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 . However, with massive overdose, clonidine's peripheral alpha-agonist properties may predominate, resulting in vasoconstriction and marked hypertension [14, 15]. The hypertension is transient because the centrally mediated sympathetic inhibition becomes the predominant effect and BP decreases . Symptoms of clonidine intoxication differ from poisoning with other substances in several reported literature which makes the clinical manifestations of clonidine poisoning more complex. Pomerleau, A. C. et al. reported that a 23-year-old man presented with severe hypertension after rubbing his entire body with compounded medicinal cream containing clonidine and toxicological analysis of initial blood samples revealed a serum clonidine concentration of 5,200 ng/ml . Farooqi, M. et al. reported that a 3.5-year-old male also presented with severe hypertension after a possible accelerated dosing error and the serum clonidine level was 300 ng/ml . Similarly, a 5-year-old boy with clonidine poisoning presented with hypertension and had a serum clonidine concentration of 64 ng/ml . Romano MJ analyzed serial serum samples obtained from a 28 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 . 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 findings 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 find 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 . 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 significant mental disorders, then with toxicological detection technology and other laboratory findings, the diagnosis of clonidine poisoning can be confirmed.
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 identified, 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 efficiently 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 , or ranging from 0.8 to 2.0 ng/ml . 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% . 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 efficient, 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 . HA230 resin hemoperfusion cartridge is of relatively specific recognition and adsorption capacity to various toxins and drugs. In clinic, the product could be used individually by all kinds of blood purification machines or used in association with other blood purification 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 detoxification 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 life-threatening symptoms, resulting in significant residual disability and accounting for a significant 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 . 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 . 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 efficiently 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 significantly reduce the serum/urine concentrations of clonidine with few side effects.