Septický šok 2001

1. Calcium sensitizers (Levosimendan): kardiotonický a vasodilatační efekt

Shrnutí účinku

• podpora inotropie

• zvyšení kontraktility bez zvýšení spotřeby kyslíku myocyty

• pozitivní efekt na „omráčený“ myokard

• zesílení efektu katecholaminů (dopamin)

• vasodilatace

• antiischemický efekt (K kanál)

• antiagregační efekt (vysoké dávky)

• antiarytmický efekt (redukce influxu kalcia)

2. Vasopresin

• Výraznější přesun krve k vitálním orgánům v neprospěch nevitálních v porovnání s adrenalinem

• Inhibice vasodilatace v septickém šoku

• Mechanismus přes V receptory (V1, V2)

• Zrat hypotenze (refrakterní na katecholaminy) u nemocných v septickém šoku a po CPB

3. Toll-like receptory (tlr)

TLR jsou považovány za nezbytné v procesu aktivace makrofágů endotoxinem (receptory CD 14). Tvorba cytokinů v makrofázích je pravděpodobně umožněna jen díky expresi TLR. Exprese TLR a jejich následná vazba na některé součásti bakteriální stěny jsou zřejmě nezbytným předpokladem spuštění reakcí, vedoucích k neutralizaci bakterií a aktivaci mechanismů specifické získané imunity. V současné době je definováno 6 subtypů TLR (TLR 1-6).

4. Protilátky proti tnf monarcs studie (esicm Annual Congress 2000)

• Posouzení účinku a bezpečnosti podávání afelimomabu (monoklonální protilátka proti TNF) u nemocných s těžkou sepsí a septickým šokem

• 157 pracovišť USA, 2634 nemocných

• Stratifikace pacientů podle výsledků hodnoty IL-6 (SEPTEST)

• Septest (+) = IL-6 1000 pg/ml, Septest (-) = IL-6 1000 pg/ml

• Afelimomab skupina v. placebo skupina

Závěr:

Afelimomab vedl u nemocných skupiny Septest (+) k signifikantnímu poklesu absolutní (o 4%) a relativní (o 14,3%) mortality

Rychlejší zvrat orgánové dysfunkce ve skupině s afelimomabem

5. Protein c !!!

Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.

• 1690 pacientů

• Placebo vs. rhAPC (drotrecogin)

• 28 denní mortalita

• předčasné ukončení pro příznivé výsledky

• zvýšené přežití o 38% v léčené skupině

• výraznější efekt u nemocných nad 65 let, se šokem a MOD

• vyšší incidence krvácení u rhAPC

Sepse 2003

• Early goal directed therapy for septic shock

• APC

• Kontrola glykemie

• Kortikoidy (u non responders na ACTH)

• Denně prováděná hemodialýza

Sepse 2006

• IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006 May;34(5):1319-25. CONCLUSIONS: Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.

• VASST studie – vasopresin u septického šoku (ESICM Meeting 2006)

• Diskuse nad SSC a APC – NEJM October 19.,

• Mikrocirkulace a její význam

• Časnost podání ATB

Sepse 2007

• Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004388. Human recombinant activated protein C for severe sepsis.

CONCLUSIONS: This review suggests that APC should not be used in sepsis with an

APACHE II score of less than 25 or, in paediatric patients. There is very weak

evidence supporting APC use in patients with severe sepsis and at high-risk of

death. As a result, policy-makers, clinicians and academics should be cautious

when promoting the use of APC to patients with severe sepsis and an APACHE II

score of 25 or greater. There is a need for further RCTs to answer with certainty

what the role of APC is for patients with severe sepsis and an APACHE II score of

at least 25. Those RCTs should be designed and conducted by non-profit

organizations.

