Juniper Publishers- JOJ

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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Background

Owing to recent improvements in the quality, shape and surface area of the implants for total hip arthroplasty, wear problems, which is one of the chronic complications of total hip arthroplasty, have been solved up to a certain level. However, instability and dislocation of the implants, which is the second most common complication after component loosening, remain unsolved, negatively affecting quality of life and furtherly causing failure of implants. Using femoral head implants smaller than the patient’s natural femoral head is a major cause of dislocation. We would like to discuss several issues of using large head implants as a bearing surface.

    Wear

Contact surface and sliding distance are major factors in the occurrence of wear particles. As the diameter of the femoral head increases, contact area and the sliding distance of the articular surface also increase. Though the degree of wear may differ by material, this increase also leads to increased volumetric wear, according to the formula υ=πγ2w (υ, volume of debris from wear; γ, radius of the femoral head; w, linear migration distance of the femoral head). Grinding and adhesion between the femoral head and the acetabular cup is the main mechanism of wear after total hip arthroplasty. In terms of wear, the sliding distance and the repetition of sliding is more important than the load given to the hip joint [1-4]. In case of metal-on-polyethylene implants, volumetric wear increase about 7.5% to 10% for each 1mm increase in femoral head diameter [1]. Frictional torque, which increases proportionally to the femoral head size, is an important factor in the destruction of the contact area between the component and the bone, and in the loosening of the component [5-8]. However, if an articular surface is resistant to wear and enables stable fixation between the component and bone while being minimally affected by changes in femoral head size, using large head implants during total hip arthroplasty may be promising due to its high stability. Therefore, choosing articular surfaces which are highly resistant to wear is a key prerequisite for the use of femoral head implants larger than 36mm [9-10].

    Dislocation

Hip joint dislocations are caused by 3 factors; patient-related, operative-related, and implant-related. Implant-related factors include femoral head size, head-to-neck ratio, head-to-metal shell size, and types of the inner liner [11-13]. Compared to small femoral heads, large femoral heads require longer distances of displacement to be dislocated, and thus is more stable. Other advantages of large femoral heads include [1] increased range of motion (ROM) in any direction, [2] decreased component-to-component impaction and while delayed bone-to-bone impingement, proper debridement of the bone causing impaction leads to increased joint motion [3] No need for the use of skirts, which are used with long-neck implants to increase stability of trunnion and femoral head socket area (due to relative increase in head-to-neck ration). For each 1mm increase in femoral head diameter, the ROM in any direction increases by 0.84±0.43 degrees, and the peak moment which resists to dislocation increases by 3.6%. Compared to 32mm-diameter femoral heads, 38mm- and 42mm-diameter femoral heads show increase in ROM of 6% and 16% respectively.

    Wear on Trunnion-bore Interface

Morse tapers achieve stability by the cone-in-cone principle, which is caused by compression between the trunnion and the femoral head socket wall. While intimate conical connection between the trunnion and the bore may enable firm contact, ingress and micromovement of the fluid may occur during cyclical mechanical loading due to preexisting microscopic gaps (crevice) on the matins surface of male and female cones. This may lead to disruption of the passive surface oxide layer and susceptibility to mechanically assisted crevice corrosion (MACC, tribocorrosion). Taper design, metal-alloy mismatch (Galvanic corrosion), implant positioning, joint loading magnitude, numbers of loading cycles, frictional torque at the bearing surface, patient and surgical factors (tissue interpositioning, failure to achieve initial engagement) are associated with the development and deterioration of MACC. Particulate debris and metal ions are released through mechanical and corrosive mechanism, and may lead to several adverse tissue reactions, and in severe cases, may case mechanical failure at the taper junction. The use of larger femoral heads increases frictional torque, and this results in additional stress at the taper junction, especially in metal-on-ceramic or ceramic-on-ceramic bearing surfaces, rather than metal-on-polyethylene or ceramic-onpolyethylene bearing surfaces. Also, increased offset between the head center and the trunnion interface center of pressure increases the bending moment, and leads to micromotion between male and female tapers, and may trigger trunnionosistype wear. These reasons provide theoretical support for why the reactions which occur on metal-on-polyethylene bearing surfaces due to metal debris from the taper junction are similar with local adverse tissue reactions caused by metal particles from metal-on-metal bearing surfaces [14-20].

While the increase in femoral head size from 32mm to 36mm leads to 10% improvement in stability, the increase in femoral head size from 40mm to 48mm only leads to 4.7% improvement. This indicates that the increase of femoral head size beyond a certain level may not significantly influence on stability. On the other hand, the peak stress imposed on the trunnion during ambulation increases as the femoral head diameter increases. Compared to 32mm-diameter femoral heads, 40mm-, 44mm- , 48mm-, 52mm-, and 56mm-diameter femoral heads showed peak stress increment of 3.5%, 9.5%, 24%, 40%, and 51% respectively. Considering pros of stability and cons of trunnionrelated problems, the use of femoral heads smaller than 40mm is recommended.

    Conclusion

Femoral heads larger than 32mm in diameter offer multiple advantages in terms of both function and activity, including improved hip joint stability, decreased dislocation rate, and increased ROM. However, various concerns, including wear generation at the trunnion-bore interface and increased component-bone interface stress due to additional frictional torque, should always be considered when using large femoral head implants. Considering the benefits in stability and trunnion-related problems, femoral heads smaller than 40mm are recommended to be used for total hip arthroplasty.

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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

Orthodontics treatments can be planned with extraction or not, decision for removing healthy teeth to correct the orthodontic malocclusions must be based on specific diagnostic criteria before indication. Our practice within the hospital Service of DFO of the MUHC of Algiers consolidated by the results of a study on the theme of extractions shows us important rates linked to the type of malocclusions prevail within our orthodontic populations as well as the moment of treatment. Among our objectives we decided to evaluate the level of dental crowding we consider when taking the decision to extract or not permanent teeth.

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Materials and Methods

The total population was composed of 664 individuals. Mean age was twelve. Subjects were excluded if they had primary dentition, lost permanent teeth or were more than 16 years old.

