William D. Hoffman

Selected Treatment Strategies for Septic Shock Based on Proposed Mechanisms of Pathogenesis

Dr. Charles Natanson (Critical Care Medicine Department, Clinical Center, National Institutes of Health [NIH], Bethesda, Maryland): Sepsis and septic shock are heterogeneous clinical syndromes that can be triggered by many microorganisms, including gram-negative bacteria, gram-positive bacteria, and fungi [1-3]. Participants in a recent consensus conference tried to define sepsis and septic shock. Sepsis was characterized as a systemic response to infection manifested by tachycardia, tachypnea, change in temperature, and leukopenia or leukocytosis. Septic shock was defined as severe sepsis accompanied by hypotension [4]. However, patients with sepsis may have one or several signs and symptoms, and no single physiologic or laboratory parameter can universally identify this syndrome. Advances in molecular biology and immunology during the past decade have increased our understanding of the pathogenesis of septic shock (Figure 1). In particular, we now believe that the hosts inflammatory response to infection contributes substantially to the development of septic shock [5-7]. Infections begin when microorganisms circumvent or penetrate host barriers such as skin and mucosa. Depending on the infecting agents virulence and the patients immunocompetence, local host defenses may be overwhelmed, resulting in microbial invasion of the bloodstream. Toxic bacterial products present in the circulation activate systemic host defenses, including plasma factors (complement and clotting cascades) and cellular components (neutrophils, monocytes, macrophages, and endothelial cells). In turn, activated cells produce potentially toxic host mediators (cytokines such as tumor necrosis factor [TNF] and interleukin-1 [IL-1], kinins, eicosinoids, platelet-activating factor, and nitric oxide) that augment the inflammatory response. This escalating immune response, in concert with microbial toxins, can lead to shock, multiple organ failure, and death. Figure 1. The pathogenesis and treatment of septic shock. Standard sepsis treatment strategies include use of antibiotics to kill invading bacteria, surgical procedures to eradicate the nidus of infection, and intensive life-support procedures such as dialysis, mechanical ventilation, and use of vasoactive drugs. Despite these approaches, the mortality rate from septic shock is high, ranging from 25% to 75% [1, 8-12]. In addition, the reported incidence of sepsis syndrome in U.S. hospitals increased 139%, from 73.6 to 175.9 per 100 000 persons discharged between 1979 and 1987 [13]. This increase may be caused by several medical trends: improved life-support technology that keeps patients who have a high risk for infection alive at the extremes of age; increased use of invasive medical procedures; advances in cancer chemotherapy and immunotherapy; and the prevalence of acquired immunodeficiency syndrome. The increasing incidence of sepsis and its high mortality rate have mobilized a search for new therapies. Development of new drugs to treat sepsis has been based in part on the premise that neutralizing bacterial toxins and potentially harmful host mediators could stop or slow this syndrome. The discussants in this conference review several of these new therapies that are directed at different elements of the inflammatory cascade, including a bacterial toxin (endotoxin), host proteins that mediate the inflammatory response (TNF and IL-1), an inflammatory cell (the neutrophil), and a low-molecular-weight messenger (nitric oxide) that causes hypotension. Other targets (eicosinoids, platelet-activating factor, bradykinin, and so on) are being evaluated to treat this syndrome. Each target selected for discussion was studied in our laboratories or evaluated in human clinical trials. Each discussant offers unique insight into the pathogenesis of septic shock and into the difficulties inherent in inhibiting a potentially toxic inflammatory mediator that may also play a role in host defense. Antiendotoxin Therapies in Septic Shock Dr. William D. Hoffman (Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland): The outer membrane of gram-negative bacteria contains lipopolysaccharides called endotoxin [14]. Endotoxin induces an inflammatory response that may protect the host from infection but may also cause multiple-organ failure and death when present in excess amounts. Specific immunochemical properties have been associated with different components of the endotoxin molecule. The O-polysaccharide chain (O-side chain) of endotoxin is exposed on the outside surface of gram-negative bacteria. The O-side chain is not toxic when injected into animals and has a molecular structure that varies among gram-negative bacteria. The core sugar and lipid A regions of endotoxin are embedded deeply in the outer bacterial membrane, and their molecular structures are similar for all gram-negative bacteria. In contrast to the O-side chain, lipid