Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: A hypothesis

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Capillary dysfunction and impaired tissue oxygenation in complex regional pain syndrome: A hypothesis
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  Topical review Capillary dysfunction and impaired tissue oxygenation in complexregional pain syndrome: A hypothesis Leif Østergaard a,b, ⇑ , Astrid Juhl Terkelsen c,d , Nanna Brix Finnerup c , Lone Knudsen c ,Kim Ryun Drasbek a , Sune Nørhøj Jespersen a,e , Peter Svensson f  , Jens Christian H. Sørensen g ,Troels Staehelin Jensen c,d a Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University, Aarhus, Denmark b Department of Neuroradiology, Aarhus University Hospital, Aarhus, Denmark c Danish Pain Research Center, Aarhus University, Aarhus, Denmark d Department of Neurology, Aarhus University Hospital, Aarhus, Denmark e Department of Physics and Astronomy, Aarhus University, Aarhus, Denmark f  Section of Clinical Oral Physiology, School of Dentistry, Aarhus University, Aarhus, Denmark g Department of Neurosurgery, Aarhus University Hospital, Aarhus, DenmarkSponsorships or competing interests that may be relevant to content are disclosed at the end of this article. 1. Introduction Complex regional pain syndrome (CRPS) presents with severepain in distal parts of a limb (hand or foot), typically after traumawithassociatedswellingandwarmthof theaffectedlimb[33]. Thecondition is associated with sensory abnormalities such as hyper-sensitivity, and with autonomic disturbances including reddeningand sweating. At onset, CRPS is dominated by either a warm,hyperemic, edematous limb (‘warm’ CRPS) or a cold, dystrophiclimbwithskinatrophy(‘cold’ CRPS) andchronicpain[11,42]. Over time, warm CRPS can progress to cold CRPS. This complex clinicalpicture has led to the assumption that inflammatory, vasomotor,andmaladaptiveneuroplasticchangesareinvolvedinthedevelop-ment and maintenance of CRPS [14].Thistopicalreviewraisesthehypothesisthathypoxiacausedbycapillary flow disturbances may play an important role in thedevelopment of CRPS and the subsequent maintenance of the con-dition as it progresses from the initial warm phase to the chroniccold phase. 2. Is tissue oxygenation impaired in CRPS? Histological examination of muscle tissue from CRPS patientswho underwent amputation revealed gross thickening of capillarybasement membranes, pericyte loss, and, in some cases, capillarynecrosis [47] (Fig. 1). Such changes would be expected to disturb capillary flow patterns, and possibly muscle ischemia (low bloodflow). The latter is supported by the cold and dystrophic appear-ance of limbs in ‘cold’ CRPS [42], by magnetic resonance spectros-copy studies that reveal muscle hypoxia [17], and by findings of reduced skin oxygenation in CRPS [27]. However, other observa-tions are difficult to reconcile with ischemia being the sole causeof CRPS. First, capillarychangesandedemapressurehavenot beenshowntoimpairtissuebloodflow[41],andskinhypoxiacannotbeexplained by edema alone [27]. Second, limb hyperperfusion has beendemonstratedinmixedpopulationsof‘warm’ and‘cold’CRPSpatients [34,41,43], although skin oxygenation is low in both groups [27]. Third, oxygen extraction fraction is dramaticallyreduced in CRPS [34,43], not elevated as one would expect in limb ischemia.Takentogether,theseobservationssuggestthatimpairedtissue oxygenation, rather than ischemia, is central to theetiopathogenesis of CRPS. 3. Relation between tissue blood flow and tissue oxygenationrevisited We recently uncovered a fundamental limitation in theassumed one-to-one correspondence between tissue blood flow(TBF) and tissue oxygenation [25]. The assumption is rooted intheclassicflow-diffusionequation[38],whichassumesthatall tis-sue capillaries are equally perfused. Normal tissue, however, dis-plays considerable