Abstract
Arginine vasopressin deficiency (AVP-D) is a rare disorder associated with a considerable risk of dysnatremia. This case involves a 59-year-old woman with idiopathic AVP-D and secondary hypocortisolemia, who developed severe hyponatremia after elective knee replacement. Postoperative pain management included nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. On day 4 of her admission, serum sodium concentration was 128 mEq/L (SI: 128 mmol/L) (reference range, 135-145 mEq/L [SI: 135-145 mmol/L]), but this was not reviewed. Feeling unwell that evening, she self-administered 200 mcg desmopressin; the next morning her sodium was 119 mEq/L (SI: 119 mmol/L); despite withholding all regular desmopressin doses for that day and the commencement of the expectant polyuria, hours later her sodium fell to 113 mEq/L (SI: 113 mmol/L). Emergency treatment involved fluid restriction and hypertonic saline, raising the sodium to 120 mEq/L (SI: 120 mmol/L) in 6 hours. Desmopressin 100 mcg was then restarted to clamp rapid overcorrection. Over 30 hours, sodium normalized with further desmopressin given as polyuria recurred: no neurological issues arose. Literature review found 14 cases of NSAIDs and opioids causing acute and severe hyponatremia in those taking desmopressin, highlighting the importance for clinicians and patients to be aware of these medication interactions.
Keywords: arginine vasopressin deficiency, desmopressin, hyponatremia, opioids, nonsteroidal anti-inflammatory drugs
Introduction
Arginine vasopressin deficiency (AVP-D), previously called cranial diabetes insipidus, is a rare condition affecting approximately 1 in 25 000 people [1]. Although desmopressin is an effective treatment, this condition is associated with significant morbidity and mortality due to risks of hyponatremia and hypernatremia. A retrospective review at a tertiary center found that 60% (27/45) of hospitalized patients with AVP-D developed dysnatremia; of these, 74% had hyponatremia (sodium ≤ 130 mEq/L [SI: ≤ 130 mmol/L]; reference range, 135-145 mEq/L [SI: 135-145 mmol/L]) and 18.5% developed significant hypernatremia [2]. A population-based matched cohort study of hospitalized patients with hypopituitarism revealed increased mortality attributable to those with AVP-D compared to controls in patients without hypopituitarism (odds ratio [OR] 3.69 [95% CI, 2.44-5.58], P < .001) [3].
Despite hyponatremia being more common than hypernatremia in AVP-D, current clinical guidelines for hospital management primarily focus on preventing and treating severe hypernatremia [4-6]. These guidelines suggest practicing “desmopressin escape” to prevent hyponatremia but do not specifically address drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids [4-8]. Only one paper addresses emergency management of severe hyponatremia with the re-introduction of desmopressin known as the desmopressin clamp [8].
This case report details a postoperative patient with known AVP-D and secondary hypocortisolemia who developed acute and severe hyponatremia secondary to commonly used analgesics of NSAIDs and opioids. Management required hypertonic saline and reinstating desmopressin to prevent rapid overcorrection of sodium levels. This case highlights the complexities for patients with AVP-D during hospital admissions, with respect to medication interactions and the prevention and management of severe hyponatremia.
Case Presentation
A 59-year-old woman with a history of idiopathic AVP-D and secondary cortisol deficiency presented for elective unicompartmental knee replacement for osteoarthritis. Diagnosed with AVP-D at age 16 years, she later developed secondary cortisol deficiency, at age 52 years, based on a low morning cortisol level and inadequate response to a short synacthen test. Magnetic resonance imaging (MRI) showed no pituitary pathology. Her thyroid and gonadal axes were intact, and her insulin-like growth factor -1 level (IGF-1) was in the normal range for age and gender. Usual medications included postmenopausal replacement with topical estrogen and oral progesterone, desmopressin (100 mcg morning and lunch, 200 mcg at night) and hydrocortisone (16 mg morning, 8 mg lunch) plus prednisolone (0.5 mg at night). Due to a previous traumatic experience with desmopressin being withheld in hospital, a clear medication plan was made together with her usual endocrinologist, to ensure her involvement and access to her own medication. She had no prior complications of hyponatremia.
