Iirola et al. Journal of Medical Case Reports 2010, 4:73 http://www.jmedicalcasereports.com/content/4/1/73 Discussion There are some previous reports on the use of long- term moderate to high dose infusions of dexmedetomi- dine in ICU patients [3], but none of these accounts have reported dexmedetomidine plasma concentrations. In our patient, the infusion rates were higher than recommended, and her dexmedetomidine plasma levels were measured over a 3-week infusion period. On the average, our patient’s observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine in humans [4]. However, the concentration of our patient’s dexmedeto- midine greatly varied even during unchanged infusion. The plasma concentration of dexmedetomidine decreased by one-third (2.9 ng/ml to 1.7 ng/ml) on days 6 to 8 despite a constant rate of infusion. The concen- tration of any drug at a steady state is dependent only on its plasma clearance and the rate of infusion. Accordingly, the calculated clearance of dexmedetomi- dine was increased by 60%. The reason for the increased clearance can only be speculated. Dexmedetomidine is almost completely eliminated by metabolism in the liver. It is mainly N-glucuronidated by glucuronyl transferases and hydroxylated by several cytochrome P450 enzymes [5], but none of the drugs which were administered at the time of the apparent change in dexmedetomidine clearance are known to induce the activities of glucuronyl transferases or cyto- chrome P450 enzymes. It is thus logical to assume that changes in hemodynamic variables could have affected the pharmacokinetics of dexmedetomidine. Although there is no direct information on the extrac- tion ratio of dexmedetomidine in humans, the reported values of dexmedetomidine clearance (40 L/h to 70 L/h in adults) [4] suggest that the extraction ratio of dexme- detomidine is rather high, and its clearance may thus be dependent on liver perfusion. This hypothesis is sup- ported by data from Ebert et al. [6] and Snapir et al. [2] who observed that high-dose target controlled infusions of dexmedetomidine produced higher plasma concentra- tions than expected, probably due to decreased cardiac output caused by dexmedetomidine itself. Unfortunately, we have no data from our patient on cardiac output or intestinal perfusion at the time of major changes in her dexmedetomidine clearance. Nevertheless, the increase in apparent dexmedetomidine clearance coincided with the general improvement of the condition of our patient. For instance, the dose rate of norepinephrine required to maintain her hemodynamic function was significantly reduced on the 5th day of the dexmedetomidine infusion. Although the dose rate of dexmedetomidine was high, its sedative effect had to be enhanced with propofol. It Page 4 of 5 is quite common that several different types of drugs acting via different mechanisms are combined during long-term ICU treatment. Our patient was commenced on clonidine because clonidine was routinely used to facilitate the termination of long sedation or opioid infu- sions at the time of the study. However, in the case of dexmedetomidine, the change to another alpha2-adreno- ceptor agonist was probably unnecessary. Our patient developed optic neuropathy probably because of cerebral ischemia secondary to hypotension, hypoxia or embolism. Although a toxic mechanism can- not be excluded, we have no reason to believe that this complication was due to dexmedetomidine. There is a plethora of underlying conditions for ischemia during critical illness and there are no previous reports of toxic neuropathy following dexmedetomidine infusion. Conclusion During our patient’s 24-day high-dose dexmedetomidine infusion, her observed plasma concentrations were on the average well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine in humans. There was, however, a marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate. We conclude that the pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care. However, the phar- macokinetics of dexmedetomidine appears to be linear even at high-dose and long-lasting administration. We observed no unexpected accumulation of dexmedetomi- dine during the infusion. Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Acknowledgements The nurses in the intensive care unit are acknowledged for their invaluable help in taking blood samples at night time. Author details 1Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FIN-20521, Turku, Finland. 2Department of Pharmacology, Drug Development and Therapeutics, University of Turku and Turku University Hospital, FIN-20521, Turku, Finland. Authors’ contributions TI, RL and EK were involved in patient care and collected her blood samples. JPK and MS analyzed the samples. TI, RL, EK, RA, JPK, MS and KTO were involved in the interpretation of data and review of literature. They also drafted and revised the manuscript. All authors read and approved the final manuscript.