Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3774_Библиотеки_им_академика_М_И_Перельмана
.pdf
16 Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
https://t.me/medicina_free
387
a digit or extremity, digital ischemia, RP, distal digital ulceration, and extremity
claudication. As TAO progresses, it involves more proximal portions of the extremity, the most dreaded consequence being extremity gangrene and amputation.
Cocaine, amphetamine, and cannabis use can present with features mimicking TAO.
The pathogenesis of TAO is largely unknown. In the early stages of disease, there
is increased expression of vascular cell adhesion molecule 1, intercellular adhesion
molecule 1, and E-selectin on endothelial cell membranes. This may lead to activation of the innate immune response and later to a highly cellular intraluminal thrombus. Other purported mechanisms include delayed type hypersensitivity or toxic
angiitis induced by smoking, aberrant Notch signal activation, endothelial dysfunction, anti-endothelial antibodies, impaired endothelium-dependent vasodilation,
abnormalities in endothelin, prothrombotic factors, and proinammatory cytokines
[44]. The diagnosis of TAO is clinical, with imaging to exclude other causes of digital ischemia such as large vessel occlusion and proximal sources of emboli.
Commonly more than two extremities are involved, and subclinical disease should
be sought. Markers of inammation and autoantibodies are usually absent, and
imaging demonstrates normal inow arteries. While CTA and MRA may be helpful
in excluding atherosclerosis, diagnostic arteriography is often needed to demonstrate the distal involvement of arteries. A typical presentation is that of segmental
arterial occlusion and corkscrew collaterals (Martorell’s sign).
Distinguishing features from atherosclerosis include disease distribution and
involvement of both upper and lower extremities, supercial venous thrombosis,
and greater severity of pain. Biopsy, usually reserved for atypical cases, demonstrates a highly cellular thrombus with relative sparing of the vessel walls [43].
The evolution of TAO is often categorized into three stages. In the acute phase,
inammation affecting the small-calibre and medium-calibre (1- to 5-mm diameter)
arteries and veins is observed. The primary features of TAO during the acute phase
include an occlusive, highly cellular arterial thrombus, polymorphonuclear cell
inltrate with leukocytoclasis, giant cells, and microabscess formation; marked
inammation of the entire vessel wall and neurovascular bundle. Multinucleated
giant cells can be seen, but brinoid necrosis and granuloma are not observed.
Although the external elastic lamina may show some disruption the internal elastic
lamina remains intact. During the intermediate or subacute phase, there is progressive organization of the occlusive thrombus, with partial recanalization and disappearance of the microabscesses. A prominent inammatory inltrate is still present
within the thrombus but is less in the vessel wall. Immunoglobulin and complement
are deposited along the inner aspect of the internal elastic lamina. The chronic phase
or end-stage lesion is characterized by thrombus organization followed by recanalization, prominent vascularization of the media, and perivascular brosis. Regardless
of the pathologic stage, the internal elastic lamina and the architecture of the vascular walls are well preserved in TAO, in contrast to atherosclerosis and systemic
vasculitis, and inammatory cell inltration is found predominantly in the intimal
layer and the thrombus [
45].
The cornerstone of treatment of TAO is complete abstinence from tobacco.
Although high level evidence is lacking, intravenous prostacyclin analogues have
388
https://t.me/medicina_free
been shown to improve ulcer healing and pain, and the endothelin-1 receptor antagonist bosentan reduced new ischaemic lesions [46]. Distal surgical revascularisation
may prevent the need for amputations and improve quality of life, however revascularisation is often technically not feasible because of diffuse, segmental arterial
involvement and the distal nature of the disease. Distal arterial spasm during dissection and poor-quality veins owing to phlebitis are other disease-specic handicaps
[43]. Recent evidence suggests that endovascular treatment is a valid strategy leading to an acceptable limb salvage rate for TAO patients, and surgical bypass to distal
target vessels could play a role in cases of previous failed endovascular treatment or
extensive soft tissue loss of the foot [47].
