Shock

1. Shock Moritz Haager, PGY-4 Dr. Lisa Campfens July 29, 2004

2. Objectives • Develop an approach to the shock patient • Are there any novel diagnostic tools? • Review the DDx of shock • Discuss specific controversies and new therapies for specific shock states • Primary focus on Hypovolemic & septic shock • Other shock etiologies covered elsewhere

3. The common thread • Shock is not a disease but a symptom of numerous possible underlying etiologies • Best defined as a state where supply of oxygen & nutrients is inadequate for metabolic demand resulting in tissue ischemia • Time is money • The longer the time spent in the shock state the more irreversible the damage • Combined mortality tends to be >20%

4. Initial Approach • Triage to resus bay • O2, monitors, IV’s x2, help • ABC’s • Intubate these pts early • Be prepared for their BP to crash • Paralyze to decrease metabolic demands • Fluid resuscitation • Which fluid? How fast? How much? • Choice of fluid, rate, and amount will depend on your DDx for underlying cause

5. Initial Approach • D – Disability & Neuro • E – Environment, Exposure, Every vital sign • There are 6 vitals – don’t forget Temp & C/S • F – Find an underlying cause • How to get a good Hx • EMS, CPS, Bystanders, Family, Roommates, Medical records – the earlier the better • Actively look for possible causes on your DDx • Focused physical including DRE • ABG, ECG, CXR • Echo, ED U/S for AAA, free fluid, tamponade

6. DDx: Mechanistic Approach

7. DDx: Empiric Approach • S - septic • S - spinal (neurogenic) • H - hypovolemic • H - hemorrhagic • O - obstructive (PE, PTX, HTX, Tamponade) • C - cardiogenic (rate, contractility, obstruction, valve) • C - cellular toxins (CN, CO, HS, ASA, Fe) • K - anaphylaCTic • E - endocrine/adrenal crisis Having a good DDx in the back of you head is absolutely KEY to providing appropriate subsequent care

8. Pediatric Shock: • S - septic • S - spinal (neurogenic) • H - hypovolemic: gastro, abdo surgicalemergency, DKA • H - hemorrhagic • O - obstructive (PE, pthrx, hthrx, ct) • C - cardiogenic (rate- SVT, contractility, obstruction, valve, congenital heart dz) • C - cellular toxins (CN, CO, HS, ASA, Fe) • K - anaphylaCTic • E - endocrine: adrenal crisis (CAH)/hypoglcemia/metabolic defects

9. Why is the DDx so important? • After primary survey & initial resus optimal further Tx can be radically different depending on etiology • E.g. fluid resus in sepsis vs. penetrating trauma • Epi for anaphylactic vs. cardiogenic shock • Re-emphasizes point that shock is a symptom – not the disease

10. Empiric Criteria for Diagnosis of Circulatory Shock • Need any 4 of: • Ill appearance or altered mental status • Heart rate > 100 beats/min • RR > 22 breaths/min or PaCO2 < 32 mm Hg • Arterial base deficit < –5 mEq/L or lactate > 4 mM • Urine output < 0.5 ml/kg/hr • Arterial hypotension > 20 minutes duration • From Rosens Textbook of Emergency Medicine

11. Diagnosing Shock • The dilemma • The more advanced the shock state, the easier it is to identify but • Significant tissue hypoxia appears to exist prior to development of significant signs & symptoms • Normal BP in face of hypovolemia means some organs are hypoperfused to maintain systemic BP • Evidence suggests we are frequently underestimating disease severity in pts w/ early shock (see Rivers study) • Early reversal of shock is key determinant of preventing MODS

12. Diagnostic Adjuncts • Base deficit • = amount of strong base required to be added to a liter of blood to normalize the pH; should > –2 mEq/L; < -4 mEq/L predicts MOF • Shock index • HR/systolic BP; should be less than 0.8 (more sensitive than either alone) • Lactate • [lactate] > 4.0 mM predicts MOF • Lactate clearance index • Serial [lactate] should decrease by 50% 1 hour w/ resus • Urine output • Should be > 0.5 ml/kg/h; requires Foley & 30 min to be accurate • SvO2 (mixed venous O2 sat) • Should be >70%; limits of physiologic compensation at 50%

13. Future Adjuncts? • NIRS (Near-Infrared Spectroscopy) • Same basic principle as SpO2 monitors except measures tissue O2 • Sublingual Tonometry • Uses sublingual vascular bed as marker for splanchnic perfusion • Thoracic bioimpedance • Similar to ECG; uses multiple electrodes to measure impedance across thorax as estimate of CO • None in common use yet; no outcome studies evaluating their utility

