Cellulitis in older people over 75 years – are there differences?

Journal Pre-proof Cellulitis in older people over 75 years – are there differences? Manoj Kumar, Vincent Jiu Jong Ngian, Clarence Yeong, Caitlin Keighley, Huong Van Nguyen, Bin Soo Ong PII:

S2049-0801(19)30180-3

DOI:

https://doi.org/10.1016/j.amsu.2019.11.012

Reference:

AMSU 1483

To appear in:

Annals of Medicine and Surgery

Received Date: 12 September 2019 Revised Date:

13 November 2019

Accepted Date: 17 November 2019

Please cite this article as: Kumar M, Jong Ngian VJ, Yeong C, Keighley C, Van Nguyen H, Ong BS, Cellulitis in older people over 75 years – are there differences?, Annals of Medicine and Surgery, https:// doi.org/10.1016/j.amsu.2019.11.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

CELLULITIS IN OLDER PEOPLE OVER 75 YEARS – ARE THERE DIFFERENCES?

Authors Manoj Kumar 1,3, Vincent Jiu Jong Ngian1,2, Clarence Yeong1, Caitlin Keighley1, Huong Van Nguyen1,2, Bin Soo Ong1,2. Bankstown-Lidcombe Hospital, Bankstown, New South Wales, Sydney, Australia1 University of New South Wales, Sydney, New South Wales, Australia2 Corresponding Author3 Dr Manoj Kumar [email protected]

Abstract Aim: To examine differences in risk factors, clinical features and outcomes of cellulitis between those 75+ years and those < 75 years admitted to a metropolitan hospital. Methods: A prospective study of patients with limb cellulitis requiring intravenous antibiotics conducted at Bankstown-Lidcombe Hospital, Australia from June 2014 to April 2015. Results: Thirty one patients were 75+ years and 69 less than 75 years. A greater proportion of older patients resided in nursing home (25.8% vs 2.9% respectively, p=0.001) and mobilized with walking aid(s) (58.1% vs 11.6% respectively, p<0.001). Significantly more older patients had documented hypertension (45.2% vs 23.2% respectively p=0.035), atrial fibrillation (33.5% vs 5.8% respectively, p<0.001), dementia (22.6% vs 1.4% respectively, p=0.001) and malignancy (16.1% vs 1.4% respectively, p=0.010). The clinical presentation of cellulitis and cellulitis severity (Eron classification) did not significantly differ in both groups; however older patients were more likely to have dependent edema (OR 4.0, 95%CI 1.3-12.6, p=0.018) and less likely to be obese (OR 0.3, 95%CI 0.1-0.8, p=0.012) or had a past history of cellulitis (OR 0.3, 95%CI 0.11.0, p=0.044) on presentation. Despite the age difference, there were no major differences in intravenous antibiotic choice, hospital length of stay, and hospital readmission rates in both groups. Older patients however, were more likely to experience complications such as falls and/ or decreased mobility (38.7% vs 15.9% respectively, p=0.020) during the cellulitis episode. Conclusion: There are minor differences in the risk factors and clinical features of cellulitis in older patients as compared to the young. Outcomes are similar except for a higher incidence of hospital related complications.

Keywords Cellulitis; older people; outcomes

1

Introduction Cellulitis is a bacterial infection of the skin involving the dermis and subcutaneous fat. In Australia, cellulitis accounts for over 250,000 hospital bed days, or 10.5% of potentially preventable hospitalizations1.While most episodes of cellulitis can be managed as an outpatient, a significant proportion, particularly older people, require hospitalization. Over a 12-month period from 2014-2015, the cellulitis hospitalization rate was 1100 per 100,000 in the 80 plus age group as opposed to 237 episodes per 100,000 in the general population.1

Cellulitis typically presents with pain, erythema, warmth and edema. Systemic symptoms including fever and tachycardia may be present although thought to be less frequent in older persons.2-6 Known risk factors for cellulitis are venous edema, lymphedema, skin conditions, traumatic injury, leg ulcers, peripheral vascular disease, fungal infections, past history of cellulitis and obesity. 7-10

Age alone does not alter treatment principles for bacterial cellulitis (including use of antibiotics); however age-related pharmacokinetics and pharmacodynamics, cognitive status and social circumstances11 may impact on treatment decisions particularly need for hospitalization.

