Perioperative Diabetes Insipidus Caused by Anesthetic Medications: A Review of the Literature : Anesthesia & Analgesia

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Perioperative Diabetes Insipidus Caused by Anesthetic Medications: A Review of the Literature

Van Decar, Lauren M. MD*; Reynolds, Emily G. BS†; Sharpe, Emily E. MD‡; Harbell, Monica W. MD*; Kosiorek, Heidi E. MS*,§; Kraus, Molly B. MD*

Author Information

From the *Department of Anesthesiology and Perioperative Medicine

†School of Medicine, Mayo Clinic, Phoenix, Arizona

‡Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota

§Department of Health Sciences Research, Mayo Clinic, Phoenix, Arizona.

Published ahead of print January 06, 2021.

Reprints will not be available from the authors.

Accepted for publication November 13, 2020.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Address correspondence to Molly B. Kraus, MD, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054. Address e-mail to [email protected].

Anesthesia & Analgesia 134(1):p 82-89, January 2022. | DOI: 10.1213/ANE.0000000000005344
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Abstract

Diabetes insipidus (DI) is a rare condition associated with the inability to effectively autoregulate water balance resulting in polyuria, polydipsia, and electrolyte abnormalities. This disease process is generally classified into either central or nephrogenic dysfunction with either decreased release or ineffective response to antidiuretic hormone (ADH), respectively.

DI has many known etiologies including genetics, medications, and surgical manipulation. However, little data are available regarding DI associated with medications commonly used for anesthesia or sedation, and no previous reviews have been published. Many surgeries are several hours in duration and require prolonged medication infusions or administration. DI presenting during anesthesia is marked by significant urine output of >125 mL/h in adults, while other symptoms might be masked intraoperatively and become evident in the recovery room.1 This significant change in total body water content characteristically produces hypernatremia that, if not identified and corrected, can lead to potentially serious neurological symptoms including weakness, lethargy, myalgias, and coma. As patients receiving anesthesia or sedation are unable to adjust their fluid intake to compensate, it is the responsibility of the anesthesiologist to replete the volume and manage any electrolyte abnormalities.

To our knowledge, there has not been a review evaluating DI associated with anesthetic agents. Due to the serious complications associated with DI, it is imperative that anesthesiologists are able to identify signs of DI in their patients and consider all possible etiologies, including anesthetics. In this review, we have compiled and analyzed published cases of DI related to commonly used anesthetic medications. The aim is to determine whether DI is more commonly associated with certain anesthetics.

METHODS

We conducted a literature review in September 2020 using medical electronic databases, PubMed, and Embase. The searches were conducted using a combination of the following subject headings and keywords including: “diabetes insipidus,” “transient diabetes insipidus,” “polyuria,” and “anesthetics,” and limited to English-language case reports published between January 1974 and September 2020 (Supplemental Digital Content, Material, https://links.lww.com/AA/D297). Perioperative cases of both diagnosed and suspected DI with polyuria were included, as well as cases of DI during sedation in the intensive care unit (ICU). In addition, citations of the papers identified were evaluated to find additional case reports or case series. Exclusion criteria included existing DI before anesthetic exposure, prior lithium use, DI attributed to anesthetics not currently used in the United States such as methoxyflurane, or DI related to surgical manipulation, such as pituitary or suprasellar surgeries (Figure 1).

F1
Figure 1.:
Flowchart of literature search. DI indicates diabetes insipidus.

Data from each case, including patient age and sex, procedure type, anesthetic drugs administered, concluded offending agent, recovery timeline in number of days postexposure, desmopressin (DDAVP) or vasopressin administration and dosage, and length of exposure, when available, were collected and summarized. Descriptive data for demographic and procedural characteristics were reported either as a mean with standard deviation (SD) or percentages. The proportion of cases in which a drug was concluded to be the offending agents out of total reported exposures was calculated and reported for each agent with a 95% confidence interval (CI).

