Septischer Schock – Licht am Ende des therapeutischen Tunnels?

Ernst Hanisch

Klinik für Allgemein-, Viszeral- und Endokrine Chirurgie

Asklepios Klinik Langen

HERFARTH, Editorial Chirurg 1995

„Die Frustration des Chirurgen, die entsteht, wenn er mitansehen muß, wie eine kleine Anastomoseninsuffizienz einen mühsam

angestrebten Erfolg zunichte machen kann, verlangt nach intensiver chirurgischer

Forschung“

Epidemiologie des Septischen Schocks: MEDAN - Datenbank 2003

Patienten N= 382

Alter [Jahre] 66,0

Liegedauer [Tage] 18,6

Respirator [Tage] 13

Letalität [%] 49

Wenzel R. N Engl J Med 2002;347:966-967

Russell J. N Engl J Med 2006;355:1699-1713

Inflammatory Responses to Sepsis

Hotchkiss R and Karl I. N Engl J Med 2003;348:138-150

The Response to Pathogens, Involving "Cross-Talk" among Many Immune Cells, Including Macrophages, Dendritic Cells, and CD4 T Cells

Feature: Septic Shock -finding the way through the maze

„Most clinicians can recognize septic shock, but if you ask them, you get a hundred definitions“

Lancet 354, Nr. 9195, December 11th 1999

Definition: SEPSIS

„Eine Sepsis liegt dann vor, wenn sich innerhalb des Körpers ein Herd gebildet hat,

von dem kontinuierlich oder periodisch pathogene Bakterien in den Blutkreislauf gelangen und zwar derart, daß durch diese

Invasion subjektive und objektive Krankheitserscheinungen ausgelöst werden“

Schottmüller 1914

Definitonen Consensus Conference ACCP/SCCM 1992

• SIRS

• SEPSIS

• SCHWERE SEPSIS

• SEPTISCHER SCHOCK

Definition SIRS

Temperatur >38° C oder <36° C

Herzfrequenz >90/min

Tachypnoe >20 Atemzüge/minoder pCO2<32

Leukozyten >12000 oder <4000

Hotchkiss R and Karl I. N Engl J Med 2003;348:138-150

Infectious and Noninfectious Causes of Fever in the Intensive Care Unit

Definition SEPSIS

Systemic Inflammatory Response to Infection

SIRS und Infektion

Definition SCHWERE SEPSISOrgandysfunktionen

• Metabolische Azidose

• Akute Enzephalopathie

• Oligurie (<0,5ml/kg für wenigstens 1h)

• Hypoxämie (paO2/FiO2<280)

• DIC

• Hypotension (<90mmHg oder Abfall um 40 mmHg vom Ausgangswert)

Definition SEPTISCHER SCHOCK

• Sepsis

• Systolischer Blutdruck <90mmHg oder Abfall >40mmHg vom Ausgangswert

• Positiv inotrope oder vasoaktive Medikation zur Korrektur der Hypotension

Therapie des Septischen Schocks

• Definitive Behandlung

• Unterstützende Behandlung

• Round table; Sibbald et al CritCareMed 1995

Erste PrioritätHERDSANIERUNG!

Ubi pus ibi evacua (Celsus)

Peritonitis-BehandlungKirschner‘sche Postulate 50.Tagung der

Deutschen Gesellschaft für Chirurgie 1926

• Verstopfung der Infektionsquelle

• Beseitigung des Exsudates

• Behandlung der Bauchhöhle mit Desinfektionsmitteln

• Ableitung des Exsudates

• Nachbehandlung

Diffuse PeritonitisEckpfeiler der Therapie

• Chirurgische Intervention ohne Verzögerung• Herdsanierung, ausgedehnte intraop Spülung• Kontinuierliche postop Lavage, Offenes

Abdomen, geplante Relap (Etappenlavage), Relap on demand

• CAVE: Adominelles Kompartment

British Journal of Surgery 2002, 89, 1516-1524

Comparison of On-Demandvs Planned Relaparotomy Strategyin Patients With Severe PeritonitisA Randomized TrialOddeke van Ruler, MD et al

JAMA, August 22/29, 2007—Vol 298, No. 8 865

Letalität und Morbidität

On-Demand Planned P

Letalität 32/112 (29) 41/113 (36) .22

Morbidität 32/80 (40) 32/72 (44) .58

Unterstützende Behandlung

• Antiinfektiöse Maßnahmen

• Volumentherapie

• Katecholamintherapie

Volumentherapie

• Sofortige und adäquate Volumensubstitution entscheidender Schritt

• Zielkriterium: Kardiale Füllungsdrucke

• Keine Evidenz, daß kolloidale den kristalloiden Lösungen überlegen sind

• Albumin nicht von Vorteil

Katecholamintherapie

• Norepinephrin Katecholamin der 1.Wahl

• Adrenalin: sehr zurückhaltender Einsatz

• Dobutamin: wenn CI erniedrigt

• Taskforce ACCM/SCCM 1999

New directions

• Niedriges Tidalvolumen (ALI/ARDS)

• Early goal-directed therapy

• Aktiviertes Protein C (Xigris)

• IgM angereichertes polyvalentes Immunglogulin (Pentaglobin)

• Niedrig-dosierte Corticosteroide

• Enge Kontrolle des Blutzuckers

New directions: Niedriges Tidalvolumen (ALI/ARDS)