14. Case 1 • 39 M stabbed multiple times by jealous lover • O/E: 355, 140, 80/p, 22, 90% RA • What do you do for him?

15. ATLS Classification of Hemorrhagic Shock Blood Products ASAP

16. Tx of Hypovolemic Shock • ABC’s • Direct pressure on any bleeder • Estimated 20% of combat deaths in Vietnam could have been prevented w/ pressure or tourniquet • Up to 2 L of fluid – then blood…right? • Depends on underlying etiology • Trauma: Blunt vs. penetrating • Dehydration etc

17. Fluid Resus in Hemorrhagic Shock • Multiple Controversies • Which fluid? • Crystalloids: NS, Ringers lactate (RL) • Colloids: Albumin, Starches, Dextrans, Gelatins • Hypertonic saline +/- dextran • Oxygen carrier substitutes • Blood products • How much fluid? How fast? • Blunt vs. penetrating trauma • What end-points should be used?

18. Historical Overview Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation. Lancet 2004; 363: 1988–96

19. Crystalloids Resuscitate both intra- & extravascular compartment Improve organ function Minimal risk of anaphylactoid reactions Inexpensive Reduce colloid oncotic pressure -- may predispose to pulmonary and peripheral edema Decrease gas exchange Delayed wound healing Colloids Require less volume Work faster Improve organ function Risk of anaphylaxis Risk of infection Risk of coagulopathy Dextrans > starches > gelatins Expensive Crystalloids or Colloids?Theoretical Pro’s & Con’s

20. Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82–S88.

21. Crystalloids or Colloids?What is the Evidence? • Meta-analysis of 16 RCT’s of isotonic crystalloids vs. colloids • Primary outcomes of mortality & pulmonary edema • Results: • No statistically significant differences found for mortality, pulmonary edema, or LOS • Subgroup Analyses • Trend in favor of crystalloids (RR 0.64, 95% CI: 0.17 to 2.42) for decreasing pulmonary edema in trials with well-described randomization methods • Trend to decreased mortality w/ crystalloids in trauma pts (RR 0.39, 95% CI: 0.17 to 0.89) • Analysis underpowered to detect small but imp differences • Concluded: • Results equivocal; unable to argue for or against either fluid due to lack of power & study heterogeneity Choi PTL, et al. Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med. 1999; 27: 200-10

22. Crystalloids or Colloids?What is the Evidence? • Meta-analysis of 18 RCT’s • Primary outcome: all cause mortality • Results • Albumin or plasma protein fraction: 7 RCTs RR1.52 (1.08 to 2.13). • Hydroxyethylstarch: 7 RCTs RR 1.16 (0.68 to 1.96). • Modified gelatin: 4 RCTs RR 0.50 (0.08 to 3.03). • Dextran: 8 RCTs RR 1.24 (0.94 to 1.65). • Colloids in hypertonic crystalloid compared to isotonic crystalloid: • albumin and hypertonic saline vs. isotonic crystalloid: 1 RCT RR of death 0.50 (0.06 to 4.33) • dextran in hypertonic crystalloid vs. isotonic crystalloid: 8 RCTs RR 0.88 (0.74 to 1.05) • Conclusions: • No benefit for colloids; should not be used Alderson, P; Schierhout, G; Roberts, I; Bunn, F. Colloids versus crystalloids for fluid resuscitation in critically ill patients . 2004; 2. The Cochrane Database of Systematic Reviews

23. Crystalloids or Colloids?What is the Evidence? • Analyzing the meta-analyses • 6 meta-analyses to date on crystalloids vs. colloids • All fail to show statistical difference • All indicate trend towards increased mortality w/ colloids in trauma pts • Many limitations in primary studies Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82–S88.

24. Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82–S88.

25. Rizoli. 2003 cont’d • Concluded • “The first limitation of a meta-analysis is that it can only be as good as the quality of the individual RCTs it includes” • “meta-analysis should be interpreted cautiously and …viewed as hypothesis generating given the limitations in both study design and limitations of the primary RCTs” • Large well done trial is needed but evidence suggests trauma pts should continue to be resuscitated w/ crystalloids Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82–S88.

26. Crystalloids or Colloids? • Conclusion • No real conclusive data to firmly support one over the other but trend towards harm w/ colloids in trauma • Lots of limitations in primary studies limits utility of meta-analyses • Given cost, ease of use, and familiarity crystalloids should continue to be our primary fluid in the ED

27. Hypertonic Saline

28. Hypertonic Saline • HTS = 7.5% saline +/- 6% dextran (HTS-D) • Dose: 4 ml/kg or 250 cc as initial bolus over 5-10 min • MOA: • shifts water 1st out of RBCs & endothelium into plasma, & then out of interstitium & tissue cell • a rapid but transient improvement in intravascular volume & hemodynamics • hemodilution and endothelial cell shrinkage  decreased capillary hydraulic pressure  improved perfusion.

