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Julien Textoris, Sandrine Wiramus, Clément Brun, Claude Martin and Marc Leone
Service d’anesthésie et de réanimation
Hôpital Nord, Assistance Publique-Hôpitaux de Marseille
Université de la Méditerranée
Sepsis is the major point of focus of drug discovery efforts in the critical care area. Severe sepsis is defined by the occurrence of an organ dysfunction in a septic patient. Septic shock is the last stage of a continuum, defined as a vascular failure refractory to fluid resuscitation and requiring vasopressors in a septic patient. The management of septic patients is based on parallel strategies including infectious source control and haemodynamic stabilisation.1 First, the burden of infection should be promptly reduced by source control measures and early use of antimicrobial agents. Second, haemodynamics should be controlled as soon as possible.
In the present overview, the role of clinical pharmacist will be discussed for the major therapeutic interventions recommended in patients with septic shock. This will be based on the knowledge that participation of a pharmacist in the daily multidisciplinary team rounds in intensive care units reduces unfavourable morbidities and cost of hospitalisation.2
Early and appropriate antimicrobial therapy
Empiric therapy is a medical term referring to the initiation of treatment prior to determination of a firm diagnosis. Empirical antimicrobial therapy should be used in patients with a suspected infection that can alter her or his outcome. In septic shock patients, several observational studies have shown that any delay in the initiation of this treatment is associated with increased mortality.3 The mortality rate increases by 1% every 10 minutes if an antibiotic is not administered. The mortality rate is significantly lower in the patients receiving antibiotics within the first hour after diagnosis than in those receiving antibiotics later.4 Thus, in patients with severe sepsis or septic shock, an empirical antimicrobial therapy should be administered within the first hour following the diagnosis.
The empirical antimicrobial therapy has to be efficient against pathogens associated with the suspected infection. Indeed, inappropriate empiric antibiotic therapy is associated with increased mortality in critically ill patients.5 For instance, increased mortality was reported in patients with empirical piperacillin-tazobactam therapy and Pseudomonas aeruginosa bacteremia due to isolates with reduced piperacillin-tazobactam susceptibility.
In order to provide an appropriate therapy, adherence to guidelines seems critical.6 These guidelines should be based on an integrative approach that takes into account the site of infection, the past medical history of the patient, the prior use of antibiotics, and the local ecology.
In order to reduce the risk of failure, the empirical antimicrobial therapy is typically broad spectrum. Most edited guidelines for severe sepsis management recommend the use of a combination of antibiotics.1 Until recently, the literature did not support these guidelines. Today, several large observational studies have shown that treatment with a combination of antibiotics is associated with improved survival in septic shock patients.7,8 A combination of antibiotics may enlarge the spectrum of activity of antibiotics. However, a well-conducted observational study shows a benefit of a combination including two antibiotics active against the targeted bacteria. This suggests a kind of synergism between antibiotics. In order to be efficient, the combination should always include a beta-lactam, except in patients with a contraindication. In a retrospective study, the combination of beta-lactam and aminoglycoside seems to be optimal, as compared with fluoroquinolones or macrolides.8 The benefit of a combination of antibiotics is only true in patients with shock. In addition, there is a need to administer larger doses in critically ill patients hospitalised in an intensive care unit than in non-critically ill patients. Hence, high doses of combined antimicrobial therapy should be the rule in the patients with septic shock.
The major limitation to this clinical approach is that it consistently leads to an overuse of antibiotics. This practice can be associated with the emergence of multi-drug resistant pathogens, infection with Clostridium difficile, and increasing costs. For this reason, the empirical antibiotic regimen should be reassessed and tailored as soon as culture and sensitivity results become available. This practice, so called ‘de-escalation’, is associated with reduced costs, decreased incidence of superinfection and minimal development of antimicrobial resistance.5 If possible, one should not omit to collect blood samples for culture before initiating the antibiotic regimen.1,3
Thus, the role of clinical pharmacist should be to help the clinicians to select the best combination of antibiotics within the first hour after severe sepsis or septic shock are diagnosed. To this purpose, the best approach is probably to elaborate with clinicians’ procedures for a rapid administration of antibiotics. An antimicrobial stewardship programme has been associated with a reduction in antimicrobial drug adverse events.9 This should help to avoid any delay in their administration. After microbiological results are available, the clinical pharmacist should stress the importance of de-escalating the empirical treatment. The general rule for the culture-based treatment is the use of low-cost antibiotics for a short duration. A study shows that in patients with Staphylococcus aureus bacteraemia, intervention by infectious diseases clinical specialists on the basis of the results significantly reduces the time to optimal antimicrobial therapy.10 Examples of empirical antimicrobial therapy according to infection site are provided in Table 1.
Septic shock is defined by vascular dysfunction requiring the need for a vasopressor. Thus, in patients not responding to fluid resuscitation, the use of vasopressors is mandatory. A level of mean arterial pressure above 65mmHg should be obtained within the first hour of management. Once this objective is obtained, management should be aimed at decreasing the plasma lactate level within the first two hours of resuscitation. In patients with septic shock, fluid resuscitation alone failed to improve haemodynamics. Hence, there is a need for vasopressors.
Guidelines recommend the use of either dopamine or norepinephrine as first line agent.1 In several observational studies, dopamine use is associated with poor outcome. The results of a clinical trial comparing dopamine and norepinephrine as first line agent in septic shock conclude that the two vasopressors produce equivalent effects. However, use of dopamine was associated with a higher rate of side-effects than that of norepinephrine, especially arrhythmia.11 The survival of patients treated with a combination of norepinephrine and dobutamine did not differ from that of patients treated with epinephrine.