Her operative procedure occurred without incident under spinal anesthesia, intravenous (IV) sedation, and local knee anesthesia. Intraoperatively she received hydrocortisone 100 mg IV and 2 liters of compound sodium lactate. Postoperatively she received 2 further doses of hydrocortisone 50 mg IV, 5 hours apart, followed the next day by increased oral steroids (hydrocortisone 20 mg morning, 10 mg lunch and late afternoon and prednisolone 1 mg at night). Usual desmopressin doses were maintained throughout this time. Analgesia included NSAIDs (celecoxib) 200 mg twice daily, oxycodone 10 mg 4 times daily and oxycodone/naloxone (targin) 10 mg/5 mg twice daily. From day 1 postoperatively she was eating, drinking, and not receiving any IV fluids. Sodium levels were stable (136 mEq/L [SI: 136 mmol/L]) on days 1 to 3.
On day 4, serum sodium dropped to 128 mEq/L (SI: 128 mmol/L), which occurred on a weekend (Saturday); this result was not reviewed, and she continued her regular desmopressin. That night, she developed periorbital tingling and anxiety, calling staff and family, concerned of feeling unwell. Believing she was becoming polyuric, she self-administered 200 mcg of desmopressin at midnight.
The following morning (day 5), her sodium was 119 mEq/L (SI: 119 mmol/L): other electrolytes and glucose levels were unremarkable.
Diagnostic Assessment
The treating physician reviewed her immediately. The patient appeared unwell, anxious, and complained of periorbital tingling. She was afebrile, heart rate of 75 beats per minute, blood pressure of 158/95 mmHg, oxygen saturations 97% on room air with a normal respiratory rate of 16 breaths per minute and a Glasgow Coma Score of 15. She had moist mucus membranes. Neurological examination was normal. Her weight was 80.6 kg (preoperative weight 74 kg) with mild generalized non-pitting edema of her hands and lower limbs, and she noted mild facial swelling.
Treatment
Management involved immediate cessation of further desmopressin (last dose was taken at midnight), fluid restriction (500 mL/24 hours), fluid balance chart, and 3 times daily electrolyte monitoring. At midday, sodium was 117 mEq/L (SI: 117 mmol/L). Polyuria was anticipated by mid-afternoon (15 hours after the last dose of desmopressin)—she passed 1 liter of urine in 5 hours; however, the sodium level dropped to 113 mEq/L (SI: 113 mmol/L) at 6 Pm prompting transfer to the intensive care unit (ICU). She remained conscious but was nauseated and dizzy.
ICU management included hydrocortisone 50 mg IV, an indwelling catheter, hourly point-of-care sodium levels and hypertonic saline (3%) totaling 500 mL over several hours (Fig. 1). An initial 100 mL bolus had no effect, so 2 further boluses were given, raising the sodium to 115 mEq/L (SI: 115 mmol/L), followed by a 2-hour infusion of 200 mL. Over 6 hours, her sodium rose to 120 mEq/L (SI: 120 mmol/L). Fluid restriction was removed and desmopressin 100 mcg orally was given to halt rapid overcorrection. Over the next 24 hours, her sodium incremented from 120 mEq/L (SI: 120 mmol/L) to 134 mEq/L (SI: 134 mmol/L). Desmopressin was administered based on polyuria onset: twice per day. The NSAIDs and opioid analgesics were discontinued as they were identified as contributing to the hyponatremia.
Figure 1.