Once hospitalized, age is an independent risk factor for increased length of stay for cellulitis with other factors being long duration of symptoms, tachycardia, hypotension, leukocytosis, hypoalbuminemia, elevated serum creatinine, bacteremia, obesity and diabetes mellitus. 12-15

2

Age is significantly associated with increased mortality from cellulitis although it is unclear if this is due to illness severity or underlying comorbidity.16 Other factors associated with mortality are delayed administration of antibiotics, presence of multiple comorbidities, previous myocardial infarction, congestive heart failure, liver disease, hypoalbuminemia, renal insufficiency, morbid obesity, lower limb edema, Pseudomonas aeruginosa infection, bacteremia and septic shock.14,17 Hospital readmission for cellulitis is also more common in older people18 particularly if there has been more than one prior episode of cellulitis19.

Aims In this prospective study, we aimed to examine differences in risk factors, clinical features, management, and outcomes of cellulitis between those 75 years or more and those less than 75 years admitted to a large metropolitan hospital.

Methods The study was conducted at Bankstown-Lidcombe Hospital, New South Wales, Australia from June 2014 to April 2015. The study was approved by the South-Western Sydney Local Health District (SWSLHD) Ethics Committee.

Between June 2014 and April 2015, potential patients were identified through review of the Bankstown Hospital inpatient list three times a week by a study investigator. We included all identified patients aged 18 years or more with a diagnosis of cellulitis of the upper and/ or lower limb(s) and excluded patients with infected ulcers on presentation, pregnant patients and those with post-operative wound infections.

The patients were then stratified into an older group (aged 75 years or more) and a younger group (74 years or less) and were followed up during their admission and for a total of 28 days post completion of intravenous antibiotics. We studied the over 75 years age group as that this age group is more descriptive of the frail older cohort.19

3

Data

collected

included

basic

demographics,

clinical

characteristics,

relevant

investigations, treatment provided and clinical outcomes. The severity of cellulitis was rated using the Eron classification.20

Data were analyzed with SPSS Version 24 and R version 3.3.1. Chi-square test was used to compare proportions. Student’s T-test was used to compare differences in means for normally distributed variables. For non-normally distributed continuous variables, non-parametric test was used to assess differences in the ranked median scores. Logistic regression was used to assess statistically significant risk factors for cellulitis in the older and younger age groups. Statistically significant results were set at an alpha level of 0.05. The study is in line with the STROCSS guidliness.21 The study also been registered on the research registry UIN :researchregistry5125.

Results One hundred and thirteen patients were identified during the study period and 100 patients (88.5%) consented to participate. Thirty-one (31.0%) patients were aged 75 years and older and 69 (69.0%) patients were 74 years or less.

The mean age was 84.4±5.8 years in the older group and 53.4±14.2 years in the younger group. The older patients had lower BMI than their younger counterparts [28.3 (±8.0) vs 36.0 (±12.3) respectively, p<0.001]. A higher proportion resided in residential aged care facilities (25.8% vs 2.9% respectively, p=0.001); and mobilized with walking aid(s) (58.1% vs 11.6% respectively, p<0.001). (Table 1)

A significantly higher proportion of older patients had documented hypertension (45.2% vs 23.2% respectively p=0.035), atrial fibrillation (33.5% vs 5.8% respectively, p<0.001), dementia (22.6% vs 1.4% respectively, p=0.001) and malignancy (16.1% vs 1.4% respectively, p=0.010). (Table 1)

4

In terms of cellulitis risk factors, after controlling for potential confounders, older patients were more likely to have dependent edema (OR 4.0 95%CI 1.3-12.6, p=0.018); but less likely to be obese (OR 0.3, 95%CI 0.1-1.0, p=0.012) or had a prior history of cellulitis (OR 0.3, 95%CI 0.1-1.0, p= 0.044) than younger patients. The risk of peripheral vascular disease, tinea pedis and cutaneous dermatitis were similar in both groups.

