Shock - Calgary Em

Shock - Calgary Em

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

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%

Initial Approach Triage to resus bay O2, monitors, IVs x2, help ABCs 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 Initial Approach D Disability & Neuro E Environment, Exposure, Every vital sign There are 6 vitals dont 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 DDx: Mechanistic Approach SHOCK Vasculature Decreased vascular tone: Neurogenic shock Septic shock Endocrine shock Increased Permeability: Anaphylaxis Sepsis & SIRS

Pump Cardiogenic: MI / ischemia Arrhythmias Cardiomyopathies Myocarditis Trauma Wall rupture Drug (BB, CCB, TCA) OD Obstructive: PE Tamponade Valves (Stenosis, thrombosis, rupture) PTX Congenital defects (Coarctation & other ductus-dependant lesions) Volume

Hypovolemia: GI losses Hemorrhage Third spacing / inflammation Anaphylaxis Burns Insensible losses Metabolic Endocrinological Causes: Addison's CAH Adrenal infarct Chronic steroids Cellular Poisons: Carbon monoxide Methemoglobinemia Hydrogen sulfide Cyanide

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 Pediatric Shock: S septic S spinal (neurogenic) H hypovolemic: gastro, abdo surgical

emergency, 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 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 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 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 Diagnostic Adjuncts Base deficit Shock index Serial [lactate] should decrease by 50% 1 hour w/ resus Urine output

[lactate] > 4.0 mM predicts MOF Lactate clearance index HR/systolic BP; should be less than 0.8 (more sensitive than either alone) Lactate = 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

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% 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 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? ATLS Classification of Hemorrhagic Shock Blood Products ASAP Tx of Hypovolemic Shock ABCs 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 bloodright? Depends on underlying etiology Trauma: Blunt vs. penetrating Dehydration etc 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? Historical Overview Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation. Lancet 2004; 363: 198896 Crystalloids or Colloids? Theoretical Pros & Cons

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 Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82S88. Crystalloids or Colloids? What is the Evidence? Meta-analysis of 16 RCTs 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. Crystalloids or Colloids? What is the Evidence? Meta-analysis of 18 RCTs 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 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:S82S88. Rizoli, SB. Crystalloids and Colloids in Trauma Resuscitation: A Brief Overview of the Current Debate. J Trauma. 2003;54:S82S88. Rizoli. 2003 contd 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:S82S88. 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 Hypertonic Saline 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. Hypertonic Saline Advantages Improves hemodynamics, lowers subsequent fluid and blood requirements, and improves DO2 Disadvantages

Rare to non-existent reports in literature Primarily related to hypernatremia, rapid volume expansion, & dextran 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

Primarily theoretical: Central pontine myelinolysis Worsened bleeding Shown in animals but not observed in human trials Interference w/ X-matching Anaphylactoid reactions (dextran) Orlinsky, M. Current controversies in shock and resuscitation.Surg Clin North Am 2001; 81(6): 1217-62

Cochrane Review Methods Results: 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) 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 CIs Bunn, F et al. Hypertonic versus isotonic crystalloid for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews. 2004 Is dextran confounding? Meta-analysis of 12 RCTs

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. 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 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 Delayed vs. Early Fluid Resuscitation 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 Delayed vs. Early Fluid Resus Pros and Cons 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 posttraumatic death after immediate exsanguination or head injury Historical Background Early 1900s fluid resus was frowned upon 50s -60s: Popularity of fluid resus

Canon in 1910 pointed out that increasing BP prior to achieving hemostasis could pop the clot 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 BPs improved survival the most 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 Criticisms

Odd / even day randomization Rapid transport times (12-13mins) Not analyzed in Intention-to-treat fashion How does this change in rural setting? 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

Cochrane Review Systematic review of RCTs 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 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 0.3107.1) 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 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 0.263.81). 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 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 lifesaving 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 So give fluidsDont give fluids? Best study to date (Bickel 1994) Tons of variables & unanswered questions

Suggests we should limit pre-OR fluid resus in penetrating trauma 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 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 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? Septic Shock 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 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 Vincent & Jacobs. Curr Opin Infect Dis 16: 309-13. 2003

Classifications reflect disease severity Diagnostic category SIRS criteria none 3 2 7 3 10 4 17 Sepsis 16 Severe sepsis Septic shock Mortality (%) 20 46 McCoy & Matthews. Drotrecogin Alfa (Recombinant Human

