Addition of Pre-wound Closure Povidone Iodine Wash Versus Direct Wound Closure Effect on Surgical Site Infections: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Surgical Site Infection, Surgical Wound Infection
Sponsor: Ain Shams University

1 
 
  
 
 
Title 
 
 
 
Addition of pre-wound closure povidone iodine wash versus direct 
wound closure effect on surgical site infections: A randomized 
controlled trial 
 
 
NCT Number: Not Yet assigned  
 
Date: 11th of September, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
 
Background 
 
Surgical site infections are post-operative infections of the incision or organ or space that was included in 
the surgical field [1]. Incisional surgical site infections (SSIs) are a growing healthcare challenge [2]. 
Currently, up to 10% of surgical procedures may be complicated by an SSI [3]. Not only do SSIs lead to 
worse patient outcomes, but they also account for a large proportion of healthcare expenditure [4-6]. In 
the United Kingdom alone, SSIs are estimated to cost the National Health Service 1 billion pounds 
annually [7]. The problem is further compounded in low- and middle-income countries (LMICs) where 
the prevalence of antibiotic-resistant infections is increasing, and national healthcare budgets are strained 
[8]. In fact, SSIs are estimated to account for additional costs of up to $30,000 in LMICs [9].  
 
The global crisis of drug-resistant bacteria has further highlighted the need for more effective 
perioperative preventive strategies to minimize healthcare-associated resistant infections [10,11]. Optimal 
surgical antisepsis is critical in reducing the incidence of SSIs, and therefore in reducing the use of post-
operative antibiotics [12,13]. Recently, there has been a renewed interest in using povidone-iodine (PVI) 
intraoperative wound irrigation to achieve this goal. The choice of PVI is especially suitable for LMICs 
where the availability of chlorhexidine preparations may be limited by scarce resources [14].  
 
A possible adjunctive role of pre-wound closure PVI irrigation in reducing incisional SSIs is still unclear 
[15,16]. A meta-analysis by López-Cano et al. analyzed data of 7,601 patients and found a reduction in 
overall SSI rate. However, the heterogeneity and uncertain quality of most studies limited the synthesis of 
conclusive evidence [17]. The possible benefits of irrigating the surface of an open incision include local 
antimicrobial effect, physical removal of debris and dilution of contamination. Recent guidelines have all 
emphasized the lack of sufficient evidence on intraoperative use of PVI [18-21]. 
 
We aim to conduct a randomized controlled trial in Ain Shams University Hospitals to compare the effect 
of adding PVI wash prior to skin closure to direct wound closure on reducing the rates of SSIs. 
 
 
Study Objective 
To assess the efficacy of povidone-iodine wash before wound closure in preventing surgical site 
infections. 
 
 
Trial Design 
Superiority, parallel group randomized controlled trial, allocation 1:1 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
 
Methods 
 
Study Setting 
Operative theatres at Ain Shams University Hospitals  
 
 
Inclusion Criteria 
o Adult patients (≥ 18 years old) 
o Open and minimally invasive surgeries 
o Emergency (any unplanned admission)  and elective (planned admission) surgical procedures 
o Clean, Clean-Contaminated, Contaminated, Dirty wounds [22], (See appendix 1)  
o Inclusion surgery list according to Current Procedural Terminology (CPT) National 
Healthcare Safety Network (NHSN) operative procedure code mapping [23] , List of 
included surgical procedures (See appendix 2) 
 
 
Exclusion Criteria 
o Povidone-iodine allergy 
o Surgeries for infected wounds.  
o Exclusion surgery list according to Current Procedural Terminology (CPT) National 
Healthcare Safety Network (NHSN) operative procedure code mapping, [23] List of 
excluded surgical procedures, (See appendix 3) 
 
 
Intervention 
o 10% povidone iodine wound wash before wound closure versus direct wound closure. 
o Antibiotic prophylaxis will be administered according to local protocols.  
o Wound dressing type and frequency will not differ between both groups.  
o Diagnosed SSIs will be managed according to local antibiograms and management guidelines. 
  
 
 Outcomes 
• 
Primary: Incidence of superficial and deep surgical site infection (SSI) within 30 days 
postoperatively 
 
• 
Secondary:  
1. Post-operative morbidity and mortality by (Clavien-Dindo classification system) [24], (See 
appendix 4) 
2. Length of hospital stay 
3. Readmission and Reoperations related to surgical site infection  
4. Infectious complications (Sepsis, septic shock, multiple-organ dysfunction syndrome, wound 
dehiscence) [25-28] 
5. Microbiology culture and sensitivity results 
6. Local adverse events for povidone-iodine application (Local irritation, poor wound healing) 
7. Cost-analysis 
 
 
 

4 
 
 
Participant Timeline 
Recruitment will start from day (18/09/2021) till sample size is reached.  
 
