The Value of Toe Pulse Waves in Determination of Risks for Limb Amputation and Death in Patients with Peripheral Arterial Disease and Skin Ulcers Or Gangrene

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The value of toe pulse waves in determination of risks for limb amputation and death in patients with peripheral arterial disease and skin ulcers or gangrene

Stefan A. Carter, MD,a and Robert B. Tate, PhD,b Winnipeg, Manitoba

Objectives: The purpose of this study was to determine whether the presence of low amplitude of pulse waves recorded from the toes is related to the risk of subsequent amputation and death in patients with skin ulcers or gangrene and peripheral arterial disease, and how the risk of low wave amplitude relates to the risk associated with low peripheral pressures. Methods: A total of 309 patients with 346 limbs with skin lesions and arterial disease referred to the vascular laboratory were followed up for an average of 5 years (range, 1-8 years). Measurements were carried out to obtain ankle and toe pressures, pressure indices, and toe pulse wave amplitude. These variables were related to the risks of major amputation and total and cardiovascular death by means of the Cox proportional hazards model. Results: Low toe pulse wave amplitude (≤ 4 mm) was associated with increased risk of amputation (relative risks 4.20 in all limbs and 2.63 in those with toe pressure ≤ 30 mm Hg; P < .01). Wave amplitude remained significantly associated with increased risk of amputation after controlling for each pressure variable (P < .01). Low pulse wave amplitude and toe/brachial index were associated with increased risks of both total and cardiovascular death in all patients (relative risks ranged from 1.43-1.73; P < .05) and in those with toe pressure of 30 mm Hg or less (relative risks 1.56- 1.90; P < .05). Conclusions: Low toe pulse wave amplitude is related significantly to increased risks of amputation and death in patients with skin lesions and arterial disease. The presence of low wave amplitude provides significant information in addition to peripheral pressures with respect to the risk of amputation. (J Vasc Surg 2001;33:708-14.)

