Severe sepsis and septic shock in pre-hospital emergency medicine: survey results of medical directors of emergency medical services concerning antibiotics,blood cultures and algorithms

Delayed antibiotic treatment for patients in severe sepsis and septic shock decreases the probability of survival. In this survey, medical directors of different emergency medical services (EMS) in Germany were asked if they are prepared for pre-hospital sepsis therapy with antibiotics or special algorithms to evaluate the individual preparations of the different rescue areas for the treatment of patients with this infectious disease. The objective of the survey was to obtain a general picture of the current status of the EMS with respect to rapid antibiotic treatment for sepsis. A total of 166 medical directors were invited to complete a short survey on behalf of the different rescue service districts in Germany via an electronic cover letter. Of the rescue districts, 25.6 % (n = 20) stated that they keep antibiotics on EMS vehicles. In addition, 2.6 % carry blood cultures on the vehicles. The most common antibiotic is ceftriaxone (third generation cephalosporin). In total, 8 (10.3 %) rescue districts use an algorithm for patients with sepsis, severe sepsis or septic shock. Although the German EMS is an emergency physician-based rescue system, special opportunities in the form of antibiotics on emergency physician vehicles are missing. Simultaneously, only 10.3 % of the rescue districts use a special algorithm for sepsis therapy. Sepsis, severe sepsis and septic shock do not appear to be prioritized as highly as these deadly diseases should be in the pre-hospital setting.     

Empirical antibiotic therapy in febrile neutropenic patients with acute leukemia

One hundred and ninety-five episodes of fever during the neutropenic phase of chemotherapy in 49 patients with acute leukemia from 1984 to 1987 were analyzed with the following results: 1) Febrile episodes occurred in 80 percent of the neutropenic (less than 500/microliters) phase lasting more than 7 days after chemotherapy. 2) Febrile episodes consisted of 44 (22%) of established septicemia and 111 (57%) of suspected septicemia. 3) The pathogens causing septicemia were 8 GPC, 38 GNB (22 Pseudomonas species) and 6 fungi. Fungemia was confirmed on an average of 4.8 days after the onset of fever. The mortality of septic events was 10 out of 17 episodes (59%) when treated with antibiotics alone, while 8 out 27 (30%) with the combination of antibiotics plus antifungal drugs. 4) The mortality of suspected sepsis was only 2 out of 111 episodes. Eighty-three (75%) of these 111 episodes responded to antibiotics alone, while 26 (23%) cases needed antibiotics plus antifungal drugs. Our results suggest that in febrile neutropenic patient empiric broad-spectrum antibiotic therapy should be initiated which is especially effective for Pseudomonas species, but if fever persists despite more than 4 or 5 days of antibiotic therapy, additional antifungal therapy should be considered.     

Corticosteroid therapy in patients with severe sepsis and septic shock

Corticosteroids have been considered for decades for the treatment of severe sepsis and septic shock, based on their pivotal role in the stress response and their hemodynamic and antiinflammatory effects. Whereas short-term therapy with high doses of corticosteroids (up to 42 g hydrocortisone equivalent for 1-2 days) has been ineffective or potentially harmful, prolonged therapy with lower doses (200-300 mg hydrocortisone for 5-7 days or longer) in septic shock has recently revealed beneficial effects in several randomized, controlled trials. Assuming relative adrenal insufficiency (RAI) and peripheral cortisol resistance, treatment with low-dose hydrocortisone improved shock reversal, reduced inflammation, and improved outcome. Shock reversal and reduction of mortality were more effective in patients with RAI, and most significant in patients with severe shock. Diagnosis of RAI with corticotropin tests in septic shock, however, is highly dependent on cut-off values and definition of RAI. Thus, it is not clear yet which patients benefit most from low-dose hydrocortisone and if treatment should be restricted to patients with RAI. In addition the role of fludrocortisone is uncertain. Nevertheless, based on current data, low-dose hydrocortisone therapy should definitely be considered in vasopressor-dependent septic shock. This review will address some critical points.     

Current management of the septic shock patient: experimental basis for treatment

Experimental research has shown that following the intravenous infusion of animals with bacteria or endotoxin a myriad of adverse vascular events occur resulting in deficient organ perfusion and cell death. The primary goals of therapy for sepsis and septic shock, therefore, should include elimination of the source of infection and/or infectious agents and prevention or reversal of adverse vascular events. The following review describes the evolution of an effective therapy for shock consisting of steroid in combination with antibiotic and discusses its relevance and application for humans in severe sepsis or septic shock.     

