Shock

1. Shock Division of Critical Care Medicine University of Alberta

2. OUTLINE • Classification • Common Pathways for Shock • Initial Management • Characterization • Mechanism of Inotropy • Catecholamines • What’s Next?

3. SHOCK A syndrome characterized by inadequate cellular oxygen delivery with widespread organ damage and dysfunction.

4. CLASSIFICATION • HYPODYNAMIC • Cardiogenic • Hypovolemic • Obstructive • HYPERDYNAMIC • Distributive

5. CARDIOGENIC SHOCK • LV infarction • RV infarction • Valvular dysfunction • Cardiomyopathy • Arrhythmias • Dynamic outflow obstruction

6. HYPOVOLEMIC • May occur with fluid loss from any compartment. • Patients with diastolic dysfunction have marked preload dependence with extreme sensitivity to volume status. • Ischemic and reperfusion injury cause endothelial dysfunction and refractory shock.

7. OBSTRUCTIVE CAUSES • Pulmonary embolism • Cardiac tamponade • Aortic dissection • Tension pneumothorax • Auto PEEP

8. DISTRIBUTIVE SHOCK • Sepsis • Anaphylaxis • Neurogenic • Adrenal insufficiency

9. WHATEVER THE ORIGINAL MODE OF SHOCK, DECOMPENSATION OCCURS VIA COMMON PATHWAYS • Hypovolemia • Vasodilatation • Myocardial depression • Mediator cascade activations • Microcirculatory dysfunction • Impaired mitochondrial respiration

10. HYPOVOLEMIA • Endothelial injury results in increased capillary permeability and diminished reflectance to albumin. • Dilation of capacitance vessels leads to venous pooling and reduction in mean systemic pressure. • Translocation of fluid to body cavities and the GI tract can occur very quickly.

11. VASODILATION • NO release after induction of iNOS. • Endothelial membrane hyperpolarization • Decreased adrenoreceptor sensitivity • ? norepinephrine inactivation by peroxynitrite • Vasopressin deficiency • Relative cortisol deficiency

12. Vessel constriction dependent on ingress of Ca++ through voltagedependent channels.

13. Activation of ATP sensitive K+ channels allows membrane hyperpolarization and inactivates Ca++ channels.

14. MYOCARDIAL DEPRESSION • Biventricular dilation and hypocontractility typical of septic shock. • EF usually 30 - 40 % but may be much lower. • Cytokine and NO mediated. • Troponin release marker for depression. • Degree of dilation associated with survival (more dilation, better prognosis).

15. MEDIATOR ACTIVATION • Infection directly activates innate immune mechanisms via TLRs. • Other shock states indirectly do so following ischemia / reperfusion injury or after bacterial translocation from the gut. • Activation of nuclear factor-b results in cytokine transcription. • Elaboration of TNF and Interleukin 1 central to development of SIRS.

16. VOLUNTEER SEPSIS MICROCIRCULATORY DYSFUNCTION

17. MICROCIRCULATORY DYSFUNCTION • Endothelial injury and loss of autoregulation • Leukocyte rolling and adherence • DIC with fibrin strands and micro thrombi • Tissue edema • Decreased capillary density and high flow shunts • Impaired oxygen diffusion

18. MITOCHONDRIAL FAILURE • Electron transport chain inhibited by NO and its metabolite peroxynitrite. • Evidence of actual mitochondrial injury. • Responsible for declining VO2 in setting of increased DO2. • Failure of cellular energetics may be key factor in organ dysfunction.

19. INITIAL MANAGEMENT • Usually necessary to initiate resuscitation prior to a full assessment. • Don’t forget the ABCs. • Responses to resuscitative maneuvers give clues to cause of shock.

20. RESPIRATORY • Encephalopathy may develop early requiring the airway to be protected. • Hypoxemia and increased work of breathing may develop insidiously. • Early intubation and ventilation will decrease O2 requirements and improve O2 transport. • Adopt a “lung protective” strategy early in course of acute lung injury.

