Pathophysiology of integument failure
As the largest organ system in the body, integument failure leads to consequences that can be varied and severe. Despite the research conducted to date, the relevant anatomic pathophysiology has yet to be fully elucidated. Additionally, the terminology of various end-of-life integument injuries is not consistent and lacks consensus.
To better understand pathophysiology of integument failure, it is important to better understand its anatomy. In 1987, Taylor and Palmer8 introduced the concept of angiosomes when describing the arterial anatomy. This 3D description of blood supply to the integument and underlying tissue laid the foundation for composite flap reconstruction. Taylor and Palmer8 found that angiosomes are linked at every tissue level either by a true (simple) anastomotic arterial connection with no caliber change or by reduced-caliber choke anastomosis. The authors also found junctional zones between adjacent angiosomes at all levels of tissue. The muscles provide an important anastomotic detour (bypass shunt) when the main source artery is obstructed. This has recently led to the development of the concept of functional angiosomes as defined by Taylor et al9; they describe separate “islands” of skin (and underlying tissue) that are vascularly supplied by a single-source vessel. Connections between these islands called anastomotic perforators are true anastomosis and choke vessels that have the potential to dilate in response to ischemia, if time permits.9 To date, no data have shown how vascular delay affects wound healing in areas of tissue loss and whether recruitment of surrounding choke vessels in the skin adjacent to integument injuries occurs. Taylor et al9 describe the pathology that occurs when the perforating vessel of the angiosome is damaged. Keeping in mind that muscle is more prone to ischemia than skin, this seems particularly relevant.
Types of integument injury
Various types of injuries can damage skin. Pressure is the most commonly diagnosed injury in hospitals and nursing homes and is often avoidable. However, skin can break down and pressure is not the primary factor instigating necrosis; these causes are unavoidable. The following section will discuss different types of common injuries.
Pressure injury. The Joint Commission defines pressure injuries as localized damage to skin and/or underlying soft tissue, typically over a bony prominence.7,10 They are at times painful, and skin may or may not lose integrity.7 The injury occurs due to pressure alone or pressure in combination with shear. The tolerance of soft tissue for pressure and shear is thought to be affected by numerous factors, including nutrition, perfusion, hydration, and other medical comorbidities.11
Skin failure. Skin failure was first described in 1991 by Irvine12 as a loss of normal temperature control with an inability to maintain core body temperature; failure to prevent percutaneous loss of fluid, electrolytes, and protein with resulting imbalance; and failure of the mechanical barrier to prevent penetration of foreign materials.
Acute skin failure. Acute skin failure describes the cause of integumentary loss in association with hemodynamic instability and/or organ system compromise in critically ill patients. In 2005, Inamadar and Palit13 described acute skin failure as a state of total dysfunction of the skin resulting from varying dermatologic conditions, including erythroderma, Stevens-Johnson syndrome, and immunologic conditions. Many of these conditions lead to unavoidable integumentary failure. The authors13 concluded that acute skin failure constitutes a dermatologic emergency requiring a multidisciplinary approach.
The term skin failure also was used by Delmore et al2 to differentiate pressure injuries from acute skin failure in ICU patients. In their study of 552 ICU patients, acute skin failure was associated with peripheral arterial disease (PAD), mechanical ventilation, respiratory failure, liver failure, and severe sepsis/septic shock, with an odds ratio of these factors varying from 1.9 to 3.8.
Etiology of integument failure
Various etiologies lead to integument failure. These are affected by different factors requiring thorough assessments and different treatments even though presenting symptoms may be similar. Therefore, it is important to understand the contributing factors to each etiology.
Functional angiosomes and integument failure. These conditions, specifically identified in critically ill patients, are associated with poor integumentary perfusion. The multifactorial interplay between cardiac output/ejection fraction, peripheral vascular disease, hypotension, sepsis, and various shock states affects the integument via the sympathetic portion of the autonomic nervous system and alpha receptors.14 Additionally, distributive shock, which arises from abnormalities of the peripheral circulation (sepsis and anaphylaxis), further implicates perfusion of the tissues to integument failure.14 When there is a significant reduction in perfusion, the risk of integumentary injury increases. Exactly at what point this occurs is multifactorial, affected by chronic conditions impacting the arterial vessels, varies by patient, and still to be understood.
