Chapter 15 Marini Pharmacotherapy

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Pharmacotherapy

Co-written with Kimberly A. Cartie-Wandmacher

of total ICU charges. Although it can be argued that almost any cost for a truly “lifesaving” drug is justified, there are not many drugs that fit that description. Obviously, therapies known to be infe- rior should not be chosen just because they are less expensive, but careful deliberation often reveals that equally effective, less expensive alternatives exist. Undoubtedly, medications represent a poten- tial opportunity for savings, but drug costs are often unreasonably targeted. This happens, partly, because pharmacy is one of the few departments of the hospital that has any idea of acquisition costs, drug utilization data, and reimbursement. It is essential to interact and collaborate with key leaders from various departments to successfully plan, prioritize, and implement medication–cost management efforts. Of course, there are practical limitations to what can be accomplished. Consider the most extreme case where all medications are eliminated; even if such a practice did not worsen outcomes, such a radical change would only reduce costs by approximately 11%. Role of the Pharmacist Many studies indicate that having a pharmacist as part of the ICU team helps identify numerous poten- tial opportunities for care improvement and cost savings. Cynically, some physicians believe that phar- macy involvement is intended only to cut costs, but pharmacists often correct, clarify and reconcile con- flicting orders, provide important drug information, suggest alternative therapies (especially in times of drug shortages), identify drug interactions, and pro- vide therapeutic drug monitoring (e.g., vancomycin, warfarin). Regardless of the effect on cost, ample data indicate that when a critical care–trained pharmacist is included in rounds, pharmacotherapy is simpli- fied, important treatments are initiated, drug-related adverse events decline, and medication errors are reduced. Unfortunately, some hospitals are reluctant

• Key Points 1. It is essential to review the medication list of every patient daily, preferably with a pharmacist special- izing in critical care. 2. In choosing a cost-effective medication therapy, con- sider not only the direct cost of the drug but also the indirect costs including labor to prepare and admin- ister the medication, nonpharmaceutical materials, and overhead, as well as drug interactions and potential adverse effects. 3. Cost savings can be achieved with strategies such as use of guidelines and protocols. 4. Pharmacokinetics and pharmacodynamics of medi- cations change frequently in the critically ill patient because of rapid fluctuations in the underlying physiology. This makes drug dosing and predictability difficult. 5. Different routes of medication administration may be advisable in critically ill patients because of changes in volume status and the availability of unique meth- ods of delivery. QUALITY IMPROVEMENT AND COST CONTROL The intensive care unit (ICU) is one of the hospi- tal’s highest consumers of pharmacy services and uses some of the most expensive (e.g., fomepi- zole, daptomycin, IVIG) and potentially dangerous (e.g., tissue plasminogen activator, four-factor pro- thrombin concentrates, insulin, argatroban) drugs. Because critically ill patients often receive 10 or more medications each day, the potential for dos- ing errors, drug interactions, and adverse events is high. In addition, medication charges can account for a large part of the ICU bill. In one hospital study, ICU pharmacy charges accounted for more than 10%

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to provide pharmacist support because quantifying savings from preventing a drug–drug interaction or an adverse event is often difficult. Quality Improvement Strategies Clinical pharmacists are trained to analyze the medication record, evaluating each medication for indication, efficacy, correct dosing, drug–drug inter- actions, and adverse effects. Daily review of the medication profile often reveals drug duplications (e.g., overlapping narcotics such as oxycodone and hydromorphone), unnecessary medications (e.g., stress ulcer prophylaxis without a clear indication), and competing medications (e.g., heparin and phy- tonadione). Daily review of the medication profile also commonly exposes drug–drug interactions (e.g., warfarin and sulfamethoxazole/trimethoprim or midazolam and fluconazole) and adverse effects (e.g., amphotericin B causing hypokalemia or a beta-lactam antibiotic such as piperacillin/tazobac- tam causing thrombocytopenia). The incidence of adverse effects is magnified by allowing multiple consulting physicians to write medication orders. Numerous ways in which medication practices can A fundamental step in improving medication safety is to establish guidelines and protocols (in written or electronic format) for medications that are fre- quently overlooked, may be used in excess, provide inadequate treatment, are difficult or dangerous to use, or are contraindicated for certain situations/ disease states. Guidelines or protocols help ensure appropri- ate ordering of prophylactic therapy. For example, patients at high risk for developing a stress ulcer should receive prophylaxis to prevent this, but they are not necessary for every patient in the ICU and may carry hazards of their own. Some physicians believe that stress ulcer prophylaxis with either an H2 blocker or a proton pump inhibitor is so inex- pensive that using it for every ICU patient may be beneficial; however, this does not take into account potential drug–drug interactions (e.g., some concur- rent drugs may need acid to be effective) or adverse effects (increased risk of thrombocytopenia, pneu- monia, and possible Clostridium difficile infections). Hence, guidelines may provide criteria for selection of appropriate candidates. be improved are discussed below. Use of Guidelines and Protocols

