Vascular Response to Burn Shock

© 2024 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of ePlasty or HMP Global, their employees, and affiliates.

A 36-year-old male was rescued by firefighters from a house fire and transferred to the burn center. He sustained deep burns to 60% of his body surface area, including his head and neck (Figure 1). The patient arrived 1 hour after injury, having received 1100 mL of normal saline. He was intubated as a precautionary measure against inhalation injury, and fluid resuscitation was continued with lactated Ringer solution, guided by the Parkland formula. The initial clinical assessment revealed the patient's body temperature to be 37.1°C, heart rate 140 beats per minute, and blood pressure within the range of 100/60 mm Hg. He had produced only 10 mL of urine, and his unburned feet were mottled, pale, and cool. A secondary survey and imaging studies revealed no further injuries. Over the ensuing 8-hour period, the patient received a total of 10600 mL of fluid, leading to an improvement in his blood pressure and a favorable increase in urine output. During the first 72 hours, the necrotic burned skin was excised and the resulting wounds closed with autograft and allograft. The allografts were eventually replaced with autografts as donor sites re-epithelialized. Following an extensive period of rehabilitation, the patient achieved a good functional outcome.

Figure 1. Presentation of the patient in the emergency room, showing full-thickness wounds to the anterior trunk, pelvis, and upper extremities.

Burn shock is a life-threatening condition marked by a generalized maldistribution of blood flow, leading to cellular and tissue hypoxia. This hypoxia may result from reduced oxygen delivery, increased oxygen consumption, inadequate oxygen utilization, or a combination of these processes.¹ Following a major burn (>40% total body surface area), there is a massive inflammatory response driven by an upsurge in circulating inflammatory mediators that include histamine, kinins, serotonin, prostaglandins, leukotrienes, interleukins (eg, IL-1β, IL-6, and IL-8), tumor necrosis factor-α (TNF-α), and thromboxane A2.² Activation of inflammatory, coagulation, and complement cascades establishes a positive feedback loop that leads to microvascular disruption, the opening of junctions between adjacent endothelial cells, and the shedding of the endothelial glycocalyx. The imbalance of hydrostatic and oncotic pressures (Starling forces) across the damaged microvascular barrier drives fluid from the vascular to the interstitial compartment in both burned and non-burned tissues. There follows a fall in cardiac output, though this may precede the reduction in effective circulating volume and persist even after adequate fluid resuscitation. Burn shock therefore comprises distributive, hypovolemic, and cardiogenic components (Figure 2).

Figure 2. Hemodynamic changes in burn shock.

Impaired tissue perfusion triggers the release of lysosomal enzymes, the accumulation of calcium, and the generation of reactive oxygen species, leading to cell injury, multisystem organ failure, and death.³ Hypoxia prompts a shift from aerobic to anaerobic cellular metabolism with the production of lactate as a marker of the severity of shock.

Multiple factors account for a fall in cardiac output. This has been attributed to circulating myocardial depressant factors, such as TNF-α, IL-1β, IL-6, and reactive oxygen species, which reduce myocardial contractility and have been shown to induce myocardiocyte apoptosis.⁴

The contraction of plasma volume reduces venous return and end-diastolic volume (preload). Cardiac output falls via the Frank-Starling mechanism, which relates the energy of muscle contraction to fiber length. Consequently, the reduced right atrial filling pressure decreases the myocardial contraction force and stroke volume.⁵

The complex relationship between preload, afterload, and contractility challenges the Starling law. The time-varying elastance model by Suga and Sugawa explains how ventricular chamber elastance (ie, the ratio of intraventricular pressure and volume, or muscle stiffness)⁶ cycles from low levels during diastole to high elastance during systole, influencing the relationship between intraventricular pressure and volume (Figure 3). Studies have shown that extensive burns can cause decreased left ventricular compliance, limiting the ability of the left ventricle to relax during diastole.⁷