Cellulitis presenting features such as pain, fever, chills and vital signs (temperature, heart rate and blood pressure) did not significantly differ between the two groups. The severity of cellulitis, as defined by the Eron classification22 also did not differ between groups with the majority of patients having Eron Classes I and II. (Table 2)

Initial laboratory results revealed that older patients had lower hemoglobin [122.1 (±16.4) vs 135.0 (±19.4), p=0.002] and albumin [38.0 (±47) vs 41.4 (±4.1), p<0.001] and higher urea level [7.9 (5.8-12.4) vs 5.8 (4.8-8.4), p=0.011] compared to their younger counterparts. CRP white cell count (WCC) and positive rate of blood culture did not differ between the two groups. (Table 2)

Older inpatients presenting with cellulitis were less likely to be referred to hospital in the home (HITH) antibiotic programs for completion of the course of intravenous antibiotics 32.3% vs 59.4% respectively, p=0.012) compared to younger patients. The antibiotic choices did not differ between the two populations, these included Cephazolin, Flucloxacillin or Tazobactam-Piperacillin. Older patients with cellulitis were more likely to experience falls or decreased mobility (38.7% vs 15.9% respectively, p= 0.020) compared to the younger group. (Table 3). Despite this, they had similar LOS to their younger counterparts [10 (7-15) vs 8 (6-13) respectively, p=0.403]. There was one death in each group and the rates of ICU admission, surgical intervention and 28-day readmission were similar in the two groups.

Discussion

5

In this study, we found that older people, despite being frailer than their younger counterparts, had similar treatment outcomes after presenting to hospital with mild to moderate limb cellulitis.

In our study, most of the potential risk factors for cellulitis were similar in the older and younger age groups; however, older patients were more likely to have dependent edema and impaired mobility, and less likely to be obese. Other conditions noted to be more common in the older group were congestive cardiac failure, atrial fibrillation, dementia and malignancy. We believe this finding reflected the higher prevalence of these conditions in the older population rather than an association with cellulitis.

Over 25% of older patients with cellulitis lived in residential aged care facilities. This finding raised the opportunity for the provision of ambulatory care antibiotic programs in aged care homes potentially avoiding the need for hospitalization for residents with cellulitis.

There were no significant differences in the clinical presentation of cellulitis between the two age groups (i.e., duration of cellulitis symptoms, heart rate, blood pressure, temperature, white cell count, CRP and Eron severity classification). Atypical and blunted physiological response to infection with age has been documented in the literature.23 In severe sepsis, a reduced physiological response can lead to rapid progression of sepsis2, 3, 22.Our results did not support a blunted response to infection in older patients with cellulitis. We, however, did not have any patients with severe sepsis to examine the inflammatory response in more detail.

In our study, older patients experienced more falls and impaired mobility during the admission for cellulitis compared to younger patients. While these factors might have made their hospital discharge planning more complex, they did not translate into an increased hospital length of stay. Previously described risk factors affecting LOS in cellulitis (comprising of age, hypoalbuminemia, bacteremia, obesity, diabetes mellitus, tachycardia, hypotension, leukocytosis, and elevated serum creatinine), 6

7,12,13,14,15

tended to be skewed towards age and hypoalbuminemia for the older group and obesity for the younger group in our study.

There were no statistically significant differences between the two groups in terms of mortality, ICU admission, and surgical intervention for cellulitis complications.

The

majority of patients in both groups had Eron Class I or II cellulitis and did not sustain physiological decompensations; however, in more severe cases of cellulitis, one would expect ageing physiology to sustain more physiological decompensations which may then influence the above parameters.

A lower proportion of older inpatients discharged to HITH programs might have been attributable to their medical comorbidities and functional criteria not meeting HITH requirements. As such, additional health resources may allow HITH programs to manage these complex patients but this would require further study. Unlike previous published literature, 18 we did not find a significant difference in the 28day readmission rate between the two age cohorts in our study. As the readmission rate was less than 5%, a study with greater number of patients would have more power to detect small differences in readmission rates.

