The effect of delays in second-dose antibiotics on patients with severe sepsis and septic shock

BackgroundEarly antibiotics are fundamental to sepsis management. Second-dose antibiotic delays were associated with increased mortality in a recent study. Study objectives include: 1) determine factors associated with delays in second-dose antibiotic administration; 2) evaluate if delays influence clinical outcomes.MethodsED-treated adults (≥18 years; n = 1075) with severe sepsis or septic shock receiving ≥2 doses of intravenous antibiotics were assessed, retrospectively, for second-dose antibiotic delays (dose time > 25% of recommended interval). Predictors of delay and impact on outcomes were determined, controlling for MEDS score, 30 mL/kg fluids and antibiotics within three hours of sepsis onset, lactate, and renal failure, among others.ResultsIn total, 335 (31.2%) patients had delayed second-dose antibiotics. A total of 1864 second-dose antibiotics were included, with 354 (19.0%) delays identified by interval (delayed/total doses): 6-h (36/67) = 53.7%; 8-h (165/544) = 30.3%; 12-h (114/436) = 26.1%; 24-h (21/190) = 8.2%; 48-h (0/16) = 0%. In-hospital mortality in the timely group was 15.5% (shock-17.6%) and 13.7% in the delayed group (shock-16.9%). Increased odds of delay were observed for ED boarding (OR 2.54, 95% 1.81–3.55), shorter dosing intervals (6/8-h- OR 2.99, 95% CI 1.95–4.57; 12-h- OR 2.46, 95% CI 1.72–3.51), receiving 30 mL/kg fluids by three hours (OR 1.42, 95% CI 1.06–1.90), and renal failure (OR 2.57, 95% CI 1.50–4.39). Delays were not associated with increased mortality (OR 0.87, 95% CI 0.58–1.29) or other outcomes.ConclusionsFactors associated with delayed second-dose antibiotics include ED boarding, antibiotics requiring more frequent dosing, receiving 30 mL/kg fluid, and renal failure. Delays in second-dose administration were not associated with mortality or other outcomes.     

Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery

The objective of this study was to assess the impact on outcome of adjuvant therapy (high-dose of immunoglobulin [Ig] M-enriched intravenous Ig, IVIG) in intensive care unit (ICU) patients who underwent surgery by abdominal sepsis. This was a prospective, randomized, double-blind, controlled study set in the medical/surgical ICUs of seven teaching hospitals. Patients with severe sepsis and septic shock of intra-abdominal origin admitted to the ICU within 24 h after the onset of symptoms were included in the study. Polyvalent IgM-enriched Ig (Pentaglobin; IVIG group) at a dosage of 7 mL/kg/day for 5 days or an equal amount of 5% human albumin (control group) was randomized. Fifty-six patients were enrolled. The overall mortality rate was 37.5.%. Twenty patients had shock and 36 had severe sepsis (the mortality rate was 55.0% and 25.0%, respectively). In the intent-to-treat analysis, the mortality rate was reduced from 48.1% in patients treated with antibiotic (ATB) plus albumin to 27.5% (P = 0.06) for patients with ATB plus IVIG. The organ failure score (1.0 +/- 0.6 vs. 1.2 +/- 0.9), organ dysfunction score (1.7 +/- 1.1 vs. 1.8 +/- 1.0), and reoperation rate (17.2% vs. 29.6%) were not different between IVIG and control groups, respectively. Eight patients (14.3%) received inappropriate ATB initial therapy (IAT), and seven died (87.5%). IAT was the only variable independently associated with death (odds ratio, 19.4) in a logistic regression model. We conclude that IVIG administration, when used in combination with adequate antibiotics, improved the survival of surgical ICU patients with intra-abdominal sepsis. The initial choice of antibiotic has a dramatic impact on outcome.     

