Abstract

A narrative literature review of risk factor or predictor for Complex Regional Pain Syndrome (CRPS) or Reflex Sympathetic Dystrophy (RSD) was performed in the English language. Female sex, elderly people between the age of 45 and 65, pregnancy, intra-articular fracture, comminuted and displaced fracture, high energy trauma, severe fracture, strong pain after fracture, decreased sympathetic vasoconstrictor response after fracture, nerve and spinal cord injury, ankle dislocation, ankle fracture, injury in the extremities, treatment to the upper limb, motor nerve injury, decreased function before operation, poor physical functioning, higher median household income, economic compensation via work disability, social or psychological stress, good to excellent school performers, osteoporosis, hypertriglyceridemia, rheumatoid arthritis, musculoskeletal comorbidities, history of allergies, skin hypersensitivity, atopic background, asthma, trouble falling asleep, menstrual cycle-related problems, history of CRPS I, chronic pain, headache/migraine, first-degree family history of headache, fibromyalgia, multiple sclerosis, surgical or manipulative treatment, immobilization, plaster cast, longer duration of anaesthesia, barbiturates, angiotensin converting enzyme inhibitors, and specific gene are reported to be a risk factor for CRPS.

It is unknown whether smoking and diabetes are risk factors for CRPS. Obesity, hypothyroidism, anemia, and heart failure may be less likely to cause CRPS. I believe that depression and anxiety are consequence of CRPS. The incidence of CRPS varies greatly among studies. First, the concept of the disease changed, and the diagnostic criteria changed accordingly. Second, decision of abnormal right-left difference of each objective sign is based on a physician’s subjectivity. Third, discrimination between CRPS and the usual course of injury is based on a physician’s subjectivity. Identification of risk factor for CRPS provides some significance. First, it helps to find etiology of CRPS. Second, if a relative disease is found, treatment of the relative disease can be applied to CRPS. Third, it is helpful in the early detection of CRPS. Forth, it becomes helpful in an injury treatment such as fracture.

Keywords:   Complex regional pain syndrome, Reflex sympathetic dystrophy, Algodystrophy, Subdeck’s atrophy, Causalgia, Risk factor, Predictor

    Introduction

Complex Regional Pain Syndrome (CRPS), which was previously referred to as Reflex Regional Dystrophy (RSD), usually occurs after injury and/or surgery. CRPS is a disease that the orthopedic surgeons would like to ignore. Risk factors for CRPS were examined with a narrative review

    Methods

A narrative literature review of risk factor or predictor for CRPS or RSD was performed in the English language. Some literatures that show risk factor or predictor for CRPS or RSD do not include the term of “risk factor” or “predictor” in the title, abstract, or key words, therefore, a systematic review is not useful to show risk factor or predictor for CRPS or RSD. I read all abstract of literatures of CRPS, RSD, causalgia between April 2003 and April 2018 using MEDLINE. In addition, in case of important literatures, I read the full text. Important old literatures before March 2003 about risk factor or predictor for CRPS or RSD are included in this review. Strictly speaking, the reported risk factors for occurrence of CRPS after stroke are often early symptoms of CRPS. In addition, orthopedic surgeons rarely treat CRPS after stroke. Therefore, risk factor for occurrence of CRPS after stroke is excluded from this review.

    Results

Demographic information

Female sex: A population based retrospective study with all Mayo Clinic and Olmsted Medical Group medical records showed that gender specific incidence rates per 100,000-person years at risk were 8.57 and 2.16 for women and men, respectively [1]. Prevalence was 35.33 vs. 5.06 per 100,000 persons years for women and men, respectively [1]. A retrospective cohort study was conducted with electronic patient record data from 600,000 patients throughout The Netherlands [2]. Females were affected at least three times more often than males (ratio: 3.4) [2]. A total of 90 patients with distal radius fracture (DRF) was prospectively treated by closed reduction and casting and CRPS I occurred in 29 patients (32.2%) [3]. Logistic regression showed that risk for CRPS I was higher in cases of women (odds ratio [OR] 5.774: 95% Confidence Interval [CI] 1.391-23.966) [3].

Thirty-nine patients were diagnosed with CRPS immediately after Open Reduction and Internal Fixation (ORIF) for limb fracture from a cohort of 185,378 in patients treated with ORIF [4]. A comparable number of male and female patients suffered from CRPS [4]. Pons et al. [5] conducted a systematic search of the literature focused on determining the potential risk factors for the onset of CRPS 1 [5]. Female, particularly postmenopausal female was one of risk factors for the onset of CRPS 1 [5]. It is not possible to draw definite conclusions as this evidence is heterogeneous and of mixed quality, relevance, and weighting strength against bias and has not been confirmed across multiple trials or in homogenous studies [5].

Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Female gender was associated with higher rate of CRPS type 1 [6]. Using the Danish Patient Compensation Association’s database, Petersen et al. [7] identified 647 patients claiming CRPS following orthopedic treatment. The following ratios were found: women: men was 4:1 [7]. Multivariate logistic regressions were performed. Female gender was one of risk factors associated with posttreatment development of CRPS [7]. Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that female gender was positively associated with CRPS [8]. Of 165 patients who had suffered a mechanical traumatic injury isolated to their hand or forearm, 84 patients were diagnosed with CRPS [9] A logistic regression showed that risk for CRPS was higher in females [9].

A cross-sectional study in patients with distal tibial fracture showed that among the 488 patients RSD occurred in 45 patients, of whom 28 (62.22%) were female and 17 (37.77%) were male; there was thus a significant difference in the prevalence of RSD in terms of gender (P = 0.00; chi square test) [10]. Crijns et al. [11] identified 59,765 patients treated for a DRF, of whom 114 (0.19%) were diagnosed with CRPS [11]. Gender (women at greater risk, OR 3.86: 95% CI 1.99-7.49; p < 0.001) was independently associated with a diagnosis of CRPS [11]. A prospective observational study with 477 patients with a DRF who had been treated surgically reported that according to the multivariate analysis, female patients was significantly more likely to develop CRPS I (p = 0.02) [12].

Age: A retrospective cohort study was conducted with electronic patient record data from 600,000 patients throughout the Netherlands [2]. The highest incidence occurred in females in the age category of 61-70 years [2]. Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. It peaks between age 45 and 55 [6]. Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that age >65 was negatively with CRPS [8]. Crijns et al. [11] identified 59,765 patients treated for a DRF, of whom 114 (0.19%) were diagnosed with CRPS [11]. Older age (OR 1.029; 95% CI 1.011-1.048; p = 0.002) was independently associated with a diagnosis of CRPS [11]. A case-control study using 249 patients with DRF who underwent surgical treatment (4% developed CRPS) showed that >60 years of age (OR 9.38: 95% CI 1.170-75.233) was a higher risk of developing CRPS [13].

Pregnancy: A population-based case-control study was conducted [14]. CRPS onset was increased during the first 6 months after pregnancy (OR 5.6: 95% CI 1.0-32.4), although based on small numbers (143 cases and 1493 controls) [14].

Condition of injury

Severity of injury: A total of 90 patients with DRF was prospectively treated by closed reduction and casting and CRPS I occurred in 29 patients (32.2%) [3]. Logistic regression showed that risk for CRPS I was higher in cases of medium and low energy trauma patients (OR 7.718: 95% CI 1.136-52.44) [3]. A prospective cohort study using 291 patients with traumatic hand injuries showed that patients with crush injuries were more likely to develop CRPS (OR 4.74: 95% CI 2.29-9.80) [15].

Severity of fracture: Pons et al. [5] conducted a systematic search of the literature focused on determining the potential risk factors for the onset of CRPS 1 [5]. Intra-articular fracture was one of risk factors for the onset of CRPS 1 [5]. Zyluk published a review about risk factors of CRPS and reported that patients with comminuted and displaced DRF (suggesting more severe trauma) showed higher incidence of CRPS than in those with minimally displaced fractures [16]. However, many studies are small and heavily biased towards DRF [16]. A prospective multicenter cohort study of 596 patients with a single fracture of the wrist, scaphoid, ankle, or the fifth metatarsal showed that dislocation and an intra-articular fracture contributed significantly to the prediction of the development of CRPS1 [17].