Early and Adequate Antibiotic Therapy in the Treatment of Severe Sepsis and Septic Shock

Severe sepsis and septic shock are conditions that pose difficult challenges to physicians and the health care system. In the past 10 years, a number of retrospective and prospective observational studies have shed light on the importance of a rapid and systematic approach to treatment of these conditions. A key component is early and appropriate use of antibiotics. Delay of even 6 h can dramatically increase hospital mortality. In addition, multivariate analyses have demonstrated that inappropriate initial antibiotics lead to worse outcomes. The treating physician can rapidly identify risk factors for initial inappropriate antibiotics at the bedside, such as recent antibiotic therapy or recent hospitalization. Organized antibiotic order sets have been shown to significantly improve timely appropriate antibiotic administration in septic patients. Finally, emerging laboratory data suggest that early in the course of septic shock, the pharmacokinetics of common broad spectrum antibiotics may be significantly altered due to increased volumes of distribution having dosing implications for antibiotics in septic shock.     

The diagnosis and management of severe sepsis and septic shock.

Shock due to or associated with sepsis may present a clinical picture quite different from that usually seen in hypovolemic or cardiogenic shock. Any trend which suggests increasing sepsis should be treated aggressively as if shock were present. The earlier such therapy is begun, the better the results tend to be. Perhaps the greatest errors in the therapy of severe sepsis and septic shock are (1) delayed control of the primary septic process, (2) giving too little fluid in the early phases of therapy (and too much later), and (3) delaying ventilator assistance if the patient's ventilation or blood gases are deteriorating.     

Cardiovascular dysfunction in sepsis and septic shock

Opinion statement The optimal therapy for the treatment of sepsis and septic shock remains controversial. Many protocols are followed, using different strategies for initial resuscitation, cardiovascular monitoring, hemodynamic intervention, and eradication of infection. Overall, an aggressive approach to the management of cardiovascular dysfunction in septic shock is warranted. Initially, large volume fluid resuscitation is instituted. Our first choice of resuscitation fluid is 0.9% normal saline. Invasive hemodynamic monitoring using a flotation pulmonary artery catheter as well as invasive arterial blood pressure monitoring is a necessity in the hemodynamic management of septic shock. If the patient remains hypotensive (mean arterial pressure < 65 mm Hg) after adequate volume resuscitation has been established (pulmonary capillary wedge pressure 12 to 15 mm Hg), then vasopressor agents must be instituted. Our first choice is usually dopamine. In patients who remain hypotensive after maximal doses of dopamine are reached, norepinephrine is added. If these agents generate excessive tachycardia or if tachyarrhythmias develop, phenylephrine can be substituted or added. Inotropic agents are useful if the patient demonstrates hypotension with a low cardiac output state. Dobutamine is the agent of choice. We initiate broad-spectrum empiric antibiotics at presentation, modifying the exact regimen based on 1) site of infection; 2) prevailing organisms and antibiotic resistance patterns in the patient’s environment; and 3) other specific risk factors (immunosuppression, chronic disease, exposure and vaccination history, invasive medical devices). When appropriate, aggressive surgical debridement is pursued. Currently, there are no clinical data to support the use of antagonists for sepsis mediators, although various clinical trials remain underway. Steroids are contraindicated except for adrenal replacement therapy.     

Rational use of antimicrobials in patients with severe acute pancreatitis

Infectious complications in severe acute pancreatitis are associated with considerable morbidity and mortality. The course of the disease is often protracted, and patients often stay in the hospital for several weeks. Diagnosis of infected pancreatic necrosis is difficult, and the treatment consists of source control and antibiotic treatment. Antibiotic use should be rational in terms of a rational indication, a rational spectrum, and a rational duration. Prophylactic antibiotics are not effective in reducing the incidence of (peri)-pancreatic infection in patients with severe disease (or even documented necrotizing pancreatitis). The only rational indication for antibiotics is documented infection. The spectrum of empirical antibiotics should include both aerobic and anaerobic gram-negative and gram-positive microorganisms. Also, fungal infections are often present in these patients, and antifungal coverage or even prophylaxis should be considered, especially if multiple risk factors for invasive candidiasis are present. Although initiation of antibiotics may be a difficult decision, stopping antibiotic therapy often proves to be even more difficult. Currently, no tools are available to guide antimicrobial treatment. Antibiotic use is only effective if proper source control has been established.     

