Ramesh Venkataraman

Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-κB DNA binding, and improves short-term survival in lethal endotoxemia

ObjectivesPrevious studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. DesignRandomized controlled laboratory experiment. SettingUniversity laboratory. SubjectsSixty-six adult Sprague-Dawley rats. InterventionsWe conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-&kgr;B DNA binding. Measurements and Main ResultsMean survival time among hemoadsorption-treated animals was 629 ± 114 vs. 518 ± 120 mins for sham-treated animals (p < .01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p < .05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-&kgr;B DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. ConclusionsHemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.

Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock.

The glycolytic intermediate, pyruvate, is capable of scavenging reactive oxygen species (ROS). However, this compound is relatively unstable and hence is not useful as a therapeutic agent. Ethyl pyruvate, a simple derivative of pyruvate, appears to be more stable, and when formulated in a calcium-containing Ringers-type balanced salt solution (REPS), has been shown to be salutary in rat models of two pathophysiological conditions—mesenteric ischemia/reperfusion and hemorrhagic shock/resuscitation—that are thought to be mediated, at least in part, by ROS. Because ROS also have been implicated in the pathogenesis of lipopolysaccharide (LPS)-induced shock, we carried out a series of experiments to determine if REPS is beneficial in this condition. Anesthetized rats were challenged with intravenous LPS (20 mg/kg). When mean arterial pressure (MAP) decreased to 60 mmHg, 3- to 5-mL boluses of either REPS (n = 10) or Ringers lactate solution (RLS; n = 10) were infused as needed to prevent MAP from decreasing further. By design, the maximal volume of fluid infused was 7 mL/kg. Resuscitation with REPS as compared with RLS prolonged survival time (498 ± 48 min vs. 362 ± 30 min;P = 0.0014). Resuscitation with REPS as compared with RLS also was associated with significantly lower circulating concentrations of nitrite/nitrate and interleukin (IL)-6 and higher plasma levels of IL-10. These data support the view that delayed treatment with REPS modulates the inflammatory response to LPS, and prolongs survival time in a lethal model of endotoxic shock.

Defining Acute Renal Failure: The RIFLE Criteria

Acute renal failure is common among critically ill patients and carries significant morbidity and mortality. The reported incidence and the attributed morbidity and mortality of acute renal failure vary widely, largely owing to the use of a wide variety of definitions for acute renal failure. Until recently, no consensus existed about how to best define, characterize, and study acute renal failure. This lack of a standard definition has been a major impediment to the progress of clinical and basic research in this field. This review outlines some of the physiologic principles that may help us better understand and define acute renal failure and describes the RIFLE criteria (an acronym comprising Risk, Injury, and Failure; and Loss, and End-stage kidney disease), a recent consensus method of defining and stratifying acute renal failure. Also discussed are many of the challenges and controversies associated with achieving consensus and developing a classification for acute renal dysfunction.

Increased plasma interleukin-6 in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation

Objectives:Brain death induces a massive inflammatory response. However, the influence of this inflammatory response on organ procurement, transplantation, and recipient outcome is unknown. We describe the inflammatory response characteristics in brain-dead organ donors and examine associations with organ transplantation and recipient survival. We test the hypothesis that increased inflammatory response is associated with fewer organs transplanted and decreased recipient survival. Design:Prospective, observational, cohort study. Setting:Two large intensive care units of tertiary care university hospitals in the United States. Patients:We recruited 30 consecutive brain-dead organ donors and 78 recipients between April 11, 2004, and November 23, 2004; recipients were followed through May 2005. Following declaration of brain death, we collected data on donor demographics, mechanism of brain death, number of organs procured and transplanted, and recipient characteristics. Plasma cytokines (tumor necrosis factor, interleukin-6, interleukin-10) were measured in donors at baseline following study enrollment, every hour for the first 4 hrs, and immediately before organ procurement for transplantation. Interventions:None. Measurements and Main Results:We examined the relationships among clinical characteristics, demographics, and cytokine response in donors and their influence on organ procurement and transplantation using multivariable regression and recipient’s 6-month hospital-free survival using a Cox proportional hazards regression. One hundred-eighteen organs were procured from 30 donors, and 91 (77%) were transplanted (mean of three organs transplanted per donor). All cytokines were increased following brain death. Older age in donors was significantly associated with lower number of organs transplanted (p < .001). Higher plasma interleukin-6 concentrations in donors before organ procurement was significantly associated with lower 6-month hospital-free survival in recipients (hazard ratio 1.77; 95% confidence interval, 1.17–2.69, p < .007). Conclusions:Among brain-dead organ donors, older age donors contribute fewer organs for transplantation, and increased donor interleukin-6 level before organ procurement is associated with lower recipient six-month hospital-free survival.