A cross-sectional study in patients with distal tibial fracture showed that the OR for RSD was 1.100 (95% CI 0.795-1.531) in patients with an injury severity score higher than the calculated mean score in patients without RSD [10]. Crijns et al. [11] identified 59,765 patients treated for a DRF, of whom 114 (0.19%) were diagnosed with CRPS. Concomitant fracture of the distal ulna (OR 1.54: 95% CI 1.05-2.23; p = 0.029) and open fracture (OR 0.414: 95% CI 0.192-0.895; p = 0.025) were independently associated with a diagnosis of CRPS [11].

A prospective observational study with 477 patients with a DRF who had been treated surgically reported that according to the multivariate analysis, those with a high energy trauma or severe fracture type were significantly more likely to develop CRPS I (p = 0.01 and 0.01, respectively) [12]. A case-control study using 249 patients with DRF who underwent surgical treatment (4% developed CRPS) showed that associated fracture (OR 12.95: 95%CI 1.614-103.861) and level of impact (OR 6.47: 95% CI 1.751-23.872) were higher risks of developing CRPS [13].

Pain due to fracture: A total of 90 patients with DRF was prospectively treated by closed reduction and casting and CRPS I occurred in 29 patients (32.2%) [3]. Logistic regression showed that risk for CRPS I was higher in cases of patients with Patient- Rated Wrist Evaluation pain subscale score >16 (OR 12.192: 95% CI 4.484-43.478) [3]. Pons et al. [5] conducted a systematic search of the literature focused on determining the potential risk factors for the onset of CRPS 1 [5] A report of higher than usual levels of pain in the early phases of trauma was one of risk factors for the onset of CRPS 1 [5]. A prospective multicenter cohort study of 596 patients with a single fracture of the wrist, scaphoid, ankle, or the fifth metatarsal showed at baseline, patients with CRPS 1 had significantly more pain than patients without CRPS 1 (P < .001) [17].

A prospective cohort study using 291 patients with traumatic hand injuries showed that patients with pain scores ≥ 5 three days after surgery had a high risk of developing CRPS compared with patients with pain scores <5 (OR 3.61: 95% CI 1.94-6.70) [15]. A prospective cohort study with 1,549 patients with wrist fracture who were managed non-surgically showed that a pain score of ≥5 in the first week after fracture should be considered a “red flag” for CRPS [18].

Decreased sympathetic vasoconstrictor response after fracture: A prospective study with 27 patients with DRF showed that the sympathetic vasoconstrictor response was diminished or absent from the first posttraumatic day to 2 weeks later in CRPS I patients and ‘borderline patients’, whereas the normal fracture patients revealed slightly impaired sympathetic nervous function on the first posttraumatic day and normal results for 2 weeks [19]. With regard to the unaffected contralateral hand, CRPS I patients also showed impaired sympathetic nervous function [19].

Location and type of injury

Type of injury: A nationwide population-based case-control study showed as follows: Injury was a risk factor for CRPS (OR 2.96: 95% CI, 2.18-4.02) [20]. In adjusted models, open wound on the upper limbs (OR 1.25: 95% CI 1.02-1.54) conferred higher CRPS risk [20]. Injury mechanisms including nerve and spinal cord injury (OR 2.42: 95% CI 1.44-4.08), muscle and joint sprain and strain (OR 1.69: 95% CI 1.40-2.03), superficial injury (OR 1.23: 95% CI 1.00-1.51), and contusion (OR 1.44: 95% CI 1.20- 1.74), but not fracture, increased the risk of CRPS [20].

Location of injury: Pons et al. [5] conducted a systematic search of the literature focused on determining the potential risk factors for the onset of CRPS 1 [5]. Ankle dislocation was one of risk factors for the onset of CRPS 1 [5] A prospective multicenter cohort study of 596 patients with a single fracture of the wrist, scaphoid, ankle, or the fifth metatarsal showed that an ankle fracture contributed significantly to the prediction of the development of CRPS1 [17]. A nationwide population-based case-control study showed that injury in the extremities rather than the trunk was an important risk factor for CRPS [20].

Treatment of the upper limb: Using the Danish Patient Compensation Association’s database, Petersen et al. [7] identified 647 patients claiming CRPS following orthopedic treatment [7]. The following ratios were found: primary diagnosis to the upper limb: lower limb was 2.5:1 [7]. Multivariate logistic regressions were performed. Treatment to the upper limb was one of risk factors associated with post-treatment development of CRPS [7].

Motor nerve injury:Of 165 patients who had suffered a mechanical traumatic injury isolated to their hand or forearm, 84 patients were diagnosed with CRPS [9]. A logistic regression showed that risk for CRPS was higher in patients with motor nerve injury [9].

Decreased function before operation:A retrospective study showed as follows: Results of multivariate analysis demonstrated that decreased function in the Japanese Orthopedic Association score for the shoulder joint before surgery was a risk factor for the development of CRPS after arthroscopic rotator cuff repair [21].

Pathological condition and stress of patient

Health condition of patient: A total of 90 patients with DRF was prospectively treated by closed reduction and casting and CRPS I occurred in 29 patients (32.2%) [3]. Logistic regression showed that risk for CRPS I was higher in cases of Medical Outcomes Study 36-Item Short-Form Health Survey physical functioning score <40 (OR 4.931: 95% CI 1.428-17.025) [3].

Social circumstances of patient:Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Higher median household income was associated with higher rate of CRPS type 1 [6].

Psychological abnormality (depression, anxiety, etc.):A cross-sectional study with 88 CRPS patients and 88 low back pain patients showed that disability and pain severity were more strongly associated with psychological factors (depression, anxiety, and kinesiophobia) in CRPS than they were in low back pain [22]. Cause and effect relationships could not be established by this cross-sectional study [22]. Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Depression and drug abuse were associated with higher rate of CRPS type 1 [6].

Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that anxiety was positively associated with CRPS [8]. Bayle- Iniguez et al. [23] performed a case-control study and reported that multivariate analysis showed a strong association with being anxious (OR 44.9: 95% CI 7.4-273) [23]. A case-control study showed that psychological factors were not associated with CRPS onset [24]. A prospective study showed that the psychological context (anxio-depressive state) showed a (subsignificant) tendency to increase the risk of CRPS I (relative risk [RR] 2.6) [25]. A systematic review reported that in summary, studies with a higher methodological quality suggested no relationship between psychological factors and CRPS1 in adults [26].

A prospective study showed that those who developed algodystrophy did not show increased distress before the onset of the condition in patients with Colles’ fractures [27]. Another prospective study showed that there were no significant differences in scores on any of the personality and depression scales between CRPS Type 1 and non-CRPS Type 1 patients after DRF [28]. A review published by Feliu et al. [29] concluded there was no evidence to support a linear relationship that established a psychologic predisposition to develop CRPS [29]. A review reported that the observed modifications in behaviour and personality of CRPS patients, in particular depression and anxiety, were a consequence of the persisting pain disease and its considerable resistance towards treatment and not the cause [30].

A prospective study using 50 patients with a DRF reported that the risk of CRPS type I was significantly increased in patients with high trait anxiety scores (P = 0.038), indicating that after DRF, patients who have an anxious personality have a higher risk of developing CRPS type I [31]. A prospective multicenter cohort study using 596 patients indicated that there was no association between psychological factors and CRPS1 [32]. A systematic review did not reveal support for specific personality or psychopathology predictors of CRPS [33]. In a retrospective cohort study of 390 patients who had undergone elective foot and/or ankle surgery, 8 (47.06%) had had a pre-existing diagnosis of anxiety and/or depression of the 17 patients with CRPS [34].

A case-control study using 249 patients with DRF who underwent surgical treatment (4% developed CRPS) showed that psychiatric history (OR 7.22: 95% CI 1.315-39.606) was a higher risk of developing CRPS [13]. Speck et al. [35] collected data from 152 patients with CRPS, 55 control patients and 55 age- and sex-matched healthy individuals [35]. Fifty-eight CRPS patients (38%), six non-CRPS pain patients (10%) and two healthy individuals (4%) met diagnostic criteria for posttraumatic stress disorder (PTSD) [35]. Initial PTSD symptom onset was prior to CRPS in 50 CRPS patients (86%) and during the course of CRPS in eight patients [35]. A logistic regression revealed that the PTSD severity score was associated with CRPS (p < 0.0001) [35].

