a b s t r a c t

Objective: Clinical research on drug intoxication is necessary for appropriate action in emergency departments (EDs). However, currently, there are no evident biomarkers for predicting adverse events (AEs) in patients with drug intoxication. We aimed to evaluate the prognostic value of serum lactate concentrations and lactate kinetics for AEs such as cardiogenic or respiratory failure in patients admitted to the ED with acute drug overdose. Methods: We conducted a single-center retrospective study by reviewing the prospective suicide registry of pa- tients visiting the ED. The primary outcome was composite AEs at any point during the ED visit or hospital stay. Results: A total of 566 patients with acute drug overdose were enrolled in this study. Of these, 62 patients had AEs, whereas 363 patients did not, yielding an AE rate of 14.6%. The median 0 h lactate concentrations in the AE and non-AE groups were 2.7 [2.1-5.1] mmol/L and 2.1 [1.4-2.9] mmol/L, respectively (p < 0.001). The median 6 h lac- tate concentrations in the AE and non-AE groups were 2.0 [1.5-3.9] mmol/L and 1.3 [0.9-2.2] mmol/L, respec- tively (p < 0.001). The area under the curve of lactate at 0 h for predicting AEs was 0.705 (95% CI: 0.659-0.748). The optimal lactate cutoff point was 4.2 mmol/L (37.1% sensitivity, 92.8% specificity). Multivariable analysis using a stepwise backward method showed that the 0 h lactate concentration was associated with AEs in acute drug intoxication after adjusting for confounders (adjusted OR of 0 h lactate, 1.47; 95% CI, 1.23-1.77). How- ever, the 6 h lactate concentrations, Lactate clearance, and delta lactate levels did not predict the outcomes.

Conclusion: Lactate concentrations and kinetics in patients admitted to the ED with an acute drug overdose exhib- ited limited prognostic utility in predicting AEs and should be interpreted with caution when considered for clin- ical decision-making.

(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Over 1.5 million patients with drug-related conditions visit emer- gency departments (EDs) in the United States annually [1,2]. Fatalities from drug intoxication have increased from 6100 in 1980 to 36,500 in 2008 [3]. In South Korea, acute intoxication accounted for 0.6%-1.3% of all ED visits, and the mortality rate was 4.8% [4,5]. As suicide attempts by drug overdose have increased, drug intoxication has become a clini- cally important issue in the healthcare system and is associated with fatal and serious complications. Thus, clinical research on drug intoxica- tion is necessary for an appropriate response to these patients in

* Corresponding author at: Department of Emergency Medicine, Korea University College of Medicine, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do 15355, Republic of Korea.

E-mail address: [email protected] (J.-H. Park).

frontline health care settings, such as in the ED. However, there are cur- rently no evident biomarkers to predict the in-hospital mortality of pa- tients with drug intoxication.

Lactate concentration is a sensitive but nonspecific indicator of met- abolic stress [6-8]. Lactate concentration is reported to exhibit excellent prognostic utility for the in-hospital occurrence of both shock and fatal- ity in the ED [7,9-11]. Moreover, lactate is an established prognostic marker for the overdose of selected drugs [12,13]. Recent research also indicates a positive association between higher levels of lactate and increased fatality in patients with acute drug intoxication [14,15]. However, only a limited number of studies have investigated the prog- nostic performance of lactate concentration in the initial evaluation of acute drug intoxication in the ED.

In this study, we evaluated the prognostic value of serum lactate concentrations for adverse events (AEs) such as cardiogenic or respira- tory failure in patients with acute drug overdose admitted to the ED. We

https://doi.org/10.1016/j.ajem.2021.07.025

0735-6757/(C) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

hypothesized that serum lactate concentrations and lactate kinetics have prognostic utility in predicting composite AEs.

1. Methods
   1. Study design and setting

We conducted a single-center, retrospective study by reviewing the prospective suicide Registry of patients who had visited the ED of a ter- tiary suburban academic hospital serving 50,000 individuals annually. The Ethics Committee approved this study (2021AS0047) and waived the requirement for informed consent.