One of the limitations of this study is the small sample size due to a short recruitment period; further study with a larger sample size would assist in validation of our findings. We decided to focus on inpatient cellulitis treatment; however a cellulitis management journey from hospital to community settings would have provided with a more complete picture.

As the number of older patients presenting with cellulitis increases as the population ages, it is important to note that for mild to moderate cellulitis, older patients perform just as well as younger patients with standard cellulitis treatments on clinical and care indicators.

7

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no financial or person support for this work with any other people or organizations.

Provenance and peer review Not commissioned, externally peer reviewed.

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References 1. National health performance authority analysis of admitted patients care national minimal data set 2013-2014 and Australian Bureau of statistics estimated resident population 30 June 2013

2. Anderson DJ, Kaye KS (2007) Skin and soft tissue infections in older adults.Clin Geriatr

Med 23(3): 595–613.

3. Laube S. Skin infections and ageing (2004) Ageing Res Rev. 2004;3(1): 69–89.

4. Weng QY, Raff AB, Cohen JM, Gunasekera N, Okhovat JP, Vedak P, et al. (2017) Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol 153(2): 141–146.

5. Gunderson CG, Martinello RA (2012) A systematic review of bacteremias in cellulitis and erysipelas. J Infect 64(2): 148–155. doi: 10.1016/j.jinf.2011.11.004.

6. Esposito S, Noviello S, Leone S (2016) Epidemiology and microbiology of skin and soft tissue infections Current Opinion in Infectious Diseases 29(2):109–115.

7. Dupuy A, Benchikhi H, Roujeau JC, Bernard P, Vaillant L, Chosidow O, et al. (1999) Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 318(7198): 1591–1594.

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8. Björnsdóttir S, Gottfredsson M, Thórisdóttir AS, Gunnarsson GB, Ríkardsdóttir H, Hilmarsdóttir I (2005) Risk factors for acute cellulitis of the lower limb: a prospective case–control study. Clin Infect Dis 41(10): 1416–1422.

9. Karppelin M, Siljander T, Vuopio-Varkila J, Kere J, Huhtala H, Vuento R, et al. (2010) Factors predisposing to acute and recurrent bacterial non-necrotizing cellulitis in hospitalized patients: a prospective case–control study. Clin Microbiol Infect 16(6): 729–734.

10. Halpern J, Holder R, Langford NJ (2008) Ethnicity and other risk factors for acute lower limb cellulitis: a U.K.-based prospective case–control study. Br J Dermatol 158(6): 1288–1292.

11. Kish TD, Chang MH, Fung HB (2010) Treatment of skin and soft tissue infections in the elderly: a review. Am J Geriatr Pharmacother 8(6): 485–513.

12. Garg A, Lavian J, Lin G, Sison C, Oppenheim M, Koo B (2017) Clinical characteristics associated with days to discharge among patients admitted with a primary diagnosis of lower limb cellulitis. J Am Acad Dermatol 76(4): 626–631.

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13. Morpeth SC, Chambers ST, Gallagher K, Frampton C, Pithie AD (2006) Lower limb cellulitis: features associated with length of hospital stay. J Infect 52(1): 23– 29.

14. Figtree M, Konecny P, Jennings Z, Goh C, Krilis SA, Miyakis S (2010) Risk stratification and outcome of cellulitis admitted to hospital. J Infect 60(6):431– 439.

15. Theofiles M, Maxson J, Herges L, Marcelin A, Angstman KB (2015) Cellulitis in obesity: adverse outcomes affected by increases in body mass index. J Prim Care Community Health. 6(4): 233–238.

16. Tan R, Newberry DJ, Arts GJ, Onwuamaegbu ME (2007) The design, characteristics and predictors of mortality in the North of England Cellulitis Treatment Assessment (NECTA). Int J Clin Pract 61(11): 1889–1893.

17. Carratalà J, Rosón B, Fernández-Sabé N, Shaw E, del Rio O, Rivera A, et al. (2003) Factors associated with complications and mortality in adult patients hospitalized for infectious cellulitis. Eur J Clin Microbiol Infect Dis 22(3): 151–157.

18. Garg A, Lavian J, Lin G, Sison C, Oppenheim M, Koo B (2017) Clinical factors associated with readmission among patients with lower limb cellulitis. Dermatology 233(1): 58–63.

