Role of intravenous lipid emulsion therapy and packed red blood cell transfusion as adjuvant treatment in the management of a child with severe organophosphate poisoning (chlorpyrifos)

Discussion

The orange-coloured liquid involved in this case was identified as chlorpyrifos, a broad-spectrum lipophilic chlorinated OP insecticide. Chlorpyrifos is rapidly metabolised by oxidative desulfuration to oxon and then undergoes hydrolysis to yield 3,5,6-trichloro-2-pyridinol.9 The active metabolite inhibits and inactivates synaptic AChE enzymes. Symptoms begin once sufficient AChE concentration has accumulated at the neuromuscular junction leading to excessive cholinergic stimulation of the muscarinic and nicotinic cholinergic receptors. Clinical manifestation of OP toxicity may be variable because cholinergic receptors are found in both sympathetic and parasympathetic nervous systems. As seen in our case, the patient’s initial presentation was consistent with severe OP poisoning. Her symptoms reflect an increased muscarinic receptor activity better remembered as the cholinergic toxidrome mnemonic DUMBBBELS (diarrhoea, urinary frequency, miosis, bradycardia, bronchorrhoea, bronchoconstriction, emesis, lacrimation and salivation). More so, she also exhibited signs of nicotinic receptor overstimulation which presented as muscle weakness, respiratory failure, tachycardia and hypertension. In moderate and severe toxicity, AChE stimulation of nicotinic receptors leads to an effect similar to that of a depolarising neuromuscular blocking agent (eg, succinylcholine) which explains our patient’s profound muscle weakness, paralysis, respiratory failure and rhabdomyolysis.10 She was also comatose and had seizures which are part of the central nervous system manifestations found in severe OP toxicity, as classically reported in the literature.10 11 In our institution, we classify OP severity based on clinical signs at presentation.2 The presence of both muscarinic and nicotinic signs, as well as central nervous system depression, classified our patient as having severe OP toxicity.

Ideally, measurement of AChE activity should be done for all patients suspected with OP poisoning. However, this should not be used as the sole basis to predict outcomes or to manage cases since measurement of AChE activity is not universally available and activity does not always directly correlate to the patient’s clinical status.6 In low-resource settings with limited ICU capacity, patients with OP poisoning who will require ventilatory support or have worse prognosis should be identified using the Peradeniya Organophosphorus Poisoning (POP) scale. This scale grades the severity of poisoning based on six clinical parameters at presentation (pupil size, presence of fasciculations, respiratory rate, pulse rate, level of consciousness and presence of seizures). Patients with higher severity on the POP scale were associated with a higher rate of morbidity and mortality.12 A recent study conducted in Pakistan among 3300 participants, including teenagers, demonstrated that patients classified as mild poisoning under the POP scale did not require atropine and were associated with the lowest risk for mortality.13 They also observed that the presence of an altered level of consciousness, fasciculations and seizures were associated with a higher score and worse outcomes. A grading of moderate (score >4) or severe (score >8) at presentation was also associated with a mortality rate of 4.4% and 33%, respectively. Although we found no published study validating the utility of this scale among young children, our patient had severe poisoning with a score of 8 at presentation. Her hospital course reflects the need for timely recognition of patients with moderate or severe poisoning at presentation, since they should ideally be managed in an ICU. Early clinical recognition of the toxidrome is still the basis to guide the initial diagnosis and management of OP poisoning.

