Providing patient care to critically ill patients by a multidisciplinary team is an emphasis of the modern day intensive care unit (ICU) because the team approach is invaluable . The intensivist-led team reduces unnecessary resource use and improves patient outcomes [2, 3, 4, 5, 6, 7]. This paper will review the influence of the pharmacist as part of the multidisciplinary ICU team and the effects on patient outcomes.
The responsibility of pharmacists for pharmacotherapeutic outcomes in the United States has increased over the years, thus solidifying their role as integral members of the healthcare team . Traditionally, American pharmacists focused on drug preparation and distribution; however, their activities have shifted with the needs of healthcare and now the emphasis is on assuming responsibility for pharmacotherapeutic outcomes [6, 8, 9, 10, 11, 12, 13, 14, 15]. Advanced pharmaceutical services in specialty practices of ambulatory care, cardiology, nephrology, pediatrics, nutrition, transplantation, and critical care continue to grow to meet patients' needs. Critical care pharmacists further specialize in burn care, cardiology, cardiovascular surgery, general surgery, nephrology, neurosurgery, neonatology, pediatrics, pulmonary medicine, and trauma.
Critical care services are often provided through ICU pharmacy satellites, whereby drugs are readily available to the patient and decentralized pharmacists are accessible to monitor therapy. Progress in developing critical care pharmacy services and clinical emphasis in pharmacy education has generated pharmacists who devote much of their time to providing pharmaceutical care as members of an intensivist-led multidisciplinary team .
Although pharmaceutical care is applied to many disciplines, the complexity of drug regimens and disease states in critically ill patients necessitates additional evaluation. The issues in this patient population that require additional attention are:
Drug-dosing adjustments for renal and hepatic dysfunction.
Monitoring and preventing drug interactions and adverse drug events (ADEs) for complex drug regimens.
Nutritional assessment for changing caloric needs and lack of oral route of administration.
Checking compatibilities of the patient's extensive list of intravenous medications [16, 17].
Prevention and treatment of life-threatening infections.
Several studies have demonstrated the positive impact of clinical pharmacy services on patient outcomes in non-ICU settings [6, 18, 19, 20]. Typically, outcomes research evaluates the effects of medical care on individuals and society in three areas: clinical, economic, and humanistic which follows the ECHO model [21, 22]. Combined these three components allow clinicians to fully understand the impact of medical care. Studying outcomes in the critically ill provides guidance for healthcare professionals to improve the quality of care.
A literature search was performed for 1 January 1966 to 31 October 2002 using the MEDLINE database. The medical subject headings (MeSH) searched were pharmacist, pharmacy, critical care, critical illness, intensive care, and ICU. This search identified 38 articles and only English-language articles were reviewed to determine the original studies that evaluated pharmacist interventions on patient outcomes: four were clinical, ten economic, and zero humanistic. In addition to the clinical outcomes studies identified by our search, other relevant articles are discussed [3, 23, 24]. This paper discusses the enhancement of outcomes by providing clinical pharmacy services to the critically ill in North America.
The provision of pharmaceutical services varies among countries; for example, pharmacists in the United States (US) have broad clinical roles compared to Israel hospital pharmacists, and US pharmacists provide more patient-oriented services but less pharmacist education services than the United Kingdom [25, 26]. This article focuses on critical care services provided in North America since this was the location of the identified studies.
Clinical outcomes research measures the consequence of treatment and disease on the patient by using discrete indicators, such as mortality rates, readmission rates, and length of stay, all of which can be influenced by the contributions of pharmacists. Clinical outcomes of pharmacists' interventions measured to date include morbidity, mortality, length of stay, and quality of care [6, 19, 20, 27]. These positive outcomes of clinical pharmacy services are documented for hospitalized patients but not specifically for ICU patients. However, surrogate clinical endpoints such as fluid management, duration of mechanical ventilation associated with sedation, achieving therapeutic serum concentrations, ADEs, medication errors, and rates of infection have been investigated for the critically ill.
Pharmacists' familiarity with intravenous (IV) medications and involvement in providing nutritional support make them ideal personnel to aid in providing fluid management [15, 28]. Twenty randomly selected critically ill, fluid restricted patients consulted for nutritional support were assigned to two groups, a control group, and a treatment group . Pharmacists assisted in fluid management of the treatment group by concentrating IV medications and adding medications to total parenteral nutrition when possible. The treatment group had a significantly less daily and cumulative fluid balance compared to the control group. Pharmacists' interventions for fluid restricted patients aid in fluid management.
Guidelines for pharmacotherapeutic management of stress ulcer prophylaxis, and sedation have been developed by pharmacists in cooperation with physicians [7, 29] and the clinical outcomes of the guidelines have been measured. Sedation guidelines were developed by a multidisciplinary team and implemented by a critical care pharmacist . A pre- and post-guideline period was compared. Changing sedatives in accordance with the guidelines was recommended by the pharmacist for 12 out of 50 patients in the post-guideline period. The median weaning time was 16 h for the pre-guideline group and 18 h for the post-guideline group, which was not significantly different. Adherence with the guidelines saved US $ 3,363 in drug costs. Although there did not appear to be a clinical benefit with regards to weaning time, there was a savings in drug costs. Two other studies with pharmacists influencing practice patterns of sedation support the pharmacist-coordinated activities resulting in lower drug costs without prolonging mechanical ventilation time [30, 31].
