Literature Review

Abstract

Kishimoto TK, Viswanathan K, Ganguly T, et al: Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358:2457-2467, 2008 Contamination of the heparin supply in the United States recently has been identified with more sophisticated assays not previously available. The Food and Drug Administration (FDA) began receiving reports of acute hypersensitivity reactions in dialysis patients beginning in November 2007. The symptoms of these reactions included hypotension, facial swelling, tachycardia, urticaria, and nausea. The Centers for Disease Control identified heparin from Baxter Healthcare (Deerfield, IL) as the common feature of the cases. This led to the recall of certain lots of Baxter-manufactured heparin. The recall was widened on February 28, 2008, to include all lots of Baxter heparin. More widespread contamination of the world supply of heparin was noted when a heparin recall was announced on March 6, 2008, in Germany after a cluster of reactions occurred in dialysis patients receiving heparin from another heparin manufacturer. On the same date, the FDA posted descriptions of analytic methods that determined the contaminant to be oversulfated chondroitin sulfate. This contaminant was subsequently found in at least 12 countries worldwide. As of April 13, 2008, at least 81 reported deaths had been documented by the FDA in patients receiving heparin during dialysis or during cardiac surgery. The identification of a biologic mechanism to explain these acute hypersensitivity reactions to oversulfated chondroitin sulfate had yet to be established. To address possible biologic mechanisms, heparin from suspected lots associated with adverse clinical events were procured from the FDA and studied. The suspected heparin was screened both for the presence of oversulfated chondroitin sulfate and any key biologic activity (in vitro and in vivo) that could link the oversulfated chondroitin sulfate contaminant to the adverse clinical events. Oversulfated chondroitin sulfate found in contaminated lots of unfractionated heparin and synthetically generated oversulfated chondroitin sulfate were found to directly activate the kinin-kallikrein system in human plasma in vitro. Such activation may lead to the generation of bradykinin, a potent vasoactive substance. Additionally, oversulfated chondroitin sulfate induced the production of the potent anaphylatoxin C5a, which also can produce profound vasodilation of the cardiovascular system. Of interest, the contaminated heparin and synthetically derived oversulfated chondroitin sulfate, and the positive control all failed to induce the amidolytic activity of kallikrein in factor XII–deficient plasma. Additionally, there was no generation of C3a and C5a in factor XII–depleted plasma activated with oversulfated chondroitin sulfate. The generation of C5a could be restored by reconstituting the factor XII–depleted plasma with purified factor XII. It is also of interest that high concentrations of oversulfated chondroitin sulfate induced little or no amidolytic activity of kallikrein, suggesting at this concentration heparin activity of the oversulfated chondroitin sulfate may inhibit or deplete factor XII. Additionally, the oversulfated chondroitin sulfate–containing heparin and synthetically derived oversulfated chondroitin sulfate induced hypotension associated with kallikrein activation when administered by intravenous infusion in a live swine model. Implication: Contaminated heparin lots that contained oversulfated chondroitin sulfate were shown to be capable of producing the potent vasoactive substances bradykinin and anaphylatoxins in vitro. Such activation appears to be entirely factor XII-dependent. Thus, there may be a biologic link between the presence of oversulfated chondroitin sulfate contaminant in unfractionated heparin and the adverse clinical events reported to the FDA. Barr L, Kolodner K: N-acetylcysteine and fenoldopam protect the renal function of patients with chronic renal insufficiency undergoing cardiac surgery. Crit Care Med 36:1427-1435, 2008 Preoperative renal insufficiency predicts postoperative renal failure after cardiac surgery. Acute postoperative renal failure is, in turn, associated with increased mortality and prolonged intensive care unit (ICU) stay. Although new renal protective drugs have become widely available, the routine application of these drugs has not yet been adopted during cardiac surgery. Both fenoldopam and N-acetylcysteine (NAC) have been previously used for renal protection in patients with preoperative renal insufficiency receiving a dye load in the cardiac catheterization laboratory. Additionally, both agents have been studied as renal protective agents during cardiac surgery, but few of these studies have been prospective, randomized, controlled, and blinded. The ability of fenoldopam and NAC to