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19. Ouchi Y, Rakugi H, Arai H, Akishita M, Ito H, Toba K, Kai I; Joint Committee of Japan Gerontological Society (JGLS) and Japan Geriatrics Society (JGS) on the definition and classification of the elderly, Redefining the elderly as aged 75 years and older: Proposal from the Joint Committee of Japan Gerontological Society

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Jul;17(7):1045-1047

20. Karppelin M, Siljander T, Aittoniemi J, Hurme M, Huttunen R, Huhtala H, et al. (2015) Predictors of recurrent cellulitis in five years. Clinical risk factors and the role of PTX3 and CRP. J Infect 70(5): 467–473.

21. Agha RA, Borrelli MR, Vella-Baldacchino M, Thavayogan R and Orgill DP, for the STROCCS Group. The STROCCS Statement: Strengthening the Reporting of Cohort Studies in Surgery. International Journal of Surgery 2017;46:198-202

22. Eron, L. J. (2000) Infections of skin and soft tissues: outcome of a classification scheme. Clinical Infectious Diseases. 31, 287 (A432).

23. Norman DC, Grahn D, Yoshikawa TT (1985) Fever and aging. J Am Geriatr Soc 33: 859.

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Table 1. Patient Characteristics Age < 75 years (N=69)

Age 75+ years (N=31)

P-value

Age mean(SD)

53.4 (±14.2)

84.4 (±5.8)

< 0.001

Female n (%)

23 (33.3%)

16 (48.5%)

0.12

BMI

36.0 (±12.3)

28.3 (±8.0)

<0.001

2 (2.9%)

8 (25.8%)

0.001

Residential Aged Care Facility Mobility

<0.001

Mobile unaided

61 (88.4%)

13 41.9%)

Mobile with aid

8 (11.6%)

18 (58.1%)

Dependent oedema

-

4.0 (1.3-12.6)

0.018

Obesity (BMI>30)

-

0.3 (0.1-0.8)

0.012

Previous cellulitis

-

0.3 (0.1-1.0)

0.044

Peripheral vascular disease

-

3.1 (0.9-10.6)

0.079

Tinea pedis

-

0.9 (0.2-4.1)

0.930

Venous dermatitis

-

0.5 (0.1-2.0)

0.302

16 (23.2%)

14 (45.2%)

0.035

AF

4 (5.8%)

11 (33.5%)

< 0.001

Dementia

1 (1.4%)

7 (22.6%)

0.001

Malignancy

1 (1.4%)

5 (16.1%)

0.010

Diabetes

23 (31.9%)

6 (19.4%)

0.24

IHD

11 (15.9%)

10 (32.3%)

0.11

CCF

10 (14.5%)

9 (29.0%)

0.10

DVT

3 (4.3%)

5 (16.1%)

0.10

PE

2 (2.9%)

5 (16.1%)

0.072

Steroid use last 3 months

3 (4.3%)

3 (9.7%)

0.37

Risk factors† OR (95% CI)

Comorbidities Hypertension

† Logistic regression – Chi-square = 17.868, p=0.007, df=6, Nagelkerke’s R2 0.230; BMI body mass index; IHD ischaemic heart disease; AF atrial fribrillation; CCF congestive cardiac failure; DVT deep vein thrombosis; PE pulmonary embolism

Table 2. Clinical Characteristics Age < 75 years (N=69)

Age 75+ years (N=31)

P-value

3.0 (2.0 - 6.0)

4.0 (2.0 - 14.0)

0.23

19 (27.5%)

6 (19.4%)

0.46

Heart rate

92 (±17)

89 (±15)

0.384

BP – Systolic

136 (±18)

143 (±24)

0.158

BP _Diastolic

75 (±12)

72 (±11)

0.227

Temperature

37.4 (±1.0)

37.3 (±1.0)

0.796

Duration of symptoms median (IQR) Fever and chills

Pain score

0.055

Mild 0-3

32 (51.6%)

14 (53.8%)

Moderate 4-7

20 (32.3%)

12 (46.2%)

Severe 8-10

10 (16.1%)