Activated Protein C) for the treatment of severe sepsis. Clin Ther 2003; 25: 396-421 INFLAMMATION PATHOGENS TNF-, IL-1, IL-6, IL-7, Proteases, Leukotrienes, Prostaglandins Bradykinin, Platelet activating factors Free oxygen radicals Endotoxins, Exotoxins Direct endothelial invasion SEPSIS TF EXPOSURE

ENDOTHELIAL INJURY ANTI-COAGULANT SYSTEM INHIBITON AT III, aPC, pS thrombomodulin ACTIVATION OF CLOTTING CASCADE FIBRINOLYTIC SYSTEM INHIBITION PAI-1 PRO-COAGULANT EFFECT MICROVASCULAR THROMBOSIS MULTI ORGAN DYSFUNTION SYNDROME SCCM Guidelines for Treatment of Septic Shock

Utilize EGDT in 1st 6 hrs Cultures before Abx Source control Aggressive rehydration with colloid or crystalloid Use dopamine or norepinephrine for refractory shock Give stress dose steroids

Give rhAPC when appropriate Keep Hb 70-90 Use low TVs & minimal peak pressure & PEEP vent strategy Use insulin therapy Avoid Supranormal oxygenation Bicarb

Dellinger et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004; 32: 858-73 Early Goal Directed Therapy Rationale behind EGDT Time is survival: Goal is to achieve balance b/w O2 delivery & consumption

Standardized approaches to ED Tx have improved outcomes in other Dz (e.g. MI) Traditional parameters of perfusion appear to be too insensitive for ongoing tissue hypoxia Early observational trials found survivors to have supranormal hemodynamic parameters Earlier Trials No consistent benefit from using goal-directed therapy to optimize oxygen delivery in ICU patients

Gattinoni et al. A trial of goal-directed hemodynamic therapy in critically ill patients. N Eng J Med 1995; 333: 1025-32 Hayes et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Eng J Med 1994; 330: 1717-22 Yu et al. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective randomized controlled study. Crit Care Med. 1993; 21: 830-8 Boyd et al. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA. 1993; 270: 2699-707 Tuchschmidt et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992; 102: 216-20 Shoemaker et al. prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94: 1176-86 Earlier Trials

Limitations: Heterogeneous study populations Small sample sizes & wide CIs Enrollment after ICU admission Tended to focus on one intervention in isolation Most used PA catheters Rivers et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Eng J Med. 2001; 345: 1368-77 Prospective RCT of 263 adult pts with sepsis treated either with traditional care or a standardized resuscitation protocol in the ED

All had arterial & central venous lines placed the EGDT group got a catheter capable of continuous O2 sat measurement EGDT discontinued once transferred to ICU all ICU staff blinded to pts assignments Primary endpoint was mortality EGDT Protocol Edwards PreSep Central Venous Oximetry Catheter Rivers et al. 2001 (contd) Found that EGDT did significantly better

In-hospital mortality 30.5% vs. 46.5%, ARR 16%, NNT = 6; OR 0.58 (95%CI 0.38 0.87) 60d mortality 44.3% vs. 56.9% Primarily explained by reduction in sudden CVS collapse deaths (10.3% vs. 21.0%) Various secondary outcomes (labs & severity scores) significantly better in EGDT group EGDT pts spent longer time in the ED EGDT survivors spent less time in hospital than standard Tx survivors (14.6 d vs. 18.4 d) Baseline SVO2 was 48% despite only 50% ventilated Rivers et al. 2001 (contd) Differences in EGDT group

More fluid early (4.9 L vs. 3.5L) More transfusions (64.1% vs. 18.5%) More inotropic support (13.7% vs. 0.8%) Less use of pulmonary artery catheters later in ICU stay (18% vs. 31.9%) Controversies Above average mortality in both Tx arms Liberal use of transfusion Use of SvO2 never thoroughly studied as resus end point is it equivalent to SmO2? Conflicts with earlier studies showing lack of benefit from using hemodynamic goals

Hayes et al. N Eng J Med 1995; 330: 1717-22 Gattinoni et al. N Eng J Med 1995; 333: 1025-32 Different time points all prior studies in ICU setting More heterogeneous patient populations Controversies Transfusion practice How does this fit with the TRICC trial? Need for IJ or SC lines Which part of protocol accounts for benefit? How will this affect department flow? Does this protocol have any applicability to other shock etiologies?