Taylor et al8 describe a pediatric patient with severe, full-thickness skin loss of the lower extremities from a meningococcal sepsis infection and associated 3D loss of entire angiosome secondary to associated perforator destruction. An association between the cutaneous perforators and tissue loss is evident from Taylor et al’s photographs (Figure 1), which show full-thickness dermal loss as well as the loss of the entire 3D structure of an angiosome. This demonstrates a real-life consequence of damage to the perforator and associated angiosome.
The complexity of differentiating causes of integumentary injury is much greater when adjoining perforator anatomy and choke vessels are taken into consideration. In the presence of arterial disease, chronic microvascular calcifications, and contributing pathology such as uncontrolled diabetes, the effects on the vascular anatomy are even more complex. No current data are available to define increased or decreased relative risk between what could be considered watershed areas of perforator intensity in the event of ischemia or relative ischemia (areas with higher and lower perforator density). Areas such as the sacral midline lack musculature; the extent to which gluteal perforators connect with the sacral angiosome, as well as the extent of midline crossover, appears uncertain. Saint-Syr et al further described the theory of perforasomes, or the vascular territory that a perforating vessel supplies.15 These perforasomes are shown to be linked via both direct and indirect linking vessels (Figure 2).
Additionally, as muscles are more prone to ischemic events from pressure, it is unclear if the temporal nature of the underlying compromise always happens at the time of noted integument breakdown. This suggests that an interval lag exists between each insult, as evidenced when considering deep tissue injury while further research is needed.
Delmore et al2 conclude that the “concept of acute skin failure remains an enigma,” and that much of what is classified currently as pressure injury might be better categorized as acute skin failure. The pathophysiology of acute skin failure results from decreased perfusion within a functional angiosome via the cutaneous arterial perforators, inability of arterial anastomotic connections to augment flow, lack of time for choke vessels to respond and vasodilate followed by tissue ischemia, and eventually associated tissue loss. The initiating events leading to this destruction vary (Figure 3).
End-of-life integument failure
Integument failure at the end of life has been described in a number of ways.18-20 Thrombley et al20 noted and named terminal tissue injuries (TTI)—spontaneously appearing skin alterations found in end-of-life patients (Figure 4). Terminal tissue injuries are characterized as rapidly evolving and enlarging areas of stained skin in non-pressure areas. This phenomenon was further validated by a recent study by Brennan et al.21 Terminal tissue injuries correspond to arterial perforators, as described by Taylor et al,8 that occur in the absence of pressure (as described previously).
Terminal ulcers as described by Kennedy18 typically occur between 1 day and 6 weeks before end of life. These terminal ulcerations have subsequently been characterized as skin failure as a result of ischemia.22 Hypotension and shock states alone will not cause spontaneous failure of the integument. Tissue perfusion, skin surface pressure, and comorbid conditions all seem to act differently on the underlying angiosome in each patient. Photos of the terminal ulcerations show that the necrotic area appears to correlate with the sacral angiosome and destruction of the arterial perforators and the lateral areas of the adjoining angiosomes (Figure 5). A component can be observed of direct pressure injury as well as injury to the underlying arterial and adjoining perforators between the sacral and gluteal angiosomes. The adjoining choke vessels are not able to dilate and additionally perfuse the necrotic area owing to the acute nature of the injury. However, this may be a factor in the healing of marginally injured areas. This ultimately may explain why pressure injuries typically do not cause systemic sepsis; the choke vessels and anastomotic vessels are permanently damaged.
Research does not suggest that end-of-life integument injuries do not have a component of pressure. The associated comorbidities that cause hypoperfusion, exacerbated at the end of life within the sacral angiosome itself, explain the etiology of these integumentary injuries. The sacrum and heels are not an anatomically privileged area. During times of hypotension, blood is shunted from the periphery and gastrointestinal tract and to the head, neck, and other major organs, making integumentary breakdown in those areas more likely.
Moisture-associated skin damage
Moisture-associated skin damage (MASD) is a type of contact dermatitis caused by prolonged exposure to various sources of moisture and is characterized by inflammation and erosion of the epidermis.23,24 Pathologic studies have shown distinct differences between superficial pressure (stage 1) injuries and moisture.25 Moisture-associated skin damage inflicts these superficial tissue injuries; they are distinguishable from those caused by pressure, but both activate pathways that can stimulate cell death and increase the skin’s sensitivity to further integument failure.