0

135.0 (±19.4)

122.1 (±16.4)

0.002

White cell count

11.3 (±5.1)

11.1 (±6.0)

0.61

Albumin

41.4 (±4.1)

38.0 (±4.7)

0.001

Creatinine – median (IQR)

88 (76-106)

93 (71-131)

0.692

Urea – median (IQR)

5.8 (4.8-8.4)

7.9 (5.8-12.4)

0.011

CRP – median (IQR)

33 (15-117)

60 (9-133)

0.919

Blood culture

29 (42.0%)

18 (58.1%)

Pathology Haemoglobin

Eron Classification

0.415

Class I

10 (14.5%)

2 (6.5%)

Class II

55 (79.7%)

26 (83.9%)

Class III

4 (5.8%)

3 (9.7%)

Class IV

0

0

BP blood pressure; CRP C reactive protein.

0.071

Table 3. Treatment, Complications and Outcomes Age < 75 years (N=69) Age 75+ years (N=31) Characteristics

P-value

Completed treatment via HiTH

41 (59.4%)

10 (32.3%)

0.012

Duration of IV antibiotic – median (IQR)

6 (4-8)

4 (2-9)

0.059

Length of hospital stay – median (IQR)

8 (6-13)

10 (7-15)

0.403

Antibiotics

0.121

Cephazolin

47 (51.1%)

16 (32.7%)

Flucloxacillin

20 (21.7%)

12 (24.5%)

7 (7.6%)

4 (8.2%)

DVT

0

0

1

PE

0

1 (3%)

0.31

11 (15.9%)

12 (38.7%)

0.020

Nosocomial infection

1 (1.4%)

3 (9.7%)

0.087

Delirium

1 (1.4%)

2 (6.5%)

0.23

Death

1 (1.4%)

1 (3.0%)

0.531

Needing surgical intervention

3 (4.3%)

2 (6.5%)

0.644

0

0

1

4 (5.8%)

0

0.308

Duration of IV antibiotic – median (IQR)

6 (4-8)

4 (2-9)

0.059

Length of hospital stay – median (IQR)

8 (6-13)

10 (7-15)

0.403

Tazobactam-piperacillin Complications

Fall or decreased mobility

Outcomes

ICU admission Readmission within 28 days

Antibiotics

0.121

Cephazolin

47 (51.1%)

16 (32.7%)

Flucloxacillin

20 (21.7%)

12 (24.5%)

HiTH hospital in the home; DVT deep vein thrombosis; PE pulmonary embolism

CELLULITIS IN OLDER PEOPLE OVER 75 YEARS – ARE THERE DIFFERENCES? 1 To examine differences in risk factors, clinical features and outcomes of cellulitis between those 75+ years and those < 75 years admitted to a metropolitan hospital. 2 A prospective study of patients with limb cellulitis requiring intravenous antibiotics conducted at Bankstown-Lidcombe Hospital, Australia from June 2014 to April 2015. 3 Thirty-one (31.0%) patients were aged 75 years and older and 69 (69.0%) patients were 74 years or less 4 In this study, we found that older people, despite being frailer than their younger counterparts, had similar treatment outcomes after presenting to hospital with mild to moderate limb cellulitis. 5 There were no significant differences in the clinical presentation of cellulitis between the two age groups (i.e., duration of cellulitis symptoms, heart rate, blood pressure, temperature, white cell count, CRP and Eron severity classification) 6 In our study, older patients experienced more falls and impaired mobility during the admission for cellulitis compared to younger patients. While these factors might have made their hospital discharge planning more complex, they did not translate into an increased hospital length of stay.