Another important example is venous thrombo- embolism (VTE) prophylaxis. Without prophylaxis, VTE occurs so frequently in the critically ill that it makes sense to use preventative therapy in almost all patients, but doing so may be overlooked, espe- cially when residents rotate or when physicians change patient assignments. An established and routinely reviewed guideline can help identify those patients who should receive chemical VTE prophy- laxis and those in whom it may be inadvisable. In such cases, nonpharmacological alternatives such as intermittent compression by pneumatic devices should be preferred. The importance of VTE pro- phylaxis has been magnified now that funding and regulatory agencies hold hospitals responsible for potentially preventable thromboembolism. To prevent excessive or inadequate treatment, it is also an excellent idea to develop guidelines for dosing medications to objective end points. Using a validated pain scale to guide opioid dos- ing can achieve better analgesia with fewer side effects. Sedation tools (e.g., Richmond Agitation Sedation Scale) with mandated drug interruptions have been shown to reduce total doses of adminis- tered drugs and to shorten the length of mechani- cal ventilation and ICU stay while lowering costs. The Clinical Institute Withdrawal Assessment of Alcohol (CIWA) scale offers yet another example. In this instance, quantification of symptoms is key to reducing length of stay and total benzodiazepine dose. Protocols help ensure safe pharmacotherapy. Tissue plasminogen activator (tPA) and argatro- ban are examples of drugs that are both potentially dangerous and unfamiliar enough to pose practical problems. For patients with ischemic stroke, tPA is often given, and yet many nurses only use this medication a handful of times during their careers. Because of its high risk for bleeding, it is beneficial to have a protocol for nurses to follow, as tPA must be administered in a very specific time frame and manner. Argatroban is usually only used in patients with suspected or confirmed heparin-induced thrombocytopenia who have a need for therapeutic anticoagulation; therefore, both nurses and physi- cians are likely to use this medication rarely. Again, because of its high bleeding risk, it is beneficial to have an established guideline to prevent complica- tions as well as treatment failures. Protocols or guidelines should be in place for medications used in patients in very high-risk

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categories and when certain medications may be contraindicated. Examples may include evaluation of pregnancy status and avoidance of pregnancy category X medications or avoidance of inappropri- ate anticoagulation in patients who have an epidural catheter in place. Many hospital pharmacists now have a mandate to automatically adjust certain medications for those patients with renal or liver dysfunction through an approved protocol, meaning that those patients can get correct dosing from time of order verification, rather than waiting for profile review. Restricted Prescribing For the most complicated, dangerous, or expensive drugs, it makes sense to restrict prescribing to phy- sicians having sufficient familiarity, special train- ing, or qualifications. Cancer chemotherapy is a one prime example. Requiring an infectious disease consultation for infrequently used, potentially dan- gerous, or high-cost antimicrobials (e.g., ganciclovir, liposomal amphotericin B, voriconazole) provides another. A final example (although there are many more) would be to restrict inhaled prostacyclin prescribing to critical care physicians experienced in treating acute respiratory distress syndrome (ARDS). Prescribing restrictions for cost control, however, should not impede the timely use of high- value therapies. Apart from ethical concerns, doing so might only reduce the acquisition cost for the drug, not saving money if outcome consequently worsens or length of stay is increased. Eliminating Duplicate Therapy A key step toward optimizing medication use is to eliminate duplicate or overlapping therapies. It is common to see patients prescribed suboptimal doses of two or more narcotics for pain or benzo- diazepines for sedation. It is also common to see a patient with asthma or chronic obstructive pul- monary disease (COPD) have inhaled corticoste- roids wastefully administered on top of high-dose parenteral or oral corticosteroids. Antibiotic ther- apy is frequently duplicated, sometimes with det- rimental effects. For example, administration of a tetracycline with a penicillin will likely reduce the efficacy of the penicillin (because of its mecha- nism of action). Administration of azithromycin and levaquin together for community-acquired pneu- monia may not be predictably deleterious, and it also has minimal additional antimicrobial benefit.

In each case, a much better strategy is to reduce the number of drugs and to dose each to optimal effect. By doing so, fewer medications will be used, and as a result, cost, risk of adverse effects, and unwanted drug interactions will all decline. Double Dipping It is always a good idea to ask if one drug can be used to achieve two purposes. For example, in a patient with pneumonia and a urinary tract infection, is there one antibiotic or combination of antibiotics that can treat both conditions? Another example would be to select a benzodiazepine or propofol for sedation over another drug class in a patient who has had a seizure; choosing the benzodiazepine or propofol simultaneously provides a “free” anticon- vulsant. Likewise, using lactulose (vs. senna or milk of magnesia) in a patient with hepatic encephalopa- thy will provide laxative therapy while decreasing ammonia levels. Making Safer and Less Costly Choices In most cases, more than one appropriate drug alter- native exists for treatment of any given condition. When two drugs are equally efficacious, it makes sense to choose the safer alternative with fewer known adverse effects or drug–drug interactions. One example would be opting to use fluconazole or voriconazole in place of amphotericin B to reduce the risk of renal injury. Similarly, many practitioners try to avoid aminoglycosides because of their poten- tial for renal injury, even though they continue to be relatively inexpensive, often substituting a more costly antibiotic. In this case, the potential cost of renal injury will outweigh any benefit of the reduced medication cost. Sometimes, however, the safer alternative is the more inexpensive one (e.g., use of fluconazole vs. amphotericin B for certain fungal infections). Drug–drug interactions should also be consid- ered when two efficacious drug alternatives exist. Midazolam is a common sedative used in the ICU because of its relatively quick onset and short dura- tion of action (especially helpful when trying to sedate while frequently assessing neurological sta- tus). However, because of its metabolism in the liver through the cytochrome system, it has over 800 known drug interactions, 42 of which are considered a major concern. If a patient is on multiple medi- cations that interact with midazolam, it may make more sense to use propofol or dexmedetomidine