M. Rischmueller et al.
16.10 Fibromuscular Dysplasia (FMD)
FMD is a noninammatory, non-atherosclerotic arterial disease of unknown aetiology in which there is distorted architecture and abnormal proliferation of the
arterial wall of medium- or small-sized arteries. Over 80% of affected individuals are women and the mean age at the time diagnosis is 52years. The true prevalence of FMD is unknown; however an incidence of 3–4% was found in a series
of potential renal donors who underwent CT Angiography. FMD has traditionally been divided histopathologically into several types according to which arterial layer is affected and to the arteriographic pattern of disease. Medial
broplasia was the most common type, comprising 80–90% of cases in the renal
arteries. However, the recent First International Consensus on the diagnosis and
management of bromuscular dysplasia [48] stated that in the contemporary
endovascular era, where tissue was rarely obtained for histopathological examination, FMD should be classied into two types on the basis of angiographic
appearance: (a) focal FMD (approximately 30% of cases) or (b) multifocal FMD
(which is characterised by areas of stenosis and dilatation- the “string of beads”
appearance). FMD is characterized by intra- arterial brotic “webs” that give rise
to a “beaded” appearance on imaging studies where the beads are larger than the
lumen of the artery.
FMD may affect any major arterial bed and clinical manifestations depend on its
distribution. Hypertension, a result of renal artery involvement, remains the most
important clinical consequence of FMD.In some patients, the condition remains
asymptomatic and incidentally discovered when imaging is performed for other
reasons, while in others it may present with arterial dissection, tortuosity, aneurysm
formation and/or end organ ischemia. In one series, renal arteries were affected in
75% and the extracranial carotid arteries in 70% of patients with FMD.Intracranial
aneurysms have been reported in over 10% of cases in the United States FMD registry. Aneurysms and/or dissection were present in about 40% of patients in the US
and European registries [49, 50]. FMD may affect the mesenteric, iliac, femoral or
popliteal arteries and result in visceral aneurysm formation or dissection, intermittent claudication or (rarely) critical limb ischemia.
16 Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
https://t.me/medicina_free
Spontaneous coronary artery dissection (SCAD) is the cause of 10–25% of cases
of acute myocardial infarction in women under 50years of age and 50% of AMIs
occurring in the post-partum period. There is a signicant association of FMD with
SCAD, and thus the International Consensus recommended “imaging of all vessels
from brain to pelvis, at least once” in patients who have had SCAD [48].
In contemporary FMD registries, only 2–7% of patients report an affected relative. There are currently no genetic tests that are specic for FMD.Current and past
smoking is associated with FMD.There may be a role for TGF-beta pathways in the
pathogenesis of the disease.
The diagnosis of FMD usually relies on a combination of clinical and imaging
ndings. CTA is the investigation of choice for assessment for renal and carotid/
vertebral FMD.MRA can be used if CT is contraindicated. Ultrasound in highly
expert hands can be used as a diagnostic test for investigation of renal FMD.However,
duplex scanning is of limited use in the diagnosis of cerebrovascular FMD, due to
the inability to image high cervical internal carotid lesions, vertebral and intracerebral lesions. Angiography, with pressure gradient measurements across lesion(s), is
recommended when intervention for renal artery lesions is indicated.
389
16.11 Summary
Much progress has been made in recent years in understanding pathogenetic mechanisms underlying the broad range of diseases we call vasculitis. The classication is
ever evolving as new discoveries are made. The advent of biologic therapy and
establishment of clinical trial consortia to enable randomised, double blind, controlled clinical trials in these rare diseases has led to major treatment advances
resulting in reduced morbidity and mortality. Basic science research has enabled
treatable causes such as viruses and genetic defects to be discovered to enable cures
in many cases of diseases which were once uniformly fatal. New challenges in this
area are the ability to identify, treat and monitor patients with IgG4-related disease
more effectively, identify strategies to prevent or safely treat irAEs caused by cancer
immunotherapy without disrupting the anti-tumour effects, increase support for
research registries and sample repositories to promote basic research as well as collaborative clinical research for these rare diseases, and improve access to groundbreaking but expensive biologic therapies. Recognition that rather than a monophasic
illness, GCA is a chronic disorder with only a minority of patients achieving longterm remission, has thrown down the gauntlet for deeper understanding of its pathogenesis to discover new therapeutic targets. Finally, given that immune mechanisms
are involved in vasculitis mimics with or without an identiable trigger, such as
TAO, further research may identify treatment targets for disease amelioration.
