Journal of Critical Care 29 (2014) 317.e5–317.e8
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Serum selenium and zinc levels in critically ill surgical patients☆,☆☆,★,★★ Ji Young Jang, MD a, Hongjin Shim, MD b, Seung Hwan Lee, MD a, Jae Gil Lee, MD, PhD a,⁎ a b
Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Surgery, Yonsei University Wonju College of Medicine, Wonju-si, Republic of Korea
a r t i c l e Keywords: Selenium Zinc Critically ill Surgical
i n f o
a b s t r a c t Purpose: The authors designed this study to determine how serum selenium and zinc affect the outcomes of critically ill surgical patients. Methods: The medical records of 162 patients admitted to a surgical intensive care unit (ICU) from October 2010 to July 2012 and managed for more than 3 days were retrospectively investigated. Results: Overall, the mean patient age was 61.2 ± 15.0 years, and the median ICU stay was 5 (3-115) days. The mean Acute Physiologic and Chronic Health Evaluation II score was 18.0 ± 8.0. Eighteen (11.1%) of the study subjects died in ICU. mean selenium levels were 83.5 ± 23.8 ng/dL in the survivor group and 83.3 ± 29.6 ng/ dL in the nonsurvivor group, and corresponding mean zinc levels were 46.3 ± 21.7 and 65.6 ± 41.6 μg/dL, respectively. Mean selenium concentrations were significantly different in patients with and without shock (77.9 ± 25.4 and 87.2 ± 23.1 ng/dL, P = .017). Furthermore, mean serum selenium was lower in patients with sepsis than in traumatic or simply postoperative patients (P b .001 and P = .038). Serum Zn was significantly lower in patients with sepsis than in patients with trauma (43.4 ± 25.4 μg/dL vs 54.8 ± 28.1 μg/dL, P = .038). Conclusions: To determine the effects of serum selenium and zinc levels on critically ill surgical patients, a large-scale prospective study is needed. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
1. Introduction Selenium (Se) is an essential trace element with antioxidative, anti-inflammatory, and immunologic functions. It is an essential component of glutathione peroxidase, which reduces reactive oxygen species (ROS), especially superoxide [1]. On the other hand, zinc (Zn) is an essential trace element with many physiological functions, for example, in the immune system and during wound healing and growth [2,3]. Many authors have examined the roles of serum Se and Zn in critically ill patients, and deficiencies in these elements have been associated with systemic inflammatory response syndrome (SIRS) and sepsis. However, the effects of serum Se and Zn on outcomes and pathophysiology remain debatable. Furthermore, few
☆ Presented at the 24th European Society of Parenteral and Enteral Nutrition (ESPEN) Congress on Clinical Nutrition and Metabolism, Barcelona, Spain, 2012. ☆☆ Competing interests: The authors have no potential conflict of interest to declare. ★ Financial support: This research was supported by the Basic Science Research Program of the National Research Foundation of Korea funded by the Korea Ministry of Education, Science, and Technology (Grant No. 2012R1A1A2007915). ★★ Authors' contributions: L.J.G. designed and J.J.Y. wrote the manuscript. S.H., L.S.H., and L.J.G. read and approved the final manuscript. ⁎ Corresponding author. Department of Surgery, Yonsei University College of Surgery, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: +82 2 2228 2100; fax: +82 2 313 8289. E-mail address: [email protected] (J.G. Lee).
studies have addressed the association between serum Se and Zn on surgical outcomes [4–9] or on critically ill surgical patients [10]. Accordingly, the purpose of this study was to evaluate the relationships between serum Se and Zn levels on the outcomes of critically ill surgical patients. 2. Patients and methods The medical records of 162 surgical patients admitted to a surgical intensive care unit (ICU) from October 2010 to July 2012 were reviewed. All 162 study subjects were managed in an ICU for more than 3 days. Medical records were reviewed retrospectively, and the following parameters were recorded and analyzed: age, sex, Acute Physiologic and Chronic Health Evaluation (APACHE) II scores, duration of ICU admission, duration of mechanical ventilation, presence or occurrence of septic shock, and mortality. Variables are presented as mean values and SDs, or as medians and ranges. Blood was drawn on the first ICU day for serum Se and Zn testing. Causes of ICU admissions were categorized as sepsis, trauma, and postoperative care without sepsis. Sepsis was defined as SIRS combined with infection. In this study, patients with peritonitis due to a perforated hollow viscus or bowel infarction were classified as having sepsis. Shock was defined as a mean blood pressure of less than 65 mm Hg or a decrease in systolic blood pressure greater than 40 mm Hg vs baseline systolic blood pressure. Patients with perfusion failure, such
0883-9441/$ – see front matter. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2013.12.003
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J.Y. Jang et al. / Journal of Critical Care 29 (2014) 317.e5–317.e8
Fig. 1. Flow diagram of the study.
