Sepsis and Septic Shock Therapy in 2012

Dr Masood ur Rahman. FCCP. Senior Consultant Intensive care

Deputy Chairman Department of Critical Care Medicine, Tawam Hospital

Al Ain, United Arab Emirates.

Objectives

• Incidence• End point of resuscitation

– CVP and ScVo2? Or ?• Update on role of

– Early Goal directed therapy– Antibiotics– Glycemic control– Steroid– Activated protien c

Severe Sepsis: Comparison With

Other Major Diseases

Severe Sepsis: Comparison With

Other Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med 2001

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med 2001

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Incidence of Severe SepsisIncidence of Severe Sepsis Mortality of Severe SepsisMortality of Severe Sepsis

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Severe Sepsis: Comparison With

Other Major Diseases

Severe Sepsis: Comparison With

Other Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med 2001

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med 2001

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*Angus DC. Crit Care Med 2001;29:1303-10*Angus DC. Crit Care Med 2001;29:1303-10

Severe Sepsis:A Growing Healthcare Challenge

Severe Sepsis:A Growing Healthcare Challenge

TodayToday

>750,000 cases of severe

sepsis/year in the US*

FutureFuture

200,000200,000

400,000400,000

600,000600,000

800,000800,000

1,000,0001,000,000

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YearYear

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300,000300,000

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500,000500,000

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Severe Sepsis CasesSevere Sepsis Cases

US PopulationUS Population

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Goals of Treatment

• ABCDE• Airway• control work of Breathing• optimize Circulation• assure adequate oxygen Delivery• achieve End points of resuscitation

SIRS- It All Starts Out So Innocent

• Clinical Response to nonspecific insult• Temperature > 380 C or < 360 C• Heart Rate > 90 per minute• Respirations > 20 per minute• WBC > 12,000 or < 4,000 or > 10% bands

• PaCO2 < 32

Members of the American College of Chest Physicians/Society of Crit Care Med Consensus Conference Committee: American College of Chest Physicians/Society of Crit Care Med Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864–874

Definition

• Sepsis- 2 or more SIRS criteria with infection• Severe Sepsis- Sepsis with evidence of organ

dysfunction• Septic Shock- Sepsis with refractory hypotension• Multiple Organ Dysfunction Syndrome (MODS)

Down a Slippery Slope

How to prevent this?

EGDT

• 263 patients randomized to goal directed or standard therapy

• In hospital mortality for EGDT patients 30.5% versus 46.5% for standard therapy

• Longer length of stay and consumption of resources for standard therapy patients

Rivers E, Nguyen B, Havstad S, et al:  Early goal-directed therapy in the treatment of severe sepsis and septic shock.   N Engl J Med 345. 1368-1377.2001; 

The Importance of Early Goal-DirectedTherapy for Sepsis Induced Hypoperfusion

Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377

In-hospital mortality

(all patients)

0

10

20

30

40

50

60 Standard therapyEGDT

28-day mortality

60-day mortality

NNT to prevent 1 event (death) = 6-8

Mort

ality

(%

)

EGDT is Liberal?

• Average of 5 Liters of crystalloid in 6 hours• After 72 hours no difference between standard and EGDT group• Timing is the key• Less intubation in EGDT group after 6 hours• Dialysis patients less intubation in EGDT

Otero, RM, Nguyen, B, Huang, DT, et al (2006) Early goal-directed therapy in severe sepsis and septic shock revisited. Chest 130,1579-1595

Wiedemann, HP, Wheeler, AP, Bernard, GR, et al Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354,2564-2575

Jones A, et al, The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis. Critical Care Medicine: October 2008 - Volume 36 - Issue 10 - pp 2734-2739

Boyd J, et al, Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Critical Care Medicine: February 2011 - Volume 39 - Issue 2 - pp 259-265

Guidelines 2008

Guidelines 2008

• There is poor relationship between CVP and blood volume as well as the inability of CVP/ΔCVP to predict the hemodynamic response to a fluid challenge. CVP should not be used to make clinical decisions regarding fluid management.

Conclusion:Applying an early quantitative resuscitation strategy to patients with sepsis impartsa significant reduction in mortality

Retrospective review of use of IV fluid used during first 4 days.VASST ( vasopressin in shock trial).? Positive fluid balance and CVP are associated with mortality.

