PRO/CON Should Early Goal-Directed Therapy Be the Standard for Sepsis?

Con: Too Many Assumptions

by Kevin Klauer, DO

 

I am actually a fan of early goal-directed therapy for sepsis. For that matter, I think stroke centers do great work and do positively impact stroke management. However, tPA, given in 1% of all stroke victims, 13% of those eligible, has little to no impact on these improvements. When we focus on management of a disease process you know what happens? The care gets better. The same is true for early goal-directed therapy (EGDT) for sepsis.

When it comes down to EGDT, there are so many treatments included in the sepsis bundle, you can’t tell what’s really working. I really doubt that every component of EGDT is a value-added step. Hey, let’s add coconut cream pie or chocolate covered cherries to the bundle. The point is, by adding coconut cream pie or anything else to EGDT, the data would look just as good. The only difference is that the patients would get a tasty treat along with all of the other components of the bundle.

Coconut cream pie cannot positively our negatively influence outcomes in sepsis. My question is, “How many pieces of coconut cream pie are already being served in this expensive sepsis cocktail?”

My initial concern is that the inclusion criteria are way too broad. In order to classify someone as septic, they must have systemic inflammatory response syndrome (SIRS) and a source of infection. To diagnose SIRS, you need 2 or more of the following:

-A temperature over 38.3C or less than 36.0C
-A heart rate over 90
-A respiratory rate over 20
-A WBC count less than 4,000 or over 12,000
-Acutely alerted mental status
-Hyperglycemia in non-diabetic patients

How many SIRS patients really don’t deserve a central line and an ICU admission? Do we really intend for those with a fever, strep tonsillitis and dehydration, who have a heart rate over 90 and a temperature of 38.5 to get the kitchen sink thrown at them? This makes no sense.

Just like many seemingly good ideas in medicine, once the train leaves the station, it takes years to slow it down, validating efficacy. This is a classic example. One study and 263 patients later (Rivers, NEJM 2001) and we have doubts surfacing nearly ten years later.

Perhaps the most compelling article raising questions about the sepsis bundle is from a consensus panel of 55 international experts revisited the components of the sepsis bundle and reviewed the recommendations, assigning a grade of strong or weak and an associated level of evidence; A = High quality, B = Moderate quality, C = Low quality and D = Very low quality. Fifteen strong recommendations were assigned only a C or D. Several items, including recombinant activated protein C (Xigris) administration, at a cost of $14,000 for a 100kg patient, and stress dose steroid therapy were classified as weak, assigned B and C, respectively. Three items with a strong recommendation and a moderate quality of evidence were the administration of crystalloid fluid resuscitation, administration of broad-spectrum antimicrobials within one hour of diagnosis of septic shock and maintaining a target hemoglobin of 7 to 9g/dL in the context of sepsis. Despite the momentum behind EGDT within 6 hours, the level of evidence supporting this recommendation was “Low quality,” a level C.

So, what does the evidence actually say regarding tight glycemic control and steroids? Physiologic stress results in hyperglycemia and suppressed adrenal function with poor responses to corticotropin or ACTH stimulation testing. Are these markers for bad disease or opportunities for intervention? The data suggests they are only markers.

With respect to intensive insulin therapy, otherwise known as “tight glycemic control,” the preponderance of evidence shows two things: No difference in mortality, and a substantially higher rate of hypoglycemic events. Treggiari reported no difference in mortality for 10,456 ICU patients treated with tight control versus no protocol at all. They also noted 3 to 4 times more likelihood for moderate to severe hypoglycemia.
Consensus is that high dose steroids are harmful. Although there is some controversy regarding low-dose, physiologic corticosteroids, strong data reflects that they do not influence mortality rates in sepsis.

Finally, there is much focus on which vasopressor is best. Following aggressive volume resuscitation, vasopressors seem like a reasonable consideration. However, there is no definitive data proving this assumption. A recent Cochrane database review reported no conclusive evidence to support one vasopressor over another or that vasopressors impact mortality at all.

Early recognition of sepsis, aggressive volume resuscitation to maintain perfusion and early broad-spectrum antibiotics are clearly interventions that positively influence mortality. The remaining components may only be stealing the credit for their success without contributing any additional positive benefit themselves.

Kevin Klauer, DO, is the Editor-in-Chief of Emergency Physicians Monthly and the Chief Medical Officer at Emergency Medicine Physicians. 

