Aminoglycoside Pharmacokinetics in Patients Undergoing Induced Hypothermia
Aminoglycoside Pharmacokinetics in Patients Undergoing Induced Hypothermia
Study Objective. To determine the effects of mild-to-moderate induced hypothermia—a neuroprotectant and/or therapeutic strategy for the management of intracranial hypertension in neurologically injured patients—on the pharmacokinetics of aminoglycoside therapy.
Design. Pharmacokinetic analysis.
Setting. Critical care unit at a university-affiliated hospital.
Patients. Three patients, aged 22, 24, and 47 years, who received tobramycin and had documented tobramycin levels while undergoing induced hypothermia for more than 24 hours for intracranial hypertension.
Measurements and Main Results. For each of the three patients, predicted pharmacokinetic parameters (volume of distribution, first-order elimination rate constant, half-life, and renal drug clearance) based on population data were compared with their actual pharmacokinetic parameters that were calculated based on observed tobramycin serum levels. All three patients had a normal creatinine clearance, estimated according to established methods. When pharmacokinetic parameters were calculated after the first tobramycin dose using a one-compartment method, all patients had a slower first-order elimination rate and a larger volume of distribution compared with predicted population estimates.
Conclusion. These findings suggest that induced hypothermia may result in impaired elimination of aminoglycosides. Caution should be exercised when attempting to use predicted pharmacokinetic parameters to dose aminoglycosides in this patient population, and first-dose pharmacokinetics should be considered to optimize the dose and dosing interval early in the course of therapy. Further investigation of this phenomenon with greater numbers of patients are needed to confirm these findings and to determine optimal dosing strategies of aminoglycosides in patients undergoing induced hypothermia.
Mild-to-moderate induced hypothermia may be used as a neuroprotectant and/or therapeutic strategy during the management of intracranial hypertension. Strong evidence supports its consideration for the management of patients after cardiac arrest, with more limited data for the management of traumatic brain injury, malignant ischemic stroke, acute liver failure, spinal cord injury, and refractory status epilepticus. In induced hypothermia, the core body temperature is lowered to 32–34°C to decrease cerebral metabolic demand, mitigate excitatory neurotransmitter overstimulation, and attenuate the inflammatory response, thereby modulating secondary brain insults.
Physiologic effects occur with nearly every organ system during mild-to-moderate induced hypothermia. Activity of temperature-dependent enzymatic systems slow, thus decreasing the metabolism of some hepatically metabolized drugs; however, the effect on the pharmacokinetics of renally eliminated drugs is yet to be determined in humans. The reabsorption of renal solute may be impaired secondary to a cold diuresis. However, renal function, as measured by creatinine clearance, is often impaired as renal vascular resistance increases with a subsequent reduction in renal blood flow. In addition, cardiac output may be decreased 25–40% secondary to bradycardia and increased systemic vascular resistance. These physiologic alterations may affect renal perfusion and, subsequently, the glomerular filtration rate and clearance of renally eliminated drugs.
Aminoglycosides represent one class of drugs that are heavily dependent on glomerular filtration rate, display a narrow therapeutic index, and require therapeutic drug monitoring to optimize effectiveness and minimize known toxicities. In the setting of induced hypothermia, alterations in normal physiology may lead to reduced renal clearance of aminoglycosides and, ultimately, to deleterious effects due to errors in dosage estimation.
Thus, to better understand the effects of induced hypothermia on the pharmacokinetics of aminoglycosides, we analyzed the data of patients who had undergone induced hypothermia for more than 24 hours and had documented aminoglycoside concentrations in their medical records. Patients were identified by cross-referencing all patients who received induced hypothermia for more than 24 hours with those who had aminoglycoside levels. Three patients were identified; all had traumatic brain injury, managed in accordance with the Brain Trauma Foundation Guidelines, with interventions directed at minimizing secondary insults, and all had received tobramycin. Patients with refractory intracranial hypertension often require progressive treatment with decompressive craniectomy, chemical paralysis, barbiturate coma, and mild-tomoderate induced hypothermia. According to our institution's protocol for induced hypothermia, the patients were cooled to a goal temperature of 32–34°C and rewarmed when deemed appropriate by the treating neurointensivist.