21. VENOUS ACCESS • Large bore peripheral IVs more effective for giving fluids rapidly. • Large caliber dual lumen dialysis catheters most effective in setting of exsanguinating hemorrhage. • Central lines should preferably be placed above diaphragm to allow monitoring of CVP and SvO2. • Beware femoral catheter sheaths which are easily displaced extravascularly as edema progresses.

22. BP MEASUREMENT • Sphygmomanometry may be inaccurate in the vasodilated patient and difficult in the constricted. • Radial arterial lines may read significantly below a central arterial pressure with vasoconstriction. • Femoral arterial lines most accurate in phase of active resuscitation but consider early relocation. • With severe atherosclerotic disease or dissection it may be impossible to measure an accurate BP.

23. CORRECTION OF HYPOTENSION • Myocardial ischemia may occur at low pressures even with normal coronary anatomy. • Potential for cerebral ischemia and watershed infarcts. • Initial measure will usually be administration of volume challenge. • It may be necessary to use vasopressors in a setting of recognized hypovolemia or hemorrhage to correct profound hypotension.

24. ASSESSMENTGOALS • Establish cause to allow definitive therapy. • Quantitate physiological derangements. • Severity of myocardial depression, volume contraction and vasodilatation vary widely in septic patients. • Document adequacy of resuscitation • Restoration of normal vital signs often not consistent with normal hemodynamics or microcirculatory function.

25. CHARACTERIZATION • IS CARDIAC OUTPUT HIGH OR LOW? • IS THE HEART FULL? • WHAT IS THE RESPONSE TO VOLUME? • WHAT IS THE RESPONSE TO INOTROPE?

26. CLINICAL EXAM • Peripheries cool and clammy or well perfused? • Pulses bounding or low volume ? • Jugular veins flat or distended ? • What is the response to leg raising ? • Is there evidence of organ hypoperfusion ? • oliguria • obtundation

27. HEMODYNAMIC MONITORING • Increases ability to characterize shock with knowledge of C.I. and S.V.R.I. • Allows measurement of oxygen delivery and consumption. • However, filling pressures a poor surrogate for estimation of ventricular filling or preload. • Useful monitoring tool in some circumstances but generally not shown to be of benefit. • ? inherently misleading • ? inadequate interpretation • ? ineffective interventions

28. ECHOCARDIOGRAPHY • Gives definitive diagnostic information in many circumstances. • Much more reliable guide to the adequacy of ventricular filling. • Should always be employed when invasive hemodynamic monitoring is being considered. • Increasing availability of bedside technology.

29. MIXED VENOUS OXIMETRY • As oxygen extraction rises relative to DO2, SvO2 falls. • Low SvO2 correlates with inadequate global DO2 and tissue hypoxia. • Normal SvO2 does not exclude areas of regional ischemia. • Measurements by intermittent sampling or reflectance oximetry. • Use as a guide for response to therapy.

30. ARTERIAL LACTATE • Multiple causes of increased lactate in sepsis. • Tissue ischemia • Hepatic hypoperfusion or failure • Increased alanine metabolism “Cori cycle” • Inhibition of pyruvate dehydrogenase • Elevation of lactate > 2mmol/L a marker for increased mortality and its failure to fall with Rx more strongly so.

31. GASTRIC TONOMETRY • Saline filled gastric balloon equilibrates with gastric mucosal pCO2. • Impaired tissue perfusion leads to accumulation of tissue pCO2 and increasing gap between tissue and arterial pCO2. • Correlates with other evidence for tissue hypoxia and with outcome. • Expensive and unwieldy. • Limited improvement in discrimination compared to lactate levels.