 

 

 

Pro References

 

1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368-1377.Angus, D. C., W. T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcilli, M. R. Pinsky. 2001. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical Care Medicine 29:1303-1310.
2. Otero R, Nguyen B, Huang, D, et al. Early Goal Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings. CHEST 2006; 130; 1579-1595.
3. Rivers E, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anesthesiol 21: 128-140.
Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005;9:R764-70.
4. Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006;34:943-9.
Sebat F, Johnson D, Musthafa AA, et al. A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest 2005;127:1729-43.
5. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34:1025-32.
Trzeciak S, Dellinger RP, Abate NL, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006;129:225-32.
6. Lin SM, Huang CD, Lin HC, Liu CY, Wang CH, Kuo HP. A modified goal-directed protocol improves clinical outcomes in intensive care unit patients with septic shock: a randomized controlled trial. Shock 2006;26:551-7.
7. Micek ST, Roubinian N, Heuring T, et al. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med 2006;34:2707-13.
Nguyen HB, Corbett SW, Steele R, et al. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med 2007;35:1105-12.
8. Sebat F, Musthafa AA, Johnson D, et al. Effect of a rapid response system for patients in shock on time to treatment and mortality during 5 years*. Crit Care Med 2007.
Chen ZQ, Jin YH, Chen H, Fu WJ, Yang H, Wang RT. [Early goal-directed therapy lowers the incidence, severity and mortality of multiple organ dysfunction syndrome]. Nan Fang Yi Ke Da Xue Xue Bao 2007;27:1892-5.
9. He ZY, Gao Y, Wang XR, Hang YN. [Clinical evaluation of execution of early goal directed therapy in septic shock]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2007;19:14-6.
10. Qu HP, Qin S, Min D, Tang YQ. [The effects of earlier resuscitation on following therapeutic response in sepsis with hypoperfusion.]. Zhonghua Wai Ke Za Zhi 2006;44:1193-6.
11. Castro R, Regueira T, Aguirre ML, et al. An evidence-based resuscitation algorithm applied from the emergency room to the ICU improves survival of severe septic shock. Minerva Anestesiol 2008.
12. Akinnusi ME, Alsawalha L, Pineda LA, El Solh AA. Outcome of septic shock in the elderly following the implementation of the sepsis bundle: a propensity-adjusted analysis. Chest 2007;132:494-.
13. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 2007;132:425-32.
14. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. Jama 2008;299:2294-303.
Zubrow MT, Sweeney TA, Fulda GJ, et al. Improving care of the sepsis patient. Jt Comm J Qual Patient Saf 2008;34:187-91.
15. Zambon M, Ceola M, Almeida-de-Castro R, Gullo A, Vincent JL. Implementation of the Surviving Sepsis Campaign guidelines for severe sepsis and septic shock: we could go faster. J Crit Care 2008;23:455-60.
16. Hiel SW, Asghar MF, Micek ST, Reichley RM, Doherty JA, Kollef MH. Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis. Crit Care Med 2009;37:819-24.
17. Focht A, Jones AE, Lowe TJ. Early goal-directed therapy: improving mortality and morbidity of sepsis in the emergency department. Jt Comm J Qual Patient Saf 2009;35:186-91.
18. Moore LJ, Jones SL, Kreiner LA, et al. Validation of a screening tool for the early identification of sepsis. J Trauma 2009;66:1539-46; discussion 46-7.
19. Puskarich M, Kline J, Jones A. Long-Term Survival Benefit from an Emergency Department Based Early Sepsis Resuscitation Protocol: A Prospective Study: 349. Academic Emergency Medicine 2009;16(4) Sup:S142&hyhen;S3.
20. Puskarich MA, Marchick MR, Kline JA, Steuerwald MT, Jones AE. One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. Crit Care 2009;13:R167.
21. Wang JL, Chin CS, Chang MC, et al. Key process indicators of mortality in the implementation of protocol-driven therapy for severe sepsis. J Formos Med Assoc 2009;108:778-87.