Application of big data bioinformatic methodology incorporating genomic, epigenetic, transcriptomic and metabolomic data, holds promise to advance our understanding of the pathogenesis and management of vasculitis.
390
https://t.me/medicina_free
M. Rischmueller et al.
References
1. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, etal. 2012 revised interna-
tional Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum.
2013;65:1–11. https://doi.org/10.1002/art.37715.
2. Al-Mousawi AZ, Gurney SP, Lorenzi AR, Pohl U, Dayan M, Mollan SP.Reviewing the patho-
physiology behind the advances in the management of giant cell arteritis. Ophthalmol Ther.
2019;8:177–93. https://doi.org/10.1007/s40123-019-0171-0.
3. Weyand CM, Watanabe R, Zhang H, Akiyama M, Berry GJ, Goronzy JJ.Cytokines, growth
factors and proteases in medium and large vessel vasculitis. Clin Immunol. 2019;206:33–41.
https://doi.org/10.1016/j.clim.2019.02.007.
4. Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM.Immune checkpoint dysfunction
in medium and large vessel Vasculitis. Am J Physiol Heart Circ Physiol. 2017;312:H1052–9.
https://doi.org/10.1152/ajpheart.00024.2017.
5. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, Calabrese LH, et al. The
American College of Rheumatology 1990 criteria for the classication of giant cell arteritis.
Arthritis Rheum. 1990;33:1122–8. https://doi.org/10.1002/art.1780330810.
6. Chung SH, Morcos MB, Ng B.Determinants of positive temporal artery biopsies in the vet-
erans health administration national database cohort. Arthritis Care Res. 2019. https://doi.
org/10.1002/acr.23897. [Epub ahead of print].
7. Dejaco C, Ramiro S, Duftner C, Besson FL, Bley TA, Blockmans D, et al. EULAR recom-
mendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum
Dis. 2018;77:636–43. https://doi.org/10.1136/annrheumdis-2017-212649.
8. Sammel AM, Hsiao E, Schembri G, Nguyen K, Brewer J, Schrieber L, etal. Diagnostic accu-
racy of positron emission tomography/computed tomography of the head, neck, and chest
for giant cell arteritis: a prospective, double-blind, cross-sectional study. Arthritis Rheumatol.
2019;71:1319–28. https://doi.org/10.1002/art.40864.
9. Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, etal. EULAR recom-
mendations for the management of large vessel vasculitis. Ann Rheum Dis. 2009;68:318–23.
https://doi.org/10.1136/ard.2008.088351.
10. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, et al.
Glucocorticoid doses and acute-phase reactants at giant cell arteritis are in a randomized trial
of tocilizumab. Arthritis Rheumatol. 2019;71:1329–38. https://doi.org/10.1002/art.40876.
11. Adler S, Reichenbach S, Gloor A, Yerly D, Cullmann JL, Villiger PM. Risk of relapse
after discontinuation of tocilizumab therapy in giant cell arteritis. Rheumatology (Oxford).
2019;58:1639–43.
12. Unizony S, Stone JH, Stone JR.New treatment strategies in large-vessel vasculitis. Curr Opin
Rheumatol. 2013;25:3–9. https://doi.org/10.1097/BOR.0b013e32835b133a.
13. Watts RA. Evolving concepts in classication of systemic vasculitis: where are we
and what is the way forward? Int J Rheum Dis. 2019;22(Suppl 1):21–7. https://doi.
org/10.1111/1756-185X.13304.
14. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The
American College of Rheumatology 1990 criteria for the classication of Takayasu arteritis.
Arthritis Rheum. 1990;33:1129–34. https://doi.org/10.1002/art.1780330811.
15. Pazzola G, Muratore F, Pipitone N, Crescentini F, Cacoub P, Boiardi L, et al. Rituximab
therapy for Takayasu arteritis: a seven patients experience and a review of the literature.
Rheumatology (Oxford). 2017;57:1151–5. https://doi.org/10.1093/rheumatology/kex249.
[Epub ahead of print].
16. Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev
Rheumatol. 2017;13:381–6. https://doi.org/10.1038/nrrheum.2017.68.
