Management of Acute Clonidine Poisoning in Adults: The Role of Resin Hemoperfusion

Clonidine poisoning in adults is rare. An observational retrospective study including 102 adults with clonidine poisoning was conducted. 57 patients with relatively mild conditions were placed in the local emergency departments (EDs) for clinical observation, while the remaining 45 were transferred to the tertiary hospital for intensive treatment, of whom 9 were given supportive care only and 36 were given hemoperfusion (HP), as well as similar supportive treatment. The main symptoms of these cases were: sleepiness, dizziness, fatigue, headache, inarticulacy, tinnitus and dry mouth. Physical examination showed hypotension, bradycardia and shallow and slow breathing. Serum and urine clonidine concentrations were signicantly elevated(cid:0)24.4 ng/ml, 313.2 ng/ml, respectively(cid:0). All cases slowly returned to their baseline state over 48 to 96 hours, which is co-related with the drawn of serum clonidine level. HP showed more ecient in reducing the serum/urine clonidine level. Clonidine poisoning is a potentially serious condition, which involves multiple system injury, including persistent central nervous system depression, cardiovascular and inhalation inhibition, often requiring intensive treatment. Patients with mild presentations only needed to be monitored and treated with symptomatic support. Of critically ill patients, HP signicantly reduced clonidine concentrations, which was effective and had few side effects.


Introduction
Clonidine is a synthetic imidazoline-derived agent, which was initially developed as an antihypertensive agent. Clonidine is also used for several unlabeled indications including ethanol and opioid withdrawal, smoking cessation, muscle spasticity, nicotine dependence,psychosis and mania, and management of attention-de cit/hyperactivity disorder (ADHD) and Tourette syndrome in children. Toxicity from overdose of clonidine has been well described in numerous case series and case reports, mostly in children [1].
Clinical manifestations are characterized by central nervous system (CNS) depression, cardiovascular effects including bradycardia and hypotension, and respiratory depression. The incidence of clonidine poisoning is increasing, and the toxidromic triad of CNS depression, bradycardia and hypotension can often appear serious [2]. Clonidine has been suggested to be a "one-pill can kill" pharmaceutical when children ingest single adult dose unintentionally [3].
Since no speci c antidote is available [4], a number of possible nonspeci c antidotes have been used for the treatment of clonidine poisoning, including activated carbons, naloxone, multiple vasopressors like dopamine, epinephrine, and norepinephrine, and atropine with variable success [5][6][7]. Currently, endotracheal intubation (ETI) is performed for somnolence and/or transport in critically ill patients, and approximately 25% were admitted to the intensive care unit (ICU) according to the Florida Poison Center's data over a period of 15 years, from 2002 to 2016 [8]. However, few case series reported in the literature mentioned the correlation between clonidine concentrations in the blood/urine and clinical presentation, treatment options, and prognosis. There continues to be controversy over monitoring the dosagedependent severity of clonidine poisoning, adjusting dosage and duration of these antidotes, and further information on the clonidine removal therapy is urgently required [2,9].
Two small-scale poisonings caused by food contaminated with clonidine powder had occurred in the suburbs around Beijing (Shunyi District in October 2009 and Huairou District in April 2010). About 30-60 minutes thereafter, a total of 102 patients developed altered mental status, sinus bradycardia and hypotension and were referred to 2 nearby EDs. Clonidine was recognized as an etiologic agent within 12 hours after the onset of poisonings, which provided the occasions to examine the manifestations of clonidine poisoning, the dose-response relationships, and the role of HP for clonidine detoxication. hospital for further management. The vasoactive agents (dopamine and atropine) used since onset were carefully recorded. On arrival to the receiving hospital, these patients remained severely somnolent, bradycardic and hypotensive. After admission, a physical examination, a chest X-ray, abdominal and cardiac ultrasound, electrocardiogram (ECG), electroencephalogram (EEG), magnetic resonance imaging (MRI) of the spine/brain and a full laboratory analysis of blood/urine parameters was performed. After consulting members of the Laboratory of Poisoning Control Center of PLA Academy, the culprit of the poisonings was identi ed as clonidine. Patient management was at the discretion of the attending physicians and 9 were given supportive care only (SC group ) and 36 were given HP, as well as similar supportive treatment modalities (HP group). The main supportive care included carefully monitoring and intermittent use of dopamine and atropine to maintain hemodynamics stability, and diuresis, supplementation of crystalloids infusion (2500 ml/patient/day), potassium calcium, vitamin B complex, and glutathione were also administered. The clonidine concentrations in serum/urine were tested repeatedly before HP and after HP.

