- Email: [email protected]
Deep Tissue Injury: How Deep is Our Understanding?
1410
COMMENTARY
Deep Tissue Injury: How Deep is Our Understanding? Anke Stekelenburg, PhD, Debby Gawlitta, PhD, Dan L. Bader, PhD, Cees W. Oomens, PhD ABSTRACT. Stekelenburg A, Gawlitta D, Bader DL, Oomens CW. Deep tissue injury: how deep is our understanding? Arch Phys Med Rehabil 2008;89:1410-3. Deep pressure ulcers, necessarily involving deep tissue injury (DTI), arise in the muscle layers adjacent to bony prominences because of sustained loading. They represent a serious type of pressure ulcer because they start in underlying tissues and are often not visible until they reach an advanced stage, at which time treatment becomes problematic. Underlying mechanisms of DTI require further investigation if appropriate preventive measures are to be determined. The present commentary illustrates a hierarchic research approach selected to study these mechanisms. To differentiate between the individual roles of deformation and ischemia in the onset of skeletal muscle damage, 2 complementary approaches have been selected. In an in vivo animal model, the effects of ischemia combined with deformation and ischemia per se were studied. An in vitro muscle model was used to study the separate effects of deformation and several aspects of ischemia, including hypoxia, glucose depletion, and tissue acidification, in more detail. Based on the results of both models a sequence of events leading to cell necrosis is proposed. Deformation levels exceeding a threshold value can result in rapid tissue damage that may persist, whereas ischemia has a more gradual effect as a result of glucose depletion and tissue acidification. Key Words: Pressure ulcer; Rehabilitation. © 2008 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HERE HAS BEEN MUCH recent focus on deep pressure ulcers, necessarily involving DTI, defined by the U.S. T National Pressure Ulcer Advisory Panel as “a pressure-related
injury to subcutaneous tissues under intact skin.”1,2 Indeed, the causation of DTI remains a topic for debate, as does how it should be classified as a pressure ulcer and how it can be incorporated in the current staging system.2,3 Nonetheless, all agree that the underlying mechanisms of DTI require further investigation if appropriate preventive measures are to be determined. What is evident is that not all DTIs progress to full-thickness defects. Thus, if early detection methods are developed, ischemic and injured tissues may be salvageable with strategies involving unloading and gradual reperfusion. Traditional theories on the mechanisms of pressure ulcer formation have implicated localized ischemia as the primary
From the Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (Stekelenburg, Gawlitta, Bader, Oomens); and the Department of Engineering and IRC in Biomedical Materials, Queen Mary, University of London, UK (Bader). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Anke Stekelenburg, PhD, Dept of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, Den Dolech 2, Eindhoven, 5600 MB, The Netherlands, e-mail: [email protected]. 0003-9993/08/8907-00723$34.00/0 doi:10.1016/j.apmr.2008.01.012
Arch Phys Med Rehabil Vol 89, July 2008
cause of the onset of damage.4-7 However, there has been recent interest in alternative mechanisms, implicating the roles of ischemia-reperfusion injury,8-10 impaired interstitial fluid flow and lymphatic drainage,11-14 and sustained deformation of cells.15-17 To study the underlying mechanisms, a hierarchic approach has been proposed.18,19 This involves examining the effects of loading, using a range of complementary model systems with increasing complexity and length scales, each incorporating 1 or more functional tissue units. Such an approach would inevitably benefit from the introduction of new technologies associated with cell engineering—namely, fluorescent probes and confocal microscopy—and noninvasive imaging techniques, such as MRI or vital microscopy. The results of this approach are described in the present commentary and are discussed in the context of DTI. THE ROLE OF DEFORMATION AND ISCHEMIA It is well established that ischemia can play a role in pressure ulcer development, although there is substantial evidence that other damaging factors are involved. It has been shown in several animal studies20-22 that muscle appears tolerant to ischemia for up to 4 hours. It is important to note that in a clinical setting, this threshold period will probably be reduced because of other aggravating factors. However, tissues that experience compression can initiate tissue breakdown within this time threshold for ischemia. Therefore, in clinical practice, pressure ulcers can develop as a result of exposure to compression for shorter time periods.23,24 This is particularly the case when the magnitude of tissue deformation is higher than normal, as predicted by the classic inverse relationship between pressure and time in the initiation of tissue damage.25 Such a situation arises when a patient is supported for extended periods on hard surfaces, such as emergency stretchers, x-ray couches, or operation tables.26 The resulting excess compression of soft tissues can lead to both a collapse of the blood vessels and high cell deformation within the tissue. The latter has been shown to result in the onset of tissue damage.17,27,28 Such observations have stimulated research on both individual and combined effects of deformation and ischemia on compression-induced tissue damage. To differentiate between the individual roles of deformation and ischemia in the onset of skeletal muscle damage, 2 complementary approaches have been selected. In an in vivo model, the effects of ischemia per se and combined with deformation on the tibialis anterior of rats were examined.29 Alternatively, the use of a well-developed in vitro muscle model28,30 has enabled the examination of the effects of cell deformation in the absence of blood vessels. In this model, partial ischemia was simulated in a number of ways. For example, the role of glucose depletion was investigated, but hypoxia (lack of oxygen) and tissue acidification also were simulated.30
