pathways to diabetic limb amputation - diabetes care

SPECIAL ARTICLE

Pathways to DiabeticLimb AmputationBasis for Prevention

Roger E. Pecoraro, MDGayle E. Reiber, PhDErnest M. Burgess, MD

We defined the causal pathways responsible for 80consecutive initial lower-extremity amputations to anextremity in diabetic patients at the Seattle VeteransAffairs Medical Center over a 30-mo interval from 1984to 1987. Causal pathways, either unitary or composed ofvarious combinations of seven potential causes (i.e.,ischemia, infection, neuropathy, faulty wound healing,minor trauma, cutaneous ulceration, gangrene), weredetermined empirically after a synthesis by theinvestigators of various objective and subjective data.Estimates of the proportion of amputations that couldbe ascribed to each component cause were calculated.Twenty-three unique causal pathways to diabetic limbamputation were identified. Eight frequent constellationsof component causes resulted in 73% of theamputations. Most pathways were composed of multiplecauses, with only critical ischemia from acute arterialocclusions responsible for amputations as a singularcause. The causal sequence of minor trauma, cutaneousulceration, and wound-healing failure applied to 72% ofthe amputations, often with the additional association ofinfection and gangrene. We specified precise criteria inthe definition of causal pathway to permit estimation ofthe cumulative proportion of amputations due to variouscauses. Forty-six percent of the amputations wereattributed to ischemia, 59% to infection, 61% toneuropathy, 81% to faulty wound healing, 84% toulceration, 55% to gangrene, and 81% to initial minortrauma. An identifiable and potentially preventablepivotal event, in most cases an episode involving minor

From the Department of Medicine, Division of General Internal Medicine, andDepartment of Orthopaedics, University of Washington School of Medicine; theDepartment of Epidemiology, University of Washington School of Public Healthand Community Medicine; and the Seattle Veterans Affairs Medical Center,Seattle, Washington.

Address correspondence and reprint requests to Roger E. Pecoraro, MD, Med-ical Comprehensive Care Unit (111M), Seattle Veterans Affairs Medical Center,1660 South Columbian Way, Seattle, WA 98108.

Received for publication 17 May 1989 and accepted in revised form 8 No-vember 1989.

trauma that caused cutaneous injury, preceded 69 of 80amputations. Defining causal pathways that predisposeto diabetic limb amputation suggests practicalinterventions that may be effective in preventingdiabetic limb loss. Diabetes Care 13:513-21, 1990

Diabetes is associated with >50% of the 120,000lower-limb amputations performed annually inthe United States for indications other thantrauma (L. Ceiss, unpublished observations). The

overall risk for amputation is increased in diabetes 15-fold beyond that for nondiabetic people (1). This is likelyto reflect, in part, the prevalence of potent pathophys-iological risk factors for amputation, including periph-eral neuropathy and severe arteriosclerosis obliterans,which have been suggested in case series of diabeticamputations. Additional possible risk factors in diabeticindividuals involve more complex pathology, i.e., fail-ure of cutaneous wound healing and gangrene, or pre-disposing environmental events, i.e., minor trauma thatcauses skin ulceration.

Most diabetic lower-limb amputations probably resultfrom combinations of contributing causes rather thanfrom unitary causes. This contrasts with lower-limb am-putations among nondiabetic people, which are likelyto result from severe peripheral vascular disease (2,3).Definition and quantitation of the major independentrisk factors for amputation and description of their com-mon interactions must precede the implementation ofstrategies for prevention of lower-extremity amputationsin diabetes.

Most of the available information about risk factorsand potential causes for amputation depends on obser-vations from surgical case series (4-6). Because case

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CAUSAL PATHWAYS TO AMPUTATION

series usually represent patients referred for heteroge-neous indications and procedures, control groups areseldom assembled. Therefore, the prevalence and se-verity of separate potential risk factors observed in thoseseries are not adequate to estimate either the relativerisks or the proportion of amputations that result fromthe occurrence of particular factors among the diabeticpopulation. Controlled epidemiological studies are nec-essary to quantify the risk due to specific potential causes.Cohort studies can define rates of disease and relativerisks but are difficult, costly, and often impractical. Thecase-control design is efficient and provides a mecha-nism for estimating relative risk due to various expo-sures. Unfortunately, only one controlled study, ananalysis of selected characteristics of Pima Indians withdiabetes, has been published describing relative risks foramputation (7).