A is toxic when given to animals [14]. Effects of Endotoxin Challenge-Endotoxemia in Sepsis Experimental observations have supported and challenged the concept that endotoxin-directed therapies can benefit patients with septic shock. Reversible organ dysfunction and hemodynamic changes that are qualitatively similar to those seen in patients with septic shock develop in animals injected with endotoxin [15] and healthy human volunteers injected with safe doses of endotoxin [16]. In addition, development of endotoxemia in patients with septic shock has been associated with severe organ damage [9]. However, neither induced tolerance to endotoxin in humans [17] nor genetic resistance to endotoxin in mice [18] is protective during gram-negative infections. In addition, increased sensitivity to endotoxin does not alter the course of gram-negative infection in animals [19]. Finally, endotoxin and endotoxemia are not necessary to produce the septic shock syndrome, and endotoxin may be only one of many bacterial products that can trigger the septic response [3, 15]. Approaches to Antiendotoxin Therapy Although no antiendotoxin therapy is in clinical use, several are being investigated (Table 1). Antibodies to the O-side chain produce serotype-specific [20], complement-dependent bactericidal activity [21]. However, serotype specificity limits the clinical utility of O-side chain therapies because treating patients empirically with an effective dose of antibody for every probable infecting bacterial strain would be difficult. This problem led to investigation of antibodies directed at core and lipid A structures of endotoxin, because these antibodies might cross-protect against diverse gram-negative bacteria [22]. Although core or lipid A antibodies were thought to mediate antiendotoxin [23] or endotoxin-clearing effects [24], the function of these antibodies is unknown and controversial [25-28]. Nevertheless, core-directed antibodies are the only antiendotoxin therapies studied in clinical trials. Other antiendotoxin agents listed in Table 1 may reduce the host inflammatory response by directly neutralizing endotoxin, increasing its clearance, antagonizing its effects on host cells, or inducing tolerance. Controlled therapeutic trials of agents that reduce the bioactivity of endotoxin and have no antibacterial effect may determine whether circulating endotoxin is a useful therapeutic target in septic shock. Table 1. Approaches to Antiendotoxin Therapies for Septic Shock* Polyclonal Antibodies Directed at Core Epitopes and Lipid A The first clinical trial of core-directed antibodies studied patients with gram-negative bacteremia treated with control (n = 100) or J5 antiserum (n = 91) [8]. In that study, 21 of 39 patients with localized gram-negative infection but no bacteremia were included in the gram-negative bacteremia group because they had been given appropriate antibiotics before blood cultures were obtained [8]. The sepsis-related mortality rate for patients with gram-negative bacteremia given J5 antiserum was 22% (compared with 39% with control serum). In a subgroup of patients who required vasopressor drugs for more than 6 hours, the mortality rate was 44% (compared with 77% with control serum). The effect of J5 antiserum on mortality from all causes or in patients with gram-negative infection was not reported [8]. Five subsequent clinical trials (Table 2) using polyclonal core-reactive antiserum or immunoglobulin to prevent or treat gram-negative sepsis showed essentially no survival benefit [29-34]. Table 2. Summary of 10 Clinical Trials with Lipopolysaccharide Core-Directed Antibodies* Monoclonal Antibodies Directed at Core Epitopes and Lipid A: E5 and HA-1A Monoclonal antibodies were developed to produce a more specific antiendotoxin therapy with less risk for transmission of infection. E5, a murine IgM, protected mice injected with bacteria [35], and HA-1A, a human IgM, protected mice and rabbits injected with bacteria [36]. However, E5 did not protect sheep given endotoxin [37], and other researchers subsequently could not reproduce the beneficial effects of HA-1A in mice and rabbits [38]. E5 Clinical Trials E5 was tested in two multicenter, randomized, placebo-controlled clinical trials (Table 2). In the first trial of 468 patients, E5 provided no significant benefit to patients with gram-negative infection. The antibody improved survival in a retrospectively identified subgroup of 137 patients with gram-negative infection without refractory shock (30% compared with 43%; P = 0.01) [39]. A second trial of 847 patients was conducted to confirm this favorable effect (Table 2). However, in the second study, E5 did not significantly improve survival in the 530 patients who had gram-negative infection without refractory shock (E5, 30% mortality compared with control, 26%; P = 0.21) [40]. Using a meta-analysis and combining data from the two trials, researchers found that E5 substantially decreased the time to recovery from organ dysfunction and improv

