|Year : 2019 | Volume
| Issue : 5 | Page : 368-374
Chronic pain following thoracotomy for lung surgeries: It's risk factors, prevalence, and impact on quality of life - A retrospective study
Prachi Kar1, K Durga Sudheshna2, Durga Padmaja1, Archana Pathy1, Ramachandran Gopinath1
1 Department of Anaesthesia and Intensive Care, Nizams Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Cardiac Anaesthesia, Narayana Hrudayalaya, Bangalore, Karnataka, India
|Date of Web Publication||13-May-2019|
Dr. Prachi Kar
Department of Anaesthesia and Intensive Care, Nizams Institute of Medical Sciences, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background and Aims: Chronic post thoracotomy pain (CPTP) is a nagging complication and can affect quality of life (QOL). Studies conducted across globe have found a wide variability in the risk factors predisposing to chronic pain following thoracotomy. As no study on CPTP is available from India, we aim to detect the prevalence of CPTP, assess the predisposing factors implicated in its causation and study the impact of CPTP on QOL. Methods: After obtaining clearance from Institutional ethics committee, medical records of patients who underwent open posterolateral thoracotomy between January 2012 and December 2015 were reviewed. Data on perioperative variables, address, and contact number were collected from the patient records. All patients were mailed the Telugu translation of medical outcome study short form -36(MOS-SF-36) QOL questionnaire and were contacted telephonically to enquire about presence of CPTP and QOL. A univariate analysis was done to assess factors associated with CPTP and a multivariate logistic regression analysis was done subsequently to identify independent risk factors of CPTP. QOL indices were compared between those patients who suffered from CPTP and those who did not. Results: The prevalence of pain in our study was 40.86% (85/208). The factors implicated in the causation of CPTP were diabetes mellitus, preoperative pain, rib resection, and duration of chest tube drainage with odds ratio of 9.8, 2.6, 6.7, and 1.03, respectively. The health-related QOL showed poor scores in all domains in patients suffering from CPTP. Conclusion: The prevalence of CPTP was high. It significantly impacts health-related QOL.
Keywords: Chronic pain, quality of life, thoracotomy
|How to cite this article:|
Kar P, Sudheshna K D, Padmaja D, Pathy A, Gopinath R. Chronic pain following thoracotomy for lung surgeries: It's risk factors, prevalence, and impact on quality of life - A retrospective study. Indian J Anaesth 2019;63:368-74
|How to cite this URL:|
Kar P, Sudheshna K D, Padmaja D, Pathy A, Gopinath R. Chronic pain following thoracotomy for lung surgeries: It's risk factors, prevalence, and impact on quality of life - A retrospective study. Indian J Anaesth [serial online] 2019 [cited 2020 Apr 1];63:368-74. Available from: http://www.ijaweb.org/text.asp?2019/63/5/368/258062
| Introduction|| |
International society for the study of pain defines chronic pain as pain that persists after 3 months. Chronic pain following thoracotomy is one of the most nagging complications. The prevalence of chronic post thoracotomy pain (CPTP) varies between 25 and 68%,,,,,,, Many studies conducted across the globe have identified various factors implicated in the development of CPTP. There is wide variability in the reported factors predisposing to post thoracotomy pain. Geographic factors may play an important role in perception of pain leading to difference in prevalence. As per our knowledge no study on CPTP is available from India. Thus, the aim of the study was to detect the prevalence of chronic pain following thoracotomy in a tertiary referral center from India, assess the predisposing factors implicated in its causation, and study the impact of CPTP on quality of life (QOL).
| Methods|| |
This retrospective study was carried out in a tertiary referral center, on all adult patients who were discharged home after undergoing open lung surgery through posterolateral thoracotomy between the period of January 2012 and December 2015. Patients belonging to American society of anesthesiologists (ASA) grades IV or V, patients undergoing emergency surgery or surgery following trauma to chest wall, patients having malignancy infiltrating into chest wall, previous thoracotomy, or patients who developed major adverse cardiovascular or cerebrovascular events (MACCE) or musculoskeletal condition affecting day-to-day activity after surgery (either in hospital or after discharge) were excluded from the study. Patients having incomplete records were also excluded from study.