Economic compensation:A case-control study using 249 patients with DRF who underwent surgical treatment (4% developed CRPS) showed that economic compensation via work disability (OR 14.4: 95%CI 1.79-115.38) was a higher risk of developing CRPS [13].

Smoking:A case-control study showed that cigarette smoking was strikingly increased in patient frequency in RSD (68% versus 37% of hospitalized controls, p less than 0.0001) [36] Pawelka et al. reported that there were 37 women and 27 men; 32% of the female and 48% of the male patients were smokers and in the general population of Vienna, these percentages are 30 and 46, respectively [37]. In a retrospective cohort study of 390 patients who had undergone elective foot and/or ankle surgery, 5 patients (29.41%) were smokers of the 17 patients with CRPS [34]. Of 301 patients who underwent carpal tunnel release (CTR), 25 patients developed CRPS and smoking did not show a relationship with the development of post-CTR CRPS [38].

Social or psychological stress:Eighty percent of all dystrophy patients had a recent life-event while only 20% of the control group members reported such an event [39]. Of 145 patients (122 patients with CRPS I and 23 patients with CRPS II), 61 patients (42.1%) reported stressful life events in a close relationship to the onset of CRPS [40]. Most frequent were conflicts within the family (n=30; 20.7%), death of relatives (n=13; 9%) or serious job-related problems (n=12; 8.3%) [40]. A systematic review reported that patients who experienced more life events appeared to have a greater chance of developing CRPS1 [26].

Good to excellent school performers:Bayle-Iniguez et al [23]. performed a case-control study and reported that multivariate analysis showed a strong association with being good to excellent school performers (OR 8.4: 95% CI 1.3-52.1) [23].

Diseases

Osteoporosis:A case-control study showed that a medical history of osteoporosis (OR 2.44: 95% CI 1.17-5.14) was associated with CRPS [24].

Diabetes:Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Diabetes was associated with a lower rate of CRPS type 1 [6]. Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that diabetes was negatively with CRPS [8]. A retrospective study showed that of the 200 stroke patients with Type 2 Diabetes Mellitus (T2DM), 108 were in the CRPS group and 92 were in the non-CRPS group [41]. There were significant differences in HbA1c (p<0.05) between the two groups [41]. Across the five HbA1c groups, there were significant differences in CRPS prevalence (p<0.01); specifically, it increased as HbA1c increased [41].

Hypertriglyceridemia:Disease analysis using a retrospective series of nine cases and a review of the literature of RSD in pregnancy reported that hypertriglyceridemia appeared to be a risk factor for RSD [42].

Rheumatoid arthritis:A prospective multicenter cohort study of 596 patients with a single fracture of the wrist, scaphoid, ankle, or the fifth metatarsal showed that patients who developed CRPS1 at a later time more often had rheumatoid arthritis (14.3% vs 5.3% non-CRPS 1) [17].

Musculoskeletal comorbidities:A prospective multicenter cohort study of 596 patients with a single fracture of the wrist, scaphoid, ankle, or the fifth metatarsal showed that patients who developed CRPS1 at a later time more often had musculoskeletal comorbidities (54.8% vs 27.6% non-CRPS 1) [17].

Allergy/hypersensitivity reactions:A case-control study showed that of the patients with CRPS I, 78 (67.8%) reported a statistically significant history of allergies compared with the 39 (33.9%) patients in the control group (P<.0001) and skin hypersensitivity testing yielded an 83.3% positive predictive value with an accuracy of 76.9% [43]. Bayle-Iniguez et al [23] performed a case-control study and reported that multivariate analysis showed a strong association with presence of an atopic background (OR 25.0: 95% CI 4.6-135) [23]. A case-control study showed that asthma (OR 3.0: 95% CI 1.3-6.9) and CRPS were related [24].

Trouble falling asleep:Bayle-Iniguez et al [23]. performed a case-control study and reported that multivariate analysis showed a strong association with having trouble falling asleep (OR 5.3: 95% CI 1.6-17.0) [23].

Diseases hard to cause CRPS:Retrospective analysis of the Nationwide Inpatient Sample database [6] from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Obesity, hypothyroidism, and anemia were associated with a lower rate of CRPS type 1 [6] Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that heart failure was negatively with CRPS [8].

Painful disorders

Chronic pain:Of 145 patients (122 patients with CRPS I and 23 patients with CRPS II), 60 patients (41.4%) had a history of chronic pain before CRPS [40]. The majority suffered from chronic low back pain (n=20; 13.7%), chronic headache (n=17; 11.7%), multiple chronic pains (n=6; 4%) or different other pains (n=17; 11.7%) [40]. A case-control study showed that in a recent history (1-year before CRPS), cases had more menstrual cyclerelated problems (OR 2.60: 95% CI 1.16-5.83) and neuropathies (OR 5.7: 95% CI 1.8-18.7) [24]. A prospective study showed that history of CRPS I was a significantly correlated factor (RR 10.4) [25]. A retrospective analysis using 190 patients with CRPS and additional 26 patients with CRPS NOS (not otherwise specified) showed that a third had already experienced other than everyday pains in the now CRPS-affected limb before the CRPS incident trigger [44]. A total of 21 patients (11.1%) experienced widespread pain in clinic [44]. Additional patients reported CRPS-concomitant regional pains, most commonly headaches/ migraines, lower back pain, and irritable bowel syndrome [44].

Headache:Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States [6]. There were 22,533 patients with the discharge diagnosis of CRPS type 1 of an inpatient sample of 33,406,123 [6]. Headache was associated with higher rate of CRPS type 1 [6]. Of 145 patients (122 patients with CRPS I and 23 patients with CRPS II), 60 patients (41.4%) had a history of chronic pain before CRPS [6]. The majority suffered from chronic low back pain (n=20; 13.7%), chronic headache (n=17; 11.7%), multiple chronic pains (n=6; 4%) or different other pains (n=17; 11.7%) [40]. A case-control study reported that headache and a firstdegree family history of headache were risk factors for CRPS [45]. A case-control study showed that a medical history of migraine (OR 2.43: 95% CI 1.18-5.02) was associated with CRPS [24].

Age and gender-adjusted standardized morbidity ratios (SMR) showed that those with CRPS were 3.6 times more likely to have migraine and nearly twice as likely to have chronic daily headache (CDH) as the general population [46]. Of those CRPS sufferers with migraine, 61.2% (41/67) reported the onset of severe headaches before the onset of CRPS symptoms [46]. More extremities were affected by CRPS in participants with migraine (median of four extremities) compared with the combined group of those CRPS sufferers with no headaches or tension-type headache (TTH) (median 2.0 extremities), P < 0.05 [46]. Migraine may be a risk factor for CRPS and the presence of migraine may be associated with a more severe form of CRPS [46].

Fibromyalgia:Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression supported the association between fibromyalgia and the development of CRPS, with estimated OR of 2.0 (P < .001) [8]. Crijns et al. [11] identified 59,765 patients treated for a DRF, of whom 114 (0.19%) were diagnosed with CRPS [11]. Comorbid fibromyalgia (OR 16.0: 95% CI 4.92-51.8; p < 0.001) was independently associated with a diagnosis of CRPS [11].

Multiple sclerosis:Schwartzman et al. [47] reported that multiple sclerosis patients (4 cases per 205 patients) were at a higher risk of developing CRPS than the general population (expected prevalence: 0.078 cases per 205 persons) [47].

Difference due to treatment

Surgery:Using the Danish Patient Compensation Association’s database, Petersen et al. identified 647 patients claiming CRPS following orthopedic treatment [7]. The following ratios were found: surgical: nonsurgical treatment was 3:1 [7]. Multivariate logistic regressions were performed. Surgical treatment was one of risk factors associated with post-treatment development of CRPS [7]. Database queries yielded 853,186 patients diagnosed or treated for DRF [8]. Multivariable logistic regression showed that surgical or manipulative treatment was positively associated with CRPS [8].

Difference of incidence due to difference of treatment for distal radius fracture:network meta-analysis showed that compared with bridging external fixation, K-wire fixation, dorsal plating, volar plating, dorsal and volar plating, plaster fixation and non-bridging external fixation might be the better treatment methods to reduce the risk of CRPS in DRF patients [48]. A total of 77 postmenopausal female patients with DRF were divided into three subgroups: 1. closed reduction and immobilisation in a plaster cast; 2. closed reduction and percutaneous fixation with K wires; 3. open reduction and fixation with a locking plate [49]. Open reduction with locking plate fixation produced better functional outcomes in the early postoperative period and reduced the risk of development of CRPS [49]. A meta-analysis compared showed that the overall incidence of complications, including CRPS, was higher with pinning/wiring in patients with unstable DRF, though the incidence of carpal tunnel syndrome and nerve defects was not different [50].

