As is always the case when providing any modality of therapy, one must decide whether the benefit of the intervention outweighs the risk that it may impose upon the patient. In the care of the critically ill, at times, the boundary between an acceptable risk and an unacceptable one can be obscured by the desire to provide life-saving or sustaining measures and the potential to create serious iatrogenic harm. Ideal pharmacologic regimens for these patients would then include drugs with a high therapeutic index (TI), defined as the ratio of therapeutic plasma levels to toxic plasma levels. In general, drugs with a favorable TI would exhibit an intended effect at a range of plasma levels far separated from a range in which the drug could cause potential harm. Often times, the critical nature of the patient’s disease dictates the use of an agent with a more unfavorable risk profile, because of either a lack of alternatives or an unsustainable progression of disease without treatment. In these challenging cases, agents with lower therapeutic indices should be selected when their intended effect can either be readily observed with recognizable changes in the patient’s vital signs and/or physical exam characteristics or directly measured with plasma concentrations.

Frequently, an agent’s intended effect and therefore clinical benefit can be augmented by selecting a different mode of administration. For example, an agent may have a low therapeutic index or limited time periods of effective plasma concentrations when given via intermittent bolus. The same agent may display more stable and therefore easier to predict serum concentrations if given via continuous intravenous infusion. Ideal candidates for continuous infusion would be agents that have a short context-sensitive half-life and do not accumulate in tissues over time, which could lead to a more prolonged effect than is intended. Examples of medications in this category might include propofol, furosemide, and nitroglycerin. In certain cases, the intended plasma concentration may not be obtained rapidly via continuous infusion alone, and a loading dose may be necessary. Once the desired effect is observed, however, patients can be maintained on an appropriate dose without being subjected to the potentially harmful effects of labile plasma concentrations of agents with a low therapeutic index.

Bioavailability refers to the fraction of active drug that reaches the systemic circulation. Drugs given via an intravenous route are thought to be 100 % bioavailable. In general, drugs given via the enteral route are subjected to absorption via the intestinal tract into the portal venous system, where it then undergoes varying amounts of metabolism in the liver before it reaches the systemic circulation. This phenomenon is referred to as the first-pass effect. This effect may lead to decreased bioavailability of enterally administered agents, delays in achieving intended effects, as well as the production of possible harmful metabolites. In critically ill patients, the enteral route of administration may be inappropriate for these reasons as well as many others. Postsurgical or trauma patients may have severe alterations in either the continuity or function of their gastrointestinal tract. Many mechanically ventilated patients will be maintained on opioid infusions leading to ileus, prolonged intestinal transit time, and delayed entry of enterally absorbed medications into the portal system.

Many therapeutic agents can be given via alternative dosing routes. Due to predictable and sustained absorption when given via subcutaneous injection, this route has become the delivery method of choice for anticoagulants including both unfractionated and low molecular weight heparin. These medications are widely given to ICU patients to prevent venous thromboembolism, a common and often disastrous development in this patient group. Other delivery routes may be chosen to target a specific site of action. Inhaled nitric oxide and tobramycin are both incredibly selective for lung capillaries and distal alveoli, respectively, when given via the inhaled route. The same can be said for nebulized agents such as the beta-agonist albuterol and the anticholinergic ipratropium bromide. Finally, the sublingual or buccal route takes advantage of the rich capillary network seen within the oral cavity and has an additional advantage of its venous drainage bypassing the portal circulation via the superior vena cava. Substances available for this route of administration will then exhibit rapid uptake and near 100 % bioavailability. Examples include sublingual nitroglycerin, the fentanyl lollipop, and sublingual olanzapine.

An agent’s volume of distribution (Vd) can be thought of as the attempt to quantify the volume in the various compartments of the body that the agent can be found. This volume not only represents the circulating blood volume and the intended site of action but is also affected by many factors including protein binding, tissue binding, and lipid solubility of the drug in question. For these reasons, the Vd of most pharmacologic agents cannot be simply estimated by quantifying the extracellular fluid volume or lean body weight of the individual, and the resultant calculated volume tends to be a figure larger than the total body volume. The condition of critically ill patients tends to complicate matters even further. Patients may have dramatic alterations in their circulating volume, and the manner in which they were resuscitated can have implications for many pharmacologic agents. Patients receiving mainly crystalloid infusions will have a large volume of distribution for hydrophilic substances. Chronically ill patients will have conditions affecting their volume of distribution as well. Congestive heart failure may lead to fluid retention, increasing the Vd for hydrophilic agents. Chronic renal failure may lead to a similar increase in Vd via fluid retention, and conditions such as the nephrotic syndrome can lead to hypoalbuminemia, decreasing the Vd for highly protein-bound substances. Patients with hepatic failure and resultant productive protein deficits will also exhibit hypoalbuminemia as well as hypogammaglobulinemia, both essential binding sites for protein-bound drugs. Chronic or critical illness can have profound effects on the body’s normal homeostatic mechanisms, often times leading to a hypercatabolic state. This can lead to muscle wasting and loss of lean body mass. This can have implications for substances that exhibit both protein binding and lipophilic peripheral tissue binding.