Patients will be introduced to and asked to participate in the trial when they arrive to the surgical ward or 
emergency department by the surgical resident. They will not be subjected to any additional steps other 
than the standard hospital protocols as our trial begins in the operating room where patients will be 
randomly allocated into 2 groups: the control group (direct wound closure) and the intervention group 
(PVI wound wash before closure).    
 
After the operation, patients will be monitored and observed at the hospital by the staff until discharge 
and will be given a specialized follow-up card. Following discharge, follow-up will be in the form of 
fixed outpatient clinic visit after the first week postoperatively and continue with phone calls made at 
regular 1-week intervals inquiring about symptoms and signs of SSI based on a questionnaire guided by 
the CDC definitions [27]. If a patient displays ≥1 symptom listed in the CDC checklist (See appendix 5), 
he/she will be invited to follow-up in our outpatient clinic and will be identified by their card. This will 
allow the physician to fill out the data collection form in their files and obtain a picture for documentation 
purposes. Follow-up will continue for a period of 30 days. 
 
 
Sample Size 
Using PASSII program for sample size calculation and assuming SSI incidence of 10% in control group 
and 5% in intervention group, setting power at 80% and α-error at 0.05, sample size of 345 patient for 
each group will be needed. We plan to enroll an additional 10% of the calculated sample size for each 
group in anticipation of a loss to follow-up rate of 10%. The total sample size will be 760 patients. 
 
Assignment of Interventions 
 
Sequence Generation 
A statistician not directly involved in the study or analysis will prepare a computer-generated 
randomization sequence. No blocking will be used. The sequence will be provided to the trialists 
in the form of serially numbered opaque envelopes containing details of either the intervention or 
the control and a random identifier. 
 
Enrolment and Allocation Concealment 
The patients will be enrolled by the resident doctors and given a study ID number. 
 
The allocation sequence will be made available to the OR head nurse in the form of sealed 
envelopes. The head nurse will provide the surgeons with closed opaque envelopes which will be 
opened by the nurse directly before wound closure. The head nurse will ensure that the envelopes 
are opened at wound closure and not before it. After the intervention/control is carried out, the 
random identifier will be noted down in the patient’s operative data collection form. Following 
that, the nurse will tear the envelope and its contents.   
 
Blinding 
The patients and outcome assessors will be blinded. The details of which intervention was used 
will not be recorded in the regular patient records. The surgeons will be blinded till directly 
before wound closure, however, because of the nature of intervention, complete blinding of the 
surgeons would be impossible. 
 
 

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Data Collection Methods 
Preoperative data collection will aim to collect baseline data about the recruited patients: patient 
identifiers, age, BMI, comorbidities including hypertension, diabetes, CKD, chronic liver disease, chronic 
heart failure, as well as any documented medication use and ASA score; through a standardized data 
collection form. All patients will be monitored by the doctors who will be responsible for filling their 
follow-up data till 30 days postoperatively (See appendix 6 for data collection forms).    
 
Teams of four (surgeons or medical students) will be recruited to collect data from included surgical 
departments, each team collecting information over a two-week interval from all patients undergoing 
included surgical procedures in the department. Teams will then follow up with patients recruited in this 
allowed interval over the 30-day follow-up period, according to the methods described above.     
 
We will obtain written informed consent from participants before surgery explaining the study procedures 
and the follow-up plans. All those who volunteer will be followed up in our clinics and provided carefree-
of-cost.  
 
 
Data Management 
Package: R (latest available version) 
 
Methods: Descriptive statistics will be presented as mean ± SD for quantitative data. If the data is 
severely skewed/not normally distributed, median and IQR will be used. N & percentile will be used for 
qualitative data. Relevant statistical tests will be reported when applicable. 
 
Statistical Methods 
Suitable statistical tests will be used for data analysis. 
 
The study participants will be divided into 4 groups (Clean, Clean-contaminate, Contaminated, Dirty). 
Each group will be stratified and analyzed separately. 
Subgroup analyses will also be performed according to the type of surgical access (open versus minimally 
invasive), and the presence or absence of Diabetes.  
The need for additional subgroup analyses will be determined at the time of completion of data collection. 
Both per-protocol and intention to treat analyses will be used and their findings will be reported. 
 
Monitoring  
The study will not employ a data monitoring committee (DMC) as the trial is conducted on an adult 
population with no perceived risk to either arm of the trial. 
 
