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A26-year-old man presented to the authors' emergency department (ED) in Lancashire at 05:15, having taken a deliberate overdose of 2,4-dinitrophenol (DNP). The patient's medical history was significant for asthma, anxiety, depression and deliberate self-harm. There was also a history of three previous overdoses (of paracetamol and zopiclone), suicidal ideation, severe acne, body dysmorphia and anabolic steroid use. He was known to mental health services.
Collateral history suggested the patient had been taking DNP orally as a bodybuilding supplement. His drug history was significant for allergies to erythromycin and tetracyline (rash) as well as citalopram intolerance (worsening anxiety and insomnia). Repeat prescriptions included diprobase and fluoxetine, though compliance was reportedly poor. The patient's social history included employment as a chef, living with his mother, being an ex-smoker of 5 pack-years and a significant alcohol intake of >160 units/week periodically.
Clinical course
The patient presented to his mother in an agitated state at 04:20, admitting to having deliberately ingested DNP (quantity unknown) at approximately 01:00 in an attempt to end his life. Emergency medical services (EMS) were called for at 04:29, dispatched at 04:31 and were with the patient by 04:51. Time on scene was short given his physical appearance and agitation; EMS observations were notable for a respiratory rate of 44, saturations of 98% on room air, normotension with a capillary refill time <2 seconds, tachycardia at 172 bpm and normothermia. The patient was alert but agitated. The EMS left the scene at 04:58 and arrived at the ED at 05:09, where the patient was admitted directly to a resuscitation bay. The attending EMS personnel had been unable to gain intravenous access or obtain an ECG because of the patient's agitated state.
Observations at ED triage demonstrated tachypnoea, tachycardia, a point-of-care glucose level of 10.0 mmol/litre, a temperature of 36.6°C and objective confusion (Glasgow Coma Scale: 13; E4, V4, M5). The patient was promptly reviewed by an emergency medicine physician and found to be in a poor condition with diaphoresis, vomiting, agitation and complaints of nausea and dizziness. All observed skin and his sclera were notably yellow in colour. This was documented on his initial assessment as jaundice, although it was later considered to be subcutaneous deposition of DNP or dermal contamination. Liver function tests, including that for bilirubin, were normal.
Collateral history from his mother indicated he had taken no overdoses since 2016 but that he had ‘stormed’ into her room in a distressed state professing to have taken this overdose and feeling very unwell.
Routine ‘overdose bloods' were taken promptly, along with arterial blood gas (ABG) measurements, which demonstrated respiratory alkalosis in keeping with his tachypnoea. Laboratory blood results from this sampling time revealed haemoconcentration and an acute kidney injury, but at this point were otherwise not particularly remarkable (Table 1).
| Measurement | Result |
|---|---|
| Haemoglobin | 185 g/litre |
| Packed cell volume | 0.56 |
| White cell count | 9.5 x 109/litre |
| Platelets | 285 x 109/litre |
| Sodium | 144 mmol/litre |
| Potassium | Haemolysed |
| Urea | Haemolysed |
| Creatinine | 173 μmol/litre |
| eGFR | 46 ml/min/1.73m2 |
| Creatinine kinase | 143 IU/litre |
| Bilirubin | 18 μmol/litre |
| INR | 0.9 |
| Aspirin | <10 mg/litre |
| Paracetamol | <10 mg/litre |
The patient continued on a worrying trajectory, with a persistent sinus tachycardia at 160–180 bpm and pyrexia at 38.4°C. As the ingested substance was known, ‘ToxBase’ (the clinical toxicology database of the National Poisons Information Service) was consulted and warned of rapid deterioration and lethality. At this point, an ED consultant became involved and both anaesthetic and intensive care input requested. Diazepam (10 mg IV) was given for agitation, the patient was fully exposed and active cooling with ice packs to the nape of the neck, groin and axillae commenced. Oxygen, via a 15 litre/minute non-rebreathe mask, was applied. Two peripheral intravenous cannulae were inserted and a bolus of crystalloid commenced.
The anaesthetic trainee on call arrived and, noting the patient's profound agitation and physiological derangement, prepared for rapid sequence induction. The intensive care trainee on call, who had been called to attend urgently, arrived at 05:45 and agreed with the need for prompt control of the situation with intubation, mechanical ventilation and immediate transfer to the ICU for aggressive management, namely active cooling and sedation as per ToxBase.