Unrevealing culture-negative severe sepsis

Sepsis involves a wide array of sources and microorganisms, only a fraction of which are microbiologically documented. Culture-negative sepsis poses special diagnostic challenges to both clinicians and microbiologists and further questions the validity of sepsis definitions.According to the 2012 Surviving Sepsis Campaign, sepsis is a ?systemic, deleterious host response to infection?, characterized as ?suspected or documented?, which can lead to severe sepsis as defined by an ?acute organ dysfunction secondary to infection? [1]. Central to this definition is the presence of an infectious process, which differentiates sepsis from other causes of severe inflammation. However, only about 40 to 60% of patients with severe sepsis or shock have a microbiologically documented infection. In a substantial proportion of patients, sepsis will remain only clinically suspected, raising the possibility of a non-infectious cause (that is, of severe systemic inflammatory response syndrome).In this issue of Critical Care, Phua and colleagues reported on a large prospective cohort study of patients (n = 1,001) presenting with severe sepsis on ICU admission and compared the characteristics and outcomes of culture-negative versus culture-positive episodes [2]. Their main findings were that culture-negative sepsis occurred in 41.5% of the cohort, was associated with female gender, less comorbidities or organ failures, and more lung infection (74.5% vs. 59.9%) than their counterparts, and included lower serum procalcitonin levels and ICU mortality; however, identification of a pathogen was not independently associated with mortality in adjusted analyses.Sepsis is a highly heterogeneous syndrome, affecting patients with various underlying conditions, and involving an array of infectious sources and microorganisms. Although the characteristics of infection were retained in attempts to better characterize sepsis through the PIRO (predisposition, infection, response and organ failure) concept [3], data are conflicting regarding their impact on outcome of patients [4,5]. The observations by Phua and colleagues [2] tend to confirm earlier epidemiological studies showing that patients with or without microbiological documentation were at similarly high risk of death [6-8]. Despite this apparent lack of influence on outcome of patients, nondocumented sepsis challenges both our understanding of sepsis and management strategy. Indeed, the highest possible rate of documentation is desirable, as this would allow for a more targeted therapy in many patients, possibly avoiding unnecessary prolonged administration of broad-spectrum antibiotics [1].Why should patients presenting with a clinical syndrome of severe sepsis have nondocumented infection? Firstly, patients may have received antibiotics prior to the onset of organ dysfunction, thus obscuring conventional cultures. For example, patients with community-acquired respiratory tract infection often receive antibiotics before ICU admission, and not surprisingly Phua and colleagues report that respiratory tract infection was associated with culture-negative sepsis [2]. They did not, however, record information on prior antibiotic treatment, and this hypothesis cannot be substantiated.Secondly, the diagnostic workup may be insufficient or incomplete, which does seem to apply to the current study because patients with positive or negative cultures appeared to have a similar number of samples taken [2].A third possible explanation is sepsis caused by unusual organisms that are difficult to identify in routine practice. Conventional microbiological methods frequently fail to indentify a microorganism due to various reasons related to technical issues or intrinsic to the microorganism. Promising studies using PCR methods showed that microbial DNA could be rapidly detected in blood of septic patients [9], and could detect potentially significant bacteria and fungi not retrieved from blood culture [9,10]. In a recent meta-analysis, the overall sensitivity and specificity for such methods to detect bacterial or fungal DNA were 0.75 and 0.92 [11]. However, even in patients with severe sepsis, the rate of positive blood PCRs was only 34.7% [9]. Patients with culture-negative sepsis described by Phua and colleagues [2] having lower serum procalcitonin levels than others also suggests that at least some of them may have had severe viral infections. Indeed, a recent study showed that approximately one-third of ICU patients with severe pneumonia had viruses found by PCR assays on nasopharyngeal swabs or bronchoalveolar lavage fluid [12].A fourth explanation is that some patients having culture-negative sepsis might actually have a noninfectious cause for the clinical syndrome. Indeed, Phua and colleagues report a few (n = 18) patients with culture-negative sepsis having an unknown source of infection [2], raising the question of whether these patients with severe systemic inflammatory response syndrome truly had an underlying infection. Indeed, numerous differential diagnoses of severe sepsis have been previously described, including various tissue injuries (for example, surgery/trauma, ischemia, and so forth), metabolic disorders (for example, thyroid storm), adverse effects of drugs, inflammatory diseases (for example, systemic lupus erythematosus, DRESS syndrome, and so forth), malignancies and subarachnoid hemorrhage [13,14]. One could reasonably hypothesize that some of these mimickers of sepsis accounted for some of the culture-negative severe sepsis in the study from Phua and colleagues [2].Although the study by Phua and colleagues leaves several questions unanswered, it highlights the persisting gaps in our current understanding of sepsis and provides insightful information on the clinical features of nondocumented sepsis [2]. In the future, clinicians should strive to formalize strategies for managing such patients, probably combining clinical findings, imaging, and conventional bacterial cultures, but also the use of biomarkers and perhaps multiplex PCR-based assays to enhance our diagnostic ability.     

