Sedative–hypnotic medications are commonly used perioperatively to provide anxiolysis, sedation, and amnesia. Among these, dexmedetomidine has advantages of providing adequate sedation while avoiding undesirable effects such as delirium/cognitive impairment, tachycardia, hypertension, and respiratory depression.1 This agent is useful for patients undergoing spine surgeries, in whom intraoperative neurophysiological testing often precludes the use of paralytics or volatile anesthetics.2
Dexmedetomidine is a selective α2-adrenergic agonist that acts centrally in the locus coeruleus and peripherally to depress noradrenergic transmission, leading to decreased alertness and a blunted autonomic response to stressors such as pain.3 In lowering catecholamine outflow, common side effects include bradycardia and hypotension.1,2 Studies in experimental animals have suggested that dexmedetomidine can also trigger diuresis of free water and micturition, likely via inhibition of vasopressin secretion by the pituitary and/or inhibition of hypothalamic paraventricular nucleus magnocellular neuronal signaling.4,5 Yet, limited clinical evidence exists to support the potential diuretic effect of dexmedetomidine in humans. Only a handful of case reports exists describing dexmedetomidine-induced diuresis.5–9
Here, we report a case of a 30-year-old woman undergoing cervical instrumented fusion surgery who received dexmedetomidine continuous infusion intraoperatively, resulting in a massive diuresis greater than any previously reported. We obtained written consent from the patient to report her health information.
A 30-year-old Caucasian woman presented for cervical fusion of C1 to C3 due to a C2 hangman’s fracture status-post motor vehicle accident 6 months before. The patient’s medical history was significant for heartburn, depression, and panic attacks. Her medications included ibuprofen, sulfamethoxazole-trimethoprim, alprazolam, aspirin, acetaminophen, clonazepam, buprenorphine-naloxone, and methocarbamol. She had been previously hospitalized 6 months earlier after the motor vehicle accident in which she sustained multiple injuries, including the cervical spine injury noted above and was treated with a halo fixation device, and a traumatic brain injury, rib fractures, and liver laceration. Subsequently, 10 days later, she was discovered to have anemia due to a left retroperitoneal hematoma and colonic perforation, necessitating Hartmann procedure with end colostomy. The anesthesia and postoperative course for this procedure was uncomplicated. The patient reported no family history of complications with anesthesia, no nausea or vomiting with anesthesia, and no previous anesthesia problems. She weighed 72 kg and had a body mass index of 27.43 kg/m2. She was a former smoker and admitted to narcotic abuse. She took her substitution therapy with buprenorphine-naloxone on the day of surgery, and ketamine was included in the anesthetic plan to facilitate multimodal analgesia.
The patient received 2 mg of intravenous (IV) midazolam for preoperative anxiolysis. For induction, propofol 150 mg, fentanyl 150 µg, lidocaine 80 mg, and ketamine 20 mg were given. Succinylcholine 100 mg was used for paralysis since the surgery team was planning to monitor motor-evoked potential during the surgery. The intubation and start of surgery were uneventful. The maintenance of anesthesia was with propofol infusion at 75–200 µg/kg/min and dexmedetomidine 0.3–0.8 µg/kg/h, titrating to hemodynamic needs. IV fentanyl, hydromorphone, and ketamine pushes were given throughout the case for intra- and postoperative pain relief. The patient also received dexamethasone 12 mg to decrease swelling. After approximately 30 minutes of starting dexmedetomidine, the patient’s urine output increased, reaching approximately 3600 mL within 1 hour. The dexmedetomidine was stopped and desmopressin (DDAVP) 23 µg was given via IV infusion and magnesium sulfate 2 g and IV potassium 10 mEq. The patient received 4000 mL of lactated Ringer’s solution over the course of the surgery. Her estimated blood loss was 100 mL, and her urine output was 4325 mL. Serial urine output is shown in the Figure. Serum electrolytes are shown in Supplementary Table 1 (http://links.lww.com/AACR/A212).
Postoperatively, the patient was hemodynamically normal, maintaining spontaneous breathing, and maintaining O2 saturation of 96% on room air. Postoperative pain management included acetaminophen, hydromorphone patient-controlled analgesia. On postoperative day 1, she was awake and alert, in no acute distress. Her pain was adequately controlled on hydromorphone patient-controlled analgesia and methocarbamol pro re nata. She was adequately hydrated and tolerating solid diet. The patient was discharged on postoperative day 3.
The most remarkable event was the onset of unexpected, massive diuresis during the intraoperative period. Causes of diuresis during the intraoperative period include overly aggressive hydration, diuretic medications, osmotic diuresis from uncontrolled hyperglycemia, nephrogenic, or central diabetes insipidus.10 At times, brain injury itself can induce central diabetes insipidus. However, in this case, the traumatic brain injury was remote (6 months before the surgery). Moreover, our patient did not have any polyuria at any time after the trauma. In our patient, we consider medication-related polyuria to be the principal differential diagnosis.
