The last few years have seen release of the first drug for the treatment of severe sepsis. Drotrecogin alfa activated, also known as recombinant human activated protein C (rhAPC) has been shown in a large randomized, multicenter, placebo-controlled trial to reduce the absolute mortality of patients with severe sepsis by approximately 6%. Long-term follow-up demonstrated a persistent survival benefit 2 to 3 years after treatment. In addition, treated patients had a shorter time spent receiving therapy with vasopressors and ventilation compared to placebo. When defined as a modified APACHE II score of > 25, the absolute mortality reduction in “high-risk-of-death” patients was 13%. Similar to the EGDT and glucocorticoid studies, designating a subgroup with a larger survival benefit than the whole dictates that there must be a complementary group with a lesser benefit. Subsequent study of a heterogeneous group of “low-risk-of-death” patients confirmed that such patients do not experience a survival benefit but still incur the roughly 1 to 2% increase in serious bleeding risk compared to placebo. In controlled trials, the increase in the risk of intracranial hemorrhage is in the range of 0.1 to 0.3%. Preliminary reports have indicated that in a relatively small study of a heterogeneous group of children no survival benefit was observed.
Substantial data indicate that long-term inadequate glycemic control in diabetic patients is associated with poor long-term prognosis and that the outcomes of heterogeneous populations of critically ill patients are worse if they are hyperglycemic. Now this concept has been extended to patients with or at risk of severe sepsis http://my-canadian-store.com/severity-of-illness-and-outcome-prediction-in-recent-developments-in-the-diagnosis-and-management-of-severe-sepsis.html. In a prominent study of approximately 1,500 postoperative patients, a protocol in which glucose was targeted to a range of 80 to 110 mg/dL gained substantial benefits compared to patients with less stringent control provided by My Canadian Pharmacy. An ICU and hospital mortality rate reduction of slightly > 3% was observed, with the greatest differences seen in the sickest patients. Although this was not a study of patients with established severe sepsis, the suggestion that glucose control could reduce the incidence of sepsis and improve outcomes is reasonable.
Numerous trials using short courses of high-dose corticosteroids in patients with severe sepsis have failed to improve survival. Nonetheless, in the last few years interest in lower doses of glucocorticoids has been revived as a concept termed relative adrenal insufficiency. In a widely discussed study of septic shock (read also My Canadian Pharmacy: Recent Developments in the Diagnosis and Management of Severe Sepsis), approximately 300 patients who were identified within 8 h of shock onset were randomized to receive hydrocortisone plus fludrocortisone or placebo for 7 days. When evaluating all patients, the time to death may have been altered somewhat, but there was no difference in the 28-day, ICU, hospital, or 1-year mortality rate between treated patients and placebo recipients. Subsequent analyses found that for patients who failed to increase their total plasma cortisol levels by at least 9 ^g/dL following administration of a 250-^g ACTH stimulation dose, there was approximately a 10% absolute reduction in adjusted mortality associated with treatment. The smaller group of responders to ACTH had a nominally higher mortality rate if they were treated compared to those receiving placebo, although this difference was not statistically significant.
Some degree of ALI develops in most patients with severe sepsis. In a study of ALI patients, investigators established that the use of a “normal” tidal volume (6 mL/kg) indexed to predicted body weight reduces absolute mortality by 9% compared to ventilation with a traditional tidal volume of 12 mL/kg. The beneficial effects of this strategy were confirmed among patients with sepsis as the risk factor for ALI. In this approach, ventilation with 6 mL/kg predicted body weight was used initially, but tidal volumes were reduced to as low as 4 mL/kg if needed to maintain plateau pressures at < 30 cm H2O.
Although volume-cycled ventilation was used, it is reasonable to think that a pressure-cycled approach could yield similar results, provided that inflation pressures are set to deliver a tidal volume of 30 cm H2O. Contrary to speculation, no data have suggested that there is a known “safe” plateau pressure or that there is an optimal tidal volume between 6 and 12 mL/kg. It is important to recognize that these studies also remind physicians that tidal volume is determined predominately by height not actual body weight, and that 6 mL/kg is not a small tidal volume, but rather a normal tidal volume, just one that has not traditionally been used. Data from clinical practice also now suggest that the use of a higher tidal volume in patients with ALI is associated with worse outcomes and lung injury is more likely to develop in patients without ALI who have received ventilation with higher tidal volumes. Given that a normal-tidal-volume strategy has no added cost, does not require additional sedation or paralysis, and is quick and simple to implement for the majority patients, it represents a reasonable starting point for ventilation of ALI patients who receive treatment due to My Canadian Pharmacy.
