Postoperative Glycemic Control and the Surgical Site Infection Incidence Among Liver Transplantation Recipients: Randomized Clinical Trial
Phase: NA
Conditions: Liver Transplantation, Surgical Wound Infection
Sponsor: Ramon Oliveira

 
1 
POSTOPERATIVE GLYCAEMIC CONTROL AND THE SURGICAL SITE INFECTION 
INCIDENCE AMONG LIVER TRANSPLANTATION RECIPIENTS: RANDOMIZED 
CLINICAL TRIAL 
 
 
Date: March 13th, 2018. 
Version: 1 
 
Author: 
Ramon Antonio Oliveira,  
Sao Paulo Registered Nurses Board: Number 265.476 
RN, MSc, PhD Candidate at University of São Paulo School of Nursing. 
Graduate Program in Adult Health Nursing.  
419, Dr. Eneias de Carvalho Aguiar, Av. Cerqueira César - São Paulo - SP, Brazil. 
E-mail: ramon.oliveira@usp.br 
Phone: +5511987001434 
 
 
 

 
2 
POSTOPERATIVE GLYCAEMIC CONTROL AND THE SURGICAL SITE INFECTION 
INCIDENCE AMONG LIVER TRANSPLANTATION RECIPIENTS: RANDOMIZED 
CLINICAL TRIAL 
 
 
ABSTRACT 
Context: The hyperglycemia is an important independent risk factor for the Surgical Site Infection 
(SSI) development among liver transplantation recipients. Objective: To evaluate the effects of an 
intensive postoperative protocol of blood glucose management on the surgical site infection 
incidence among liver transplantation recipients. Material and methods: It is an open-label clinical 
trial that will be randomized into 2 groups of blood glucose (BG) control: patients will undergo BG 
control regular in the facility chosen to research development (BG targeted 130-180 mg/dL) and the 
second one will undergo intensive BG control (BG targeted 80 - 130 mg/dL) until patients are 
eating at least 50% of a full liquid diet or receiving bolus tube feedings. A computer program will 
be employed to generate the randomized schedule that will be put into sequentially numbered 
opaque sealed envelopes by an external expert to research. A finger prick device will be used to 
measure the blood glucose. A blinded adjudication committee to analyse the primary endpoint SSI 
will adopt the SSI criteria given by the Centers for Disease Control and Prevention. The research 
proposal will be registered on ClinicalTrials.gov database. Central tendency and dispersion 
measures, Pearson's χ2 test, Fisher's Exact Test, Mann-Whitney, Wilcoxon-Mann-Whitney and 
survival analysis by Kaplan-Meier estimated and Log-rank test will be used for data analyses. 
Expected outcomes: The results of the study should contribute to establishing better clinical 
practices on glycemic control in the liver transplantation recipient’s postoperative period aiming to 
reduce SSI incidence and its associated morbidity and mortality. 
 
 
Descriptors: Glycemia. Surgical Wound Infection. Liver Transplantation. Perioperative Nursing. 
 
 

 
3 
1 INTRODUCTION 
 
The Surgical Site Infections (SSI's) are the most frequent healthcare-associated infections 
and are an important infectious complication in the postoperative period among liver transplantation 
(LT) recipients (1-3). SSI incidence among LT recipients, whose allografts were from deceased 
donors, varied from 9.6% to 35.5% according to a recent literature review(4). In general surgical 
procedures, SSI increases the length of stay, morbidity and healthcare costs. Besides that, among 
LT recipients SSI can raise the risks of the allografts dysfunctions, acute rejections and as a 
consequence a reduction in the recipient’s survival(5-7). 
 
There are several risk factors for SSI among LT recipients. There is a relationship among 
supply sterilization quality, the characteristics of surgical procedure, the operation room 
environment as well as the allograft's and recipient's conditions and SSI occurrence(8-12). In regard 
to LT recipients, results from previous research highlighted hyperglycemia as an important 
independent predictor of SSI. Furthermore, regarding this population, it is known from 
observational studies that LT recipients affected by hyperglycemia are exposed, approximately, to 
three times the risk of SSI comparatively to LT recipients not exposed(13-16). 
 
