Pharmacokinetics/Pharmacodynamics

Nonantibiotic drugs: PD studies of other drugs in critically ill patients are sparse.

The PD parameter for continuous infusions of many anticoagulants is the change in activated partial

thromboplastin time. Unfractionated heparin infusions are predictable in most patient populations.

However, in critically ill patients, less than one-half of patients (44%) reached therapeutic activated

partial thromboplastin times within 24 hours of heparin infusion initiation (Neth J Med 2013;71:

466-71). Concern for a variable response in critically ill patients has led to the development of

modified dosing nomograms/protocols. Researchers have found a shortened time to therapeutic

activated partial thromboplastin times in critically ill patients receiving unfractionated heparin and

direct thrombin inhibitors (argatroban and bivalirudin) with nomograms.

As with antibiotic PD studies, most PD studies of other drugs have shown a decreased response

in critically ill patients. For example, critically ill patients in septic shock had a reduced response

Med 1993;21:31-9). Trauma patients with edema have lower AUCs for anti-Xa activity than do non-

edematous patients (J Trauma 2005;59:1336-43). Mechanically ventilated patients with chronic

obstructive pulmonary disease were studied for covariates affecting acetazolamide therapy. Mixed-

effects modeling found the Simplified Acute Physiology Score II, serum chloride concentrations,

and concomitant corticosteroids to be the main covariates interacting with acetazolamide PD.

focus of TDM is on drugs with a narrow therapeutic index and aims to achieve two goals: (1) maximize

efficacy and (2) reduce toxicity. Use of TDM in critically ill patients is extremely important because changes

in the PK variables previously described can result in less-than-desirable drug concentrations. Table 2

highlights commonly used medications in the ICU and their corresponding therapeutic ranges. One of the

main limitations of TDM is the lack of clinically available assays. In addition, assays for some drugs may

not be sufficiently cost-effective or timely, thus limiting their routine use in some institutions. These issues

usually result in TDM being available for a very limited spectrum of drugs. Although not ubiquitous, TDM

is being incorporated more often to assist with PD target attainment. Examples include β-lactam antibiotics

and azole antifungals.

Monitoring of blood concentrations depends on the intended use and interpretation of those

concentrations. Most TDM occurs as a method to confirm a therapeutic concentration in a patient

with signs and/or symptoms of toxicity or decreased efficacy. In this case, a concentration is measured

during the appropriate time interval (Table 2), and a clinician interprets the concentration. If needed,

the clinician modifies the drug dosing according to clinical experience. This method may produce

variable results. Critically ill patients require important considerations. For example, if extended-

interval dosing is being used, the likelihood of an increased Vd must be considered. Patients with ARC

have the potential to have a prolonged drug-free period. Finally, the status of a critically ill patient can

change rapidly. Monitoring for decreased kidney function is essential to avoid accumulation.