Why the TRICC trial does not contradict Rivers et al Different patient population Euvolemic pts Enrolled within 72 hrs of ICU admission Only 6% had Dx of sepsis, and only 26.5% had any infection at all Supporting data Success of hemodynamic optimization appears time-dependent

Meta-analysis of ICU pts Studies instituting PAC goal-directed therapy later than 12 hrs or after onset of organ failure failed to show benefit Studies that intervened early found to result in significant mortality reduction of 23% (95%CI 16-30) Kern et al. Meta-analysis of hemodynamic optimization in high-risk patients. Crit Care Med 2002; 30: 1686-92 Fluids in Sepsis How much fluid? Till they froth at the mouth!! These pts need a ton of fluid average of 6L in Rivers study Note difference compared to approach to penetrating trauma

Vasopressors Just need a little squeeze.. Vasopressors: Dopamine: Dose: 1-5 ug/kg/min: 10ly dopaminergic effect 5-10 ug/kg/min :10ly beta effect 10-20 ug/kg/min : 10ly alpha effect Levophed:

Dose: 0.01 3 ug/kg/min MOA: 10ly potent alpha agonist Some beta effect Controversies Used to be thought that it worsened tissue perfusion More recent studies contradict this Norepinephrine or Dopamine 1st

in septic shock? Tons of animal data; very few clinical studies Decreased mortality w/ norepinephrine vs. dopamine in one NON-randomized trial Theoretical benefits w/ norepinephrine Less tachycardia No effect on HPA or cerebral perfusion pressure Increased GFR Decreased lactate levels

Improved splanchnic blood flow Vincent & de Backer. Crit Care 2003; 7: 6-8 On the other hand dopamine is quickly available and familiar Bottom line = either will do as an initial pressor Antibiotics SCCM Guidelines

Draw appropriate cultures first Give antibiotics within 1 hr of recognition of septic syndrome Antibiotics should be broad-spectrum & chosen to cover most likely organisms based on presentation & local resistance patterns Arrange for further diagnostic studies to rule out surgically correctable foci of infection once appropriate Remove lines & tubes if appropriate GIVE ABX EARLY Autopsy studies in persons who died in the intensive care unit show that failure

to diagnose and appropriately treat infections with antibiotics or surgical drainage is the most common avoidable error Hotchkiss & Karl. The pathophysiology and treatment of sepsis. N Eng J Med. 2003; 348: 138-50 Local ID recommendations: Quick reference guide Undifferentiated febrile shocky pt w/ no focus

Ceftriaxone Gentamicin or quinolone Meningitis Ceftriaxone + macrolide or resp quinolone Urinary tract Intraabdominal

Respiratory Ceftriaxone +/- vancomycin +/- ampicillin Ancef + flagyl + gentamicin (24 hr dosing) Ceftriaxone + flagyl Pip-tazo Carbapenem

Necrotizing fasciitis IVIG + penicillin + clindamycin + surgery Dr. Dan Gregson personal communication A Plea from Dr. Kortbeek When inserting central lines, chest tubes etc

Wear a sterile gown Wear a mask Prep & drape a huge area Communicate potential dirty lines to admitting service Ventilatory Strategies Background Traditional vent parameters TV 10 15 ml/kg, minimal PEEP to maintain normal PCO2, PO2 & pH ARDS mortality as high as 90% in the 70s

(currently 30-40%) Gattinoni et al. Physiologic rationale for ventilator setting in acute lung injury / acute respiratory distress syndrome patients. Crit Care Med. 2003; 31(S): S300-04 ARDS-Net trial Multicenter RCT of 861 adults with ARDS Randomized within 36 hrs of intubation to: Control group Vt 12 ml/kg predicted body wt on AC mode Adjusted Vt to keep plateau pressure b/w 45-50 cm H2O Low Vt group

Vt 6-8 ml/kg predicted body wt on AC mode Adjusted Vt to keep plateau pressure b/w 25-30 cm H20 Followed for 180 days Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute . N Eng J Med. 2000; 342: 1301-8 respiratory distress syndrome ARDS-Net trial (contd) Primary outcomes

In hospital mortality Ventilator-free days in first 28 days Secondary outcomes Organ failure Barotrauma Plasma IL-6 levels ARDS-Net trial (contd) Results: Low Vt group had Sig decreased mortality 31.0% vs. 39.8% ARR 8.8% (95%CI 2.4-15.3%); NNT = 11

