The document discusses cellular response and biochemical markers of shock. It summarizes that cellular response to shock is reflected in clinical manifestations and lactate is the most important biochemical marker of shock, supported by evidence. However, other markers like procalcitonin, D-dimers, and protein C have conflicting evidence and need further validation to diagnose infection in patients with sepsis or septic shock. Nitrite/nitrate concentration and procalcitonin level may be the most suitable tests for defining patients with septic shock.

1. Suad Al-Sulimani R2

2. Definition of shock in term of cellular function Path physiology & clinical finding of different types of shock Biochemical shock markers Evidence based clinical values

3. Profound hemodynamic and metabolic disturbance characterized by failure of the circulatory system to maintain adequate perfusion of vital organs

4. Aerobic Metabolism METABOLISM 6 CO 2 6 H 2 O 36 ATP HEAT (417 kcal) 6 O 2 GLUCOSE

5. Anaerobic Metabolism GLUCOSE METABOLISM 2 LACTIC ACID 2 ATP HEAT (32 kcal)

6. Inadequate Cellular Oxygenation Anaerobic Metabolism Metabolic Failure Metabolic Acidosis Inadequate Energy Production Lactic Acid Production Cell Death!

7.  Peripheral vasoconstriction…  peripheral vascular resistance…  afterload…  blood pressure.

8.  Peripheral vasodilation…  peripheral vascular resistance…  afterload…  blood pressure.

9.  fluid volume…  preload…  contractility (Starling’s Law)…  cardiac output.  blood pressure.

10.  fluid volume…   preload…  contractility (Starling’s Law)…  cardiac output.  blood pressure.

11. 􀂇 The human body responds to acute hemorrhage by activating 4 major physiologic systems: the hematologic system, the cardiovascular system, the renal system, and the neuroendocrine system.

13. 􀂇 Platelets are activated which form an immature clot on the bleeding source 􀂇 The damaged vessel exposes collagen, which subsequently causes fibrin deposition and stabilization of the clot

14. Hypovolemic Shock: Cardiovascular System 􀂇 Increases the heart rate, increasing myocardial contractility, and constricting peripheral blood vessels. 􀂇 This response occurs secondary to an increase in release of norepinephrine and a decrease in baseline vagal tone (regulated by the baroreceptors in the carotid arch, aortic arch, left atrium, and pulmonary vessels).

15. 􀂇 The cardiovascular system also responds by redistributing blood to the brain, heart, and kidneys and away from skin, muscle, and GI tract.

16. Hypovolemic Shock: Renal System 􀂇 The kidneys respond to hemorrhagic shock by stimulating an increase in rennin secretion from the juxtaglomerular apparatus.

17. Plasma volume  [Na+] &/Or Kidney (juxtaglomerular apparatus) Detected by Releases Renin Angiotensinogen Angiotensin I… Converts Via ACE (A ngiotensin C onverting E nzyme) Angiotensin II…

18. Angiotensin II…  vasoconstriction  PVR  BP!  thirst Fluid volume ADH (anti-diuretic hormone) Adrenal cortex Releases Aldosterone Na+ reabsorption

19.  CO R.A.S. Activation  Dyspnea O 2 supply Volume/ Preload  SVR Peripheral & pulmonary edema Impaired myocardial function Myocardial O 2 demand Catecholamine Release

20.  Sympathetic Tone Or  Parasympathetic Tone Vascular Tone Massive Vasodilation  SVR & Preload  Cardiac Output Tissue perfusion

21. Systemic Inflammatory Response Syndrome (SIRS) Systemic inflammatory response to a variety of severe clinical insults manifested by ≥ 2 of the following conditions ● Temperature >38ºC or <36ºC ● Heart rate >90 beats/min ● Respiratory rate >20 breaths/min or PaCO2 ,<32 torr (<4.3 kPa) ● White blood cell count >12,000 cells/mm3, <4000 cells/mm3, or >10% immature (band) cells

22. Sepsis ● The presence of SIRS associated with a confirmed infectious process

23. Severe Sepsis ● Sepsis with either hypotension or systemic manifestations of hypoperfusion – Lactic acidosis, oliguria, altered mental status

24. Septic Shock ● Sepsis with hypotension despite adequatefluid resuscitation, associated with hypoperfusion abnormalities

25. Hemodynamic Alterations Hyperdynamic State (“Warm Shock”) Tachycardia. Elevated or normal cardiac output. Decreased systemic vascular resistance. Hypodynamic State (“Cold Shock”) Low cardiac output .

26. Protein c activation

27. Cytokine production leads to massive production of endogenous vasodilators. Structural changes in the endothelium result in extravasation of intravascular fluid into interstitium and subsequent tissue edema.

28. Plugging of select microvascular beds with neutrophils, fibrin aggregates, and microthrombi impair microvascular perfusion. Organ-specific vasoconstriction

29. Loss of Sympathetic Responsiveness : Down-regulation of adrenergic receptor number and sensitivity, possible altered signal transduction. Vasodilatory Inflammatory Mediators. Endotoxin has direct vasodilatory effects. Increased Nitric Oxide Production.

