Terminal skin lesions remain an enigma in the world of wound care. They were first described by the French neurologist Dr Jean-Martin Charcot in the 19th century. In 1877, Charcot described a pear-shaped sacral skin ulcer, “decubitis ominosus,” which heralded death and ascribed it to a neurotrophic theory. Over the next century and a half, the etiology of terminal skin lesions has remained a mystery despite advances in medicine, and the incidence has not been well established.

There are many morphologic descriptions of these ulcerations, and experienced clinicians can clinically differentiate these lesions from typical pressure injuries (PIs). However, some ulcerations may be unrecognized, and some terminal skin ulcers may be mistaken for PIs; this, in its turn, may cause hospitals not to receive reimbursement because of perceived deficient preventive skin care.

Several clinical manifestations have been described, including Kennedy terminal ulcerations, “3:30 syndrome” ulcers, and Trombley-Brennan terminal tissue injuries (TB-TTIs).1–4 They have various morphologic skin changes, anatomic sites, and development speeds. Most terminal skin changes occur in the sacral, coccygeal, and gluteal areas; fewer reports have described them on the lower extremities, spine, or ribs.1–4 Some of these lesions do not ulcerate, and some have been seen even in children on vasoactive agents.5 These lesions have been observed both in areas under pressure (eg, sacrum and gluteal areas) and in areas without any external pressure (eg, anterior legs). Some are symmetrical (eg, pear- or butterfly-shaped in sacral and gluteal areas), but unilateral lesions have also been seen (eg, unilateral gluteal lesions as seen in “3:30 syndrome”). Moreover, TB-TTIs on lower extremities are usually linear. Terminal skin lesions also have various degrees of epidermolysis with transient blistering.

Despite the seeming variability among terminal skin lesions, they share more similarities than differences. The two biggest differences between Kennedy terminal ulceration and TB-TTI lesions are the time to death and the additional locations involved in TB-TTIs (Table). The observation that TB-TTIs do not ulcerate likely has to do with the fact that these patients die rapidly; thus, these lesions do not have time to evolve and form ulcerations. The additional locations seen in TB-TTIs may be due to speed and degree of hypotension. Unfortunately, Trombley, Brennan, and colleagues did not provide data on BP measurements prior to the deaths of their patients, so no definitive conclusions can be drawn.3,4

Table. - CHARACTERISTICS OF KTUs AND TB-TTIs Characteristic KTUs TB-TTIs Predominant location Sacrum, buttocks Sacrum, buttocks, legs Shape Butterfly, pear-shaped Butterfly (sacrum), linear (legs) Color Purple Bruise-like Time of onset Sudden Sudden Time to death Days to weeks Hours to days

Abbreviations: KTUs, Kennedy terminal ulcers; TB-TTI, Trombley-Brennan terminal tissue injuries.

It has been observed that terminal ulcerations develop due to hypoperfusion of tissues in the final stages of life and can herald death. However, although everyone develops hypotension before death, not everyone develops terminal skin changes. The laws of nature apply to all; so what is different between these two groups? The authors aimed to explore the cause of terminal skin lesions.

Possible Contributing Factors

Evaluation of patient characteristics did not provide an answer regarding susceptibility to terminal skin lesions. Age, sex, race, and known preexisting medical conditions did not seem to stand out among the described patients with these terminal lesions. Further, Reitz and Schindler5 report the development of a terminal skin lesion in a child, which would argue against a purely atherosclerotic theory of these changes.

These ulcerations have primarily been described in dying and critically ill patients on vasoactive agents. The established constants include death and preexisting hypotension, whether it was treated or not. Hypotension, regardless of etiology, seems to be a common denominator.

In 2021, at the National Pressure Injury Advisory Panel conference “NPIAP Unavoidable Skin Changes at the End of Life—Are They Really Pressure Injuries?” a dermatology team from Miami University presented histopathology slides of patients with terminal skin ulcerations. Apart from nonspecific ischemic changes, no unique features were detected. However, if the pathophysiology of dying is the same and the histopathology is unrevealing, perhaps the anatomy can shed some light on the issue. Is the anatomy different if all humans are built the same? It turns out that it is.