Resuscitation
While preoxygenation was being undertaken and rapid sequence induction drugs prepared, the patient became unresponsive and globally flaccid. The monitored 3-lead ECG demonstrated a change from sinus tachycardia to broad complex bradycardia, which deteriorated rapidly to asystole as defibrillation pads were being applied. Loss of cardiac output was confirmed, cardiorespiratory resuscitation started as per Advanced Life Support (ALS) guidelines (Resuscitation Council UK, 2015) and tracheal intubation undertaken.
Resuscitation efforts included the administration of calcium chloride, an insulin/dextrose infusion and sodium bicarbonate 8.4%. This was in view of a first intra-arrest femoral venous blood gas (VBG) result, demonstrating profound respiratory acidosis associated with hyperkalaemia.
It was clear from the outset that resuscitation efforts would need to be continued for a prolonged period; therefore, an external automated chest compression device was applied. This was welcomed as staff were finding it increasingly difficult to maintain an appropriate depth and force of chest compressions. It then became increasingly apparent that the patient's chest wall (and entire body) were becoming rigid, such that the external compression device was rendered ineffective and discontinued. Simultaneously, manual ventilation was proving very difficult. Given these findings, a brief discussion was had as to whether this was representative of the warnings from ToxBase regarding muscle rigidity. It was agreed that dantrolene would be given in as efficient a manner as possible.
With intravenous access repeatedly failing and further cannulation attempts proving futile, 100 mg of dantrolene was obtained from theatre and administered via a tibial intraosseous device. Muscular rigidity persisted, with chest compressions and ventilation remaining difficult. A further femoral VBG revealed an altered picture of profound metabolic acidosis, though a respiratory component suggested adequate ventilatory support after dantrolene administration.
A summary of this patient's blood gases are given in Table 2, from initial assessment in resuscitation via ABG to the point of a second intraresuscitation VBG.
| Arterial blood gas 05:18 | Femoral blood gas 06:23 | Femoral blood gas 06:42 | |
|---|---|---|---|
| pH | 7.49 | 7.16 | 7.09 |
| Pa or PvO2 | 10.45 kPa | 1.6 kPa | – |
| Pa or PvCO2 | 4.08 kPa | 16.9 kPa | 3.5 kPa |
| Base excess | 0.9 mmol/litre | 8.2 mmol/litre | −20.4 mmol/litre |
| Bicarbonate | 23 mmol/litre | 43.9 mmol/litre | 7.9 mmol/litre |
| Potassium | 5.4 mmol/litre | 8.8 mmol/litre | 5.0 |
| Lactate | 1.78 mmol/litre | – | – |
Resuscitation efforts were continued to a total of 33 x 2-minute cycles, during which documented 14 x 1 mg doses of intraosseous adrenalin were given. At just over 1 hour of ALS algorithm management, a team decision was taken to cease. The patient's mother, who was outside the cubicle and being kept updated as to our best efforts, was informed and dignified care after death procedures were undertaken.
Asystole had persisted throughout CPR. Non-expert focused echocardiography was undertaken towards the end of resuscitation efforts, suggesting cardiac standstill with no pericardial effusion or chamber dilatation. The time of death was recorded as 07:03 and the police were informed as per protocol.
During the resuscitation, an ED nurse had telephoned the National Poisons Information Service (NPIS), available on the ToxBase website, to request expert advice on the specific situation. A toxicology consultant subsequently contacted the ED and highlighted the significant risk to staff from DNP contamination and transdermal absorption. All staff members were contacted (several having gone home after morning handover) and advised to undertake thorough handwashing and to shower. No staffillness or symptomatology were reported.
Discussion
DNP is an industrial chemical used in the manufacture of munitions, pesticides, dyes and as a chemical in photograph development (ToxBase, 2018).
Reports of occupational DNP poisoning date back to the First World War among a group of French miners, with the first noted death in 1918 (Warthin, 1918). Animal studies demonstrated effects including weight loss (Tainter et al, 1933). In 1933, Maurice Tainter at Stanford University noted the marked weight loss associated with human ingestion of DNP (Grundlingh et al, 2011). As a result, it became popular and was available without a prescription (Siegmueller and Narasimhaiah, 2010), with dosages of 3–5 mg/kg (Cutting and Tainter, 1932) being associated with a 50% increase in metabolic weight and subsequent weight loss.
