Ketamine-Induced Syndrome of Inappropriate Antidiuretic Hormone Secretion and Hyponatremia

Ketamine is a dissociative anesthetic commonly used for the induction and maintenance of anesthesia and has a well-known role in analgesia. However, it also has the potential for addiction, which can lead to neurological, psychological, systemic, and biochemical consequences. In this case report, we are highlighting a rare case of a young Asian female with Ketamine addiction who presented with urinary complaints. The patient was found to have hyponatremia and laboratory tests were consistent with a syndrome of inappropriate antidiuretic hormone (SIADH) release in the absence of other causes.


Introduction
Ketamine is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor [1]. It is distinct from other general anesthetics and drugs used for sedation and analgesia as it causes a trance-like cataleptic state characterized by profound unconsciousness, amnesia, deep analgesia with retention of ocular, protective airway reflexes, and cardiopulmonary stability [2]. Ketamine is also famous as a dissociative anesthetic. Ketamine is available in liquid and powder form and is being abused by many individuals [3]. Because of its reinforcing out-of-body experiences and rewarding properties, Ketamine has become a recreational drug, particularly in the context of raves, and its recreational use has grown progressively worldwide in the past few decades [4].

Case Presentation
A 31-year-old Asian female with a past medical history of Ketamine abuse and hemorrhagic cystitis presented with progressive difficulty in urination for one week. It was associated with painful urination, increased frequency, and lower abdominal pain, which gets worse at the time of urination. The patient denied fever, chills, nausea, vomiting, blood, pus or foul smell in urine, headache, dizziness, or lethargy. The patient is well known to our facility and has been seen multiple times for a similar problem. In her last admission, she was diagnosed to have Ketamine induced hemorrhagic cystitis. Of note, the patient has been addicted to Ketamine for a long period. The patient denied using other medications and recreational substances.
Vitals: heart rate 115/min, blood pressure 115/91 mmHg, respiratory rate 18/min temperature 98.8F. Physical exam was notable for a thin lean female, lying on the bed in no acute distress, mild supra-pubic tenderness noted. No crackles on lung auscultation, abdominal distention, costovertebral angle tenderness, or pedal edema were noted. Pertinent laboratory studies ( Table 1) showed white blood cell (WBC) count 11.8 k/µL, serum sodium 121 mmol/L, serum potassium 4.7 mmol/L, blood urea nitrogen (BUN) 22.22 mg/dL, creatinine 1.0 mg/dL, serum osmolality 270 mosmol/kg, thyroid-stimulating hormone (TSH) 2.16 mciu/L, random cortisol 25 µg/dL, urine sodium 76 mmol/L, urine chloride 59 mmol/L and urine osmolality 425 mosm/kg. Urinalysis was consistent with urinary tract infection WBC > 50/hpf, high leukocyte esterase, and moderate abundant bacteria in the presence of symptoms. However, the red blood cell count was 2-5 cells/hpf.  The patient was started on Ceftriaxone, Pyridium (Phenazopyridine) for symptomatic relief of urinary symptoms and fluid restriction <1 L/day. The patient's presenting symptoms resolved, and serum sodium level improved to 124 mEq/L and 128 mEq/L in a couple of days. Nothing grew in the urine culture. The patient was discharged on Pyridium as needed, water restriction less than 1 L/day, advised to quit Ketamine use and outpatient follow up with primary care provider for continuity of care.  The antidiuretic hormone acts at the renal collecting tubules, where it inhibits renal excretion and promotes the reuptake of water into the vascular system. This increases total body water (TBW) and blood volume, diluting serum sodium concentrations. As a physiologic reflex, the increase in TBW transiently promotes urinary sodium excretion in an attempt to normalize the extracellular volume and equilibrate sodium concentration gradients. This reflexive process further reduces plasma sodium concentration and causes hyponatremia [6].
The patient described in our case report is a young Asian female with a history of Ketamine addiction, who was hyponatremia (defined as a serum sodium level less than 135 mmol/L) on admission. No evidence of dehydration or volume overload was found during clinical evaluation. Hyponatremia improved on avoidance of Ketamine and water restriction. On our assessment, the results satisfied the 1967 Bartter and Schwartz diagnostic criteria for SIADH, namely evidence of hyponatremia with corresponding hypo-osmolarity, continued renal excretion of sodium, and no evidence of volume depletion, and subsequent correction of hyponatremia by fluid restriction. Alternate causes of hyponatremia including hepatic disease, cardiac failure, adrenal, and hypothyroidism were absent [6]. Naranjo score of 9 was calculated, suggesting that the correlation between ketamine and hyponatremia was definitive [6]. Hence, a diagnosis of ketamine-induced SIADH was made. It is proposed that Ketamine also centrally stimulates the release of antidiuretic hormone from the hypothalamus [6]. We believe this pathophysiologic mechanism was responsible for precipitating SIADH in this case.

Conclusions
Our case is of clinical significance for providers who use Ketamine for sedation and pain management and also for hospitalists and internists who encounter patients with Ketamine addiction or abuse potential. Ketamine use could result in SIADH and possible synergistic effects when different drugs that potentiate SIADH are combined. By being aware of this effect, providers can develop a better appreciation and awareness, and they should monitor, detect, and manage as appropriate.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.