Sepse 2008

Nová guidelines:

• EGDT během prvních 6 hodin

• Hemokultury před podáním ATB

• Podání ATB během 1 hodiny od diagnozy TS nebo SS, zúžení po K+C

• Doba podávání ATB 7-10 dní

• Noradrenalin nebo dopamin s cíl MAP nad 65 torr

• Dobutamin inotropikum první volby

• Steroidy jen při hypotenzi nereagující (poorly responsive) na tekutiny a vasopresory

• Aktivovaný protein C u TS nebo SS u pacientů s vysokým rizikem smrti

• Hb 7-9 g/L

• UPV – limitace plateau pressure, PEEP vždy

• Elevace hlavy

• Konservativní tekutinový režim u nemocných, kteří nejsou v šoku

• Sedace – daily interruptions

• Kontrola glykemie

• CRRT ekvivalentní IHD

• Prevence ulcerací GIT a DVT

• Zvažování omezení terapie “where appropriate”

Early intravenous unfractionated heparin and mortality in septic shock.

Crit Care Med. 2008 Nov;36(11):2973-9.

Zarychanski R, Doucette S, Fergusson D, Roberts D, Houston DS, Sharma S, Gulati

H, Kumar A.

BACKGROUND: Sepsis and septic shock represent a systemic inflammatory state with

substantial pro-coagulant elements. Unfractionated heparin is a known

anticoagulant, which also possesses anti-inflammatory properties. Unfractionated

heparin has been shown to increase survival in experimental models of septic

shock. OBJECTIVE: To evaluate the impact of intravenous therapeutic dose

unfractionated heparin in a cohort of patients diagnosed with septic shock.

DESIGN: Retrospective, propensity matched, multicenter, cohort study. SETTING:

Regional intensive care units in Winnipeg, Canada between 1989 and 2005.

PATIENTS: Two thousand three hundred fifty-six patients diagnosed with septic

shock, of which 722 received intravenous therapeutic dose heparin. MEASUREMENTS

AND MAIN RESULTS: The primary outcome of study was 28-day mortality, and

mortality stratified by severity of illness (Acute Physiologic and Chronic Health

Evaluation II quartile). Safety was assessed by comparing rates of

gastrointestinal hemorrhage, intracranial hemorrhage, and the need for

transfusion. By using a Cox proportional hazards model, systemic heparin therapy

was associated with decreased 28-day mortality (307 of 695 [44.2%] vs. 279 of 695

[40.1%]; hazard ratio 0.85 [confidence interval (CI) 95% 0.73-1.00]; p = 0.05).

In the highest quartile of severity of illness (Acute Physiologic and Chronic

Health Evaluation II score 29-53), heparin administration was associated with a

clinically and statistically significant reduction in 28-day mortality [127 of

184 (69.0%) vs. 94 of 168 (56.0%); hazard ratio 0.70 (CI 95% 0.54-0.92); p =

0.01]. The use of intravenous unfractionated heparin was associated with

successful liberation from mechanical ventilation [odds ratio of 1.42 (CI 95%

1.13-1.80); p = 0.003], and successful discontinuation of vasopressor/inotropic

support [odds ratio of 1.34 (CI 95% 1.06-1.71); p = 0.01]. No significant

differences in the rates of major hemorrhage or need for transfusion were

identified. CONCLUSION: Early administration of intravenous therapeutic dose

unfractionated heparin may be associated with decreased mortality when

administered to patients diagnosed with septic shock, especially in patients with

higher severity of illness. Prospective randomized trials are needed to further

define the role of this agent in sepsis and septic shock.

Probiotics in critically ill patients.

Madsen K.

J Clin Gastroenterol. 2008 Sep;42 Suppl 3 Pt 1:S116-8.

Severe sepsis with associated multisystem organ dysfunction is a leading cause of

death in patients hospitalized in intensive care units. The gastrointestinal

system plays a key role in the pathogenesis of multisystem organ dysfunction

owing to a breakdown of intestinal barrier function and increased translocation

of bacteria and bacterial components into the systemic circulation. During

critical illness, alterations occur in gut microflora owing to several factors,

including changes in circulating stress hormones, gut ischemia,

immunosuppression, the use of antibiotics, and lack of nutrients. The importance

of endogenous strains of probiotic bacteria such as Bifidobacterium and

Lactobacillus in maintaining intestinal barrier function and also in modulating

mucosal and systemic immune responses is becoming evident from numerous studies.

Bacteria in synbiotic (prebiotic and probiotic combinations) and probiotic

(mutistrain combinations) preparations are being used experimentally in the

treatment of acute pancreatitis, liver transplantation, and in trauma patients.

