3. Sepsis

Question 1

What is it

Answer 1

SCCM/ESICM 2016

Defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3) as evidenced by the following

Organ dysfunction
as an increase of two or more points in the SOFA score
(e predictive validity of the SOFA score for in-hospital mortality was superior to that for the SIRS criteria)

Infection – There are no clear guidelines to help the clinician identify the presence of infection or to causally link an identified organism with sepsis.
clinical suspicion derived from the signs and symptoms of infection as well as supporting radiologic and microbiologic data and response to therapy.

Question 2

Septic shock

Answer 2

Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone

despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL)

Question 3

SIRS:

Answer 3

SIRS: this comprises features of the inflammatory response in the absence of an
identifiable pathogen, end-organ damage or the need for circulatory support. It is
therefore distinct from sepsis and its variants.

pathogen has been isolated,
then the working diagnosis in a patient shifts from SIRS to sepsis, severe sepsis or
septic shock. Once end-organ damage supervenes the diagnosis becomes that of early
multiple organ dysfunction syndrome (MODS

Question 4

The ‘Sepsis Six’:

Answer 4

this is a simple care bundle If initiated within the first
hour associated mortality is substantially reduced (up to 50%).

The elements consist
of
(1) Oxygen at high flows to maintain SpO2 >94%,
(2) Blood cultures,
(3) Antibiotics, broad spectrum, given intravenously,

(4) Fluid resuscitation (e.g. 20 ml.kg–1 initially),
(5) Lactate measurement: a level >4 mmol l–1 is consistent with
severe sepsis and
(6) Urine output monitoring (hourly). (This shouldn’t be too
difficult to remember, but if your mind goes blank the acronym ‘OBAFLU’ may
act as a mnemonic.)

Question 5

care bundle

Answer 5

a bundle being defined as a group of
interventions that together have a greater effect on beneficial outcome than when the
individual interventions are given in a disparate manner)

Question 6

Dx?

Answer 6

they cannot identify patients whose organ dysfunction is truly secondary to an underlying infection.

Thus, a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock.

. The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when followup data returns (eg, positive blood cultures in a patient with endocarditis) or a response to antibiotics is evident. Importantly, the identification of a culprit organism, although preferred, is not always feasible since in many patients no organism is ever identified. In some patients this may be because they have been partially treated with antibiotics before cultures are obtained.

Question 7

Epidemology

Answer 7

437 per 100,000 person-years and sepsis appears to be responsible for 6 percent of US hospital admissions. Gram positive bacteria are the pathogens that are most commonly isolated from patients with sepsis

Question 8

Risk factors

Answer 8

sepsis include intensive care unit (ICU) admission, a nosocomial infection, bacteremia, advanced age, immunosuppression, previous hospitalization (in particular hospitalization associated with infection), and community-acquired pneumonia. Genetic defects have also been identified that may increase susceptibility to specific classes of microorganisms.

Question 9

Clinical presentation and diagnosis

Answer 9

suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status

Question 10

Prognosis

Answer 10

– Sepsis has a high mortality rate that appears to be decreasing. Estimates range from 10 to 52 percent with rates increasing linearly according to the disease severity of sepsis. Following discharge from the hospital, sepsis carries an increased risk of death as well as an increased risk of further sepsis and recurrent hospital admissions. Poor prognostic factors include the inability to mount a fever, leukopenia, age >40 years, certain comorbidities (eg, AIDS, hepatic failure, cirrhosis, cancer, alcohol dependence, immunosuppression), a non-urinary source of infection, a nosocomial source of infection, and inappropriate or late antibiotic coverage

Question 11

The inflammatory response:

Answer 11

The inflammatory response: this is systemic rather than localized and is part of an
exaggerated or uncontrolled host response to a pathological insult

complex, comprising a sequence of reactions which involves not only the secretion
of key signalling molecules such as the

1. cytokines -
   interleukins IL-1, 5, 6, 8, 11 and 15, tumour necrosis factor, colony-stimulating
   factors, interferons and platelet-activating factor
2. also the activation of complement
3. kinins and histamine lead to vasodilatation and increased capillary permeability,
4. while leukotrienes stimulate inward granulocyte migration.
5. CRP

Other aspects of immune function, such as cell-mediated and humoral immunity,
may also be mobilized

Question 12

Procoagulant–anticoagulant balance:

Answer 12

sepsis alters this balance in favour of procoagulant factors.

Endothelial cells appear to upregulate tissue factor and thereby
activate coagulation and the formation of microvascular thrombus.

The anticoagulant factors suppress coagulation and enhance fibrinolysis.