Sepsis and the heart

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.     

Sepsis management -- antibiotic therapy

Sepsis is one of the most frequent infectious problems at Intensive Care Units, and sepsis is associated with significant mortality. The latter could not be markedly reduced in the last years, despite a number of advances in the field of volume substitution, catecholamines, and endocrinologic therapy. The reason might be that important steps towards overcoming of sepsis are the surgical resection of infectious foci and an adequate antibiotic treatment. A critical role plays the growing resistance of pathogens against the common antibiotics. Since no major progress in the development of new antibiotics can be expected for the next years, sepsis treatment must be focused on prevention of infection, and on an optimised application of current antibiotic substances. The key factors are a broad and high dose initial treatment, a de-escalation strategy according to the clinical course, and -with exceptions- a limitation of treatment to 7 to 10 days. Rotation of antibiotics should be performed, if problems with resistances exist or no specialist for infectious diseases is available on the Intensive Care Unit.     

Diagnose und kausale Therapie der Sepsis

The high mortality and morbidity of severe sepsis and septic shock had not been reduced during the two recent decades despite a number of advances in the field of supportive and adjunctive sepsis therapies. The reasons might be deficits in important steps towards overcoming sepsis such as progress in the early diagnosis, surgical resection of the infectious focus and an adequate antibiotic treatment. However, growing resistance of pathogens against the common antibiotics has been detected worldwide. In contrast no major progress in the development of new antibiotics, mainly for the treatment of Gram-negative non-fermenter infections such as Pseudomonas aeruginosa, can be predicted for the next years. Therefore, sepsis treatment must focus on prevention of infection and on an optimized application of current antibiotic substances. The key factors are a broad spectrum, high dose and early initiation of treatment, a de-escalation strategy oriented to the clinical course supported by the application of novel molecular markers and, with exceptions, a limitation of treatment to 7–10 days. A closer cooperation between microbiologists, infection control specialists and clinical infectious disease consultants may be a key factor to overcome the dramatic problems of the future.     

Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival

DESIGN: The objectives were to characterize the prognostic factors and evaluate the impact of inappropriate empiric antibiotic treatment and systemic response on the outcome of critically ill patients with community-acquired bloodstream infection (BSI). PATIENTS: A prospective, multicenter, observational study was carried out in 339 patients admitted in 30 ICUs for BSI. RESULTS: Crude mortality was 41.5%. Septic shock was present in 184 patients (55%). The pathogens most frequently associated with septic shock or death were Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae, which accounted for approximately half of the deaths. Antibiotic treatment was found to be inappropriate in 14.5% of episodes. Patients in septic shock with inappropriate treatment had a survival rate below 20%. Multivariate analysis identified a significant association between septic shock and four variables: age > or = 60 years (odds ratio [OR], 1.96), previous corticosteroid therapy (OR, 2.58), leukopenia (OR, 2.32), and BSI secondary to intra-abdominal (OR, 2.38) and genitourinary tract (OR, 2.29) infections. The variables that independently predicted death at ICU admission were APACHE (acute physiology and chronic health evaluation) II score > or = 15 (OR, 2.42), development of septic shock (OR, 3.22), and inappropriate empiric antibiotic treatment (OR, 4.11). This last variable was independently associated with an unknown source of sepsis (OR, 2.49). Mortality attributable to inappropriate antibiotic treatment increased with the severity of illness at ICU admission (10.7% for APACHE II score < 15 and 41.8% for APACHE II score > or = 25, p < 0.01). CONCLUSIONS: Inappropriate antimicrobial treatment is the most important influence on outcome in patients admitted to the ICU for community-acquired BSI, particularly in presence of septic shock or high degrees of severity. Initial broad-spectrum therapy should be prescribed to septic patients in whom the source is unknown or in those requiring vasopressors.     

