Mortality After Lower Extremity Amputation: What We Know Now

Nearly every day while discussing diabetic foot education and preventative care, a patient will tell me they knew someone who had a diabetic foot ulcer followed by amputation(s), and who later passed away. These patients already understand that a link between amputation and death exists without any academic understanding of the process. At the same time, I’ve heard patients half-jokingly request a replacement leg and refer to Oscar Pistorius, the double amputee who competed in the 2012 Olympics. It seems fair to say that patients understand there is a difference in young, otherwise healthy amputees and those suffering from peripheral vascular disease and diabetes.

Wukich and colleagues reported major amputation as the most feared complication of diabetes, even greater than death itself.¹ This fear may be more founded than it initially sounds. Patients with diabetes and amputations score very low on quality of life assessments.² However, this does not necessarily mean major amputation is always the least desirable outcome when compared to other options in patients with diabetic ulcerations or in heroic limb salvage cases. Confounding the association of low quality of life and major amputation, some authors have found that low scores on quality of life assessments may actually predict amputation and death.³ This suggests it is not a direct cause and effect relationship.

Some studies report improved quality of life after major amputation in those who are able to ambulate,^4,5 a concept emphasized by Wukich and Raspovic.⁶ If not specifying ambulation status, evidence reveals little or no difference between minor amputation, ulceration, or major amputation,^2,7,8 although infected ulcerations seem to result in the lowest quality of life scores.² A recent systematic review concluded that ambulating with a prosthesis showed the greatest improvement in quality of life following major amputation.⁹

Thus, aside from an active infection, it appears that losing one’s ability to ambulate should truly be among the most daunting complications of diabetes. It is possible that patients intuitively associate amputation with the loss of ambulation and thus have chosen amputation on surveys as a symbol or proxy for loss of ambulation.

Although not feared as much as amputation, death is certainly a reasonable fear. Five-year mortality after major amputation ranges from 40–82% after below-knee amputations and 40–90% after above-knee amputations, with an overall average of about 62%.^10,11 A myriad of studies consistently demonstrate higher mortality rates with more proximal amputations.^12–19

A Closer Look at the Stats on Amputation and Mortality

However, even minor amputations show high mortality, as evidenced by a recent meta-analysis demonstrating a 5-year mortality rate of 44%.²⁰ Even without having an amputation, the 5-year mortality in those with ulcerations is roughly 40%.²¹ In patients with critical limb ischemia, reports place the same number at 43%.²²

Mortality after amputation shows associations with advanced age, renal disease, peripheral vascular disease, coronary artery disease, cerebrovascular disease, dementia, and frailty scores.^10,11,23 The primary cause of death seems to be secondary to vascular complications rather than directly from the amputation. One study found the risk of death from vascular disease (mainly cardiac and cerebrovascular disease) was 11 times greater than from amputation or ambulation-related conditions (pneumonia, sepsis, pressure ulcer).²⁴ While studies often report cause of death based on what individuals die with rather than what they die of, the consensus strongly suggests that vascular disease is the predominant cause of mortality.

Combining the above data helps elucidate both the reason for mortality and what we may do to prevent it. With a baseline mortality of just below 50% in 5 years for those individuals with either ulcerations or critical limb ischemia, it is unlikely that by avoiding an amputation we would decrease mortality much beyond this level without additional interventions. Many individuals undergoing major amputation have already had either an ulceration and/or critical limb ischemia, and a substantial percentage of them have undergone a minor amputation before progressing to a major amputation. Studies also find advanced age to be associated with more proximal amputation.¹⁰ Thus, some increase in mortality rate in major amputations compared to those with ulcerations or minor amputations would be expected, in addition to the inherent risk the actual amputation itself entails. It is interesting to note that minor amputations have a very similar mortality rate to those with ulcerations. This may correlate with the rate of ambulation following different amputation levels. The influence ambulation has on mortality is a very intriguing explanation. Correlation is not causation and caution must be taken.

How Does Ambulation Status Connect With Mortality?

