SHOCK

1. SHOCK Core Rounds August 7, 2003 Dr. Rob Hall PGY4 Dr. Gil Curry MD, FRCPC

2. JOHN-WEST

3. Shock Talk:outline • A few cases • Approach to and ddx of shock • Detailed review of major causes • Focus on septic, hypovolemic, cardiogenic shock for literature review • Controversies in management of sepsis, hypovolemic shock, cardiogenic shock

4. “ Shock is the transition between illness and death”

5. Definitions of Shock • Clinical manifestations of the inability of the circulatory system to adequately supply tissues with nutrients and remove toxic waste • Inadequate blood flow secondary to decreased cardiac output or mal-distributed output that results in irreversible tissue damage

6. Ill appearance or decreased LOC HR > 100 RR > 22 or PC02 < 32 Base deficit < -5 or lactate > 4 Urine output < 0.5 ml/kg/hr Hypotension > 20 minute duration NOTES Can be in shock without being hypotensive Base deficit = amount of base required to neutralize the pH (normal is > -2) Rosen’s Empiric Cirteria for the Diagnosis of Shock: 4 out of 6 criteria

7. Pre - heart hypovolemia, venous pooling Heart contractility, arrythmias, mech obstruction Post - heart loss of vascular tone, inability to deliver to tissues, inability of tissues to utilize Quantitative hypovolemic, hemorrhagic, obstructive, myocardial dysfunction Qualitative sepsis, anaphylaxis, neurogenic, dyshemoglobinemia, cellular poisons Classification of Shock: find your own way to classify shock and remember the ddx

8. Etiological Classification: man this guy looks SSHHOCCKE… • S - septic • S - spinal (neurogenic) • H - hypovolemic • H - hemorrhagic • O - obstructive (PE, pthrx, hthrx, ct) • C - cardiogenic (rate, contractility, obstruction, valve) • C - cellular toxins (CN, CO, HS, ASA, Fe) • K - anaphylaCTic • E - endocrine/adrenal crisis

9. Pathophysiology • Common final pathway = cellular injury • FIVE unifying features of shock • intracellular calcium overload • intracellular hydrogen ion • cellular and interstitial edema • catabolic metabolism • inflammation

10. Undifferentiated Shock: Thorough history, complete physical, shot gun investigations………ya, but what are some tips? • History • Paramedics, caregivers, witnesses, family, and old chart are keys to give you historical clues • Get someone on the phone EARLY (ie: in resusc bay) who can tell you what was going on • Physical • Don’t forget the chemstrip, rectal, AAA exam • Investigations • STAT echo can be very useful • Emerg ultrasound will soon be available

11. Shock Trivia • Patient in shock but is bradycardic: why? • Elderly, medications, neurogenic shock, intraabdominal pathology (vagal tone) • Shock index • HR/SBP > 0.9 suggest shock • Lactate clearance index • Patient is under – resuscitated if lactate has not decreased by 50% since last measurement • Gastric/Rectal Tonography • Balloon probe measure mucosal pH as an indicator of gut perfusion

12. Septic Shock

13. Definitions:Consensus conference on definitions for sepsis: Critical Care Medicine 2000. Volume 28 (1): 232 - 235 • SIRS (Systemic Inflammatory Response Syndrome) • temp > 38 or < 36 • HR > 90 • RR > 20 or PaC02 < 32 • wbc > 12, < 4, or > 10% bands • Sepsis = SIRS + documented infection • Severe Sepsis = Sepsis + MODS (Mulitorgan dysfuntion) • Septic Shock = Sepsis + Hypotension refractory to volume resuscitation (requiring vasopressors)

14. Management of Septic Shock • Intubate/ventilate • Control airway • Decrease work of breathing • Fluids • Boluses of NS or RL • Adults: bolus 1-2 L and repeat • Peds: bolus 20 ml/kg and repeat • Pressors after 2-3 boluses but keep fluids running • Require a lot of fluid • Absolute hypovolemia: increase incensibles, poor intake • Relative hypovolemia: vasodilation and decreased SVR

15. Dopamine: 1-5 ug/kg/min ~ dopaminergic 5-10 ug/kg/min ~ beta activity >10 ug/kg/min ~ alpha activity Preferred agent for many Effects well established Physicians comfortable with use Levophed: 0.01 – 3 ug/kg/min Potent alpha agonist Some beta propertiesConcern with levophed worsening end organ hypoperfusion Older studies: levophed used as last resort and thus poor outcomes Hesselvik JF, et al., Crit Care Med 1989 Vasopressors:Most common choices

16. Norepinephrine • Norepinephrine improves renal blood flow and tissue oxygenation in patients with septic shock: • Desjars et al., Crit Care Med 1989 • Rendl-Wenzel et al., Intensive Care Med 1993. • Meadows et al., Crit Care Med 1988 • Martin C., et al., Crit Care Medicine 2000