Statistical analysis
Descriptive statistics were used to summarize demographic and practice data. Continuous variables with normal distribution were presents as mean ± standard deviation (SD); non-normal variables were reported as median (interquartile range, IQR), and number (percentage) as indicated. Normal distribution was determined using Kolmogorov-Smirnov test. Pearson's chi-squared test and Wilcoxon Mann-Whitney Utest were used to compare the clinical ndings in the SC group and HP group. Spearman rank correlation analysis was used to analyze the correlation between non-normal variables. A p-value of < 0.05 was considered statistically signi cant. Statistical analysis was performed using IBM SPSS version 26.0 for Windows (SPSS Inc., Chicago, IL, USA).

Clinical data from local EDs
All the patients developed drowsiness and fatigue approximately 30-60 minutes after ingestion, which prompted colleagues/restaurant staff to seek immediate medical assistance. Local CDC, police and toxicologist soon arrived at the scene of the poisonings, by sampling and analyzing the results, they concluded that the poisoning was caused by workers eating noodles contaminated with clonidine in the Shunyi District, while tourists in Huairou District have been poisoned by the presence of a powdered form of clonidine in their starches. A report from the Laboratory of Poisonous Substance Detection, The Fifth Medical Center of PLA General Hospital con rmed that the poison was single-drug poisoning of clonidine tested by HPLC-MS/MS. Upon arrival to the referring EDs, all patients underwent gastric lavage, and dopamine, atropine and rehydration support therapy continued without severe inhalation suppression or oxygenation drop beyond normal values requiring intubation. After treatment, 57 patients became awake and their blood pressure and heart rate tended to be stable. After 48-96 hours of carefully monitored and treatment, they were discharged from the local EDs.
Of the 45 cases, the median age was 19-62 (IQR: 30 (23.0, 40.5)), 22 (48.9%) were female. They were divided into SC group (2 male and 7 female) and HP group (20 male and 16 female). All the 45 patients developed hypotension (< 90/60 mmHg) and dopamine in doses of 6 to 50 ug/kg/minute was used in 42 of them, who developed unbearable headache or dizziness, or the heart rate is less than 40 beats/minute. All of them developed bradycardia, and injections of atropine (dosage: 0.5 to 1.0 mg intravenous (IV) bolus, may repeat every 3 to 5 minutes up to a maximum dose of 3.0 mg/day) are used in 38 of them who developed an extremely low heart rate less than 45 beats/minute or with unbearable headache or dizziness. All the clinical data and the amount of dopamine and atropine were listed in Table 1   There were signi cant differences between HP group and S C group in the dosage of dopamine/atropine used before/after admission and serum clonidine concentrations; Females were signi cantly more likely to be admitted to the SC group; Serum clonidine concentration had signi cant positive correlation with the level in urine. There was no statistical difference in length of hospital stay between the two groups.*P < 0.05 Effective removal of clonidine by HP  [10].
With the process of treatment, the patients' mental status and cardiovascular inhibition gradually improved, which was consistent with the drawn of serum/urine clonidine level. 19 cases were given the 2nd HP, and 5 cases the 3rd. All cases returned to their baseline state over 48 to 96 hours, which was related with the reduction of serum/urine clonidine level. HP showed more e cient in reducing the serum clonidine level than conventional supportive medical treatment, as shown in Table 2 and Fig. 1.

Wakening the patient prevents intubation
The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness [11]. The somnolence is often accompanied by respiratory depression, decreased oxygen saturation and is frequently treated with ETI, a procedure with signi cant morbidity [12]. Whether the patient's mental state can keep awake is of great signi cance in judging the severity, guiding treatment and evaluating prognosis. In our study, by observing the change in level of consciousness from somnolence to wakefulness after treatment and the dynamic change of clonidine concentration in blood and urine accordingly, the relationship between mental state and the concentration in blood and urine could be judged, which was listed in Table 3. Patients tended to be somnolent when the serum concentration exceeded 10.9 ng/ml (urine 154.2 ng/ml), while patients generally remained awake when the serum concentration was less than 4.2 ng / ml (urine 107.5 ng/ml). *P < 0.05

Favourable prognosis
Throughout the whole process of treatment, variable doses of dopamine, atropine were administered to all the 45 patients, 5 cases awoke following the rst HP treatment. Then, the patients in both groups gradually became awake and other clinical manifestations improved. There were no obvious adverse effects in either of the two groups. There were no deaths in the study. All patients were fully recovered before discharge.