17. Dietz SM, van Stijn D, Burgner D, Levin M, Kuipers IM, Hutten BA, etal. Dissecting Kawasaki
disease: a state-of-the-art review. Eur J Pediatr. 2017;176:995–1009. https://doi.org/10.1007/
s00431-017-2937-5.
https://doi.org/10.1093/rheumatology/kez091.
16
https://t.me/medicina_free
Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
18. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, etal. Diagnosis,
treatment, and long-term management of Kawasaki disease: a scientic statement for health
professionals from the American Heart Association. Circulation. 2017;135:e927–99. https://
doi.org/10.1161/CIR.0000000000000484
19. Coit P, Direskeneli H, Sawalha AH.An update on the role of epigenetics in systemic vasculitis.
Curr Opin Rheumatol. 2018;30:4–15.
20. Al-Hussain T, Hussein MH, Conca W, Al Mana H, Akhtar M. Pathophysiology of
ANCA-associated vasculitis. Adv Anat Pathol. 2017;24:226–34.
PAP.0000000000000154
21. Lopalco G, Rigante D, Venerito V, Emmi G, Anelli MG, Lapadula G, et al. Management
of small vessel vasculitides. Curr Rheumatol Rep. 2016;18:36. https://doi.org/10.1007/
s11926-016-0580-1.
22. Sharma A, Dogra S, Sharma K.Granulomatous vasculitis. Dermatol Clin. 2015;33:475–87.
https://doi.org/10.1016/j.det.2015.03.012.
23. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, etal. Nomenclature of sys-
temic vasculitides. Arthritis Rheum. 1994;37:187–92. https://doi.org/10.1002/art.1780370206.
24. Jones RB, Hiemstra TF, Ballarin J, Blockmans DE, Brogan P, Bruchfeld A, etal. Mycophenolate
mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a
randomised, non-inferiority trial. Ann Rheum Dis. 2019;78:399–405. https://doi.org/10.1136/
annrheumdis-2018-214245.
25. Walsh M, Merkel PA, Peh C-A,Szpirt WM, Puechal X, Fujimoto S, etal. Plasma exchange
andglucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020;382:622–31.
https://doi.org/10.1056/NEJMoa1803537.
26. Faverio P, Bonaiti G, Bini F, Vaghi A, Pesci A.Mepolizumab as the rst targeted treatment for
eosinophilic granulomatosis with polyangiitis: a review of current evidence and potential place
in therapy. Ther Clin Risk Manag. 2018;14:2385–96. https://doi.org/10.2147/TCRM.S159949.
27. Hetland LE, Susrud KS, Lindahl KH, Bygum A. Henoch-Schonlein purpura: a literature
review. Acta Derm Venereol. 2017;97:1160–6. https://doi.org/10.2340/00015555-2733.
28. Lopez-Mejias R, Castaneda S, Genre F, Remuzgo-Martinez S, Carmona FD, Llorca J, etal.
Genetics of immunoglobulin-A vasculitis (Henoch-Schonlein purpura): an updated review.
Autoimmun Rev. 2018;17:301–15. https://doi.org/10.1016/j.autrev.2017.11.024.
29. Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis.
Rheumatology (Oxford). 2009;48:475–82. https://doi.org/10.1093/rheumatology/kep026.
30. Emmi G, Bettiol A, Silvestri E, Di Scala G, Becatti M, Fiorillo C, etal. Vascular Behcet’s
syndrome: an update. Intern Emerg Med. 2018;176:995–1009.
s11739-018-1991-y
31. Emmi G, Silvestri E, Squatrito D, D’Elios MM, Ciucciarelli L, Prisco D, etal. Behçet’s syn-
drome pathophysiology and potential therapeutic targets. Intern Emerg Med. 2014;9:257–65.
https://doi.org/10.1007/s11739-013-1036-5.
32. Hatemi G, Christensen R, Bang D, Bodaghi B, Celik AF, Fortune F, etal. 2018 update of
the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis.
2018;77:808–18. https://doi.org/10.1136/annrheumdis-2018-213225.
33. Retamozo S, Gheitasi H, Quartuccio L, Kostov B, Corazza L, Bové A, etal. Cryoglobulinaemic
vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients.
Rheumatology (Oxford). 2016;55:1443–51.