preserve renal function was examined in 79 adult patients with chronic renal insufficiency (creatinine clearance ≤40 mL/min) undergoing cardiac surgery. Group 1 received intravenous fenoldopam, 0.1 μg/kg/min, started at surgical induction and continued for 48 hours. Group 2 received NAC, 600 mg, orally twice a day from preoperative day 1 to postoperative day (POD) 1. Group 3 received both fenoldopam and NAC, and group 4 served as controls. The nadir in creatinine clearance over 72 hours after cardiac surgery previously has been shown to be a good predictor of dialysis, mortality, and length of hospital stay.3 Therefore, the primary outcome in the present study was the effect of treatment on creatinine clearance on POD 3. Secondary outcomes included mortality, ICU and hospital length of stay, total hospital costs, the change in weight between admission and POD 3, and the percent change in creatinine clearance by POD 4. All groups showed a decline in postoperative creatinine clearance. However, the reduction in creatinine clearance in the fenoldopam group was significantly less (−1.47 mL/min ± 2.06 standard error [SE]) than the control group (−8.15 mL/min ± 2.18 SE; p < 0.028). Similarly, the reduction in creatinine clearance in the NAC group was significantly less (−0.67 mL/min ± 2.11 SE) than the control group (p = 0.019). Although the combined administration of fenoldopam and NAC also significantly reduced creatinine clearance (p = 0.01), the effect was not additive. Despite a significantly reduced decline in creatinine clearance in the treatment groups, none of the measured secondary outcomes (eg, mortality, dialysis dependence, ICU length of stay, hospital length of stay, and hospital cost) differed significantly between the treatment and control groups. Creatinine clearance eventually returned to baseline preoperative values in both the fenoldopam and NAC groups. Implication: Both fenoldopam and NAC significantly reduce the decline in renal function early after cardiac surgery in patients with pre-existing renal insufficiency. However, combined administration of both of these drugs does not further increase renal protection. Although no measured secondary outcome (eg, mortality, dialysis use, ICU length of stay, hospital length of stay, and cost) significantly differed between the treatment groups and control, it may be that this study was underpowered with respect to these outcomes. Thus, larger randomized trials are still needed to determine the clinical relevance of these findings. Szlam F, Taketomi T, Sheppard CA, et al: Antithrombin affects hemostatic response to recombinant activated factor VII in factor VIII-deficient plasma. Anesth Analg 106:719-724, 2008 Although approved for the treatment of hemorrhage in hemophiliacs undergoing surgery, the off-label use of recombinant activated factor VII (rFVIIa) is also increasing both in trauma and cardiovascular surgical patients. However, unlike hemophiliacs, trauma and cardiovascular surgical patients are at a greater risk of thromboembolic complications with rFVIIa. One possible explanation is that antithrombin (AT) levels are often reduced during states of trauma and major surgery. To address the question of why nonhemophiliacs given rFVIIa are at a greater risk of thromboembolic complications, thromboelastography and thrombin-generation (Thrombinoscope; Thrombinoscope BV, Maastricht, The Netherlands) assays were performed on factor VIII–deficient plasma with varying quantities of AT and then exposed to a clinically relevant dose of rFVIIa. Assessing for a prothrombotic effect of low AT in factor VIII–deficient plasma treated both with and without rFVIIa may explain in part the hypercoagulable state that may develop in nonhemophiliacs receiving rFVIIa. Delayed thrombus formation based on thromboelastography in factor VIII–deficient plasma was predictably reversed with rFVIIa. Improved thrombus formation in factor VIII–deficient plasma and responses to rFVIIa were observed when antithrombin levels were 20% to 50% of normal. Thrombin generation in factor VIII–deficient plasma increased in an inverse relationship to AT levels. Implication: The use of rFVIIa is rapidly expanding outside of its approved indication for hemostasis in the hemophiliac patient. Among the 185 thromboembolic events reported to the FDA after rFVIIa administration, 75 events occurred in patients given the drug for surgical bleeding, and 17 events occurred in hemophiliacs. It is not uncommon to see AT levels decreased up to 60% of normal after cardiovascular surgery. With reduced AT levels, both thromboelastography and thrombin-generation indicate enhanced thrombin formation and clot strength in factor VIII–deficient blood with and without exposure to rFVIIa. This study therefore shows a potential mechanism whereby reduced AT levels may contribute to the development of thromboembolic