severe sepsis and septic shock what’s new? p moine department of anesthesiology

Severe sepsis and septic shockSevere sepsis and septic shockWhat’s new?What’s new?

P MoineP Moine

Department of AnesthesiologyDepartment of Anesthesiology

Epidemiology (USA, 1995)Epidemiology (USA, 1995)

Incidence of Severe Sepsis

- 750,000 patients / year

- 225,000 (29%) surgical patients

Mortality 29%

- 215,000 deaths per year

- 9.3% of all deaths in the United States

- Mortality 38% for age > 85

Cost $17 Billion Annually

Angus DC et al. Crit Care Med 2001

Special Articles

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012R. Phillip Dellinger, Mitchell M. Levy, Andrew Rhodes, Djillali Annane, Herwig Gerlach, Steven M. Opal, Jonathan E. Sevransky, Charles L. Sprung, Ivor S. Douglas, Roman Jaeschke, Tiffany M. Osborn, Mark E. Nunnally, Sean R. Townsend, Konrad Reinhart, Ruth M. Kleinpell, Derek C. Angus, Clifford S. Deutschman, Flavia R. Machado, Gordon D. Rubenfeld, Steven A. Webb, Richard J. Beale,Jean-Louis Vincent, Rui Moreno, and the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup*Critical Care Medicine 2013; 41(2):580-637

Early Goal Directed therapyEarly Goal Directed therapyRivers E et al. N Engl J Med 2001Rivers E et al. N Engl J Med 2001

- Indications: Hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L

- This protocol should be initiated as soon as hypoperfusion is recognized and should not be delayed pending ICU admission.

- Goals during the first 6 hrs of resuscitation:- CVP 8-12 mm Hg / CVP 12-15 mmHg if MV- MAP ≥ 65 mm Hg- Urine output ≥ 0.5 mL/Kg/Hr- Superior vena cava oxygenation saturation ScVO2 or mixed venous oxygen

saturation (SVO2) 70% or 65% respectively

- Targeting Resuscitation Suggestion: Lactate normalization as a marker of tissue hypoperfusion

Surviving Sepsis Guidelines: International Guidelines Surviving Sepsis Guidelines: International Guidelines for Management of Severe Sepsis and Septic shock: for Management of Severe Sepsis and Septic shock:

20122012Dellinger RP et al. Crit Care Med 2013Dellinger RP et al. Crit Care Med 2013

““Early Goal-Directed Therapy”Early Goal-Directed Therapy”Early quantitative resuscitation of the septic patient Early quantitative resuscitation of the septic patient

during the first 6 hrs after recognitionduring the first 6 hrs after recognition

Cardiac filling pressures are not appropriate to predict Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challengehemodynamic response to volume challenge

Osman D et al. Crit Care Med 2007Osman D et al. Crit Care Med 2007

Individual values and mean ± SD of pre-infusion CVP in Responders and NonRespondersPatients exhibiting an increase in cardiac Index induced by the 500 ml 6% hydroxyethyl starch volume

challenge (over 20 mins) of ≥ 15% and < 15% are classified as R and NR, respectively

All consecutive fluid challenges performed in 96 mechanically ventilated patients hospitalized for severe sepsis and septic shock monitored with a PAC. The decision to give fluid was based on the

presence of at least one clinical sign of acute circulatory failure or associated signs of hypoperfusion.

8±4 mmHg 9±4 mmHg

Poor Predictors of fluid responsiveness

8 mmHg CVP threshold value for prediction of volume responsiveness:ROC curve AUC : 0.58 (95% CI, 0.49-0.67)

Pre-infusion CVP of <8 mmHg fluid responsiveness prediction:

SS 62%SP 54%PPV 51%NPV 65%

Pre-infusion CVP of <12 mmHg fluid responsiveness prediction:

SS 82%SP 28%PPV 47%NPV 67%

Cardiac filling pressures are considered as the gold standard for guiding fluid therapy in patients with sepsis and septic shock

Central venous pressure: A useful but not so simple Central venous pressure: A useful but not so simple measurement.measurement.

