Surviving Sepsis Campaign

International
Guidelines For Management Of Sepsis And Septic
Shock 2021
Introduction
• Sepsis is a life-threatening organ dysfunction caused by a
dysregulated host response to infection
• It kills 1/3 to 1/6 of affected patients
• Early identification and appropriate management improves outcomes
qSOFA
• qSOFA has 3 variables, when 2 are present, it is considered positive
• GCS < 15
• RR ≥ 22/min
• SBP ≤ 100 mmHg
• Results were contradictory as for the use of this score
• More specific but less sensitive than having 2 of 4 SIRS criteria
Blood lactate
• Elevated levels significantly increase the likelihood of a final sepsis
diagnosis
• Normal levels significantly decrease this likelihood
• The level alone is neither sensitive nor specific enough to rule in or
out the diagnosis of sepsis
Measures of fluid status
• Failure to give 30mL/kg of fluids within the first 3h increases the
mortality
• HR, CVP and SBP alone are poor predictors of the fluid status
• Dynamic parameters
• Response to a passive leg raise or a fluid bolus, using stroke volume (SV),
stroke volume variation (SVV), pulse pressure variation (PPV), or
echocardiography, where available
Measures of fluid status
• When fluids are needed beyond the initial resuscitation, CO or SV are
measured with repeated small boluses
• If CO or SV measurements are not possible
• A passive leg-raise test is performed for 60-90s, a > 15% increase in pulse
pressure indicate that the patient is fluid responsive
• During acute resuscitation, serum lactate level should be interpreted
considering the clinical context and other causes of elevated lactate
Measures of fluid status
• Temperature of the extremities, skin mottling and capillary refill time
are validated and reproducible signs of tissue perfusion
• Resuscitation strategies targeting CRT normalization were more effective than
aiming normalization or decreasing lactate levels by 20% q2h in the first 8 h of
septic shock
• 28-day mortality: 34.9% in the peripheral perfusion group and 43.4% in the
lactate group (not reach statistically significant)
Infections
• 1/3 of patients initially diagnosed with sepsis turn out to have non-
infectious conditions
• Rapid assessment for likelihood of infectious cause
• History and clinical examination
• Tests for infectious and non-infectious causes of acute illness and immediate
• Treatment for acute conditions that can mimic sepsis
• Whenever possible this should be completed within 3h of presentation
Sepsis without shock
• There were 2 RCT that found no significant difference in mortality
despite differences in time-to-antimicrobials
• Observational studies suggest that mortality may increase after
intervals exceeding 3-5h
Procalcitonin
• Procalcitonin is undetectable in healthy states
• Rises rapidly in response to pro-inflammatory stimuli, especially bacterial
infections
• In a meta-analysis of 30 studies, it had a pooled sensitivity of 77% and
specificity of 79% for sepsis in critically ill patients
MRSA
• Patient-related risk factors
• History of MRSA infection or colonization
• Recent IV antibiotics
• History of recurrent skin infections or chronic wounds
• Invasive devices
• Hemodialysis
• Recent hospital admission and severity of illness
• Failure to cover MRSA can be harmful
• Unnecessary coverage may also be harmful
MDR
• No difference in mortality or other outcomes between empiric mono-
or combination-antibiotic therapy in sepsis or septic shock
• Risk for MDR
• Infection or colonization with antibiotic-resistant organism in the past year
• Local prevalence of resistant organisms
• Hospital-acquired infection
• Broad-spectrum antibiotic use in the past 90 days
• Use of selective digestive decontamination
• Travel to highly endemic countries in the past 90 days
MDR
• In the targeted phase double coverage is not necessary except
possibly for patients with highly-resistant organisms with no proven
safe and efficacious therapeutic option
Beta-lactams
• As opposed to conventional intermittent infusion (infusion ≤ 30 min),
administration by prolonged IV infusion, either as an extended
infusion (over at least half of the dosing interval) or as a continuous
infusion, results in sustained beta-lactam concentrations which align
with the pharmacodynamics of these drugs
