Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01997658 |
| Other study ID # |
REB 13 - 0294 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
October 2014 |
| Est. completion date |
October 30, 2018 |
Study information
| Verified date |
April 2021 |
| Source |
University of Calgary |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background: Reducing postoperative complications remains a dominant challenge for all
clinicians. By minimizing the incidence of adverse outcomes, health care costs and patient
recovery can be improved. A number of studies have documented that fewer postoperative
adverse events occur with the preoperative use of glucocorticoids (GC). Two small manuscripts
support the use of GC with particular reference to liver resection.
Major hepatectomy can be associated with numerous adverse outcomes (hemorrhage, bile leak,
liver failure, wound infection other infectious complications). This rate approaches 54% in
some trials. Additionally, the liver is responsible for numerous metabolic functions and
actively participates in the acute phase response via the generation of inflammatory
mediators and cytokines. Glucocorticoids play an important role in suppressing the
over-synthesis of pro-inflammatory cytokines and therefore may assist in reducing
postoperative complications. These pro-inflammatory cytokines recruit leukocytes at the site
of injury, leading to hepatic parenchymal cell damage. Decreasing pro-inflammatory cytokine
ratio may therefore reduce hepatic damage.
Methods: The investigators will complete a randomized controlled trial evaluating the
incidence of postoperative complications and overall hospital length of stay in adult
patients following preoperative vs. no administration of 500 mg of methylprednisolone (MP)
within 30 minutes of starting a hepatectomy. This trial will employ block randomization and
intention to treat protocols. Four HPB surgeons at University of Calgary will participate in
the trial with a planned inclusion of all patients scheduled to undergo hepatectomy in a
period of 2 years.
Analysis: Standard statistical analysis will include normally or near-normally distributed
variables reported as means and non-normally distributed variables as medians. Means will be
compared using the student's t test and medians using the Mann-Whitney U test. Differences in
proportions among categorical data will be assessed using Fischer's exact test. A p value <
0.05 will represent statistical significance for all comparisons.
Hypothesis: Preoperative GC administration will decrease the incidence of postoperative
complications and overall hospital length of stay following hepatectomy.
Potential Impact: Health care utilization and economics are an expanding area of importance.
Reducing post-hepatectomy complications are crucial to this end.
Description:
Introduction:
Major hepatectomy lead to significant postoperative anatomical and physiological changes. The
liver dictates the systemic metabolic environment and helps maintain homeostasis. When
segments of liver are removed, it is challenged to regenerate and restore cellular volume, as
well as continuing to perform mandated metabolic functions. Major hepatectomy can result in
multiple complications (hemorrhage, biliary fistulae, wound infection, liver failure) with an
overall complication rate up to 54% in some studies.
Recent studies purport that preoperative administration of GC may suppress the acute phase
response during the early postoperative period. GCs are steroid hormones with a variety of
immunological and biochemical functions (anti-inflammatory attenuation of the acute phase
response by binding to intra-cytoplasmic GC receptors and therefore increased transcription
of anti-inflammatory proteins interleukin-10 (IL-10), IL-1-receptor antagonist (IL-Ra),
lipocortin-1 and neutral endopeptidase, or direct inhibition of activated transcription
factors (nuclear factor kB, activator protein-1)). GC can also suppress gene expression by
altering the chromatin structure and tightening DNA coils.
The acute phase response is a neuro-humoral and time-limited defensive mechanism, which aims
to restore homeostasis. It is characterized by fever, leukocytosis, gluconeogenesis, as well
as changes in lipid, carbohydrate and protein metabolism. Activation of the
hypothalamus-pituitary-adrenal axis, coagulation and compliment pathways is also one of the
salient features of the acute phase response. It is regulated by cytokine receptor
antagonists (IL-1Ra) and soluble cytokine receptors. Cytokines are soluble, low molecular
weight glycoproteins that act as inflammatory mediators and can be broadly divided into pro
and anti-inflammatory cytokines. At low concentrations, they have a paracrine effect, while
in high concentrations they act systemically. These pro-inflammatory cytokines (IL-1, IL-2,
IL-6 and tumor necrosis factor (TNF) alpha) remain in the plasma for at least 24 hours after
generation. They also attract leukocytes (neutrophils and macrophages) to the site of injury
and are detrimental if produced in large amounts. Oka et al have demonstrated that increasing
levels of IL-6 are directly related to an increased rate of postoperative complications.
