Objectives Evaluate recent literature on the management of sepsis Apply new and potentially controversial recommendations from the Surviving Sepsis Guidelines to patient cases. Surviving Sepsis Campaign Guidelines: Update (Early Goal Directed Therapy and Fluids) Simon Lam, PharmD Cleveland Clinic Outline Definitions, epidemiology, and pathophysiology Goals of therapy Protocolized, quantitative resuscitation Transfusion Fluid therapy choice Definitions Sepsis Systemic inflammatory response secondary to infection Severe sepsis Sepsis with organ dysfunction Septic shock Acute circulatory failure leading to ineffective tissue perfusion Hypotension unresponsive to fluid resuscitation Levy MM. CCM 23;31:125 6 Sepsis Incidence and Outcomes Hospital admissions for severe sepsis common and rising Over 75, cases per year Increased 13% per year from 24 to 29 Annual US costs exceed $24 billion Eleventh most common cause of death in the US Mortality rate depends on severity of illness Range 15% (sepsis) to 7% (septic shock and multi organ failure) Angus DC. CCM 21;29:133 1 Gaieski DF. CCM 213;41:1167 74 Martin GS. NEJM 23;348:1546 54 214 American Society of Health-System Pharmacists 1
Septic Shock Pathophysiology Features of each shock type Decreased preload Increased venous capacitance Loss of intravascular contents Impaired cardiac output Decreased stroke volume from low preload Cytokine induced myocardial dysfunction Vasodilation Inappropriate activation of vasodilatory mechanisms Failure of vasoconstrictive pathways Maldistribution of blood flow to organs or in the microcirculation Case MN is a 65 year old female presented to the emergency department with hospital acquired pneumonia Labs and vitals 138 3.8 99 15 4 1.8 198 18.8 8.5 25.5 115 Temp 1.9 F (38.3 C) HR 15 beats/min RR 31 breaths/min BP 8/55 (mean 63 mm Hg) Lactate 5.5 mmol/l Intubated and placed on mechanical ventilation Landry DW. NEJM 21;345:588 95 Dellinger RP. CCM 23;31:946 55 Would you recommend placement of a central line and initiation of resuscitation protocol to target CVP and ScvO2? Yes No SSC Recommendations: Initial Resuscitation Protocolized, quantitative resuscitation of patients with sepsis induced tissue hypoperfusion Goals during the first six hours of resuscitation Central venous pressure (CVP) 8 12 mm Hg Goal 12 15 mm Hg in mechanically ventilated patients MAP 65 mm Hg Urine output (UOP).5 ml/kg/hr Central venous oxygen saturation (ScvO2) 7% or mixed venous oxygen saturation (SvO2) 65% Dellinger RP CCM 213;41:58 637 Surviving Sepsis Campaign (SSC) Guidelines Joint collaboration between the Society of Critical Care Medicine and the European Society of Intensive Care Medicine Goal is to reduce mortality from sepsis by 25% Evidence based consensus guidelines for the management of severe sepsis and septic shock Third iteration of guidelines published in 213 Sponsored or endorsed by 3 international organizations % Mortality Severe Sepsis Mortality Over Time 4 35 3 25 2 15 1 5 2 21 22 23 24 25 26 27 28 29 21 211 212 No. of patients 278 3783 4668 5221 6375 6987 7627 8529 8797 1277 11367 12213 12512 Dellinger RP CCM 213;41:58 637 Kaukonen KM. JAMA 214;311:138 16 214 American Society of Health-System Pharmacists 2
