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Evidence-based clinical practice guidelines

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Evidence-based medicine is the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients.

Listing evidence-based guidelines of the American Venous Forum has been a hallmark of the Handbook, and the fth edition is no exception. At the end of each chapter a table summarizes the relevant clinical practice guidelines.

The guidelines are based on the GRADE system.

2,3

The

grade of recommendation of a guideline can be Strong (1) or Weak (2), depending on the risk and burden of a particu- lar diagnostic test or a therapeutic procedure to the patient vs. the expected benet. It also considers patient values and

preferences and other contextual factors (Table0.1).

The implications of a Grade 1 or Strong recommen-

dation are that the potential benets of an intervention clearly outweigh the potential harms and burdens. Virtu-

ally all well-informed patients would choose such an intervention, and the physician can condently recommend the treatment. In contrast, for Grade 2 or Weak recommen- dations, the benets and risks will be more balanced or uncertain; thus, different patients could choose different treatment options according to their values and preference. The physician must be familiar with the underlying data before making such a recommendation and should counsel patients appropriately. The word “Recommend” is used for Grade 1, Strong recommendation, and the word “Suggest” is used for Grade 2, Weak recommendation.

Letters A, B, and C mark the quality of evidence (A,

High quality, B, Moderate quality, C, Low to very low quality). The pyramid of evidence illustrates the type of studies

that provide different levels of evidence to formulate the guidelines (Figure0.1).

TABLE 0.1 Grades of recommendation and quality of evidence for clinical practice guidelines

Beneﬁt vs. risk and burdens

Benets clearly outweigh risk and burdens, or vice versa

Benets closely balanced with risks and burden

Uncertainty in the estimates of benets, risks, and burden; benets, risks, and burden may be closely balanced

Methodologic quality of supporting evidence

RCTs without important limitations or overwhelming evidence from observational studies

RCTs with important limitations (inconsistent results, methodologic aws, indirect, or imprecise) or exceptionally strong evidence from observational studies

Observational studies or case series

RCTs without important limitations or overwhelming evidence from observational studies

RCTs with important limitations (inconsistent results, methodologic aws, indirect, or imprecise) or exceptionally strong evidence from observational studies

Observational studies or case series

Implications Grade of

Strong recommendation, can apply to most patients in most circumstances without reservation

Strong recommendation but may change when higher-quality evidence becomes available

Weak recommendation, best action may differ depending on circumstances or patients’ or societal values

Very weak recommendation: other alternatives may be equally reasonable

recommendation

1 (Strong)

2 (Weak)

Quality of evidence

A (High)

B (Moderate)

C (Low to very low)

A (High)

B (Moderate)

C (Low to very low)

xxv

xxvi Evidence-based clinical practice guidelines

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0.1 The pyramid of scientic evidence.

With level A evidence, condence in the treatment effect

is high, and further research would be unlikely to change the estimate of effect. In contrast, if the level of evidence is C, further research would very likely affect the estimate of the effect. Both the strength of the recommendations and the quality of evidence are color-coded in the guideline tables for easy recognition (Table0.1).

In contrast to several previous practice guidelines, graded recommendations in this edition, like the most recent two guidelines published on chronic venous dis-

4,5

are most trustworthy since all are supported by

ease, recent systematic reviews or meta-analysis to minimize bias. Some of the guidelines in this book were adopted from widely accepted and trusted multi-institutional or international guidelines,

6,7

all based on systematic reviews

of the relevant topics.

When a systematic review was not available, ungraded consensus statements were made, based on a comprehensive review of the literature, combined with unanimous consensus of an expert writing panel of published guidelines. Some of these topics, however, had minimal or low-quality evidence. Ungraded Good Practice Statements are recommendations that are supported only by indirect evidence. The topic, however, is usually noncontroversial and agreed upon by most stakeholders. The Implementation Remarks, published in previous guidelines and included in this volume, contain technical information that supports the implementation of specic recommendations.

Clinical practice guidelines and consensus statements, published in the fth edition of the Handbook, should not be used as dogma when a diagnostic test is selected or a therapeutic procedure is performed. Scientic evidence should always be combined with the clinical experience of the physician, the patient’s values and preferences, the cost of the procedure, and the availability of expertise and new technology (Figure0.2).

