[105] In other studies, paraoxon failed to produce apnea in a rat model, although postinjection and throughout the study, there was a significant decrease in the respiratory frequency and a significant increase in the expiratory time without modifications in the inspiratory time.[106]

Other features

Gastrointestinal symptoms [Table 1] occur early in OP poisoning and are rapidly reversed with atropine therapy. There are concerns that atropine slows down intestinal transit time and prolongs OP toxicity. In one series, persistence of the OP in the gut was demonstrated 10-day after poisoning.[107] Atropine therapy may also preclude early enteral feeding in OP poisoned patients. However, in a pilot study, early administration (by 48-h) of hypocaloric feeds was associated with gastric stasis in only 6.9% of patients receiving enteral feeds.[108]

Pancreatitis is not uncommon in OP poisoning[109,110,111,112] and reported in 12.8%.[112] Metabolic complications such as hyperglycemia and glycosuria[6,113] and OP intoxication presenting as diabetic ketoacidosis[114] are also described.

Conclusions

Three facets of approach to the symptoms and signs in OP poisoning have been presented. Although all OP compounds are generally considered within a single group entity, it is recognized that di-methyl and diethyl OP poisoning have different outcomes.[3] Each individual compound also has unique characteristics and outcomes.[115] Other differences such as lipid solubility, biochemical characteristics (oxon-thion), WHO class[116] and nature of solvent used further make each OP compound unique. These need to be kept in mind when approaching a patient with OP poisoning.