Early goal-directed therapy reduces mortality in adult patients with severe sepsis and septic shock: Systematic review and meta-analysis

Introduction:

Survival sepsis campaign guidelines have promoted early goal-directed therapy (EGDT) as a means for reduction of mortality. On the other hand, there were conflicting results coming out of recently published meta-analyses on mortality benefits of EGDT in patients with severe sepsis and septic shock. On top of that, the findings of three recently done randomized clinical trials (RCTs) showed no survival benefit by employing EGDT compared to usual care. Therefore, we aimed to do a meta-analysis to evaluate the effect of EGDT on mortality in severe sepsis and septic shock patients.

Methodology:

We included RCTs that compared EGDT with usual care in our meta-analysis. We searched in Hinari, PubMed, EMBASE, and Cochrane central register of controlled trials electronic databases and other articles manually from lists of references of extracted articles. Our primary end point was overall mortality.

Results:

A total of nine trails comprising 4783 patients included in our analysis. We found that EGDT significantly reduced mortality in a random-effect model (RR, 0.86; 95% confidence interval [CI], 0.72–0.94; P = 0.008;   I² =50%). We also did subgroup analysis stratifying the studies by the socioeconomic status of the country where studies were conducted, risk of bias, the number of sites where the trials were conducted, setting of trials, publication year, and sample size. Accordingly, trials carried out in low to middle economic income countries (RR, 0.078; 95% CI, 0.67–0.91; P = 0.002; I² = 34%) significantly reduced mortality compared to those in higher income countries (RR, 0.93; 95% CI, 0.33–1.06; P = 0.28; I² = 29%). On the other hand, patients receiving EGDT had longer length of hospital stay compared to the usual care (mean difference, 0.49; 95% CI, –0.04–1.02; P = 0.07; I² = 0%).

Conclusion:

The result of our study showed that EGDT significantly reduced mortality in patients with severe sepsis and septic shock. Paradoxically, EGDT increased the length of hospital stay compared to usual routine care.     

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.     

Total gastrectomy with substitute stomach

A modified technique of jejunum-reservoir after total gastrectomie for gastric cancer is recommended. The advantages of this method are the simplicity of technique, the preservation of duodenal passage, the avoiding of reflux and the normal emptying time of reservoir.     

FAM chemotherapy +/- aminoglutethimide in the treatment of pancreatic carcinoma

Human pancreas contains receptors for estrogens and androgens as well as aromatase activity. FAM chemotherapy was administered to 14 patients with pancreatic cancer (seven at Stage IV). The median survival of these patients was 24.4 +/- 4.8 weeks. FAM chemotherapy plus aminoglutethimide/hydrocortisone (AG/HC) (250 mg bid AG + 20 mg bid HC) was administered to 14 patients (seven at stage IV). The median survival of this group was 17.3 +/- 2.9 weeks (P = 0.74 vs FAM alone). We conclude that addition of AG/HC does not add to the survival of patients with carcinoma of the pancreas treated with chemotherapy.     

Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation

Background

Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post-operative renal function in renal transplant recipients.

Methods

120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (−5 to +5 mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE ≤ −15 mEq/L or bicarbonate ≤ 10 mEq/L or PH ≤ 7.15). Minute ventilation was adjusted to keep PaCO₂ within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24 h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days.

Results

In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed.

Conclusion

Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function.     

Effects of enamel matrix derivative on non-surgical management of peri-implant mucositis: a double-blind randomized clinical trial

Background

Peri-implant diseases have been recognized as being among the ever-increasing complications related to dental implants. The aim of this study was to evaluate the adjunctive use of enamel matrix derivative (EMD) to mechanical debridement (MD) in patients with these conditions in terms of clinical parameters and cytokine levels of peri-implant crevicular fluid (PICF).

Methods

In the present double-blind clinical trial, 46 patients with peri-implant mucositis (PM) were randomly divided into control and test groups. Two different therapeutic protocols, consisting of non-surgical MD alone (control group) and MD with the application of EMD (test group), were considered for the two groups. Clinical parameters [bleeding on probing (BOP) and probing depth (PD)] and sampling from PICF were carried out before treatment and 3 months postoperatively. The levels of IL-6 and IL-17 cytokines in PICF were evaluated by enzyme-linked immunosorbent (ELISA).

Results

Three-month post-interventional assay revealed significant improvements in BOP and PD in the test group in comparison to the control group (P < 0.0001). Relative to control, IL-6 and IL-17 levels were reduced significantly (p < 0.05) in the test group compared to the control group.

Conclusion

Application of EMD can be considered an adjunct to MD in the non-surgical treatment of PM. However, complete recovery was not observed using either treatment approach showing that management of implant-associated disease is still a significant clinical problem.

     

RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC)

Ral (Ras like) leads an important proto‐oncogenic signaling pathway down‐stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non‐malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene‐specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl–geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR‐Knockout) also revealed an elevated level of RalA‐GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.