ICU patient. What level of training and experience should be expected of the person ordering the sedation? Who should be monitoring the level of anesthesia— and who therefore has responsibility for understanding and maintaining control over the anesthetic agent monitor? Who should be titrating the level of inhaled anesthetic—and coordinating the overall management, including adjusting other sedative/hypnotic drugs doses, opioids, or even vasopressors or inotropic agents when the inhaled agent alters hemodynamics? Hospital accreditation standards have four defined categories of sedation and analgesia: minimal sedation (anxiolysis), moderate sedation/analgesia (conscious sedation), deep sedation/analgesia, and anesthesia (11), but the transition from one level to another can be difficult to manage or assess. The addition of volatile agents to the current regimens used in the ICU will further complicate the management decisions. In addition, a great deal of data have recently been published demonstrating the influence of anesthetic management on long-term outcome (14). These studies document the importance of the anesthesiologist in clinical decision making. How the results of these studies affect the decision to provide inhalational anesthesia in the ICU setting is not clear, but the knowledge and skills that are required to manage the patient who is receiving a different drug provided through a different delivery system than is common in the ICU must be ensured. This debate about the potential value of inhaled anesthetics, therefore, should not be perceived as a turf battle but rather as a patient safety issue. Spe-
cific guidelines exist for sedation by nonanesthesia practitioners (13), with the intent of optimal patient safety. A similar process must be provided for the safe administration of inhaled anesthetics to the ICU patient, before this practice is accepted as viable and appropriate. In addition, if this technique is to gain broadbased acceptance, it will require that a more representative group of critical care providers, including ICU physicians from multiple specialties, nurses, and respiratory therapists, define the knowledge, skills, and standards for its use. Finally, should studies be reported demonstrating improved outcomes with inhalation agents when used to sedate critically ill patients, the extension of this practice will become important. Until such data exist about the safety, outcomes and appropriate guidelines are defined; however, general anesthetics in the unit should remain a novelty. Gerald A. Maccioli, MD, FCCM; Critical Health Systems, Inc. Neal H. Cohen, MD, MPH, MS, FCCM UCSF School of Medicine
REFERENCES 1. Sackey PV, Martling C-R, Nise G, et al: Ambient isoflurane pollution and isoflurane consumption during intensive care unit sedation with the Anesthetic Conserving Device. Crit Car Med 2005; 33:585–590 2. Proietti L, Longo B, Gulino S, et al: Techniques for administering inhalation anesthetics agents, professional exposure and early neurobehavioral effects. Med Lav 2003; 94:374 –379 3. Burm AG: Occupaional hazards of inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 2003; 17:147–161
4. Eger EI: Fetal injury and abortion associated with occupational exposure to inhaled anesthetics. AANA J 1991; 59:309 –312 5. Bozkurt G, Memis D, Karabogaz G, et al: Genotoxicity of waste anaesthetic gases. Anaesth Intensive Care 2002; 30:597– 602 6. Virgili A, Scapellato ML, Maccea I, et al: Occupational exposure to anesthetic gases at several hospitals. G Ital Med Lav Ergon 2002; 24:447–50 7. Meiser A, Sirtl C, Bellgardt M, et al: Desflurane compared with propofol for postoperative sedation in the intensive care unit. Br J Anaesth 2003; 90:273–280 8. Sepncer EM, Willatts SM: Isoflurane for prolonged sedation in the intensive care unit: Efficacy and safety. Intensive Care Med 1992; 18:415– 421 9. Kong KL, Willatts SM, Prys-Roberts C: Isoflurane compared with midazolam for sedation in the intensive care unit. BMJ 1989; 289:1277–1280 10. Wengrower D, Gozal D, Goldin E: Familial dysautonomia: Deep sedation and management in endoscopic procedures. Am J Gastroenterol 2003; 97:2250 –2252 11. Joint Commission on Accreditation of Healthcare Organization. Standards and intents for sedation and anesthesia care. Comprehensive accreditation manual for hospitals. Oakbrook Terrace, IL, Joint Commission on Accreditation of Healthcare Organizations, January 2001 12. Buhre W, Rossaint R: Perioperative management and monitoring in anesthesia. Lancet 2003; 362:1839 –1846 13. Practice Guidelines for sedation and analgesia by non-anesthesiologists. An updated report by the American Society of Anesthesiologists Task Force on sedation and analgesia by non-anesthesiologists. Anesthesiology 2002; 96:1004 –1017 14. Silber JM, Kennedy SK, Even-Shoshan O, et al: Anesthesiologist direction and patient outcomes. Anesthesiology 2000; 93:152–163