It is firmly established that patients with peripheral to the life and limb of patients with such low pressures.8 arterial disease have a high incidence of cardiovascular However, others found a better prognosis.9 Also, many events and death in addition to a risk of major amputation. patients with toe pressure of 30 mm Hg or less do not The rates of cardiovascular events and mortality are have clinical manifestations of critical ischemia and have a greater than can be accounted for by the presence of con- better prognosis than those with rest pain or skin lesions,9 ventional risk factors and increase with the severity of the suggesting that some patients have a better tissue perfu- obstruction as assessed with distal pressure measure- sion. Impaired perfusion and the resulting changes in the ments.1-5 In patients who also have skin ulcers, gangrene, microcirculation play an important role in bringing about or rest pain, the risks were reported to be extremely high, critical ischemia and its complications.6,7,10,11 Such and their fate was considered to be comparable to that of changes are associated with effects in remote vascular beds patients with a virulent malignancy.6 and may be related to the excessively high rates of cardio- The Second European Consensus Document pro- vascular events and mortality in patients with peripheral posed ankle systolic pressure of 50 mm Hg or less or toe arterial disease.12-14 systolic pressure of 30 mm Hg or less as hemodynamic evi- Abnormalities of various parameters related to micro- dence of critical ischemia.7 These criteria were challenged circulation have been demonstrated in limbs with arterial because of the finding of a worse than expected prognosis disease. However, no one method has been accepted as a routine laboratory procedure to evaluate distal perfusion. From the Departments of Medicine, Physiology,a and Community Health This is because measurements of microcirculatory parame- Sciences,b University of Manitoba, and Vascular Laboratory, St Boniface ters are more difficult to standardize than pressure mea- General Hospital.a surements and are often time-consuming. Pulse waves can Competition of interest: nil. be recorded from the toes quickly and easily with photo- Supported in part by a grant from the St Boniface General Hospital 15 Research Foundation. plethysmography. Their amplitude is related to blood Reprint requests: Stefan A. Carter, MD, Vascular Laboratory, St Boniface flow,16 and therefore, it can be considered to be a crude General Hospital, 409 Tache Avenue, Winnipeg, Manitoba, Canada, index of distal perfusion. Indeed, pulse wave or pulse vol- R2H 2A6 (e-mail: [email protected]). ume recordings have been recommended for the assess- Copyright © 2001 by The Society for Vascular Surgery and The American ment of circulation in diabetic patients7 and of limbs for Association for Vascular Surgery. 17,18 0741-5214/2001/$35.00 + 0 24/1/112329 severe ischemia. We reported that after controlling doi:10.1067/mva.2001.112329 for toe pressure and ankle/brachial index (ABI), the odds 708 JOURNAL OF VASCULAR SURGERY Volume 33, Number 4 Carter and Tate 709 for the presence of rest pain or skin lesions were about Follow-up and statistical analysis. The patients in four times higher in the presence of pulse waves with low this prospective cohort study were followed up with tele- amplitude compared with patients with high amplitude.15 phone interviews and the review of charts and health The primary aim of this study was to assess whether the records. The therapy of the patients including decisions presence of a pulse wave of low amplitude in the toes of concerning arterial reconstruction, amputation, and treat- patients with arterial obstruction and skin lesions is ment of those who did not undergo revascularization was related to the subsequent limb amputation and death. We managed by the patients’ attending physicians. Informa- also wanted to determine whether combination of mea- tion was sought about the occurrence and cause of death, surements of pressure and of pulse wave amplitude pre- major amputation, and reconstructive vascular surgery dicts prognosis better than pressure measurements alone. or angioplasty. A total of 213 patients (69%) died during follow-up. Those who did not die were followed up for an PATIENTS AND METHODS average of 5 years (range, 1-8 years). The follow-up was Patients studied. The study was approved by The 99% complete to 3 years and 95% to 4 years. Committee on the Use of Human Subjects in Research of Data of continuous variables are reported as mean ± the University of Manitoba. A total of 333 patients (378 SEM unless otherwise indicated. Pearson correlation extremities) with skin ulcers or gangrene were referred to coefficients were calculated for the relationships of the the vascular laboratory at St Boniface General Hospital continuous variables. The significance of the differences 1 over a period of 4 ⁄2 years. In 32 limbs of 24 patients, the between pairs of means was tested with the two-sample ABI and toe/brachial index (TBI) were greater than 0.90 Student t test. and 0.50, respectively, indicating either the absence of The Cox proportional hazards model22 was used to overt arterial disease or the presence of mild obstruc- assess the relative risks of major amputation and total and tion.19,20 These patients were excluded from further study. cardiovascular death associated with demographic and clin- The remaining 346 limbs of 309 patients were considered ical characteristics, with categoric variables of pressure cut- to have significant arterial disease. Severe obstruction was off values, and with the pulse wave amplitude 4 mm or less. defined by the presence of toe pressure 30 mm Hg or less. The categoric variable, a pulse wave amplitude of 4 mm or This subgroup consisted of 234 limbs of 217 patients. less, was previously demonstrated to be associated with Measurements. Pressure and pulse wave measure- increased odds ratios for the occurrence of rest pain, skin ments were carried out after each patient rested for at least lesions, or both.15 The reproducibility of this discriminant 20 minutes with the body and extremities covered with a value of amplitude was assessed previously.15 It was found heating blanket to buffer the measurements from the that in 96% of the limbs the amplitude remained below or potential effects of cool outdoor temperatures.15,21 The above 4 mm when tested on separate days. Interaction room temperature was approximately 23ºC. between the pressure variables and wave amplitude was Ankle, toe, and brachial systolic pressures were mea- tested for in the Cox models. The relative risks and 95% sured with the use of the previously reported meth- CIs were determined in the whole group with arterial dis- ods.15,19,20 The ABI and TBI were calculated as the ratios ease and in the subgroup with severe disease (toe pressure of the ankle and toe pressure to the brachial systolic pres- ≤ 30 mm Hg). Kaplan-Meier curves23 were constructed to sure, respectively. In 60 limbs (17%) of 52 patients, either illustrate the relationship of cutoff values of pressures and ankle pressures could not be measured because the flow of pulse wave amplitude to the outcomes. continued despite the inflation of the blood pressure cuffs In patients who had both legs with skin lesions in the to 300 mm Hg or the measurements were clearly unreli- study, the data from the limb with more severe disease able because of “partial arterial wall incompressibility” were used in the assessment of the risks for death. The when normal or near normal ankle pressures were associ- level of significance was set at 0.05 for all analyses. ated with grossly abnormal monophasic arterial flow sounds over the ankle arteries. Ankle pressures in these RESULTS limbs were considered as missing values. Toe pressures The objective of this study was to assess the relation- were measured routinely in the hallux. In 21 limbs, pres- ship of pulse wave amplitude, alone and with pressure val- sure was measured in the second toe because of previous ues, with the outcomes. Therefore, the results given below amputation or lesions of the hallux.20 In 16 limbs (4.6%), are based on 266 limbs (238 patients) in which there were lesions or amputations precluded measurement of pressure valid measurements of ankle and toe pressures and of toe in any digit. pulse waves. Implications of excluding the patients in Pulse waves were recorded from the plantar aspect of whom one or more of the three measurements were the toes with photocell plethysmography, and their ampli- unavailable is discussed. tude was measured in millimeters of deflection as described previously.15 The mean of measurements of at General characteristics of the patients least three pulse waves in the toe with the wave with the There were 139 men and 99 women with the mean largest amplitude was used. In 16 limbs (4.6%), waves age of 72 years ± SD 10 years and 74 years ± SD 9 years, could not be recorded because of extensive skin lesions or respectively. Thirty percent were current smokers, 45% amputation of all digits. were previous smokers, and 25% had never smoked. The JOURNAL OF VASCULAR SURGERY 710 Carter and Tate April 2001

