1. Introduction

Excited delirium syndrome (ExDS) is defined as acute exhaustive mania and is associated with severe psychomotor agitation, violence, unexpected strength, hallucinations, and paranoia. Hyperthermia, rhabdomyolysis, high blood potassium, metabolic acidosis, cardiovascular and autonomic collapse are symptoms of this life-threating condition [1]. People in a state of ExDS are in an altered mental state with agitation, aggression, paranoia, and panic attacks and are therefore very difficult for police to restrain [2]. When death occurs during a police intervention, a number of questions arise regarding the cause of death, especially when police place the individual in a prone position and use chokeholds, expert grips, handcuffs or pepper spray [3, 4, 5]. Three unexpected deaths in restrained persons with ExDS were analysed. Pepper spray in combination with cocaine intoxication may enhance delirium symptoms because of their synergistic stimulation on dopamine release [6, 7, 8].

2. Case presentations

The authors collected data from law enforcement, prosecution, emergency medical staff, coroners, toxicologists and forensic pathologists and present three unexpected deaths during physical restraint with the use of pepper spray in persons in a state of ExDS (Table 1). The local Ethical Board approved the case presentations, granting waiver of informed consent.

3. Discussion

To date, more than 70 cases of deaths while in custody during restraint directly or indirectly related to exposure to oleoresin capsicum (OC) or pepper spray have been reported in the literature [3, 4, 5]. Most of the victims were in a state of ExDS [3]. O’Halloran reported seven deaths in custody that involved the use of OC spray during the arrest process. In four cases, the death was certified as due to ExDS, in one case the cause of death was listed as asphyxia by compression of the neck and chest due to restraint, and the manner of death was listed as homicide. In no case was the use of OC responsible for the onset of death [9]. Steffee et al. [10] reported that exposure to OC was associated with sudden death in two individuals with ExDS. Similarly, Granfield et al. [4] reported 30 cases of death in custody following OC exposure. Both reviews concluded that OC was not the cause of death in any of the cases, but asphyxia, drug-related factors or natural heart disease were noted. Pollanen et al. [11] reported four deaths in custody during restraint associated with ExDS in combination with OC [11, 12]. Cocaine enhances dopaminergic neurotransmission in the brain by blocking dopamine uptake and prolonging the duration of dopamine in the extracellular space [13]. Chronic cocaine users are particularly prone to developing ExDS, because cocaine can also augment dopamine release as a compensatory adaptive mechanism [14]. Cathinones inhibit dopamine and norepinephrine reuptake, while amphetamines and methamphetamine-like cathinones inhibit the uptake of monoamines dopamine, serotonin and epinephrine, and are at the same time a stimulus for their release [15]. ExDS symptoms are mostly caused by excessive dopamine in the synapses of dopaminergic neurons in the central nervous system [14].

Pepper spray is an incapacitating agent extracted from a plant chilli pepper (Capsicum annuum) and used for restraint and self-defence [3, 16]. Pepper sprays contain from 0.18% to 1.33% major capsaicinoids [6, 17], with a lethal oral dose in humans being 0.5–5 g/kg [18]. The active ingredient is oily OC which causes immediate and transient local inflammatory response at the site of exposure. Burning pain, itching and redness of the skin, swollen eyelids with blurred vision and lacrimation are the most commonly reported symptoms. When inhaled or ingested OC causes a burning sensation in the nasal and oral mucosa with sore throat, chest tightness and dyspnea. Significant systemic effects are uncommon, with only 2.8% of victims in need of medical assistance, mostly due to associated conditions, such as asthma [10, 19]. The irritating symptoms last from 20 minutes to two hours, and skin rashes, itching and sore throat usually disappear within days [6, 18]. In only one case of a young male without any known illness or misuse of drugs did the use of pepper spray cause ventricular fibrillation [6].