• 1. Selection of participants

Patients with acute drug overdose admitted to the ED from January 1, 2017 to December 31, 2019 were enrolled if they met the inclusion criteria. Patients who met both criteria were included: drug overdose with any prescription or over-the-counter drug at an exposure greater than its Therapeutic dose for a suicide attempt, and acute presentation within 24 h of exposure. The exclusion criteria were: age < 18 years, non-drug intoxication (e.g., pesticides or plants), trauma, chronic pre- sentation (i.e., non-acute), no serum lactate concentration measure- ment in the ED, and incomplete data (e.g., transfer to a different institution, left against medical advice, or left the hospital for any other reason).

• 1. Methods of measurement

Our institution has a Crisis Intervention Team (CIT) and a suicide registry for individuals who attempted suicide and subsequently visited the ED [16]. The team comprises two full-time social workers who con- duct an initial counseling session in the ED and continue to do so for up to 4 weeks after discharge. The registry contains demographic data, psy- chological consultation results, and clinical outcomes of the patients. Using data from the registry, a trained researcher (registered nurse) ret- rospectively retrieved the baseline characteristics, clinical and labora- tory data, and patient outcomes from the electronic medical records. Two emergency physicians assessed clinical acceptance and supervised the process. All individuals who had attempted suicide and were discharged from the ED or the hospital attended a follow-up phone call at week 1 and week 4. The follow-up call was conducted by research assistants trained in medical abstraction. They checked the medical con- dition (physical and mental health) of the patient and recorded the data using standardized data collection forms.

Lactate concentrations were measured using the Cobas 8000 c702 (Roche Diagnostics System, Rotkreuz, Switzerland), an automated sys- tem for immunoassays. The initial venous serum lactate concentration was measured at the bedside within 1 h of ED presentation in patients with suspected acute drug overdose as part of clinical care. After the first measurement, the lactate concentration was measured multiple times (6, 12, or 24 h from the initial measurement, depending on the medical condition of the patient) while the patient remained in the ED. The range of normal values for serum lactate concentration was 0.5-2.2 mmol/L. Lactate clearance (%) was defined as [((0 h lactate-6 h lactate)/0 h lactate) x 100]. Delta lactate was calculated as [0 h lactate-6 h lactate].

• 1. Outcome measures

The primary outcome was composite AEs at any point during the ED visit or hospital stay. We defined AEs as acute drug intoxication-related adverse outcomes, as follows: vasopressor use, High-flow oxygen ther- apy or ventilator care, anti-arrhythmic drug use, complications warranting inpatient treatment (acute kidney injury, toxic hepatitis, or Severe rhabdomyolysis), intensive care unit stay, or death.

• 1. Data analysis

A descriptive analysis of the general characteristics of the patients was conducted. The categorical variables are reported as frequencies with percentages. The continuous variables are expressed in terms of the median and interquartile range or the mean +- standard deviation, according to their distribution. We used a chi-squared test or Fisher’s exact test, as appropriate, for categorical data, and the Mann-Whitney U test for continuous data.

receiver operating characteristic curves were constructed to determine the Diagnostic test characteristics and the optimal cutoff point for lactate concentrations. The accuracy of ROC analysis is mea- sured by the area under the ROC curve (AUC). The AUC reflects the over- all accuracy and separation performance of a biomarker. AUCs are expressed using 95% confidence intervals (CIs). The optimal cutoff point was defined as the lactate concentration that maximized the sum of the sensitivity plus the specificity rounded to the nearest integer (Youden index).

To determine the association between lactate concentrations and the study outcomes, we performed univariable analysis. Variables with a p-value <0.1 or judged as significant confounders were subjected to a backward multivariable logistic regression analysis to evaluate pos- sible independent associations. Finally, adjusted odds ratios (aORs) with 95% CI were calculated to evaluate the association between lactate con- centrations and outcomes. The Hosmer-Lemeshow goodness-of-Fit test was performed to evaluate the fit of the logistic regression model.

All statistical tests were two-tailed, and p-values <0.05 were consid- ered statistically significant. Statistical analyses were performed using R software (version 3.6.1, CRAN) and MedCalc statistical software (ver- sion 20; MedCalc Software, Ostend, Belgium).

1. Results

Of the patients screened during the study period, 566 patients with acute drug overdose were identified. Of these, 425 patients were ana- lyzed (Fig. 1). Overall, 62 patients had AEs and 363 patients did not, which yielded an AE rate of 14.6%. The median age of the included pa- tients was 42 years, and 128 patients (30.1%) were men. The baseline characteristics and laboratory parameters of the patients are

Fig. 1. Flow diagram of enrollment and study outcomes.