Cox survival curves, adjusted for Age, (APACHE) II score. severity of shock (dose of norepinephrine),

• limitation of study– Retrospective– Type of IV fluid not

documented– Unable to determine if

CVP and fluid balance are independetly effect the out come.

• Conclusion– A more positive fluid balance

both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock.

– Central venous pressure may be used to gauge fluid balance <12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter.

How to decide end point of resucitation?

• Static hemodynamic measure – CVP , PAOP

• Dynamic hemodynamic measure – Respiratory changes in the radial artery pulse pressure( pulse pressure variation), – Aortic blood flow peak velocity, – Brachial artery blood flow velocity– Stroke volume variation

• Mixed venous saturation (SvO2)

• Central venous saturation (ScvO2)

• Lactic acidosis

Which is better measure dynamic versus static?

• Increasing evidence that dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and controlled ventilated with a sufficient tidal volume

Intensive Care Med. 2003;29(3):476.

Am J Respir Crit Care Med. 2000;162(1):134.

Intensive Care Med. 2005;31(9):1195

Get a Leg Up!

• Passive leg raise (PLR) increased radial arterial pulse pressure.

• Pulse pressure = Systolic BP-Diastolic BP.

• D PP= 9% correlates with fluid response.

• Change with PLR correlated with an increase in stroke volume.

• PLR changes correlated with stroke volume changes when same patients received a fluid bolus.

, Crit Care Med 2010; 38:819–825.

How accurate are they?

PPV better than CVP

Crit Care Med 2009 Vol. 37, No. 9

Got Ultrasound ?

IVC diameter changes with volume IVC diameter will decrease during inspiration

Diameter will increase with expiration

Caval Index = 100 x (IVC expiration-IVC inspiration)/IVC expiration.

caval index is greater than 50% it suggests low central venous pressure (CVP less than 8 mmHg) and high probability of fluid responsiveness

Limitations need to be considered Blehar DJ, et al, Identification of congestive heart failure via respiratory variation of inferior vena cava diameter, Am J Emerg Med - 01-JAN-2009; 27(1): 71-5

Nagdev, et al, Emergency Department Bedside Ultrasonographic Measurement of the Caval Index for Noninvasive Determination of Low Central Venous Pressure, Volume 55, Issue 3 March 2010, 290-295

Got Alternative Technology ?

Impedance cardiography Napoli A, Machan J, et al, The Use of Impedance Cardiography in Predicting Mortality in Emergency Department Patients

With Severe Sepsis and Septic Shock, Academic Emergency Medicine 2010; 17:452–455

The placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate hemodynamic parameters

Esophageal Doppler-Minimally Invasive Option

• Deltex CardioQ• Placement of flexible orogastric

or nasogastric probe• Doppler technology• Measures blood flow velocity

in descending aorta• Able to derive values for

cardiac output, preload and contractility

New guideline 2012?

• Dynamic measures such as delta pulse pressure or stroke volume variation to determine the adequacy of fluid resuscitation, rather than such static measures as central venous pressure.

Annual meeting of the Society for Academic Emergency Medicine (SAEM) 2012

ScVO2 Revisited

• Lactate vs ScVO2

Venous Oxygen Saturation

• Measure of global oxygen extraction• Central versus mixed• Compromised by cirrhosis or shunt

ScVo2

• Svo2 ≥has significant impact on mortality than rest of the components of resuscitation bundle.

• Failure to achieve ScVo2≥ 70 within first 6 hours is associated with significantly high mortality( 14%).

Pope et al:Annal of emergency medicine 2010

CCM 2010

Lactate?

Serum lactate identifies hypoperfusion

Shapiro N, et al, Serum Lactate as a Predictor of Mortality in Emergency Department Patients with Infection, Annals of Emergency Medicine, Volume 45, Issue 5 (May 2005), 524-528

Got Lactate ?