Evidence-based guidelines provide the foundation for best care. When planning care, we should recognize, however, that in most cases, guidelines are developed from the results of studies of average, usually low- to moderate-risk patients and that a deviation from the guidelines could be necessary under unusual circumstances. Making the most appropriate decision also requires patient-centered communication skills by the health care provider, who is aware of the informed preferences of his or her patient. Optimal patient care therefore requires both evidence-based medicine and shared decision making. Shared decision making is essential, humane and kind, and “the sort of thing that breathes life, joy and purpose into the practice of medi-

cine.”

It is the intention of the authors and editors of this volume to help in the evaluation and treatment of patients with those ideals in mind, which were suggested by Dr. William J. Mayo already in 1910, that “The best interest of the patient is the only interest to be considered.”

Peter Gloviczki, MD, PhD, FACS

Evidence-based clinical practice guidelines xxvii

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0.2 Shared decision making by the patient and the health care provider is paramount to come to the right decision about the best

care for the patients.

REFERENCES

1. Sackett DL. Evidence-based medicine. Spine (Phila Pa 1976) 1998;23(10): 1085–1086.

2. Guyatt G, Gutterman D, Baumann MH, etal. Grading strength of recommendations and quality of evidence in clinical guidelines: Report from an American college of chest physicians task force. Chest 2006;129(1):174–181.

3. Murad MH, Montori VM, Sidawy AN, etal. Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework. J Vasc Surg 2011;53(5):1375–1380.

4. Gloviczki P, Lawrence PF, Wasan SM, etal. The 2022 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society

clinical practice guidelines for the management of varicose veins of the lower extremities. Part I. Duplex scanning and treatment of supercial truncal reux: Endorsed by the Society for Vascular Medicine and the International Union of Phlebology. J Vasc Surg Venous Lymphat Disord 2023;11(2):231–261.e6.

5. Gloviczki P, Lawrence PF, Wasan SM, etal. The 2023 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed by the Society of Interventional Radiology and the Society for Vascular Medicine.

J Vasc Surg Venous Lymphat Disord 2024;12(1):101670.

6. Stevens SM, Woller SC, Kreuziger LB, etal. Antithrombotic therapy for VTE disease: Second update of the CHEST guideline and expert panel report. Chest 2021;160(6):e545–e608.

7. Ortel TL, Neumann I, Ageno W, etal. American Society of Hematology 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4(19):4693–4738.

8. Montori VM, Ruissen MM, Hargraves IG, Brito JP, Kunneman M. Shared decision-making as a method of care. BMJ Evid Based Med 2023;28(4):213–217. DOI: 10.1136/bmjebm-2022-112068.

Abbreviations

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25(OH)D 25-hydroxyvitamin D AAGSV anterior accessory great saphenous

vein AASV anterior accessory saphenous vein ACA anticardiolipin antibodies ACCP American College of Chest

Physicians ACG adjustable compression garment ACH acetylcholine ACP activated protein C ACT activated clotting time ACVRL1 activin receptor-like kinase-1 ADP adenosine diphosphate AF atrial brillation AHA American Heart Association AK above the knee AM arterial malformation AMP adenosine monophosphate AP anterior-posterior aPE antiphosphatidylethanolamine APG air plethysmography APS antiphospholipid antibody

syndrome aPTT activated partial thromboplastin

time ASA aspirin ASD atrial septal defect ASV anterior saphenous vein ASVAL Ablation Selective des Varices sous

Anesthesie Locale ATTRACT Acute Venous Thrombosis:

Thrombosis Removal with

Adjunctive Catheter-Directed

Thrombolysis trial AV axillary vein AVF American Venous Forum AVF arteriovenous stula AVM arteriovenous malformation AVVS/AVVQ Aberdeen Varicose Vein Scores or

Questionnaire ARTE ablation related thrombus

extension b.i.d. bis in die=twice daily

before the current (common) era

/ bFGF basic broblast growth factor BK below the knee BMI body mass index BNP brain natriuretic peptide

BV brachial vein C4b-BP C4b-binding protein CA cyanoacrylate CAC cyanoacrylate closure CAE cyanoacrylate embolization cAMP cyclic adenosine monophosphate CAPS catastrophic antiphospholipid

antibody syndrome

CaVenT Catheter-Directed Thrombolysis in

Acute Iliofemoral Vein Thrombosis

trial CBS cystathione β synthase CBT catheter-based treatment CCJ costoclavicular junction CD-31 cluster of differentiation-31 CDT catheter-directed thrombolysis CDT complex decongestive therapy  common era CE contrast-enhanced CEAP C, clinical; E, etiology; A, anatomy;

