Masterclass Guides: Critical Limb Ischaemia

March - April 2023

GUIDES

Introduction

This Masterclass Guide provides a concise overview of critical limb ischaemia.

Critical Limb Ischaemia

Keywords

■ Peripheral arterial disease (PAD)

■ Atherosclerosis

■ Critical limb ischaemia

What is Critical Limb Ischaemia?

■ Critical limb ischaemia occurs in 5-10% of patients with Peripheral Arterial Disease (PAD), a chronic condition, usually caused by atherosclerosis (Figure 1), that results in lower extremity arterial obstruction and poor circulation. Early stages of PAD are often asymptomatic. As the disease progresses, patients may develop intermittent claudication or chronic limb-threatening ischemia (CLTI)1,2

■ It is characterized by resting lower extremity pain, ulceration, gangrene, increased risk of cardiovascular events, amputation, and death1,2

■ Prevalence is high among elderly patients with PAD affecting between 1520% of individuals over the age of 70 years3

■ As lipids accumulate within vessel walls there is subsequent hardening causing a significant reduction in blood flow to target tissues4

■ The corresponding reduction in oxygenation at peripheral tissue can lead to claudication or resting pain5,6

■ CLTI carries a mortality rate of 20% within 6 months of diagnosis and 50% at 5 years5,6

Diagnosis

■ The diagnosis of CLTI involves clinical findings (such as ischemic rest pain) and objective findings including ankle-brachial pressures

■ (<50 mmHg with rest pain or <70 mmHg with foot ulcer or gangrene), toe systolic pressure (<30 mmHg with rest pain or <50 mmHg with foot ulcer or gangrene), and transcutaneous oxygen pressure (<30 mmHg with foot ulcer or gangrene) (Figure 2)7

Impact

■ The prevalence of CLTI is projected to grow in coming years as the trend in risk factors such as age, diabetes, smoking, and the unknown effects of vaping product use increases

■ The poor clinical prognosis associated with CLTI leads to significant reduction in quality of life (QOL) due to ischemic resting pain, non-healing ulcers, and recurrent infection8

■ Chronic limb ischemia not only affects the patient, but also impacts caregivers who must handle the patient’s lack of mobility, pain control needs, wound care, and other issues

■ Economically, the annual cost of new Medicare patients with CLTI alone is $12 billion9

■ This healthcare cost is largely attributed to high inpatient expenditure, need for complex wound care and interventions, prolonged hospitalizations, and high readmission rates

■ Vascular disease

■ Ankle brachial pressure index (ABPI)

■ Diabetes

Presence of chronic ischemic rest pain plus Ankle pressure <50 mmHg or Toe pressure <30 mmHg

Presence of foot ulcers or gangrene plus Ankle pressure <70 mmHg

Toe systolic pressure <50 mmHg or TcPO2 <30 mmHg

Figure 2:

Figure 1: Atherosclerosis.

Critical Limb Ischaemia

Management and Treatment of Critical Limb Ischaemia

■ Due to the complex poly-vasculopathy associated with PAD, a holistic approach to management is needed7

■ Management with early-stage PAD or advanced stage CLTI should focus on pain management, promotion of wound healing, reduction of cardiovascular risk factors, and optimization of glycemic control

■ Pain management is fundamental to improve quality of life

■ Common modalities for treating pain include peripheral revascularization; however, for those unable to undergo revascularization acetaminophen and nonsteroidal antiinflammatory drugs are often first line

■ Scheduled dosing of analgesics is superior to an as-needed regimen for sustained relief

■ Some pain associated with PAD may be neuropathic, prompting a careful differential in evaluating pain as the use of neuropathic pain agents may provide the best control

■ Cardiovascular risk factors should be managed with a multifaceted approach

■ Smoking cessation should begin early and routinely addressed as it has been shown to reduce mortality and improve amputation-free survival10

■ Uncontrolled dyslipidemia contributes to the development and progression of PAD and can be treated with statin therapy to reduce cardiovascular events11

■ Hypertension should be controlled according to guidelines

■ Hyperglycemia is a risk factor of PAD and attention to glycemic control is required. Glycemic control involves both medication management and subsequent monitoring of HbA1c, which has been shown to be a predictor of major amputation12,13

