Trovafloxacin

The development of an adverse drug reaction (ADR) is a common occurrence in the ICU. Estimates for the incidence of ADRs in ICU patients are variable and have been reported to be as high as 29.7 per 100 admissions in some medical centers. (1) As an indication of the global significance of this issue, the World Health Organization (2) has published the following definition of ADR: "Any noxious, unintended, and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis, or therapy. This excludes therapeutic failures, intentional or accidental poisoning or drug abuse, and adverse effects due to errors in administration or compliance." Prevention of adverse drug events and emphasizing patient safety are current priorities for the Joint Commission for the Accreditation of Health Care Organizations. (3) It is therefore essential for intensivists to understand the magnitude of the problem of ADR in the ICU, its prevalence, its predisposing factors, and methods to minimize it.

The article by Wilson et al (4) in this issue of CHEST (see page 1674) serves as a reminder about the multiplicity of mechanisms by which ADRs can occur. While managing a group of ICU patients who required various degrees of sedation, the authors observed the development of metabolic derangements characterized by some or all of the following: an increase in the anion gap, a decrease in serum bicarbonate, an elevated osmolar gap, acidemia, organ system failure, and shock. These derangements occurred during the administration of benzodiazepines in the ICU. This reaction was limited to the IV forms of two specific agents: lorazepam and diazepam. Patients receiving midazolam did not experience the adverse reaction. Further investigation confirmed that the reaction was not related to the benzodiazepine at all. It was related to the diluent used to dissolve these two agents and prepare them for IV administration: propylene glycol.

For the intensivist, several lessons can be learned from this article. ADRs that manifest during or after the use of an agent may not be related to that agent at all. They may be related to or aggravated by the method of delivery. Examples of this include the diluent used, as in this case, or to the rate of delivery, as is sometimes experienced with rapid infusion of drugs such as vancomycin. (5)

Another lesson is the importance of understanding the concepts of "splitters" and "lumpers" and the impact of these concepts on drug management and ADRs. It is tempting, convenient, and sometimes accurate to expect the same pattern of response from different agents belonging to the same pharmacologic class. We advise patients to use an "antihistamine" or a "bronchodilator" for their respective indications, assuming that irrespective of the individual agent used, the physiologic response will be reasonably similar. We intuitively avoid a whole class of agents when one member of the class is associated with a side effect. Thus we avoid [beta]-blockers in COPD, and "narcotics" in patients being liberated from mechanical ventilation. Although this "lumper" approach is easily defensible in clinical practice, it can be confusing in the setting of management of ADRs. "Splitting," especially in an ICU setting, is more advisable. Splitting midazolam from the other benzodiazepines was clearly the right approach in the study by Wilson et al, (4) since it correctly identified the diluent and not the benzodiazepine as the offending agent. Imagine the tremendous negative impact on antimicrobial therapy if the hepatic complications of trovafloxacin (6) were attributed to the class of quinolones and not the specific drug itself!

The ICU has been known to be the land of polypharmacy for many years. (7) In this setting, the potential for drug/drug interaction is immense. In that regard, the development of an ADR after the administration of a certain medication may be a result of interaction with another agent in vivo. The intensivist should evaluate each agent used not only in the context of its effect and mechanism of action, but also in the context of its interaction with other prescribed agents. Better yet, ICUs should have the infrastructure, information technology, personnel, and protocols that could anticipate such interactions and minimize, if not prevent, their occurrence. The framework for such an approach has already been published in a Supplement articles to a previous issue of CHEST. Such a policy is advocated by the Joint Commission for the Accreditation of Health Care Organizations. (9)

ICU patients are at high risk for single and multiple organ failure as well as failure of organ systems. (10-12) Impairment of renal and hepatic function predisposes patients to significant complications resulting from ADRs. The list of agents that may be implicated is huge and will not be covered here. Intensivists should remember the impact of organ dysfunction on drug metabolism, distribution, and effect. Drug doses must be adjusted, as their metabolic pathways are altered by the development of specific organ dysfunction. Our ability to anticipate and prevent such outcomes can be facilitated by the establishment of standardized approaches as mentioned above.