Magder S. Crit Care Med 2006Magder S. Crit Care Med 2006

• CVP measurements are frequently used for the assessment of cardiac preload and volume status / Criticized because CVP poorly predicts cardiac preload and volume status

• CVP is determined by the interaction of 2 functions – Cardiac function– Return function – Which defines the return of blood from the vascular reservoir to the

heart

• Thus, the CVP by itself has little meaning!• A CVP measurement must be interpreted in the light of a measure of cardiac output, or at least a surrogate of cardiac output, such as venous oxygen saturation or pulse pressure variations.

CVP < 0 mmHg Low CVP Low CVP High CVP High CVP

VolumeReturn Function

Normal Hypovolemia Hypervolemic

Hypervolemic

Normal

Cardiac function

Normal Normal Very dynamic

heart

Normal Decreased

Assessing cardiac preload or fluid responsiveness? It Assessing cardiac preload or fluid responsiveness? It depends on the question we want to answer.depends on the question we want to answer.

Michard F and Reuter DA. Intensive Care Med 2003Michard F and Reuter DA. Intensive Care Med 2003

Schematic representation of the ventricular preload/stroke volume relationship of a normal and a failing ventricle. The increase in stroke volume (ΔSV) as a result of cardiac preload increase (ΔP) depends on ventricular function (i.e. on the slope of the curve = dotted line). Assessing the baseline preload is not useful for predicting the hemodynamic effect of an increase in preload.

There is a physiologic reason explaining that even the most accurate marker of ventricular preload will never be a reliable predictor of volume responsiveness. Indeed, the slope of the Frank-Starling curve depends on the systolic function.

PAOP and CVP: No better than flip of a coinPAOP and CVP: No better than flip of a coin

Cardiac filling pressures are not appropriate to predict Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challengehemodynamic response to volume challenge

Osman D et al. Crit Care Med 2007Osman D et al. Crit Care Med 2007

- Septic patients require volume.- Giving pressors to an under-resuscitated patient can cause tissue hypoxemia and ischemia- Giving too much fluid days is associated with an increased risk of mortality, and may lead to prolonged ventilatory support and ICU length of stay.

How do I decide if my hypotensive septic patient needs fluids, pressors, or an inotrope?

Fluid resuscitation in septic shock: a positive fluid balance and Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased elevated central venous pressure are associated with increased

mortalitymortality..Boyd JH et al. Crit Care Med 2011Boyd JH et al. Crit Care Med 2011

A more positive fluid balance both early (at 12 hrs) 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.



Cox survival curves, adjusted for age, APACHE II score, and severity of shock (dose of norepinephrine) areShown for fluid balance quartiles at 12 hrs and 4 days – Quartiles 3 and 4 have significant increases in Mortality compared to both quartiles 1 and 2. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs.

Man drinking lots of water

Comparison of two fluid-management strategies in acute lung injuryComparison of two fluid-management strategies in acute lung injuryWiedemann HP et al. N Engl J Med 2006Wiedemann HP et al. N Engl J Med 2006

Mean (+/-SE) cumulative fluid balance during the first seven days: Conservative group -136+/-491 ml vs Liberal group 6992+/-502 ml (P<0.001). In the conservative group: Significant improvement of the oxygenation index and the lung injury score, increase of the number of ventilator-free days (14.6+/-0.5 vs. 12.1+/-0.5, P<0.001) and days not spent in the intensive care unit (13.4+/-0.4 vs. 11.2+/-0.4, P<0.001) during the first 28 days.

Assessment of Volume Responsiveness during Assessment of Volume Responsiveness during Mechanical Ventilation: Recent advancesMechanical Ventilation: Recent advances

Monnet X and Teboul JL. Critical Care 2013Monnet X and Teboul JL. Critical Care 2013

Controversy surrounding resuscitation targets- CVP is used for the assessment of cardiac preload and volume status •While the committee recognized the controversy surrounding resuscitation targets, an early quantitative resuscitation protocol using CVP and venous blood gases can be readily established in both emergency department and ICU settings. Recognized limitations to static ventricular filling pressure estimates exist as surrogates for fluid resuscitation, but measurement of CVP is currently the most readily obtainable target for fluid resuscitation.•Targeting dynamic measures of fluid responsiveness during resuscitation, including flow and possibly volumetric indices and microcirculatory changes, may have advantages. Available technologies allow measurement of flow at the bedside; however, the efficacy of these monitoring techniques to influence clinical outcomes from early sepsis resuscitation remains incomplete and requires further study before endorsement.•Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (e.g., change in pulse pressure, stroke volume variation) or static (e.g., arterial pressure, heart rate) variable.