Fixation:Pons et al. [5] conducted a systematic search of the literature focused on determining the potential risk factors for the onset of CRPS 1 [5]. Immobilisation was one of risk factors for the onset of CRPS 1 [5]. Field et al. [51] reported that in patients who had objective signs of algodystrophy the plaster cast was significantly tighter during the first three weeks than in patients who did not develop algodystrophy [51].

Perioperative factors:Thirty-nine patients were diagnosed with CRPS immediately after Open Reduction and Internal Fixation (ORIF) for limb fracture from a cohort of 185,378 in patients treated with ORIF [4]. A longer duration of anaesthesia, but not regional anaesthesia, was significantly associated with a higher incidence of CRPS [4].

A total of 301 patients who underwent carpal tunnel release were randomly distributed to undergo one of the following techniques: general anesthesia, regional intravenous anesthesia with lidocaine, regional intravenous anesthesia with lidocaine and clonidine, or axillary plexus block [38]. Twenty-five of them developed CRPS [38]. Predominance was not observed among the anesthetic techniques used [38].

Medicine

A total of 126 neurosurgical patients was treated with barbiturates, and 108 control patients were treated with carbamazepine or phenytoin [52]. A total of 25 barbituratestreated patients (27.6%) experienced shoulder-hand syndrome (SHS) and none of the patients in the control group developed SHS [52]. A retrospective case-control study (186 cases and 697 controls) showed that current use of Angiotensin Converting Enzyme (ACE) inhibitors was associated with an increased risk of CRPS (adjusted OR 2.7: 95% CI 1.1-6.8) [53]. The association was stronger if ACE inhibitors were used for a longer time period (adjusted OR 3.0: 95% CI 1.1-8.1) and in higher dosages (adjusted OR 4.3: 95% CI 1.4-13.7) [53]. None of the other antihypertensive drug classes was significantly associated with CRPS [53]. Forty-seven patients with metastatic renal cell carcinoma were treated with Everolimus and 3 developed unilateral leg pain related to RSD [54].

Gene

Huehne et al. [56] reported that particular ACE gene polymorphism is unlikely to be a predisposing factor for CRPS I [54]. Huehne et al. [56] tested a GT-repeat polymorphism in the Neutral Endopeptidase (NEP) promoter region as well as 18 tag Single Nucleotide Polymorphisms (SNPs) in six linkage disequilibrium blocks in the NEP gene region in 320 CRPS patients and 376 controls [56]. No significant genetic association was observed. Thus, Huehne et al. [56] concluded that the NEP gene did not seem to be a major risk factor for CRPS [56]. Fifteen of 163 patients with DRF were diagnosed with CRPS I and significant association was detected for the rs1048101 polymorphism of the alpha1a-adrenoceptor [57].

All other tested variants were not associated with CRPS I. This study suggests the rs1048101 single nucleotide polymorphism within the alpha1a-adrenoceptor as one risk factor for the development of CRPS I after DRF [57]. Smith theorizes that genetic alterations including functional polymorphisms of Nrf2 (a master regulator of the transcription of multiple antioxidants) may render certain subjects more or less susceptible to developing CRPS after surgery or trauma [57].

    Discussion

>Difference of incidence

The incidence of CRPS varies greatly among studies. Three factors explain it. First, the concept of the disease changed, and the diagnostic criteria changed accordingly. Second, decision of abnormal right-left difference of each objective sign is based on a physician’s subjectivity. Third, we have to distinguish between CRPS and the usual course of injury. CRPS has many aliases. RSD, the former major disease name, was renamed CRPS. The concept of CRPS (or RSD) changed, and the diagnostic criteria changed accordingly. Even if the identical patients are diagnosed by the identical physician, the incidence of CRPS depends to a large extent on the diagnostic criteria used [17]. Of the 596 participants after a single fracture, 42 (7.0%) were diagnosed with CRPS1 according to the Harden and Bruehl criteria [59], 289 (48.5%) according to the International Association for the Study of Pain criteria [60] and 127 (21.3%) according to the criteria of Veldman [61]. The problem of right-left difference is serious. Almost all CRPS occur in the extremities. There are many diagnostic criteria for CRPS (or RSD), however, all criteria are combinations of right-left difference of some subjective symptoms and right-left difference of some objective signs.

The difference between right-left difference corresponding to diagnostic criteria and right-left difference not corresponding to diagnostic criteria, in other words, the difference between abnormal range right-left difference and normal range rightleft difference, is unclear. The decision is made based on a physician’s subjectivity. Therefore, even if the identical patients are diagnosed with the identical criteria, the diagnosis depends on physicians. Operators are not more likely to diagnose the patients who were operated by himself/herself as having CRPS. CRPS usually occurs after injury and operation. Naturally, there is right-left difference in pain, skin temperature, and skin color of the both limbs after injury and operation. A physician’s subjectivity decides whether these right-left differences are natural course or abnormal. It is similar to afore mentioned right-left difference.

Is CRPS-associated factor cause of CRPS or consequence of CRPS?

Is CRPS-associated factor that was found with case-control studies cause of CRPS or consequence of CRPS? In case of age, certain age is never consequence of CRPS, but cause (or risk factor) of CRPS. In case of depression and anxiety, they cause a chicken-and-egg situation. Many case-control studies or retrospective studies showed that depression and/or anxiety were positively associated with CRPS [6,8,13,23,24]. Of five prospective studies, three studies showed no association between psychological factors and CRPS [27,28,32]. One study showed a (sub-significant) tendency to increase the risk of CRPS [25]. One study showed that patients who have an anxious personality have a higher risk of developing CRPS [31]. Systematic review and/or meta-analysis of prospective studies alone were not published; however, I believe that depression and anxiety are consequence of CRPS at the moment.

Significance or risk factor

Identification of risk factor for CRPS provides some significance. First, it helps to find etiology of CRPS. Second, if a relative disease is found, treatment of the relative disease can be applied to CRPS. Third, it is helpful in the early detection of CRPS. Forth, it becomes helpful in an injury treatment such as fracture. Menstrual cycle-related problems [24]. headaches/ migraines [6,40,44,45], lower back pain [44], irritable bowel syndrome [44], fibromyalgia [6,11], widespread pain [44] are risk factors for CRPS. And female sex is also a risk factor for CRPS [1-7]. These indicate that CRPS may be included in central sensitivity syndrome.

Steroids are effective to some extent in the early stage of CRPS [62-72]. however, these are not effective in a chronic stage of CRPS. There are few evidence-based effective treatments for CRPS. There are many evidence-based effective treatments for FM or headache, therefore, it is possible to use them as treatments for CRPS. In some patients with a chronic stage of CRPS, objective signs such as swelling, local heat, redness disappear, and pain alone persists on the affected limb, further pain spreads to the trunk and/or other limbs. In such a patient, it is almost impossible to distinguish between chronic stage of CRPS and FM or chronic widespread pain (incomplete form of FM). If we know risk factors for CRPS, it is useful to detect CRPS early. If CRPS occurs after operation, treatment outcomes are decreased. Knowledge of risk factors for CRPS is important to decrease occurrence of CRPS. Cowell et al. [72] reported that simple practice changes (a patient information leaflet, a local gold standard for care of DRF, education for staff regarding risk factors and early warning signs of CRPS, and simple patient and staff visual aids) reduced the incidence of CRPS from 25% to 1% after DRF [73].

A severe pain after injury may be a risk factor of CRPS, however, it may be an early symptom of CRPS. In any case, a severe pain after injury should be alleviated as soon as possible in some way. Until only recently, in Japan, almost all physicians did not know FM and some physicians consider FM equivalent to Piltdown Man (fabricated Homo sapiens). Therefore, physicians who treat FM is very rare like Nippon Nippon, endangered bird. Knowledge of FM has spread in Japanese orthopedic surgeons in an unfortunate state. Some Japanese orthopedic surgeons do not want to operate patients with FM. One of the reasons is that FM is a risk factor for CRPS. An patient with comminuted and displaced DRF underwent a conservative treatment and suffered from serious malunion. Initially, surgery was planned, however, treatment suddenly changed to a conservative therapy immediately after she explained that she suffered from FM. It is an inappropriate use of knowledge of FM or risk factor for CRPS.