On the other hand, the addition of low-dose vasopressin to norepinephrine did not significantly improve the survival of septic shock patients. A positive effect on survival was observed in a pre-determined (norepinephrine dose <15µg/kg/min) subgroup of patients with moderate shock.12 Terlipressin is a pro-drug of vasopressin. It is the only drug available in several European countries. It seems to be more efficient on V1 receptors than vasopressin. There is no large randomised clinical trial on the use of terlipressin. In contrast, nitric oxide inhibitors were associated with an increased mortality in septic shock patients.
With respect to inotropes, significant cardiac failure requiring therapeutic support is observed in about 20% of patients with septic shock. Indications for inotropes should be based on multimodal monitoring showing an inadequate balance between the oxygen need and delivery. Central venous oxygen saturation measured on a sample collected in the upper cava territory below 70% seems a good marker of cardiac dysfunction.1 A low cardiac index, measured by invasive devices or echocardiography may help the decision. In these patients, the first step is to control whether the pre-load has been adequately corrected. The second step is the introduction of inotropes in order to improve the cardiac work. In our opinion, this decision should be based on a strong rationale. Edited guidelines recommend the use of dobutamine. The level of evidence for other inotropic support, such as levosimendan or isoproterenol is not sufficient to use these drugs in clinical practice.
The pharmacist should be involved in the elaboration and implementation of care bundles that make it possible to provide adequate treatment at the right time. In addition, interventions should aim to reduce medical errors in the management of high-risk drugs.
The role of adjunctive treatment remains a matter of debate
Current guidelines recommend the use of low-dose hydrocortisone.1 This treatment should be administered in all septic shock patients.
In the literature, this treatment is always associated with an accelerated weaning of norepinephrine. Unfortunately, there is no evidence linking accelerated weaning of vasopressors with an improvement in survival.
Relative adrenal insufficiency is frequent in patients with septic shock. A French, randomised, multicentre clinical trial showed that low-dose hydrocortisone administration was associated with reduced mortality.13 This was only true in the patients with adrenal insufficiency. The confounding role of fludrocortisone has been recently discarded. Low-dose hydrocortisone is an inexpensive treatment, and few side-effects were reported in the first trial. Hence, this treatment was rapidly included in the practice of intensivists. Unfortunately, a large randomised clinical trial entitled CORTICUS failed to confirm these results.14 In addition, side-effects were reported at a significantly higher rate in the patients treated with steroids. Detractors stressed several limitations of this trial: the high rate of inappropriate antimicrobial therapy, failure to reach the enrolment target of 800 patients, low mortality rate in the control group, the use of etomidate and late use of hydrocortisone administration. However, large observational studies using adequate propensity scores confirm the results of the CORTICUS trial.3,4 In France, a randomised clinical trial (APPROCHS (NCT00625209)) tests this hypothesis again in severe septic shock patients. In the light of the current evidence, low-dose steroids should be reserved for septic shock patients with increasing doses of norepinephrine after a few hours of resuscitation.
The coagulation pathway is based on the rationale that patients with severe sepsis develop disseminated intravascular coagulation resulting in microvascular dysfunction and misuse of oxygen. In line with this concept, drotrecogin alfa (activated) (Xigris®, Lilly) was tested in patients with severe sepsis. Drotrecogin alfa (activated) is an anticoagulant inhibiting factor V and factor VIII. It has also anti-inflammatory and anti-apoptotic properties and may thereby prevent organ tissue damage. The PROWESS (recombinant human activated protein C worldwide evaluation in severe sepsis) trial randomly allocated a 96-hour infusion of drotrecogin alfa (activated) or placebo. A 6.1% absolute decrease in mortality was found in patients who received drotrecogin.15 As this drug is an anticoagulant, its administration is associated with an increased risk of bleeding. Guidelines recommend its use in selected patients without contraindication. The drug was licensed by both the US Food and Drug Administration and the European Medicines Evaluation Agency. However, use of drotrecogin alfa (activated) in patients with severe sepsis remains a hot topic. The results of the PROWESS study, of which the method was matter of some debate, were never confirmed in another randomized trial. However, animal models confirmed that drotrecogin alfa (activated) increases survival in septic animals. Cohort studies also showed that drotrecogin alfa (activated) use is associated with increased survival.3,4 This drug seems effective only when administered within the first 24 hours after the onset of norepinephrine infusion. One limitation of the cohort studies is the low numbers of patients with septic shock treated with drotrecogin alfa (activated).
In order to strengthen these findings, two clinical trials are ongoing. A randomised multicentre clinical trial entitled PROWESSshock (NCT00112164) should test the efficacy of drotrecogin alfa (activated) in patients with septic shock. In parallel, a study entitled APPROCHS (NCT00625209) compares septic shock patients treated with hydrocortisone, drotrecogin alfa (activated), both of them, or double placebo.
The pharmacist may be involved in the implementation of care bundles aiming to screen patients eligible to receive drotrecogin alfa (activated). After this step, it is critical to monitor the treatment, its duration, and its management in patients requiring emergent invasive procedures. It has been shown that such intervention in prescribing drotrecogin alfa (activated) for patients with severe sepsis might reduce direct medical costs and promote earlier goal-directed therapy.16
The management of patients with severe sepsis and septic shock requires pre-determined protocols, elaborated on the basis of evidence available in the literature (see Figure 1). Administering an appropriate empirical antimicrobial treatment within the first hour of diagnosis is a low-cost intervention which has been associated with reduced mortality. Thus, all efforts should be made to optimise this prescription process. In order to stabilise haemodynamics, clinicians should use norepinephrine as first line vasopressor, after an adequate fluid challenge. The place of adjunctive treatments remains matter of debate. In this context, the role of clinical pharmacist is crucial (see Figure 2). She or he should participate in the design of care bundles, implement interventions aimed at preventing medication errors, select the most cost-effective treatments, and prevent side-effects of these treatments.
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