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Published on 1 November 2003

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Advances in severe sepsis management

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Jean-Louis Vincent
MD PhD
Head
Department of Intensive Care

Sophie Lorent
Pharmacy
Erasme Hospital
Free University of Brussels
Belgium
E:jlvincen@ulb.ac.be

Sepsis affects some 30–50% of intensive care unit (ICU) patients,(1–3) with an annual incidence of about 250 cases per 100,000 population in the Western world.(4) Severe sepsis is associated with high mortality rates and is responsible for some 150,000 deaths each year in countries of the European Union. In addition to the human costs in terms of morbidity and mortality, severe sepsis carries considerable financial burden, with annual costs in the USA estimated at $16.7 billion.(5) The incidence of severe sepsis seems to be increasing, and although mortality rates may have fallen slightly, the total number of deaths from severe sepsis continues to increase.(4) The last couple of years have seen huge advances in the management of severe sepsis, notably with the development of drotrecogin alfa (activated),(6) and these new strategies will be the focus of this paper.

Resuscitation
The initial management of severe sepsis and septic shock involves adequate and rapid resuscitation. The basics of resuscitation have remained essentially unchanged for decades, and adequate oxygenation and fluid administration are the keystones to success. Importantly, Rivers et al(7) demonstrated that early goal-directed resuscitation, initiated within the first six hours of hospital attendance (ie, often before a patient reaches the ICU), reduced mortality from 46.5% in the group assigned to standard therapy to 30.5% in the group assigned to early, goal-directed therapy (p=0.009). Awareness of sepsis as a possible diagnosis and rapid institution of appropriate resuscitation can therefore save lives.

Assessing adequacy of resuscitation is not always simple, and various techniques have been introduced to help in the monitoring of the regional perfusion of patients with severe sepsis, as local blood flow and oxygenation may remain impaired even when systemic parameters are apparently normal. One of the most recent approaches to attract attention is orthogonal spectral imaging (OPS) techniques that are relatively noninvasive and can be used sublingually to monitor the microcirculation.(8)

The optimum resuscitation fluid is still unclear, with the ongoing crystalloid/colloid debate, and choices are often influenced by local practices and physician preferences, as well as costs and availability. The use of albumin has undergone some scrutiny since the publication of a meta-analysis suggesting it was associated with increased mortality,(9) but other studies have not supported these findings(10) and the jury is still out on this issue. The place of blood transfusions has also undergone something of a rethink since Hebert et al suggested that a lower transfusion threshold (the haemoglobin value at which transfusion is normally indicated) than the previously widely accepted 10g/dl may be associated with improved outcomes.(11) However, anaemia is also associated with worse outcomes, and this is not a clear black-and-white situation. Indeed, a more recent multicentre observational study (the Sepsis Occurrence in Acutely Ill Patients: SOAP) does not suggest any link between blood transfusions and mortality, although this may be due to the now widespread use of deleukocyted blood, which has been shown to reduce post-transfusion infection rates.(12) Clearly, this is an area that requires further study before definitive guidelines can be established, but in general, with the possible exception of those with cardiovascular disease, patients may well tolerate, and even benefit from, lower haemoglobin levels than previously thought.

Most patients with septic shock will also require vasopressor agents, and the available catecholamines have also come under considerable scrutiny in recent years in an attempt to determine which, if any, is superior, in terms of restoring blood pressure and tissue perfusion. Dopamine is considered by many as the vasopressor of choice, increasing blood pressure but not at the expensive of the regional circulation.(13) However, others claim that norepinephrine is superior when used as a firstline drug.(14) In a recent clinical trial dopamine had a slightly better profile on the splanchnic circulation than norepinephrine, and epinephrine was associated with impaired splanchnic circulation.(15)