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(short acting, but more expensive) or lorazepam (longer acting, but similar cost). For each patient, the clinician must decide if the safety advantages between the two equally effective options justify the cost. When two courses of therapy are equally safe and effective, cost should definitely be considered. For example, a urinary tract infection with Escherichia coli could be treated with generic enteral amoxicil- lin for pennies or with much more expensive (and broader coverage) intravenous extended spectrum penicillin for hundreds of dollars. Generic equiva- lents are almost always less expensive. Sometimes the choice is between two expensive drug therapies, as is the case with inhaled nitric oxide and nebu- lized prostacyclin for treatment of ARDS. Neither compound has proven outcome benefits, but both lower pulmonary artery pressures and may, at least temporarily, improve oxygenation in life-threatening hypoxemia. A protocol detailing who might qualify to receive these treatments and who has authority to prescribe them can save a large hospital hundreds of thousands of dollars annually with little compro- mise in treatment quality. Establishing an automatic substitution program in which the least expensive therapeutically equiva- lent compound is substituted for a brand named medication also saves money. Hospitals may bundle medications together with a manufacturer to secure lower costs for all medications in that bundle. For example, the hospital may decided to buy a proton pump inhibitor, a cephalosporin antibiotic, and an antifungal together to get a better pricing on all three than they could get individually. This may mean that a hospital will specify a preferred proton pump inhibitor or histamine blocker on formulary for use in preventing stress ulcers. Often, patients are changed to the preferred agent on admission to lower costs to deliver hospital care. Other saving opportunities include allowing for automatic substitution of oral agents for intravenous agents when the gut works and bioavailability is favorable. For example, oral flu- oroquinolones offer almost 100% bioavailability with significant cost savings over the parenteral route. The process of therapeutic substitution requires a proac- tive pharmacy committee and consensus, though not necessarily universal agreement, among local experts that the substitutions are reasonably equivalent. Reducing the number of like medications stocked by the pharmacy can also produce benefits. Pharmacy size is reduced, fewer personnel are necessary to

track and manage inventory, and waste is reduced as fewer expired drugs are discarded. In the case of restriction or substitution, however, a multidisci- plinary pharmacy committee must remain open to well-reasoned arguments for formulary additions or exceptions, and a process for formulary waiver must exist for emergency situations. Modifying Frequency and Route of Administration Surprisingly, the cost of a course of therapy often depends more on the route and frequency of admin- istration than it does on the drug acquisition cost. A patient is typically charged on average $20 to $40 for preparation of any intravenous medication. If the acquisition cost of that drug is $1, but is given four times a day, the preparation cost will far exceed the acquisition cost. In that situation, it may make more fiscal sense to choose an equivalent drug with higher acquisition cost that only needs to be given once daily. One example of this strategy is choos- ing ertapenem (given once daily) over piperacillin– tazobactam (given four times daily) for treatment of intra-abdominal infections. Even though ertapenem is more expensive to acquire, its overall daily cost is less. Other examples include substitution of once- daily tiotropium for ipratropium, which must be administered four times daily, or use of once daily low molecular weight heparin (LMWH) instead of unfractionated heparin (UFH) every 8 hours for venous thrombosis prophylaxis. Reducing the number of scheduled administrations each day has also been shown to be associated with fewer missed doses and thereby fewer treatment failures. As already mentioned, the route of therapy can impact costs. In general, the cost of an equivalent dose of an oral medication is one tenth to one hun- dredth that of the same drug given intravenously. This vast discrepancy exists because intravenous preparations are usually more expensive to purchase, some drug is frequently wasted (in single-use only vials), and there are substantial labor costs associ- ated with stocking, retrieving, mixing, transport- ing, and administering an intravenous preparation. Essentially, all patients eating or tolerating enteral nutrition can receive oral/enteral medications. In fact, many medications, including benzodiazepines, histamine blockers, proton pump inhibitors, narcot- ics, and some antibiotics, have equal bioavailability when given orally and intravenously. Hence, almost any time an intravenous preparation is changed to an oral route, substantial savings can be achieved.

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Continuous infusion is the most costly method of administration because a dedicated line, infusion pump, specialized cassettes, and tubing (all of which are expensive) are required. Also, each infusion site increases the risk of infection, and the mere pres- ence of an intravenous catheter in a patient with fever is likely to prompt an expensive evaluation as well as empiric antibiotics. Furthermore, if a central venous catheter must be inserted for access (e.g., for vasopressor therapy), the danger of infection persists and the risks of arterial puncture and pneu- mothorax are added. Sometimes switching from continuous infusion to intermittent intravenous dosing (e.g., benzodiazepines) or from continuous infusion to extended-duration infusion (e.g., antibi- otics) may provide cost savings with additional ben- efits or at least minimized harm. Intermittent dosing of longer-acting agents can free up an intravenous line for administration of other required medica- tions and blood products and in the process may avoid insertion of other catheters. Examples of this include using intermittent lorazepam (longer acting) in substitution of a continuous midazolam infusion or intermittent intravenous metoprolol (every 4 to 6 hours) in place of esmolol, which must be given as a continuous infusion. The belief is often wrong that giving a medi- cation by continuous infusion is mandated by the pharmacokinetics of the drug or confers more accurate control over its effects. Exact titration of a plasma drug level is rarely necessary or achievable, and drug levels often do not correlate with effects. Critically ill patients commonly have such altered pharmacodynamics that short-acting drugs can often have prolonged actions, many of which relate to the pH of the drug (basic vs. acidic) and whether it is hydrophilic versus lipophilic, both of which will be discussed later in this chapter. In addition, con- tinuous infusions may obscure signs that the drug is no longer necessary. Continuously infused sedatives should undergo a daily reduction or holiday for this reason and doing so may help prevent ventilator-