Sex and severe sepsis

Epidemiological studies document that males are more prone than females to develop severe sepsis and this is confirmed by Sakr and colleagues in the previous issue of Critical Care. However, the impact of gender on prognosis of severe sepsis is a matter of debate. Sakr and colleagues report a higher mortality in septic females than in males. This puzzling result might be explained by confounding factors such as age, nosocomial infections, follow-up period, and case mix. The impact of sexual hormones in older females is less relevant. Treatments aimed at modifying sexual hormone profile are promising but need to be tested in future trials.In the previous issue of Critical Care, Sakr and colleagues [1] reported an epidemiologic study they performed in 24 intensive care units (ICUs) in the Piedmont region of Italy. The study documents a lower prevalence of severe sepsis (SS) but a higher ICU mortality in females than in males.The study''s results on outcome are puzzling. Most previous studies report either no effect of gender or a protective effect of being a female. Several confounding factors might account for this result: the number of included patients with SS was small (305, including only 85 females), the period of inclusion during spring and summer induced a seasonal bias with different sources of SS as compared with winter, the percentage of ICU-acquired SS was high (61% in females), and females with SS were significantly older than males (67.7 versus 63.1 years); only 12 female patients were younger than 50 years of age. The median length of stay was short, precluding an interpretation of the Kaplan-Meier curve. No information on hospital or long-term outcome is provided. Studies with long-term follow-up have shown that male gender was associated with a worse prognosis. Weycker and colleagues [2] reported 5-year mortality rates of 77.5% in males and 70.2% in females. Also, it should be noted that the global incidences of SS for the whole population (7.8%) and for females (6%) were low and that ICU mortality rates for all patients (51.1%) and for females (63.5%) were very high given the values of simplified acute physiology score (SAPS) and Sequential Organ Failure Assessment (SOFA).SS has been identified as a major factor in ICU bed occupancy, ICU cost, and ICU mortality [3-6]. The incidence of SS and septic shock is increasing over time [5-8] because of better diagnostic tools or refined definition [9] but more importantly because of change in case mix (older patients and patients with comorbidities and immunosuppression). The ICU population is getting older, and the sex ratio is in favor of females after 80 [10,11]. Moreover, immunosenescence might explain the higher incidence of SS in older patients [12], and atypical clinical presentation might increase the delay of diagnosis and treatment, both contributing to a higher mortality in older patients [11]. Since female patients were older than males in the study by Sakr and colleagues, age might have contributed to the higher mortality in female patients.The impact of gender on prognosis may be related to sexual steroid hormone, although the contribution of young females (<50 years) to the whole population of SS is small (only 12 out of 85 female patients). In fact, numerous animal experiments suggest that gender may influence outcome and that a better outcome can be observed when hormonal status is orientated toward a female phenotype. During experimental hemorrhagic shock in male rats, outcome is improved by the administration of testosterone blocker or by castration [13]. In the same model, the outcome of female mice is improving when circulating estrogens are at their maximal values (that is, during the prelutenizing phase) [14]. When proestrus and ovariectomized rodents are subjected to sepsis by cecal ligation and puncture after trauma-hemorrhage, ovariectomized mice exhibit a significantly higher death rate. Finally, in this animal model, estrogen administration in males and ovariectomized females prevents immune function impairment (assessed by interleukin-1 and interleukin-6 macrophage production) and cardiac contractility decreases. Similar results have been observed in experimental endotoxic challenge in rats [15]. An intravenous endotoxic bolus decreases blood pressure in male rats, but blood pressure is not modified in female animals. Interestingly, this deleterious effect of endotoxin in male rats is abolished by prior surgical castration [15].Several clinical studies report increased estradiol levels in male patients with septic shock whereas circulating testosterone levels were dramatically decreased. In a preliminary observational survey performed in our ICU, circulating estradiol levels, measured during the first three days following ICU admission, were dramatically increased (reaching about six times the control levels) in a cohort of 40 male patients with SS or septic shock (unpublished data). Moreover, circulating estradiol values correlated with SAPS II, and the highest levels were observed in the most severe patients (patients with shock or with a fatal outcome). Mean circulating testosterone levels were dramatically decreased (reaching only a third of normal lower value) and never reached the minimal normal value of healthy men. Patients with shock had the lowest testosterone levels, but measured testosterone values did not differ according to outcome.Given these clinical observations, it seems that sexual hormonal pattern among male patients with SS is adaptative in order to minimize deleterious effects of testosterone. There is little room, if any, for testosterone blockade. A sexual hormonal therapeutic modulation in SS and septic shock aimed at increasing circulating estradiol levels is appealing. This hypothesis needs to be assessed through randomized controlled trials.     