Anatomic Aberrancies

Anatomic aberrancies (embryogenic developmental abnormalities) are common and often go unnoticed. However, they can and do lead to clinical abnormalities. A well-known example is a congenital defect of the pancreas, pancreas divisum, which occurs in approximately 10% of the population and can cause “idiopathic” pancreatitis in a subset of individuals with this congenital malformation. Biliary duct abnormalities have been described as well: Although most individuals have one common bile duct, many have accessory bile ducts. The term “duct of Luschka” describes the most common abnormal accessory bile duct, which is seen in 12% to 50% of individuals.6 It has a very small diameter of 2 mm, and if it is not identified during cholecystectomy, patients may develop postoperative biliary pancreatitis with significant mortality.6 Anatomic aberrancies teach us to be attentive to variations that may have significant clinical implications.

Many arterial aberrancies branch off arteries with smaller diameters than the original arteries.10,11 Based on Poiseuille’s law, blood vessels with smaller diameters originating from unusual anatomic sites produce significant drops in flow rate in the affected areas at times of systemic hypotension. This results in decreased perfusion leading to arterial ischemia, tissue hypoxia with tissue necrosis, and subsequent inflammation.7 Depending on the persistence of the hypotension, these changes may evolve and either improve or worsen.

There is likely an element of reperfusion injury involved in cases of recurrent hypotension.8 Tissue hypoxia results in distinct skin alterations: whitish changes are indicative of ischemic necrosis, and purplish discoloration occurs from accumulation of red blood cells caused by damaged blood vessels (secondary hemorrhagic changes).7 These changes are likely responsible for the typical morphologic skin manifestations seen in people with terminal skin ulcerations. Morphologic skin changes depend on factors such as the degree and duration of systemic hypotension, atherosclerotic blood vessel changes, size of the involved blood vessel branches, external pressure exerted on the vessels, development of collateral arterial supply, and recurrence of hypotension leading to recurrent reperfusion injuries. These are the reasons why not every person with arterial aberrancies at end of life develops terminal skin ulcers and why there may be variability in their clinical presentation.

Anatomic arterial aberrations in the pelvis and lower extremities have primarily been described in the obstetric, orthopedic, and vascular surgical literature when anatomic aberrancies could lead to excessive intraoperative bleeding or ischemia.9 They are also well described in atlases of anatomic aberrancies. Most terminal lesions develop in the sacral or bilateral gluteal areas or lower extremities. Following are the anatomic aberrancies that these authors posit are the likely culprits of terminal skin changes.

EFFECTS OF ANATOMIC ABERRANCIES ON THE DEVELOPMENT OF TERMINAL SKIN LESIONS

The median sacral artery (MSA) and lateral sacral artery (LSA) provide blood supply to the sacrum and coccyx (Figure 1).10,11 The MSA is short, measuring 2 to 4 cm in length, and can be located in the midline or on either side of the body.12,13 According to some studies, it is agenetic in 2.1% of individuals, in which case the sacral area blood supply is dependent on collateral circulation and is likely very susceptible to ischemic insults.10,11 When the MSA is present, it originates from the aorta in 90% of cases; third, fourth (most commonly), or fifth lumbar artery in 6% of cases; and common iliac artery in 4% of cases (Figure 2).10,11 The MSA is a relatively small vessel measuring approximately 2 mm in diameter. In comparison, the infrarenal aorta measures 2 cm in diameter, the lumbar artery measures 3 mm, and the common iliac artery measures 1 cm.10,11,14

Figure 1.:

NORMAL ANATOMY AND SIZES OF PELVIC ARTERIES

Figure 2.:

MSA AND LSA AGENESISMSA agenesis occurs in 2.1% of individuals, and LSA agenesis is seen in 0.3%.Abbreviations: LSA, lateral sacral artery; MSA, median sacral artery.

The LSA originates from the posterior division of the internal iliac artery but is absent in 0.3% of individuals (Figure 1).15 In some cases, the superior or inferior branches of the LSA may be absent or replaced by other arteries. Although the LSA typically originates from internal iliac arteries (approximately 7 mm in diameter), it can also originate from superior or inferior gluteal arteries (1–1.5 mm in diameter; Figure 3).

Figure 3.:

MSA ABERRANCIESTypically, MSA comes off from an aorta in 90% of cases. MSA aberrancies come off from a common iliac artery in 4% and from lumbar arteries in 6% of cases.Abbreviation: MSA, median sacral artery.