RESULTS

The PubMed and Embase searches and citations reviewed identified 158 reports that were screened and 136 were excluded. We identified 29 unique cases of DI attributed to an anesthetic in 25 publications (Table 1). Patient demographics and surgical characteristics are provided in Table 2. The anesthetic agents used included sevoflurane, propofol, dexmedetomidine, ketamine, and remifentanil. The use of sevoflurane was present in the highest number of cases at 16 (55.2%), followed by propofol 14 cases (48.2%), dexmedetomidine in 14 cases (48.2%), ketamine in 12 cases (41.4%), and remifentanil in 8 cases (27.6%).

Table 1. - Reported Cases in the Literature of DI and Polyuria Related to an Anesthetic Agents
Anesthetic agents administered
First author Patient (age/gender) Surgery/procedure Ketamine Dexmedetomidine Remifentanil Sevoflurane Propofol infusion Presumed causative agent Start of presumed causative agent to onset of signs of DI (h) Return to normal UOP after end of exposure (h) Full recovery in no. of days postexposure DDAVP/vasopressin and dose Length of anesthetic exposure (h) Length of sedation exposure (d)
1 Soo et al2 66/male Posterior laminectomy with instrumentation from L2–L5 (spine/ortho) X X Propofol <1 <1 0 None 8
2 Kassebaum et al3 13/male Parathyroidectomy (neuro/ENT) X X Propofol <1 1 DDAVP-unknown dose-responsive 5
3 Hong et al4 48/male EDAS (vascular) X X Inconclusive 3 1 DDAVPa-5 μg divided doses-responsive
4 Hong et al4 46/female Surgical revascularization for Moya Moya disease (vascular) X X Inconclusive 3 1 DDAVPa-2 μg divided doses-responsive
5 Granger and Ninan5 23/male Anterior and posterior discectomy and spinal fusion (spine/ortho) X X X Dexmedetomidine 1 1 None 9
6 Ji and Liu6 71/female Posterior spinal decompression and fusion (spine/ortho) X X X Dexmedetomidine <1 0 None 7
7 Haldar et al7 25/female Endoscopic endonasal excision of tuberculum sellae meningioma (neuro/ENT) X X Dexmedetomidine “Initial stages of surgery” <1 2 None 6
8 Adams and Cassara8 12/female Posterior spinal fusion (spine/ortho) X X X X Dexmedetomidine <1 <1 0 None 4.5
9 Greening et al9 40/male Posterior spinal fusion (spine/ortho) X X Dexmedetomidine <1 <2 1 None 6
10 Pratt et al10 50/male Sedation in ICU X X Dexmedetomidine 2 h of increased dose (24 h after initial dose) <1 0 None
11 Selvaraj and Panneerselvam11 45/female Mandibulectomy and free flap for carcinoma of buccal mucosa (neuro/ENT) X X Dexmedetomidine 0.5 0 None
12 Xu and Wan12 72/male Sarcoma resection (spine/ortho) X X X Dexmedetomidine <1 1 None 7
13 Chow et al13 67/male Sedation in ICU X X Dexmedetomidine Unclear 2 DDAVPa-unknown dose
14 Muyldermans et al14 34/male Sedation in ICU X X Sevoflurane “During the next 7 d” 5 DDAVP-2 μg 7
15 Schirle15 18/male Free flap of left latissimus dorsi to left lower extremity (general) X Sevoflurane <1 <1 0 None 1.5
16 Maussion et al16 34/male Sedation in ICU X X X Sevoflurane 48 4 None 2
17 Cabibel et al17 27/male Sedation in ICU X X X Sevoflurane Unclear Days 8 DDAVPa-4 μg Nonresponsive 13
18 Cabibel et al17 43/male Sedation in ICU X X X Sevoflurane Unclear Days 16 DDAVP-4 μg three times daily for 3 d (36 μg) Nonresponsive 4
19 Cabibel et al17 64/male Sedation in ICU X Sevoflurane Unclear Days >6 DDAVPa-unknown dose Nonresponsive 6
20 Otsuka et al18 60/female Left upper lobectomy (general) X Sevoflurane Unclear Days 14 DDAVP-unknown dose-responsive 4
21 Gaffar et al19 18/female Internal carotid artery bypass (vascular) X X X X Ketamine 2 0 DDAVPa-4 μg
22 Kataria et al20 42/male Exploratory laparotomy and splenectomy (general) X Ketamine “Shortly after initiation” Days 5 DDAVP-2 μg daily-responsive 7
23 Hatab et al21 2/female Sedation in PICU X X Ketamine 7 Unclear Vasopressina-180 mU over 12 h 7
24 Sakai et al22 28/male Sedation in ICU X Ketamine 1 DDAVPa-30 μg divided doses-responsive 8
25 Herity et al23 59/female Sedation in ICU X X Ketamine 32 1 Vasopressina DDAVP-10 μg 2
26 Herity et al23 23/male Sedation in ICU X X Ketamine 55 0 Vasopressina 2
27 Ansar et al24 29/male Sinus surgery (neuro/ENT) X Inconclusive 2 1 DDAVPa-2 μg 5
28 Chen et al25 62/male Neck dissection and free flap (neuro/ENT) X X X Dexmedetomidine 0.5 <2 0 Vasopressin 15
29 Kirschen et al26 30/female Cervical fusion (spine/ortho) X X X Dexmedetomidine 0.5 <2 0 DDAVPa-23 μg Responsive
Blank spaces indicate insufficient data obtained from the case report.
Abbreviations: DDAVP, desmopressin; DI, diabetes insipidus; EDAS, encephaloduroarteriosynangiosis; ENT, otolaryngology; ICU, intensive care unit; neuro, neurosurgery; ortho, orthopedic surgery; PICU, pediatric intensive care unit; UOP, urine output.
aDDAVP/vasopressin was administered intraoperatively or concurrently with sedation.

