Capillary Leak and Acute Lung Injury After Burn

Overview¶

Thermal injury sets off a systemic increase in microvascular permeability that defines the early physiology of the major burn. Burns induce systemic microvascular hyperpermeability that produces shock and, if untreated, cardiovascular collapse ^[24256679]. Massive leakage of fluid from the vascular space depletes plasma and reduces effective circulating volume, generating severe tissue edema, hypotension, and shock, particularly in extensive injury ^[22480675]. Massive tissue edema after thermal injury is a well-recognized entity whose pathogenesis involves changes in most of the physical forces governing fluid flux across the capillary and in how fluid accumulates in the interstitium ^[15879742].

The same systemic response injures the lung. Even in the absence of inhalation injury, acute lung injury is a common cause of morbidity and mortality in patients with severe burns ^[11965445]. The contemporary view holds that acute lung injury is a common complication of severe burns with a complex pathogenesis and high morbidity and mortality ^[38890721]. Progressive pulmonary insufficiency appears to be a near-universal lung response to injuries that damage the pulmonary-capillary endothelium ^[1092877], and burn-related acute lung injury is characterized by diffuse interstitial and alveolar edema from an uncontrolled inflammatory response and damage to the alveolar-capillary barrier ^[39704476]. This page covers the capillary-leak mechanism that drives burn shock and resuscitation, the pulmonary injury that follows, the biomarkers used to assess permeability, and the management and outcome data that bound clinical care.

Epidemiology¶

Acute lung injury is common after extensive burns, particularly when the burned area exceeds 30% TBSA ^[15896507]. Burn injury carries the highest reported incidence of ARDS among all predisposing conditions ^[29697443]. Across ventilated burn patients, reported ARDS incidence ranges from roughly a third to nearly half. In a cohort of intubated burn patients, 53.6% and 45.2% developed ARDS by the American-European Consensus and Lung Injury Severity Score definitions, respectively ^[10654206]. A military burn cohort reported an ARDS prevalence of 32.6% with crude overall mortality of 16.5% ^[24553555]. In a separate series, prevalence was 34% by the Berlin definition and 30.5% by the AECC definition ^[27070223], while another reported an incidence of 43% ^[27520712]. ARDS was diagnosed in 38.6% of patients on invasive mechanical ventilation in one ICU series ^[28149245].

A 2021 meta-analysis pooled the incidence of ARDS in burn patients at 24% (95% CI 0.20-0.28) with mortality as high as 31% ^[34869410]. Incidence was higher among patients on mechanical ventilation, those diagnosed by the Berlin definition, and those with inhalation injury ^[34869410]. Larger and full-thickness burns and inhalation injury recur as risk factors: ARDS patients in one series had larger %TBSA and full-thickness burns ^[27520712], and inhalation injury, burn surface area over 40%, and full-thickness burn area over 20% TBSA were identified as risk factors in another ^[30174564]. Pulmonary abnormalities are found in 30-80% of burn fatalities ^[25445004], and patients with inhalation injury had a 73% incidence of respiratory failure in an early series ^[8273836].

Pathophysiology¶

Microvascular permeability and the Starling forces¶

The barrier that fails is the endothelium. Maintenance of normal vascular permeability depends on the integrity of endothelial barrier function, regulated by intracellular junctions, cell-matrix adhesion, and the cytoskeletal contractile apparatus ^[18396754]. The major drivers of systemic microvascular leakage in burns are an increase in vascular permeability triggered by inflammatory mediators and a rise in vascular hydrostatic pressure from vessel dilation ^[18396754]. Increase of microvascular permeability is one of the most important pathological events in the pathogenesis of trauma and burn injury ^[22480675].

Increased permeability to protein is only one component of burn edema. The pathogenesis of burn edema involves changes in most of the physical forces controlling fluid flux across the capillary and how fluid accumulates in the interstitium ^[15879742]; increased capillary permeability to protein is but one of these changes ^[15879742]. An initial profoundly negative interstitial pressure that draws fluid into the tissues and a marked increase in interstitial space compliance are equally important ^[15879742]. A host of mediators, especially oxidants, produce these physical changes, and some inhibitors, especially antioxidants, appear beneficial ^[15879742]. At the cellular level, burn plasma drives endothelial hyperpermeability through phosphorylation of myosin light chain, a required element of the contractile response that opens the barrier ^[14672924]. The functional stakes are high: mice deficient in myosin light chain kinase-210 showed greatly attenuated microvascular hyperpermeability to albumin and fluid and significantly improved survival ^[17577141].

Local versus systemic edema¶

A defining feature of the burn response is that edema is not confined to the wound. Local burn-tissue and generalized nonburn-tissue edema occur initially after injury because of the release of histamine, which increases microvascular permeability ^[2357324]. Generalized edema increases with burn wound size, paralleling elevated IL-2 and endothelin-1 levels, reduced C1 inhibitor levels, and leukocytosis in the first postburn week ^[9095417]. This distinction between local and remote edema is clinically central: the systemic component, not the local wound alone, drives the resuscitation requirement ^[24256679]. The essence of burn shock is this rapid and extensive fluid transfer across both burned and nonburned tissue ^[33987417].