29. Advantages Improves hemodynamics, lowers subsequent fluid and blood requirements, and improves DO2 Many animal studies and clinical trials demonstrate this Decreased inflammatory response may limit ischemia / reperfusion injury and thus decrease MOF May be neuroprotective Small fluid volume required Disadvantages Primarily theoretical: Rare to non-existent reports in literature Primarily related to hypernatremia, rapid volume expansion, & dextran Central pontine myelinolysis Worsened bleeding Shown in animals but not observed in human trials Interference w/ X-matching Anaphylactoid reactions (dextran) Hypertonic Saline Orlinsky, M. Current controversies in shock and resuscitation.Surg Clin North Am 2001; 81(6): 1217-62

30. Cochrane Review • Methods • Systematic review of mortality in17 studies of HTS or HTS-D vs. isotonic crystalloids in trauma, burn, & surgical pts • Only 6 were adequate methodology (5/6 trauma trials) • Results: • Trauma: RR for death w/ HTS 0.84 (0.61-1.16) • Burns: RR for death w/ HTS 1.49 (0.56-3.95) • Surgery: RR for death w/ HTS 0.62 (0.08-4.57) • Conclusions: • Data too limited to exclude or prove benefit from HTS • Need more & larger trials to narrow CI’s • Bunn, F et al. Hypertonic versus isotonic crystalloid for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews. 2004

31. Is dextran confounding? • Meta-analysis of 12 RCT’s • Analyzed HTS & HTS-D separately in hypotensive trauma pts • Results • 4/6 HTS trials “positive” but non-significant pooled OR 0.98 (0.71 - 1.36) • 7/8 HTS-D trials “positive” but non-significant pooled OR 1.20 (0.94 - 1.57) • Only 1/8 trials reached statistical significance • Concluded • HTS-D appears better than HTS, and both may be better than isotonic crystalloids (but fails to reach significance) • Wade, CE et al. Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: A meta-analysis of controlled clinical studies. Surgery 1997;122:609-16.

32. HTS: Conclusion • Looks promising, lots of theoretical benefits, but so far no convincing evidence its better (or worse) than isotonic crystalloids • Data limited • Small studies • Heterogeneous populations • Different solutions used • Virtually all adult studies – unable to extrapolate to peds

33. Oxygen-carriers • 3 basic types • Hemoglobin-based • Surface-modified hemoglobins • Intramolecular cross-linked hemoglobins • Polymerized hemoglobins • PolyHeme – promising; in Phase III trials • Hemopure – approved in S. Africa; trials ongoing • Hemolink – promising; trials ongoing • Perfluorocarbons • Work by allowing large amts of O2 to dissolve in them but studies disappointing to date • Liposome-encapsulated Hemoglobin • Costly, potential RES overload • Jury is still out on these but they are coming

34. Delayed vs. Early Fluid Resuscitation

35. The Golden Hour • Perspective • Hypotension occurs after ~1/3 loss of blood volume (~1.5 L in 70 kg adult) • Death occurs after ~50% loss of blood volume • Rate of bleeding determines “golden hour” • 25 cc/min – hypotensive at 1 hr; dead at 2 hrs e.g. liver laceration • 100 cc/min – hypotensive at 15 min, dead at 30 min e.g. vascular injury

36. Delayed Bleeding from injured vessels will decrease due to clot formation, vasoconstriction etc Fluid resus may increase hemorrhage: Raises BP increasing hydraulic pressure Vasodilate Dilute clotting factors Early Fluid resus increases perfusion & DO2 to end organs Prolonged hypoperfusion leads to MODS = main cause of post-traumatic death after immediate exsanguination or head injury Delayed vs. Early Fluid ResusPro’s and Con’s

37. Historical Background • Early 1900’s fluid resus was frowned upon • Canon in 1910 pointed out that increasing BP prior to achieving hemostasis could “pop the clot” • 50’s -60’s: Popularity of fluid resus • based on animal data where rapid reversal of shock induced by controlled blood loss (e.g. through phlebotomy) w/ IV fluids improved survival • Subsequent studies of uncontrolled blood loss (e.g. razor wire into aorta) found decreased survival w/ aggressive fluid resus • Raising BP caused more bleeding • Limited resus targeting lower BP’s improved survival the most

