Sepsis

A life-threatening organ dysfunction due to a dysregulated host response to infection, where:

The definition of sepsis has remained necessarily vague, as the clinical diagnosis of sepsis is based on a constellation of non-specific features. Drawing a line which neatly includes the septic and excludes other illnesses is therefore not currently possible.

This is the Sepsis-3 definition, which moved the definitional goalposts from trying to pin down “sepsis” to trying to identify patients with clinically suspected infection who had a high mortality.

Organ dysfunction
⩾2 ↑ in SOFA score.
Septic shock
Sepsis, with:
- ↓ BP requiring vasopressors
- Lactate >2mmol/L

Management of febrile neutropaenia and neutropaenic sepsis is covered under Febrile Neutropaenia.

Epidemiology and Risk Factors

Major global healthcare burden:

High number of cases
High mortality
~30%.

Host response is highly heterogenous, and is affected by:

Patient factors:
- Comorbidities
- Genetics
Pathogen factors:
- Pathogen virulence
- Location of infection

Pathophysiology

Progression from a localised infection to systemic involvement requires:

Activation of pattern-recognition receptors
- Toll-like receptors
- C-type lectin receptors
- Retinoic acid inducible gene-1-like receptors
Receptor activation leads to complex, simultaneous alteration of multiple metabolic pathways:
- Pro-inflammatory
- Anti-inflammatory
  Simultaneously with pro-inflammatory processes.
- Neurohormonal
- Metabolic change
- Coagulation activation
  Tend towards a prothrombotic, antifibrionolytic state which may promote microvascular thrombosis and organ ischaemia.
- Macrovascular dysfunction
- Microvascular dysfunction
- Endothelial dysfunction
  - Glycocalyx disruption resulting in ↑ fluid extravasation

Immune paralysis:

Survival of the initial septic phase may lead to:
- A dysfunctional immune system
- Infections classically associated with immunocompromise

Vasodilation occurs via several mechanisms:

Acidosis
- K⁺ efflux leading to membrane hyperpolarisation
  ↓ Ca²⁺ entry into vascular smooth muscle.
- Catecholamine resistance
↑ NO production
Induced by cytokines and bacterial endotoxin.
Adrenal suppression
Endogenous vasopressin suppression

Septic cardiomyopathy:

↓ Diastolic function

Aetiology

Any progression of localised infection may lead to sepsis; the most common in adults include:

Lung
~60%.
Abdominal
~20%.
Primary bacteraemia
Renal or GU

Lung causes are less common in children, with the difference made up with CNS infections and ↑ primary bacteraemia.

Organisms most commonly associated with sepsis include:

Gram negative
60%.
- Pseudomonas
  20%.
- E. coli
  15%.
Gram positive
- S. aureus
  20%.
Fungi

Source of Infection
Organ System	Common	Uncommon	ICU-Associated
Systemic	Viral Primary bloodstream	Malaria Tuberculosis
Respiratory	Pneumonia Dental Sinusitis Otitis Mastoiditis	Epiglottitis Oropharyngeal abscess Pleuritis	VAP HAP Sinusitis
Cardiovascular	Devices PPM	Endocarditis Prosthetic valves Pericarditis	CLABSI
Neurological		Meningitis Encephalitis Discitis Epidural abscess V-P shunt	EVD-associated Ventriculitis Meningitis
Genitourinary	UTI CAUTI PID	Pyelonephritis Endometritis Prostatitis Tampon retention Streptococcal toxic shock.	Acalculous cholecystitis
Gastrointestinal	Cholecystitis Cholangitis Pancreatitis Diverticulitis Appendicitis	Spontaneous bacterial peritonitis Polymicrobial peritonitis Infective colitis C. difficile Liver abscess Splenic abscess	C. difficile
Integumentary	Cellulitis	Septic arthritis Osteomyelitis Prosthetic joints Psoas abscess Necrotising fasciitis Muscular abscess	Surgical site infections Pressure area infections
Notes: Classified by relative incidence in each category, rather than overall incidence Sources of potentially occult infection are italicised

Clinical Features

Heterogenous and non-specific features:

Tachycardia
Temperature
- 35% normothermic
- 10% hypothermic
- 55% hyperthermic
  - Often fluctuant
  - Less likely to be present in the:
    - Elderly
    - Immunosuppressed
    - Malnourished