as, oliguria, mental change, and organ failure, or administered a vasopressor were included. All statistical calculations were performed using SPSS version 20.0 (SPSS, Inc, Chicago, Ill). t Test and analysis of variance were used to identify clinical variables associated with outcomes. Statistical significance was accepted for P b .05. This study was approved by the Severance Hospital institutional review board (institutional review board approval no. 2013-0015-001). 3. Tests for serum Se and Zn About 10 mL of blood was drawn from peripheral vein or central catheter on the first ICU day for serum Se and Zn testing. This blood was centrifuged at 3000 rpm for 10 minutes and then serum samples were sent to the outside laboratory at room temperature. Selenium expressed in nanograms/milliliter was measured by graphite furnace atomic absorption spectrometry with Atomic Absorption Spectrometer–Graphite Furnace (VARIAN, Sydney, Australia) using a hollow cathode lamp source at λ = 196.0 nm. The reference value of serum Se is 95.0 to 165.0 ng/mL. Serum Zn was analyzed by inductively coupled plasma-mass spectrometry using the Varian 820-MS system (VARIAN). The reference value for serum Zn is 66 to 110 μg/dL. Table 1 Patient characteristics Variable Age (y) Sex (male) HTN DM Chronic kidney disease Coronary artery occlusive disease Malnutrition Obesity APACHE II score ICU stay (d) Duration of MV (d) Se (ng/dL) Zn (μg/dL) Causes of admission Sepsis Trauma Postoperative Procalcitonin in sepsis patients(ng/mL) Shock Mortality
n
%
103 57 31 10 13 15 40
63.6 35.2 19.1 6.2 8.0 9.3 24.7
61.2 ± 15.0
4.1. Demographics A total of 162 patients were enrolled, and 103 (63.6%) were men. The mean patient age was 61.2 ± 15.0 years, and the median length of ICU stay was 5 (3-115) days. The mean APACHE II score was 18.0 ± 8.0. Eighty-nine patients were supported by mechanical ventilation for 2 (1-38) days. Sixty-five patients (40.1%) experienced shock. One hundred thirty-six of the study subjects underwent surgical intervention. Twenty patients with trauma were managed conservatively, and 6 patients with sepsis were managed nonoperatively. Ninety-five (69.9%) of the 136 underwent an emergency operation. The major cause of ICU admission was sepsis (80; 49.4%), and this was followed by trauma (47; 29.0%) and postoperative care (35; 21.6%). Of the 80 patients with sepsis, 44 (55.0%) had panperitonitis due to a bowel perforation and 23 (28.8%) had an intestinal obstruction with strangulation. Seven patients underwent operations due to necrotizing pancreatitis, necrotizing fasciitis, intestinal obstruction without strangulation, and postoperative hemorrhage. Six patients were managed conservatively without operation (Fig. 1). Sixty-five (40.1%) patients experienced shock, and 18 of these patients died. Mean serum levels of Se and Zn on the first ICU day were 83.5 ± 24.4 ng/dL and 48.4 ± 25.3 μg/dL, respectively (Table 1).
4.2. Selenium, Zn, and mortality When patients were dichotomized as survivors (n = 144) and nonsurvivors (n = 18), mean APACHE II scores (17.3 ± 7.8 vs 23.3 ± 8.3) and durations of mechanical ventilation (2 [1-24] days vs 6 [1-38]
18.0 ± 8.0 5 (3-115) 2 (1-38) 83.5 ± 24.4 48.4 ± 25.3 80 47 35 76 65 18
4. Results
49.4 29.0 21.6 9.47 (0-200) 40.1 11.1
HTN indicates hypertension; DM, diabetes mellitus; MV, mechanical ventilation.
Table 2 Comparison between survivors and nonsurvivors
Age (y) APACHE II Hospital stay (d) ICU stay (d) Duration of MV (d) Se level (ng/dL) Zn level (μg/dL) Results of Student t test.