34. Bledsoe JR, Della-Torre E, Rovati L, Deshpande V.IgG4-related disease: review of the histo-
pathologic features, differential diagnosis, and therapeutic approach. APMIS. 2018;126:459–76.
https://doi.org/10.1111/apm.12845.
35. Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH.Clinical phenotypes of
IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis.
2019;78:406–12. https://doi.org/10.1136/annrheumdis-2018-214603.
36. Mattoo H, Mahajan VS, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, etal. Clonal
expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy
Clin Immunol. 2016;138:825–38. https://doi.org/10.1016/j.jaci.2015.12.1330.
.
.
.
https://doi.org/10.1097/BOR.0000000000000451.
https://doi.org/10.1097/
https://doi.org/10.1007/
https://doi.org/10.1093/rheumatology/kew194.
391
392
https://t.me/medicina_free
M. Rischmueller et al.
37. Mattoo H, Stone JH, Pillai S. Clonally expanded cytotoxic CD4+ T cells and the pathogen-
esis of IgG4-related disease. Autoimmunity. 2017;50:19–24.
4.2017.1280029
38. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated antineutrophil cyto-
plasmic antibody–positive vasculitis: prevalence among patients with high titers
of antimyeloperoxidase antibodies. Arthritis Rheum. 2000;43:405–13. https://doi.
org/10.1002/1529-0131(200002)43:2<405::aid-anr22>3.0.co;2-5
39. Hacking S, Uppal NN, Khan N, Ionescu M, Bijol V. Systemic p-ANCA vasculitis with fatal
outcome, arising in the setting of methimazole use. Clin Nephrol Case Stud. 2019;7:23–6.
https://doi.org/10.5414/CNCS109759.
40. Radic M, Martinovic Kaliterna D, Radic J.Drug-induced vasculitis: a clinical and pathological
review. Neth J Med. 2012;70:12–7.
41. Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from
cancer immunotherapy. Nat Rev Rheumatol. 2018;14:569–79. https://doi.org/10.1038/
s41584-018-0074-9.
42. Wigley FM, Flavahan NA.Raynaud’s phenomenon. N Engl J Med. 2016;375:556–65. https://
doi.org/10.1056/NEJMra1507638.
43. Weinberg I, Weinberg MD. Non-atherosclerotic arterial disorders of the lower extremities.
panvascular medicine. Berlin: Springer; 2015. p.3007–30.
44. Dellalibera-Joviliano R, Joviliano EE, Silva JS, Evora PRB.Activation of cytokines corroborate
with development of inammation and autoimmunity in thromboangiitis obliterans patients.
Clin Exp Immunol. 2012;170:28–35.
45. Akar AR, İnan MB, Baran Ç. Thromboangiitis obliterans. Curr Treat Options Rheumatol.
2016;2:178–95. https://doi.org/10.1007/s40674-016-0047-6.
46. Narvaez J, Garcia-Gomez C, Alvarez L, Santo P, Aparicio M, Pascual M, etal. Efcacy of
bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): a case series
and review of the literature. Medicine (Baltimore). 2016;95:e5511. https://doi.org/10.1097/
MD.0000000000005511.
47. Lee CY, Choi K, Kwon H, Ko G-Y, Han Y, Kwon T-W, etal. Outcomes of endovascular treat-
ment versus bypass surgery for critical limb ischemia in patients with thromboangiitis obliterans. PLoS One. 2018;13:e0205305. https://doi.org/10.1371/journal.pone.0205305.
48. Gornik HL, Persu A, Adlam D, Aparicio LS, Azizi M, Boulanger M, et al. First interna-
tional consensus on the diagnosis and management of bromuscular dysplasia. Vasc Med.
2019;24:164–89. https://doi.org/10.1177/1358863x18821816.
49. Kadian-Dodov D, Gornik HL, Gu X, Froehlich J, Bacharach JM, Chi YW, etal. Dissection and
aneurysm in patients with bromuscular dysplasia: ndings from the U.S. registry for FMD.J
Am Coll Cardiol. 2016;68:176–85.