Assessment

History

Epidemiological Risk Factors
Factor	Details	Causative Organisms
Healthcare	Recent hospital admission	Wound infection Hospital-acquired MRO
	Antibiotic	MRO Fungal infection Viral infection C. difficile
	Lines and devices	Line infection Coagulase-negative staphylococci
	Blood Transfusion	CMV West Nile virus Parvovirus B19 Malaria HTLV Prion disease
	Leech use	Aeromonas hydrophlia
Travel history	Tropical	Malaria Dengue Meiliodosis Strongyloidosis
	LMIC	Tuberculosis Zoonoses Salmonellosis Hepatitis
	Hospitalised	MRO
Lifestyle	Alcohol	Opportunistic Pneumonia
	IVDU	Primary bacteraemia Endocarditis Skin/soft tissue Hepatitis Tetanus Botulism
Domestic	Infectious contact	Similar infection
	Spa	Atypical pneumonia Legionella spp. Mycobacterium avium Pseudomonas Fungal
	Air conditioning	Atypical pneumonia Pseudomonas Fungus
	Institutionalised: School Boarding Barracks Prison Nursing home	Pneumococci Meningococci Influenzae Tuberculosis
Animals	Domestic companions: Cats Dogs	Toxoplasmosis Bartonellosis Pasteurella Tularaemia Tuberculosis Capnocytophagus
	Birds	Chlamydia Avian influenzae West Nile virus Toxoplasmosis Salmonellosis Campylobacter
	Rodents	Hantavirus Leptospirosis Listeriosis Rabies Salmonellosis Tularaemia Borreliosis
	Farm animals: Sheep Cattle Pigs Goats	Q-fever Brucellosis Chlamydia Mycobacterium bovis Toxoplasmosis E. coli O157:H7 Tularaemia Erysipelothrix Streptococcus suis
	Horses	Brucellosis Leptospirosis Salmonellosis Anthrax Rabies
	Ticks	Rickettsia spp. Borreliosis
	Bats	Lyssavirus Rabies Salmonellosis
Occupational	Healthcare	MRO Exposure-prone procedures HIV Hepatitis Tuberculosis
	Soil contact	Aeromonas hydrophilia Leptospirosis Histoplasmosis Tuberculosis Tetanus
	Treated water	Legionella Pseudomonas
Immunocompromise	Vaccination	Diptheria Tetanus COVID Influenza H. influenzae Pneumococcus Meningococci
	Pregnant	Group B Streptococci Listeria
	Splenectomy	Meningococci Pneumococcus H. influenzae
	Immunosuppressed	Opportunistic Fungal
Food	Unpasteurised milk	Listeria E. coli Brucellosis Campylobacter Mycobacterium bovis Salmonella Shigella Bacillus cerus
	Undercooked meat and eggs	Salmonella Toxoplasmosis Listeria
	Shellfish	Vibrio vulnificus Hepatitis A

Exam

Investigations

Laboratory:

Blood
- CRP
  - Non-specific marker of inflammation
    - May be more specific for Strep. pneumoniae infection
      This may also better identify patients in whom steroid would be appropriate.
  - Rises 4-6 hours after onset of infection, doubles ~8 hourly
  - Correlates with severity of infection
    - Rapid ↓ indicates response
- Procalcitonin
  - Relatively more specific marker of inflammation
    Elevated in:
    - Bacterial infection
      Produced in response to bacterial endotoxin.
      - Levels rise in 6-8 hours
        Prior to cultures flagging positive.
      - Not ↑ in viral or fungal infections
      - Not ↑ in local bacterial infection without a systemic response
    - Burns
    - TLS
    - Major surgery
    - Multi-organ failure
    - ESRD
      Renally cleared.
  - No better than clinical judgment in discriminating infectious vs. non-infectious causes
  - Expensive, requires serial measurements
- Blood cultures
  Prior to antibiotics.
- Galactomannan
  - Presence suggestive of fungal infection, particularly aspergillosis
  - Risk of false positives from other fungal infections or concomitant β-lactam use
- (1→3)-β-D-glucan antigen
  Cell wall component of most fungi. Improves sensitivity and specificity in combination with galactomannan.

Diagnostic Approach and DDx

Diagnosis of sepsis is difficult.

Clinical
- Signs are non-specific
  - Changes with local infection
  - May not be present in:
    - Elderly
    - Immunocompromised
- Findings may reflect other forms of shock
Laboratory
- Markers are non-specific
- Microbiological samples:
  - Take significant time to process
    Requires treatment to be initiated in advance of knowing.
  - Must distinguish infection from colonisation
    Requires clinical interpretation.