List of Abbreviations DTI MRI
deep tissue injury magnetic resonance imaging
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
The in vivo animal study, using MRI to estimate tissue damage, showed that compressive loading of the tibialis anterior for 2 hours led to irreversible damage to the muscle tissue. In contrast, ischemic loading resulted in reversible tissue changes,29,31 characterized by features such as swelling, disruption of small membranes, and intercellular damage, each recoverable within hours after unloading. Persistent or irreversible damage, however, indicates gross necrosis of the tissue. The areas of damage development observed in the in vivo study corresponded well with the regions displaying high shear strains during loading.29 This implied that large deformation, in conjunction with ischemia, provided the main trigger for early irreversible muscle damage. In the in vitro murine muscle model, different aspects of ischemia were studied. It should be recognized that the time scale of events found in this tissue-engineered model will certainly differ from that in a clinical setting. However, the processes that take place during ischemia, including hypoxia, glucose depletion, and tissue acidification, are comparable in both in vivo and in vitro situations. In the first series28 of the in vitro experiments it was shown that in the presence of hypoxia alone, cell viability was maintained well above 70% for a 22-hour period. By contrast, the effect of cell deformation alone was evident within an hour, and cell death was progressively enhanced— up to 60% for large deformations— over the 22-hour period. During an extended study, it became evident that hypoxia induced anaerobic metabolism of the muscle cells within 22 hours. This resulted in a production of lactic acid which, because of its limited removal in the simulated state of ischemia, accumulated in the muscle model. The muscle cells appeared to tolerate lactic acid levels up to 23mmol/L, above which their viability was compromised. These findings suggest not only a very early role of cellular deformation in damage development but also an important role for tissue acidification after oxygen deprivation. In addition, the study30 showed that the muscle cells were not able to tolerate glucose deprivation for periods exceeding 24 hours. Based on the results of the in vitro and in vivo studies, a sequence of events leading to cell necrosis is proposed (fig 1). After tissue compression, mechanical properties and local geometry determine the local effects inside the tissues as a result of external loading. These factors, in conjunction with the
1411
magnitude and period of compression, determine the degree of occlusion of the viscoelastic blood vessels. After vessel collapse, the tissue suffers from ischemia. The subsequent state of hypoxia, with associated oxygen deprivation, causes the cells of the vascularized tissues to change their metabolism to an anaerobic pathway. By eliminating the oxygen requirement for their energy production, the cells deplete their glucose deposits and produce an accumulation of lactic acid. A state of hypoxia will, in addition, down-regulate the metabolic demands by a phenomenon called oxygen conformance.32,33 This delays glucose depletion and acid accumulation, both of which can result in cellular death (here referred to as necrosis), possibly preceded by apoptosis, a process causing programmed cell death. If the increasing concentrations of lactic acid remain below a toxic threshold, which was 23mmol/L in our muscle model, the associated metabolism will be down-regulated. Combining the findings of both in vivo and in vitro studies, a series of external pressure–time curves can be proposed (fig 2). The classic form based on the original data of Reswick and Rogers25 is shown as a dashed line in each figure. To this has been added a solid line representing the relationship caused by ischemia alone (see fig 2B). The low risk of tissue damage at the left-hand side of time-point i indicates tissue tolerance to an ischemic insult for this time period. In addition, for external pressures less than ii no blood vessels will collapse, and hence no ischemia will occur. Figure 2C indicates a combination of ischemia, deformation, and other factors. The very high external pressures indicated by point iii will result in structural cell damage and form an initial plateau in the curve. Beyond this, the curve follows the combined effects of deformation and ischemia (point iv). At point v, equilibrium is attained, such that regardless of the time period, the low external pressures will not result in tissue damage. Experimental evidence for these adjustments to the classic curve has been provided by recent studies involving single muscle cells34 and in vivo animal models in which high loads were applied for short periods.35 Considering the importance of local tissue deformation in damage development the curves in figure 3 are proposed, for which the amount of damage as a function of time and strain is indicated. Damage is classified here as both reversible and
Fig 1. Proposed sequence of events during tissue compression. The mechanical properties of the compressed tissues and the geometry will determine the amount of deformation and ischemia experienced. The deformation will start damaging the tissue once Tdef1, the lower deformation threshold, is exceeded. The tissue’s cells will start programmed cell death, called apoptosis, eventually resulting in finalized cell death, called (cellular) necrosis. Once the deformation exceeds (Tdef2), the cells will immediately die from necrosis. The induced ischemia will cause the supplies of oxygen and glucose to decrease. The oxygen deprivation will slow down metabolic processes and shift them toward anaerobic metabolism, causing increased lactate production. When the lactate concentration exceeds Tlac or glucose levels fall below Tglu, cell death will be induced, possibly through apoptosis.