50. Plouin PF, Baguet JP, Thony F, Ormezzano O, Azarine A, Silhol F, etal. High prevalence of
multiple arterial bed lesions in patients with bromuscular dysplasia: the ARCADIA registry
(assessment of renal and cervical artery dysplasia). Hypertension. 2017;70:652–8. https://doi.
org/10.1161/hypertensionaha.117.09539.
.
https://doi.org/10.1111/j.1365-2249.2012.04624.x.
https://doi.org/10.1016/j.jacc.2016.04.044.
https://doi.org/10.1080/0891693
.
Further Reading
Al-Hussain T, Hussein MH, Conca W, Al Mana H, Akhtar M.Pathophysiology of ANCA-associated
vasculitis. Adv Anat Pathol. 2017;24:226–34. https://doi.org/10.1097/PAP.0000000000000154.
Al-Mousawi AZ, Gurney SP, Lorenzi AR, Pohl U, Dayan M, Mollan SP. Reviewing the patho-
physiology behind the advances in the management of giant cell arteritis. Ophthalmol Ther.
2019;8:177–93. https://doi.org/10.1007/s40123-019-0171-0.
Gornik HL, Persu A, Adlam D, Aparicio LS, Azizi M, Boulanger M, et al. First International
Consensus on the diagnosis and management of bromuscular dysplasia. Vasc Med.
2019;24:164–89. https://doi.org/10.1177/1358863x18821816.
Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
https://t.me/medicina_free
16
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, etal. 2012 revised international Chapel
Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11.
https://doi.org/10.1002/art.37715.
McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis,
treatment, and long-term management of kawasaki disease: a scientic statement for health
professionals from the American Heart Association. Circulation. 2017;135:e927–99.
doi.org/10.1161/CIR.0000000000000484
Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH.Clinical phenotypes of IgG4-
related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis.
2019;78:406–12.
Weyand CM, Watanabe R, Zhang H, Akiyama M, Berry GJ, Goronzy JJ.Cytokines, growth factors
and proteases in medium and large vessel vasculitis. Clin Immunol. 2019;206:33–41. https://
doi.org/10.1016/j.clim.2019.02.007.
https://doi.org/10.1136/annrheumdis-2018-214603.
.
393
https://
Chapter 17
https://t.me/medicina_free
Sepsis andSeptic Shock
BenjaminReddi
Key Learning Points
Sepsis is dened as life-threatening organ dysfunction caused by a dysregulated
•
host response to infection
• Sepsis is common and associated with high mortality
• Sepsis involves activation of both inammatory and anti-inammatory pathways
promoting broad-ranging dysregulation of cardiovascular, coagulation, neuronal,
bioenergetic, endocrine and other systems
•
Early source control plus rational, timely antibiotic selection are crucial to maxi-
mise survival
• Management of circulatory shock is complex, therapy should be titrated and
responsive to individual patient parameters
17.1 Introduction andDenitions
Sepsis is the primary cause of death from infection. It has been traditionally conceptualised as an excessive host inammatory response provoked by infection and until
recently sepsis was dened as the development of two or more systemic inammatory response syndrome (SIRS) criteria (Box 17.1) as a consequence of infection,
and severe sepsis as sepsis complicated by organ dysfunction [1]. Sepsis and severe
sepsis were considered increasingly perilous stages of a pathobiologic natural history culminating in septic shock ‘sepsis-induced hypotension persisting despite
adequate uid resuscitation’ and death.