The development and emergency care of severe hyponatremia. The patient's usual doses of desmopressin were administered during the perioperative and postoperative periods, alongside nonsteroidal anti-inflammatory drugs and opioid analgesics; serum sodium levels remained stable for the first 3 days. On day 4, serum sodium decreased to 128 mEq/L (SI: 128 mmol/L), but this change was not noted, and usual medication regimen continued. At midnight, the patient felt unwell and self-administered an additional dose of desmopressin. By day 5, sodium had further declined to 119 mEq/L (SI: 119 mmol/L), prompting cessation of all subsequent desmopressin doses. Despite anticipated polyuria developing at 3 Pm, sodium levels dropped sharply to a low of 113 mEq/L (SI: 113 mmol/L), necessitating transfer to the intensive care unit for hypertonic saline administration, delivered as 3 boluses of 100 mL each and one 200 mL infusion over 2 hours. When sodium reached 120 mEq/L (SI: 120 mmol/L) after 6 hours in total, desmopressin was reintroduced to “clamp” rapid correction. Additional desmopressin doses were administered at the onset of polyuria, occurring twice daily for 2 days, after which the previous regimen of 3 times per day was resumed.
Outcome and Follow-up
The patient improved once her serum sodium reached 120 mEq/L (SI: 120 mmol/L). Sodium correction was achieved over a 30-hour period. She left the ICU after 3 days, once sodium levels had stabilized and remained within the normal range.
Desmopressin was administered according to polyuria, resulting in twice-daily dosing for 2 days, then reverting to her usual regimen. Her revised inpatient management included daily weight measurement and electrolyte monitoring. She was discharged home on postoperative day 16, with her weight returned to baseline (73.9 kg). No neurological sequalae occurred.
Discussion
This case highlights the risk of hyponatremia in patients with AVP-D when desmopressin is used with NSAIDs and opioids, and the complexities of managing severe in-hospital hyponatremia in this group.
Hyponatremia is a known risk of desmopressin usage. A population-based study reporting a 13-fold higher rate of hyponatremia in adults using desmopressin (146/1000 person years), compared to those on oxybutynin (11/1000 person years) [9]. Hyponatremia is associated with substantial mortality and morbidity, as highlighted in a 2014 case series where three of 15 desmopressin users with severe hyponatremia died and 10 suffered serious permanent neurological sequalae [10].
AVP-D guidelines recommend withholding or delaying a weekly dose of desmopressin, known as “desmopressin escape,” to allow polyuria [4, 6, 7, 11] as this reduces the risk of out of hospital hyponatremia [12]. However, guidelines provide minimal precautions for potential drug interactions that enhance desmopressin action. The 2016 Endocrine Society hypopituitary guidelines warn against combining desmopressin with antiepileptic drugs (carbamazepine, oxcarbazepine, lamotrigine, perampanel, and felbamate) due to enhanced renal responsiveness to desmopressin [7], and one review cautions with excessive beer intake [11]. NSAIDs and/or opioid medications are not mentioned.
To date, 14 case reports (2003 to present) describe symptomatic hyponatremia (sodium ≤ 125 mEq/L (SI: ≤ 125 mmol/L)) with desmopressin plus NSAIDs and/or opioids [13-21] (Table 1). Most patients presented with seizures and reduced conscious states within days of starting these medications. The mechanism is via AVP-independent pathways that enhance water permeability in the collecting duct and promote proximal water and salt reabsorption; thus, an antidiuretic effect leading to enhanced water retention [22, 23]. NSAIDs are deliberately utilized to treat AVP-resistance for this reason [24].
Table 1.