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Results

The most frequent reason for consultation among the population was the dental crowding. The role of hereditary origin was important but in many cases the jaws have not grown large enough. Another frequent ethology of the dental crowding was the early extraction of the primary teeth (Table 1 & 2).

Extraction frequency among the total population was 52, 6%, the predominant pattern was to extract 4 teeth (66.5% of cases), with first premolars in large majority (80.6%). Our findings show a marked difference in the level of dental crowding between those treated with extraction and those treated without extraction [1].

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Discussion

Decision to extract among the population seems to be related to the discrepancy between expected arch length and space offered in class I or in Class II or Class III. These criteria is an argument for extraction, however the dental crowding can be attributed to the early extraction of the temporary teeth, steatogenic dysfunctions and narrow dental arches [2,3]. It is important to prevent such etiologist to avoid or reduce prescribing extraction for orthodontic therapy.

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Conclusions

Our study revealed an important percentage of extractions among our patients. More non-extraction treatment is required with: Early age treatment, space maintenance if premature loss of primary teeth, functional appliances and transverse expansion [4,5].

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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

This article describes the method of preoperative testing of orthopedic implants material for compatibility with recipient’s body by using Atomic Force Microscopy (AFM) and research the influence of tissue reactions on the implant’s surface.

Keywords:  Implants; Biocompatibility; Testing of material; Atomic force microscopy

    Introduction

Every year orthopedic surgeons perform about 2,500,000 operation arthroplasty on various joints. In Europe in the past 5 years, the number of surgical operations in the endoprosthesis has increased by 80%. Orthopedic doctors used the big spectra of implants which consist of (endoprotes of the thigh, knee, shoulder, elbow joint, joints on the ankles and even small joints of the feet and fingers). Unfortunately, each of these implants is foreign body for our organism. Rejection reaction or manifestation of hypersensitivity to the implant material is observed in 6 - 30% of cases of surgical intervention [1-15]. Immune reaction is one of the causes of complications of bone tissue on implants. The rejection reaction to the body on exogenous materials (implants) is manifested as a local aseptic inflammation with the formation of a fibro capsule around them, that leading to loss of their functional properties. The recipient organism reaction to foreign body depends on both branches of immune system, and particular importance to them has the absorption of immunoglobulins class G (IgG) and reaction of the body cells to surface of the implants [10].

Certain electron in homogeneity of the surface of materials plays the role of the binding centers of Ig and cells. Adhesion of IgG on surface of the implants provokes to the activation of the immune system, that leading to the development of persistent non-infectious (aseptic) inflammation. Material of implants that contact with the recipient organism determined by allocation of the last anti-inflammatory mediators like interleukin-1 and interleukin-6, which cause the process that can leads to selective dissolution of the components of implants and, in the future, it can cause to the destruction of implant. Selective dissolution of implants products can lead to toxic effects on cells, or stimulate synthesis of some proteins. Absorption or accumulation proteins of various toxic substances, protein complexes with nickel, chromium and cobalt ions, and formation around the material dense layer of the extracellular matrix, is important for the biological behavior of the material (attachment cells or bacteria to surface of materials).

Adhesion of proteins depends on the chemical properties of the material, and on its physical characteristics (wettability, superficial energy, etc.). Creating of expressive physical method for controlling of the compatibility of materials according is extremely necessary. In addition, the possibility of individual selection of materials, taking into account the immune status of the recipient organism, raises the problem of certification of materials to a qualitatively new level [11,12,16]. The purpose of study was determine the possibility of using Atomic Force Microscope (AFM) for predict the reaction of the organism to the implant (foreign body).

    Materials and Methods

In newer present methods that are available for investigating internal and intermolecular forces acting between bimolecular. The AFM are the most effective research tool. This method covers a range of entropy forces in Femto-Newtons (1015 Newtons) for determine the force required to break covalent bonds in several nano-Newtons (10-9 Newtons). The Atomic Force Microscope (AFM), allows you to determine the strength of the interaction Antigen - Antibody and structure of individual macromolecules, such as DNA (intra-molecular forces) [16,17]. A wide range of controlled interactions creates real prerequisites for successful solving of a number of applied problems with the help of nanobiosensory technologies implemented on the hardware software basis of AFM. In recent years, have been made convincing attempts to use AFM for the diagnosis of cancer that based on the testing of the specific adhesion of IgG to malignant cells and their contact elasticity.

The AFM study of bioadhesive separation force was carried out on a scanning probe microscope Dimension 3000 NanoScopeIIIa (Veecocorp.) Both in air (at a temperature of 22oС and a relative humidity of 30%) and in a liquid medium (0.9% solution of sodium chloride). The velocity of the vertical movement of the probe selected in the range from 20 to 20,000 nm/sec. For measurements, used contact probes from SiNNDNP- 20 (VeecoInc.) with V-shaped cantilever. The average radius of the edge of the probe 30 nm, the cantilever’s rigidity 0.06 N / m. The control of the form of the tip performed before and after measurements using the “blind reconstruction” method using the test grid TGT-1 (NT-MDT). Clarification of the value of the cantilever hardness was carried out by analyzing the spectrum of its temperature noise.

The scheme of measurements is presented in Figure 1. At the initial moment, the probe modified by the antibody (AT) is far from the surface of the sample (point 1) and the interaction surface of the surface-AT is zero. Next, the AFM system of vertical movement of the probe leads the probe to the surface, controlling the distance to the accuracy of the angstrom (10-10 m). At a certain minimum distance between the probe and the surface, the “capture” of the modified probe is carried out by the surface under the action of the attraction forces (point 2). With further approximation of the probe and the surface begins to act repulsive forces that prevent the penetration of the probe into the surface. After reaching the maximum value of the repulsion force given by the operator based on the conditions of the experiment (point 3) begins the inverse vertical movement of the probe. At the same time, the surplus of all the forces holding the modified probe near the surface is balanced by the force of elastic deformation of the probe console at the point 4, in which there is a separation from the surface. Thus, the maximum value of the force of the bioadgezial interaction corresponds to the magnitude of the detachment force of the probe from the surface (point 4), which is equal to the strength of the elastic deformation of the probe console, measured by the detection system of the AFM, by the value of its deflection d (Figure 1).