They include protein C, its co-factor protein S, antithrombin III and tissue factor-pathway inhibitor. All are decreased by sepsis

Question 13

Causes and clinical features:

Answer 13

the final common pathway to the inflammatory response can be triggered
by numerous insults such as
trauma,
major surgery and
challenges to the immune system by various antigens,

including infective agents and the transfusion of blood and blood products.

The major infective sources are respiratory (30–50%),
urinary tract (10–20%) and abdominal (20–25%).

Consistent with the diagnostic criteria described earlier, patients typically exhibit tachycardia, disturbed temperature regulation, tachypnoea, a narrowed pulse pressure secondary to the reduced effective circulating volume and oliguria.

The hypoperfusion is responsible for the lactic acidosis that is a typical feature of the condition
These clinical signs are relatively non-specific.

Question 14

Supplementary Information and Clinical Considerations

Question 15

De-escalation of fluid therapy in sepsis (June 2022)

Answer 15

In a recent trial of over 1500 adults with sepsis who had received at least 1 liter of fluid and were within 12 hours of the onset of shock,

individuals assigned to restrictive IVF strategy (ie, infusion stopped; small boluses given when needed for organ perfusion, low urine output, or insensible losses) compared with a standard IVF strategy had similar 90-day mortality and adverse effect

restrictive approach to fluid de-escalation. However, the volume of fluid in both groups was lower than that previously reported in early resuscitation sepsis studies suggesting that practice has evolved toward a de-escalation approach that is restrictive

Question 16

Initial management of sepsis and septic shock involves consideration of:

Answer 16

resuscitation
early administration of appropriate antibiotics following blood cultures
early source control
judicious fluid resuscitation, avoiding excess fluids
noradrenaline for refractory hypotension (septic shock)
inotropes for septic cardiomyopathy
therapies for refractory hypotension

Question 17

TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION*

Answer 17

TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION*:

1. Measure lactate level
2. Obtain blood cultures prior to administration of antibiotics
3. Administer broad spectrum antibiotics
4. Administer 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L

Question 18

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION:

Answer 18

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION:

5. Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥65mmHg
6. In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or if initial lactate was ≥4 mmol/L, re-assess volume status and tissue perfusion and document findings (see below).
7. Re-measure lactate if initial lactate elevated.

DOCUMENT REASSESSMENT OF VOLUME STATUS AND TISSUE PERFUSION WITH EITHER:

Repeat focused exam (after initial fluid resuscitation) by licensed independent practitioner including vital signs, cardiopulmonary, capillary refill, pulse, and skin findings.
OR TWO OF THE FOLLOWING:

Measure CVP
Measure ScvO2
Bedside cardiovascular ultrasound
Dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge

Question 19

Goals of resus

Answer 19

Mean arterial pressure (MAP) >65 mm Hg
Urine output >0.5 mL/kg/hr
Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C)
In patients with elevated lactate levels targeting resuscitation to normalize lactate (grade 2C)

Question 20

abx

Answer 20

Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy

Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B).

Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B)
Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C)

Question 21

1. Initial fluid resuscitation

Answer 21

Most patients need no more than 2-3 L (30 ml/kg IBW) IV in total (see Fluid bolus therapy)

physiological reasoning: treat relative volume depletion due to vasodilation in sepsis
consistent with SSG consistent with recent early goal directed therapy (EGDT) studies (ARISE, PROMISE, PROCESS) showing no additional benefit for protocolized care as described by Rivers et al, 2001

current trends are for restricted volumes of fluid management tailored to clinical context (e.g. a septic patient presenting with severe diarrhoea and dehydration likely requires larger amounts of fluid therapy)

Use crystalloid (0.9% NaCl or balanced salt solutions such as Hartmanns or Plasmalyte)

Consider blood transfusion if bleeding or anaemic
in non-bleeding patients target Hb >70g/L
transfusion trigger of Hb <70 g/L supported by TRICC (Hébert et al, 1999), TRISS (Holst et al, 2014) and

Question 22

Consider early vasopressors (see below)

Answer 22

Consider early vasopressors (see below)

if critically ill and hypotensive do not delay vasopressor administration pending central line insertion

it is acceptable to give vasopressors (e.g. noradrenaline infusion) via a proximal peripheral venous line (e.g. large bore cannula in antecubital fossa) in the short-term (e.g. first 6 hours) with close observation for extravasation (Loubani and Green, 2015; Cardenas-Garcia et al, 2015))

low dose dilute noradrenaline via a perpheral route led to improved control of shock at 6 hours in a phase II trial (CENSER) (Permpikul et al, 2019)

Consider early intubation and mechanical ventilation if critically ill (to facilitate procedures and decreased work of breathing/ oxygen consumption)

