Current opinions about the definition of critical limb ischemia: A debate still open after three decades

Abstract

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease. It is clinically defined as rest pain with or without skin ulcer or gangrene and carries a very poor prognosis with a high rates of limb amputation and cardiovascular mortality. Despite the first definition of CLI has been published more than 30 years ago, the debate about what it really is, is still open. Over the years the hemodynamic parameters utilised to define the critical level of limb perfusion have changed. This has raised some question about the apparent confusion about the definition of CLI. Moreover, a new term such as “limb threatening ischemia” has replaced the definition of CLI in recent guideline. Therefore, it becomes necessary to understand the evolution of the concept and the definition of CLI, to interpret the future trend.

Hence, this work analysing the guideline documents on peripheral arterial disease that have defined the CLI to date, aims to clarify the path that has brought to the current conceptual changes of the definition of CLI.

Keywords

Critical limb ischemia limb amputation risk chronic limb threatening ischemia

1. Introduction

Critical limb ischemia (CLI) is determined by the most advanced stage of peripheral arterial disease (PAD). It is clinically defined as rest pain with or without skin ulcers or gangrene [1, 2] and is associated with macro but also with microcirculatory as well as with rheological disorders [3]. CLI carries a very poor prognosis with a high rates of limb amputation and cardiovascular mortality [1].

Despite the first paper on CLI has been published in 1982 [4] till now the debate about its definition is still open. Almost all the guidelines on PAD have agreed on clinical definition of CLI as rest pain with or without skin ulcers or gangrene, but the discussion remains open about the hemodynamic criteria. The thresholds proposed by TASC II in 2007 [1] are higher than those qualifying CLI by the Second European consensus document on chronic critical leg ischemia [5].

Furthermore, an emerging new definition of “limb threatening ischemia” has recently replaced the term CLI in the last European Society of Cardiology PAD guidelines [6].

Hence this work wants to analyse how the most utilised guidelines on PAD have defined the CLI to date in order to clarify the path that has brought to the current discussion about the definition of CLI.

2. Methodology and results

A revision of the most consulted PAD guidelines and classifications from the 1982, year of the first publication of the term CLI to date has been conducted. The guidelines and classifications examined have been:

European consensus on Critical Limb Ischemia, 1989 [7];

Second European Consensus document on Chronic Critical Leg Ischemia, 1992 [5];

Recommended Standards for Reports Dealing with Lower Extremity Ischemia: revised version, 1997 [8];

Management of Peripheral Arterial Disease (PAD). TASC Working Group. TransAtlantic InterSociety Consensus, 2000 [9];

Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II), 2007 [1];

Guidelines for Critical Limb Ischaemia and Diabetic Foot, 2011 [10];

Update and Validation of the Society for Vascular Surgery Wound, Ischemia, and Foot Infection threatened limb classification system, 2014 [11];

American Heart Association (AHA) Guideline on the Management of Patients with Lower Extremity Peripheral Artery Disease, 2016 [12];

European Society of Cardiology (ESC) Guidelines on the Diagnosis and Treatment of Peripheral Arterial Disease, 2017 [6].

The clinic and hemodynamic criteria for defining the CLI have been reported for each document and results are shown in Table 1.

Table 1
Definition criteria of CLI in guidelines

Clinical definition Ankle/brachial index Systolic ankle pressure Toe ankle pressure TcPO2

EWG consensus [7] Rest pain >2 weeks, or ulceration or gangrene of the foot ≤50 mmHg

EWG II consensus [5] Rest pain >2 weeks, or ulceration or gangrene of the foot ≤50 mmHg ≤30 mmHg

Rutherford classification [10] Class 4 ischemic rest pain <40 mmHg <30 mmHg

Class 5 minor tissue loss nonhealing ulcer, focal gangrene with diffuse pedal ischemia <60 mmHg <40 mmHg

Class 6 major tissue loss extending above TM level, functional foot no longer salvageable

TASC [9] Rest pain more than 2 weeks, with or without ulcers or gangrene attributable to PAD <50–70 mmHg ≤30–50 mmHg ≤30–50 mmHg

TASC II [1] Rest pain, ulcers or gangrene attributable to PAD <50 mmHg rest pain <30 mmHg. rest pain ≤30–50 mmHg

<70 mmHg ulcers or gangrene <50 mmHg, ulcers or gangrene

Guidelines for critical limb ischaemia and diabetic foot. [10] Rest pain or a wound, ulcer or toe gangrene

WIfi classification [11] Ischemia grade 3 <0.39 ≤50 mmHg ≤30 mmHg.