In association with sedation, the complications of neuromuscular blocker administration are ADEs that may be prevented by diligent monitoring. Although neuromuscular blocking agents are used less commonly, they are still used . The critical evaluation of neuromuscular blocking agents and train of four monitoring by pharmacists improves neuromuscular recovery time and spontaneous ventilation . In addition, the cost associated with these complications of neuromuscular blockade is reduced [33, 34].
Another approach to preventing ADEs is monitoring drugs with narrow therapeutic ranges. A survey of 547 hospitals in the United States indicates that 80.6% of hospitals provide pharmacokinetic consultations . Individualized pharmacokinetic monitoring results in more consistent achievement of predetermined acceptable ranges and prevention of aminoglycoside-associated nephrotoxicity [35, 36]. The impact of therapeutic drug monitoring of intravenous theophylline regimens by pharmacists in the medical ICU results in 85% of regimens being in the acceptable range . There were significantly less blood samples drawn and less ADEs with the pharmacist-initiated regimens.
In a landmark study, Leape and colleagues  measured the incidence of ADEs before and after pharmacist participation on medical rounds in the ICU. It was found that the rate of ADEs decreased by 66%, from 10.4 per 1,000 patient-days in the control period to 3.5 ADEs per 1,000 patient-days with pharmacist interventions. Pharmacist activities included clarifying/correcting orders, providing drug information, recommending alternative therapies, and identifying drug interactions.
The ICU pharmacist's participation in patient-care rounds offers similar benefits for reducing medication administration errors. A recent multicenter evaluation reported a 3.3% incidence of medication administration errors , which is less than the 6.6% reported in previous investigations . One of the major differences between this study compared with others is the involvement of critical care pharmacists.
The inappropriate use of antibiotics in ICU patients is associated with a higher mortality; therefore, reducing misuse could improve the outcomes of these patients . Critical care pharmacists routinely recommend appropriate antibiotic therapies [40, 41]. In a study by Kaye et al., the ability of pharmacist involvement to decrease the rate of infection was measured indirectly through the efforts of a multidisciplinary critical care 'bug' team . The ICU pharmacist's contributions were obtaining and installing a pharmacy computer system and recommending suitable antibiotic therapies. The team reduced and stabilized the rate of ventilator-associated pneumonia within their institution. This study highlights the fact that valuable contributions made by pharmacists are often accomplished through the efforts of a multidisciplinary team.
In summary, the contributions of critical care pharmacists illustrated in Table 1 for improving clinical outcomes are observed through the reduction of ADEs, medication errors, and ventilator-associated pneumonia. These surrogate endpoints are used because of the difficulties associating interventions directly with mortality and length of stay. Future studies determining the influence of critical care pharmacists on broader outcomes need to reduce confounding variables. Defining subsets of patients, as opposed to general applications to the entire ICU population, and drug-specific endpoints can assist in this task. More studies are needed to demonstrate the full benefit of pharmacists on a wide variety of clinical outcomes for critically ill patients.
Costs and resource use are higher in ICU patients compared with non-ICU patients . The ICU accounts for approximately 5% of hospital admissions and 15–20% of the hospital budget, of which about 14% is attributed to pharmacy charges, ranking it as the fourth most costly ICU charge [42, 43, 44, 45]. Costly and highly used drug therapies should be a target in the reduction of ICU costs . The ICU is thus an ideal setting to promote cost savings while optimizing patient care.
In an effort to put into perspective the numerous studies completed on the economic impact of clinical pharmacy services, Schumock and colleagues published a review of the literature on this topic . A total of 104 articles, published from 1988 to 1995, were appraised. A positive financial benefit was described in 89% of these studies. However, most of the studies were not performed in the ICU. The ten economic evaluations of clinical pharmacy services provided in critically ill patients are highlighted. The cost data presented are those reported in the original studies (i.e., they have not been adjusted to reflect present values).
Economic outcomes are reported in two categories—namely, cost savings and cost avoidance—although these terms are often interchanged in the literature. Many studies calculate cost savings using the acquisition cost of the original therapy prescribed without intervention subtracting the cost of therapy after the pharmacist's intervention [44, 47, 48]. One Canadian study that focused on cost savings found a net saving of Canadian $ 10,010 (US $ 6,230) during pharmacist 54 working days, based strictly on drug acquisition costs. The most resource-intensive activities were the provision of drug information and therapeutic consultations. If clinical pharmacy services were extended to 7 days per week, there would be a projected annual cost savings of Canadian $ 67,664 (US $ 42,080) .