For modified of the surfaces of probe were applied antibodies. As antibodies used total IgG, which were isolated from the serum of the patient’s blood. AB was applied to the ACM with a solution at a concentration of 0.1 μg / ml. (0.9% NaCl solution). The measurements were carried out both in air and in water, in order to check the difference between the data obtained, whether they are essential for the evaluation of the bioadhesion forces. During measurements in the atmosphere on the surface of the sample due to the presence of capillary forces, a so-called capillary bridge is formed, which makes a significant contribution to the amount of adhesive forces. Thus, the value of separation strength when measured in the air is greater than during measurements in water. However, as it has been established, qualitative correlations between the values of the separation forces for different samples are retained. In clinical trials included patients, with joint diseases, that in future will have arthroplasty according to treatment protocols.

In the perioperative period, sampling of 5 ml of patient’s venous blood is performed in vacuum container, from which was prepared serum, according to the standard method, was isolated total IgG [18]. After purification and dilution, an appropriate concentration of IgG, 2 μg/ml, is applied to the AFM probe. The probes with the applied IgG patient were tested for the compatibility of the implant material with the patient’s body. The value of the confinement of probe with IgG of recipient to the surface of the implant was considered to evaluate the compatibility of the material with the patient’s body. The higher value of the strength retention, more likely development of the reaction of implant rejection by the organism. The basis for the hip implant was the titanium alloy Ti6Al4V, the characteristics of which are given in Table 1.

    Results

For the period 2015-2016, in the clinic of the State Institution of Science “Research and Practice Center of Preventive and Clinical Medicine” State Administrative Department, was performed a test of the compatibility of the material of orthopedic implants in endoprosthetics of large joints with the recipient organism with the help of AFM in 11 patients [13,18]. Patients underwent surgical intervention (arthroplasty of the hip and knee joints). In Table 2 show the strength of the IgG surface of the prosthetic element. The force of confinement clean probe with the surface of the implant ranged from 5-8 nN. Thus, according to the AFM, one can confidently say that in all cases the recipient develops a local aseptic inflammation at the site of the implant. Reliability of the obtained values p ≤ 0,005. Listed in Table 3 data suggest that in the course of time, the patient only increases the CRP and the number of segmental neutrophils. And the results of testing with AFM remain at 49-56 nN, which testify to the constant reaction of the organism to the implant. So the stress of immune system of this patient is constantly maintained by the presence of the implant, and the specificity of IgG to the prosthesis remains very high.

    Discussion

The variety of the reaction of the receptor’s tissues to the foreign body that is introduced into the body depends on its immune status and the primary reaction of the cells of the body to the surface of the implants is of particular importance [14]. The development of modern high-tech branches of medicine, including orthopedics, traumatology and dentistry, places high demands on the quality of implantable materials. The main of them - medical and biological, based on the absence of toxic, carcinogenic and corrosive properties in the material. Biomaterials should be biocompatible and have the technological qualities that allow, in the case of a certain treatment, to obtain the necessary structure that is characterized by frictional stability and low thermal conductivity [15,19]. At the same time, implant materials should perform not only substitution function, but gradually integrate into the surrounding bone, promote the formation and remodeling of bone tissue.

Scientific evidence suggests that activation of developments in the creation of new and improved known biomaterials for medicine [10,11,17]. It should be noted that even a minor modification of the biomaterial (elemental composition, phase state, topography and surface structure, etc.) can significantly alter its properties. Therefore, the medical-biological research of artificial biomaterials remains relevant and significant [15,17]. An approach developed to solve the problem of individual prediction of the degree of compatibility of implant materials with the recipient organism on the basis of nanobiosensors controlled by the AFM hardware and software system is appropriate and relevant. Today, the development of optimal conditions for nanobiosensory testing of implants with AFM and the study of the effects of reactions of tissues of the recipient on the surface of implants will significantly increase the effectiveness of surgical treatment of diseases of the locomotor system by selecting / selecting optimally compatible implants with the recipient organism [8,9,17,20].

    Conclusions

Development of optimal conditions for testing the implant with the body of the recipient using Atomic Force Microscopy (AFM) will significantly increase the effectiveness of surgical treatment of orthopedic disorders.

The method of testing the compatibility of the implant material with the recipient’s body using AFM can allow:

a. At the preoperative stage, determine the possibility of occurrence of processes of rejection of the implant.

b. Provide compatibility with body implants and choose the most appropriate and / or to provide drugs to prevent rejection.

c. Data received through research, allow the doctor to choose the necessary tactics of patients in the postoperative period.

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Abstract

Breast cancer (BC) is the most frequent tumor worldwide. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 12-18% of all BCs. Breast cancer (breast cancer) is the most common oncological disease in women in the Uzbekistan. Data from epidemiological studies show that TNBC is more common in young women (up to 50 years) before menopause. In addition, the likelihood of TNBC is higher in women with early menarche, the first pregnancy at an earlier age, a short period of breastfeeding, and an increased body mass index. It should be not that the prognosis for TNBC does not depend on the degree of differentiation of the tumor, the presence of lymph node metastases, the size of the tumor or the treatment performed. The aggressiveness of TNBC was also confirm by the maximum risk of recurrence during the first three years after surgical treatment with a maximum mortality within the first 5 years. TNBC is a subtype of tumors with a special character of metastasis. Based on the above, we have undertaken the present work, having set ourselves the following goal: to improve immediate and long-term results of treatment of patients with locally advanced thyroid cancer by using the most effective diagnostic methods and comprehensive treatment.

Keywords:  Triple negative BC; Neoadjuvant; Adjuvant and metastatic chemotherapy; Paclitaxel; Docetaxel; Gemisitabin

    Introduction

Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers: the risk of relapse is much higher for the first 3-5 years but drops sharply and substantially below after those hormone-positive breast cancers. In this review, data on the use of gemsitabini in metastatic triple-negative BCs are analyzed, concluding they are effective in any clinical setting (neoadjuvant, adjuvant, and metastatic). The available data show the clinical potential of based combinations in terms of long-duration response, increased survival, and better quality of life of patients with triple-negative metastatic BC. The ongoing trials will give further information on the better management of this type of tumor. In 2016, 1,380,000 new cases and 458,000 deaths for BC were reported worldwide, of which there were 332,000 new cases and 79,000 deaths in Asia [1,4].