B. Reddi (*)
Intensive Care Unit, Royal Adelaide Hospital and Discipline of Acute Care Medicine,
The University of Adelaide, Adelaide, SA, Australia
e-mail: benjamin.reddi@adelaide.edu.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_17
395© Springer Nature Switzerland AG 2020
396
B. Reddi
https://t.me/medicina_free
Box 17.1
SIRS (systemic inammatory response syndrome) dened as two or more of:
• Temperature >38°C or <36°C
• Heart rate >90/min
• Respiratory rate >20/min or PaCO2 <32mmHg
• Leucocyte count >12,000/mm3 or <4000/mm3 or >10% immature bands
Table 17.1 Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score
Respiratory Cardiovascular Liver Coagulation CNS Renal
Mean arterial
b
b
pressure/
catecholamines
a
dobutamine dose
Dopamine 5.1–15a
or adrenaline ≤0.1
or noradrenaline
a
≤0.1
Dopamine >15a or
adrenaline >0.1
noradrenaline >0.1
PaO
/FiO2
2
mmHg
Score
0 ≥400 MAP ≥70 <20 ≥150 15 <110
1 <400 MAP <70 20–32 <150 13–14 110–170
2 <300 Dopamine <5
3 <200
4 <100
a
Catecholamine doses are given as μg/kg/min for at least 1h
b
With respiratory support
Bilirubin
μmol/L
or any
33–101 <100 10–12 171–299
102–204 <50 6-9 300–440 or
a
>204 <20 <6 >440 or urine
a
or
a
Platelets
3
×10
/μL
Glasgow
coma
score
Creatinine
μmol/L
urine output
<500mL/day
output
<200mL/day
Recently this paradigm has been challenged. Not only is sepsis now recognised
to involve activation of both inammatory and anti-inammatory pathways but, in
addition, broad-ranging dysregulation of cardiovascular, coagulation, neuronal, bioenergetic, endocrine and other systems. These manifestations are not captured by a
simple inammation-based denition and, not surprisingly, the SIRS-based denition shows poor divergent and convergent validity in identifying patients at risk of
poor outcome [2, 3].
Improved understanding of the pathobiology of sepsis is recognised in the development of the Third International Consensus Denitions for Sepsis and Septic
Shock (SEPSIS-3) which recommend that sepsis be dened as life-threatening
organ dysfunction caused by a dysregulated host response to infection [4]. Organ
dysfunction is dened as an increase in the Sequential [Sepsis-related] Organ
Failure Assessment (SOFA) score of 2 points or more (Table17.1) [5] and ‘infection’ as the invasion of sterile tissue by organisms resulting in infectious pathology.
Thus dened, sepsis is associated with an in-hospital mortality >10%. Septic shock
is dened as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients
17 Sepsis andSeptic Shock
https://t.me/medicina_free
with septic shock can be identied with a clinical construct of sepsis with persisting
hypotension requiring vasopressors to maintain MAP ≥65 mmHg and having a
serum lactate level >2mmol/L despite adequate volume resuscitation. With these
criteria, hospital mortality is in excess of 40% [4]. Although the SEPSIS-3 denition better discriminates those patients with presumed infection at high risk of poor
outcome, there remain challenges. No simple and unambiguous clinical criteria or
biological, imaging, or laboratory features uniquely identify a septic patient and it
is not clear how a clinician identies a ‘dysregulated host response’ at the bedside.
Furthermore, commonly no causative organism is identied and the diagnosis of
infection, and thus sepsis, remains presumed. Nevertheless, the new denition utilises objective, easily obtained variables, reects the complex pathobiology of sepsis and identies a population of patients with infection at high risk of death. It is
widely accepted as the basis for sepsis research and quality assurance.
397
17.2 Epidemiology
A recent meta-analysis found a population incidence rate of around
288/100,000- person years for hospital treated sepsis. Poor representation of low and
middle-income countries in the published data notwithstanding, the authors extrapolate global estimates of 31.5 million cases of sepsis perannum with 5.3 million
attributable deaths [6]. Data from the USA indicate that the incidence of septic
shock has been increasing over the last decade and as many as 50% of patients hospitalised with septic shock die [7] with survivors frequently suffering marked longterm cognitive decline and functional impairment [8]. Patients frequently require
intensive care unit (ICU) management making this condition a signicant nancial burden.
Risk factors for developing sepsis include extremes of age (<2 or >55years),
concurrent chronic and serious illness (such as cancer, diabetes), impaired immunity (including breach of natural barriers: burns, indwelling lines, surgical wounds
etc.) and protein calorie malnutrition.
17.3 Aetiology
A causative organism may only be identied in as few as 50% of patients with sepsis [9]. Likely organisms vary according to the primary site of infection, mode and
location of acquisition, immune and vaccination status of the host and local microbial ecology. Hence, a reasoned history often suggests likely culprits and antimicrobials can be tailored accordingly.
Accurate contemporary, global information regarding primary sites of infection
and causative agents for sepsis are lacking. A recent study enrolling over 3000
patients with septic shock from Europe, Australasia and Saudi Arabia identied the
Соседние файлы в папке Библиотека им академика М.И. Перельмана