and vancomycin are inexpensive to purchase, their costs are increased by the need for frequent peak and trough levels (currently, each vancomycin level costs in excess of $50), along with frequently moni- tored creatinine levels. Another example is the use of UFH versus LMWH for therapeutic anticoagula- tion. Although LMWHs carry a higher acquisition cost, because of ease of administration and lack of drug level monitoring, they often end up costing less overall. UFH, when being used for therapeu- tic anticoagulation, is usually given as a continuous infusion and is therefore associated with the need for an intravenous line and all of its associated prob- lems and costs, as described previously. In addition, continuously infused UFH requires frequent moni- toring of coagulation status, which implies costs of testing as well as associated nursing efforts to evalu- ate labs and make infusion adjustments. Avoiding Competing Therapies It makes no sense to provide one drug that negates or counteracts the effect of another. Yet, it happens frequently when pharmacists are not monitoring the medication profile. One example is the use of two agents that directly compete for the same sub- strates (e.g., use of nonsteroidal anti-inflammatory drugs [NSAIDs] and aspirin in acute myocardial infarction, or use of buprenorphine or other par- tial antagonists with opioids). One medication may also bind with another, making it less effective (e.g., simultaneous use of calcium carbonate antacids that chelate fluoroquinolone antibiotics). Finally, it is important to think about situations in which side effects of certain medications may counteract those of another (e.g., giving propofol, which is well known to cause hypotension, to a patient receiving a vasopressor). We often want to maintain or restart outpatient medications soon after admission, but careful thought must be given to whether or not it is appropriate to do so. It may be best, for example, to hold bupropion (which can lower seizure threshold) in a patient admitted for a traumatic brain hemor- rhage or antihypertensive agents (e.g., ACE inhibi- tors or diuretics) in a patient admitted for septic shock on vasopressors. Optimizing Dosing One of the most important areas for safety improvement, which also often reduces drug cost, is careful attention to dosing as organ function changes. Most medications should be dosed less

associated pneumonias. Drug Monitoring Costs

A hidden cost of drug use is the coincident need to monitor drug levels and indices of organ func- tion (e.g., serum creatinine for potentially neph- rotoxic drugs, liver function tests for potentially hepatotoxic drugs, creatine kinase for daptomycin or platelets for linezolid). Although aminoglycosides

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frequently or with smaller doses with renal and/or liver dysfunction. Renal function can be assessed and tracked by serum creatinine, used in conjunction with equa- tions that approximate creatinine clearance (most often using the Cockcroft–Gault equation). There are several good guides for dosing adjustments for almost any medication in renal dysfunction, but it is important to remember two vital things: first, serum creatinine usually lags behind actual declines in renal function by 1 to 3 days, and second, the cal- culated creatinine clearance is not valid until renal function plateaus. Therefore, it is advisable to follow trends in renal function, calculating an estimated creatinine clearance on a daily basis, and follow- ing urine output. A defensible strategy for adjust- ing drugs eliminated by the kidney is to assume that once the urine output is less than 0.5 mL/kg/h, the glomerular filtration rate is effectively zero. Just as there are times when doses must be reduced, occa- sionally drug requirements increase. Pregnancy and fully resuscitated major burn patients will have very high volumes of distribution and will likely require higher drug doses to have the same effect. Likewise, extensively traumatized and head-injured patients are often hypermetabolic in the first 2 weeks after injury and will, therefore, need more drug to accom- plish the same effect during this period. Dosing adjustments in liver dysfunction are more difficult (very few references exist on how to make them) because there is no in vivo surrogate (like serum creatinine for renal dysfunction) to predict their drug clearance. Patients at risk for impaired liver function include those who are malnourished or are on low-protein diets and those patients who exhibit clinical signs of hepatotoxicity (nausea, vom- iting, jaundice, hepatomegaly). Liver tests can also be helpful and are used to determine the level of liver dysfunction. These include serum bilirubin (levels above 4 to 5 mg/dL), prothrombin time (>1.5 times control), serum albumin (below 2.0 g/dL), and elevated alanine aminotransferase (ALT) and aspar- tate aminotransferase (AST) (usually three times the upper limit of normal). The reduction in clearance associated with liver disease can also be calculated by the Child–Pugh score, which assigns a score from 5 to 15 based on levels of encephalopathy, ascites, bilirubin, albumin, and prothrombin time. Using that score, patients are then categorized into Child– Pugh A (5 to 6 points, least severe liver disease), B (7 to 9 points, moderately severe liver disease), or C (10 to 15 points, most severe liver disease). Dose

