Zinc and Inflammation in Sepsis

NCT01328509 | Completed

• 1 other identifier: 11/AL/0137
• Study Type: observational
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the proposed project is to investigate measures of zinc status in relation to oxidative stress and inflammation in patients with sepsis. We hypothesise that zinc depletion can modulate inflammatory responses, leading to increased oxidative stress and mitochondrial dysfunction. Sepsis is a severe infection is the leading cause of death in critically ill patients \[1\]. Zinc deficiency impairs overall immune function and resistance to infection \[2\]. In vitro exposure of monocytes to lipopolysaccharide (LPS) leads to decreased cellular zinc content \[3\] and zinc redistribution has been shown in human volunteers in response to LPS \[4\]. Zinc depletion occurs in hospitalized patients including those with infections, the elderly, alcoholics, trauma or burns \[5-8\], conditions which are common among critically ill patients with sepsis. In a mouse model of sepsis, zinc depletion prior to sepsis resulted in more inflammation and more severe organ injury and increased mortality \[9\]. In patients with sepsis, early feeding with zinc resulted in faster recovery of organ function compared with control \[10\]. Zinc status is likely to be compromised in the critically ill and that zinc depletion may affect inflammatory responses and recovery. Although zinc is not an antioxidant itself, it binds to metallothionein \[11\] and zinc supplementation decreases oxidative stress \[12\]. Oxidative stress has been consistently reported in patients with sepsis \[13-15\]. We have recently shown that protection of mitochondrial function with antioxidants can reduce organ damage in rats \[16\]. Pentraxin-3 is an inflammatory marker which is regulated in part by antioxidants and plays a key role in innate immunity \[17\]. The consequences of zinc deficiency may relate, in part, to its effects on nuclear factor NFκB, a transcription factor crucial to the signalling networks involved in sepsis \[18\]. Higher NFκB activity is associated with increased mortality in patients with sepsis \[19,20\]. It is likely that compromised antioxidant defences and inflammation occurs as a consequence of zinc deficiency. We propose to measure plasma zinc and metallothionein mRNA status in relation to inflammatory markers including key cytokines, pentraxin-3, markers of oxidative stress and antioxidant status in patients with sepsis.

Conditions

Sepsis

Keywords

Zinc

Outcome Measures

Primary Outcomes (1)

• Plasma zinc concentration

  Plasma zinc will be measured in patients with sepsis and non-spetic critically ill control patients.

  14 days

Secondary Outcomes (6)

• Interleukin-6

  14 days

• Pentraxin-3

  14 days

• Plasma lipid peroxide

  14 days

• Plasma total antioxidant capacity

  14 days

• Metallothionein mRNA

  14 days

Study Arms (2)

Sepsis

Patients with sepsis

Control

Patients with no clinical evidence of sepsis, but who are critically ill

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Successive patients admitted to the Intensive Care Unit at Aberdeen Royal Infirmary who fulfil the following criteria for sepsis, given below, within a 24h time window. • .

You may qualify if:

• admitted to ICU with clinical suspicion or evidence of acute infection PLUS two or more of the following:
• Core temperature \<36 degrees C or \>38 degrees C
• Tachycardia; heart rate \> 90 beats/min.
• Tachypnoea; respiratory rate \> 20 breaths/min or mechanical ventilation
• White blood count \>12 x 10 9/l or \<4 x 10 9/l
• Control patients
• admitted to ICU with no clinical evidence or suspicion of infection

You may not qualify if:

• under 16 years old
• pregnant or lactating
• HIV positive
• receiving corticosteroids or other known immuno-modulatory drugs
• treated with statins in the last month
• have cancer
• have autoimmune disorders
• consent/assent is refused

Sponsors & Collaborators

• University of Aberdeen: lead
• UK Intensive Care Society: collaborator

Study Sites (1)

Aberdeen Royal Infirmary

Aberdeen, Scotland, AB41 8TK, United Kingdom

Location

Related Publications (23)

• Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003 Apr 17;348(16):1546-54. doi: 10.1056/NEJMoa022139.

  PMID: 12700374 BACKGROUND

• Rink L, Gabriel P. Zinc and the immune system. Proc Nutr Soc. 2000 Nov;59(4):541-52. doi: 10.1017/s0029665100000781.

  PMID: 11115789 BACKGROUND

• Goode HF, Rathbone BJ, Kelleher J, Walker BE. Monocyte zinc and in vitro prostaglandin E2 and interleukin-1 beta production by cultured peripheral blood monocytes in patients with Crohn's disease. Dig Dis Sci. 1991 May;36(5):627-33. doi: 10.1007/BF01297030.

  PMID: 2022165 BACKGROUND

• Gaetke LM, McClain CJ, Talwalkar RT, Shedlofsky SI. Effects of endotoxin on zinc metabolism in human volunteers. Am J Physiol. 1997 Jun;272(6 Pt 1):E952-6. doi: 10.1152/ajpendo.1997.272.6.E952.

  PMID: 9227437 BACKGROUND

• Goode HF, Penn ND, Kelleher J, Walker BE. Evidence of cellular zinc depletion in hospitalized but not in healthy elderly subjects. Age Ageing. 1991 Sep;20(5):345-8. doi: 10.1093/ageing/20.5.345.

  PMID: 1755390 BACKGROUND

• Schmuck A, Roussel AM, Arnaud J, Ducros V, Favier A, Franco A. Analyzed dietary intakes, plasma concentrations of zinc, copper, and selenium, and related antioxidant enzyme activities in hospitalized elderly women. J Am Coll Nutr. 1996 Oct;15(5):462-8. doi: 10.1080/07315724.1996.10718625.

