Anesthetic Clinical Pharmacology

E   Narrative Review Article

CME
Perioperative Diabetes Insipidus Caused by Anesthetic
Medications: A Review of the Literature
Lauren M. Van Decar, MD,* Emily G. Reynolds, BS,† Emily E. Sharpe, MD,‡ Monica W. Harbell, MD,*
Heidi E. Kosiorek, MS,*§ and Molly B. Kraus, MD*
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Diabetes insipidus (DI) is an uncommon perioperative complication that can occur secondary
to medications or surgical manipulation and can cause significant hypovolemia and electrolyte
abnormalities. We reviewed and evaluated the current literature and identified 29 cases of DI
related to medications commonly used in anesthesia such as propofol, dexmedetomidine, sevo-
flurane, ketamine, and opioids. This review summarizes the case reports and frequency of DI
with each medication and presents possible pathophysiology. Medication-induced DI should be
included in the differential diagnosis when intraoperative polyuria is identified. Early identifica-
tion, removal of the agent, and treatment of intraoperative DI are critical to minimize complica-
tions. (Anesth Analg 2022;134:82–9)

GLOSSARY
ADH = antidiuretic hormone; AQP-2 = aquaporin-2; AVP = arginine vasopressin; CI = confidence
interval; DDAVP = desmopressin; DI = diabetes insipidus; EDAS = encephaloduroarteriosynan-
giosis; ENT = otolaryngology; GABA = gamma-Aminobutyric acid; ICU = intensive care unit; neuro
= neurosurgery; NMDA = N-methyl-d-aspartate; ortho = orthopedic surgery; PICU = pediatric
intensive care unit; SD = standard deviation; UOP = urine output

D
iabetes insipidus (DI) is a rare condition asso- by significant urine output of >125 mL/h in adults,
ciated with the inability to effectively auto- while other symptoms might be masked intraopera-
regulate water balance resulting in polyuria, tively and become evident in the recovery room.1 This
polydipsia, and electrolyte abnormalities. This dis- significant change in total body water content charac-
ease process is generally classified into either central teristically produces hypernatremia that, if not iden-
or nephrogenic dysfunction with either decreased tified and corrected, can lead to potentially serious
release or ineffective response to antidiuretic hor- neurological symptoms including weakness, lethargy,
mone (ADH), respectively. myalgias, and coma. As patients receiving anesthesia
DI has many known etiologies including genetics, or sedation are unable to adjust their fluid intake to
medications, and surgical manipulation. However, compensate, it is the responsibility of the anesthesi-
little data are available regarding DI associated with ologist to replete the volume and manage any electro-
medications commonly used for anesthesia or seda- lyte abnormalities.
tion, and no previous reviews have been published. To our knowledge, there has not been a review
Many surgeries are several hours in duration and evaluating DI associated with anesthetic agents. Due
require prolonged medication infusions or adminis- to the serious complications associated with DI, it is
tration. DI presenting during anesthesia is marked imperative that anesthesiologists are able to identify
signs of DI in their patients and consider all possible
etiologies, including anesthetics. In this review, we
From the *Department of Anesthesiology and Perioperative Medicine
and †School of Medicine, Mayo Clinic, Phoenix, Arizona; ‡Department have compiled and analyzed published cases of DI
of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, related to commonly used anesthetic medications.
Minnesota; and §Department of Health Sciences Research, Mayo Clinic,
Phoenix, Arizona. The aim is to determine whether DI is more com-
Accepted for publication November 13, 2020. monly associated with certain anesthetics.
Funding: None.
The authors declare no conflicts of interest. METHODS
Supplemental digital content is available for this article. Direct URL citations We conducted a literature review in September 2020
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.anesthesia-analgesia.org). using medical electronic databases, PubMed, and
Address correspondence to Molly B. Kraus, MD, Department of Embase. The searches were conducted using a com-
Anesthesiology and Perioperative Medicine, Mayo Clinic, 5777 E Mayo Blvd, bination of the following subject headings and key-
Phoenix, AZ 85054. Address e-mail to kraus.molly@mayo.edu.
words including: “diabetes insipidus,” “transient
Reprints will not be available from the authors.
Copyright © 2021 International Anesthesia Research Society
diabetes insipidus,” “polyuria,” and “anesthet-
DOI: 10.1213/ANE.0000000000005344 ics,” and limited to English-language case reports