P, pathophysiology CFD color-ow duplex ultrasonography cFN bronectin CFV common femoral vein CHIVA conservative hemodynamic

ambulatory treatment of venous

insufciency CHIVA Cure Conservatrice et

Hemodynamique de l’Insufsance

Veineuse en Ambulatoire CI condence interval CIV common iliac vein CIVIQ Chronic Venous Insufciency

Questionnaire CLF ClosureFast CM capillary malformations cm centimeter CMS Centers for Medicare & Medicaid

Services CNS central nervous system

carbon dioxide

COPD chronic obstructive pulmonary

disease CP ClosurePlus CPT Current Procedural Terminology

code book CrCl creatinine clearance CRP C-reactive protein

xxix

xxx Abbreviations

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CS conventional surgery CT computed tomography CTV computed tomography venography CUS compression ultrasound CV contrast venography CVA cerebrovascular accident CVC central venous catheter CVD chronic venous disease CVI chronic venous insufciency CVM congenital vascular malformation CVT central venous thrombosis Cx43 Connexin43 CXVUQ Charing Cross Venous Ulceration

Questionnaire

dceMRI dynamic contrast-enhanced

magnetic resonance imaging

DIC disseminated intravascular

coagulation DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DP dynamic pressure DTI direct thrombin inhibitor DUS duplex ultrasound DVR deep vein reux DVT deep vein thrombosis DWI diffusion-weighted imaging ECG electrocardiogram ECM extracellular matrix ECS elastic compression stockings ECMO extracorporeal membrane

oxygenation ECOG Eastern Cooperative Oncology

Group ECTR endothelial cell turnover rate EGF epidermal growth factor EHIT endovenous (or endothermal)

heat-induced thrombosis EIV external iliac vein EKG electrocardiography ELISA enzyme-linked immunosorbent

assay ELS elastic compressive stockings EMMPRIN extracellular matrix

metalloproteinase inducer EN enteral nutrition ENG endoglin EPCR endothelial cell protein C receptor EPC endothelial progenitor cell ePTFE expanded polytetrauoroethylene

graft EQ-5D EuroQol questionnaire ERK extracellular signal-regulated kinase ETA endothermal ablation EVF European Venous Forum EVLA endovenous laser ablation EVLT endovenous laser therapy EVOH ethylene copolymer and vinyl

alcohol EVRF endovenous radiofrequency FDA Food and Drug Administration FGFR-2 broblast growth factor receptor-2

FPDL ashlamp pumped dye laser FPNI ferroportin gene FS foam sclerotherapy FSE free precession sequence FV femoral vein FVIII factor VIII FVL factor V Leiden mutation FXIII factor XIII gal3 galectin 3 gal3bp galectin 3 binding protein GFR glomerular ltration rate GI gastrointestinal GM-CSF granulocyte-macrophage colony

stimulating factor GPIba glycoprotein Iba GRE standard gradient recalled echo GSV great saphenous vein GVM glomuvenous malformation GWOT global war on terrorism HFE hemochromatosis C282Y HFVM high-ow vascular malformation HGF hepatocyte growth factor HHC hyperhomocysteinemia HHT hereditary hemorrhagic

telangiectasia HIF-1 hypoxia inducible factor-1 HIT heparin-induced thrombocytopenia HITT heparin-induced thrombocytopenia

and thrombosis HL&S high ligation and stripping HLM hemolymphatic malformation HOPE Heart Outcomes Prevention

Evaluation trial HP hydrostatic pressure HR hazard ratio HQL, HRQL health-related quality of life HRT hormone replacement therapy Ht height IAC Intersocietal Accreditation

Commission IBD inammatory bowel disease ICAM-1 intercellular adhesion molecule-1 ICG indocyanine green ICU intensive care unit IED improvised explosive device IF iliofemoral IFN-γ interferon-γ Ig immunoglobulin IJV internal jugular vein IL-12p40 interleukin-12p40 IL-1α interleukin-1α

interleukin-1β

IL-1β INR international normalized ratio of

prothrombin time of blood

coagulation IPC intermittent pneumatic

compression IPG impedance plethysmography IPL intense pulsed light IRR incidence rate ratio

