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An 87-Year-Old Man With Hypotension and Confusion After Cystoscopy* FREE TO VIEW

Sachin Yende, MBBS; Richard Wunderink, MD, FCCP
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*From Methodist Lebonheur Healthcare, Physicians Research Network, Memphis, TN.

Correspondence to: Sachin Yende, MBBS, Physicians Research Network, Crews Wing, Suite 501, Methodist Lebonheur Healthcare, 1265 Union Ave, Memphis, TN 38104-3499

Chest. 1999;115(5):1449-1451. doi:10.1378/chest.115.5.1449
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An 87-year-old man was found unresponsive in his hospital bed the morning after undergoing bladder cystoscopy with glycine bladder irrigation for evaluation of hematuria. Clotted blood was observed in the bladder without a specific bleeding site. The patient was observed overnight and hydrated with IV 5% dextrose in 45% normal saline solution at 75 mL/h. His past history was significant for hypertension, nephrolithiasis, stage IIB prostate cancer status post radiation therapy, and coronary artery disease.

On examination after transfer to the ICU, he was afebrile with a BP of 80/42 mm Hg and pulse of 116/min. Respiration rate was 24/min and oxygen saturation was 84% on room air. The patient responded only to painful stimuli. The remainder of the neurologic exam was normal without focal findings. On auscultation, crackles were heard throughout both lungs.

Laboratory results on admission to the ICU are summarized in Table 1. Prothrombin time and partial thromboplastin time were elevated to 16 and 44 s respectively, with an international normalized ratio of 1.3. No schistocytes were seen in the peripheral smear. Abnormal coagulation studies corrected with mixing studies. Fibrinogen was within normal limits but d-dimer was positive. The ammonia level was elevated at 77 μmol/L (normal 47 to 65 μmol/L). Arterial blood gases revealed the pH to be 7.26, Po2 83 mm Hg, Pco2 29 mm Hg on a nonrebreather face mask. Chest radiograph revealed cardiomegaly, mild perihilar interstitial infiltrates and increase in the pulmonary vasculature suggestive of pulmonary edema. ECG revealed nonspecific ST-T wave changes. Cardiac isoenzymes were within normal limits.

The patient was intubated, started on vasopressors, and a pulmonary artery catheter was placed. Initial parameters included a cardiac index of 2.1 L/min/m2, pulmonary capillary wedge pressure of 18 mm Hg, central venous pressure 16 mm Hg and systemic vascular resistance of 2,100 dynes · s · cm−5. A CT scan of the brain was negative and EEG was consistent with metabolic encephalopathy.

What is the most likely diagnosis? How would you proceed with therapy?

Glycine toxicity occurs in patients who are undergoing transurethral prostatectomy or continuous bladder irrigation with glycine-containing solutions. Solutions of 1.5% glycine (200 mOsm/L), which are slightly hypotonic compared with serum, are the most commonly used urinary bladder irrigants. Although these solutions are continuously aspirated during cystoscopy, a small amount of fluid can be absorbed through venules along the bladder wall. In addition, a ruptured prostatic capsule or lacerated urinary bladder can promote increased glycine absorption. Absorbed glycine initially remains in the extracellular compartment. As an osmotically active agent, glycine attracts water from the intracellular space and produces a dilutional hyponatremia and an elevated osmolal gap. Cystoscopy using mannitol or sorbitol irrigants can also produce abnormalities in serum sodium concentrations and osmolality.

Glycine is eventually transported into the intracellular space and undergoes breakdown into its metabolites of creatinine, carbon dioxide, water, ammonia, serine, glucose, hippurate, glyoxylate, formate, and oxalate. Renal excretion of glycine, glycine metabolites, and excess extracellular free water subsequently adjusts electrolytes and serum osmolality back toward baseline values. During this corrective phase, patients can have normal serum sodium concentrations or hyponatremia—both with or without osmolal gap—depending on the amount of glycine absorbed and the degree of free water excretion. Classifying patients on the basis of their electrolyte and osmolar status is important in guiding therapy. Successful outcomes of therapy hinge on effective therapy of the dilutional hyponatremia and elimination of glycine and its toxic metabolites.

The diagnoses of glycine toxicity depends on the prompt recognition of the constellation of laboratory abnormalities it produces in a patient who has undergone glycine bladder irrigation. The most important laboratory abnormality is hyponatremia with elevated osmolal gap. An increased concentration of serum ammonia occurs from the metabolism of glycine metabolism to ammonia. Hypocalcemia, which may be severe, can result from the formation of complexes of calcium and oxalic acid, another metabolic breakdown product of glycine. Osmotic hemolysis of cells can lead to anemia and thrombocytopenia.

