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Drug UpdateAprotinin and the Systemic Inflammatory Response Associated with Cardiopulmonary Bypass Reviewer: Mark A. Chaney, MD
Numerous well-controlled laboratory and clinical investigations have confirmed the safety and efficacy of aprotinin therapy for reducing perioperative bleeding and transfusion requirements in patients subjected to cardiopulmonary bypass (CPB). Although the effects of aprotinin on perioperative hemostasis are well-documented, recent investigations indicate the drug may substantially reduce the systemic inflammatory response syndrome (SIRS) observed in patients subjected to CPB. It has been known for many years that CPB induces a SIRS in patients following cardiac surgery that can lead to major organ injury and postoperative morbidity. Initiation of CPB sets into motion an extremely complex and multifaceted response involving complement activation (both classic and alternative pathways) along with activation of platelets, neutrophils, monocytes, and macrophages, thus initiating the coagulation, fibrinolytic, and kallikrein cascades, increasing blood levels of endotoxin and cytokines (interleukins, tumor necrosis factor, etc.), and increasing endothelial cell permeability. The three primary intersecting protease pathways that are activated include the kinin-kallikrein pathway, the fibrinolytic-coagulation pathway, and the complement system pathway. Transvascular migration of activated leukocytes occurs into tissues, proteases and neutrophil elastase are released, which cause additional vascular and parenchymal damage. The ensuing SIRS is amplified further by the release of additional mediators (endotoxins, cytokines, etc.). The basic physiologic insults caused by CPB have been associated with major postoperative morbidity, including neurologic dysfunction, pulmonary dysfunction, renal dysfunction, hematologic abnormalities. Additional clinical manifestations associated with SIRS include increased metabolism, fluid retention, myocardial edema, and detrimental hemodynamic alterations. Serine proteases play a central role in the three primary pathways that lead to SIRS associated with CPB (kinin-kallikrein, fibrinolytic-coagulation, complement system). Also, serine proteases likely affect other aspects of the SIRS, including activation of platelets. Aprotinin is a nonspecific serine protease inhibitor that inhibits activity of a wide variety of proteases, including trypsin, plasmin, kallikrein, and elastase in a dose-dependent manner. Recent investigations indicate that aprotinin attenuates numerous aspects of the SIRS observed in patients following exposure to CPB. For example, aprotinin has been shown to substantially attenuate multiple markers of kinin-kallikrein pathway activation and complement system pathway activation in patients following exposure to CPB. It decreases bradykinin formation, decreases neutrophil release of elastase, and likely inhibits plasmin (thus decreasing fibrinolytic activity). Aprotinin also modulates many components of neutrophil activation and extravasation and attenuates leukocyte hyperactivation. Thus, the drug inhibits leukocyte extravasation and transmigration across endothelial surfaces, providing a potential mechanism for the observation that aprotinin substantially decreases leukocyte accumulation in the lungs of patients exposed to CPB. Additional potentially beneficial effects of aprotinin include decreases in tumor necrosis factor levels, decreases in interleukin-6 and interleuken-8 levels, increases in interleukin-10 levels, and decreased CD11b and CD18 upregulation. Aprotinin also likely inhibits thrombin-mediated platelet aggregation by preventing proteolytic activation of protease-activated receptors on the surface of platelets. Thus, the drug may reduce amplification of the cell-mediated inflammatory response or platelets indirectly through effects on plasma proteases and directly via effects on protease-activated receptors on the surface of platelets. Aprotinin is also associated with decreased P-selectin surface expression on platelets and decreased leukocyte-platelet complexes. Thus, aprotinin may limit leukocyte recruitment and infiltration by inhibiting platelet-leukocyte interactions. In summary, it appears that aprotinin has the ability to substantially decrease activation and amplification of the multiple plasma protease pathways that lead to the SIRS observed in patients exposed to CPB. Thus, aprotinin may prove to be beneficial in helping prevent clinical morbidity (neurologic, pulmonary, renal, and/or hematologic) associated with the SIRS in patients undergoing cardiac surgery with CPB.