• A loading dose should be given before the continuous infusion
• Drug stability and drug-drug compatibility issues are important
Source control
• Drainage of an abscess
• Debriding infected necrotic tissue
• Removal of a potentially infected device
• Definitive control of a source of ongoing microbial contamination
Source control
• Foci of infection readily amenable to source control
• Intra-abdominal abscesses
• GI perforation
• Ischemic bowel or volvulus
• Cholangitis
• Cholecystitis
• Pyelonephritis associated with obstruction or abscess
• Necrotizing soft tissue infection
• Other deep space infection (empyema or septic arthritis)
• Implanted device infections
Source control
• Source control should be done within 6h
• Reduced survival after that point
• Prolonged efforts at medical stabilization in lieu of source control for
severely ill patients, particularly those with septic shock, are generally
not advised
• The least invasive option that will effectively achieve source control
should be pursued
De-escalation of antibiotics
• Most studies were observational, and there are concerns that de-
escalation is used primarily in patients who are getting better, which is
why the reported improved short-term mortality should be
interpreted with caution
Duration of antibiotic therapy
Normal saline solution
• Potential side effects
• Hyperchloremic metabolic acidosis
• Renal vasoconstriction
• Increased cytokine secretion
• Concerns about AKI
• A meta-analysis of 14 RCT of patients with sepsis showed that
balanced crystalloids were associated with decreased mortality
compared to saline
Albumin
• No clear benefit with its routine use
• To be considered albumin in patients who received large volumes of
crystalloids is supported by evidence showing higher BP at early and
later time points, higher static filling pressures, and lower net fluid
balance
• Limited data precludes a cutoff value for crystalloid infusion above
which albumin might be considered as part of resuscitation
Norepinephrine
• Potent α-1, β-1 adrenergic receptor agonist
• Vasoconstriction and increased MAP
• Minimal effect on HR
• In settings where norepinephrine is not available, epinephrine or
dopamine can be used as an alternative, but efforts to improve the
availability of norepinephrine are encouraged
Dopamine
• Activity is dose-dependent on dopamine-1, α-1 and β-1
• Lower dose: vasodilation via dopamine-1 receptor receptor in renal,
splanchnic, cerebral and coronary beds
• Higher dose: α-adrenergic activity predominates increasing SVR, β-adrenergic
activity leads to dose-limiting arrhythmia
• Noradrenaline is more potent than dopamine as vasoconstrictor
• Special attention should be given to patients at risk for arrhythmias
when using dopamine and epinephrine
Epinephrine
• Potent β-1 adrenergic receptor
• Moderate β-2 and α-1 receptor activity
• Dose-dependent activity
• Low dose: β-1 activity leads to increased CO, decreased SVR, variable effects
on MAP
• Higher doses: increased SVR and CO
• Epinephrine can increase aerobic lactate by stimulating muscle β-2
receptors
• Challenging use of serum lactate to guide resuscitation
Vasopressin
• V1 receptor on smooth muscle leads to vasoconstriction
• Concentration is elevated in early septic shock but decreases to
normal range after 24 to 48h
• Relative vasopressin deficiency since with hypotension its concentration is
expected to increase (significance unknown)
• Dose is not titrated to response
• Fixed dose of 0.03 U/min
• In clinical trials, used at 0.06 U/min
• Catecholamine-sparing effect
• Sensible to start it when norepinephrine dose 0.25-0.5 µg/kg/min
Vasopressin
• With high dose of norepinephrine, α-1 receptors is saturated and
downregulated
• Another drug targeting the same receptors (epinephrine) is of limited utility
• Vasopressin more adequate in this scenario
• Some evidence suggests that vasopressin might be superior to
norepinephrine in terms of clinical outcomes
• However, higher costs and lower availability
Selepressin
• Highly selective V1 agonist
• Does not share the typical V1b and V2 receptor effects of vasopressin
• Such as increased pro-coagulant factors, salt, and water retention, nitric
oxide, and corticosteroid release
• Failed to demonstrate clinical superiority over norepinephrine
Angiotensin II