complications in nonhemophiliac patients treated with rFVIIa. Fergusson DA, Hébert PC, Mazer CD, et al: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358:2319-2331, 2008 Both aprotinin and the lysine analogs aminocaproic acid and tranexamic acid have been shown to be effective in reducing blood loss after cardiovascular surgery. In recent years, the safety and relative benefit of aprotinin have come into question. A large observational study by Mangano et al revealed increased incidence of myocardial infarction, stroke, and renal failure requiring dialysis in patients who received aprotinin as an antifibrinolytic. Other meta-analyses of placebo-controlled trials have suggested that aprotinin saves lives and decreases the risk of stroke and repeat surgery for massive bleeding. Some have suggested that the increased mortality in observational studies occurs in higher risk patients who are more likely to experience other significant complications. To address the question of safety of aprotinin in high-risk patients, the BART study (Blood Conservation Using Antifibrinolytics in a Randomized Trial) was conducted in 19 Canadian cardiac surgical units between August 2002 and October 2007. This multicenter, blinded, randomized, controlled study compared 3 antifibrinolytic agents routinely used in cardiac surgery. Patients were assigned randomly to 1 of 3 groups: aprotinin, tranexamic acid, and aminocaproic acid. All patients had cardiac procedures defined as high risk for the development of massive bleeding and included repeat cardiac procedures, mitral valve replacement, combined coronary artery bypass graft (CABG) and valve procedure, and/or surgery of the ascending aorta or aortic arch. The primary study outcome was massive postoperative bleeding and was defined as bleeding from chest tubes exceeding 1.5 L in 8 hours and/or the transfusion of more than 10 units of packed red blood cells in a 24-hour period. Secondary outcomes were 30-day in-hospital death from any cause and serious adverse clinical events. A total of 2,331 patients were included in the intention-to-treat analysis: 781 aprotinin, 770 tranexamic acid, and 780 aminocaproic acid. The study was terminated early based on the recommendation of the independent data and safety monitoring committee because of a disturbing and strong trend toward higher mortality in the aprotinin group on the basis of interim data from 2,163 patients. In the analysis of massive bleeding the aprotinin group had a rate of 9.5% and the lysine analog group of 12.1%. The relative risk of massive bleeding among patients receiving aprotinin as compared with both lysine analogs was 0.79. The 30-day death rate from any cause was 6.0% in the aprotinin group versus 3.9% in the tranexamic acid group and 4% in the aminocaproic acid group. The relative risk of death was 1.53 in the aprotinin group versus the lysine analogs. Moreover, the difference in mortality between the aprotinin and lysine analog groups was primarily because of cardiac causes of death and not renal failure or stroke. The incidence of myocardial infarction, stroke, cardiogenic shock, or renal failure did not differ among aprotinin versus tranexamic acid or aminocaproic acid. However, the likelihood that the myocardial infarction or cardiogenic shock would result in death was higher in the aprotinin group versus the other lysine analogs. Also, the relative risk of developing right ventricular failure was much greater in the aprotinin group versus tranexamic acid (relative risk, 3.46) and aminocaproic acid (relative risk, 7.01). This appears to indicate that the right ventricular failure may be implicated in the increased incidence of cardiac death after aprotinin exposure in high-risk cardiac surgical patients. Finally, even though there was a doubling of serum creatinine in the aprotinin group, it did not appear to be a contributing factor in the cause of death in the aprotinin group. Implication: The high-risk patient population in which aprotinin was supposed to provide a significant advantage in fact worsened 30-day mortality despite only modest reductions in blood loss. Therefore, use of aprotinin cannot currently be justified in high-risk cardiac surgical patients. Mehta RH, Grab JD, O'Brien SM, et al: Clinical characteristics and in-hospital outcomes of patients with cardiogenic shock undergoing coronary artery bypass surgery: Insights from the Society of Thoracic Surgeons National Cardiac Database. Circulation 117:876-885, 2008 Patients who experience cardiogenic shock represent a small proportion of patients who undergo CABG (2%), but these patients contribute to 14% of all CABG-related deaths. Identifying the clinical and angiographic features that predict adverse outcomes after CABG surgery in the United States remains challenging. To date, the vast majority of studies have focused on small