The clinical presentation of glycine toxicity that includes nausea, vomiting, hypotension, mental status changes, and thrombocytopenia may be difficult to distinguish from sepsis. The mechanism of hypotension is unclear but it does correlate with the amount of glycine absorbed. The toxic effects of glycine itself, hyponatremia, release of vasoactive mediators, and hypocalcemia are each hypothesized to play a role. Metabolic encephalopathy may be related to hyponatremia, hypo-osmolality, and hyperammonemia. Glycine is an inhibitory neurotransmitter and may worsen the encephalopathy. Pulmonary edema can be precipitated by fluid overload especially in patients with underlying cardiac dysfunction. Transient visual disturbances are a common symptom and may be a direct neurotoxicity of glycine.

Although some aspects of therapy for glycine toxicity are not yet clearly defined, effective electrolyte and fluid management are central to a good clinical outcome. Asymptomatic patients with serum sodium concentrations > 120 mEq/L usually respond to simple discontinuation of glycine infusions. If serum sodium concentrations are < 120 mEq/L or symptoms of glycine toxicity are present, the serum osmolal gap should guide therapy. In patients with a normal serum osmolal gap, hyponatremia occurs as a result of excess extracellular free water. Correction of hyponatremia in this setting may require hypertonic saline in some patients. Serum sodium should not be corrected faster than 0.5 mEq/h or > 10 mEq/L in the first 24 h so as to avoid central pontine myelinolysis. In patients with elevated osmolal gaps, hyponatremia is secondary to glycine itself. Such patients should be considered for hemodialysis to augment renal excretion of glycine and prevent the formation of toxic metabolites. In patients with renal failure, hemodialysis is necessary because they are unable to excrete glycine or free water. Correction of other electrolyte abnormalities and treatment of associated acidosis are also important.

The severity of glycine toxicity is directly related to the amount of glycine absorbed into the systemic circulation. Patients with severe glycine toxicity, therefore, should be evaluated for an underlying bladder rupture or urethral tear that might otherwise be clinically occult.

In the present patient, the clinicians noted that the calculated plasma osmolality (2 × Na + glucose/18 + BUN/2.8) of 248 mOsm/kg was considerably lower than the measured plasma osmolality of 288 mOsm/kg indicating the presence of an osmolal gap. The combination of hyponatremia, elevated osmolal gap, acidosis, hypocalcemia, hyperammonemia, hemolytic anemia, and thrombocytopenia after cystoscopy, suggested the diagnosis of glycine toxicity, although sepsis could not be excluded. The patient was initially started on antibiotics and dopamine with careful correction of his electrolyte abnormalities. He subsequently required dobutamine and norepinephrine. Dialysis could not be performed because of persistent hypotension. A cystogram was negative for bladder perforation, but positive blood cultures for Escherichia coli, suggested loss of bladder wall integrity. Adult respiratory distress syndrome, renal failure, and small bowel ischemia complicated the patient’s course, and he died on day 14 of his hospitalization.

  1. Glycine toxicity presents with mental status change, hypotension, respiratory depression, hemolytic anemia, and thrombocytopenia resembling septic shock and disseminated intravascular coagulopathy.

  2. Glycine toxicity should be suspected in patient’s post transurethral prostatectomy or undergoing continuous bladder irrigation and confirmed by the constellation of hyponatremia, hyperammonemia, hypocalcemia, and an increase in osmolal gap.

  3. Severe glycine toxicity should raise the suspicion for bladder or urethral injury, with an associated risk of infectious complications.

  4. Therapy for glycine toxicity, although controversial, depends on the serum sodium, osmolal gap and symptoms experienced by the patient.

  5. Symptoms of glycine toxicity are directly related to the amount of systemic glycine absorption and can be prevented by monitoring the absorption of glycine.

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Verilli RA, Uhlman RC, Viek NF, et al. The hypotensive effect of a prostatic extract. J Urol 1962; 87:184

Hahn R, Stalberg H, Carlstrom K, et al. Plasma atrial natriuretic peptide concentration and renin activity during overhydration with 1.5% glycine solution in conscious sheep. Prostate 1994; 24:55–61

Hoekstra PT, Kannoski R, McCamish MA, et al. Transurethral prostatic resection syndrome-a new perspective: encephalopathy with associated hyperammonemia. J Urol 1983; 130:704–707

Roesch RP, Stoelting RK, Lingeman JE, et al. Ammonia toxicity resulting from glycine absorption during a transurethral resection syndrome: time for reappraisal. Crit Care Med 1990; 18:1479–1480

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Table Graphic Jump Location
Table 1. Admission and Second Hospital Day Laboratory Findings



Table Graphic Jump Location
Table 1. Admission and Second Hospital Day Laboratory Findings


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