Outline how the pathophysiological changes in septic shock affect the pharmacokinetics and pharmacodynamics of commonly used antimicrobials.
Answer and interpretation
The major changes in pharmacokinetic parameters of critically ill patients include alterations in volume of distribution (Vd) and clearance (Cl). Subsequently, these alterations affect the concentrations of antimicrobials in the body and the extent to which they are cleared.
The Vd is the volume in which the total amount of drug would have to be evenly distributed in to equal the same concentration as in the plasma. The toxins produced by various bacteria often lead to endothelial damage and result in increased capillary permeability. This leads to the phenomenon of “third spacing” where fluid shifts into the interstitial space from the intravascular space. These fluid shifts will increase the Vd of hydrophilic antimicrobials. Generally speaking, hydrophilic antimicrobials have a low Vd and therefore are greatly affected by these fluid shifts. Since lipophilic antimicrobials have a larger Vd, they typically distribute further into tissues and are less affected by these fluid shifts.
Patients in the ICU often have hypotension as a result of septic shock, which requires the administration of fluid boluses. Additionally, heart failure and renal failure lead to more oedematous states where patients can retain large amounts of fluid. These situations also lead to increases in Vd of hydrophilic drugs.
Changes in protein binding can also have a substantial effect on the Vd, especially for drugs that are highly protein bound. Only unbound or free drug is microbiologically active. Hypoalbuminemia in critically ill patients can result in decreased binding of drugs and subsequently higher free concentrations of drugs. While free drug will distribute into tissues, critically ill patients often have greater amounts of fluid in the interstitial space causing the antimicrobial concentrations in the tissues to remain low.
The administration of large volumes of fluid and use of vasopressors leads to a hypermetabolic state in which cardiac output and glomerular filtration rate are increased. The term often used to describe this enhanced elimination is augmented renal clearance. These physiological changes affect the clearance of drugs and can lead to sub-therapeutic levels of antimicrobials that are typically cleared by the kidneys. In contrast, decreased organ perfusion in the presence of end organ damage can lead to kidney and/or liver failure in which concentrations of these antimicrobials would be increased. Inadequate clearance or metabolism of these drugs would lead to accumulation and potential toxicity. Typically, equations such as Cockroft-Gault are used to estimate renal function; however, these are often not good predictors of renal function in critically ill patients due to the acute and rapid changes such patients often experience. Since many antimicrobials are dosed based on renal function it is even more challenging to ensure adequate doses are being administered. The most accurate way to calculate renal function is the use of 8- or 12-hour creatinine collections. In situations where renal replacement therapy is utilized, careful consideration of timing and supplemental dosing post-dialysis would be needed depending on the antimicrobial agent
- Pass rate: 44%
- Highest mark: 7.5
Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.
After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.
He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE. He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.
His one great achievement is being the father of three amazing children.
On Twitter, he is @precordialthump.