adjustments for drugs with a high hepatic extraction ratio can be made based on Child–Pugh scores if no drug studies are available. For patients in class A Child–Pugh, doses should be about 50% of normal, for patients in class B doses should be about 25% of normal, and for patients in class C it is generally recommended that a drug that is not affected by liver disease be used instead. Unfortunately, there are no convincing studies that affirm this dosing strategy. In general, drugs having a low hepatic extraction ratio are less problematic, because fluctuations in the unbound drug fraction will be rather small and will not significantly alter blood/plasma clearance of the drug. Dose adjustments for low hepatic ratio drugs should be aimed at maintaining normal total (i.e., bound plus unbound) plasma concentrations. “Pro”-drugs for which the metabolite is more biologi- cally active (e.g., erythromycin, enalaprilat, codeine) should be avoided. Although there are limited data on dosing drugs in hepatic dysfunction, more infor- mation continues to surface on specific drugs and, if available, should be consulted. Contrary to conventional wisdom, organ failure does not always mean thankless difficulty for phar- macotherapy. For example, many antibiotics have longer dosing intervals in renal dysfunction, thereby reducing cost and nursing time. Meropenem, for example, is normally dosed every 8 hours but is reduced to once daily in end-stage kidney disease. Another instance would be intentionally using a medication that is cleared by a failing organ to get a prolonged therapeutic effect (e.g., vancomycin in end-stage renal disease). Stopping Ineffective/Unnecessary Treatments Another method to improve safety while reducing costs is to eliminate ineffective prescribing habits. An example is provided by the use of dilute UFH to prevent clotting of most intravenous catheters. It is clear that this process is rarely necessary (saline works just as well), increases cost, and can lead to heparin-induced thrombocytopenia. Another exam- ple is repeated dosing of serotonin (5-HT) antago- nists for nausea and vomiting. Even though 5-HT antagonists are effective when single doses are given to prevent postoperative nausea and vomiting, there are little data to suggest that redosing of these agents adds benefit. Cost savings can also be achieved by addressing stop dates for medications. The most frequent exam- ple of this is seen with antibiotics. Broad-spectrum antibiotics should be tailored once culture data

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returns in order to reduce cost as well as prevent bac- terial resistance. A classic example of this is stopping vancomycin or linezolid when there are no gram-pos- itive bacteria on cultures. Stop dates on antibiotics should be placed when ordering antibiotics; almost every non-necrotizing pneumonia can be treated with 7 days of therapy (as long as the patient clinically improves early in therapy), and most intra-abdominal infections are now treated with 4 to 5 days of therapy. Placing appropriate stop dates at time of order entry will prevent continuation of antibiotic treatment for days or even weeks longer than what is needed. Often, medication profile review reveals con- tinuation of outpatient medications of questionable or no value during hospitalization. Most patients do not need vitamins or antihistamines, for example, during critical illness. It is generally recommended that oral hypoglycemic agents be held in critical ill- ness (opting to use insulin instead) because of fluc- tuating oral intake. Similarly, alpha-blockers (e.g., tamsulosin) can be held for those patients with uri- nary catheters in place. In general, at least initially, it is probably most appropriate to hold outpatient medications and reevaluate restarting them on a day-to-day basis. Shortening of ICU or Hospital Stay The choice of a more expensive drug may result in net cost savings by reducing the length of hospital stay. For patients needing therapeutic anticoagulation (e.g., for VTE or pulmonary embolism), LMWH or UFH are both options. LMWHs are generally more expensive, but because they may be given via subcuta- neous injections in an outpatient setting (vs. intrave- nous UFH and oral warfarin), it may be the best cost saving option, and patients may be able to discharge days sooner. Another example is in choice of seda- tives. Both propofol and dexmedetomidine are more expensive sedation options than either midazolam or lorazepam (both benzodiazepines). However, because propofol and dexmedetomidine are both shorter act- ing and may be more easily titrated off, they may lead to fewer ventilator and ICU days, thereby making them the more cost-effective choices. PHARMACOKINETICS Patients in the ICU are often given 10 or more med- ications simultaneously. As the number of medica- tions, severity of illness, and patient age increase, so does the risk of an adverse drug reaction. Although few physicians have enthusiasm for studying

pharmacokinetics (the sum of the processes the body is conducting on the drug, including absorp- tion, distribution, metabolism, and excretion) or pharmacodynamics (the physiologic and biochemi- cal effects of the drug on the body), understanding the basic concepts is essential to providing quality care. The critical care physician must develop a healthy respect for medications with narrow thera- peutic margins and serious side effects. Intensivists must also learn how pharmacokinetics and phar- macodynamics differ between critically ill and ambulatory patients. Five major concepts are key to understanding appropriate drug dosing: absorp- tion, distribution, and protein binding, metabolism, elimination, and half-life. Absorption Absorption is the ability of a drug to move from the site of administration into the bloodstream. The extent of absorption is typically measured in terms of bioavailability (the fraction of an administered dose that reaches systemic circulation). All drugs, other than those given by the intravenous route, are affected by absorption, but few studies have evalu- ated the affect that specific critical illnesses have on this process. Many factors may affect absorption including, gastric pH, gastrointestinal (GI) motility, bowel wall edema, splanchnic perfusion, first-pass metabolism, and enteral feeding interactions. In states of decreased perfusion, the body’s physiologic response is to shunt blood toward vital organs and away from the GI tract, which may decrease enteral absorption. In patients requir- ing vasopressor therapy, it is well documented that there are differing degrees of alterations in splanch- nic perfusion. Bowel edema is a common cause of inefficient absorption. There are many reasons for decreased gastric motility, including abdominal surgery, medications (e.g., opioids), ileus, immobility, traumatic brain injury, and electrolyte abnormalities (especially cal- cium or potassium). Absorption from the GI tract is favored when the drug is nonionized and lipophilic because absorption occurs by passive diffusion. The rate of absorption in the intestine will be greater than that in the stomach, even if the drug is pre- dominately ionized in the intestine or largely non- ionized in the stomach. Any factor that accelerates gastric emptying such as right-sided positioning or use of motility agents (e.g., erythromycin, metoclo- pramide) will be likely to increase the rate of drug