Hypothetical Illustration of MSA Blood Flow

In the following section, the authors will provide an example to illustrate the physics of blood flow in the MSA when hypotension is absent. The calculations are general because some variables cannot be calculated (eg, the length and branching of blood vessels, blood viscosity, etc).

According to Hagen-Poiseuille’s flow rate law, the velocity of the steady flow of a fluid through a narrow pipe (such as a blood vessel) is proportional to the radius of the pipe to the fourth power, meaning that a small increase in diameter leads to a much greater flow rate.16 Increased pressure also increases the flow rate. Flow rate is inversely related to the length of the pipe and the coefficient of viscosity, meaning that longer pipes and more viscous fluids will have slower flow rates. Thus, decreasing the pressure gradient will decrease blood flow, leading to tissue hypoperfusion and resulting in ischemia. Blood flow occurs at the level of blood vessels (arteries and veins), and perfusion occurs at the level of the capillary bed. Blood flow is not the same as perfusion because insufficient blood flow will not allow tissue perfusion.17

The Hagen-Poiseuille equation for fluid flow in a pipe says:16

∆p=8μLQπR4

where ∆p is the pressure difference between the two ends, L is the length of pipe, μ is the dynamic viscosity, Q is the volumetric flow rate, and R is the pipe radius. As shown in Figure 4, the pressure difference between the two ends is calculated as ∆p = p1 − p2. That is why fluid flows from left to right with flow rate of Q.16

Figure 4.:

BLOOD FLOW ( Q ) IN THE PIPE IS DEPENDENT ON THE PRESSURE DIFFERENCE ( p 1- p 2)

If blood flows from a wider vessel to a narrower vessel, a pressure gradient will be defined as pressure drop per unit length:16

Pressure gradient≡∆pL=8μQπR4

The pressure gradient changes by 1R4 when μ (viscosity) and Q (flow rate) do not change. Out of three variables—pipe radius, pipe length, and fluid viscosity—pipe radius is the most critical element of blood flow. According to Poiseuille’s law for resistance, the resistance to the blood flow in the vessel can be calculated as:

R∝ƞLr4

where R (vessel resistance) is directly proportionate to the length (L) of the vessel and the viscosity (ƞ) and inversely proportional to radius to the fourth power (r4). If the length of the blood vessel doubles, it will double the resistance to flow. If the fluid viscosity doubles, it will double the resistance. However, if vessel diameter doubles, it will decrease flow resistance by 16-fold.

Below are examples of pressure gradient changes if blood flows from a usual, wider vessel (eg, infrarenal aorta) versus from a narrower aberrant vessel (eg, common iliac artery or a lumbar artery) to the MSA.

 (1) 2 cm (diameter of the infrarenal aorta) to 0.2 cm (diameter of the MSA): Pressure gradient increases 10,000 times.  (2) 1 cm (diameter of the common iliac artery) to 0.2 cm (diameter of the MSA): Pressure gradient increases 625 times.  (3) 0.3 cm (diameter of the lumbar artery) to 0.2 cm (diameter of the MSA): Pressure gradient increases approximately 5 times.

Whereas the aorta and common iliac arteries are elastic, the lumbar artery and MSA are muscular.18 Elastic arteries have more elastic fibers in the tunica media and constrict little.18 They are located by the heart and pulmonary arteries, and their elasticity enables them to maintain a constant pressure gradient. In contrast, muscular arteries contain more smooth cells in the tunica media and can constrict.18 When hypotension develops, muscular arteries clamp down and constrict, whereas elastic arteries do not change significantly. Hypotension will cause a further significant increase in the pressure gradient between elastic and muscular arteries and only a modest increase between two muscular arteries.

Reviewing the flow gradients, flow is highest if the MSA originates from its typical location (ie, aorta). Flow rate decreases significantly if it originates from the narrower lumbar or common iliac artery. Blood flow depends on the pressure gradient, and it decreases if the pressure gradient drops. It is evident that if the MSA is congenitally absent (as in 2.1% of individuals) or if it originates from the lumbar artery (6% of individuals), blood flow is significantly decreased, even in normotensive conditions. Based on the above calculations, the pressure gradient is approximately 2,000 times lower if the MSA originates from the aberrant lumbar artery than when it originates from the infrarenal aorta. Hypotension causes constriction of smaller arteries and affects the pressure gradient even more. Development of systemic hypotension will doubtless worsen perfusion of the sacrum, and ischemia will likely lead to terminal skin changes if collaterals cannot compensate.