Reduced cardiac output causes a drop in arterial blood pressure via the formula Arterial pressure = cardiac output x systemic vascular resistance. Baroreceptor reflexes increase sympathetic activity, elevating heart rate, contractility, and peripheral resistance. Paradoxically, an elevated heart rate may reduce cardiac output by shortening diastolic filling time. Vasoconstriction and increased hematocrit levels contribute to the elevation of afterload, further reducing stroke volume and cardiac output (Figure 2). This culminates in a cycle of low blood pressure, coronary insufficiency, myocardial ischemia, and progressive myocardial dysfunction.⁸ Significantly, the release of catecholamines, glucocorticoids, and other stress hormones mediate a prolonged hypermetabolic and hyperdynamic cardiovascular response, allowing for the coexistence of shock alongside a normal or elevated blood pressure.⁴

Figure 3. Time-varying elastance concept adapted from Suga and Sugawa et al. Pressure-volume (PV) loops portray cardiac cycle variations linked to ventricular elastance. Dashed lines are elastance curves at different time points, and small black circles denote isochronic points on distinct PV loops. Each loop illustrates a heart cycle, progressing counter-clockwise through (A) diastolic filling phase with minimal ventricular elastance for efficient low-pressure rapid filling, (B) isovolumetric contraction generating higher pressures via increased elastance until its peak, (C) ejection phase follows the opening of the aortic valve to an end systolic pressure–volume point on the ESPVR curve, (D) isovolumetric relaxation where falling pressure accompanies diminishing elastance. With mitral valve opening, the cycle restarts, characterized by increasing elastance that generates a subsequent PV loop. The end-systolic pressure–volume points for differently loaded ejections all fall along an approximately linear end-systolic pressure–volume relationship, the slope of which represents ΔP/ΔV (elastance at a specific time point). Thus the cardiac cycle can be regarded as cyclical changes in the elastance of the ventricular chamber. The red loop represents one heart cycle. The blue and green loops represent cycles with reduced and increased preloads, respectively.

The Starling equation defines the forces governing fluid transport between the microcirculation and the interstitial space. The net fluid filtration rate across the capillary (J_v) is expressed mathematically in the Starling equation.⁹

Flow direction is driven by the disparities in capillary hydrostatic pressure and the interstitial hydrostatic pressure (P_c-P_i), which drives fluid out of the capillary, and the colloid osmotic pressure of the blood and interstitial fluid (π_p-π_i), which draws fluid back into the capillary. The capillary filtration coefficient (K_f), the product of the capillary surface area and its hydraulic conductivity (water permeability), characterizes the ease of fluid accumulation. The reflection coefficient (σ) indicates capillary permeability, with values ranging from 0 (permeable) to 1 (impermeable) and a normal value of about 0.9 (Figure 4).

Figure 4. Starling's equilibrium under physiological conditions. (Pressures are approximations.) (A) The hydrostatic pressure at the arteriolar end of a capillary is 32 mm Hg and at the venular end 15 mm Hg. These are opposed by the hydrostatic pressure in the interstitium (-2mm Hg). A negative elastic force is provided by the hyaluronic acid and collagen molecules of the interstitial space, which exist in a coiled state. The net hydrostatic pressure gradient forcing fluid out of the capillaries is therefore 34 mm Hg at the arteriolar end and 17 mm Hg at the venular end. (B) The ultrafiltration is opposed by the difference between the blood colloid osmotic pressure of 28 mm Hg and the interstitial osmotic pressure of 8 mm Hg so that the net osmotic pressure drawing fluid into the capillary at the arterial and venous ends is 20 mm Hg. (C) The net filtration pressures at the arterial and venous ends of the capillary are 14 and -7 mm Hg, respectively, so that fluid will leave the capillary at the arterial end and be reabsorbed at the venous end. Normally about 15% of the fluid is left in the tissues, and it is then removed by the lymphatic capillaries and returned to the circulation.