Randomization in clinical trials of titrated therapies: unintended consequences of using fixed treatment protocols.

Objective:Clinical trial designs that randomize patients to fixed treatment regimens may disrupt preexisting relationships between illness severity and level of therapy. The practice misalignments created by such designs may have unintended effects on trial results and safety. Methods:To illustrate this problem, the Transfusion Requirements in Critical Care (TRICC) trial and the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) trial were analyzed. Results:Publications before TRICC indicated that clinicians used higher transfusion thresholds in patients with ischemic heart disease compared with younger, healthier patients (p = .001). The trial, however, randomized patients (n = 838) to liberal (10 g/dL hemoglobin) or restrictive (7 g/dL) transfusion thresholds. Thirty-day mortality was different and opposite in the liberal compared with the restrictive arm depending on presence (21 vs. 26%) or absence (25 vs. 16%) of ischemic heart disease (p = .03). At baseline in ARMA, consistent with prior publications, physicians set ventilator volumes lower in patients with high airway pressures and poor compliance (8.4–10.6 mL/kg interquartile range) than patients with less severe abnormalities (9.6–12 mL/kg) (p = .0001). In the trial, however, patients (n = 861) were randomized to low (6 mL/kg) or high (12 mL/kg) tidal volumes. In patients with low compliance (<0.6 mL/kg), 28-day mortality was higher when tidal volumes were raised rather than lowered (42 vs. 29%), but this effect was reversed in patients with higher compliance (21 vs. 37%; p = .003). Conclusions:In TRICC and ARMA, randomization to fixed treatment regimens disrupted preexisting relationships between illness severity and therapy level. This created noncomparable subgroups in both study arms that received care different and opposite from titrated care, that is, practice misalignments. These subgroups reduced the interpretability and safety of each trial. Characterizing current practice, incorporating current practice controls, and using alternative trial designs to minimize practice misalignments should improve trial safety and interpretability.

Endotoxin in Septic Shock

Endotoxin is a lipopolysaccharide located on the outer membrane of gramnegative bacteria. Over the last 60 years, researchers have given endotoxin to animals and human volunteers to induce septic shock and investigated the pathophysiologic events associated with this syndrome [1, 2]. Recently, researchers evaluated the effects of antibody therapies directed against endotoxin in septic patients [3, 4]. The inconclusive results of these studies have raised new questions about the role of endotoxin in live bacterial infections [5]. To help answer questions about endotoxin, we review its biochemistry, its possible role in human disease, and its relationship to clinical antibody therapies.

Postoperative troponin-T predicts prolonged intensive care unit length of stay following cardiac surgery.