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 E  Narrative Review Article

published between January 1974 and September 2020 more days to recover after discontinuation of the
(Supplemental Digital Content, Material, http:// agent (Table 2). In some cases, anesthetic-induced DI/
links.lww.com/AA/D297). Perioperative cases of polyuria was suspected, and the presumed offend-
both diagnosed and suspected DI with polyuria were ing agent was removed resulting in prompt resolu-
included, as well as cases of DI during sedation in the tion of symptoms.2,7–10,15,25,26 For instance, Haldar et al7
intensive care unit (ICU). In addition, citations of the reported, “that within 1 hour there was a spontaneous
papers identified were evaluated to find additional and dramatic decrease in urine production.” Pratt et
case reports or case series. Exclusion criteria included al10 reported “as dexmedetomidine was discontinued,
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existing DI before anesthetic exposure, prior lithium the patients urine output returned to [the patient’s
use, DI attributed to anesthetics not currently used baseline of] 45 from 275 mL/h.” Frequency of DDAVP
in the United States such as methoxyflurane, or DI and vasopressin administration are noted in Tables 1
related to surgical manipulation, such as pituitary or and 2. The majority of patients were treated with
suprasellar surgeries (Figure 1). intravenous fluid replacement and monitoring of elec-
Data from each case, including patient age and sex, trolytes, plasma, and urine osmolality. Endocrinology
procedure type, anesthetic drugs administered, con- was consulted in 4 cases.3,4,6,7 Though there was no
cluded offending agent, recovery timeline in num- note of any long-term complications from DI in the
ber of days postexposure, desmopressin (DDAVP) or reported cases, 2 cases developed AKI that resolved
vasopressin administration and dosage, and length of with treatment.16,17
exposure, when available, were collected and sum-
marized. Descriptive data for demographic and pro- DISCUSSION
cedural characteristics were reported either as a mean As DI is a rare complication of anesthesia or sedation,
with standard deviation (SD) or percentages. The pro- it may be underappreciated and therefore diagnosis
portion of cases in which a drug was concluded to be and appropriate treatment may be delayed. From our
the offending agents out of total reported exposures findings, although DI can be caused by several anes-
was calculated and reported for each agent with a thetic agents, dexmedetomidine was the associated
95% confidence interval (CI). agent in the majority of case reports when it was pres-
ent. There are varying proposed mechanisms for how
RESULTS these anesthetic agents can result in DI.
The PubMed and Embase searches and citations Dexmedetomidine is a highly selective, short act-
reviewed identified 158 reports that were screened ing alpha-2 agonist.27 A few studies have evaluated
and 136 were excluded. We identified 29 unique cases dexmedetomidine and the development of DI. Canine
of DI attributed to an anesthetic in 25 publications and rat studies have demonstrated that alpha-2 ago-
(Table 1). Patient demographics and surgical charac- nists decrease both central arginine vasopressin (AVP)
teristics are provided in Table 2. The anesthetic agents release and peripheral nephrogenic response to AVP,
used included sevoflurane, propofol, dexmedetomi- resulting in a diuretic response.28–31 Though this poly-
dine, ketamine, and remifentanil. The use of sevo- uric response has not been demonstrated in human
flurane was present in the highest number of cases studies, a growing number of case reports has sug-
at 16 (55.2%), followed by propofol 14 cases (48.2%), gested a link between dexmedetomidine use and DI.5–
dexmedetomidine in 14 cases (48.2%), ketamine in 12 13,25,26
Case reports have implicated both continuous
cases (41.4%), and remifentanil in 8 cases (27.6%). infusions for several hours as well as a single loading
In all cases except 3, the authors attributed dose of 1 μg/kg.12
the development of DI to a causative agent. Sevoflurane is a commonly used volatile anesthetic
Dexmedetomidine was concluded to be the causative and was the second most frequently implicated cause
agent in the highest percentage of exposures at 73.3% of DI in 43.8% of exposures in our study.32 There are
(95% CI, 49.2-95.3), followed by sevoflurane in 43.8% several proposed mechanisms by which sevoflurane
of exposures (95% CI, 19.8-70.1), and ketamine in may cause renal injury and resultant DI.33–35 Morita
50.0% of exposures (95% CI, 21.1-78.9). Propofol was et al36 suggest that sevoflurane can cause a transient
implicated as the causative agent in the least number impaired Aquaporin-2 (AQP-2) response to AVP,
of the cases at 14.3% (95% CI, 0.2-42.8). Remifentanil resulting in reduced urinary concentration capac-
and other opioids were never implicated as causing ity. A second proposed mechanism is nephrotoxicity
DI (Figure 2). from inorganic fluoride production during sevoflu-
Time to resolution of symptoms was highly vari- rane metabolism.13 Schirle15 and Otsuka et al18 both
able in the 29 reported cases and varied with dura- reported cases of intraoperative polyuria and hyper-
tion of medication exposure. Of the 18 surgical cases, natremia that was associated with short-term sevo-
8 patients recovered on the day of exposure, whereas flurane exposure. It has also been associated with
more than half of the sedation cases required 2 or long-term exposure in several case reports, as well

