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Apparent Dexmedetomidine-Induced Polyuric Syndrome in an Achondroplastic Patient Undergoing Posterior Spinal Fusion

Greening, Allison MD*; Mathews, Letha MD*; Blair, James DO*

doi: 10.1213/ANE.0b013e31823299c1
Anesthetic Pharmacology: Case Report
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A 40-year-old achondroplastic patient underwent posterior spinal fusion under general endotracheal anesthesia. Anesthesia was maintained with isoflurane, and sufentanil, dexmedetomidine, and lidocaine infusions. Urine output increased from 150 mL/hr to 950 mL/hr the fourth hour. An increasing serum sodium, low urine-specific gravity, and increased serum osmolarity occurred simultaneously with the polyuria. Within 2 hours of discontinuing the dexmedetomidine infusion urine output greatly decreased. Within 24 hours all signs of the polyuric syndrome resolved spontaneously. Alpha2 agonists block arginine-vasopressin release and action; however, a polyuric syndrome has not been reported in the human literature.

Published ahead of print October 14, 2011 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.

Funding: None.

Conflict of Interest: See Disclosures at the end of the article.

This work was previously presented, in part, as a poster presentation at the 2010 American Society of Anesthesiologists Annual Meeting.

Reprints will not be available from the authors.

Address correspondence to Allison Greening, MD, Vanderbilt University Medical Center, Department of Anesthesiology, Educational Affairs, 2301 VUH, Nashville, TN 37232-7237. Address e-mail to allison.greening@gmail.com.

Accepted August 9, 2011

Published ahead of print October 14, 2011

Achondroplastic patients commonly have spinal stenosis, which is often repaired by decompressive laminectomy and posterior spinal fusion. As part of a balanced anesthetic we frequently use dexmedetomidine, a highly selective α-2 agonist with imidazoline receptor affinity that provides sedation without respiratory depression, for these cases. Dexmedetomidine has several known side effects; however, increased urine output or a polyuric syndrome associated with an increasing serum sodium, low urine specific gravity, and increased serum osmolarity is not among those commonly reported in humans, despite animal and in vitro evidence supporting such a finding.14

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CASE DESCRIPTION

A 40-year-old achondroplastic Caucasian man with a failed spinal fusion presented for repeat laminectomy and fusion at L2-S1. His medical history was significant for hypertension, hydrocephalus, a prior ventriculo-peritoneal shunt placement, and spinal stenosis. His exercise tolerance was 3 metabolic equivalents and he ambulated with a cane. He had undergone an L2 to L5 laminectomy and fusion in 2007, which was subsequently revised in 2009. His medications included losartan, carisoprodol, hydrocodone-acetaminophen, meloxicam, gabapentin, and tamsulosin. All preoperative laboratory values were within normal limits. He had no known drug allergies. His physical examination revealed achondroplasia, his height was 142 cm, and his weight was 107 kg. The patient gave permission for his case to be written and the IRB at Vanderbilt University Medical Center granted approval for this purpose.

On the day of surgery he was premedicated with 800 mg gabapentin and 2 mg of midazolam and was taken to the operating room. Standard ASA monitors were applied and general anesthesia was induced with propofol, ketamine, sufentanil, and vecuronium. His trachea was intubated using a videolaryngoscope. An arterial line, and a second, large bore peripheral IV were placed and the patient was placed in the prone position. Anesthesia was maintained with isoflurane, a dexmedetomidine infusion at 0.5 mcg/kg/hr without a bolus, and lidocaine and sufentanil infusions. The procedure lasted 6 hours during which time he received 7 L of crystalloid, 500 mL of 5% albumin, and 250 mL of cell saver blood. The estimated blood loss was 2300 mL and urine output totaled 2995 mL.

His urine output began to increase within the first hour and reached 950 mL/hour by the fourth hour. The patient became mildly hypotensive and tachycardic but responded to intravascular volume replacement and a phenylephrine infusion titrated to maintain his mean arterial blood pressure >65 mm Hg. Serum Na increased from 136 to 145 mEq/L on serial blood gas measurements. Treatment included intravascular volume repletion with crystalloid and colloid, including 2 L of ½ normal saline, and a polyuric work up was initiated. In the absence of other contributing factors the dexmedetomidine infusion was stopped. Within 2 hours his urine output decreased to <200 mL/hr. At the conclusion of the procedure the patient was returned to the supine position and his trachea was extubated. Cognitive and neurologic examinations were the same as baseline and within normal limits. The patient was taken to the neuro intensive care unit and observed for further signs or symptoms of a polyuric syndrome. Serum osmolarity and sodium peaked at 298 mOsm/kg H2O and 148 mEq/L, respectively, shortly after admission to the intensive care unit; the urine osmolarity had already begun normalizing and was 1.009 at that time. Over the next 24 hours all laboratory values returned to their normal ranges. The patient was subsequently discharged home on postoperative day 6 without further complications. Preoperative, intraoperative, and postoperative fluid balances and laboratory values are shown in Table 1.