Following exposure, OPs are well absorbed in the lungs, gastrointestinal tract, mucous membranes and conjunctivae. The onset and severity of symptoms depend on the route, lipophilicity, quantity, degree of exposure and the OP to which the patient was exposed to.10 14 But more importantly, depending on the chemical properties of the active OP ingredient, most agricultural insecticides are formulated with a mixture of solvents, including, but not limited to, dimethoate, cyclohexanone, xylene and methanol.14 Based on other chlorpyrifos-based insecticides, aromatic hydrocarbons such as xylene are common additives.15 16 For HomeTrek insecticide, the mixture combines chlorpyrifos (48% concentration) with Solvesso 150, an aromatic hydrocarbon solvent naphtha. Although Solvesso 150 is minimally toxic with an oral LD50 of 7050 mg/kg, significant ingestion may cause central nervous system depression, respiratory tract inflammation and gastrointestinal tract irritation.17 18 As seen in our patient, hydrocarbons may lead to aspiration pneumonitis and these solvents potentially complicate the management of OP toxicity. Although the importance of solvents to human poisoning remains unclear, particular attention to the characteristics and chemical nature of these additives and solvents remains in keeping. Insecticides with potential risk for human toxicity should explicitly include a brief description of their major additives and solvents in their product label to guide clinical management in cases of inadvertent exposure.

In brief, the preferred approach in OP poisoning involves decontamination, resuscitation and stabilisation following the ABCDE approach (airway, breathing, circulation, disability and exposure). If a patient has imminent signs of respiratory failure, airway must be immediately secured since respiratory depression with hypoxia is the most common cause of mortality among those with severe OP poisoning.14 To prevent secondary cutaneous and inhalational exposure to OPs which may compromise health service delivery, healthcare staff involved in decontamination and resuscitation should be mindful of their own safety and wear appropriate proper protective equipment.19 After the initial management, antimuscarinic antagonists (eg, atropine and glycopyrrolate) and AChE reactivators (eg, pralidoxime or obidoxime) should be given as antidotes without delay. In our institution, atropine is the preferred therapy used for OP toxicity because oximes are not readily available.2 However, as seen in our patient, severe OP toxicity may necessitate large atropine doses to cause iatrogenic toxicity manifesting as tachycardia, hypoactive bowel sounds, hyperthermia, delirium and urinary retention.20 In these cases, dosing should be de-escalated, and treatment should be shifted to another antidote. Regrettably, an alternative antidote was not an option in our setting.

In the management of OP poisoning, it is important to be familiar with three types of OP-associated paralysis. Type I paralysis occurs during the acute cholinergic crisis. Within 48 hours after poisoning, these patients develop profound muscle weakness with severe muscle fibre ischaemia and necrosis.21 22 Type II paralysis (intermediate syndrome) occurs 48–72 hours after poisoning which is associated with the development of neck flexion weakness, decreased deep tendon reflexes, cranial nerve weakness, proximal limb weakness and progression of respiratory depression. Type III OPIDP occurs 2–3 weeks after poisoning.23 Some patients with OPIDP experience distal symmetric polyneuropathy, such as leg muscle cramping, depression of deep tendon reflex and some signs of pyramidal tract involvement. Neurophysiological studies among those with OPIDP show degeneration of the anterior columns of the thoracic and lumbar part of the spinal cord.24 Biochemically, this process occurs when the initial phosphorylation of the neuropathy target esterase ‘ages’ and is thought to be an important prerequisite in the development of OPIDP.25 In addition, the onset and duration of clinical symptoms of OP poisoning depend on the characteristics of OP ingested. OPs with hydrophilic nature are associated with more severe clinical symptoms at presentation but also tend to resolve faster. In contrast, lipophilic OPs with large volume of distribution are associated with recurrent toxicity and delayed clinical manifestations due to the gradual redistribution of OPs from fat stores that protect OPs against drug metabolism.14 In some reports, cholinergic symptoms from lipophilic OPs lasted for 2–3 months with positive detection of residual OPs at 48–75 days postingestion.26 A 3-year-old well child was also reported to have experienced life-threatening OPIDP with transient bilateral vocal cord paralysis following chlorpyrifos ingestion that occurred 2 weeks postingestion and with complete recovery after 6 weeks.27 Because our patient ingested a highly lipophilic OP, we were wary that our patient might develop intermediate syndrome and OPIDP. Fortunately, both syndromes did not occur during her hospital stay and on follow-up.