Survivors (n = 144)
Nonsurvivors (n = 18)
P
61.0 ± 15.0 17.3 ± 7.8 18.5 (3-201) 5 (3-38) 2 (1-24) 83.5 ± 23.8 46.3 ± 21.7
62.4 ± 14.9 23.3 ± 8.3 29 (3-114) 10 (3-115) 6.0 (1-38) 83.3 ± 29.6 65.6 ± 41.6
.701 .002 .482 .036 .004 .966 .068
J.Y. Jang et al. / Journal of Critical Care 29 (2014) 317.e5–317.e8 Table 3 Differences between patients without shock and patients with shock
Sepsis (n) Se level (ng/dL) Zn level (μg/dL)
Without shock (n = 97)
With shock (n = 65)
P
40 (41.2%) 87.2 ± 23.1 50.2 ± 24.2
40 (61.5%) 77.9 ± 25.4 45.8 ± 26.7
.015 .017 .273
Results of Student t test.
days) were nonsignificantly different between the 2 groups. Furthermore, mean Se levels (83.5 ± 23.8 ng/dL vs 83.3 ± 29.6 ng/dL, respectively; P = .966) and mean Zn levels (46.3 ± 21.7 μg/dL vs 65.6 ± 41.6 μg/dL, respectively; P = .068) were also nonsignificantly different (Table 2). 4.3. Selenium, Zn, and shock Mean Se levels were significantly different between the nonshock and shock groups (87.2 ± 23.1 ng/dL vs 77.9 ± 25.4 ng/dL, respectively; P = .017). However, mean Zn levels were not significantly different (50.2 ± 24.2 μg/dL vs 45.8 ± 26.7 μg/dL, respectively; P = .273; Table 3). 4.4. Selenium, Zn, and causes of ICU admission Patients were also classified according to sepsis (80; 49.4%), trauma (47; 29.0%), and postoperative status (35; 21.6%). Mean serum Se was significantly lower in the sepsis group (75.7 ± 26.7 ng/dL) than in the trauma group (94.6 ± 19.8 ng/dL, P b .001) and in the postoperative status group (86.4 ± 17.6 ng/dL, P = .038). In addition, serum Zn was significantly lower in patients with sepsis than in patients with trauma (43.4 ± 25.4 μg/dL vs 54.8 ± 28.1 μg/dL, P = .038). However, the mean serum Zn levels of patients with sepsis and simple postoperative patients were not significantly different (43.4 ± 25.4 μg/dL vs 51.4 ± 18.4 μg/dL, respectively; P = .255; Table 4). 5. Discussion Sepsis is the common cause of death in ICUs, and the mortality rate is 25% in cases of uncomplicated sepsis and up to 50% to 80% in patients with multiple-organ failure [11]. Reactive oxygen species produced during electron transport in the inner membrane of mitochondria exhibit strong tissue toxicity, and thus, several antioxidant defense systems have evolved to remove ROS [12]; known components of the antioxidant defense system include
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superoxide dismutase, catalase, ascorbic acid, α-tocopherol, and glutathione peroxidase [12]. The balance between ROS production and antioxidant protection is referred to as oxidative balance [13]. In sepsis, endotoxins produced by invading bacteria induce inflammatory responses; by up-regulating proinflammatory cytokine, ROS, and nitric oxide levels; and by promoting the leukocyte adhesion and migration [12]. Accordingly, inflammatory response increases intracellular oxidative stress, resulting in mitochondrial dysfunction and enhanced ROS production. Selenium acts as cofactor of glutathione peroxidase and as an important component of the antioxidant defense system and, thus, facilitates its physiologic function [14]. Furthermore, serum levels of Se and glutathione peroxidase activity are positively correlated, and critically ill patients with SIRS exhibit depressed serum Se and glutathione peroxidase activity levels [15], which suggest that depressed serum Se is associated with elevated ROS production and inflammatory response. Furthermore, Se levels in critically ill patients with SIRS or sepsis have been shown to be correlated with mortality [16,17]. Zinc acts as a cofactor of numerous transcription factors and enzyme systems and is involved in cell-mediated innate immunity, wound healing, and growth [18,19]. Furthermore, it has been reported that in critically ill patients under ICU care, plasma Zn levels were lower in patients with sepsis [20]. Thus, it appears that serum Se and Zn deficiencies are related to SIRS and sepsis, and thus, many studies have been conducted to evaluate their effects on outcomes and the effects of their intravenous (IV) augmentation. In critically ill patients with SIRS or sepsis, IV high-dose Se infusion reduced the occurrences of early ventilator-associated pneumonia and hospital-acquired pneumonia, rapidly reduced Sequential Organ Failure Assessment scores [21], and reduced mortality [22]. However, a recent study found no differences between 500 μg IV Se, 300 μg IV Se, 20 mg of Zn, antioxidant, and control groups in terms of 28-day mortality, length of ICU stay, length of hospital stay, or duration length of mechanical ventilation [23]. Thus, in critically ill patients with SIRS or sepsis syndrome, serum levels of Se and Zn are depressed, but their IV replacement remains controversial. Most of the previous studies have focused on ICU patients with SIRS or sepsis, and relatively few have addressed surgical patients. Furthermore, most studies have focused on serum Zn levels [4–6,8]. In cardiac surgery patients, Se was found to be decreased postoperatively [9] and to be associated with operative risk and mortality [7]. In a study by Linko et al [2], serum Zn levels in operative patients were significantly lower than in nonoperative patients, which suggests that surgery might increase oxidative stress
Table 4 Selenium and Zn levels with respect to reasons for ICU admission
Se (ng/dL) Zn (µg/dL)
1 2 3
1 2 3
Sepsis (n = 80)
Trauma (n = 47)
Postoperative (n =35)
F
P
75.7 ± 26.7 43.4 ± 25.4
94.6 ± 19.8 54.8 ± 28.1
86.4 ± 17.6 51.4 ± 18.4
10.309 3.394
b.001 .036
Sea
n
Mean
SD
Homogeneity of variance
Sepsis Trauma Postoperative
80 47 35 162
75.7 94.6 86.4 83.5
26.7 19.8 17.6 24.4
0.018 0.018 0.018 0.018
b0.001 0.038
Znb
N
Mean
SD
Homogeneity of variance
1
Sepsis Trauma Postoperative
80 47 35 162
43.4 54.8 51.4 48.4
25.4 28.1 18.4 25.3
0.105 0.105 0.105 0.105
Results of analysis of variance. a Post hoc tests = Dunnett T3 method. b Post hoc testsb = Tukey method.