The qSOFA is a quick screening tool to identify patients who should be considered for sepsis workup, and requires ⩾2 of:

Altered mentation
RR >22
SBP <100mmHg

There is a substantial overlap in features with HLH (see Haemophagocytic Lymphohistiocytosis); consider HLH as a differential diagnosis in septic patients without a source.

Management

Early antibiotics (<1 hour) with blood cultures (2-3 sets) prior
Determine haemodynamic goals and target with:
- Fluids
- Vasopressors

Resuscitation:

Each hour delay in antibiotic administration is associated with a 12% ↓ in survival.

C
- Target MAP >65mmHg
  Consider ↑ (e.g. MAP >70mmHg) if renal failure, poorly controlled hypertension.
- Fluid resuscitation
  10-20mL/kg up to 30mL/kg total.
  - Crystalloid most effective
    - Albumin equivalent outcomes with potentially ↓ total volume delivered, and haemodynamic goals are achieved move quickly
    - Starch harmful
  - Use dynamic measures of fluid responsiveness to assess need for more therapy
    - Passive leg raise
    - Pulse pressure variation
- Arterial line
  If vasopressors required.
- Vasopressors
  - Noradrenaline 1^st line
    - ↑ Preload due to venoconstriction
    - ↑ SVR due to vasoconstriction
    - Maintain or ↑ CO
      B₁ effects ↑ CO, compensating for ↑ in afterload.
  - Consider adrenaline as 2^nd line
  - Vasopressin as 3^rd line
  - End-of-the line vasopressor options without much supporting evidence include:
    - Methylene blue
      1mg/kg bolus over ~30 minutes.
    - Hydroxycobalamin
      5g.
    - Terlipressin
    - Angiotensin II
- Assess CO
  - Inotropic support if:
    - Adequately volume resuscitated
    - Evidence of ↓ perfusion:
      - ↑ Lactate
      - ↓ Central capillary refill
      - Echocardiography
    - Pre-existing LV dysfunction
  - VA ECMO
    Appropriate in selected patients with myocardial dysfunction, acknowledging high mortality of this cohort.

Early use of noradrenaline is associated with ↓ mortality.

Average total IV fluid resuscitation at:

6 hours is ~4.2L ±1.4L
72 hours is ~6.8L ±3L

Specific therapy:

Pharmacological
- Antibiotics
  - Empirical
    Tailored to likely sources and resistance patterns.
- Corticosteroids
  - Remain somewhat controversial
  - Appropriate for patients:
    - With another indication for steroids
    - Sepsis with CAP
  - May be appropriate in septic patients:
    - Refractory to vasopressors
    - Otherwise high risk
  - Unlikely to change mortality or outcome
  - Will spare vasopressors
  - May ↓ ventilator days and speed shock resolution
- Toxic Shock cover
  If treating TSS, or empirical if clinically likely.
  - Clindamycin
  - IVIG
Procedural
- Source control
- Removal of short-term intravascular catheters if catheter-related sepsis is likely
  This includes arterial catheters.
Physical

My approach is to use corticosteroids in septic patients with:

CAP
On previous steroid supplementation
With noradrenaline ⩾0.15μg/kg/min

Supportive care:

F
- pH >7.15
  ↑ Cardiac sensitivity to catecholamines.
  - Sodium bicarbonate
  - THAM
- iCa >1.1mmol/L
  Very low supporting evidence.
H
- Hb >70

Disposition:

Preventative:

Marginal and Ineffective Therapies

Drugs:

β-blockade
- Esmolol probably most well studied
  - Very high control group mortality
  - May reflect reversal of harmful exogenous β-agonists
Activated protein C
Vitamin C
IVIG
No proven role outside of TSS.

Resuscitation targets:

CVP targeting
ScvO₂ targeting
PAC targeting
Use of PAC does not improve and may worsen outcome.

Blood Purification:

High-volume haemofiltration
CRRT with target dose >35mL/kg/hr.
Polymyxin B Haemoperfusion
CRRT with Polymyxin B bound to the filter, which binds bacterial endotoxin.
High cut-off haemofiltration
CRRT with larger pores, allowing filtration of middle-molecular weight proteins which include pro- and anti-inflammatory cytokines.