Immunomodulation
In the last few years we have finally witnessed a breach in the brick wall against which so many researchers have metaphorically banged their heads in the search for an effective immunomodulatory treatment for patients with sepsis. Many years of intense research into the pathophysiology of sepsis were finally rewarded as our understanding of the close links between coagulation and sepsis led to the development of drotrecogin alfa (activated), marketed as Xigris, a recombinant form of activated protein C that reduces mortality in patients with severe sepsis. Activated protein C is a naturally occurring anticoagulant agent with additional anti-inflammatory properties, including reducing leukocyte adhesion and activation,(16,17) reducing nuclear translocation of nuclear-factor-kappa B (NF-kB), with a resultant fall in synthesis of cytokines(18) and activation of antiapoptosis pathways.(19) The mechanisms underlying these effects are as yet uncertain but may involve protease-activated receptors (PARs) and the endothelial protein C receptor (EPCR).(20,21) A randomised, controlled trial involving 1,690 patients with severe sepsis from 164 ICUs in 11 countries worldwide(6) showed that, at a dose of 24mg/kg/h for 96 hours, drotrecogin alfa (activated) caused a 6.1% absolute reduction in mortality risk (30.8% mortality in placebo group versus 24.7% in treatment group, p=0.005), giving a 19.4% reduction in the relative risk of death (ie, 16 patients needed to be treated to save one life). Vasopressor requirements and duration of mechanical ventilation were also reduced,(22) and, importantly, the beneficial effects on outcome appear to be maintained over time. As expected, there is an increased risk of severe bleeding in patients treated with drotrecogin alfa (activated), although this is mostly associated with interventions, and, if a surgical procedure is necessary during treatment, the infusion should be stopped two hours before the intervention and restarted 12 hours after adequate haemostasis has been obtained. Because of these risks, drotrecogin alfa (activated) is contraindicated in patients at high risk of bleeding, including those with: active internal bleeding; trauma with an increased risk of life-threatening bleeding; recent haemorrhagic stroke, intracranial or intraspinal surgery, or severe head trauma; presence of an epidural catheter; and intracranial neoplasm or mass lesion or evidence of cerebral herniation. Before administration, drotrecogin alfa (activated) vials must be reconstituted with sterile water for injection; they must then be kept at room temperature of between 20–25°C and used within three hours. When administering drotrecogin alfa (activated) via an intravenous infusion pump, the reconstituted drotrecogin alfa (activated) must be further diluted into infusion bags of normal (0.9%) saline to achieve a final concentration of between 100 and 200mg/ml.

The development of drotrecogin alfa (activated) has been an exciting step forward in the management of severe sepsis, and other immunomodulating agents will certainly also be developed. Sepsis is such a complex process it is unlikely that a single drug will cure all; much more likely is that a combination of drugs will be necessary, and not necessarily the same “cocktail” for each patient. A new staging system, the PIRO (predisposition, infection, response, organ dysfunction) system, has recently been introduced by a group of leaders in this field to help characterise patients according to their disease (much like the TMN [tumour–nodes–metastasis] system for staging cancer patients).(23) Although it is still early days in its development, this system may be useful in determining which management strategies should be employed in which patients.

In addition to the advances with drotrecogin alfa (activated), corticosteroids have also come into the spotlight recently, with Annane et al(24) showing that moderate doses of hydrocortisone (50mg intravenous bolus every six hours), given to patients with septic shock for a period of seven days, reduced mortality in patients with relative adrenal insufficiency. Whether this strategy is also effective in patients with severe sepsis remains to be determined, but it needs to be included in our management protocols for patients with septic shock.

Finally, for completion, nutrition should not be forgotten; indeed, early, adequate nutrition is essential for correct immune function, although the optimal nutritional regimen is yet to be defined. Enteral nutrition has been thought to be preferable to parenteral nutrition, by enhancing gut function and possibly preventing bacterial translocation, but a recent interim analysis of a randomised controlled trial has reported increased mortality rates in patients with severe sepsis receiving enteral nutrition compared with the patients receiving parenteral nutrition.(25) The optimal choice of nutrition is also unclear, although formulas containing immune-enhancing nutrients, antioxidants and branched-chain amino-acids may be superior. Further study is required to fully assess the role of nutrition in the patient with septic shock.