1
0.038 0.255
2
3
b0.001
0.038 0.142
0.142
2
3
0.038
0.255 0.819
0.819
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and systemic inflammation. The present study was conducted on surgical patients admitted to an ICU, and almost all patients enrolled had lower serum Zn and Se levels than the reference norm. Furthermore, serum Se was lower in septic patients than in patients with trauma or simple postoperative patients. Sepsis was diagnosed in patients with panperitonitis associated with hollow viscus perforation (44; 55.0%) and in patients with intestinal obstruction and strangulation (23; 28.8%). These findings suggest that surgical sepsis is related to increased oxidative stress and that serum Se and Zn reductions were caused by antioxidation defensive mechanisms. We found no Se or Zn level differences between survivors and nonsurvivors, but significantly lower Se levels in patients with shock; of the 65 patients with shock, 40 had sepsis, whereas only 40 of the 97 patients without shock had sepsis (P = .015). This study is limited by its retrospective nature and relatively small patient numbers. However, few studies have been conducted to evaluate the effects of serum Se and Zn in surgical patients, and these were performed in cardiac patients, whereas in the present study, patients had experienced trauma or had gastrointestinal sepsis requiring surgical intervention or postoperative sepsis.
6. Conclusion Serum Se was found to be significantly lower in critically ill surgical patients with shock. In addition, Se levels were obviously more depressed in septic patients than in traumatic and simple postoperative patients. However, serum Se level was not found to affect mortality or hospital stay. On the other hand, serum Zn level was found to be significantly lower in septic patients than in traumatic patients. In this study, Se and Zn did not show any significance to predict the patient's outcome. To more precisely determine the roles of serum Se and Zn, a large-scale prospective study is needed.
References [1] Daniels LA. Selenium metabolism and bioavailability. Biol Trace Elem Res 1996;54: 185–99. [2] Linko R, Karlsson S, Pettila V, Varpula T, Okkonen M, Lund V, et al. Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand 2011;55:615–21. [3] Demling RH, DeBiasse MA. Micronutrients in critical illness. Crit Care Clin 1995;11:651–73. [4] Zamparelli R, Carelli G, Pennisi MA, Baruffi E, Schiavello R, Intonti MA, et al. Zinc and copper metabolism during open-heart surgery. Scand J Thorac Cardiovasc Surg 1986;20:241–5.
