Lorazepam-induced Hyperosmolality and Hypernatremia
Alice Chang, MDResident
Baylor College of Medicine
Nadeem Anis, MD
Albert Einstein College of Medicine
Long Island Jewish Medical Center
New Hyde Park, NY
Professor and Senior Associate Dean
University of Missouri-Kansas City School of Medicine
Case Presentation
A 44-year-old black woman presented to the emergency department with a 2-day history of worsening dyspnea and chest pain. She also had fever and chills, cough productive of green expectorant, and myalgias following a 4-day alcoholic binge drinking. Her medical history included asthma and a seizure disorder, for which she was taking albuterol (Proventil), theophylline (eg, Bronkodyl, Elixophyllin, Theolair), phenytoin (Dilantin), and phenobarbital (Solfoton). Initial physical examination showed: temperature, 38.3?C; blood pressure (BP), 91/52 mm Hg; heart rate, 144 beats/min; respiratory rate, 40/min; oxygen saturation, 84% on room air. Lung auscultation revealed diffuse bilateral rales and rhonchi. Her abdomen was soft and nontender, with positive bowel sounds. Initial laboratory findings included: neutrophils, 51%; bands, 35%; lymphocytes, 7%; and monocytes, 3%.
In the emergency department, the patient experienced increasing shortness of breath and rapid respirations. Oxygen saturation was 87% on 100% oxygen via a nonrebreather mask. A chest x-ray revealed a 5- lobe infiltrate suggestive of adult respiratory distress syndrome (ARDS). The patient was intubated, sedated, and admitted to the intensive care unit (ICU).
She was given intravenous (IV) lorazepam (Ativan), which was titrated for sedation and alcohol withdrawal precautions. She was also given IV thiamine. As her systolic BP dropped below 90 mm Hg, dopamine was started. Her hypotension was thought to be due to sepsis. Antibiotic therapy was initiated with cefotaxime sodium (Claforan), clindamycin (Cleocin), and azithromycin (Zithromax) to cover gram-positive, atypical, and anaerobic bacteria. The patient continued to be agitated while receiving a lorazepam drip infusion at 30 to 100 mg/hour.
On hospital day 2, her serum lactic acid level and anion gap were elevated (Table), and she had a profound metabolic acidosis, with a serum bicarbonate level of 10 mEq/L. Blood cultures confirmed sepsis. Lorazepam was continued at a rate of 15 to 20 mg/hour. The working diagnosis was now pneumococcal pneumonia with sepsis and ARDS, and ischemia was ruled out.
By hospital day 3, the patient required 40 to 50 mg/hour of lorazepam for sedation, with additional midazolam for breakthrough agitation. She began to develop increasing diuresis (input/output, 4138/5790 mL). IV fluids were changed from 5% dextrose in 0.45% normal saline to 5% dextrose in 0.2% normal saline.
On hospital day 4, the patient remained sedated on 34 to 50 mg/hour of lorazepam. Serum sodium levels continued to increase despite administering 5% dextrose in 0.2% normal saline at 125 mL/hour. IV fluids were changed to 5% dextrose in water at 100 mL/hour, but the patient continued to diurese. There was a significant difference between the calculated and measured serum osmolalities. Lactic acid concentration continued to be elevated.
The patient's IV fluids were increased to a rate of 150 mL/hour, with an additional 250 mL of free water bolus added via the nasogastric tube every 4 hours. Diabetes insipidus was suspected as a cause of the diuresis, and she was given 5 units of vasopressin (Pitressin). After the vasopressin dose, urine output dropped from 300 to 150 mL/hour, only to increase again shortly thereafter. In addition, the high urine osmolality did not correlate with the clinical picture of diabetes insipidus.
On hospital day 5, primary care, endocrine, and critical care teams concluded that the propylene glycol (PG) solvent used in the lorazepam was likely responsible for the osmotic diuresis. Lorazepam was discontinued, and morphine sulfate was substituted for sedation. Serum sodium concentration peaked at 162 mEq/L and began to drop. The diuresis improved, and IV fluids were changed back to 5% dextrose in 0.45% normal saline. Measured serum osmolality declined as well, but urine osmolality continued to be elevated.
A serum PG level drawn on hospital day 4 measured 986 mg/dL, and the corresponding urine PG level was 3000 mg/dL, thus confirming the cause of the toxicity.
On hospital day 6, her serum sodium concentration was close to normal, and the anion gap normalized. Urine output also fell. The patient was extubated on hospital day 8.
After the lorazepam was stopped, her condition stabilized. She continued to improve over the next few days and was discharged on hospital day 15.
Discussion
Sedatives are often used for ventilatory support in the ICU. Large doses may be required to ensure adequate sedation, increasing the risk for adverse events not only from the parent product but also from the solvent used in its preparation. When using drug therapies generally deemed to be safe, physicians must be aware of toxicity and other complications that can result from the compounds used in a drug's preparation. This case illustrates the development of lorazepam-induced toxicity caused by the solvent used in the infusion, which led to osmotic diuresis and resultant hypernatremia.
