Therapeutic Benefit of Preoperative Supplemental Vitamin D in Patients Undergoing Major Surgical Procedures.

NCT ID: NCT02138591

Last Updated: 2017-06-16

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-29
• Study Completion Date: 2016-05-31

Brief Summary

Vitamin D (Vitamin D) deficiency is very common. We recently showed that 97% of 204 patients admitted to Truman Medical Center were Vitamin D deficient (<30 ng/ml). However, the consequences of Vitamin D deficiency, particularly with respect to infection, are not well understood. It is known that production of cathelicidin, an important antimicrobial peptide, is critically dependent upon Vitamin D. It is also established that levels of cathelicidin correlate inversely with urinary tract infection risk. We hypothesize that restoration of Vitamin D levels to normal in patients undergoing major surgery will result in significant decreases in levels of perioperative infections due to restoration of normal levels of circulating Vitamin D, which in turn will elevate cathelicidin levels. As an initial test of this hypothesis, we propose a double-blind, prospective, randomized study of pre-operative Vitamin D supplementation. Fifty subjects undergoing surgery will receive daily Vitamin D3 (50,000 IU) for five days pre-operatively, with controls receiving placebo. Levels of Vitamin D, calcium, cathelicidin, and the pro-inflammatory protein resistin, will be monitored before Vitamin D supplementation (pre-operatively) and after Vitamin D supplementation (post-operative days 1 and 2). The effect of these changes should be to decrease the incidence of infectious complications. We expect to observe Vitamin D levels increase to normal, and cathelicidin levels become elevated. We expect to see increased levels of resistin in patients developing infections. This study will provide strong pilot evidence for future NIH funding.

Detailed Description

The long term goal in our research is to develop and implement effective, evidence-and mechanism-based interventions to improve outcomes for surgical and trauma patients. Of potential importance, findings from our own recent pilot studies have established that > 95% of patients seen at Truman Medical Center (TMC) are seriously Vitamin D deficient with plasma levels significantly lower than normal. Our objective in this application, therefore, is to assess the short term therapeutic benefit of high dose Vitamin D in patients admitted to TMC for elective major abdominal surgery. We propose to measure plasma Vitamin D and Calcium levels before supplementation (pre-operatively), and after supplementation (post-operatively), and monitor the biomarker proteins cathelicidin and resistin at the same times. Data on Vitamin D levels will be used to assess direct biochemical effects. Measurement of cathelicidin levels will provide additional information. Since Vitamin D has been shown to induce increased expression of this antimicrobial protein. Monitoring of circulating levels of resistin provides a highly sensitive early measure of infection (unpublished observations). Calcium levels will also be monitored since there is a significant chance that pre-operative calcium levels will be low in some patients, and that supplementation with vitamin D may increase the calcium level.

Measures of secondary clinical outcomes will include length of hospital stay and incidence of post-operation infection. Our central hypothesis is that, relative to patients receiving peri-operative standard of care, patients receiving 250,000 units of Vitamin D pre-operatively will manifest levels of Vitamin D to within the normal range and will have elevated levels of cathelicidin. We further hypothesize that patients receiving Vitamin D will have reduced incidence of infection, which will correlate with lower levels of resistin, and will exhibit trends toward shorter hospital stay. Our proposed specific aims are:

Specific Aim #1: Determine biochemical consequences of Vitamin D supplementation in elective surgery patients We hypothesize that preoperative supplementation with high dose Vitamin D will result in levels of Vitamin D in treated patients within the normal range, corresponding with significant increases in plasma levels of cathelicidin, relative to control patients receiving standard of care.

Specific Aim # 2: Evaluate clinical benefits of Vitamin D supplementation in post-elective surgery patients We postulate that patients given Vitamin D will trend toward lower rates of post-surgery infection, as evidenced by the absence of circulating resistin and decreased detection of pulmonary or wound-site infection, and will have shorter hospital stays relative to patients receiving standard of care.

It is our expectation that, at the completion of this pilot study, we will have provided strong evidence that plasma levels of Vitamin D, as measured by 25-OHD, can be reproducibly raised to normal levels as measured in post-surgery patients and that the administered Vitamin D will have detectable biochemical benefits. We further expect that, while the power of the proposed study will not be sufficient for statistically valid results, there will be trends toward clinical benefits in Vitamin D treated patients. Collectively, these findings would provide strong evidence to support feasibility of an NIH-supported Phase I trial to assess Vitamin D benefits in surgery and/or trauma.

Conditions

Vitamin d Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Vitamin D3

Vitamin D3 (cholecalciferol) 50,000 IU by mouth daily for each of the five days prior to surgery.

Blood draw pre-operatively Blood draw post-operative Day 1 Blood draw post-operative Day 2

Group Type: EXPERIMENTAL

Blood draw pre-operatively

Intervention Type: PROCEDURE

Pre-Operative blood draw of approximately 32ml will check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Blood draw post-operative Day 1

Intervention Type: PROCEDURE

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Blood draw post-operative Day 2

Intervention Type: PROCEDURE

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Placebo pill

Placebo pill by mouth daily for each of the five days prior to surgery. Blood draw pre-operatively Blood draw post-operative Day 1 Blood draw post-operative Day 2

Group Type: PLACEBO_COMPARATOR

Blood draw pre-operatively

Intervention Type: PROCEDURE

Pre-Operative blood draw of approximately 32ml will check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Blood draw post-operative Day 1

Intervention Type: PROCEDURE

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Blood draw post-operative Day 2

Intervention Type: PROCEDURE

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Interventions

Blood draw pre-operatively

Pre-Operative blood draw of approximately 32ml will check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Intervention Type: PROCEDURE

Blood draw post-operative Day 1

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Intervention Type: PROCEDURE

Blood draw post-operative Day 2

Blood draw of approximately 32ml to check the following: Vitamin D (25-OHD), Calcium, Cathelicidin and Resistin levels in the blood.