32. RESEARCH TOOLS • Direct measurement tissue pO2. • Near infrared spectroscopy. • Redox state of cytochrome oxidase • Luminescent oxygen probes • Redox state of NADH • Microdialysis • tissue lactate • PET scanning • ATP levels

33. MANAGEMENT GOALS • Normalize vital signs. • Normalize global O2 transport. • Eliminate evidence of tissue dysoxia. • Definitive Rx of cause: • Source control and antibiotics in sepsis • Thrombolysis of PE • PCI in MI • Organ protective strategies

34. OPTIMIZE PRELOAD • Fundamental to any resuscitation strategy FLUID CHALLENGES MUST BE OF ADEQUATE VOLUME , BE INFUSED RAPIDLY AND THE EFFECTS OBSERVED IMMEDIATELY • Monitoring of response to volume challenge • Clinically • Hemodynamic parameters • Echocardiographically

35. CHOICE OF FLUID • No evidence of increased efficacy of albumin compared to crystalloid solutions. • Limited trials of non albumin colloids (i.e. Pentaspan). • Large volumes of N/S contribute to metabolic acidosis. • Pentaspan contributes to coagulopathy in large volumes or in already coagulopathic patients. • Some evidence of improved efficacy with hypertonic saline solutions.

36. ? OPTIMAL HEMATCRIT • Transfused blood recognized to be immunosuppressive and to independently contribute to mortality. • Limitation of oxygen carrying capacity of stored RBCs due to low levels of 2,3 DPG. • In absence of myocardial ischemia a transfusion trigger of < 7g/l improved or did not worsen outcome. • In presence of lingering evidence of tissue hypoxia transfusion to Hb 10 g/l should be considered.

37. MECHANISMS OF INOTROPY

38. DIFFERENTIAL RESPONSIVENESS • The effects of any vasoactive agent may be quite different depending on numerous premorbid and postmorbid considerations. • Pharmacokinetic as well as pharmacodynamic variation occurs. • Evidence of genetic polymorphism of receptor populations and signal transduction systems.

39. PREMORBID ISSUES • Diabetes • Hypertension • Hx of CHF • Use of vasoactives

40. PRELOAD • Development of tachycardia in response to inotropes often indicative of low preload. • Absence of pressor response or active deterioration in response to inotropes may result from dynamic left ventricular outflow tract obstruction (DLVOTO).

41. DLVOTO • Anterior mitral valve leaflet impinges on LVOT. • Results in MR and/or obstruction. • Classically found in HOCM. • Common occurrence in setting of LVH and under filling.

42. INOTROPY IN ENDOTHELIAL INJURY • Ischemia / reperfusion injury. • Massive endothelial apoptosis associated with sepsis. • Loss of autoregulation. • Paradoxical responses. • Diminished catecholamine metabolism.

43. ALTERED KINETICS • Significant metabolism of norepinephrine and dopamine in the lung. • Dopamine most prone to variable kinetics particularly with combined hepatic and renal dysfunction. • Milrinone is renal excreted with markedly prolonged half-life in renal failure and unknown kinetics on CVVHD.

44. The number of receptor subtypes seems to be creeping up with ever more complex interactions.

45. RECEPTOR POPULATIONS CHF associated with change in number and type of receptors. • Decreased numbers of 1 receptors • Increased expression of 3 receptors • Increased expression of 1 receptors

46. ALTERED G PROTEIN COUPLING • Most vasoactive agents activate G protein coupled receptors (GPCR). • Increased substitution of Gi subunit into heterotrimer causing decreased responsiveness. • Overexpression of Gi in sepsis. • Stimulated by increased NO production.

47. PATHWAYS FOR RECEPTOR DESENSITIZATION • Phosphorylation by GPCR kinase and subsequent internalization linked to receptor activation. • Phosphorylation by serine / threonine kinases not linked to receptor activation.

48. SECOND MESSENGER GENERATION • Phospholipase C • Adenyl cyclase • NOS • Guanylate cyclase All subject to polymorphism and multiple control systems

49. CORTISOL • Increases transcription and expression of adrenergic receptors. • Required for synthesis of catecholamines. • Reduces transcription of iNOS. • True and relative cortisol deficiency seems common in sepsis.

50. CATECHOLAMINES