case series from high-volume centers and may not be representative of the broader cardiac surgical community. To answer the question of which clinical factors are predictive of mortality in patients with cardiogenic shock having CABG surgery, the Society of Thoracic Surgeons (STS) National Cardiac Database was analyzed from 2002 to 2005. The STS National Cardiac Database was reviewed for in-hospital death, death within 30 days of the operation, and major morbidity in all patients both with and without cardiogenic shock who underwent CABG surgery. The CABG surgery was done either alone or in conjunction with aortic valve replacement, mitral valve surgery, or ventricular septal wall repair. The STS database defines cardiogenic shock as a clinical state of hypoperfusion evidenced by a systolic blood pressure below 80 mmHg and/or a cardiac index of <1.8 L/min/m2 despite maximal treatment or the presence of intravenous inotropes and/or the presence of an intra-aortic balloon pump (IABP) to maintain a systolic blood pressure of >80 mmHg and/or a cardiac index >1.8 L/min/m2. In addition to the identification of clinical risk factors, the development of a bedside tool that would be predictive of early surgical mortality in patients with cardiogenic shock after CABG surgery was sought. Preoperative cardiogenic shock was present in 14,956 (2.1%) of the 708,593 patients who underwent CABG surgery during the 2002 to 2005 time interval. Patients who experienced cardiogenic shock had more comorbid conditions, a higher incidence of myocardial infarction within 24 hours before CABG (45% v 7%, p < 0.0001), had 1.5 times the incidence of significant left main disease, and an ejection fraction of 15% lower than in the group without cardiogenic shock. Mortality was higher for patients operated on within 24 hours of their myocardial infarction (26%) compared with those operated on later (18%-20%). Multivariable analysis was performed on 12,339 of the 14,956 cardiogenic shock patients who met inclusion criteria, and a full model identified 18 independent risk factors that increased the likelihood of death in patients with cardiogenic shock undergoing CABG surgery. Good correlation existed between predicted and observed outcomes across the risk continuum in cardiogenic shock patients undergoing CABG operation. A simplified model was constructed that retained the predictive power of the full model and showed reasonable fit with observed versus predicted rates of death (Hosmer-Lemeshow, p = 0.09 for lack of fit). The simplified model coefficients were converted to an additive risk score. The additive risk score assigns points that contribute to the increased likelihood of death in patients with cardiogenic shock who may undergo CABG surgery. Advanced age, elevated baseline serum creatinine above 1.9, operation type (salvage versus elective or emergent), extent of operation, and previous cardiovascular surgery were the most significant predictors of early 30-day mortality. The odds ratio for mortality for CABG with mitral valve surgery and ventricular septal repair were 1.75 and 4.55, respectively. The odds ratio for elevated serum creatinine was 3.4, and for salvage CABG surgery the odds ratio was 3.32. Interestingly, the odds ratio for mortality was higher for female sex (1.63) and for immunosuppressive therapy (1.66) compared with more traditional risk factors such as ejection fraction (1.61) and myocardial infarction within 1 week (1.27). The presence of an IABP had an odds ratio of 1.57, and its presence could reflect an overall poorer cardiovascular status for the patient, thereby increasing mortality. Implication: A predictive model for early mortality in patients with cardiogenic shock having CABG surgery was constructed based on review of the STS National Cardiac Database. Surgical risk factors were identified as predictors of early mortality and include both the type of surgery and the extent of surgery. Incomplete revascularization as a salvage operation and CABG surgery either with mitral valve surgery or ventricular septal repair were associated with a significant increase in early mortality. Additionally, patient risk factors that reflected the patients' overall medical condition such as advanced age, elevated baseline serum creatinine, previous cardiovascular surgery, chronic use of immunosuppressive agents, and presence of an IABP were strong independent predictors of increased mortality in patients presenting with cardiogenic shock after CABG surgery. Kathiresan S, Melander O, Anevski D, et al: Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358:1240-1249, 2008 Plasma levels of low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs) are associated with future cardiovascular risk. Roughly 50% of the variation in LDL and HDL levels is heritable. Moreover, single nucleotide polymorphisms associated with