A model to define the causes of diabetic amputationthat can account for interactions of multiple synergisticcauses, both concurrent and sequential, would be usefulto anticipate clinical circumstances that convey high risk.These features are implicit in the concept of a causalpathway to amputation. Each diabetic amputation im-plies the existence of a completed causal pathway ofpredisposing factors. There is a need to recognize com-monly occurring causal pathways among individuals re-quiring amputation and to estimate their frequencies tofirst identify and then test effective preventive strategiesand interventions.

This investigation was designed to address three is-sues. First, what were the responsible causal pathwaysin 80 consecutive diabetic male subjects requiring aninitial lower-extremity amputation during a 30-mo pe-riod at a single hospital, and what proportions of theamputations were caused by sensory neuropathy, is-chemia, infection, minor trauma, skin ulceration, failedwound healing, and gangrene? Second, what was theprevalence among these cases of a limited number ofadditional conditions or circumstances, e.g., negligentself-care practices due to patient lack of knowledge ornoncompliance, which probably contributed to ampu-tation risk but cannot necessarily be supported as es-sential component causes? Third, could a pivotal eventbe identified that initiated the causal pathway leadingto each amputation?

RESEARCH DESIGN AND METHODS

We studied 80 consecutive diabetic male veterans, aged30-85 yr, who required first amputations of the affectedlower extremity for indications other than trauma at theSeattle Veterans Affairs Medical Center from October1984 to April 1987. Patients were excluded if they hadhad a previous amputation involving the same extrem-ity. A concurrently selected control population included236 diabetic male veterans, aged 30-85 yr, scheduledfor elective surgical procedures not related to diabetesand chosen from a predefined list of operative proce-dures performed by surgeons from eight subspecialty

services. Subjects were excluded as controls if they gavea history of previous amputation or had lower-extremityulcers or infections that had persisted for >4 wk. In thisstudy, control subjects were used exclusively for cal-culations of population-attributable risk percent for spe-cific measures of ischemia and neuropathy.

All patients admitted for inpatient care or outpatientsurgery during the study were screened for the diagnosisof diabetes by one of the investigators (G.E.R.). The di-agnosis required 7) previous diagnosis of diabetes by aphysician; 2) a history of receiving prescribed hypogly-cemic medication; or 3) in the absence of a previousdiagnosis, laboratory determination of hemoglobin A]c

^6.3% and/or fasting plasma glucose >140 mg/dl. Thepopulation from which diabetic amputees and controlsubjects were selected included 19,508 individuals ad-mitted and 1659 patients scheduled for outpatient sur-gery. One hundred percent of the 80 diabetic individ-uals fulfilling the case eligibility criteria agreed toparticipate, whereas 236 of 239 eligible potential con-trol subjects participated (98.7% participation rate).

The purpose of identifying causal pathways to dia-betic amputation is to link important responsible events,pathophysiological factors, and other conditions con-tributing to amputation cause in a manner that may sug-gest specific clinical strategies for anticipating and pre-venting diabetic limb loss. An effective model shoulduse a definition of the causal pathway that permits as-similation of empirical information derived from actualrepresentative amputation cases. The model should ac-commodate causes for a particular amputation that mightoccur early in a causal sequence, i.e., cutaneous ul-ceration, as well as causes that represent the final pre-cipitating circumstance necessary for a particular am-putation to occur, e.g., gangrene. For clarity andsimplicity, the causal pathway should be concise andexclude nonessential factors. Finally, the causal path-way should be defined in a way that provides insightinto the potential usefulness of interventions directedtoward removal or negation of particular elements of thecausal chain.