Another factor to be considered is the fact that ADRs related to drug metabolism do not necessarily result from impaired organ function. They may also be an expected outcome of normal metabolic pathways, which occasionally result in the accumulation of injurious byproducts. Prolonged administration of agents with such toxic metabolites can result in ADRs even when the organ systems remain intact. Two prominent examples of agents commonly used in the ICU that possess such potential are sodium nitroprusside and procainamide. Intensivists must be aware of the byproducts of normal metabolic pathways of the agents they use and anticipate such adverse outcomes. Here again, the establishment of standard procedures can mitigate this eventuality.

In addition to ADRs with toxic implications, the intensivist should also remember that some adverse outcomes may be related to administration of ineffective agents. Some agents, such as nitroprusside, levophed, and activated drotrecogin [alpha], lose efficacy on exposure to light, while others lose their therapeutic effects when mixed with other agents in the same infusion bag (eg, dopamine and sodium bicarbonate). Poor response to improperly administered therapy is another form of ADR that can be prevented with proper anticipation.

The article by Wilson et al (4) is interesting in its own right. It identifies a significant complication of commonly utilized ICU medications. It should alert us to be more vigilant about knowing the various components of agents we prescribe. Occasionally, injectable medications are not packaged as single agents but are bound or mixed with other constituents that in themselves can induce ADRs. Careful attention to the composition of these agents should be a second nature to us. This study is also valuable because it heightens our sense of alertness to the diverse mechanisms by which ADRs occur. Finally, this article helps us focus on our role as patient advocates. It is imperative that intensivists take the lead in promoting the implementation of standardized procedures to ensure that patient safety remains a primary goal in the ICU.

REFERENCES

(1) Safety monitoring of medicinal products: guidelines for setting up and running a pharmacovigilance centre. London, UK: Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring, EQUUS, 2000

(2) Bowman L, Carlstedt BC, Black CD. Incidence of adverse drug reactions in adult medical inpatients. Can J Hosp Pharm 1994; 47:209-216

(3) Joint Commission on Accreditation of Healthcare Organizations. 2005 comprehensive accreditation manual for hospitals. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations, 2005

(4) Wilson KC, Reardon C, Theodore AC, et al. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines: a case series and prospective, observational pilot study. Chest 2005; 128:1674-1681

(5) Sivagnanam S, Deleu D. Red man syndrome. Crit Care 2003; 7:119-120

(6) Chen HJL, Bloch KJ, Maclean JA. Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med 2000; 342:359-360

(7) Buchanan N, Cane RD. Drug utilization in a general intensive care unit. Intensive Care Med 1978; 4:75-77

(8) Kelley MA, Angus D, Chalfin D, et al. The critical care crisis in the United States: a report from the profession. Chest 2004; 125:1514-1517

(9) Leape LL, Kabcenell AI, Gandhi TK, et al. Reducing adverse drug reactions: lessons from a breakthrough series collaborative. Jt Comm J Qual Improv 2000; 26:321-331

(10) Guidet B, Aegerter P, Gauzit R, et al. Incidence and impact of organ dysfunctions associated with sepsis. Chest 2005; 127:942-951

(11) Durham R, Moran JJ, Mazuski J, et al. Multiple organ failure in trauma patients. J Trauma Injury Infect Crit Care 2003; 55:608-616

(12) Zygun D. Non-neurological organ dysfunction in neurocritical care: impact on outcome and etiological considerations. Curr Opin Crit Care 2005; 11:139-143

Basim A. Dubaybo, MD, FCCP

John D. Dingell VAMC and Wayne State University School of Medicine

Dr. Dubaybo is Professor and Assistant Dean, Wayne State University School of Medicine, and Chief of Staff, John D. Dingell VAMC.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Corresponaence to: Basim A. Dubaybo, MD, FCCP, Professor and Assistant Dean, Wayne State University School of Medicine, 3990 John R, 3-Hudson, Harper University Hospital, Division of Pulmonary, Critical Care and Sleep Medicine, Detroit, MI 48201; e-mail: bdubaybo@med.wayne.edu

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