Mechanisms of Hypoalbuminemia in Sepsis
Hypoalbuminemia in sepsis results from multiple simultaneous mechanisms: increased transcapillary escape of albumin into the extravascular space (especially in early sepsis), hemodilution from fluid resuscitation and increased plasma volume, suppressed hepatic albumin synthesis via NF-κB activation by lipopolysaccharide, and increased peripheral catabolism of albumin in tissues. 1, 2, 3
Primary Pathophysiologic Mechanisms
Increased Capillary Permeability and Albumin Redistribution
Accelerated transcapillary escape is the dominant mechanism during early sepsis (first 24-48 hours), with albumin transcapillary escape rate (TER) significantly elevated on days 1 and 6 after infection, though absolute efflux increases only during day 1. 1
Once albumin leaks into the extravascular space, it becomes retained in tissues where it undergoes catabolism, contributing to net protein loss from the body. 1, 2
The increased vascular permeability in sepsis allows albumin (a 60 kDa molecule) to cross the endothelial barrier more readily, reducing the oncotic pressure gradient and promoting further fluid shifts. 4
Importantly, albumin supplementation does not reverse this increased permeability—even when serum albumin is nearly doubled (from 10.3 to 18.5 g/L), the transcapillary escape rate remains unchanged at approximately 6.7%/hour. 5
Hemodilution and Volume Expansion
Increased plasma volume from fluid resuscitation and the systemic inflammatory response directly dilutes serum albumin concentration, accounting for a substantial portion of the observed hypoalbuminemia. 1
The increased cardiac output and renal blood flow characteristic of early sepsis (in absence of acute kidney failure) further expands the intravascular volume. 4
Suppressed Hepatic Synthesis
Lipopolysaccharide (LPS) directly suppresses albumin gene expression in hepatocytes by activating the NF-κB signaling pathway, representing a transcriptional mechanism of reduced albumin production. 3
This suppression occurs despite the liver's attempt to compensate—paradoxically, some septic patients demonstrate supranormal albumin synthetic rates (mean 215 mg/kg/day, range 21-447 mg/kg/day) even while maintaining severely depressed serum levels (mean 1.98 g/dL). 2
The lack of correlation between serum albumin levels and hepatic synthetic capacity indicates that serum albumin does not reliably reflect hepatic function or visceral protein status in critically ill patients. 2
Increased Peripheral Catabolism
Extravascular protein redistribution and increased peripheral catabolism are major factors responsible for hypoalbuminemia, particularly as sepsis progresses beyond the acute phase. 2
After the initial phase of increased transcapillary escape, other catabolic mechanisms predominate since albumin efflux returns to normal by day 10 while hypoalbuminemia persists. 1
Clinical Implications for Beta-Lactam Pharmacokinetics
Hypoalbuminemia increases the free fraction of highly protein-bound beta-lactams (cefazolin, ceftriaxone, ertapenem), leading to increased volume of distribution, enhanced tissue penetration, and accelerated elimination through glomerular filtration. 4
This pharmacokinetic alteration necessitates measuring albumin or plasma proteins at treatment onset and during therapeutic drug monitoring to guide antibiotic dosing in septic patients. 4
Temporal Evolution
Early sepsis (days 1-6): Increased transcapillary escape and hemodilution dominate. 1
Late sepsis (day 10 onward): Peripheral catabolism and suppressed synthesis become more important as transcapillary escape rates normalize. 1
Throughout all phases, net albumin loss from the body continues, reflecting the combined impact of all mechanisms. 1