AHA/ACC PAD guideline [12] Chronic (>2 wk) ischemic rest pain, nonhealing ulcers, or gangrene attributable to PAD.

	Clinical definition	Ankle/brachial index	Systolic ankle pressure	Toe ankle pressure	TcPO2
EWG consensus [7]	Rest pain >2 weeks, or ulceration or gangrene of the foot		≤50 mmHg
EWG II consensus [5]	Rest pain >2 weeks, or ulceration or gangrene of the foot		≤50 mmHg	≤30 mmHg
Rutherford classification [10]	Class 4 ischemic rest pain		<40 mmHg	<30 mmHg
	Class 5 minor tissue loss nonhealing ulcer, focal gangrene with diffuse pedal ischemia		<60 mmHg	<40 mmHg
	Class 6 major tissue loss extending above TM level, functional foot no longer salvageable
TASC [9]	Rest pain more than 2 weeks, with or without ulcers or gangrene attributable to PAD		<50–70 mmHg	≤30–50 mmHg	≤30–50 mmHg
TASC II [1]	Rest pain, ulcers or gangrene attributable to PAD		<50 mmHg rest pain	<30 mmHg. rest pain	≤30–50 mmHg
			<70 mmHg ulcers or gangrene	<50 mmHg, ulcers or gangrene
Guidelines for critical limb ischaemia and diabetic foot. [10]	Rest pain or a wound, ulcer or toe gangrene
WIfi classification [11]	Ischemia grade 3	<0.39	≤50 mmHg	≤30 mmHg.
AHA/ACC PAD guideline [12]	Chronic (>2 wk) ischemic rest pain, nonhealing ulcers, or gangrene attributable to PAD.

3. Discussion

Examining the definition of CLI in the guidelines and classifications that have succeeded in the spam of almost 30 years, it is clear that all documents have agreed on the clinical definition of CLI as rest pain with or without skin ulcers or gangrene. But regarding the hemodynamic criteria there is an evident variation of threshold values to date.

In 1989 the EWG defined the systolic ankle pressure (SAP) ≤50 mmHg to select CLI as more accurate than ankle brachial index (ABI) [7]. In 1991 the EWG, including the diabetic patients in CLI definition, addressed the systolic toe pressure (STP) ≤30 mmHg as more accurate than SAP to select CLI, because the higher calcification of foot arteries in the diabetics [5]. In 1997 Rutherford, suggesting a different need of perfusion to heal the skin lesion of CLI, recommended SAP < 40 mmHg or STP < 30 mmHg as class 4, ischemic rest pain and SAP < 60 mmHg or STP < 40 mmHg for class 5, minor tissue loss and class 6, major tissue loss [8]. The TASCs changed again the thresholds suggesting SAP < 50–70 mmHg or STP≤30–50 mmHg and introducing TcPO2≤30–50 mmHg to select CLI [1, 9].

In 2011, the European Society of Vascular Surgery, highligthing the confusion, stated that the STP and TcPO2 were indicated to select CLI, avoiding indicating any cut off value for CLI [10].

Coming to more recent period, in 2014, the Society for Vascular Surgery, in the Threatened Limb Classification System: risk stratification based on wound, ischemia, foot infection (WIfi) defined ischemia from grade 0 to 3 and the grade 3 by ankle brachial index (ABI) <0.39, SAP≤50 mmHg or STP≤30 mmHg [11], In 2016 the AHA guideline on PAD, proposed to define CLI measuring ABI, Toe brachial index (TBI), TcPO2, or skin perfusion pressure (SPP) not indicating any value to define CLI [12]. Finally, in 2017 the PAD ESC guidelines endorsed the WIFI classification criteria [6].

The data of this study highlight a struggled investigation about the best hemodynamic parameter to select CLI over the years. But the systolic ankle pressure (SAP) or the systolic toe pressure (SPT) that have been reported as the most recommended procedures to measure the level of limb ischemia, have had a lot of variation. In guidelines their values ranged from 50 mmHg and ≤30 mmHg in 1992 [5] by 50–70 mmHg and 30–50 mmHg in 2007 [1]. This means as observed to the European Society of Vascular Surgery that patients categorized as CLI by TASC II cannot be qualified using the second European consensus definitions.

This apparent confusion in threshold values is to be understood as the result of the evolution of the concept of the CLI over the time.

It has been necessary to widen the indications to the actual need of treatment of revascularization. The continuous variation of hemodynamic parameters over the years seems to be a necessary step to include within the CLI definition all those patients with PAD and not healing skin lesions. This category of patients, with high risk of limb amputation, would benefit from the revascularization of the lower limb.