Emergency department sepsis screening tool decreases time to antibiotics in patients with sepsis

Recent literature has highlighted the importance of early identification and treatment of sepsis; however, limited data exists to help recognize sepsis in the emergency department (ED) through use of a screening tool. The purpose of this study was to evaluate the impact of a sepsis screening tool implemented in an academic medical center ED on compliance with the 3-hour sepsis bundle.This was a retrospective cohort study that included a total of 115 patients, of which 58 were in the pre-tool group and 57 were in the post-tool group. There was no difference in 3-hour bundle compliance between groups (36.2% vs. 47.4%, P?=?0.26). There was no difference in the following bundle components: lactate (79.3% vs. 80.7%, P?=?0.85), blood cultures (86.2% vs. 96.5%, P?=?0.09), blood cultures before administering antibiotics (91.4% vs. 100%, P?=?0.57) and adequate fluids administration (44.7% vs. 41.9%, P?=?0.820). A significantly higher number of patients received antibiotics within 3?h in the post-tool group (58.6% vs. 89.5%, P?<?0.001). Statistically significant secondary outcomes included average time to antibiotics (P?=?0.04), administering antibiotics within an hour (P?>?0.001), and ICU length of stay (P?=?0.03). There was no difference in 30-day mortality, however mortality was numerically lower in the post-tool group (36.2% vs. 26.3%, P?=?0.25).Although implementation of an ED sepsis screening tool did not increase 3-hour bundle compliance, it did increase the proportion of patients receiving timely antimicrobial therapy and demonstrated a trend towards decreased mortality.     

Exogenous activated protein C in severe sepsis

Exogenous activated protein C combines a marked anti-inflammatory effect on the vascular endothelium and anticoagulative and profibrinolytic activities. The total results of this action are better multiple organ microcirculation and, as a result, elimination and even prevention of irreversible changes in the vitally important organs. The many-sidedness and potency of this effect make the agent essential for intensive therapy of severe sepsis of various etiology. The Russian cooperative study of the efficacy of the exogenous activated protein C--drotrecogine alpha (activated)--has shown that its inclusion into therapy for sepsis with multiple organ dysfunction and septic shock results in longer estimated survival. With this, the best results are observed when therapy is initiated within 48 hours since the development of multiple organ deficiency.     

Activated protein C in severe sepsis.

A recent large trial has shown that recombinant activated protein C reduced mortality in severe sepsis. This is the first real advance in the pharmacotherapy of sepsis since the introduction of antibiotics in the last century.     

Antithrombin III in patients with severe sepsis

Objectives: To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis. Design: Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial. Setting: Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden. Patients: 42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo. Interventions: Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo. Measurements and results: All patients were evaluated for safety and for 30-day all-cause mortality. Conclusions: The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis. Received: 4 June 1997 Accepted: 24 April 1998     

