Serial Blood and Urine Drug Concentration Measurement in a Patient Withacute Intoxication Bytramadoland Zolpidem Resulting in Qt Prolongation: Case Report

Background: QT prolongation is a well-known complication when tramadol or zolpidem is ingested in large amounts acutely. However, the blood drug concentration resulting in QT prolongation or tachyarrhythmia when tramadol and zolpidem are ingested simultaneously in large amounts has not yet been reported. We report a case of acute intoxication by tramadol and zolpidem resulting in QT prolongation in a patient in whomserial blood and urine tramadol and zolpidemconcentrationswere determined. Case presentation:A 38-year-old male patient presented tothe emergency medical centrebecause ofpoisoning from 3 g of tramadol and 50 mg of zolpidemat 3 h before hisemergency department(ED) visit.During supportive treatment, he developed QT prolongation without clinical manifestations. He was discharged ve days after admission without any sequelae. We measured the blood and urine concentrations of tramadol and zolpidemat various time points, which revealed ablood tramadol concentration-dependent change in QTc intervals and increasing blood tramadol concentration at 8 h after the ED visit,with a sustainedlow zolpidem concentration.Tramadol and zolpidem are metabolized by the same enzyme, cytochrome P450 3A4.Therefore, competitive inhibition bya P450 3A4isoenzyme may lead to increases indrugtoxicity. The QT interval in patients acutely intoxicated bytramadol should be evaluated carefully, particularlywhen tramadol is co-ingested with other drugs. Conclusions:Considering the half-life of tramadolor zolpidem and potential for continued absorption of drugs remaining in the gastrointestinal tract, it is necessary to observe patients viacardiac monitoring for more than 36 hafteracute intoxication.The blood concentration of tramadol may increaseand result in QT prolongationeven afterappropriate initial treatment.


Background
Tramadol and zolpidem are well-known analgesics and hypnotics widely used to treat pain or insomnia. Recently, cardiac safety concerns regarding administration of zolpidem have been raised by a case of long QT syndrome complicated by torsade de pointes tachyarrhythmia [1]. QT prolongation is a wellknown complication that occurs when tramadol is ingested in large amounts acutely. The toxic and lethal blood concentrations of tramadol and zolpidem have been reported in post-mortem cases. However, the blood drug concentration resulting in QT prolongation or tachyarrhythmia when tramadol and zolpidem are ingested simultaneously in large amounts has not been reported. Herein, we report a case of acute intoxication from these drugs resulting in QT prolongation in a patient by evaluating serial blood and urine concentrations of the drugs.

Case Presentation
A 38-year-old male presented to the emergency department (ED) with a chief complaint of acute intoxication. He reported that he had ingested 60 tablets of Tridol® (tramadol hydrochloride 50 mg, YUHAN, Seoul, South Korea) and 5 tablets of Zolpiram® (zolpidem tartrate 10 mg, Whan In Pharm, Seoul, South Korea) 4 h prior and had been treated for psychiatric disorders, including depression, anxiety, and insomnia, for many years. He had also been diagnosed with Wolff-Parkinson-White syndrome 6 years prior.
At the time of the visit, the patient scored 14 points (E3V5M6) on the Glasgow coma scale. His blood pressure was 152/105 mmHg, heart rate was 98 beats/min, breathing rate was 20 breaths/min, body temperature was 37.0 °C, and oxygen saturation was 95%. Neurological examination revealed no abnormal cranial re ex or brainstem signs. The results of an arterial blood test showed respiratory acidosis and hypoxemia (pH, 7.37; pCO 2 level, 52 mmHg; pO 2 level, 73 mmHg; HCO 3 (Fig. 2). The QTc interval decreased to 524 ms, 485 ms at 24 h, 36 h after exposure respectively (Fig. 3,4).
The patient was hospitalized in the intensive care unit for close cardiac monitoring. After informed consent was obtained, serial blood and urine samples were collected at 8-or 12-h intervals from the time of the ED visit and sent to the National Forensic Service of Korea for drug concentration analysis.

Discussion And Conclusions
This is the rst report describing the determination of blood and urine concentrations of tramadol and zolpidem at regular time intervals in a patient. Tramadol, a synthetic opiate, is used in pain treatment. It is metabolized by the cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4, and its elimination half-life is known to be 9 h [2]. Several cases of tramadol poisoning have been reported, including lethal intoxications [3,4], and the toxic concentration is known to be > 2 mg/L [5]. The blood drug concentration was reported to be 7.7 mg/L in one post-mortem case from acute tramadol poisoning death and 48.34 mg/L in other cases [6]. A previous study in 2016 reported prolonged QTc intervals in 18.4% of QTc prolongation that was well-correlated with plasma drug concentrations [8]. However, unlike the study by Keller et al., which was conducted while patients took prescriptions normally, this case involved a patient with acute overdose poisoning from an estimated total of 3 g of tramadol and 50 mg of zolpidem. In the present case, a serial blood tramadol concentration-dependent change in the QTc interval was observed, which is consistent with the ndings of Keller et al. The patient's blood concentration and QTc interval simultaneously increased in the 8 h after the ED visit despite general treatment of the patient for acute poisoning. This suggests the potential for continued absorption of drug components remaining in the gastrointestinal tract, as the time to peak concentration is independent of the dose and depends only on the rates of absorption and elimination [9]. Zolpidem is also mainly metabolized by cytochrome P450 3A4 [10] and may have a synergistic effect in tramadol poisoning because it undergoes metabolism via the same pathway, and this interaction can enhance QT prolongation by decreasing drug clearance. However, in this case, zolpidem levels remained below the therapeutic concentration; thus, the effect of acute ingestion of zolpidem was minimal.
In conclusion, considering the half-life of tramadol or zolpidem and potential for continued absorption of drugs remaining in the gastrointestinal tract, it is necessary to observe patients via cardiac monitoring for more than 36 h in acute intoxication. The blood concentration of tramadol may increase and result in QT prolongation even after appropriate initial treatment, as observed in this case. Consent for publication Written informed consent was obtained from the patient for publication of this case report and

List Of Abbreviations
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