Early quantitative resuscitation of the septic patient Early quantitative resuscitation of the septic patient during the first 6 hrs after recognitionduring the first 6 hrs after recognition

Serial blood lactate levels can predict the development Serial blood lactate levels can predict the development of multiple organ failure following septic shock.of multiple organ failure following septic shock.

Bakker J et al. Am J Surg 1996Bakker J et al. Am J Surg 1996

Lactate clearance was defined as the percent decrease in lactate from emergency department presentation to hour 6.Lactate clearance = [(Lactate at ED presentation – Lactate at 6 hrs)/Lactate at ED presentation] x 100

Early lactate clearance is associated with improved outcome Early lactate clearance is associated with improved outcome in severe sepsis and septic shockin severe sepsis and septic shock

Nguyen HB et al Crit Care Med 2004Nguyen HB et al Crit Care Med 2004

Early lactate clearance is associated with biomarkers of Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ inflammation, coagulation, apoptosis, organ

dysfunction and mortality in severe sepsis and sepstic dysfunction and mortality in severe sepsis and sepstic shockshock

Nguyen HB et al. J Inflamm 2010Nguyen HB et al. J Inflamm 2010

Lactate clearance vs central Venous oxygen saturation Lactate clearance vs central Venous oxygen saturation as goals of early sepsis therapyas goals of early sepsis therapy

Jones AE et al. JAMA 2010Jones AE et al. JAMA 2010

Outcome effectiveness of the severe sepsis Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance resuscitation bundle with addition of lactate clearance

as a bundle item: as a bundle item: A multi-national evaluation.A multi-national evaluation.

Nguyen HB et al. Crit Care 2011Nguyen HB et al. Crit Care 2011

Outcome effectiveness of the severe sepsis Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance resuscitation bundle with addition of lactate clearance

as a bundle item: as a bundle item: A multi-national evaluation.A multi-national evaluation.

Nguyen HB et al. Crit Care 2011Nguyen HB et al. Crit Care 2011

Ratio of the relative risk of death reduction for the Modified SSC Bundle compared with the

Primary SSC Bundle was:1.94 (95% CI: 1.45 – 39-1)

Fluid therapy of severe sepsis/septic shockFluid therapy of severe sepsis/septic shock



1. Crystalloids as the initial fluid of choice in the resuscitation 2. Against the use of hydroxyethyl starches for fluid resuscitation3. Albumin in the fluid resuscitation when patients require substantial

amounts of crystalloids.4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion

with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent).

4. The rate of fluid infusion should be of 500 mL to 1,000 mL over 30 min5. Fluid challenge technique be applied wherein fluid administration is

continued as long as there is hemodynamic improvement either based on dynamic (e.g., change in pulse pressure, stroke volume variation) orstatic (e.g., arterial pressure, heart rate) variables

CHEST TrialHydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive CareMyburgh JA et al. N Engl J Med 2012Conclusions: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy.

VISEP TrialIntensive Insulin therapy and pentastarch resuscitation in severe sepsisBrunkhorst FM et al. N Engl J Med 2008Conclusions: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses.

CRYSTMAS TrialAssessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis. The CRYSTMAS studyGuidet B et al. Crit Care 2012Conclusions: Significantly less volume was required to achieve hemodynamic stabilization for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups.6S TrialHydroxyethyl startch 130/0.42 versus Ringer’s acetate in severe sepsis.Perner A et al. N Engl J Med 2012Conclusions: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at 90 day and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate.