Sepsis and intracellular calcium homeostasis, a sparkling story*
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epsis and septic shock remain major clinical and economic burdens, despite important advances in the understanding of their pathophysiology and the introduc-
*See also p. 598. Key Words: Ca2⫹ homeostasis; Ca2⫹ sparks; cecal ligation and puncture model; myocardial dysfunction; sepsis Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000155773.51773.44
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tion of novel therapeutic strategies (1–3). Angus et al. (4) performed a large-scale study to determine the incidence, cost, and outcome of severe sepsis in the United States. They projected that severe sepsis affects approximately 750,000 people annually (1995) and accounts for 215,000 deaths per year in the United States. The annual total costs were estimated at $16.7 billion. Furthermore, although the overall mortality rate among patients with sepsis has declined over the last 2 decades, the incidence of severe
sepsis is still rising at an estimated rate of 1.5– 8.7% per year (4, 5). This increased incidence is related to the aging of the population, the increased use of invasive procedures and immunosuppressive medications, and the growing prevalence of antimicrobial resistance. Sepsis is a clinical syndrome that results from the systemic inflammatory response to infection and is characterized by multiple organ dysfunction. In many cases, the effects on the cardiovascular system dominate the clinical presentaCrit Care Med 2005 Vol. 33, No. 3
tion and are the main cause of the associated mortality and morbidity. In the 1960s, with the introduction of pulmonary artery catheters to measure occlusion pressure and cardiac output, it was established that the typical hemodynamic picture of patients with sepsis includes hypotension, decreased systemic vascular resistance, and fluid resuscitation dependent elevated cardiac index (1). Later, with the help of portable radionuclide imaging, it was shown that these patients frequently have a reduced left ventricular ejection fraction and that the elevated cardiac output is obtained mainly by compensatory cardiac dilation (6). Currently, the existence of sepsis-induced myocardial dysfunction is confirmed by numerous in vitro and in vivo studies. Initially, myocardial dysfunction was thought to be due to decreased myocardial perfusion leading to ischemic injury, but studies by, for example, Cunnion et al. (7) convincingly disproved this theory. Subsequently, the landmark studies by Parrillo’s group (8) revealed the presence of a circulating depressant factor, later identified as a synergistic combination of tumor necrosis factor-␣ and interleukin-1 as a causative factor. Extensive research has now uncovered many aspects of the immunologic cascade that is triggered by sepsis and results in myocardial dysfunction (2), but much controversy continues about the subcellular mechanisms that are ultimately responsible for myocyte contractile dysfunction. For example, it is not clear whether dysfunction mainly results from altered intracellular calcium (Ca2⫹) transients and homeostasis or from changes in cardiac myofilament properties (including their Ca2⫹ sensitivity). Most studies show a clear decrease in Ca2⫹ sensitivity (9, 10), but this decrease appears to be unrelated to structural changes in the contractile proteins actin or myosin because maximal Ca2⫹-activated tension tends to be unchanged. Presumably, the underlying mechanism involves changes in the regulatory proteins tropomyosin and/or the troponin complex (9, 11). Studies with levosimendan, a drug that sensitizes troponin-C to Ca2⫹, show marked improvements of left ventricular function in animals with experimental septic shock (12). However, Behrends and Peters (13) reported that similar positive effects were also seen in hearts from control animals, suggesting either that decreased Ca2⫹ sensitivity does not play a major role in sepsisCrit Care Med 2005 Vol. 33, No. 3