■ Antiplatelet therapy with aspirin or clopidogrel is indicated for secondary prevention in patients with PAD

GUIDES

■ Use of intermittent pneumatic compression (IPC) devices have become an alternative treatment for patients unable to undergo angioplasty, open reconstruction, or without reconstruction options

■ IPC devices utilize sequential inflation and deflation compression pressure targeted to the affected limb

■ Mechanistic evaluation of IPC devices has revealed increased distal perfusion through increased popliteal, gastrocnemial, collateral arterial, and skin blood flow in patients with CLTI14

■ Evaluation with Doppler ultrasound identifies similar increases in both cutaneous and arterial perfusion following IPC use15-18

■ It has been postulated that IPC devices enhance blood flow through increasing the arteriovenous pressure gradient14

■ As blood is forced proximally out of the dependent foot and calf there is a reduction in the venous pressure19

■ Reduced venous pressure increases the arteriovenous pressure gradient augmenting arterial inflow20

■ The integrity of the arteriovenous pressure gradient is an important component of local vasoregulation via the venoarteriolar reflex (VAR) and has been shown to be impaired in patients with PAD. The VAR is an adaptive mechanism that creates venous distention, precapillary vasoconstriction, and subsequent decrease in capillary uptake in the sitting position21,22

■ As blood is moved proximally out of the dependent leg there is a decrease in venous pressure that allows precapillary sphincters to dilate again

■ Use of IPC devices has been found to temporarily suspend the VAR by increasing blood flow and temporarily abolishing postural vasoconstriction20

■ To summarize, proposed mechanisms for the effects of IPC include increased arteriovenous pressure gradient, stimulation of endothelial vasodilation, suspension of the VAR, and stimulation of collateral artery angiogenesis14,20,23

■ IPC devices are available as foot only, calf only, foot and calf, or foot, calf, and thigh. These devices utilize high pressure compression in the range of 80 - 140 mmHg with variable cycling each minute. IPC devices are typically prescribed to be used for 4 - 6 hours if CLTI has resulted in wounds, or rest pain is present24

■ A recent systematic review of available IPC devices found improvements in limb salvage, major adverse cardiovascular events, pain relief, quality of life, wound healing, and hemodynamics, varying by protocol and device used24

Holistic approach

Intermittent Pneumatic Compression and Venoarteriolar Reflex

GUIDES

Stimulation of the lymphatics and production of Nitric Oxide (NO) hypothesis

■ Underrecognized in the context of PAD and the use of arterial stimulation by IPC are the effects seen within the lymphatic system. Similar to the arterial endothelium, the lymphatics produce Nitric Oxide (NO) during contraction as a result of shear flow25

■ The lymphatic bulb-valve regions appear to contain the largest density of eNOS, producing approximately a 30 - 50% higher NO concentration compared to the tubular regions25

■ Under environments of increased fluid shear across the lymphatic endothelium there is increased production of NO which causes suppression of lymphatic contraction and pumping (Figure 3)26-29

■ However, the role of NO within the lymphatic system during periods of high lymphatic flow can be thought of as a 'brake' that decreases contractility while simultaneously increasing the diastolic relaxation period, thereby allowing adequate lymphatic refilling and stroke volume30,31

■ This paradoxical effect of NO on lymphatic contractility does not account for increased fluid movement unless the importance of diastolic relaxation is appreciated. IPC use in patients with PAD seems to result in improved fluid management and redistribution from the tissue beds

■ It is hypothesized that stimulation of the lymphatics and production of NO via increased shear force results in increased diastolic relaxation and subsequent filling within the lymphatics and therefore allows for a delayed, albeit increased stroke volume of lymph fluid increasing the propensity of immune cell recognition and activation and increased immune surveillance

■ Beyond increased immune surveillance, NO is also known to exert innate broad-spectrum antimicrobial activity through multiple mechanisms described in the literature without any observation of antimicrobial resistance32-36

■ This is an important area of continued study as systemic production of NO via IPC use or supplementation with L-arginine as a precursor to NO production may be of benefit from not just an arterial point of view, but lymphatic as well