“We recommend against the use of hydroxyethyl starches (HES) for fluid resuscitation of severe sepsis and septic shock”

Effects of fluid resuscitation with colloids vs crystalloids on mortalityEffects of fluid resuscitation with colloids vs crystalloids on mortalityIn critically ill patients presenting with hypovolemic shockIn critically ill patients presenting with hypovolemic shock

The CRISTAL Randomized TrialThe CRISTAL Randomized TrialAnnane D et al. JAMA 2013Annane D et al. JAMA 2013

All patients requiring vasopressors have an A-line placed as soon as practical if resources are available

Vasopressor therapy initially to target a MAP ≥ 65 mmHg Norepinephrine (NE) as the first choice vasopressor Epinephrine (added to and potentially substituted for NE)

when an additional agent is needed to maintain adequate blood pressure

Low Dose Vasopressin is not recommended as the single initial vasopressor

Vasopressin (0.03-0.04 u/min) can be added to NE with intent of either raising MAP or decreasing NE dosage

Higher vasopressin doses should be reserved for salvage therapy

Dopamine as an alternative vasopressor agent to NE only in highly selected patients with low risks of tachyarrhythmias and absolute or relative bradycardia

Low-dose dopamine should not be used for renal protection Phenylephrine is not recommended except in circumstances

where NE is associated with serious arrhythmias, CO is known to be high and blood pressure persistently low, or as salvage therapy



VasopressorsVasopressors

Comparison of dopamine and norepinephrine in the Comparison of dopamine and norepinephrine in the treatment of shocktreatment of shock

De Backer D et al. for the SOAP II Investigators. N Engl J Med 2010De Backer D et al. for the SOAP II Investigators. N Engl J Med 2010

Dopamine NE

CorticosteroidsCorticosteroids



Corticosteroids not to be administered for the treatment of sepsis in the absence of shock

Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability.

In the case this is not achievable, we suggest iv hydrocortisone alone at a dose of 200 mg per day.

When hydrocortisone is given, use continuous flow Not using the ACTH stimulation test to identify adults with

sepstic shock who would receive hydrocortisone In treated patients hydrocortisone tapered when

vasopressors are no longer required

Inotropic therapyInotropic therapy



A trial of dobutamine infusion up to 20 mcg/kg/min be administered or added to vasopressor (if in use) in the presence of myocardial dysfunction or ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP.

Not using a strategy to increase CI to predetermined supranormal levels

Blood Product AdministrationBlood Product Administration



Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when HgB concentration decreases to < 7 g/dL to target a HgB concentration of 7-9 g/dL in adults.

Not using erythropoietin as a specific treatment of anemia associated with severe sepsis

Fresh Frozen plasma not to be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures

Administer platelets prophylactically when counts are ≤10,000/mm3 in the absence of apparent bleedings, when counts are ≤20,000/mm3 if the patient has significant risks of bleedings. Administer platelets when counts are <10,000/mm3 for active bleedings, surgery, or invasive procedures.

• Appropriate cultures – At least 2 sets of blood cultures – both aerobic and anaerobic bottles

before antimicrobial therapy is initiated if such cultures do not cause significant delay > 45 min in the start of antimicrobial administration

– With an indwelling catheters inserted >48 hrs: One blood culture drawn percutaneously and one drawn through each lumen of each vascular access device

– Other sites such as urine, CSF, wounds, respiratory secretions, or other body fluids that may be he source of infection

– Use of the 1,3 -D-glucan assay, mannan and anti-mannan antibody assays, if available and invasive candidiasis is in differential diagnosis of cause of infection

• Imaging studies performed promptly to confirm a potential source of infection



Severe sepsis/septic shock DiagnosisSevere sepsis/septic shock Diagnosis

Antimicrobial therapyAntimicrobial therapy

• Administration of effective intravenous antimicrobials therapy within 1 hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy

• Antimicrobial agents with a spectrum of activity likely to treat the responsible pathogen(s)

• Combination therapy ≤ 3-5 days• All patients should receive a full loading dose of each agent• Patients with abnormal and vacillating renal or hepatic function

require “daily” adjustment.• Drug serum concentration monitoring to maximize

efficacy/minimize toxicity• Daily reassessment of antimicrobial therapy for de-escalation,

when appropriate • Daily assessment of the total duration, 7-10 days



Duration of hypotension before initiation of effective Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of antimicrobial therapy is the critical determinant of

survival in human septic shocksurvival in human septic shockKumar et al., Crit Care Med 2006Kumar et al., Crit Care Med 2006

Mortality risk (expressed as adjusted odds ratio of death) with increasing delays in initiation of effective antimicrobial therapy.