Recent studies have shown treatment of patients with multiple trauma or acute

pancreatitis with synbiotic preparations resulted in reduced rates of infection,

sepsis, and mortality in patients. Enterally fed patients in the intensive care

unit treated with a probiotic compound demonstrated enhanced immune function and

decreased incidence of diarrhea. Results from these clinical trials are

encouraging, and warrant further investigation to clarify which probiotic

bacterial strains are of most benefit to this population.

Benefits and risks of tight glucose control in critically ill adults: a

meta-analysis.

JAMA. 2008 Aug 27;300(8):933-44.

Wiener RS, Wiener DC, Larson RJ.

CONTEXT: The American Diabetes Association and Surviving Sepsis Campaign

recommend tight glucose control in critically ill patients based largely on 1

trial that shows decreased mortality in a surgical intensive care unit. Because

similar studies report conflicting results and tight glucose control can cause

dangerous hypoglycemia, the data underlying this recommendation should be

critically evaluated. OBJECTIVE: To evaluate benefits and risks of tight glucose

control vs usual care in critically ill adult patients. DATA SOURCES: MEDLINE

(1950-2008), the Cochrane Library, clinical trial registries, reference lists,

and abstracts from conferences from both the American Thoracic Society

(2001-2008) and the Society of Critical Care Medicine (2004-2008). STUDY

SELECTION: We searched for studies in any language in which adult intensive care

patients were randomly assigned to tight vs usual glucose control. Of 1358

identified studies, 34 randomized trials (23 full publications, 9 abstracts, 2

unpublished studies) met inclusion criteria. DATA EXTRACTION AND ANALYSIS: Two

reviewers independently extracted information using a prespecified protocol and

evaluated methodological quality with a standardized scale. Study investigators

were contacted for missing details. We used both random- and fixed-effects models

to estimate relative risks (RRs). RESULTS: Twenty-nine randomized controlled

trials totaling 8432 patients contributed data for this meta-analysis. Hospital

mortality did not differ between tight glucose control and usual care overall

(21.6% vs 23.3%; RR, 0.93; 95% confidence interval [CI], 0.85-1.03). There was

also no significant difference in mortality when stratified by glucose goal ([1]

very tight: < or = 110 mg/dL; 23% vs 25.2%; RR, 0.90; 95% CI, 0.77-1.04; or [2]

moderately tight: < 150 mg/dL; 17.3% vs 18.0%; RR, 0.99; 95% CI, 0.83-1.18) or

intensive care unit setting ([1] surgical: 8.8% vs 10.8%; RR, 0.88; 95% CI,

0.63-1.22; [2] medical: 26.9% vs 29.7%; RR, 0.92; 95% CI, 0.82-1.04; or [3]

medical-surgical: 26.1% vs 27.0%; RR, 0.95; 95% CI, 0.80-1.13). Tight glucose

control was not associated with significantly decreased risk for new need for

dialysis (11.2% vs 12.1%; RR, 0.96; 95% CI, 0.76-1.20), but was associated with

significantly decreased risk of septicemia (10.9% vs 13.4%; RR, 0.76; 95% CI,

0.59-0.97), and significantly increased risk of hypoglycemia (glucose < or= 40

mg/dL; 13.7% vs 2.5%; RR, 5.13; 95% CI, 4.09-6.43). CONCLUSION: In critically ill

adult patients, tight glucose control is not associated with significantly

reduced hospital mortality but is associated with an increased risk of

hypoglycemia.

Antithrombin III for critically ill patients.

Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005370.

BACKGROUND: Critical illness is associated with uncontrolled inflammation and

vascular damage which can result in multiple organ failure and death.

Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties

but the efficacy and any harmful effects of AT III supplementation in critically

ill patients are unknown. OBJECTIVES: To assess the benefits and harms of AT III

in critically ill patients. SEARCH STRATEGY: We searched the Cochrane Central

Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE;

