Key Point

Many novel therapies, targeting everything from gene expression to inflammation, are currently under study for use in treating critically ill patients.

PHOENIX—Researchers have been taking crucial first steps toward new treatments for critical illness, especially sepsis and ARDS. At the annual meeting of the Society of Critical Care Medicine (SCCM), five of those researchers described their most recent efforts to develop “magic bullets”—therapies targeting specific molecules such as the complement activation product C5a or particular events such as apoptosis, which raise the risk of poor outcomes in the critically ill.¹

MAINTAINING THE C5A BALANCE

Cooperating with investigators from the University of Ulm Medical School in Germany, Peter A. Ward, MD, found a fivefold to sixfold increase in plasma levels of C5a in animals and humans with sepsis. C5a aids in the recruitment of inflammatory cells, activation of phagocytes, release of granule-based enzymes, and in the generation of oxidants—all changes that contribute to tissue damage and innate immune system dysfunction.²

Patients with septic shock also showed a profound loss of the C5a receptors C5aR and C5L2. “If you compare the nonsurvivors with the survivors, the lower the C5a receptor content goes, the greater the likelihood that these patients will not survive,” said Dr. Ward, the Godfrey D. Stobbe Professor of Pathology at the University of Michigan in Ann Arbor.

Dr. Ward found two effects of C5a blockade in rats—attenuation of C5a-receptor loss and of sepsis-associated clotting and fibrinolytic pathway depletion. “The responsiveness to C5a, we think, is a result of a balance between engagement of C5aR and C5L2,” he said, “and if the amount of C5a is kept to a reasonably limited level, the result is a counterbalance between the effects of C5a and C5L2.”

TARGETING APOPTOSIS

Richard S. Hotchkiss, MD, arrived at the SCCM meeting with a mission: “To convince you that apoptosis is an important pathophysiologic event in sepsis,” he said, “and that prevention of apoptosis by multiple independent methods has now been shown to improve survival.”

Animal experiments have provided strong evidence that sepsis induces extensive lymphocyte apoptosis and that this cell death contributes greatly to immunosuppression and mortality. However, death from sepsis was remarkably reduced in a number of studies of septic mice genetically altered to overexpress the antiapoptotic protein Bcl-2. “Bcl-2 acts predominantly to prevent mitochondrial cell death,” explained Dr. Hotchkiss, Professor of Anesthesiology at Washington University in St. Louis.

Improved survival has also been observed in septic mice with a knockout of the Fas apoptosis receptor and in those treated with AIDS antiretroviral therapy, which reduced apoptosis. “Other potential new therapies in sepsis include caspase inhibitors,” Dr. Hotchkiss said. Caspases, a family of proteases that are activated in apoptosis, physically disassemble cells. Several caspase inhibitors appeared to improve morbidity and mortality in animal models of sepsis.

Ethyl pyruvate, an anti-inflammatory agent and peroxide scavenger, has also been found to reduce mortality in animals with sepsis and deserves careful evaluation in clinical trials, asserted Mitchell P. Fink, MD, Professor of Anesthesiology and Critical Care Medicine at the University of Pittsburgh in Pennsylvania. In vivo and mouse models indicate that ethyl pyruvate works in sepsis not by targeting apoptosis but by inhibiting high mobility group box-1 protein and nuclear factor kappa-B.

“Ethyl pyruvate has been shown to improve survival or ameliorate organ system dysfunction in many other [animal] models,” added Dr. Fink, “including alcoholic hepatitis, pancreatitis, coronary occlusion and reperfusion, endotoxic shock, burn injury, extrahepatic biliary stasis, and postsurgical ileus.”

GENE-ENHANCEMENT STRATEGIES

Researchers have had little success in treating chronic disease by enhancing therapeutic gene expression because they have not been able to permanently alter the genome. “But to treat shock, sepsis, or ARDS, we do not really want a permanent change in gene expression,” pointed out Clifford S. Deutschman, MD, Professor of Anesthesia at the University of Pennsylvania in Philadelphia. “They are transient diseases that require transient changes [in gene expression],” he said.

The benefit of such a change in the expression of heat shock protein 70, the most abundant of the responsive heat shock proteins, has been studied in rats with ARDS.³ The protein, which was administered with an adenovirus vector, halved 48-hour mortality. It also attenuated cell dropout and decreased interstitial fluid accumulation, neutrophil infiltration, and exudation of protein into the alveoli. “Modulation of heat shock protein production may improve outcome in ARDS,” concluded Dr. Deutschman.

In a talk not dealing with treatment on a genetic or molecular level, W. Alan Mutch, MD, discussed the benefits of biologically variable mechanical ventilation. This technology involves the addition of biological noise to computer-controlled or control-mode ventilation, explained Dr. Mutch, Professor of Anesthesia and Neuroanesthesia at the University of Manitoba in Winnipeg.

To illustrate, he reported that the respiratory rate of a 70-year-old woman was found to vary from six to 22 breaths per minute over 1,600 breathing cycles as she sat quietly reading a book. “This is the kind of variation we reinstitute back into the mechanical ventilator,” he said.

In porcine models of acute lung injury with mechanical ventilation at low tidal volumes, this strategy was associated with a decreased risk of volume trauma; it also resulted in sustained improvements in arterial oxygenation, arterial oxygen tension, and respiratory system compliance and in better recruitment of atelectatic lungs compared to conventional control-mode ventilation.⁴

“Biological noise or variability is important to maximize life-support devices,” Dr. Mutch maintained. Furthermore, he added, the computational biology used to re-create biological variability has an important part to play in 21st-century medicine.

—Timothy Begany

Reference
1. Fink MP, Ward PA, Hotchkiss RS, et al. Magic bullets in critical care research. Presented at: annual meeting of the Society of Critical Care Medicine; January 17, 2005; Phoenix, Ariz.
2. Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005;23:821-852.
3. Weiss YG, Maloyan A, Tazelaar J, et al. Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome. J Clin Invest. 2002;110:801-806.
4. Boker A, Graham MR, Walley KR, et al. Improved arterial oxygenation with biologically variable or fractal ventilation using low tidal volumes in a porcine model of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;165:456-462.

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