22. Michaud I, Pietropaoli AP, Trawick DR, et al. Early Fluid Resuscitation and Outcome in Severe Sepsis and Septic Shock. Am J Resp Crit Care Med 2003.
Verceles A, Schwarcz RM, Birnbaum P, Mannam P, Patrick H. S.E.P.S.I.S: Sepsis Education Plus Successful Implementation and Sustainability in the absence of a rapid response team. Chest 2005;128:181S(2).
23. Armstrong R, Salfen SJ ea. Results of Implementing a Rapid Response Team Approach in Treatment of Shock in a Community Hospital. Infectious Disease Society of America 2005;43rd Annual Meeting Abstract Book:154.
24. Rogove H, K P. Collaboration for Instituting the Surviving Sepsis Campaign In a Community Hospital. Crit Care Med 2005;33:110S.
25. Stenstrom RJ, Hollohan K, Nebre R, et al. Impact of a sepsis protocol for the management of patients with severe sepsis and septic shock in the emergency department. JCMU 2006;8:S16.
26. Gaieski D, McCoy J, Zeserson E, Chase M, Goyal M. Mortality Benefit After Implementation of Early Goal Directed Therapy Protocol for the Treatment of Severe Sepsis and Septic Shock. Ann Emerg Med 2005;46:4-.
27. Fried JC, Gagneja P, Haq MS. Institution of a sepsis protocol in a community hospital and its effect on mortality in septic shock. Chest 2006;130:222S.
28. Mullon J, Subramanian S, Haro L, et al. Sepsis order set improves adherence to evidence-based practices. Chest 2006;130(4):134S-5S.
29. Kiibler A, Duszynska I, Rarleczko B, Grotowska V. Implementation of severe sepsis bundles by the intensive Care Units in Poland – preliminary results. Infection 2007;35:10.
30. Nobre V, Schauenburg P, Pugin J. Adherence to resuscitation and management sepsis bundles: impact on outcome. Am J Resp Crit Care Med 2006;175:A562.
31. Ikeda D, Hayatdavoudi S, Winchell J, Rincon T, Yee A. The impact of using a standard protocol for the surviving sepsis 6 and 24 hour bundles in septic patients on total ICU risk adjusted mortality. Crit Care Med 2006;34:A108.
32. Castellanos-Ortega A, Suberviola B, González-Castro A, et al. Impact of sepsis care bundles on hospital mortality in 135 consecutive patients with septic shock. Critical Care 2007;11:P70.
33. Hayatdavoudi S, Ikeda D, Seiver A, et al. Impact of a protocol treating severe sepsis on renal function and survival of septic shock patients in an open adult ICU. Crit Care Med 2006;34:A18.
34. Kinsella MT, Biltoft JM, Marez H, Glaser D, Kwong N, Restrepo CI. Improving mortality from severe sepsis by implementation of surviving sepsis guidelines at a community teaching hospital. Crit Care Med 2006;34:A109.
35. Gaieski DF, Zeserson E, Goyal M. Early goal-directed therapy may be effective in cohorts excluded from the Rivers trial. Crit Care Med 2005;33:A160.
36. Antro C, Merico F, Scalabrino E, Noto P, Fascio Pecetto P, Gai V. Implementation of the Survival Sepsis Campaign Guidelines for Severe Sepsis and Septic Shock in the Emergency Department. Ann Emerg Med 2006;48:67.
37. Douglas I, Marchlowska P, Rains R, et al. A statewide implementation of surviving sepsis campaign bundles by the colorado critical care collaborative. Crit Care Med 2006;34:A99
38. Varpula M. Implementation of early goal-directed therapy in Finland. Critical Care 2007;11:P69.
39. Kubler A, Duszynska W, Barteczko B, Grotowska M. Implementation of severe sepsis bundles by the intensive care units in poland – preliminary results. Infection 2007;35:10.
40. Tanios MA, Zabow M, Epstein SK. The impact of implementing severe sepsis management guidelines on mortality ina community based-teaching hospital. Chest 2007;132:494a-.
41. Meredith AH, Simpson SQ. Improvement in Sepsis Diagnosis and Mortality after Implementation of the Surviving Sepsis Campaign. Am Rev Respir Dis and Crit Care 2007.
42. Becker ML. LIFE Campaign: Implementation of Sepsis Bundle Results in Significant Cost Savings. Ann Emerg Med 2007;50:S82.
43. McGrath ME, Lada P, Rebholz CM, et al. Does Introduction of a Sepsis Protocol Reduce Time to Antibiotics or Improve Outcomes for Critical Septic Patients? A Before and After Study. Ann Emerg Med 2007;50:S19-S20.