The concern about maintaining normoglycaemia in acute care facilities is not recent; several 
studies have been done including on clinical and surgical patients from some medical specialities 
showing the morbidity and mortality reduction throughout the adoption of strict glycaemic control 
protocols (17-19). 
However, among critical surgical patients the LT recipients are highlighted; since they are 
exposed to impairment in blood glucose metabolism in the perioperative period as a consequence of 
an intraoperative acute stress state, blood loss and transfusions, the reperfusion phase, use of 
glucocorticoids and catecholamines(20, 21).  
Results from previous studies pointed the hyperglycaemia among LT recipient as a frequent 
complication, 94% of them presented it at least once in the transplantation’s postoperative period(22, 
23).  

 
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The high blood glucose levels can produce electrolyte and acid-base disturbances besides 
altered plasmatic distribution of sodium(24). There are impairments to the white blood cells 
activities, such as reduction in the adherence, chemotaxis, phagocytosis and superoxide formation.  
Lymphocytes apoptosis combined with T-cell activities suppression besides attenuation of 
immunoglobulin's work as a consequence of glycosylation(25, 26).  
In spite of evidence from laboratory studies that indicate remarkable impairments caused by 
hyperglycemia in immune model animals immunologic system, uncertainties remain to evaluate the 
glycaemic control as a strategy for SSI prevention. Analysing the guidelines to prevent SSI 
published by World Health Organization(27), Centers for Disease Control and Prevention (United 
States of America)(1), National Institute for Health and Care Excellence (United Kingdom)(28), 
Society for Healthcare Epidemiology of America (United States of America)(29) and Brazilian 
Health Regulatory Agency(30) conditional recommendation regard the adoption of strategies to strict 
glycaemic control in the postoperative phase, besides there is no consensus about how glycaemic 
level could work as a protective factor for SSI among patients who underwent general surgeries. 
Moreover, there have been few investigations evaluating the hyperglycaemia effects or 
blood glucose control in the postoperative phase of LT recipients(15, 16, 23, 31).  Besides the few 
studies concerned on the topic among LT recipients(14-16, 20, 23, 31), the majority of them were 
observational studies, designed as retrospective cohorts, which could compromise the body's 
evidence quality(14, 15, 20, 23, 31). Besides that, in the previous studies enrolled patients underwent 
liver-kidney transplantation(14-16,
 31), which can cause negative impact on the effects of glycemic 
control analyses and there is research where recipients presented lower means of Model for End-
Stage Liver Disease (MELD) from 19.0 to 28.2(14-16, 20, 23, 31) that are lower MELD means than the 
observed in Brazilian transplantation centres. Finally, we observed the absence of clear criteria for 
SSI diagnosis in some studies(15, 16, 20, 23). 
It is known that the preoperative screening in living donor LT of donors and recipients as 
baseline characteristics are different of LT whose allografts came from deceased donors; for 

 
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instance, liver-kidney recipients who undergo to distinct immunosuppression schemes. 
Furthermore, lower MELD scores represent LT recipients that could be exposed to diverse risk 
factors for SSI when compared to LT recipients who the MELD score is higher(32).  
Thus, it sounds appropriate that research aiming to evaluate the effect of strict blood glucose 
control on SSI incidence among LT recipients should be made. In addition, nurse-initiated blood 
glucose control protocols, among critically ill patients, are frequently developed(23, 33, 34). And, a 
recent literature review pointed to the lack of prospective studies that addressed the evaluation of 
the outcomes of strict glycaemic control among LT recipients on SSI incidence(21). 
The study hypothesis is: the postoperative strict glycaemic control reduces the SSI incidence 
among LT recipients. 
 
2 RESEARCH OBJECTIVE 
 
To evaluate the effects of a postoperative strict blood glucose control protocol 
comparatively to an institutional protocol on the SSI incidence among LT recipients.  
3 METHODS 
 
The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) were 
used to write this methods chapter(35). 
 
It is a randomized open-label clinical trial, in other words, the researchers will not try to 
blind the patients(36). Among the research designs, the randomized clinical trial stands out on the 
observational designs as a result of the greater capacity to demonstrate causality. It particularly 
stems from a random allocation process that could remove the possibility of effects observed being 
explained by differences between the use of co-interventions or by other bias in the outcomes 
analyses(37, 38). 
 
