Correspondence

Sepsis — Theory and Therapies

N Engl J Med 2003; 348:1600-1602April 17, 2003

Article

To the Editor:

Hotchkiss and Karl (Jan. 9 issue)1 rightly stress the complex nature of the interaction between circulating proinflammatory and antiinflammatory factors and emphasize the importance of the immunologic depression that ensues. However, in their evaluation of potential therapies, they neglect to mention the role of extracorporeal blood-purification techniques, which have been shown to reduce mortality and attenuate shock in experimental models of sepsis. Unlike experimental antibody therapies, hemofiltration has already been used effectively in the treatment of sepsis in humans with concomitant shock, multiorgan failure, or both and in those without these conditions.2,3 Furthermore, other randomized, controlled studies of blood purification in critically ill patients with sepsis or multiorgan dysfunction have confirmed that it results in improvement in hemodynamic and clinical out-comes4,5 and the restoration of monocyte responsiveness.6 Therapies using highly permeable membranes and techniques of high-volume exchange hemofiltration also show promise for possible application in patients with sepsis, even in the absence of renal failure. The use of sorbents to enhance the removal of endotoxins and cytokines is also under evaluation.3 Taken together, such observations support the view that there is a role for blood-purification techniques in the treatment of sepsis.

Claudio Ronco, M.D.
St. Bortolo Hospital, 36100 Vicenza, Italy

Rinaldo Bellomo, M.D.
Austin and Repatriation Medical Center, Heidelberg, VIC 3084, Australia

Gehrard Lonneman, M.D.
Clinic of Nephrology and Dialysis, Langenhagen, Langenhagen, Germany

6 References

1. 1

   Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-150
   Full Text | Web of Science | Medline

2. 2

   Phu NH, Hien TT, Mai NTH, et al. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam. N Engl J Med 2002;347:895-902
   Full Text | Web of Science | Medline

3. 3

   Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002;28:1434-1439
   CrossRef | Web of Science | Medline

4. 4

   Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978-986
   CrossRef | Web of Science | Medline

5. 5

   Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;356:26-30
   CrossRef | Web of Science | Medline

6. 6

   Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med 2002;30:1250-1255
   CrossRef | Web of Science | Medline

To the Editor:

Hotchkiss and Karl state that the protective mechanism of insulin in sepsis is unknown. However, the recent literature provides ample evidence that insulin is a very potent antiinflammatory agent. In a study in animals, Jeschke et al.1 showed that the use of insulin resulted in significant dose-dependent decreases in serum levels of the inflammatory cytokines interleukin-1β, interleukin-6, macrophage inhibitory factor, and tumor necrosis factor (TNF) and increases in the levels of the antiinflammatory cytokines interleukin-2 and interleukin-4. Insulin has been observed to cause suppression of intranuclear nuclear factor-κβ, intercellular adhesion molecule 1, and monocyte chemotactic protein both in vitro and in vivo.2,3 Insulin also has the ability to induce the release of nitric oxide.4

Pradeep K. Agarwal, M.D.
West Jefferson Medical Center, Marrero, LA 70072
pradeep.agarwal@att.net

Rekha Kumari, M.D.
Louisiana State University Medical School, New Orleans, LA 70112

4 References

1. 1

   Jeschke MG, Einspanier R, Klein D, Jauch KW. Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med 2002;8:443-450
   Web of Science | Medline

2. 2

   Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NFkappaB and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab 2001;86:450-453
   CrossRef | Web of Science | Medline

3. 3

   Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001;86:3257-3265
   CrossRef | Web of Science | Medline

4. 4

   Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 1996;98:894-898
   CrossRef | Web of Science | Medline

To the Editor:

In their model of sepsis, Hotchkiss and Karl propose that there is an initial “hyperimmune status,” in which antiinflammatory strategies could save lives, and a “hypoimmune status” that eventually develops in others, which may be treated with proinflammatory strategies. This hyperimmune or hypoimmune status is determined at the time of diagnosis, when the patient is severely ill. We propose an alternative model, incorporating the first encounter between microbes and host (Figure 1Figure 1Proposed Model of the Influence on the Pathogenesis of Sepsis of the Capacity to Produce Inflammatory Cytokines.): microorganisms either induce a large amount of proinflammatory cytokines, leading to effective microbial killing and recovery, or lead to a low initial cytokine response with an ineffective host defense. In the latter case, the microbial load expands greatly, leading to massive production of cytokines and septic shock. Immune paralysis and a poor outcome may follow septic shock.