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absorption, whereas any factor that delays gastric emptying is expected to have the opposite effect, regardless of the characteristics of the drug. Enteral feeding may also affect drug absorption. Drugs given through an enteral feeding tube may adhere to the lumen of the tube (e.g., phenytoin, warfarin, amiodarone) or have incompatibilities with feeding tube formulations that limit bioavail- ability (e.g., fluoroquinolone antibiotics bind to cat- ions in the tube feeds). Given the physiologic shunting of blood to vital organs during shock, drugs may be slowly absorbed if given via the subcutaneous route. Common drugs used this way include insulin, UFH, and LMWH. Rates of absorption vary widely depending on the specific drug and local blood flow. In patients who are on vasopressor therapy or have more than a 10-kg fluid weight gain, the subcutaneous route should be considered less than normally reliable. Distribution and Protein Binding The distribution of a drug depends largely on two things: hydrophilicity and acid dissociation con- stant. During critical illness, changes in protein concentrations are known to occur that affect both the free (active) amount of drug available and the overall volume of distribution ( V d ). Generally, decreased protein binding leads to increased free drug and overall increased V d . Albumin concen- trations are usually decreased during critical ill- ness secondary to increased vascular permeability and decreased production and catabolism, thereby increasing the potential amount of free drug avail- able. Hypoalbuminemia generally affects drugs that carry an acidic or neutral charge (e.g., amiodarone, midazolam, morphine, phenytoin, propofol) because these bind well to albumin. Conversely, alpha-1 gly- coprotein concentrations increase during times of stress. This leads to lessened activity of drugs hav- ing basic charge (e.g., azithromycin, carvedilol, fen- tanyl, nicardipine, phenobarbital) because they are bound to alpha-1glycoprotein. Hydrophilic drugs (high-water solubility) have lower volumes of distribution than lipophilic (high- lipid solubility) drugs. Hydrophilic drugs (e.g., beta- lactams, vancomycin, aminoglycosides, morphine, hydromorphone) tend to distribute within the plasma volume and consequently depend on tissue perfusion for distribution. Therefore, in patients with poor perfusion secondary to shock (especially

those on vasopressors) or disease state (peripheral vascular disease, diabetes), hydrophilic drugs will not distribute as well. In contrast, lipophilic drugs (e.g., azithromycin, fluoroquinolones, fentanyl, midazolam, propofol) have sufficient volumes of distribution to penetrate tissues, independent of perfusion. Therefore, lipophilic drugs are minimally affected by shifts in fluid (as may be seen in large- volume fluid resuscitation). Generally speaking, lipophilic drugs are minimally affected by changes encountered in critical illness. Metabolism The liver has a major role in the metabolism of many drugs, and critical illness, along with drug proper- ties (extraction ratio and protein binding), can affect hepatic clearance. Hepatic drug elimination depends on blood flow, intrinsic clearance (the sum of all hepatic enzyme and transport activity involved in the removal of drug from the blood), and drug protein binding. Hepatic blood flow is likely to be impaired dur- ing hypovolemia or cardiogenic/hemorrhagic shock. Mechanical ventilation may impede venous return and hepatic blood flow. Drugs with high extrac- tion ratios (e.g., fentanyl, morphine, nitroglycerin, propofol) depend more on blood flow to the liver than on protein binding or enzyme function and will be most affected in these conditions. Conversely, metabolism of drugs with low extraction ratios (e.g., ceftriaxone, fluconazole, lorazepam, methadone and many others) depend less on hepatic blood flow and more on protein binding and enzyme function; these are significantly affected by moderate or severe liver failure or cirrhosis. Elimination Although the kidneys eliminate most drugs and their metabolites (through glomerular filtration and tubular secretion), drug elimination can also take place via the biliary tract, feces, and respira- tion. Dosing adjustments for drugs at steady state is calculated by estimating creatinine clearance (often using the Cockgroft–Gault or Jelliffe equations). When severe oliguria or anuria develops, however, it is difficult to assess true renal function. Critical illness can lead to augmented renal clearance, especially in patients who are less than 55 years of age, after trauma, (particularly head