The STROCSS Guideline Item

Item description

no. 1

2a 2b

2c 2d 3

Page Number

Title. The words “cohort” and the area of focus should appear in the title (e.g. disease, exposure/intervention or outcome). Whether the study is retrospective or prospective should also be stated. Abstract - Introduction What is the background and scientific rationale for the research question. Abstract - Methods - Describe the study design (cohort design, retrospective or prospective, single or multi-centre, etc), what was done to each group, how, when was it done and by whom. Abstract - Results What was found. Give the results for the main outcomes. Abstract - Conclusion - What have we learned and what does it mean. Where should future research go. Explain the scientific background and rationale for the cohort study. What

2

1 1

1 1 3

are objectives, research questions and the hypotheses. 4a

4b

4c

5a 5b

5c 5d 6a

6b 6c

7a

Registration and ethics State the research registry number in accordance with the declaration of Helsinki - "Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject" (this can be obtained from; ResearchRegistry.com or ClinicalTrials.gov or ISRCTN). Even retrospective studies should be registered prior to submission. Ethical Approval - State whether ethical approval was needed and if so, what the relevant judgement reference from the IRB or local ethics committee was? If ethical approval was not needed, state why. Protocol - Was a research protocol developed apriori? Where can it be accessed. Was it published in a journal e.g. IJS Protocols, BMJ Open, etc, if so, provide the reference. Study design - State the research is a cohort study and whether prospective or retrospective in design, whether single or multi-centre. Setting - Describe the setting(s)and nature of the institution in which the patient was managed; academic, community or private practice setting? Location(s), and relevant dates, including periods of recruitment, exposure, follow-up, and data collection Cohort Groups - State the number of groups in the study. What interventions will each group receive? Sub-group – Analysis. Any planned sub-group analyses are specified / Describe any methods used to examine subgroups and interactions. Participants - State any eligibility (inclusion/exclusion) criteria and the sources and methods of selection of participants. Describe length and methods of follow-up. Recruitment - State the methods of how patients or participants were recruited to each group, over what time periods. Sample size calculation Whether there was calculation of margin of error or a prior analysis to determine study population, or mention of how appropriate study sample was determined. Pre-intervention considerations - e.g. Patient optimisation: measures taken prior to surgery or other intervention e.g. treating hypothermia/hypovolaemia/hypotension in burns patients, ICU care for

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3 3

3 4,5 4,5

4,5 4,5

NA

7b

7c

7d

7e

7f

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10b

10c

11a

sepsis, dealing with anticoagulation/other medications and so on. Types of intervention(s) deployed - To include reasoning behind treatment offered (pharmacological, surgical, physiotherapy, psychological, preventive) and concurrent treatments (antibiotics, analgesia, anti-emetics, nil by mouth, VTE prophylaxis, etc). Medical devices should have manufacturer and model specifically mentioned. Peri-intervention considerations - Administration of intervention (what, where, when and how was it done, including details for surgery; anaesthesia, patient position, use of tourniquet and other relevant equipment, preparation used, sutures, devices, surgical stage (1 or 2 stage, etc) and operative time. Pharmacological therapies should include formulation, dosage, strength, route and duration). Authors are encouraged to use figures, diagrams, photos, video and other multimedia to explain their intervention. Who performed the procedure(s) - Operator experience for each group (position on the learning curve for the technique if established, specialisation and prior relevant training). Quality control - What measures were taken to reduce inter or intraoperator variation. What measures were taken to ensure quality and consistency in the delivery of the intervention e.g. independent observers, lymph node counts, etc

Post-intervention considerations - e.g. post-operative instructions and place of care. Important follow-up measures - diagnostic and other test results. Future surveillance requirements - e.g. imaging surveillance of endovascular aneurysm repair (EVAR) or clinical exam/ultrasound of regional lymph nodes for skin cancer. Outcomes - What primary and secondary (if any) outcomes will be assessed and how are they defined. Definitions should be clear and precise. Appropriate references to validation of outcome measures used should be provided if they exist. Statistical methods Clearly outlined statistical tests used to compare the outcomes between an intervention group and a comparison group, state whether preexisting differences and known confounders were controlled. The statistical package used should be mentioned. Participants recruited with a flow diagram - Report numbers involved in each group and use a flow diagram to show recruitment, nonparticipation, cross-over, withdrawal from the study with reasons. Comparison between groups including a table - Provide a table comparing the demographic, clinical/prognostic features (co-morbidities, tumour staging, smoking status, etc) and relevant socioeconomic characteristics of each group and whether numerical differences are significant (using p-values and/or confidence intervals as appropriate). Were the groups matched and if so, how. Changes - Any changes in the interventions during the course of the study (how has it evolved, been altered or tinkered with, what learning occurred, etc) together with rationale and a diagram if appropriate. Degree of novelty for a surgical technique/device should be mentioned and a comment on learning curves should be made for new techniques/devices. Outcomes and follow-up - Clinician assessed and patient-reported outcomes (when appropriate) should be stated for each group (size of