[5] Cornelisse C, Van der Sluys Veer J, Binsma JJ, Van den Hamer CJ. Investigation of the zinc status of surgical patients—II. Influence of vascular reconstruction on the zinc status. Int J Rad Appl Instrum B 1986;13:557–63. [6] Nuutinen LS, Ryhanen P, Pihlajaniemi R, Hollmen A, Tyrvainen L. The levels of zinc, copper, calcium and magnesium in serum and urine after heart-valve replacement. Effects of oxygenator type and postoperative parenteral nutrition. Infusionsther Klin Ernahr 1981;8:214–7. [7] Koszta G, Kacska Z, Szatmari K, Szerafin T, Fulesdi B. Lower whole blood selenium level is associated with higher operative risk and mortality following cardiac surgery. J Anesth 2012;26:812–21. [8] Alfieri MA, Leung FY, Grace DM. Selenium and zinc levels in surgical patients receiving total parenteral nutrition. Biol Trace Elem Res 1998;61:33–9. [9] Stoppe C, Schalte G, Rossaint R, Coburn M, Graf B, Spillner J. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients. Crit Care Med 2011;39: 1879–85. [10] Shim H, Jang JY, Lee SH, et al. Correlation of the oxygen radical activity and antioxidants and severity in critically ill surgical patients—study protocol. World J Emerg Surg 2013;8:18. [11] Marshall JC, Vincent JL, Guyatt G, Angus DC, Abraham E, Bernard G, et al. Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum. Crit Care Med 2005;33: 1708–16. [12] Victor VM, Espulgues JV, Hernandez-Mijares A, Rocha M. Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondriatargeted antioxidants. Infect Disord Drug Targets 2009;9:376–89. [13] Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth 2011;107:57–64. [14] Burk RF. Selenium: recent clinical advances. Curr Opin Gastroenterol 2001;17: 162–6. [15] Manzanares W, Biestro A, Galusso F, Torre MH, Manay N, Pittini G, et al. Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill? Intensive Care Med 2009;35:882–9. [16] Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P. Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 1998;26:1536–44. [17] Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R. Selenium replacement in patients with severe systemic inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27:1807–13. [18] Prasad AS. Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Biol 2012;26:66–9. [19] Lansdown AB, Mirastschijski U, Stubbs N, Scanlon E, Agren MS. Zinc in wound healing: theoretical, experimental, and clinical aspects. Wound Repair Regen 2007;15:2–16. [20] Besecker BY, Exline MC, Hollyfield J, Phillips G, Disilvestro RA, Wewers MD, et al. A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr 2011;93:1356–64. [21] Manzanares W, Biestro A, Torre MH, Galusso F, Facchin G, Hardy G. High-dose selenium reduces ventilator-associated pneumonia and illness severity in critically ill patients with systemic inflammation. Intensive Care Med 2011;37: 1120–7. [22] Alhazzani W, Jacobi J, Sindi A, Hartog C, Reinhart K, Kokkoris S, et al. The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2013;41: 1555–64. [23] Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013;368:1489–97.
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Serum selenium and zinc levels in critically ill surgical patients☆,☆☆,★,★★ Ji Young Jang, MD a, Hongjin Shim, MD b, Seung Hwan Lee, MD a, Jae Gil Lee, MD, PhD a,⁎ a b
Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea Department of Surgery, Yonsei University Wonju College of Medicine, Wonju-si, Republic of Korea
a r t i c l e Keywords: Selenium Zinc Critically ill Surgical
i n f o
a b s t r a c t Purpose: The authors designed this study to determine how serum selenium and zinc affect the outcomes of critically ill surgical patients. Methods: The medical records of 162 patients admitted to a surgical intensive care unit (ICU) from October 2010 to July 2012 and managed for more than 3 days were retrospectively investigated. Results: Overall, the mean patient age was 61.2 ± 15.0 years, and the median ICU stay was 5 (3-115) days. The mean Acute Physiologic and Chronic Health Evaluation II score was 18.0 ± 8.0. Eighteen (11.1%) of the study subjects died in ICU. mean selenium levels were 83.5 ± 23.8 ng/dL in the survivor group and 83.3 ± 29.6 ng/ dL in the nonsurvivor group, and corresponding mean zinc levels were 46.3 ± 21.7 and 65.6 ± 41.6 μg/dL, respectively. Mean selenium concentrations were significantly different in patients with and without shock (77.9 ± 25.4 and 87.2 ± 23.1 ng/dL, P = .017). Furthermore, mean serum selenium was lower in patients with sepsis than in traumatic or simply postoperative patients (P b .001 and P = .038). Serum Zn was significantly lower in patients with sepsis than in patients with trauma (43.4 ± 25.4 μg/dL vs 54.8 ± 28.1 μg/dL, P = .038). Conclusions: To determine the effects of serum selenium and zinc levels on critically ill surgical patients, a large-scale prospective study is needed. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
1. Introduction Selenium (Se) is an essential trace element with antioxidative, anti-inflammatory, and immunologic functions. It is an essential component of glutathione peroxidase, which reduces reactive oxygen species (ROS), especially superoxide [1]. On the other hand, zinc (Zn) is an essential trace element with many physiological functions, for example, in the immune system and during wound healing and growth [2,3]. Many authors have examined the roles of serum Se and Zn in critically ill patients, and deficiencies in these elements have been associated with systemic inflammatory response syndrome (SIRS) and sepsis. However, the effects of serum Se and Zn on outcomes and pathophysiology remain debatable. Furthermore, few
☆ Presented at the 24th European Society of Parenteral and Enteral Nutrition (ESPEN) Congress on Clinical Nutrition and Metabolism, Barcelona, Spain, 2012. ☆☆ Competing interests: The authors have no potential conflict of interest to declare. ★ Financial support: This research was supported by the Basic Science Research Program of the National Research Foundation of Korea funded by the Korea Ministry of Education, Science, and Technology (Grant No. 2012R1A1A2007915). ★★ Authors' contributions: L.J.G. designed and J.J.Y. wrote the manuscript. S.H., L.S.H., and L.J.G. read and approved the final manuscript. ⁎ Corresponding author. Department of Surgery, Yonsei University College of Surgery, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: +82 2 2228 2100; fax: +82 2 313 8289. E-mail address: [email protected] (J.G. Lee).