Arch Phys Med Rehabil Vol 89, July 2008
1412
A
Low risk
ii Time
B
High risk
Low risk Time
i
External pressure
High risk
External pressure
External pressure
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
C
iii iv
High risk
v
Low risk Time
Fig 2. Proposed modifications to the original curve of Reswick and Rogers.25 (A) The original Reswick and Rogers curve with high- and low-risk regions for pressure damage. (B) A graph (solid line) is imposed, representing the damage threshold resulting from ischemia. Before time point i, ischemia will not lead to damage, and below pressure at point ii, blood vessels will not be sufficiently collapsed to cause ischemia. (C) The proposed risk curve due to deformation, ischemia, and other factors. Above external pressure point iii, all time spans will lead to damage. At point iv, the curve follows the Reswick and Rogers curve, and at point v the curve plateaus because at pressures lower than this, no damage will occur.
persistent damage, as defined earlier in the commentary. Figure 3 shows that the threshold for persistent damage depends on both time and strain. It should be noted that the very high deformations that can occur—for example, on hard support surfaces—require a very short period of time to cause persistent damage. DISCUSSION Although pressure ulcers are relatively uncommon in healthy subjects,36 they can result from excessive loading and/or sustained immobilization. Such extreme conditions are indicated in figure 2C. However, they can be prevented by additional cushioning of hard surfaces or minimizing the loading time of tissues by turning regimens or other pressure-relief strategies. By contrast, in unhealthy subjects different combinations of compromising factors can become important. These include malnutrition, age, certain physical conditions, medication, and dehydration. Each factor may affect the mechanical properties and/or geometry of tissues and also influence the tissue tolerance thresholds for deformation or lactate accumulation. In addition, circulatory disturbances and immobility affect tissue oxygenation and sustenance. The aforementioned factors represent just a fraction of those occurring in the general patient population. In addition, combinations of these factors may act synergistically to aggravate the extent and onset of the damage.
Fig 3. Development of reversible and persistent damage as a function of time and strain.
Arch Phys Med Rehabil Vol 89, July 2008
The current use of risk assessment scores account for only some of these factors, and this may limit their overall sensitivity and specificity for the occurrence of pressure ulcers. As an example, people with spinal cord injury have a wellestablished increased risk for the development of DTI. Considering the scheme in figure 1, both larger deformations due to atrophy and/or flaccidity of muscles and reduced perfusion are commonly found in the musculature of their load-bearing tissues.37,38 In addition, because of their immobilization, the loading period is increased compared with healthy subjects, the effect of which is indicated in figures 2 and 3. Additional conditions, such as fever or inflammation, can further increase their risk of DTI development. A temperature rise can, for example, increase the rate of metabolic processes which, in turn, will accelerate oxygen depletion and lactate accumulation (see fig 1). In summary, 2 hours of ischemia applied to the tibialis anterior muscle of rats resulted in reversible tissue changes. In contrast, when deformation was added to the loading protocol, irreversible damage, consisting of gross necrosis of the tissue, was found. A threshold level is proposed above which deformation results almost instantly in tissue damage. Currently, numeric models are being developed to predict those threshold values. Ischemia has a more gradual effect on muscle tissue because of the inherent ability of cells to compensate for short-term ischemia. Glucose depletion and tissue acidification play important roles in tissue damage due to ischemia. Although the roles of deformation and ischemia were highlighted in the present commentary, the importance of other factors contributing to damage development in compressed tissues should also be considered. Examples include the effects of compression on lymphatic flow and the diffusion of particularly large molecules inside loaded tissues. This latter issue is currently under investigation in our laboratory. CONCLUSIONS It is evident that the understanding of DTI is significantly deepened by fundamental studies applying the latest noninvasive research technologies. The next challenge will be to develop objective early detection methods to estimate the risks associated with internal local deformations and time, in combination with intrinsic patient-specific factors. This method may combine assessment of physical parameters and biomarkers derived from blood, urine, or the skin indicating the early development of deep tissue injury.
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
