Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm.

The results of recent anticytokine trials for sepsis syndrome have been disappointing. Several Phase II and Phase III clinical trials have shown a modest benefit in various subsets of patients; however, there has been no reported benefit in the primary endpoint of 28-day all-cause mortality. The failure of these trials is clearly multifactorial, and causes include the overall complexity of the inflammatory response, heterogeneity of the patient populations, absence of a hypercytokine response at the time of drug treatment, and the relatively short half-life of the administered drugs. The failure of anticytokine therapies may represent inadequate application of the treatment modality rather than any inherent weakness of the treatment itself. We have recently initiated a Phase I clinical trial examining the role of the anti-inflammatory cytokine IL-10 during surgical repair of a thoracoabdominal aortic aneurysm. This study may overcome some of the-design limitations of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdominal aortic aneurysms is relatively low, the patient population is homogeneous and the surgical injury associated with its repair reproducible. Additionally, postoperative mortality and morbidity rates are significant. Most importantly, the operative repair is associated with an obligatory visceral ischemia and reperfusion injury that appears to be associated with a proinflammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNFalpha and IL-1 synthesis, and antagonizes their actions through upregulation of cytokine antagonists. Furthermore, IL-10 administration has been associated with only minimal adverse side effects during Phase I and Phase II trials.

Intraoperative autologous transfusion during elective infrarenal aortic reconstruction: a decision analysis model.

PURPOSE: The use of intraoperative autologous transfusion devices expanded during the last decade as a result of the increased awareness of transfusion-associated complications. This study was designed to determine whether routine use of an intraoperative autologous transfusion device (Haemonetics Cell Saver [CS]) during elective infrarenal aortic reconstructions is cost-effective ($50,000/QALYs threshold). METHODS: A decision analysis tree was constructed to model all of the complications that are associated with red blood cell replacement during aortic reconstructions for both abdominal aortic aneurysm (AAA) and aortoiliac occlusive disease (AIOD). It was assumed that a unit of CS return (CSR; 250 ml/unit) equaled a unit of packed red blood cells (PRBCs) and that all CS transfusions were necessary. Transfusion requirements (AAA:PRBC = 2.8 +/- 3.2 units, CSB = 3.7 +/- 3.2 units; AIOD:PRBC = 3.1 +/- 3.0 units, CSR = 2.1 +/- 1.7 units) were determined from retrospective review of all elective aortic reconstructions (AAA, N = 63; AIOD, N = 75) from Jan. 1991 to June 1995 in which the CS was used (82.1% of all reconstructions). Risk of allogenic transfusion-related complications (transfusion reaction, hepatitis B, hepatitis C, human immunodeficiency virus, human T-cell lymphotropic virus types I and II) and their associated treatment costs (expressed in dollars and quality-adjusted life years (QALYs) were obtained from the medical literature, institutional audit, and a consensus of physicians. RESULTS: Routine use of the CS during elective infrarenal aortic reconstructions was not cost-effective in our practice. Use during reconstructions for AAA repairs cost $263.75 but added only 0.00218 QALYs, for a rate of $120,794/QALY. Use during reconstructions for AIOD was even more costly at $356.68 and provided even less benefit at 0.00062 QALYs, for a rate of $578,275/QALY. The sensitivity analyses determined that the routine use of the CS would be cost-effective in our practice only for AAA repairs if the incidence of hepatitis C were tenfold greater than the baseline assumption. The model determined that CS was cost-effective if the CSR exceed 5 units during reconstructions for AAA and 6 units during reconstructions for AIOD. CONCLUSIONS: The routine use of the CS during elective infrarenal aortic reconstructions is not cost-effective. The use of the device should be reserved for a select group of aortic reconstructions, including those in which cost-effective salvage volumes are anticipated. Alternatively, the CS should be used as a reservoir and activated as a salvage device if significant bleeding is encountered.

Intraoperative autologous transfusion during elective infrarenal aortic reconstruction.