A model for causation that meets these objectives hasbeen described by Rothman (8,9). Therefore, to corre-spond with Rothman's conceptualization of "sufficientcause," we defined the causal pathway to diabetic lower-limb amputation as a set of minimal conditions and eventsthat inevitably produce disease; "minimal" implies thatnone of the conditions or events is superfluous. In dis-ease etiology, the completion of a sufficient cause maybe considered equivalent to the onset of disease (8). Aspart of this construct, "component causes" have beendefined as causes of interest that are not sufficient inthemselves but are required components of one or moredistinctive sufficient causes (8,9). Consequently, the lackof any component cause from the minimal necessary setrenders the remaining component causes insufficient (Fig.1). The causal pathway concept is valuable in diseaseprevention because the disease effect can be delayed orprevented by removing any individual component of asufficient causal pathway, which then renders the joint

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R.L PECORARO, G.E. REIBER, AND E.M. BURGESS

SUFFICIENT CAUSE :

— INEVITABLY PRODUCESTHE EFFECT

— RESTRICTED TO THEMINIMAL NUMBER OFCOMPONENT CAUSES

REQUIRED FORCAUSATION

COMPONENT CAUSE :

— NOT SUFFICIENT IN ITSELF

— REMOVAL OR BLOCKING RENDERS ACTION OFOTHER COMPONENTS INSUFFICIENT

FIG. 1. Diagram of sufficient and component causes. A-E represent causes that are not sufficient in themselvesbut that are required components of a sufficient cause thatinevitably produces effect. Adapted from Rothman (8,9).

action of the other components insufficient. Figure 2shows a representation of a hypothetical causal pathwayto an individual amputation according to this model.

Consideration was limited to seven potential causes,based on available historical and quantitative data. Theseseven causes were suggested by previous literature ondiabetic amputations. They included the four majorpathophysiological mechanisms implicated in diabetic-limb loss, neuropathy, ischemia, infection, and wound-healing failure (10-13); two common soft tissue com-plications, cutaneous ulceration and gangrene; andminor trauma, which represents a frequent initiatingenvironmental event encompassing direct accidental in-jury or trauma from repetitive mechanical pressure fromfootwear.

Subjects were interviewed to obtain a detailed stan-dardized medical history including demographic infor-mation, general medical history, specific diabetes his-tory, history of the current lesion and previous foot andleg complications, health care, self-care, and life-style.Hospital and outpatient medical records were abstractedfor the 5 yr preceding study enrollment. Before surgerythe lower extremities of all subjects were examinedto document cutaneous lesions and skin or soft tissueinfections, with findings recorded on a wound-codingsheet. All subjects were evaluated directly by one or

NEUROPATHY MINOR TRAUMA ULCERATION FAULTY HEALING GANGRENE

BASELINEPATHOLOGY

4. ENVIRON-MENTALEVENT

4.•

SKINLESION

4. INTERCURRENT .PATHO- n

PHYSIOLOGY

L INTERCURRENTr PATHO-PHYSIOLOGY

ACCUMULATION of COMPONENTCAUSES TO FORM A SUFFICIENT CAUSE

COMPLETEDCAUSAL CHAIN

JOAMFUTATIOl

FIG. 2. Representation of causal pathway to individual amputation, which includes essential contributions from un-derlying diabetes-related pathophysiology (neuropathy), initiating environmental event (minor trauma), formation offoot lesion, and subsequent healing complications. Eventual occurrence of gangrene is terminal event of this causalchain, which requires participation of all preceding components before becoming sufficient to cause amputation.Theoretically, amputation could have been avoided by elimination of any one component cause before convergenceof causal chain.


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more of the investigators during interviews (G.E.R.), pre-surgical examinations and wound assessments (R.E.P.,E.M.B., G.E.R.), and/or amputation surgery (E.M.B.,R.E.P.).

Lesions were photographed. Sensory perception (vi-bration, touch, two-point discrimination, and stereog-nosis), Doppler segmental blood pressures, and trans-cutaneous oxygen tension at standardized sites (14)were measured on each subject by the same technician.Blood was drawn by venipuncture after overnight fastshortly after hospital admission for determination of rou-tine clinical chemistry and hematology values, a panelof plasma nutritional indicators (albumin, carotene,zinc, ascorbic acid, pyridoxine, and zinc-protoporphyrinheme ratio), and glycosylated hemoglobin.