Abstract and Introduction
Abstract
Study Objective. To determine the effects of mild-to-moderate induced hypothermia—a neuroprotectant and/or therapeutic strategy for the management of intracranial hypertension in neurologically injured patients—on the pharmacokinetics of aminoglycoside therapy.
Design. Pharmacokinetic analysis.
Setting. Critical care unit at a university-affiliated hospital.
Patients. Three patients, aged 22, 24, and 47 years, who received tobramycin and had documented tobramycin levels while undergoing induced hypothermia for more than 24 hours for intracranial hypertension.
Measurements and Main Results. For each of the three patients, predicted pharmacokinetic parameters (volume of distribution, first-order elimination rate constant, half-life, and renal drug clearance) based on population data were compared with their actual pharmacokinetic parameters that were calculated based on observed tobramycin serum levels. All three patients had a normal creatinine clearance, estimated according to established methods. When pharmacokinetic parameters were calculated after the first tobramycin dose using a one-compartment method, all patients had a slower first-order elimination rate and a larger volume of distribution compared with predicted population estimates.
Conclusion. These findings suggest that induced hypothermia may result in impaired elimination of aminoglycosides. Caution should be exercised when attempting to use predicted pharmacokinetic parameters to dose aminoglycosides in this patient population, and first-dose pharmacokinetics should be considered to optimize the dose and dosing interval early in the course of therapy. Further investigation of this phenomenon with greater numbers of patients are needed to confirm these findings and to determine optimal dosing strategies of aminoglycosides in patients undergoing induced hypothermia.
Introduction
Mild-to-moderate induced hypothermia may be used as a neuroprotectant and/or therapeutic strategy during the management of intracranial hypertension. Strong evidence supports its consideration for the management of patients after cardiac arrest, with more limited data for the management of traumatic brain injury, malignant ischemic stroke, acute liver failure, spinal cord injury, and refractory status epilepticus. In induced hypothermia, the core body temperature is lowered to 32–34°C to decrease cerebral metabolic demand, mitigate excitatory neurotransmitter overstimulation, and attenuate the inflammatory response, thereby modulating secondary brain insults.
Physiologic effects occur with nearly every organ system during mild-to-moderate induced hypothermia. Activity of temperature-dependent enzymatic systems slow, thus decreasing the metabolism of some hepatically metabolized drugs; however, the effect on the pharmacokinetics of renally eliminated drugs is yet to be determined in humans. The reabsorption of renal solute may be impaired secondary to a cold diuresis. However, renal function, as measured by creatinine clearance, is often impaired as renal vascular resistance increases with a subsequent reduction in renal blood flow. In addition, cardiac output may be decreased 25–40% secondary to bradycardia and increased systemic vascular resistance. These physiologic alterations may affect renal perfusion and, subsequently, the glomerular filtration rate and clearance of renally eliminated drugs.
Aminoglycosides represent one class of drugs that are heavily dependent on glomerular filtration rate, display a narrow therapeutic index, and require therapeutic drug monitoring to optimize effectiveness and minimize known toxicities. In the setting of induced hypothermia, alterations in normal physiology may lead to reduced renal clearance of aminoglycosides and, ultimately, to deleterious effects due to errors in dosage estimation.
Thus, to better understand the effects of induced hypothermia on the pharmacokinetics of aminoglycosides, we analyzed the data of patients who had undergone induced hypothermia for more than 24 hours and had documented aminoglycoside concentrations in their medical records. Patients were identified by cross-referencing all patients who received induced hypothermia for more than 24 hours with those who had aminoglycoside levels. Three patients were identified; all had traumatic brain injury, managed in accordance with the Brain Trauma Foundation Guidelines, with interventions directed at minimizing secondary insults, and all had received tobramycin. Patients with refractory intracranial hypertension often require progressive treatment with decompressive craniectomy, chemical paralysis, barbiturate coma, and mild-tomoderate induced hypothermia. According to our institution's protocol for induced hypothermia, the patients were cooled to a goal temperature of 32–34°C and rewarmed when deemed appropriate by the treating neurointensivist.
Source...