38. Bickell, WH et al. Immediate versus Delayed Fluid Resuscitation for Hypotensive Patients with Penetrating Torso Injuries. NEJM 1994; 331: 1105-09 • RCT of 598 pts >16 yo w/ penetrating torso trauma in urban setting • Odd/even day randomization into early (prehospital ATLS protocol) or delayed (no fluids until in OR) fluid resuscitation • Results • Sig increased survival in delayed group (70% vs. 62%, P = 0.04) • Significantly prolonged PT/PTT in immediate resus group -- ?clinical significance

39. Criticisms • Odd / even day randomization • Rapid transport times (12-13mins) • How does this change in rural setting? • Not analyzed in Intention-to-treat fashion • ITT analysis of data failed to show sig benefit • Relatively small volumes of fluids used • High mortality rates in both groups • Most of the benefit appeared to occur in pts w/ tamponade

40. Cochrane Review • Systematic review of RCT’s looking at • Early vs. delayed fluid resus • Large vs. small volume fluid resus • Found 4487 potential papers – only 6 met the inclusion criteria • Unable to combine the results quantitatively due to heterogeneity Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004

41. Cochrane Review • Early versus delayed fluids: • Bickel 1994: • 598 hypotensive penetrating torso trauma pts • Mortality 116/309 (38%) vs. 86/289 (30%) • RR for death w/ early fluids was 1.26 (95% CI 1.00-1.58) • Blair 1986: • 50 hypotensive pts w/ UGIB • Mortality 2/24 (8%) vs. 0/26 (0%) • RR for death w/ early blood transfusion was 5.4 (95% CI 0.3-107.1) • Turner 2000: • 1309 trauma pts • Mortality 73/699 (10.4%) vs. 60/610 (9.8%) • RR for death with early fluids was 1.06 (95% CI 0.77-1.47). Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004

42. Cochrane Review • Large vs. small volume fluid resus • Dunham 1992: • 36 hypotensive trauma pts. • Mortality 5/20 (25%) vs. 5/16 (31%) • RR for death for large volume was 0.80 (95% CI 0.28-2.29) • Dutton 2002: • 110 hypotensive blunt & penetrating trauma pts • Mortality 4/55 (7.3%) vs. 4/55 (7.3%) • The RR for death w/ large volume was 1.00 (95% CI 0.26-3.81). • Fortune 1987 • 25 pts; No mortality data Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004

43. Cochrane Review • “This review found insufficient evidence for or against the use of early or larger volume fluid resuscitation in the treatment of uncontrolled haemorrhage. While vigorous fluid resuscitation may be life-saving in some patients, results from clinical trials are inconclusive.” Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding. (Cochrane Review). In: The Cochrane Library, Vol 2; 2004

44. So give fluids…Don’t give fluids? • Best study to date (Bickel 1994) • Suggests we should limit pre-OR fluid resus in penetrating trauma • Tons of variables & unanswered questions • At what time point does reversal of benefit occur? i.e. when does the wait become too long? • How does this apply to blunt trauma? • In pigs there appears to be a middle ground – is there an ideal SBP at which we should maintain pts? • Different etiologies of shock likely need different approaches • How does choice of resus fluid figure in all of this? • Limiting resus to attain SBP ~90 mm Hg • makes intuitive sense, and is recommended by some authorities BUT at this point has not been adequately studied

45. Experimental Treatments in Hemorrhagic Shock • Vasopressin • Promising in porcine models • Oxygen carriers • No large clinical trials yet • FVIIa concentrate • No conclusive evidence yet – stops bleeding but also appears to cause thrombotic complications

46. Case 2 • 65 M presents w/ fever & AMS • PMHx: DM, HTN, • O/E: 392, 122, 100/45, 24, 90% RA, GCS14 • CXR: bilateral pulm infiltrates • What do you want to do for him?

47. Septic Shock

48. Epidemiology • Incidence variable but on the rise • ~ 1/1000 – 260/1000 pts days • Larger # of elderly, HIV, chemotherapy, organ transplant, and dialysis pts in addition to diabetics, alcoholics etc • Mortality ranges from 3% for pts w/ no SIRS criteria to 46% for septic shock • Locally ~250 ICU admissions for sepsis per year

49. Latest ACCP/SCCM Consensus Definitions • Infection = invasion of organ system(s) by microorganisms • Sepsis = systemic host response to infection requiring > 1 signs & symptoms of sepsis • Severe sepsis = sepsis w/ organ failure • Septic shock = severe sepsis w/ cardiovascular failure requiring vasoactive medications • Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

50. Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003