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Master in Emergenza-Urgenza

Master in Emergenza-Urgenza. Prof. Paola Failli Farmacologia Giugno 2009. Trattamento dello shock. Classificazione dello Shock. Ipovolemico Traumatico Cardiogeno Settico (Iperdinamico/Ipodinamico) Neurogeno Ipoadrenalico (da insufficienza corticosurrenale).

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Master in Emergenza-Urgenza

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  1. Master in Emergenza-Urgenza Prof. Paola Failli Farmacologia Giugno 2009

  2. Trattamento dello shock

  3. Classificazione dello Shock • Ipovolemico • Traumatico • Cardiogeno • Settico (Iperdinamico/Ipodinamico) • Neurogeno • Ipoadrenalico (da insufficienza corticosurrenale)

  4. R. P. Dellinger, Critical Care Medicine 2003; 31(3):946-955

  5. Septic Shock • Caused by the systemic response to a severe infection. • Most frequently in elderly or immunocompromised patients and in those who have undergone an invasive procedure in which bacterial contamination has occurred. • Infections of the lung, abdomen, or urinary tract are most common, and approximately half of the patients have bacteremia. • Gram-positive and -negative bacteria, viruses, fungi, rickettsiae, and protozoa have all been reported to produce the clinical picture of septic shock, and the overall response is generally independent of the specific type of invading organism.

  6. Septic Shock • Clinical consequence of toxic components of the infectious organisms, e.g., the endotoxin of gram-negative bacteria or the exotoxins and enterotoxins of gram-positive bacteria: metabolic and circulatory derangements driven by the systemic infection and the release. • Organism toxins lead to the release of cytokines, including IL-1 and TNF-alpha , from tissue macrophages. • Increase of tissue factor expression and fibrin deposition and disseminated intravascular coagulation may develop. The inducible form of NO synthase is stimulated, and NO, a powerful vasodilator, is released. Hemodynamic changes in septic shock occur in two characteristic patterns: early, or hyperdynamic, and late, or hypodynamic, septic shock.

  7. Septic Shock • Hyperdynamic Response • In hyperdynamic septic shock, tachycardia is present, the cardiac output is normal, and the systemic vascular resistance is reduced while the pulmonary vascular resistance is elevated. The extremities are usually warm. However, splanchnic vasoconstriction with decreased visceral flow is present. The venous capacitance is increased, which decreases venous return. With volume expansion cardiac output becomes supranormal. Myocardial contractility is depressed in septic shock by mediators including NO, IL-1, and/or TNF-a . Inflammatory mediator-induced processes include increased capillary permeability and continued loss of intravascular volume.

  8. Septic Shock • Hyperdynamic Response • In septic shock, in contrast to other types of shock, total oxygen delivery may be increased while oxygen extraction is reduced due to maldistribution of microcirculatory perfusion and impaired utilization. • The toxicity of the infectious agents and their byproducts and the subsequent metabolic dysfunction drive the progressive deterioration of cellular and organ function. Acute respiratory distress syndrome, thrombocytopenia, and neutropenia are common complications.

  9. Septic Shock • Hypodynamic Response • As sepsis progresses, vasoconstriction occurs and the cardiac output declines. The patient usually becomes markedly tachypneic, febrile, diaphoretic, and obtunded, with cool, mottled, and often cyanotic extremities. Oliguria, renal failure, and hypothermia develop; there may be striking increases in serum lactate.

  10. N C RIEDEMANN et al, Nature Med,. 2003, 9 pp 517 - 524

  11. Excessive inflammatory mediator production during sepsis. • Various stimuli can cause activation of different cell types and serum proteins, as well as the coagulation and complement systems, leading to excessive production of pro-inflammatory cytokines and chemokines and upregulation of adhesion molecules on endothelial cells and polymorphonuclear leukocytes (PMNs). Monocytes, PMNs and other phagocytes release large amounts of granular enzymes and generate ROS in response to the original stimulus in the early (hyperreactive) phase of sepsis. As result of excessive pro-inflammatory mediator production, vascular permeability increases, tissue damage and organ failure occur and crucial innate immune functions become defective, resulting in increased susceptibility toward infection in the later (hyporeactive) phase of the immune response, often along with immune paralysis. DIC, disseminated intravascular coagulopathy. N C RIEDEMANN et al, Nature Med,. 2003, 9 pp 517 - 524

  12. Changes in septic shock mortality (1958-2002) R. P. Dellinger, Critical Care Medicine 2003; 31(3):946-955

  13. Wheeler AP, Bernard GR, N Engl J Med 1999 Jan 21;340(3):207-14

  14. N C RIEDEMANN et al, Nature Med,. 2003, 9 pp 517 - 524

  15. Sprung: N Engl J Med, Volume 358(2).January 10, 2008.111-124

  16. Background: • Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin.

  17. Methods: • In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test.

  18. Results: • Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). • In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.

