2,4‐Dinitrophenol: ‘diet’ drug death following major trauma

Summary

There has been a resurgence in the illicit use of 2,4‐dinitrophenol by people wishing to achieve rapid weight loss. Despite its availability, the drug is banned for human consumption as it is toxic and can have fatal consequences. We present the case of a 23‐year‐old man who regularly consumed 2,4‐dinitrophenol to generate fat loss without apparent ill effect. He was involved in a high‐speed road traffic collision and sustained limb‐threatening injuries. The combination of emergency surgery, trauma and 2,4‐dinitrophenol consumption culminated in deterioration under anaesthesia, with subsequent death from multiorgan failure in the intensive care unit 48 h later. Previous cases have reported death from 2,4‐dinitrophenol toxicity alone. We believe this is the first reported case of 2,4‐dinitrophenol toxicity triggered by the additional physiological stress of polytrauma and emergency surgery.

Introduction

The UK National Poisons Information Service has recorded a sharp rise in enquiries relating to 2,4‐dinitrophenol (DNP) toxicity. Marketed as a fat burner or weight‐loss supplement, it is particularly popular with younger adults, has no safe dose and is highly toxic. In May 2019, Public Health England released an alert stating frontline staff should be vigilant for cases of DNP poisoning [1].

A precursor for 2,4,6‐trinitrotoluene (TNT), DNP was initially used by the French in First World War munition factories. In the early 1930s it was proposed as a drug to treat obesity because it increased the metabolic rate, but was later withdrawn due to side‐effects including liver failure and death [2, 3].

Dinitrophenol is now typically sold online as a weight loss supplement. It is used by bodybuilders, and people with eating disorders or body dysmorphic disorder, among others, to achieve rapid weight loss while retaining muscle mass [4]. The primary mechanism of action is uncoupling of oxidative phosphorylation, which causes energy to be released as heat without the production of adenosine triphosphate [4]. This in turn increases the basal metabolic rate as fat is burned to generate energy. Consequently, clinical features of overdose include uncontrolled hyperthermia due to failure of thermoregulatory homeostasis. Additional features of DNP toxicity include tachycardia, tachypnoea and diaphoresis that can rapidly progress to cardiovascular collapse and eventually death [4]. There are numerous reported fatalities from DNP overdose, in part due to its narrow therapeutic window and unregulated manufacture.

We present what we believe to be the first report of a patient who had regularly been taking DNP without apparent adverse effects, but subsequently died following the additional physiological stress response to trauma and operative intervention under anaesthesia.

Report

A 23‐year‐old, 93‐kg man was admitted to a major trauma centre following a high‐speed road traffic collision on his motorcycle. He sustained fractures to his right femur, foot and ankle, a fracture‐dislocation of his right elbow and an unstable lumbar fracture producing altered leg sensation. Given the clinical urgency, he was transferred straight to the operating theatre from the emergency department (ED). Pre‐anaesthetic assessment revealed a previous uneventful mammoplasty, and a drug history comprising DNP, reloxifen, exemestane and two types of steroid, but was otherwise unremarkable. His medications were non‐prescription and taken to burn fat, increase muscle bulk and prevent gynaecomastia from steroid usage. Before anaesthesia he was tachycardiac (120 beats per min), hypertensive (170/50 mmHg) and felt warm to touch. These observations were considered to be in keeping with the stress and systemic inflammatory responses from major trauma, ketamine administration in ED and anxiety before emergency surgery.

After transfer to our main operating theatre complex, anaesthesia was induced with fentanyl, ketamine and midazolam; rocuronium was used for neuromuscular blockade to facilitate tracheal intubation. Anaesthesia was maintained with remifentanil and sevoflurane in the anaesthetic room, then switched to desflurane in the operating theatre due to the anticipated length of multiple procedures. An arterial catheter, temperature probe and urinary catheter were inserted for monitoring.