This study will be performed by two groups, the first one composed of LT recipients who 
undergo a standard blood glucose protocol, standardized in the facility selected to conduct this 
research. That protocol consists in a glucose control according to the result of finger prick test and 

 
6 
subcutaneous injection of regular insulin (BG targeted 130 - 180 mg/dL). The second group will be 
constituted of patients who undergo a strict blood glucose control (BG target 80 - 130 mg/dL) by a 
continuous intravenous insulin infusion. 
3.1 STUDY SETTING 
 The study will be conducted in a tertiary referral hospital, service provider for Brazilian 
Public Health System situated in the countryside of São Paulo State. It is an academic and research 
hospital licensed by Brazilian Ministry of Health to perform LT since 2009; 40 LT are done each 
year(39). 
3.2 ELIGIBILITY CRITERIA 
Patients eligible for the trial must be 18 years of age or older, recipients of LT whose 
allograft came from deceased donors. 
The patients that underwent any kind of surgery with or without prosthesis implant in the 30 
days before the LT or are submitted to multiple organ transplantation will be excluded from the 
trial. 
3.3 SAMPLE SIZE 
 
Based on previous studies that showed the reduction of any infection incidence among LT 
recipients the sample size was calculated on the basis of the primary hypothesis(16, 40). 58 patients 
are required to have an 80% chance of detecting, as significant at the 5% level, a decrease in the 
primary outcome measure from 40% in the control group to 10% in the experimental group. Thus, 
the sample calculation pointed will need 29 patients allocated in each group. 
3.4 SEQUENCE GENERATION AND CONCEALMENT 
  
Participants will be randomly assigned to either standard control or strict control with a 1:1 
allocation as a per computer-generated randomisation schedule; the procedure will be performed by 
an independent statistician.  
 
The randomization schedule will be put into sequentially numbered sealed opaque envelopes 
by an external expert to research. 

 
7 
3.5 RECRUITMENT 
 
All the candidates for LT or representatives, during the ambulatory pre-transplant evaluation 
in the facility selected to conduct the study, will be contacted by the to check the inclusion and 
exclusion criteria, as well to explain the possible risks and the benefits of participating in research 
following the consent form will be signed.  
3.6 ALLOCATION   
  
After the patients' acceptance in participating in the research, in the ICU admission, any 
bedside blood glucose reading equal or superior to 130 mg/dL in the first 24 hours of the 
postoperative period will determine the LT recipient's allocation in the study. The sealed opaque 
envelope will be opened by an independent Registered Nurse to allocate the participant in the 
standard blood glucose control group or strict blood glucose control group. 
3.7 INTERVENTIONS 
To implement the protocols of glycaemic control, the researcher has established, in an 
earlier study, a previous relationship with the surgeons and intensive care doctors(13). Consequently, 
there will be for each LT recipient a medical order of the randomised intervention. 
3.7.1 STRICT GLYCEMIC CONTROL GROUP 
The strict protocol adopted to conduct the study was proposed by Keegan e Cols.(23) (2010) 
to be used among adult LT recipients that consists of a continuous intravenous insulin infusion. The 
targeted blood glucose range is 80-130 mg/dL. The procedure must be stopped when the patient can 
ingest at least 50% of liquid diet or receive bolus tube feedings (Appendix A). 
3.8 STANDARD GLYCEMIC CONTROL GROUP 
The control group will be submitted to the standard (targeted BG: 130-180 mg/dL) 
institutional blood glucose control that is an escalating subcutaneous insulin dose for a given blood 
glucose reading, as follows: 
 
   
 

 
8 
 
 
Figure 1 - Subcutaneous insulin scheme. São Paulo, 2017. 
Blood glucose reading 
Subcutaneous human regular insulin 
dose 
≤ 180 mg/dL 
- 
≥181 mg/dL and ≤250 mg/dL 
5 IU* 
≥251 mg/dL and ≤300 mg/dL 
10 IU* 
≥301 mg/dL 
15 IU* 
* UI: International Unity. 
Source: Facility selected to conduct the study. 
 