However, as the use of DNP became more widespread, it became apparent that ‘a new toxicologic problem seems to be developing’ (Tainter, 1935), with serious cases of deliberate and accidental poisoning observed. DNP was subsequently banned by the Federal Food, Drug and Cosmetic Act of 1938 (Colman, 2007) and described as ‘extremely dangerous and not fit for human consumption’ (Grundlingh et al, 2011).
Following this, the use of DNP and toxicity reports waned for many decades only to see a resurgence fuelled by illegal sales over the internet. After the death of a Finnish bodybuilder, the UK's Food Standards Agency (FSA) issued a health warning in 2003 and the sale of DNP in the UK is illegal (FSA, 2019). DNP-related fatalities are on the increase in the UK (Thomas, 2019) with five cases reported to the National Poisons Information Service between January and June 2018, compared with only three cases in all of 2016 and 2017. Since 2011, 23 fatalities have been attributed to DNP in the UK, although this includes only deaths reported to the National Poisons Information Service, the FSA and the Office for National Statistics. Although most cases describing DNP toxicity and death involve oral ingestion, illness and mortality may also be caused through dermal contact and inhalation (Lu et al, 2011).
Regardless of the route, DNP causes the uncoupling of oxidative phosphorylation, preventing the storage of energy in the form of adenosine triphosphate (ATP) (Tainter et al, 1933; Grundlingh et al, 2011; Ma et al, 2017; ToxBase, 2018). This leads to increases in heat production and basal metabolic rate, necessitating catabolic weight loss to meet energy requirements. A case series of 113 patients reported an average 4 kg weight loss over 40 days (Tainter et al, 1933). The ensuing sympathetic toxicological profile may progress to profound hyperthermia, methaemoglobinaemia, seizures, coma, muscle rigidity, rhabdomyolysis, multi-organ failure, cardiorespiratory arrest and death. This may occur despite early intervention and maximal medical therapy (Thomas, 2018). Dermal contact results in distinct yellow discolouration of the skin, or black in severe exposure (Lu et al, 2011).
DNP is sold illicitly as a weight-loss or bodybuilding preparation and is available as a powder and a tablet/capsule. The latter are typically offered in 100 mg or 200 mg preparations with a suggested dose of 2–10 mg/kg/day for one week, cycled with a week off (ToxBase, 2018). There is significant variability in response and toxicity, with these ‘recommended’ weight loss dosages risking significant harm.
This case report describes a fatality that manifested most of the cardinal features of significant, acute ingestion of DNP through suspected intentional overdose of an unknown quantity. Case reports of survival are not common in significant acute ingestion. However, there are case reports of survival where patients ingested staggered doses of more than twice the typical daily regimen (Ma et al, 2017) and in a symptomatic patient after acute ingestion of 2.4 g (van Veenendaal et al, 2011). Doses of 10–20 mg/kg may prove fatal (Harris and Cocoran, 1995), with one review article (Grundlingh et al, 2011) stating the lowest recorded lethal human dose was 4.3 mg/kg, again demonstrating a significant risk of harm within the ‘typical’ dosage regimen.
Similarly, one early case report highlighted death from the ingestion of 2.8 g divided over 5 days (Poole and Haining, 1934). Most reported fatalities relate to acute, intentional ingestion of an estimated 2.8–5 g (Siegmuller and Narasimhaiah, 2010; Bradbury and Vale, 2011; Grundlingh et al, 2011; Holborow et al, 2016) i.e. >28 100 mg tablets/capsules. However, the authors note that the illicit sale of DNP suggests that wide variation in standardisation, manufacture, product dosage and labelling are likely to exist.