NA

NA

NA

NA

NA

4,5

3

Table 1,2,3

5

5,6,7

11b

11c

12 13

effect with raw numbers and percentages) with inclusion of the time periods at which assessed. Relevant photographs/radiological images should be provided e.g. 12-month follow-up.Make it clear which confounders were adjusted for and which were not. Intervention adherence/compliance and tolerability - How was this assessed. Describe loss to follow-up (express as a percentage and a fraction) or cross-over between group and any explanations for them. Complications and adverse or unanticipated events - Described in detail and ideally categorised in accordance with the Clavien-Dindo Classification. How they were prevented, mitigated, diagnosed and managed. Blood loss, wound complications, re-exploration/revision surgery, 30-day post-op and long-term morbidity/mortality may need to be specified. Summarise key results

5,6,7

NA

7

Discussion of the relevance of the findings and rationale for conclusions Relevant literature, implications for clinical practice guidelines, how have the indications for a new technique/device been refined and how do outcomes compare with established therapies and the prevailing gold standard should one exist and any relevant hypothesis generation. The rationale for any conclusions. Strengths and limitations of the study

7

7

17a

State what needs to be done next, further research with what study design(s). State the key conclusions from the study and key directions for future research State any conflicts of interest

17b

State any sources of funding

7

14 15 16

7

7 7

Annals of Medicine and Surgery The following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated. Please state any conflicts of interest All authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.

No conflict of interest from any of the authors

Please state any sources of funding for your research All sources of funding should be declared as an acknowledgement at the end of the text. Authors should declare the role of study sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. If the study sponsors had no such involvement, the authors should so state.

No funding was obtained for the research

Ethical Approval Research studies involving patients require ethical approval. Please state whether approval has been given, name the relevant ethics committee and the state the reference number for their judgement. Ethics approval was taken from South-Western Sydney Local Health District (SWSLHD) Ethics Committee

Consent Studies on patients or volunteers require ethics committee approval and fully informed written consent which should be documented in the paper. Authors must obtain written and signed consent to publish a case report from the patient (or, where applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the submission process that such consent has been obtained, and the manuscript must include a statement to this effect in a consent section at the end of the manuscript, as follows: "Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request”. Patients have a right to privacy. Patients’ and volunteers' names, initials, or hospital numbers should not be used. Images of patients or volunteers should not be used unless the information is essential for scientific purposes and explicit permission has been given as part of the consent. If such consent is made subject to any conditions, the Editor in Chief must be made aware of all such conditions. Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.

All authors have consented to publication

Author contribution Please specify the contribution of each author to the paper, eg study concept or design, data collection, data analysis or interpretation, writing the paper, others, who have contributed in other ways should be listed as contributors.

Bin Soo Ong – Supervisor ,study concept Manoj Kumar-Wrting the paper Huong Van Nguyen-writing the paper Clarence Yeong-Data collection Vincent Ngian- data analysis ,study concept Caitlin Keighley- study concept ,data collection

Registration of Research Studies In accordance with the Declaration of Helsinki 2013, all research involving human participants has to be registered in a publicly accessible database. Please enter the name of the registry and the unique identifying number (UIN) of your study. You can register any type of research at http://www.researchregistry.com to obtain your UIN if you have not already registered. This is mandatory for human studies only. Trials and certain observational research can also be registered elsewhere such as: ClinicalTrials.gov or ISRCTN or numerous other registries.

1.

Name of the registry: Research Registry

2.

Unique Identifying number or registration ID: researchregistry5125

3.

Hyperlink to the registration (must be publicly accessible): https://www.researchregistry.com/browse-theregistry#home/registrationdetails/5d7a4d440ba5620010271dc1/

Guarantor

The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish

Dr Manoj Kumar