Mediators¶

Multiple vasoactive and inflammatory mediators converge on the endothelial barrier. Histamine is an early driver: burn injury and intradermal bradykinin or histamine produce permeability changes visualized as dye-release lesions, and antihistamine pretreatment ablates the histamine effect but not the effect of thermal injury or bradykinin itself ^[2286602]. In the burned ear, histamine content did not change while bradykinin content rose significantly after the burn, and antihistamine depressed vasopermeability while non-steroidal anti-inflammatory drugs had no effect ^[2076852]. Prostanoids appear to play a lesser direct role; in one model, prostaglandins produced during thermal trauma did not greatly contribute to edema formation or the increase in vascular permeability ^[504695].

Reactive oxygen and nitrogen species are central effectors. The changes in cardiopulmonary function after burn and smoke injury are mediated at least in part by reactive oxygen and nitrogen species ^{[16798035][19517070]}, and nitric oxide rapidly combines with superoxide to form highly toxic species such as peroxynitrite ^[19517070]. Burn injury initiates lipid peroxidation in capillary endothelial cells and alters microvascular permeability ^[11020047]. In a thermal-injury model, lung permeability rose to a maximum of 2.5-fold by 4 hours after burn, implicating the nitrosative pathway in pulmonary barrier failure ^[11220644]. Cytokines and neutrophils are repeatedly implicated: tumor necrosis factor-alpha and neutrophils are important participants in burn-induced lung injury ^[11965445], TNF-alpha combined with burn-activated neutrophils roughly doubled albumin flux across an endothelial monolayer ^[10923002], and bronchoalveolar lavage from thermally injured animals showed elevated TNF-alpha and IL-1 ^[10486240]. Vascular endothelial growth factor rises after burn: serum VEGF increases immediately and peaks around day 14 at 22-fold above controls, normalizing after wound closure as local and general tissue edema resolve ^[15145186].

Endothelial glycocalyx¶

The endothelial glycocalyx is an additional injured interface. Disruption of the glycocalyx causes shedding of structural glycoproteins, primarily syndecan-1, leading to endothelial dysfunction ^[30502286]. In severe burns, serum syndecan-1 and hyaluronic acid rise sharply and remain elevated, peaking around the ninth day ^[32385998]. Heparin-binding protein has been proposed as a mediator of the early burn-induced increase in vascular permeability ^[19477593], and glycocalyx-associated syndecan-4-positive neutrophils fall significantly after burn ^[24107637]. However, the quantitative link between glycocalyx shedding and measurable leak is weak: syndecan-1 did not correlate tightly with albumin leakage, and a raised syndecan-1 concentration alone cannot be extrapolated to indicate increased capillary leakage of albumin and fluid ^[33350618].

Acute lung injury and the gut-lung axis¶

The lung is injured both directly and as a remote target of the systemic response. Neutrophil accumulation in the lung is implicated in the pathogenesis of this distant organ injury after burn ^[10443288]. A gut-derived pathway contributes: burn-induced gut injury produces biologically active factors carried in the mesenteric lymph, but not portal plasma, that injure endothelial cells and activate neutrophils, contributing to distant organ injury ^[14758175]. Lymphatic division before thermal injury ameliorated burn-induced increases in lung permeability, bronchoalveolar lavage protein content, pulmonary myeloperoxidase, and alveolar apoptosis, supporting the hypothesis that gut-derived factors in mesenteric lymph contribute to postburn respiratory failure ^[10593331]. Inhibition of inducible nitric oxide synthase and neutrophil depletion each reduced lung myeloperoxidase and peroxynitrite, linking the nitrosative and neutrophil pathways to lung damage ^[12973176].

Assessment¶

Pulmonary capillary integrity and lung water can be measured to detect injury early. A quantitative method using Tc-99m-labeled albumin to measure increased pulmonary capillary permeability allows early diagnosis of acute respiratory distress ^[6226097]. Extravascular lung water is closely related to pulmonary edema, and dynamic monitoring of extravascular lung water has been used to predict and quantify it ^[26320320]. Patients with parenchymal inhalation injury had elevated admission extravascular lung water volumes ^[7256543], and chest radiograph density changes in severely burned adults without inhalation injury preceded detectable increases in extravascular lung water ^[11302596]. The pulmonary vascular permeability index distinguished the type of burn-induced pulmonary edema, with an area under the ROC curve of 0.987, and extravascular lung water index, permeability index, and intrathoracic blood volume index together aid differential diagnosis of edema type ^[26564565]. Enlargement of the vascular pedicle on radiograph was associated with early burn-related pulmonary edema and proposed as a clinical predictor ^[3769564]. Tc-99m DTPA lung clearance is accelerated in inhalation burns and has been proposed as a clinically useful measure ^[1292391].

