Ketamine is a parenterally administered, general anesthetic used largely for short term diagnostic and surgical procedures, but which has been limited in use because of its psychological side effects including vivid hallucinations, agitation and confusion. Ketamine also has major abuse potential and is used illicitly as a recreational drug. Long term ketamine use can cause inflammation and irritation to the urinary bladder and urethra, and similar changes have recently been described in the biliary tract, resulting in an acute or chronic cholestatic liver injury that can resemble sclerosing cholangitis.
Ketamine (kee' ta meen) is an arylcyclohexylamine anesthetic that acts as a noncompetitive inhibitor of N-methyl-D-apartate (NMDA) receptors in the brain. Ketamine infusions rapidly produce anesthesia and a unique cataleptic state with profound analgesia, amnesia and unresponsiveness, but often with maintenance of muscle tone, involuntary movements, open eyes and spontaneous breathing. The effect is called dissociative anesthesia, which can be associated with vivid hallucinations, agitation and delirium during emergence. These adverse effects of ketamine are less in children, but have limited its usefulness as a routine anesthetic agent in adults. The lack of severe respiratory depression and relative maintenance of cardiac function with ketamine anesthesia has made it useful in patients with high risk of bronchospasm or hypotension. Ketamine was approved for use in the United States in 1970. Current indications are as the sole anesthetic agent for short term diagnostic and surgical procedures, for induction of anesthesia prior to other general anesthetic agents, and as an adjunct to low potency agents. Ketamine is available as liquid solution for intramuscular or intravenous injection in vials of 50 mg/mL in several generic forms and under the brand name of Ketalar. Ketamine is also used experimentally as therapy of severe forms of chronic pain for which it is given chronically or intermittently. Because of its profound neuropsychiatric effects, ketamine has become a recreational drug of abuse (“Special K”) in which it is used as a powder orally or by inhalation in doses that cause hallucinations and dissociative feelings. Ketamine has unique psychological side effects including dissociative states, hallucinations and emergence delirium that can occur in 12% of recipients and can arise up to 24 hours after anesthesia. Ketamine is also associated with elevation in blood pressure and pulse, variable effects on respiration (stimulation, suppression), increase in intraocular pressure and, with chronic use, severe irritative and inflammatory urinary tract and bladder symptoms.
Short term use of ketamine for anesthesia has been associated with rare instances of serum enzyme elevations, but not with clinically apparent liver injury. With chronic or intermittent use, however, unusual biliary and hepatic complications have been described. In a manner similar to its effects on the urinary tract, ketamine can also cause abnormalities in the biliary system with dilation and irregularity of the intra- and extra-hepatic bile ducts. Patients typically developed right upper quadrant pain and tenderness associated with elevations in serum alkaline phosphatase and aminotransferase levels, with minimal or no increase in bilirubin (Case 1). Biliary imaging may reveal dilation and irregularity of the intra- and extra-hepatic bile ducts with fusiform dilation of the common bile duct suggestive of choledochal cysts. Liver biopsy demonstrates changes suggestive of chronic liver obstruction or sclerosing cholangitis. Discontinuation of ketamine is usually followed by slow improvement and the abnormalities found on biliary imaging may no longer be demonstrable several months later.
Likelihood score: B (highly likely cause of clinically apparent biliary and hepatic injury).
Mechanism of Injury
The mechanism by which ketamine causes urinary and biliary abnormalities is not known, but the high concentrations of ketamine metabolites in urine and bile may cause direct toxic injury to surface epithelium with repeated use. Ketamine undergoes extensive hepatic metabolism, largely via the cytochrome P450 system (CYP 3A4). The hepatobiliary injury might be due to a direct effect of ketamine or to a toxic intermediate of its metabolism on the biliary epithelial cell.