Conclusion
Severe sepsis and septic shock are important causes of morbidity and mortality in ICU patients. Improved understanding of the pathophysiology of sepsis has led to exciting new developments in therapies for sepsis that can improve outcomes, and new agents are continually being discovered and tested. Current areas of research interest include adenosine receptors,(26) caspase inhibitors,(27) antibodies to high-mobility-group protein,(28) platelet- activating factor acetylhydrolase(29) and high-flux haemofiltration.(30) Further study will certainly discover other effective agents and strategies, and the challenge will be how to determine which treatment(s) to give to which patient. These are certainly exciting times for all involved in the management of patients with severe sepsis.

References

  1. Sands KE, Bates DW, Lanken PN, et al. JAMA 1997;278:234-40.
  2. Vincent JL, Bihari D, Suter PM, et al. JAMA 1995;274:639-44.
  3. Alberti C, Brun-Buisson C, Burchardi H, et al. Intensive Care Med 2002;28:108-21.
  4. Martin GS, Mannino DM, Eaton S, Moss M. N Engl J Med 2003;348:1546-54.
  5. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Crit Care Med 2001;29:1303-10.
  6. Bernard GR, Vincent JL, Laterre PF, et al. N Engl J Med 2001;344:699-709.
  7. Rivers E, Nguyen B, Havstad S, et al. N Engl J Med 2001;345:1368-77.
  8. De Backer D, Creteur J, Preiser JC, et al. Am J Respir Crit Care Med 2002;166:98-104.
  9. Cochrane Injuries Group. BMJ 1998;317:235-40.
  10. Wilkes MM, Navickis RJ. Ann Intern Med 2001;135:149-64.
  11. Hebert PC, Wells G, Blajchman MA, et al. N Engl J Med 1999;340:409-17.
  12. Hebert PC, Fergusson D, Blajchman MA, et al. JAMA 2003;289:1941-9.
  13. Vincent JL, De Backer D. Crit Care 2003;7:6-8.
  14. Sharma VK, Dellinger RP. Crit Care 2003;7:3-5.
  15. De Backer D, Creteur J, Silva E, Vincent JL. Crit Care Med In press 2003.
  16. Grinnell BW, Hermann RB, Yan SB. Glycobiology 1994;4:221-5.
  17. Murakami K, Okajima K, Uchiba M, et al. Blood 1996;87:642-7.
  18. White B, Schmidt M, Murphy C, et al. Br J Haematol 2000;110:130-4.
  19. Joyce DE, Gelbert L, Ciaccia A, et al. J Biol Chem 2001;276:11199-203.
  20. Mosnier LO, Griffin JH. Biochem J 2003;373:65-70.
  21. Riewald M, Petrovan RJ, Donner A, et al. Science 2002;296:1880-2.
  22. Vincent JL, Angus DC, Artigas A, et al. Crit Care Med 2003;31:834-40.
  23. Levy MM, Fink MP, Marshall JC, et al. Crit Care Med 2003;31:1250-6.
  24. Annane D, Sebille V, Charpentier C, et al. JAMA 2002;288:862-71.
  25. Bertolini G, Iapichino G, Radrizzani D, et al. Intensive Care Med 2003;29:834-40.
  26. Sitkovsky MV. Biochem Pharmacol 2003;65:493-501.
  27. Joshi VD, Kalvakolanu DV, Hebel JR, et al. Infect Immun 2002;70:6896-903.
  28. Wang H, Bloom O, Zhang M, et al. Science 1999;285:248-51.
  29. Schuster DP, Metzler M, Opal S, et al. Crit Care Med 2003;31:1612-9.
  30. Cole L, Bellomo R, Journois D, et al. Intensive Care Med 2001;27:978-86.

Resources
International Sepsis Forum
W:www.sepsisforum.org
Critical Care Forum
W:http://ccforum.com
National Initiative in Sepsis Education
W:www.nise.cc

Meetings
33rd Critical Care Congress
Orlando, FL, USA
19–25 February 2004 W:www.sccm.org/edu/annualcongress.html
24th International Symposium of Intensive Care and Emergency Medicine
Brussels, Belgium
30 March – 2 April 2004
W:www.intensive.org
Annual Congress of the European Society of Intensive Care Medicine Berlin, Germany
10–13 October 2004
W:www.esicm.org
Chest 2003
Annual Meeting of the American College of Chest Physicians
Seattle, WA, USA
23–28 October 2004
W:www.chestnet.org



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