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 Perioperative Diabetes Insipidus Review
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Figure 1. Flowchart of literature search. DI

indicates diabetes insipidus.

as in a European retrospective review that looked associated DI suggests that this complication may be
at long-term use of sevoflurane for sedation in the rare and associated with prolonged use.
ICU.14,16,17,37 Given the common use of sevoflurane Ketamine is an N-methyl-d-aspartate (NMDA)
use in anesthesia, the presence of 7 case reports of receptor antagonist, which blocks excitatory

84   
www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
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Table 1. Reported Cases in the Literature of DI and Polyuria Related to an Anesthetic Agents
Anesthetic agents administered
Return to
Start of Full
normal Length of Length of
Patient Dexme- Presumed presumed recovery DDAVP/
Surgery/ Keta Remi- Sevoflu- Propofol UOP after anesthetic sedation
First author (age/ detomi- causative causative agent in no. of vasopressin
procedure mine fentanil rane infusion end of exposure exposure
gender) dine agent to onset of days post and dose
exposure (h) (d)
signs of DI (h) exposure
(h)
1 Soo et al2 66/male Posterior laminectomy with X X Propofol <1 <1 0 None 8
instrumentation from
L2–L5 (spine/ortho)
2 Kassebaum 13/male Parathyroidectomy X X Propofol <1 1 DDAVP-unknown 5
E  Narrative Review Article

et al3 (neuro/ENT) dose-

responsive

January 2022 • Volume 134 • Number 1

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 X X Inconclusive 3 1 DDAVPa-2 μg
for Moya Moya disease divided doses-
(vascular) responsive
5 Granger and 23/male Anterior and posterior X X X Dexmedetomidine 1 1 None 9
Ninan5 discectomy and spinal
fusion (spine/ortho)
6 Ji and Liu6 71/female Posterior spinal X X X Dexmedetomidine <1 0 None 7
decompression and
fusion (spine/ortho)
7 Haldar et al7 25/female Endoscopic endonasal exci- X X Dexmedetomidine “Initial stages of <1 2 None 6
sion of tuberculum sellae surgery”
meningioma (neuro/ENT)
8 Adams and 12/female Posterior spinal fusion X X X X Dexmedetomidine <1 <1 0 None 4.5
Cassara8 (spine/ortho)
9 Greening et al9 40/male Posterior spinal fusion X X Dexmedetomidine <1 <2 1 None 6
(spine/ortho)
10 Pratt et al10 50/male Sedation in ICU X X Dexmedetomidine 2 h of increased <1 0 None
dose (24 h after
initial dose)
11 Selvaraj and 45/female Mandibulectomy and free X X Dexmedetomidine 0.5 0 None
Panneer flap for carcinoma of
selvam11 buccal mucosa (neuro/ENT)
12 Xu and Wan12 72/male Sarcoma resection (spine/ X X X Dexmedetomidine <1 1 None 7
ortho)
13 Chow et al13 67/male Sedation in ICU X X Dexmedetomidine Unclear 2 DDAVPa-
unknown
dose
14 Muyldermans 34/male Sedation in ICU X X Sevoflurane “During the next 5 DDAVP-2 μg 7
et al14 7 d”
15 Schirle15 18/male Free flap of left latissimus X Sevoflurane <1 <1 0 None 1.5

