Early goal-directed therapy in the treatment of severe sepsis and septic shock.

BACKGROUND: Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. METHODS: We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. RESULTS: Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001). CONCLUSIONS: Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.     

A controlled trial of methylprednisolone in the emergency treatment of acute asthma

Ninety-seven acutely ill patients with bronchial asthma were enrolled in a double-blind, placebo-controlled, randomized trial of intravenous methylprednisolone (125 mg), given on presentation in the emergency room in addition to standard emergency treatments for asthma. Subjective and spirometric indexes of the severity of the asthma were similar on entry into the study in all patients, but only 9 of 48 patients (19 percent) treated with methylprednisolone required hospital admission, as compared with 23 of 49 patients (47 percent) in the control group (P less than 0.003). Our results suggest that prompt use of glucocorticoids in the emergency treatment of severe asthma can prevent significant morbidity, reduce the number of hospitalizations, and effect substantial savings in health care costs.     

Procalcitonin kinetics as a prognostic marker in severe sepsis/septic shock

Background and Aims:

To evaluate the prognostic value of change (fall) in serum procalcitonin level (PCT) in critically ill adults with severe sepsis/septic shock.

Methods:

This was a prospective observational study in a general purpose Intensive Care Unit of a teaching Institute. PCT was measured at admission (D0) and after 72–96 h (D4) by electrochemi-luminescence immunoassay (BRAHMS PCT kit) in adults (>18 years) admitted with severe sepsis or septic shock. Change in procalcitonin values from D0 to D4 was correlated with the primary outcome, that is, 28 days mortality. All results are reported as median (interquartile range).

Results:

A total of 171 (100 males) of 181 patients were included. The median age was 46 years (range 19–79). 137 patients were in septic shock and 34 in severe sepsis. The sequential organ failure assessment (SOFA) score in all patients was 11 (9–14).91 (53.2%) patients survived at 28 days (survivors). The baseline procalcitonin was similar in two groups (3.48 [1.04–15.85] vs. 5.27 [1.81–23.57] ng/ml in survivors and nonsurvivors [NS] respectively). The procalcitonin change was 1.58 (0.20–8.52) in survivors and 0.28 (–1.38–6.17) in NS (P = 0.01). The C-statistic of percentage change in procalcitonin from D0 to D4 to predict survival was 0.73 (95% confidence interval [CI]: 0.65–0.82) when compared to 0.78 (95% CI: 0.71–0.86) for change of SOFA score. For an absolute fall in procalcitonin of >1 ng/ml, a 70% fall predicted survival with 75% sensitivity and 64% specificity.

Conclusions:

In critically ill-patients with severe sepsis/septic shock, change (fall) in procalcitonin is associated with good outcome.     

The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study

To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients.     

The impact of selenium administration on severe sepsis or septic shock: a meta-analysis of randomized controlled trials

IntroductionThe efficacy of selenium administration to treat severe sepsis or septic shock remains controversial. We conduct a systematic review and meta-analysis to explore the impact of selenium administration on severe sepsis or septic shock.MethodsWe search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2020 for randomized controlled trials (RCTs) assessing the effect of selenium administration on severe sepsis or septic shock. Meta-analysis is performed using the random-effect model.ResultsFive RCTs involving 1482 patients are included in the meta-analysis. Overall, compared with control group in septic patients, selenium administration is not associated with reduced 28-day mortality (RR=0.93; 95% CI=0.73 to 1.19; P=0.58), but results in substantially decreased all-cause mortality (RR=0.78; 95% CI=0.63 to 0.98; P=0.03) and length of hospital stay (MD=-3.09; 95% CI=-5.68 to -0.50; P=0.02).ConclusionSelenium administration results in notable decrease in all-cause mortality and length of hospital stay, but shows no substantial influence on the 28-day mortality, length of ICU stay, duration of vasopressor therapy, the incidence of acute renal failure, adverse events, and serious adverse events for septic patients.     

Safety and efficacy of polymyxin B in multidrug resistant Gram-negative severe sepsis and septic shock

Background and Aims:

The emergence of multidrug resistant strains of Gram-negative bacteria, especially the lactose nonfermenters like Pseudomonas and Acinetobacter, in the intensive care units have prompted renewed worldwide interest in the polymyxins. However, perceived nephrotoxicity has been a major vexation limiting their early and regular use in severe sepsis. This study was conducted to assess the safety and efficacy of polymyxin B in patients with severe sepsis and septic shock.