• Synthetic human preparation
• Limited demonstration of safety
Terlipressin
• Prodrug converted to lysine vasopressin
• Produces a slow release with a half-life of 6h
• Undesirable consequences are higher with its use
Inotropes
• Can be used in patients with persistent hypoperfusion after adequate
fluid resuscitation, and in patients with myocardial dysfunction, based
on suspected or measured low CO and elevated cardiac filling
pressures
• In an observational study of 420 patients with septic shock, the use of
an inotropic agent (dobutamine, levosimendan, epinephrine, or
milrinone) was independently associated with increased 90-day
mortality
Inotropes
• Meta-analyses showed that dobutamine + norepinephrine had no
clear impact on mortality when compared to no inotropic agents
• The panel considered the network meta-analysis as a higher quality
than observational studies and issued a suggestion to use inotropes
only in selected situations
Dobutamine
• Response may be blunted in sepsis with a preserved chronotropic
effect causing tachycardia without an increase SV
• No evidence supporting its superiority over epinephrine
• Both should be discontinued in the absence of improvement in hypoperfusion
or in the presence of adverse events
Levosimendan
• Ca-sensitizing drug with inotropic and vasodilatory properties
• Use did not impact mortality
• Associated with a lower likelihood of successful weaning from
mechanical ventilation and a higher risk of supraventricular
tachyarrythmia
Arterial lines
• Insertion of an arterial catheter permits safe, reliable and continuous
measurement of arterial pressure and allows real time analysis so that
therapeutic decisions can be based on immediate and accurate blood
pressure information
• Benefits outweigh the risks
• Removed as soon as continuous hemodynamic monitoring is no
longer required
Peripheral vasopressors
• When using vasopressors peripherally, they should be administered
only for a short period of time and in a vein in or proximal to the
antecubital fossa
• Administration through a peripheral IV is safe
• Extravasation 3.4% and no reported episodes of tissue necrosis or limb
ischemia in a recent review
• Administration of vasopressors for a short period of time (< 6 h) in a well-
placed peripheral catheter proximal to the antecubital fossa is unlikely to
cause local tissue injury
• If still needed after, a central venous access should be obtained
High-flow nasal canula
• NIV complications
• Gastric insufflation
• Aspiration
• Facial skin breakdown
• Excessively high tidal volumes
• Patient discomfort
High-flow nasal canula
• High-flow nasal canula
• Warming and humidification of secretions
• High flows better match patient demands
• Washout of nasopharyngeal dead space
• Modest positive airway pressure effect
• Air flows as high as 60L/min
• FiO2 as high as 95-100%
• Less effective at reducing work of breathing and supplying PEEP
High-flow nasal canula
• A large RCT showed improved 90-day survival with HFNC compared
with NIV
• In a post hoc analysis, if PaO2/FiO2 ≤ 200 mmHg, HFNC resulted in lower rates
of intubation
Prone ventilation
• In a recent meta-analysis
• Improved survival when PaO2/FiO2 < 200, within the first 36h of intubation,
for > 12h/day
Corticosteroids
• Accelerate resolution of shock
• Increase vasopressor-free days
• No clear effect on short- or long-term mortality
• Optimal dose, timing of initiation and duration remain uncertain
Corticosteroids
• The typical corticosteroid used in adults with septic shock is IV
hydrocortisone
• Dose of 200 mg/day given as 50 mg IV q6h or as a continuous infusion
• Suggestion to be commenced at a dose of norepinephrine or epinephrine
≥0.25 mcg/kg/min at least 4 h after initiation
Blood transfusion
• A restrictive transfusion strategy typically includes a Hb trigger of 7
g/dL
• However, RBC transfusion should not be guided by Hb alone
• Assessment of a patient’s overall clinical status and consideration of
extenuating circumstances such as acute MI, severe hypoxemia or acute
hemorrhage is required
VTE prophylaxis
• Significantly lower rates of DVT with LMWH compared with UFH
• No differences in significant bleeding, PE or mortality
Insulin therapy
• Following initiation of an insulin therapy, a typical target blood
glucose range is 144–180 mg/dL (8–10 mmol/L)