Intraoperative autologous transfusion devices have been purported to reduce allogenic transfusions and their associated complications. However, the value of their routine use during elective cardiovascular operations remains undefined. This study was designed to examine the efficacy of the Haemonetics Cell Saver (CS) during elective aortic reconstructions and identify predictors of clinically significant (> or = 500 cc) and cost-efficient (> or = 1250 cc) salvage volumes. The medical records of all patients undergoing elective infrarenal aortic reconstructions between January 1991 and June 1995 were retrospectively reviewed to determine blood loss, CS return, predictors of clinically significant/ cost-efficient CS returns, blood products transfused, and estimated cost per unit CS return. The CS was used for 138 (82.1%) of all reconstructions during the study period. Estimated blood loss (2127 +/- 1467 vs 1415 +/- 1047) and CS return (927 +/- 790 vs 515 +/- 408) were significantly greater in patients with aneurysms (AAA, N = 63) compared to those with aortoiliac occlusive disease (AIOD, N = 75). CS returns > or = 500 cc were common (79.4% AAA, 52.0% AIOD) and predictors of > or = 500 cc CS returns were large aneurysms (6.79 +/- 1.84 vs 5.72 +/- 0.71 cm) and male sex (82.0 vs 46.2%) in AAA patients and lower preoperative platelet counts (262 +/- 93 vs 311 +/- 113 K/mm3), concomitant renal revascularizations (20.5 vs 0%), and prolonged operative time (7.9 +/- 2.4 vs 6.9 +/- 2.1 hr) in AIOD patients. In contrast, CS returns > or = 1250 cc were relatively uncommon (28.6% AAA, 5.3% AIOD), and predictors of these CS returns were found only for AAA patients and included any concomitant vascular procedures (38.8 vs 15.6%) and the need for suprarenal aortic clamping (27.8 vs 6.7%). Despite the use of the CS, 73.8% of all patients required allogenic packed red blood cells with a mean of 3.0 +/- 3.1 units transfused in the perioperative period; no difference was seen between AAA and AIOD patients. The calculated cost for a unit of CS return was +128.77 for the AAA patients and +231.91 for the AIOD patients. Not using the CS and substituting the return with allogenic packed red blood cells would have saved +252.80 and +352.84 for the AAA and AIOD patients, respectively. Routine use of the CS during elective infrarenal aortic reconstructions is not cost efficient and should be abandoned. Use of the device should be reserved only for complex reconstruction.

Glutamine preserves gut glutathione levels during intestinal ischemia/reperfusion.

Intestinal ischemia/reperfusion (I/R) causes formation of reactive oxygen intermediates (ROI) which lead to mucosal cell injury. Glutathione (GSH), an ROI scavenger, protects tissues from ROI-mediated cell injury. Since GSH biosynthesis is partially dependent on glutamine (Gln) levels, we tested the hypothesis that intravenous Gln infusion will assist in maintaining mucosal cell GSH levels and decrease membrane lipid peroxidation during intestinal I/R. The external jugular vein of male Sprague-Dawley rats was cannulated and infused with normal saline (NS) at 2 cc/hr. After 3 days, matched pairs of rats received either NS alone or NS+ 3% Gln for an additional 24 hr. Next, mucosal GSH levels were measured after a sham I/R in 6 rats and after either 30 or 60 min of ischemia/60 min of reperfusion in a group of 8 and 12 rats, respectively. Finally, conjugated diene (CD), a byproduct of membrane lipid peroxidation, was measured following 60 min of ischemia/60 min of reperfusion in a separate group of 12 rats. Control rats had the highest GSH levels and there was no difference between NS vs NS + 3% Gln rats (2.50 +/- 0.48 vs 2.50 +/- 0.43, P = NS). With 30 and 60 min of ischemia/60 min of reperfusion, GSH levels were significantly lower in NS-infused rats compared to those in NS + 3% Gln-infused rats (30 min: 1.54 +/- 0.14 vs 1.80 +/- 0.16, P < 0.05; 60 min: 1.27 +/- 0.15 vs 1.52 +/- 0.20, P < 0.04). In addition, CD levels were lower in NS + 3% Gln-infused rats compared to those in NS alone-infused rats (5.58 +/- 0.87 vs 7.94 +/- 0.55, P < 0.04). In conclusion, Gln supplementation partially maintains gut GSH levels during bowel I/R, which in turn lessens I/R-induced cell membrane lipid peroxidation.