Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

OBJECTIVES: Disulfiram is an adjunct in the treatment of alcohol use disorders, but case reports indicate that disulfiram ethanol reactions are not always recognized in the emergency department. Our first aim is to remind of this risk with two case reports of life-threatening reactions not immediately considered by the emergency physician. The second aim is to estimate the probability that a disulfiram reaction goes unrecognized with the use of a retrospective study of patients admitted to the emergency department.
METHODS: Clinical files of patients admitted between October 1, 2010 and September 30, 2014 to the emergency department were retrospectively screened for the key words "ethanol use" and "disulfiram". Their diagnoses were then scored by a panel regarding the probability of an interaction.
RESULTS: Seventy-nine patients were included, and a disulfiram-ethanol reaction was scored as either 'highly likely', 'likely' or 'possible' in 54.4% and as 'doubtful' or 'certainly not present' in 45.6% of the patients. The interrater agreement was 0.71 (95% CI: 0.64-0.79). The diagnosis was not considered or only after a delay in 44.2% of the patients with a 'possible' to 'highly likely' disulfiram interaction. One patient with a disulfiram overdose died and was considered as a 'possible' interaction. DISCUSSION AND
CONCLUSIONS: A disulfiram ethanol interaction can be life threatening and failure to consider the diagnosis in the emergency department seems frequent. Prospective studies with documentation of the intake of disulfiram and evaluation of the value of acetaldehyde as a biomarker are needed to determine the precise incidence. Improving knowledge of disulfiram interactions and adequate history taking of disulfiram intake may improve the care for patients.

Introduction

Disulfiram (DIS) is primarily used as an adjunct in the treatment of alcohol use disorders [1-4]. DIS and its active metabolite S-methyl N,N-diethylthiocarbamate sulfoxide irreversibly inhibit the enzyme aldehyde dehydrogenase which leads to the accumulation of acetaldehyde with effects known as a DIS ethanol reaction (DER) [5, 6]. Recovery of enzymatic activity depends on de novo aldehyde dehydrogenase synthesis that takes place in 6 or more days [7]. A DER may occur after even small quantities of alcohol which usually leads to an unpleasant reaction [3]. A DER has been described occasionally after ingestion of either food cooked in alcohol or alcohol-based sauces and following excessive use of alcohol-containing cosmetics [8, 9]. Inhalation of alcohol vapour from hand sanitizers may transiently produce ethanol levels that are high enough to cause a mild DER [9, 10]. The necessity for supervised ingestion and the goal of sustained abstinence instead of reduced drinking are advocated because the use of even small amounts of ethanol during therapy can present as an emergency [4]. A DER may indeed not just be unpleasant with symptoms such as flushing of the face, throbbing in the head and pulsating headache but can also induce alarming systemic effects [11, 12]. These may even be life threatening with e.g. hemodynamic shock [11, 13–16], hypotension [12, 11–26], ST-segment depression [11, 14, 20, 26–28], stroke [21], cardiovascular collapse [12, 16, 19], cardiogenic shock [29], cardiac arrhythmias [12, 19], myocardial ischemia [17, 23], myocardial injury [28], myocardial infarction [12, 19, 30–32], unconsciousness [12, 19], convulsions [12, 19], dyspnea [19], respiratory difficulties [12, 19] and bronchospasm [17, 24, 33]. It should be noted that some case reports of DER concern DIS overdoses [25, 29, 38] and that sudden death has been reported as a DER with high therapeutic doses [11, 17, 34–36] and in DIS intentional overdoses combined with ethanol [37, 38]. Patients with a DER may seek help in the ED as illustrated in many case reports and a DER may initially go unrecognized [14–16, 24, 29]. The aims of the present study are (1) to highlight the clinical picture of a severe DER admitted to an ED with two illustrative cases and (2) to estimate the probability that a DER goes unrecognized with the use of a retrospective study of patients admitted to the emergency department.

Materials and methods

The two case reports were observed by the authors SC and ES respectively. The assessment of the diagnostic process of a DER was carried out in the ED of the University Hospital of Ghent (Belgium) with a census of about 33 000 patients annually. The electronic files of all patients admitted between October 1, 2010 and September 30, 2014 were retrospectively screened for the term DIS or the registered name Antabuse® based on the following data fields: reason for admission, home medication history, diagnosis and treatment. It was also noted whether ethanol intake was mentioned in the history upon admission. Furthermore, data on symptoms, vital parameters, ethanol and lactate concentrations were collected and outcome was also registered. For systolic and diastolic blood pressure the lowest values observed in the ED were used.

Based on these data the likelihood of a DER was assessed independently by a panel of 6 authors (KS, ES, SC, WB, TD and LH) using a scoring between 1 and 5, with 1 being ‘most likely’, 2, 3, 4 and 5 being ‘likely’, ‘possible’, ‘doubtful’ and ‘certainly not’ respectively. This was done for each case individually and the medium scores were calculated. In advance, the panel members received a number of papers about symptoms and signs of a DER [11, 20–23, 25, 27–29, 33, 36–40]. Moreover, DER symptoms reported in at least two scientific papers or in at least one of two reference handbooks [11, 12] were summarized in a table.

Patients with a medium DER score between 1 and 3 and those with a score between 3 and 5 were considered as group A and B respectively.