Historical data, wound descriptions and coding, pho-tographs, and objective neurological, vascular, and lab-oratory data were collated in each case for review bythe investigators, and causes of amputation were as-signed and recorded independently on a standardizedsummary worksheet.

The criteria for assignment of causes by the investi-gators to individual cases included a synthesis of objec-tive and subjective considerations. Guidelines wereagreed on in advance for evaluation of data and assign-ment oi potential causes. Assignment of neuropathy asa cause required objective evidence of sensory neurop-athy of the lower extremities and a judgment by theinvestigators that the existence of neuropathy was anessential component in the causal pathway to amputa-tion. Assignment of ischemia required objective evi-dence of substantially impaired arterial circulation of thelower extremities from physical examination of the skin,cutaneous appendages, and arterial pulses, usually ac-companied by an ankle/arm index ^0.70 and/or localtranscutaneous oxygen tension <20 mmHg (14-18).These findings had to be consistent with a clinical judg-ment by the investigators that circulatory impairmentrepresented a critical contribution to the causal pathwayto amputation. Presence of ulceration or gangrene wasdetermined by physical examination, and to qualify asa component cause required documentation in the med-ical record that it was considered as an indication foramputation. Major infection was documented by directphysical examination, review of microbiological cultureresults, and/or radiology and pathology reports consis-tent with osteomyelitis. Furthermore, to qualify as acomponent cause, infection had to be overwhelming orunresponsive to medical and surgical treatment. Wound-healing failure was implicated as a cause if there wasno healing progress after 6 wk in the case of major cu-taneous ulceration, and this was judged by clinicians orinvestigators to have been a direct or indirect indicationfor the amputation. Minor trauma was assigned as acause if it was clearly documented by medical historyand was judged by the investigator to have initiated asequence of subsequent pathological events that termi-nated in limb amputation.

The predominant and final criterion for assignment of

a component cause was a unanimous consensus by theinvestigators that a synthesis of the relevant data justifiedthe assignment of that factor as an essential contributingcause for the particular amputation. For each amputa-tion, the final element in the causal chain was identifiedfirst. If the final cause was not by itself sufficient, oneor more additional required component causes wereselected using the standardized summary worksheet.Rarely was there disagreement among investigators re-garding assignment of the final causes or most causalconstellations. In the few cases in which there was initialdisagreement, final consensus was achieved with amodified Delphi procedure (19). The Delphi procedureis a method used in arriving at consensus. It was mod-ified by allowing face-to-face discussions after the initialround of independent assessment until there was unan-imous agreement on assignments of cause. The inves-tigators represent complementary areas of professionalexpertise, including clinical diabetology (R.E.P.), or-thopedic and amputation surgery and rehabilitation(E.M.B.), and nursing, public health, and epidemiology(G.E.R.).Statistical analysis. Results are reported with standarddescriptive statistics. The frequencies of each compo-nent cause, final cause, and complete causal pathwaywere computed. Values of population-attributable riskpercent, an expression in percentage terms of the pro-portion of amputation cases in the total diabetic popu-lation due to the risk factor, which can be estimatedfrom the odds ratio and the proportion of the populationexposed (20), were calculated for indicators of signifi-cant ischemia among diabetic amputees and surgicalcontrol subjects. Values were calculated independentlyfor measurements of transcutaneous oxygen tension,which was <20 mmHg at the dorsal foot, and for ankle/arm index, which was ^0.70 for the affected limb (14-18,21). Similarly, the population-attributable risk per-cent for significant peripheral sensory neuropathy wascalculated from the frequency of absent distal vibratorysensation among patients and control subjects to indi-cate impaired protective sensation.

RESULTS

The 80 subjects receiving initial lower-extremity am-putations had a mean ± SD age of 63.4 ± 11.9 yr andhad a clinical duration of diabetes of 13.3 ± 10.5 yr.Insulin-dependent diabetes mellitus occurred in 11 sub-jects and non-insulin-dependent diabetes mellitus in 69.These and other characteristics were not statistically dif-ferent among control subjects (Table 1). The amputationlevels included 12 above knee, 35 below knee, 5 trans-metatarsal, and 28 toe amputations.