Dexmedetomidine, an α2-adrenergic agonist, is the most likely causative factor, here not only because of the temporal relationship between the initiation of dexmedetomidine infusion and massive diuresis, but also for biologically plausible reasons. There are 3 effects of dexmedetomidine on vasopressin that could cause diuresis, based on animal and clinical studies. These include (1) direct drug effect at the level of the hypothalamus-neurohypophysis to decrease antidiuretic hormone (ADH) secretion via stimulation of α2-adrenergic receptors in the paraventricular nucleus5,11; (2) direct drug effect at the level of the renal collecting tubules to counteract the effect of ADH on water permeability via interference with release of renin or atrial natriuretic peptide5; and (3) indirect drug effect to decrease the stress experienced by the body and its subsequent secretion of stress hormones, including ADH.12 Still, none of these proposed mechanisms can explain the magnitude of the diuresis in the present case or the rarity with which it has been reported in the literature, suggesting that other factors are likely involved.
Empirically, there are case reports showing a temporal relationship between dexmedetomidine administration and diuresis5–9 (Table). Intriguingly, 4 of these cases involved patients undergoing posterior spinal fusion surgery: 1 in the thoracolumbar region, 2 in the lumbar region, and 1 in the cervical region.5,6,8,9 The rate of diuresis in these studies ranged from approximately 500 to 1000 mL/h. By comparison, our patient produced urine at an average rate of 1350 mL/h from time of initiation of dexmedetomidine until the time of DDAVP initiation (Figure). We were interested in seeing if there would be any dose-response relationship and calculated a correlation coefficient given these previous studies and found a R2 = 0.308. There appears to be no clear dose-response relationship between the dexmedetomidine infusion rate and urine output, although the onset of diuresis generally occurred within the first 60 minutes of drug administration (Table). Consistent with this observation, others have reported that another α2-adrenergic agonist, clonidine, may also lead to a prompt diuresis during anesthesia.13
On the other hand, ketamine, which we also used in this patient’s case, might also induce diuresis,11 possibly by antagonism of either N-methyl-d-aspartate or non–N-methyl-d-aspartate glutamate receptors in the posterior pituitary, impairing release of ADH, causing diuresis. We feel that this mechanism is unlikely in our case because of the low dose of ketamine used. We started a ketamine bolus dose of 20 mg/h at least 150 minutes before the onset of the diuresis and continued with this agent until the end of the case.
Although there is yet to be a scientific explanation for the susceptibility of patients undergoing spinal procedures to experience dexmedetomidine-induced diuresis, this is a potential complication to anticipate in such clinical circumstances. It may rather be that dexmedetomidine continuous infusion is typically used during maintenance in these procedures because motor-evoked potential monitoring precludes the use of volatile anesthetic agents and muscle relaxant, although it should be noted that dexmedetomidine may still interfere with such monitoring, especially at higher doses.14 Interestingly, there are some case reports of development of diabetes insipidus after trauma to the spine without any associated intracranial trauma (eg, see Ref. 15). The mechanism here appears to be perturbation of hypothalamohypophyseal axis secondary to changes in the blood flow caused either by hypotension or by embolic phenomenon.15 This is not a plausible mechanism in our case because the patient experienced neither hypotension nor hypovolemia.
Others have simply replaced ongoing fluid loss rather than pharmacologically counteracting the diuretic effect of dexmedetomidine.5,6,8,9 In our case, we opted to admit DDAVP because the diuresis was rapid and massive. Moreover, at that time, we were uncertain of the exact cause for such a dramatic response. Our case demonstrates that, in the event of severe drug-induced diuresis, DDAVP may be safely administered intraoperatively in conjunction with close monitoring of electrolyte and volume status.
In summary, we report a case of likely dexmedetomidine-induced massive diuresis in a patient undergoing spinal surgery. We caution other practitioners to be vigilant of this potential side effect and to consider dexmedetomidine-induced diuresis in the differential diagnosis of an anesthetized patient with unexplained polyuria.
Name: Gregory W. Kirschen, PhD.
Contribution: This author helped conceive the work, analyze the data, and draft the manuscript.
Name: Ethan Kim, MD.
Contribution: This author helped conceive the work, analyze the data, and draft the manuscript.
Name: Rishimani S. N. Adsumelli, MD.
Contribution: This author helped conceive the work, analyze the data, and edit the manuscript.
This manuscript was handled by: BobbieJean Sweitzer, MD, FACP.
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