Moisture-associated skin damage is influenced both by intrinsic factors (ie, perspiration, skin pH, psychological stress) and extrinsic factors (ie, chemical or biological irritants, medication metabolites, and infections). Woo et al24 reported that patients with bowel or bladder incontinence are 5 times more likely to develop pressure injuries (5.6%–50%), with the highest percentage found among critically ill patients. However, the pathways that damage the stratum corneum of the sacrum due to the presence of chronic urine and stool and ultimately lead to an increased risk of pressure injury (per Woo et al’s description24) are far more complex; as such, tissue destruction cannot always be attributed to pressure injury alone. Excess ammonia from incontinence creates an alkaline environment that promotes integumentary damage and potentiates the effect of fecal enzymes on the skin.24 Independently, medical conditions such as neurological issues can augment urologic spasticity, increasing incontinence and its downstream effects. Drugs and their stool or urine metabolites can further exacerbate skin breakdown.2
Biofilm and infection in MASD injuries facilitate frank integumentary failures. Biofilm degrades epithelium, utilizing the ceramidase enzyme, initiating integumentary breakdown, and permitting subsequent bacterial colonization and infection.26 Once present, bacteria compete for oxygen within the tissue, impairing perfusion and leading to integumentary death.
Moisture-associated skin damage tissue injury can closely mimic pressure, but it requires different treatment and prevention pathways. As more experience with MASD accumulates, its role as a factor acting synergistically with pressure during wound development becomes more evident.
Vasopressors and integument failure
Critically ill patients are recognized as at risk for integument breakdown over the torso.27,28 Mean arterial pressure (MAP) has long been used to measure tissue perfusion29,30; a MAP less than 80 independently results in delayed wound healing and chronic wounds.31 Additionally, end-organ perfusion is determined to be compromised if MAP is less than 60, but the overall effect on the skin has yet to be elucidated.29,30 A MAP of less than 60 alone is not enough to cause acute integumentary failure throughout the body, underscoring acknowledgment that a complex interplay of factors must be present.
Multiple studies report inconsistent results regarding the risk of skin breakdown and the use of vasopressors. Vasopressors are known to act via various mechanisms at different dosages. Most have alpha agonists effects and cause vasoconstriction of the integument’s perforators and choke vessels. A 2015 retrospective study by Cox and Roche3 of 306 patients requiring vasopressor use in the ICU found a direct correlation between the use of 2 agents (norepinephrine with added vasopressin) and pressure ulcer development. These agents synergistically create an additive risk for skin breakdown by lowering perfusion to skin throughout the body. Presumably, the threshold integumentary failure, due to decreased arterial flow, becomes more pronounced with decreased perfusion (alpha agonist) effects of these medications with any risk factor.
No single factor leads to integument breakdown. It appears that the multifactorial interplay among hypotension/shock, MAP less than 60, and vasopressor use increases the risk of integument breakdown. Other factors, including smoking,32 diabetes, immobility, nutrition, and PAD, further increase this risk.
Most common sites of integumentary failure
Sacrum. Breakdown of sacral integument is commonly observed both in acute and chronic care settings. The sacrum is more prone to ischemic insult in times of shock than is the lateral portion of the buttocks that lies directly over musculature. This difference is likely due to the paucity of cutaneous perforators from the superior and inferior branches of the lateral sacral artery that supply the single sacral angiosome compared with the relatively large number of vessels supplying the multiple buttock angiosomes.33
The 2017 research by Yamada et al34 investigated the conditions associated with microvessel occlusion, a condition known to contribute to sacral integument failure. The authors hypothesized that even red blood cells stacked within sacral microvessels may cause enough pressure within the vessel to decrease perfusion into the sacral angiosome and promote integument failure. Their study34 concluded that the interaction among external pressures, intrinsic comorbid factors (lower back anatomy, tissue elasticity, microvasculature stiffness, and pressure within vessels), and extrinsic comorbid factors (patient weight and posture) influence vascular occlusion, which result in sacral integument failure.
Extrapolating from the results of the Yamada et al study,34 the pathophysiology of sacral integument failure is likely multifactorial and a result of external pressure, internal pressure, and comorbid factors on the angiosome microvasculature and the angiosome itself. No single factor causes sacral integument breakdown; when pressure and comorbid factors are present and interact synergistically, integument failure can result. If this is the case, integument breakdown in the sacrum continues to be a risk in health care settings.27
Heel. The heel of the foot is another common site of integument failure. The skin of the foot and ankle are comprised of 6 angiosomes supplied by 3 major arteries, creating significant vascular redundancy within a normally perfused foot.35 In contrast, the plantar heel is comprised of a single angiosome supplied by 2 arteries: the calcaneal branch of the posterior tibial artery and the calcaneal branch of the peroneal artery.36 Similar to the rest of the foot and ankle, perforator crossover is substantial in the heel of the foot.29,33
Other comorbid factors influencing angiosome perfusion, such as chronic hypoxia/reperfusion injury, impaired nutrient supply, growth factor abnormalities, and chronic inflammation, also affect tissue sensitivity to pressure.35 Furthermore, a history of uncontrolled diabetes, which destroys the microvascular circulation, is a confounding factor not easily measured, especially when coupled with loss of major perforators.
