Renal Replacement Therapy
In addition to intermittent hemodialysis (IHD), continuous renal replacement therapy (CRRT),7,8,9 especially continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF), is often provided to ICU patients with acute and chronic kidney injury. Removal of solutes and fluid from blood through semipermeable membranes occurs by means of either diffusion and/or convection during RRT. While IHD utilizes diffusion for clearance, CVVH utilizes convection and CVVHDF utilizes a combination of both. Small molecules (MW < 1000 Da) are removed effectively by IHD with conventional hemofilters (small pores). Modern high-flux membranes (large pores) utilized in CRRT are permeable to large molecules (30,000-50,000 Da) and therefore, most drug molecules. The characteristics of high-flux hemofilters and the continuous, prolonged nature of CRRT result in efficient solute removal and enhanced drug clearance. In general, the relative extent of drug removal in CRRT is CVVHDF greater than CVVH greater than IHD. However, the extent of CRRT clearance still depends on specific physiochemical properties of the drug and how CRRT is prescribed and delivered. Compared to IHD or patients with renal failure, drugs that are normally cleared by the kidney may require a much higher dose during CRRT. Drugs with a high Vd (> 1 L/kg), high PPB (> 80%), and predominant nonrenal clearance may need no dose adjustment due to poor CRRT removal.
Only unbound and water-soluble drug molecules are removed effectively during CRRT. It is evident that an increase in unbound fraction secondary to changes in systemic pH, plasma protein concentrations, organ function, and drug interactions can contribute to increased CRRT elimination. Another potential mechanism for solute removal during CRRT is “adsorption.” The clinical significance of drug adsorption to the dialysis circuitry and membrane is unclear. Many published data are available to guide proper drug dosing in CRRT. However, these dosing recommendations have been derived from diverse patient populations in which different modes of CRRT were prescribed. Other clinical and patient variables, such as interruptions or inconsistency of CRRT delivery, fluid overload, and residual renal function, may also affect drug clearance. Thus, dosing in patients requiring CRRT needs to be individualized. Drugs such as analgesics, sedatives, and cardiovascular agents can be dosed based on clinical response. Therapeutic drug monitoring (TDM) is available for some antiepileptics, antimicrobials, and cardiovascular agents. The turnaround time for TDM should be short enough for the monitoring to be clinically relevant.
As a general rule, a proper LD is usually required for an agent with a long T1/2 to achieve therapeutic plasma levels rapidly. This initial dose is determined largely by the Vd of the drug and need not be adjusted in CRRT. However, Vd might be increased significantly in ICU patients as described in the PK section. Using vancomycin as an example, a regular or even higher LD (25 mg/kg or more) should be administered initially. Subsequent MDs require modification based on the PK and PD characteristics, and CRRT clearance. For medications such as most beta-lactam antibiotics that are renally cleared, 50% to 100% of the regular MD has been recommended for patients undergoing CRRT. It is important to recognize that aggressive antibiotic dosing during CRRT along with proper monitoring is always preferred to underdosing in patients with septic shock, especially within the first few days of therapy. The nurse in charge of the CRRT delivery should also document the actual delivery of CRRT and must inform the physicians and pharmacists if any significant interruptions of CRRT occur. This information should be communicated every 6 to 8 hours, if not more often, to ensure timely dosing adjustment. This rule should also be followed when CRRT is discontinued or a different CRRT mode is prescribed.
Plasmapheresis and Therapeutic Plasma Exchange
These are automated extracorporeal apheresis techniques designed to remove or reduce the concentration of large-molecular-weight substances such as immunoglobulins and autoantibodies from the plasma. This treatment may increase drug CL. During the process, plasma proteins are removed. Drugs with a small Vd and/or high PPB, such as basiliximab, ceftriaxone, and propranolol, may be removed significantly and supplemental doses may be required at the completion of plasmapheresis. Another approach to retain drug efficacy is to schedule the plasmapheresis toward the end of the dosing interval, allowing the regular dose to be administered at the completion of the session.10
Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation (ECMO)11,12 is an advanced life support system to provide support for patients with respiratory and/or or cardiac failure who have failed conventional management. ECMO may influence PK through hemodilution (increased Vd) as well as by binding or sequestration of drugs in the ECMO circuit. Significant sequestration of opioids (fentanyl, morphine), benzodiazepines (diazepam, lorazepam, midazolam), nitroglycerin, propofol, and antimicrobials (ampicillin, cefazolin, voriconazole) has been reported. This sequestration can lower serum drug concentrations and potentially reduced the therapeutic effect. There is limited data available to guide dosing adjustment in adult patients. Most of the data have been derived from pediatric populations. Decreased serum levels of gentamicin, heparin, phenobarbital, phenytoin, and vancomycin have been reported in neonates maintained on ECMO. It is important to note that children supported by ECMO require a relative larger volume (compared to their body size) to prime the circuit and blood transfusion is frequently utilized to maintain acceptable hemoglobin levels. Although pediatric data may not be applicable to adults, higher LD and MD may be needed to maintain therapeutic levels in adult ICU patients requiring ECMO support. Proper monitoring to guide dose adjustment is essential. Serum drug monitoring is not possible for many drugs used in ICU. Tailoring therapy to the individual clinical response is often a more practical approach.