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Abstract

Bone grafts have been used in orthopedic reconstructive procedures for over a hundred years. Use of autografts is considered to be the ideal choice, but limited availability and associated complications makes their use unfeasible in all orthopedic reconstructive procedures. Alternatives such as allografts and bone graft substitutes were introduced in 1980’s. Although the use of bone allografts in U.S.A has increased over the last few years, compilation of data to quantify their utilization is still lacking. We performed a retrospective chart review study to quantify the bone allograft utilization in laminectomies and discectomies performed at Beaumont Hospital Royal Oak between October 1, 2017 and December 31, 2017.

We determined the type and quantity of bone allografts that were issued for each of the included 79 laminectomies and 55 discectomies. This was followed by quantitative analysis of the specific bone allograft used for each included procedure in addition to calculating the “tissue crossmatch to transplant ratio”. Amongst 79 cases of laminectomies, the bone allograft that was issued and used in highest quantity was Crushed Cancellous (CRC). Amongst 55 cases of discectomies, Grafton Putty (GRP) was issued and used in highest quantity. Trinity Elite Medium (TRN-M) was issued for highest number of laminectomy cases (45.5%) and was also used in most number of laminectomy cases (44.3%). GRP was issued for and used in most cases of discectomies (69% and 63.6% respectively). Judicious use of allografts during orthopedic reconstructive procedures can help in minimizing tissue wastage and in reducing health care cost burden.

Keywords: Allografts; Laminectomies; Discectomies; Utilization; Bone substitutes

Abbreviations: TRN-M: Trinity Elite Medium; TRN-S: Trinity Elite Small; GRP: Grafton Putty; GRM: Grafton Matrix; ALF: AlloFuse; CRC: Crushed Cancellous; ALS: AlloStem; MAP3: Multipotent Adult Progenitor 3; CSP: Cervical Spacer; UNI: UniLIF; BI4: Bio4

    Introduction

Use of bone grafts in orthopedic reconstructive procedures has been in practice for over a hundred years [1]. Autograft is considered to be the ideal option in these procedures; however, limited availability of bone autografts and the associated bone and donor site morbidity was the driving force behind the introduction of bone allografts in early 1980s [2]. A well-established bone dispensing service at the level of community hospitals seems to be imperative due to the increasing volume of orthopedic reconstructive procedures being performed now. Beaumont Hospital in Royal Oak, Michigan has one of the largest tissue and bone dispensing services in the country maintaining strict traceability of the tissues. Despite the increasing use of bone allografts in U.S.A, there is still a lack of data in literature to quantify the utilization of bone allografts. We performed a retrospective chart review study to quantify the utilization of different bone allografts used in laminectomies and discectomies performed at Beaumont Hospital Royal Oak between October 1, 2017 and December 31, 2017.

    Materials and Methods

After obtaining the required Institutional Review Board approval from Beaumont Research Institute, we extracted 153 cases of laminectomies and discectomies performed at Beaumont Hospital Royal Oak between October 1, 2017 and December 31, 2017 using the Beaumont Health EMR system. Out of these 153 cases, 19 cases that involved both laminectomy and discectomy in the same operative procedure were excluded. We then reviewed the remaining 134 cases of spine surgeries (79 cases of laminectomies and 55 cases of discectomies) to determine:

    Results

The bone allograft that was issued and used in highest quantity in the 79 reviewed cases of laminectomies was Crushed Cancellous (CRC) followed by Trinity Elite Medium (TRN-M). A total of 127 CRC units were issued for laminectomies and out of these, 110 CRC units were used. In comparison, the bone allograft that was issued and used in highest quantity in the 55 reviewed cases of discectomies was Grafton Putty (GRP). A total of 74 units of GRP were issued for discectomies and out of these, 43 GRP units were used. A detailed breakdown of different allografts utilized in laminectomies and discectomies is shown is table 1 and table 2 respectively.

TRN-M: Trinity Elite Medium; TRN-S: Trinity Elite Small; GRP: Grafton Putty; GRM: Grafton Matrix; ALF: AlloFuse; CRC: Crushed Cancellous

TRN-M: Trinity Medium; TRN-S: Trinity Small; GRP: Grafton Putty; GRM: Grafton Matrix; CRC: Crushed Cancellous; ALS: AlloStem; MAP3: Multipotent Adult Progenitor 3; CSP: Cervical Spacer; UNI: UniLIF; BI4: Bio4

Amongst the main bone allografts issued for laminectomies, more than 80% of issued CRC units were used; whereas close to 65% of issued units of TRN-M and GRM were used. Amongst the main bone allografts issued for discectomies, close to 90% of issued CRC units were used; whereas almost 80% of issued TRN-M units were used and almost 60% of issued GRP units were used. Figures 1 & 2 represent percentage wise usage of different allografts in laminectomies and discectomies respectively. The unused units were returned back to our tissue service, except for those that got wasted after being issued for the procedure. Out of all the bone allografts issued for laminectomies, one TRN-M unit got wasted. Similarly, out of all the bone allografts issued for discectomies, one TRN-S unit got wasted (Figures 1 & 2).

Amongst the 79 reviewed cases of laminectomies, TRN-M either alone or in combination with another allograft was issued for most cases of laminectomies (36 out of 79 cases; 45.5%), followed by CRC either alone or in combination with another allograft (34 out of 79 cases; 43%). TRN-M either alone or in combination with another allograft was also the tissue that was used in most cases of laminectomies (35 out of 79 cases; 44.3%) followed by CRC (34 out of 79 cases; 43%). These findings are shown in (Figure 3). Out of all bone allografts utilized in discectomies, GRP was issued for most cases of discectomies (38 out 55 cases; 69%); while ALS, BI4, CSP and UNI were each issued for least number of discectomies (1.8%). Out of all the bone allografts issued for discectomies, GRP was used in most number of discectomies (35 out 55 cases; 63.6%); while CSP and UNI were not used in any of the discectomy cases. These findings are shown in Figure 4. The proportion of bone allografts used in laminectomies versus discectomies was statistically significant (p = 0.025) (Figure 4).

    Discussion

Bone grafts and bone graft substitutes are used to provide structural support and to augment bone healing. Autologous, allogeneic, and artificial bone grafts each have their own advantages and drawbacks. New operative techniques in addition to advancement in allografts and synthetic bone grafts over the last few decades have influenced the selection of bone grafts used in orthopedic reconstructive procedures [3]. Autologous bone graft is considered the prime option, but it still carries the risk of bone and donor site morbidity [4]. In addition, limited availability of autologous bone grafts is a barrier in their utilization particularly in orthopedic procedures that require large amounts of bone grafts [5]. Limited quantity of autologous bone grafts in addition to increasing number of orthopedic reconstructive procedures being performed now has led to a higher demand for bone allografts and bone graft substitutes. The number of bone grafting procedures performed each year in the United States is estimated to be around 500,000 to 600,000 [6]. Approximately 1400 products are available in the international market for use as bone fillers, but an optimal bone graft substitute with little or no associated complications and risks does not exist at this time [4]. Consensus regarding the use of a specific type of bone graft for any orthopedic procedure still does not exist [7].

Despite the increasing use of bone allografts in U.S.A, there is still a lack of data in literature to quantify the utilization of bone grafts. S Mohd et al. [2] in 2017 also acknowledged that there was still a lack of data to assess the awareness and understanding of orthopedic community about bone banking in Malaysia [2]. Results from an awareness survey conducted by S Mohd et al. [2] regarding tissue banking and bone grafts showed that 82.5% respondents were aware about tissue banking, however only 12.5% knew about the existence of tissue banks in Malaysia [2].

Meermans G et al. [8] in 2007 evaluated the indications and results of the allograft utilization from the local bone bank and concluded that out of 131 allografts stored in the bone bank, only 20 were discarded [8]. In our study, out of 295 bone allograft units issued for laminectomies, only one TRN-M unit got wasted. Similarly, out of 152 bone allograft units issued for discectomies, only one TRN-S unit got wasted. The concept of bone banking originated in early 20th century and bone allograft utilization has increased in popularity since then [9]. The need for establishment of bone bank in community hospitals is supported and justified by the increasing volume of orthopedic reconstructive procedures being performed in community hospitals over the last few years [10]. Community hospital bone banks can prove to be a very beneficial and cost-effective tool for the healthcare structure in general, if guidelines to ensure proper screening of donor bone and dependable preservation of bone grafts are followed strictly [10].