Limitation
The major limitation of this study is the retrospective nature and treatments were not randomized, but determined by attending physicians after consulting the toxicologist's opinion. The 45 patients had received variable doses of dopamine, atropine, activated carbons and naloxone before admission to the tertiary hospital, which may have led to changes in the clinical presentation of patients, making scienti c clinical grouping di cult. Naloxone was administered only in a few severely poisoned patients, and did not exceed 10 mg as indicated. So it's hard to tell if naloxone's clinically effective. However, administration of high dose naloxone (10 mg IV bolus) was proved to be effective in reversing the effects of clonidine poisoning [2]. The second major limitation is that HP is more di cult to be applied in children than in adults, while clonidine poisoning mainly occurs in children.

Discussion
Clonidine, an alpha-2 adrenergic agonist that crosses the blood-brain barrier, has been prescribed historically as an antihypertensive agent. Clonidine treats hypertension by stimulating α2 receptors in the brain, which decreases cardiac output and peripheral vascular resistance, lowering blood pressure [13].
However, with massive overdose, clonidine's peripheral alpha-agonist properties may predominate, resulting in vasoconstriction and marked hypertension [14,15]. year old man following a 100 mg accidental overdose of clonidine and found that there was a hypertensive response when the serum clonidine concentration was above 50 ng/ml and a hypotensive response when below 50 ng/ml [19]. In our study, the mean median concentrations of Clonidine in blood and urine were 24.4 (ranging from 3.5 to 64.0) ng/ml and 313.2 (ranging from 50.1 to 590.7) ng/ml, respectively and no one was found hypertensive. All above ndings were consistent with our patients' presentation, having hypotension with elevated serum clonidine concentrations less than 64.0 ng/ml. The patterns of clonidine poisoning are changing and there exists great difference between adults and children. Through the literature review, we can nd that most cases of clonidine poisoning occur in children, it is related to its wider popularity in pediatric patients for the treatment of ADHD, Tourette syndrome, and sleep disturbances. Clonidine is now used in small amounts in drug withdrawal treatment, in injections, tablets, capsules or patches, and in both children and adults. And its clinical applications as anti-hypertensive agents and nasal decongestants, are very rare. In the past, most clonidine overdoses occurred when a child ingested a grandparent's antihypertensive medications, however, recently case series were involved medication prescribed for children with ADHD or other clinical use in children and occurred in the children's own home [20]. The main poisoning patterns of clonidine in adults include oral overdose, intravenous overdose, excessive use of transdermal patch, for suicide purposes or by mishandling [17,21,22]. Our reports have highlighted the emerging new pattern of clonidine poisoning in adults. It takes about 30-60 minutes from clonidine ingestions to the onset of signi cant mental disorders, then with toxicological detection technology and other laboratory ndings, the diagnosis of clonidine poisoning can be con rmed.
Generally, at therapeutic doses, clonidine has a number of anticholinergic side effects that include dry mouth, constipation, and sedation. While at toxic doses, it can cause hemodynamic instability and depression. However, overdose results in a toxidrome not easily identi ed, and there is no consensus on how to assess the severity of clinical manifestations. Currently, clinicians assess the degree of intoxication by means of changes in mental status, cardiovascular and respiratory suppression, and then decide on clinical treatment decisions such as the need for ETI and naloxone consumption, application of vasoactive drugs. In theory, studying the correlation between clonidine levels in blood and urine and clinical manifestations and prognosis can help assess severity and guide treatment. Unfortunately, few cases reported on clonidine concentrations, so their relation to clinical manifestations had been seldom analyzed. Our study found a correlation between clonidine concentrations in the blood and urine and clinical presentations including mental disorders, cardiac inhibition. Decreasing the concentrations e ciently and awakening the patients quickly may prevent the high-risk procedure of ETI and duration at ICU. Our study showed that patients could keep awake and relatively safe when clonidine concetrations were less than 4.2 (2.8, 6.6) and 107.5 (72.9, 140.3) in serum and urine respectively. The therapeutic serum clonidine concentrations are variably reported, typically < 4.0 ng/ml [17], or ranging from 0.8 to 2.0 ng/ml [16]. So toxicity can occur frequently with inadvertent double dosing and the narrow therapeutic index suggests that the frequency of severe ingestions will continue in the future.
