Julian Diaz

Oxidative stress in critically ill patients with systemic inflammatory response syndrome

ObjectiveTo evaluate whether critically ill patients with systemic inflammatory response syndrome, on admission to an intensive care unit, had more severe oxidative stress than those without this syndrome. DesignA prospective, cohort study. SettingA mixed medical and surgical adult intensive care unit with 12 beds. PatientsA total of 68 consecutive patients admitted to the intensive care unit. InterventionsVenous blood samples were routinely obtained within 24 hrs of admission. Measurements and Main ResultsPatients’ plasma total antioxidant capacity, the lipid peroxidation products malondialdehyde and 4-hydroxynonenal, reduced sulfhydryl groups, and nitrites/nitrates were measured by spectrophotometric technique at admission to the intensive care unit. Myeloperoxidase (enzyme-linked immunosorbent assay) and polymorphonuclear elastase (immuno-activation assay) were also measured on admission to the intensive care unit. The patients with criteria of systemic inflammatory response syndrome (n = 20) had higher Acute Physiology and Chronic health Evaluation III scores (determined by collecting the worst value within 24 hrs after admission to the intensive care unit) and plasma concentrations of lipid peroxidation products and nitrites/nitrates and lower plasma concentration of reduced sulfhydryl groups and plasma total antioxidant capacity than patients without the syndrome (n = 48). Moreover, the markers for leukocyte activation, myeloperoxidase and polymorphonuclear elastase, presented higher concentrations in the plasma of patients with systemic inflammatory response syndrome. ConclusionsPatients admitted to the intensive care unit with criteria of systemic inflammatory response syndrome had a more severe oxidative stress than patients without this syndrome.

Plasma redox status relates to severity in critically ill patients

Objective To determine the relation between plasma redox status and severity of illness for patients admitted to an intensive care unit (ICU). Design A prospective cohort study. Setting A mixed medical and surgical adult ICU with 12 beds. Patients A total of 73 consecutive patients admitted to the ICU. Interventions Venous blood samples were routinely obtained within 24 hrs of admission. Measurements and Main Results Plasma total antioxidant capacity and lipoperoxides were measured by spectrophotometric technique at admission to the ICU. The plasma ratio total antioxidant capacity (mM)/lipoperoxides (&mgr;M) was used as an index of plasma redox status. Plasma concentration of the markers of leukocyte activation myeloperoxidase (enzyme-linked immunosorbent assay) and polymorphonuclear-elastase (immunoactivation assay) were also measured at admission to the ICU. Analysis of correlation between plasma ratio total antioxidant capacity/lipoperoxides and APACHE III score showed a negative association (p < .001, Spearman correlation test). Myeloperoxidase and polymorphonuclear-elastase correlated positively with Acute Physiology and Chronic Health Evaluation III scores (r2 = 0.58;p < .001; and r2 = 0.05;p = .035; respectively). Conclusions Plasma redox status relates to severity in critically ill patients. We propose that it would be reasonable to provide antioxidant therapy as part of routine management of patients admitted to a mixed ICU, regardless of the specific reason for ICU admission. Plasma redox status might become useful to evaluate the risk in critically ill patients.

Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes

Objective To assess the association of hot flushes during postmenopause with oxidative stress and to determine whether hormone replacement therapy (HRT) affects the plasma redox status of postmenopausal women. Methods We conducted a prospective clinical study of 49 postmenopausal women who have (n = 29) or do not have (n = 20) hot flushes. Twelve of the postmenopausal women with hot flushes and six without were treated with HRT (estradiol patches and medroxyprogesterone acetate) for 4 months. Plasma level of estradiol, total antioxidant status, reduced sulfhydryl groups, lipoperoxides, total cholesterol, and triglycerides were measured at 4-month intervals in both groups, before and after treatment. Results Postmenopausal women who have hot flushes, had lower total basal antioxidant status in plasma (.9 ± .01 compared with 1.14 ± .01 mmol/L), lower concentration of reduced sulfhydryl groups (145 ± 4 compared with 200 ± 3 μmol/L), and higher concentration of lipoperoxides (2.88 ± .04 compared with 2.61 ± .04 μmol/L) than women without hot flushes. After HRT, total antioxidant status and reduced sulfhydryl groups increased, and lipoperoxides decreased similarly in both groups. Hormone replacement therapy decreased the frequency of hot flushes per day from 11.2 ± 0.8 to 1.4 ± 0.3. Conclusion Hot flushes in postmenopausal women were associated with the oxidative process. Hormone replacement therapy decreases oxidative stress and the number of episodes of hot flushes. Because oxidative stress is associated with a high risk for cardiovascular diseases, HRT might protect women with hot flushes.