Table I. Hemodynamic characteristics of limbs with arterial disease

Arterial disease (n = 266) Severe disease (n = 181)*

% Below % Below Variable Cutoff value Mean ± SEM cutoff value Mean ± SEM cutoff value

Ankle pressure 50 mm Hg 82 ± 2 17 68 ± 2 27 ABI 0.50 0.56 ± 0.01 46 0.47 ± 0.01 64 Toe pressure 30 mm Hg 25 ± 1 68 13 ± 1 100 Toe pressure 20 mm Hg — 50 — 73 TBI 0.10 0.26 ± 0.01 39 0.09 ± 0.01 53 Wave amplitude 4 mm 13 ± 1 41 7 ± 1 58

*Toe pressure ≤ 30 mm Hg.

presence of comorbidities was assessed on the basis of the were not associated with significantly increased risk of entries in the hospital charts and the physicians’ records. death. Renal failure was associated with increased risk of Ischemic heart disease was present in 45% of the patients, total and cardiovascular death (relative risks of 4.2 [95% cerebrovascular disease in 24%, hypertension and diabetes CI, 2.7-6.4] and 5.3 [95% CI, 3.3-8.3], respectively; P < each in 56%, and renal failure in 11%. .01). Older patients had a higher total and cardiovascular mortality rate with an increase in risk of about 30% for a Hemodynamic characteristics 10-year increase in age (P < .01). The presence of renal Table I shows the mean values of pressures and of failure or an increase in age was not associated with signif- pulse wave amplitude and percentages of the limbs below icantly higher risks of amputation. Ischemic heart disease, various cutoff values. Although 17% of the limbs in the cerebrovascular disease, hypertension, and smoking status whole group had ankle pressure of 50 mm Hg or less, were not significantly associated with increased risks of larger proportions had low toe pressure, ABI, TBI, and amputation or death. wave amplitude. In the group with severe disease, propor- Toe pressure and wave amplitude were significantly tions of limbs below the cutoff values were all larger. lower in the limbs with larger skin lesions, and ankle pres- As expected, there were highly significant correlations sure was higher in the diabetic patients. An increase in age among toe pressures, ankle pressures, and pulse wave was associated with a significant decrease in pressures and amplitude with P equal to .001 or less in all cases. The cor- pulse wave amplitude. There were no significant differ- relation coefficients were 0.69 between ankle and toe ences in the pressures or wave amplitude between patients pressure and 0.66 between ABI and TBI. The correlation with and without renal failure. Therefore, the effects of coefficients of ankle pressure and ABI with pulse wave hemodynamic variables on limb amputations were ad- amplitude were 0.37 and 0.39, and of toe pressure and justed for the presence of diabetes and the size of the TBI with wave amplitude, 0.50 and 0.53, respectively. lesions. The effects on death were adjusted for the age of Although significant, these values of the coefficients sug- the patients. gest that ankle pressures, toe pressures, and wave amplitude each provide different information. The relationship of the hemodynamic parameters to the outcomes Outcomes The effects on amputation. Table II shows the rela- Major amputation was carried out during follow-up in tive risks of a major amputation associated with the cutoff 73 limbs (27%). It was primary in 58 extremities and sec- values of the pressures and of the wave amplitude in all ondary in 15. Arterial reconstructive surgery was done in 266 limbs and in the subgroup of 181 limbs with severe 69 extremities (26%) and transcutaneous angioplasty in disease. All the pressure values below the cutoff points and three (1%). The total mortality rate during follow-up was the low wave amplitude were associated with a significant 66%. Cardiovascular death accounted for 80% of the increase in the risk of amputation. The relative risks asso- deaths. ciated with the low wave amplitude were as high or higher than the highest relative risk among the pressure cutoff The relationship of the demographic characteristics to points. Importantly, Table III shows that when wave the outcomes amplitude was included in models along with each pres- The presence of diabetes was associated with the rela- sure variable separately, the relative risk of amputation tive risk of 1.8 (95% CI, 1.1-3.0) for major amputation associated with low wave amplitude remained considerably (P < .05), but there was no significant effect of diabetes on and significantly increased in each case. the total or cardiovascular mortality rate. Larger skin Fig 1 shows the Kaplan-Meier curve for limb survival lesions (area > 2 cm2) were associated with the relative risk for all limbs and the four curves representing the sub- of 3.7 (95% CI, 2.3-5.9) for amputation (P < .001), but groups above and below the cutoff values of ABI and wave JOURNAL OF VASCULAR SURGERY Volume 33, Number 4 Carter and Tate 711

