Transcript Fluid resuscitation in septic shock

Severe sepsis and septic shock
What’s new?
P Moine
Department of Anesthesiology
Epidemiology (USA, 1995)
 Incidence of Severe Sepsis
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750,000 patients / year
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225,000 (29%) surgical patients
 Mortality 29%
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215,000 deaths per year
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9.3% of all deaths in the United States
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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: 2012
R. 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 therapy
Rivers E et al. N Engl J Med 2001
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
“Early Goal-Directed Therapy”
Early quantitative resuscitation of the septic patient
during the first 6 hrs after recognition
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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:
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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
Cardiac filling pressures are not appropriate to predict
hemodynamic response to volume challenge
Osman D et al. Crit Care Med 2007
Cardiac filling pressures are considered as the gold standard for guiding fluid therapy
in patients with sepsis and septic shock
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.
Poor Predictors of fluid responsiveness
8±4 mmHg
9±4 mmHg
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%
Individual values and mean ± SD of pre-infusion CVP in Responders and NonResponders
Patients 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
Central venous pressure: A useful but not so simple
measurement.
Magder 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
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CVP
< 0 mmHg
Low CVP
Low CVP
High CVP
High CVP
Volume
Return
Function
Normal
Hypovolemia
Hypervolemic
Hypervolemic
Normal
Cardiac
function
Normal
Normal
Very dynamic
heart
Normal
Decreased
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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.
Assessing cardiac preload or fluid responsiveness? It depends on
the question we want to answer.
Michard 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.
Cardiac filling pressures are not appropriate to predict
hemodynamic response to volume challenge
Osman D et al. Crit Care Med 2007
PAOP and CVP: No better than flip of a coin
How do I decide if my hypotensive septic patient needs fluids,
pressors, or an inotrope?
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- 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.
Fluid resuscitation in septic shock: a positive fluid balance and elevated central
venous pressure are associated with increased mortality.
Boyd 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.
Fluid resuscitation in septic shock: a positive fluid balance and elevated central
venous pressure are associated with increased mortality.
Boyd JH et al. Crit Care Med 2011
Fluid resuscitation in septic shock: a positive fluid balance and elevated central
venous pressure are associated with increased mortality.
Boyd JH et al. Crit Care Med 2011
Fluid resuscitation in septic shock: a positive fluid balance and elevated central
venous pressure are associated with increased mortality.
Boyd JH et al. Crit Care Med 2011
Cox survival curves, adjusted for age, APACHE II score, and severity of shock (dose of norepinephrine) are
Shown 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.
Comparison of two fluid-management strategies in acute lung injury
Wiedemann 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.
Man drinking lots of water
Assessment of Volume Responsiveness during Mechanical
Ventilation: Recent advances
Monnet X and Teboul JL. Critical Care 2013
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Early quantitative resuscitation of the septic patient
during the first 6 hrs after recognition
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.
Serial blood lactate levels can predict the development of
multiple organ failure following septic shock.
Bakker J et al. Am J Surg 1996
Early lactate clearance is associated with improved outcome
in severe sepsis and septic shock
Nguyen HB et al Crit Care Med 2004
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 biomarkers of
inflammation, coagulation, apoptosis, organ dysfunction and
mortality in severe sepsis and sepstic shock
Nguyen HB et al. J Inflamm 2010
Lactate clearance vs central Venous oxygen saturation as goals
of early sepsis therapy
Jones AE et al. JAMA 2010
Outcome effectiveness of the severe sepsis resuscitation bundle
with addition of lactate clearance as a bundle item:
A multi-national evaluation.
Nguyen HB et al. Crit Care 2011
Outcome effectiveness of the severe sepsis resuscitation bundle
with addition of lactate clearance as a bundle item:
A multi-national evaluation.
Nguyen 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)
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Fluid therapy of severe sepsis/septic shock
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Crystalloids as the initial fluid of choice in the resuscitation
Against the use of hydroxyethyl starches for fluid resuscitation
Albumin in the fluid resuscitation when patients require substantial
amounts of crystalloids.
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).
The rate of fluid infusion should be of 500 mL to 1,000 mL over 30 min
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) variables
“We recommend against the use of hydroxyethyl starches (HES) for fluid resuscitation
of severe sepsis and septic shock”
CHEST Trial
Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care
Myburgh JA et al. N Engl J Med 2012
Conclusions: 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.
CRYSTMAS Trial
Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs.
0.9% NaCl fluid replacement in patients with severe sepsis. The CRYSTMAS study
Guidet B et al. Crit Care 2012
Conclusions: 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 Trial
Hydroxyethyl startch 130/0.42 versus Ringer’s acetate in severe sepsis.
Perner A et al. N Engl J Med 2012
Conclusions: 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.
VISEP Trial
Intensive Insulin therapy and pentastarch resuscitation in severe sepsis
Brunkhorst FM et al. N Engl J Med 2008
Conclusions: 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.
Effects of fluid resuscitation with colloids vs crystalloids on mortality
In critically ill patients presenting with hypovolemic shock
The CRISTAL Randomized Trial
Annane D et al. JAMA 2013
Effects of fluid resuscitation with colloids vs crystalloids on mortality
In critically ill patients presenting with hypovolemic shock
The CRISTAL Randomized Trial
Annane D et al. JAMA 2013
Effects of fluid resuscitation with colloids vs crystalloids on mortality
In critically ill patients presenting with hypovolemic shock
The CRISTAL Randomized Trial
Annane D et al. JAMA 2013
Effects of fluid resuscitation with colloids vs crystalloids on mortality
In critically ill patients presenting with hypovolemic shock
The CRISTAL Randomized Trial
Annane D et al. JAMA 2013
Effects of fluid resuscitation with colloids vs crystalloids on mortality
In critically ill patients presenting with hypovolemic shock
The CRISTAL Randomized Trial
Annane D et al. JAMA 2013
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Vasopressors
 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
Comparison of dopamine and norepinephrine in the treatment of shock
De Backer D et al. for the SOAP II Investigators. N Engl J Med 2010
Dopamine
NE
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Corticosteroids
 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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Inotropic 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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Blood 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.