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Optical Mapping, A New Technique for Evaluation of Anti- and Pro-Arrhythmic Properties of Medications
Reviewer: K.W. Tim Park, MD
Optical mapping is a new technique developed by David S. Rosenbaum and coworkers, which allows visualization of cardiac action potentials and their propagation in the intact heart (1,2) and may thus represent a quantum leap from microelectrode techniques on isolated myocytes. The heart is stained with the voltage-sensitive dye di-4-ANEPPS (10 mM) by direct coronary perfusion. The dye may be excited using a quasi-monochromatic light of wavelength 540 ± 10 nm from a tungsten-halogen lamp. Fluoresced and scattered light is then collected using a high numerical aperture lens (50 mm, F1.8), long-pass filtered (610 nm), and focused onto a 12 x 12 element photodiode array. Photocurrent from each photodiode is converted to a voltage with the use of low-noise current-to-voltage amplifiers and then undergoes post-amplification with AC coupling and low-pass anti-alias filtering. A charge-coupled, coaxially mounted video detection unit images the surface of the heart, so that the mapping sites could be determined relative to the surface landmarks such as the epicardial coronary arteries. The sampling rate used is approximately 10 times the highest frequency content of action potentials, so that cardiac action potentials could be accurately reconstructed from digitized waveforms. The high signal-to-noise ratio of the system makes it possible to detect action potential amplitude changes as small as 1 % of the baseline action potential. The end result of all these electromechanical handiworks is that action potentials on the surface of the intact heart can be recorded with the temporal, spatial, and voltage resolutions of 1.0 ms, 0.8 mm, and 1.0 mV, respectively. Each action potential measured represents an average local transmembrane potential and therefore is insensitive to far field influences and less sensitive to biological variability often seen in isolated myocytes. The system allows quantitative analysis of action potential duration (APD), conduction velocity, and cardiac wavelength (l) in the intact heart. l is determined either directly from isopotential maps as the extent of depolarized tissue (i.e., distance from the depolarizing head of the wave to the point of recovery at the tail) or as the product of mean APD and mean conduction velocity within the region of depolarized tissue. To illustrate the use of optical mapping, note that the stability of reentrant arrhythmias such as ventricular tachycardia is determined by the relationship between l and reentrant path length (2). The effect of a drug on the stability of reentrant arrhythmias, i.e., the drug's pro- or anti-arrhythmic effect can be evaluated by visualizing the changes in l upon administration of the drug. The ACE inhibitor enalaprilat was determined by optical mapping to increase APD, but to have no effect on the conduction velocity and thus minimal effect on l (3). As a result, the medication did not have a sufficient antiarrhythmic effect to suppress the initiation of ventricular fibrillation or reentrant ventricular tachycardia. Future application of the technique may include studying antiarrhythmic effects of currently used antiarrhythmics under general anesthesia (especially since the antiarrhythmic efficacy of these drugs has never been proven in surgical settings) and the arrhythmogenicity of epinephrine or cocaine in the presence of anesthetics.
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Appetite Suppressants and Valvular Regurgitation Reviewer: K.W. Tim Park, MD Fenfluramine and phentermine are appetite suppressant medications that had been used for treatment of morbid obesity for decades until their voluntary withdrawal in 1997. Fenfluramine is a racemic mixture of N-ethyl-a-methyl-3-(trifluoromethyl)-benzene-ethanamine hydrochloride and dexfenfluramine is the d-isomer of fenfluramine. The appetite suppressant activity of both fenfluramine and dexfenfluramine is based on their ability to promote the rapid release of serotonin, inhibit its reuptake, and possibly have a serotonin-mimetic receptor-agonist activity (1). Dexfenfluramine is relatively selective for the central serotoninergic system. Phentermine, on the other hand, is nonadrenergic and may work by interfering with pulmonary clearance of serotonin. Phentermine was approved for use in the US in 1959 and fenfluramine in 1973; the approval of dexfenfluramine came much later in 1996. They were primarily used as a monotherapy for short periods (< 3 months). In 1992, a series of studies suggested the potential for the long-term use of fenfluramine in combination of phentermine and their use increased exponentially in the ensuing years (2). In 1996, prescriptions for these drugs in the US numbered more than 18 million (3). From 1994 - 96, sonographers in Fargo, ND, noticed an apparently high incidence of valvular regurgitation in obese patients on the diet drugs. Their patients, along with a few others, were reported as a case series of 24 patients in 1997 (1); this paper was made public at the time of its acceptance for publication in June 1997, immediately raising public awareness and concern before controlled data could be obtained. Five of the patients in the case series underwent a surgical replacement of the mitral or aortic valve. In at least two of the 5, endocardial fibroplastic changes were noted, similar to what is seen with malignant carcinoid syndrome (where there is a high level of circulating serotonin) or ergot alkaloid-induced valve disease. And serotonin was implicated as playing a role in diet suppressant-induced valvular regurgitation, although serotonin levels had not been measured in any of the patients in the case series and, when measured, are actually lower in patients on fenfluramine/phentermine with normal urinary levels of the serotonin metabolite 5-HIAA (4,5). Understandably, ensuing studies examining the association between the diet drugs and valvular regurgitation could not be prospective, controlled, and randomized, especially since the drugs were withdrawn from the market in September 1997. Weissman et al. (6) performed echocardiography on patients who had been undergoing a randomized, controlled efficacy trial of dexfenfluramine prior to its withdrawal. They found that, when examined within a month of stopping the medication, there was no significant difference between those who had taken the diet drug and the controls in the incidence of aortic regurgitation (AR) of mild or greater severity or mitral regurgitation (MR) of moderate or greater severity. Their patients had been on dexfenfluramine for an average of about 70 days. It should be noted that the diet drugs had been used for decades in short-term (< 3 months) monotherapy without any report of association with AR or MR. Various other retrospective reviews have been reported on the association of the diet drugs fenfluramine/phentermine and AR/MR (2, 7-11). The association is by no means incontrovertible and the reported prevalence of AR/MR in those who took the appetite suppressants has ranged from somewhat less than 1 % to about 30 %. Taken together, the reports appear to show that there is an increased incidence of valvular regurgitation, mostly AR of mild degree, in those who have taken the drugs in high doses (> 60 mg/d) and for an extended period of time (³ 9 months) (8). Now that fenfluramine and phentermine are out of the market, the most important remaining question may have to do with the natural history of the drug-induced valvular regurgitation. Hensrud et al. (12) followed 19 subjects who had received fenfluramine and phentermine for a mean of 41 weeks. Although 5 of the 19 had mild AR on termination of the drugs, the same 5 no longer had evidence of AR when re-examined echocardiographically 6 months later. Similar regression has been reported by others (13, 14). Since it has been more than 3 ½ years since withdrawal of the drugs, fenfluramine/phentermine-associated valvular regurgitation may be unlikely to be encountered now and may just be a lesson in history. References:
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