Table 2. - Summary of Case Reports of Diabetes Insipidus or Polyuria Due to Anesthesia or Sedation
Demographics (N = 29)
 Age (y) 39.7 (19.6), range: 2–72
 Male 19 (65.5%)
 Female 10 (34.5%)
Procedure type
 Sedation 11 (37.9%)
 Spine/ortho 7 (24.1%)
 Neurosurgery/ENT 5 (17.2%)
 Vascular 3 (12.5%)
 General 3 (12.5%)
Exposure duration
 Surgical cases (N = 18)
  Mean (h) 6.5 (3.2), range: 1.5–15
  Unspecified 5
 Sedation cases (N = 11)
  Mean (d) 5.67 (3.6), range 2–13
  Unspecified 2
Treatment
 DDAVP 15 (51.7%)
 Vasopressin 4 (13.8%)
 None 11 (37.9%)
Symptom resolution (no. of days postexposure)
 Surgical cases (N = 18)
  0 8 (44.4%)
  1 7 (38.9%)
  ≥2 3 (16.7%)
 Sedation cases (N = 11)
  Unclear 1 (9.1%)
  0 2 (18.2%)
  1 2 (18.2%)
  ≥2 6 (54.5%)
Agents (present in report)
 Sevoflurane 16 (55.2%)
 Propofol 14 (48.2%)
 Dexmedetomidine 14 (48.2%)
 Ketamine 12 (41.4%)
 Remifentanil 8 (27.6%)
Offending agent (as concluded by author)
 Dexmedetomidine 11 (37.9%)
 Sevoflurane 7 (24.1%)
 Ketamine 6 (20.7%)
 Inconclusive 3 (10.3%)
 Propofol 2 (6.9%)
 Remifentanil 0 (0%)
Data are expressed as mean (standard deviation) or count (%) where appropriate.
Abbreviations: DDAVP, desmopressin; ENT, otolaryngology; ortho, orthopedic surgery.

In all cases except 3, the authors attributed the development of DI to a causative agent. Dexmedetomidine was concluded to be the causative agent in the highest percentage of exposures at 73.3% (95% CI, 49.2-95.3), followed by sevoflurane in 43.8% of exposures (95% CI, 19.8-70.1), and ketamine in 50.0% of exposures (95% CI, 21.1-78.9). Propofol was implicated as the causative agent in the least number of the cases at 14.3% (95% CI, 0.2-42.8). Remifentanil and other opioids were never implicated as causing DI (Figure 2).