Dosing Adjustment in Obese Patients
Most recent reports indicate that 12% to 37% of ICU patients are obese. Obesity presents unique challenge because only limited PK data are available to guide dosing. Many drug investigations either exclude or do not include enough obese patients for data extrapolation. In general, both Vd and CL of drugs are altered by obesity. Lipophilic medications are distributed to adipose tissue and a larger dose is required to achieve therapeutic serum or tissue levels. Loading doses of lipophilic agents, such as phenytoin, should be based on the actual body weight followed with MD adjusted based on serum concentrations. Also, higher doses of sedatives and opioids (most are lipophilic) are usually required initially for the desired sedative or analgesic effect. However, obese patients are also at increased risk for drug accumulation after prolonged infusion or frequent dosing. Thus, proper dose titration to goal or patient response is essential. More hydrophilic medications with smaller Vd and limited distribution to adipose tissue may be dosed based on adjusted weight as per Equation 15–6.13
*See Equation 15–4 for ideal body weight.
Since most antimicrobial agents are hydrophilic, adequate blood concentrations may be achieved at the usual recommended doses. However, more aggressive antibiotic dosing approaches may be indicated based on the severity of the infection and the safety profile of the agent chosen. Again, with limited data to support dosing, seeking assistance from an experienced clinical pharmacist is recommended. Close monitoring for drug efficacy and toxicity is essential in the management of obese ICU patients.
Therapeutic Drug Monitoring
Serum drug concentrations of some medications may need to be monitored to ensure therapeutic effect without excessive toxicity (Table 15–2). Timing of a blood sample in relation to previous dose influences the interpretation of a drug concentration measurement. As a general rule, TDM should be done when steady state has been reached (after 4-5 half-lives). Check a peak level “immediately” after a LD is rarely justified. To confirm if a LD is adequate or further LD is needed, the level should be checked after the completion of the distribution phase. Most drugs, such as vancomycin and aminoglycosides, have a distribution phase of 30 to 60 minutes after IV administration. Digoxin is an exception to this rule. The distribution phase of digoxin is prolonged and a level (if indicated) should be drawn at least 4 to 6 hours after an IV dose or 6 to 8 hours after an oral dose. Otherwise, the measured serum digoxin level will be falsely high and misleading. Although a peak level may be required for some medications (ie, AGs), most drug levels should be checked as steady-state troughs just before the next dose is due. These trough levels represent the lowest level in the blood which can be used to guide dose adjustment based on clinical assessment. If trough monitoring is not feasible, another approach is sampling blood for drug levels consistently during a dosing interval after the completion of distribution phase. This means drawing a level at the same time of the day when such monitoring is indicated. The trend of serum drug concentration changes can then be used to guide MD adjustment. After a target level is achieved, drug levels only need to be rechecked as clinically indicated such as in patients with acute changes in organ function, suspected toxicity, or clinical failure. Also, it is important to allow at least 2 to 4 hours to elapse after any form of renal replacement therapy before sampling blood if a drug level is indicated. This is to allow redistribution of the drug from other tissues into the intravascular space. Otherwise, a falsely low level may lead to unnecessary dosing increase. The extent of this rebound of serum concentration after dialysis is more significant for a drug with a larger Vd and/or after prolonged therapy secondary to increased tissue drug accumulation.
Table 15–2Therapeutic ranges for drugs commonly used in ICU. |Favorite Table|Download (.pdf) Table 15–2 Therapeutic ranges for drugs commonly used in ICU.