Twenty-three unique causal pathways were repre-sented among the 80 consecutive cases of diabetic lower-limb amputation. Twenty-two causal pathways (96%)were multicomponent, with only one observed pathway


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R.E. PECORARO, G.E. REIBER, AND E.M. BURGESS

TABLE 1Characteristics of diabetic amputees and control subjects

nAge (yr)

Mean ± SDMedianRange

Clinical duration of diabetes (yr)Annual income <$15,000 (%)Education <12 yr (%)White (%)Smoking history (%)

CurrentEverNever

Amputees

80

63.4 ±11.962.5

31-8513.3 ± 10.5

6267.586

3672.528

Controls

236

61.1 ± 10.063.0

31-8310.9 ± 9.7

57.86082

2478.422

attributed to a unitary cause, ischemia. The eight mostfrequent pathways observed together accounted for 73%of all diabetic amputations (Fig. 3).

The proportions of amputations attributed to individ-ual component causes are listed in Table 2. Each pro-portion was calculated as the sum of the amputationfractions that resulted from causal pathways that con-tained that component cause (9). Because of the re-stricted definition of causal pathway adopted for thisanalysis (see RESEARCH DESIGN AND METHODS), this cal-

cn

C/5Om

mOcC/5

[GJ [GJ [GJ |G% Of 80 LEA's !9 8 5 4

73% 27%

FIG. 3. Most unique causal pathways required interactionof pathophysiological components (ischemia [I], neurop-athy [N], infection [INF], faulty wound healing [FH]), path-ological conditions (ulceration [U], gangrene [G]), and en-vironmental events (minor trauma [T]). Prevalent triad offactors (dashed boxes) leading to amputation included Tcausing U, which was subsequently complicated by FH.LEA, lower-extremity amputation. These are 23 causal path-ways and 80 LEAs.

culation provides an estimate of the proportion of am-putations that might have been prevented by the reso-lution or removal of the particular component factorfrom the causal chain.

There was a trend for neuropathy, minor trauma, ul-ceration, and faulty wound healing to be represented ina higher proportion of causal pathways among amputeesabove the median age (62 yr) compared with the youngerhalf of the case population (Table 2). However, this trendreached statistical significance at P < 0.05 only for faultywound healing, which occurred in most cases but wasmore common in older subjects. The prevalence of is-chemia, infection, and gangrene as component causeswas similar in both age strata.

Failure of normal wound healing after cutaneous ul-ceration, a condition well recognized in diabetes butwith complex etiologies that are not entirely explained,emerged in this analysis as the most prevalent patho-physiological component cause (81%) leading to am-putation (13). Considered an independent causal factor,wound failure illustrated many of the interactions thatlink separate potential amputation causes into criticalcombinations that are sufficient in concert to bring aboutamputation. Cutaneous ulcers complicated by woundfailure occurred in 58 of 80 cases (72%). Similarly,wound-healing failure was eventually associated withunsuccessfully treated infection or gangrene, forcing thesurgical decision for amputation in 42% of the cases.

A particular critical triad of component causes, aninitial episode of minor trauma, resulting in cutaneousulceration and subsequent failure to heal, preceded 72%of amputations. Absent protective sensation was consid-ered to be a component cause in 82% of these ampu-tations. Infection was a common complicating factor inthe various causal pathways to amputation and mostoften affected cases with chronic wound-healing failure.Sixty-one percent of the cases involving the triad of mi-nor trauma, ulceration, and wound-healing failure alsohad a major infection that was considered essential tothe causal pathway leading to amputation.

Ischemia was found to be a causal factor in 46% ofthe amputations. Of the seven potential causal factorsconsidered, ischemia was the only cause found to besingularly responsible for lower-limb amputation. Threeamputations in individuals with severe peripheral arte-rial disease were precipitated by acute arterial occlu-sions. Critical ischemia was associated with 62% of caseswith nonhealing ulceration, with gangrene associatedwith half of those cases.