BC in the territory of the Republic among urban and rural population by determining the average annual intensive and standardized incidence rates for the years 2008-2010. The highest standardized incidence rates registered in Tashkent city (22,5%x>00), Navaiy (12,4%00), Bukhara (11,1%00) and Tashkent regions (11,0%00) and lowest in Surkhandarya (6,3%00) and Kashkadarya (7,5%00). On the territory of the Republic those in urban areas more often suffer from cancer of the breast (13,2%x>00) than rural (8,5%00) [2,3]. The highest incidence was within the age intervals 50-59 - 18,0%00, 60-69 - 31,2%00, 70 years and older -19,3%00. In the structure of mortality of the female population of Uz from malignant neoplasms. The greatest proportion is malignant breast tumors (20.4%) [3,6].

According to Cancer Registry of the Republican Oncology scientific center (RONTS), in 2012 in the general structure of cancer of malignant neoplasms of women for patients with breast cancer (24.6%) occupy the 1st ranked place, ahead of patients with cervical cancer (12.4%),(5.9%), ovaries (5.0%) and the uterus body (4.4%) [7,8]. According to the Ministry of Health of Uzbekistan, the most common cancer in the country is breast cancer. This type of cancer is diagnosed in 9.1 cases per 100 thousand of the population. According to experts, the hereditary factor is important in the development of breast cancer in women, it is on the maternal line. It is transmitted in 45-75% of cases, if there are mutations of BRSA 1-2 genes. To prevent breast cancer, women under the age of 50 years should undergo ultrasound of the breast.

Women aged 50 years and older should undergo mammogram of the breast. Also, all the representatives of the fair sex need to conduct self-examination of the breast every month. At any suspicion of the presence of compaction in the mammary glands, consultation of a mammologist is necessary, noted in the Ministry of Health %) [4,5,8]. Despite the improvement of the methods of diagnosing this pathology, more than 50% of primary patients annually turn to the oncologist in the III and IV stages of the disease. Purpose of the study is to evaluate the effectiveness of various chemotherapy regimens for neoadjuvant, adjuvant and palliative poly chemotherapy (metastatic) in patient’s triple negative breast cancer with improved long-term treatment outcomes.

    Materials and Methods of Research

The object of our study will be patients with breast cancer with a triple negative phenotype. In total, retrospective and prospective groups of patients treated in 2012-2017 will be studied in Tashkent City oncology in the department of oncology and chemotherapy (n = 99), patients with triple negative breast cancer. Thus, the patients included in the study were characterized by a set of unfavorable signs: in 93% of cases the tumors were characterized by high Ki-67, in 53%- 87.7% of cases - by II-IV grade of malignancy. Criteria for selecting patients: Progression of breast cancer was detected in the period from 12 to 60 months after the operative removal of the primary tumor (metachronous metastases); ECOG 0-1. The age of patients older than 18 years.

The presence of the result of immuno histochemical analysis of the primary tumor and in the experimental group a comparative analysis of the primary tumor and distant metastases. Functional status according to ECOG (FS) was from 0 to 2. All patients had measurable normal kidney and liver function, satisfactory parameters of general and biochemical blood tests (leukocytes> 4.5 x 109 / L, neutrophily> 2.0 x 109 / L, hemoglobin> 9 g / dL, blood transfusions were not tolerated for the last two weeks, platelets> 100 x 109 / L, creatinine <130 μmol / L, total bilirubin <1.5 of the upper limit of normal (CGI), ALT and ACT <1.5 VGN. After randomization, patients in a 2: 1 ratio were included in two treatment groups: 1) chemotherapy with doxorbicin, and/or 2) chemotherapy with platinum drugs. As chemotherapy, the following options were used: taxanes (docetaxel or paclitaxel), platinum, anthracyclines, gemcitabine, doxorubicin, cyclophosphani, capecitabine.

    Results

The triple-negative BCs (TNBCs)

The most important biological markers, not only for classification of BC but also for, the therapeutic strategy are the hormonal receptors (estrogen [ER] and progesterone [PgR] receptor) and the HER2 receptor status [5]. Tumors that are ER-, PgR-, and HER2-negative are known as TNBC and account for about 12-20% of BCs [4]. These tumors develop earlier in life, especially in premenopausal women, and have a poorer prognosis than the other types of BC due to the higher aggressiveness. These factors may be a major reason for the high-risk relapse, and shorter progression-free survival (PFS) and overall survival (OS) reported for this disease [3-6]. The main general characteristics of TNBC are summarized in Table 1.

The gene expression assay classifies BCs into at least five groups, including luminal A, luminal B, HER2-enriched, basallike (BL), and normal breast-like. More recent gene expression array analysis has identified six different groups of TNBC, including two BLs (BL1 and BL2), an immune-modulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype [11,12]. BC subtypes arrays, 25% of relapses were basal, 32% HER2, 10% luminal A, 28% luminal B, and 5% normal breast-like. Importantly, the intrinsic subtype at relapse was significantly associated with post relapse survival (P=0.012). At the 2016 on 1,100 women diagnosed in 2016 with TNBC in the Uzbekistan. This population reflects the current clinical practice in the Uzbekistan at the time: 34% were at stage I, 42% at stage II, 15% at stage III, and 6% at stage IV, with a 24-month OS of 97%, 93%, 71%, and 27%, respectively. The median OS in metastatic disease was 13 months [7-10].

The treatment of TNBCs

A proportion of TNBC is highly sensitive to chemotherapy but with a short PFS and a lower OS [15]. Current therapeutic strategies include chemotherapeutic drugs (anthracyclines, taxanes, platinum derivatives, and gemsitabine) and biological drug [11,16]. The efficacy of anthracyclines and gemsitabine in metastatic BC is higher in ER-negative tumors; for this reason, both classes are indicated as first-line treatment of TNBC, even if with a short-lasting benefit [14]. Another group of drugs with proven activity in TNBC are the platinum derivatives cisplatin and carboplatin [13-16].