Case reports of NSAIDs and opioids causing serious hyponatremia with desmopressin
| Year and paper | Case | Likely drug | Treatment |
|---|---|---|---|
| 2003 Gomez García et al [13] | 55-year-old woman with hemophilia, given desmopressin for dental procedure and ibuprofen: 1 day Seizure and found comatose next day Na 124 mEq/L (SI: 124 mmol/L) | NSAID ibuprofen | Recovered |
| In hospital fluid restriction alone | |||
| 2005 Callréus et al [14] | 6 cases taking desmopressin for nocturnal enuresis and Na ≤ 125 mEq/L (SI: ≤ 125 mmol/L) | 5 cases NSAID various types | Recovered |
| 1 case both NSAID and opioids | Details not presented | ||
| 2013 Bergoglio et al [15] | 46-year-old male with AVP-D taking NSAID for 1 week for back pain. Presented with obtundation and Na 113 mEq/L (SI: 113 mmol/L) | NSAID aceclofenac | Recovered |
| Hypertonic saline initially, then observation | |||
| Desmopressin restarted on day 3 | |||
| 2013 Shirazian et al [16] | 87-year-old woman with nocturnal enuresis presented with weakness 1 week after taking intermittent ibuprofen and told to drink more. Na 115 mEq/L (SI: 115 mmol/L) | NSAID ibuprofen | Recovered |
| Treated with fluid restriction, reintroduction desmopressin on polyuria, then hypertonic saline. Continued further desmopressin with onset of polyuria | |||
| 2013 Verrua et al [17] | 50-year-old male with AVP-D presented with weakness followed by seizure and coma. Had been taking ketoprofen for 3 days prior for back pain. Na 113 mEq/L (SI: 113 mmol/L) | NSAID ketoprofen | Recovered |
| Initial hypertonic fluid, tolvaptan 7.5 mg administered on day 1, desmopressin withheld & gradually restarted on day 3, and the usual regimen was reached on day 6 | |||
| 2017 Bhat et al [18] | 19-year-old woman with AVP-D receiving hydrocodone for a wisdom tooth extraction. Day 4 post-procedure presented with nausea and reduced conscious state. Na 121 mEq/L (SI: 121 mmol/L) | opioid hydrocodone | Recovered |
| Hypertonic saline | |||
| Desmopressin restarted after 24 hours, then continued at a reduced dose | |||
| 2019 Bojdani, et al [19] | 50-year-old male with chronic schizophrenia treated with clozapine, lamotrigine and fluoxetine and desmopressin for urinary incontinence. Taking meloxicam for 16 days for chronic bilateral knee pain while in hospital. Developed a seizure. Na 121 mEq/L (SI: 121 mmol/L) | NSAID meloxicam | Recovered |
| Fluid restriction and tapering of desmopressin | |||
| 2021 Pinto et al [20] | 10-year-old male with AVP-D. Femur fracture, ibuprofen 600 mg 6 hourly and hydromorphone 1 mg 4 hourly. Seizure 24 hours later. Na 108 mEq/L (SI: 108 mmol/L) | NSAID ibuprofen | Recovered |
| opioid hydromorphone | Fluid restricted, and doses of desmopressin given on day 2 onwards | ||
| 2024 Nägele et al [21] | 67-year-old male with AVP-D. Had a seizure and car accident (normal sodium). Treated with fentanyl, tramadol and NSAID for vertebral fractures and levetiracetam for seizures. Four days later, another seizure. Na 124 mEq/L (SI: 124 mmol/L) | NSAID | Recovered |
| FentanylTramadol | Ceased medications and changed neuroleptic drug to lacosamide | ||
| Levetiracetam | No details of the emergency treatment of hyponatremia given | ||
Serum sodium normal range 135-145 mEq/L (SI: 135-145 mmol/L).
Abbreviations: AVP-D, arginine vasopressin deficiency; Na, serum sodium; NSAID, nonsteroidal anti-inflammatory drug.
Interestingly, our patient gave a history that that she had noted previously not needing her usual desmopressin doses when taking tramadol and “cold and flu” tablets (containing codeine), but the relevance was not recognized until now. Large database analysis found tramadol and codeine are unlikely to cause hyponatremia alone but contributory when combined with medications known to increase hyponatremia risk [25].
Recent case series report 3 patients with AVP-D taking glucagon like peptide 1 receptor agonists (GLP-1 RA) for diabetes/weight loss required desmopressin dose reductions due to hyponatremia [26]. GLP-1 RA induce natriuresis and polyuria by suppressing endogenous AVP, but in the presence of exogenous AVP, less water is excreted, posing a potential drug interaction risk.
Severe hyponatremia from any cause carries high mortality. Rapid correction risks osmotic demyelination syndrome (ODS). Current guidelines for hyponatremia recommend considering desmopressin to prevent rapid overcorrection [27, 28]. In a case series of 15 patients with AVP-D and hyponatremia, the only 2 who survived without complications had desmopressin recommenced during correction with hypertonic saline [10]. Our patient had rapid sodium correction over 30 hours, but her hyponatremia was considered acute (<48 hours). She received desmopressin when her sodium reached 120 mEq/L (SI: 120 mmol/L), with further doses aligned to polyuria onset. Fortunately, she had no neurological sequelae. Only one guideline for AVP-D highlights using desmopressin to “clamp” sodium during the correction of hyponatremia [11].