Other:

Hydroxy-ethyl starch resuscitation fluids
↑ AKI and mortality.

Anaesthetic Considerations

Complications

Complications of sepsis include:

B
- ARDS
C
- Septic cardiomyopathy
D
- Septic encephalopathy
  Impaired mental function in the setting of extracranial infection.
  - 10-80% of septic cases
  - ↑ Mortality associated with ↓ GCS
  - Potential contributors include:
    - Bacterial endotoxin
    - Cytokine release
    - Haemodynamic collapse
F
- AKI

Septic AKI

Epidemiology of septic AKI:

Occurs in 22% of ICU patients with sepsis
Associated with ↑ in mortality to 38%

Management:

Preventative
Most effective method:
- Low dose vasopressors
  Achieving a MAP >80mmHg may reduce requirement for RRT.
- Note that excessive IV fluid is ineffective
  - May worsen oedema
    Aim euvolaemia.
  - Septic AKI is not a low-flow state
  - Balanced solutions are beneficial
  - Avoid starch and gelatin colloids
- Treat the sepsis

Prognosis

High mortality:

ICU death 28-40%
~30% when adjusted for severity.

Key Studies

Fluid:

FEAST (2011)
- 3170 African children aged 60 days to 12 years with febrile illness, ↓ conscious state, and ↓ perfusion; without malnourishment, gastroenteritis, or non-infectious shock
- Multicentre (6), un-blinded, allocation concealed, block-randomised trial
- 3600 patients would provide 80% power for 5% ↓ ARR of death, assuming control mortality of 11%
- Patients without severe hypotension (3141) randomised to one of:
  - 20-40mL/kg 0.9% saline
  - 20-40mL/kg 5% albumin
  - No fluid
  - Volumes of fluid were ↑ (from 20 to 40mL) after a protocol amendment partway through the trial
  - Fluid groups received additional fluid if impaired perfusion
  - All patients treated on general paediatric wards (no ICU available), and transfused if Hb <5g/dL
- 48 hour mortality was significantly ↑ in fluid groups
  Saline 10.5%, albumin 10.6%, control 7.3%.
  - RR for saline vs. control: 1.44 (CI 1.09-1.9)
- Stopped early for harm
- Most deaths occurred at <24 hours
- Weaknesses:
  - Clinical criteria for shock diagnosis are non-specific
  - >50% had malaria, which behaves differently with IVT
  - Significant anaemia may be made worse by haemodilution

A separate arm of FEAST protocolised management of severe hypotension, but there were only 29 patients and the discussion adds complexity disproportionate to insight so I have excluded it from this summary.

ARISE (2014)
- 1600 non-pregnant adults with sepsis and refractory hypotension or hypoperfusion who had commenced antibiotics
- Multi-centre (51), unblocked, block-randomised trial
- EGDT vs. control
  - EGDT
    - River’s algorithm used
  - Control
    - Usual care
    - Arterial line and CVC permitted
    - ScVO₂ measurement not permitted
- No difference in all cause mortality (18.6% vs. 18.8%)
SAFE (2004)
- ~7000 Australian adult ICU patients requiring fluid administration, excluding post-cardiac surgery, liver transplant, and burns
- Multicentre, double-blinded RCT, stratified by trauma diagnosis and site
  Special fluid administration sets were used to hide the albumin.
- 4% albumin vs. 0.9% saline
- No change in 28-day mortality (20.9% vs. 21.1%)
- No statistically significant difference in ICU length of stay, duration of organ support. However:
  - Trauma subgroup had an almost significant ↑ mortality (13.6% vs. 10%, RR 1.36 (CI 0.99-1.86))
  - Sepsis subgroup had a more insignificant ↓ mortality (30.7% vs. 35.3%, RR 0.87 (CI 0.74-1.02))
- Less cumulative fluid balance at end of day 1 and 2 in the albumin group (by ~1:1.4), although this difference started resolving at day 3 and had gone at day 4

Note that 4% Albumin is hypotonic at 260mOsmol/L. This may contribute to the poor outcomes seen in the neurosurgical group, and is explored elegantly by Iguchi et al.