Data were analyzed as frequencies (percentages) for categorical variables and as means (± standard deviations) for continuous variables. Independent t-test was used to compare continuous data between groups A and B. Fisher’s Exact Test or Pearson Chi-Square Test was used for comparison of distribution between and within the groups for the diagnosis of DER, symptoms, vital parameters including cardiovascular collapse and outcome.

The inter-rater agreement of the probability of the diagnosis of a DER was assessed with a weighted kappa with quadratic weights.

For all analyses, a two-tailed significance level of p<0.05 was used. The statistical analyses were performed with IBM SPSS 25.0 for Windows.

The study was approved by the ethical committees of the University Hospital of Ghent, the Jan Yperman hospital (Ieper) and the Algemeen Stedelijk Ziekenhuis (ASZ) hospital Aalst. All data were fully anonymized before being assessed. Consent for publication of raw data was not obtained. The requirement for informed consent was waived by the ethics committee.

Results

Case reports

Case 1

A 43-year-old man with schizophrenia under treatment with haloperidol, risperidone, clorazepate and DIS at a dose of 400 mg/day was found comatose at home (Glasgow Coma Score: 3/15). He was pale with cold extremities, hypotensive (blood pressure: 50/20 mmHg) and hypothermic (32°C). His respiration was depressed with a pulse oximetry saturation of 60%. The patient was endotracheally intubated and ventilated with improvement of the oxygen saturation, but the hypotension persisted. On admission to the ED the arterial blood gas showed a metabolic acidosis (pH 7.19) with increased lactate 7.17 mmol/L (normal upper limit: 1.60 mmol/L) and an ethanolemia of 1.46 g/L. Serum creatinine was increased to 0.19 mmol/L (normal upper limit: 0.08 mmol/L). An ethylene glycol or methanol poisoning was initially suspected but serum concentrations later appeared to be negative and toxicological screening was positive for benzodiazepines only.

A chest X-ray and cerebral CT-scan were normal. A DER was diagnosed and the patient was treated with crystalloids, noradrenaline infusion and external warming resulting in improvement of the blood pressure. He developed a ventilator associated pneumonia treated with amoxicillin/clavulanic acid and rhabdomyolysis (CK 44 000 IU/L: normal upper limit: 190 IU/L) treated with fluids, alkalinisation and mannitol 15%. He made a good recovery, but his renal function was decreased with a creatine of 0.32 mmol/L (normal upper limit: 0.08 mmol/L) at the 10th day after admission.

Case 2

A 49-year-old man with a history of severe alcohol abuse became unwell and was transported by emergency medical technicians to the ED at 3 pm. The family informed them that the patient was under treatment with DIS and had used 7 units of beer in the afternoon resulting in abdominal pain and thirst. Neither medication nor empty blisters were found at his home. Upon admission he showed a generalized erythema, decreased consciousness with a Glasgow Coma Score of 13/15 (Eye movement: 3, Verbal response: 4, Motor reaction: 6), tachycardia (125 beats/min) and a low blood pressure (70/30 mmHg). The first attending physician, a 1st year trainee in emergency medicine, tentatively diagnosed an anaphylactic shock but asked advice from the consultant in emergency medicine. The latter confirmed the presence of an erythema and found a diffusely painful abdomen on palpation. Auscultation of heart and lungs was normal. The patient was tachypneic with a peripheral oxygen saturation of 95% at room air. An arterial blood gas showed a pH of 7.50 (normal values 7.35–7.45), a bicarbonate of 20.8 mmol/L (normal values: 22–26 mmol/L), a base excess of -1.3 (normal values –3.5 to +3.5), a pCO2 of 27.1 mmHg (normal values: 35–45 mmHg), a pO2 of 83.8 mmHg (normal values: 83–108 mmHg), and a lactate of 4.1 mmol/L (normal values: 0.9–1.7 mmol/L). Further laboratory data showed a blood glucose of 179 mg/dl (normal values: 74–106 mg/dl), a sodium concentration of 133 mmol/L (normal values:136–145 mmol/L) and potassium concentration of 3.8 mmol/L (normal values: 3.6–4.8 mmol/L). The ethanolemia was 0.89 g/L and the consultant in emergency medicine diagnosed a DER. Because severe hypotension persisted even after a fast fluid bolus infusion of one liter of a balanced crystalloid solution, intravenous noradrenaline was started under invasive blood pressure monitoring. Administration of fomepizole was considered but not deemed necessary as the blood pressure rapidly recovered in the intensive care unit where noradrenaline could be discontinued, and the erythema disappeared. The patient could be discharged from the intensive care unit after 24 hrs.

Retrospective analysis of ED patients with a history of DIS treatment and ethanol use

During the study period, 79 patient records containing both the term Antabuse® or DIS together with a history of ethanol intake, were included. The demographics and scores for a DER as assessed by the panel are shown in Table 1. The mean age was 46.72 ± 10 years and male patients were overrepresented (59.5%).

Table 1

Demographics and DER scores of patients with a history of DIS treatment and ethanol use admitted to the ED of the University Hospital of Ghent between October 1, 2010 and September 30, 2014.

Scores are given as the medium value and the range of the individual scores by the 6 panel members. Patients are grouped (A and B) according to the likelihood of a DER.