Numerous improved secondary outcomes Conclusions General consensus in the literature that ARDS trial results are valid, and that VT should be 6-8 ml/kg Plateau pressures should be kept to < 30 cm H2O PEEP should be used to minimize alveolar collapse at pressures as low as possible (start 5-10 cm H2O) Steroids Background Anti-inflammatory effects

Basis for large dose (primarily methylprednisolone 30 mg/kg followed by 5 mg/kg }steroid trials in 80s 2 large RCTs failed to show benefit Veterans administration. Effect of high-dose glucocorticoid therapy on mortality in patients wit clinical signs of systemic sepsis. N Eng J Med. 1987; 317: 659-65 Bone et al. A controlled clinical trial of high dose methylprednisolone in the treatment of severe sepsis and septic shock. N Eng j Med. 1987; 317: 653-58 Meta-analysis of 9 RCTs found no benefit, and possibly increased mortality w/ large dose steroids RR 1.13, 95%CI 0.99 1.29

Cronin et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med. 1995; 23: 1430-39 Background Concept of adrenal insufficiency Stress steroid response essential Taking out adrenals increases septic & hemorrhagic shock mortality in animals -- reversible with exogenous steroids Bilateral adrenal necrosis or infarction noted in ~30% of septic pts at autopsy Multiple factors affect HPA axis during stress Studies of sepsis pts have shown that up to 42% have adrenal or HPA dysfunction which correlates w/ increased

mortality Multiple studies document improved catecholamine response in steroid-treated septic shock Prigent et al. Clinical review: Corticotherapy in sepsis. Crit Care 2004; 8: 122-29 Annane et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71 Multicenter DBRCT of 300 adult septic shock pts tested with short corticotropin test & randomized to Placebo or

Hydrocortisone 50 mg q6h IV & fludrocortisone 50 ug PO OD for 7 days Primary outcome 28d survival Annane et al contd Results No significant difference in mortality for all pts Non-responders treated w/ steroids had decreased 28d mortality

Less reliance on vasopressors 53 vs. 63%; ARR 10%, OR 0.54 (95%CI 0.31-0.97) NNT = 10 Non-responders: Median time to withdrawal 7 vs. 10 d; HR 1.91 (95%CI 1.29-2.84) All pts: Median time to withdrawal 7 vs. 9 d; HR 1.54 (95%CI 1.10-2.16) No significant differences in adverse events Criticisms

Possible inclusion of true adrenal insufficiency Use of fludrocortisone in addition to hydrocortisone Not widely practiced CORTICUS trial ongoing to evaluate hydrocortisone alone in septic shock Underpowered to detect harm in responders

High mortality rate in placebo group Trend towards harm in responders needs clarification Avoid steroids for all approach Change of entry criteria during study No analysis of pts recruited before & after DX of adrenal insufficiency What is a normal serum cortisol during stress? Most controversial area -- Nobody knows No clear cut normal range: Serum cortisol levels variable & poorly reflective of biologic action during stress

Elevated and depressed cortisol levels are both associated w/ increased morbidity & mortality Current approach to Dx based on consensus opinion & limited literature Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N Eng J Med. 2003; 348: 727-34 Serum free cortisol measurements appear to be more predictive & may become new standard Harnrahian et al. Measurement of serum free cortisol in critically ill patients. N Eng J Med 2004; 350: 1629-38

Suggested diagnostic approach Draw a random cortisol level Perform a ACTH stim test Administer 250 ug of cosyntropin IV Draw serum cortisol levels at 0, 30, and 60 min Give dexamethasone 2-4 mg in ED Does not interfere w/ ACTH stim test Treatment should be stopped if test negative Serum cortisol levels >1242 nmol/L have been found to be

associated w/ significantly greater mortality Suggests that exogenous steroids could be harmful Sam et al. Cortisol levels and mortality in severe sepsis. Clin Endo. 2004; 60: 29-35 Interpreting results Random cortisol < 414 nmol/L (15 ug/dL) suggestive of adrenal insufficiency start steroids

>938 nmol/L (34 ug/dL) suggestive of steroid resistance replacement unlikely to help 414 938 nmol/L base decision on ACTH stim test result ACTH stim test >250 nmol/L (9 ug/dL) change adrenal insufficiency unlikely <250 nmol/L (9 ug/dL) change suggestive of adrenal insufficiency start steroids Cooper & Stewart. Corticosteroid insufficiency in acutely ill patients. N Eng J Med. 2003; 348: 727-34 Steroid conclusions Think of steroids in pts w/ apparent septic

shock refractory to standard treatment Draw baseline cortisol levels & do ACTH stim test Use dexamethasone in the ED Do NOT give steroids card blanche Await trials on use of free cortisol Recombinant Human Activated Protein C (rhAPC = Drotrecogin alfa = Xigiris aka superdrug) Background No pharmacologic agent shown to reduce in sepsis mortality in phase III trials.