Gangrene as a cause for amputation occurred in com-bination with both ischemia and infection. Gangreneoccurred in 55% of all amputated limbs and was asso-ciated with critical ischemia, alone, or in combinationwith major infection in 40% of the amputations. How-ever, in 24% of all amputations, infection accompaniedgangrene as a component cause without involvement ofpreexisting ischemia.

Another way to estimate the proportion of amputa-tions that might have been prevented by removal of a


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TABLE 2inULL i.

Proportion of amputations due to individual causes and final component causes

Component cause

IschemiaInfectionNeuropathyFaulty wound healingUlcerationGangreneMinor trauma

All cases

46596181845581

Amputation

<62 yr (n = 40)

48525270755072

proportion (%)

Median age split

>62 yr (n = 40)

45657092926090

P*

1.000.360.170.020.070.500.09

As final componentin pathway (%)

541

14

40

*Yates correction with

particular component cause is to calculate the popula-tion-attributable risk percent from case-control data (20).This parameter was calculated for specific measures ofischemia and neuropathy that were performed in thediabetic amputation cases and control subjects. Theseestimates were compared with the proportion of am-putations attributed to ischemia or neuropathy in thecausal pathway analysis for internal validation. Becausediabetic control subjects were ineligible for study par-ticipation if they had nonhealing ulcers, persistent in-fections, or gangrene, similar calculations could notbe performed for the remaining factors considered aspotential component causes. For both ischemia andneuropathy, the etiologic fraction estimated by popu-lation-attributable risk percent was comparable to thepercentage estimate from the corresponding causalpathway analysis. The amputation proportion attribut-able to ischemia was 46% compared with a population-attributable risk percent of 36% calculated for ankle/arm index <0.70, and 49% for dorsal foot transcuta-neous oxygen tension <20 mmHg (Table 2). The pro-portion attributed to neuropathy by causal pathwayanalysis was 61% compared with a population-attrib-utable risk percent of 72% calculated for individualswith absent distal vibratory sensation.

The final component cause in the causal pathway, thefactor that triggered the surgeon's decision to amputate,was rarely sufficient in itself to bring about amputation,yet is often considered the responsible cause for a par-ticular amputation. As noted above, acute ischemia wasthe solitary and therefore the final and responsible suf-ficient cause in three cases. In the remainder of the cases,which involved multiple component causes, the re-sponsibility for amputation could not be due to only thefinal cause, but by definition was shared by the variouscontributory component causes. Furthermore, the finalcause in the causal pathway did not accurately reflectthe estimate of the proportion of amputations attributedto that causal factor (Table 2). For example, ischemiawas considered to be the final cause in only 5% of thecases, yet its elimination as a component cause would

have obviated the causal pathway to 46% of the am-putations.

A pivotal antecedent event, defined as a componentcause that triggered a sequence of events culminatingin lower-extremity amputation, could be clearly iden-tified in 86% of the cases. In 58 of 80 cases (73%) thesewere traumatic events causing tissue injury. These in-cluded shoe-related repetitive pressure leading to cuta-neous ulceration in 36% of all cases, accidental cuts orwounds in 8%, thermal trauma (2 cases of frostbite, 4burns) in 8%, and decubitus ulceration in 8%. Suddenvascular occlusions were implicated as pivotal events in6 cases; 3 cases represented singular causes, corre-sponding to the only unitary causal pathway observed(Fig. 3). Miscellaneous pivotal events included iatro-genic occurrences (2 cases), development of parony-chiae (2 cases), and sinus tract formation during an ep-isode of podagra (1 case).