LSA and Superior Gluteal Artery

It is likely that the LSA and superior gluteal artery are also involved in the formation of terminal skin lesions because they are all interconnected and create a circulatory network. Collaterals of the LSA include the spinal artery, MSA, and inferior and superior gluteal arteries.14 Collaterals of the superior gluteal artery include the LSA, deep circumflex iliac, lateral circumflex femoral, and inferior gluteal arteries.14

Like the LSA, the superior gluteal artery also originates from the internal iliac artery.14 Typically, it splits from the internal iliac artery as a solitary branch. The superior and inferior gluteal arteries arise from the internal iliac artery as a common trunk in 23.1% of individuals.14 In 7% of cases, four arteries—the superior gluteal, inferior gluteal, obturator, and internal pudendal arteries—share the same trunk.14 In this case, the flow gradient would be decreased in all four arteries by 25% at the time of hypotension because they share the same trunk.

Persistent Sciatic Artery

Terminal injuries on the lower extremities may result from a persistent sciatic artery. The sciatic artery is a continuation of the internal iliac artery and provides the initial blood supply to the developing lower limb of the fetus.14 It normally regresses by the third month of embryonic development when the superficial femoral artery is formed.14 A lack of regression leads to a persistent sciatic artery that is often accompanied by an underdeveloped femoral arterial system.14 There are six anatomic variants of the persistent sciatic artery that may explain variability of manifestations of terminal skin lesions on the lower extremities.14 A persistent sciatic artery may be asymptomatic or associated with acute or chronic limb ischemia, limb claudication, and so forth.9 The estimated incidence of discovering a persistent sciatic artery on angiogram is 0.025% to 0.6%.14 Persistent sciatic artery is most often unilateral, although bilateral persistence occurs with an estimated incidence of up to 32%.9,14

Collateral Circulation

One cannot underestimate the significance of collaterals: Developed collateral circulation likely helps limit the prevalence of terminal skin lesions. A study by Clark et al19 involving 19 women who underwent bilateral internal iliac artery ligation to control obstetric hemorrhage illustrates the importance of collateral arterial circulation. Despite ligation of the afferent arteries, bleeding was fully controlled in only 42% of patients and continued in the remaining 58% of patients because of collaterals.19 Further, newborns with agenesis of the MSA or LSA do not manifest any necrotic skin changes at birth because of established compensatory collateral blood flow. Collateral arterial supply is likely a saving grace in many cases of arterial aberrancies. Because anatomic arterial aberrancies are defects of embryogenic development, several anatomic vascular malformations may coexist.

Arterial aberrancies leading to terminal skin lesions may also mimic or contribute to PIs appearing at the time of profound hypotension. However, the theory of arterial aberrancies differs from the angiosomal hypothesis of vascular occlusions proposed by some authors.20 Vascular territories supplied by a blood vessel (angiosomes) were developed based on typical artery locations and do not consider arterial aberrancies. There are 40 angiosomes in the body.20 However, a clear predilection exists for terminal skin lesions to occur in a few specific locations (eg, sacrococcygeal and gluteal area, lower legs), and the angiosomal hypothesis does not explain why terminal lesions occur in certain anatomic locations. It also stipulates that vascular occlusion of the blood vessel supplying the affected vascular territory is the mechanism of injury.20 Instead, the authors believe terminal lesions arise because decreased blood flow exposes previously compensated arterial aberrancies at the time of hypotension.

CONCLUSIONS

This analysis posits that anatomic arterial aberrancies of the affected vessels may be responsible for terminal skin lesions. External pressure certainly plays some role in contributing to terminal skin lesions located in the pressure areas. However, the amount of exerted pressure may not be sufficient to cause a PI, and terminal skin lesions may not form without the underlying anatomic arterial aberrancy. Arterial aberrancies may also mimic or contribute to PIs resulting from significant hypotension among individuals who survive hypotensive episodes.

In the same way that Mendeleev predicted gallium, germanium, and scandium and identified their characteristics in “Mendeleev’s Periodic Table” before their discovery, the authors delineate anatomic aberrancies leading to terminal skin lesions and suggest the modalities (antemortem abdominal computed tomography angiography with lower-extremity runoff, or postmortem evaluation of aberrant blood vessels) to confirm this hypothesis. The authors request that the wound care community collaborate in confirming or disputing this hypothesis.