This study was approved by institute ethics committee. Written consent was considered unnecessary in this very low risk study and thus verbal informed consent was approved by the ethics committee. The case records and anaesthesia charts of all patients deemed suitable for the study as per above-mentioned inclusion and exclusion criteria were retrieved from the electronic database of cardiothoracic surgery department and anaesthesia department, respectively.
Data on age, sex, weight, ASA physical status, smoking, comorbidities (hypertension, diabetes mellitus), presence of preoperative moderate to severe pain over the ipsilateral thorax, malignancy, preoperative chemotherapy/radiotherapy, use of thoracic epidural analgesia (TEA), duration of surgery, duration of anaesthesia, rib resection, type of surgery, number of chest drains, duration of chest tube drainage, and postoperative surgical site infection was collected. The cell phone numbers and the address of the patients were also noted.
Before the initiation of study, the medical outcome study short form -36(MOS-SF-36) QOL questionnaire was translated to local language (Telugu), which is the vernacular language of this region. Standard procedure was followed for preparing translated version which is as follows. Four competent professionally experienced bilingual (native Telugu speaking, but proficient in English) translators were involved in the translation process. Two translators independently translated the English version of questionnaire to Telugu with culturally equivalent adaptations. Emphasis was given to conceptual rather than literal equivalence. The forward translations were reviewed by the investigators and translators together and a final consensus on the questionnaire was reached. This questionnaire was subjected to backward translation to English by the other two translators. The backward translation was reviewed again by investigators and translators for conceptual equivalence with the original version. In case of discrepancies, required modification in the language was done to suit the general public.
All patients were sent a letter by post, which contained information regarding the study and also the Telugu translation of MOS-SF-36 QOL questionnaire. This was done to enable them decide on their wish to participate in the study and to prepare for answering the QOL questionnaire. One month after dispatch of the letter, telephonic interviews were started.
Two trained interviewers telephonically contacted the patients on phone numbers retrieved from the case records. After obtaining the verbal informed consent, the patients were asked about the presence or absence of pain at the thoracotomy site. The nature and severity of pain was also noted along with day of surgery to telephonic interview time interval (in months). Patients also answered to the health-related QOL MOS-SF-36 questionnaire. Patients who refused to participate in the study or failed to comprehend the questionnaire due to poor literary skills at the time of telephonic interview were excluded. Letter was resent to patients who had not received the earlier letter and interviewed fifteen days later. Patients whose cell phone number were not reachable or patients who did not attend call even after three attempts were excluded from the study. Patients who had expired or had MACCE after hospital discharge were also excluded from study.
Standard anaesthesia technique as per institution protocol was used in all patients. Thoracic epidural catheter was inserted in all patients except for contraindication or patient refusal. A balanced anesthesia technique including O2/air/sevoflurane/fentanyl infusion was used in all patients. Muscle relaxation was maintained with atracurium infusion. Postoperative pain was measured by visual analog scale (VAS) every 4th hourly and analgesia was managed by epidural infusion of bupivacaine 0.125% continuously during the intensive care unit stay. Injection Paracetamol 1 gm was administered 6th hourly in all patients and Tramadol 100 mg was given as rescue analgesic as and when necessary (VAS >4). Chest tube was removed when there was no air leak or when pleural drain was <100 mL for 24 h. Two experienced surgical teams were involved in the surgical procedures. Standard posterolateral thoracotomy with or without rib resection was used in all patients.
Data were analyzed using SPSS version 20 (2011, IBM, Armonk, NY, United States of America). Continuous variables were expressed as mean ± standard deviation (S.D). Categorical variables were expressed as numbers and percentages. Continuous variables were analyzed using Students' t test and chi square test was used to analyze categorical variables. A P value of less than 0.05 was considered significant. Variables with significant P value were further subjected to multiple forward step-wise logistic regression analysis to identify the independent risk factor.
| Results|| |
As shown in flow diagram of [Figure 1], data from 208 patients were analyzed after pre- and post-telephonic exclusion. Their baseline characteristics are summarized in [Table 1].
|Figure 1: Flow chart of patient recruitment. ASA- American society of Anaesthesiologists, MACCE- Major adverse cerebral and cardiovascular events|
Click here to view
The point prevalence of CPTP at the time of telephonic interview was 40.86% (85/208 patients). Forty-five patients (52.9%) complained of mild pain, while moderate and severe pain was experienced by 28.23% (24) and 18.82% (16) patients, respectively. Majority of patients, 36 (42.3%) complained of a numb type of pain. The other varieties of pain reported were, dull aching 15 (17.6%), throbbing 12 (14.1%), itchy 6 (7.05%), shooting 5 (5.8%). Rest 11 patients could not describe the nature of their pain.