Other factors contributed to many amputations, al-though their participation could not be unequivocallyconsidered to be causal, based on current understand-ing of their effects. Nutritional impairment believed to im-pede normal tissue repair, indicated by plasma ascorbicacid and/or zinc levels <2SD below the laboratorymean (i.e., <0.36 mg/dl and <60 |xg/dl, respectively),was found in over half the amputees (51 cases). Otherlaboratory nutritional parameters indicated significantdeficiencies among amputees compared with the con-trol population, including plasma albumin (3.59 ± 0.10vs. 4.17 ± 0.03 g/dl, P < 0.001), carotene (61.6 ± 4.4vs. 88.3 ± 3.5 g/dl, P < 0.001), and the zinc-proto-porphyrin heme ratio, a sensitive measure of marrowerythropoiesis (65.9 ± 3.9 vs. 50.9 ± 2.2 jxmol/mol,P < 0.001) (22). Mean ± SD hospital admission weightsof the 80 amputee patients averaged 178 ± 35 lbs com-pared with 192 ± 40 lbs for the 236 hospitalized dia-betic control subjects. Body mass index (kg/m2) for am-putation cases was 25.8 ± 5.6 compared with 27.6 ±5.3 for control subjects, with P < 0.01 significantly dif-ferent. Calculations of desirable weight and estimates ofthe subjects' maximum weights did not differ between


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amputees and control subjects, suggesting that ampu-tees had sustained significant weight losses (23).

Edema impaired local cutaneous blood flow of theaffected extremity in 31 cases (39%). Negligent self-carepractices that contributed to a subsequent amputationwere ascribed to lack of knowledge of appropriate footcare principles in 19 cases (24%) and to noncompliancewith medical recommendations in 22 cases (28%). In-adequate social support contributed to eight amputa-tions (10%).

DISCUSSION

Empirically derived causal pathways represent theassembly of essential component factors andevents that act together to culminate in individualamputations. These causal pathways incorporate

interactions between important risk factors that wouldbe less obvious in traditional epidemiological study de-signs. Causal pathways may include particular criticalexposures that may be difficult to specify in the case-control design, particularly among control subjects, inwhom no memorable consequence is likely to be trig-gered by the exposure (e.g., the episode of minor trauma,which could produce ulceration in the insensitive foot).Although analyses of the time sequences necessary forinteractions of potential risk factors may be problematicin case-control studies, the time dimension is implicitin the causal pathway concept. Each contributing causerepresents a logical and necessary precedent to relatedsequential events that combine ultimately to constitutea sufficient cause for amputation. The causal pathwaymodel can also incorporate synergistic causes that areconcurrent and independent rather than sequential. Theseattributes of the model are shown in Fig. 2 to illustratea causal pathway that was observed in two of our cases.

Several conclusions are apparent from our analysis ofthe causes for 80 consecutive diabetic amputations.Definition of the common causal pathways that predis-pose to diabetic limb amputation offers an intuitive con-text for designing and implementing effective publichealth and individual patient-specific interventions toprevent amputations. The value of this approach is itsability to estimate the proportion of cases in the popu-lation that are due to particular factors (Table 2), and toassess the importance of eliminating those factors as partof a disease-prevention strategy. However, some causalfactors may be inherently difficult or impossible to elim-inate, e.g., foot anesthesia as a result of sensory neu-ropathy. Alternatively, measures could be instituted tostructure the environment to minimize the potential forinjury. Attempts to modify others may subject certainpatients to substantial additional risks (e.g., elective vas-cular surgery in certain high-risk individuals). The causalpathway concept facilitates selection of accessible,practical, and low-risk foci for interventions that mighteffectively and safely interrupt the causal chain and pre-

vent a substantial proportion of lower-extremity ampu-tations (e.g., prevention of foot trauma, early treatmentof lower-extremity infections, improved ulcer healing).

We confirmed that multiple causes usually interact tobring about each individual diabetic limb amputation.The frequent participation of multiple factors, each ofwhich is rarely sufficient by itself to produce amputa-tion, may explain the limited success achieved by sin-gular intervention aimed at limb salvage. This ob-servation supports the emphasis by experts in themanagement of diabetic foot problems who recommenda multidisciplinary team approach to prevention, diag-nosis, and treatment (10,12,24).

The occurrence of a critical causal sequence impli-cating minor trauma, skin ulceration, and faulty woundhealing in 72% of diabetic limb amputations has im-portant ramifications. This finding documents and un-derscores the importance of wearing appropriate pro-tective footwear by diabetic patients with impairedprotective sensation secondary to sensory neuropathy.Continued research toward understanding the basis forfaulty wound healing in diabetes and the developmentof effective therapies to accelerate wound repair, e.g.,the topical application of human polypeptide growthfactors to heal diabetic skin ulcers (25), may bring re-alization of the goals of the National Diabetes AdvisoryBoard to reduce the amputation rate in diabetes by 40%before the year 2000 (26).