Clonidine is a fat-soluble compound with a molecular weight of 230 Da, a high distribution volume and a serum drug-protein binding rate of 20-40% [11]. Clonidine is < 50% metabolized in the liver to inactive metabolites, yet the metabolism of clonidine is poorly understood. Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces [11,23]. Clearance of serum clonidine using hemodialysis (HD) is not e cient, and the patient's persistent hemodynamic instability seriously affects the use of HD. However, HP provides advantages compared with HD and has a very small effect on hemodynamics while clearing clonidine from the body [10]. HA230 resin hemoperfusion cartridge is of relatively speci c recognition and adsorption capacity to various toxins and drugs. In clinic, the product could be used individually by all kinds of blood puri cation machines or used in association with other blood puri cation devices for serum HP treatment. The product is especially applicable in clearing fat-soluble macromolecules, circle-sized micromolecules as well as drugs combined with serum proteins. In the present case, the patient's general condition was improved after starting resin-based sorbent HP.
However, endogenous clearance in patients with normal kidney function also played important role in clonidine's removal. Evaluating clonidine elimination is dependent on creatinine clearance and extracorporeal clearance by HP. Therefore, large amount of crystalloids infusion must be considered and intravenous diuretics for good urine output is functional. Despite these multiple confounders, we feel that HP played prominent a role in the detoxi cation of clonidine.
Although most of the clonidine poisonings reported in the literature resulted in minimal toxic effects and required only supportive care, clonidine poisoning is a potentially serious problem exhibiting lifethreatening symptoms, resulting in signi cant residual disability and accounting for a signi cant proportion of ICU admissions. Retrospective study from the American Association of Poison Control Centers National Poison Data System from 2000-2011 showed that clonidine poisoning caused 7 cardiac arrests and 3 deaths [3]. As clonidine ingestions are increasing, intubations will increase and more complications will occur. A lack of reported cases in adults and criteria for assessing the severity of clonidine poisoning has sometimes resulted in aimless treatment or over-treatment, including both level of monitoring and interventions with either antidotes or intubation and ventilation.
Marc Ghannoum et al. suggested that nephrologists and critical care physicians should be commonly involved in the treatment of severely poisoned patients, and various extracorporeal techniques including HP be applied to enhance the elimination of poisons [24]. In HP, blood passes through a charcoal or resin column to which poisons are adsorbed. HP can remove free and protein-bound serum poisons regardless of their molecular size. Our study showed that removal of clonidine e ciently from the body by HP could modify the time course and reduce its severity.
Clonidine has a narrow therapeutic index and clonidine poisoning is a potentially serious condition. Extracorporeal therapy provides the possibility of removing the toxins in the body directly and HP can signi cantly reduce the serum/urine concentrations of clonidine with few side effects.

Conclusions
Clonidine poisoning is a potentially serious condition, which involves multiple system injury, including persistent central nervous system depression, cardiovascular and inhalation inhibition, often requiring intensive treatment. Elevated clonidine concentrations were closely associated with higher risk of clinical presentations. Patients with mild presentations only needed to be monitored and treated with symptomatic support. Of critically ill patients, HP signi cantly reduced clonidine concentrations, which was effective and had few side effects.

Declarations
Ethics approval and consent to participate This was an observational single-center retrospective study, and ethical approval was achieved from the Ethics Committee of the Fifth Medical Center of PLA General Hospital and the study was conducted in accordance with the Declaration of Helsinki for experimental and clinical studies.

Consent for publication
Not applicable. 1a, Clonidine elimination was dependent on creatinine clearance with normal kidney function and extracorporeal clearance by HP. HP showed signi cantly more e cient in reducing the serum clonidine level than conventional supportive medical treatment; P<0.05; 1b The change of urine clonidine level before and after HP was signi cant and HP showed more e cient in reducing urine clonidine concentrations than treatments in SC group.