Fig 1. Limb survival in whole group and in subgroups according to ABI and pulse wave amplitude. ABI, Ankle/brachial index.

Table II. Relative risks and 95% CIs of major amputa- Table III. Relative risks and 95% CIs of major amputation associated with variables of pressure and pulse wave tion associated with low pulse wave amplitude (≤ 4 mm) amplitude after controlling for binary pressure variables

Arterial disease Severe disease Adjusted relative risks for Variable (73/266)* (64/181)* low wave amplitude

Ankle ≤ 50 mm Hg 2.80 (1.67-4.68)† 1.95 (1.15-3.32)‡ Pressure variable Arterial Severe ABI ≤ 0.50 4.19 (2.51-6.99)† 2.58 (1.45-4.58)§ controlled for disease disease Toe ≤ 30 mm Hg 4.20 (2.09-8.46)† — in the model (73/266)* (64/181)* Toe ≤ 20 mm Hg 3.24 (1.94-5.41)† 1.96 (1.04-3.69)‡ TBI ≤ 0.10 2.77 (1.73-4.41)† 1.76 (1.05-2.95)‡ Ankle 3.70 (2.17-6.33)† 2.36 (1.32-4.24)‡ Amplitude ≤ 4 mm 4.20 (2.56-6.89)† 2.63 (1.50-4.59)† ABI 2.67 (1.54-4.65)† 2.15 (1.21-3.81)‡ Toe (30 mm Hg) §2.97 (1.69-5.23)† — After controlling for the presence of diabetes and the size of the lesions. Toe (20 mm Hg) 3.08 (1.70-5.58)† 2.37 (1.32-4.24)† *Number of amputations/number of limbs at risk. TBI 3.38 (1.94-5.89)† 2.40 (1.35-4.27)‡ †P < .001. ‡P < .05. After controlling for the presence of diabetes and the size of the lesions. §P < .01. *Number of amputations/number of limbs at risk. †P <.001. ‡P <.01. §In all limbs with arterial disease, there was significant interaction between toe pressure (30 mm Hg) and pulse wave amplitude. The relative risk of amplitude (Appendix, online only). The risk of amputa- amputation was 2.61 (95% CI, 1.50 - 4.55; P < .05) in limbs with toe pres- tion was the greatest in the limbs in which the ABI and sure ≤ 30 mm Hg. Among the limbs with toe pressure > 30 mm Hg, there were only three limbs with pulse wave amplitude ≤ 4 mm, and all three pulse wave amplitude were both below the cutoff points. were amputated within 6 months. It was the lowest when both variables were above the cutoff points. In the limbs in which only one variable was below the cutoff point, the risk was intermediate. Low wave amplitude was associated with a higher rate of ampu- significantly associated with increased risk of total and car- tation in limbs with ABI both above and below 0.50. diovascular death in the whole group of 238 patients with The effects on mortality. Tables IV and V show the arterial disease, as well as in the subgroup of 168 patients relative risks for total and cardiovascular death, respec- with severe disease. When TBI and amplitude were tively, associated with the cutoff values of the pressures included together in the models, neither remained signifi- and of the wave amplitude. There was no significant asso- cant. Fig 2 illustrates that there was lower survival in ciation between the ankle pressure, toe pressure, or ABI patients with low pulse wave amplitude and that this sur- and increased risks of total death (Table IV). ABI and toe vival pattern was similar in patients with TBI below or pressure 20 mm Hg or less were significantly associated above 0.10 (Appendix, online only). with increased risk of cardiovascular death only in the One year after the entry into the study, 23% of the whole group (Table V). On the other hand, TBI of 0.10 patients were dead, 15% were alive but had a major ampu- or less and pulse wave amplitude of 4 mm or less were each tation, and 62% were alive without amputation. Fig 3 illus- JOURNAL OF VASCULAR SURGERY 712 Carter and Tate April 2001