References 1. Donnelly J; National Pressure Ulcer Advisory Panel. Should we include deep tissue injury in pressure ulcer staging systems? The NPUAP debate. J Wound Care 2005;14:207-10. 2. Black J, Baharestani M, Cuddigan J, et al. National Pressure Ulcer Advisory Panel’s updated pressure ulcer staging system. Urol Nurs 2007;27:144-50, 156. 3. Ankrom MA, Bennett RG, Sprigle S, et al. Pressure-related deep tissue injury under intact skin and the current pressure ulcer staging systems. Adv Skin Wound Care 2005;18:35-42. 4. Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehabil 1959;40:62-9. 5. Dinsdale SM. Decubitus ulcers: role of pressure and friction in causation. Arch Phys Med Rehabil 1974;55:147-52. 6. Daniel RK, Priest DL, Wheatley DC. Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehabil 1981;62: 492-8. 7. Peirce SM, Skalak TC, Rodeheaver GT. Ischemia-reperfusion injury in chronic pressure ulcer formation: a skin model in the rat. Wound Repair Regen 2000;8:68-76. 8. Ytrehus K, Reikeras O, Huseby N, Myklebust R. Ultrastructure of reperfused skeletal muscle: the effect of oxygen radical scavenger enzymes. Int J Microcirc Clin Exp 1995;15:155-62. 9. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002; 10:620-30. 10. Tsuji S, Ichioka S, Sekiya N, Nakatsuka T. Analysis of ischemiareperfusion injury in a microcirculatory model of pressure ulcers. Wound Repair Regen 2005;13:209-15. 11. Krouskop TA, Reddy NP, Spencer WA, Secor JW. Mechanisms of decubitus ulcer formation—an hypothesis. Med Hypotheses 1978;4:37-9. 12. Miller GE, Seale J. Lymphatic clearance during compressive loading. Lymphology 1981;14:161-6. 13. Reddy NP, Cochran GV. Interstitial fluid flow as a factor in decubitus ulcer formation. J Biomech 1981;14:879-81. 14. Braden B, Bergstrom N. A conceptual schema for the study of the etiology of pressure sores. Rehabil Nurs 1987;12:8-12. 15. Landsman AS, Meaney DF, Cargill RS 2nd, Macarak EJ, Thibault LE. 1995 William J. Stickel Gold Award. High strain rate tissue deformation. A theory on the mechanical etiology of diabetic foot ulcerations. J Am Podiatr Med Assoc 1995;85:519-27. 16. Bouten CV, Knight MM, Lee DA, Bader DL. Compressive deformation and damage of muscle cell subpopulations in a model system. Ann Biomed Eng 2001;29:153-63. 17. Wang YN, Bouten CV, Lee DA, Bader DL. Compression-induced damage in a muscle cell model in vitro. Proc Inst Mech Eng [H] 2005;219:1-12. 18. Bouten CV, Breuls RG, Peeters EA, Oomens CW, Baaijens FP. In vitro models to study compressive strain-induced muscle cell damage. Biorheology 2003;40:383-8. 19. Bouten CV, Oomens CW, Baaijens FP, Bader DL. The etiology of pressure ulcers: skin deep or muscle bound? Arch Phys Med Rehabil 2003;84:616-9. 20. Labbe R, Lindsay T, Walker PM. The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia. J Vasc Surg 1987;6:152-7.
1413
21. Belkin M, Brown RD, Wright JG, LaMorte WW, Hobson RW 2nd. A new quantitative spectrophotometric assay of ischemiareperfusion injury in skeletal muscle. Am J Surg 1988;156:83-6. 22. Strock PE, Majno G. Microvascular changes in acutely ischemic rat muscle. Surg Gynecol Obstet 1969;129:1213-24. 23. Aronovitch SA. Intraoperatively acquired pressure ulcer prevalence: a national study. J Wound Ostomy Continence Nurs 1999; 26:130-6. 24. Bliss M, Simini B. When are the seeds of postoperative pressure sores sown? Often during surgery. BMJ 1999;319:863-4. 25. Reswick JB, Rogers JE. Experience at Rancho Los Amigos hospital with devices and techniques to prevent pressure sores. In: Kenedi RM, Cowden JM, editors. Bedsore biomechanics. London: Macmillan Pr; 1976. p 301-10. 26. Bader DL, White SH. The viability of soft tissues in elderly subjects undergoing hip surgery. Age Ageing 1998;27:217-21. 27. Breuls RG, Bouten CV, Oomens CW, Bader DL, Baaijens FP. Compression induced cell damage in engineered muscle tissue: an in vitro model to study pressure ulcer aetiology. Ann Biomed Eng 2003;31:1357-64. 28. Gawlitta D, Li W, Oomens CW, Baaijens FP, Bader DL, Bouten CV. The relative contributions of compression and hypoxia to development of muscle tissue damage: an in vitro study. Ann Biomed Eng 2007;35:273-84. 29. Stekelenburg A, Strijkers GJ, Parusel H, Bader DL, Nicolay K, Oomens CW. Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model. J Appl Physiol 2007;102:2002-11. 30. Gawlitta D, Oomens CW, Bader DL, Baaijens FP, Bouten CV. Temporal differences in the influence of ischemic factors and deformation on the metabolism of engineered skeletal muscle. J Appl Physiol 2007;103:464-73. 31. Stekelenburg A, Oomens CW, Strijkers GJ, Nicolay K, Bader DL. Compression-induced deep tissue injury examined with magnetic resonance imaging and histology. J Appl Physiol 2006;100:1946-54. 32. Arthur PG, Giles JJ, Wakeford CM. Protein synthesis during oxygen conformance and severe hypoxia in the mouse muscle cell line C2C12. Biochim Biophys Acta 2000;1475:83-9. 33. Boutilier RG. Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol 2001;204:3171-81. 34. Peeters EA, Oomens CW, Bouten CV, Bader DL, Baaijens FP. Mechanical and failure properties of single attached cells under compression. J Biomech 2005;38:1685-93. 35. Linder-Ganz E, Engelberg S, Scheinowitz M, Gefen A. Pressuretime cell death threshold for albino rat skeletal muscles as related to pressure sore biomechanics. J Biomech 2006;39:2725-32. 36. Bliss MR. Pressure injuries: causes and prevention. Hosp Med 1998;59:841-4. 37. Scelsi R. Skeletal muscle pathology after spinal cord injury: our 20 year experience and results on skeletal muscle changes in paraplegics, related to functional rehabilitation. Basic Appl Myol 2001;11:75-85. 38. Castro MJ, Apple DF Jr, Staron RS, Campos GE, Dudley GA. Influence of complete spinal cord injury on skeletal muscle within 6 mo of injury. J Appl Physiol 1999;86:350-8.