Ibuprofen NAC Anti-TNF- mAb vs. placebo (NORASEPT II) IL-1 receptor antagonist vs. placebo PAF receptor antagonist vs. placebo High dose steroids Bradykinin antagonist (Deltibant) Tissue factor pathway inhibitor AT III vs. placebo (KYBERSEPT) Etc, etc until now (maybe)

PROWESS Trial: Bernard et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Eng J Med 2001; 344: 699-709 Multicenter DBRCT of 1690 adult pts w/ severe sepsis Randomized to rhAPC infusion @ 24 ug/kg/h for 96 hrs Placebo Primary outcome All-cause mortality at 28d Bernard et al. contd Results

rhAPC significantly reduced mortality 28d mortality 24.7% APC vs. 30.8% placebo ARR 6.1% (95% CI 1.9-10.4); NNT = 16 rhAPC had non-significant increase in risk of serious bleeding 3.5% vs. 2.0% (p=0.06), NNH = 67 Sounds great, but dont forget to read the fine print Post hoc analyses Pts w/ APACHE II scores <25 did worse w/ rhAPC than w/ placebo Benefit decd w/ less organ dysfunction

ARR single organ system 1.7% ARR multi-organ failure 7.4% More benefit in pts w/ septic shock rather than sepsis Pts not in DIC did worse w/ rhAPC than w/ placebo Cost $335 Cdn per 5 mg vial 0.024 mg x 70g kg x 96 hrs = ~161 mg or 32 vials = $10, 800 Cdn per treatment

Is it cost-effective? Yes, if used selectively. Cost per life-year gained APACHE II <25 $19, 723 USD APACHE II >25 $575,054 USD Total cost to our system CHR ICU pharmacy budget 2001: $1.6 million USD Cost if rhAPC was used in pts w/ APACHE II > 25: $482,800 USD Manns et al. An economic evaluation of activated protein C for severe sepsis. N Eng J Med. 2002; 347: 993-1000

The Future ADDRESS Trial Placebo-controlled trial of rhAPC in lower-risk pts w/ severe sepsis Trials in pediatric populations Trials examining use of heparin in conjunction w/ rhAPC Development of more defined criteria for selecting pts likely to benefit from rhAPC Septic Shock Summary Mortality reduction strategies:

EGDT: ARR 16.0% ARDSNet vent strategy ARR 8.8% Steroids ARR 10.0% rhAPC ARR 6.1% Insulin ARR 3.4% Dex in Meningitis ARR 8.0% Early appropriate Abx Source control Case 3 56F w/ SOB & pleuritic CP & syncope PMHx: Breast CA, Hx of DVT O/E: 370, 110, 80/40, 86% RA, big fat red leg

ECG: deep S in I, Q in III, inverted T in III, RV strain pattern CXR: Hamptons hump, Westermark sign Echo: high right-sided pressures, RV dilation D-dimer: 7.0 Are you going to thrombolyse her? Obstructive Shock: PE 25% mortality for shock 2o to PE 2/3 of pts w/ fatal PE die within 1 hr of presentation BUT

Only a few pts w/ massive PE exhibit shock many more exhibit RV dysfunction but never deteriorate into shock Indications for thrombolysis Very controversial Shock is the one indication most experts agree on Based only on hemodynamic improvements No good mortality data Wood. The presence of shock defines the threshold to initiate thrombolytic therapy in patients with pulmonary embolism. Crit Care Med. 2002. 28:15371546 PE + Shock: Thrombolyze?