The study showed that the prevalence of pain was high (58.3%) in patients interviewed within 12 months' time frame after surgery. The prevalence decreased and remained nearly constant between 13–24 and 25–36 months. Thereafter, it further decreased to a value of 26% at >48 months.
[Table 1] shows the factors significantly associated with the causation of chronic pain. On univariate analysis, diabetes mellitus, preoperative moderate to severe pain on ipsilateral thorax, rib resection, duration of chest tube drainage, and postoperative surgical site infection were found to be significant factors. However, multivariate regression identified diabetes mellitus, preoperative moderate to severe pain on ipsilateral thorax, rib resection, and duration of chest tube drainage as independent predictors of CPTP [Table 2]. SF-36 questionnaire was used to assess the effects of chronic pain on QOL. All the components of QOL questionnaire were found to have significantly lower values in patients with CPTP as compared to those, who did not have CPTP [Figure 2].
|Table 2: Results of logistic regression showing risk factors for development of chronic post thoracotomy pain|
Click here to view
|Figure 2: Comparison of SF-36 domain scores in patients having and not having CPTP. PF- physical function, RP (role physical)- role limitations due to physical problems, BP-body pain, GH-general health, VT-vitality, SF-social function, RE (role emotional)- role limitations due to emotional problems, MH- mental health|
Click here to view
| Discussion|| |
Our study found the prevalence of chronic pain following thoracotomy to be high (40.86%). The prevalence of CPTP varies across studies between 25% and 68%.,,,,,,, The significant risk factors implicated in the genesis of chronic pain in our study were diabetes mellitus, preoperative moderate to severe pain over ipsilateral thorax, rib resection, and duration of chest tube drainage. The QOL in patients having CPTP was poorer compared to those not having it.
Some degree of tissue and nerve injury is inevitable following thoracotomy but all patients do not develop CPTP. In an attempt to answer this discrepancy, many researchers have looked in to the risk factors associated with development of chronic pain. There may be great variation in the risk factors in Indian context, due to differences in geographic, cultural, ethnicity, and socioeconomic status. A recent study by Saxena et al. found higher prevalence of chronic pain in Indian patients as compared to Pan Asian region. Antony and Merghani concluded that lower socioeconomic and educational background was associated with a lower complaint of chronic pain in patients receiving home-based nursing care. As there are no previous research on CPTP in Indian subcontinent, considering the above-mentioned factors we aimed to study the same.
A younger age (<60 years) was found to have a causal relation with chronic pain in many studies.,, Further, a study by Mongarden concluded that patients with chronic pain were about 10 years younger than those not having it. This association could possibly be due to the fact that younger patients have a stronger inflammatory and immune reaction and increased neuroplastic response. However, we failed to elicit any influence of age on CPTP probably because of an overall younger study population.
Females have consistently revealed a greater sensitivity to pain both in experimental and clinical models., Gender-specific differences in pain sensitivity has also been found in many studies on chronic post thoracotomy pain.,, However in a recent meta-analysis in cancer patients, pain was not found to be significantly different in males and females. Our study also could not elicit any contribution of gender in the genesis of pain.
Our study revealed that diabetic patients had a 9.8 odd of developing chronic pain as compared to nondiabetics. Painful polyneuropathy is a well-known entity in patients with diabetes. It's mechanism is complex and is due to interplay of various inflammatory, microvascular, and immune mechanisms., However, literature on the association of diabetes mellitus and development of chronic pain is sparse. We hypothesize that pre-existing neuropathy in diabetic patients may be accentuated due to surgical stress resulting in chronic pain. Wang et al. also reported an odds ratio of 6.6 for developing chronic pain in patients with diabetes.