Table 1

Table 1

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DISCUSSION

The plasma sodium increase, low urine specific gravity, and high plasma osmolarity seen in this case are consistent with a polyuric syndrome and perhaps diabetes insipidus, though without evidence of either decreased arginine-vasopressin (AVP) production (central diabetes insipidus) or decreased AVP responsiveness (nephrogenic diabetes insipidus) we cannot conclusively call the polyuria and associated changes diabetes insipidus. Although the patient did not have a recent magnetic resonance imaging of the head to exclude intracranial pathology, the temporal relation of the polyuria and the dexmedetomidine infusion suggest that the 2 are related. Extensive basic science and animal research show that α2-adrenoceptor agonists including dexmedetomidine decrease both central AVP release and peripheral AVP sensitivity via a variety of mechanisms5; however, the human literature remains sparse.

When administered to dogs under general anesthesia, dexmedetomidine causes a diuretic effect associated with decreased urine osmolarity, increased free water clearance, and a dose-related reduction in plasma AVP levels.6,7 Medetomidine, the prototype of the selective α2-agonists with imidazoline-receptor affinity, induces a diuresis in dogs that is associated with low urine osmolarity, high plasma osmolarity, low plasma AVP, and increased plasma atrial natriuretic peptide levels and is reversed by both yohimbine and atipamezole. Yohimbine, an α2 antagonist that lacks imidazoline receptor affinity, reverses the diuresis in a nondose-dependent manner, whereas atipamezole, a potent and highly specific antagonist of centrally and peripherally located α2-adrenoceptors with imidazoline receptor affinity does so in a dose-dependent manner.8 Additionally, verapamil enhances, whereas Bay K 8644, a calcium channel agonist, dose-dependently decreases the diuretic activity of dexmedetomidine in rats. This is supported by literature suggesting that calcium channel antagonists may both directly inhibit renal tubular water and electrolyte reabsorption and also block the inhibitory actions of angiotensin and vasopressin on renin secretion, lending credence to the theory that dexmedetomidine shares these two mechanisms.9

Centrally, dexmedetomidine inhibits AVP release from isolated rat hypothalamic paraventricular magnocellular neurons. This is due to a decrease in neuronal firing rate secondary to hyperpolarization by a G-protein coupled, inwardly rectifying potassium channel mediated by α2-adrenergic receptors.2 Peripherally, dexmedetomidine inhibits AVP-dependent sodium and water transport in the rat cortical collecting duct via an α2-mediated mechanism that appears to be coupled to a G-protein that inhibits adenylyl cyclase.4 Dexmedetomidine also appears to completely inhibit AVP-stimulated osmotic water permeability in the rat intermedullary collecting duct.3 It is also possible that dexmedetomidine acts peripherally via imidazoline receptors to increase sodium and free water excretion in a non-AVP dependent manner at a site other than the collecting duct.4 Clonidine, another α2 agonist with known diuretic properties, has been shown to increase diuresis via decreased expression of aquaporin-2 receptors in the rat collecting duct, and dexmedetomidine has been postulated to share this mechanism, thus providing a further mechanism for the reduction in salt and water resorption.1

In the human literature, patients randomized to dexmedetomidine versus propofol intensive care unit sedation after coronary artery bypass graft were noted to be significantly less likely to require high-dose diuretics, though urine output was not reported.10 Additionally, those receiving dexmedetomidine as an adjunct to epidural analgesia after thoracotomy are reported to have significantly greater cumulative postoperative urine output and significantly better preserved perioperative renal function compared with a control group, suggesting a beneficial effect on glomerular filtration.11

Although there are basic science mechanisms to support a dexmedetomidine-induced polyuric syndrome with substantial evidence in the animal literature, cases of this pharmacodynamic phenomenon have not been reported in humans and the polyuric syndrome has not found its way into the human endocrine literature.12,13 It is unclear why the magnitude of this patient's polyuric syndrome was so great; he had no known electrolyte imbalances or preexisting renal dysfunction. It is possible that his losartan and/or meloxicam use may have predisposed him to renal effects of dexmedetomidine, and the α1-blocker, tamsulosin, may have modulated the α2 effect in some way, though there is no way to determine this. This case brings attention to a phenomenon well outlined in both basic science and animal literature but which is in neither the human anesthetic nor endocrine literature, where it deserves further mention and study. It is unknown how well the mechanisms outlined in animal research, including studies done on rat and dog kidney and hypothalamus preparations, may apply to humans.

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DISCLOSURES

Name: Allison Greening, MD.

Contribution: This author helped write the manuscript and literature review.

Conflicts: Allison Greening reported no conflicts of interest.

Attestation: Allison Greening approved the final manuscript.

Name: Letha Mathews, MD.

Contribution: This author helped write the manuscript and literature review.

Conflicts: Letha Mathews reported no conflicts of interest.

Attestation: Letha Mathews approved the final manuscript.

Name: James Blair, DO.

Contribution: This author helped write the manuscript and literature review.

Conflicts: James Blair is PI of a study currently evaluating dexmedetomidine in spine surgery and has received funding from Hospira, Inc. for the conduct of the study.

Attestation: James Blair approved the final manuscript.

This manuscript was handled by: Steven L. Shafer, MD.

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