Critical limb ischemia

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Critical limb ischemia (CLI), also referred to as limb threat, is an advanced stage of peripheral artery disease (PAD). It is defined as a triad of ischemic rest pain, arterial insufficiency ulcers, and gangrene. The latter two conditions are jointly referred to as tissue loss, reflecting the development of surface damage to the limb tissue due to the most severe stage of ischemia. Compared to the other manifestation of PAD, intermittent claudication, CLI has a negative prognosis within a year after the initial diagnosis, with 1-year amputation rates of approximately 12% and mortality of 50% at 5 years and 70% at 10 years.[1]

CLI was conceived to identify patients at high-risk for major amputation, but the increasing prevalence of diabetes mellitus has led to a broader conception of limb threat that includes the risk of amputation associated with severely infected and non-healing wounds.[2]


Critical limb ischemia is further subdivided into rest pain and tissue loss:

Rest pain[edit]

Rest pain is a continuous burning pain of the lower leg or feet. It begins, or is aggravated, after reclining or elevating the limb and is relieved by sitting or standing. It is more severe than intermittent claudication, which is also a pain in the legs from arterial insufficiency.

Tissue loss[edit]

Tissue loss is the development of arterial insufficiency ulcers or gangrene due to peripheral artery disease.


Critical limb ischaemia is diagnosed by the presence of ischaemic rest pain, arterial insufficiency ulcers and gangrene. Other factors which may point to a diagnosis of critical limb ischaemia are a Buerger's angle of less than 20 degrees during Buerger's test, a capillary refill of more than 15 seconds or diminished or absent pulses.

Critical limb ischaemia is different from acute limb ischaemia. Acute limb ischaemia is a sudden lack of blood flow to the limb, for example caused by an embolus whereas critical limb ischaemia is a late sign of a progressive chronic disease.


Treatment mirrors that of other symptoms of peripheral artery disease, and includes modifying risk factors, revascularization via vascular bypass or angioplasty, and in the case of tissue loss, wound debridement.


In 2011 pCMV-vegf165 was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[3][4]

In 2014, a landmark clinical trial was initiated to better understand the optimal revascularization technique for the treatment of CLI. As of April 2017, the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) has enrolled nearly half of the 2100 patients needed to complete the trial.[5]A similar study, BASIL 2 (Bypass Versus Angio plasty in Severe Ischaemia of the Leg), is being conducted in the United Kingdom.[6]


  1. ^ Varu, Vinit N; Hogg, Melissa E; Kibbe, Melina R (2010). "Critical limb ischemia". Journal of Vascular Surgery. 51 (1): 230–41. doi:10.1016/j.jvs.2009.08.073. PMID 20117502. 
  2. ^ Mills, Joseph L; Conte, Michael S; Armstrong, David G; Pomposelli, Frank B; Schanzer, Andres; Sidawy, Anton N; Andros, George; Society for Vascular Surgery Lower Extremity Guidelines Committee (2014). "The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: Risk stratification based on Wound, Ischemia, and foot Infection (WIfI)". Journal of Vascular Surgery. 59 (1): 220–34.e1–2. doi:10.1016/j.jvs.2013.08.003. PMID 24126108. 
  3. ^ "Gene Therapy for PAD Approved". 6 December 2011. Retrieved 5 August 2015. 
  4. ^ Deev, Roman V; Bozo, Ilia Y; Mzhavanadze, Nina D; Voronov, Dmitriy A; Gavrilenko, Aleksandr V; Chervyakov, Yuriy V; Staroverov, Ilia N; Kalinin, Roman E; Shvalb, Pavel G; Isaev, Artur A (2015). "PCMV-vegf165 Intramuscular Gene Transfer is an Effective Method of Treatment for Patients with Chronic Lower Limb Ischemia". Journal of Cardiovascular Pharmacology and Therapeutics. 20 (5): 473–82. doi:10.1177/1074248415574336. PMID 25770117. 
  5. ^ Menard, Matthew T; Farber, Alik; Assmann, Susan F; Choudhry, Niteesh K; Conte, Michael S; Creager, Mark A; Dake, Michael D; Jaff, Michael R; Kaufman, John A; Powell, Richard J; Reid, Diane M; Siami, Flora Sandra; Sopko, George; White, Christopher J; Rosenfield, Kenneth (2016). "Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST‐CLI) Trial". Journal of the American Heart Association. 5 (7): e003219. doi:10.1161/JAHA.116.003219. PMC 5015366Freely accessible. PMID 27402237. 
  6. ^ Popplewell, Matthew A; Davies, Huw; Jarrett, Hugh; Bate, Gareth; Grant, Margaret; Patel, Smitaa; Mehta, Samir; Andronis, Lazaros; Roberts, Tracy; Deeks, Jon; Bradbury, Andrew (2016). "Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: Study protocol for a randomised controlled trial". Trials. 17: 11. doi:10.1186/s13063-015-1114-2. PMC 4704263Freely accessible. PMID 26739146. 

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