Sepsis Progress in the Past 1.5 Decades 2 22 Rivers EGTD Annane Steroids PROWESS Leuven 1 ARMA SAFE Kumar Early ABX Leuven 2 CATS SSC 1 24 26 28 21 CORTICUS SOAP II VASST SSC 2 NICE SUGAR VISEP PROWESS SHOCK Myburgh Voluven Perner Tetraspan SSC 3 Feb 213 21 213 214 PROCESS ALBIOS ARISE TRISS Early Goal Directed Therapy (EGDT) Sepsis criteria Study Interventions Standard (S) Goals set (CVP, MAP, UOP) EGDT Addition of ScvO 2 to goals Protocol driven method for achieving goals Systolic BP 9 mm Hg Lactate 4 mmol/l Arterial catheter Central venous catheter CVP 8 12 mm Hg MAP <65 mm Hg 65 mm Hg ScvO 2 7% <8 mm Hg <7% Despite fluids (2 3 ml/kg) Crystalloids Colloids Vasopressors PRBC for Hct 3% <7% Dobutamine 6 Hours Rivers E. NEJM 21;345:1368 77 6% 4% 2% % EGDT Outcomes n = 263 Standard EGDT p=.3 p=.9 p=.1 56.9% 46.5% 49.2% 44.3% 3.5% 33.3% Hospital Mortality 28 Day Mortality 6 Day Mortality Rivers E NEJM 21;345:1368 77 Controversies with EGDT Unclear intervention leading to study s positive findings Use of a goal directed protocol Addition of ScvO 2 monitoring Lactate clearance non inferior to ScvO 2 as a goal Both? High control arm mortality Use of CVP as a resuscitation goal Fluid responsiveness better predicted by dynamic markers Jones AE. JAMA 21;33:739 46 Durairaj L, Schmidt GA. Chest 28;133:252 63 Huang DT. ICM 213;39:176 75 PROCESS STUDY Hypothesis Is protocol based care superior to usual care Is EGDT with central hemodynamic monitoring better than protocol based therapy PROCESS Inclusion Criteria Site 31 centers 4, ED visits / year Use lactate as screening for cryptic shock No formalized sepsis resuscitation protocol No routine use of oximetric central venous catheter Patient Similar to Rivers study 18 yo 2 SIRS criteria Hypotension SBP < 9 mmhg or requiring vasopressor after fluid challenge (1 L) Enroll within 12h of arrival and 2h within shock Yealy DM. NEJM 214;37:1683 93 Yealy DM. NEJM 214;37:1683 93 214 American Society of Health-System Pharmacists 3
PROCESS 3 Arms PROCESS Differences in Therapy Protocol based EGDT OximetricCVC CVP: 8 12 mmhg MAP > 65 mmhg ScvO2 >7% Early Detection and Fluid Administration Protocol based Standard 2 large bore IV Fluids Vasopressors Transfusion goal (7.5 g/dl) Usual Care All decisions based on resuscitation team Protocol Implemented by Dedicated Team IV Fluids 6 Hours (L) 6 5 4 3 2 1 EGDT Protocol Usual EGDT (n=439) Protocol (n=446) Usual (n=456) Pressor* 55% 52% 44% Dobutamine* 8% 1% 1% PRBC* 14% 8% 8% *p<.5 Yealy DM. NEJM 214;37:1683 93 Yealy DM. NEJM 214;37:1683 93 PROCESS Outcomes PROCESS Secondary Outcomes 6% 4% 2% 21% EGDT Protocol Usual p=.66 p=.83 32% 31% 18% 19% 34% Reaching MAP goal* EGDT Protocol Usual 83 84 77 ICU Admission* 91% 85% 86% AKI* 3% 6% 2.8% *p<.5 % Hospital Mortality 9 Day Mortality Yealy DM. NEJM 214;37:1683 93 Yealy DM. NEJM 214;37:1683 93 PROCESS VS. RIVERS Rivers PROCESS Design Single Center Multi Center No. of patients 263 1341 Year 21 214 APACHE II 21 21 ScvO 2 49% 71% PRBC / Dobutamine 64% / 14% 14% / 8% Lactate (mmol/l) 7 5 Mortality usual care 46.5% 19% PROCESS Conclusions Early recognition, fluid, and antibiotics remain crucial No mortality difference observed when comparing protocolized resuscitation to usual care Progress of care may have discounted importance of strict hemodynamic monitoring and resuscitation goals Yealy DM. NEJM 214;37:1683 93 Rivers E NEJM 21;345:1368 77 214 American Society of Health-System Pharmacists 4