Pepper spray in combination with cocaine use can be a lethal combination, as capsaicin potentiates the effects of cocaine [7]. OC in pepper spray causes neurogenic inflammation and interacts with the Transient Receptor Potential Vanilloid subtype 1 (TRPV1) receptors in dopaminergic neurons, and enhances dopaminergic neurotransmission. Marinelli et al. [18] reported in preclinical research that the use of OC increased the activity of dopamine neurons in brain tissue, and that the effects were also concentration dependent. Through these receptors, OC can potentiate the effect of cocaine by blocking reuptake of dopamine [7, 8]. The pathophysiological consequences of cocaine use on the human body are cardiovascular and, psychological changes, along with hyperthermia and damage to other organs [19]. Initially, the body reacts with tachycardia, hypertension and euphoria, but after some time catecholamines are depleted and blood pressure falls [20]. Simultaneously, cocaine blocks cardiac specific sodium channels which slows electrical conduction throughout the heart, resulting in bradycardia. In a short time, a cocaine user progresses from tachycardia with hypertension to bradycardia with hypotension and low cardiac output [21]. Changes in CNS (central nervous system) neurotransmitters, signal molecules and their regulation lead to euphoria and other psychological states [22]. Due to extreme excitation, feelings of endless strength and unrealistic cognition of their surroundings, a user can become extremely physically active, even aggressive, generating increased body heat. Overheating and hyperthermia become dangerous not only because of extensive muscle work but also the body’s diminished ability of heat regulation – a direct action of cocaine on the dopamine receptors’ up- and down-regulation [21]. Along with extreme physical activity and delusions, cocaine can result in decreased appreciation for pain, causing bruising to the extremities [21]. A high concentration of waste products, protein parts and cellular debris in addition to low perfusion and the direct toxic effect of cocaine are devastating for kidney function [23, 24, 25]. Nonselective adrenergic activity and hypoperfusion can cause myocardial ischemia [26], and multisystemic organ failure [21]. Although most patients with ExDS will survive, the mortality is approximately 10% [1]. The mechanism of death in ExDS individuals struggling against restraints remains a topic of debate [27]. Patients in ExDS are often in a state of heavy physical exertion involving antigravity muscles and extremities before and during the physical restraint generating a metabolic acidosis from high oxygen consumption [28]. Stimulant drugs such as cocaine may promote further metabolic acidosis and impair normal behavioural regulatory responses [27]. Concurrent electrolyte abnormalities predisposing to arrhythmias can occur [1]. Restrictive positioning of combative patients may impede appropriate respiratory compensation for this acidemia [27]. It has been shown that the use of the hobble restraint in the prone position decreases mean forced vital capacity by 39.6%, mean forced expiratory volume by 41%, mean heart rate by 21.3%, and mean cardiac output by 37.4% [29]. Strömmer et al. [30] reported that aggressive restraint (i.e., manhandling, handcuffs, and hobble ties) was more common in ExDS and fatal cases. They concluded that a diagnosis of ExDS is far more likely to be associated with both aggressive restraint and death. There is no evidence to support ExDS as a cause of death in the absence of restraint; and a restraint-related asphyxia must be considered a likely cause of the death. Therefore, as recommended by Royal College of Emergency Physicians (RCEM), patient restraint time in ExDS patients should be kept to an absolute minimum - the degree of restraint used must be justifiable, reasonable, for the minimum time necessary and proportional to the situation [31] and followed by aggressive sedation, hydration, monitoring and transport of patients by EMS [1]. The role of EMS personnel is also to increase the awareness of ExDS among medical and law enforcement personnel which would lead to better early recognition and management of ExDS individuals leading to earlier interventions that prevent sudden death. Protocols or guidelines combing law enforcement and EMS efforts to manage these patients should be developed [1].

