Expanded gentamicin volume of distribution in critically ill adult patients receiving total parenteral nutrition

Abstract

Aminoglycoside antibiotics distribute into the extracellular fluid compartment and are eliminated by the kidney via glomerular filtration. Malnutrition and total parenteral nutrition influence the fluid and electrolyte status of the patient, and cause organ changes. The purpose of this clinical study was to characterize the kinetic behaviour of gentamicin in the parenterally fed critically ill adult patient. Eighty-six critically ill adult patients treated with gentamicin for severe Gram-negative infections were enrolled in the study (mean +/- SD): age, 60 +/- 14 years; weight, 69.4 +/- 10.2 kg; height, 163 +/- 10 cm; 22 females and 64 males. Four study groups were defined (2 x 2): total parenteral nutrition vs. fluid therapy, and acute renal failure vs. normal renal function. The drug was administered by intermittent intravenous infusion. Blood samples were drawn at steady-state, 5 min before the next dose ('trough') and 30 min after the termination of the infusion ('peak'). Gentamicin serum concentration was determined by fluorescence polarization immunoassay. Gentamicin pharmacokinetic parameters were estimated by non-linear regression analysis, assuming a one-compartment model and first-order elimination from the central compartment. Treatment of malnutrition with total parenteral nutrition increased gentamicin volume of distribution (P < 0.001), but did not affect total body clearance (P = 0.75). This change tended to produce lower peak concentrations (< 4 micrograms/ml, P = 0.07), thus potentially compromising therapeutic effectiveness. There was no significant influence on trough concentrations (P = 0.56). Patients receiving fluid therapy had a volume of distribution of 0.34 +/- 0.08 litre/kg, while those fed by the intravenous route showed larger values (0.43 +/- 0.12 litre/kg), irrespective of their renal function. This may be explained by the extracellular water expansion caused by stress, malnutrition, and parenteral refeeding. Gentamicin dosage regimens in critically ill adult patients on total parenteral nutrition should be formulated on the basis of larger volumes of distribution and to attain therapeutic serum concentrations higher doses may be required.

Protein Binding of Drugs

“…The major source of energy, during the postoperative period, appears to be the body fat stores. Fat is mobilized and transported mainly as FFA bound to serum albumin, as has already been mentioned (Ronchera-Oms et al, 1995).…”

Netilmicin in the neonate: pharmacokinetic analysis and influence of parenteral nutrition

“…Total parenteral nutrition (TPN) [1,2] has been found to increase aminoglycoside volumes of distribution (Vd) and decrease peak concentrations in critically ill adult patients compared to those receiving fluid therapy (FT), possibly through expansion of the extracellular compartment from the large hypertonic osmotic load administered during PN and secondary increases in aminoglycoside clearance. Consequently, higher than usual doses have been recommended for critically ill adult patients in order to attain therapeutic serum concentrations and avoid treatment failures.…”

Drug disposition in obesity and protein–energy malnutrition

“…In PCM, the Vd of aminoglycosides (e.g. tobramycin) is increased, while the clearance is reduced (46,48,50) . This lends itself to a higher (mg/kg) dose with longer intervals between doses.…”

“…A drug's Vd may be increased or decreased in PCM (46)(47)(48)(49) . Renal drug clearance may be reduced or unchanged in severe PCM (50)(51)(52) .…”