studies have addressed the association between serum Se and Zn on surgical outcomes [4–9] or on critically ill surgical patients [10]. Accordingly, the purpose of this study was to evaluate the relationships between serum Se and Zn levels on the outcomes of critically ill surgical patients. 2. Patients and methods The medical records of 162 surgical patients admitted to a surgical intensive care unit (ICU) from October 2010 to July 2012 were reviewed. All 162 study subjects were managed in an ICU for more than 3 days. Medical records were reviewed retrospectively, and the following parameters were recorded and analyzed: age, sex, Acute Physiologic and Chronic Health Evaluation (APACHE) II scores, duration of ICU admission, duration of mechanical ventilation, presence or occurrence of septic shock, and mortality. Variables are presented as mean values and SDs, or as medians and ranges. Blood was drawn on the first ICU day for serum Se and Zn testing. Causes of ICU admissions were categorized as sepsis, trauma, and postoperative care without sepsis. Sepsis was defined as SIRS combined with infection. In this study, patients with peritonitis due to a perforated hollow viscus or bowel infarction were classified as having sepsis. Shock was defined as a mean blood pressure of less than 65 mm Hg or a decrease in systolic blood pressure greater than 40 mm Hg vs baseline systolic blood pressure. Patients with perfusion failure, such
0883-9441/$ – see front matter. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2013.12.003
317.e6
J.Y. Jang et al. / Journal of Critical Care 29 (2014) 317.e5–317.e8
Fig. 1. Flow diagram of the study.
as, oliguria, mental change, and organ failure, or administered a vasopressor were included. All statistical calculations were performed using SPSS version 20.0 (SPSS, Inc, Chicago, Ill). t Test and analysis of variance were used to identify clinical variables associated with outcomes. Statistical significance was accepted for P b .05. This study was approved by the Severance Hospital institutional review board (institutional review board approval no. 2013-0015-001). 3. Tests for serum Se and Zn About 10 mL of blood was drawn from peripheral vein or central catheter on the first ICU day for serum Se and Zn testing. This blood was centrifuged at 3000 rpm for 10 minutes and then serum samples were sent to the outside laboratory at room temperature. Selenium expressed in nanograms/milliliter was measured by graphite furnace atomic absorption spectrometry with Atomic Absorption Spectrometer–Graphite Furnace (VARIAN, Sydney, Australia) using a hollow cathode lamp source at λ = 196.0 nm. The reference value of serum Se is 95.0 to 165.0 ng/mL. Serum Zn was analyzed by inductively coupled plasma-mass spectrometry using the Varian 820-MS system (VARIAN). The reference value for serum Zn is 66 to 110 μg/dL. Table 1 Patient characteristics Variable Age (y) Sex (male) HTN DM Chronic kidney disease Coronary artery occlusive disease Malnutrition Obesity APACHE II score ICU stay (d) Duration of MV (d) Se (ng/dL) Zn (μg/dL) Causes of admission Sepsis Trauma Postoperative Procalcitonin in sepsis patients(ng/mL) Shock Mortality
n
%
103 57 31 10 13 15 40
63.6 35.2 19.1 6.2 8.0 9.3 24.7
61.2 ± 15.0
4.1. Demographics A total of 162 patients were enrolled, and 103 (63.6%) were men. The mean patient age was 61.2 ± 15.0 years, and the median length of ICU stay was 5 (3-115) days. The mean APACHE II score was 18.0 ± 8.0. Eighty-nine patients were supported by mechanical ventilation for 2 (1-38) days. Sixty-five patients (40.1%) experienced shock. One hundred thirty-six of the study subjects underwent surgical intervention. Twenty patients with trauma were managed conservatively, and 6 patients with sepsis were managed nonoperatively. Ninety-five (69.9%) of the 136 underwent an emergency operation. The major cause of ICU admission was sepsis (80; 49.4%), and this was followed by trauma (47; 29.0%) and postoperative care (35; 21.6%). Of the 80 patients with sepsis, 44 (55.0%) had panperitonitis due to a bowel perforation and 23 (28.8%) had an intestinal obstruction with strangulation. Seven patients underwent operations due to necrotizing pancreatitis, necrotizing fasciitis, intestinal obstruction without strangulation, and postoperative hemorrhage. Six patients were managed conservatively without operation (Fig. 1). Sixty-five (40.1%) patients experienced shock, and 18 of these patients died. Mean serum levels of Se and Zn on the first ICU day were 83.5 ± 24.4 ng/dL and 48.4 ± 25.3 μg/dL, respectively (Table 1).