In low doses, GC reduce short term mortality, reverse the shock process and improve
hemodynamics in septic shock patients. In a meta-analysis of 17 RCTs, Annane et al found that
28-day mortality for a low-dose dexamethasone (DXA) group, versus control group was 35.3% vs.
38.5%. Shock reversal was also increased in the DXA group (66.9% vs. 58.6%) and the ICU stay
was decreased by 4.49 days.
Preoperative use of GC improves cardiac functions after coronary artery bypass grafting. The
likely underlying mechanism for this cardio-protective effect is reduced release of
pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha with a concurrent increased release of
anti-inflammatory cytokine IL-10.
In cases of laparoscopic cholecystectomy, 50% to 75% of patients express nausea and vomiting
in the early postoperative period. In a meta-analysis, Karanicolas et al found that the
absolute risk of nausea in low risk patients. Similarly DXA decreases the absolute risk of
vomiting from 12% to 5% in low risk and 30% to 12% in high risk groups as compared to
placebo. Although the quality of evidence is low regarding postoperative pain in
post-cholecystectomy patients, researchers have found less postoperative pain in the DXA
group.
Gomez-Hernandez et al also suggested that a preoperative single dose of DXA decreased
postoperative nausea, vomiting and pain in patients undergoing mastectomy (28.6% vs. 60% in
the early postoperative period). The patients in placebo group required more anti-emetic
medications. DXA reduced postoperative pain significantly and fewer patients requested
analgesia (10 vs. 21). Additionally there was no increase in adverse events, morbidity and
mortality in the steroid group.
Preoperative use of DXA significantly improves postoperative pain, nausea, vomiting and vocal
function within the first 48 hours after thyroid surgery.
Subclinical renal dysfunction is frequently noted following liver transplantation. This
occurs mainly due to hepatic ischemia/reperfusion injury. Turner et al suggested that GC
decrease the incidence of renal tubular dysfunction when given at the time of induction of
anesthesia. The main difference in serum creatinine level was noted on postoperative day 3
(164.8 mumol/L in the saline group vs. 88.5 mumol/L in the MP group). Additionally, patients
in the saline group suffered from more complications (47% vs. 12%).
Studies have suggested that GC limit the peritoneal inflammatory response and therefore help
in recovery and fatigue in the early postoperative period. Low levels of IL-6 and IL-13 were
found in the peritoneal fluid of patients receiving GC on postoperative day 1. Schulze et al
observed improved pulmonary function and early mobilization in a MP group, as compared to
placebo, in colon surgery patients. Furthermore, they noted a significant decrease in IL-6, C
reactive protein and pain scores. The appetite was increased significantly in patients on GC,
however there was no difference in wound healing and other infectious complications
(including anastomotic leaks). In colorectal surgery, GC do not appear to increase
postoperative complications. A double blind, randomized clinical trial consisting of 30
patients undergoing colonic surgery, showed that there was no significant difference in
postoperative IL-6, C reactive protein, pain scores, bowel functions, mobilization, hospital
length of stay, complications and readmission rates between the two groups when a single 8 mg
preoperative dose of DXA was given to the interventional group.
A recent systematic review and meta-analysis of 11 moderate quality RCTs suggested decreased
postoperative complications and hospital length of stay of patients undergoing major
abdominal surgery following preoperative use of GC. In the case of liver resection surgery,
Aldrighetti et al found decreased serum ALT, AST, total bilirubin, IL-6, TNF-alpha, hospital
length of stay and postoperative complications following a single preoperative GC dose.
The dominant clinical rationale for not using preoperative steroids is to avoid related side
effects. A substantial number of studies have documented fewer adverse events in MP groups as
compared to placebo, suggesting there is a need to reconsider the steroid-free protocol in
the preoperative period. Further appropriately designed and well-powered studies are urgently
needed to evaluate the effects of preoperative GC use. As a result, we have planned a
prospective RCT at the University of Calgary to determine the role of GC in reducing
postoperative complications and hospital length of stay for patients undergoing partial
hepatectomy.
Recruitment:
Contact information for study candidates will be obtained by the project's research staff
from the offices of the four participating surgeons. Patients will be contacted prior to
surgery by the research staff and will be provided information regarding the study. Patients
who consent to participate will be randomized (the clinic at the time of consent completion
and operative scheduling).