Intervention Type: PROCEDURE

Other Intervention Names

Venipuncture; Venipuncture; Venipuncture

Eligibility Criteria

Inclusion Criteria

• English Speaking
• Age 18 years or older
• Patient undergoing major elective surgery with planned open abdominal incisions, and planned hospitalization of two days or longer.

Exclusion Criteria

• Pregnant
• Non-English Speaking
• Chronic severe kidney disease (Stage III, IV, V)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Truman Medical Center

OTHER

Sponsor Role: collaborator

University of Missouri, Kansas City

OTHER

Sponsor Role: lead

Responsible Party

Dustin Neel

Co-Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Charles Van Way III, M.D.

Role: STUDY_DIRECTOR

Truman Medical Center and University of Missouri Kansas City

Dustin Neel, MD

Role: PRINCIPAL_INVESTIGATOR

Truman Medical Center and University of Missouri Kansas City

Locations

Truman Medical Center Hospital Hill

Kansas City, Missouri, United States

Countries

United States

References

Flynn L, Zimmerman LH, McNorton K, Dolman M, Tyburski J, Baylor A, Wilson R, Dolman H. Effects of vitamin D deficiency in critically ill surgical patients. Am J Surg. 2012 Mar;203(3):379-82; discussion 382. doi: 10.1016/j.amjsurg.2011.09.012. Epub 2011 Dec 28.

Reference Type: BACKGROUND

PMID: 22206852 (View on PubMed)

Bacon CJ, Gamble GD, Horne AM, Scott MA, Reid IR. High-dose oral vitamin D3 supplementation in the elderly. Osteoporos Int. 2009 Aug;20(8):1407-15. doi: 10.1007/s00198-008-0814-9. Epub 2008 Dec 20.

Reference Type: BACKGROUND

PMID: 19101755 (View on PubMed)

von Restorff C, Bischoff-Ferrari HA, Theiler R. High-dose oral vitamin D3 supplementation in rheumatology patients with severe vitamin D3 deficiency. Bone. 2009 Oct;45(4):747-9. doi: 10.1016/j.bone.2009.06.012. Epub 2009 Jun 17.

Reference Type: BACKGROUND

PMID: 19539796 (View on PubMed)

Amrein K, Sourij H, Wagner G, Holl A, Pieber TR, Smolle KH, Stojakovic T, Schnedl C, Dobnig H. Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study. Crit Care. 2011;15(2):R104. doi: 10.1186/cc10120. Epub 2011 Mar 28.

Reference Type: BACKGROUND

PMID: 21443793 (View on PubMed)

Serrone R, Loveless B, Frankel E, Ross V, Geehan D, Van Way, CW III. vitamin D Deficiency in Patients Admitted to a Midwestern Urban Hospital. Poster presentation at Clinical Nutrition Week, American Society of Parenteral and Enteral Nutrition, Phoenix, AZ, 2013

Reference Type: BACKGROUND

Braun AB, Litonjua AA, Moromizato T, Gibbons FK, Giovannucci E, Christopher KB. Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill. Crit Care Med. 2012 Dec;40(12):3170-9. doi: 10.1097/CCM.0b013e318260c928.

Reference Type: BACKGROUND

PMID: 22975885 (View on PubMed)

Schwalfenberg GK. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res. 2011 Jan;55(1):96-108. doi: 10.1002/mnfr.201000174. Epub 2010 Sep 7.

Reference Type: BACKGROUND

PMID: 20824663 (View on PubMed)

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. doi: 10.1093/ajcn/69.5.842.

Reference Type: BACKGROUND

PMID: 10232622 (View on PubMed)

Ilahi M, Armas LA, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. Am J Clin Nutr. 2008 Mar;87(3):688-91. doi: 10.1093/ajcn/87.3.688.

Reference Type: BACKGROUND

PMID: 18326608 (View on PubMed)

Gombart AF, Bhan I, Borregaard N, Tamez H, Camargo CA Jr, Koeffler HP, Thadhani R. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin Infect Dis. 2009 Feb 15;48(4):418-24. doi: 10.1086/596314.

Reference Type: BACKGROUND

PMID: 19133797 (View on PubMed)

White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):234-8. doi: 10.1016/j.jsbmb.2010.03.034. Epub 2010 Mar 17.

Reference Type: BACKGROUND

PMID: 20302931 (View on PubMed)

Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009 Apr 23;7:28. doi: 10.1186/1479-5876-7-28.

Reference Type: BACKGROUND

PMID: 19389235 (View on PubMed)

van der Does AM, Bergman P, Agerberth B, Lindbom L. Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections. J Leukoc Biol. 2012 Oct;92(4):735-42. doi: 10.1189/jlb.0412178. Epub 2012 Jun 13.

Reference Type: BACKGROUND

PMID: 22701042 (View on PubMed)

Other Identifiers

14-149

Identifier Type: -

Identifier Source: org_study_id