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Severe sepsis/septic shock Diagnosis
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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 b-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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial therapy
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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
antimicrobial therapy is the critical determinant of survival in
human septic shock
Kumar et al., Crit Care Med 2006
Timeliness
Mortality risk (expressed as adjusted odds ratio of death) with increasing delays
in initiation of effective antimicrobial therapy.
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial therapy
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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
Choice of empirical antimicrobial therapy
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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 factors
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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 Risk
Factor for Hospital Mortality Among Critically Ill Patients
Kollef et al., Chest 1999
Appropriatness
Does initial appropriate therapy lower mortality? YES
Antimicrobial Therapy Escalation and Hospital Mortality Among
Patients With Health-Care–Associated Pneumonia.
A Single-Center Experience
Zilberberg MD et al. Chest 2008
Hospital mortality among HCAP patients
still alive and in the hospital beyond 48 h
according to the early choice of empiric
treatment.
Mortality among HCAP patients still alive
and in the hospital beyond 48 h who
initially received inappropriate antibiotics
stratified by antibiotic escalation.
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial therapy
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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
Beta-lactam antibiotic monotherapy versus beta-lactamaminoglycoside antibiotic combination therapy for sepsis
Paul M et al. Cochrane Database of systemic Reviews 2006
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64 trials randomizing 7586 patients with urinary tract, intraabdominal, skin and soft tissue infections, pneumonia, and infection
of unknown origin.
Antibiotics administered intravenously.
Combination antibiotic treatment
– New broad-spectrum beta-lactam vs less potent beta-lactam aminoglycoside (44 studies).
– One beta-lactam vs the same beta-lactam - aminoglycoside (20
studies).
Beta-lactam antibiotic monotherapy versus beta-lactamaminoglycoside antibiotic combination therapy for sepsis
Paul M et al. Cochrane Database of systemic Reviews 2006
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Combination antibiotic treatment
– Did not improve the clinical efficacy
– Overall, adverse events rates did not differ between the study
groups,
– But increased risk of kidney injury
– Did not prevent the development of secondary infections.
Emerging concepts in optimizing antimicrobial therapy of septic
shock: Speed is life but hammer helps too.
Kumar A and Kethireddy S. Crit Care 2013
“Faster clearance of pathogens should result in improved outcomes
in severe sepsis and septic shock.”
Antibiotic prescription patterns in the empiric therapy of severe
sepsis: Combination of antimicrobials with different mechanisms
of action reduces mortality.
Diaz-Martin A et al for the Edusepsis Study Group. Crit Care 2012
DCCT – Different-Class Combination Therapy – Defined as the concomitant use of two or
more antibiotics of different mechanistic classes (beta-lactam with aminoglycosides,
fluoroquinolones, or macrolides/clindamycin)
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial therapy / Combination initial therapy
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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”
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial 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
Prospective determination of serum ceftazidime concentrations
in intensive care units
Aubert G et al. Ther Drug Monit 2010
Drug concentration monitoring / Dose adaptation
Ceftazidime: iv loading dose 2 g – continuous infusion 2-6 g depending on creatinine clearance
n = 92 patients
Serum concentration/MIC ratio (P. aeruginosa MIC breakpoint ≤8 mg/L) ≥5 in 84% of the patients
Continuous Infusion of Beta-Lactam Antibiotics in Severe
Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial
Dulhunty JM et al. Clin Infect Dis 2013
Continuous Infusion of Beta-Lactam Antibiotics in Severe
Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial
Dulhunty JM et al. Clin Infect Dis 2013
Clinical outcomes with extended or continuous versus short-term
intravenous infusion of carbapenems and piperacillin/tazobactam:
A systematic review and meta-analysis.
Falagas 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 extended
Infusion.
Clinical outcomes with extended or continuous versus short-term
intravenous infusion of carbapenems and piperacillin/tazobactam:
A systematic review and meta-analysis.
Falagas 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.
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Antimicrobial 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
New Treatment Paradigm
• Hit hard and early with appropriate
antibiotic(s) maximizing empirical coverage
with subsequent formal reduction in
antibiotic therapy
• De-escalate when possible
• Short treatment duration
Routine use of a real-time polymerase chain reaction method
for detection of bloodstream infections in neutropenic patients.
Paolucci M and al. Diagn Microbiol Infect Dis 2013
Non-culture-based diagnostic methods
(Polymerase chain reaction, mass
Spectroscopy, 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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Renal 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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Nutrition
 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
Surviving Sepsis Guidelines: International Guidelines for
Management of Severe Sepsis and Septic shock: 2012
Dellinger RP et al. Crit Care Med 2013
Early Goal Directed therapy
Rivers E et al. N Engl J Med 2001
Static and dynamic
parameters/tests
NO more HES
Fluid challenge
30 mL/kg
Rate of Fluid infusion
500-1000 ml / 30 mins
NE
Epinephrine
X
Lactate
Clearance
Antimicrobial stewardship and the role of PK-PD in the
modern antibiotic era
Owens RC, Ambrose PG. Diagn microbiol Infect Dis 2007
•
STEWARDSHIP of these precious resources has become a focus
– Appropriate prescription
– Appropriate timing
– Appropriate selection
– Appropriate dosing
– De-escalation
– Appropriate duration