Outcome and Management
Clinically apparent hepatobiliary injury associated with ketamine arises during chronic rather than acute exposure, and is most commonly associated with ketamine abuse or experimental applications as in the therapy of chronic pain syndromes. Most patients improve once ketamine is stopped and no instances of cirrhosis or hepatic failure from ketamine use have been described. Patients may require intensive abuse counseling and management.
Case 1. Sclerosing cholangitis due to recreational ketamine use.
[Modified from: Turkish A, Luo JJ, Lefkowitch JH. Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis. Hepatology 2013, 58: 825-7. PubMed Citation]
A 21 year old man who had been using ketamine recreationally developed fever, abdominal pain and abnormal liver tests. He had been inhaling ketamine daily for at least 9 months and had developed recurrent acute renal failure and bilateral hydronephrosis. He also admitted to alcohol binges, but denied injection drug use or a history of acute hepatitis. Liver tests showed a total bilirubin of 0.7 mg/dL, ALT 257 U/L, AST 276 U/L, alkaline phosphatase 384 U/L and GGT 985 U/L (normal <59). Liver tests had also been abnormal when he was admitted for episodes of acute renal failure and then pyelonephritis 6 and 2 months previously, which were attributed to ketamine abuse (Table). Tests for hepatitis A, B and C were negative as were tests for Wilson disease and autoantibodies. Ultrasound showed an echogenic liver with normal portal vein blood flow, and abdominal computerized tomography showed no hepatic or bile duct abnormalities. He was treated with antibiotics for suspected pyelonephritis and improved. Two months later, however, he was readmitted with recurrent symptoms and renal abnormalities and was again found to have elevations in ALT and alkaline phosphatase. A liver biopsy showed concentric fibrosis around intrahepatic bile ducts, with bile duct proliferation and mild portal inflammatory changes suggestive of sclerosing cholangitis. He was enrolled in a drug rehabilitation program and liver tests improved, although alkaline phosphatase levels remained slightly elevated. In follow up, magnetic resonance cholangiopancreatography (MRCP) revealed normal intra- and extra-hepatic bile ducts without dilation or narrowing.
|Medication:||Ketamine (by inhalation daily for 9 months)|
|Pattern:|| Cholestatic (R=1.2)|
|Severity:||1+ (liver enzyme elevations without jaundice)|
|Recovery:||Partial upon stopping ketamine|
|Other medications:||None mentioned|
|Days After Starting
||Days After Stopping
||Alk P (U/L)
||Acute renal failure
A young man with a history of inhalation ketamine abuse developed recurrent bouts of cystitis and pyelonephritis and was found to have evidence of hepatobiliary disease. Liver tests suggested a chronic cholestatic pattern of injury, but CT and MRCP imaging were unremarkable. A liver biopsy showed changes typical of sclerosing cholangitis or chronic biliary obstruction. Thus, the normal MRCP did not rule out this form of biliary sclerosis that can affect both large and small bile ducts.
REPRESENTATIVE TRADE NAMES
Ketamine – Generic, Ketalar®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO.
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Pappachan JM, Raj B, Thomas S, Hanna FW. Multiorgan dysfunction related to chronic ketamine abuse. Proc (Bayl Univ Med Cent) 2014; 27: 223-5. PubMed Citation (59 year old man who inhaled ketamine daily for 3 years developed weight loss, anorexia and urologic symptoms and was found to have hydronephrosis, common bile duct dilatation and jaundice [bilirubin 2.0 mg/dL, ALT 46 U/L, Alk P 970 U/L, albumin 2.3 g/dL], which improved on stopping ketamine use and all liver tests were normal 2 months later).
Bevan R, Burke D. Ketamine as a possible cause of cirrhosis in a patient with chronic pain. Frontline Gastroenterol 2014; 5: 208-10. PubMed Citation (55 year old woman on ketamine for chronic pain for 10 years, developed abnormal liver tests [bilirubin 0.5 mg/dL, ALT 188 U/L, Alk P 228 U/L] and liver biopsy showed bridging fibrosis, but imaging showed no irregularities; no follow up information provided).
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