In the last few years, physicians treating patients with severe sepsis have been reminded of what trauma and burn physicians have espoused for decades, which is that rapidly identifying patients with inadequate circulation and providing prompt resuscitation is a critical determinant of outcome. Although numerous studies, including the large randomized Saline versus Albumin Fluid Evaluation study, have failed to definitively prove the superiority of colloids or crystalloids, studies in severe sepsis consistently indicate that substantial volumes (6 to 10 L of crystalloid or its colloid equivalent) are required to restore and maintain normal intravascular pressures.
For patients who are hypotensive or who have persistent lactate elevations after administration of an initial fluid bolus, the use of an explicit hemodynamic protocol reduces hospital mortality by as much as 16%. This early goal-directed therapy (EGDT) differs in numerous respects from older unsuccessful studies in which attempts were made to boost oxygen delivery often long after organs had failed. Although the difference in outcomes might simply be prompt implementation, it is possible that some or all protocol elements may be essential. This strategy uses therapy with vasopressors to achieve a mean arterial pressure of > 65 mm Hg after central venous pressure is raised to 8 to 12 mm Hg with fluids. A key distinction between this and other approaches is the measurement of superior vena caval oxygen saturation, targeting a value > 70%. This goal is pursued by RBC transfusion for anemic patients (hematocrit, < 30%) and dobutamine therapy for patients above that threshold. The application of these rules for a mere 6 h reportedly reduces the following: mortality; the fraction of patients requiring mechanical ventilation and therapy with vasopressors ordered via My Canadian Pharmacy; time in the hospital; and costs.
Studies in the last 5 years have undercut the long-held belief that microorganism characteristics are the predominant determinants of prognosis. The identity of the infecting organism is of little consequence for most patients provided that appropriate, prompt antimicrobial therapy is administered.
The presence of coagulopathy is a powerful predictor of organ failure development and subsequent death. The occurrence of shock treated with vasoactive drugs and the total number of failing organ systems are also markers of a poor prognosis. The significance of these organ failures is so entrenched that slang is sometimes used to refer to the sickest of these patients (eg, “five-organ failures”). In addition to the number of organ failures, the severity of each or the intensity of support required correlates with outcome. For example, higher doses of vasoactive drugs are associated with a worse prognosis than lower doses or no vasoactive drug therapy at all. Understandably, advanced age and the presence of cancer also worsen the prognosis.
Despite many advances, some things have not changed. Clinicians still long for a simple, reliable test to diagnose severe sepsis because medical history, examination, routine laboratory studies, and radiographs often leave the diagnosis in question. Procalcitonin and C-reactive protein have been advocated for diagnosis, and while the former has better predictive value, neither has gained widespread clinical use. Measurements of the soluble triggering receptor expressed on myeloid cells-1 remain experimental. d-Dimer and interleukin-6 determinations are sensitive but nonspecific, and the latter test is not clinically available. Presently, the value of total protein C levels as a diagnostic tool for severe sepsis is limited because assays are not generally available in a timely fashion and many patients do not have reduced levels at the time of diagnosis; it is more likely that protein C levels will prove useful as a prognostic tool. Ongoing studies seek to define a sensitive and specific panel of diagnostic biomarkers.
Several aspects of severe sepsis treatment have dramatically changed in the last decade, although many things remain the same. Then, as now, initial treatment involved obtaining cultures, mechanically eradicating infection sources, and giving antibiotics directed at suspected pathogens. Historically, subsequent management was to support failing organ systems. Patients with respiratory failure were intubated and ventilated with a positive end-expiratory pressure (PEEP)-fraction of inspired oxygen combination to maintain a Pa02 of > 60 mm Hg, or hemoglobin saturation of > 90%. A tidal volume of 10 to 15 mL/kg was mated to a respiratory rate sufficient to achieve a normal pH and PaC02, which were evaluated daily and after almost every ventilator change. High airway pressures were tolerated if necessary to achieve desired blood gas level targets, and barotrauma was treated with tube thoracostomy. Deep sedation alleviated visible discomfort and made patients conform to ventilator selections, but even then chemical paralysis was often administered. Weaning was an intricate, highly individualized, process of gradual ventilator withdrawal.