• Recent prospective study reveals utility of lactate clearance

• Potential use as resuscitation endpoint

Nguyen HB, et al, Early lactate clearance is associated with improved outcome in severe sepsis and septic shock Critical Care Medicine - Volume 32, Issue 8 (August 2004)

Arnold R, et al, Multicenter Study Of Early Lactate Clearance as a Determinant Of Survival in Patients With Presumed Sepsis, SHOCK Vol. 32, No. 1, pp. 35-39, 2009

Jones A, et al, Lactate Clearance Versus Central Venous Oxygenation as Endpoints of Early Sepsis Therapy: A Randomized Clinical Trial. (49), Critical Care Medicine. 37(12), December 2009

Adams BD, Bonzani TA, Hunter CJ. The anion gap does not accurately screen for lactic acidosis in emergency department patients. Emerg Med J 2006;23:179–8

Colloids

• Option in addition to crystalloids• Albumin is SAFE• Subset analysis suggests mortality decrease• Possible anti-inflammatory component

The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-2256.

Brunkhorst F , et al, Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis, NEJM 2008;358:125-139.

Kirschenbaum L, Effect Of Resuscitative Fluids On Cell Activation In Septic Shock (439), Critical Care Medicine. 37(12):A1-A542, December 2009

Mullen M, Use of Concentrated Albumin in the Emergency Department May Improve Morbidity in Severe Sepsis and Septic Shock (482), Critical Care Medicine. 37(12):A1-A542, December 2009

Delaney A, et al, The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis, Crit Care Med. 2011 Feb;39(2):386-91

The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis*

Delaney A, et al,, Crit Care Med. 2011

Feb;39(2):386-91

Conclusionuse of albumin-containingsolutions for the resuscitation of patients with sepsis was associated with lower mortality compared with other fluid resuscitation regimens. Until the results of ongoing randomized controlled trials are known, clinicians should consider the use of albumin-containing solutions for the resuscitation of

patient swith sepsis.

Better than crystalloids in septic patient ?

New Twist on Pressors

• Epinephrine and norepinephrine plus dobutamine compared in 330 patients

• No difference in mortality at 28 days• No statistical difference in adverse effects

Annane D, Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial .  The Lancet , Volume 370 , Issue 9588, Pages 676 - 684 D, 2007

Vasopressin versus norepinephrine?

• Results of a multi-center trial of septic shock patients receiving 0.03 units/min of vasopressin versus norepinephrine

• 776 patients• No difference in mortality• Trend toward improved outcome

with vasopressin in less severe shock

• Higher doses may be future intervention

Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-887.

Luckner G , Comparison of two dose regimens of arginine vasopressin in advanced vasodilatory shock. Crit Care Med OCT-2007; 35(10): 2280-5

Low dose vasopressin plus steroid better than Norepinephrine plus steroids

• Post hoc analysis of patients in VAAST

• Review of patients with norepinephrine (293) and steroids and vasopressin (295) and steroids

• 28 day mortality difference 44.7% versus 35.9% (p=0.03)

• ? Increased responsiveness to catecholamines

• ? Increased vasopressin levels• ? Decreased inflammationRussell J, et al, Interaction of vasopressin infusion, corticosteroid treatment, and

mortality of septic shock, Crit Care Med 2009 Vol. 37, 811-8

Blood?!!

• Hebert did not address severe sepsis/tissue hypoxia• 79% EGDT patients did show improvement in ScVO2• Need to consider infection issues/ALI/age of PRBC’s• Vincent-Observational study (n=1040) did not show

increased mortality with transfusion • Napolitano- Transfusion needs on individual basis

Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care: Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999; 340:409–417T

Friedlander M, et al, The relationship of packed cell transfusion to red blood cell deformability in systemic inflammatory response syndrome patients, SHOCK 1998 Feb;9(2):84-8.

Vincent JL, Sakr Y, et al, Are blood transfusions associated with greater mortality rates? Results of the Sepsis Occurrence in Acutely Ill Patients study. Anesthesiology. 2008 Jan;108(1):31-9.

Napolitano L, et al, Clinical Practice Guideline: Red Blood Cell Transfusion in Adult Trauma and Critical Care, Crit Care Med 2009, Vol 37 (12), 3124-3157

Early Antibiotics:

• Kumar (2009)- 5000 patient study• 20 % patients received inappropriate antibiotics• Increased mortality by factor of 5 • Combination therapy needs to be considered• Rise of Extended Spectrum Beta Lactam (ESBL) Gram Negative

infection

Kumar A, et al, Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009 Nov;136(5):1237-48.