Clinical characteristics and laboratory findings of the enrolled patients

Variables	Total (n = 425)	Adverse Events (+) (n = 62)	Adverse Events (-) (n = 363)	p-value
Sex, male	128 (30.1%)	25 (40.3%)	103 (28.4%)	0.081
Age, year	42 (30-52)	49 (34-63)	41 (30-51)	0.002
Vital signs
Systolic blood pressure, mmHg	118 (106-134)	113 (94-135)	119 (107-134)	0.037
Diastolic blood pressure, mmHg	75 (64-82)	66 (52-81)	76 (66-82)	0.001
Mean arterial pressure, mmHg	89 (79-99)	84 (66-99)	90 (80-99)	0.005
Respiratory rate, /min	18 (8-20)	18 (18-20)	18 (18-20)	0.004
Heart rate, /min	89 (76-100)	90 (70-106)	89 (78-100)	0.706
SpO2, %	98 (96-99)	96 (92-98)	98 (96-99)	< 0.001
Glasgow coma scale score	15 (12-15)	12 (8-15)	15 (12-15)	< 0.001
lactate values
0 h Lactate, mmol/L	2.2 (1.4-3.1)	2.7 (2.1-5.1)	2.1 (1.4-2.9)	< 0.001
6 h Lactate, mmol/L	1.4 (1.0-2.3)	2.0 (1.4-3.9)	1.3 (0.9-2.1)	< 0.001
Lactate clearance, %	28.6 (6.9-44.4)	32.0 (12.2-48.1)	28.6 (5.2-43.6)	0.311
Delta lactate, mmol/L	0.5 (0.1-1.1)	0.9 (0.3-1.6)	0.5 (0.1-1.1)	0.005
Blood gas analysis
pH	7.39 (7.37-7.42)	7.37 (7.33-7.42)	7.39 (7.37-7.42)	0.005
pCO2, mmHg	40.0 (35.7-43.6)	39.0 (34.0-48.8)	40.0 (36.0-43.3)	0.418
pO2, mmHg	87.2 (75.0-99.0)	81.3 (69.8-91.7)	88.2 (76.2-99.2)	0.028
HCO3, mEq/L	23.6 (21.6-25.7)	23.9 (20.4-26.4)	23.6 (21.8-25.6)	0.833
Adverse events
Total	-	81 (100%)	-	-
Cardiovascular dysfunction	-	25 (40.3%)	-	-
Respiratory dysfunction	-	23 (37.1%)	-	-
Acute kidney injury	-	5 (8.1%)	-	-
Toxic hepatitis	-	5 (8.1%)	-	-
Rhabdomyolysis	-	21 (33.9%)	-	-
Mortality	-	2 (3.2%)	-	-
Length of hospital or ED stay, h	14.9 (9.8-24.3)	42.3 (21.2-168.0)	13.7 (9.3-20.1)	< 0.001

ED, emergency department.

Continuous measures are presented as medians with interquartile ranges (25th and 75th percentile). Categorical variables are presented as counts and percentiles.

Fig. 2. The 0 h and 6 h lactate concentrations according to the outcome. Box-plot of lactate concentrations for the adverse event and no-adverse event groups. The box-plot presents the median, 25th and 75th quartiles, outliers, and extreme outliers.

summarized in Table 1 according to the occurrence of AEs. Lactate con- centrations according to the AEs are presented in Fig. 2. The median 0 h lactate concentrations were 2.7 (2.1-5.1) mmol/L in the AE group and

2.1 (1.4-2.9) mmol/L in the non-AE group, with a significant difference between the values (p < 0.001). The median 6 h lactate concentrations in the AE and non-AE groups were 2.0 (1.5-3.9) mmol/L and 1.3 (0.9-2.2) mmol/L, respectively (p < 0.001). Cardiovascular dysfunction (25/81 cases, 40.3%) was the most common AE in patients with acute drug intoxication. The most common drug exposures in the included patients and the AE ratios are summarized in Table 2.

