Prognosis and Prediction Prognostic value of serum zinc levels in critically ill patients

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Introduction
Critically ill patients are those who are dependent on advanced monitoring instruments and therapy for survival because of dysfunction or failure of 1 or more organs/ systems [1]. These patients have immediate requirement for any form of organ support such as intubation, ventilation, and inotropes or are likely to experience acute cardiac, respiratory, or neurological deterioration, requiring such support.
Recently, the number of critically ill patients has increased because of prolongation of life in the general population and developments in medical aspects. Because of this increase in the number of cases, medical care given to critically ill patients has begun to be one of the most popular issues of modern medicine. Several studies have been conducted in the literature with critically ill patients with regard to prognostic factors, nutrition, intensive care unit scoring systems (eg, Acute Physiology and Chronic Health Evaluation [APACHE] II and Sequential Organ Failure Assessment [SOFA] scores) [2][3][4][5].
Critically ill patients are generally exposed to an increased oxidative stress, which is proportional to the severity of their condition [2,3,6]. A network of functionally overlapping antioxidant defense mechanisms aims at protecting cells from reactive oxygen and nitric oxide species [7]. It is formed by trace element-dependent enzymes such as superoxide dismutase, catalase, and glutathione peroxidase.
Zinc is a trace element that is essential for life and required for normal function of many enzymes and transcription-related factors. Intact zinc homeostasis must be present for normal function of the immune system, oxidative stress responses, glucose control, neurocognitive function, and wound healing [8][9][10][11]. Zinc is found in all tissues and cells. The regulation of zinc homeostasis in the whole body is tightly controlled by intestinal absorption and intestinal and renal excretion [12]. The primary functions of zinc are carried out at the intracellular level.
Inflammation and infection are known to be associated with reduced plasma levels of zinc. It has been shown that zinc is acutely redistributed from the serum to other tissues, particularly the liver, where zinc is required for the synthesis of acute phase proteins [13]. In the setting of acute severe dietary zinc deficiency, the fractional absorption of zinc increases to nearly 100%, and excretion in feces and urine is essentially eliminated [12]. However, in several studies, initiation of the stress response has resulted in acutely increased urinary zinc excretion [14]. Thus, the normal regulatory mechanisms for zinc homeostasis may be initially impaired in the setting of the stress response, resulting in an acute decrease in zinc availability stemming from increased tissue sequestration of zinc and increased zinc excretion [8,15].
In this prospective study, we explored the hypothesis that a decline in serum zinc concentrations among critically ill patients is related to mortality, length of stay in the intensive care unit and in the hospital, and APACHE II and SOFA scores.

Methods
This study was conducted in accordance with the requirements of local ethical committee and was in compliance with the Helsinki Declaration.

Patients
This prospective study was conducted in the intensive care unit of Selcuk University Meram Faculty of Medicine, emergency medicine department. All patients (≥18 years old) admitted to the intensive care unit from September 2009 through November 2009 were enrolled the study within the first 24 hours after admission. Burn victims, alcoholics, and patients with gastrointestinal (GI) fistulae and severe diarrhea were excluded from the study.

Protocol
The demographic characteristics of patients, such as age and sex, and APACHE II and SOFA scores were recorded. Blood samples were collected in the first 24 hours after admission to the intensive care unit. For analysis of serum zinc, copper, C-reactive protein (CRP), and albumin levels, 5 mL of venous blood was placed into vacutainer tubes and metal-free tubes.
The patients were followed up for the length of stay in the intensive care unit, length of stay in the hospital, and 28-day mortality until they were discharged from the hospital or died. Patients who were transferred from the intensive care unit to a ward were followed up for a maximum of 28 days.