Impaired ambulatory status, even prior to ulceration, is a predictive factor for both future major amputation and significantly higher mortality.²⁵ This association may indicate overall poor health status, which could also increase amputation risk. With this in mind, it is difficult not to be persuaded that the inability to ambulate might contribute, at least partially, to increased mortality. One study of below-knee amputees found 5-year mortality to be about 70% in nonambulatory individuals compared to about 31% in those who could walk.²⁶ Similarly, a 3-year study found the absence of prosthesis fitting to be an independent predictor of mortality following a multivariable logistic regression.²⁷ Other research has found that inpatient rehabilitation is associated with more prosthetics and lower mortality compared to those sent home or to skilled nursing.²⁸ In nursing home residents undergoing revascularization, similar patterns emerged where preoperative nonambulation is associated with increased mortality.²⁹ This demonstrates that even without amputation, lack of ambulation leads to increased mortality within similar populations.

Previous theories implicated energy expenditure after amputation as a possible contributor to the elevated mortality. Amputees have demonstrated greater energy expenditure at a given speed than nonamputees.³⁰ However, the increased mortality risk is not primarily associated with amputees who use prosthetics, but rather with those who are not ambulatory.

Unfortunately, only about two-thirds of individuals will ambulate after a major amputation.^26,31 In a recent study, 1-year ambulation status was noted at 67% after below-knee amputations but only in 50% after above-knee amputations when considering only those who could ambulate prior to surgery.³² As one would expect, those with limited preoperative ambulatory ability do much poorer.³³ Obesity and a high modified frailty index have also been shown to predict nonambulatory status.³⁴ In a review of 256 major amputees, no patients were able to ambulate at one year with bilateral major amputations, dementia or on dialysis.³⁴ Compared to below-knee amputations, transmetatarsal amputations have significantly higher rates of ambulation.³⁵ Ambulation rates after transmetatarsal amputations have been reported at 77%.³⁶ Similarly high rates have been reported in midfoot amputations that have healed.³⁷

However, patients with minor amputations face a high incidence of reoperation and reamputation.³⁸ Generally, as the amputation becomes more proximal, healing rates improve and reamputation rates decrease. Izumi and colleagues reported 5-year reamputation rates of 52% in toes, 50% in rays, 43% in midfoot, and 13% after major amputations.³⁹ This is partially due to loss of anatomy as the contralateral amputation rate generally increases with more proximal index amputation.³⁹ Minor amputations also have higher rates of readmission and infections.⁴⁰ While minor amputations are not without their risks, given their ambulation rates, they are generally preferable in most situations when a successful outcome is plausible. Fortunately, recent data has suggested an improved ambulatory status after distal amputation, and this ambulation status is significantly associated with decreased mortality.⁴¹

Is Increased Ambulation Beneficial for Patients Following Amputation?

Beyond the binary conditions of ambulation versus nonambulation, it is important to recognize that increased ambulation or activity correlates with reduced mortality. In a large meta-analysis of step counts, more daily steps were strongly associated with a decrease in both all-cause mortality and cardiovascular mortality.⁴² Moreover, prolonged sitting is associated with increased mortality in a dose-like response and only neutralized by high levels of moderate physical activity.⁴³ In patients with diabetes, 1-year mortality decreased by 39% in those who walked a mere 2 hours per week and further decreased in individuals who did more activity.⁴⁴ In another convincing 5-year prospective study in patients with diabetes, individuals who started cycling at the beginning of the study had a staggering reduction in a multivariate-adjusted hazard ratio of all-cause mortality of 0.65 (95% CI, 0.46-0.92) compared to those who did not start cycling.⁴⁵ Aside from individual studies in patients with diabetes, a recent meta-analysis on physical activity found benefits for both all-cause mortality and cardiovascular disease mortality.⁴⁶

While it is well-known that more physical activity equates to better survival, it is actually those who have more comorbidities and are the least active who benefit most from even mild amounts of increased activity.⁴⁷ Clearly those individuals who are able to ambulate following either minor or major amputation have a greater advantage given their accessibility to participate in physical activity and exercise. Although theoretically, those who are wheelchair bound also have the ability to exercise, this has been uncommon for this population in my practice.