Abbreviations xxxi

https://t.me/med1917

ISCVS International Society for

Cardiovascular Surgery ISS Injury Severity Score ISSVA International Society for the Study

of Vascular Anomalies ISTH International Society of

Thrombosis and Hemostasis ITGA9 integrin α9 IUA International Union of Angiology IUP International Union of Phlebology IV iliac vein IV intravenous injection IVC inferior vena cava IVUS intravenous or intravascular

ultrasound JNK c-Jun N-terminal kinases JUPITER Justication for the Use of Statins

in Prevention: an Intervention Trial

Evaluating Rosuvastatin kDa kilo-Dalton kg kilogram KO knockout KTP potassium titanyl phosphate L liter LA lupus anticoagulant LA-ICGFA laser-assisted indocyanine green

uorescence angiography LDS lipodermatosclerosis LDUH low-dose unfractionated heparin LE lower extremity LEDVT lower extremity deep vein

thrombosis LFA-1 lymphocyte function-associated

antigen-1 LFT liver function test LFVM low-ow vascular malformation LGV left gonadal vein LM lymphatic malformation LMWH low-molecular-weight heparin LRV left renal vein LS liquid sclerotherapy LV left ventricle LVA lymphaticovenous anastomosis LVR lymphovenous reconstruction MAP kinase/MAPK mitogen-activated protein kinase MAUDE FDA Manufacturer and User Facility

Device Experience database MCP-1 monocyte chemoattractant

protein-1 MCT medium-chain triglyceride MDCT multiple detector computed

tomography MHz megahertz, unit of frequency MIP-1β macrophage inammatory

protein-1β MKK MAPK kinase mL milliliter MLD manual lymphatic drainage mm millimeter mmHg millimeters of mercury MMP-1, -2 ... matrix metalloproteinase-1, -2 ...

MOCA mechanochemical endovenous

ablation or mechanical occlusion chemically assisted

MPFF micronized puried avonoid

fraction MRI magnetic resonance imaging MRL magnetic resonance

lymphangiography mRNA messenger ribonucleic acid MRV magnetic resonance venogram ms milliseconds MTFR, MTHFR methylenetetrahydrofolate

reductase MT-MMP membrane-type matrix

metalloproteinase mTOR mammalian target of

rapamycin MTS May–Thurner syndrome MVT mesenteric venous thrombosis nBCA or NBCA N-butyl cyanoacrylate NCNS non–central nervous system Nd:YAG neodymium-doped yttrium

aluminum garnet lasers NETS neutrophil extracellular traps NGAL neutrophil gelatinase-associated

lipocalin NHS-TAS National Health Services

Health Technology Assessment

Survey NIH National Institutes of Health NIVL nonthrombotic iliac vein lesion NLN National Lymphedema Network nm nanometer NOAC novel oral anticoagulant NORVIT Norwegian Vitamin trial NPV negative predictive value NR nonreported NS nutcracker syndrome NSF nephrogenic sclerosing brosis NSQIP National Surgical Quality

Improvement Project database NTNT nonthermal nontumescent

technique OC oral contraceptive OCP oral contraception OR odds ratio PA pulmonary artery PAI-1 plasmin activator inhibitor-1 PAGSV posterior accessory great saphenous

vein PASTE postablation supercial thrombus

extension PAV posterior arch vein PCDT pharmacomechanical

catheter-directed thrombolysis PCF physician-compounded foam PCP pneumatic compression pump PCP pretest clinical probability score PCS pelvic congestion syndrome PCV postcapillary venule PD polidocanol

xxxii Abbreviations

https://t.me/med1917

PDA patent ductus arteriosus PDGFR-α and -β platelet-derived growth factor

receptor-α and -β PE pulmonary embolism PEM polidocanol endovenous microfoam PERT pulmonary embolism response

team PFO patent foramen ovale PFV profunda femoris vein PIC or PICC peripherally inserted central

catheter PIN perforate–invaginate technique of

stripping PIOPED Prospective Investigation of

Pulmonary Embolism Diagnosis

study PISA-PED Prospective Investigative Study of

Acute Pulmonary Embolism

Diagnosis PMN polymorphonuclear neutrophil PN parenteral nutrition POL polidocanol PP primary patency rate PPG photoplethysmography ppRb phosphorylated protein

retinoblastoma PPV positive predictive value pRb protein retinoblastoma PREVAIT PREsence of Varices After