capillary transit time heterogeneity (CTH). Wegeneralized the flow-diffusion equationto express tissue oxygena-tion in terms of TBF, CTH, and tissue oxygen tension (P t O 2 ) [25].Fig. 2A shows the classic flow-diffusion equation, and how tissueoxygenation is reduced by increasing levels of CTH, at constant   2014 The Authors. Published by Elsevier B.V. on behalf of International Association for the Study of Pain.This is anopenaccessarticleunder the CCBY-NC-SAlicense( ⇑ Corresponding author at: Aarhus University Hospital, Department of Neurora-diology, Center of Functionally Integrative Neuroscience and MINDLab, Building10G,5thfloor,Nørrebrogade44, AarhusC8000, Denmark. Tel.:+4578464091;fax:+45 7846 1622. E-mail address: (L. Østergaard). PAIN  xxx (2014) xxx–xxx Pleasecitethisarticleinpressas:ØstergaardLetal.Capillarydysfunctionandimpairedtissueoxygenationincomplexregional painsyndrome:Ahypoth-esis. PAIN  (2014),  P t O 2 . Accordingly, tissue oxygenation during vasodilation dependson both TBF and the parallel homogenization of capillary flows. If capillaryflowpatternsarepoorlyregulated,aconditioncalledcap-illary dysfunction, bloodpasses throughcapillaries at transit timestoo short to permit efficient extraction of oxygen by the tissue. If CTH is high, this ‘oxygen loss’ may in fact exceed the benefits of vasodilation—a phenomenon called malignant CTH. Paradoxically,failuretosuppressnormalvasodilatoryresponsesunderthesecon-ditions is predicted to result in uncontrolled hyperemia, tissuehypoxia, and tissue damage, consistent with the so-called luxuryperfusion syndrome observed in several tissues after ischemia-reperfusion [32]. If TBF responses can be suppressed, then theresulting, lower P t O 2  increases blood–tissue concentration gradi-ents and oxygen extraction so that some level of tissue function(eg, muscle work) can be maintained [25]. 4. Blood flow regulation in normal muscle and skin Thesympatheticnervoussystemisinvolvedintheregulationof resting blood flow in skin and muscle. In muscle, vessel tone isunder baroreceptor control for blood pressure maintenance, andvascular innervation by  a 1  and  a 2  adrenergic fibers suppressresting blood flow so that sudden removal of sympathetictone increases muscle blood flow 2- to 3-fold [22]. Meanwhile,stimulation of   b 2 -adrenoreceptors causes vasodilation. Duringmuscle work, tissue hypoxia, low pH, and the release of adenosineand nitric oxide increases blood flow. Muscle blood flow is inter-rupted by muscle contractions, and sustained tetanic contractionssuchasthoseusedinananimalmodelofchronicpain[48]arethuslikelytoresultinmusclehypoxia.Inskin,stimulationofadrenergicfiberscausesvasoconstriction,andstimulationofcholinergicfiberscauses vasodilation and an increase in blood flow [26], althoughthe extent of active cholinergic vasodilation, especially on distalbody parts, remains under debate [39]. CRPS is localized to thelimbs where muscle and overlying skin most often receive theirblood supply from different vascular branches [44]. 5. Blood flow regulation and oxygen extraction fraction in CRPS Skin blood flow in CRPS can be subdivided according to threedistinct phases [15,30]. In the acute or ‘warm’ phase of CRPS, the affected limb is usually warmer than the contralateral limb. Thishasbeenascribedtofunctional inhibitionof thesympatheticvaso-constriction of the dermal arterioles involved in thermoregulation[50,51], to ongoing inflammation, and to increased blood flow inunderlying muscle and soft tissue (see below) [41]. The acutephase is often followed by an intermediate phase in which skinblood flow and temperature alternate between warm and cold[15,30]. Then, some patients develop a cold or chronic phase of  CRPS [15,30], in which both nutritional and thermoregulatory skin flow is reduced. This hypoperfusion has been interpreted ascatecholamine hypersensitivity [15], but this