A summary of the main signs and symptoms that may be encountered during patient assessment is given in Table 3.
| Airway | Obstruction (Glasgow Coma Scale (GCS)) |
| Breathing | Tachypnoea |
| Hypoxia | |
| Circulation | Tachycardia |
| Dysrhythmia | |
| Hyper/hypotension | |
| Cardiac arrest | |
| Disability | Agitation |
| Combative | |
| Reduced GCS score | |
| Seizure | |
| Vomiting | |
| Exposure | Hyperthermia |
| Flushed | |
| Discoloured yellow/black | |
| Rash | |
| Pruritis |
The treatment of DNP poisoning is essentially supportive in terms of airway management, cardiorespiratory support, sedation and hyperthermia management. All cases of severe toxicity should be discussed with the National Poisons Information Centre immediately (UK: 0344 892 0111 Ireland: (01) 809 2566). In the event of public or workplace exposure, the Chemical Incident Hotline (UK: 0344 892 0555) ought to be contacted immediately, as well as the hazardous area response team.
Initial personal protective equipment (PPE) and decontamination efforts should follow national (ToxBase, 2018; National Institutes for Health US National Library of Medicine (NIH US NLM), 2019) and local policies for hazardous substances, with personal protection being paramount. The patient should be disrobed and treated in a well-ventilated area. The National Library of Medicine in the US, is available in both desktop and mobile phone app formats. This service recommends chemical protective clothing including gloves, boots and goggles and, in confined spaces, the use of respirators and other breathing apparatus (NIH US NLM, 2019). Industrial incidents involving DNP are an extreme hazard, notably around the risk of explosion if DNP is subjected to friction, shock, heat or fire. Detailed discussion of this is outside the remit of this case report; however, priorities include specialist team activation, immediate leak/spill isolation to 100 m and scene evacuation to an 800 m cordon (NIH US NLM, 2019).
The risk to responders in cases of patient DNP ingestion is low, although PPE must be used and care taken to avoid contact with contaminated surfaces or skin. Given the propensity towards rapid deterioration and death, and the potential benefits of early and aggressive critical care input, strong consideration should be given to activating local services that can provide critical care interventions. This may include advanced airway management, sedation, rapid sequence induction, invasive monitoring, vasoactive medications and invasive cooling. Given the risk of contamination, patient instability and extreme agitation, the use of a helicopter as a means of conveyance is unlikely to be permitted.
Dantrolene has been reported as potentially beneficial in controlling hyperthermia, similar to its effects in malignant hyperthermia (Kumar et al, 2002). Some proponents suggest it should be used early in DNP toxicity (Siegmuller and Narasimhaiah, 2010) and at a higher initial dose than suggested by ToxBase (2018). Conversely, some have argued that dantrolene has no place in the management of DNP toxicity, suggesting it is biologically implausible as a treatment (van Schoor, 2018).
All patients presenting to health professionals with suspected DNP ingestion should be conveyed to hospital, regardless of symptomatology or suspected dose. Patients ingesting large quantities of DNP acutely at one time tend to become unwell at around 7–8 hours, with symptoms consistently developing in less than 10 hours (Bartlett et al, 2010; Grundlingh et al, 2011), although onset may occur in less than 4 hours (Purvine, 1936). The average time from ingestion to death is in the region of 14 hours. As such, the time period for presentation, recognition, treatment instigation and escalation of care is short. Asymptomatic patients with a suspected or confirmed history of DNP exposure should be observed and monitored for a minimum of 12 hours, and this should include checks on cardiac rhythm, respiratory rate, oxygen saturations and temperature.
Conclusion
Given the recent increase in reported deaths, DNP use seems to be on the rise among bodybuilders, weight-loss enthusiasts and those intending to harm themselves. As it is an unregulated, illicitly supplied substance with considerable inter-user variability, responding EMS staff must be vigilant. The safety of responding EMS staff is paramount, with the use of PPE and specialist advice recommended.
Prompt management with fluids, anxiolysis and hyperthermia treatment should be instigated within available prehospital standard operating procedures, with EDs pre-alerted about the patient's arrival. The receiving department should be made aware of suspected or confirmed DNP ingestion, so ToxBase can be consulted and preparatory actions undertaken, including the involvement of anaesthetic and intensive care personnel.
Dantrolene, although its use is debated, remains part of the recommended treatment where muscle rigidity is observed. However, its consideration should not preclude the early instigation of other supportive therapies and monitoring.
All those exposed to DNP should follow ToxBase advice for decontamination and seek hospital assessment and specialist advice if in any doubt.