If in 1992 the diabetic patients would had been out of the definition of CLI they could not being indicated for treatment [5]. Therefore, over the years the haemodynamic criteria of CLI have been varied in order to allow the revascularization to a greater number of patients that. according to the criteria of previous years, would have been excluded from the treatment.

Very recently a position paper of European Society of Vascular Medicine (ESVM) has reported some confusion about the definition of CLI caused by the uncertain hemodynamic definition criteria [13].

If by one hand the opinion of the ESVM highlights the need of a consensus about the haemodynamic criteria for CLI [13], on the other hand the diagnosis of CLI cannot be reduced to a mere search of a numerical value. It would be not aware of the complexity that characterizes the patient.

So, the search of a single hemodynamic parameter that defines the CLI may not be a good strategy because the amputation risk is not only solely determined by the presence of ischemia but also by other factors.

In fact, as evidenced by the WIFI classification the role of ischemia has changed in the definition of CLI over the last 30 years. The ischemia maintains an important role but is one of the factors with the level of infection and the size of the wound, to determine the risk of amputation and the need for revascularization of the limb [11].

The modern concept of a CLI as a multifactorial nosologic entity is much closer to the patient’s clinical need than an anatomical lesion of the peripheral arterial tree that leads to hypoperfusion and ischemia. The CLI cannot be summarised only by a measure of a hemodynamic parameter. It is a complex clinical condition influenced by systemic conditions of the patient.

The WIfi classification has switched off to a different view of the CLI introducing the new term of Limb Threatening Ischemia [11] that has been endorsed by the European Society of Cardiology replacing the term CLI in the last guidelines on PAD [6].

The definition of LTI as expressed by WIfi classification could have a remarkable success because it has a greater adaptability to the patient’s condition with skin lesions and PAD. In particular, the success of the LTI definition could be sustained by the enormous increase in endovascular procedures in patients with peripheral arteriopathy and skin lesions that do not heal. As witnessed by the high salvage limb of some studies and also by recent meta-analyses [14 –16].

In fact, the healing of the wounds of these patients depends not only on the degree of ischemia, but also on the extent and depth of the wound and the presence and severity of the infection. Thus, as reported by Mills some patients with moderate ischemia can heal faster with revascularization or even require healing of large wounds, even if they do not meet the current CLI criteria. Other patients with CLI can heal with wound care alone, without revascularization, or can be managed with analgesics for long periods of time while maintaining a functional limb [11].

The new term of LTI seems to be the one that currently responds better to the needs of patients. It is also likely that this new definition might replace the term of CLI in the next future. Hence it should therefore be recalled that the term CLI has had a strong impact in the improvement of the prognosis for the patient with PAD. Before the appearance in the nosology of the definition of CLI the PAD was imagined and treated as a slow progression disease, leading the patient to an unavoidable amputation of the limb. After the definition of CLI in nosology, the prognosis with respect to limb salvage and survival in CLI patients and in the whole population of PAD patients, has improved over the years [17 –22].

Large population-based studies in a heterogeneous PAD population >65 years of age have highlighted that the adjusted odds ratio of lower extremity amputation per year between 2000 and 2008 was 0.95 (95% CI:0.95–0.95, P < 0.001) [23, 24]. Guidelines regarding CLI definition strongly influenced the work also in highlighting the importance of secondary prevention in PAD survival, such as smoking cessation, management of hypertension and diabetes, lipid lowering, and antiplatelet therapies [25]. Today all PAD and CLI guidelines consider the effectiveness of statins, antiplatelet therapy, and ACE inhibitors to reduce cardiovascular events and mortality proven in the PAD population [7, 13]. Moreover, to the statin therapy is associated an improved infrainguinal autogenous venous graft patency, with a 3.2-fold increased risk of graft occlusion in patients without therapy with statins [26].

4. Conclusions

This work shows how over the years the guidelines on PAD have reported different definitions of CLI’s diagnostic criteria particularly of hemodynamic criteria. However, it seems that the concept of CLI has advanced over the year and that the lack of consensus on the definition of the hemodynamic values has been only the evolution of the concept of CLI itself. In recent years ischemia seems to have lost the role of the only factor determining the risk of amputation. Today, ischemia is considered one of the factors, along with the severity of the infection and the characteristics of the lesion. Ischemia continues to have a significant role in the management of the patient with CLI, but it does not seem that the identification of a single or multiple numerical factors would define the need to revascularize a limb with CLI.

Because of this new concept of the CLI, this work, even with its limit, wanted to outline some features that have led to the evolution of the definition and the concept of CLI in the hope of being helpful for future works.

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