Conclusion

Our study results showed that 4 main vendor specific bone allografts (CRC, TRN-M, TRN-S and GRM) were issued for laminectomies; whereas GRP was found to be the only main vendor specific bone allograft that was requested and issued for discectomies. Our study demonstrated that the “tissue crossmatch to transplant ratio” was 1.5 for laminectomies and 1.85 for discectomies. We conclude that judicious use of allografts during orthopedic reconstructive procedures and increased awareness about bone allografts amongst orthopedic and neurospine community can be helpful in minimizing the tissue wastage, thereby ensuring adequate availability of these tissues in addition to reducing the health care cost burden.

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Introduction

In a developed country like the United Kingdom (UK), there is a substantial change in the age structure of the population due to the increasing life expectancy. The section of the population that has shown to be the most affected increase is the super elderly (>85 years). As per UK’s 2016 mid-year population estimates, super elderly forms 2.1% of the whole population and it is expected that, by mid-2039, more than 1 in 12 of the population is projected to be aged 80 or over [1].

Magnitude of the problem

Fracture neck of femur continues to be the second most leading cause for hospital admission in the older population [2]. It is the commonest serious injury for the older people [3]. Additionally, it is associated with a total cost to health and social services of over £1 billion per year, which is equivalent to approximately 1% of the whole NHS budget[3]. Surgery is indubitably the treatment of choice for fracture neck of femur even in the geriatric population [4,5]. On the whole, the seriousness of this injury is not completely attributable to the surgical aspect in the treatment of this injury. In this cohort of patients, the associated medical challenges generally dictate the outcome of the injury. This is due to the fact that, the super elderly is generally frail and have multiple medical comorbidities. To begin with, their pre-injury level is suboptimal and the hip fracture destabilises them further and thereby resulting in increased morbidity and mortality. The perioperative mortality rate ranges from 2.3 to 13.9% [6]. However, this risk does not end with discharge from the hospital. Nearly a third of these patients die within a year of the injury, which is almost double the rate when compared to the younger cohort (65-84 years) [7]. Among those who survive, 60% fail to remain independent in all their activities of daily living [8]. Hence understanding the allied medical, psychological and functional aspects of this distinct subgroup of super elderly patients is required to improve their outcomes after a hip fracture.

Pre-existing co-morbidites

The most common comorbities in the elderly patients include hypertension (50-60%), hearing loss (35%), dementia (30%), repeated falls (25%), cancer (20%), vision loss (20%), chronic obstructive pulmonary disease, diabetes (10-20%), cardiac failure (15%) and coronary artery disease (15%) [9,10]. These comorbidities primarily influence the outcome after hip fracture and hence need to be recognised at the time of admission.Early recognition would help in stabilising these co-existing conditions. However, this does not imply that medical interventions be instituted that may potentially delay the surgery beyond the 48-hour cut off [11].Delayed surgery has been shown to be linked with worse outcomes. It is of utmost importance to identify and promptly treat correctable comorbidities like anaemia, anticoagulation, volume depletion, electrolyte imbalance, uncontrolled diabetes, uncontrolled heart failure, correctable cardiac arrhythmia or ischaemia, acute chest infection and exacerbation of chronic chest conditions so that these patients can be operated within the golden period of 48 hours.

Post-operative morbidities

In addition to the above mentioned pre-existing medical conditions, hip fractures can precipitate further medical issues which complicate the recovery of these patients. These include pain (both from the injury and the surgery), delirium, infections, decubitus ulcers, deep vein thrombosis, pulmonary embolism, restricted mobility and depression. Prevention and prompt recognition of these complications go a long way in improving the outcome of hip fractures. Special mention regarding delirium is warranted as it is a common problem which is usually under-recognised and sub optimally treated in this subset of patients with a fracture neck of femur. Patients who have had femoral neck fractures can experience delirium three times more than patients undergoing non-orthopaedic surgery [12]. There is increased mortality and morbidity associated with delirium [13]. Various risk factors have been identified for delirium and the cause is usually multifactorial [14]. These include advanced age, dementia, polypharmacy, hypoxia, infection, pain, fluid and electrolyte disturbance, hypotension, malnutrition, unfamiliar environment, existing visual and auditory impairment and sleep deprivation. Robertson and Robertson in their study have shown that early intervention can reduce the prevalence of delirium by 50% [15]. It is pertinent to note that most of these factors do not operate in isolation; rather they are so closely interrelated that one factor can lead to the other like a chain reaction. Hence, targeting these risk factors through a multidisciplinary approach comprising the geriatric physician, nursing care, pain team, physiotherapist, dietician, pharmacist and relatives of the patients can significantly reduce the incidence of delirium in the super elderly.

Prevention

Successfully surviving the hip fracture and returning to the previous level of activity may seem to be the target at focus. However, studies have shown that, these patients are at increased risk of a second hip fracture. The risk has been calculated to be six-fold higher [16].The two main elements of this increased risk are low bone mineral density and falls [17]. There is ample evidence for the pharmacological treatment of low bone mineral density [18,19] and it is being increasingly practiced.Falls on the other hand need a holistic approach for its prevention.Falls are the fundamental mechanism for nearly 95% of fracture neck of femur. After sustaining a fall, the subsequent probability of suffering another fall is three times more [18]. These patients should undergo a multifactorial assessment for the risk factors contributing to a fall and appropriate interventions in the form of strength and balance training, home hazard assessment and intervention.Vision assessment, medication review with modification/withdrawal should be implemented[20].

    Conclusions

With the projected increase in the number of super elderly and in turn the increased burden of treatment of hip fractures, it is vital to understand the complexity and multifactorial nature of the situation of this subsection of patients and henceforth utilise a multidisciplinary approach for improving the outcomes after neck of femur fractures.

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Abstract

Introduction: Limb amputation is a major life changing surgery used in many disciplines as a planned primary procedure or as a salvage procedure in tumours, trauma, and peripheral vascular disease. However, amputation carries a high rate of wound complications such as infection, dehiscence, and impaired healing. These complications may result in further surgical intervention, prolonged hospitalisation, and decreased quality of life for patients. Whilst the use of negative pressure wound therapy (NPWT) in the treatment of chronic wounds has demonstrated improved wound outcomes by increased wound healing, wound shrinkage, and decreasing wound oedema; literature for the use of NPWT in amputations is scarce.

Aim: To evaluate the wound healing outcomes of patients after lower limb amputation treated with and without the use of NPWT. Patients for the intervention group were chosen from an amputation database whom had received NPWT from 2015 to 2017. A control group was established by an independent investigator from a prospective amputation database whilst matching patients in the intervention group for age, gender, type of amputation and method of closure. Outcomes assessed were the presence of wound complications, additional surgical procedures, and drainage volumes.

Results: Patients in both the intervention group (n=9) and control group (n=9) were well matched for demographics. The intervention group had a higher yield of mean drainage volumes compared to the control group of 285.6ml and 220.0ml respectively. Additionally, the intervention group demonstrated fewer patients with wound complications compared to the control group at 2 versus 5 patients respectively.

Conclusion: The data presented above demonstrates a positive trend in the reduction of wound complications with the use of NPWT. Despite being statistically insignificant, we believe that there is evidence to suggest the potential of NPWT in amputation therapy. Therefore, a prospective investigation with a larger sample size is warranted for further assessment of the effectiveness of NPWT as routine therapy for amputations.

Keywords: Negative pressure wound therapy; Wound healing; Amputation; Wound infection; Dressings; Sarcoma

Abbreviations: NPWT: Negative Pressure Wound Therapy; VAC: Vacuum Assisted Closure; WOLLF: Wound Management of Open Lower Limb Fractures

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Introduction

Amputations are utilised for many indications, as planned primary procedures such as peripheral vascular disease or tumours, or as a salvage procedure for severe trauma or infections. Decisions to amputate in complex cases are usually a multidisciplinary decision with extensive patient and family counselling, preoperatively if possible [1,2]. In trauma, amputation may be considered as management in the presence of a high grade open fracture, severe vascular injury, significant nerve injury, or failed salvage. However due to the nature of trauma, other factors associated to the injury or patient’s physical condition may compound wound healing and amputation success. These factors include the presence of shock or compartment syndrome, extent of the injury, comorbidities, age, fluid status, and level of atherosclerosis [3].