LDL and HDL can affect lipid levels and may alter a patient's cardiovascular risk. To ascertain whether or not the presence of multiple polymorphisms of LDL/HDL increased cardiovascular risk, 9 single nucleotide polymorphisms were studied in 5,414 patients from the cardiovascular cohort of the Malmo Diet and Cancer Study. A genotype score was created on the basis of the number of unfavorable alleles that were associated with elevated LDL levels and decreasing HDL levels. Cardiovascular events were obtained via the patients' 10-digit identification number of each Swedish citizen with 3 separate registries: the Swedish Hospital Discharge Register, the Swedish Cause of Death Register, and the Stroke Register of Malmo. Each subject had multivariate adjustment of LDL or HDL levels on the basis of age, sex, diabetes, and baseline lipid levels. Multivariable proportional-hazard models were constructed to examine the association between the genotype score and the time of first cardiovascular event. During the 10.6-year follow-up, 137 men and 101 women had an incident first cardiovascular event prespecified as myocardial infarction, ischemic stroke, or death because of myocardial infarction. LDL cholesterol scores increased from 152 mg/dL for those with a genotype score of 6 or less to 171 mg/dL for a score of 13 or more. There was an increased incidence rate of first cardiovascular events according to the genotype score from 3.1 per 1,000 persons with a genotype score of <6 to 11 per 1,000 persons with a genotype score of >13. Implication: During a 10-year follow-up period, a panel of 9 lipid polymorphisms predicted the risk of a first cardiovascular event and provided independent information beyond that obtained from baseline lipid levels and other established cardiovascular risk factors. Therefore, there appear to be other underlying genetic mechanisms that predict cardiovascular risk beyond just static lipid levels. Additionally, further research is needed to understand the pharmacogenetic impact of these polymorphisms on patients receiving antilipidemic therapy. Compton FD, Zukunft B, Hoffman C, et al: Performance of a minimally invasive uncalibrated cardiac output monitoring system (Flotrac™/Vigileo™) in hemodynamically unstable patients. Br J Anaesth 100:451-456, 2008 Less invasive means of cardiac output (CO) determination are increasingly being used both in and out of the ICU to provide early assessment of the hemodynamically unstable patient. The FloTrac/Vigileo CO system (Edwards Lifescience LLC, Irvine, CA) allows CO determination from the arterial pressure waveform of a peripheral arterial catheter. A lack of calibration and ease of use render it suitable for use in the emergency department. Recent studies have called into question the reliability of the FloTrac/Vigileo CO system when compared with more established means of CO determination such as the pulmonary artery catheter and transpulmonary thermodilution-derived systems. Despite recent modifications of the FloTrac/Vigileo CO algorithm, the question of reliability of such measurements in the hemodynamically unstable patient deserves attention. To address this question, 25 hemodynamically unstable patients admitted to the medical ICU of Charité University Medicine Campus (Benjamin Franklin, Berlin, Germany) were consecutively enrolled in a prospective open study comparing the FloTrac/Vigileo CO system with the PiCCO transpulmonary thermodilution system. A total of 324 measurements were recorded with a mean of 13 measurements per patient over 3 days. All patients but one received continuous catecholamine infusions at time of study entry and during 315 of 324 measurements. When CO measurements were compared, CI values obtained with the radial artery–derived FloTrac/Vigileo system were significantly lower than the CI measured with the PiCCO system using the femoral arterial catheter (p < 0.001). Also, the FloTrac/Vigileo system showed a limited agreement in tracking intraindividual CO changes by the delta CI when compared with the PiCCO system, with large limits of agreement in the delta CI (1.6 L/min/m2) and a high percentage of error (159.6%). The use of catecholamine infusions did not bias the CI determination by either method. Implication: Despite an updated software algorithm compensating for vascular tone changes, the FloTrac/Vigileo CO system underestimates CO in hemodynamically unstable ICU patients compared with the PiCCO transpulmonary thermodilution system. Thus, the minimally invasive FloTrac/Vigileo CO system is unreliable compared with traditional, invasive CO measures in the hemodynamically unstable ICU patient. Articles reviewed in this issue were selected from those published in the following journals: Anesthesia and Analgesia, British Journal of Anaesthesia, Circulation, Critical Care Medicine, and New England Journal of Medicine.