Data analysis
Descriptive statistics were computed for age, sex, APACHE II score, SOFA score, length of stay in intensive care unit, length of stay in the hospital, and 28-day mortality. The overall mean serum zinc, copper, CRP, albumin levels, and the zinc-albumin ratio were calculated.
The patients were divided into groups as those with APACHE scores lower than 25 and 25 or higher, those with SOFA scores lower than 8 and 8 or higher, and survivors and nonsurvivors. For each group, the serum zinc, copper, and CRP levels; zinc-albumin ratios; and length of stay in the intensive care unit and hospital were computed. The differences between the groups for these parameters were compared using the Mann-Whitney U test.
Correlations of serum zinc levels and zinc-albumin ratios with CRP levels, APACHE II scores, SOFA scores, and the length of stay in intensive care unit and in the hospital were examined using simple linear regression and Spearman correlation.
Data analysis was performed using SPSS 13.0 software.

Results
A total of 36 patients were enrolled during the study period. The median age of patients was 70.5 years (range, 18-87 years). Of 36 patients, 19 (52.8%) were female and 17 (42.7%) were male. The median APACHE II score was 17.5 (range, 7-39), the median SOFA score was 4.5 (range, 0-16), the median length of stay in the intensive care unit was 3.5 days (range, 1-28 days), and the median length of stay in the hospital was 9.5 days (range, 1-28 days). Of 36 patients, 6 died during the study period. The mortality rate was 16.7% (Table 1).
Blood samples were obtained from a total of 36 patients who had been included in the study in the first 24 hours after having been admitted to the intensive care unit. Serum zinc, copper, albumin, and CRP levels and zinc-albumin ratios were tabulated in Table 2. Only 4 (11%) of 36 patients had normal serum zinc levels (11.1-19.5 μmol/L), whereas 34 (94%) of 36 patients had normal serum copper levels (80-155 μg/dL). Zinc-albumin ratios were parallel with serum zinc levels, and 4 (11%) patients had zinc-albumin ratios of higher than 0.40.
The correlations of serum zinc levels and zinc-albumin ratios with CRP levels, APACHE II scores, SOFA scores, and length of stay in the intensive care unit and in the hospital were assessed. Serum zinc levels were found to inversely correlate with SOFA scores (r = −0.41, P b .01) (Fig. 1).
There was no statistically significant correlation of zincalbumin ratios with CRP levels and APACHE II and SOFA scores.
The 36 patients were divided into 2 groups according to APACHE scores. Of these patients, 24 had APACHE II scores lower than 25 and 12 had scores of 25 or higher. There were no statistically significant differences between the groups in terms of serum zinc, copper, CRP, or albumin levels; zinc-albumin ratios; length of stay in the intensive care unit; and length of stay in the hospital ( Table 3).
The 36 patients were divided into 2 groups according to SOFA scores. Of these patients, 25 had SOFA scores lower than 8 and 11 had scores of 8 or higher. There was no statistically significant difference between the groups in terms of serum copper, CRP, or albumin levels; zinc-albumin ratios; length of stay in the intensive care unit; and length of stay in the hospital. The patients with SOFA scores of 8 or higher had significantly lower serum zinc levels compared with the patients with SOFA scores of lower than 8 (P b .01) ( Table 4).
The 36 patients were divided into 2 groups according to survival. Of these patients, 30 were survivors and 6 were nonsurvivors. There were no statistically significant differences between the groups in terms of serum zinc, copper, CRP, and albumin levels; zinc-albumin ratios; and length of stay in the intensive care unit. However, the length of stay in the hospital for nonsurvivors was significantly shorter than that of survivors (P b .01) ( Table 5).