Following a burn, inflammatory mediators create endothelial gaps, increasing capillary permeability as the reflection coefficient σ drops to 0.3. Increased interstitial compliance from hydration and matrix denaturation raises the capillary filtration coefficient (K_f ). Arteriolar vasodilatation increases capillary hydrostatic pressure (P_c) while capillary interstitial pressure (P_i) becomes more negative. The fragmentation of matrix proteins to create osmotically active molecules and the unraveling of the tightly coiled collagen framework contribute to this negative force.¹⁰ These changes cause an increase in (P_c-P_i) and a decrease in (π_p-π_i), promoting fluid efflux from the capillary. If the rate of fluid filtration exceeds lymph flow, edema occurs.¹¹ (Figure 5).

Figure 5. (A) Physiological fluid shifts. (B) Microvascular forces across the capillary after thermal injury. Transvascular fluid flux across the capillary wall increases with elevation of P_c, π_I,and k_f and with decreases in σ, π_p, and P_i.

Burn injuries, however, also disrupt the glycocalyx directly or by inflammation and ischemia. The glycocalyx is a semipermeable meshwork of glycoproteins and proteoglycans coating the lumen of the capillary that blocks colloid osmotic absorptive forces and retains the reflection coefficient (σ) of nearly 1. The revised Starling equation incorporates the role of the glycocalyx as J_v = K_f [(P_c-P_i) + σ(π_p-π_g)],where π_{g =} subglycocalyx oncotic pressure.¹²

Key regulators of endothelial permeability are tight junctions (TJs) and adherence junctions (AJs) that connect endothelial cells via cytoskeleton-associated proteins. Tight junctions consist of integral membrane proteins, such as junctional adhesion molecules (JAMs), occludins, and claudins, which link to the actin cytoskeleton via cytoplasmic zona occludens proteins (ZO-1, ZO-2, ZO-3) and cingulin (Figure 6A).

Figure 6. Molecular organization of (A) tight junctions. JAMS, (junctional adhesion molecules) ZO (zona occludens proteins). (B) VE-cadherin, which is represented as a dimer. Adhesion proteins known to link VE-cadherin to actin filaments are p120, β-catenin (β-cat), α-catenin (α-cat), and Plakoglobin (Plako).

Adherence junctions feature the transmembrane protein vascular endothelial cadherin (VE-cadherin). VE-cadherin's extracellular (EC) region has 5 EC domains that mediate rigid cell-cell adhesion by homodimerizing with neighboring cell VE-cadherin domains in the presence of Ca²⁺ ions. Its cytoplasmic (carboxyl) domain interacts with proteins, including p120, β-catenin, and plakoglobin. β-catenin and plakoglobin associate with α-catenin, connecting the complex to the actin cytoskeleton (Figure 6B).¹³

The disruption of the endothelial barrier is triggered by the release of inflammatory mediators, including vascular endothelial growth factor (VEGF), TNF-α, platelet-activating factor (PAF), IL-8, thrombin, and histamine. These mediators bind to specific chemical receptors, which activate signaling pathways that result in cytoskeletal remodeling, opening paracellular gaps.¹¹

Extensive reviews have described several signaling transduction pathways that modulate endothelial permeability, including cytosolic calcium and various protein kinases, including Rho kinase (ROCK), mitogen-activated protein kinases (MAPKs), and protein kinase C (PKC).^14,15 One of the primary mechanisms involves the phosphorylation of myosin light chains by myosin light chain kinase (MLCK), which induces the formation of intercellular gaps through actin-myosin interactions and cell contraction. However, MLCK is inhibited by myosin light chain phosphatase (MLCP). RhoA, released via G protein coupling receptors on the cell membrane, acts via its downstream effecter, ROCK, to induce the phosphorylation of MLCP. This attenuates MLCP's phosphatase activity, increasing phosphorylated MLC, and sustaining endothelial cell contraction.