30. Infection Inflammatory Mediators Endothelial Dysfunction Vasodilation Hypotension Vasoconstriction Edema Maldistribution of Microvascular Blood Flow Organ Dysfunction Microvascular Plugging Ischemia Cell Death

31. Normal compensation includes : Progressive vasoconstriction Increased blood flow to major organs Increased cardiac output Increased respiratory rate and volume Decreased urine output

32. In shock, the hydrostatic pressure decreases and the oncotic pressure is constant, as a result: The fluid exchange from the capillary to the extracellular space decreases. The fluid return from the extracellular space to the capillary increases. That will increase the blood volume, which will increase BP and will help to compensate shock situations. This system is known as the “Fluid shift system”

33. Cellular Response to Shock Tissue perfusion Na + Pump Function ATP synthesis Anaerobic metabolism Cellular edema  Vascular volume Impaired cellular metabolism O 2 use  Intracellular Na + & water Impaired glucose usage Stimulation of clotting cascade & inflammatory response

37. pyruvate + NADH + H + = lactate + NAD +

38. =Accelerated aerobic glycolysis =Carbohydrate metabolism > mitochondrial oxidative capacity Hypoxia blocks oxidative phosphoeration =Increase the lactate /pyruvate ratio =Normal ratio around 10/1

39. Reduced lactate clerance Puruvate dehydrogenase Dysfunction PDH shifts Pyruvate to Krebs cycle not lactate Subnormal level in muscle in sepsis

40. Protien catabolism Aas converted to Puruvate then lactate in hibition of mitochondrial respiration sepsis , drugs

42. Gluconeogenesis 20% - Cori cycle in liver Oxidation 80%

44. Lactate Serum Lactate as a Predictor of Mortality in Emergency Department Patients With Infection Annals of Emergency Medicine 2005,45:524-528 . = An initial serum lactate may be useful in risk stratification in patients presenting to the emergency department with infections. = There appears to be an increasing trend of mortality with elevated initial lactate levels. 22.4% patients with an initial lactate level > 4.0 mmol/L died within 3 days

45. Lactate levels greater than 2.5 mmol/L are associated with an increase in mortality.Levels greater than 4 mmol/L in patients with suspected infection have been shown to increase mortality odds 5-fold Ann Emerg Med . May 2005;45(5):524-8.

46. Intensive Care Med. 2001;27:74-83. Abstract Elevated serum lactate levels are predictive of an increased mortality in ED patients with sepsis or septic shock. Current evidence indicates that monitoring serial values and determining the time to clearance is a strong predictor of patient outcome.

47. =decline in lactate levels of at least 10% during the first 6 hours of therapy correlated with a mortality rate of < 20%. = normalization of serum lactate levels within 12-24 hours is associated with the best chance of patient survival. = Patients whose lactate levels do not return to normal within 48 hours have significantly higher rates of organ dysfunction and death . Emerg Med J. 2006;23:622-624 Am J Surg. 2006;191:625-630.

52. Protein C Baseline protein C levels were an independent predictor of sepsis outcome. Day 1 changes in protein C, regardless of baseline levels, were also predictive of outcome. The association of DrotAA treatment, increased protein C levels, and improved survival may partially explain the mechanism of action Critical Care 2006, 10:R92doi:10.1186/cc4946

53. Procalcitonin ] Procalcitonin (PCT) has been proposed as a more specific [and better prognostic marker than CRP, although its value has also been challenged . It remains difficult to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome , and there is a continuous search for better biomarkers of sepsis. J Crit Care 2004, 19:152-157 Lancet Infect Dis 2007

54. base deficit has shown poor correlation with serum lactate and is affected by numerous conditions, including crystalloid resuscitation. As a result, base deficit should not be considered a reliable surrogate for serum lactate . J Trauma. 2004;57:898-912 . Base Defecit

55. BNP High concentrations of natriuretic peptides were observed in severe sepsis, septic shock and in multiple organ failure, probably due to increased secretion by mediators of the inflammatory process.The highest concentrations of ANP and BNP were found in lethal conditions

56. Therefore, the assessment of natriuretic peptide may be used in scoring a patient's clinical status, for precise diagnosis in doubtful situations, and for determining appropriate treatment

57. =D dimmers are grossly elevated in sepsis. = Protein C are lowered . = Procalcitonin also considered as bimarker for sepsis The potential role of biomarkers for diagnosis of infection in patients presenting with severe sepsis remains undefined. have failed to accurately differentiate sepsis from similar critical illnesses Am J Med. 2003; 115:529-535 .

58. Take home massege = Cellular response to shock is reflected as clinical manifestation =Lactate is the most important biochemical markers of shock supported by evedience = other markers has aconflicted evdiences that need to be validated

59. OBJECTIVES: To determine and compare the respective concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, soluble TNF receptors, nitrite/nitrate (NO2-/NO3-), and procalcitonin in the plasma of patients with septic shock CONCLUSIONS: These observations showed that increase of proinflammatory cytokines was a consequence of inflammation, not of shock. In this study comparing various shock and infectious states, measurements of NO2-/NO3- concentration and procalcitonin concentration represented the most suitable tests for defining patients with septic shock

63. Symptoms of shock 3. Cold and clammy skin : As a result of vasoconstriction. Shock decreases the skin surface temperature as a result of vasodilatation, which will increase the internal body temperature. Because the skin plays a major role in controlling body temperature as it will help in exchanging heat with the external environment. There are two mechanisms to get red of the excess heat: Hyperventilation ( Minimal effect in humans) Vasodilatation of the vessels Flush ( Increase blood flow to the skin) BP Real shock