hypothesis is notsupported by recent results [45]. Instead, increasing evidencesuggests that endothelium-dependent vasodilation is suppressed,a condition called endothelial dysfunction [9,40]. Endothelial dysfunction is associated with increased levels of reactive oxygenspecies (ROS) in the arteriolar vessel walls, and reduced levels of nitric oxide (NO), which relaxes vascular smooth muscle cells.Long-term exposure of artery and arteriole walls to ROS and lowNO causes remodeling and thickening of the vessel walls, whichbecome more rigid and develop abnormal focal constrictions. Suchmorphological changes are indeed observed in CRPS patients [10].Muscle or whole-limb blood flowregulationis difficult to studyin CRPS. In patients with ‘warm’ CRPS, Matsumura et al. foundreduced pH and high venous oxygen saturation (low oxygenextraction fraction) in the affected limb, and radiographic signsconsistentwithfastbloodtransitsandAVshunting[34]. InchronicCRPS patients, Tan et al. reported reduced venous oxygen satura-tion (high oxygen extraction fraction), profound thickening of cap-illary endothelium and basement membranes in muscle, andevidence of severe hypoxia [43]. In a mixed population of individ-ualswith‘warm’and‘cold’CRPS,ofwhom>90%showedseveretis-sue edema, Schurmann et al. found elevated blood flow in theaffected arm, but no correlation between skin temperature andlimb blood flow [41]. 6. Inflammation and edema in CRPS CRPS is associated with exaggerated inflammatory responses[3] and increased vascular permeability to macromolecules in theaffectedextremity [36]. It is generallyassumedthat the inflamma-tionisneurogenic,mediatedbythedepolarizationofsmallsensoryafferents, mainly nociceptive C-fibers, in the skin. These depolari-zations trigger the release of neuropeptides such as CGRP andsubstance P (SP), which induce local inflammation, protein extrav-asation, vasodilatation, and the release of cytokines [18]. Accord- ingly, skin levels of SP, CGRP, and inflammatory cytokines areelevated in CRPS [2,20,23,28]. Tissue hypoxia in itself may also eli- cit inflammation by up-regulating nuclear factor– j B transcription Fig. 1.  (A) Gross thickening of the basal membrane in a capillary from the soleusmuscle of a 46-year-old male CRPS patient [47]. Note the multiple basal membranelayers with cell debris from pericytes between the laminae (arrows). (B) Normalmuscle capillary with a red blood cell, obtained from a 41-year-old female controlsubject. Note the endothelial cell (e), pericyte (p), and thin surrounding basalmembrane (arrow). Although all patients in the study by van der Laan et al. [47]revealed severe changes in capillary and basement membrane morphology, itshould be kept in mind that biopsy material from amputations invariablyrepresents tissue from severe cases of CRPS. Figure from van der Laan et al. [47], reproduced with permission from the publisher.2  L. Østergaard et al./PAIN    xxx (2014) xxx–xxx Pleasecitethisarticleinpressas:ØstergaardLetal.Capillarydysfunctionandimpairedtissueoxygenationincomplexregionalpainsyndrome:Ahypoth-esis. PAIN  (2014),  Blood Flow and TissueOxygenation IncreasingCTHOxygenationgainby homogenization HigherOEF MalignantCTHTissue hypoxia Classic Flow-diffusion Equation (CTH=0) TissueBlood Flow [mL/100mL/min]    O  x  y  g  e  n   A  v  a   i   l  a   b   i   l   i   t  y   [  m   L   O    2    /   1   0   0  m   L   /  m   i  n   ] A Fig. 2.  (A) Relation between tissue blood flow (TBF; measured in mL/100mL tissue/min), and tissue oxygenation, expressed as the maximummetabolic rate (mL O 2 /100mL tissue/min)thatcanbesupportedbytheblood,accordingtotheclassicflow-diffusionequation[38],whichassumesnegligiblecapillarytransittimeheterogeneity(CTH)(fullblackcurve). Dashed greylinesschematicallyshowtheeffectsof increasinglevels of CTH, at fixedtissueoxygentension(P t O 2 ) [25]. Innormal tissue, CTHis highduringrest,but CTH is reduced in parallel with increases in TBF (B). This gives rise to efficient oxygen extraction at higher TBF values, despite the decreasing slope of the classical flow-diffusion equation. Conversely, failure of CTH to fall during vasodilation, so-called capillary dysfunction, renders vasodilation inefficient as a means of increasing tissueoxygenation. Note how the grey curves increase little towards high TBF. The lower grey curve illustrates the malignant CTH phenomenon. Eventually, TBF can reach a limitbeyond which further vasodilation would reduce tissue oxygenation. Failure to suppress normal vasodilation during elevated metabolic needs would therefore lead to acondition of uncontrolled hyperemia, tissue hypoxia, and severe tissue damage. This phenomenon resembles the luxury perfusion syndrome [32] observed in some organsaftertissuereperfusion.Wehypothesizethatthishemodynamicabnormalityispresentin‘warm’CRPS(C).IfTBFresponsescanbesuppressed,thentheresultingreductionintissue oxygentensionwill increase blood–tissue concentrationgradients, andincrease the oxygenextractionfraction. Suppressionof normal flowresponses, for example, byendothelial dysfunction, permits better oxygen extraction and some level of tissue function, for example, muscle work. We hypothesize that ‘cold’ CRPS is characterized bysuppression of resting and activity-related blood flow (D). L. Østergaard et al./PAIN    xxx (2014) xxx–xxx  3 Pleasecitethisarticleinpressas:ØstergaardLetal.Capillarydysfunctionandimpairedtissueoxygenationincomplexregional painsyndrome:Ahypoth-esis. PAIN  (2014),  factors, which act as regulators of inflammation and orchestrateimmune responses to protect the host, including the productionof tumor necrosis factor, a key pro-inflammatory cytokine [13]. 7. Capillary dysfunction hypothesis of CRPS We hypothesize that CTH is elevated in tissue injury and acuteinflammationasaresultofthefollowing:capillarycompressionbyincreased interstitial pressure (which occurs at only half the pres-sure needed for arteriolar compression) caused by local hemor-rhage and edema [49]; capillary constriction due to vasoactiveblood break-down products [29]; and disturbed blood rheologydue to abnormal adhesion of erythrocytes and white blood cellsto the capillary wall in inflammation [35]. These factors have beenshown to disturb capillary flow patterns and effectively shuntblood through the capillary bed [35,49]. We hypothesize that theincreased blood flow and reduced oxygen extraction in both skinand muscle in ‘warm’ CRPS reflect failure to suppress TBF in thepresence of malignant CTH, that is, ‘luxury perfusion’. We furtherspeculate that that the high oxygen extraction fraction [43] foundin chronic ‘cold’ CRPS represents suppression of resting blood flowand bloodflowresponses by endothelial dysfunction [40] to main-tain tissue oxygenation. Vasospasms, rather than being the sourceofischemiaCRPSandCRPSmodels[6,7],arethuspredictedtocom-pensate for downstream capillary dysfunction by attenuating the‘oxygen loss’ that occur as blood is shunted through the capillariesat high flow rates. We believe that the intrinsic ROS productionthroughout these phases causes permanent capillary wall damage,propagating the condition [43,47]. These scenarios are illustratedin Fig. 2B to E.ThekeyeventsinthehypothesizedCRPSetiologyareprolongeddisturbances of CTHby the factors above, and oxidative damage tocapillarywallsandtissue(Fig.2).Nicotineup-regulatestheexpres-sion of adhesion molecules in the capillary endothelium [1] andincreases leukocyte rolling [54]. Smoking would therefore beexpected to worsen capillary flow disturbances and increase therisk of developing CRPS, whereas prompt reduction of the tissueswelling and inflammation would be expected to reduce the risk.We speculate that these mechanisms may contribute to theincreased prevalence of smokers among CRPS patients [21] andthe benefits of corticosteroid treatment in preventing CRPS [5].Meanwhile, we speculate that administration of vitamin C (a ROSscavenger)reduces theriskof developingCRPS[55] byattenuatingoxidative capillary wall damage. 