Persons who are in a life-threatening condition in which they may harm themselves and others need both police attention and appropriate treatment. The initial aim of the management of an individual with ExDS should be the rapid tranquilization (sedation) and minimization of their hyper-exertional state [32]. Therefore, pharmacologic agents should be administered for sedation and prolonged physical restraint should be avoided [32]. Benzodiazepines, antipsychotics, and ketamine have all been suggested as candidate agents to treat ExDS [14, 32, 33]. Benzodiazepines such as lorazepam, diazepam or midazolam bind to gamma aminobutyric acid (GABA) receptors, which are the main inhibitory transmitter in the human brain and can be given intravenously, intramuscularly, intraosseously or even intranasally (midazolam) [32, 33]. Doses of benzodiazepines are typically much higher in ExDS patients than those routinely used in the treatment of agitated or anxious persons. Caution must thus be used, as high doses may cause hypotension and oversedation, with possible synergistic effects if the patient has ingested alcohol or other sedatives [33]. Typical and atypical antipsychotics are also used to treat ExDS. First generation antipsychotics such as haloperidol and droperidol antagonize dopamine in the CNS, and are often used to treat agitation and delirium of psychiatric origin. These medications should be used only with continuous cardiac monitoring because of the risk of QTc interval prolongation degenerating into malignant arrhythmias [32, 33]. Functional N-methyl-_D-aspartate (NMDA) antagonists produce dose-dependent and significant protection against the convulsant effects, and thus attenuate cocaine-induces convulsions and lethality [34, 35]. Anticonvulsant efficacy is achieved by blockade of both competitive and noncompetitive modulatory sites on the NMDA receptor complex [34]. Ketamine, a dissociative anesthetic that acts as an NMDA receptor antagonist, has shown improved clinical results in controlling patients with agitation in a prehospital environment [36, 37]; but should also only be used with continuous cardiac monitoring by experienced medical personal to avoid malignant arrhythmias and hemodynamic collapse.

Supportive treatment via the administration of intravenous (IV) fluids and cooling measures should be initiated after initial sedation. Patients with ExDS can be dehydrated due to increased fluid loss from hyperthermia, hyperventilation (insensible water loss) and profound sweating (diaphoresis) [32, 33]. Therefore, IV fluid replacement therapy is used in most ExDS patients. In the case of hyperthermia, there are several potential treatment options including external cooling, cooled IV fluids or ice packs applied to the neck, groin or axilla [32, 33]. A high index of suspicion for the development of acidosis, rhabdomyolysis and disseminated intravascular coagulation (DIC) should be maintained during the patient workup [32].

4. Conclusions

ExDS can be triggered by different causes such as psychiatric disorders and stimulant drugs, including cocaine. Since excited delirium is a life-threatening situation, police forces should act promptly to stabilize the situation. The use of excessive force, pepper spray, chokehold and prolonged restraint in prone position with hands and legs cuffed at the back during arrest may result in worse patient outcomes. The presence of a medical emergency team is recommended in such cases, with the goals of quick and safe tranquilization, workup of the patient with regular monitoring of vital signs and releasing the patient from restraints. Each patient should later be examined in an emergency department. National guidelines and recommendations need to be developed and implemented with regard to such situations, and all potential participants must be educated about this medical condition and the recommended actions.

Author contributions

RK has contributed to the conception and design of the work, acquisition, analysis, and interpretation of the data and has substantively revised the drafted work. TČG has contributed substantially to the conception and design of the work, the acquisition and interpretation of the data. MS has contributed to the design of the work, analysis and interpretation of the clinical data and has substantively revised the drafted work. IG has contributed to the design of the work, analysis and interpretation of the clinical data and has substantively revised the drafted work. All authors read and approved the final manuscript.

Ethics approval and consent to participate

An ethical approval is not required. The ethics committee is from University Medical Centre Maribor. As the paper does not include identification numbers of the patients, neither the figures of the patients, the ethics committee decided that a written application and approval are not required. The ethical committee email is eticna.komisija@ukc-mb.si.

Acknowledgment

We would like to thank to Supreme State Prosecutor’s Office of the Republic of Slovenia, the Specialised State Prosecutor’s Office of the Republic of Slovenia with a Special Section for providing the relevant information. Thanks to all the peer reviewers for their opinions and suggestions.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.