Can we prevent acute kidney injury

Objective:To review the literature on prevention of acute kidney injury (AKI). Data Source:MEDLINE- and PubMed-based review of literature published from 1965 to 2007. Conclusions:AKI is very common among critically ill patients. Even mild forms of AKI have significant attributable mortality. Hence, it is imperative that every effort to prevent AKI be made in clinical practice. However, there are very few interventions that have been shown to consistently prevent AKI. Measures such as adequate hydration, maintenance of adequate circulating blood volume and mean arterial pressure, and avoidance of nephrotoxins are still the mainstay of prevention. Loop diuretics and “renal-dose” dopamine have been clearly shown not to prevent AKI and may, in fact, do harm. Among the remaining pharmacologic options, N-acetylcysteine has the strongest evidence in prevention of AKI. Fenoldopam and theophylline need further investigation before being used to prevent septic AKI and contrast nephropathy, respectively. The role of prophylactic dialysis in preventing contrast nephropathy needs to be investigated further.

Feasibility study of cytokine removal by hemoadsorption in brain-dead humans.

Background:Inflammatory cytokines occur in the circulation and in the tissues after brain death and have been associated with dysfunction of donor organs before and after transplantation. Objective:To determine the feasibility of removing cytokines using a hemoadsorption device. Design:Two-center, randomized, open-label, feasibility study in which brain-dead subjects were randomized to two treatment groups. Setting:Two U.S. academic hospitals. Participants:Eight brain-dead subjects deemed unsuitable for organ donation by respective organ procurement organizations. Main Outcome Measures:After obtaining consent from families, subjects were treated with hemoadsorption for 4 hrs using CytoSorb. Effects on cytokines (tumor necrosis factor, interleukin [IL]-6, and IL-10) were assessed both across the device and in the plasma over time. Feasibility for cytokine removal was assessed using objective criteria. Results:Cytokine removal across the CytoSorb device ranged from 4% to 30% and was not significantly different from 1 hr to 4 hrs. Overall removal was greatest for IL-6, 28% (p = .006), and least for tumor necrosis factor, 8.5% (p = .13). Plasma concentrations of both IL-6 and tumor necrosis factor, but not IL-10, were significantly reduced after the first hour of therapy; mean differences were −13% ± 7% for IL-6 (p = .039), −23% ± 9% for tumor necrosis factor (p = .02), and −2% ± 7% of IL-10 (p = 23). However, plasma concentrations for all three cytokines increased over time and were above baseline by the end of the intervention. No adverse effects of therapy were observed. However, removal of cortisol and triiodothyronine was similar to removal of cytokines. Conclusions:Hemoadsorption for removal of cytokines in brain-dead subjects is feasible. Evaluation of possible clinical benefit will require controlled trials in actual donors. However, the significant capacity for cytokine removal and absence of adverse events suggest that such trials are warranted.

Preload responsiveness is associated with increased interleukin-6 and lower organ yield from brain-dead donors

Objective:Brain death induces dramatic changes in hemodynamics. Ischemic injury and inflammation resulting from inadequate resuscitation might influence organ yield for transplantation. Using functional hemodynamic monitoring in brain-dead organ donors, we test the hypothesis that donor preload (fluid) responsiveness is associated with increased inflammatory response and lower organ yield for transplantation. Design:Prospective, observational, pilot study. Setting:A large intensive care unit of a university hospital in the United States. Patients:Twenty-one brain-dead organ donors between July 2006 and April 2007. Interventions:None. Measurements and Main Results:Following declaration of brain death, we collected data on donor demographics, mechanism of brain death, and number of organs procured and transplanted. Functional hemodynamics were monitored using pulse contour analysis technique. Plasma tumor necrosis factor, interleukin-6, and interleukin-10 concentrations were measured at study enrollment, after 4 hrs, and immediately before organ procurement for transplantation. Preload responsiveness (pulse pressure variation >13%) was observed in 48% of donors (mean ± sd pulse pressure variation, 19.2% ± 4.8%). Plasma interleukin-6 and tumor necrosis factor concentrations at study enrollment were greater in preload responsive donors: mean concentrations of interleukin-6 in preload responsive vs. unresponsive donors were 5420 ± 9102 vs. 378 ± 631 pg/mL (p = .009), and mean concentrations of tumor necrosis factor were 60.5 ± 103.6 vs. 15.7 ± 10.1 pg/mL (p = .048). Preload responsive compared with unresponsive donors had significantly increased interleukin-6 (p = .013) and tumor necrosis factor (p = .044) concentrations over time. Fewer organs were transplanted from preload responsive donors: mean organs transplanted from preload responsive vs. unresponsive donors were 1.8 ± 0.9 vs. 3.7 ± 2.5 (p = .034). In multivariable regression, older donor age (p = .028) and increased plasma interleukin-6 concentration (p = .035) were significantly associated with lower number of organs transplanted. Conclusions:Preload responsiveness is common in brain-dead organ donors and is associated with higher inflammatory response and lower organ yield. A controlled trial of preload optimization is warranted in brain-dead donors.

