2,833 publications from this institution
Ischemic conditioning induces a series of cellular modifications that may prevent injury from further hypoxic episodes, but there are few data in sepsis. In this randomized controlled study, we evaluated the effects of ischemic conditioning on the microcirculation, organ function, and survival time in an ovine model of septic shock.Sepsis was induced in 14 anesthetized, mechanically ventilated adult sheep by injecting autologous feces into the abdominal cavity. Animals were then randomized to ischemic pre- and post-conditioning or no conditioning (both n = 7). Remote ischemic conditioning was performed by inflating the balloon of a catheter in the aortic bifurcation for 2 min, followed by a 4-min deflation period. The procedure was performed four times before sepsis induction and 4-hourly afterward. Animals were followed until death or for a maximum of 30 h. Hemodynamic, oxygenation, and microcirculatory variables were monitored. The conditioned group had higher mixed venous oxygen saturation from 8 h after randomization, higher cardiac index, and oxygen delivery from 16 h, and higher mean arterial pressure and lower lactate levels from 20 h. They also had greater renal blood flow, urine output, and creatinine clearance. Microcirculatory variables were better preserved in the conditioned than in the control group from 6 h after randomization: the median proportion of perfused vessels was 91 (89-93)% versus 89 (86-90)% (P = 0.024) and there was less heterogeneity. Oliguria, hypotension, and death occurred later in the conditioned than in the control group. In this sepsis model, remote ischemic pre- and post-conditioning therefore decreased organ dysfunction, preserved the microcirculation, and prolonged survival.
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In 36 hemodynamically stable septic patients, we explored whether changes in gastric mucosal-arterial PCO(2) gradient (PCO(2)gap) induced by a short-term dobutamine infusion may reveal hepatosplanchnic hypoperfusion. Hepatosplanchnic blood flow (HSBF) was determined by the continuous indocyanine green infusion technique and gastric mucosal PCO(2) (Pg(CO(2))) by saline tonometry. In each patient, hemodynamic measurements, blood samples, and Pg(CO(2)) determinations were performed three times: first at baseline (DOB 0), second during a dobutamine infusion at a dose of 5 microgram/kg/min (DOB 5), and third at a dose of 10 microgram/kg/min (DOB 10). The results were analyzed by Wilcoxon's matched-pairs signed rank test and are presented as medians with ranges. The PCO(2)gap decreased preferentially in groups of patients with inadequate hepatosplanchnic perfusion, i.e., with a low fractional HSBF (HSBF/CI), defined as the ratio of the HSBF to the simultaneous cardiac index, or a high gradient between the mixed venous blood and the suprahepatic blood O(2) saturations (DSvh(O(2))). In the 11 patients with a DSvh(O(2)) above 20% at baseline, PCO(2)gap decreased from 12.1 (6.3 to 19.5) mm Hg at DOB 0 to 6.2 (2.5 to 19. 3) mm Hg at DOB 5 (p < 0.001 versus DOB 0), and to 4.2 (0.1 to 35.9) mm Hg at DOB 10 (p < 0.05 versus DOB 5), whereas in the 25 patients with a DSvh(O(2)) below 20% at baseline, PCO(2)gap did not change significantly. At no time was the PCO(2)gap correlated with HSBF/CI or DSvh(O(2)). We conclude that although the PCO(2)gap does not correlate well with global indexes of gut oxygenation, such a simple dobutamine infusion test could identify patients with inadequate hepatosplanchnic perfusion.
Severe sepsis is a common and frequently fatal condition. Evidence showing a link between the coagulation system and the inflammatory response to sepsis led to the development of drotrecogin alfa (activated) as an agent in the treatment of sepsis. This recombinant form of the natural protein, activated protein C (Xigris, Eli Lilly Co.), has been shown to significantly reduce mortality in a large randomised, controlled Phase III study involving 1690 patients. The exact mode of action of drotrecogin alfa (activated) remains uncertain, although it clearly combines anticoagulant and anti-inflammatory properties. Although associated with an increased risk of bleeding, this is usually procedure-related rather than spontaneous. Although costly, this is a drug that effectively reduces mortality rates in patients with severe sepsis.
Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
Recent advances in technology and better understanding of mechanisms underlying disease are beginning to enable us to better characterize critically ill patients. Instead of using nonspecific syndromic groupings, such as sepsis or acute respiratory distress syndrome, we can now classify individual patients according to various specific characteristics, such as immune status. This "personalized" medicine approach will enable us to distinguish patients who have similar clinical presentations but different cellular and molecular responses that will influence their need for and responses (both negative and positive) to specific treatments. Treatments will be able to be chosen more accurately for each patient, resulting in more rapid institution of appropriate, effective therapy. We will also increasingly be able to conduct trials in groups of patients specifically selected as being most likely to respond to the intervention in question. This has already begun with, for example, some new interventions being tested only in patients with coagulopathy or immunosuppressive patterns. Ultimately, as we embrace this era of precision medicine, we may be able to offer precision therapies specifically designed to target the molecular set-up of an individual patient, as has begun to be done in cancer therapeutics.
The first ICUs were established in the late 1950s and the specialty of critical care medicine began to develop. Since those early days, huge improvements have been made in terms of technological advances and understanding of the pathophysiology and pathogenesis of the disease processes that affect critically ill patients. Progress in therapeutics has been less dramatic, but process of care has improved steadily with important changes, including less iatrogenicity, better communication with patients and families, and improved teamwork, which have helped improve outcomes for ICU patients. Critical care medicine is one of the fastest-growing hospital specialties and, looking back, it is clear just how far we have come in such a relatively short period of time. With the ICU set to occupy an increasingly important place in hospitals worldwide, we must learn from the past and wisely embrace new developments in technology, therapeutics, and process, to ensure that the goals of critical care medicine are met in the future.