Materials and Methods:

Forty-five patients with sepsis admitted in our medical-surgical intensive care units were identified from pharmacy records to have received polymyxin B. We retrospectively reviewed the clinical and microbiologic outcomes as well as occurrence of renal failure temporally related to the use of intravenous polymyxin B.

Results:

polymyxin B was used in severe sepsis and septic shock with the isolated organism being resistant to other available antimicrobials or clinical deterioration despite carbapenem use. Overall mortality was 52% and among patients who received at least eight days of intravenous polymyxin B, 67% patients with initial septic shock and 62% with severe sepsis survived. The target multidrug resistant organism was cleared in 88% of subjects evaluated by repeat microbiologic testing. Acute renal failure developed in only two patients (4%).

Conclusions:

Polymyxin B has acceptable effectiveness against nosocomial multidrug resistant Gram-negative sepsis. The associated nephrotoxicity has been found to be significantly lower than previously reported even in patients with background renal impairment and established risk factors of renal failure.     

Prognostic value of venoarterial carbon dioxide gradient in patients with severe sepsis and septic shock

Aim

To investigate the changes in the venoarterial carbon-dioxide gradient (V-a Pco₂) and its prognostic value for survival of patients with severe sepsis and septic shock.

Methods

The study was conducted in General Hospital Holy Spirit from January 2004 to December 2007 and included 71 conveniently sampled adult patients (25 women and 46 men), who fulfilled the severe sepsis and septic shock criteria and were followed for a median of 8 days (interquartile range, 12 days). The patients were divided in two groups depending on whether or not they had been mechanically ventilated. Both groups of patients underwent interventions with an aim to achieve hemodynamic stability. Mechanical ventilation was applied in respiratory failure. Venoarterial carbon dioxide gradient was calculated from the difference between the partial pressure of arterial CO₂ and the partial pressure of mixed venous CO₂, which was measured with a pulmonary arterial Swan-Ganz catheter. The data were analyzed using Kaplan-Meier survival analysis, along with a calculation of the hazard ratios.

Results

There was a significant difference between non-ventilated and ventilated patients, with almost 4-fold greater hazard ratio for lethal outcome in ventilated patients (3.85; 95% confidence interval, 1.64-9.03). Furthermore, the pattern of changes of many other variables was also different in these two groups (carbon dioxide-related variables, variables related to acid-base status, mean arterial pressure, systemic vascular resistance, lactate, body mass index, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology II Score, and Sepsis-related Organ Failure Assessment score). Pco₂ values (with a cut-off of 0.8 kPa) were a significant predictor of lethal outcome in non-ventilated patients (P = 0.015) but not in ventilated ones (P = 0.270).

Conclusion

V-a Pco₂ was a significant predictor of fatal outcome only in the non-ventilated group of patients. Ventilated patients are more likely to be admitted with a less favorable clinical status, and other variables seem to have a more important role in their outcome.Although oxygen delivery (Do₂) in septic shock can be elevated, oxygen consumption (Vo₂) is impaired (1). This could be a consequence of mitochondrial dysfunction in sepsis (2,3). Blood circulation is slow and consequently the elimination of CO₂ from the tissue is slower, making the tissue CO₂ concentration high. Venoarterial carbon dioxide gradient (V-a Pco₂) was calculated from the difference between the partial pressure of arterial CO₂ (Paco₂) and the partial pressure of mixed venous CO₂ (Pvco₂), which was measured with a pulmonary arterial Swan-Ganz catheter. The venoarterial CO₂ gradient (V-a Pco₂) is influenced by two other factors: the dissociative curve of CO₂ and tissue blood flow. The curve of CO₂ dissociation from hemoglobin follows the so-called Haldane''s effect, in which oxygen and its bonding with hemoglobin allows easier release of carbon dioxide in lungs (4). Experimental models have shown that in toximia, venous hypercapnia is a more significant contributor to the increase in the venoarterial CO₂ gradient than arterial CO₂ values (4-7). Elevated V-a Pco₂ has also been described in patients with sepsis, cardiogenic shock, acute myocardial infarction, and congestive heart failure, as well as cardiac arrest following cardiopulmonary resuscitation and heart surgery (8-13).In septic patients, the significance of the connection between an elevation of V-a Pco₂ and the course and outcome of the illness is not sufficiently known. It has been established that V-a Pco₂ shows a negative exponential relationship with the cardiac index (CI) (14,15). The negative association with CI has been observed not only in septic shock patients but also in postoperative patients without sepsis. In patients with a lethal outcome, CI was reduced, but V-a Pco₂ was not an independent predictor of outcome (14,16).The aim of this study was to investigate the changes in V-a Pco₂ to better understand the possibilities of using it as a predictor of clinical outcomes in patients with severe sepsis and septic shock.     

TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.     

Left atrial function for outcome prediction in severe sepsis and septic shock: An echocardiographic study

Left ventricular function and B-type natriuretic peptide (BNP) assessments are used to predict mortality in septic patients. Left atrial function has never been used to prognosticate outcome in septic patients.

Objectives:

To assess if deterioration of left atrial function in patients with severe sepsis and septic shock could predict mortality.

Methods:

We studied 30 patients with severe sepsis or septic shock with a mean age of 49.8±16.17. Echocardiographic parameters were measured on admission, Day 4, and Day 7, which comprised left ventricular ejection fraction (EF), and atrial function that is expressed as atrial ejection force (AEF). All patients were subjected to BNP assay as well. Multivariate analyses adjusted for APACHE II score was used for mortality prediction.

Results:

The underlying source for sepsis was lung in 10 patients (33%), blood in 7 patients (23.3%), abdomen in 7 patients (23.7%), and 3 patients (10%) had UTI as a cause of sepsis. Only one patient had CNS infection. In-hospital mortality was 23.3% (7 patients). Admission EF showed a significant difference between survivors and non survivors, 49.01±6.51 vs.. 56.44±6.93% (P<0.01). On the other hand, admission AEF showed insignificant changes between the same groups, 10.9±2.81 vs. 9.41±2.4 k/dynes P=0.21, while BNP was significantly higher in the non survivors, 1123±236.08 vs. 592.7±347.1 pg/ml (P<0.001). The predicatable variables for mortality was Acute Physiology and Chronic Health Evaluation II score, BNP, then EF.

Conclusion:

In septic patients, left atrial function unlike the ventricular function and BNP levels can not be used as an independent predictor of mortality.     

Clinical outcome and predictors of mortality in children with sepsis,severe sepsis,and septic shock from Rohtak,Haryana: A prospective observational study

Background:

Information regarding early predictive factors for mortality and morbidity in sepsis is limited from developing countries.

Methods:

A prospective observational study was conducted to determine the clinical outcome and predictors of mortality in children with sepsis, severe sepsis, and septic shock. Children aged 1 month to 14 years admitted to a tertiary care pediatric intensive care unit (PICU) with a diagnosis of sepsis, severe sepsis, or septic shock were enrolled in the study. Hemodynamic and laboratory parameters which discriminate survivors from nonsurvivors were evaluated.

Results:

A total of 50 patients (30 [60%] males) were enrolled in the study, of whom 21 (42%) were discharged (survivors) and rest 29 (58%) expired (nonsurvivor). Median (interquartile range) age of enrolled patients were 18 (6, 60) months. Mortality was not significantly predicted individually by any factor including age (odds ratio [OR] [95% confidence interval [CI]]: 0.96 [0.91-1.01], P = 0.17), duration of PICU stay (OR [95% CI]: 1.18 [0.99-1.25], P = 0.054), time lag to PICU transfer (OR [95% CI]: 1.02 [0.93-1.12], P = 0.63), Pediatric Risk of Mortality (PRISM) score at admission (OR [95% CI]: 0.71 [0.47-1.04], P = 0.07) and number of organ dysfunction (OR [95% CI]: 0.03 [0.01-1.53], P = 0.08).

Conclusion:

Mortality among children with sepsis, severe sepsis, and septic shock were not predicted by any individual factors including the time lag to PICU transfer, duration of PICU stay, presence of multiorgan dysfunction, and PRISM score at admission.     

Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction

To evaluate the role of activated cytotoxic cells in patients with severe sepsis (n = 32) or septic shock (n = 8), direct (granzymes A and B) as well as indirect markers (cytokines) for cytotoxic cell activation were measured. Elevated IL-12p40 levels had been detected in 58% of the sepsis patients, whereas only a few had detectable TNF-alpha, IFN-gamma, or IL-12p70 levels. Granzymes A and B levels were elevated in 42.5% and 22.5%, respectively. IL-12p40 inversely correlated with disease severity. Inflammatory parameters (IL-6) and coagulation markers were significantly lower and higher, respectively, in patients with elevated IL-12p40 and granzyme B levels, as compared to those with normal levels. Elevation of granzyme A directly correlated with the increase of apoptotic markers. Activated cytotoxic cells reflected by elevated granzymes A and/or B were found in 50% of our sepsis patients. This group showed a higher mortality and a worse organ function.     

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.     

Treatment of LD100 Escherichia coli septic shock with netilmicin and methylprednisolone in baboons

Treatment efficacy with netilmicin sulphate/methylprednisolone sodium succinate in a severe septic shock baboon model, using an LD₁₀₀ of liveEscherichia coli, was evaluated. All the animals treated with both netilmicin and methylprednisolone were premanent ( 7 days) survivors, whereas none of the untreated baboons lived more than 24 hours. These results indicate that, in a baboon model, netilmicin is an effective alternative to gentamicin (with methylprednisolone) in the treatment of severe septic shock.     

Use of intravenous immunoglobulin therapy in the treatment of septic shock, in particular severe invasive group A streptococcal disease

Group A streptococcus (GAS) is a β-hemolytic bacterium often found in the throat and skin. The two most severe clinical manifestations of GAS are streptococcal toxic shock syndrome and necrotizing fasciitis. Intravenous immunoglobulin (IVIg) is a gamma globulin made from purified pooled plasma of thousands of donors, consisting mainly of IgG. We report the case of a 40-year-old man admitted after 2 days of vomiting and severe right-sided chest pain. He was hypotensive with a sinus tachycardia, pyrexial, and vasodilated. The only other positive finding was a swollen and erythematous chest wall. Muscle layer biopsies and blood cultures soon grew extensive GAS, and an initial diagnosis of necrotizing fasciitis was made. The clinical syndrome was of severe septic shock secondary to invasive GAS. The patient quickly deteriorated with a worsening metabolic acidosis. Despite maximal intensive care therapy including fluids, vasoactive agents, and also activated protein C, the patient continued to remain profoundly hypotensive. A decision was made to commence IVIg, with the aim of immunomodulation of the inflammatory cascade seen in sepsis. Over the next 24 hours the patient improved, was extubated 3 days later, and subsequently discharged from hospital after 2 weeks. Although the evidence for the use of IVIg in severe invasive GAS disease is limited, we feel that on reviewing the available literature its use in this case was justified. The limited worldwide supply and high costs, together with a limited evidence base, warrant restricting its use to cases in which conventional therapy has failed. The literature for use of intravenous immunoglobulin in invasive GAS infection will be reviewed in this article.     

Does vasopressin improve the mortality of septic shock patients treated with high-dose NA

Aim of Study:

In Surviving Sepsis Campaign Guidelines 2012, noradrenalin (NA) is recommended as a first choice vasopressor. Although vasopressin (VP) is recommended for the treatment of NA-resistant septic shock, the optimal parameters for its administration remain unclear.

Materials and Methods:

We conducted a retrospective study to evaluate the clinical outcomes of the administration of VP to adult septic shock patients who were undergoing high-dose NA (≥0.25 μg/kg/min) therapy in our Intensive Care Unit between January 2010 and December 2013. We defined high-dose NA as a dose of >0.25 μg/kg/min, based on the definition of low-dose NA as a dose of 5–14 μg/min because the average body weight of the patients in this study was 53.0 kg.

Results:

Among 29 patients who required the administration of high-dose NA, 18 patients received VP. Although the patient background physiological conditions and NA dose did not differ between the two groups, the survival rate of the VP-treated patients was significantly lower (33%) than that of the patients who were managed with a high-dose of NA-alone (82%) (P = 0.014). The lactate clearance did not change after the administration of VP, whereas it improved when in NA treatment alone.

Conclusion:

The results suggest that the administration of VP did not improve the mortality among septic shock patients when administered in addition to high-dose NA.