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SECTION I • Techniques and Methods in Critical Care

trauma) or postoperative, have sepsis, are diagnosed with hematologic malignancies, or have significant burn injuries. Although there is no universally accepted definition of augmented renal clearance, a value of 10% above the upper limit of normal (GFR > 160 mL/min/1.73 m 2 in men and >150 mL/ min/1.73 m 2 in women) has been proposed. Optimal dosing of drugs in the acute kidney injury of critical illness is difficult because con- clusive data are lacking. The Kidney Disease: Improving Global Outcomes (KDIGO) work group suggests that drug dosing be adjusted according to FDA-approved labeling. Even less is known about drug dosing in patients undergoing renal replace- ment therapy. In such cases, pharmacists should help specify appropriate schedules. Of course, when available, protocols based on fluctuations in renal function may also assist in dosing adjustments. Half-life After administration, most drugs exhibit a two-phase concentration profile corresponding to initial distri- bution and then elimination. The serum half-life ( t 1/2 ) is the time required for initial drug concentra- tion to fall by 50% without further supplementa- tion. The t 1/2 incorporates distribution and clearance effects to give a useful index for predicting the time required to achieve steady state (usually 5 half-lives) and to determine the dosing interval. With repeated

intermittent dosing, most drugs accumulate and wash out exponentially to their final concentra- tions (first-order kinetics). Drug monitoring before steady state will underestimate the eventual peak, and trough concentrations and should, therefore, be avoided (Fig. 15-1). Unfortunately, the stated half-life of drugs typically is determined in healthy individuals and rarely accurately reflects the kinet- ics of a compound in the critically ill. Commonly, long-term dosing and dysfunction of several organ systems prolongs half-life. For example, drugs that rely on renal elimination may have a prolonged functional half-life in patients with renal dysfunc- tion (e.g., active metabolites of midazolam, carbape- nem antibiotics), and similarly, drugs that rely on metabolism by the liver (e.g., propofol, argatroban) may have prolonged effects in patients with hepatic dysfunction.

ROUTES OF ADMINISTRATION Goals of Drug Administration

The aim of drug therapy is to rapidly achieve and maintain effective, nontoxic tissue drug concentrations. In critically ill patients, these goals are frequently met by combining appropriate loading doses followed by maintenance regimens. During intermittent dosing, drug levels may demonstrate peaks and troughs that potentially expose patients

Single Loading Dose Kinetics

Intermittent Dosing Without Load

Steady State Concentration

100%

Continuous Infusion

50%

DRUG CONCENTRATION (% Steady State Level) 25%

1

2

3

4

5

6

NUMBER OF HALF-LIVES

FIGURE 15-1. Dosing and elimination kinetics. After a single dose, drug concentration falls expo- nentially to undetectable levels over approximately five half-lives ( dashed line ). During continuous infusion or intermittent administration of smaller maintenance doses (without load), a steady-state concentration is not achieved until five half-lives have elapsed ( solid line ). The therapeutic range can be achieved and maintained quickly by combining a large initial loading dose with a maintenance schedule of either type.

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CHAPTER 15 • Pharmacotherapy

to toxic or subtherapeutic levels. In an attempt to avoid these fluctuations, many drugs in the ICU are given as a continuous or titratable infusion (vaso- pressors, sedatives, analgesics). Other drugs (espe- cially antibiotics) may avoid these fluctuations in peak and trough levels and achieve goal therapeu- tic ranges by extended infusion. Instead of infusing in over 1 hour, they may be infused over 8 hours. Highly lipid-soluble drugs, drugs with long half- lives, and those with a large volume of distribution may progressively accumulate for long periods of time before toxic side effects emerge. Deterioration of renal or hepatic function may impair drug excre- tion. The addition of new drugs to an established regimen may also alter metabolism, compete for protein binding or alter absorption. Inhalation Use of inhaled drugs offers the advantage of rapid absorption across a rather large surface area with minimal adverse effects. Targeting the drug to the target organ generally allows for a lower dose than is needed with systemic delivery, with fewer and less severe adverse effects. There are distinct disadvan- tages to this delivery method, however, including need for ancillary equipment (e.g., spacer), incon- sistent dosing technique, low efficiency of lung deposition, contamination of ambient air, and loss of drug. There are three types of devices to deliver aero- solized drugs, and all can be clinically effective if used correctly; these include the metered-dose inhaler (MDI), the dry powder inhaler (DPI), and nebulizer. Although lung deposition efficacy has increased with newer-generation devices, it remains in the 40% to 50% range. Use of inhaled drugs in the ICU is appealing to reduce the number of drugs given parenterally, but this method of drug delivery is complicated by depo- sition of the aerosol particles in the ventilator circuit and the endotracheal tube. Both inhaled beta-adren- ergic (albuterol) and anticholinergic (ipratropium) agents have proven efficacy in mechanically ven- tilated patients. Efficacy of drug delivery depends on several factors, including type of nebulizer used, proximity to the airway opening, actuation of an MDI into an in-line chamber spacer, midinspira- tory timing of MDI actuation, ventilator mode, tidal volume, circuit humidification, and ventilator duty cycle. With proper technique, it has been shown