Lastly, critically ill patients can exhibit violations in normally contiguous boundaries between various bodily compartments which can have implications on both an agent’s site of intended action and the possibility of acting upon an unintended compartment, which can lead to severe consequences. Examples of this include the diffuse capillary leak seen in sepsis, the localized pulmonary endothelial disruption seen in patients with the acute respiratory distress syndrome (ARDS), and disruptions of the blood-brain barrier by hemorrhage, tumor, or trauma. Prior knowledge of these disease states can have profound impact on an individualized pharmacologic regimen. For example, patients with elevated intracranial pressure may receive the osmotic diuretic mannitol in an attempt to draw interstitial fluid from the brain across the impermeable membrane of the blood-brain barrier. If this medication is given to a patient with elevated intracranial pressure with a disrupted blood-brain barrier, which can be the case with an intraparenchymal hemorrhage, the osmotic load will then be delivered to the brain parenchyma itself. This can lead to the disastrous consequence of localized tissue edema and an unintended increase in intracranial pressure.

The body’s metabolism and disposal of a drug can be drastically altered by critical illness. Disruptions in the major metabolic and excretory organs such as the liver and kidneys as well as alterations in both regional and systemic circulation can all affect the efficiency in which a drug is ultimately cleared.

Renal insufficiency, whether chronic or acute, can have multiple implications on drug clearance. Substances which are eliminated unchanged in the urine will remain in circulation and therefore have a prolonged half-life. This can be said about digoxin, insulin, and the aminoglycoside antibiotics. Some drugs are not metabolized directly by the kidneys but may rely on them for excretion of active metabolites. These metabolites, as in the case of morphine and its active metabolite morphine-6-glucuronide, can contribute to a prolonged effect when they are not efficiently cleared by the failing kidneys. Since renal clearance is dependent on glomerular filtration, often times the extent of impairment in renal clearance can be estimated with reasonable accuracy by the decrease in calculated creatinine clearance, which can be used to estimate glomerular filtration rate (GFR). Dosing adjustments for patients with lower GFR can then be made that result in either a decreased dose or increased dosing interval. For drugs with low therapeutic indices, this would ideally be done in conjunction with measurement of plasma levels. A major determinant of how much drug within the intravascular compartment reaches the processing and filtration sites within the kidney is systemic blood flow, as the kidneys normally receive about 25 % of the cardiac output. Patients with heart failure may fail to produce enough cardiac output to support the systemic circulation, and septic patients may exhibit profound decreases in peripheral vascular resistance. Either of these scenarios may result in decreased glomerular filtration and renal clearance. In the case of patients with fulminant renal failure requiring renal replacement therapy, the question often arises whether or not an administered drug will be filtered out into the dialysate. In general, agents that are highly water soluble, of low molecular weight, and with low Vd that do not display significant protein binding are thought to be susceptible to either hemodialysis or peritoneal dialysis. Other important factors to consider include the area and porosity of the dialyzing membrane.

In contrast to the relative predictability of renal insufficiency’s effect on drug clearance, the patient with liver failure presents a challenge in the interpretation of to what extent their hepatic dysfunction may alter drug metabolism and elimination. The first level of complexity lies in the fact that for some substances, hepatic clearance is dependent not only on the inherent metabolic capability of the hepatocellular CYP450 system but on hepatic blood flow as well. Drugs with a high hepatic extraction ratio, meaning that they are efficiently metabolized and cleared by hepatocytes, are more affected by delivery via hepatic blood flow than metabolic capacity and are therefore classified as flow-limited. Critically ill patients may have multiple etiologies of decreased hepatic blood flow such as portal venous thrombosis, constriction of the splanchnic circulation from vasopressor therapy, or fibrosis of the liver from cirrhosis, therefore providing an intraparenchymal obstruction to hepatic blood flow. Substances which are less efficiently processed may rely more on the availability of hepatocytes for metabolism and are thought to be capacity limited.

Secondly, indices of hepatic dysfunction such as the Child score or MELD score do not readily correlate with the diseased liver’s ability to conjugate and biotransform substances. The myriad of effects seen in patients with hepatic disease including the decreased production of albumin and gamma globulin and therefore reductions in drug protein binding can also have effects on clearance, mainly for drugs that are capacity limited. Finally, cirrhosis has been shown to have varying effects on different enzymes within the CYP450 system. While some enzymes’ activity may be drastically reduced, others may not be affected or even show increased activity in cirrhosis.