Guidelines for the treatment of TNBCs

There are no specific guidelines for the management of TNBC, the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and Associazione Italiana di Oncologia Medica (AIOM) Guidelines recommend that TNBC be treated with chemotherapy (monotherapy or combination therapy) but do not specify the most appropriate drugs. Taxanes and their combinations recommended by NCCN, ESMO, and AIOM guidelines for triple-negative BC (Table 2).

The ESMO Guidelines states that cytotoxic chemotherapy is the standard of care for the treatment of TNBC and that the choice of the regimen should be made after consideration of disease-related factors (disease-free survival [DFS], previous therapies and response, tumor burden, and need for rapid disease/symptom control) and patient-related factors (patient preferences, biological age, menopausal status, comorbidities and performance status, and socioeconomic and psychological factors). Combination chemotherapy is more often required because of frequent visceral involvement, aggressive course, and risk of rapid patient deterioration. Finally, there is no a standard approach for chemotherapy after first line [16,17].

The role of taxanes in TNBC

The role of taxanes in TNBC is well established after the many studies evaluating the efficacy of taxane-based regimens in neoadjuvant, adjuvant, and metastatic disease settings. Neoadjuvant therapy has been used for a long time for reducing the size and the extension of locally advanced tumors, but now it is extensively used also in early BC not suitable for primary conservative surgery, with an added predictive value for the longterm outcome of the disease. Actually the best efficacy target for neoadjuvant therapy is expressed as pathological complete response (pCR). The predictive value of pCR as a surrogate for long-term clinical benefit has been recently confirmed by the retrospective pooled analysis of Cortazar et al [18].

This meta-analysis was based on the pCR, overall response rate (ORR), and event-free survival (EFS) data of 12 international clinical trials on a total 11,550 patients. The analysis compared the three main definitions of pCR in order to establish their association with long-term efficacy: ypT0 ypN0 (no invasive and in situ tumor in the breast and auxiliary lymph nodes); ypT0/is ypN0 (no invasive tumor in the breast and axiliary lymph nodes, independent of the presence of in situ ductal carcinoma); and ypT0/is ypN0/is (no invasive tumor in the breast, independent of the presence of in situ ductal carcinoma or lymph nodes involvement). The better combination between pCR and longterm effect was observed in patients with an aggressive tumor (TNBC; high-grade; ER/PgR-positive, HER2-negative; HER2- positive; and ER- and PgR-negative) [19].

Several studies on neoadjuvant therapy confirmed the sensitivity of TNBC to cytotoxic drugs, as well as the importance of platinium-based chemotherapy. Rouzier et al evaluated the molecular-based chemosensitivity patients treated with carboplatin and taxanesneoadjuvant therapy, and a pCR was observed in 45% of BL tumors and in 6% of luminal tumors (A and B) [20-21]. The study evaluated in 53 women randomized to neoadjuvant doxorubicin and docetaxel for four cycles or doxorubicin and cyclo phosphamide (AC) for four cycles followed by docetaxel for four cycles. The overall was 10.6% (7% with the two-drug regimen and 14.3% with the triplet one). The efficacy of taxane-based neoadjuvant therapy was further confirmed by more recent trials. Wu et al evaluated the efficacy of neoadjuvant therapy with docetaxel plus epirubicin, and the OS in 64 patients with TNBC and in 65 patients with non-TNBC. A pCR was observed in 25.9% of TNBCs, significantly higher than in the other subtypes (P=0.019) [24].

The New England Journal of Medicine published a report by Bear et al of another trial of neoadjuvant chemotherapy with or without carboplatini. This Phase III randomized trial assigned 46 patients with HER2-negative BC to receive docetaxel (100 mg/m2 every 21 days) or docetaxel (75 mg/m2 day 1) plus capecitabine (825 mg/m2 twice a day days 1 to 14) or docetaxel (75 mg/m2 day 1) plus gemcitabine (1,000 mg/m2 days 1 and 8) for four cycles. All regimens were followed by AC for a further four cycles. All patients were also randomized to receive carboplatini (AUC=5) or not for the first six cycles of chemotherapy. Results showed first of all that the addition of carboplatini and gemcitabine did not improve the rate of docetaxel alone and showed increased toxicity and that the toxicity of carboplatini was manageable and as expected from previous trials and, significantly increased the overall pCR rate (34.5% vs 28.2%) (P=0.02).

The multiple logistic regression model showed that TNBC subtype, high grade, and smaller tumor size were associated with higher rates in the breast, but when considering the breast and nodes, the addition of carboplatini was significantly related to a better result in hormone receptor-positive tumors only. In the randomized 45 patients with TNBC were treated with weekly paclitaxel plus liposomal doxorubicin (once a week for 18 weeks) every 3 weeks and were randomized to receive weekly carboplatin (area under the time-concentration curve [AUC] =2) or not. The pCR (ypT0ypN0) rate was 16% higher with the addition of carboplatin (53.2% vs 36.9%) (P=0.005). The toxicity was also significantly higher, with 53% discontinuation (41% with AUC reduced to 1.5). Data on the BRCA mutation are not yet available in order to assess the correct role of carboplatin [18,19].

The adjuvant setting

Studies in adjuvant setting also confirmed the activity and relevance of taxanes in TNBCs. Hayes et al retrospectively analyzed the histological samples of 52 patients enrolled in the study in order to evaluate the role of HER2 status on clinical end points. Patients were divided in four groups: endocrine receptor- and HER2-negative (TNBC); endocrine receptor- and HER2-positive; endocrine receptor-positive and HER2-negative; endocrine receptor-negative and HER2-positive. Adding taxanes/cyclophosphani with anthracycline improved DFS both in HER2-positive patients, independently from endocrine receptor status, and in TNBC patients.