Objective:To evaluate the use of postoperative cardiac troponin T (cTnT) for the prediction of prolonged intensive care unit length of stay following cardiac surgery. Design:Prospective, single-center, observational cohort study of patients following cardiac surgical procedures. The enrollment period was from October through December 2000. Patients were enrolled on admission to the intensive care unit and followed until hospital discharge. Setting:The cardiac surgical intensive care unit of the Massachusetts General Hospital. Patients:A total of 222 consecutive patients were enrolled. Interventions:None. Measurements and Main Results:Perioperative clinical factors and serum concentrations of cTnT measured every 8 hrs after surgery were recorded. These clinical factors and the results of serum cTnT measurement were correlated with the need for prolonged intensive care unit length of stay (defined as >24 hrs). Univariable analysis identified factors predictive of prolonged intensive care unit length of stay. Stepwise logistic regression identified independent predictors of prolonged intensive care unit length of stay. Multiple linear regression was used to explore the direct relationship between cTnT concentrations at several postoperative time points and intensive care unit length of stay. At each time point assessed, cTnT concentrations from patients requiring a prolonged intensive care unit length of stay were significantly higher (all p < .001) than in those individuals with normal length of stay. In contrast, creatine kinase isoenzymes were not significantly different between patients with normal or prolonged intensive care unit length of stay. Multivariable analysis demonstrated that an immediate postoperative cTnT concentration ≥1.58 ng/mL was the strongest predictor of a prolonged intensive care unit length of stay (odds ratio, 5.6; 95% confidence interval, 2.9–10.8). Multiple linear regression analysis revealed that intensive care unit length of stay increased by 0.32 days with each incremental 1.0 ng/mL increase in cTnT measured at 18–24 hrs postprocedure. Conclusions:Elevated postoperative cTnT concentrations can prospectively identify patients requiring prolonged intensive care unit length of stay after cardiac surgery.

Reduced Argatroban Doses after Coronary Artery Bypass Graft Surgery

Background: The Food and Drug Administration–approved argatroban dose for heparin-induced thrombocytopenia (HIT) is 2 μg/kg/min (0.5 μg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) 1.5–3 times baseline. Recent data suggest that reduced doses are required after cardiovascular surgery. Objective: To characterize dosing requirements, aPTTs, factors affecting dosage, and clinical outcomes in patients administered argatroban after coronary artery bypass graft (CABG) surgery. Methods: Charts of 39 patients who underwent CABG surgery and were administered argatroban postoperatively for laboratory-confirmed HIT (n = 25), antibody-negative suspected HIT (n = 10), or previous HIT requiring anticoagulation (n = 4) were retrospectively reviewed. Patient characteristics, argatroban dosing information, aPTTs (target range 45–90 sec), and outcomes were summarized. Regression analyses explored potential effectors of dosage. Results: Patient features, argatroban dosing patterns, and aPTTs were similar among groups. Many patients had laboratory evidence of some hepatic and/or renal dysfunction (median [range] bilirubin 1.0 [0.3–8.0] mg/dL, creatinine clearance 47 [18–287] mL/min). Overall, median argatroban doses were 0.5 μg/kg/min initially and 0.6 μg/kg/min during therapy (median duration 5.3 days). After argatroban initiation, aPTTs were greater than 90 seconds at first assessment in 4 patients (3 with abnormal hepatic function test results) initially administered 0.5, 1, 2, and 2 μg/kg/min, respectively. Within approximately 16 hours of therapy, 33 (85%) patients achieved consecutive therapeutic aPTTs. No association was detected between mean dose during therapy and preoperative ejection fraction, routine hepatic or renal function test results (other than blood urea nitrogen [BUN]), or surgery type. A clinically insignificant association existed between dose and BUN: there was an approximately 0.15 μg/kg/min dose decrease for each 10 mg/dL BUN increase. One patient developed thrombosis, 1 underwent finger amputation, 7 died (5 after argatroban cessation), and 4 had significant bleeding. Conclusions: These findings suggest that reduced initial argatroban doses (eg, 0.5 μg/kg/min), adjusted to achieve therapeutic aPTTs, provide rapid, adequate anticoagulation in postoperative CABG patients with presumed or previous HIT. Prospective study of reduced initial dosing in this setting is warranted.