4.2. Selenium, Zn, and mortality When patients were dichotomized as survivors (n = 144) and nonsurvivors (n = 18), mean APACHE II scores (17.3 ± 7.8 vs 23.3 ± 8.3) and durations of mechanical ventilation (2 [1-24] days vs 6 [1-38]
18.0 ± 8.0 5 (3-115) 2 (1-38) 83.5 ± 24.4 48.4 ± 25.3 80 47 35 76 65 18
4. Results
49.4 29.0 21.6 9.47 (0-200) 40.1 11.1
HTN indicates hypertension; DM, diabetes mellitus; MV, mechanical ventilation.
Table 2 Comparison between survivors and nonsurvivors
Age (y) APACHE II Hospital stay (d) ICU stay (d) Duration of MV (d) Se level (ng/dL) Zn level (μg/dL) Results of Student t test.
Survivors (n = 144)
Nonsurvivors (n = 18)
P
61.0 ± 15.0 17.3 ± 7.8 18.5 (3-201) 5 (3-38) 2 (1-24) 83.5 ± 23.8 46.3 ± 21.7
62.4 ± 14.9 23.3 ± 8.3 29 (3-114) 10 (3-115) 6.0 (1-38) 83.3 ± 29.6 65.6 ± 41.6
.701 .002 .482 .036 .004 .966 .068
J.Y. Jang et al. / Journal of Critical Care 29 (2014) 317.e5–317.e8 Table 3 Differences between patients without shock and patients with shock
Sepsis (n) Se level (ng/dL) Zn level (μg/dL)
Without shock (n = 97)
With shock (n = 65)
P
40 (41.2%) 87.2 ± 23.1 50.2 ± 24.2
40 (61.5%) 77.9 ± 25.4 45.8 ± 26.7
.015 .017 .273
Results of Student t test.
days) were nonsignificantly different between the 2 groups. Furthermore, mean Se levels (83.5 ± 23.8 ng/dL vs 83.3 ± 29.6 ng/dL, respectively; P = .966) and mean Zn levels (46.3 ± 21.7 μg/dL vs 65.6 ± 41.6 μg/dL, respectively; P = .068) were also nonsignificantly different (Table 2). 4.3. Selenium, Zn, and shock Mean Se levels were significantly different between the nonshock and shock groups (87.2 ± 23.1 ng/dL vs 77.9 ± 25.4 ng/dL, respectively; P = .017). However, mean Zn levels were not significantly different (50.2 ± 24.2 μg/dL vs 45.8 ± 26.7 μg/dL, respectively; P = .273; Table 3). 4.4. Selenium, Zn, and causes of ICU admission Patients were also classified according to sepsis (80; 49.4%), trauma (47; 29.0%), and postoperative status (35; 21.6%). Mean serum Se was significantly lower in the sepsis group (75.7 ± 26.7 ng/dL) than in the trauma group (94.6 ± 19.8 ng/dL, P b .001) and in the postoperative status group (86.4 ± 17.6 ng/dL, P = .038). In addition, serum Zn was significantly lower in patients with sepsis than in patients with trauma (43.4 ± 25.4 μg/dL vs 54.8 ± 28.1 μg/dL, P = .038). However, the mean serum Zn levels of patients with sepsis and simple postoperative patients were not significantly different (43.4 ± 25.4 μg/dL vs 51.4 ± 18.4 μg/dL, respectively; P = .255; Table 4). 5. Discussion Sepsis is the common cause of death in ICUs, and the mortality rate is 25% in cases of uncomplicated sepsis and up to 50% to 80% in patients with multiple-organ failure [11]. Reactive oxygen species produced during electron transport in the inner membrane of mitochondria exhibit strong tissue toxicity, and thus, several antioxidant defense systems have evolved to remove ROS [12]; known components of the antioxidant defense system include
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superoxide dismutase, catalase, ascorbic acid, α-tocopherol, and glutathione peroxidase [12]. The balance between ROS production and antioxidant protection is referred to as oxidative balance [13]. In sepsis, endotoxins produced by invading bacteria induce inflammatory responses; by up-regulating proinflammatory cytokine, ROS, and nitric oxide levels; and by promoting the leukocyte adhesion and migration [12]. Accordingly, inflammatory response increases intracellular oxidative stress, resulting in mitochondrial dysfunction and enhanced ROS production. Selenium acts as cofactor of glutathione peroxidase and as an important component of the antioxidant defense system and, thus, facilitates its physiologic function [14]. Furthermore, serum levels of Se and glutathione peroxidase activity are positively correlated, and critically ill patients with SIRS exhibit depressed serum Se and glutathione peroxidase activity levels [15], which suggest that depressed serum Se is associated with elevated ROS production and inflammatory response. Furthermore, Se levels in critically ill patients with SIRS or sepsis have been shown to be correlated with mortality [16,17]. Zinc acts as a cofactor of numerous transcription factors and enzyme systems and is involved in cell-mediated innate immunity, wound healing, and growth [18,19]. Furthermore, it