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dorsi to left lower extremity
(general)

85
(Continued)

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Table 1. Reported Cases in the Literature of DI and Polyuria Related to an Anesthetic Agents
Anesthetic agents administered

86   
Return to
Start of Full
normal Length of Length of
Patient Dexme- Presumed presumed recovery DDAVP/
Surgery/ Keta Remi- Sevoflu- Propofol UOP after anesthetic sedation
First author (age/ detomi- causative causative agent in no. of vasopressin
procedure mine fentanil rane infusion end of exposure exposure
gender) dine agent to onset of days post- and dose
exposure (h) (d)
signs of DI (h) exposure
(h)

16 Maussion 34/male Sedation in ICU X X X Sevoflurane 48 4 None 2

et al16
17 Cabibel et al17 27/male Sedation in ICU X X X Sevoflurane Unclear Days 8 DDAVPa-4 μg 13
Nonrespon-
sive
Perioperative Diabetes Insipidus Review

18 Cabibel et al17 43/male Sedation in ICU X X X Sevoflurane Unclear Days 16 DDAVP-4 μg 4

www.anesthesia-analgesia.org
three times
daily for 3 d
(36 μg) Non-
responsive
19 Cabibel et al17 64/male Sedation in ICU X Sevoflurane Unclear Days >6 DDAVPa- 6
unknown
dose Nonre-
sponsive
20 Otsuka et al18 60/female Left upper lobectomy X Sevoflurane Unclear Days 14 DDAVP-unknown 4
(general) dose-
responsive
21 Gaffar et al19 18/female Internal carotid artery X X X X Ketamine 2 0 DDAVPa-4 μg
bypass (vascular)
22 Kataria et al20 42/male Exploratory laparotomy and X Ketamine “Shortly after Days 5 DDAVP-2 μg 7
splenectomy (general) initiation” daily-
responsive
23 Hatab et al21 2/female Sedation in PICU X X Ketamine 7 Unclear Vasopres- 7
sina-180 mU
over 12 h
24 Sakai et al22 28/male Sedation in ICU X Ketamine 1 DDAVPa-30 8
μg divided
doses-
responsive
25 Herity et al23 59/female Sedation in ICU X X Ketamine 32 1 Vasopressina 2
DDAVP-10 μg
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 X X X Dexmedetomidine 0.5 <2 0 Vasopressin 15
flap (neuro/ENT)
29 Kirschen 30/female Cervical fusion (spine/ortho) X X X Dexmedetomidine 0.5 <2 0 DDAVPa-23 μg
et al26 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.
a
DDAVP/vasopressin was administered intraoperatively or concurrently with sedation.

ANESTHESIA & ANALGESIA

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 E  Narrative Review Article