44. Victorino J, de la vega F, Mallmann L, Draghetti V, Oliveira R, Torres G. A Real Life Experience: 10-Month Implementing Early Goal-Directed Therapy for Severe Sepsis and Septic Shock in the ICU. Am Rev Respir Dis and Crit Care 2007.
45. Venkatram S, Belova E, Basir R, Loganathan R, Soni A. Implementation of Early Goal Directed Therapy (EGDT) in an Inner City Hospital. Am Rev Respir Dis and Crit Care 2007.
46. Yan J, Cai G. A multicentre study on early goal-directed therapy of severe sepsis and septic shock patients in the ICU: collaborative study group on early goal-directed therapy in Zhejiang Province, China. Critical Care 2008;12:P417.
47. Cannon C, Holthaus C, Rivers E, et al. Improving outcome in severe sepsis and septic shock:  results of a prospective multicenter collaborative. The Journal of Emergency Medicine 2009;37:217–36.
48. Na S, Joshi M, Li C-h, et al. Implementation of a 6-hour severe sepsis bundle in multiple asian countries is associated with decrease mortality. Chest 2009;136:20S-e-.
Patel GP. A MULTIDISCIPLINARY APPROACH TO IMPROVE OUTCOMES IN PATIENTS WITH SEPTIC SHOCK. Chest 2009;136:10S-c-.
49. Girardis M, Rinaldi L, Donno L, et al. Effects on management and outcome of severe sepsis and septic shock patients admitted to the intensive care unit after implementation of a sepsis program: a pilot study. Crit Care 2009;13:R143.
50. Mccaig L, Burt C: National Hospital Ambulatory Medical Care Survey: 2001 Emergency Department Summary. Advance Data From Vital and Health Statistics, Center for Disease Control and Prevention, National Center for Health Statistics, 2003. Report No. 335
51. Rogove H, Pyle K. Collaboration for instituting the surviving sepsis campaign in a community hospital. Crit Care Med 2005; 33 (12 Suppl A 28):110S.
Huang DT, Angus DC, Dremsizov TT, et al. Cost-effectiveness of early goal-directed therapy in the treatment of severe sepsis and septic shock [abstract]. Crit Care 2003; 7(suppl): S116
52. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006; 34:1025–1032
Trzeciak S, Dellinger RP, Abate NL, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006; 129:225–232
53. Huang D, Clermont G, Dremsizov T, et al. Implementation of early goal-directed therapy for severe sepsis and septic shock: A decision analysis. Crit Care Med 2007; 35: 2090-2100.
54. Shorr A, Micek S, Jackson W, et al. Economic implications of an evidence-based sepsis protocol: Can we improve outcomes and lower costs? Crit Care Med 2007; 35: 1257-1262.
55. Becker ML. LIFE Campaign: Implementation of Sepsis Bundle Results in Significant Cost Savings. Ann Emerg Med. 2007; Vol 50, 3; S82.
56. Wilson RF, Wilson RA, Gibson D, Sibbald WJ. Shock in the emergency department. JACEP 1976; 5(9):  678-690.
57. Pederson T, Moller A, Hovhannisyan K. Pulse oximetry for perioperative monitoring. Cochrane Database Syst Rev. 2009 Oct 7; (4).
58. Greenberg S, Murphy G, Vender J. Current use of the pulmonary artery catheter. Curr Opin Crit Care. 2009 Jun; 15 (3): 249-253.

Con Citations

1.  Maryn McKenna, Controversy Swirls Around Early Goal-Directed Therapy in Sepsis: Pioneer Defends Ground-Breaking Approach to Deadly Disease. Annals of Emergency Medicine – December 2008 (Vol. 52, Issue 6, Pages 651-654
2.   HYPERLINK “http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dellinger%20RP%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract” Dellinger RP, Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008.  HYPERLINK “javascript:AL_get(this, ‘jour’, ‘Intensive Care Med.’);” Intensive Care Med. 2008 Jan;34(1):17-60.
3.  Treggiari, M.M., et al., Intensive insulin therapy and mortality in critically ill patients:  Crit Care 12(1):R29, February 29, 2008.
4.  Sprung, C.L., et al., Hydrocortisone therapy for patients with septic shock. N Engl J Med 358(2):111, January 10, 2008.
5.  Jones, A.E., What vasopressors should be used to treat shock? Ann Emerg Med 49(3):367, March 2007.