Novel approaches to the treatment of acute renal failure.

Acute renal failure (ARF) occurs frequently in hospitalised patients and is associated with significant morbidity and mortality. Many therapeutic strategies have been undertaken both to prevent acute renal injury and, once ARF occurs, to improve renal function and reduce mortality. Among the available pharmacological options, no specific therapy has been shown to alter the course of ARF. This article reviews the efficacy of several strategies in experimental renal disease and raises the possibility that similar interventions might be available to the clinician in the near future for the prevention and management of ARF. The prospect of these novel strategies, together with the ever-increasing understanding of the complex pathophysiology of ARF, offers the promise of effective and more physiological therapeutic interventions in this new millennium.

Trial of shift scheduling with standardized sign-out to improve continuity of care in intensive care units.

Background:Since 2003, the Accreditation Council for Graduate Medical Education requires residency programs to restrict to 80 hrs/wk, averaged over 4 wks to improve patient safety. These restrictions force training programs with night call responsibilities to either maintain a traditional program with alternative night float schedules or adopt a “shift” model, both with increased handoffs. Objective:To assess whether a 65 hrs/wk shift-work schedule combined with structured sign-out curriculum is equivalent to a 65 hrs/wk traditional day coverage with night call schedule, as measured by multiple assessments. Design:Eight-month trial of shift-work schedule with structured sign-out curriculum (intervention) vs. traditional call schedule without curriculum (control) in alternating 1–2 month periods. Setting:A mixed medical–surgical intensive care unit at a tertiary care academic center. Subjects:Primary subjects: 19 fellows in a Multidisciplinary Critical Care Training Program; Secondary subjects: intensive care unit nurses and attending physicians, families of intensive care unit patients. Interventions:Implementation of shift-work schedule, combined with structured sign-out curriculum. Measurements:Workplace perception assessment through Continuity of Care Survey evaluation by faculty, fellows, and nurses through structured surveys; family assessment by the Critical Care Family Needs Index survey; clinical assessment through intensive care unit mortality, intensive care unit length of stay, and intensive care unit readmission within 48 hrs; and educational impact assessment by rate of fellow didactic lecture attendance. Main Results:There were no statistically significant differences in surveyed perceptions of continuity of care, intensive care unit mortality (8.5% vs. 6.0%, p = .20), lecture attendance (43% vs. 42%), or family satisfaction (Critical Care Family Needs Index score 24 vs. 22) between control and intervention periods. There was a significant decrease in intensive care unit length of stay (8.4 vs. 5.7 days, p = .04) with the shift model. Readmissions within 48 hrs were not different (3.6% vs. 4.9%, p = .39). Nurses preferred the intervention period (7% control vs. 73% intervention, n = 30, p = .00), and attending faculty preferred the intervention period and felt continuity of care was maintained (15% control vs. 54% intervention, n = 11, p = .15). Conclusions:A shift-work schedule with structured sign-out curriculum is a viable alternative to traditional work schedules for the intensive care unit in training programs.

Vascular surgery critical care: perioperative cardiac optimization to improve survival.

Objective:To review the literature on perioperative cardiac management of patients who are scheduled to undergo vascular surgery. Data Source:MEDLINE- and PubMed-based review of literature published from 1965 to 2005. Conclusions:Perioperative cardiac events (myocardial infarction, heart failure) remain the leading cause of morbidity and mortality in vascular surgery patients. Existing guidelines allow physicians to cost-effectively streamline preoperative cardiac risk assessment and stratification. Perioperative optimization of volume status and cardiac function and the routine use of perioperative beta-blockers can significantly improve outcomes after major vascular surgery. Perioperative addition of statins to beta-blockers in high-risk patients undergoing vascular surgery merits further evaluation. Preoperative coronary revascularization should be restricted to patients with unstable cardiac symptoms.