17. Dopamine versus norepinephrine • Martin et al., Chest 1993 and Marik et al., JAMA 1994 • Many small studies (n=20) like these two that showed a benenfit in physiological markers with norepinephrine • Levophed has favourable effect on hemodynamics and end organ perfusion as compared to dopamine • A mortality benefit for levophed over dopamine has never been shown

18. Pressor summary • Make sure the pump is full first • Dopamine/Levophed first line agents • Levophed may be the superior agent in septic shock • Titrate up doses fast (q 5-10 min to effect) • Add second agent if needed • Invasive monitoring required

19. Sepsis and Antibiotics • Bochud et al., Intensive Care Medicine 2001: reviewed 4 retrospective studies of septic patients and abx choice • N=1190 • Appropriate Abx mort rate~28% • Inappropriate Abx mot rate~49% • P<0.001 • Early ED antibiotics have also shown to decrease mortality in many disease subgroups (pneumonia, meningitis, urosepsis)

20. EARLY and APPROPRIATE initiation of antibiotic coverage are CRUCIAL emergency department interventions in the patient with septic shock

21. Empirical antibiotic choices • Target suspected source of infection • Refer to SANDFORD’s recommendations • Use maximum doses of antibiotics • Broad spectrum = grm +ves, grm –ves, anaerobes • Amp + Gent + Flagyl • Piperacillin/Tazobactam being used more often • Imipenum as monotherapy (big gun) • Neutropenic: cover pseudomonas (ceftazidime, cipro, tobramycin)

22. Newer approaches to septic shock: • Vasoactive mediators • vasopressin, nitric oxide • Coagulation Cascade • protein C, protein S, antithrombin III • Inflammatory mediators • anti TNF antibodies, anti LPS, TFPI, interleukins, IVIG

23. Question: how to get an intensivist talking at a wine and cheese party? Answer: just say…… There is NO evidence for steroid use in septic shock Recombinant activated Protein C is killing patients

24. Steroids in septic shock Rationale: • Anti-inflammatory • Relative adrenal insufficiency in many of cases of refractory shock • Upregulates catecholamine receptors • Hopefully immunosuppression and bleed risk did not counter benefits

25. Early mega-dose steroid trials “supraphysiologic” doses Solumedrol 30/mg/kg x 3-4 doses Trend towards increased mortality Increase incidence of GI bleeding Increased incidence of secondary infections 1990’s trial’s with lower dose steroids “physiologic doses” aimed to replace steroids for a “Relative adrenal insufficiency” Researchers hoped get catecholamine sensitivity and anti-inflammatory effects still Steroids and Sepsis

26. Steroids and Sepsis:Bollaert et al.,Critical Care Medicine 1998 • Double-blind, placebo controlled, small study • Solu-cortef 100mg IV q 8hrs x 5days vs. placebo • Outcome Steroid group Placebo • Shock reversal @7d: 68% 21% p=.007 • Mortality 32% 63% p=.09 • No increase adverse outcomes • Showed more shock reversal at 7 days with low dose steroids

27. Steroids and Sepsis: Briegel et al., Crit Care Med 1999. • Another small RCT (n=40) • Randomized to solu-cortef 100mg IV then low dose infusion vs placebo • Outcome Steroid group Placebo • Time to shock reversal 2 days 7 days (p=.005) • No increase adverse outcomes, no diff in mortality • Showed earlier shock reversal with low dose steroids

28. Steroids and Sepsis:Annane. JAMA 2002. • Largest prospective trial of low dose steroids • RCT, blinded, N = 300 • Randomized to low dose hydrocortisone (50 mg iv q6hr) + fluticasone vs placebo • Did ACTH stim test on everyone • Mortality decreased 10% in “non-responders” • 63% -> 53% (p = 0.02) • Criticisms of their definitions of non-responders and how they did the stim test exist

29. Steroids and Sepsis:Review article in Chest May 2003 • High dose steroids clearly shown to increase mortality • There is some evidence for benefit from low dose steroids in sepsis • Current debate over low dose steroids unresolved and needs further study

30. Steroids and Sepsis:Take home message • There is no current indication for the ED initiation of low dose steroids in sepsis unless adrenal crisis is suspected • You should be aware that ICU will likely do an ACTH stim test and may give steroids

31. Antithrombotic Profibrinolytic Anti-inflammatory Activated Protein C and Sepsis

32. Activated Protein C and Sepsis:drotrecogion (Zigris) • PROWESS TRIAL (Bernard. NEJM 2001) • Multicentered RCT, N = 1690 • Mortality 30.8% in placebo, 24.7% in treatment group (p= 0.005) • ARR 6.1% for NNT 16 • RRR of 19% • Serious bleeding 3.5% vs 2.0% (p=0.06) • Enrollement criteria changed ½ way through!