“resuscitate before you intubate” (e.g. fluids, vasopressors) and avoid exacerbation of acidaemia due to apnoea (see Intubation, Hypotension and Shock)
use protective lung ventilation (VT 6 mL/kg PBW, Pplat <30 cmH20)

Question 23

Source control

Answer 23

aggressive early identification and treatment of source of infection
e.g. septic screen, swab and culture potentially infected sites, advanced imaging (e.g. CT)

operative interventions such as laparotomy, incision and drainage of abscesses
may require minimally invasive approaches initially (e.g. cholecystostomy) followed by
later definitive therapy (e.g. cholecystectomy)

consider removal of pre-existing in situ devices

Question 24

ASSESS FOR FURTHER FLUID THERAPY

Answer 24

ASSESS FOR FURTHER FLUID THERAPY

This is a highly controversial area of sepsis management!

Target mean arterial pressure (MAP) >65 mmHg initially in most patients

early insertion of intra-arterial line for continuous monitoring
consider modifying MAP target according to clinical response (patient may be well perfusion at lower targets) and pre-existing blood pressure (e.g. consider higher target if previous hypertension)
SEPSISPAM found no benefit of targeting MAP 80-85 mmHg versus MAP 65-70 mmHg, however those with pre-existing hypertension had less renal replacement therapy but more atrial fibrillation with the higher MAP target (Asfar et al, 2014)

Question 25

Perform frequent assessment of response to therapy and target appropriate end-points

Answer 25

Perform frequent assessment of response to therapy and target appropriate end-points

SSG recommends ongoing fluid resuscitation according to response using dynamic or static variables
Frequent clinical reassessment (especially after fluid bolus therapy)

Assess heart rate, blood pressure, peripheral perfusion, urine output, and mental state (if unintubated)
e.g. SSG recommends a target urine output of > 1 mL/kg/h

Consider monitoring lactate clearance (see Lactate Clearance vs ScvO2 Monitoring in Sepsis)
e.g. >10% clearance over 2 hours
lactate screening may help detect occult septic shock

No need to specifically target CVP >8-12 mmHg
CVP monitoring is a widespread convention for assessing fluid status but its use is lacking in evidence

SSG recommends CVP >8-12 based on arbitrarily chosen target from Rivers et al, 2001

Question 26

NORADRENALINE FOR REFRACTORY HYPOTENSION

Answer 26

NORADRENALINE FOR REFRACTORY HYPOTENSION

If hypotensive and not responsive to fluid boluses will need vasopressor support (see Inotropes, vasopressors and other vasoactive agents)

e.g. following 2L IV crystalloid (20-30 mL/kg)
noradrenaline is first line agent (SSG recommendation) (see Noradrenaline)
maintains coronary perfusion by increasing diastolic blood pressure through systemic arterial vasoconstriction
increases preload by venoconstriction
adrenaline is an acceptable alternative (SSG recommendation; CAT study showed no difference between adrenaline and noradrenaline) (see Adrenaline)

Question 27

ONGOING SUPPORTIVE CARE AND MONITORING

Answer 27

ONGOING SUPPORTIVE CARE AND MONITORING

admission to HDU/ICU if sepsis/ septic shock for active management
monitoring

invasive arterial blood pressure monitoring
T,P,R, SpO2

ETCO2

CVP is often monitored

seek and treat complications of underlying disease and therapies
supportive care (comprehensive mnemonic “FASTHUGS IN BED Please“)
invasive arterial BP monitoring

Venous Thromboembolism (VTE) Prophylaxis

Stress Ulcer Prophylaxis

glucose control (e.g. insulin infusion to target glucose 6-10 mmol/L) (see Glucose Control in ICU)

delirium management (see Delirium and Septic encephalopathy)
protocolised sedation for intubated patients (Sedation in ICU)

seek and treat complications of underlying disease and therapies

Question 28

ASTHUGS IN BED Please“

Answer 28

Fluid therapy and feeding

Analgesia, Antiemetics and ADT*

Sedation and Spontaneous breathing trial

Thromboprophylaxis, Tetanus prophylaxis

Head up position (30 degrees) if intubated

Ulcer prophylaxis

Glucose control

Skin/ eye care and suctioning

Indwelling catheter

Nasogastric tube

Bowel care

Environment (e.g. temperature control, appropriate surroundings in delirium)

De-escalation (e.g. end of life issues, treatments no longer needed)

Psychosocial support (for patient, family and staff)

Question 29

ProMISe

Answer 29

ProMISe (protocolised management of sepsis) trial which enrolled 1,260 patients in the UK, have
suggested that following appropriate fluid resuscitation and intravenous antibiotics
in patients with septic shock, the manipulation of haemodynamic indices according
to strict EGDT protocols makes no difference to outcome