Data collection:
Patients will be tracked postoperatively for the development of complications and overall
length of hospital stay. Information will be collected by chart review from the operative
report and patient record by research staff.
Data elements to be collected will include, but not be limited to:
- Date of birth, Gender
- Surgeon, procedure, surgery duration
- Antibiotic prophylaxis
- Estimated blood loss, Transfusion
- Wound closure technique, peroperative drain, Wound infection or disruption
- Hepatic failure
- Acute kidney injury
- Intraperitoneal abscess, surgical site infection
- Pneumonia, Blood stream infection, Pulmonary embolism, Deep venous thrombosis
- Hypoglycemic incidents
- Bile leak (requiring percutaneous drainage or via an operatively placed drain)
- Anastomotic gastrointestinal leaks (combined colorectal / hepatic resection)
- Preparation type (ETOH based, chlorhexidine or iodine based)
- Time to oral intake
Patient records:
- Preoperative chemotherapy
- Preoperative albumin level
- Preoperative PVE and /or TACE
- Underlying liver disease (cirrhosis)
- ASA score
- Length (if any) of hepatic inflow occlusion,
- Length of hospital stay & mortality
- Co-morbidities (smoking, diabetes, hypertension, COPD, Ischemic heart disease,
arrhythmias, metastatic cancer, AIDS, obesity, alcohol abuse,psychosis, anemias etc.)
- Glucocorticoids - methylprednisolone given, dose, route of administration and time
before starting surgery.
The investigators will also track IL-6 and C-Reactive protein (CRP) levels on postoperative
day 1 (with daily blood work) as a marker of global immune function. Definition of
complications can be found in appendix 2.
Power calculation to determine sample size:
The largest surgical trial to date recruited a total of 73 patients. There are 5 small
hepatic resection RCTs available for analysis (all trials utilized MP). The largest of these
studies noted a decrease in overall complications from 54% to 14% with GC use. With a
consistent volume of hepatectomies (100+ per year at FMC), and a planned inclusion/capture
for our group's resections of nearly 100%, we expect to randomize over 100 patients in each
arm in 2 full years. With an alpha = 0.5, probability = 80%, predicted effect size of 0.30
(2-tailed test), the sample size required would be 84 patients.
Additional comments:
Methylprednisolone (MP) is the best choice of GC because it: (1) has a 5-fold higher
anti-inflammatory action compared to cortisol, (2) has reduced effects on electrolytes, (3)
duration of MP biologic action is 36 hrs (half life = 2.8 hrs) so both phases of
ischemia-reperfusion injury will be covered, and (4) 500 mg of MP results in a defined and
predictable response of >1 ug/ml in blood and >10 ug/ml in liver tissue.
Resources:
This project is built on an existing research team who work collaboratively with the
Principal Investigator to carry out the project effectively and efficiently. An experienced
research assistant will assist in data collection, analysis, preparing reports for
publications and organizing research meetings.
Appendix 2:
Hepatic failure; Hyperacute and/or acute onset of coagulopathy (INR>1.5), reduction in
synthetic function, and encephalopathy requiring therapy.
Acute kidney injury; An abrupt (<48 hrs) reduction in kidney function (absolute increase in
serum creatinine > or equal to 26.4 umol/L, a > 50% increase in serum creatinine or a
reduction in urine output of less than 0.5 ml/kg per hour for more than six hours.
Intraperitoneal abscess; Identified on cross-sectional imaging. Bile leak; Either requiring
percutaneous drainage or evidence of bile in an operatively placed closed suction drain.
Wound disruption, dehiscence or hernia Pneumonia; Blood stream infection; Urinary tract
infection; Surgical site infection.
Anastomotic gastrointestinal leaks (combined colorectal/hepatic resections); GI leak
confirmed by imaging (fistulogram, CT) and requiring intervention.
Deep venous thrombosis; Identified on ultrasonography or cross sectional imaging prompted by
clinician suspicion or incidental imaging.
Pulmonary embolus; Identified on cross-sectional or V/Q scan imaging. Hypoglycemic incidents;
Blood glucose <3.0 mm/L with concurrent patient symptoms of hypoglycemia.
Read more »