Arch Phys Med Rehabil Vol 89, July 2008
COMMENTARY
Deep Tissue Injury: How Deep is Our Understanding? Anke Stekelenburg, PhD, Debby Gawlitta, PhD, Dan L. Bader, PhD, Cees W. Oomens, PhD ABSTRACT. Stekelenburg A, Gawlitta D, Bader DL, Oomens CW. Deep tissue injury: how deep is our understanding? Arch Phys Med Rehabil 2008;89:1410-3. Deep pressure ulcers, necessarily involving deep tissue injury (DTI), arise in the muscle layers adjacent to bony prominences because of sustained loading. They represent a serious type of pressure ulcer because they start in underlying tissues and are often not visible until they reach an advanced stage, at which time treatment becomes problematic. Underlying mechanisms of DTI require further investigation if appropriate preventive measures are to be determined. The present commentary illustrates a hierarchic research approach selected to study these mechanisms. To differentiate between the individual roles of deformation and ischemia in the onset of skeletal muscle damage, 2 complementary approaches have been selected. In an in vivo animal model, the effects of ischemia combined with deformation and ischemia per se were studied. An in vitro muscle model was used to study the separate effects of deformation and several aspects of ischemia, including hypoxia, glucose depletion, and tissue acidification, in more detail. Based on the results of both models a sequence of events leading to cell necrosis is proposed. Deformation levels exceeding a threshold value can result in rapid tissue damage that may persist, whereas ischemia has a more gradual effect as a result of glucose depletion and tissue acidification. Key Words: Pressure ulcer; Rehabilitation. © 2008 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation HERE HAS BEEN MUCH recent focus on deep pressure ulcers, necessarily involving DTI, defined by the U.S. T National Pressure Ulcer Advisory Panel as “a pressure-related
injury to subcutaneous tissues under intact skin.”1,2 Indeed, the causation of DTI remains a topic for debate, as does how it should be classified as a pressure ulcer and how it can be incorporated in the current staging system.2,3 Nonetheless, all agree that the underlying mechanisms of DTI require further investigation if appropriate preventive measures are to be determined. What is evident is that not all DTIs progress to full-thickness defects. Thus, if early detection methods are developed, ischemic and injured tissues may be salvageable with strategies involving unloading and gradual reperfusion. Traditional theories on the mechanisms of pressure ulcer formation have implicated localized ischemia as the primary
From the Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (Stekelenburg, Gawlitta, Bader, Oomens); and the Department of Engineering and IRC in Biomedical Materials, Queen Mary, University of London, UK (Bader). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Anke Stekelenburg, PhD, Dept of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, Den Dolech 2, Eindhoven, 5600 MB, The Netherlands, e-mail: [email protected]. 0003-9993/08/8907-00723$34.00/0 doi:10.1016/j.apmr.2008.01.012
Arch Phys Med Rehabil Vol 89, July 2008
cause of the onset of damage.4-7 However, there has been recent interest in alternative mechanisms, implicating the roles of ischemia-reperfusion injury,8-10 impaired interstitial fluid flow and lymphatic drainage,11-14 and sustained deformation of cells.15-17 To study the underlying mechanisms, a hierarchic approach has been proposed.18,19 This involves examining the effects of loading, using a range of complementary model systems with increasing complexity and length scales, each incorporating 1 or more functional tissue units. Such an approach would inevitably benefit from the introduction of new technologies associated with cell engineering—namely, fluorescent probes and confocal microscopy—and noninvasive imaging techniques, such as MRI or vital microscopy. The results of this approach are described in the present commentary and are discussed in the context of DTI. THE ROLE OF DEFORMATION AND ISCHEMIA It is well established that ischemia can play a role in pressure ulcer development, although there is substantial evidence that other damaging factors are involved. It has been shown in several animal studies20-22 that muscle appears tolerant to ischemia for up to 4 hours. It is important to note that in a clinical setting, this threshold period will probably be reduced because of other aggravating factors. However, tissues that experience compression can initiate tissue breakdown within this time threshold for ischemia. Therefore, in clinical practice, pressure ulcers can develop as a result of exposure to compression for shorter time periods.23,24 This is particularly the case when the magnitude of tissue deformation is higher than normal, as predicted by the classic inverse relationship between pressure and time in the initiation of tissue damage.25 Such a situation arises when a patient is supported for extended periods on hard surfaces, such as emergency stretchers, x-ray couches, or operation tables.26 The resulting excess compression of soft tissues can lead to both a collapse of the blood vessels and high cell deformation within the tissue. The latter has been shown to result in the onset of tissue damage.17,27,28 Such observations have stimulated research on both individual and combined effects of deformation and ischemia on compression-induced tissue damage. To differentiate between the individual roles of deformation and ischemia in the onset of skeletal muscle damage, 2 complementary approaches have been selected. In an in vivo model, the effects of ischemia per se and combined with deformation on the tibialis anterior of rats were examined.29 Alternatively, the use of a well-developed in vitro muscle model28,30 has enabled the examination of the effects of cell deformation in the absence of blood vessels. In this model, partial ischemia was simulated in a number of ways. For example, the role of glucose depletion was investigated, but hypoxia (lack of oxygen) and tissue acidification also were simulated.30