Fig 2. Patient survival in whole group and in subgroups according to TBI and pulse wave amplitude. TBI, Toe/brachial index.

Fig 3. Total mortality and major amputation rates after 1 year of follow-up according to ABI and pulse wave amplitude. ABI, Ankle/brachial index.

Table IV. Relative risks and 95% CIs of all-cause death Table V. Relative risks and 95% CIs of cardiovascular associated with variables of pressure and pulse wave death associated with variables of pressure and pulse amplitude wave amplitude

Arterial disease Severe disease Arterial disease Severe disease Variable (158/238)* (113/168)* Variable (127/238)* (94/168)*

Ankle ≤ 50 mm Hg 1.26 (0.86-1.83) 1.24 (0.83-1.85) Ankle ≤ 50 mm Hg 1.38 (0.91-2.08) 1.30 (0.84-2.01) ABI ≤ 0.50 1.34 (0.98-1.84) 1.35 (0.91-2.02) ABI ≤ 0.50 1.50 (1.05-2.13)† 1.38 (0.89-2.14) Toe ≤ 30 mm Hg 1.10 (0.78-1.56) — Toe ≤ 30 mm Hg 1.27 (0.85-1.89) — Toe ≤ 20 mm Hg 1.33 (0.97-1.82) 1.54 (0.97-2.46) Toe ≤ 20 mm Hg 1.47 (1.03-2.10)† 1.57 (0.94-2.63) TBI ≤ 0.10 1.43 (1.05-1.96)† 1.58 (1.07-2.34)† TBI ≤ 0.10 1.73 (1.22-2.46)‡ 1.90 (1.22-2.96)‡ Amplitude ≤ 4 mm 1.54 (1.12-2.09)‡ 1.59 (1.08-2.35)† Amplitude ≤ 4 mm 1.66 (1.17-2.35)‡ 1.56 (1.02-2.39)†