TimelinessTimeliness

Choice of empirical antimicrobial therapyChoice of empirical antimicrobial therapy

• Timing [Community-acquired/Healthcare-associated / Early-onset vs Late-onset nosocomial infection]

• Patient’s history– Drug allergies / intolerances– Recent receipt of antibiotics (3 months)– MDR pathogen risk factors / Underlying diseases– Prior colonization/infection by MDR pathogen [VRE, MRSA,

Pseudomonas aeruginosa, Acinetobacter baumaanii, Stenotrophomonas, AmpC Enterobacter spp and other GNB, ESBL enterobacteriaceae]

• Severity of sepsis• Site of infection / Diagnosis• High frequency of antibiotic resistance in the community [MRSA, ESBL

enterobacteriaceae]• Local epidemiology / High frequency of specific pathogens and antibiotic

resistances in the specific hospital unit [VRE, MRSA, Pseudomonas aeruginosa, Acinetobacter baumaanii, Stenotrophomonas, AmpC Enterobacter spp and other GNB, ESBL enterobacteriaceae]

MDR Risk factorsMDR Risk factors

• Recent and prolonged exposure to antimicrobial therapy in preceding 90 days • Current hospitalization of 5 days or more • Neutropenia <500 neutrophil cells/µL • Immunosuppressive disease and/or therapy / Severe immunodeficiency

– Recipients of solid organ (liver, heart, renal, lungs)– Recipients of bone marrow transplant – Recent chemotherapy ≤30 days – AIDS [CD4 cell count <200 cells/µL, or other evidence of AIDS], – High-dose corticosteroids [20 mg/day prednisone equivalent for >5 days], – Treatment with azathioprine sodium or cyclosporine

• Malignant conditions (solid tumor, hematological malignancy)• Structural lung disease (bronchiectasis or cystic fibrosis)• Recent travel in a continent/country at risk for MDR pathogens (Asia, Middle East, Africa, India,

Italia, Greece) • Presence of risk factors for health-care associated sepsis/Relevant risk for opportunistic pathogens:

– Hospitalization for 2 days or more in the preceding 90 days (3 months) (in the previous year)– Severe illness / Elderly (> 60-65 y) or severely disabled with repeated and chronic contact with

health care / Karnofsky index < 70– Residence in a nursing home or extended care facility – Invasive devices at presentation / Home infusion therapy (including antibiotics) / Home wound

care– Chronic dialysis within 30 days – Family member with multidrug-resistant pathogen

Inadequate Antimicrobial Treatment of Infections: A Inadequate Antimicrobial Treatment of Infections: A Risk Factor for Hospital Mortality Among Critically Ill Risk Factor for Hospital Mortality Among Critically Ill

PatientsPatientsKollef et al., Chest 1999Kollef et al., Chest 1999

Does initial appropriate therapy lower mortality? YESDoes initial appropriate therapy lower mortality? YES

AppropriatnessAppropriatness

Antimicrobial Therapy Escalation and Hospital Mortality Antimicrobial Therapy Escalation and Hospital Mortality Among Patients With Health-Care–Associated Among Patients With Health-Care–Associated

Pneumonia. Pneumonia. A Single-Center ExperienceA Single-Center ExperienceZilberberg MD et al. Chest 2008Zilberberg MD et al. Chest 2008

Hospital mortality among HCAP patientsHospital mortality among HCAP patientsstill alive and in the hospital beyond 48 hstill alive and in the hospital beyond 48 haccording to the early choice of empiric according to the early choice of empiric treatment.treatment.

Mortality among HCAP patients still Mortality among HCAP patients still alive and in the hospital beyond 48 alive and in the hospital beyond 48 h who initially received h who initially received inappropriate antibioticsinappropriate antibioticsstratified by antibiotic escalation.stratified by antibiotic escalation.