	All patients	Group A				Group B
Score DER		Highly likely	Likely	Possible	Total	Doubtful or certainly not
Medium score	NAa	1	> 1 and ≤ 2	> 2 and ≤ 3	NA	> 3 and ≤ 5
Gender	Nb = 79 (%)	N = 17 (%)	N = 7 (%)	N = 19 (%)	N = 43 (%)	N = 36 (%)
Male	47 (59.5)	10 (58.8)	5 (71.4)	8 (42.1)	23 (53.5)	24 (66.7)
Female	32 (40.5)	7 (41.2)	2 (28.6)	11 (57.9)	20 (46.5)	12 (40.5)
Age (years)	46.72 ± 10	47.7 ± 10.9	41.7 ± 13.8	46.5 ± 8.6	46.16 ± 10.43	47.4 ± 10

a NA: not applicable

b N: number of patients

A DER was considered by the panel as either ‘highly likely’, ‘likely’ or ‘possible’ in 43 patients (54.4%) (group A) and as ‘doubtful’ or ‘certainly not’ in 36 patients (45.6%) (group B) (Table 1). The estimated kappa of inter-rater agreement for the 5 classes was 0.71 (95% CI: 0.64–0.79).

The admitting clinician did not consider the diagnosis of a DER in 19 out of the 43 (44.2%) patients in group A (Table 2). In the subgroup of patients with a highly likely DER this figure was 29.4% and in one patient the diagnosis was made but only after a delay.

Table 2

Consideration of the diagnosis of DER by the treating physician in patients with a history of DIS treatment and ethanol use admitted to the ED of the University Hospital of Ghent between October 1, 2010 and September 30, 2014.

	Group A			p-value
	Highly likely	Likely	Possible
Diagnosis DER	Na = 17 (%)	N = 7 (%)	N = 19 (%)
Immediate	11 (64.7)	6 (85.7)	6 (31.6)	0.021b
Delayed	1 (5.9)	0	0
Not considered	5 (29.4)	1 (14.3)	13 (68.4)

a N: number of patients

b Fisher’s Exact Test

Table 3 summarizes the clinical characteristics, vital parameters, laboratory data, therapy and outcome in the two groups.

Table 3

Clinical characteristics and outcome in patients with a history of DIS treatment and ethanol use admitted to the ED of the University Hospital of Ghent between October 1, 2010 and September 30, 2014.

Patients are grouped (A and B) according to the likelihood of a DER as attributed by the panel.

