Mechanism of Vasoplegia in Sepsis and Why Fluid Resuscitation Improves Hypotension
Vasoplegia in sepsis results from a complex disruption of vascular tone control through multiple pathways including excessive nitric oxide production, vasopressin deficiency, and inflammatory mediator release, while fluid resuscitation improves hypotension primarily by correcting relative hypovolemia and increasing preload rather than directly reversing the vasoplegic state itself. 1
Pathophysiologic Mechanisms of Vasoplegia
Vasoplegia represents a profound loss of vascular tone control through multiple simultaneous mechanisms that create an imbalance between vasoconstrictors and vasodilators 1:
Primary Vasodilatory Pathways
- Nitric oxide overproduction occurs through activation of inducible nitric oxide synthase (iNOS), leading to excessive vasodilation 1
- Prostacyclin (PGI2) upregulation contributes to systemic vasodilation 1
- Vasopressin deficiency develops during septic shock, removing a critical vasoconstrictor mechanism 1
- Elevated vasodilator peptides including adrenomedulin (AM) and calcitonin gene-related peptide (CGRP) accumulate and promote vasodilation 1
Secondary Mechanisms
- Oxidative stress induces endothelial dysfunction and creates vascular hyporeactivity to vasoconstrictors 1
- Catecholamine inactivation occurs through oxidation, reducing the effectiveness of endogenous and exogenous vasopressors 1
- ATP-sensitive potassium channel (KATP) overactivation contributes to vascular smooth muscle relaxation and hypotension 1
- Elevated circulating endothelin paradoxically occurs but fails to maintain vascular tone due to receptor dysfunction 1
Why Fluid Resuscitation Improves Hypotension
The Three Pathophysiologic Contributors
Septic shock involves three distinct but overlapping mechanisms 2:
- Relative and absolute hypovolemia (relative > absolute)
- Decreased vascular tone (vasoplegia)
- Myocardial dysfunction
Fluid's Primary Mechanism of Action
Fluid resuscitation addresses the hypovolemic component rather than directly reversing vasoplegia. The improvement in blood pressure occurs through:
- Increased preload from volume expansion, which improves cardiac output in fluid-responsive patients 2
- Improved organ perfusion pressure when adequate intravascular volume is restored 3
- Correction of relative hypovolemia caused by vasodilation and increased vascular capacitance 2
Critical Limitation: Fluid Responsiveness
Only 33-50% of septic patients demonstrate sustained cardiac output improvements after fluid boluses 2. This limited response occurs because:
- Sepsis-mediated glycocalyx injury impairs the ability to retain intravascular volume 2
- Vasoplegia creates a "leaky" vascular system where fluid redistributes rapidly 2
- The primary problem is vascular tone, not volume, in many patients 4
Clinical Implications and Modern Resuscitation Strategy
Initial Fluid Resuscitation
- Administer at least 30 mL/kg of crystalloid within the first 3 hours for sepsis-induced hypoperfusion 3, 5
- Use a pragmatic approach with small boluses (10 mL/kg over 20-30 minutes) and reassess response based on clinical perfusion markers 2
- Stop fluid administration when no improvement in tissue perfusion occurs or signs of fluid overload develop 6
Early Vasopressor Strategy
Because vasoplegia is the dominant mechanism in many patients, a strategy of restricted fluid with early low-dose norepinephrine is increasingly recommended 2, 7:
- Initiate norepinephrine early (0.05-0.1 µg/kg/min) when hypotension persists despite initial fluid challenge 2
- Target a mean arterial pressure of 65 mmHg as the initial goal 3, 5
- Norepinephrine directly addresses vasoplegia through α1-agonist activity, restoring vascular tone 4
Why This Combined Approach Works
- Fluid corrects the hypovolemic component (both absolute and relative) 2
- Norepinephrine directly reverses vasoplegia by providing exogenous vasoconstriction when endogenous mechanisms fail 4
- Early vasopressor use prevents fluid overload while maintaining adequate perfusion pressure 7
Common Pitfalls and Caveats
Excessive Fluid Administration
- Fluid overload worsens outcomes when vasoplegia is the dominant mechanism rather than hypovolemia 7
- Practice is evolving toward smaller-volume resuscitation paired with earlier vasopressor initiation 7
- Monitor for pulmonary edema, increased jugular venous pressure, and worsening respiratory function 5
Delayed Vasopressor Initiation
- Vasoplegia marked by low diastolic blood pressure is a major contributor to hypotension in septic shock 2
- Waiting too long to start vasopressors while administering excessive fluid can worsen outcomes 7
- Occult blood volume depletion should always be suspected when high vasopressor doses are required 8