ARISE PROCESS PROMISE ARISE Near identical protocol compared to PROCESS 2 arm study EGDT and usual care Initiation of ABX mandated prior to randomization N=16 Peake SL. NEJM 214;371:1496 56 ARISE Treatment / Outcomes More therapies used in EGDT group 2L vs. 1.7L Vasopressor: 76% vs. 66% PRBC: 14% vs. 7% Dobutamine: 15% vs. 3% 2% 15% 1% 5% % 9d mortality 18.6% 18.8% EGDT Usual SSC Response Required monitoring via CVC does not confer survival benefit in all patients who have received timely antibiotics and fluid resuscitation Results of PROCESS and ARISE trials have not demonstrated any adverse outcomes Therefore, no harm exists in keeping current SSC guidelines intact Yealy DM. NEJM 214;37:1683 93 Possible SSC Clarifications Early recognition and antimicrobials remain cornerstones of therapy Resuscitation should be systematically targeted to clinician specified criteria for preload and evidence of hypoperfusion Blood pressure goals should be individualized to optimize perfusion NQF SEPSIS Measure lactate level Obtain blood cultures prior to antibiotics Administer broad spectrum antibiotics Administer 3 ml/kg crystalloids for hypotension of lactate > 4 mmol/l Apply vasopressor (for hypotension that does not respond to initial fluid resuscitation to maintain MAP > 65) Patients with septic shock or initial lactate > 4 mmol/l measure CVP and ScvO2 Remeasure lactate 214 American Society of Health-System Pharmacists 5
Case, continued The medical team inserted a central venous catheter in the right internal jugular vein Pertinent data HR 115 beats/min in sinus rhythm MAP 59 mm Hg UOP.3 ml/kg/hr CVP 3 mm Hg A venous blood gas was sent from the catheter ScvO 2 59% Lactate 6.3 mmol/l Which of the following is the recommended initial fluid choice for a patient with severe sepsis or septic shock? Hydroxyethyl starch 5% albumin Lactate Ringer s solution Normal saline SSC Recommendations: Fluids Crystalloids as the initial fluid of choice for resuscitation Against the use of hydroxyethyl starches (HES) Albumin in fluid resuscitation when patients have required substantial amounts of crystalloids Initial fluid challenge of at least 3 ml/kg crystalloid Fluid challenge technique Levy MM. CCM 23;31:125 6 2% 1% % HES in ICU patients and Severe Sepsis Diverse ICU population HES p=.26 18% 17% 9 Day Mortality 7% n=7 p=.4 6% Renal Replacement Therapy 6% 4% 2% % Severe Sepsis HES Control n=84 p=.3 51% 43% 9 Day Mortality p=.4 22% 16% Renal Replacement Therapy Myburgh JA N Engl J Med 212;367:191 11 Perner A N Engl J Med 212;367:124 34 Albumin versus Saline for Fluid Resuscitation 28 Day Mortality Albumin Saline RR (95% CI) Overall 726/3473 (2.9) 729/346 (21.1).99 (.91 1.9) Severe sepsis Yes 185/63 (3.7) 217/615 (35.3).87 (.74 1.2) No 518/2734 (18.9) 492/272 (18.1) 1.5 (.94 1.17).5 1 2 Favors albumin Favors saline Significantly lower mortality favoring albumin on multivariate analysis of severe sepsis subgroup The SAFE Study Investigators. N Engl J Med 24;35:2247 56 The SAFE Study Investigators. Intensive Care Med 211;37:86 96 Sepsis Fluid Resuscitation Meta Analysis Design Prospective randomized trials of albumincontaining solutions Only included patients with sepsis Results Seventeen studies with 1977 participants Allocation to albumin associated with a reduction in mortality Odds ratio.82 (95% confidence interval.67 1., p =.47) Delaney AP. CCM 211;39:386 91 214 American Society of Health-System Pharmacists 6