induced cardiomyopathy or, perhaps more likely, that reduced Ca2⫹ sensitivity during sepsis is not due to a direct effect on troponin-C but is related to, for example, increased troponin-I phosphorylation (11). The sequence of events linking Ca2⫹ transients to myocyte contraction and relaxation involves Ca2⫹ influx through Ltype Ca2⫹ channels during membrane depolarization, binding to the ryanodine receptor, and the subsequent Ca 2⫹ induced Ca2⫹ release from the sarcoplasmic reticulum (SR) that increases intracellular Ca2⫹ concentration to levels resulting in activation of the contraction cycle. The sequence ends with resequestration of Ca2⫹ in the SR via Ca2⫹adenosine triphosphatase (SERCA) and Ca2⫹ cell extrusion by the Na⫹-Ca2⫹ exchanger. Several of these steps were previously reported to be altered during sepsis. As examples, Zhong et al. (14) reported on reduced L-type Ca2⫹ currents, whereas Dong et al. (15) found a reduction in the number of Ca2⫹ release channels leading to impaired SR Ca2⫹ release. Wu et al. (16) described altered phospholamban phosphorylation, which modulates Ca 2⫹ -adenosine triphosphatase and thus SR Ca2⫹ uptake, and in a later publication the same group also found reduced SERCA protein levels (17). Furthermore, multiple studies report either increased or decreased intracellular Ca2⫹ concentrations. Interpreting these findings and judging their relative importance are highly complicated by at least three factors. First, the various processes involved are time-dependent and the studies differ with respect to progression of sepsis. Second, the effects may vary between the different species and preparations used. Third, there are major differences between experimental models of sepsis: The most widely used model is the endotoxin model that employs injection of lipopolysaccharide, but the polymicrobial model of cecal ligation and puncture (CLP) is a more realistic model of clinical sepsis (18). In this issue of Critical Care Medicine, Dr. Zhu and colleagues (19) used the CLP model to test the hypothesis that alterations in intracellular Ca2⫹ homeostasis underlie sepsis-induced myocyte dysfunction. They isolated cardiomyocytes from rats at 24 and 48 hrs after CLP (or sham operation) and determined various intracellular Ca2⫹ characteristics in relation to mechanical function (cell shortening). Interestingly, the authors used confocal
microscopy imaging of Ca2⫹ “sparks” to investigate SR Ca2⫹ release. This sophisticated methodology enables visualization of transmembrane Ca2⫹ kinetics at the molecular level mediated by discrete Ca2⫹-permeable channels and transporters. Over the last decade this microdomain imaging has revealed detailed spatial and temporal patterns of Ca 2⫹ dynamics that may help to explain how this simple ion can serve as such a versatile intracellular messenger for so many different physiologic processes (20). With regard to mechanical function, Dr. Zhu and colleagues found a significantly reduced shortening after stimulation at 48 hrs after CLP but no changes at 24 hrs. Consistently, the elevation in systolic intracellular Ca2⫹ concentration was largely unchanged at 24 hrs but was reduced at 48 hrs after CLP. The decay toward normal resting levels was prolonged at both time points, and an increased diastolic level was found in the 48-hr CLP group. In the resting cell, Ca2⫹ sparks represent spontaneous openings of a cluster of ryanodine receptors that normally occur at a low rate and constitute a small dynamic Ca2⫹ leak. Dr. Zhu and colleagues found that in sepsis, the Ca2⫹ spark frequency was significantly increased, leading to an overall increased leakage of SR Ca2⫹ in the resting state. As a consequence, resting intracellular Ca2⫹ concentration was increased and SR Ca2⫹ content was found to be reduced in the late stage of sepsis (48 hrs). The increased SR Ca2⫹ leakage is a new component of abnormal Ca2⫹ handling during sepsis and may help to explain both diastolic and systolic myocardial dysfunction frequently found in septic patients. In theory, this may offer a new therapeutic target different from most strategies that target earlier proinflammatory mediators. Clearly, follow-up studies are required to judge the relevance for the human situation, but the article by Dr. Zhu and colleagues provides interesting new insights in the pathophysiology of myocardial dysfunction in sepsis. Paul Steendijk, PhD Department of Cardiology Leiden University Medical Center Leiden, The Netherlands
REFERENCES 1. Kumar A, Haery C, Parrillo JE: Myocardial dysfunction in septic shock: Part I. Clinical manifestation of cardiovascular dysfunction.