Kumar A, Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis. Critical Care Medicine: September 2010 - Volume 38 - Issue 9 - pp 1773-1785

Quinn JP, Clinical significance of extended-spectrum beta-lactamases. European Journal of Clinical Microbiology & Infectious Diseases, Volume 13, Supplement 1 1994 , S39-S42

Early Antibiotics(Even in the ED)

• ED based retrospective study• 231 patients• Time to appropriate antibiotics mortality factor• Less than 1hour - 19% mortality• Greater than 1 hour - 33.2 % mortality

Gaieski D, et al, Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department, Crit Care Med 2010; 38:1045–1053.

Got Glucose ?

• Glycemic control impacts critical illness• Maintenance of blood glucose between 80-110 mg/dl• Absolute reduction in ICU mortality• Reduction of in-hospital mortality by 34% • Reduction in morbidity as well• Mixed support in follow-up studies

Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367

Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461.

Krinsley JS, Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004 Aug;79(8):992-1000

Carr J, Sellke F, et al, Implementing Tight Glucose Control After Coronary Artery Bypass Surgery Ann. Thorac. Surg., Sep 2005; 80: 902 - 909.

Not So Nice, Sugar….

• Intensive versus Conventional Glucose Control in Critically Ill Patients, NEJM, March 26, 2009

• 6104 randomized patients• Intensive (80-108) versus conventional (less than 180)• Increase 90 day mortality 27.5% versus 24.9% with tight

control• Expect a possible wider range (?140-180)

Nice-Sugar Investigators, Intensive versus Conventional Glucose Control in Critically Ill Patients, N Engl J Med 2009;360:1283-97

Still important……

• Retrospective cohort 259,040 patients• Review risk adjusted mortality in this cohort• Hyperglycemia does affect mortality• Risk varies with admission diagnosis• Adjusted mortality lowest with glucose 111 to

145 mg/dL

Falciglia M, et al, Hyperglycemia-related Mortality in Critically Ill patients Varies with Admission Diagnosis, Critical Care Medicine. 37(12):3001-3009, December 2009

CORTICUS

• CORTICUS- Randomized, controlled study hydrocortisone vs placebo in septic shock.

• 500 patients multi-center, multinational study

• No difference in the overall 28-day mortality rate

• Cosyntropin responsiveness made no difference• Tapered steroids• Cosyntropin test called into question• Shock resolution faster with steroids

Sprung CL, Annane D, et al, Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24

Update

• Most recent literature-comprehensive meta-analysisReview of 17 studies

• Overall steroids do not affect 28 day mortality• 12 studies of low dose prolonged steroids did

suggest improved outcome• Recommended for vasopressor refractory

shock

Annane D, et al, Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in AdultsA Systematic Review, JAMA. 2009;301(22):2362-2375.

Activated protien C?

• Activated Protein C- Anti-inflammatory, anti-thrombotic, profibrinolytic properties

• 28 day mortality study/1690 randomized patients• Mortality decrease and relative risk reduction statistically

significant• Mortality decrease from 30.8% to 24.7%• First agent in 20 years to modify course of severe sepsis• Increased bleeding risk (3.5% vs 2.0%)• Exclusion criteria extensive

Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709

Low Tidal Volume Mechanical Ventilation

• Multicenter, randomized trial of over 800 patients• Comparison of 12 ml/kg versus 6ml/kg tidal volume• Lower volumes to keep plateau pressure 30 mm H2O

or less• More recent smaller trial 6 ml/kg vs 10 ml/ kg• Less inflammatory markers• Less incidence of ALI/ Stopped early

The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308

Determann R, Ventilation with lower tidal volumes as compared to conventional tidal volumes for patients without acute lung injury - a preventive randomized controlled trial, Critical Care 2010, 14:R1 (7 January 2010)

Putting It All Together

• Early goal directed therapy still valid/ Likely to change• Early aggressive antibiotics remain key/ Resistance emerging• Glycemic control still has benefit• Consider adrenal insufficiency in fluid resuscitated shock• Low tidal volume remains the best practice• Exciting new therapies/ monitoring on horizon• Activated protien C is History

What Should We Do

Impact of order sets

What are We Doing At Tawam

• Implementing sepsis clinical pathway.• Sepsis care set

Establishing Measure

• SEPSIS RESUCITATION BUNDLE– Serum Lactate measured– Blood culture obtained before antibiotics

administered.– Timing of antibiotics– CVP goal– Central venous saturation

• SEPSIS MANAGEMENT BUNDLE– Glycemic control– Plateau pressure – Low dose steroids administered

THANK YOU