List of Abbreviations DTI MRI
deep tissue injury magnetic resonance imaging
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
The in vivo animal study, using MRI to estimate tissue damage, showed that compressive loading of the tibialis anterior for 2 hours led to irreversible damage to the muscle tissue. In contrast, ischemic loading resulted in reversible tissue changes,29,31 characterized by features such as swelling, disruption of small membranes, and intercellular damage, each recoverable within hours after unloading. Persistent or irreversible damage, however, indicates gross necrosis of the tissue. The areas of damage development observed in the in vivo study corresponded well with the regions displaying high shear strains during loading.29 This implied that large deformation, in conjunction with ischemia, provided the main trigger for early irreversible muscle damage. In the in vitro murine muscle model, different aspects of ischemia were studied. It should be recognized that the time scale of events found in this tissue-engineered model will certainly differ from that in a clinical setting. However, the processes that take place during ischemia, including hypoxia, glucose depletion, and tissue acidification, are comparable in both in vivo and in vitro situations. In the first series28 of the in vitro experiments it was shown that in the presence of hypoxia alone, cell viability was maintained well above 70% for a 22-hour period. By contrast, the effect of cell deformation alone was evident within an hour, and cell death was progressively enhanced— up to 60% for large deformations— over the 22-hour period. During an extended study, it became evident that hypoxia induced anaerobic metabolism of the muscle cells within 22 hours. This resulted in a production of lactic acid which, because of its limited removal in the simulated state of ischemia, accumulated in the muscle model. The muscle cells appeared to tolerate lactic acid levels up to 23mmol/L, above which their viability was compromised. These findings suggest not only a very early role of cellular deformation in damage development but also an important role for tissue acidification after oxygen deprivation. In addition, the study30 showed that the muscle cells were not able to tolerate glucose deprivation for periods exceeding 24 hours. Based on the results of the in vitro and in vivo studies, a sequence of events leading to cell necrosis is proposed (fig 1). After tissue compression, mechanical properties and local geometry determine the local effects inside the tissues as a result of external loading. These factors, in conjunction with the
1411
magnitude and period of compression, determine the degree of occlusion of the viscoelastic blood vessels. After vessel collapse, the tissue suffers from ischemia. The subsequent state of hypoxia, with associated oxygen deprivation, causes the cells of the vascularized tissues to change their metabolism to an anaerobic pathway. By eliminating the oxygen requirement for their energy production, the cells deplete their glucose deposits and produce an accumulation of lactic acid. A state of hypoxia will, in addition, down-regulate the metabolic demands by a phenomenon called oxygen conformance.32,33 This delays glucose depletion and acid accumulation, both of which can result in cellular death (here referred to as necrosis), possibly preceded by apoptosis, a process causing programmed cell death. If the increasing concentrations of lactic acid remain below a toxic threshold, which was 23mmol/L in our muscle model, the associated metabolism will be down-regulated. Combining the findings of both in vivo and in vitro studies, a series of external pressure–time curves can be proposed (fig 2). The classic form based on the original data of Reswick and Rogers25 is shown as a dashed line in each figure. To this has been added a solid line representing the relationship caused by ischemia alone (see fig 2B). The low risk of tissue damage at the left-hand side of time-point i indicates tissue tolerance to an ischemic insult for this time period. In addition, for external pressures less than ii no blood vessels will collapse, and hence no ischemia will occur. Figure 2C indicates a combination of ischemia, deformation, and other factors. The very high external pressures indicated by point iii will result in structural cell damage and form an initial plateau in the curve. Beyond this, the curve follows the combined effects of deformation and ischemia (point iv). At point v, equilibrium is attained, such that regardless of the time period, the low external pressures will not result in tissue damage. Experimental evidence for these adjustments to the classic curve has been provided by recent studies involving single muscle cells34 and in vivo animal models in which high loads were applied for short periods.35 Considering the importance of local tissue deformation in damage development the curves in figure 3 are proposed, for which the amount of damage as a function of time and strain is indicated. Damage is classified here as both reversible and
Fig 1. Proposed sequence of events during tissue compression. The mechanical properties of the compressed tissues and the geometry will determine the amount of deformation and ischemia experienced. The deformation will start damaging the tissue once Tdef1, the lower deformation threshold, is exceeded. The tissue’s cells will start programmed cell death, called apoptosis, eventually resulting in finalized cell death, called (cellular) necrosis. Once the deformation exceeds (Tdef2), the cells will immediately die from necrosis. The induced ischemia will cause the supplies of oxygen and glucose to decrease. The oxygen deprivation will slow down metabolic processes and shift them toward anaerobic metabolism, causing increased lactate production. When the lactate concentration exceeds Tlac or glucose levels fall below Tglu, cell death will be induced, possibly through apoptosis.