Interim analysis will be done on reaching 50% of the total sample size by an independent statistician 
blinded for the intervention allocation. The unblinded data will be reported to the Ain Shams Surgical 
Research Group. The primary purpose of this analysis would be to determine if the study should be 
prematurely terminated in the case of patient harm. The final decision on the matter will reside with the 
Ain Shams Surgical Research Group and the study’s principal investigators. 
 
In our study an adverse event will be defined as any medical occurrence in a subject with a probable 
causal relation to the intervention.  
 
Adverse events will be collected after the subject has provided consent and enrolled in the study. 
The known as well as novel adverse effects of the study intervention (povidone iodine) will be 
investigated and recorded until the period of patient follow up is completed. 
 

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Ethics and Dissemination  
 
Ethical Approval 
This protocol, the template informed consent forms (Arabic and English versions), and any subsequent 
modifications will be reviewed and approved by the applicable IRB [institutional review board] with 
respect to scientific content and compliance with applicable research and human subjects’ regulations 
prior to starting the study. 
 
 
Protocol Amendments 
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the 
patient or may affect patient safety, including changes of study objectives, study design, patient 
population, sample sizes, study procedures, or significant administrative aspects will require a formal 
amendment to the protocol. Such amendments will be reviewed and approved by the IRB prior to 
implementation in accordance with local regulations. 
 
Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on 
the way the study is to be conducted will be agreed upon by the principal investigators and documented. 
 
 
Informed Consent and Participant Rights 
Surgical residents will introduce and discuss the trial to patients answering all questions and/or concerns 
they might have. Patients will then be able to have an informed discussion with the participating 
consultant. Surgical residents will then obtain written consent from patients willing to participate in the 
trial. Consent forms are provided for all patients involved in the trial in Arabic or English language. 
 
The informed consent will be a tiered consent. Participants will be given the option to consent for the use 
of their data in current protocols or for future ancillary research unrelated to the clinical condition under 
study as well. 
 
All participants will also be given a special follow up card. Any complications, if present, will be treated 
at the Ain Shams University Hospitals at no additional cost.  
 
 
Healthcare-Information Security and Privacy 
All study-related information will be stored securely at the study site. All participant information will be 
stored in locked file cabinets in areas with limited access. All data collection, process, and administrative 
forms will be identified by a coded ID [identification] number only to maintain participant confidentiality. 
All records that contain names or other personal identifiers, such as locator forms and informed consent 
forms, will be stored separately from study records identified by code number. All local databases will be 
secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any 
other listings that link participant ID numbers to other identifying information will be stored in a separate, 
locked file in an area with limited access. 
 
The Ain Shams Surgical Research Group will oversee the data storing process. All Principal Investigators 
will be given access to the cleaned data sets. All data sets will be password protected. To ensure 
confidentiality, data dispersed to project team members will be blinded of any identifying participant 
information. 
 
 

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Conflicts of Interest 
All principal and team investigators declare no conflict of interest. 
 
 
Publication Policy 
The primary and secondary outcome papers of the trial are expected to be published in the relevant 
journals regardless of the trial results. The selection of the journal will be decided by the Ain Shams 
Surgical Research Group. All papers and abstracts stemming from this trial must be approved by the Ain 
Shams Surgical Research Group before they are submitted. The study results will be released to the 
participating physicians, medical students, patients and to the general medical community. 
 
 
Authorship 
Each participant will be recognized on any resulting publications as PubMed-citable co-authors. A 
corporate authorship model will be used. 
 
The study protocol will be publicly available after submission to the clinicaltrails.gov website.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