Science Citation Index Expanded; International Web of Science; CINAHL; LILACS;

and the Chinese Biomedical Literature Database (up to November 2006). We

contacted authors and manufacturers in the field. SELECTION CRITERIA: We included

all randomized clinical trials, irrespective of blinding or language, that

compared AT III with no intervention or placebo in critically ill patients. DATA

COLLECTION AND ANALYSIS: Our primary outcome measure was mortality. We each

independently abstracted data and resolved any disagreements by discussion. We

presented pooled estimates of the intervention effects on dichotomous outcomes as

relative risks (RR) with 95% confidence intervals (CI). We performed subgroup

analyses to assess risk of bias, the effect of AT III in different populations

(sepsis, trauma, obstetric, and paediatric patients), and the effect of AT III in

patients with or without the use of concomitant heparin. We assessed the adequacy

of the available number of participants and performed a trial sequential analysis

to establish the implications for further research. MAIN RESULTS: We included 20

randomized trials with a total of 3458 participants; 13 of these trials had high

risk of bias. When we combined all trials, AT III did not statistically

significantly reduce overall mortality compared with the control group (RR 0.96,

95% CI 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and

sensitivity analyses were carried out. Analyses based on risk of bias, different

populations, and the role of adjuvant heparin gave insignificant differences. AT

III reduced the multiorgan failure score among survivors in an analysis involving

very few patients. AT III increased bleeding events (RR 1.52, 95% CI 1.30 to

1.78). AUTHORS' CONCLUSIONS: AT III cannot be recommended for critically ill

patients based on the available evidence. A randomized controlled trial of AT

III, without adjuvant heparin, with prespecified inclusion criteria and good bias

protection is needed.

Empirical fluconazole versus placebo for intensive care unit patients: a

randomized trial.

Ann Intern Med. 2008 Jul 15;149(2):83-90.

Schuster MG, Edwards JE Jr, Sobel JD, Darouiche RO, Karchmer AW, Hadley S,

Slotman G, Panzer H, Biswas P, Rex JH.

BACKGROUND: Invasive infection with Candida species is an important cause of

morbidity and mortality in intensive care unit (ICU) patients. Optimal preventive

strategies have not been clearly defined. OBJECTIVE: To see whether empirical

fluconazole improves clinical outcomes more than placebo in adult ICU patients at

high risk for invasive candidiasis. DESIGN: Double-blind, placebo-controlled,

randomized trial conducted from 1995 to 2000. SETTING: 26 ICUs in the United

States. PATIENTS: 270 adult ICU patients with fever despite administration of

broad-spectrum antibiotics. All had central venous catheters and an Acute

Physiology and Chronic Health Evaluation II score greater than 16. INTERVENTION:

Patients were randomly assigned to either intravenous fluconazole, 800 mg daily,

or placebo for 2 weeks and were followed for 4 weeks thereafter. Two hundred

forty-nine participants were available for outcome assessment. MEASUREMENTS: A

composite primary outcome that defined success as all 4 of the following:

resolution of fever; absence of invasive fungal infection; no discontinuation

because of toxicity; and no need for a nonstudy, systemic antifungal medication

(as assessed by a blinded oversight committee). RESULTS: Only 44 of 122 (36%)

fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful

outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.78]). The main reason

for failure was lack of resolution of fever (51% for fluconazole and 57% for

placebo). Documented invasive candidiasis occurred in 5% of fluconazole

recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.49]).

Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse

events resulting in discontinuation of the study drug. Discontinuation because of

abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%)

placebo recipients. Limitations: Twenty-one randomly assigned patients were not

included in the analysis because they either did not meet entry criteria or did

not have postbaseline assessments. Fewer fungal infections than anticipated

occurred in the control group. Confidence bounds were wide and did not exclude

potentially important differences in outcomes between groups. CONCLUSION: In

critically ill adults with risk factors for invasive candidiasis, empirical

fluconazole did not clearly improve a composite outcome more than placebo.

Recently published papers: a little less ventilation, a little more oxygen

please?

Crit Care. 2008;12(3):152. Epub 2008 May 27.

Ball J.

Recent papers discussed include two large, multicentre, high-positive

end-expiratory pressure trials in acute lung injury and reflects upon the

usefulness of such trial designs. Further papers considered include the emerging

story of beta2-agonists for pulmonary oedema, highlights the newly described,

iatrogenic demon, of ventilator-induced diaphragm injury, promotes the addition

of B-type natriuretic peptide testing to the prediction of extubation success,

and muses again over the oxygen debate.

Recommendations for the diagnosis and management of corticosteroid insufficiency