	All patients	Group A				Group B	P value
		Highly likely	Likely	Possible	Total	Doubtful or certainly not
Symptoms	N = 79 (%)	N = 17 (%)	N = 7 (%)	N = 19 (%)	N = 43 (%)	N = 36 (%)
Confusion	18 (22.8)	4 (23.5)	1 (14.3)	7 (36.8)	12 (27.9)	5 (13.9)	> 0.05a
Flushing	14 (17.7)	11 (64.7)	1 (14.3)	2 (10.5)	14 (32.6)	0	< 0.001a
Decreased consciousness	14 (17.7)	6 (35.3)	3 (42.9)	3 (15.8)	12 (27.9)	2 (5.6)	0.016a
Nausea	13 (16.5)	7 (41.2)	1 (14.3)	3 (15.8)	11 (25.6)	2 (5.6)	0.017a
Vomiting	10 (12.7)	3 (17.6)	1 (14.3)	3 (15.8)	7 (16.3)	3 (8.3)	> 0.05b
Palpitations	6 (7.6)	2 (11.8)	0	3 (15.8)	5 (11.6)	1 (2.8)	> 0.05b
Dyspnoe	6 (7.6)	2 (11.8)	0	3 (15.8)	5 (11.6)	1 (2.8)	> 0.05b
Retrosternal pain	5 (6.3)	3 (11.8)	0	2 (10.5)	4 (9.3)	1 (2.8)	> 0.05b
Headache	5 (6.3)	1 (5.9)	2 (28.6)	1 (5.3)	4 (9.3)	1 (2.8)	> 0.05b
Tremor	5 (6.3)	1 (5.9)	2 (28.6)	1 (5.3)	4 (9.3)	1 (2.8)	> 0.05b
Abdominal pain	5 (6.3)	0	1 (14.3)	1 (5.3)	2 (4.7)	3 (8.3)	> 0.05b
Epileptic insult	4 (5.1)	0	1 (14.3)	1 (5.3)	2 (4.7)	2 (5.6)	> 0.05b
Vertigo	3 (3.8)	0	1 (14.3)	2 (10.5)	3 (7)	0	> 0.05b
Diaphoresis	2 (2.5)	1 (5.9)	0	0	1 (2.3)	1 (2.8)	> 0.05b
Pruritus	1 (1.3)	0	0	1 (5.3)	1 (2.3)	0	> 0.05b
Myalgia	1 (1.3)	0	0	1 (5.3)	1 (2.3)	0	> 0.05b
Hyperventilation	1 (1.3)	0	0	1 (5.3)	1 (2.3)	0	> 0.05b
Respiratory difficulties/depression	1 (1.3)	0	0	0	0	1 (2.8)	> 0.05b
Vital parameters	N = 78 (1 missing value)	N = 17	N = 7	N = 19	N = 43	N = 35 (1 missing value)
Systolic blood pressure (mmHg)	101.99 ± 21.18	92.06 ± 4.8	78 ± 8.36	106.47 ± 4.67	96.14 ± 22.66	109.17 ± 2.85	0.006c
Diastolic blood pressure (mmHg)	59.59 ± 17.33	49.65 ± 3.53	43.57 ± 6.03	61.79 ± 3.48	54.02 ± 16.39	66.43 ± 2.73	0.001c
	N = 79 (%)	N = 17 (%)	N = 7 (%)	N = 19 (%)	N = 43 (%)	N = 36 (%)
Cardiovascular collapse	1 (1.3)	0	0	1 (5.3)	1 (2.3)	0	> 0.05b
	N = 77 (2 missing values)	N = 17	N = 7	N = 18 (1 missing value)	N = 42 (1 missing value)	N = 35 (1 missing value)
Heart rate (beats/minute)	105.75 ± 19.27	112.82 ± 4.12	111.71 ± 5.31	103.78 ± 5.31	108.76 ± 19.26	102.14 ± 3.2	> 0.05c
	N = 66 (13 missing values)	N = 14 (3 missing values)	N = 7	N = 16 (3 missing values)	N = 37 (6 missing values)	N = 29 (7 missing values)
Temperature (°C)	36.35 ± 0.94	36.24 ± 0.2	36.68 ± 0.19	36.12 ± 0.39	36.27 ± 1.14	36.45 ± 0.11	> 0.05c
Ethanolemia (g/l)	N = 70 (9 missing values)	N = 15 (2 missing values)	N = 7	N = 16 (3 missing values)	N = 38 (5 missing values)	N = 32 (4 missing values)
	1.82 ± 1.17	1.31 ± 0.21	1.14 ± 0.55	2.08 ± 0.22	1.60 ± 1.04	2.07 ± 0.23	> 0.05c
Lactate (mmol/l)	N = 24 (55 missing values)	N = 7 (10 missing values)	N = 2 (5 missing values)	N = 6 (13 missing value)	N = 15 (28 missing value)	N = 9 (27 missing values)
	4.03 ± 3.20	4.44 ± 2.34	3.50 ± 2.99	4.87 ± 1.96	4.48 ± 2.14	3.27 ± 4.51	> 0.05c
Therapy	N = 79 (%)	N = 17 (%)	N = 7 (%)	N = 19 (%)	N = 43 (%)	N = 36 (%)
Fluid loading	37 (46.8)	13 (76.5)	6 (85.7)	8 (42.1)	27 (62.8)	10 (27.8)	0.002a
Vasopressors	1 (1.3)	0	0	1 (5.3)	1 (2.3)	0	> 0.05b
Outcome	N = 78 (%) (1 missing value)	N = 17 (%)	N = 7 (%)	N = 18 (%) (1 missing value)	N = 42 (%) (1 missing value)	N = 36 (%)
ED observ. + disch. to psychiatry	28 (35.9)	6 (35.3)	2 (28.6)	5 (27.8)	13 (31)	15 (41.7)	> 0.05b
ED observation and discharge home	27 (34.6)	7 (41.2)	5 (71.4)	7 (38.9)	19 (34.6)	8 (22.2)
Discharge to psychiatry	9 (11.5)	3 (17.6)	0	1 (5.6)	4 (9.5)	5 (13.9)
ED observ. and discharge to a ward	6 (7.7)	0	0	2 (11.1)	2 (4.8)	4 (11.1)
Discharge home	5 (6.4)	1 (5.9)	0	2 (11.1)	3 (7.1)	2 (5.6)
ICU	2 (2.6)	0	0	0	0	2 (5.6)
Death	1 (1.3)	0	0	1 (5.6)	1 (2.4)	0

N: number of patients

a Pearson Chi Square test

b Fisher’s Exact Test

c Independent T-test

Flushing, decreased consciousness and nausea were significantly more frequently reported in group A than in group B (p<0.001, p = 0.016 and p = 0.017 respectively). Mean systolic and diastolic blood pressures were significantly lower in group A than in group B (p = 0.006 and p = 0.001 respectively). There were no differences between group A and B regarding heart rate and body temperature.

One case of cardiovascular collapse was observed (group A) in a 41 years old man who was found at home with decreased consciousness and a collateral history from relatives of an acute overdose with DIS and diazepam. Upon arrival of the ambulance, he still had respiratory activity, but the cardiac rhythm evolved to asystoly upon arrival of a Mobile Intensive Care Unit team.

During resuscitation, including external cardiac massage and endotracheal intubation which revealed aspiration of food, he developed a ventricular fibrillation. Following one direct current shock there was a return of spontaneous circulation. In the ED his laboratory data revealed a severe acidosis (pH of 7.0; normal values: 7.35–7.45), an increased lactate (7.28 mmol/L; normal upper limit: 1.60 mmol/L), renal insufficiency (creatinine 0.21 mmol/L; normal values: 0.064–0.103 mmol/L) and an ethanolemia of 0.9 g/L. A chest X-ray showed a pneumonia and he was treated in the ICU with artificial ventilation, antibiotics and hemodialysis. His cardiorespiratory and renal functions initially improved but he remained unresponsive and neurological examinations showed postanoctic damage. The patient eventually died 9 days after admission.