REFERENCES 1. Latimer S, Shaw J, Hunt T, Mackrell K, Gillespie BM. Kennedy terminal ulcers: a scoping review. J Hosp Palliat Nurs 2019;21(4):257–63. 2. Roca-Biosca A, Rubio-Rico L, De Molina-Fernández MI, Martinez-Castillo JF, Pancorbo-Hidalgo PL, García-Fernández FP. Kennedy terminal ulcer and other skin wounds at the end of life: an integrative review. J Tissue Viability 2021;30(2):178–82. 3. Brennan MR, Thomas L, Kline M. Prelude to death or practice failure? Trombley-Brennan terminal tissue injury update. Am J Hosp Palliat Care 2019;36(11):1016–9. 4. Trombley K, Brennan MR, Thomas L, Kline M. Prelude to death or practice failure? Trombley-Brennan terminal tissue injuries. Am J Hosp Palliat Care 2012;29(7):541–5. 5. Reitz M, Schindler CA. Pediatric Kennedy terminal ulcer. J Pediatr Health Care 2016;30(3):274–8. 6. Oulad Amar A, Kora C, Jabi R, Kamaoui I. The Duct of Luschka: an anatomical variant of the biliary tree—two case reports and a review of the literature. Cureus 2021 25;13(4):e14681. 7. Goljan EF. Cell injury. In: Rapid Review Pathology. 4th ed. Philadelphia, PA: Elsevier; 2014:8–36. 8. Kumar V, Abbas AK, Aster JC. Cell injury, cell death, and adaptations. In: Robbins & Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier; 2020:33–71. 9. Shehzad KN, Monib S, Mensa M, Halawa MO. Bilateral persistent sciatic arteries complicated by unilateral acute lower limb ischaemia. J Surg Case Rep 2019;2019(4):rjz119. 10. Turnstall R. Internal iliac arteries. In: Tubbs RS, Shoja MM, Loukas M, eds. Bergman’s Comprehensive Encyclopedia of Human Anatomic Variation. Hoboken, NJ: John Wiley & Sons, Inc; 2016:694–740. 11. Sahni D, Aggarwal A, Gupta T, et al. Abdominal aorta. In: Tubbs RS, Shoja MM, Loukas M, eds. Bergman’s Comprehensive Encyclopedia of Human Anatomic Variation. Hoboken, NJ: John Wiley & Sons, Inc; 2016:619–81. 12. Güvençer M, Dalbayrak S, Tayefi H, et al. Surgical anatomy of the presacral area. Surg Radiol Anat 2009;31(4):251–7. 13. Singhatanadgige W, Kang DG, Wiranuwat D, Tanavalee C, Yingsakmongkol W, Limthongkul W. Awareness of middle sacral artery pathway: a cadaveric study of the presacral area. J Orthop Surg (Hong Kong) 2018;26(1):2309499017754094. 14. Patel A. Lower limb arteries. In: Tubbs RS, Shoja MM, Loukas M, eds. Bergman’s Comprehensive Encyclopedia of Human Anatomic Variation. Hoboken, NJ: John Wiley & Sons, Inc; 2016:741–51. 15. Al Talalwah W, Al Dorazi SA, Soames R. Variation of the lateral sacral artery in relation to sciatic neuropathy. Adv Anat 2014;2014:259654. 16. Ostadfar A. Fluid mechanics and biofluids principles. In: Biofluid Mechanics. Principles and Application. Cambridge, MA: Academic Press; 2016:1–60. 17. Plourde G, Briard JN, Shemie SD, Shankar JJS, Chassé M. Flow is not perfusion, and perfusion is not function: ancillary testing for the diagnosis of brain death. Can J Anaesth 2021;68(7):953–61. 18. Mescher AL. The circulatory system. In: Junqueira’s Basic Histology. Text & Atlas. 16th ed. New York, NY: McGraw Hill; 2013:215–35. 19. Clark SL, Phelan JP, Yeh SY, Bruce SR, Paul RH. Hypogastric artery ligation for obstetric hemorrhage. Obstet Gynecol 1985;66(3):353–6. 20. Yap TL, Alderden J, Lewis M, Taylor K, Fife CE. Angiosomal vascular occlusions, deep-tissue pressure injuries, and competing theories: a case report. Adv Skin Wound Care 2021;34(3):157–64.