No clinical benefit was observed in HER2-negative and endocrine receptor-positive tumors. This explorative analysis suggests that paclitaxel added to the adjuvant regimen significantly improves the outcome in TNBCs [20-22]. The study of conducted on 52 patients, evaluated in the adjuvant setting the efficacy of AC followed by weekly or 3-weekly (q3w) docetaxel or paclitaxel. The results showed an improvement both in DFS and 5-year OS with weekly paclitaxel with respect to q3w paclitaxel. In TNBCs, the benefit of conventional weekly paclitaxel in term of DFS was 37% higher than the q3w regimen [23,24,26].

The metastatic setting

Conventional gemsitabine have a central role in the treatment of metastatic BC, based on several evidences of their benefits on clinical outcomes, such as OS, time to progression (TTP) [25,26]. Even if conventional gemsitabine demonstrated to be more active in endocrine receptor-negative tumors and are indicated in the first-line treatment of TNBC (although a specific benefit in this setting was not observed), it should be considered that they are commonly used in adjuvant therapy and cannot be rechallenged in case of short disease-free interval (<12 months). Fan et al evaluated the efficacy of gemsitabine combined with cisplatin or capecitabine with docetaxelin the first-line treatment of patients with metastatic TNBC [27]. The ORR was significantly higher in patients treated with gemsitabine plus cisplatin than with docetaxel plus capecitabine (63% vs 15.4%) (P=0.001), as were the median PFS (10.9 vs 4.8 months) (P<0.001) and median OS (32.8 vs 21.5 months) (P=0.027), confirming the role of platinum in TNBC [29].

The TNBC trial was based on the hypothesis that because BRCA1/2germline mutations produce BCs that have defects in homologous recombination DNA repair, carboplatin would be lethal to cells with germline and somatic mutations in BRCA1/2. In other words, carboplatin might be an especially good therapy in terms of exploiting the defect in homologous recombination DNA repair, and this is why patients with BRCA1/2 mutations were included with TNBC patients. The results showed no significant difference in response rates between carboplatin and gemsitabini in the overall patient group or in patients who received either agent as first-line therapy and then crossed over to the other agent as second-line treatment [28,30]. In conclusion, the main reason of failure in metastatic BC is resistance to the standard drugs, which can be intrinsic or acquired. Patients with disease progression or resistance could not have a crossresistance with other drugs, such as capecitabine, gemcitabine, which demonstrated their efficacy in patients with advanced BC pretreated with carboplatini with gemsitabin.

    Conclusion

TNBC is characterized by the absence of ER-, PgR-, and HER2-negativity: for this reason the only therapeutic option is chemotherapy. Even if these tumors are chemosensitive, as showed by the high pCR obtained with neoadjuvant therapy, metastatic patients have a short PFS; this the chemosensitivity does not translate in an improvement of PFS or OS, and the overall prognosis for these tumors is poor. The studies performed taxanes with platinium based chemotherapy demonstrated their efficacy in the treatment of TNBC in by setting neoadjuvant, and cyclo phosphan with doxorubisin or doxetaxel more effectively in adjuvant regimens, gemsitabines with platinium was detected more metastatic triple negative breast cancer, international and national guidelines recommend the as possible active first-line therapeutic options for TNBC.

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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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Introduction

Increasing the healing rate of a wound by applying an externally controlled negative pressure is known as Negative Pressure Wound Therapy (NPWT). Negative pressure drains serve as an excellent atmospheric bandage [1,2] and NPWT can be used for treating wounds which usually take a long time to heal or do not heal at all when treated using conventional treatment methods [3] and also diabetic foot disease which has become a major global burden [2]. Though, international organizations have already developed NPWT machines, their cost is around 7 to 8 thousand [4], which is unbearable to a developing country like India. Increasing healthcare costs and the growing burden of non-healing wounds is a challenging issue in India. Due to their high cost, NPWT devices are not available in Indian civil hospitals [5-7].

As a result, the patients with non-healing wounds Increases the healthcare cost of the country due to their long stays at hospitals and suffer changes in their life style. Especially, diabetic foot amputees lose their legs due to non-healing wounds. A manually operated low cost NPWT device was therefore developed at our General Hospital. It has demonstrated the success of the therapy to, many patients with non healing ulcers, traumatic raw area. In our hospital we have applied this system to patients operated with split thickness grafts and flaps. We have observed early take of graft and early settlement of flaps But one problem identified with this machine is that it is being operated manually and its inability to maintain pressure at a regular value, But the desired pressure range in NPWT is -50 to -175mmHg while the optimal value is -125mmHg [5]. objective of the this research is to develop a reliable, low power consuming, user friendly, portable and low cost NPWT system to treat different types of wounds and to Test the system clinically at a plastic surgery department to Evaluate its performance.

Aims and Objective

a. To study effect of Negative pressure wound therapy on post-operative Outcomes in Patients operated with skin graft and flap. b. To study impact of negative pressure wound therapy on local infection. c. To develop a manually operated low cost NPWT device. d. To study duration of the graft take with use of the device.

Materials and Methods

This study is a single institutional observational cohort study of Negative Pressure Wound Therapy post operatively for the purpose of early graft take and early settlement of flap. Data will be prospectively collected in a standardized fashion. The analyzed preoperative variables include patient demographics, co morbid conditions, and laboratory values, culture and sensitivity of wound, site and condition of wound. After application graft and flap and application of negative pressure wound therapy patient will be observed for any local or systemic complication, wound contraction, progress of graft take length of hospital stay (LOS), wound condition, morbidity will be assessed [8-10].

Indications for Use

The Negative Pressure Wound Therapy System (NPWT) is an integrated wound management system for use in acute and extended settings. It is intended to create an environment that promotes wound healing by secondary or tertiary (delayed primary) intention by preparing the wound bed for closure, reducing edema [10], promoting granulation tissue formation and perfusion and by removing exudates and infectious material [11,12]. It is indicated for patients with chronic, acute, traumatic, sub-acute and dehisced wounds, partial-thickness burns, ulcers (such as diabetic, pressure or venous insufficiency], flaps and grafts. The Negative Pressure wound therapy is an effective barrier to bacterial penetration and may help reduce infection [13,14].