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J Cardiothorac Vasc Anesth 2001; 15: 364 –376 Kumar A, Krieger A, Symeoneides S, et al: Myocardial dysfunction in septic shock: Part II. Role of cytokines and nitric oxide. J Cardiothorac Vasc Anesth 2001; 15:485–511 Riedemann NC, Guo RF, Ward PA: Novel strategies for the treatment of sepsis. Nat Med 2003; 9:517–524 Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310 Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546 –1554 Parker MM, Shelhamer JH, Bacharach SL, et al: Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984; 100:483– 490 Cunnion RE, Schaer GL, Parker MM, et al: The coronary circulation in human septic shock. Circulation 1986; 73:637– 644 Parrillo JE, Burch C, Shelhamer JH, et al: A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in
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vitro myocardial cell performance. J Clin Invest 1985; 76:1539 –1553 Wu LL, Tang C, Liu MS: Altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins during sepsis. Am J Physiol Regul Integr Comp Physiol 2001; 281: R408 –R416 Yasuda S, Lew WY: Lipopolysaccharide depresses cardiac contractility and betaadrenergic contractile response by decreasing myofilament response to Ca2⫹ in cardiac myocytes. Circ Res 1997; 81:1011–1020 Tavernier B, Li JM, El Omar MM, et al: Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 2001; 15: 294 –296 Oldner A, Konrad D, Weitzberg E, et al: Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 2001; 29:2185–2193 Behrends M, Peters J: The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts. Intensive Care Med 2003; 29: 1802–1807 Zhong J, Hwang TC, Adams HR, et al: Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Physiol 1997; 273:H2312–H2324
15. Dong LW, Wu LL, Ji Y, et al: Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock 2001; 16:33–39 16. Wu LL, Tang C, Dong LW, et al: Altered phospholamban-calcium ATPase interaction in cardiac sarcoplasmic reticulum during the progression of sepsis. Shock 2002; 17: 389 –393 17. Wu G, Yang SL, Hsu C, et al: Transcriptional regulation of cardiac sarcoplasmic reticulum calcium-ATPase gene during the progression of sepsis. Shock 2004; 22:46 –50 18. Villa P, Sartor G, Angelini M, et al: Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin. Clin Diagn Lab Immunol 1995; 2:549 –553 19. Zhu X, Bernecker OY, Manohar NS, et al: Increased leakage of sarcoplasmic reticulum Ca2⫹ contributes to abnormal myocyte Ca2⫹ handling and shortening in sepsis. Crit Care Med 2005; 33:598 – 604 20. Wang SQ, Wei C, Zhao G, et al: Imaging microdomain Ca2⫹ in muscle cells. Circ Res 2004; 94:1011–1022
One more piece in the septic myocardial depression puzzle?*
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ontroversy has surrounded the real origin of septic induced myocardial dysfunction since early studies by Brand and Lefer (1) described a myocardial depressant factor in cats subjected to an hemorrhagic shock. Since then, this complex entity has been ascribed to inflammatory mediators (2), nitric oxide generation (3), interstitial myocarditis (4), coronary ischemia (5), endothelin receptor antagonist (6), and apoptosis (7). Although not fully understood, myocardial depression/injury in sepsis remains a challenge for intensive care practitioners. Parrillo et al. (8) and Parker et al. (9) extensively described this entity, and we have learned that a different pattern exists between survivors and nonsurvivors. The
*See also p. 605. Key Words: myocardial depression; myocardial injury; ionic dishomeostasis; sepsis; burn Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000155777.78666.B8
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former exhibit reduced ejection fraction and increased ventricular dimensions that promptly return to normal as sepsis resolves, whereas the latter exhibit polymorphonuclear cell infiltrates and edema within the myocardium (4) probably rendering the myocardium less compliant and therefore unable to compensate for reduced performance. Liberation of troponin from the myocardium corroborates this hypothesis (10).Troponin is a very sensitive and specific marker of myocardial injury in sepsis and can be related to the observed myocardial dysfunction. In this issue of Critical Care Medicine, Dr. Sikes and coworkers (11) were very auspicious in developing an experimental model in which cardiac function, cellular sodium and calcium, myocardial pH, and high-energy phosphates were examined in perfused hearts after sepsis alone or complicated by previous burn injury as well as after amiloride treatment. The same authors (12) have already shown that sepsis in the presence of a previous burn injury impaired cardiac performance and exacerbated the myocardial contractile dysfunc-
tion that was characteristic of either burn alone or sepsis alone. Earlier, they postulated that burn trauma could alter intracellular cardiomyocyte calcium and sodium homeostasis (13). Sodium accumulation by cardiomyocytes has been shown to occur in several models of myocardial dysfunction mainly as a result of cellular energy deficit. By using nuclear magnetic resonance spectroscopy to examine the ionic status of the heart, they were able to demonstrate in a very elegant manner that cardiomyocyte sodium and calcium accumulation occurred despite no changes in myocardial energy levels. Moreover, they were able to demonstrate that amiloride administration prevented sodium and calcium accumulation within the cardiomyocytes thereby improving myocardial contraction. Studying myocardial contraction in sepsis has been a difficult task in vivo since catecholamines tend to mask an actually dysfunctioning heart. One can better describe cardiac dysfunction in a Langendorff perfused heart as did Dr. Sikes and coworkers. Using this model, they were able to demonstrate conclusively a reduction in developed left venCrit Care Med 2005 Vol. 33, No. 3