that four (4) puffs of an MDI will produce signifi- cant and near-maximal therapeutic effects that are comparable to those obtained with 6 to 12 times the same dose given by a nebulizer. Apart from its labor saving, quicker delivery and lower cost advantages, many practitioners consider MDIs more efficacious to prescribe during mechanical ventilation. Endotracheal Instillation The endotracheal route of administration utilizes the absorptive capacity of the lung. A drug solution is introduced through the endotracheal tube and allowed to migrate into the lower respiratory tree. Delivery to the distal site of absorption is facilitated by insufflation using a manual ventilator (or similar device such as an artificial manual breathing unit). The proposed site of circulatory absorption is the alveolar capillary circulation. Only certain drugs are safe and effective when given this way. There are several considerations when using the endotracheal route of drug administration. First, the proper technique must be employed. Patients must be tilted (avoid a fully upright position) to allow the drug to filter into the lower respiratory tree. Adequate ventilation also plays an important role in distribution. Most reports suggest manual ventilation at least 5 to 10 times afterward to assure maximal distribution. Drugs should be diluted in 0.25 mL (for pediatric patients) to 10 mL (for adults) of 0.9% saline or sterile water. Somewhat arbitrary recommendations for endotracheal dos- ing are 2 to 3 times the usual intravenous doses for nearly all candidate drugs. Endotracheal drug administration has typically been reserved for cardiopulmonary resuscitation in which no intravenous access is available. Drugs typ- ically given in this situation can be remembered by the mnemonic NAVEL (naloxone, atropine, vaso- pressin, epinephrine, and lidocaine). Epinephrine, atropine, and naloxone are reported to be effective and appear to have no added adverse effects when given via the endotracheal route. There are risks with other drugs, however. Sodium bicarbonate may inactivate lung surfactant, isoproterenol and cal- cium chloride are reported to cause tissue necrosis, and bretylium is poorly absorbed and does not result in adequate blood levels. When the more reliable intraosseous (IO) access can be quickly attained and immediately accomplished, endotracheal dos- ing is seldom used (see below).

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SECTION I • Techniques and Methods in Critical Care

Intraosseous (IO) Intraosseous infusion is a rapid and safe method for obtaining parenteral access in patients with difficult venous access. Infusion of fluids and drugs into the bone marrow space has been researched since the 1920s, and it has since been verified that fluids and drugs administered through the IO space reach the central circulation as quickly as those given via a central venous catheter and faster than those given via a peripheral catheter. Mean IO pressures are close to the mean systemic pressure—much closer to central venous than to arterial values. IO can also be used for drawing blood samples. Although sometimes used when establishing urgent venous access proves difficult, the most frequent clinical situations in which IO is utilized remain cardiopul- monary resuscitation and trauma. A wide variety of drugs are delivered safely through IO access including adenosine, amio- darone, atropine, epinephrine, insulin, morphine, propofol, and many others. Theoretically, any medi- cation that can be given intravenously can be given via IO access. Each drug should be flushed with 10 mL of fluid to keep it from dwelling in the med- ullary cavity. In the arrest setting, blood concentrations of drugs will vary by IO injection site. For instance, peak blood concentrations are achieved faster for sternal IO than for tibial IO. In addition to slower peak concentrations, the peak concentration achieved by the tibial route may be only two thirds of that delivered via the sternum. Sternal IO time to peak blood concentrations and total delivered dose appear similar to central venous administration. Risks to using the IO route include osteomyelitis, bacteremia, soft tissue infection, and extravasation. Intravenous Injection The intravenous (IV) route is the most reliable route of drug administration and avoids problems of bio- availability and delays associated with absorption. Unfortunately, the IV route can result in danger- ously high peak drug concentrations, especially when a drug is infused rapidly through a central venous catheter. Cardiac toxicity can occur with phenytoin (hypotension) or potassium (dysrhyth- mias) during rapid IV infusions of these medica- tions. IV infusions allow the administration of drugs that would otherwise be too caustic, unstable, or

poorly absorbed to dose via other routes. At steady state, continuous infusions will sustain drug levels, limit peaks and troughs, and avoid the associated problems of subtherapeutic levels and toxicity. It must be kept in mind, however, that if the patient develops renal or hepatic dysfunction, continuous infusion rates should be adjusted to avoid excessive drug accumulation. Continuous IV infusion is the most costly method of drug administration and often is not necessary. For example, intermittent dosing of pain medications and sedatives is often just as effective and often shortens ICU length of stay. High costs arise from two sources: IV drugs are typically the most expensive formulations and substantial costs are also incurred in securing and maintaining IV access. The incremental costs of inserting an IV line are often overlooked and are increased even more if complications (e.g., hemothorax, pneumo- thorax, or catheter-related sepsis) occur. IV dosing can be avoided for many medications that achieve similar blood concentrations when given orally. Bioavailability for some orally given medications approaches 100% (e.g., fluoroquinolones, flucon- azole, metronidazole). Subcutaneous Injections Subcutaneous (SQ) injections may be appropriate if the drug is non-irritating and administered in a small volume (approx. 1 mL or less). Advantages of SQ administration include relatively rapid onset in nonshock states, reasonably uniform absorption (in normal patients), and avoidance of first-pass metabolism. Disadvantages of SQ administration include localized pain, abscess formation, infection, expensive cost, nerve damage, and local hemato- mas. Typical drugs that are given via this route in the ICU include insulin and anticoagulants (e.g., UFH and LMWHs). Critical illness can affect SQ absorption, mak- ing this route of administration less desirable in this population. During circulatory shock, blood is shunted to vital organs, depriving the subcu- taneous tissue of normal perfusion. One study evaluating the use of enoxaparin in patients receiving vasopressors found that the anti–factor Xa levels were significantly lower and not within the recommended therapeutic range. Profound edema (>10 kg of fluid weight gain) also impedes absorption. Morbid obesity may also make true