Regarding the therapy in our series of patients, fluid loading was significantly more frequent in group A (p = 0.002) with a vasopressor being needed in one patient of this group. Plasma lactate was available in only about 30% of all patients and was not significantly higher in group A than in B. Ethanolemia was available in 77% of the patients with a mean value that was higher in group B than in group A, but not significantly so.

Regarding the outcome most patients could either be discharged home or had to be admitted to a ward preceded by an ED observation in some cases. The discharge pattern was not different between group A and B.

Discussion

DIS is mainly used in the pharmacotherapy of alcohol use disorders but also for the treatment of cocaine and other stimulant dependence [41-43]. More recent interest in disulfiram for treating various cancers has provided some renewed clinical interest [44-46]. A meta-analysis of the efficacy of disulfiram in treatment of alcohol dependence concluded that evidence from well-controlled trials does not adequately support an association with preventing return to any drinking or improvement in other alcohol consumption outcomes [2]. Moreover, experiencing a DER seems not to be associated with any differences in treatment outcome but with a significant earlier discontinuation of DIS therapy [47]. Other publications [1, 3, 4] concluded that the drug is valuable but in these, adequate supervision was guaranteed. In this respect immediate recognition and treatment of a DER in the ED is an important aspect of DIS therapy. These reactions are indeed sometimes life threatening and require adequate therapy. Moreover, these DER’s in the ED can offer valuable feedback to the treating physician as they signal problems with abstinence from ethanol.

The first aim of our study was to remind clinicians of these severe reactions with two illustrative case reports observed in the ED. The first patient developed renal insufficiency (presumably resulting from a combination of hypoperfusion and rhabdomyolysis) and both cases showed severe hypotension and are highly suggestive for a DER. Importantly both cases also illustrate that the recognition of a DER is not always immediately made by the clinicians which can lead to a delayed or even missed diagnosis [14–16, 29].

As far as we know there are no systematic studies on the frequency and the detection of ED admissions for DER. Therefore, the second aim of this paper was to study this aspect by analyzing the clinical files for the presence of a DER in all patients admitted to an ED with a history of DIS treatment and ethanol intake. In this retrospective study, 79 patient records contained the term DIS and mentioned ethanol use representing about 20 patients per year.

It should be noted however, that this figure may be an underestimate since medication history by the emergency physician may have been incomplete as shown by studies in which a pharmacist actively was involved in the medication history [48].

Moreover, due to the irreversible inhibition of the enzyme aldehyde dehydrogenase, which leads to a prolonged accumulation of acetaldehyde, the history should also take a recent stop of DIS into account. A false feeling of security may be present in patients who recently stopped the intake, and this may lead them not to mention this to the admitting clinician. A prospective study with a thorough medication history would shed more light on the incidence of potential DER’s in the ED.

Because the diagnosis of a DER in a retrospective study of routine clinical practice is relying on the interpretation of clinical data, we analyzed the clinical files with a panel composed of emergency physicians and a clinical pharmacist. This analysis was done independently by each member to avoid mutual influence and was preceded by providing literature data on DER’s including a case of DIS overdose. This may have increased the awareness of a DER in the panel members and the likelihood of ascribing a picture of clinical aspects to a DER. Patients with signs such as flushing, decreased consciousness, nausea, hypotension and a need for fluid therapy were significantly more frequently categorized by the panel in group A than group B. This is presumably explained by the fact that these are indeed well-known features of a DER.

The kappa value for the inter-rater variability of 0.71 can be considered as moderate [49] to substantial [50]. This rather large interobserver variability may be explained by the fact that a DER remains a clinical diagnosis.

In 45.6% of the patients a DER was scored as ‘doubtful’ or ‘certainly not present’ (group B). Five patients in this group had a negative ethanolemia which contrasts with only one patient in group A. This negative ethanolemia may have contributed to the assignment by the panel of patients to group B.

Besides the negative ethanolemia other explanations for the assignment of patients to group B should also be considered. First the clinical signs of a DER have been described to be much weaker in patients with alcoholic liver disease than in those without [51]. Therefore, in future studies of DER’s in the ED it would be of interest to study the presence of alcoholic liver disease.

A second explanation may be that patients in group B were less adherent to their DIS therapy and had not taken DIS in the two weeks prior to admission. A third explanation may be that the clinical information in the files of group B patients was more frequently incomplete or inaccurate because the admitting clinician implicitly ascribed DER symptoms to ethanol poisoning alone. The fact that the mean ethanolemia in group B is higher than in group A favors this hypothesis. Future prospective studies with a focus on accurate and complete DIS medication history and determining blood concentrations, use of a checklist of signs of DER by clinicians and assessment of the presence of alcoholic liver disease would give better insight into the real incidence of DER’s in the ED. Finally, a fourth explanation for the assignment of patients to group B may be that clinical symptoms and acetaldehyde plasma concentrations under treatment with DIS appear to decrease after repetitive exposure to ethanol [52].

In view of the uncertainties in the clinical evaluation, a biochemical indicator would be of interest to objectivate which patients suffered from a DER. In our study plasma lactate seemed higher in group A than in group B (not statistically significant) and may also have been considered by the panel members as an argument for diagnosing a DER. A high number of lactate values were missing, which could explain why the lactate level was not significantly higher in group A. A systematic study of plasma lactate in patients with a possible DER is needed to evaluate its value as a biochemical marker and whether it adds further information to the parameter of hypotension.

