Pharmacokinetics/Pharmacodynamics

For most drugs, the kidneys are the primary site for excretion of the parent drug, metabolites, or both.

Urinary excretion of a drug depends on filtration, secretion, and reabsorption. Patients in the ICU may

have increased, decreased, or normal renal excretion of drugs. The state of renal excretion depends

on many variables and can change rapidly. This is especially true in ICU patients, for whom a clinical

condition can contribute to both increased and decreased excretion, depending on how that condition

progresses.

Glomerular filtration rate (GFR) is the variable most widely used to describe kidney function. The

National Kidney Foundation defines normal kidney function as 140 ± 30 mL/minute/1.73 m2 for

healthy young men and 126 ± 22 mL/minute/1.73 m2 for healthy young women. Although there

is no standard definition for increased GFR, an increase of 10% above the upper end of normal

(greater than 160 mL/minute/1.73 m2 in men and greater than 150 mL/minute/1.73 m2 in women)

ARC – Conditions such as surgery, trauma, burns, and early sepsis have been associated with

increased renal blood flow. This is usually believed to be caused by an increased cardiac output

coupled with vasodilation. The resulting ARC is believed to be a response to an inflammatory

insult (e.g., systemic inflammatory response syndrome).

One study found glomerular hyperfiltration in 17.9% of patients admitted to the ICU. Most of

2008;36:674-80). These data are supported by a study showing young, postoperative trauma

patients with peak creatinine clearance (CrCl) values as high as 190 mL/minute/1.73 m2. A

more recent study found significant risk factors for the ARC to be age 50 or younger, trauma,

and a modified sequential organ failure score of 4 or less. Finally, a study of 133 trauma

patients found age 56 or younger, SCr less than 0.7 mg/dL, and male sex to be independent risk

factors for ARC. From this, study investigators developed a model to predict ARC in patients,

the ARC in trauma intensive care (ARCTIC) score. A score of 6 or higher had a sensitivity

of 0.843, a specificity of 0.682, a positive predictive value of 0.843, and a negative predictive

value of 0.682.

ii.

A study of burn patients found an increase in iohexol clearance with a median value of 155

mL/minute/1.73 m2 on day 1 of admission. In this small study, clearance had returned to the

expected baseline of 122 mL/minute/1.73 m2 by day 7 (Burns 2010;36:1271-6). In addition,

several studies have shown increased excretion of renally eliminated drugs in burn patients,

likely related to the second phase (hyperdynamic) of burn injury, which generally begins

48 hours after the burn injury. Examples include vancomycin, ciprofloxacin, imipenem,

fluconazole, and aminoglycosides.

iii.

Fluid administration would be expected to improve cardiac output and thus renal blood flow.

Animal studies have confirmed that the administration of crystalloids can transiently increase

CrCl. Sheep administered normal saline and 3% hypertonic saline have a significantly higher

calculated CrCl than controls. However, no human studies have verified ARC in critically ill

patients after fluid administration.

iv.

Vasoactive drugs would be expected to improve cardiac output and thus renal blood flow.

However, studies of humans did not corroborate this expectation and, instead, were only

able to establish an improvement in CrCl in a subset of patients with impaired CrCl before

norepinephrine administration. Although studies were unable to show development of ARC,

patients receiving vasopressors for shock states might be expected to have normal renal blood

flow and CrCl, assuming they are not experiencing AKI. The duration of ARC is not well

established, but the peak CrCl appears to occur at about days 4–5 in most studies, with CrCl

returning to normal by day 7 in one study.