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Vasodilators for Sepsis: Targeting the Microcirculation

Aaron Mittel, MD

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Background …

(September 2020)

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Sepsis

  • Life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3)

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Increased oxygen consumption

Low SVR

Maldistribution of blood flow

Impaired microcirculatory perfusion

Singer et al. JAMA. 2016 Feb 23; 315(8): 801–810.

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Precedent

  • Nitroglycerin used in sepsis for 40+ years
    • 1978: 8 patients with intra-abdominal sources of infection, hypertension, volume overload, clinical heart failure treated with NTG paste1
      • Hemodynamic improvement
      • 37% in-hospital mortality
  • 9% of EGDT patients in the original Rivers paper received nitroglycerin2
    • Median baseline ScvO2 = 46%
    • Generally for HYPERtension

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“It is becoming increasingly evident that disordered microcirculatory flow is associated with systemic inflammation, acute organ dysfunction, and increased mortality”3

  1. Cerra FB et al. J Surg Res, 25 (1978), pp. 180-183
  2. Rivers. N Engl J Med 2001; 345:1368-1377
  3. Otero. Chest 2006 Nov;130(5):1579-95.

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Early Goal Directed Therapy (Rivers protocol)

Rivers. N Engl J Med 2001; 345:1368-1377

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The Microcirculation

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“Business end of the cardiovascular system”

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  • Circulation of blood in smallest blood vessels
    • Terminal arterioles, meta-arterioles, capillaries, venules
    • Lymphatic capillaries
  • Mediate blood flow and nutrient transport to tissues

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Jackson WF, Fundamental Biology and Mechanisms of Disease – Ch 89: Microcirculation. Vol 2, 2012:1197-1206

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The Microcirculation

Cecconi. Lancet 2018 Jul 7;392(10141):75-87

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Sepsis

  • Life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3)
  • Microcirculatory and mitochondrial distress syndrome (MMDS)

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  • Ineffective delivery and utilization of substrates… particularly oxygen

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  • MMDS 🡪 vasoactive mediators 🡪 loss of arteriolar tone 🡪 endothelial injury 🡪 capillary leak 🡪 systemic hypotension
  • MMDS 🡪 ineffective oxygen delivery and utilization 🡪 systemic inflammation + coagulation abnormalities 🡪 multiorgan failure

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Trzeciak S. Crit Care, 9 (2005), pp. S20-S26

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Rationale for Targeting Microcirculation

  • Correction of macro-hemodynamic variables may not lead to normal tissue perfusion

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  • Impaired microcirculatory flow 🡪 lacticemia despite normal macro-hemodynamics
  • Improved microcirculatory flow 🡪 improved tissue oxygenation

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Trzeciak S. Crit Care, 9 (2005), pp. S20-S26

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Rationale for Targeting Microcirculation

Vincent JL. Critical Care 2005, 9(suppl 4):S9-S12

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MMDS Pathophysiology

  • Glycocalyx dysfunction
  • Capillary occlusion
    • Stiff leukocytes
    • Stiff RBCs
    • Endothelial cell swelling
    • Platelet/fibrin clots
  • Altered vasomotor tone
    • Endothelial cell dysfunction
    • Vasoactive mediators released by injured tissue

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  • Reduced functional capillary density

Vincent JL. Critical Care 2005, 9(suppl 4):S9-S12

Thiago. Shock, Vol. 47, No. 3, pp. 269–275, 2017

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Vasodilators???

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MMDS Pathophysiology

Trzeciak S. Crit Care, 9 (2005), pp. S20-S26

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Vasodilators in the Microcirculation

Legrand et al. Ann. Intensive Care (2019) 9:102

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Vasodilator Effects on the Microcirculation

Spronk et al. Lancet, 360 (2002), pp. 1395-1396.

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Vasodilator Effects on the Microcirculation

Thiago. Shock, Vol. 47, No. 3, pp. 269–275, 2017

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Vasodilator Agent of Choice

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Nitroglycerin?

Prostacyclin?

Dobutamine?

Inhaled nitric oxide?

Topical acetylcholine?

?

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Multivariable Microcirculatory Model

Thiago. Shock, Vol. 47, No. 3, pp. 269–275, 2017

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Microvascular Agent(s) of Choice

  • IV fluids = hydrostatic pressure
  • Diuretics = hydrostatic pressure
  • Colloids = oncotic pressure
  • Hemoglobin = oxygen concentration
  • Temperature, pH, 2,3-DPG = oxygen dissociation
  • Vasopressors = vasomotor tone
  • Vasodilators = perfusion pressure
  • Inotropes = blood flow rate
  • Immunomodulators = endothelial activity
    • Steroids, APC, etc
  • Anticoagulants = blood clotting activity

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Conclusion

Sepsis = life threatening organ dysfunction caused by a dysregulated host response to infection with microcirculatory and mitochondrial dysfunction

  1. Fluid loading/unloading may improve macro- and microcirculatory flow
  2. Vasopressors may augment microcirculatory perfusion pressure (though carry risk of increasing venous pressure)
  3. Inotropes, e.g. dobutamine, may improve microcirculatory flow
  4. Vasodilators may improve microcirculatory flow
  5. Other agents, e.g. PRBCs, anti-inflammatory drugs, diuretics, may improve microcirculatory flow

Idealized goal: patient-specific intervention

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