Circulating biomarkers have been studied for prediction and titration. Pro-atrial natriuretic peptide on day 7 correlated with the SOFA score and discriminated ALI/ARDS with an ROC value of 0.90, exceeding age, TBSA, and inhalation injury ^[23006832]. The A2 domain of von Willebrand factor, combined with %TBSA and inhalation injury in a three-variable model, identified patients at risk ^[29697443]. The abbreviated burn severity index predicted ARDS, with an area under the curve of 0.905 for ABSI of 9 or greater, in a young single-etiology cohort (flammable starch-powder burn) ^[29886117]. Neutrophil-to-lymphocyte ratio and related hematologic markers correlate with ARDS severity and adverse outcomes ^[38834610]. Albumin-leak measures have also been explored: the albumin-to-creatinine ratio is elevated early after injury and appears to correlate with the level of microvascular permeability ^[16856552], and B-type natriuretic peptide and proteinuria have prognostic potential and may help adjust individual resuscitation ^[21722363]. The indocyanine green dilution method can overestimate plasma volume after burns, complicating volume assessment ^[9776091].

Management¶

The capillary-leak physiology dictates resuscitation. Massive transvascular loss of plasma reduces effective circulating volume, and if fluids are not adequately restored, burn shock develops ^{[6162412][22480675]}. The choice and timing of fluid interact with the leak. In experimental work, crystalloid resuscitation was associated with rising extravascular lung water, which increased further with injury ^[6546182], and plasma proteins fell further with dextran colloid (50%) than with crystalloid (30%) ^[6184182]. Lactated Ringer's plus early fresh frozen plasma reduced Evans blue dye extravasation compared with Ringer's alone, while late plasma did not ^[38764137]. Albumin pharmacokinetics in burns show plasma-volume expansion of roughly twice the infused volume with a plasma-volume-expansion half-life near six hours ^[32366324].

The interaction between colloid and the nitrosative pathway is a caution from animal models. Restoration of extracellular fluid in early burn shock with albumin markedly augmented lung neutrophil deposition and the increase in lung permeability ^[15804472], and using hypertonic saline in thermal-injury resuscitation without inhibition of inducible nitric oxide synthase was reported as dangerous in one model ^[15489641]. For established hypoxemic respiratory failure, lung-protective and rescue strategies have been examined: high-frequency oscillatory ventilation served as rescue therapy in patients with severe oxygenation failure though it had no impact on mortality ^[11570532], and in a smoke/burn ARDS sheep model a paracorporeal artificial lung achieved significantly lower ventilator settings than volume-controlled ventilation (tidal volume 210 vs 425 mL; FiO2 21% vs 100%) ^[12400738]. Burn and smoke injury reduced the arterial-oxygen-to-inspired-oxygen ratio and increased pulmonary measures of injury in a sheep model ^[21075825].

Complications and Outcomes¶

ARDS is a frequent and lethal complication. Acute respiratory distress syndrome is a common cause of death in burn patients ^[36302307]. Reported incidence is 34-43% in ventilated burn patients, with mortality reaching 59% in the severe form ^[31696126], and the 2021 meta-analysis pooled mortality at 31% ^[34869410]. ARDS develops in the first postburn week in the large majority of cases; 86% of cases arose within the first week in one series ^[27520712], and most patients developed ARDS within seven days in another, with the highest single-day incidence on day 2 ^[34519822]. Independent risk factors for ARDS across cohorts include age, inhalation injury, larger TBSA and full-thickness burn, pneumonia, and transfusion of fresh frozen plasma ^{[24553555][32211213][30174564]}. In a large database analysis, 10.3% of patients developed ARDS, with TBSA, injury severity, inhalation injury, alcohol use disorder, and emergency-department hypotension as independent predictors ^[39484997]. Infection and inhalation injury are common precipitants of established ARDS ^[41480133].

Special Considerations¶

Patients with large TBSA burns and inhalation injury are at elevated risk for burn shock and multiorgan dysfunction, leading to significant morbidity ^[40996144]. Inhalation injury is a recurrent independent risk factor for moderate-to-severe ARDS and respiratory failure in burn cohorts ^{[24553555][8273836]}.

Controversies and Evidence Gaps¶

The animal-to-human translation of mechanism remains incomplete, and effective causal therapy for capillary leak is lacking. Edema due to capillary leak is a generalized, life-threatening event in sepsis and major burns for which there is no causal treatment ^[24769395]. Whether thermal injury increases pulmonary capillary membrane permeability has been directly contested: one clinical study found no evidence that thermal injury increases pulmonary capillary membrane permeability ^[12065363]. The relationship between macrohemodynamic stabilization and microcirculatory injury is also unsettled; stabilizing macrohemodynamic conditions may not necessarily improve microcirculatory derangements ^[28792428].

Biomarker performance is mixed. Although syndecan-1 rises with glycocalyx injury, it does not reliably quantify capillary leak, and a raised concentration alone cannot indicate increased albumin and fluid leakage ^[33350618]. Diagnostic definitions are debated: the Berlin definition appears to stratify ARDS severity better than the AECC definition in burn patients ^{[24685349][27070223]}, yet the low mortality associated with early ARDS in one burn study challenges the Berlin criteria for early diagnosis ^[38777667]. Anti-permeability strategies remain experimental; few clinical trials aimed at decreasing edema have been performed ^[15879742], and barrier-stabilizing mediators are an emerging but unproven concept ^[22480675].

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