|Drugs ||Therapeutic Rangea |
|Amikacin || |
Peak: depends on dosing strategy and severity/site of infection
Trough < 5 μg/mL
|Carbamazepine ||4-12 μg/mL |
|Gentamicin || |
Peak: depends on dosing strategy and severity/site of infection
Trough < 2 μg/mL
|Digoxin ||0.5-1.2 μg/L |
|Phenobarbital ||15-40 μg/mL |
|Phenytoin || |
Total: 10-20 μg/mL
Freeb: 1-2 μg/mL
|Theophylline (in COPD) ||5-10 μg/mL |
|Tobramycin || |
Peak: depends on dosing strategy and severity/site of infection
Trough < 2 μg/mL
|Valproic acid ||50-140 μg/mL |
|Vancomycin ||15-20 μg/mL (10-15 is acceptable for less severe infections) |
Adverse drug events (ADEs)14,15,16,17 are defined as harm or injury caused by the use of a drug. These events can occur at any stage in treatment. Approximately 25% of ADEs are either unpredictable or caused by an allergic reaction. The rest ADRS (> 70%) are dose related or predictable based on pharmacologic characteristics. Critically ill patients are at high risk for ADEs because of their organ dysfunctions as well as the complexity of the medications they are prescribed. Acute renal failure in ICU patients has been linked to increased morbidity/mortality, length of stay, and cost. Up to 20% of all cases of renal failure in ICUs may be associated with drug toxicity. The benefit of using any nephrotoxic agent (Table 15–3) in ICU patients needs to be weighed against the risk. Patients should be monitored carefully and evidence-based preventive measures should be provided whenever possible. Efforts should also be directed to minimize the exposure to other potential causes of renal injury. Adequate hydration with isotonic fluid and maintenance of renal perfusion are crucial for reducing renal toxicity associated with many agents including acyclovir, amphotericin B, radiocontrasts, and sulfonamides. Aggressive diuretic therapy should be used with caution when a patient is maintained on a therapy with known nephrotoxicity. If drug-induced renal failure is suspected, the therapy should be discontinued whenever possible. Medication profiles should be reviewed for proper dose adjustment while renal supportive care is provided. Many drugs used in ICU have been associated with prolongation of the QT interval (Table 15–4). Amiodarone and methadone are the 2 most frequently reported drugs to cause prolonged QT interval and torsades de pointes based on the data from the Food and Drug Administration (FDA) Adverse Event Reporting System (January 2004 to December 2007). Patients receive concurrent medications with QT prolongation potential should be monitored properly. Clinical decisions about drug discontinuation should be made based on the extent of QT prolongation. The risk of developing torsades de points is significantly increased in patients with QT intervals of greater than 500 msec.
Table 15–3Medications frequently associated with nephrotoxicity in ICUs (not all inclusive). |Favorite Table|Download (.pdf) Table 15–3 Medications frequently associated with nephrotoxicity in ICUs (not all inclusive).
Angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists
Aminoglycosides—amikacin, gentamicin, tobramycin, etc
Amphotericin B—including all lipid complex formulations
Antivirals—acyclovir, foscarnet, cidofovir, pentamidine
Beta-lactams—penicillins and cephalosporins may cause interstitial nephritis in rare cases
Sulfonamides—sulfadiazine, sulfamethoxazole, etc
Diuretics—secondary to intravascular volume depletion
Nonsteroidal anti-inflammatory agents (include cyclooxygenase-2 inhibitors)
Table 15–4Medications associated with prolonged QT intervala in ICUs (not all inclusive). |Favorite Table|Download (.pdf) Table 15–4 Medications associated with prolonged QT intervala in ICUs (not all inclusive).
Inhaled—Halothane, Enflurane, Isoflurane, Sevoflurane
SSRIsb—Citalopram, Fluoxetine, Venlafaxine
Fluoroquinolones—Levofloxacin > Moxifloxacin > Ciprofloxacin
Macrolides—Erythromycin (esp. high-dose IV) > Clarithromycin > Azithromycin
Azole antifungalsc—(Ketoconazole, Itraconazole) > voriconazole > Fluconazole
5-HT3 antagonists—Dolasetron > Ondansetron
Neuromuscular blocking and reversal agents
Atropine, Glycopyrrolate, Neostigmine
Drug-drug interations (DDIs) are major contributors to ADEs but can easily be prevented or managed when identified in advance. It has been estimated that at least 11% of patients admitted to a general ICU may experience DDIs. Polypharmacy, altered organ function, and advanced age are risk factors identified. DDIs may contribute to adverse events and compromise patient care with increased morbidity, mortality, and health care cost. Most DDIs can be classified as PK or PD interactions. A PK interaction occurs when one drug alters the absorption, distribution, metabolism, or elimination of another agent. A PD interaction occurs when one agent enhances or antagonizes the pharmacologic action of another agent. Antibiotics and antithrombotic agents have frequently been implicated in DDIs. Drugs that are potent inhibitors or inducers of liver cytochrome P-450 enzyme system should be used with caution. Among many of the P-450 isoenzmes identified, CYP3A4 is involved in liver metabolism of up to 50% of medications. Protease inhibitors (ie, ritonavir), macrolides (ie, erythromycin), and triazoles (ie, fluconazole, posaconazole, voriconazole) are potent CYP3A4 inhibitors. Serious DDIs with significant toxicity may develop if any of these agents is initiated concurrently with a drug that is also a CYP3A4 substrate (ie, amiodarone, cyclosporine, tacrolimus, HMG-CoA reductase inhibitors). Warfarin, an agent with narrow therapeutic index, is metabolized by several CYP enzymes, especially CYP1A2, 2C9, 2C19, and 3A4. Rifampin, a potent inducer of CYP2C9, can result in decreased warfarin effect while CYP2C9 inhibitors (ie, amiodarone, sulfonamides, voriconazole, and metronidazole) can increase the effect of warfarin. Alternative medications with minimal or no DDI should always be considered. If this approach is not possible, most of the DDIs encountered clinically can be monitored with careful dosing adjustment. A multidisciplinary team approach, especially with the presence of a clinical pharmacist on rounds, may facilitate the detection, prevention, and resolution of potential DDIs. Potential DDIs should be evaluated at the time a medication is initiated or discontinued, especially if a high-risk medication (Table 15–5) is involved.