ALBIOS (2014)
- 1818 Italians within 24 hours of severe sepsis, without head injury, heart failure, or specific indication for albumin
- Multicentre (100) open-label, randomised trial, with stratification by ICU and time of sepsis onset
- 80% power for 7.5% ARR (!) ↓ in 28-day mortality, with control mortality of 45%
- 20% albumin vs. crystalloid
  - 20% albumin
    - 300mL 20% albumin on randomisation
    - Further 20% targeting serum albumin >30g/L
    - Crystalloid as clinically indicated
  - Crystalloid
    - Crystalloid as clinically indicated
- No mortality difference (31.8% vs. 32%)
- 20% albumin is safe and improves haemodynamics, but does not provide a survival advantage
CLOVERS (2023)
- ~12,000 patients with sepsis and hypotension after 1L IVT
  - Within 24 hours of hospital admission
  - <3L of IVT
    i.e. 1-3L of IVT received by randomisation.
- Restrictive vs. liberal fluid strategy
  - Restrictive: Up to 2L IVT, then noradrenaline
    Rescue fluids allowed.
  - Liberal: 2L bolus at randomisation, further 500mL boluses
    Rescue vasopressors allowed, and recommended after 5L (6-8L total) IVT.
- No change in mortality, ventilator free days, ICU free days, ARDS
- ↑ ICU admission in restrictive group
- Strong safety profile of peripheral vasopressors
CLASSIC (2022)
- ~1500 non-pregnant, non-burned Europeans with sepsis within 12 hours of diagnosis
- Restrictive vs. liberal fluid strategy
  - Restrictive: Crystalloid given for severe hypoperfusion, overt losses, or to ensure at least 1L/24 hours
  - Liberal: Crystalloid given based on surviving sepsis guidelines, to replace losses
- Vasopressors as per trial protocol
- No difference in mortality
- Small difference in volume administered (~2L at day 5)

Early Goal Directed Therapy:

Early Goal-Directed Therapy is (?was) a protocolised pathway for sepsis management, targeting specific haemodynamic goals in order to maximise DO₂ and thus restore cellular oxygen balance:
- CVP 8-12mmHg
- MAP 65-90mmHg
- UO >0.5mL/kg/hr
- ScvO₂ >70%
- Haematocrit >30%
The comfort of this physiological approach did not survive the crucible of real-word RCT evaluation, and EGDT has been subsequently dismissed
The principles of aggressive, goal-directed (but not CVP and ScvO₂-directed) therapy live on
Rivers et al (2001)
- Single-centre, non-randomised, non-blinded trial
- High control group mortality (46.5%)
- Significant hospital ↓ mortality in EGDT arm (30% vs. 46%)
- Use of ScvO₂ target was not based on prior evidence
- Effect may be due to presence of experience clinician at the bedside directing therapy
ARISE (2014)
- 1600 non-pregnant adults with sepsis and refractory hypotension or hypoperfusion who had commenced antibiotics
- Multi-centre (51), unblocked, block-randomised trial
- EGDT vs. control
  - EGDT
    - River’s algorithm used
  - Control
    - Usual care
    - Arterial line and CVC permitted
    - ScVO₂ measurement not permitted
- No difference in all cause mortality (18.6% vs. 18.8%)
ProCESS (2014)
- 1,351 American adults with sepsis admitted from the emergency department
- Multicentre (31), randomised, unblinded
- EGDT vs. protocolised care vs. control
- No change in mortality between groups (21% vs. 18% vs 19%)

Steroids:

The rationale for steroids is that they may:
- C
  - Limit ↓ inotropy due to bacterial endotoxin
  - ↑ Catecholamine function
  - ↓ NO synthetase production
- I
  - Correct adrenal insufficiency
  - Dampen hyperactive immune response
CORTICUS (2008)
- 488 adults with severe sepsis
- Multicentre (52), double-blinded, block randomised trial
- Hydrocortisone vs. placebo
  - Hydrocortisone
    - Hydrocortisone 50mg IV Q6H for 5 days
    - Tapered over 6 days
  - Placebo
- Underpowered due to lower-than-expected control group mortality
- Slow recruitment despite large number of sites, suggests selection bias
- No difference in 28 day mortality (39.2% vs 36.1%)
- Secondary outcomes insignificant except faster shock reversal (3.8 vs. 5.8 days) in hydrocortisone group
ADRENAL (2018)
- 3658 adults with septic shock requiring vasopressors and mechanical ventilation, without various exotic infections
- Multicentre (69), international, double-blinded RCT
- 3800 patients gives 90% power to detect 5% ARR from a baseline mortality of 33%
- Hydrocortisone vs. placebo
  - Hydrocortisone
    200mg/day via continuous infusion.
- No difference (27.9% vs. 28.8%) in 90 day mortality
- Secondary outcomes favour steroids:
  - ↓ Ventilator days (3 vs. 4 days)
  - ↓ Time to shock resolution
  - ↓ ICU length of stay (10 vs. 12 days)
  - ↓ Blood transfusion (37% vs. 41.7%)
APROCCHSS (2018)
- 1241 Frenchpersons with probable septic shock for <24 hours, requiring >6 hours vasopressors
- Multicentre (34)
- 320 patients per group to detect 10% ↓ in 90 day mortality at 95% power
- Trial initially also planned to investigate drotrecogin alfa in a factorial design, which required revising trial design after its withdrawal
- Steroids vs. placebo
  - Steroids
    - Hydrocortisone 50mg IV Q6H
    - Fludrocortisone 50μg PO/NG mane
  - Both groups had plasma cortisol and short synacthen test performed
- Very high dose of vasopressors at randomisation
  - Majority had noradrenaline with mean dose of ~1μg/kg/min
  - Several had adrenaline with a mean dose at ~2μg/kg/min (!!)
- Significant ↓ 90 day mortality in intervention group (43% vs. 49%, RR 0.88 (CI 0.78 - 0.99))
- Secondary outcomes broadly favour steroids

Vitamin C:

The rationale for Vitamin C is that:
- Levels are ↓ in the critically ill
- Oxidative stress is ↑ in the critically ill
- Vitamin C has antioxidant effects that may alleviate some oxidative stress
Marik et al (2017)
- 47 non-pregnant Americans with severe sepsis or septic shock and pro-calcitonin >2ng/mL
- Single-centre, retrospective, observational study
- Vitamin C 1.5g QID (7 days), hydrocortisone 50mg QID (4 days, then 3 day taper), and thiamine 200mg BD (4 days) vs. standard care
- Significant ↓ in hospital mortality with the “metabolic cocktail” (8.5% vs. 40.4%)
- Prompted a slew of RCTs that reversed this finding
CITRIS-ALI (2019)
- American English-speaking adults mechanically enilated patients with ARDS and suspected or proven infection with ⩾2 SIRS criteria
- Randomised, double-blinded, placebo-controlled, multi-centre (7)
- Vitamin C (50mg/kg) vs. placebo
- No significant difference in SOFA score, CRP, or thrombomodulin
- Secondary outcomes indicate ↓ 28 day mortality (28% vs 46%), ICU-free days to day 28, and hospital-free days to day 60 in the vitamin C group
VITAMINS (2020)
- Adults admitted with Septic Shock, not at imminent risk of death
- Multicentre pilot RCT performed based on the now-infamous Marik study
- Randomised to vitamin C (1.5g Q6H), hydrocortisone (50mg Q6H), and thiamine (200mg Q12H) vs. hydrocortisone (50mg Q6H)
- No difference in time alive and free of vasopressors
- Not powered for mortality outcomes
LOVIT (2022)
- 872 adults with suspected infection requiring ICU admission and vasopressors in Canada, France, and New Zealand
- 50mg/kg Vitamin C vs Placebo
- Significantly ↑ death (44.5% vs 38.5%) and persistent organ dysfunction (9.1% vs 6.9%) in vitamin C group

Other:

CENSER (2018)
- 456 adults with hypotension and sepsis, without septic shock or other significant acute disease
- Single-centre, blinded RCT
- 300 patients provides 80% power to detect 20% ↑ “shock resolution” at 6 hours, compared to 60% in control group
  MAP sustained >65mmHg >15 minutes with >2 hours of UO >0.5mL/kg/hr or ↓ lactate by >10% from initial level.
- Noradrenaline vs. placebo
  - Noradrenaline
    - 0.05μg/kg/min for 24 hours without titration
  - D5W placebo
  - Open-label vasopressors if MAP <65
- Greater shock resolution at 6 hours in noradrenaline group (76% vs 48%)
- More interestingly, over half of the patients had norad given peripherally and no extravasation injuries occurred
ANDROMEDA-SHOCK (2019)
- 424 adult south Americans with septic shock requiring vasopressors despite 20mL/kg volume resuscitation
- Multicentre (28), randomised, clinician unblinded, assessor blinded
- 90% power for 15% ARR (!) for mortality
- Peripheral perfusion-targeted resuscitation vs. lactate targeted resuscitation
  - Peripheral perfusion
    - Finger pad capillary refill time Q30 minutely, then hourly until normalisation
    - Targeted capillary refill time <3s
  - Lactate targeted
    - Lactate measured Q2H for 8 hours
    - Targeting ↓ lactate by 20% every 2 hours until normal
  - Failure to normalise was targeted with escalating protocols:
    - Fluid responsiveness
      - PPV or VTI change following passive leg raise
      - 500mL crystalloid
    - Vasopressor test
      - MAP ↑ to 80-85
        
