The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients

Background

Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.

Methods

In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.

Results

During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).

Conclusion

High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.     

Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study

Most studies of pain, including chronic pain, agree that depression and pain are interrelated, although the neurobiology of this relationship remains unknown. Neuroimaging studies suggest a specific role of the prefrontal brain regions in the mechanisms of mood disorders and chronic pain. The present study examines the interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex, cingulate and thalamus), depression (as measured by the Beck Depression Inventory), and pain (as measured by short form of the McGill Pain Questionnaire) in 10 chronic back pain (CBP) patients with depression, and compared to the relationship between regional brain NAA levels and depression in 10 normal subjects (sex and age-matched). Reduction of NAA levels was demonstrated in the right DLPFC of CBP patients with depression, as compared to the normal controls (p < 0.02, two-tailed t-test). The depression levels in CBP patients were highly correlated with NAA levels in the right DLPFC (r = -0.99, p < 0.0001), and were unrelated to the other studied regional NAA in both groups, including the right DLPFC in normal subjects (p < 10(-6); comparing the difference between r values in the right DLPFC between the two groups). The pain levels in CBP patients were also associated with the right DLPFC (r = -0.62, p < 0.05), although these relationships were much weaker as compared to depression-NAA correlations (p < 0.0001; comparing the difference between r values). The interrelationships between NAA across brain regions were examined using correlation analysis, which detected different connectivity patterns between CBP patients with depression and normal subjects. These findings provide evidence for a stronger association of prefrontal NAA to depression than to pain in CBP, which may reflect the common neurobiological substrate underlying these conditions in CBP patients. Spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the depression and pain measures might be used for segregation of their circuitries in the chronic pain brain.     

The role of oxygen in thymocyte apoptosis

Signals generated by T cell receptor (TCR) cross-linking (or phorbol 12-myristate-13-acetate + Ca²⁺ ionophore), glucocorticoids or ionizing radiation all stimulate apoptotic cell death in thymocytes by signals that are initially distinct from each other. However, when these stimuli were administered to thymocyte cultures that were maintained under an atmosphere containing less than 20 ppm oxygen as opposed to one that contained 18.5 % molecular oxygen, cell death was inhibited or abrogated, suggesting that the induction of death by all three different stimuli depend on the presence of molecular oxygen. Studies of the effects of the cysteine analog N-acetyl cysteine (NAC) with normal thymocytes demonstrated that this antioxidant inhibited the induction of death by each of the different stimuli in a manner that paralleled anaerobiosis. Furthermore, studies with thymocytes demonstrated that the induction of nur77, a gene shown to be involved in thymocyte apoptosis signaled through the TCR or its surrogates, is not inhibited by NAC or dependent upon molecular oxygen. The possible implications for negative selection of NAC-mediated inhibition of TCR-signaled thymocyte cell death was examined in thymic organ culture. Treatment of these cultures with NAC provided significant protection against staphylococcal enterotoxin B-mediated deletion of Vβ8-expressing thymocytes.     

羧甲基壳聚糖、盐酸氨基葡萄糖及N-乙酰氨基葡萄糖对大鼠胰岛细胞生长及胰岛素分泌量的影响

通过胶原酶消化法获得大鼠胰岛单层细胞 ,并用转板以及碘乙酸处理的方法除去其中的成纤维细胞 ,得到比较纯的胰岛内分泌细胞 ,以此为材料研究了羧甲基壳聚糖、盐酸氨基葡萄糖、N 乙酰氨基葡萄糖对大鼠胰岛细胞生长和胰岛素释放的影响。实验结果表明 ,羧甲基壳聚糖、盐酸氨基葡萄糖、N 乙酰氨基葡萄糖均能够促进大鼠胰岛细胞的生长。采用放射免疫法测定培养的胰岛细胞分泌胰岛素含量 ,结果表明 ,羧甲基壳聚糖具有刺激大鼠胰岛细胞胰岛素释放的作用。     

Two Siblings with Complete Carbamyl Phosphate Synthetase I Deficiency

A female infant, who showed hyperammonemia in the neonatal period, died on 43rd postnatal day. Her female sibling also died on 42nd day after birth with an identical clinical picture and hyperammonemia. Urinary organic acids were negative in both cases. Their blood amino acids showed no specific pattern, and urinary orotic acid excretion was normal. The first two urea cycle enzymes and N-acetyl L-glutamate synthetase of the liver tissues of these two infants obtained at autopsy were assayed. They revealed a selective deficiency of carbamyl phosphate synthetase I.     

Magnetic resonance spectroscopy of brain in epilepsy

The current applications of magnetic resonance spectroscopy (MRS) in the clinical management of epileptic patients are reviewed. A major contribution of MRS to epilepsy is its ability to determine lateralisation before surgical resection of the diseased brain region. Phosphorus-31 and proton single-voxel MRS identify abnormalities in high-energy metabolism, neuronal function and neurotransmitter levels, but information can only be obtained from restricted regions of the brain. Spectroscopic imaging techniques (also known as chemical shift imaging) provide a metabolic mapping of the whole brain. They expand the range of applications of MRS to other types of epilepsy (neocortical, frontal) than temporal lobe epilepsy, which is the most often studied. Also, spectral editing techniques in proton MRS make it possible to detect and monitor drug-induced variations of GABA in the human brain, opening new insights into patient response to drug therapy of epilepsy. MRS is playing an increasing role in the noninvasive characterisation and management of epileptic patients. Received: 1 December 1999     

Beneficial Effects of N-Acetyl Cysteine on Pancreas and Kidney Following Experimental Pancreatic Ischemia-Reperfusion in Rats

OBJECTIVE:

To evaluate the protective effects of N-acetyl cysteine on the pancreas and kidney after pancreatic ischemia reperfusion injury in a rat model.

METHODS AND MATERIALS:

Pancreatic ischemia reperfusion was performed in Wistar rats for 1 hour. Revascularization was achieved followed by 4 h of reperfusion. A total of 24 animals were divided into four groups: Group 1: sham; Group 2: pancreatic ischemia reperfusion without treatment; Group 3: pancreatic ischemia reperfusion plus N-acetyl cysteine intravenously; and Group 4: pancreatic ischemia reperfusion plus N-acetyl cysteine per os. Blood and tissue samples were collected after reperfusion.

RESULTS:

There were significant differences in amylase levels between Group 1 (6.11±0.55) and Group 2 (10.30±0.50) [p=0.0002] as well as between Group 2 (10.30±0.50) and Group 4 (7.82±0.38) [p=0.003]; creatinine levels between Group 1 (0.52 ± 0.07) and Group 2 (0.77±0.18) [p=0.035] as well as between Group 2 (0.77±0.18) and Group 3 (0.48±0.13) [p=0.012]; and pancreatic tissue thiobarbituric acid reactive substance levels between Group 1 (1.27±0.96) and Group 2 (2.60±3.01) [p=0.026] as well as between Group 2 (2.60±3.01) and Group 4 (0.52±0.56) [p=0.002]. A decrease in pancreatic tissue GST-α3 gene expression was observed in Group 2 in comparison to Group 1 (p =0.006), and an increase was observed in Groups 3 and 4 when compared to Group 2 (p= 0.025 and p=0.010, respectively).

CONCLUSION:

This study provides evidence that N-acetyl cysteine has a beneficial effect on pancreatic ischemia reperfusion injury and renal function in a rat model.