ALBIOS: Study Design Patients with severe sepsis / septic shock (6 24hr) ALBIOS Outcomes (n=1818) Albumin Albumin: [3 ml at 2% in 3* hr] + Crytalloids Placement of arterial line and CVC Randomization Volume Replacement (Rivers Protocol) Crystalloid Crystalloids Caironi P. NEJM 214;37:1412 21 Treatment / Vitals 7d net fluid: 347 ml vs. 122 ml (p=.4) Lower HR (p=.2) Higher MAP (p=.3) Time to hemodynamic stability: 3d vs. 4d (p=.7) Mortality 5% p=.29 4% p=.94 43.6% 41.1% 3% 31.8% 32.% 2% 1% % 28d 9d Caironi P. NEJM 214;37:1412 21 ALBIOS Subgroup 9 Day Mortality Albumin Crystalloid RR (95% CI) Overall 41.1% 43.6%.94 (.85 1.5) Time <6h 4.6% 4.6% 1. (.82 1.22) 6 24h 413% 35.%.92 (.81 1.5) Septic shock Yes 37.% 32.7 1.13 (.92 1.39) No 518/2734 (18.9) 492/272 (18.1).87 (.77.99) Evidence Grade: Albumin Method Level 1: All evidence that supports what I already believe Level 3: All evidence that refutes what I already believe Favors.5 albumin 1 Favors 2 crystalloids Caironi P. NEJM 214;37:1412 21 Should Chloride be Avoided? RIFLE Class Chloride Liberal (n = 76) Chloride Restrictive (n = 773) Risk 71 (9.) 57 (7.4).16 Injury 48 (6.3) 23 (3.).2 Failure 57 (7.5) 42 (5.4).1 Injury and Failure 15 (13.8) 65 (8.4) <.1 Data presented as n (%). Classification per the serum creatinine criteria of Risk, Injury, Failure, Loss, and End Stage (RIFLE). p IV Crystalloids and Mortality Outcome Balanced fluid (n=3365) No Balanced fluid (n=3365) Hospital Mortality 19.6% 22.8%.1 ARF with dialysis 4.5% 4.7% NS Hospital LOS (d) 11.3 11.3 NS p No difference in mortality: 15% vs 13%, p=.44 Yunos NM. JAMA 212;38:1566 72 Raghunathan K. CCM 214;42:1585 91 214 American Society of Health-System Pharmacists 7
Hospital Mortality (%) 25 2 15 1 5 IV Crystalloids and Mortality % 1% 2% 3% 4% 5% 6% 7% 8% 9% Percent of Total Fluid That is Balanced by Day 2 Raghunathan K. CCM 214;42:1585 91 Possible SSC Clarifications Consider balanced fluids Patients with increased risk for renal dysfunction Large volume of saline have been given Electrolyte and acid/base abnormalities from saline administration Insufficient data to routinely recommend albumin supplementation post initial resuscitation Case, continued The patient was given a total of 4 liters of Ringer s Lactate over 3 hours Updated patient data MAP 65 mm Hg UOP.4 ml/kg/hr CVP 12 mm Hg Lactate 5.9 mmol/l ScvO 2 52% Hgb=7.7 g/dl Would you recommend giving PRBC to optimize oxygen delivery? Yes No SSC Recommendations: Transfusion During first 6 hours of resuscitation if central venous oxygenation is below goal despite volume repletion, transfusions to achieve HCT 3% is a treatment option Once tissue hypoperfusion has resolved, PRBC transfusion when Hgb < 7. g/dl is recommended Outcome TRISS Study Lower Hgb (n=52) Higher Hgb (n=496) #of PRBC 1545 388 <.1 Median PRBC / pt. 1 ( 3) 4 (2 7) p <.1 9d mortality 43% 45%.44 Ischemic events 7.2% 8.%.64 Vasopressor use Ventilator use RRT use NS NS NS Levy MM. CCM 23;31:125 6 Holst LB. NEJM 214;371:1381 91 214 American Society of Health-System Pharmacists 8
SSC Recommendations: Transfusion For most critically ill patients a transfusion target when Hgb <7. g/dl seems reasonable Key Takeaways EGDT In the setting of early recognition and early fluids and antimicrobial administration, clinician driven resuscitation goals most likely sufficient Fluids Preliminary data suggest no additional harm and possible benefit with balanced crystalloids infusion Routine replacement of albumin not recommended PRBC Target of Hgb >7. g/dl most likely sufficient for most critically ill patients Surviving Sepsis Campaign Guidelines: Update (Early Goal Directed Therapy and Fluids) Simon Lam, PharmD Cleveland Clinic Adjunctive Therapies in the Management of Septic Shock Jeremy DeGrado, PharmD BCPS Clinical Pharmacy Specialist Critical Care Brigham and Women s Hospital Boston, MA Outline Antimicrobial therapy Hemodynamic support Vasoactive agents Corticosteroids Glycemic control The team wishes to initiate antimicrobial therapy for MN as soon as possible. Which regimen would you recommend? Ceftazidime + Vancomycin Cefepime + Levofloxacin + Vancomycin Ceftriaxone + Levofloxacin Gentamicin + Ceftazidime + Vancomycin 214 American Society of Health-System Pharmacists 9