Arch Phys Med Rehabil Vol 89, July 2008
1412
A
Low risk
ii Time
B
High risk
Low risk Time
i
External pressure
High risk
External pressure
External pressure
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
C
iii iv
High risk
v
Low risk Time
Fig 2. Proposed modifications to the original curve of Reswick and Rogers.25 (A) The original Reswick and Rogers curve with high- and low-risk regions for pressure damage. (B) A graph (solid line) is imposed, representing the damage threshold resulting from ischemia. Before time point i, ischemia will not lead to damage, and below pressure at point ii, blood vessels will not be sufficiently collapsed to cause ischemia. (C) The proposed risk curve due to deformation, ischemia, and other factors. Above external pressure point iii, all time spans will lead to damage. At point iv, the curve follows the Reswick and Rogers curve, and at point v the curve plateaus because at pressures lower than this, no damage will occur.
persistent damage, as defined earlier in the commentary. Figure 3 shows that the threshold for persistent damage depends on both time and strain. It should be noted that the very high deformations that can occur—for example, on hard support surfaces—require a very short period of time to cause persistent damage. DISCUSSION Although pressure ulcers are relatively uncommon in healthy subjects,36 they can result from excessive loading and/or sustained immobilization. Such extreme conditions are indicated in figure 2C. However, they can be prevented by additional cushioning of hard surfaces or minimizing the loading time of tissues by turning regimens or other pressure-relief strategies. By contrast, in unhealthy subjects different combinations of compromising factors can become important. These include malnutrition, age, certain physical conditions, medication, and dehydration. Each factor may affect the mechanical properties and/or geometry of tissues and also influence the tissue tolerance thresholds for deformation or lactate accumulation. In addition, circulatory disturbances and immobility affect tissue oxygenation and sustenance. The aforementioned factors represent just a fraction of those occurring in the general patient population. In addition, combinations of these factors may act synergistically to aggravate the extent and onset of the damage.
Fig 3. Development of reversible and persistent damage as a function of time and strain.
Arch Phys Med Rehabil Vol 89, July 2008
The current use of risk assessment scores account for only some of these factors, and this may limit their overall sensitivity and specificity for the occurrence of pressure ulcers. As an example, people with spinal cord injury have a wellestablished increased risk for the development of DTI. Considering the scheme in figure 1, both larger deformations due to atrophy and/or flaccidity of muscles and reduced perfusion are commonly found in the musculature of their load-bearing tissues.37,38 In addition, because of their immobilization, the loading period is increased compared with healthy subjects, the effect of which is indicated in figures 2 and 3. Additional conditions, such as fever or inflammation, can further increase their risk of DTI development. A temperature rise can, for example, increase the rate of metabolic processes which, in turn, will accelerate oxygen depletion and lactate accumulation (see fig 1). In summary, 2 hours of ischemia applied to the tibialis anterior muscle of rats resulted in reversible tissue changes. In contrast, when deformation was added to the loading protocol, irreversible damage, consisting of gross necrosis of the tissue, was found. A threshold level is proposed above which deformation results almost instantly in tissue damage. Currently, numeric models are being developed to predict those threshold values. Ischemia has a more gradual effect on muscle tissue because of the inherent ability of cells to compensate for short-term ischemia. Glucose depletion and tissue acidification play important roles in tissue damage due to ischemia. Although the roles of deformation and ischemia were highlighted in the present commentary, the importance of other factors contributing to damage development in compressed tissues should also be considered. Examples include the effects of compression on lymphatic flow and the diffusion of particularly large molecules inside loaded tissues. This latter issue is currently under investigation in our laboratory. CONCLUSIONS It is evident that the understanding of DTI is significantly deepened by fundamental studies applying the latest noninvasive research technologies. The next challenge will be to develop objective early detection methods to estimate the risks associated with internal local deformations and time, in combination with intrinsic patient-specific factors. This method may combine assessment of physical parameters and biomarkers derived from blood, urine, or the skin indicating the early development of deep tissue injury.
UNDERSTANDING DEEP TISSUE INJURY, Stekelenburg