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%)
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Spine/ortho 7 (24.1%)
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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) Figure 2. Number of times drug was reported to be the offending
Surgical cases (N = 18) agent out of total reported exposures.
  0 8 (44.4%)
  1 7 (38.9%)
  ≥2 3 (16.7%) release. Inoue et al42 evaluated propofol’s effects on
Sedation cases (N = 11) neurosecretory cells in the hypothalamus of rats. In a
  Unclear 1 (9.1%) rat model, propofol was found to inhibit the release of
  0 2 (18.2%)
  1 2 (18.2%)
AVP from the supraoptic nuclei in the hypothalamus.
  ≥2 6 (54.5%) Though this study has not been reproduced in human
Agents (present in report) studies, it suggests a potential mechanism of action
Sevoflurane 16 (55.2%) for propofol-induced DI.2–4
Propofol 14 (48.2%)
Dexmedetomidine 14 (48.2%) Remifentanil was not implicated as the causative
Ketamine 12 (41.4%) agent in any of the cases and was only considered
Remifentanil 8 (27.6%) in 1 case. Of note, both mu and kappa opioid recep-
Offending agent (as concluded by author)
tors have been localized on rodents’ hypothalamus
Dexmedetomidine 11 (37.9%)
Sevoflurane 7 (24.1%) and posterior pituitary, and have been implicated in
Ketamine 6 (20.7%) inhibiting secretion of AVP.43–45 While it is theoreti-
Inconclusive 3 (10.3%) cally possible for opioid use to cause DI or polyuria,
Propofol 2 (6.9%)
Remifentanil 0 (0%)
it is less likely given the absence of reported cases of
suspected opioid-induced DI. It is possible that there
Data are expressed as mean (standard deviation) or count (%) where
appropriate.
is a different receptor distribution in humans, sub-
Abbreviations: DDAVP, desmopressin; ENT, otolaryngology; ortho, ortho- clinical effects, or lack of awareness to this potential
pedic surgery. complication.
DI is widely recognized in the context of pituitary
and suprasellar surgeries.46–48 Given that this associa-
glutamatergic receptors located in both spinal and tion is already well established, those case reports were
supraspinal locations.38 Studies have shown that not included in this review. Of the 3 cases categorized
glutamate plays a role in stimulation and secretion as neuro/otolaryngology (ENT) cases, only 1 involved
of AVP from the neurohypophysis.39,40 Inhibition of an endonasal skull base approach that was proximal to
this excitatory neurotransmitter by ketamine is a pro- the structures of the hypothalamic-pituitary axis.7 The
posed mechanism by which it can transiently inhibit authors noted the polyuria began before any tumor
AVP release lead to the development of DI.19–22 Aida et resection. There are no other well-documented asso-
al41 demonstrated significantly increased urine output ciations between procedure type and DI, and none
associated with intraoperative ketamine use. were identified in our study. Eleven of the 29 cases
Propofol was indicated as the causative agent in were associated with prolonged sedation, potentially
the lowest percentage of cases. The gamma-Ami- indicating that the duration of exposure is important.
nobutyric acid (GABA)-mediated inhibition that is This is consistent with the literature surrounding other
caused by propofol is also postulated to inhibit AVP types of drug-induced DI, such as lithium exposure,

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 Perioperative Diabetes Insipidus Review

in which duration matters.49 Alternatively, DI may go agents, particularly dexmedetomidine, as potential

unrecognized in a short procedure since it is often the contributors when patients develop signs of DI. E
continued high urine output for several hours that
alerts the providers. Future studies should examine ACKNOWLEDGMENTS
the relationship between duration of anesthetic expo- The authors thank Diana Almader-Douglas, AHIP, MLS,
sure and development of DI. for her help with conducting the literature search.
For the anesthesiologist, identification of DI is reli-
ant on laboratory evaluation and high level of clinical DISCLOSURES
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suspicion, as symptoms of DI are often masked under Name: Lauren M. Van Decar, MD.
Contribution: This author helped write the manuscript.
anesthesia. Several step-wise algorithms in inter-
Name: Emily G. Reynolds, BS.
nal medicine and endocrinology exist to assist with Contribution: This author helped write the manuscript.
diagnosis and include confirmation of hypotonic Name: Emily E. Sharpe, MD.
polyuria, identifying the type of polyuria-polydipsia Contribution: This author helped review and edit the
syndrome, and finally identifying the underlying manuscript.
Name: Monica W. Harbell, MD.
etiology.50
Contribution: This author helped review and edit the
In the operating room, diagnostic emphasis manuscript.
should be placed on confirmation of polyuria with Name: Heidi E. Kosiorek, MS.
urine volumes >150 mL/kg/24 h at birth, >100 mL/ Contribution: This author helped analyze the data.
kg/24 h up to 2 years of age, and >50 mL/kg/24 h Name: Molly B. Kraus, MD.
above 2 years of age.50 For the average adult patient, Contribution: This author helped with formatting, study con-
ception, design reviewing, and editing.
urine output >125 mL/h is consistent with poly- This manuscript was handled by: Ken B. Johnson, MD.
uria. Urinary osmolality and specific gravity should
be obtained and levels <300 mOsm/kg and <1.003, REFERENCES
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Anesthesiologists must consider these anesthetic Care Medicine; January 2019, 2019.

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