Antimicrobials/Source Control Appropriate cultures prior to antimicrobials Does not delay initiation > 45 minutes Effective IV antimicrobials within first hour Patient specific factors Medication specific factors Double coverage when appropriate De escalation when appropriate Source control Dellinger RP, et al. Crit Care Med 213;41(2):58 637 Frequency Time from EGDT Qualification to Appropriate Antibiotics 16 14 12 1 8 6 4 2 1hr 1 2hrs 2 3hrs 3 4hrs 4 5hrs 5 6hrs Mortality 25% 37% 35% 42% 5% 67% Gaeiski DF, et al. Crit Care Med 21;38(3) Alive Dead Patient Case (continued) Initiated on norepinephrine at 5 mcg/min, titrated quickly up to 12 mcg/min MAP = 57 mm Hg CVP = 12 ScVO2 = 72% Urine output = 2 to 3 ml/hr Lactate = 5.3 ICU team is looking to initiate a second vasoactive agent due to low MAPs What is your recommendation for a second vasoactive agent and MAP goal? Phenylephrine for MAP > 65 mm Hg Epinephrine for MAP > 85 mm Hg Vasopressin for MAP > 65 mm Hg Dobutamine for MAP > 85 mm Hg Vasoactive Agents 28 SCCM Recommendations NE or DA as 1 st line agent EPI first alternative EPI, PE, VP not recommended as initial vasopressors VP as adjunctive therapy for effect equivalent to NE monotherapy Dellinger RP, et al. Crit Care Med 213;41(2):58 637 Dellinger RP, et al. Crit Care Med 28;36(1):296 327 212 SCCM Recommendations NE 1 st line agent EPI first alternative/substitution VP as adjunctive therapy to increase MAP & decrease NE VP not recommended as initial vasopressor DA and PE only in selected patient populations Goals of Cardiovascular Resuscitation Cumulative Survival (%) 1 75 5 25 High target group Low target group 28 6 9 No. at risk Day Low target 379 256 233 225 High target 375 249 227 219 Asfar P, et al. NEJM 214; 37:1583 93 (adapted) 214 American Society of Health-System Pharmacists 1
Difference in 6 hour total equivalent volume (ml) Initiation of Vasopressors 6 5 4 3 2 1 Overall p<.1 1 2 3 4 5 6 Initiation Time of Vasoactive Agents (hrs after onset of hypotension Complications of Catecholamine Therapy Tachycardia/ tachyarrhythmias Reflex bradycardia (phenylephrine) myocardial oxygen supply myocardial oxygen consumption CO/CI Hollenberg SM, et al. Crit Care Med 24;32:1928 48 Limb ischemia splanchnic blood flow lactate Dopamine Prolactin suppression glucose TSH risk of ARF Phenylephrine Efficacy? Morelli, et al. 28 (n = 32 pts w/septic shock) Randomized, double blind controlled trial MAP with NE vs. PE No difference in % pts achieving goal MAP, CO, SVR Safety? Morelli, et al. 28 (n = 15 pts w/septic shock) Open labeled crossover study HR with PE vs. NE splanchnic perfusion, creatinine clearance, arterial lactate Morelli A, et al. Crit Care 28;12:R143 Morelli A, et al. Shock 28;29:446 451 Survival Probability Annane 27 NE + DOB vs. EPI 1..9.8.7.6.5.4.3.2.1 RR.81; p=.3 RR.75; p=.8 RR.86; p=.31 1 2 3 4 5 6 7 8 9 Days Annane D, et al. Lancet 27;37:676 684 (adapted) NE + DOB EPI EPI vs. NE CAT Study NE vs. DA in Shock Study Outcomes Variable EPI NE p value Time to MAP goal, median 35.1 4.26 Vasopressor free days 26 25.4.31 28 day mortality, no (%) 31 (22.5) 36 (26.1).48 Study drug discontinued, no (%) 18 (12.9) 4 (2.8).2 6% 4% 53% p=.1 49% DA n = 1679 NE Heart rate (bpm) 15 1 5 * p <.1 * * * EPI NE Lactate (mmol/l) 1 5 * p <.1 * * * * 2% % p<.1 24% p<.1 12% 7% 4% 28-Day Mortality Arrhythmias Skin ischemia Baseline 4h 8h 12h 16h Myburgh JA, et al. Intensive Care Med 28;34:2226 2234 (adapted) Baseline 4h 8h 12h 16h De Backer D, et al. N Engl J Med 21;362:779 89 214 American Society of Health-System Pharmacists 11