8 
 
References 
 
1. National Healthcare Safety Network, Centers for Disease Control and Prevention. Surgical site 
infection (SSI) event. http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf. Published January 
2021. Accessed February 10, 2021. 
2. Owens CD, Stoessel K. Surgical site infections: epidemiology, microbiology and prevention. J Hosp 
Infect. 2008;70 Suppl 2:3-10. doi:10.1016/S0195-6701(08)60017-1 
3. European Centre for Disease Prevention and Control. Annual Epidemiological Report 2016 – 
Surgical site infections. [Internet]. Stockholm: ECDC; 2016 [cited 2021 January 31]. 
4. Awad SS. Adherence to surgical care improvement project measures and post-operative surgical site 
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5. Centers for Disease Control and Prevention. The direct medical costs of healthcare-associated 
infections in U.S. hospitals and the benefits of prevention. 
http://www.cdc.gov/hai/pdfs/hai/scott_costpaper.pdf. Published 2009. Accessed February 10, 2021. 
6. Badia JM, Casey AL, Petrosillo N, Hudson PM, Mitchell SA, Crosby C. Impact of surgical site 
infection on healthcare costs and patient outcomes: a systematic review in six European countries. J 
Hosp Infect. 2017;96(1):1-15. doi:10.1016/j.jhin.2017.03.004 
7. Nosocomial Infection National Surveillance Service (NINSS). Surgical site infection in English 
hospitals: a national surveillance and quality improvement program. Public Health Laboratory 
Service. 2002. 
8. GlobalSurg Collaborative. Surgical site infection after gastrointestinal surgery in high-income, 
middle-income, and low-income countries: a prospective, international, multicentre cohort study. 
Lancet Infect Dis. 2018;18(5):516-525. doi:10.1016/S1473-3099(18)30101-4 
9. Monahan M, Jowett S, Pinkney T, et al. Surgical site infection and costs in low- and middle-income 
countries: A systematic review of the economic burden. PLoS One. 2020;15(6):e0232960. Published 
2020 Jun 4. doi:10.1371/journal.pone.0232960 
10. Spellberg B, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: a call to action 
for the medical community from the Infectious Diseases Society of America. Clin Infect Dis. 
2008;46(2):155-164. doi:10.1086/524891 
11. Ventola CL. The antibiotic resistance crisis: part 2: management strategies and new agents. P T. 
2015;40(5):344-352. 
12. Dohmen PM. Antibiotic resistance in common pathogens reinforces the need to minimise surgical site 
infections. J Hosp Infect. 2008;70 Suppl 2:15-20. doi:10.1016/S0195-6701(08)60019-5 
13. Roberts CD, Leaper DJ, Assadian O. The Role of Topical Antiseptic Agents Within Antimicrobial 
Stewardship Strategies for Prevention and Treatment of Surgical Site and Chronic Open Wound 
Infection. Adv Wound Care (New Rochelle). 2017;6(2):63-71. doi:10.1089/wound.2016.0701 
14. Lee I, Agarwal RK, Lee BY, Fishman NO, Umscheid CA. Systematic review and cost analysis 
comparing use of chlorhexidine with use of iodine for preoperative skin antisepsis to prevent surgical 
site infection. Infect Control Hosp Epidemiol. 2010;31(12):1219-1229. doi:10.1086/657134 
15. Norman  G, Atkinson  RA, Smith  TA, Rowlands  C, Rithalia  AD, Crosbie  EJ, Dumville  JC. 
Intracavity lavage and wound irrigation for prevention of surgical site infection. Cochrane Database 
of Systematic Reviews 2017, Issue 10. Art. No.: CD012234. DOI: 
10.1002/14651858.CD012234.pub2. Accessed 31 January 2021. 

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16. Fournel I, Tiv M, Soulias M, Hua C, Astruc K, Aho Glélé LS. Meta-analysis of intraoperative 
povidone-iodine application to prevent surgical-site infection. Br J Surg. 2010;97(11):1603-1613. 
doi:10.1002/bjs.7212 
17. López-Cano M, Kraft M, Curell A, et al. A Meta-analysis of Prophylaxis of Surgical Site Infections 
with Topical Application of Povidone Iodine Before Primary Closure. World J Surg. 2019;43(2):374-
384. doi:10.1007/s00268-018-4798-0 
18. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention 
Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784–791. 
doi:10.1001/jamasurg.2017.0904 
19. National Institute for Health Research Global Research Health Unit on Global Surgery. Delphi 
prioritization and development of global surgery guidelines for the prevention of surgical-site 
infection. Br J Surg. 2020;107(8):970-977. doi:10.1002/bjs.11530 
20. National Institute for Health and Care Excellence (2008) Surgical site infection: prevention and 
treatment of surgical site infection. Clinical guideline 74. London: National Institute for Health and 
Care Excellence. https://www.nice.org.uk/guidance/cg74. Accessed Feb 2021 
21. Allegranzi B, Zayed B, Bischoff P, et al. New WHO recommendations on intraoperative and 
postoperative measures for surgical site infection prevention: an evidence-based global perspective. 
Lancet Infect Dis. 2016;16(12):e288-e303. doi:10.1016/S1473-3099(16)30402-9 
22. Onyekwelu I, Yakkanti R, Protzer L, Pinkston CM, Tucker C, Seligson D. Surgical Wound 
Classification and Surgical Site Infections in the Orthopaedic Patient. J Am Acad Orthop Surg Glob 
Res Rev. 2017;1(3):e022. Published 2017 Jun 13. doi:10.5435/JAAOSGlobal-D-17-00022 
23. https://www.cdc.gov/nhsn/xls/cpt-pcm-nhsn.xlsx 
24. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with 
evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. 
doi: 10.1097/01.sla.0000133083.54934.ae. PMID: 15273542; PMCID: PMC1360123. 
25. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for 
Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 
26. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for 
Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. 
doi:10.1007/s00134-017-4683-6 
27. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ 
dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638. 
28. Rosen RD, Manna B. Wound Dehiscence. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure 
Island (FL): StatPearls Publishing; 2021 Jan-. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK551712/  
 