Critical Limb Ischaemia

Case study

■ To further illustrate this notion, a case-example is given of a patient presenting to the wound clinic after smoking cessation 3 years prior for progressive wounds. Additional pertinent information includes recent angiogram and stent placement, tibial run off, and an ABI 0.65.The patient was evaluated and brought to the operative suite for wound debridement using ultrasonic debridement (Misonix, Farmingdale NY, United States) with a polyhexamethylene biguanide solution. Initial consultation and post-operative debridement is shown in Figure 4 and Figure 5, respectively

■ Following debridement, the patient was prescribed moist-to-moist hypochlorous acid (Vashe®, Urgo Medical North America, Fort Worth, TX), changes 3 times daily while in the hospital in addition to a robust micronutrient regimen including: 1 mg folate daily, 1 mg vitamin B12 daily, 10,000 IU vitamin D daily, 1 tablet MPFF twice daily, and 2,000 IU vitamin C Daily. She was prescribed IPC (ArtAssist® AA-1000, ACI Medical, San Marcos, California, United States) use dosing for a total of 6 hours daily with her leg in a gravity dependent position. Initially, the patient could not tolerate compression on the affected right side due to pain and was only applied to her unaffected contralateral limb. After approximately 3 weeks, granulation tissue on the affected right leg improved with decreased pain, allowing bilateral IPC compression use

■ The goal of using the IPC device on the unaffected limb was to establish a systemic increase in NO production for possible benefit in the wound dependent limb until IPC could be tolerated. Direct manual-lymph drainage (MLD) was also utilized like dermal stimulation with fuzzy-whale 8mm longitudinal compression (Edemawear®, Quart Medical, Kitchener, Ontario, Canada). Edemawear® works through dermal microdeformation, similar to the effects seen in negative pressure wound therapy (NPWT) that has been well documented to support wound healing37,38

■ Microdeformation in the totality of the wound bed results in a pulling shear force stimulating GCX restoration and biofluid movement. This concept was validated in a recent murine model study, but also highlighted the stimulation to endothelial GCX regeneration is vitally linked to the lymphatic regeneration capabilities which resonates with the improve fluid mobility seen in the patient.39 IPC use in patients with CLTI also stimulates the lymphatics, which would teleologically be appropriate given the decreased rates of cellulitis, improved angiogenesis, and dermal regeneration seen, all of which relate to lymphatic system functionality

■ This regimen provides a well-tolerated form of compression for patients with ABIs of 0.4 and above. As the 8mm compression is not constrictive, it is well tolerated by patients with pain. Functionally, there are benefits from the effects of stimulating dermal lymphatic functionality, decreasing interstitial edema in cases of extreme CLTI, and therefore increasing microvascular perfusion at the 5-micron level with resolution of underlying interstitial edema

Figure 4: Initial consultation right lower extremity CLTI. Figure 5: Post-operative debridement right lower extremity CLTI.

Figure 3: Shear-induced Nitric Oxide Production via Heparan Sulfate and Glypican-1 Mechanotransduction and PECAM1- Phosphorylation leading to eNOS activation and NO synthesis.

Critical Limb Ischaemia

Discussion

■ There is a significant proportion of patients with PAD or CLTI who are not candidates for conventional revascularization procedures. In these patients there is clear benefit from the use of IPC devices, including decreased rates of amputation, improved wound healing, increased QOL, and reduced pain17,24,40,41

■ Although causality study designs are lacking, numerous proposed mechanisms for the microvascular changes associated with PAD/ CLTI have been published

■ The potential effects IPC devices may have on these microvascular changes have unfortunately not been established to date. The improved oscillatory micro shear and subsequent re-establishment of GCX intracellular signal transduction with continued IPC use may play a role in the regeneration of healthy vascular endothelium

■ Pre- and post-treatment biopsy evaluation following IPC use may allow for the objective and anatomical understanding of the microvascular effects seen with IPC use in PAD/CLTI

■ The importance of continued investigation into the systemic effects of endothelial cell dysfunction remains prudent to advancing arterial, venous, and lymphatic disease