Sarcomas, both bone and soft tissue, are typically treated with a wide surgical resection and adjuvant therapy [4-6]. This group of patients are subject to a higher risk of adverse wound outcomes due to the nature of their disease and adjuvant treatments received. Sarcomas have high mitotic and invasive activity that can interrupt wound healing by inducing a chronic inflammatory environment, delaying wound granulation and maturation [7,8]. Furthermore, the use of adjuvant chemotherapy and radiotherapy can cause damage to proliferative cells and healthy tissue, which causes an additional delay in wound healing [9,10]. Where the tumour is large and high grade, or where limb sparing surgery has failed or is not possible, an amputation may be the most appropriate treatment plan [11,12].

Amputations are life changing operations which are associated with a further increased risk of complications compared to limb sparing procedures and resections. In 2009, Harris et al quote 24.8% of lower limb amputations encounter wound complications by 3 months post-op [13]. In this study, the most common wound complications were infections (34.2%) and wound dehiscence (13.4%). Another study by Jensen et al in 1982 demonstrated 14% of above knee amputation patients suffered from wound complications, with 2% leading to further re-amputation. Comparatively, the same study showed that 40% of below knee amputation patients had wound complications, of which 28% required further re-amputation [14].

Over the last 15 years, negative pressure wound therapy (NPWT) has contributed to improved wound healing outcomes in surgical patients with the initial use to fill voids in chronic wounds. The mode of NPWT in our institute is the Vacuum Assisted Closure (VAC) (ActiV.A.C, KCI San Antonio, Texas). NPWT consists of a semi-occlusive dressing attached to a suction device to create a negative pressure environment thereby promoting wound healing [15]. This is achieved on a macroscopic and microscopic level. Macroscopically, the collapse of the pores of the foam or mesh dressing by 80% transfers centripetal forces to the wound surface causing wound shrinkage [16,17]. This reduces the wound site to sub atmospheric pressure, assisting in the removal of excess fluid in the wound, creating further compression on the wound site and minimising potential deadspace within the wound [18]. Microscopically, NPWT induces undulation of the wound surface which transmits shear and hydrostatic forces to the individual cells via the extracellular fluid and matrix [19]. This provides alteration of the cell shape to promote cell proliferation, migration and differentiation [20]. Additionally, NPWT can assist in optimising neuropeptide and nerve fibre growth in wound healing [21]. It has also been hypothesised that NPWT can reduce bacterial wound infections, however there is insufficient evidence to support this.

Since its advent in 1990, NPWT has been primarily used for tissue loss and open wounds [22]. However, there is an emerging body of evidence indicating the benefit of NPWT in closed wound treatment. In 2006, Stannard et al demonstrated a reduction in wound healing time with drainage of haematomas to 1.6 days from 3.1 days with use of NPWT, and a further reduction in rates of infection of wound sites from 16% to 8% [23]. The same study investigated the use of negative pressure in high risk lower extremity fractures to show a statistically significant reduction in the time taken for the wound to dry from 4.8 days compared to 1.8 days [23]. Another study by Stannard et al in 2012 demonstrated a 1.9 times increase in the risk of wound infection in patients not using NPWT [24].

The use of NPWT in severe open fractures was evaluated by Stannard et al in 2009, quoting that patients on NPWT were only one-fifth as likely to develop deep infections as compared to those without [25]. Presently, the WOLLF trial aims to evaluate the efficacy of NPWT in a pragmatic multicentre randomised controlled trial with patient reported outcomes as their primary outcome measure [26]. A pilot study conducted within our institution by Kong et al showed a clinically and statistically significant improvement in wound complication rates when used following sarcoma resection. Our study demonstrated a lower mean drain volume and a lower proportion of wound complications in the NPWT group [27]. Currently, there is evidence for the benefit of NPWT in reducing wound complications, and for its use in trauma and elective surgery. However, literature on the benefits of NPWT in amputation surgery is scarce.

Aim

We aim to evaluate the wound healing outcomes of sarcoma patients after lower limb amputation treated with and without the use of negative pressure wound therapy.

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Method

A case controlled study was conducted on a cohort of predominantly sarcoma patients that received NPWT as routine therapy for amputations between 2015 and 2017. An intervention group containing 9 consecutive patients that received NPWT were matched from a database against a control group of 9 patients who did not receive NPWT. The intervention group was matched on patient age at operation, gender, type of amputation, and method of closure. The control group was constructed at random by an independent investigator from a prospective amputation database. Patients from both groups were grouped by their amputation indication of being sarcoma or non-sarcoma. The non-sarcoma group contained patients with wound breakdown, trauma with secondary osteomyelitis, and bone loss.

Outcomes assessed were; wound complications, additional surgical procedures due to wound breakdown or infection, duration of drain usage, drainage volumes. Additionally, use of adjuvant chemotherapy or radiotherapy before or after surgery was recorded as these interventions are known to influence wound healing. All patients were treated with 40mg enoxaparin subcutaneously as routine post-operative venous thromboembolism prophylaxis. NPWT was applied with a mesh and occlusive dressing attached to a vacuum pump for a minimum of 3 days. The dressing was removed after a satisfactory wound review by the treating surgeon. To assess the non-inferiority between both groups, a Shapiro-Wilk normality test was applied and further statistical analysis performed using MiniTab version 17 (Minitab for Windows, Minitab Inc., State College, PA, USA).

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Results

9 consecutive patients from May 2015 to May 2017 received VAC dressings as a routine procedure following amputations. The demographics and outcomes for both groups are compared in the tables below. As outlined in Table 1 & 2, the groups were well matched in terms of patient demographics and confounding factors, with no statistical significance between the intervention and control group. This includes the modified Glasgow Prognostic Score (mGPS) which measures serum albumin and CRP, and has been shown predict survival across multiple cancers. NPWT dressings in the intervention group were utilised for a mean of 5.6 days (range 3-10, median 5), with no adverse reactions encountered. Suction drains were used in patients post-operatively in the intervention and control group for 8 patients and 4 patients respectively, with a similar mean duration of 4.40 days in the intervention group and 3.75 days in the control group. Regarding the outcomes measured, there was no significant difference in the mean volume drained with or without the use of NPWT (285.6ml versus 220.0ml). The intervention group had 2 patients which encountered wound complications compared to 5 patients in the control group, however this did not reach statistical significance (p=0.335).

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Discussion

Despite the non-statistical significance in the proportion of patients with wound complications following amputations, there is a trend to suggest the potential for NPWT to improve outcomes which certainly warrants further investigation. This could in part be explained by limited participants, but also by the higher rates of prior chemotherapy and radiotherapy in the intervention group. Quantitatively, the use of NPWT could decrease wound complications in amputation patients by reducing dead space, minimising wound oedema, and presenting a favourable biological environment for wound healing. Wound complications can incur an increase in healthcare expenditure in a multitude of modes; increased hospital stay, usage of antibiotics, and wound breakdown leading to secondary surgical intervention and revisions. [13, 14, 28] In 2005, Ploeg et al investigated morbidity and mortality following lower limb amputation. This investigation found that wound infection was the most common complication in below knee amputations (10.4%) [28]. In the same study, 3 of 7 patients requiring reoperation were due to wound infections [28]. Quality of life is also adversely affected by wound complications, and causes further loss of function or psychological impact on patients with major life changing surgery [27].

The current cost of a reusable ActiVAC unit (KCI, Texas) within our institution is ₤6,500, with each negative pressure dressing costing approximately ₤25 individually. Although the initial implementation of NPWT as routine therapy may increase the individual cost of patient treatment, the potential reduction in wound complications and hence further treatment costs may help to reduce overall costs. Philbeck et al conducted a retrospective cost analysis in 1999, to compare the clinical and cost effectiveness of NPWT therapy on chronic wound therapy in home healthcare. This study saw a mean reduction of USD $8,919 per patient [29]. The current cost for each individual hospital bed is quoted by the Department of Health at ₤400 per day. Furthermore, a study by Daniel de Alcântara Jones et al in 2016 quoted a mean reduction of 7.2 days in patient with NPWT compared to control [30].