Contraindications

Do not place foam dressings of the Negative Pressure Wound Therapy System directly in contact with exposed blood vessels, anastomotic sites, organs, or nerves. Negative Pressure Wound Therapy is contraindicated for patients with:

a. Malignancy in the wound b. Untreated osteomyelitis c. Non-enteric and unexplored fistulas d. Necrotic tissue with eschar present e. Vasculitis f. HIV and HbsAg positive Patients g. Sensitivity to products used in dressing

After debridement of necrotic tissue and complete removal of eschar, Negative Pressure Wound Therapy may be used.

Mechanism of Action

The Negative Pressure Wound Therapy is the first active, non-invasive wound care product, used by a secure local regulated sub-atmospheric pressure technique. The exact mechanisms to explain this treatment are not known yet. Researches by Argenta et al. [12,13] postulated that interrelated factors are the basis for the success of the technique. These factors can be devised in 3 subgroups:

Removing

Tissues surrounding the chronic wounds are characterized by localized collection of interstitial or third-space fluid. This third space fluid or edema caused by increased capillary permeability in wound. Wound cell and nourishment of wound decrease due to Edema fluid oxygenation. This collection of third-space fluid contains factors which inhibits or suppresses mitosis, protein synthesis and fibroblasts collagen synthesis. An active withdrawal of this fluid removes the excess of third space wound fluid and its inhibitory factors. The active withdrawal also results in the removing of wound debris.

Improving

The collection of third space fluid mechanically compromises the micro-vascularisation and lymphatic system. By removing the third space fluid and its inhibitory factors, this result in increased vascularisation, reduced venous after load and an increased delivery of oxygen and nutrients as well. These changes improve the rate of granulation formation and the concentration of growth factors. An additional mechanism of the Negetive Pressure Wound Therapy is the mechanical stimulation of cells migration by tensile forces placed on the surrounding tissues [10]. Adequate wound perfusion essential for tissue repair. Blood supply required for delivery of cells, factors & elements like Platelets, Neutrophils, Monocytes, Nutrients, and Oxygen etc. Peripheral blood supply essential for wound healing processes to continue. It Helps fight infection and Delivers oxygen & nutrients for healing [11,12,13].

Reducing

Besides reducing of third space fluid, We know that successful wound healing correlates with bacterial counts of less than 1,00,000 organism per gram of tissue. Bacterial counts of human wounds treated by Negative Pressure Wound Therapy have demonstrated a significant decrease after 3-4 days usually until less than 1000 per gram of tissue [14,15].

NPWT for Split Thickness Grafts

NPWT has been used instead of traditional bolstering methods to provide skin graft fixation. Improved qualitative skin graft take and quantitative improvement in skin graft success (e.g. repeat grafts) have been described in observational studies and two randomized trials [16,21]. Moisidis E & Heath T, et al. [17] conducted a trial in which 60 patients are randomly assigned to NPWT dressing connected to An aspiration to NPWT dressing connected to aspiration system versus NPWT dressing not connected to an aspiration system after STSG. NPWT was associated with significant reduction in graft loss.

1. Loss of graft area: zero versus 4.5cm2 in control group 2. Median duration of hospital stay: 13.5 versus 17 days

In our study, median duration of hospital stay was 11 days for split thickness skin graft with NPWT. Median duration of hospital stay was 13 days for flaps. Moisidis and colleagues compared a standard bolster dressing with an NPWT dressing, although quantitative graft take was similar between two groups but NPWT significantly improved the qualitative appearance of the graft.

NPWT for Flaps

The usefulness of NPWT over vascularised flaps is controversial. Morgan and colleagues specifically reported that NPWT does not increase the risk of flap failure rates or complication. However NPWT has also been shown to reduce tissue edema and improve venous congestion and contouring of flaps all of which consider beneficial. Eisenhardt, et al. [18] specifically reported that NPWT does not increase the risk of flap failure rates or complication. In our study there was reduction of tissue edema and there is no flap failure with NPWT.

Discussion

In the present study of Use of Negative Pressure Wound Therapy in Post-operative Patients with Skin Grafts and Flaps, 30 cases admitted in our ward were studied. Maximum (90.0%) numbers of patients in this study were males. Most of the patients admitted with soft tissue defect were suffered from road traffic accident and Most of the populations in road traffic accidents are males (Figure 1)In our study maximum number of population was between age group of 40 to 60 years (30%), followed by young population between 10 to 20 years (20%) and 20 to 30 years (20%). Least number of patients is above 60 years of age (Figure 2)Causes aft raw area and soft tissue defect in our study was road traffic accident (73.33%) followed by post cellulites raw area (13.33%), post operative dehisced flaps (6.66%) and chronic ulcers (6.66%) (Figure 3) Maximum numbers of patient were having less than 50cm (70%) area for application of negative pressure wound therapy Five patients are having surface area of 50 to 100cm. There are three patients with size more than 200 cm and one patient with size between 100 to 200cm(Figure 4) In our study 63% patients are having good amount of healthy granulation over wound most of which achieved by pre operative application of negative pressure wound therapy. 36% patients are having unhealthy granulation tissue (Figure 5)93.33% Patients treated with gauze application. 6.66% patients treated with presterilised foam application (Figure 6)Only one patient is having is having graft take less than 70%. 41% patients are having graft take of a 100%. 29% patients are having graft take of 95%. Patients having 90% and 80% of graft take are 12.5 percentages each (Figure 7)Maximum no. of patient treated with split thickness skin grafting [19] with excellent results. 3 patients were treated with transposition flap and application of negative pressure wound therapy to both transposition flap and adjacent graft, 2 patients were having gastrocnemius flap for upper third defect of leg. In 2 patients negative pressure wound therapy applied over reverse surely artery flap after division and inset. 2 patients are of fillet flap of great toe. In One patient NPWT applied over groin flap after division and inset and in one patient NPWT it is applied over abdominal flap after dehiscence of suture line after division and inset (Figure 8). 1 patient with split thickness skin grafting was having infection in scar, while 1 patient was having pain over dressing area. One patient with gastrocnemius flap was having skin rash at edge of flap area which is managed by daily dressing (Table 1)Maximum Patients with split thickness skin grafting were given 2 settings of negative pressure wound therapy each of 3 days (50.00%) out of 24 patients (Figure 9)Out of 30 patients 19 patients (63.33) were having negative culture reports. 4 patients were having proteus mirabilis (13.33), 5 patients were having pseudomonas (16.66), 2 patients (6.66%) were  having klebsiella organism in there bacteriological culture. One patient with pseudomonas culture on raw area shoes graft take of 70%. As end point of result was complete graft take and flap settlement there is no organism were found on bacteriological culture (Figure 10) Out of 19 patients with split thickness graft 16 patients((63.33%) were treated with intermittent NPWT and 3 patients were treated with continuous NPWT. 9 patients (81.81%) of flaps treated intermittent NPWT 2 patients were treated with continuous NPWT (Figure 11)Acute and Chronic wound management represents a considerable burden on health services and requires considerable manpower, frequent consultations and adjunct therapies. Chronic wounds affect patient's ability to function in their environment causing financial social and psychological consequences as well as affecting their quality of life [1-6]. Regardless of etiology, wounds are difficult to treat if coexisting factors (e.g., infection or diabetes mellitus) prevent regular wound healing [22,23]. Wounds represent a significant risk factor for hospitalization, amputation, sepsis, and even death, and from the patient's perspective, wound therapy is often uncomfortable or painful. Topical Negative pressure devices are believed to hasten the take of graft, removing wound exudates, increasing local blood flow, provide immobilization of graft, applying mechanical pressure to promote wound closure and reducing bacterial load in the wound. In addition to providing an optimal wound bed environment, topical negative pressure has been shown to increase local blood flow to the wound site in initial animal studies. Adequate perfusion is essential to proper take of the graft in order to provide nutrients and to remove inflammatory mediators to the wound and to remove local edema. An important factor in wound healing is the growth of granulation tissue. Initial studies by Morykwas et al. [24,25,26] showed a significant increase in rate of granulation tissue formation in wounds treated with NPWT Device compared with control wounds treated with saline-moistened gauze. Argenta et al. [22] reported finding from animal study as well as human clinics trials showing that a fourfold increase in blood flow levels when 125mmHg sub-atmospheric pressures was applied. A significantly increased rate of granulation tissue formation (p<= 0.5) was reported with continuous (63.3% -/+ 26.1%) and intermittent (103% -/+ 35.3%) application of negative pressure wound therapy.