  PMID: 8892172 BACKGROUND

• Goode HF, Kelleher J, Walker BE. The effects of acute infection on indices of zinc status. Clin Nutr. 1991 Feb;10(1):55-9. doi: 10.1016/0261-5614(91)90082-n.

  PMID: 16839895 BACKGROUND

• Berger MM, Cavadini C, Chiolero R, Dirren H. Copper, selenium, and zinc status and balances after major trauma. J Trauma. 1996 Jan;40(1):103-9. doi: 10.1097/00005373-199601000-00019.

  PMID: 8576970 BACKGROUND

• Knoell DL, Julian MW, Bao S, Besecker B, Macre JE, Leikauf GD, DiSilvestro RA, Crouser ED. Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. Crit Care Med. 2009 Apr;37(4):1380-8. doi: 10.1097/CCM.0b013e31819cefe4.

  PMID: 19242332 BACKGROUND

• Beale RJ, Sherry T, Lei K, Campbell-Stephen L, McCook J, Smith J, Venetz W, Alteheld B, Stehle P, Schneider H. Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial. Crit Care Med. 2008 Jan;36(1):131-44. doi: 10.1097/01.CCM.0000297954.45251.A9.

  PMID: 18007263 BACKGROUND

• Bell SG, Vallee BL. The metallothionein/thionein system: an oxidoreductive metabolic zinc link. Chembiochem. 2009 Jan 5;10(1):55-62. doi: 10.1002/cbic.200800511.

  PMID: 19089881 BACKGROUND

• Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol. 2008 May;43(5):370-7. doi: 10.1016/j.exger.2007.10.013. Epub 2007 Nov 1.

  PMID: 18054190 BACKGROUND

• Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med. 1995 Apr;23(4):646-51. doi: 10.1097/00003246-199504000-00011.

  PMID: 7712754 BACKGROUND

• Cowley HC, Bacon PJ, Goode HF, Webster NR, Jones JG, Menon DK. Plasma antioxidant potential in severe sepsis: a comparison of survivors and nonsurvivors. Crit Care Med. 1996 Jul;24(7):1179-83. doi: 10.1097/00003246-199607000-00019.

  PMID: 8674332 BACKGROUND

• Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med. 1997;23(5):768-74. doi: 10.1016/s0891-5849(97)00059-2.

  PMID: 9296454 BACKGROUND

• Lowes DA, Thottakam BM, Webster NR, Murphy MP, Galley HF. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med. 2008 Dec 1;45(11):1559-65. doi: 10.1016/j.freeradbiomed.2008.09.003. Epub 2008 Sep 17.

  PMID: 18845241 BACKGROUND

• Hill AL, Lowes DA, Webster NR, Sheth CC, Gow NA, Galley HF. Regulation of pentraxin-3 by antioxidants. Br J Anaesth. 2009 Dec;103(6):833-9. doi: 10.1093/bja/aep298. Epub 2009 Oct 28.

  PMID: 19864306 BACKGROUND

• Otsu K, Ikeda Y, Fujii J. Accumulation of manganese superoxide dismutase under metal-depleted conditions: proposed role for zinc ions in cellular redox balance. Biochem J. 2004 Jan 1;377(Pt 1):241-8. doi: 10.1042/BJ20030935.

  PMID: 14531733 BACKGROUND

• Paterson RL, Galley HF, Dhillon JK, Webster NR. Increased nuclear factor kappa B activation in critically ill patients who die. Crit Care Med. 2000 Apr;28(4):1047-51. doi: 10.1097/00003246-200004000-00022.

  PMID: 10809280 BACKGROUND

• Bohrer H, Qiu F, Zimmermann T, Zhang Y, Jllmer T, Mannel D, Bottiger BW, Stern DM, Waldherr R, Saeger HD, Ziegler R, Bierhaus A, Martin E, Nawroth PP. Role of NFkappaB in the mortality of sepsis. J Clin Invest. 1997 Sep 1;100(5):972-85. doi: 10.1172/JCI119648.

  PMID: 9276714 BACKGROUND

• Kwon CS, Kountouri AM, Mayer C, Gordon MJ, Kwun IS, Beattie JH. Mononuclear cell metallothionein mRNA levels in human subjects with poor zinc nutrition. Br J Nutr. 2007 Feb;97(2):247-54. doi: 10.1017/S0007114507328614.

  PMID: 17298692 BACKGROUND

• Goode HF, Kelleher J, Walker BE. Zinc concentrations in pure populations of peripheral blood neutrophils, lymphocytes and monocytes. Ann Clin Biochem. 1989 Jan;26 ( Pt 1):89-95. doi: 10.1177/000456328902600114.

  PMID: 2735753 BACKGROUND

• Mertens K, Lowes DA, Webster NR, Talib J, Hall L, Davies MJ, Beattie JH, Galley HF. Low zinc and selenium concentrations in sepsis are associated with oxidative damage and inflammation. Br J Anaesth. 2015 Jun;114(6):990-9. doi: 10.1093/bja/aev073. Epub 2015 Mar 31.

  PMID: 25833826 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Peripheral whole blood will be sampled from an indwelling arterial line and plasma will be separated. Peripheral blood mononuclear cells will be separated using single density gradient centrifugation and RNA extracted. Nuclear extracts of MNC will also be prepared.

MeSH Terms

Conditions

Sepsis

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Helen Galley, PhD

  University of Aberdeen

  PRINCIPAL INVESTIGATOR

• Nigel Webster, PhD

  University of Aberdeen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 31, 2011
• First Posted: April 4, 2011
• Study Start: January 1, 2012
• Primary Completion: May 1, 2013
• Study Completion: May 1, 2013
• Last Updated: July 8, 2013

Record last verified: 2013-07

Locations

GB (1)