 
 
 
 
 
 
 
 
 

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Appendices: 
(1)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

11 
 
Algorithm for wound classification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

12 
 
(2) Included surgeries  
1. Vascular surgeries 
a) Abdominal aortic aneurysm repair (Resection of abdominal aorta with anastomosis or 
replacement) 
b) Limb amputation (Total or partial amputation or disarticulation of the upper or lower 
limbs, including digits) 
c) Shunt for dialysis 
d) Carotid endarterectomy (Thromboendarterectomy, including patch graft, Reoperation, 
carotid, thromboendarterectomy, more than 1 month after original operation)  
 
2. Hepatobiliary surgeries   
a) Bile duct, liver, and pancreatic surgery (Excision of bile ducts or operative 
procedures on the biliary tract, liver, or pancreas) 
b) Gallbladder surgery (Cholecystectomy and cholecystostomy) 
c) Liver transplant 
 
3. Gastrointestinal surgeries 
a) Appendectomy 
b) Intestinal resection and anastomosis 
c) Segmental colectomies (Incision, resection, or anastomosis of the large intestine; includes 
large-to-small and small-to-large bowel anastomosis)  
d) Bariatric procedures 
e) Gastric surgery (Incision or excision of stomach; includes subtotal or total 
gastrectomy)  
f) Spleen surgery 
g) Rectal surgery 
 
4. Exploratory laparotomy (abdominal operations not involving the gastrointestinal tract or 
biliary system; includes diaphragmatic hernia repair through abdominal approach) 
 
5. Neck surgeries  
a) Thyroid and/or parathyroid surgery 
b) Sialoadenectomy  
c) Major excision or incision of the larynx and radical neck dissection 
6. Thoracic surgeries  
a) Heart transplant 
7. Neurosurgery  
a) Laminectomy (Exploration or decompression of spinal cord through excision or 
incision into vertebral structures) 
8. Urological surgeries 
a) Kidney transplant 
b) Kidney surgery (Resection or manipulation of the kidney with or without removal of 
related structures) 
c) Prostate surgery (Suprapubic, retropubic, radical, or perineal excision of the prostate; 
does not include transurethral resection of the prostate) 
 

13 
 
9. OB&GYN 
a) Cesarean section 
b) Abdominal hysterectomy 
c) Ovarian surgery 
d) Vaginal hysterectomy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

14 
 
 (3) Excluded surgeries  
1. Anal surgeries 
2. Surgery for infected wounds 
a. Debridement for necrotizing fasciitis 
b. Laparotomy for intra-abdominal abscess 
3. Breast surgery 
Excision of lesion or tissue of breast including: 
a) Radical, Modified, or Quadrant resection. 
b) Lumpectomy. 
c) Incisional biopsy. 
d) Mammoplasty 
4. Cardiac surgery 
• Procedures on the heart; includes valves or septum 
5. Coronary artery bypass graft with both chest and donor site incisions 
6. Coronary artery bypass graft with chest incision only 
7. Pacemaker surgery 
8. Craniotomy 
• Excision, repair or exploration of the brain or meninges 
9. Spinal fusion 
• Spinal fusion or refusion - Immobilization of spinal column 
10. Open reduction of fracture 
• Open reduction of fracture or dislocation of long bones with our without internal or 
external fixation 
11. Herniorrhaphy 
• Repair of inguinal, femoral, umbilical, or anterior abdominal wall hernia 
12. Hip prosthesis 
13. Knee prosthesis 
14. Peripheral vascular bypass surgery 
15. Ventricular shunt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

15 
 
(4) Clavien-Dindo classification system:    
 
Grades 
Definition 
Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological interventions 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgesics, 
diuretics and electrolytes and physiotherapy. This grade also includes wound 
infections opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for 
grade I complications. 
Blood transfusions and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic, or radiological intervention 
       - IIIa Intervention not under general anesthesia 
       - IIIb Intervention under general anesthesia 
Grade IV Life-threatening complication (including CNS complications) * requiring 
IC/ICU-management 
       - IVa Single organ dysfunction (including dialysis) 
       - IVb Multiorgan dysfunction 
Grade V 
Death of a patient 
 
 
 
 
 
 
 
 
 
 
 

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(5) Outpatient clinic follow-up form:

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(6) Data collection form:  
 
 
 
 

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