Fig. 3 shows the ROC curve of lactate levels, combined 0 h and 6 h lactate levels, lactate clearance, and delta lactate for predicting AEs. The AUC of lactate at 0 h for predicting AEs was 0.705 (95% CI: 0.659-0.748), which was statistically and clinically significant. The opti- mal lactate cutoff point for AEs was greater than or equal to 4.2 mmol/L (37.1% sensitivity, 92.8% specificity). The AUC of 6 h lactate was 0.683 (95% CI: 0.636-0.727), and the optimal cutoff point was greater than or equal to 1.9 mmol/L (58.1% sensitivity, 70.0% specificity). The AUC of the combined lactate levels, lactate clearance, and delta lactate was 0.707 (95% CI: 0.661-0.750), 0.540 (95% CI: 0.454-0.617), and 0.612

(95% CI: 0.564-0.658), respectively. There was no significant difference between the prognostic values of 0 h lactate, 6 h lactate, and combined lactate levels (DeLong method, 0 h vs. 6 h, p = 0.368; 0 h vs. combina- tion, p = 0.768; 6 h vs. combination, p = 0.178). The sensitivity, speci- ficity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for each factor are pre- sented in Table 3.

The univariable and multivariable logistic regression analysis results for the risk factors for an AE in acute drug overdose are shown in Table 4. The univariate analysis showed that age, mean arterial pressure, respi- ration rate, SpO₂, Glasgow coma scale score, 0 h lactate level, 6 h lactate level, and delta lactate were significant risk factors. To assess the inde- pendent factors and the ability of lactate concentrations to predict AEs, we subjected the variables to multivariable logistic regression analysis using a stepwise backward method based on the results of the univariable analysis. Multivariable analysis showed that the 0 h lactate concentration at the initial ED presentation was associated with AEs in patients with an acute drug overdose after adjusting for confounders (aOR for 0 h lactate; 1.47, 95% CI; 1.23-1.77). However, the 6 h lactate level, lactate clearance, and delta lactate were not associated with AEs. The goodness-of-fit of the model was 0.780 (Hosmer-Lemeshow test).

Major intoxication drugs ingested by patients included in the study

Drug class?	Subjects	Adverse events (+)	Adverse events (-)	p-value
Total	425 (100%)	62 (100%)	363 (100%)	-
Benzodiazepines	86 (20.2%)	14 (22.6%)	72 (19.8%)	0.496
Non-benzodiazepine hypnotics	77 (18.1%)	12 (19.4%)	65 (17.9%)	0.626
Antidepressants	49 (11.5%)	5 (8.1%)	44 (12.1%)	0.164
BB/CCB	39 (9.2%)	11 (17.7%)	28 (7.7%)	0.005
Acetaminophen	28 (6.6%)	3 (4.8%)	25 (6.9%)	0.782
Antihistamine	27 (6.4%)	4 (6.5%)	23 (6.3%)	1.000
TCA	17 (4.0%)	5 (8.1%)	12 (3.3%)	<0.001
Antipsychotics	16 (3.8%)	3 (4.8%)	13 (3.6%)	0.049
NSAIDs	16 (3.8%)	0 (0.0%)	16 (4.4%)	0.255
Anticonvulsants	15 (3.5%)	1 (1.6%)	14 (3.9%)	0.124
Opioids	7 (1.6%)	3 (4.8%)	4 (1.1%)	0.067
Antidiabetics	4 (0.9%)	1 (1.6%)	3 (0.8%)	0.469
Unknown	19 (4.5%)	1 (1.6%)	18 (5.0%)	-
Others	27 (6.4%)	0 (0%)	27 (7.4%)	-

BB/CCB, b-adrenergic antagonists and calcium channel blockers; TCA, triCyclic antidepressants; NSAIDs, Non-steroidal anti-inflammatory drugs.

?The drug classes are listed in descending order of the frequency of ingestion. Multiple Drug overdoses were classified under a single clinically relevant drug class considering the impact of the drugs on the patient outcomes.

Fig. 3. Receive operating characteristic curve for predicting adverse events using emergency department lactate concentrations and kinetics.

1. Discussion

This study assessed the prognostic value of lactate values in the pre- diction of composite AEs in consecutive patients with acute drug over- dose admitted to the ED. The elevated 0 h lactate concentration helped predict the AEs associated with drug intoxication. However,

the 6 h lactate value, lactate clearance, and delta lactate were not predic- tors of the outcome. Our results suggested that the initial 0 h lactate concentration can be a useful biomarker for clinical decision-making in patients with acute drug overdose admitted to the ED.