NE vs. DA in Septic Shock Meta Analysis Study DA n/n NE n/n 28 Day Mortality RR (95% CI) Martin 1/16 7/16 1.43 (.73 2.8) Marik 6/1 5/1 1.2 (.54 2.67) Ruokonen 3/5 4/5.75 (.32 1.74) Mathur 19/25 14/25 1.36 (.9 2.5) De Backer 291/542 249/52 1.8 (.98 1.19) Patel 67/134 51/118 1.16 (.89 1.51) Overall 396/732 33/676 1.12 (1.1 1.2) Overall effect p =.35 Heterogeneity p =.77, I 2 = % De Backer D, et al. Crit Care Med 212;4:725 3 1 2 3 Favors DA Favors NE Vasopressin Activity Receptor Level Location Effect V1 (V1a) 1-2 pmol/l Vascular smooth muscle V2 < 1 pmol/l Renal collecting ducts V3 (V1b) Vasoconstriction Fluid retention? Anterior pituitary ACTH release Landry DW et al. N Engl J Med 21;345:588 595 Hollenberg SM. Chest 27;132:1678 1687 Szumita PM et al. Am J Health Sys Pharmacy 25; 62:1931 6 Holmes CL et al. Crit Care 23;7:427 434 VASST Vasopressin Levels VASST NE requirements Time Norepinephrine group (pmol/l) Vasopressin group (pcmol/l) Baseline 3.2 3.2 6 hour no change 73.6 24 hour no change 98. Rate of NE (mcg/min) Median + IQR 25 Norepinephrine 2 15 Vasopressin 1 5 1 2 3 4 Time from study drug (days) Russell JA et al. N Engl J Med. 28;358:877 87 Russell JA et al. N Engl J Med. 28;358:877 87 (adapted) VASST Mortality All Patients NE group (%) VP group (%) p value 28-day mortality 39.3 35.4.26 9-day mortality 49.6 43.9.11 Less Severe NE group (%) VP group (%) p value Shock 28-day mortality 35.7 26.5.5 9-day mortality 46.1 35.8.4 VASST Timing is Everything! Restoration of organ perfusion Antimicrobial therapy & source control Vasopressin administration Time to VP NE Mortality VP Mortality initiation < 12 hours 4.5% 33.2% > 12 hours 37.5% 37.7% Russell JA et al. N Engl J Med. 28;358:877 87 Russell JA. Crit Care 211;15:226 245 214 American Society of Health-System Pharmacists 12
Percent VASST Renal Function Using RIFLE Criteria p=.3 p=.2 p=.1 Asfar Trial MAP (mm Hg) NE rate (mcg/kg/min) Day Day 1 Day Day 1 Day Day 4 Fluid Balance (ml) RRT (%) Death 28d (%) Lowtarget 74 74.35.45 1,63,28 35.8 34 74 84.4.58 1,595 2,4 33.5 36 High Target Annane 7 8.94 1.9 1,586 2,767 24.8 34 Debacker 58 76.54.82 2,1 8,3 17 48 Myburgh 7 73.26.17 2,232 5,712 22.1 26 Rivers 76 81 NA NA 3,5 1,62 NA 49 Russell 72 73.28.2 1,5 11, 43.6 39 Gordon AC, et al. Intensive Care Med 21;36:83 91 Russell JA. NEJM 214 Case (continued) MN is initiated on vasopressin at.4 units/min in addition to norepinephrine 12 mcg/min for goal MAP > 65 and UO > 4 ml/hr MAP = 62 HR = 95 CVP = 13 ScVO2 = 75 UO ~ 25 ml/hr Lactate = 4.9 With MAP and UO goals not achieved on 2 vasoactive agents, the topic of low dose corticosteroids is raised. What is your recommendation? Wait 12 24 hours to see if achieve hemodynamic stability Administer hydrocortisone 2 mg/day ASAP for hemodynamic support and mortality benefit Administer the high dose ACTH stimulation test to determine cortisol response (> 9 mg/dl) Avoid corticosteroids due to immunosuppression Corticosteroids in Septic Shock 28 SCCM Recommendations IV