PG is a colorless, odorless liquid frequently used as a vehicle for IV medications, such as lorazepam, or other drugs, such as diazepam, digoxin (Lanoxin), or phenytoin, multivitamins, and even cosmetics.1 Of medications containing PG, lorazepam has the highest proportion at 80%.1 Other commonly used medications, such as hydralazine, trimethoprim/sulfamethoxazole (Bactrim, Septra), phenytoin, digoxin, and diazepam have only 40% PG.1 Approximately 45% of PG is eliminated by the kidneys, while the remaining 55% is metabolized to lactic acid, pyruvic acid, or acetone by hepatic alcohol dehydrogenase.2 PG is osmotically active and can cause an elevation in serum osmolality. Although PG toxicity has not been well studied, case reports have described hyperosmolality, lactic acidosis, increased anion gap, and renal dysfunction in patients receiving agents that use PG as a vehicle for drug delivery.2-4
Our patient began experiencing increased diuresis and elevated serum sodium levels on the third day of lorazepam administration. In addition, she had elevated lactic acid levels and hyperosmolality similar to that described in earlier case reports.2-6 The unique feature of hypernatremia in our patient was likely caused by the amount of PG she was exposed to. Compared with previously published reports,4-6 our patient received as much as 2 to 5 times higher daily doses of lorazepam.
The lorazepam infusion we used contained 1 mg of lorazepam per 1 mL of solution. Each 1 mL of the base solution dispensed contains 2 mg of lorazepam and 0.18 mL of polyethylene glycol 400 in PG with 2.0% benzyl alcohol as a preservative.5,7 The amount of PG was 0.8 mL in the lorazepam 2 mg/mL solution.5,7 Our patient received a 1:1 concentration for infusion, containing 0.4 mL (415 mg) of PG. (The density of PG is 1.036.) We calculated the amount of PG received based on the dose of lorazepam (mg/hour) over a 24-hour period, assuming the same rate as the previous hour if it was not recorded hourly on the nursing flow sheets. We calculated that she received 240 mL (249 g) of PG on the first day of sedation, 192 mL (199 g) on the second day, 472 mL (490 g) on the third day, 368 mL (382 g) on the fourth day, and 68 mL (71 g) on the fifth day, when lorazepam was discontinued. Over the entire course of therapy, the patient received a total of 3350 mg of lorazepam, of which 1390 g was PG. As a food additive, the maximum acceptable intake of PG is 25 mg/kg, or 1975 mg/day, for a person weighing 75 kg.8
Our patient developed an osmolar gap with lactic acidosis beginning on the third day of lorazepam administration. Her hypernatremia, diuresis, and hyperosmolality resolved within 48 hours of discontinuing the lorazepam.
Hypernatremia is defined as a serum sodium level of more than 145 mEq/L. Its cause is frequently iatrogenic in hospitalized patients, most often, a net water loss or a hypertonic sodium gain.9 Sodium is functionally impermeable through cell membranes and contributes to tonicity, inducing the movement of water across membranes.9 Hypernatremia is, therefore, a state of hypertonic hyperosmolality.
Our patient's hypernatremia was likely the result of osmotic diuresis and a water deficit, as suggested by a urine output significantly greater than fluid intake over several days. Due to necessary sedation for ventilatory therapy and alcohol withdrawal, the patient was not able to drink water in response to thirst, the normal initial physiologic reaction to increased serum sodium levels. Other causes of hypernatremia include pure water loss as in diabetes insipidus (congenital or acquired nephrogenic or neurogenic), hypotonic water loss (loop diuretics), gastrointestinal disturbances (vomiting, nasogastric drainage, diarrhea), burns, excessive sweating, hypertonic sodium gain due to the ingestion of sodium chloride, ingestion of sea water, Cushing's syndrome, and primary hyperaldosteronism.9 Correction of sodium levels is important in patients with long-duration hypernatremia to prevent cerebral edema. A rate of 0.5 mEq/L every hour or 10 mEq/L daily is advised.9
Our patient was successfully managed and recovered despite having PG-induced toxicity, with a PG level nearly incompatible with life. The alternatives to IV sedation with lorazepam include oral lorazepam or substituting another benzodiazepine through the gastrointestinal tract. This may also be done once PG toxicity is suspected and the patient requires rapid weaning while maintaining the therapeutic effects of the sedative.6 The addition of a narcotic, such as fentanyl citrate (Sublimaze) or morphine, can lessen the amount of lorazepam required for sedation by acting synergistically with one another.6
Conclusion
This case illustrates the importance of being familiar with the agents used in a drug's preparation in addition to the drug itself. Lorazepam is used in many clinical situations and could cause life-threatening side effects when used at high doses. Patients receiving a continuous infusion of lorazepam or other agents that use PG as a solvent should be monitored carefully for increases in serum osmolality, diuresis, and hypernatremia.
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