The ARDSNetwork, NEnglJMed 2000,342:1301-1308

6ml/kg 12 ml/kg

Letalität 30 % 40 %

New directions: Early goal directed therapy

Rivers E et al; NEnglJMed 2001,345:1368-1377

ZVD >8-12mmHg Kristalloide/Kolloide

MAP >65mmHg Vasoaktive Substanzen

Urinproduktion >0,5ml/kg/h

ScvO2 >70% SaO2>93%;Hkt>30%CI

New directions: EGDT-Letalität

Standard(n=133)

EGDT(n=130)

Alle Pat. 46,5 % 30,5 %

Schwere Sepsis 30 % 14,9%

Sept. Schock 56,8% 42,3 %

28 Tage 49,2 % 33,3 %

60 Tage 56,9% 44,3 %

New directions: Aktiviertes Protein C (Xigris) - PROWESS; Bernard et al, NEnglJMed

2001,344,699-709

Placebo (n=840) Xigris(n=850)

No surgery 72,6% 73,5%

Site of infectionLUNG 53,6% 53,6%

ABDOMEN 19,9% 20%

URINARYTRACT

10,2% 10%

OTHER 16,3% 16,4%

New directions: Aktiviertes Protein C (Xigris) Letalität

Placebo 31,3%

Xigris 24,8%

ARR 6,5(95%CI 2,2-10,7)

Surviving Sepsis — Practice Guidelines, Marketing Campaigns,and Eli LillyPeter Q. Eichacker, M.D., Charles Natanson, M.D., and Robert L. Danner, M.D.

n engl j med 355;16 october 19, 2006

Eichacker P et al. N Engl J Med 2006;355:1640-1642

Timeline of Controlled Trials of rhAPC, Regulatory Actions, Yearly Sales, and the Marketing Initiative by Eli Lilly

Conclusion

In our systematic review, we have shown that antithrombin III seems ineffective in any population of critically ill patients regarding mortality and it even increases the risk of bleeding events.

Its use in critically ill patients cannot be recommended based on the available evidence nor in patients without adjuvant heparin, but it may be relevant to explore this further in future trials.

Management of Sepsis

• …I agree that surgical patients who have single-organ dysfunction are at increased risk for death when they are treated with activated proteinC and therefore should not receive this treatment.

• James A Russel, NEnglJMed 356;11, March 15, 2007

•

Intensive Insulin Therapy and PentastarchResuscitation in Severe SepsisFrank M. Brunkhorst, et al

N Engl J Med 2008;358:125-39

New directions: Enge Kontrolle des Blutzuckers (<110mg%)

LETALITÄTvan den Berghe et al, NEnglJMed 2001,345,1359-

1367 KonventionelleTherapieN=783

Insulin Therapie

N=765

Alle Patienten 10,9% 7,2%

>5 Tage ICU 26,3% 16,8%

New directions: Niedrig dosierte Corticosteroide

Annane et al, JAMA 2002, 288:862-871

Placebo Corticosteroide

Letalität(28 Tage)

61 % 55 %

Hotchkiss R and Karl I. N Engl J Med 2003;348:138-150

Immunologic Response of Three Hypothetical Patients with Sepsis

Factor 1.03

Factor 1.07

Factor 1.37

Factor 1.56

Factor 2.1Relative Risk 0.48

Relative Risk 0.64

Relative Risk 0.73

Relative Risk 0.93

Relative Risk 0.97

Increase of Survival following Therapy

Pentaglobin® n = 194

IVIG or Pentaglobin® n = 492

IVIG n = 298

Anti-Zytokin MABs n = 4318

Anti-Endotoxin MAB n = 2826

Cochrane ReviewThe Cochrane Library, update 2003(the Cochrane Library, Issue 1, 2003. Oxford: Update Software)

Intravenous immunoglobulin for treating sepsis and septic shock

Sepsis: Time to reconsider the conceptJean Carlet, MD; Jonathan Cohen, MD; Thierry Calandra, MD, PhD; Steven M. Opal, MD; Henry Masur, MD

Crit Care Med 2008 Vol. 36, No. 3, 964

The organ in which infection takes place is also of paramount importance.

For example, it is known that defense mechanisms in the lung and in the peritoneum are quite dissimilar, leading to differential effects of compounds aimed at manipulating the same inflammatory network

Another issue is perhaps more difficult to address. If taken to its logical conclusion, clinical trials would need to be carried out in a much more precisely and narrowly defined population.

This represents a real challenge to the pharmaceutical industry because of the potential (or perceived) limitation to the market. Interestingly,this does not seem to be the case in oncology, and several companieshave now started to take tentative steps in this direction in the field of severe infection.

Patient entry into studies of sepsis using a broad definition is indeed more readily accrued, but the advantage of rapid accrual is outweighed by the disadvantage of treating a very heterogeneousgroup of patients.

Special ArticleSurviving Sepsis Campaign: International guidelines formanagement of severe sepsis and septic shock: 2008

R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Jean M. Carlet, MD; Julian Bion, MD; Margaret M. Parker, MD; Roman Jaeschke, MD;Konrad Reinhart, MD; Derek C. Angus, MD, MPH; Christian Brun-Buisson, MD; Richard Beale, MD; Thierry Calandra, MD, PhD;Jean-Francois Dhainaut, MD; Herwig Gerlach, MD; Maurene Harvey, RN; John J. Marini, MD; John Marshall, MD; Marco Ranieri, MD;Graham Ramsay, MD; Jonathan Sevransky, MD; B. Taylor Thompson, MD; Sean Townsend, MD; Jeffrey S. Vender, MD;Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; for the International Surviving Sepsis Campaign Guidelines Committee

Crit Care Med 2008 Vol. 36, No.1, 296