In addition to plasma lactate, measurement of acetaldehyde in plasma or red blood cells may be of interest as reported in some case reports [14]. Plasma concentrations of acetaldehyde increase during ethanol challenge in volunteers treated with DIS [53]. However, further studies are required to assess the sensitivity and specificity of acetaldehyde in the diagnosis of DER as plasma and red blood cell acetaldehyde already increase in abstinent alcoholic patients treated with DIS [54] and the increase in acetaldehyde appears to diminish after repeated exposure to ethanol [52]. The relationship of acetaldehyde levels with a DER is not fully understood [55]. Determination of the presence of DIS and its active metabolites in plasma may be considered to document a DER but one should be aware that the enzyme inhibiting effect of these compounds may still be observed following their disappearance as they are considered irreversible inhibitors [56-58].

Besides documenting a DER, monitoring retrospective alcohol use in patients on DIS treatment may be useful to verify abstinence. In this context, urinary ethylglucuronide (a breakdown product of ethanol) was shown to be a promising biomarker of ethanol exposure as it can be detected up to 5 days after drinking alcohol [59].

An important finding in our study is that the admitting emergency physicians did not consider the diagnosis of a DER even in patients for which the panel scored a DER as highly likely. Also, in the highly likely category, the diagnosis of DER in one patient was made only after a delay. Likewise, such a delay also occurred in the presented case reports. In the first case report the clinician initially suspected methanol or ethylene glycol poisoning and in the second case there was a temporary misinterpretation of DER symptoms as an anaphylactic reaction. These diagnostic failures or delays, which are also regularly reported in the literature [14–16, 29, 37] may have important consequences. Unnecessary diagnostic investigations can be avoided as well as the futile use of dopamine as a vasopressor as it is ineffective due to the inhibition of dopamine betahydroxylase by DIS [13, 22]. Moreover, in some resistant cases of DER, specific therapy with fomepizole should be considered.

Fomepizole, an inhibitor of alcohol dehydrogenase, limits the progression of the DER by blocking ethanol metabolism to acetaldehyde [17, 26, 27, 60]. Therefore, clinicians should be better aware of DER’s and consider these reactions especially in the differential diagnosis of patients with features of e.g. an anaphylactic shock or distributive shock. Finally, it obviously is important that DER’s are recognized and reported to the physician treating the alcohol use disorder to direct further therapy.

Regarding the outcome, most patients needed at least observation in the ED followed by admission to a ward which implicates a considerable workload and cost. One patient in our retrospective series ultimately died and it is important to note that according to his sister he took an overdose of DIS.

High doses, as used in older treatment regimens, have been described to lead to more severe DER’s [34] and several cases of a life threatening [24–25, 38] and even fatal DER [37] have been described after DIS overdose. Although we did not dose DIS, this fatal case in our study was considered by the panel as a possible DER. The panel probably assumed that the patient died because of the decreased consciousness with vomiting that resulted in hypoxia with cardiac arrest leading to irreversible brain damage. Clinicians admitting patients with a DIS overdose should also be aware of this increased risk of a severe DER.

There are some limitations to this study. We may have underestimated the incidence of DER’s in the ED because of the retrospective nature of this research. This may be due to incomplete medication history of DIS use and the failure to recognize and register symptoms and disturbances related to a DER. Furthermore, the diagnosis was made on clinical grounds as in routine clinical practice and the differential diagnosis was not always elaborated to exclude other causes for the symptoms.

Future prospective studies with adequate history taking are therefore necessary to determine the real incidence of a DER. Determining blood concentrations of DIS or its more easily detected metabolites like carbon disulphide, could document the intake of DIS and the utility of acetaldehyde measurements should be assessed.

Conclusion

In summary, the present study illustrates that a DER can be severe and even life threatening and that the diagnosis is not readily considered or may be delayed in the ED. This can have important consequences regarding the urgent treatment of these patients and for the feedback to the clinicians supervising the treatment with DIS. Enhancing awareness of the signs and symptoms of a DER by education combined with more attention for an adequate history of ethanol use and DIS therapy, also when recently stopped, may improve the care of these patients. Future prospective studies to determine the precise incidence of DER in the ED and to explore the diagnostic value of biochemical markers are necessary.

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7 Sep 2020

PONE-D-20-14245

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

PLOS ONE

Dear Dr. Desmet,

Thank you for submitting your manuscript to PLOS ONE; I apologise for the unusually delayed review timeframe. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Your manuscript has been assessed by two reviewers, whose comments are appended below. In addition to addressing the concerns that they have raised, please ensure that you clarify whether the records used in this study were anonymised and/or whether the IRB waived the requirement for informed consent. Furthermore, we note that one or more reviewers has recommended that you cite specific previously published works. As always, we recommend that you please review and evaluate the requested works to determine whether they are relevant and should be cited. It is not a requirement to cite these works.

Please submit your revised manuscript by Oct 19 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Emily Chenette

Deputy Editor-in-Chief

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a clinically important piece of work that points to a relevant problem and investigates it in an interesting, intelligent way. Only some important literary quotations are still missing from my point of view:

1) Page 13, line 222: Disulfiram is also increasingly used for the following conditions: cocaine addiction, tumor diseases and pathological gambling. Please cite papers for each disease. This makes the examination all the more relevant.