hydrocortisone only in pts w/o BP response to fluid and vasopressor therapy No ACTH stim test No dexamethasone +/ fludrocoritsone Wean steroids if off pressors No shock = No steroids Steroids < 3 mg/d hydrocort 212 SCCM Recommendations IV hydrocortisone if no BP response to fluid and vasopressor therapy No ACTH stim test Wean steroids if off pressors No shock = No steroids Hydrocortisone 2 mg/day Hydrocortisone continuous infusions Percent PROGRESS Registry Beale R, et al. Crit Care 21;14:R12 214 American Society of Health-System Pharmacists 13
Diagnosis of RAI in Septic Shock Days to Shock Reversal with LD CS Steroid responsiveness (37%) Baseline cortisol 14.1 mcg/dl vs. 33.3 mcg/dl (p<.1) 95% pts had cortisol < 25 mcg/dl Test Steroid Responsive (Sensitivity) Steroid Unresponsive (Specificity) Random Cortisol 96% 57% Nonresponders Annane 22 CORTICUS 28 Placebo LD CS p value Placebo LD CS p value 1 7.1 6. 3.9.6 Responders 7 9.49 5.8 2.8 <.1 All patients 9 7.1 5.8 3.3 <.1 LD test 54% 97% HD test 22% 1% Marik PE, et al. Crit Care Med 23;31:141 145 Annane D, et al. JAMA 22;288:862 871 Sprung CL, et al. N Engl J Med 28;358:111 124 Annane 22 Mortality CORTICUS 28 Mortality p=.4 p=.96 p=.9 Percent Percent p=.69 p=1. p=.51 Annane D, et al. JAMA 22;288:862 871 Sprung CL, et al. N Engl J Med 28;358:111 124 Heterogeneity of LD CS RCTs Annane 22 SAPS II ~ 6 Placebo mortality 61% Enrolled w/in 8hr CS w/in 4hr pressor initiation MAP 55 mmhg Hydrocort + fludrocort x 7d 6% medical patients 77% non responders Appropriate antibiotics > 9% patients Time to AA ~ 6 hours CORTICUS 28 SAPS II 48 Placebo mortality 32% Enrolled w/in 72hr CS w/in?? pressor initiation SBP 94 mm Hg Hydrocort x 11d (taper) 35% medical patients 46.7% non responders Appropriate antibiotics???? Cumulative percent patients off vasopressors 1 8 6 4 2 Early Administration of LDCS in Septic Shock Early LDCS p <.1 2 4 6 Days of vasopressors Late LDCS % survival 1 8 6 4 2 Late LDCS p =.18 Early LDCS 4 8 12 16 2 24 28 Survival (days) Annane D, et al. JAMA 22;288:862 871 Sprung CL, et al. N Engl J Med 28;358:111 124 Katsenos CS, et al. Crit Care Med 214; 42:1651 1657 (adapted) 214 American Society of Health-System Pharmacists 14
Vasopressin and LDCS VASST Vasopressin + Low Dose Corticosteroids Percentage of Clinicians Steroids (n=589) VASST (n=779) No steroids (n=19) VP (n=296) NE (n=293) VP (n=11) NE (n=89) Patients in Septic Shock Hsu JL, et al. Crit Care 212;16:447 449 Russell JA et al. Crit Care Med 29;37:811 818 14 VASST VP + LDCS VP levels VASST VP + LDCS Survival Vasopressin levels (pmol/l, median + IQR) 12 1 8 6 4 2 Corticosteroids No corticosteroids Baseline 6 hours 24 hours Patients who NE group (%) VP group (%) p value received steroids (n=589) 28-day mortality 44.7 35.9.3 9-day mortality 55.5 45.2.1 Days alive w/o OD (survivors) 1 4.8 Russell JA et al. Crit Care Med 29;37:811 818 (adapted) Russell JA et al. Crit Care Med 29;37:811 818 Bauer, et al Time from pressor initiation to first CS dose = 22.2 hours Median time to withdrawal of vasopressor support (p =.9) CS = 65 hours No CS = 2 hours Patients alive w/o vasopressors at day 7 (p =.2) CS = 8.9% No CS = 47.6% CS independently associated with survival w/o vasopressors at day 7 VP + LDCS Synergy? Probability of Cumulative Survival Bauer SR, et al. J Crit Care 28;23:5 56 Torgersen C, et al. Intensive Care Med 211 (adapted) 1..8.6.4.2 Torgersen, et al p=.1 VP + LD CS VP 5 1 15 2 25 3 Days Number of days of VP infusion 25 2 15 1 5 VP + LDCS Pilot Hydrocortisone Placebo Hydrocortisone Placebo Gordon AC, et al. Crit Care Med 214; 42:1325 1333 (adapted) Vasopressin received (hundred units) 12 1 8 6 4 2 214 American Society of Health-System Pharmacists 15