After controlling for the age of the patients. After controlling for the age of the patients. *Number of deaths/number of patients at risk. *Number of cardiovascular deaths/number of patients at risk. †P < .05. †P < .05. ‡P <.01. ‡P < .01. JOURNAL OF VASCULAR SURGERY Volume 33, Number 4 Carter and Tate 713 trates the fate of the subgroups of patients after 1 year of finding is similar to reports that other measures of micro- follow-up according to the cutoff values of ABI and of circulation are useful in the assessment of prognosis in wave amplitude. When the ABI was 0.50 or less and toe addition to pressures.24,25 wave amplitude was 4 mm or less, the mortality rate was Although the amplitude of the pulse waves recorded about 50% higher, and the proportion of patients alive with plethysmography depends on the characteristics of with a major amputation was about three times higher the recording system, it is likely that systems other than than among patients with an ABI of 0.50 or less but ours for recording pulse volume or the wave amplitude higher wave amplitude. Those with an ABI of 0.50 or less with plethysmography would give similar findings.17,26 and high wave amplitude had a similar 1-year outcome to Although we chose the cutoff value of 4 mm on the basis patients with an ABI of more than 0.50. of our previous experience,15 other cutoff values (eg, 3 or 6 mm) gave similar results. This finding also supports the Patients with missing measurements notion that analyses of wave amplitude recorded with To compare the effects of pulse wave and pressure other systems would produce similar results. Because the variables alone and in combinations, we based the previous amplitude of the waves and the values of distal pressures results on the 238 patients in whose limbs there were valid are affected by temperature,15,21,27 it is important to mea- measurements of ankle and toe pressures and of toe pulse sure after the patient rests under a warming blanket to wave amplitude. Therefore, patients in whom one or more obtain reliable results. of these measurements were missing could not be It is unclear why low toe pulse wave amplitude is asso- included. The subgroup of the 71 patients with at least ciated with lower patient survival and worse prognosis to one missing measurement had similar percentages of the limb. Damping of the pulse waves distal to the site of patients with ischemic heart disease, cerebrovascular dis- obstruction results in a lower amplitude of the waves, sim- ease, hypertension, and similar smoking status compared ilar to the effect of the obstruction on the pressure val- with the sample without missing values. However, there ues.28,29 However, pulse wave amplitude also depends on was a higher percentage of diabetic patients (78% vs 56%) skin blood flow16 and may be related to events in the and more than twice the percentage of patients with renal microcirculation that are brought about by the presence of failure. As might be expected, patients in whom toe pres- severe ischemia.7,11,30 The presence of low amplitude of sure or wave recording or both could not be done had pulse waves recorded during reactive hyperemia was asso- more extensive lesions and a higher rate of amputation. ciated independently with the occurrence of ischemic On the other hand, those in whom the ankle pressure heart disease and related death.31 measurements were not valid or could not be obtained All our patients had arterial disease and skin lesions because of arterial wall calcification had a higher total and and thus fit the classification of Fontaine IV and the recent cardiovascular mortality rate, but the rate of amputation definition of critical limb ischemia of the TransAtlantic was similar to the rate in the group of patients with all the Inter-Society Consensus Group.32 Furthermore, two measurements. However, the inclusion of all patients with thirds of the sample consisted of patients with toe pressure the missing measurements did not change the percentage of 30 mm Hg or less, which indicates severe obstruc- of those who died during the first year of follow-up. The tion.7,9,18,20 The fate of our patients was generally similar percentage who were alive but had an amputation to that in recent findings from vascular surgical centers, increased from 15% to 19%. which, however, dealt with groups that tended to have more severe arterial disease, a fewer proportion of patients DISCUSSION with diabetes, and a higher rate (60%-90%) of surgical The results demonstrate that low amplitude of the intervention compared with 26% in our sample.33-35 In pulse waves recorded from the toes is associated with an the studies from surgical centers after 1 year of follow-up, increased risk of amputation and of total and cardiovascu- 20% to 32% of patients died, which is similar to the 23% of lar death in patients with skin lesions and arterial disease. our patients. The percentage of patients alive with a major This is the case in the analyses of all our patients and in the amputation after 1 year ranged from 21% to 26% in the subgroup with more severe disease (toe pressure ≤ 30 mm studies from surgical centers, compared with 19% in our Hg). Low values of all pressure variables are associated sig- series. The percentage alive without a major amputation nificantly with an increased risk of amputation. On the was 58% in our sample compared with a range of 47% to other hand, a TBI of 0.10 or less is the only pressure vari- 55% in the surgical series. These results on amputation and able associated significantly with increased total death and death are similar to other estimates7,32 and also suggest has the strongest association with increased cardiovascular that although arterial surgery decreases the severity or death among the pressure variables. Importantly, eliminates arterial obstruction and thus improves progno- increased risks associated with a low wave amplitude, with sis for the limb, the mortality rate does not appear to be few exceptions, are as high or higher than the risks associ- altered. This is likely due to the fact that patients who have ated with low pressure values. The risk of a major ampu- severe arterial obstruction with skin breakdown and criti- tation associated with the combination of low ankle or toe cal limb ischemia represent a group with severe general- pressure variables with low pulse wave amplitude is greater ized atherosclerosis with involvement of the vessels that than the risk associated with individual variables. This supply the vital organs. JOURNAL OF VASCULAR SURGERY 714 Carter and Tate April 2001

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Neumann FJ, Waas W, Diehm C, Weiss T, Zimmermann R, Tillmanns Submitted May 24, 2000; accepted Sep 5, 2000.