Pharmacology & Poisoning
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A 21 year old migrant fruit-picker is brought to ED unwell after accidentally ingesting some liquid fertiliser while working on the farm. He is sweating with excessive lacrimation. His observations are: BP 90/60, HR 60 bpm, RR 16, SpO2 97% OA. What is the most appropriate management?
Answer:
All patients with suspected significant exposure to organophosphates should be treated presumptively, as treatment needs to be started before test results are returned. The initial approach is focused on cardiorespiratory resuscitation and supportive care. This involves very early use of rapidly escalating doses of atropine (2 mg intravenously initially, followed by double doses (e.g. 4 mg, 8 mg, 16 mg, etc.) every 5 minutes until secretions are controlled and chest is clear), as well as intravenous fluids, airway maintenance, and ventilation.Organophosphate Poisoning
Pharmacology & Poisoning
Last Updated: 17th March 2023
Poisoning occurs after dermal, respiratory, or oral exposure to either organophosphate pesticides (e.g. chlorpyrifos, dimethoate, malathion, parathion) or nerve agents (e.g. tabun, sarin), causing inhibition of acetylcholinesterase at nerve synapses.
Pathophysiology
Organophosphates are used as pesticides in a wide range of settings including agricultural spraying, domestic baits and sprays, termite treatments, and lice and tick products. They may also be used as chemical weapon nerve agents; however, these are different from pesticides in that they have been specifically selected for their unfavourable characteristics.
The primary mode of action of organophosphates is to inhibit neuronal acetylcholinesterase (AChE). This leads to excessive acetylcholine at sympathetic, parasympathetic, central nervous system (CNS), and neuromuscular junction sites. Parasympathetic effects are predominant early on in most poisonings, causing excessive secretions, bronchospasm, diarrhoea, and pinpoint pupils. Sympathetic effects may lead to hypertension and tachycardia. CNS cholinergic effects are important in severe poisonings, as they contribute to seizures and respiratory failure. Neuromuscular junction stimulation leads to early fasciculations and may lead to weakness that persists for days to weeks beyond the other features.
Clinical features
In most cases, diagnosis is based on a history of exposure with characteristic signs of cholinergic excess. This can be difficult when the patient is inadvertently exposed or is unconscious or confused. A therapeutic trial of atropine should be ordered in all suspected cases or if diagnosis is in doubt, as this is a quick and safe way to confirm diagnosis.
The onset of symptoms and signs may be rapid or delayed by up to 1 day, depending on whether the agent requires metabolic activation for its toxicity. A history of working with pesticides and/or previous self-harm, depression, drug or alcohol addiction, or mental illness may support the diagnosis.
Minimal exposure (e.g. dermal) may result in an influenza-like syndrome (e.g., fatigue, runny nose, headache, dizziness, anorexia, sweating, diarrhoea, and muscle weakness). Nausea and vomiting are common. The patient may also report visual disturbances such as blurred vision, or incontinence.
The most specific features on examination are fasciculations (e.g. of the periorbital, chest, or leg muscles) and excessive secretions (e.g. lacrimation, salivation, or bronchorrhoea). A distinctive odour from the solvent may be noticed. The pupils are typically pinpoint and will not respond to naloxone. Chest crackles and rhonchi may be present from excess mucous secretions, indicating bronchospasm, or pulmonary oedema. Faecal or urinary incontinence may be noted. Mild to moderate hypothermia is often present on admission if atropine treatment has not been given. Seizures and respiratory failure are more common with severe poisoning (e.g., due to deliberate ingestion or chemical warfare).
The mnemonic DUMBELS (Diarrhoea, Urination, Miosis, Bronchorrhoea, Emesis, Lacrimation, Salivation) can be used to remember the cholinergic features.
Deep tendon reflexes are frequently increased early on and decreased or absent later. Delayed-onset central nervous system and peripheral (predominantly motor) neuropathy are uncommon, but may be severe and can lead to permanent disability.
Heart rate and BP are not helpful signs, as they may be increased or decreased. Oxygen saturation is usually low. The patient may be semi-conscious or in a coma.
Investigations
- Response to atropine
- All patients with suspected poisoning should receive a therapeutic trial of atropine (1 to 2 mg given intravenously).
- After atropine administration, patients who have not been poisoned by organophosphates will tend to have dry skin and mucous membranes, increased heart rate, moderately dilated pupils, and decreased bowel sounds.
- If few or none of these features are seen, the likelihood of organophosphate poisoning is greatly increased.
- Cholinesterase activity
- This test is used when diagnosis needs confirmation, but is considered less useful than an atropine trial because treatment needs to be initiated before the test results are available.
- Plasma cholinesterase is usually depressed below normal in significant organophosphate poisoning; however, while this is a sensitive marker of exposure, it is not a good marker of severity.
- Chest x-ray
- Aspiration pneumonia is a very common complication, and CXR should be ordered if chest signs are focal or not responsive to atropine
- ECG
- QT prolongation and arrhythmias may occasionally be seen on ECG, therefore, an ECG should be ordered in symptomatic patients and repeated if an abnormal heart rate or hypotension are persistent
- ABG
- Blood gases should be ordered to monitor for respiratory failure and metabolic acidosis.
Management
- All patients with suspected significant exposure should be treated presumptively, as treatment needs to be started before test results are returned.
- The initial approach is focused on cardiorespiratory resuscitation and supportive care. This involves very early use of rapidly escalating doses of atropine (2 mg intravenously initially, followed by double doses (e.g. 4 mg, 8 mg, 16 mg, etc.) every 5 minutes until secretions are controlled and chest is clear), as well as intravenous fluids, airway maintenance, and ventilation.
- After the patient is stabilised, the next step is decontamination. The single most important step is the prompt removal of clothing (down to underwear if possible). This should be as quick as possible and ideally within 15-20 minutes following exposure. Dry decontamination should then be undertaken using dry absorptive materials such as paper tissue (e.g. blue roll, paper towel, toilet paper), surgical dressings, cloths etc. to gently blot or rub any exposed skin surfaces, starting at the face/head/neck and moving down and away from the body. Where hair is contaminated wet decontamination of hair is recommended but this should follow the disrobe and dry decontamination process. Evidence suggests that for non-caustic chemicals immediate disrobing followed by dry decontamination is a safer, quicker and more effective option. This also reduces or eliminates the risk associated with the wash-in effect, where the dermal absorption of certain chemicals may be significantly enhanced by the presence of water, particularly organophosphorus compounds and sulfur mustard. Thus the default process for non-caustic chemicals is to disrobe followed by dry decontamination.
- Pralidoxime (an oxime) can also be given to reactivate inhibited acetylcholinesterase. However, it only reactivates 'non-aged' acetylcholinesterase-organophosphate complexes. Pralidoxime is, therefore, of limited or no effectiveness against organophosphates that form rapidly aging acetylcholinesterase complexes. Pralidoxime is often given in severe poisoning cases, but evidence is conflicting.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