In our case, the NSAIDs and opioid were considered primary causes of hyponatremia, as onset was 4 to 5 days postoperatively, she was not receiving any IV fluids and had appropriate steroid replacement for secondary hypocortisolemia. Cortisol deficiency can cause hyponatremia via AVP-dependent and AVP-independent mechanisms [29]. AVP-independent mechanisms include impaired aquaresis related to reduced renal blood flow, glomerular filtration, and direct effects on the water permeability of the distal tubules [29].
In our case, multiple factors delayed earlier intervention: unrecognized biochemical results, our patient's weight gain, and reported new symptoms (periorbital tingling and anxiety). Furthermore, access to her desmopressin and self-administration may have been influenced by cognitive changes because of the hyponatremia, as well as further exacerbating it. Efforts have been made to increase awareness and education for both patients with AVP-D and medical professionals, as errors and omissions have occurred during hospital admissions [12, 30]. As a result of these errors, recommendations include adopting the term AVP-D instead of cranial diabetes insipidus and ensuring patients have ready access to desmopressin in hospital, to avoid missed doses leading to hypernatremia [4, 6, 12].
To improve outcomes and reduce mortality in AVP-D, ongoing education is required, both in hospital and ambulant settings. Hyponatremia from commonly used medications such as NSAIDs and opioids is underappreciated and requires consideration of “desmopressin escape” when commencing these medications. All patients with AVP-D requiring hospital care should ideally have a multidisciplinary team familiar with this condition, working collaboratively with patients daily during their admission.
Learning Points
AVP deficiency (AVP-D) is a serious medical condition that predisposes patients to significant complications during hospitalization, including hypernatremia but more commonly, hyponatremia.
NSAIDs and opioids can lead to hyponatremia in those with AVP-D, so education for “desmopressin escape” should be discussed in all patients with AVP-D.
Severe hyponatremia in those with AVP-D require specialist care with use of hypertonic saline, but desmopressin must be reintroduced to “clamp” the sodium during the correction phase.
Management of severe hyponatremia in those with AVP-D and cortisol deficiency must also include stress steroid dosing.
It is recommended that care for hospitalized patients with AVP-D involve staff who have experience in managing this disorder, incorporating daily assessment of electrolyte levels, regular monitoring of body weight, fluid balance evaluation, mental status checks, and comprehensive review of medications—encompassing both desmopressin dosing schedules and newly introduced prescriptions.
Acknowledgements
We are grateful for the expert clinical care provided by the staff at St Vincent's Private Hospital Melbourne Intensive Care Unit for their rapid response and working collaboratively with the treating physicians. We acknowledge our patient for her proactive attitude in managing her condition.
Abbreviations
- AVP-D
arginine vasopressin deficiency
- ICU
intensive care unit
- IV
intravenous
- NSAID
nonsteroidal anti-inflammatory drug
Contributor Information
Carmela Caputo, Department of Endocrinology, St Vincent’s Hospital, Melbourne 3065, Australia; Department of Medicine, The University of Melbourne, Melbourne 3010, Australia.
Nupoor Tomar, Department of Endocrinology, St Vincent’s Hospital, Melbourne 3065, Australia.
Sasha Beitner, Department of Medicine, The University of Melbourne, Melbourne 3010, Australia; The Department of Medicine, The Royal Melbourne Hospital, Melbourne 3050, Australia.
Contributors
All authors made individual contributions to authorship. C.C. was involved in the diagnosis and management of the patient, manuscript preparation, and revision, and is accountable for all aspects of work. S.B. was involved in diagnosis and management of this patient. N.T. produced the figure. All authors reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed Patient Consent for Publication
Signed informed consent obtained directly from the patient
Data Availability Statement
Original data generated and analyzed during this study are included in this published article.
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Associated Data
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Data Availability Statement
Original data generated and analyzed during this study are included in this published article.