8. Origin of pain in CRPS The mechanisms by which ischemia might create pain havebeen reviewed by Coderre et al. [7,37]. Briefly, tissue hypoxiawould be expected to result in elevated lactate levels and acidosissecondary to energy depletion, as observed in the muscle and skinof CRPS patients [4,17,27]. Indeed, exercise increases pain in CRPSpatients [7], and increased lactate levels correlate with the degreeofpaininanimalmodels[7].Bothnociceptordischargesinrelationto the initial injury, and ectopic discharges thought to occur inC-fibers in animal models of hypoxia and inflammation [7], arelikely to initiate and maintain central sensitization [53].Meanwhile, tissue hypoxia and inflammation are also known toincrease the levels of pro-inflammatory cytokines thought toproduce neuropathic pain [12,52]. 9. Conclusion and perspectives Based on a chronic postischemic pain model [8] and earlierobservations of vascular abnormalities in CRPS [6], Coderre et al.have proposed that CRPS is initiated by a compartment-like syn-drome, during which injury-related edema compresses tissuemicrovessels and causes severe ischemia [7] and that subsequentreperfusion causes microvascular injury and a permanent state of vasospasm, slow flow, and deep tissue ischemia [6,7]. We haveextendedthisnotionbyproposingthatcapillaryflowdisturbances,rather than arteriolar compressions or vasospasms, and tissuehypoxia rather than ischemia, may be central disease entities inCRPS.Direct demonstration that a reduction of tissue CTH alleviatesCRPS symptoms and improves TBF would support the predictionthat capillary dysfunction is central to CRPS etiopathogenesis.Phosphodiesterase (PDE) inhibitors reduce platelet aggregation[19], decrease blood viscosity [24], and increase the flexibility of  erythrocytes [24]. By these hemorheologic effects, PDE inhibitorswould therefore be expected to reduce CTH, and hence improvetissue oxygenation. The PDE inhibitor tadalafil indeed improvesmuscle force (indicative of improved muscle oxygenation) andreduces pain in some CRPS patients [16]. We speculate that therecent failure of tadalafil to elevate limb temperature [37] is theresult of capillary dysfunction, which causes a dissociationbetween tissue oxygenation on one hand, and limb blood flow/temperature on the other. Studies in a post-ischemic pain modelconfirm that systemic PDE [46], as well as topical PDE applicationeither alone or in combination with vasodilators [37], relieve allo-dynia while reversing the suppression of flow responses [31], con-sistent with a role of elevated CTH and tissue hypoxia in thismodel. Conflict of interest statement The authors declare no conflicts of interest.  Acknowledgements This study was supported by the Danish Ministry of Science,Innovation, and Education (MIND Lab ; L.Ø., N.B.F., S.N.J., P.S., andT.S.J.). References [1] Albaugh G, Bellavance E, Strande L, Heinburger S, Hewitt CW, Alexander JB.Nicotine induces mononuclear leukocyte adhesion and expression of adhesionmolecules, VCAM and ICAM, in endothelial cells in vitro. Ann Vasc Surg2004;18:302–7.[2] Bernateck M, Karst M, Gratz KF, Meyer GJ, Fischer MJ, Knapp WH, Koppert W,Brunkhorst T. The first scintigraphic detection of tumor necrosis factor-alphain patients with complex regional pain syndrome type 1. Anesth Analg2010;110:211–5.[3] Birklein F, Schmelz M. Neuropeptides, neurogenic inflammation and complexregional pain syndrome (CRPS). Neurosci Lett 2008;437:199–202.[4] Birklein F, Weber M, Neundorfer B. Increased skin lactate in complex regionalpain syndrome: evidence for tissue hypoxia? 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