References 1. Donnelly J; National Pressure Ulcer Advisory Panel. Should we include deep tissue injury in pressure ulcer staging systems? The NPUAP debate. J Wound Care 2005;14:207-10. 2. Black J, Baharestani M, Cuddigan J, et al. National Pressure Ulcer Advisory Panel’s updated pressure ulcer staging system. Urol Nurs 2007;27:144-50, 156. 3. Ankrom MA, Bennett RG, Sprigle S, et al. Pressure-related deep tissue injury under intact skin and the current pressure ulcer staging systems. Adv Skin Wound Care 2005;18:35-42. 4. Kosiak M. Etiology and pathology of ischemic ulcers. Arch Phys Med Rehabil 1959;40:62-9. 5. Dinsdale SM. Decubitus ulcers: role of pressure and friction in causation. Arch Phys Med Rehabil 1974;55:147-52. 6. Daniel RK, Priest DL, Wheatley DC. Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehabil 1981;62: 492-8. 7. Peirce SM, Skalak TC, Rodeheaver GT. Ischemia-reperfusion injury in chronic pressure ulcer formation: a skin model in the rat. Wound Repair Regen 2000;8:68-76. 8. Ytrehus K, Reikeras O, Huseby N, Myklebust R. Ultrastructure of reperfused skeletal muscle: the effect of oxygen radical scavenger enzymes. Int J Microcirc Clin Exp 1995;15:155-62. 9. Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002; 10:620-30. 10. Tsuji S, Ichioka S, Sekiya N, Nakatsuka T. Analysis of ischemiareperfusion injury in a microcirculatory model of pressure ulcers. Wound Repair Regen 2005;13:209-15. 11. Krouskop TA, Reddy NP, Spencer WA, Secor JW. Mechanisms of decubitus ulcer formation—an hypothesis. Med Hypotheses 1978;4:37-9. 12. Miller GE, Seale J. Lymphatic clearance during compressive loading. Lymphology 1981;14:161-6. 13. Reddy NP, Cochran GV. Interstitial fluid flow as a factor in decubitus ulcer formation. J Biomech 1981;14:879-81. 14. Braden B, Bergstrom N. A conceptual schema for the study of the etiology of pressure sores. Rehabil Nurs 1987;12:8-12. 15. Landsman AS, Meaney DF, Cargill RS 2nd, Macarak EJ, Thibault LE. 1995 William J. Stickel Gold Award. High strain rate tissue deformation. A theory on the mechanical etiology of diabetic foot ulcerations. J Am Podiatr Med Assoc 1995;85:519-27. 16. Bouten CV, Knight MM, Lee DA, Bader DL. Compressive deformation and damage of muscle cell subpopulations in a model system. Ann Biomed Eng 2001;29:153-63. 17. Wang YN, Bouten CV, Lee DA, Bader DL. Compression-induced damage in a muscle cell model in vitro. Proc Inst Mech Eng [H] 2005;219:1-12. 18. Bouten CV, Breuls RG, Peeters EA, Oomens CW, Baaijens FP. In vitro models to study compressive strain-induced muscle cell damage. Biorheology 2003;40:383-8. 19. Bouten CV, Oomens CW, Baaijens FP, Bader DL. The etiology of pressure ulcers: skin deep or muscle bound? Arch Phys Med Rehabil 2003;84:616-9. 20. Labbe R, Lindsay T, Walker PM. The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia. J Vasc Surg 1987;6:152-7.
1413
21. Belkin M, Brown RD, Wright JG, LaMorte WW, Hobson RW 2nd. A new quantitative spectrophotometric assay of ischemiareperfusion injury in skeletal muscle. Am J Surg 1988;156:83-6. 22. Strock PE, Majno G. Microvascular changes in acutely ischemic rat muscle. Surg Gynecol Obstet 1969;129:1213-24. 23. Aronovitch SA. Intraoperatively acquired pressure ulcer prevalence: a national study. J Wound Ostomy Continence Nurs 1999; 26:130-6. 24. Bliss M, Simini B. When are the seeds of postoperative pressure sores sown? Often during surgery. BMJ 1999;319:863-4. 25. Reswick JB, Rogers JE. Experience at Rancho Los Amigos hospital with devices and techniques to prevent pressure sores. In: Kenedi RM, Cowden JM, editors. Bedsore biomechanics. London: Macmillan Pr; 1976. p 301-10. 26. Bader DL, White SH. The viability of soft tissues in elderly subjects undergoing hip surgery. Age Ageing 1998;27:217-21. 27. Breuls RG, Bouten CV, Oomens CW, Bader DL, Baaijens FP. Compression induced cell damage in engineered muscle tissue: an in vitro model to study pressure ulcer aetiology. Ann Biomed Eng 2003;31:1357-64. 28. Gawlitta D, Li W, Oomens CW, Baaijens FP, Bader DL, Bouten CV. The relative contributions of compression and hypoxia to development of muscle tissue damage: an in vitro study. Ann Biomed Eng 2007;35:273-84. 29. Stekelenburg A, Strijkers GJ, Parusel H, Bader DL, Nicolay K, Oomens CW. Role of ischemia and deformation in the onset of compression-induced deep tissue injury: MRI-based studies in a rat model. J Appl Physiol 2007;102:2002-11. 30. Gawlitta D, Oomens CW, Bader DL, Baaijens FP, Bouten CV. Temporal differences in the influence of ischemic factors and deformation on the metabolism of engineered skeletal muscle. J Appl Physiol 2007;103:464-73. 31. Stekelenburg A, Oomens CW, Strijkers GJ, Nicolay K, Bader DL. Compression-induced deep tissue injury examined with magnetic resonance imaging and histology. J Appl Physiol 2006;100:1946-54. 32. Arthur PG, Giles JJ, Wakeford CM. Protein synthesis during oxygen conformance and severe hypoxia in the mouse muscle cell line C2C12. Biochim Biophys Acta 2000;1475:83-9. 33. Boutilier RG. Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol 2001;204:3171-81. 34. Peeters EA, Oomens CW, Bouten CV, Bader DL, Baaijens FP. Mechanical and failure properties of single attached cells under compression. J Biomech 2005;38:1685-93. 35. Linder-Ganz E, Engelberg S, Scheinowitz M, Gefen A. Pressuretime cell death threshold for albino rat skeletal muscles as related to pressure sore biomechanics. J Biomech 2006;39:2725-32. 36. Bliss MR. Pressure injuries: causes and prevention. Hosp Med 1998;59:841-4. 37. Scelsi R. Skeletal muscle pathology after spinal cord injury: our 20 year experience and results on skeletal muscle changes in paraplegics, related to functional rehabilitation. Basic Appl Myol 2001;11:75-85. 38. Castro MJ, Apple DF Jr, Staron RS, Campos GE, Dudley GA. Influence of complete spinal cord injury on skeletal muscle within 6 mo of injury. J Appl Physiol 1999;86:350-8.
Arch Phys Med Rehabil Vol 89, July 2008