New challenges in the diagnosis, management, and prevention of central venous catheter-related infections

Catheters are the leading source of bloodstream infections in critically ill patients. Because the clinical signs of infection are nonspecific, such infections are overly suspected, which results in unnecessary removal of catheters. A conservative approach might be attempted in mild infections, whereas catheters should always be removed in cases of severe sepsis or septic shock. Nowadays, comprehensive unit-based improvement programs are effective to reduce catheter-related bloodstream infections (CR-BSIs). Rates of CR-BSI higher than 2 per 1000 catheter-days are no longer acceptable. A locally adapted checklist of preventive measures should include cutaneous antisepsis with alcoholic preparation, maximal barrier precaution, strict policy of catheter maintenance, and ablation of useless catheters. Antiseptic dressings and, to a lesser extent, antimicrobial-coated catheters, might be added to the prevention strategies if the level of infections remains high despite implementation of a prevention program. In the case of CR-BSI in intensive care units (ICUs), the catheter should be removed. In the case of persistence of fever or positive blood cultures after 3 days, inadequate antibiotic therapy, endocarditis, or thrombophlebitis should be ruled out.     

Drug intervention trials in sepsis: divergent results

CONTEXT: Important advances have been made in our understanding of severe sepsis. Outcome can be improved by targeted interventions, including early and appropriate antibiotic therapy and goal-directed resuscitation, and might be further improved by selective decontamination of the digestive tract, tight control of glucose, and possibly by giving corticosteroids to selected patients. Drugs that target specific steps in the septic cascade include cytokine inhibitors, anti-endotoxins, and the three naturally occurring anticoagulants. Only one of these trials, which assessed the efficacy of activated protein C, reported significant improvements in outcome. Translation of these results into practice has been hampered by high drug costs, and by apparent discrepancies between interim results and final outcomes in two of the trials with natural anticoagulants. STARTING POINT: Recently, Steven Opal and colleagues (Crit Care Med 2004; 32: 332-41) reported a randomised trial with platelet-activating-factor acetylhydrolase to suppress the inflammatory response in septic patients. No effects on outcome were observed (mortality 24% with placebo vs 25% with the intervention). By contrast, Jose Garnacho-Montero and colleagues, in a cohort study (Crit Care Med 2003; 31: 2742-51), saw large mortality reductions with initially appropriate choice of antibiotics in septic patients (19.8% reduction overall and 43.4% in patients with septic shock). These benefits were higher than those even in the most successful trial with an antisepsis agents, underscoring the importance of basic measures in severe sepsis. WHERE NEXT? Initial management in severe sepsis should include early goal-directed fluid resuscitation, appropriate antibiotic treatment, and surgical-site control. Intensive-care units should be run by specialists, with adequate medical and nursing staffing. Tight regulation of glucose, selective decontamination of the digestive tract, and moderate-dose corticosteroids in selected cases should be considered. Expensive new drugs, such as activated protein C, might further improve outcome, but should be considered only when organisational aspects and supportive care have been optimised.     

Diagnose und kausale Therapie der Sepsis

The high mortality and morbidity of severe sepsis and septic shock had not been reduced during the two recent decades, despite a number of advances in the field of supportive and adjunctive sepsis therapies. The reason might be that important steps towards overcoming of sepsis are progress in the early diagnosis, the surgical resection of the infectious focus and an adequate antibiotic treatment. However, worldwide growing resistances of pathogens against the common antibiotics are detected. In opposite, no major progress in the development of new antibiotics, mainly for the treatment of Gram-negative non-fermenter infections like Pseudomonas aeruginosa, can be predicted for the next years. Therefore, sepsis treatment must be focused on prevention of infection, and on an optimised application of current antibiotic substances. The key factors are a broad, high dose, and early applicated initial treatment, a de-escalation strategy according to the clinical course supported by the application of novel molecular markers, and – with exceptions – a limitation of treatment to 7 to 10 days. A closer cooperation between microbiologists, infection control specialists and clinical infectious disease consultants may be a key factor to overcome the raising problems in the future.     

Current therapy for sepsis.

The treatment of severe sepsis and septic shock remains a challenge as we approach the next millennium. Although more attention is being given to guidelines and care pathways for sepsis, these are unfortunately based primarily on consensus opinion. Additional research into supportive interventions in this potentially devastating disease is needed. Priorities in the management of sepsis include rapid reversal of hypotension and hypoperfusion, followed by empiric antibiotic therapy and definitive localization and treatment of infection nidus. A wide variety of adrenergic agents may be useful in sepsis. Initial therapy for hypoperfusion, however, should be targeted toward establishing adequate intravascular volume and left ventricular preload. Adjunctive therapy to prevent complications during the intensive care unit stay is important.     