InTervention study PRF pulse repetition frequency proBNP prohormone of BNP PROM patient-reported outcome measure PSGL-1 P-selectin glycoprotein ligand-1 PSVs peak systolic velocities PT prothrombin time PTA percutaneous transluminal

angioplasty PTFE polytetrauoroethylene PTS post-thrombotic syndrome PTT partial thromboplastin time PV perforating vein PV popliteal vein PVI primary venous insufciency PVL primary venous leiomyosarcoma PVS peritoneovenous shunt PWS Parkes–Weber syndrome qd quaque die=every day QoL quality of life qPCR quantitative real-time polymerase

chain reaction RA right atrium RBC red blood cell RCC renal cell cancer RCT randomized controlled trial REVAS recurrent varices after surgery RF radiofrequency RFA radiofrequency ablation RFiTT radiofrequency-induced

thermotherapy RIETE Computerized Registry of Patients

with Venous Thromboembolism

RIJV right internal jugular vein rPSGL PSGL-1 receptor RR relative risk RV right ventricle rVCSS revised Venous Clinical Severity

Score RVF residual volume fraction RVO residual venous obstruction S&L stripping and ligation SA-β-Gal β-galactosidase SALP suction-assisted protein lipectomy SBP systolic blood pressure s-CT spiral computed tomography SDF-1 stromal cell-derived factor-1 SEPS subfascial endoscopic perforator

surgery SEV supercial epigastric vein SF-36 Short Form 36-Item health survey SFJ saphenofemoral junction SGP strain-gauge plethysmography SIR Society of Interventional Radiology SLE systemic lupus erythematosus SMA superior mesenteric artery SMC smooth muscle cell SNP single nucleotide polymorphism SNR signal-to-noise ratio SOB shortness of breath SP secondary patency rate SPE surgical pulmonary embolectomy SPGR spoiled gradient recalled echo SPJ saphenopopliteal junction SQ subcutaneous injection SSFP steady-state free precession SSV small saphenous vein STS sodium tetradecyl sulfate SVC superior vena cava SVI secondary venous insufciency SVS Society for Vascular Surgery SVT supercial vein thrombosis TAFI thrombin activatable brinolysis

inhibitor

99m

Tc-fSC

Tc–sulfur colloid TD thoracic duct TDD mechanical needle disruption

technique TDE thoracic duct embolization TED thromboembolic deterrent

stocking TEE transesophageal echocardiogram TF tissue factor TGC time gain compensation TGF-β1 transforming growth factor-β1 TIA transient ischemic attacks TIMP-1 tissue inhibitor of

metalloproteinases-1 TIPP transilluminated powered

phlebectomy TIPS transjugular intrahepatic

portosystemic shunt TLPS transarterial lung perfusion

scintigraphy

tumor necrosis factor-α

TNF-α

Abbreviations xxxiii

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TORPEDO Thrombus Obliteration by Rapid

Percutaneous Endovenous Intervention in Deep Venous

Occlusion trial tPA tissue plasminogen activator TREAT echo-shared angiographic technique TRICKS time-resolved imaging of contrast

kinetics TRISS Trauma Injury Severity Score TRPV transient receptor potential

vanilloid channel TSOAC target-specic oral anticoagulant TT thermal tumescent TVI total vascular isolation UE upper extremity UEDVT upper extremity deep vein

thrombosis UFH unfractionated heparin UGFS ultrasound-guided foam

sclerotherapy uPA urokinase plasminogen activator uPAR urokinase plasminogen receptor US ultrasound VAD venoactive drug VAS visual analog scale VATS video-assisted thoracoscopy VBAS V block–assisted sclerotherapy VCAM-1 vascular adhesion molecule-1 VCSS Venous Clinical Severity Score VDS Venous Disability Score

VEGF vascular endothelial growth factor VEINES-QOL/Sym venous insufciency epidemiologic

and economic study of quality of life

VESPA Venous Enhanced Subtracted Peak

Arterial study

venous lling index

VFI

VFT venous lling time

VISP Vitamin Intervention for Stroke

Prevention trial VITRO Vitamins and Thrombosis trial VKA vitamin K antagonist VLA-4 very late antigen-4 VLNT vascularized lymph node transfers VLU venous leg ulcer VM venous malformation Vn vitronectin VP ventilation–perfusion VQ ventilation and perfusion

scintigraphy VSDS Venous Segmental Disease Score VT vein thrombosis VTE venous thromboembolism VTOS venous thoracic outlet syndrome VV varicose vein VVSymQ Varicose Vein Symptom

Questionnaire vWF von Willebrand factor WBC white blood cell β2-GPI β2-glycoprotein I m micrometer

PART

Basic considerations

https://t.me/med1917

of venous disorders

1 A historical review of venous and lymphatic disease

Thomas F. O’Donnell Jr.