Depletion of liver glutathione potentiates the oxidative stress and decreases nitric oxide synthesis in a rat endotoxin shock model.

Objective To verify the effects of liver glutathione depletion on redox status and nitric oxide system in a rat endotoxic shock model. Design Prospective, randomized, controlled study on rats. Setting A cardiocirculatory research laboratory. Subjects A total of 28 Sprague-Dawley male rats (200–250 g body weight) were divided into four experimental groups. Interventions Arterial blood, liver, and lung samples were taken from each animal under sodium pentobarbital (40 mg/kg ip) anesthesia 4 hrs after lipopolysaccharide (LPS group: 5 mg/kg ip; n = 7) or vehicle (control group: isotonic NaCl sterile solution ip; n = 7) treatments,. Phorone (250 mg/kg ip) was injected to deplete glutathione in another two experimental groups of rats 30 mins before LPS (phorone+LPS group; n = 7) or vehicle (phorone group; n = 7) treatments, and 4 hrs later the same samples as in LPS and control groups were taken under anesthesia. Measurements and Main Results Compared with the control group, the LPS group presented higher plasma concentration of end products of nitric oxide metabolism nitrites/nitrates, higher lung activity of inducible nitric oxide synthase, and oxidative stress defined by increased plasma concentration of the lipid peroxides malonaldehyde and 4-hydroxynonenal, and decreased plasma total antioxidant capacity. Treatment with phorone depleted liver glutathione (80% to 90%). In the liver glutathione-depleted animals, the oxidative stress induced by LPS was potentiated and blunted the increases in inducible nitric oxide synthase and plasma nitrites/nitrates. Conclusion These results show that depletion of the liver glutathione increases the oxidative stress and decreases nitric oxide synthesis of LPS-induced shock in rats.

Implication of soluble and membrane HLA class I and serum IL-10 in liver graft acceptance

Membrane HLA class-I expression (mHLA-I), soluble HLA class-I antigens (sHLA-I) and interleukin (IL)-10 are different factors implicated in the special acceptance of liver allograft. In this study, pre- and post-operative levels of mHLA-I in peripheral blood lymphocytes (PBL) and serum sHLA-I were analyzed in 86 liver transplants, immunosuppressed with Cyclosporine-A, methylprednisolone and azathioprine, and classified into acute-rejection (AR, n = 28) and non-acute-rejection (NAR, n = 58) groups. Serum IL-10 was studied in 47 recipients (AR-group, n = 16 and NAR-group, n = 31). Pre-transplant values of mHLA-I and sHLA-I showed a bimodal distribution (high/low) in NAR-recipients, but in AR-patients were mainly included in the low expression/secretion zone (mHLA-I, p < 0.02 and sHLA-I, p < 0.05). Consequently, average pre-transplant mHLA-I (868 +/- 109 versus 998 +/- 123, p < 0.05) and sHLA-I (1.3 +/- 0.4 versus 2.02 +/- 0.7 microg/ml, p < 0.01) was lower in the AR- than in the NAR-group. After transplant both parameters decreased in the NAR-group, but increased in AR-recipients previous to and on rejection diagnosis day. Additionally, serum IL-10 levels were significantly higher (p < 0.01) in the NAR than in the AR-group during the first 24 h post-transplant. In conclusion, low pre-transplant mHLA-I and sHLA-I levels pre-dispose liver recipients to acute rejection, whereas early post-transplant increases of serum IL-10 appear to be related to a good liver allograft acceptance.