Hydrocortisone Bolus vs. Infusion Blood glucose (mg/dl) Continuous HC (2mg/d) Bolus HC (5 mg) 3 5 mg HC 2 1 p =.47 p <.1 p =.2 Case (continued) MN is started on IV hydrocortisone 1 mg every 8 hours in addition to NE and VP infusions Blood glucose levels 198 mg/dl (pre LD CS) 235 mg/dl 31 mg/dl 228 mg/dl 12 3 6 18 Hours Weber Carstens S, et al. Intensive Care Med 27;33:73 733 (adapted) Would you advocate for tight glycemic control using an intensive intravenous insulin protocol? Yes No Glycemic Control 28 SCCM Recommendations 212 SCCM Recommendations Protocolized approach Goal glucose < 15 mg/dl Monitor every 1 2 hours All patients receive glucose Caution with POCT values Protocolized approach 2 glucose levels > 18 mg/dl Upper limit 18 mg/dl Monitor every 1 2 hours Caution with POCT values Intensive Insulin Therapy Select RCTs of glucose control in the ICU Leuven I Leuven II VISEP Glucontrol NICE Sugar Population SICU MICU Sepsis Mixed Mixed Mixed ICU Centers Single Single 18 19 42 Samp size 1548 12 488/537 111 ~63 Excluded 14 863 1,612? 34,67 Stopped early No No Yes Yes No Primary Diet TPN 85% TPN 85% 6% TPN 27% TPN 25% TPN APACHE II ~9 ~23 ~2 ~15 ~21 Mortality ICU: ~ 7% ICU: ~25% 28 D: ~27% ICU: ~16% 28 D: ~21% Hos: ~1% Hos: ~4% Hos: ~22% Protocol Leuven Leuven Leuven Variable? NICE Target 8-11 8-11 8-11 8-11 81-18 Control < 18 < 18 < 18 14-18 144-18 Hospital Mortality (%) 4 35 3 25 2 15 1 5 Q1 Q2 Q3 Q4 p<.1 Glycemic Variability p<.1 p=.1 p=.1 7 99 1 119 12 139 14 179 18+ Mean glucose levels during ICU stay (mg/dl) Krinsley JS. Crit Care Med 28;36:38 313 (adapted) 214 American Society of Health-System Pharmacists 16
Mortality Probability Diabetes vs. No Diabetes Non Diabetics.16.14 9 14 mg/dl.12.1.8 8 11 mg/dl.6.4.2 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 Days Post ICU Admission Lanspa MJ, et al. Chest 213;143:1226 1234 (adapted) Intensive Insulin Therapy What We Know Variability with POCT devices Hyperglycemia is associated with poor outcomes Hypoglycemia is associated with poor outcomes Intensive insulin therapy should be driven by protocols/guidelines to optimize efficacy and safety What We Would Like to Know Validated guidelines/protocols to ensure safety Optimal target range DM vs. Non DM Optimal glucose metrics Effect of glycemic variability Other Adjunctive Therapy Concerns in Septic Shock Management Inotropic therapy Beta blockade Immunoglobulins Mechanical ventilation PAD/NMB management Renal replacement therapy Sodium bicarbonate VTE prophylaxis Stress ulcer prophylaxis Nutrition Selenium Key Takeaways Antimicrobial therapy Must be appropriate and early Vasoactive agent(s) Resuscitation must be perfusion directed Norepinephrine preferred in majority of shock pts Low dose corticosteroids Patients with refractory shock who receive LDCS early are most likely to benefit Synergistic effect when administered with vasopressin Intensive intravenous insulin Patient specific goals depending on h/o diabetes Must be done safely Questions? Adjunctive Therapies in the Management of Septic Shock Jeremy DeGrado, PharmD BCPS Clinical Pharmacy Specialist Critical Care Brigham and Women s Hospital Boston, MA 214 American Society of Health-System Pharmacists 17
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