2) Page 15, line 283: There are biochemical markers, which can improve and verify a hidden DSR, please cite this paper and discuss it: Urinary Ethylglucuronide Assessment in Patients Treated With Disulfiram: A Tool to Improve Verification of Abstention and Safety, Mutschler et al, Clin Neuropharmacol . Nov-Dec 2010;33(6):285-7. doi: 10.1097/WNF.0b013e3181fc9362.

3) Diskussion: I think it would be also interesting to short discuss this paper by Mutschler et al: Experienced Acetaldehyde Reaction Does Not Improve Treatment Response in Outpatients Treated With Supervised Disulfiram, Clin Neuropharmacol . Jul-Aug 2011;34(4):161-5. doi: 10.1097/WNF.0b013e3182216fd5.

4) It would be interesting to discuss the effect of the drug in more detail (biological effect, psychological effect). Furthermore pharmacogenetic aspects.

Reviewer #2: This study provides a new perspective on the difulfiram-ethanol reaction (DER) and is useful to emergency room clinicians. Assuming the statistical analysis to be adequate and appropriate, the main body of the research seems to need no modification. However, a few peripheral points would benefit from clarification or expansion.

1. Describing the DER as an ‘aversive reaction’ tout court reinforces the widespread but incorrect notion that disulfiram (DSF) works by ‘aversion’ – i.e. the repeated coupling of drinking with an unpleasant response. In reality, most patients never deliberately test out DSF’s acataldehydaemic potential because the vicarious knowledge of that potential deters them from drinking while ALDH inhibition persists. The mechanism is deterrence, not aversion.

2. DSF and its active metabolite S-methyl N,Ndiethylthiolcarbamate

sulfoxide do not have long half-lives and are usually undetectable after 48 hours. However, because it is an irreversible ‘suicide inhibitor’ of ALDH, ALDH inhibition persists until the body produces new ALDH in adequate quantities. This process is probably genetically determined and can be as short as a couple of days or as long as 10 days – occasionally more.

3. Carbon disulphide – another metabolite of DSF – may be easier to detect than DSF itself. It, too, persists for about two days after the last dose.

4. DSF dosage information was not systematically collected in the study but one patient is recorded as having 400mg daily. Although bioavailability can vary with the manufacturing process, a starting dose of 200-250-mg is usually appropriate, though some supervised DSF programmes use 400/400/5-600mg on Monday/Wednesday/Friday. Dosage will only need increasing if the patient risks drinking and gets no reaction or only a very mild one.

5. Although I have never had occasion to use fomepizole, I think it deserves a slightly longer discussion, including its mode of action. I also think there may be a case for using it in any severe case of suspected DER pending further investigations or confirmation.

6. The authors say that even small quantities of alcohol can cause a DER. ‘Small’ is a rather elastic but in reality, small amounts such as in sauces never cause a reaction, or only an extremely mild one, though patients who inadvertently swallow small amounts of an alcoholic sauce sometimes have a panic attack that can superficially resemble a DER. Some very recent papers have drawn attention to the fact that inadvertently inhaling alcohol in hand-sanitisers can cause a DER, probably because of a rapid but transient build-up of acetaldehyde in lung tissues that then passes directly and quickly to the heart and brain. While COVID persists, this may be worth mentioning. However, the total amount of alcohol inhaled – compared with the amount in even one glass of wine – is so small that severe DERs from this route seem very unlikely and alcohol absorption directly through the skin is negligible.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Colin Brewer

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Oct 2020

Dear Editor-in-chief,

Dear Reviewers,

First of all, we would like to thank you and the reviewers for the time spent on reviewing the manuscript and the thoughtful comments helping us improving the article. In the attached letter we would like to answer the comments and questions listed.

Reviewer #1

1. Page 13, line 222: Disulfiram is also increasingly used for the following conditions: cocaine addiction, tumor diseases and pathological gambling. Please cite papers for each disease. This makes the examination all the more relevant.

Other conditions in which disulfiram is used for (including references) have been added to the manuscript (line 229-231).

2. Page 15, line 283: There are biochemical markers, which can improve and verify a hidden DSR, please cite this paper and discuss it: Urinary Ethylglucuronide Assessment in Patients Treated With Disulfiram: A Tool to Improve Verification of Abstention and Safety, Mutschler et al, Clin Neuropharmacol . Nov-Dec 2010;33(6):285-7. doi: 10.1097/WNF.0b013e3181fc9362.

The authors thank you for this contribution and have adapted the text accordingly (line 313- 316).

3. Diskussion: I think it would be also interesting to short discuss this paper by Mutschler et al: Experienced Acetaldehyde Reaction Does Not Improve Treatment Response in Outpatients Treated With Supervised Disulfiram, Clin Neuropharmacol . Jul-Aug 2011;34(4):161-5. doi: 10.1097/WNF.0b013e3182216fd5.

The authors thank you for this addition and have incorporated this interesting observation in the manuscript (line 234-235 ; reference 47).

4. It would be interesting to discuss the effect of the drug in more detail (biological effect, psychological effect). Furthermore pharmacogenetic aspects.