Beta-lactam antibiotic monotherapy versus beta-Beta-lactam antibiotic monotherapy versus beta-lactam-aminoglycoside antibiotic combination therapy lactam-aminoglycoside antibiotic combination therapy

for sepsis for sepsis Paul M et al. Cochrane Database of systemic Reviews 2006Paul M et al. Cochrane Database of systemic Reviews 2006

• 64 trials randomizing 7586 patients with urinary tract, 64 trials randomizing 7586 patients with urinary tract, intra-abdominal, skin and soft tissue infections, intra-abdominal, skin and soft tissue infections, pneumonia, and infection of unknown origin. pneumonia, and infection of unknown origin.

• Antibiotics administered intravenously. Antibiotics administered intravenously. • Combination antibiotic treatment Combination antibiotic treatment

– New broad-spectrum beta-lactam vs less potent beta-New broad-spectrum beta-lactam vs less potent beta-lactam - aminoglycoside (44 studies). lactam - aminoglycoside (44 studies).

– One beta-lactam vs the same beta-lactam - One beta-lactam vs the same beta-lactam - aminoglycoside (20 studies). aminoglycoside (20 studies).

Beta-lactam antibiotic monotherapy versus beta-Beta-lactam antibiotic monotherapy versus beta-lactam-aminoglycoside antibiotic combination therapy lactam-aminoglycoside antibiotic combination therapy

for sepsis for sepsis Paul M et al. Cochrane Database of systemic Reviews 2006Paul M et al. Cochrane Database of systemic Reviews 2006

• Combination antibiotic treatment Combination antibiotic treatment – Did not improve the clinical efficacy Did not improve the clinical efficacy – Overall, adverse events rates did not differ between the Overall, adverse events rates did not differ between the

study groups, study groups, – But increased risk of kidney injuryBut increased risk of kidney injury– Did not prevent the development of secondary Did not prevent the development of secondary

infections.infections.

Emerging concepts in optimizing antimicrobial therapy Emerging concepts in optimizing antimicrobial therapy of septic shock: Speed is life but hammer helps too.of septic shock: Speed is life but hammer helps too.

Kumar A and Kethireddy S. Crit Care 2013Kumar A and Kethireddy S. Crit Care 2013

““Faster clearance of pathogens should result in improved Faster clearance of pathogens should result in improved outcomes outcomes

in severe sepsis and septic shock.”in severe sepsis and septic shock.”

Antibiotic prescription patterns in the empiric therapy Antibiotic prescription patterns in the empiric therapy of severe sepsis: Combination of antimicrobials with of severe sepsis: Combination of antimicrobials with different mechanisms of action reduces mortality.different mechanisms of action reduces mortality.

Diaz-Martin A et al for the Edusepsis Study Group. Crit Care 2012Diaz-Martin A et al for the Edusepsis Study Group. Crit Care 2012

DCCT – Different-Class Combination Therapy – Defined as the concomitant use of two ormore antibiotics of different mechanistic classes (beta-lactam with aminoglycosides, fluoroquinolones, or macrolides/clindamycin)

• Neutropenic patients with severe sepsis• Patients with difficult to treat, multidrug-resistant bacterial

pathogens such as Pseudomonas spp and Acinetobacter spp• Patients with severe infection associated with respiratory failure

and septic shock• Pseudomonas bacteremia• Bacteremic Streptococcus pneumoniae infections• Endocarditis• “Immunosuppressed patients”



Antimicrobial therapy / Combination initial therapyAntimicrobial therapy / Combination initial therapy

Prospective determination of serum ceftazidime Prospective determination of serum ceftazidime concentrations in intensive care unitsconcentrations in intensive care units

Aubert G et al. Ther Drug Monit 2010Aubert G et al. Ther Drug Monit 2010

Ceftazidime: iv loading dose 2 g – continuous infusion 2-6 g depending on creatinine clearance

Serum concentration/MIC ratio (P. aeruginosa MIC breakpoint ≤8 mg/L) ≥5 in 84% of the patients

n = 92 patients

Drug concentration monitoring / Dose adaptationDrug concentration monitoring / Dose adaptation