Lipoprotein metabolism in patients with severe sepsis

OBJECTIVE: Lipoproteins have been implicated to play a role in innate immunity. Changes in lipoprotein levels have been reported in a variety of inflammatory disorders. Not much is known about lipoprotein metabolism in patients with severe sepsis. We conducted an ancillary study in a multiple-center phase III sepsis trial to investigate the dynamics of plasma lipoproteins in patients with severe sepsis. DESIGN: Prospective analysis in patients meeting criteria for severe sepsis as part of a multiple-center sepsis study (KyberSept) with antithrombin III (Kybernin P). SETTING: University hospital intensive care unit. PATIENTS: Seventeen patients were included in the study. INTERVENTIONS: Randomized patients received a loading dose of 6000 IU of antithrombin III (Kybernin P) or placebo followed by a 96-hr continuous infusion of 250 IU/hr antithrombin III (Kybernin P) or placebo. In each patient, serial blood samples for total cholesterol, lipoprotein cholesterol, triglycerides, apolipoprotein A-1, apolipoprotein B, and C-reactive protein determination as well as clinical data were collected over 28 days. MEASUREMENTS AND MAIN RESULTS: Plasma cholesterol levels rapidly decreased from 2.67 +/- 2.02 mmol/L on day 0 to a nadir of 1.41 +/- 0.70 mmol/L on day 3, followed by a slow increase to 4.18 +/- 1.94 mmol/L on day 28. High-density lipoprotein (HDL) cholesterol concentrations decreased rapidly from 0.84 +/- 0.92 mmol/L to a nadir of 0.42 +/- 0.35 mmol/L on day 3, to show a slow increase during the following 4 wks to 0.84 +/- 0.42 mmol/L. The low-density lipoprotein (LDL) cholesterol concentrations were already low (0.94 +/- 0.81 mmol/L) at study entry, to show a progressive increase to subnormal values (2.01 +/- 0.94 mmol/L) at 4 wks. Nadir and recovery lipoprotein concentrations were significantly different (paired Student's t-test, p <.05). A significant correlation was found between HDL cholesterol and apolipoprotein A-1 (r =.714, p <.05) and between LDL cholesterol and apolipoprotein B (r =.733, p <.05). There was no statistical difference in lipoprotein concentrations either between survivors and nonsurvivors or between patients receiving antithrombin III or placebo.Serum amyloid A was a major apoprotein (45%) in HDL at the start of the sepsis and was slowly replaced by apolipoprotein A-1 during recovery. A positive correlation was found between plasma C-reactive protein concentrations and serum amyloid A concentrations in HDL (r =.684, p <.05). No other relevant correlations were found between inflammatory and lipoprotein parameters. CONCLUSIONS: In patients with severe sepsis, lipoprotein concentrations rapidly change and can be reduced to 50% of recovery concentrations. The pattern of early rapid decline is found primarily in the HDL and a slow recovery in both HDL and LDL fractions. The correlation between apolipoprotein and lipoprotein cholesterol concentrations suggests a decline in lipoprotein particles. During severe sepsis, HDL is shifted to acute phase HDL, which is enriched in serum amyloid A and depleted of cholesterol and apolipoprotein A-1. Lipoprotein concentrations are unable to discriminate between survivors and nonsurvivors.     

Anticoagulant modulation of inflammation in severe sepsis

Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severelyill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis.     

The role of neutrophils in severe sepsis

Neutrophils are key effectors of the innate immune response. Reduction of neutrophil migration to infection sites is associated with a poor outcome in sepsis. We have demonstrated a failure of neutrophil migration in lethal sepsis. Together with this failure, we observed more bacteria in both peritoneal exudates and blood, followed by a reduction in survival rate. Furthermore, neutrophils obtained from severe septic patients displayed a marked reduction in chemotactic response compared with neutrophils from healthy subjects. The mechanisms of neutrophil migration failure are not completely understood. However, it is known that they involve systemic Toll-like receptor activation by bacteria and/or their products and result in excessive levels of circulating cytokines/chemokines. These mediators acting together with LPS stimulate expression of iNOS that produces high amounts of NO, which in turn mediates the failure of neutrophil migration. NO reduced expression of CXCR2 on neutrophils and the levels of adhesion molecules on both endothelial cells and neutrophils. These events culminate in decreased endothelium-leukocyte interactions, diminished neutrophil chemotactic response, and neutrophil migration failure. Additionally, the NO effect, at least in part, is mediated by peroxynitrite. In this review, we summarize what is known regarding the mechanisms of neutrophil migration impairment in severe sepsis.     

Pharmacologic treatment related to severe sepsis

Severe sepsis is a complex syndrome often resulting in multiple organ dysfunction. This is an extremely challenging problem to manage in the intensive care unit, with mortality rates remaining at unacceptably high levels. Death of patients afflicted by this condition generally results from organ dysfunction syndromes related to hypoperfusion abnormalities. Management of patients with severe sepsis or septic shock can be very complex and challenging, utilizing a significant amount of resources. Pharmacologic support of patients with severe sepsis or septic shock primarily involves agents to support and improve perfusion at the microvascular level. It is important to understand the pharmacologic properties of the medications utilized to manage patients with these conditions. The information presented in this article is based on the best evidence currently available in order to assist the critical care nurse in understanding the pharmacologic therapy related to treatment of severe sepsis and septic shock.