Critically ill patients often are incapable of communicating their feelings because of delirium, obtundation, or endotracheal intubation. This makes psychological evaluation quite difficult, as surrogate markers of pain intensity, (e.g., tachycardia, hypertension, and diaphoresis) are inherent in the host response to critical illness.

Most of the vasopressors and vasodilators administered in the ICU by continuous intravenous (IV) infusion have relatively straightforward pharmacokinetic (PK) behavior: They are water-soluble molecules that are bound very little to plasma proteins. In contrast, the hypnotics and opioids used in TIVA have high lipid solubility and most are extensively bound to plasma proteins, causing their PK behavior to be far more complex. Figure 20-1 shows the disappearance curves of fentanyl and nitroprusside after bolus injection. The fentanyl curve has three phases: a very rapid phase (with a half-life of 0.82 minutes) lasting about 10 minutes, during which the plasma concentration decreases more than 90% from its peak value; an intermediate phase (with a half-life of 17 minutes) lasting from about 10 minutes to an hour; and finally a terminal, very slow phase (with a half-life of 465 minutes) beginning about an hour after bolus injection. After a single bolus injection of fentanyl, the terminal phase occurs at plasma concentrations below which there is a pharmacologic effect. However, after multiple bolus injections or a continuous infusion, this latter phase occurs at therapeutic plasma concentrations. Thus, fentanyl behaves as a short-acting drug after a single bolus injection but as a very long-lasting drug after a continuous infusion of more than an hour in duration (i.e., fentanyl accumulates). Thus, it is inappropriate to speak of the half-life of fentanyl.

The disappearance curve of nitroprusside has two phases: A very rapid phase (with a half-life of 0.89 minute) lasting about 10 minutes, during which the plasma concentration decreases more than 85% from its peak value, and a terminal phase (with a half-life of 14 minutes). It may be slightly slower in offset as compared with fentanyl during the initial 10 minutes after a bolus injection, but it does not accumulate at all even after a prolonged infusion.

The PK behavior of the lipid-soluble hypnotics and analgesics given by infusion may be described by their context-sensitive half-times. This concept may be defined as follows: When a drug is given as an IV bolus followed by an IV infusion designed to maintain a constant plasma drug concentration, the time required for the plasma concentration to fall by 50% after termination of the infusion is the context-sensitive half-time (CSHT) [1]. Figure 20-2 depicts the CSHT curves for the medications most likely to be used for TIVA in ICU patients.

PK behavior in critically ill patients is unlike that in normal subjects for several reasons. Because ICU patients frequently have renal and/or hepatic dysfunction, drug excretion is significantly impaired. Hypoalbuminemia, common in critical illness, decreases protein binding and increases free drug concentration [2]. Because free drug is the only moiety available to tissue receptors, decreased protein binding increases the pharmacologic effect for a given plasma concentration. Alterations in intravascular and extravascular volume status are common in ICU patients and can also affect drug concentration. It is therefore more important in the ICU patient that the doses of medications used for TIVA are individualized for a particular patient.

People 65 years of age and older comprise the fastest growing segment of the population and constitute the majority of patients in many ICUs. Aging leads to (a) a decrease in total body water and lean body mass; (b) an increase in body fat and, hence, an increase in the volume of distribution of lipid-soluble drugs; and (c) a decrease in drug clearance rates, due to reductions in liver mass, hepatic enzyme activity, liver blood flow, and renal excretory function. There is a progressive, age-dependent increase in pain relief and electroencephalographic suppression among elderly patients receiving the same dose of opioid as younger patients. There is also an increase in CNS depression in elderly patients following administration of identical doses of benzodiazepines.

Head-injured patients require a technique that provides effective yet brief anesthesia, so that the capacity to assess neurologic status is not lost for extended periods of time. In addition, the technique must not adversely affect cerebral perfusion pressure. If the effects of the anesthetics dissipate too rapidly, episodes of agitation and increased intracranial pressure may occur that jeopardize cerebral perfusion. In contrast, if the medications last too long, there may be difficulty in making an adequate neurologic assessment following the procedure.

Postoperative myocardial ischemia following cardiac and noncardiac surgery strongly predicts adverse outcome [3]. Accordingly, sufficient analgesia should be provided during and after invasive procedures to reduce plasma catecholamine and stress hormone levels.

The association between sepsis and acute renal failure has been recognized for many years. Risk of an adverse drug reaction is at least 3 times higher in azotemic patients than in those with normal renal function. This risk is magnified by excessive unbound drug or drug metabolite(s) in the circulation and changes in the target tissue(s) induced by the uremic state.

Liver failure alters the volumes of distribution of many drugs by impairing synthesis of the two major plasma-binding proteins, albumin and α₁-acid glycoprotein. In addition, reductions in hepatic blood flow and hepatic enzymatic activity decrease drug clearance rates.