In the operating theatre, serial arterial blood gas analysis showed significant deterioration with worsening acidaemia, rising lactate and persistent hyperkalaemia (see online Supporting Information Table S1°C and end‐tidal carbon dioxide partial pressures increased significantly even with adjustments to ventilation. Oliguria developed despite aggressive fluid resuscitation and pharmacologic blood pressure support (metaraminol at 7.5 mg.hr^‐1, then noradrenaline 0.07 μg.kg^‐1.min^‐1). Advice was sought from specialists including other consultants in anaesthesia and intensive care, the national malignant hyperthermia centre and a professor of toxicology with expertise in DNP. Volatile anaesthesia was switched to propofol infusion, a clean breathing circuit was established with charcoal filters, dantrolene was administered and active cooling measures were undertaken, including cold intravenous (i.v.) fluids. The loading dose of dantrolene administered was 240 mg, with two further 120 mg boluses in the operating theatre. Deterioration continued as evidenced by sustained blood gas derangement (see online Supporting Information Table S1) despite continued treatment including a total of roughly 8000 ml of i.v. fluid (Hartmann’s solution; sodium chloride 0.9%; two units of blood), and insulin with glucose; therefore, only the patient’s femur and foot were operated on. Fifty millilitres of sodium bicarbonate 8.4% were administered after the penultimate arterial blood gas in the operating theatre and the patient was transferred to the intensive care unit (ICU) with his trachea intubated and lungs ventilated.

Following transfer to ICU from the operating theatre, compartment syndrome in the patient’s right forearm was diagnosed so an immediate bedside fasciotomy was performed. At the same time continuous veno‐venous haemofiltration (CVVH) was initiated for metabolic derangement and severe hyperkalaemia. Within 6 h of arrival on the ICU, the patient’s plasma potassium concentration peaked at 9.0 mmol.l^‐1 so a second CVVH machine was added. Four further fasciotomies for compartment syndrome were required over his admission due to continued rhabdomyolysis (peak creatinine kinase 303,981 iu.l^‐1).

Within 24 h of ICU admission, maximum dose infusions of noradrenaline (1 μg.kg^‐1.min^‐1) and vasopressin (0.04 iu.min^‐1) were required to maintain a target mean arterial pressure of 65 mmHg. Further boluses of crystalloid and packed red cells were given to limited effect. Acidosis and hyperkalaemia continued to worsen despite the addition of a sodium bicarbonate infusion and continued renal replacement therapy. The patient subsequently developed disseminated intravascular coagulation and worsening liver failure, requiring multiple units of fresh frozen plasma, fibrinogen concetrate and platelets. Forty‐eight hours into his ICU admission and 58 h since hospital arrival, he deteriorated further and suffered a cardiac arrest due to ventricular fibrillation. His cardiac rhythm progressed to asystole refractory to resuscitation, which ultimately led to his death.

Discussion

We present a polytrauma patient’s clinical deterioration associated with emergency surgery, initially manifesting as increasing carbon dioxide production, rising temperature, metabolic acidosis and hyperkalaemia. Two primary diagnoses were considered: DNP toxicity and malignant hyperthermia.

Management in the operating theatre included active cooling measures and the administration of multiple doses of dantrolene, with a temporary stabilisation of arterial blood gases. Dantrolene is the pharmacological treatment for malignant hyperthermia and a total of almost 9 mg.kg^‐1 was administered. Malignant hyperthermia is triggered by halogenated volatile anaesthetic agents and suxamethonium but is rare, occurring in approximately 1 in 50,000 to 70,000 anaesthetics [5]. In a malignant hyperthermia crisis there is a loss of skeletal muscle calcium homeostasis; dantrolene specifically reverses this pathophysiological process by binding to the ryanodine receptors of the sarcoplasmic reticulum, preventing further calcium release. With improved understanding of the pathophysiology and clinical features and with the use of dantrolene, mortality from malignant hyperthermia has declined from more than 80% to around 4% [5].