N-acetylcysteine Exerts Protective Effects and Prevents Lung Redox Imbalance and Peroxynitrite Generation in Endotoxemic Rats

The aim of this study was to determine in endotoxemic rats the effects of N-acetylcysteine on lung redox imbalance and plasma peroxynitrite generation. Eighty male Wistar rats were divided in two sets of five experimental groups. Six hours after vehicle (Control group: isotonic NaCl sterile solution i.p.; n=7), lipopolysaccharide (LPS group: 1 mg/Kg i.p.; n=8), N-acetylcysteine plus LPS (NAC+LPS group, n=8), NAC plus the nitric oxide synthesis inhibitor N(w)-nitro-L-arginine methyl ester plus LPS (NAC+NAME+LPS group; n=8), or NAME plus LPS (NAME+LPS group; n=9), arterial blood and lung samples were taken from each animal under sodium pentobarbital anesthesia. In five additional groups treated as described above, in vivo plasma oxidation of dihydrorhodamine (DRH) 123 to rhodamine (RH)123 was measured as index of peroxynitrite formation. LPS treated rats presented increased plasma lactate, thrombocytopenia and both, decreased reduced thiols and increased lipid peroxidation in lung tissue. Moreover, LPS produced increments in plasma concentration of nitrites/nitrates and DRH 123 oxidation. Pretreatment with NAC prevented all these changes induced by LPS except the increment in plasma concentration of nitrites/nitrates. The protective effects seen in LPS rats pretreated with NAC were not observed in the NAC+NAME+LPS group. In conclusion, the results of this study show that in endotoxemia induced by LPS in rats, NAC produces protective effects on lung redox balance and prevents peroxynitrite anion generation.

Preoperative metabolic profile of patients undergoing orthotopic liver transplantation.

To the Editor:It is shown that the progressive alteration of the liver and kidney functions complicates the preoperative management of patients treated with orthotopic liver transplantation (OLT) and unbalances metabolic and hemodynamic stability (1, 2). Our aim is to establish the preoperative metabolic profile of the OLT patient and determine whether there are differences between patients with acute or chronic hepatic insufficiency. With the consent of our hospital’s Clinical Research Committee, we studied 81 adult patients undergoing OLT classified into two groups:cirrhosis group(n 5 62) and fulminant hepatic failure group(n 5 19). In the first group, the decision to indicate OLT was based on diagnoses of: alcoholic cirrhosis (n 5 34), postnecrotic cirrhosis (n5 22), and primary biliary cirrhosis (n 5 6); whereas for the second group was: viral (n 5 15) and unknown etiology (n 5 4). According to the Child-Pugh classification, we classed the cirrhotic patients as: stage B (n 5 33) and stage C (n 5 29). In the patients with fulminant hepatic failure, the time between indication for OLT and surgery was 446 19 hr (range 8–61). Ages were: 38 6 19 yr (range 20–59) for the fulminant hepatic failure group; and 486 13 yr (range 18–60) for the cirrhosis group. Females predominated in the fulminant hepatic failure (13 females and six males) and males in the cirrhosis group (48 males and 14 females). The anesthetic technique was the same for both groups and was induced with the standard technique. The metabolic profile consisted of 16 clinical laboratory parameters determined in arterial blood samples collected immediately before the anesthesia induction and were considered as preoperative values. The Mann-Whitney test was used to compare the mean parameters between groups. The results of laboratory parameters are expressed in Table 1. The preoperative metabolic status of both groups of patients shows that the acid-base balance is within reference values. The difference is in the concentration of plasma lactate, which in the fulminant hepatic failure group exceeds the range of reference, but as there is no decrease in plasma bicarbonate levels or bases deficit, it can be deduced that the accumulation of plasma lactate in these patients is the result of the decrease in liver metabolism rather than excess production (3). The preoperative glucemia values are discretely above normal in both groups. This finding is interesting as there are authors who have reported the existence of hypoglucemia in patients with fulminant hepatic failure (4, 5). Ammonia is another of the metabolic parameters, which in fulminant hepatic failure group exceeds the interval of reference as its clearing depends on the metabolism of the liver (6, 7). There are a number of metabolic magnitudes, the blood concentrations of which are closely related to kidney function and which are often affected by hepatic insufficiency (1, 4–7). These include potassium, total magnesium, ionized magnesium, total calcium and ionized calcium, sodium, osmolality, and blood urea nitrogen. In our two groups, they all remained within their corresponding range of reference. In conclusion, the preoperative metabolic status of patients with acute or chronic hepatic insufficiency treated with OLT is well conserved, as most of the parameters assessed remain within the range of reference. However, any alteration suggests that the metabolic function of the liver is more affected in the patients with fulminant hepatic failure.