This model explains the low level of natural TNF production in patients who have recovered from meningococcal sepsis1 and the high ratio of interleukin-10 to TNF in patients with fatal infections.2 Our model also explains the high concentrations of circulating cytokines in septic shock, which result from high bacterial loads rather than an inadequate “hyperimmune response.”3

Mihai G. Netea, M.D.
Jos W. Van der Meer, M.D.
Bart Jan Kullberg, M.D.
University Medical Center St. Radboud, 6500 HB Nijmegen, the Netherlands
m.netea@aig.umcn.nl

3 References

1. 1

   Westendorp RGJ, Langermans JAM, de Bel CE, et al. Release of tumor necrosis factor: an innate host characteristic that may contribute to the outcome of meningococcal disease. J Infect Dis 1995;171:1057-1060
   CrossRef | Web of Science | Medline

2. 2

   van Dissel JT, van Langevelde P, Westendorp RGJ, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998;351:950-953
   CrossRef | Web of Science | Medline

3. 3

   Cannon JG, Tompkins RG, Gelfand JA, et al. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis 1990;161:79-84
   CrossRef | Web of Science | Medline

Author/Editor Response

Although we agree with Dr. Ronco and colleagues that extracorporeal blood-purification techniques may hold promise for the treatment of sepsis, definitive studies have yet to be performed. Dialysis does improve survival among patients with sepsis who have established renal insufficiency. It is not certain that dialysis, plasmapheresis, or plasma exchange will improve outcomes in patients with sepsis who do not have renal failure.1 Studies in animals and humans that have examined this issue have been inconclusive.2,3 There is also a potential for harm, since this therapy may result in hemodynamic instability, hypocalcemia, and seizures and could potentially remove beneficial compounds or molecules as well. Finally, the type of extracorporeal blood-purification technique, the duration of therapy, and the subgroup of patients with sepsis who are most likely to benefit have yet to be determined.

We agree with Drs. Agarwal and Kumari that insulin has antiinflammatory effects that may contribute to its beneficial effect in sepsis. We also maintain that the other actions of insulin — that is, the correction of hyperglycemia and the prevention of apoptosis — may be responsible for its most important therapeutic effect in sepsis. In this regard, a recent study showed that the benefit of intensive insulin therapy in critically ill patients was related more to the correction of hyperglycemia than to the dose of insulin used.4 We would again stress the importance of meticulous monitoring of blood glucose in order to prevent devastating hypoglycemic brain injury.

Although we agree that the model proposed by Dr. Netea and colleagues applies to some patients with sepsis, we believe that their paradigm does not reflect the clinical scenario in others. For example, in some patients with sepsis, a robust cytokine response does not appear to be mounted at any point during the illness. It is this failure to mount an appropriate response to the invading pathogen that results in illness and death in such patients. We speculate that the key to effective treatment of sepsis may be to identify the patient's current immune status in relation to the control of the infection. Some patients may have an excessive and damaging immune response that is reflected in high circulating concentrations of proinflammatory cytokines. In other patients, the problem may be the lack of a proinflammatory-cytokine response and an excessive antiinflammatory-cytokine response. Thus, therapy to enhance or repress the immune system will be based on the state of the patient's current immune response, the organism, and the risk of death.5

Richard S. Hotchkiss, M.D.
Irene E. Karl, Ph.D.
Washington University School of Medicine, St. Louis, MO 63110
hotch@morpheus.wustl.edu

5 References

1. 1

   Carcillo JA, Kellum JA. Is there a role for plasmapheresis/plasma exchange therapy in septic shock, MODS, and thrombocytopenia-associated multiple organ failure? We still do not know -- but perhaps we are closer. Intensive Care Med 2002;28:1373-1375
   CrossRef | Web of Science | Medline

2. 2

   Hoffmann JN, Faist E. Removal of mediators by continuous hemofiltration in septic patients. World J Surg 2001;25:651-659
   CrossRef | Web of Science | Medline

3. 3

   Stegmayr BG. Is there a future for adsorption techniques in sepsis? Blood Purif 2000;18:149-155
   CrossRef | Web of Science | Medline

4. 4

   Van Den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359-366
   CrossRef | Web of Science | Medline

5. 5

   Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002;166:1197-1205
   CrossRef | Web of Science | Medline

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   Jong Hwa Jung, Ji Ha Lee, Seiji Shinkai. (2011) Functionalized magnetic nanoparticles as chemosensors and adsorbents for toxic metal ions in environmental and biological fields. Chemical Society Reviews 40:9, 4464
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   Inge K. Herrmann, Martin Urner, Fabian M. Koehler, Melanie Hasler, Birgit Roth-Z'Graggen, Robert N. Grass, Urs Ziegler, Beatrice Beck-Schimmer, Wendelin J. Stark. (2010) Blood Purification Using Functionalized Core/Shell Nanomagnets. Small 6:13, 1388-1392
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4. 4

   Ravindra L. Mehta. (2005) Continuous renal replacement therapy in the critically ill patient. Kidney International 67:2, 781-795
   CrossRef