  19. Hydrocortisone Therapy for Patients with Septic Shock • In our study, the use of low-dose hydrocortisone had no significant effect on the rate of death in patients with septic shock at 28 days, regardless of the patients' adrenal responsiveness to corticotropin. The proportion of patients in whom reversal of shock was achieved was similar in the two groups, though this goal was achieved earlier in patients who received hydrocortisone

  20. Human recombinant activated protein C for severe sepsis(Review) Martí-Carvajal A, Salanti G, Cardona AF. Human recombinant activated protein C for severe sepsis. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD004388. DOI: 10.1002/14651858.CD004388.pub3.

  21. Background • Sepsis is a common, expensive and frequently fatal condition. There is an urgent need for developing new therapies to further reduce severe sepsis-induced mortality. One of those approaches is the use of human recombinant activated protein C (APC). • Objectives • We assessed the clinical effectiveness of APC for the treatment of patients with severe sepsis or septic shock. • Search strategy • We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 2);MEDLINE (1966 to 2005); EMBASE (1980 to 2005) and LILACS (1982 to 2005). We contacted researchers and organizations working in the field. • We did not have any language restriction. • Selection criteria • We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. • Data collection and analysis • We independently performed study selection, quality assessment and data extraction.We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I-squared (I2). We used a random-effects model.

  22. Main results • We included four studies involving 4911 participants (4434 adults and 477 paediatric patients). For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.92, 95% confidence interval (CI) 0.72 to 1.18; P = 0.50, I2 = 72%). The effectiveness of APC did not seem to be associated with the degree of severity of sepsis (two studies): for an APACHE II score less than 25 the RR was 1.04 (95% CI 0.89 to 1.21; P = 0.70), and in participants with an APACHE IIscore of 25 or more the RR was 0.90 (95% CI 0.54 to 1.49; P = 0.68). APC use was, however, associated with a higher risk of bleeding (RR 1.48 (95% CI 1.07 to 2.06; P = 0.02, I2 = 8%). Two studies were stopped early because there was little chance of reaching the efficacy endpoint by completion of the trial. • Authors’ conclusions • This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. • Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

  23. Authors’ conclusions • This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. • Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

  24. R. P. Dellinger, Critical Care Medicine 2003; 31(3):946-955

  25. Cardiovascular changes associated with septic shock and the effects of fluid resuscitation. • A, normal (baseline) state. B, in septic shock, left ventricular blood return is reduced due to a combination of capillary leak (inset), increased venous capacitance (VC), and increased pulmonary vascular resistance. The stroke volume is further compromised by a sepsis-induced decrease in left and right ventricular (RV) contractility. Tachycardia and increased left ventricular compliance serve as countermeasures to combat low cardiac output, the latter by increasing left ventricular preload. However, cardiac output remains low to normal. Finally, a decrease in arteriolar (systemic vascular) resistance allows a higher stroke volume at any given contractility and left ventricular filling state, but also the potential for severe hypotension, despite restoration of adequate left ventricular filling. C, aggressive fluid resuscitation compensates for capillary leak, increased venous capacitance, and increased pulmonary vascular resistance by re-establishing adequate left ventricular blood return. Decreased arteriolar resistance (AR), tachycardia, and increased left ventricular compliance compensate for decreased ejection fraction. Ejection fraction increases as left ventricular filling increases. The net result is that after adequate volume resuscitation, most patients with severe sepsis have a high cardiac output, low systemic vascular resistance state. VR, venous return; RA, right atrium; LA, left atrium; LV, left ventricle; AO, aorta; →, blood flow(cardiac output); =>, contractility. R. P. Dellinger, Critical Care Medicine 2003; 31(3):946-955

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