Complication

Minimal complication encounters in present study. Bleeding occurs in one patient with operated case of gastrocnemius flap with application of NPWT over surface. There is a discontinuation in application of NPWT in one patient due to excessive pain. One of the patients with NPWT develops peripheral skin infection leading to discontinuation of NPWT [23]. Even unethical given the large effects observed in uncontrolled studies. Clinical and economical importance of NPWT has increased in recent times because it is an innovative and commercially successful concept for the management of difficult to treat wound of nearly every etiology [19,20]. The results of our study showed that indigenous NPWT is an effective tool in management of Split thickness graft, post surgical dehisced wounds and flaps. It is cost effective as compared to imported / local commercial NPWT devices available in the market. Indigenous NPWT is safe with minimal adverse events.

Results

A. Negative pressure wound therapy is cost effective as compared to commercially available negative pressure wound therapy B. Negative pressure wound therapy improve quantitative take of graft and decreases hospital stay. C. Negative pressure wound therapy is useful option on dehisced flap to reduce edema and for early settlement of flap (Figures 12-25)

Case 1

Case 2:

28 year old male with history of post traumatic raw area over dorsum of foot.

Case 3:

Crush injury to right hand due to hand caught in ganna machine.

Case 4:

Operated case of crush hand injury of right hand with filleting of second and third digit with raw area over dorsum of hand.

Conflict of Interest

None

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Post-operative infection of the implant is one of serious complications of knee arthroplasty and may lead the removal of the implant to eradicate the infection. The most common causative agents are reported to be Gram positive such as Staphylococcus aureus and Staphylococcus epidermidis [1] and less commonly Streptococci but Gram negative bacterial infection by Escherichia coli, Pseudomonas and Proteus are also frequently reported [2].

The discrepancy started with the demonstration of increase in the frequency of infections in the perioperative antibiotics administered group when compared to controls [3], the demonstration of effectiveness of antibiotic administration before exposure and leading to decrease in the infection frequency [4] but at the same time an alarming increase in the incidence of antibiotic resistant bacterial infections in the hospital setting [5]. Thus, the administration of prophylactic antibiotics may be a boon for one patient at the risk of bane for all the population. A serious consideration should be given to the selection of an appropriate antibiotic in appropriate dosage and for an appropriate period of time. The choice is difficult because of the number of factors that should be considered such as spectrum (it should cover common causative agents), Pharmacodynamic and Pharmacokinetic (Minimum inhibitory concentration, halflife and dosage) [6]. In the very beginning, penicillin's were used   but due to wide spread development of penicillin resistance and evolution of MRSA led to the replacement of penicillin's by cephalosporins which are currently used according to AAOS guidelines [6,7]. The development of antibiotic resistance is considered and vancomycin and clindamycin can be added to the regimen in areas where antibiotic resistance is common or if the patient is allergic to Beta-lactam antibiotics. There is evidence of development of resistance against vancomycin in strains of Staphylococci and enterococci, few of the most common causative agents of infection after arthroscopy. If the regimen of prophylactic antibodies is not properly regulated we will be soon reaching a blind end with no antibiotic effective against the infection [6,7].

The antibiotic resistance is geographically distributed, different in different regions of the world [6]. The selection of prophylactic antibiotic should be based on recent literature while considering antibiotic resistance and patient allergy. Thus, collaboration between the local infection control authorities and the surgery department should be established to define an appropriate prophylactic antibiotic regimen to ensure maximum benefits and minimum risks for the technique [6].   This is important that more elaborative studies are carried in this regard and clinical trials should be encouraged to have better analysis of the outcomes. Also, infectious diseases experts and orthopedic surgeons should go along well to address the condition. Thorough registry of the resistant strains of the population should be noted and the antibiotic regimens should be improvised accordingly. Although, it requires more work than normal but that would be an ideal approach in weighing the application of the antibiotics versus not administering them. To read more articles in Journal of Orthopedic & Orthoplastic Surgery

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