Pharmacokinetic/pharmacodynamic variations during sepsis/septic shock

Sepsis, a heterogeneous syndrome, is usually associated with uncontrolled body response to a systemic infection leading to dysregulated pro- and anti-inflammatory cascades.(1) This, subsequently, leads to immune suppression, tissue damage, and organ failure. With time, the natural body compensation is lost and a state of shock, characterized by profound hypotension and abnormal cellular metabolism, ensues. Sepsis and septic shock are thus considered major challenges in critical care management due to the high rates of complications, including morbidity and mortality. Successful management of sepsis/septic shock necessitates implementation of urgent treatment measures targeting the underlying infection, as well as improving patient's hemodynamics.(2) Treatment measures include administration of antimicrobials, vasoactive drugs, sedatives, analgesics, along with others with the aim of achieving effective, yet safe concentrations of different administered medications at the targeted site of action.(3) However, this aim of efficient medication dosing attainment can be challenging in critically ill septic patients. The host response to sepsis is usually associated with tremendous changes of different physiological processes.(3,4) Different studies have shown that such pathophysiological alterations were linked to dysregulations in both pharmacokinetic (PK) and pharmacodynamic (PD) properties of different administered medications and thus result in complicated drug dosing.(3,4) Pharmacokinetics of a given therapy is usually linked to the administered dose and the corresponded changes of concentrations inside the body with time, whereas pharmacodynamics describes the resultant relation between the obtained drug concentration and its pharmacological effect. In-vivo efficacy of an administered medication is largely driven by its intrinsic PK and PD properties. Variations in PK/PD are not always universal or easily predictable, and different aspects can affect the overall discrepancies. Those aspects include disease, patient and drug related factors.(5) For instance, the alterations of PK/PD properties seen with sepsis can be different from those seen with septic shock. A similar thing applies to the drug properties where the therapeutic concentrations of a lipophilic medication might be less prone to changes as compared to a hydrophilic therapy. Likewise, the co-existence of different conditions that influence overall medications' pharmacokinetics can complicate proper prediction of therapeutic concentrations. This is frequently encountered in critically ill patients presenting with sepsis/septic shock and requiring the use of renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO), plasmapheresis, or even all in certain individuals. A deep understanding of various pathophysiologic changes seen in critically ill patients and their effects on the overall drug PK/PD is thus essential. This ensures that personalized dosing regimens are tailored to each patient to achieve an optimized therapy rather than using a “one size fits all” model of drug dosing. The implementation of personalized tailored therapy based on patient specific parameters, along with the utilization of therapeutic drug monitoring can successively give rise not only to improved clinical efficacy but also to decreased toxicity and antimicrobial resistance. Subsequently this would result in improved patient outcomes and survival.