Throughout the management of this patient, we maintained frequent contact with the national malignant hyperthermia centre in Leeds. Since damaged muscle produces unreliable contraction studies, these were not performed, however, genetic screening blood samples analysed post‐mortem did not reveal any potentially pathogenic variants known to be associated with malignant hyperthermia. A diagnosis of malignant hyperthermia is reached by an unexplained, unexpected increase in end‐tidal carbon dioxide, heart rate and temperature. The consensus opinion between the treating clinicians and the malignant hyperthermia centre was that this was not malignant hyperthermia, and that a diagnosis of DNP toxicity would explain the clinical findings. Furthermore, a subsequent toxicology report showed that the blood concentration of DNP detected in this case was of a level consistent with previous fatal cases of DNP poisoning. Mortality from cases of DNP toxicity is high, and our patient demonstrated virtually all the features of a DNP crisis, and notably did not have certain key features of malignant hyperthermia (Table 1).

Table 1.

Clinical features of 2,4‐dinitrophenol (DNP) toxicity and malignant hyperthermia [2, 5] that were present or absent in this patient.

We considered that, as our patient had been taking DNP regularly over a number of months, it is possible there were other contributing factors. Systemic inflammatory response syndrome (SIRS) secondary to major trauma was likely a further component. Features of SIRS include hyperthermia and tachycardia, and SIRS itself can progress to acute kidney injury, acute lung injury and multiorgan failure.

Ketamine was used for analgesia in the ED and for induction of anaesthesia. Ketamine is known to produce stimulation of the sympathetic nervous system and can provide a relatively haemodynamically stable induction of anaesthesia [6]. For this reason, it is a common anaesthetic agent for acute major trauma patients. The elimination half‐life is 2–3 h and does not produce the other clinical features we report, so was ruled out as a cause [7]. Furthermore, there are no reports describing similarly presenting deleterious effects of sympathetic overactivity with the use of ketamine and we do not believe that the use of ketamine contributed to the effects of DNP or sympathetic overactivity seen.

Other differential diagnoses were considered including neuroleptic malignant syndrome, but there was no history of antipsychotic or dopaminergic drug use. Serotonin syndrome would have been unlikely as the patient was not exposed to any known triggers such as selective serotonin reuptake inhibitors or stimulant drugs of abuse, nor did he exhibit signs of agitation or behavioural disturbance. Propofol‐related infusion syndrome was considered; however, sedation was switched to midazolam (along with alfentanil) within 12 h of ICU admission due to cardiovascular instability, and postoperative propofol dosing did not exceed 4 mg.kg^‐1.hr^‐1.

Since 2000, there have been increasing reports of death from DNP intake. Some cases have been linked to deliberate overdoses, others as an unintended consequence of use as a weight loss or bodybuilding supplement [8, 9]. In contrast to this report, prior reports of death have been attributed solely to DNP use and there did not seem to be precipitating factors causing the toxic effects of DNP to manifest. While this patient’s injuries were extensive, we think it unlikely that he would have died as a result of the major trauma without the presence of DNP.

We considered MH as a potential cause but have effectively ruled it out in this case. The features of DNP toxicity as described by Toxbase [2] were virtually all present here (Table 1). Our patient had undergone elective breast reduction surgery in Poland within the previous year; DNP was omitted around the time of surgery and that procedure was uneventful. The elimination half‐life of DNP has been estimated at 10.3 h [10]. While a planned elective procedure cannot be considered to be equivalent to the scenario we describe, it demonstrates an uneventful prior anaesthetic. Although this does not exclude the possibility of malignant hyperthermia, together with negative genetic screening, the presence of toxic levels of DNP, and the lack of response to dantrolene, we consider a diagnosis of malignant hyperthermia very unlikely. This conclusion was supported by the national malignant hyperthermia centre, so family screening was not undertaken.

In contrast to the majority of case reports where DNP toxicity has directly led to death, we have described a different circumstance. The chain of events here is a recent ingestion of DNP, plus a systemic inflammatory response from polytrauma, triggering a runaway DNP crisis, likely exacerbated by a surgical stress response. This case highlights the importance of increased awareness of the effects of DNP. The early signs of DNP toxicity are relatively non‐specific, and toxicity under anaesthesia may be virtually indistinguishable from malignant hyperthermia, other than treatment failure and clues from the drug history. If a patient is taking DNP and is due for elective surgery, surgery should be timed to allow for cessation and clearance of DNP.

Supporting information

Table S1 Serial arterial blood gas analysis (*venous sample taken at pre‐emptive CVVH catheter insertion).