Page 1759 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

1228 PART 11: Special Problems in Critical Care

immediate therapeutic effect may be vital. Nevertheless, a rational to five half-lives pass in a matter of minutes. Administration of a loading
approach to critical care therapeutics should reduce the incidence of dose, calculated as follows, rapidly achieves the desired target level (but
iatrogenic pharmacotherapeutic complications of critical illness. does not alter the time required to attain steady-state conditions):
The key principles underlying this approach, which relates PK param-
eters to choices of drug regimen, may be summarized as follows: Loading Dose = Vd × Cp

1. The appropriate loading dose is determined by estimation of the where Cp is the desired plasma concentration.
volume of distribution of the agent in the patient; the regimen for The appropriate loading dose is primarily determined by the dis-
administering this dose is chosen based on the desired effect site tribution characteristics of the drug (Vd) and the body habitus and
and the distribution half-life for the agent. volume status of the patient. Usual volume of distribution values are
2. The maintenance dose is chosen to equal the elimination rate of the readily available for most drugs; however, the effects of alterations in
body habitus, nutrition, and volume status are much more difficult
agent at steady state (the product of CL × Cp ).
ss to quantify. Estimates of drug distribution characteristics are further
3. Steady-state plasma drug level and stable drug effect are not obtained confounded in critically ill patients by dynamic hypercatabolic losses
until three to five half-lives (see Table 125-2 and Fig. 125-2) of fat and lean body mass, accompanied by massive third-space volume
have passed. retention or intravascular volume depletion, often associated with devel-
4. Many adverse drug reactions are predictable and preventable by opment of hypoalbuminemia and relative hyperglobulinemia. Following
individualization of therapeutics and by consideration of known or a period of marked positive fluid balance in a hospitalized patient,
potential drug interactions. the weight increment may be used to estimate the total body water
increase. Otherwise, estimates of altered body water content are usually
Patient characteristics are used to estimate physiologic and patho- empiric, although therapeutics in some specific disease states have been
physiologic variables affecting drug disposition. Several patient char- studied in sufficient detail to provide useful information. For example, a
acteristics should be routinely considered, including age, gender, drug decreased aminoglycoside loading dose is required in volume-depleted
allergies, body habitus, volume status, plasma protein concentrations, acute renal failure. Furthermore, “uremic substances” that accumulate
and parameters of organ function (gastrointestinal tract, circulatory, in renal failure appear to displace some drugs from tissue-binding sites,
renal, and liver function). thus reducing their Vd regardless of volume status. As a result, the
Age, gender, body habitus, and volume status are variables used to appropriate digoxin loading dose is decreased by 50% in the presence of
estimate expected parameters of drug disposition, based on population renal failure; Vd is also decreased for methotrexate and insulin in renal
PK/PD data. For most dosing calculations, the lesser of lean (or ideal) failure patients. Reduced Vd may be seen with older age and volume
and actual body weight is used. Lean body weight (LBW) is calculated depletion from vomiting, diarrhea, blood loss, and diuretics. Increased
from the patient’s height: For males, LBW (kg) = 50 + (2.3 × each inch drug Vd often develops from early goal-directed therapy for sepsis,
above 5 feet). For females, LBW (kg) = 45.5 + (2.3 × each inch above edematous states, such as cirrhosis and acute hepatic failure, nephritic
feet). Some drugs are dosed according to actual weight or to patient syndrome, right and left heart failure, and many illnesses associated with
body surface area, the latter obtainable from published nomograms shock requiring aggressive volume repletion to maximize end organ per-
using height and weight. fusion. The Vd of many drugs is increased in patients with moderate to
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Using these data, we approach the design of individualized drug severe chronic kidney disease (CKD) as well as in those with preexisting
therapy for ICU patients as follows: CKD who develop AKI. If the Vd of a drug is significantly increased
■ ROUTE OF DRUG ADMINISTRATION in CKD patients, a loading dose will likely be needed even if one was not
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routinely recommended for those with normal renal function.
Oral bioavailability of the agent may be inadequate to achieve systemic Determination of the ideal or lean body weight is difficult in the pres-
effect owing to luminal conditions (alkaline pH or tube feeds) or first- ence of obesity, cachexia, or combinations of the above factors, such as
pass metabolism (by luminal bacteria, intestinal enzymes, or hepatic in a typical hypercatabolic patient with sepsis, acute renal failure, and
enzymes). Intravenous drug administration is often preferred in the postresuscitation volume overload. Loading dose regimens may also be
ICU, even for administration of highly bioavailable drugs, for several altered based on the relationship between the desired onset of effect to
reasons. Rapid onset and offset of effect may be desirable to rapidly initi- the distribution pattern at the effect site, as discussed above in contrast-
ate therapy, while retaining the capacity for titration. Acute decompen- ing the standard loading dose regimens for lidocaine and digoxin.
sated heart failure and cirrhosis will reduce oral bioavailability due to Volume of distribution for a given drug is reported in units of volume
bowel edema and impaired intestinal perfusion. A less appreciated cause per weight in a normal patient. In the critically ill patient, the altera-
of reduced absorption is intestinal atrophy with associated decreased tions in weight and body fluid compartments will alter the distribution
surface area and cellular enzyme activity which can occur as a result of of the drug. A reasonable approach to approximate these alterations in
as little as 3 days of reduced enteral feeding. Formulation properties the calculation of the loading dose of hydrophilic drugs is to adjust the
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(eg, extended-release preparations) do not affect the extent of absorp- normal volume of distribution in proportion to the estimation of the
tion, but rather the rate of absorption and potentially the peak drug patient’s water compartment. It is reasonable to assume that water com-
concentration after each dose. prises approximately 10% of adipose tissue weight (estimated as actual
■ LOADING DOSE body weight minus lean body weight). In addition, the net weight gain
secondary to fluid resuscitation will contribute to the volume of distri-
Many therapies initiated in the ICU are intended to have a rapid onset bution for water-soluble drugs. Mathematically, we can express this by
of effect. Whether administered by continuous intravenous infusion, the following:
intermittent intravenous bolus, or oral dosing, plasma drug concentra- Adjusted Vd = (Vd Based on Ideal Body Weight)
tion and therapeutic effect will not reach steady-state levels until three to
five half-lives have passed; such a delay may be unacceptable, particularly + (10% of Adipose Tissue Weight)
for drugs that have a prolonged half-life (which may be a normal feature + (Net Weight Gain From Fluid Resuscitation)
and impaired elimination [eg, aminoglycosides with renal failure]). ■ MAINTENANCE DOSE
of a drug’s disposition [eg, digoxin], or caused by organ dysfunction
Conversely, drugs that have a very short half-life (eg, nitrovasodilators, Administration Regimen: In the critical care setting, the administration
esmolol, atracurium, and propofol) may achieve a rapid therapeutic effect regimen usually consists of a choice between intermittent intravenous
when administered by infusion but without a loading bolus, since three bolus therapy and continuous intravenous infusion. Factors considered

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