severe acute hyperammonemia can be caused by opportunistic infections

This patient has developed severe acute hyperammonemia (HA), a rare but potentially fatal cause of neurologic changes and coma in the posttransplant period. In recipients of solid organ transplants, and particularly in the lung transplant (LT) population, HA is now well described and can affect 1% to 4% of LT recipients; it can be a cause of mortality in 50% to 75% of cases if not recognized and treated. In addition to the usual causes of HA, such as hepatic dysfunction or possibly an unmasking of partial urea cycle disorders under the high metabolic stress of surgery, systemic infection is a well described unique cause of HA in the LT population. In LT recipients and other immunocompromised hosts, systemic opportunistic infections with urease-producing bacteria, Mollicutes such as Mycoplasma hominis or Ureaplasma urealyticum and parvum, have been implicated as a major cause of HA, as these microbes metabolize urea as an energy source and produce ammonia as a by-product. This is now so commonly recognized as a cause of HA in LT recipients that antibiotics covering these organisms (eg, doxycycline and levofloxacin) should be added to the regimen empirically while awaiting polymerase chain reaction test results and cultures once any clinically significant elevated ammonia level is found. Treatment of these organisms has resulted in improvement in ammonia levels and clinical findings, and can be lifesaving, although the process may resolve slowly. Long-term cognitive impairment can result.

Patients with HA present with unexplained neurologic findings, usually within the first 2 weeks to 30 days after LT surgery, and these include confusion, lethargy, agitation, nausea and vomiting, mental status changes, mood changes, somnolence, and ataxia and can progress to encephalopathy, seizures, loss of consciousness, and coma. Cerebral edema has been described. The diagnosis is often difficult to make because these changes may be attributed to ICU delirium, sedation, analgesics, or immunosuppression in this population in the early postoperative period. The acuity of the ammonia elevation partially accounts for the dramatic neurologic findings seen in these patients.

LT recipients with HA should undergo assessment for the suspected Mycoplasma or Ureaplasma organisms from blood and BAL. The organisms can be difficult to isolate, and polymerase chain reaction testing and culture are most helpful. The antibiotics that cover these organisms include tetracyclines, fluoroquinolones, and macrolides, and are often used in combination, usually with doxycycline and a quinolone or macrolide.

Treatment goals in HA are aimed at increasing ammonia elimination, decreasing ammonia production, and aiming for neuroprotective strategies. In addition to the unique LT-specific HA therapy discussed, one sometimes initiates the usual treatment for HA, including lactulose and rifaximin. Lactulose decreases ammonia absorption from the gut but does not improve mortality in acute HA in LT recipients, and it is not directed at the cause of HA in this population because the source of the ammonia production is not in the gut. In addition, diarrhea, dehydration, and electrolyte derangements can result. Rifaximin, which is an antibiotic, is directed at reducing the gut microbiomes’ ammonia production but again is not as helpful in this kind of HA. Intermittent hemodialysis helps to decrease ammonia levels acutely and is an excellent way to clear ammonia from the bloodstream. However, rebound HA often occurs between sessions, and continuous renal replacement therapy is sometimes added to provide constant ammonia removal between hemodialysis sessions or is used as the primary mode of dialysis. Peritoneal dialysis can be used to remove ammonia but is generally not indicated in acute HA, unless that is the only dialytic method available. Agents that can promote urea production, such as L-arginine/L-citrulline, L-ornithine/L-aspartate, and carglumic acid are often added. Nitrogen scavengers that reduce the production of ammonia by preventing glycine and glutamine degradation, such as sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, glycerol phenylbutyrate, and branched chain amino acids and levocarnitine (similar to branched chain amino acid) are also used. Dietary adjustments include decreased meat-based proteins, elimination of exogenous nitrogen sources from food to reduce substrates for aminogenesis, and an increase in amino acid supplementation. This patient also started receiving L-arginine, sodium benzoate, and levocarnitine, and dietary adjustments were made.

It is unclear whether calcineurin agents such as tacrolimus or cyclosporine are a contributing cause of the HA in LT recipients, but this has been postulated. However, there are no clear data on switching agents in the management of HA. Because the cause of HA in LT recipients is often the bacteria mentioned, continuing current management will not resolve the HA.123456789

A 68-year-old man undergoes bilateral lung transplant for idiopathic pulmonary fibrosis. His immediate postoperative course is unremarkable, and he undergoes extubation 24 h after surgery. He is receiving tacrolimus, mycophenolate mofetil, prednisone, voriconazole, ganciclovir, vancomycin, and cefepime. At 48 h after transplant, he is downgraded to the step-down unit. Twelve hours later, the nurses note new onset agitation and confusion, and he is pulling at his lines and remaining chest tubes. He also complains of nausea and vomiting. He becomes increasingly somnolent, has a single tonic-clonic seizure, and is minimally responsive. He is upgraded back to the ICU and undergoes intubation for airway protection. He is afebrile and hemodynamically stable. Neurologic examination is nonfocal. Laboratory tests reveal a WBC count of 10,100/µL (10.1 × 109/L) and hemoglobin concentration of 12.2 g/dL (122 g/L). (The hemoglobin has been stable since coming out of the operating room). Electrolyte levels and renal and liver function are normal. Tacrolimus level is therapeutic. Head CT scanning and MRI results are unremarkable. EEG is without ongoing seizure activity. Ammonia is 285 µg/dL (203 µmol/L). Lactulose, rifaximin, and intermittent hemodialysis are started.

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Footnotes

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