Therefore, the reduction of only a small number of bed days would quickly offset the costs of NPWT as a routine therapy [30,31]. There is increasing evidence for the use of NPWT conducted in the field of oncology, trauma, and vascular surgery. Whilst primary outcomes differ between studies, NPWT has displayed positive outcomes via increased rate of wound healing, with a decreased rate of wound complications and adverse events. Future prospective studies and meta-analyses could include a larger cohort of patients to prove the statistical significance of the use of NPWT in sarcoma patients with amputations. Additionally, a cost analysis could be performed to justify an initial investment into the introduction of NPWT as routine therapy.

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Conclusion

This study demonstrates that the rate of wound complications in patients following amputation is lower with NPWT compared to control with a definite positive trend. Importantly, no adverse events in relation to the use of NPWT were encountered. Current literature presents increasing evidence that the potential benefits of NPWT could outweigh the increased treatment cost of routine NPWT usage in amputations. Additionally, NPWT may improve outcomes with regards to patient health and quality of life, an outcome which should be addressed in future prospective trials. An appropriately powered randomised control trial involving sarcoma patients within our institution has been ethically approved and seeks to expand upon the hypothesis of the benefits of NPWT.

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Editorial

Low back ache is one of the most common complain of patients reporting to any Orthopaedic outpatient department. After exclusion of post traumatic, osteopenic and inflammatory arthropathy for chronic back ache, the bulk of the etiology is either tuberculosis or anaplastics (metastasis being the most common anaplastic condition).In my country, due to the increased prevalence of Tuberculosis and the practical acceptance of trial first line Anti Tubercular Therapy, it is the first diagnosis that comes to our mind while anaplastic conditions are our last bet. More often than not, on getting the traid of constitutional symptoms, spondylodiscitis and raised ESR, we start trial first line ATT, forgetting that the features of TB and anaplastics may mimic each other. Only after failure to respond to trial first line ATT, we go for Gene Xpert test (for Drug resistance tuberculosis), biopsy (for tuberculosis or analytics) and tests for the work up of metastasis of unknown origin to check for Drug Resistance TB or anaplastics. The delay in the correct diagnosis and thereby the correct treatment, the lag period, may be long enough to worsen the prognosis of an anaplastic condition on one hand or to increase the emergence of drug resistance tuberculosis on the other.

The diagnosis of TB by history taking, clinical examination and imaging (X ray or MRI) has its own limitations as there is no pathognomonic finding on an MRI that reliably distinguishes tuberculosis from other spinal infections or from a possible neoplasm [1,2]. And, differentiating spinal TB from pyrogenic and fungal vertebral osteomyelitis as well as primary and metastatic spinal tumors may be difficult when only clinical and radiographic findings are considered [3,4]. Hence, Refinement of diagnostic criteria on MRI is also being done which concludes that a eight point MRI criteria of the vertebral lesions are likely to enhance the diagnostic ability of tuberculous and non tuberculous pathologies thereby reducing the dependency on histopathologic diagnosis or invasive method for early initiation of therapy [5]. MRC Trials on spinal tuberculosis and clinical practice over several decades have confirmed that in the regions where tuberculosis is prevalent, a clinical diagnosis supported by radiographs is adequate for starting the treatment, but, for cases not responding to chemotherapy, a biopsy may be required [6].

There is a definite need felt as per studies for a biopsy to be added routinely for the diagnosis of TB. In the absence of an abscess or bone fragments, image-guided biopsy is essential to establish the diagnosis [7]. The tissue obtained by percutaneous methods may not be sufficient for conclusive diagnosis. But, the absolute need for histological diagnosis in areas where the disease is endemic and facilities for biopsy and histopathology are scarce is still controversial [8]. There have been case reports of anaplastic conditions being diagnosed and treated as TB Spine [9-11]. MDR TB of the spine is a different disease and is here to stay with the imaging appearance becoming more complex with the onset of MDR TB [12,13]. The most important cause of the development of MDRTB is the patients receiving erratic, unsupervised second line drugs, added individually and often in incorrect doses, so giving a patient ATT without diagnosis actually increases the chances and spread of MDR, XDR TB [14].

The Xpert test has showed a sensitivity of 95.6% and specificity of 96.2% for spinal TB, available within 48 hours compared with a median of 35 days for cultures. It has also been used as an initial diagnostic test for TB detection and rifampicin resistance detection in patients suspected of having TB, MDRTB, or HIV-associated TB with a good sensitivity and specificity. Developments in this gene testing are also going on by ways of Gene Xpert Omni and Xpert Ultra. The point we need to ponder over is: can it be used as a routine first line test for diagnosis of spinal tuberculosis to include or exclude drug resistance tuberculosis?

We should not treat everything as TB. The correct diagnosis should be done before starting ATT. Literature recommends the use of biopsy and it is Safe, easy, reproducible, and has a high diagnostic yield. Also, it is always better to be medico legally safe. In today's day and age such a delay in the correct diagnosis is not acceptable and hence it is recommended not to be over dependant on imaging and on our bias towards TB, and anaplastics should be investigated by biopsy and other tests and ruled out at the onset rather than being a diagnosis of excusion (i.e. after exclusion of TB). Histopathology is important to exclude anaplastics and till anaplastics is not excluded we should not be sure it is TB because it should be borne in mind that failure to diagnose anaplastics is more dangerous than failure to diagnose MDR TB [15-17].

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Introduction

Ultrasonography and MRI are two advancements in Medical Science being used at an advanced rate in this era. Magnetic Resonance Imaging works by scanning the Patient's Protons as they align along the Magnetic Field created by scanner, the protons in the patient's tissues align themselves along the direction of the magnetic field. A radiofrequency pulse then deflects the protons which as they realign produce a signal which is detected and an image is produced [1]. The principle behind ultrasonography is the Ultrasound waves, which are inaudible high-frequency mechanical vibrations that are formed when a generator produces electrical energy which is converted to acoustic energy through the transducer. The signals are received as they are transmitted back and an Image is formed [2].

The Achilles Tendon is a conjoined tendon of Gastrocnemius and Soleus muscles of the calf and it attaches to calcaneus. The tendon is thickest tendon of the body and is covered by Fascia and is prominent behind the bone; the gap being filled by Adipose tissue and areolar tissue. Just like every other body part, pathologies of Achilles Tendon undergo several tests before being diagnosed. These include palpation, calf squeeze test and Simmonds-Thompson test. But MRI and USG are the more new and advanced methods helping in differentiating normal and abnormal Achilles Tendon [3].

MRI and USG are analogous for detection of full thickness and partial thickness tendon pathologies. In specialized hospital settings, USG is readily available, cost-effective procedure, but gives only minute details about nerve lesions [4]. In a study Ultrasonography detected abnormality in 65% of symptomatic tendons, normal morphology in 68% of asymptomatic tendons while MRI identified abnormal morphology in 56% of symptomatic tendons, normal morphology in 94% of asymptomatic tendons [5]. A case report by Peck & et al significantly emphasized on importance of Ultrasonography as a better tool to be used at emergency ground for diagnosing Achilles tendon rupture [6].

The main advantage of ultrasonography over MRI is its easy availability, repeatability, comparison with contralateral side, low cost and ease of examination with dynamic capability. Infections can be detected with USG, but related bony involvement is difficult to detect and evaluate. MRI offers an advantage of distinguishing bony involvement with high accuracy [7]. A review article on lower extremity injury pattern highlighted that ultrasonography has a dynamic role in formulating a diagnosis of Achilles tendon rupture and is more used in this regard [8]. Ultrasonography will be used complementary to MRI in musculoskeletal imaging and is to be considered essential before any MRI for proper diagnosis [9].

The above all discussion embarks on the importance of both the modalities in Achilles Tendon injury. The literature supports Ultrasonography to be the most valid and widely used tool due to its more accuracy and easy accessibility but along with it mentions MRI advancement being pivotal for diagnosis and prognosis. The prime objective for a clinician or radiologist is diagnosis of the disease and Ultrasonography has been an important tool for this purpose. The norm of using USG as the primary tool for investigating tendinopathies shall be an appropriate step for the family medicine practitioners, Orthopaedics doctors and sports medicine practitioners for early interventions in Achilles tendon rupture.

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