DOI: 10.1097/01.CCM.0000127043.16078.2A

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Issn Print: 0090-3493

Publication Date: 2004/06/01


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Rotation of Propofol and Midazolam for Long-Term Sedation: The authors reply

Judith Jacobi; Richard R. Riker; Gilles L. Fraser; H. Scott Bjerke; David W. Crippen; Michael F. Mascia

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We thank Dr. Price for thoughtful comments regarding additional experience gained with prolonged use of lorazepam (1). The sedation and analgesia guidelines were published in January 2002, but the majority of the work to compile these evidence-based recommendations was completed from 1999 through early 2001. Data published since that time have increased our knowledge of the issues associated with lorazepam administration. Although these guidelines are a starting point for standardization of care, many recommendations are based on expert opinion and limited clinical trials. Stimulation of additional research is a desired outcome.
We agree that drug precipitation, prolonged sedation, tolerance, and excipient toxicity from propylene glycol are significant potential problems with long-term use of parenteral lorazepam, and we discussed those concerns in our document. Recently, single cases (similar to the References 2 and 3 that you cite) and an additional prospective series of adult patients developing lorazepam-associated propylene glycol toxicity have been presented or published (2–5). Elevations of the osmolar gap may predict patients at risk of toxicity from propylene glycol (4).
Each milliliter of the 2 mg/mL lorazepam product in the United States contains polyethylene glycol-400 and 830 mg of propylene glycol because of limited solubility. For dilution, the 2 mg/mL commercial concentration is recommended, with preparation of 1 mg/mL or 0.16 mg/mL solutions. The more concentrated 4 mg/mL lorazepam product is not recommended for further dilution. There may be formulation differences in the product used in the United Kingdom that may contribute to the precipitation problem that was noted.
Although we can only speculate on the etiology of the escalating lorazepam dosing requirements suggested by Dr. Price, potential factors include withdrawal from other substances or inadequate analgesia. The prolonged sedation described in the single patient may have been the result of the use of high doses or slow drug clearance.
The study by Barr et al. (6) represents an elegant assessment of the pharmaco-kinetics and pharmacodynamics of lorazepam vs. midazolam for short-term sedation (72 hrs) of selected postoperative patients. The authors demonstrated a lorazepam elimination half-life of 15.9 hrs vs. 12.2 hrs for midazolam and subsequently a more rapid emergence from midazolam sedation. Their model suggests emergence times of 3–5 hrs for midazolam and 10–12 hrs for lorazepam following 12 hrs of continuous light sedation, but more delayed awakening following deeper levels of sedation. Because five half-lives are required to clear any drug from the body, immediate awakening from sedation is not expected; however, multiple metabolic, neurologic, and other etiologies potentially contribute to depression of mental status. With long-term use, active metabolites of midazolam produce prolonged and unpredictable sedation, especially with concurrent renal insufficiency (7). Propofol should also be used with caution in long-term sedation because of the apparent potential for cardiovascular and metabolic complications (8).
Thus, it appears that risks and benefits are inherent to all drugs used for continuous sedation in the ICU. Titration with active tapering to a goal level of sedation or in anticipation of extubation within 2–3 days and the use of a daily drug holiday remain our best tools to detect and prevent excessive sedation (1).
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