South Korea has the highest rate of suicides among the nations of the Organization for Economic Cooperation and Development [17,18]. The suicide rate has increased by approximately two-fold over the past

20 years and poses an immense socioEconomic burden on the healthcare system in South Korea [16,19]. With respect to suicide at- tempts, drug overdose and pesticide intoxication appeared to be the most prevalent methods. Drug overdose and pesticide intoxication accounted for 0.7%-1.3% of all ED visits, and the hospitalization and mortality rates of Intoxicated patients in major emergency centers in 2005 were reported to be 41.5% and 4.8%, respectively [4,5,20].

Acute drug intoxication requires ED visits for resuscitation. Thus, clinical research on drug intoxication is necessary to respond appropri- ately to these patients in frontline healthcare settings, such as in the ED. However, the complexity of the responses to drug overdose hinders the prediction of clinical progress, which leads to an extended stay in the ED. This poses a limitation to efficient ED operation.

Currently, biomarkers for predicting mortality in patients of acute

drug overdose are not known. Although severity predictors have been developed in the ICU [21], it is difficult to identify early predictors in the field of clinical toxicology due to the variety of drug types and their dynamic characteristics. APACHE II is a prognostic indicator that can be used in toxicology but is difficult to apply in the ED as it has 15 to 30 complex components [22].

Lactate is a pathophysiological marker and a metabolic byproduct [8]. Lactate concentrations are increased during hypoxia and several Critical illnesses and activated in response to stress [7-11]. Hyper- lactatemia was shown to be correlated with the mortality of patients with and without infection admitted to the ED [9,23]. Moreover, hyperlactatemia is associated with the severity of intoxication with metformin and acetaminophen [12,13]. Although the physiological

Table 3

Diagnostic test characteristics of lactate concentrations, delta lactate, and lactate clearance for adverse events.

	AUC (95% CI)	Sensitivity, %	Specificity, %	Optimal cutoff point	PPV, %	NPV, %	+LR	-LR
0 h lactate	0.705 (0.659-0.748)	37.1 (25.2-50.3)	92.8 (89.7-95.3)	4.2 mmol/L	46.9	89.6	5.18	0.68
6 h lactate	0.683 (0.636-0.727)	58.1 (44.8-70.5)	70.0 (65.0-74.6)	1.9 mmol/L	24.8	90.7	1.93	0.60
0 h lactate +6 h lactate	0.707 (0.661-0.750)	40.3 (28.1-53.6)	91.7 (88.4-94.4)	4.9, 1.5 mmol/L	45.5	90.0	4.88	0.65
Lactate clearance	0.540 (0.454-0.617)	37.1 (25.2-50.3)	74.9 (70.1-79.3)	43.5%	20.2	87.5	1.48	0.84
Delta lactate	0.612 (0.564-0.658)	53.2 (40.1-66.0)	68.3 (63.3-73.1)	0.8 mmol/L	22.3	89.5	1.68	0.68

NPV, negative predictive value; PPV, positive predictive value; +LR, positive likelihood ratio; -LR, negative likelihood ratio.

Table 4

Univariable and multivariable analyses? of predictors of adverse events

Variable	Unadjusted OR	95% CI	p-value	Adjusted OR	95% CI	p-value
Age	1.03	1.01-1.04	< 0.001	-	-	-
Mean arterial pressure	0.97	0.95-0.98	< 0.001	0.98	0.96-1.00	0.096
Heart rate	1.00	0.99-1.01	0.948	-	-	-
Respiratory rate	1.16	1.05-1.28	0.003	1.14	1.02-1.27	0.024
SpO2	0.76	0.69-0.84	< 0.001	0.88	0.78-0.99	0.031
Glasgow coma scale score	0.77	0.71-0.84	< 0.001	0.82	0.74-0.91	< 0.001
0 h lactate	1.55	1.33-1.83	< 0.001	1.47	1.23-1.77	< 0.001
6 h lactate	1.63	1.37-1.96	< 0.001	-	-	-
Lactate clearance	1.00	1.00-1.01	0.431	-	-	-
Delta lactate	1.38	1.13-1.73	0.004	-	-	-

CI, confidence interval; OR, odds ratio.