An effect of continuous and intermittent renal replacement therapy on antibiotic treatment in critically ill patients with sepsis - a practice-based perspective of vancomycin and gentamycin therapies

Sepsis and septic shock are common cause of hospitalisation in intensive care unit. Acute kidney injury is an accompanying manifestation of sepsis/septic shock leading to worsening of morbidity and also mortality and requiring use of intermittent or continual renal replacement therapy. Life saving effect is attributed to early and effective antibiotic therapy. Therapeutic drug monitoring and do-sage adjustment is important for successful treatment. Despite therapeutic drug monitoring of both antibiotic agents vankomycin and gentamicin the treatment still rises many questions about the convenient use in septic patients due to their nephrotoxicity.     

Concurrent neonatal Proteus mirabilis infection in dizygotic twins

A case of concomitant infection with Proteus mirabilis in dizygotic twin neonates is presented. The first twin presented with meningitis and septic shock at eight days of age and subsequently died. An investigation of the asymptomatic second twin revealed a urinary tract infection that resolved with antimicrobial therapy. It is recommend that when infection with this virulent organism is diagnosed in one twin, the second twin should be fully evaluated for sepsis and empirical antimicrobial therapy should be considered.     

Neuromuscular and Central Nervous System Manifestations of <Emphasis Type="Italic">Clostridium perfringens</Emphasis> Infections

Abstract Infections with Clostridium perfringens usually manifest locally or spread to sepsis with multiorgan involvement, hemolysis or septic shock. Central nervous system (CNS) manifestations are rare and most frequently comprise meningitis with or without pneumencephalon, encephalitis, plexitis, cerebral abscess, or subdural empyema. The course of CNS affections is usually foudroyant and the outcome fatal. Neuromuscular manifestations of C. perfringens infections are much more frequent than CNS manifestations and comprise myonecrosis (gas gangrene), rhabdomyolysis, myositis, fasciitis, affection of the neuromuscular transmission, or affection of the peripheral nerves. C. perfringens infections usually start from the site of a recent surgical wound or trauma, a gastrointestinal or urogenital problem, or occur in association with malignancy. In quite a number of cases the source of origin remains speculative. Treatment of choice is surgical debridement of the infectious focus with radical removal of all necrotic tissue, resection of the corresponding lymphatics in addition to antibiotic therapy with penicillin G, aminoglycosides, or clindamycin or hyperbaric oxygenation. Despite these therapeutic options, the prognosis of CNS and neuromuscular involvement in an infection with C. perfringens is still poor. Only focal infections or clostridial brain abscesses may eventually have a more favorable outcome, if surgery and antibiotics are instantly provided. Generally, early recognition of the infectious agent is of paramount importance to prevent from spreading and the development of severe hemolysis, septic shock, or death.     

Blood glucose control in patients with severe sepsis and septic shock

The main pathophysiological feature of sepsis is the uncontrollable activation of both pro- and anti-inflammatory responses arising from the overwhelming production of mediators such as pro- and anti-inflammatory cytokines. Such an uncontrollable inflammatory response would cause many kinds of metabolic derangements. One such metabolic derangement is hyperglycemia. Accordingly, control of hyperglycemia in sepsis is considered to be a very effective therapeutic approach. However, despite the initial enthusiasm, recent studies reported that tight glycemic control with intensive insulin therapy failed to show a beneficial effect on mortality of patients with severe sepsis and septic shock. One of the main reasons for this disappointing result is the incidence of harmful hypoglycemia during intensive insulin therapy. Therefore, avoidance of hypoglycemia during intensive insulin therapy may be a key issue in effective tight glycemic control. It is generally accepted that glycemic control aimed at a blood glucose level of 80-100 mg/dL, as initially proposed by van den Berghe, seems to be too tight and that such a level of tight glycemic control puts septic patients at increased risk of hypoglycemia. Therefore, now many researchers suggest less strict glycemic control with a target blood glucose level of 140-180 mg/dL. Also specific targeting of glycemic control in diabetic patients should be considered. Since there is a significant correlation between success rate of glycemic control and the degree of hypercytokinemia in septic patients, some countermeasures to hypercytokinemia may be an important aspect of successful glycemic control. Thus, in future, use of an artificial pancreas to avoid hypoglycemia during insulin therapy, special consideration of septic diabetic patients, and control of hypercytokinemia should be considered for more effective glycemic control in patients with severe sepsis and septic shock.