The authors agree with these comments. The manuscript has been adapted based on the suggestions provided.

Although this is a very interesting comment, we feel that a discussion on the biological and psychological effects is beyond the scope of this paper. We would therefore suggest not including it. It is not clear to us to which specific pharmacogenetic aspects of disulfiram the reviewer is alluding.

Reviewer #2

1. Describing the DER as an ‘aversive reaction’ tout court reinforces the widespread but incorrect notion that disulfiram (DSF) works by ‘aversion’ – i.e. the repeated coupling of drinking with an unpleasant response. In reality, most patients never deliberately test out DSF’s acataldehydaemic potential because the vicarious knowledge of that potential deters them from drinking while ALDH inhibition persists. The mechanism is deterrence, not aversion.

The authors agree with these comments. The manuscript has been adapted and the term « aversive reaction » has been omitted throughout the entire manuscript.

2. DSF and its active metabolite S-methyl N,Ndiethylthiolcarbamate sulfoxide do not have long half-lives and are usually undetectable after 48 hours. However, because it is an irreversible ‘suicide inhibitor’ of ALDH, ALDH inhibition persists until the body produces new ALDH in adequate quantities. This process is probably genetically determined and can be as short as a couple of days or as long as 10 days – occasionally more.

The authors thank you for this contribution and have adapted the text accordingly (line 62-66 & line 308-311).

3. Carbon disulphide – another metabolite of DSF – may be easier to detect than DSF itself. It, too, persists for about two days after the last dose.

The authors thank you for this contribution and have adapted the text accordingly (line 352-353).

4. DSF dosage information was not systematically collected in the study but one patient is recorded as having 400mg daily. Although bioavailability can vary with the manufacturing process, a starting dose of 200-250-mg is usually appropriate, though some supervised DSF programmes use 400/400/5-600mg on Monday/Wednesday/Friday. Dosage will only need increasing if the patient risks drinking and gets no reaction or only a very mild one.

The dosage of disulfiram was not systematically reported in this study. This fell beyond the scope of the study. The authors agree that a gradual increase of the dosage of disulfiram may be preferable.

5. Although I have never had occasion to use fomepizole, I think it deserves a slightly longer discussion, including its mode of action. I also think there may be a case for using it in any severe case of suspected DER pending further investigations or confirmation.

The authors agree with these comments. The manuscript has been adapted based on the suggestions provided (line 328-329).

6. The authors say that even small quantities of alcohol can cause a DER. ‘Small’ is a rather elastic but in reality, small amounts such as in sauces never cause a reaction, or only an extremely mild one, though patients who inadvertently swallow small amounts of an alcoholic sauce sometimes have a panic attack that can superficially resemble a DER. Some very recent papers have drawn attention to the fact that inadvertently inhaling alcohol in hand-sanitisers can cause a DER, probably because of a rapid but transient build-up of acetaldehyde in lung tissues that then passes directly and quickly to the heart and brain. While COVID persists, this may be worth mentioning. However, the total amount of alcohol inhaled – compared with the amount in even one glass of wine – is so small that severe DERs from this route seem very unlikely and alcohol absorption directly through the skin is negligible.

The authors thank you for this addition and have incorporated this interesting observation in the manuscript (line 66-70).

Kindest regards,

Dr. Tania Desmet

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

27 Oct 2020

PONE-D-20-14245R1

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

PLOS ONE

Dear Dr. Desmet,

Thank you for submitting your manuscript to PLOS ONE. Thank you for submitting the revised manuscript. There were minor revisions recommended by one of our reviewers. Before we can accept this manuscript for publication, we ask you to consider addressing the reviewer's comments.

Please submit your revised manuscript by November 26, 2020. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Steve Lin

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I suggest the publication of this clinically important paper.

..............................................................................................................................................................

Reviewer #2: I am sorry if I seem difficult to satisfy but despite your agreement that the term 'aversive' is inappropriate, it still appears in Line 67, Please replace it with 'unpleasant'.

Similarly, you have again claimed a long half-life for disulfiram, despite accepting that it is the effect on ALDH that is prolonged, not the half-life. Please correct this.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Dr Colin Brewer

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Nov 2020

Dear Editor-in-chief,

Dear Reviewers,

First of all, we would like to thank you and the reviewers for the time spent on reviewing the manuscript and the thoughtful comments helping us improving the article. In the attached letter we would like to answer the comments and questions listed.

Reviewer #2

1. I am sorry if I seem difficult to satisfy but despite your agreement that the term 'aversive' is inappropriate, it still appears in Line 67, Please replace it with 'unpleasant'.

The authors thank you for this contribution and have adapted the text accordingly (line 67).

2. Similarly, you have again claimed a long half-life for disulfiram, despite accepting that it is the effect on ALDH that is prolonged, not the half-life. Please correct this.

The authors thank you for this contribution and have adapted the text accordingly (line 258- 259).

Kindest regards,

Dr. Tania Desmet

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

18 Nov 2020

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward.

PONE-D-20-14245R2

Dear Dr. Desmet,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Steve Lin

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

23 Nov 2020

PONE-D-20-14245R2

Recognition of a disulfiram ethanol reaction in the emergency department is not always straightforward

Dear Dr. Desmet:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Steve Lin

Academic Editor

PLOS ONE