Discussion
Today, one of the leading issues in critical care is nutrition. Nutritional support given to the patients in the catabolic phase is the most important factor that affects the length of stay in the intensive care unit and in the hospital, the prognosis, and the mortality of critically ill patients. Provision of adequate nutritional support to critically ill  patients also reduces the cost of the critical care. Studies about critical care have stated that trace elements should be added to the basic components of nutrition, such as lipids, carbohydrates, and proteins, in nutrition protocols [3,5,8,15]. The 5 important essential trace elements approved by the Food and Drug Administration for parenteral use are as follows: zinc, selenium, copper, chromium, and manganese. Of these, zinc is the most abundant in the body, mostly intracellular. Its role in wound healing has been appreciated for many years and hence its extensive use in burns [16]. Patients who are at risk for zinc deficiency at the time of admission include elderly patients from long-term care facilities, alcoholics, burn victims, and those with prolonged GI losses. Patients who develop GI fistulae, severe diarrhea, short bowel syndrome, and pancreatic insufficiency are also at high risk for developing zinc deficiency [17]. For this reason, burn victims, alcoholics, and patients with GI fistulae and severe diarrhea were excluded from the study.
The commonest clinical manifestation of zinc deficiency in critically ill patients seems to be a peculiar rash, described as acrodermatitis enteropathica [18]. The rash is also often seen on the face around the ala nasi and in the gluteal areas. Other manifestations include glucose intolerance, abnormal hemostasis, loss of hair, altered taste and smell perception, and diarrhea. Zinc deficiency causes a decrease in the work capacity of muscles, with detrimental effects on respiratory function [19], and has been shown to increase respiratory tract infections [20] and worsen hepatic dysfunction [21].
In addition to being a cofactor in more than 300 enzymes, zinc is essential for membrane integrity, DNA synthesis, and cell proliferation, and thus, it is needed for all highly proliferating cells, especially the immune cells [22]. Zinc has been shown to play an important role in the regulation of the immune response, particularly T cellmediated function [23,24].
Much clinical research has focused on the antioxidant micronutrients vitamins C and E, copper, selenium, and zinc. Clinical trials have been carried out in sepsis, trauma, and burns, which are characterized by intense oxidative stress and inflammatory response. In a systematic review of randomized studies, overall antioxidant supplements were associated with a significant reduction in mortality [25].
One of the most important questions about zinc status in critically ill patients is the following: should serum zinc levels be measured in critically ill patients on admission and monitored during the stay in the intensive care? A prospective, randomized, double-blind, placebo-controlled study has confirmed that antioxidant micronutrient status is altered on admission in critically ill patients with organ failure [3]. The correlation between low plasma zinc levels and organ failure had been demonstrated in a pilot study conducted in an intensive care unit of a tertiary care children's hospital. Furthermore, the investigators found that low plasma zinc concentrations were common in critically ill children on admission [15]. In our study, serum zinc levels and zinc-albumin ratios of 89% of the patients were found to be below the reference ranges on admission to the intensive care unit. Moreover, serum zinc levels were found to inversely correlate with SOFA scores, and these data are in compliance with the literature. Another important problem in critically ill patient management is infections and related septic complications. Bacterial pathogens require zinc, so in effect, the decreased plasma zinc levels induced by the acute phase response could be protective by limiting zinc availability to bacteria. A temporary decrease in plasma zinc may also be beneficial in limiting the cytokine response during the inflammation [8,13]. However, in a recent study of genomic responses of children with systemic inflammatory response syndrome/ sepsis, decreased plasma zinc levels were associated with nonsurvival in the setting of septic shock [26]. In an experimental murine model of polymicrobial sepsis, subacute zinc deficiency significantly increased systemic inflammation, organ damage, and mortality [27]. In our study, there was no statistically significant relationship between serum zinc levels and mortality. However, the number of nonsurvivors in our study patients was only 6. We think that if the number of cases increases, the relationship between the low serum zinc levels and mortality can be demonstrated.
Because plasma copper levels are potentially subject to the same alterations in acute stress as plasma zinc, we also measured plasma copper concentrations in these patients. However, serum copper levels in our study were found to be in the reference ranges. These data suggest that alterations in serum zinc levels are specific in critically ill patients.

Conclusions
Serum zinc concentrations were found to inversely correlate to SOFA scores in this study. This result supports the fact that organ failure and critical illness lead to a decline in serum zinc concentrations and that zinc administration may be beneficial for critically ill patients. Furthermore, critically ill patients are at risk for zinc deficiency, and hence, zinc status must be monitored by clinicians.