33. Activated Protein C and Sepsis • The FDA is confused • Study stopped early because of “remarkable effect”, FDA approved the drug • Further discussion and controversy: FDA limited its use to only sicker patients (based on APACHE score) and asked for further study • Critical Care Medicine. 31(1). S85-96 • Recent review on rhAPC • Highlights problems with PROWESS study and FDA approval --------- calls for further study

34. Activated Protein C and Sepsis • Take home messages: • rhAPC is expensive (10,000 per course) • rhAPC has been shown to decrease mortality although the effect is modest (ARR 6%) • There is NO role for ED initiation of rhAPC • May be used in ICU

35. 15 yo male Attempted hanging Cut down from tree HR 75, BP 85/30 Why is he in shock? Case

36. Neurogenic Shock:Definitions • Spinal Shock • initial loss of spinal cord function following SCI including motor, sensory, and sympathetic function • Neurogenic Shock • loss of sympathetic autonomic function due to spinal cord injury

37. Neurogenic Shock: Pathophysiology • Hypotension • Due to loss of sympathetic tone thus vasodilation and decreased SVR • Usually only occurs with lesions at or above T6 because lower lesions leave enough of the body with intact sympathetics that the BP doesn’t drop • Bradycardia (absolute or relative) • Due to unopposed parasympathetic (VAGAL) tone to the heart • Usually only occurs with lesions at or above T4 because sympathetic innervation to heart is at T4

38. Neurogenic Shock:Management • Fluids • Atropine 0.5 mg – 1.0 mg iv • NOTE: may see bradycardia or bradyasystolic arrest due to stimulation from laryngoscopy so have atropine ready if intubating • Vasopressors • Epinephrine 1:10,000 (1ml prn to effect) • Phenylephrine: 10 mg in 100ml NS (1ml is 100 ug) • Ephedrine

39. Hemorrhagic Shock

40. Hemorrhagic Shock:Classification

41. Hemorrhagic Shock:Definition • Hemorrhage vs Hemorrhagic shock? • Rosen’s definition of hemorrhagic shock = Requires 4 out of 6 empiric criteria for shock • Ill or decreased LOC • U/o < 0.5 ml/kg/hr • HR > 100 • RR > 22 or PC02 < 32 • BD < -5 or lactate > 4 • Hypotension > 20 minutes

42. Hemorrhagic Shock: Management • V: vascular access, crystalloid bolus X 2, blood transfusion prn, identify and treat cause • Controversies • Which fluid? • When to fluid resuscitate? • How fast should fluid be given? • Optimal endpoints of resuscitation? • Blunt versus penetrating trauma

43. Hemorrhagic Shock Which fluid to give?

44. Colloids • Albumin, protoplasm protein fraction, hydroxyethylstarch, pentastarch, gelatin, dextran • Advantages • less fluid required, more volume in vascular space, potential to draw fluid in from tissues • Disadvantages • expensive, allergic reactions, coagulopathies

45. Colloids • Cochrane Database of Systematic Reviews. BMJ 1998: 317:235-40. • Objective: effect of albumin on mortality • Study: 30 RCTs total 1419 patients • Results: RR of death 1.46 hypovolemia, 2.40 burns, 1.69 hypoalbuminemia • Pooled RR of death 1.68 (1.26,2.23) • Conclusion: albumin increases mortality

46. Colloids • Cochrane Database 2003. Colloids versus crystalloids for fluid resuscitation. • Albumin: 18RCTs RR1.52 (1.08,2.13) • HES: 7 RCTs RR 1.16 (0.68,1.96) • Gelatin: 4 RCTs RR 0.50(.08,3.03) • Dextran: 8 RCTs RR 1.24 (.94,1.65) • Conclusion: No evidence that colloids reduce risk of death in trauma, burns, or surgery

47. Colloids:Summary • There is NO evidence that colloids decrease mortality in the resuscitation of critically ill patients.

48. Hypertonic Saline • Advantages • less volume, stays in vascular space, draws fluid • Disadvantages • hypernatremia, hyperosmolarity, seizures, coagulopathy, anaphylactoid rxns with dextran • Details • Hypertonic saline (7.5% NaCl) +/- 6% dextran • Most often given as a 250 cc bolus (~ 4ml/kg) over 5-10 min

49. Hypertonic Saline • Animal evidence • improved hemodynamics and mortality • Human evidence: Wade et al 1997: • HS and HSD in trauma patients • Metanalysis of 8 RCTS of HSD and 6 HS • HS (7.5% saline): no difference in mortality • HSD (+6%dextran): decreased mortality in 7/8 trials overall 3.5%; trend only ---> Not stat sign

50. Hypertonic Saline • Cochrane Database 2003. Alderson P. Colloids vs crystalloids for fluid resuscitation. • Part of this systemic review looked at Hypertonic Saline + Dextran and effect on mortality • Study: metanalysis of 8 RCTs • Results: pooled RR of 0.88 (0.74, 1.05) • Conclusion: there is a trend toward reduction in mortality with HSD although not statistically significant