F2
Figure 2.:
Number of times drug was reported to be the offending agent out of total reported exposures.

Time to resolution of symptoms was highly variable in the 29 reported cases and varied with duration of medication exposure. Of the 18 surgical cases, 8 patients recovered on the day of exposure, whereas more than half of the sedation cases required 2 or more days to recover after discontinuation of the agent (Table 2). In some cases, anesthetic-induced DI/polyuria was suspected, and the presumed offending agent was removed resulting in prompt resolution of symptoms.2,7–10,15,25,26 For instance, Haldar et al7 reported, “that within 1 hour there was a spontaneous and dramatic decrease in urine production.” Pratt et al10 reported “as dexmedetomidine was discontinued, the patients urine output returned to [the patient’s baseline of] 45 from 275 mL/h.” Frequency of DDAVP and vasopressin administration are noted in Tables 1 and 2. The majority of patients were treated with intravenous fluid replacement and monitoring of electrolytes, plasma, and urine osmolality. Endocrinology was consulted in 4 cases.3,4,6,7 Though there was no note of any long-term complications from DI in the reported cases, 2 cases developed AKI that resolved with treatment.16,17

DISCUSSION

As DI is a rare complication of anesthesia or sedation, it may be underappreciated and therefore diagnosis and appropriate treatment may be delayed. From our findings, although DI can be caused by several anesthetic agents, dexmedetomidine was the associated agent in the majority of case reports when it was present. There are varying proposed mechanisms for how these anesthetic agents can result in DI.

Dexmedetomidine is a highly selective, short acting alpha-2 agonist.27 A few studies have evaluated dexmedetomidine and the development of DI. Canine and rat studies have demonstrated that alpha-2 agonists decrease both central arginine vasopressin (AVP) release and peripheral nephrogenic response to AVP, resulting in a diuretic response.28–31 Though this polyuric response has not been demonstrated in human studies, a growing number of case reports has suggested a link between dexmedetomidine use and DI.5–13,25,26 Case reports have implicated both continuous infusions for several hours as well as a single loading dose of 1 μg/kg.12

Sevoflurane is a commonly used volatile anesthetic and was the second most frequently implicated cause of DI in 43.8% of exposures in our study.32 There are several proposed mechanisms by which sevoflurane may cause renal injury and resultant DI.33–35 Morita et al36 suggest that sevoflurane can cause a transient impaired Aquaporin-2 (AQP-2) response to AVP, resulting in reduced urinary concentration capacity. A second proposed mechanism is nephrotoxicity from inorganic fluoride production during sevoflurane metabolism.13 Schirle15 and Otsuka et al18 both reported cases of intraoperative polyuria and hypernatremia that was associated with short-term sevoflurane exposure. It has also been associated with long-term exposure in several case reports, as well as in a European retrospective review that looked at long-term use of sevoflurane for sedation in the ICU.14,16,17,37 Given the common use of sevoflurane use in anesthesia, the presence of 7 case reports of associated DI suggests that this complication may be rare and associated with prolonged use.

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist, which blocks excitatory glutamatergic receptors located in both spinal and supraspinal locations.38 Studies have shown that glutamate plays a role in stimulation and secretion of AVP from the neurohypophysis.39,40 Inhibition of this excitatory neurotransmitter by ketamine is a proposed mechanism by which it can transiently inhibit AVP release lead to the development of DI.19–22 Aida et al41 demonstrated significantly increased urine output associated with intraoperative ketamine use.

Propofol was indicated as the causative agent in the lowest percentage of cases. The gamma-Aminobutyric acid (GABA)-mediated inhibition that is caused by propofol is also postulated to inhibit AVP release. Inoue et al42 evaluated propofol’s effects on neurosecretory cells in the hypothalamus of rats. In a rat model, propofol was found to inhibit the release of AVP from the supraoptic nuclei in the hypothalamus. Though this study has not been reproduced in human studies, it suggests a potential mechanism of action for propofol-induced DI.2–4

Remifentanil was not implicated as the causative agent in any of the cases and was only considered in 1 case. Of note, both mu and kappa opioid receptors have been localized on rodents’ hypothalamus and posterior pituitary, and have been implicated in inhibiting secretion of AVP.43–45 While it is theoretically possible for opioid use to cause DI or polyuria, it is less likely given the absence of reported cases of suspected opioid-induced DI. It is possible that there is a different receptor distribution in humans, subclinical effects, or lack of awareness to this potential complication.