3.9 THE BLOOD GLUCOSE MEASURE 
 
As an institution routine, either the standard group and the strict group will be submitted to a 
finger prick test each hour by nursing staff, trained by the researcher, under the supervision of a 
Registered Nurse employing a bedside glucose meter (FreeStyle Precision Pro® Abbott) calibrated 
following the manufacturer advice. 
3.10 PRIMARY OUTCOME 
 
Surgical site infection following the Centers for Disease Control and Prevention defining 
criteria:  
 
SSI occurs within 30 or 90 days after the operation and involves skin or subcutaneous tissue 
of the incision, deep soft tissues or organ and spaces, which were opened or manipulated during an 
operation(1).  
 
LT does not involve the presence of implants left in place thereby the period for detecting 
SSI is within 30 days after the operation, where day 1 = the procedure date(1). 
3.11 SECONDARY OUTCOMES 
The frequency of variables between both groups will be analysed as follows: 
 Hyperglycaemia > 250 mg/dL(23); 
 Hypoglycaemia < 60 mg/dL(23); 
 Time for SSI development; 
 Time of mechanical ventilation through ICU stay; 
 ICU stay; 

 
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 Postoperative ward stay; 
 Death within 90 days after LT. 
3.12 EVALUATION OF PRIMARY OUTCOME 
3.12.1 Through hospital stay 
 
 
 
The researcher will evaluate the surgical wound on alternate days before the dressing 
changes and patient's bathing.  
3.12.2 The period following the hospital discharge until the 30th postoperative day 
 
The researcher will contact the liver transplant recipient on alternate days by telephone to 
detect any signs and symptoms of SSI. Also, the surgical wound will be evaluated every 7 days 
during the ambulatory doctor's assessment. 
3.12.3 Evaluation of surgical wound during the hospital stay and after discharge 
 
Facing a suspected SSI case, given the CDC criteria fulfilment, immediately the researcher 
will communicate with the healthcare team and proceed to register in the nursing records.  
 
After that, the researcher will take a picture of the surgical site, using a digital camera 
designated for this activity. The clinical records and image will be sent to the adjudication 
committee for evaluation. 
3.13 ADJUDICATION COMMITTEE 
 
Will be formed by three health professional experts on SSI diagnosis and treatment. They 
will evaluate the classification in SSI or non-SSI only for the research purpose. As a result, these 
procedures will not affect the implementation or not of SSI treatment by the healthcare team.  
 
In regard to the establishment of adjudicated SSI, the committee will follow the CDC SSI 
defining criteria and the simple majority will be respected. 
3.14 SAFETY MONITORING 
 
For unicentric open-labelled clinical trial, the Data Safety Monitoring Inboard is not 
necessary, following the National Institutes of Health from United States of America statement(41). 
However, when 50% of the collected sample is reached the interim analyses will be done by an 

 
10 
independent statistician and a health professional expert, according to the criteria: strongly positive 
or negative results and futility proposed by Holubkov and cols.(42).  
3.15 ETHICAL PROCEDURES 
University of Sao Paulo School of Nursing Ethics Committee approved the research 
proposal (Approval number 2.444.780). 
 All the legal requirements from resolution Nº 466/2012 of Brazilian National Health 
Council will be followed (43).   
The data from donors will be collected from the recipient medical records. In Brazilian 
Transplant System, the identities of donors are not available in the recipient records as a measure to 
maintain confidentiality (44). 
3.16 STATISTICAL ANALYSES PLAN 
 A Microsoft Excel for Mac 2011® database will be constructed. The data will be typed into 
two different files to ensure accuracy by an automated check. Afterwards, the data will be 
transferred to the software Statistical Package for the Social Sciences® for Windows® version 22.0. 
The results will be computed with a statistician support, following the research objectives 
and methods. The following tests will be employed:   
 Central tendency and dispersion measures. 
 The categorical variables will be analysed by the Pearson's χ2 test or Fisher's exact test. 
 The continuous variables will be analysed by the Student t-test or Mann-Whitney. 
 Survival analysis by Kaplan-Meier estimate and Log-rank test. 
 Visual inspection of residuals from QQ plot will be used to determine the normality. 
 The significant level adopted will be α=0,05. 
4 SCHEDULE 
Activity 
Semester/Year 
 Data collection 
1º - 2º/2018 and 1º/2019 
 Visitor student program 
2º/2019 
 Write chapters: results, discussion and conclusion 
1º/2020 
 Dissertation completion, deposit and defense 
2º/2020 
 

 
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