Integument failure in the heel is most commonly associated with pressure. Many patients who develop heel pressure ulcers have undiagnosed arterial insufficiency or PAD because there is no way to identify the loss of the lateral peroneal artery branches by physical examination.29,33
In patients with either microvascular disease or gross vascular disease, small dermal breaks eventually develop into chronic wounds and can be exacerbated by factors other than pressure. For example, translocation of bacteria biofilm production with subsequent translocation across the heel stratum corneum promotes further integumentary breakdown and permits bacterial colonization and infection.26 These bacteria compete with living tissue for oxygen, resulting in relative ischemia and leading to integumentary compromise and death of the skin in the heel. Researchers and clinicians are seeking to determine whether this lowers the threshold by which pressure can cause skin breakdown or, in the presence of arterial disease and active offloading, it increases the risk of integumentary comprise due to lack of perfusion.
Risk factors for integument failure
Multiple comorbid or risk factors influence integument breakdown, affecting patients’ quality of life while increasing medical expenses. These risk factors usually overlap between integument failure and pressure injury; therefore, identifying which patients are at high risk for skin breakdown is critical.37 Major risk factors include the following.
Body mass index. Body mass index (BMI) has a complicated effect on pressure injuries in ICU patients. Patients who are underweight (BMI < 19) and those who are morbidly obese (BMI ≥ 40) appear to have an increased risk of pressure injury.38 Yet, obese patients with a BMI between 25 and 40 seem to be protected from pressure injury. Hyun and others38-40 found that, although extremely obese patients had lower Braden scores upon ICU admission (P < .001), they presented with a significantly higher incidence of pressure ulcers (P < .001). The interplay among all of these factors was found to affect the avoidability or unavoidability of integumentary loss, unanticipated results that are likely due to the multifactorial etiology of integument breakdown.
Stress. Choe et al41 recently identified psychological stress as a factor that influences the severity of MASD. Psychological stress increases integumentary production of endogenous glucocorticoids that destabilize skin barrier function.41,42 These study authors also noted marked improvement in skin barrier function following administration of selective serotonin reuptake inhibitors (SSRIs).41 Although stress is an important aspect of patient recovery, few studies are available and more research effort is warranted.
Uncontrolled diabetes mellitus. Uncontrolled diabetes mellitus (DM) often presents with hypertension and associated renal problems. These conditions can lead to calcified blood vessels and microvascular damage, resulting in decreased perfusion of flow through blood vessels to the skin and causing various skin problems and breakdowns, regardless of the types of DM.43 Due to the high prevalence of DM, especially in elderly patients, it should be taken into consideration when evaluating integument failures.
Malnutrition and hydration. Malnutrition and hydration have long been associated with wound development and impaired healing, including pressure ulcers.44,45 Chronic wounds are usually seen among the elderly with comorbidities and, frequently, with malnutrition.46,47 Malnutrition has been suggested to double the risk of developing pressure ulcers.48 Although more research is needed, evaluations of malnutrition in patients at high risk of either skin breakdown or chronic wounds is warranted due to its possible role in integument breakdown.
Assessing for integument failure
Multiple scales have been designed to assess the risk of integument breakdown, including the Braden, Norton, and Risk Assessment Pressure Sore (RAPS) scales.39,49,50 The Braden Scale is one of the most commonly used scales in the United States and is clinically validated with a high capacity to predict skin failure.39,49,51,52 This scale consists of 6 subscales measuring 6 risk factors (Sensory Perception, Moisture, Activity, Mobility, Nutrition, and Friction/Shear).49 A lower Braden score indicates a reduced level of functioning and, therefore, a higher risk for integument failure.53
Although other scales can be utilized to assess the risk of skin breakdown (pressure injury), the Braden Scale is among the risk assessment instruments that are balanced between sensitivity and specificity50 and can be applied to more than pressure injury. More importantly, the Braden Scale is a proxy for many of the comorbidities known to contribute to causes of acute integument failure. Taking comorbidities into account while treating critically ill patients is crucial because they may render a patient’s tissue unable to tolerate even the briefest time of ischemia without negative consequences.