DI is widely recognized in the context of pituitary and suprasellar surgeries.46–48 Given that this association is already well established, those case reports were not included in this review. Of the 3 cases categorized as neuro/otolaryngology (ENT) cases, only 1 involved an endonasal skull base approach that was proximal to the structures of the hypothalamic-pituitary axis.7 The authors noted the polyuria began before any tumor resection. There are no other well-documented associations between procedure type and DI, and none were identified in our study. Eleven of the 29 cases were associated with prolonged sedation, potentially indicating that the duration of exposure is important. This is consistent with the literature surrounding other types of drug-induced DI, such as lithium exposure, in which duration matters.49 Alternatively, DI may go unrecognized in a short procedure since it is often the continued high urine output for several hours that alerts the providers. Future studies should examine the relationship between duration of anesthetic exposure and development of DI.

For the anesthesiologist, identification of DI is reliant on laboratory evaluation and high level of clinical suspicion, as symptoms of DI are often masked under anesthesia. Several step-wise algorithms in internal medicine and endocrinology exist to assist with diagnosis and include confirmation of hypotonic polyuria, identifying the type of polyuria-polydipsia syndrome, and finally identifying the underlying etiology.50

In the operating room, diagnostic emphasis should be placed on confirmation of polyuria with urine volumes >150 mL/kg/24 h at birth, >100 mL/kg/24 h up to 2 years of age, and >50 mL/kg/24 h above 2 years of age.50 For the average adult patient, urine output >125 mL/h is consistent with polyuria. Urinary osmolality and specific gravity should be obtained and levels <300 mOsm/kg and <1.003, respectively, are consistent with hypotonic urine. It is prudent to rule out other causes of polyuria including hyperglycemia, uremia, or iatrogenic causes including diuretic or mannitol administration.50 Serum electrolytes and osmolality should also be obtained, and a high sodium (>146 mmol/L) and plasma osmolality (>300 mOsm/kg) are typically seen with DI.50 Treatment should focus on replacement of free water deficit with a balanced salt solution, pharmacotherapy including DDAVP or vasopressin as appropriate, and close monitoring of patient’s fluid and electrolyte status. Ultimately, all patients in the reported cases documented recovery suggesting that drug-induced DI may be transient and reversible by identifying and removing the offending agent.

Since this is a retrospective review of the literature, this study has inherent limitations. Further, we were reliant on the authors’ determination of causative agent in each report. Future prospective studies are necessary to further evaluate this subject of drug-induced DI related to anesthetics.

CONCLUSIONS

Perioperative DI is a rare occurrence with potential for significant patient harm if it is not recognized and treated in an appropriate and timely fashion. Several commonly used anesthetic medications, including dexmedetomidine, sevoflurane, and ketamine, have been implicated in the development of transient DI or polyuria in case reports. However, little data are available to determine the true incidence of DI with the administration of these anesthetic medications. Anesthesiologists must consider these anesthetic agents, particularly dexmedetomidine, as potential contributors when patients develop signs of DI.

ACKNOWLEDGMENTS

The authors thank Diana Almader-Douglas, AHIP, MLS, for her help with conducting the literature search.

DISCLOSURES

Name: Lauren M. Van Decar, MD.

Contribution: This author helped write the manuscript.

Name: Emily G. Reynolds, BS.

Contribution: This author helped write the manuscript.

Name: Emily E. Sharpe, MD.

Contribution: This author helped review and edit the manuscript.

Name: Monica W. Harbell, MD.

Contribution: This author helped review and edit the manuscript.

Name: Heidi E. Kosiorek, MS.

Contribution: This author helped analyze the data.

Name: Molly B. Kraus, MD.

Contribution: This author helped with formatting, study conception, design reviewing, and editing.

This manuscript was handled by: Ken B. Johnson, MD.

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