As seen in our case, some patients may develop seizures, and benzodiazepines remain as the first-line antiseizure medication.6 Other complications of OP toxicity are hyperglycaemia from excessive adrenergic stimulation, hyperamylasaemia from OP-induced pancreatitis, transaminitis from OP-induced liver injury and aspiration pneumonitis.10 28 Other adjunctive therapy in OP toxicity includes giving sodium bicarbonate, magnesium sulfate, intravenous lipid emulsification and packed RBC transfusion.20 29 Sodium bicarbonate may enhance OP clearance through pH-mediated hydrolysis, while magnesium sulfate reduces synaptic acetylcholine release by blocking calcium channel receptors.20

Because of our patient’s worsening clinical status, development of atropine toxicity and unavailability of oximes in our setting, we considered both lipid emulsion therapy and packed RBC transfusion as adjunctive treatment. Recent studies show intravenous lipid emulsion therapy may be given as an antidote to lipophilic local anaesthetic cardiotoxicity with favourable outcome.30 By acting as a ‘lipid sink’ to sequester lipophilic toxins from target tissues, lipid emulsion therapy may help redistribute the poison.7 A small cohort study in India compared participants with OP poisoning who received a single dose of 20% intravenous lipid emulsion therapy to historical controls but found no significant reduction in the risk for mortality.31 However, one systematic review which included six randomised controlled trials among participants with OP poisoning reported that treatment with 20%–30% intravenous lipid emulsion therapy significantly lowered the risk of mortality and progression to respiratory failure.32 Although pooled data showed significant benefit, we were unable to retrieve the results from these trials published in foreign language preventing proper evidence appraisal. Clinicians who will consider lipid emulsion therapy should be aware that acute pancreatitis, acute respiratory distress, lipaemia, cardiac arrest and hypersensitivity reactions have been reported following treatment, although causality has yet to be established.33

On top of lipid emulsion therapy, we also considered giving packed RBC transfusion because of its potential to restore AChE activity by delivering additional erythrocyte cholinesterase to scavenge circulating OPs and its potential to decrease total atropine requirement especially in our patient who developed toxicity.8 34 35 Two studies showed this effect where the recovery of the measurable AChE level was significantly faster by 10–20 hours and total atropine requirement was significantly lower by 20%–30% among those who received packed RBC transfusion (200–400 mL).8 29 These studies also showed that transfusion of fresh RBCs which are stored for less than 10 days showed superiority compared with those in longer storage since AChE activity declines with time.29 To the best of our knowledge, this is the first case report where a small child with severe OP toxicity was successfully treated with both intravenous lipid emulsion therapy and packed RBC transfusion as adjuncts to atropine due to the development of iatrogenic toxicity. Although both adjuncts showed favourable effect for our patient, further studies on their use should be conducted, and careful patient selection should be done to avoid any harm.

On follow-up, we used an electrometric method (Michel) to measure our patient’s RBC cholinesterase activity. This method is based on the hydrolysis of AChE and the production of acetic acid that subsequently decreases the pH of the reaction mixture.36 Our patient’s measured RBC cholinesterase assay taken on day 10 postingestion had an activity that was 45% below normal. It is expected that immediately after an acute ingestion, the decrease in the patient’s RBC cholinesterase activity would be far greater. Hence, our diagnosis of severe OP toxicity. Consistent with the lipophilic nature of chlorpyrifos, repeat RBC cholinesterase assay was still 17% below normal levels at day 35 post-OP ingestion.

This case highlights the active role that paediatricians must play in parental education and anticipatory guidance. Prevention is most important in keeping our children safe from dangerous substances and harmful objects. Especially among those households with children who are ambulatory, curious and exploratory by nature, chemical or toxic substances should not be transferred to juice bottles and canisters which are enticing to unsuspecting children. Here we report the role of intravenous lipid emulsion therapy and packed RBC transfusion as adjuvant treatment in the management of a small child with severe OP poisoning (chlorpyrifos) complicated by atropine toxicity.