Some patients seem to be reluctant to increase activity following minor amputations and ulcerations due to the fear of recurrence of an ulceration. This is a valid concern given reulceration rates after healed ulcerations are about 34% at 1 year, 61% after 3 years, 70% after 5 years, and even higher after amputation.⁴⁸ Prior to a healed ulceration, patients are often advised to stay off the foot as much as possible, as step count is inversely correlated to ulceration healing.⁴⁹ Yet, physical activity and exercise is recommended even in those with significant comorbidities by the American Diabetes Association.⁵⁰ Increasing daily weight-bearing activity has not been shown to increase re-ulceration rates after an ulcer has healed.⁵¹ In fact, lower activity levels are actually associated with ulceration recurrence and possibly variation in daily steps.^52,53

Simply instructing patients to immediately return to activity upon healing may be inappropriate. Recommendations often include extending the use of an offloading device for a month or more and gradually returning to activity in a slow and progressive manner.⁵⁴ Patients also misunderstand the relationship between weight loss and exercise. The physical activity levels that are recommended may improve cardiovascular health, but are unlikely to provide weight loss without caloric restrictions.⁵⁵ Nevertheless, many other benefits beyond weight loss are reaped from physical activity and exercise for patients with diabetes, including improved glycemic control and positive effects on depression.^56,57

As the major cause of death following amputation appears to be vascular disease, physical activity is not the only treatment one can suggest. A recent study of 5-year mortality following lower amputation due to vascular disease suggests that survival may be improving, with the authors implicating the possibility that increased statin use could be among the contributors.²⁴ DeCarlo and colleagues noted medium- and high-intensity statins, but not low-intensity statins, were associated with lower mortality after major amputation, with only 44% receiving appropriate statin therapy.⁵⁸ Others have found that in patients with critical limb ischemia or claudication, adherence to all of the American College of Cardiology and the American Heart Association (ACC/AHA) recommended guidelines (stop smoking and receive antiplatelet therapy, statin medications, and angiotensin‐converting enzyme (ACE) inhibitors) confers a significant mortality benefit compared to those who adhered with 3 or fewer therapies.⁵⁹ It may be helpful to be educated on the recommendations and to aid in identifying areas of possible improvements in our high-risk patients. Admittedly, though, this is mostly outside our scope of practice as foot and ankle surgeons.

In Conclusion

Given the considerable web of confounders and selection bias that are inherit to the data, it is difficult to confidently separate markers of disease states from cause and effect. For example, consider a bedridden elderly man with diabetes, dementia, and critical limb ischemia on dialysis with extensive calcaneal osteomyelitis. In cases such as this, some would suggest a more proximal amputation. It is unlikely that there is much we can do to change his trajectory. The decision for a more proximal amputation would be in part determined by his preoperative ambulation status and disease state in addition to his foot pathology. It is also likely that his mortality risk is rather high within the next 5 years regardless of which procedures are decided upon.

Considering this individual as one data point within retrospective studies, one can see some of the selection biases that occur. In order to truly elucidate cause and effect, a prospective randomized trial is needed. Due to ethical and practical concerns, this is extremely unlikely. Thus, we are left in a situation to put the pieces of the puzzle together as best we can in order to make the best decisions possible for the patient in front of us.

Current review of the available literature has provided a compelling case for emphasizing ambulation and function above the proximity of the amputation site, though these are somewhat related. This typically favors minor amputation, but at the same time, the probability of healing must also be considered. Ideally, an algorithm or test would help physicians determine the exact likelihood of healing. However, even with this information, providers must balance the chance of successful healing to what is deemed acceptable risk of failure. It seems many times we struggle with not only a general guess at what the risk of failure is, but also the uncertainty of how much risk is too much to attempt limb salvage. Having a better understanding of our priorities and its implications on both life expectancy and quality of life hopefully provides insight to reducing mortality in patients with severely limited life expectancy.

Dr. Thorud is a Fellow of the American College of Foot and Ankle Surgeons and practices at Mercyhealth in McHenry, IL.

References

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