Table 15–5High-risk medications for potential drug-drug interactions in ICUs (not all inclusive). |Favorite Table|Download (.pdf) Table 15–5 High-risk medications for potential drug-drug interactions in ICUs (not all inclusive).
|Medications ||Comments |
Valproic acid is a P-450 enzyme system inhibitor, barbiturates, carbamazepine and phenytoin are P-450 enzyme system inducers;
*Decrease GI absorption of phenytoin with concurrent enteral nutrition—may be overcome by using higher dose.
Interact with any agent that can affect hematologic system and hemostasis, such as antibiotics, antiplatelets.
*Warfarin is highly plasma protein bound (PPB—99%) and can be displaced by other high PPB agents.
Calcium channel blockers
Amiodarone and calcium channel blockers interact with each other and many drugs that rely on P-450 enzyme system for clearance.
Serum digoxin level may be doubled or tripled with concurrent amiodarone, Cardizem, and verapamil administration—if combination is crucial, reduce digoxin maintenance dose by 35%-50% after regular loading dose.
Benzodiazepines, opioids, propofol
|Synergistic sedative effect, goal-directed sedation with daily wake-up assessment if feasible to avoid excessive sedation. |
|GI absorption is impaired by concurrent polyvalent cations, such as Zn, Fe, Al, Mg; cause prolonged QT interval—potentiate other drugs that cause prolonged QT. |
Proton pump inhibitors
|Increased gastric pH results in decreased GI absorption of certain HIV regimens, itraconazole, ketoconazole, and iron supplement. |
|HIV antiretroviral regimens || |
Ritonavir-boosted regimens: many inhibit P-450 enzyme system.
Atazanavir, nelfinavir, and rilpivirine: GI absorption is reduced with stress ulcer prophylaxis.
|Many interactions with medications that inhibit or induce P-450 enzyme system. |
Many Interactions via potent inhibition of P-450 enzyme system; cause prolonged QT interval—potentiate other drugs that cause prolonged QT.
*GI absorption is gastric pH dependent.
|Cause prolonged QT interval—potentiate other drugs that cause prolonged QT; inhibit P-450 enzyme system; erythromycin is the most potent inhibitor. |
Acyclovir, Aminoglycosides, Amphotericin b, Cidofovir, Cotrimoxazole, Foscarnet, Tenofovir, etc
|Close monitoring of renal function is essential—concurrent administration of these drugs need clear risk and benefit assessment; acute renal failure can also lead to excessive dosing or toxicity from other renally eliminated medications. |
Medication Errors and Prevention
Medication errors (MEs) are a reality of medicine.18,19,20 Harmful MEs are reported more frequently in the ICU than in the non-ICU setting. Although ME data are generally underreported, it has been estimated, that critically ill patients experience an average of 1.7 MEs per day, and many patients suffer a potential life-threatening ME during their ICU stay. Reduction of MEs is the focus of many hospital quality improvement programs. Several interventions have been shown to decrease MEs in the ICU. Improved medication safety can be accomplished by medication standardization (prophylaxis for venous thromboembolism and stress ulcer, standardized IV concentrations, etc.) computerized physician order entry, barcode technology, smart intravenous infusion devices, and medication reconciliation programs. “Medication reconciliation” has been incorporated into National Patient Safety Goal #3 as of July 2011. Patient's complete medication regimen should be reviewed at the time of ICU admission and transfer, and should be compared with the regimen being considered for the new setting of care. This process is to ensure consistencies in medication regimens and prevent possible harms from unintentional medication omissions or therapeutic duplicates. Elimination of situational risk factors, such as inadequate trainee supervision, excessive nurse and physician work hours or work load, and distractions from the work flow, can prevent MEs. In addition, multidisciplinary team approach with physicians, physician assistants, nurses, and pharmacists is essential to medication oversight and error interception.