TEA was used in 181 patients for intraoperative and postoperative analgesia, while in the rest, analgesia was maintained with intravenous analgesics. The results of this study did not show a relationship between TEA and CPTP. Similar results were noted by earlier investigators., The smaller sample of patients without TEA could have limited the establishment of statistical relation between TEA and CPTP. We could not test the relationship between acute postoperative pain and CPTP as the pain management protocols in the intensive care unit ensured a VAS <4 in all patients using other analgesic regimens even in the absence of TEA.
There is a well-documented relationship between preoperative pain and development of chronic pain in hernia, amputation, and hysterectomy patients; however, little information is available on CPTP in post thoracotomy patients.,, A study by Hetmann et al. could not elicit association between chronic preoperative pain in extra thoracic regions and postoperative pain, However in another study by Kampe et al., 33.5% patients with preoperative pain in thoracic region developed CPTP., Our study is in agreement with the later. Many of the studies on CPTP excluded patients who had preoperative pain or were on preoperative analgesics., This could be the reason for inadequacy of literature to establish a relation between preoperative pain and CPTP. It is perceived that prolonged activation of pain centers (as in patients with chronic preoperative pain and inadequate pain control) may lead to central sensitization causing chronic pain syndromes. Painful stimuli cause changes in the peripheral and central nervous systems, which increase the impact of painful stimuli and can also cause nonpainful stimuli to be experienced as painful.,,
Neurologic injury during the time of surgery is the likely source of development of long-term CPTP. The nerve injury may occur from use of rib retractors, rib resection, or use of improper suturing techniques., Studies have proven that modification in surgical techniques to preserve intercostal nerve decreased the incidence of CPTP.,, Rib resection is often carried out during thoracotomy to improve exposure, prevent rib fracture, and injury to posterior costovertebral elements. Although Maguire et al. concluded that rib resection was associated with higher amount of intercostal nerve injury, the literature on association of rib resection and CPTP is controversial. Opinion varies as to whether rib resection causes trauma to intercostal nerves or prevents trauma from rib spreading. In a retrospective study of 1000 patients, Richardson et al. concluded that that incidence of CPTP was lower in patients who had rib resection than who did not. However in another study by Hansen, the development of CPTP was higher (14.8%) in patients who had a rib resected than those who did not (3.1%).
Earlier studies have found positive correlation between number of chest drains and chronicity of pain; however, our study could not demonstrate any such association. Longer duration of chest tube drainage was a significant factor for development of chronic pain in our study which is consistent with the result of previous studies.,,, Peng et al. showed that chest tube drainage >4 days increased the prevalence of chronic pain in post thoracotomy patients. Moreover a study by Miyazaki et al. clearly showed evidence of damage to intercostal nerve on chest tube insertion. Using the current concept of threshold testing, their study showed that chest tube placement was harmful to both myelinated (Aα and Aß) and unmyelinated C fibers.
QOL in patients with CPTP has always been a concern. Many studies have attempted to evaluate QOL earlier, some with subjective questions and others with a structured questionnaire. English SF36 questionnaire is available online, free of cost by Research and development (RAND). It was translated to Telugu using standard protocol as described earlier and was used for our study [Appendix 1 is available online [Additional file 1]]. Necessary changes were done to achieve cultural equivalence as suggested by Sinha et al. It looks at eight aspects of QOL, physical function (PF), role limitations due to physical problems (role physical, RP), body pain (BP), general health (GH), vitality (VT), social function (SF), role limitations due to emotional problems (role emotional, RE), and mental health (MH). Scores in each category ranges from 0 to 100, 0 being worst QOL and 100 being best. Our study revealed that CPTP led to lower scores in all domain of SF36 questionnaire. Peng et al. used the Chinese version of the SF-36 questionnaire and concluded that PF and BP components were most affected in patients with CPTP. Only PF and vitality components were found to be decreased in another study by Kinney et al. However, this study followed up the patients only for 3 months and it is possible that emotional and mental changes might have developed later and thus were missed in the observation.