Continuous Infusion of Beta-Lactam Antibiotics in Continuous Infusion of Beta-Lactam Antibiotics in Severe Sepsis: A Multicenter Double-Blind, Randomized Severe Sepsis: A Multicenter Double-Blind, Randomized

Controlled TrialControlled TrialDulhunty JM et al. Clin Infect Dis 2013Dulhunty JM et al. Clin Infect Dis 2013

Clinical outcomes with extended or continuous versus short-term Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: intravenous infusion of carbapenems and piperacillin/tazobactam:

A systematic review and meta-analysis. A systematic review and meta-analysis. Falagas ME et al. Clin Infect Dis 2013Falagas ME et al. Clin Infect Dis 2013

Forest plot depicting the risk ratios of mortality of patients receiving extended or continuous versus Short-term infusion of carbapenems and piperacillin/tazobactam, stratified by continuous and extendedInfusion.

Clinical outcomes with extended or continuous versus short-term Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: intravenous infusion of carbapenems and piperacillin/tazobactam:

A systematic review and meta-analysis. A systematic review and meta-analysis. Falagas ME et al. Clin Infect Dis 2013Falagas ME et al. Clin Infect Dis 2013

Forest plot depicting the risk ratios of mortality of patients receiving extended or continuous versus short-term infusion of carbapenems and piperacillin/tazobactam, stratified by the administered antibiotics.

New Treatment Paradigm

• Hit hard and early with appropriate Hit hard and early with appropriate antibiotic(s) maximizing empirical antibiotic(s) maximizing empirical coverage with subsequent formal coverage with subsequent formal reduction in antibiotic therapyreduction in antibiotic therapy

• De-escalate when possible De-escalate when possible • Short treatment durationShort treatment duration

Routine use of a real-time polymerase chain reaction Routine use of a real-time polymerase chain reaction method for detection of bloodstream infections in method for detection of bloodstream infections in

neutropenic patients.neutropenic patients.Paolucci M and al. Diagn Microbiol Infect Dis 2013Paolucci M and al. Diagn Microbiol Infect Dis 2013

Non-culture-based diagnostic methods(Polymerase chain reaction, massSpectroscopy, microarrays)- Quicker identification of pathogens- Quicker identification of resistances- Useful for difficult-to-culture pathogens- Useful in clinical situations where antimicrobial agents has been administered before culture samples were been obtained

Renal Replacement therapy/Bicarbonate therapyRenal Replacement therapy/Bicarbonate therapy



Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure

Use continuous therapy to facilitate management of fluid balance to hemodynamically unstable septic patients

Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirement in patients with hypoperfusion-induced lactic acidemia with pH >7.15

NutritionNutrition



Administer oral/enteral feedings as tolerated rather than either complete fasting or provision of only iv glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock

Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding, up to 500 calories per day, advancing only as tolerated.

Use enteral nutrition rather than TPN alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days

Use nutrition with no specific immunomodulating supplementation

Early Goal Directed therapyEarly Goal Directed therapyRivers E et al. N Engl J Med 2001Rivers E et al. N Engl J Med 2001

Static and dynamicparameters/tests Fluid challenge

30 mL/kg

LactateClearance

X

NEEpinephrine

Rate of Fluid infusion 500-1000 ml / 30 mins

NO more HES

Antimicrobial stewardship and the role of PK-PD in Antimicrobial stewardship and the role of PK-PD in the modern antibiotic erathe modern antibiotic era

Owens RC, Ambrose PG. Diagn microbiol Infect Dis 2007Owens RC, Ambrose PG. Diagn microbiol Infect Dis 2007

• STEWARDSHIP of these precious resources has become a focus STEWARDSHIP of these precious resources has become a focus – Appropriate prescriptionAppropriate prescription– Appropriate timingAppropriate timing– Appropriate selectionAppropriate selection– Appropriate dosingAppropriate dosing– De-escalationDe-escalation– Appropriate durationAppropriate duration

severe sepsis and septic shock what’s new? p moine department of anesthesiology

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