has been reported that in critically ill patients under ICU care, plasma Zn levels were lower in patients with sepsis [20]. Thus, it appears that serum Se and Zn deficiencies are related to SIRS and sepsis, and thus, many studies have been conducted to evaluate their effects on outcomes and the effects of their intravenous (IV) augmentation. In critically ill patients with SIRS or sepsis, IV high-dose Se infusion reduced the occurrences of early ventilator-associated pneumonia and hospital-acquired pneumonia, rapidly reduced Sequential Organ Failure Assessment scores [21], and reduced mortality [22]. However, a recent study found no differences between 500 μg IV Se, 300 μg IV Se, 20 mg of Zn, antioxidant, and control groups in terms of 28-day mortality, length of ICU stay, length of hospital stay, or duration length of mechanical ventilation [23]. Thus, in critically ill patients with SIRS or sepsis syndrome, serum levels of Se and Zn are depressed, but their IV replacement remains controversial. Most of the previous studies have focused on ICU patients with SIRS or sepsis, and relatively few have addressed surgical patients. Furthermore, most studies have focused on serum Zn levels [4–6,8]. In cardiac surgery patients, Se was found to be decreased postoperatively [9] and to be associated with operative risk and mortality [7]. In a study by Linko et al [2], serum Zn levels in operative patients were significantly lower than in nonoperative patients, which suggests that surgery might increase oxidative stress
Table 4 Selenium and Zn levels with respect to reasons for ICU admission
Se (ng/dL) Zn (µg/dL)
1 2 3
1 2 3
Sepsis (n = 80)
Trauma (n = 47)
Postoperative (n =35)
F
P
75.7 ± 26.7 43.4 ± 25.4
94.6 ± 19.8 54.8 ± 28.1
86.4 ± 17.6 51.4 ± 18.4
10.309 3.394
b.001 .036
Sea
n
Mean
SD
Homogeneity of variance
Sepsis Trauma Postoperative
80 47 35 162
75.7 94.6 86.4 83.5
26.7 19.8 17.6 24.4
0.018 0.018 0.018 0.018
b0.001 0.038
Znb
N
Mean
SD
Homogeneity of variance
1
Sepsis Trauma Postoperative
80 47 35 162
43.4 54.8 51.4 48.4
25.4 28.1 18.4 25.3
0.105 0.105 0.105 0.105
Results of analysis of variance. a Post hoc tests = Dunnett T3 method. b Post hoc testsb = Tukey method.
1
0.038 0.255
2
3
b0.001
0.038 0.142
0.142
2
3
0.038
0.255 0.819
0.819
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J.Y. Jang et al. / Journal of Critical Care 29 (2014) 317.e5–317.e8
and systemic inflammation. The present study was conducted on surgical patients admitted to an ICU, and almost all patients enrolled had lower serum Zn and Se levels than the reference norm. Furthermore, serum Se was lower in septic patients than in patients with trauma or simple postoperative patients. Sepsis was diagnosed in patients with panperitonitis associated with hollow viscus perforation (44; 55.0%) and in patients with intestinal obstruction and strangulation (23; 28.8%). These findings suggest that surgical sepsis is related to increased oxidative stress and that serum Se and Zn reductions were caused by antioxidation defensive mechanisms. We found no Se or Zn level differences between survivors and nonsurvivors, but significantly lower Se levels in patients with shock; of the 65 patients with shock, 40 had sepsis, whereas only 40 of the 97 patients without shock had sepsis (P = .015). This study is limited by its retrospective nature and relatively small patient numbers. However, few studies have been conducted to evaluate the effects of serum Se and Zn in surgical patients, and these were performed in cardiac patients, whereas in the present study, patients had experienced trauma or had gastrointestinal sepsis requiring surgical intervention or postoperative sepsis.
6. Conclusion Serum Se was found to be significantly lower in critically ill surgical patients with shock. In addition, Se levels were obviously more depressed in septic patients than in traumatic and simple postoperative patients. However, serum Se level was not found to affect mortality or hospital stay. On the other hand, serum Zn level was found to be significantly lower in septic patients than in traumatic patients. In this study, Se and Zn did not show any significance to predict the patient's outcome. To more precisely determine the roles of serum Se and Zn, a large-scale prospective study is needed.
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