Meta-analysis 9 RCTs of 461 pts: lytics vs. heparin Only 1 study (n=8) demonstrated mortality benefit (all pts in shock) No statistically sig benefit for 10 outcomes: Pooled RR for death w/ lytics: 0.63 (0.32-1.23) No sig difference in shock subset analysis Pooled RR for recurrence : 0.59 (0.30 1.18)

Statistically sig increase in serious bleeds RR 1.76 (1.04 2.98), NNH = 17 Thabut et al. Thrombolytic Therapy of Pulmonary Embolism: A Meta-Analysis J Am Coll Cardiol 2002;40:1660 7 Conclusion: No good literature support for thrombolysis in PE but Small studies (underpowered)

No good studies looking at shock exclusively Good physiologic and observational data to support use in PE + shock Most experts agree it should be given in shock OK, So what is the dose? Standard regimen: Alteplase: 10 mg IV bolus, then 90 mg over 2 hours Rapid regimen: Alteplase: 0.6 mg/kg over 15 min Case 4 48 yo Male w/ crushing RSCP radiating to L

arm & jaw while shoveling snow PMHx: DM, HTN, Chol, Smoker, Obese FHx: 3 brothers, 6 sisters, 2 fathers, 2 mothers all w/ MIs in their 40s Pale, diaphoretic, vomiting, GCS 8, SOB 373, 120, 75/palp, 22, 89% RA ECG: tombstones in V2-4 w/ reciprocal changes What do you want to do with him? Approach to Cardiogenic Shock

ABCs Consider DDx & identify etiology MI, myocarditis, dissection, arrhythmia, LV wall rupture, cardiomyopathy, PE, valve, tamponade, ODs, etc Your Tx plan is CRRRAP C Contractility (inotropes, IABP)

R Rate control R -- Rhythm control R Reperfusion strategies (PTCA, lytics) A Afterload reduction P Preload (fluids) Management Are you going to cath him? Lyse him? Anything else? Reperfusion Strategies PTCA or Lytics? The SHOCK Trial RCT of 302 pts w/ AMI & shock randomized to surgical (PTCA or CABG) vs. medical (lysis) Tx No significant mortality difference at 30d ARR 9.3% (20.5 to -1.9%)

Sig dec in mortality at 6 mo in surgical group ARR 12.8% (23.2 0.9%) Benefit sustained at 1 year Important Considerations PTCA appears to be slightly better than thrombolysis for all comers Keeley et al. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 1320 No trial has ever shown benefit of

reperfusion alone in shock pts IABP appears to be essential Case 5 49 F w/ fever, AMS, N&V, abd pain PMHx: HTN, Asthma, RA O/E: 384, 125, 85/30, 24, 87% RA CXR: RLL pneumonia Fluids, Abx, pressors still hypotensive What is going on? Dont forget about meds Pt is on prednisone 50 mg PO OD for last 20 years!!!! Etiology of Adrenal Crisis Pre-existing or New Adrenal Insufficiency

Addisons Chronic steroids Sepsis Adrenal infarcts / hemorrhage Pituitary infarct / hemorrhage Acute Precipitant Surgery Anesthesia Procedures Infection MI/CVA/PE

Alcohol/drugs Hypothermia Adrenal Crisis Tx: As for sepsis Draw a random cortisol level Perform a ACTH stim test Administer 250 ug of cosyntropin IV Draw serum cortisol levels at 0, 30, and 60 min Give dexamethasone 2-4 mg in ED

Does not interfere w/ ACTH stim test Treatment should be stopped if test negative Serum cortisol levels >1242 nmol/L have been found to be associated w/ significantly greater mortality Suggests that exogenous steroids could be harmful Sam et al. Cortisol levels and mortality in severe sepsis. Clin Endo. 2004; 60: 29-35 Case 6 32 yo M mountain biking goes over handlebars & lands on his head PMHx: none O/E: 370, 45, 80/60, 12, 95% RA, GCS 15 Tx? Why is he bradycardic?

Why is he hypotensive? Neurogenic Shock Differentiate b/w: Spinal shock: Loss of all cord function below level of injury occuring in first 24 hrs (occ several days) Neurogenic hypotension: Part of spinal shock get disruption of sympathetic innervation & unopposed vagal tone No reflex tachycardia (>T4) & peripheral vasodilation (>T6) Dx of exclusion in trauma

areflexia, flaccid paralysis, vasodilation, bradycardia Neurogenic Shock: Tx R/O other causes of shock 1st Tends to respond to Trendelenburg Fluids May require

Atropine 0.5 1.0 mg IV NB: Pre-Tx prior to intubation to avoid unopposed vagal stimulation bradyarrest Pressors: dopamine Generally should not require aggressive Tx: consider other causes Key Points Shock is a symptom, not a disease General approach (ABCs), then DDx is KEY!! SSHHOCCKE mnemonic or mechanistic approach

Empiric investigations & treatment is indicated

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