?Multivariable logistic regression analysis with a stepwise backward method based on the univariable analysis results. The goodness-of-fit of the multivariable logistic model was tested using the Hosmer-Lemeshow test (p = 0.780).

mechanism underlying lactate production in acute drug intoxication re- mains controversial, Cheung et al. reported an association between the initial lactate concentrations measured in the ED and mortality and demonstrated its prognostic utility for mortality after drug overdose, with an optimal cutoff point of 5.0 mmol/L [14]. Thus, the optimal lac- tate cutoff point helps identify patients for whom ICU admission is war- ranted or should at least be seriously considered. Furthermore, the authors suggested that a lactate concentration of less than 2.0 mmol/L may indicate a low-risk subset of patients for medical clearance in the absence of a clinical toxidrome. However, the study was limited by the fact that the time-point of lactate concentration measurement was not recorded.

We hypothesized that lactate concentrations (0 h and 6 h), particu- larly the kinetic parameters (clearance and delta), exhibit prognostic value. Based on our observations, an elevated initial lactate concentra- tion was associated with the occurrence of composite AEs. However, the 6 h lactate value, lactate clearance, and delta lactate were not predic- tors of the outcome. The ability to predict outcomes in patients with drug intoxication based on varying time-course patterns of lactate con- centrations during the ED stay was limited. Treatment or resuscitation, such as that using vasopressors and ventilator care early during ED pre- sentation, may have influenced the time-course of lactate concentra- tions and the occurrence of AEs, which may have compromised the prognostic value.

There were some differences between the findings reported by Cheung et al. and those of our study. The demographics of the subject population were different. There were 24 fatalities (1.7%) in the study by Cheung et al., whereas there were 2 mortalities (0.4%) in our study. Thus, drug intoxication-related mortality was relatively low in our study [5,20]. Accordingly, composite AEs were the outcome in our study, whereas mortality was targeted in the study by Cheung et al. The mortality of patients with acute drug intoxication corresponds to the final prognosis rather than to the clinical course in the ED. Patients who experience fatality in their clinical course need aggressive resusci- tation early during ED stay. Thus, lactate levels exhibit limited effect in aiding medical decision-making in such situations. Furthermore, only a single ED lactate concentration was considered in the analysis, and sub- sequent lactate concentrations (even if changed or abnormal) were not considered in the analysis. The main strength of our study was the anal- ysis of various lactate concentrations, with an evaluation of all consecu- tive patients visiting the ED for an acute drug overdose. Therefore, our data can provide an interesting insight into the markers associated with acute drug overdose presentations in patients visiting the ED.

This study had several limitations. First, this was not a prospective but a retrospective study, in which data from an observational suicide registry was reviewed. Thus, the inherent bias of retrospective studies could not be eliminated. Additionally, cases of apparent accidental acute drug overdose were excluded from our suicide registry and were not included in our analysis. However, there were only a few cases of apparent accidental acute drug overdose, and we believe their

exclusion did not introduce a bias in our study findings. Second, the study was conducted at a single institution and there were fewer cases of fatal outcomes among the enrolled patients. Therefore, our re- sults may not be applicable to other study populations with different demographics. Third, the type of drug was not included in the analysis. Various types of drugs and the quantity of ingestion further complicate the interpretation of the results [14,24]. Further, we did not analyze drug combinations that specifically tend to produce AEs. Fourth, the time elapsed between drug overdose and ED presentation, which varied among patients, was not considered in the analysis. This could be asso- ciated with the initial lactate concentration. Finally, the AUC of lactate concentrations showed a sub-optimal performance. Thus, multi- biomarker approaches may be better than lactate concentration mea- surement alone for assessing acute drug intoxication.

1. Conclusions

The lactate concentrations and kinetics in patients with acute drug overdose admitted to the ED exhibited limited prognostic utility in predicting AEs and should be interpreted with caution for clinical decision-making. Even though the implications of these results may be helpful in risk stratification of the patients early in the course of ED pre- sentation, the lactate levels were not an absolute risk predictor. Pro- spective studies are needed to identify the early prognostic indicators for AEs associated with acute drug intoxication. Better outcome predic- tors should be explored further.

Author statement

S.J. Kim and J.H. Pak designed and conceived the study and wrote the manuscript. S.J. Ahn performed the statistical analysis. J.H. Song,

J.Y. Kim, and H.J. Cho provided professional suggestions.

Funding

None.

Ethics statement

The institutional review board for clinical research at Korea Univer- sity Ansan Hospital approved the study (IRB No. 2021AS0047).

Declaration of Competing Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgments

Not applicable.

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