2 Development and anatomy of the venous system

Peter Gloviczki

3 The physiology and hemodynamics of the normal venous circulation

Frank T. Padberg Jr.

4 The epidemiology, genetics, and risk factors for acute venous thrombosis

Samuel Jessula and Anahita Dua

5 Pathogenesis and new insights into acute and chronic venous thrombosis

Andrea T. Obi, Peter K. Henke, and Thomas W. Wakeeld

Edited by Michael C. Dalsing

6 Epidemiology, genetics, and risk factors for chronic venous disease

Eri Fukaya

7 Pathogenesis and hemodynamics of varicose veins and chronic venous insufciency of the lower limb

John Blebea

8 Molecular mechanisms of chronic venous disease and its progression to venous leg ulcer

Joseph D. Raffetto and Raouf A. Khalil

9 Classication of chronic venous disorders of the lower limbs

Fedor Lurie and Patrick Sullivan

CHAPTER

A historical review of venous and

https://t.me/med1917

1.1 INTRODUCTION

Since this handbook focuses on the evidence for the diagnosis and treatment of venous and lymphatic disease, this chapter on the history of these disorders will emphasize methods investigators employed to provide evidence for the pathophysiology, diagnosis, and treatment. Fundamental to this understanding is how the perception of disease etiology during a specic era inuences treatment. Given the space limitations of the handbook, it will rely on the premise that “the guiding principles behind all historical writing must be selection and interpretation.” cess will focus the discussion of history to events before the twenty-rst century, the latter of which are contemporary periods covered in each of the individual chapters of the handbook. The chapter will be divided into venous disease: acute and chronic and lymphedema.

1.2 CHRONIC VENOUS DISEASE

The selection pro-

lymphatic disease

Thomas F. O’Donnell Jr.

1.1 The Ebers Papyrus—the earliest known historical docu-

mentation of varicose veins in the year 1550 treatment: “Instruction concerning swelling of blood vessels. If thou examine a swollen blood vessel under the skin of a limb and its aspect increases, becomes sinuous and serpentine, like something swollen with air, then thou will say concerning it, it is a swollen blood vessel—Thou shall not touch something like this.”

BC—warned against

1.2.1 The earliest evidence

The recognition of varicose veins can be dated back to the Ebers papyrus (1550 ) (Figure1.1). In this written record, as one of the two oldest preserved medical documents, varicose veins (VVs) are described as “torturous and solid with many knots, as if blown up by air.” discovery of a mummy from the New Kingdom or Egyptian empire (1580–1085), provided the rst evidence of a venous ulcer (VLU).

1.2.2 The Graeco-Roman period (332 BC–395 AD):The intertwining of philosophy and medical thought

The Greeks were the rst to view disease as an actual illness rather than as a punishment from the gods (Figure1.2). The Greeks’ contribution was based on philosophy with a rational system of thought, which was integrated into medical culture. Scientic inquiry to a great degree replaced superstition. Drawing on this logic, the Greeks explored the relationship not only between cause and effect but also on how certain treatments resulted in cure or failure.

DOI: 10.1201/9781003328971-2

The

Venous disease was one of the principal medical diseases of that time. Hippocrates, the “father of medicine,” recommended venous treatment because of its causal relationship to VLUs. He introduced vein puncture, cautery, and compressive bandages as forms of treatment and taught that standing up can aggravate VLUs. Fear of hemorrhage dictated that only minor operations be performed.

Hippocrates was inuenced by the prevalent theory of the day in developing his evidence for treatment of disease. The Pythagorean theory held that Nature was made of four elements (water, earth, wind, and re) and would serve as the basis for Hippocrates’s humoral doctrine—the body consisted of four uids, or “humors” (black bile, yellow bile, phlegm, and blood) (Figure1.3). An excess or decit of one of the four humors was thought to be responsible for disease. Specic to venous disease, Hippocrates believed that varices were lled with black bile but were outside main channels. As a result, physicians should avoid pressing humors back into the body because ulcers served as a drain to the outside for these humors. The humoral theory did not depend on religious beliefs or magic, but rather clinical signs with rational conclusions. It was to dominate medical thought for the next 15 centuries.

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