A limitation of this study that it is a single center retrospective study. The shortcomings of telephonic interview and self-reporting of pain by patients must be kept in mind. We did not study the effect of psychosocial factors like anxiety, depression, malignant disease, social network, and social status on CPTP which may have had significant impact on development of chronic pain and QOL. Details of postdischarge analgesic medication intake were also not sought. Further prospective studies are required to study the effect of minimizing risk factors on prevalence of CPTP.
| Conclusion|| |
CPTP is a common complication in patients undergoing thoracotomy. All domains of medical outcome study short form-36 QOL questionnaire were significantly affected by it.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bayman EO, Parekh KR, Keech J, Selte A, Brennan TJ. A prospective study of chronic pain after thoracic surgery. Anesthesiology 2017;126:938-51.
Guastella V, Mick G, Soriano C, Vallet L, Escande G, Dubray C, et al
. A prospective study of neuropathic pain induced by thoracotomy: Incidence, clinical description, and diagnosis. Pain 2011;152:74-81.
Kinney MA, Hooten WM, Cassivi SD, Allen MS, Passe MA, Hanson AC, et al
. Chronic post thoracotomy pain and health-related quality of life. Ann Thorac Surg 2012;93:1242-7.
Maguire MF, Ravenscroft A, Beggs D, Duffy JP. A questionnaire study investigating the prevalence of the neuropathic component of chronic pain after thoracic surgery. Eur J Cardiothorac Surg 2006;29:800-5.
Mongardon N, Pinton-Gonnet C, Szekely B, Michel-Cherqui M, Dreyfus JF, Fischler M. Assessment of chronic pain after thoracotomy: A 1-year prevalence study. Clin J Pain 2011;27:677-81.
Peng Z, Li H, Zhang C, Qian X, Feng Z, Zhu S. A retrospective study of chronic post-surgical pain following thoracic surgery: Prevalence, risk factors, incidence of neuropathic component, and impact on qualify of life. PLoS One 2014;9:e90014.
Steegers MA, Snik DM, Verhagen AF, Van Der Drift MA, Wilder-Smith OH. Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain 2008;9:955-61.
Wang HT, Liu W, Luo AL, Ma C, Huang YG. Prevalence and risk factors of chronic post-thoracotomy pain in Chinese patients from Peking Union Medical College Hospital. Chin Med J (Engl) 2012;125:3033-8.
Sinha R, Van Den Heuvel WJ, Arokiasamy P. Validity and reliability of MOS short form health survey (SF-36) for use in India. Indian J Community Med 2013;38:22-6.
] [Full text]
Saxena AK, Jain PN, Bhatnagar S. The prevalence of chronic pain among adults in India. Indian J Palliat Care 2018;24:472-7.
] [Full text]
Antony T, Merghani TH. The influence of demographic and psychosocial factors on the intensity of pain among chronic patients receiving home-based nursing care. Indian J Palliat Care 2016;22:362-5.
] [Full text]
Pluijms WA, Steegers MA, Verhagen AF, Scheffer GJ, Wilder-Smith OH. Chronic post-thoracotomy pain: A retrospective study. Acta Anaesthesiol Scand 2006;50:804-8.
Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choiniere M. A systematic literature review of 10 years of research on sex/gender and pain perception – part 2: Do biopsychosocial factors alter pain sensitivity differently in women and men? Pain 2012;153:619-35.
Racine M, Tousignant-Laflamme Y, Kloda LA, Dion D, Dupuis G, Choiniere M. A systematic literature review of 10 years of research on sex/gender and experimental pain perception – part 1: Are there really differences between women and men? Pain 2012;153:602-18.
Gotoda Y, Kambara N, Sakai T, Kishi Y, Kodama K, Koyama T. The morbidity, time course and predictive factors for persistent post-thoracotomy pain. Eur J Pain 2001;5:89-96.
Ochroch EA, Gottschalk A, Troxel AB, Farrar JT. Women suffer more short and long-term pain than men after major thoracotomy. Clin J Pain 2006;22:491-8.
Ahmed Y, Popovic M, Wan BA, Lam M, Lam H, Ganesh V, et al
. Does gender affect self-perceived pain in cancer patients? -A meta-analysis. Ann Palliat Med 2017;6:S177-84.
Ten Hoope W, Looije M, Lirk P. Regional anesthesia in diabetic peripheral neuropathy. Curr Opin Anaesthesiol 2017;30:627-31.
Zychowska M, Rojewska E, Przewlocka B, Mika J. Mechanisms and pharmacology of diabetic neuropathy – experimental and clinical studies. Pharmacol Rep 2013;65:1601-10.