Cost avoidance is calculated using the cost of the therapy that would have been incurred prior to an intervention subtracting the cost of the actual therapy with the intervention [44, 47]. In a study by Miyagawa and Rivera, cost avoidance over 13 weeks (332 interventions) was US $ 18,030 based on acquisition costs (although this was reported as cost avoidance, based on the definition above, it would be considered to represent cost savings) . Most often these changes in costs were associated with discontinuation of, or changes in, antimicrobial therapy. A similar study by Chuang et al., which evaluated 310 interventions over a period of 13 weeks, concluded that comparable interventions contributed to the majority of the reported cost savings (US $ 79,723) . Cost savings/avoidance in these two studies differed greatly even though the study duration and the types and number of interventions were similar. This demonstrates the difficulty in assessing costs between studies. The differences can be explained by the fact that the study by Miyagawa and Rivera used 1985 US $ to calculate costs whereas the study by Chuang et al. used 1994 US $, and also that Chuang et al. used cost avoided plus cost saved to calculate total cost savings.
The cost of providing clinical pharmacy services should be accounted for in any economic evaluation; however, only two studies included this component. The studies subtracted the cost of pharmacy services from the evaluations and reported a cost avoidance of US $ 2,218 per month , and an annual saving of US $ 25,140. The annual savings were based on a 250-day work year and assumed the clinical pharmacist devoted approximately 2 h per day, 5 days per week to providing services . The cost benefit of a critical care pharmacist varies depending on the type of unit and institution, number of interventions, number of beds monitored, and the pharmaceutical services provided at each institution; however, the presence of a critical care pharmacist consistently demonstrated a significant economic advantage. Table 2 lists the pharmacist's interventions and the resulting economic benefit.
More precise studies involving sophisticated cost accounting (direct/indirect costs) are needed. Helpful economic evaluations include cost-benefit analyses for determining which interventions are most valuable and cost-effectiveness analyses for deciding which approach is most useful to accomplish the intervention. Performing a sensitivity analysis would provide estimations on some of the uncertainties in the economic evaluations. Although critical care pharmacists improve economic outcomes for healthcare institutions, further studies are needed to provide a better understanding of these savings.
Humanistic outcomes measure the function and overall well-being of patients using quality-of-life assessment tools. Quality of life has been studied in the ICU using different types of scales, including the Nottingham Health Profile, the Perceived Quality of Life scale, the Post-Traumatic Stress Syndrome questionnaire, the EuroQol questionnaire, and the Medical Outcome Study Short Form 36 (SF-36) [52, 53, 54, 55]. The impact of a pharmacist on health-related quality of life, however, has been assessed primarily in the ambulatory setting, using SF-36 [56, 57].
It may be easier to measure the effects of a pharmacist in an ambulatory clinic, where the pharmacist is adjusting medications for a specific disease-state under the guidance of a physician, than in the ICU since the well-being of the patient is influenced by many factors, not just the actions of the pharmacist. To our knowledge, there is no published study evaluating the impact of pharmacist interventions on the quality of life of the critically ill patient. However, there is literature to support pharmacist development of sedation/agitation scales that improves monitoring sedation and, ultimately, the quality of life .
Possibly a more realistic approach to evaluating critical care pharmacy services on humanistic outcomes would be to isolate a specific task and measure its benefits on patient well-being. For example, it is known that sedatives influence the patient's quality of life  and ICU pharmacists manage sedative medications, therefore the effects of providing this service could be measured using a quality-of-sedation tool to gain insight into the patient's satisfaction. Understanding the patient's perspective would be useful for improving the level of care.
Justifying critical care pharmacy services
A joint position paper by the American College of Clinical Pharmacy (ACCP) and the Society of Critical Care Medicine (SCCM) outlined the fundamental, desirable, and optimal activities of critical care pharmacists (Table 3) [16, 17]. The pharmacists' activities promoted by these organizations focus on patient safety and optimization of the medication-use process. Examples of pharmacist involvement include assuring a safe, accurate, and rapidly responsive drug distribution system for critically ill patients, the development of multidisciplinary guidelines for stress ulcer prophylaxis, sedation, hemoglobin management, antifungal use, and biotechnological approaches to sepsis [7, 29]. Research and teaching are important higher level (more specialized) functions of ICU pharmacists, and are distinguishing components of the desirable and optimal levels of critical care pharmacist services. Presently no data exists regarding improved patient outcomes/safety of providing daily teaching to members/staff of the ICU team, nor of the value of pharmacist-driven research as independent investigators. This position paper provides the framework for justifying pharmacy services.
An effective approach to justifying critical care pharmacists is emphasizing their role in the prevention of ADEs and medication errors. The incidence of ADEs in the ICU is reported to be 19 events per 1,000 patient-days, as compared with 10 events per 1,000 patient-days in non-ICU patients . Since pharmacists have been shown to reduce the number of ADEs by 66%, and ADEs are associated with a high incidence of mortality, the critical care pharmacist ensures added patient safety and potential annual cost savings of US $ 270,000 [37, 61].
The addition of a critical care pharmacist must be marketed as potential cost savings since administrators are required to cost justify additional personnel . There are at least ten studies discussing the economic benefit of critical care pharmacists [7, 37, 44, 47, 48, 49, 50, 51, 61, 63]. Critical care pharmacists have the potential to save between US $ 25,140 and US $ 318,891 annually [44, 47].