Ignite Creation Date:
2024-05-06 @ 2:13 AM
Last Modification Date:
2024-10-26 @ 11:15 AM
Study NCT ID:
NCT01997658
Status:
COMPLETED
Last Update Posted:
2021-04-28
First Post:
2013-05-14
Brief Title:
Preoperative Glucocorticoid Use in Major Hepatectomy
Sponsor:
University of Calgary
Organization:
University of Calgary
Study Overview
Official Title:
Preoperative Glucocorticoid Use in Major Hepatectomy - A Randomized Controlled Trial
Status:
COMPLETED
Status Verified Date:
2021-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 students t test and medians using the Mann-Whitney U test Differences in proportions among categorical data will be assessed using Fischers exact test A p value 005 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
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 students t test and medians using the Mann-Whitney U test Differences in proportions among categorical data will be assessed using Fischers exact test A p value 005 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
Detailed 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 353 vs 385 Shock reversal was also increased in the DXA group 669 vs 586 and the ICU stay was decreased by 449 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 286 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 ischemiareperfusion 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 1648 mumolL in the saline group vs 885 mumolL 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 projects 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 abusepsychosis 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 inclusioncapture for our groups resections of nearly 100 we expect to randomize over 100 patients in each arm in 2 full years With an alpha 05 probability 80 predicted effect size of 030 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 28 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 ugml in blood and 10 ugml 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 andor acute onset of coagulopathy INR15 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 264 umolL a 50 increase in serum creatinine or a reduction in urine output of less than 05 mlkg 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 colorectalhepatic 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 VQ scan imaging Hypoglycemic incidents Blood glucose 30 mmL with concurrent patient symptoms of hypoglycemia
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 353 vs 385 Shock reversal was also increased in the DXA group 669 vs 586 and the ICU stay was decreased by 449 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 286 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 ischemiareperfusion 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 1648 mumolL in the saline group vs 885 mumolL 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 projects 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 abusepsychosis 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 inclusioncapture for our groups resections of nearly 100 we expect to randomize over 100 patients in each arm in 2 full years With an alpha 05 probability 80 predicted effect size of 030 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 28 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 ugml in blood and 10 ugml 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 andor acute onset of coagulopathy INR15 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 264 umolL a 50 increase in serum creatinine or a reduction in urine output of less than 05 mlkg 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 colorectalhepatic 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 VQ scan imaging Hypoglycemic incidents Blood glucose 30 mmL with concurrent patient symptoms of hypoglycemia
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None