Brennan TJ, Kehlet H. Preventive analgesia to reduce wound hyperalgesia and persistent postsurgical pain: Not an easy path. Anesthesiology 2005;103:681-3.
Hu JS, Lui PW, Wang H, Chan KH, Luk HN, Tsou MY, et al
. Thoracic epidural analgesia with morphine does not prevent postthoracotomy pain syndrome: A survey of 159 patients. Acta Anaesthesiol Sin 2000;38:195-200.
Brandsborg B, Nikolajsen L, Hansen CT, Kehlet H, Jensen TS. Risk factors for chronic pain after hysterectomy: A nationwide questionnaire and database study. Anesthesiology 2007;106:1003-12.
Nikolajsen L, Ilkjaer S, Kroner K, Christensen JH, Jensen TS. The influence of preamputation pain on postamputation stump and phantom pain. Pain 1997;72:393-405.
Poobalan AS, Bruce J, Smith WC, King PM, Krukowski ZH, Chambers WA. A review of chronic pain after inguinal herniorrhaphy. Clin J Pain 2003;19:48-54.
Kampe S, Geismann B, Weinreich G, Stamatis G, Ebmeyer U, Gerbershagen HJ. The influence of type of anesthesia, perioperative pain, and preoperative health status on chronic pain six months after thoracotomy-A prospective cohort study. Pain Med 2017;18:2208-13.
Hetmann F, Schou-Bredal I, Sandvik L, Kongsgaard UE. Does chronic pre-operative pain predict severe post-operative pain after thoracotomy? A prospective longitudinal study. Acta Anaesthesiol Scand 2013;57:1065-72.
Maguire MF, Latter JA, Mahajan R, Beggs FD, Duffy JP. A study exploring the role of intercostal nerve damage in chronic pain after thoracic surgery. Eur J Cardiothorac Surg 2006;29:873-9.
Katz J. Prevention of phantom limb pain by regional anaesthesia. Lancet 1997;349:519-20.
Jahangiri M, Jayatunga AP, Bradley JW, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl 1994;76:324-6.
Rogers ML, Henderson L, Mahajan RP, Duffy JP. Preliminary findings in the neurophysiological assessment of intercostal nerve injury during thoracotomy. Eur J Cardiothorac Surg 2002;21:298-301.
Cerfolio RJ, Bryant AS, Maniscalco LM. A nondivided intercostal muscle flap further reduces pain of thoracotomy: A prospective randomized trial. Ann Thorac Surg 2008;85:1901-6; discussion 6-7.
Cerfolio RJ, Bryant AS, Patel B, Bartolucci AA. Intercostal muscle flap reduces the pain of thoracotomy: A prospective randomized trial. J Thorac Cardiovasc Surg 2005;130:987-93.
Cerfolio RJ, Price TN, Bryant AS, Sale Bass C, Bartolucci AA. Intracostal sutures decrease the pain of thoracotomy. Ann Thorac Surg 2003;76:407-11; discussion 11-2.
Karmakar MKHo AM. Postthoracotomy pain syndrome. Thorac Surg Clin 2004;14:345-52.
Richardson J, Sabanathan, S, Mearns, A.J, Sides, C, Goulden, C.P. Post-thoracotomy neuralgia. Pain Clin 1994;7:7. Post-thoracotomy neuralgia. Pain Clin 1994;7:87-97.
Hansen JL. Intercostal neuralgia following thoracoabdominal surgery. Acta Chir Scand Suppl 1973;433:180-2.
Buchheit Tpyati S. Prevention of chronic pain after surgical nerve injury: Amputation and thoracotomy. Surg Clin North Am 2012;92:393-407, x.
Van De Ven TJJohn Hsia HL. Causes and prevention of chronic postsurgical pain. Curr Opin Crit Care 2012;18:366-71.
Miyazaki T, Sakai T, Yamasaki N, Tsuchiya T, Matsumoto K, Tagawa T, et al
. Chest tube insertion is one important factor leading to intercostal nerve impairment in thoracic surgery. Gen Thorac Cardiovasc Surg 2014;62:58-63.
[Figure 1], [Figure 2]
[Table 1], [Table 2]