Our results highlight other exposures and interactionsthat increase amputation risk. Critical infection is a fre-quent concomitant of the prolongation or failure of cu-taneous wound healing. Furthermore, in many casesmajor infection is a precursor to gangrene, independentof chronic ischemia from severe peripheral vascular dis-ease. The prevalence of limb edema associated withdiabetic amputation in our study confirms the previouslyreported strong association of edema from various causeswith diabetic gangrene (27). The common occurrenceof patient lack of knowledge and noncompliance withcritical aspects of diabetic foot care principles supportsthe role of professional and patient education and mo-tivation in preventive care.

The smoking status of the 80 amputees and 236 con-trol subjects, assessed by personal interview, indicatedthe "ever smoked" prevalence was 72.5 and 78.4%,respectively (Table 1). Similar prevalence findings formales in these age groups were reported in the NationalHealth Interview Survey (28). An analysis of the data ofamputees and control subjects, removing the effects ofage, yielded no statistically significant elevated risk foramputation associated with smoking based on "currentsmoker" or "ever smoked" status (odds ratio 1.32, 95%confidence interval [Cl] 0.70, 2.97 and odds ratio 0.75,95% Cl 0.41, 1.37, respectively) (29).

Smoking has been described as a major risk factor fordevelopment of atherosclerosis in nondiabetic popula-tions. This description has been applied to diabetic pop-ulations, although based on less rigorous data. Although


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smoking, hypertension, and lipoprotein abnormalitieshave been associated with development of atheroscle-rosis, which is more common in diabetes, factors otherthan atherosclerosis and ischemia participate in the pro-gression of limb pathology in many cases that culminatein amputation of the diabetic limb. Causal pathway datapresented herein suggest that even though ischemia wasa causal factor in ~50% of the amputations, other fac-tors were more often a component cause or the finalcomponent in the amputation pathway.

There are limitations inherent in the analysis of causalpathways to define sufficient causes for diabetic limbamputation. The ascertainment of causes was not en-tirely objective, although the method was designed touse quantitative objective data as the basis for the sub-jective synthesis of component factors leading to a con-sensus designation of the sufficient cause for each in-dividual amputation. However, because control datawere not considered in the assignment of causal path-ways, the certainty of results could not be describedstatistically, e.g., with CIs, as would be done for con-trolled epidemiological investigations.

Several features of this study, however, support thevalidity of the observed frequency distribution of causalpathways. The cases comprise a consecutive series ofincident amputations accumulated over 2.5 yr at thesame medical center that serves veterans within a de-fined catchment region. The subjective considerationsby the investigators can be viewed as an integration ofthe pertinent objective data within a framework of rel-evant clinical experience. This permitted the definitionof causal pathways that are substantially intuitive, log-ical, and germane to a real-world clinical context. Thestudy design considered important potential causes, i.e.,pivotal episodes of minor trauma, and delineated sig-nificant sequences of causal events that would be dif-ficult to measure or evaluate in other study designs. Al-though causal pathway analysis does not permitassessment of the relative risk from independent expo-sures, it does suggest the proportion of amputations likelyto accrue from various common constellations of com-ponent causes, many of which could not be readilyspecified in case-control studies. We calculated thepopulation-attributable risk percent, a standard objec-tive epidemiological measure, for parameters of is-chemia and neuropathy, and obtained internal valida-tion of the amputation proportions estimated for thosecomponent causes from their cumulative participationin causal pathways.

Interventions incorporating these observations nowneed to be assessed in controlled prospective interven-tion trials to prevent amputations in diabetic individualsin various populations and clinical settings.

ACKNOWLEDGMENTS

This work was supported by Veterans Affairs Rehabili-tation R&D, Veterans Affairs Health Services R&D,

Washington State Diabetes Control Program, and Dia-betes Research and Education Foundation.

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