        If target normalised, MAP maintained
        
        Otherwise MAP target set to 65
    - Inodilator test
      - Dobutamine or milrinone
- ↑ Mortality in lactate group (43.4% vs 34.9%)
- Underpowered for outcome
FABLED (2019)
- Adults in the ED with suspected severe sepsis
- Multi-centre (7) diagnostic cohort study
- 2 sets of blood cultures taken before antibiotics via separate venepuncture
- 1-2 sets of cultures taken 30-240 minutes after antibiotics
- Significant ↓ in positive cultures post antibiotics
  - ~30% positive pre-antibiotic, compared to ~20% positive post-antibiotic
    RRR ~33%.
  - More pronounced ↓ in positive post-antibiotic cultures if organism was sensitive to antibiotic used
    RRR ~50%.
  - Positive post-antibiotic cultures were associated with ↑ time to positivity, suggesting ↑ bacterial burden
CandiSep (2022)
- 342 Adults with sepsis at risk of invasive candidiasis, but without proven fungal infection and not on fungal treatment
- Blood cultures performed and randomised to:
  - (1→3)-β-D-Glucan testing performed on blood cultures
    Fungal cell wall component that can be detected prior to cultures becoming positive.
  - Standard cultures
- β-D-Glucan group received more (57% vs 27%) and earlier (1.1 vs 4.4 days) antifungal treatment without a change in mortality
- Lower power than anticipated due to lower mortality
- Lower rates of invasive candidiasis than anticipated
TRISS (2014)
- 998 Scandanavian adults with septic shock and Hb <90g/dL, without active haemorrhage, burns, ACS< previous transfusion, or transfusion reactions
- Multicentre (32), block randomised, stratified by site and haematological malignancy
- 80% power for 9% ARR ↓, assuming 45% control mortality
- Restrictive vs. liberal transfusion
  - Restrictive threshold <70g/dL
  - Liberal threshold <90g/dL
  - Single unit RBC given when threshold met
- No change in 90 day mortality
- Secondary outcomes: ↑ Number of patients and units transfused in liberal group
Morelli et al (2013)
- 154 β-blocker-naïve Italians with sepsis and a normal CI requiring noradrenaline admitted to a single ICU in Rome
- Single-centre, phase 2, unblinded RCT
- Randomised to esmolol vs. usual care
  - Esmolol group had infusion adjusted to achieve HR 80-94
  - All patients received:
    - PAC
    - Hydrocortisone 300mg/day via continuous infusion
    - Levosimendan if ↓ DO₂ and Hb >80
    - CVP and PCWP guided fluid resuscitation and MvO₂
- Significant ↓ in HR and mortality in esmolol group, which must be contextualixed against the… high… 80% control group mortality
- High dose vasopressors at randomisation (~0.4μg/kg/min NA), despite normal lactates
LeoPARDS (2017)
- 516 British adults with suspected sepsis ( by possible infection and ⩾2 SIRS criteria)
- Multicentre (34), double-blind, placebo-controlled RCT
- 90% power to detect a mean difference in SOFA score of 0.5
- Levosimendan vs. standard care
  - Levosimendan
    0.1µg/kg/min, ↑ to 0.2µg/kg/min at 2-4 hours if tolerated and continued for up to 24 hours.
  - Placebo
- Study drug commenced after adequate fluid resuscitation and restoration of target MAP
- No difference in mean SOFA score, ↑ haemodynamic instability and mean ventilator days in levosimendan group

References

Bellomo R, Kellum JA, Ronco C et al. Acute kidney injury in sepsis. Intensive Care Med. 2017 Jun;43(6):816-828. doi: 10.1007/s00134-017-4755-7. Epub 2017 Mar 31.
Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. New England Journal of Medicine. 2023;388(6):499-510.
Singer, M., Deutschman, C.S., Seymour, C.W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G.R., Chiche, J.-D., Coopersmith, C.M., Hotchkiss, R.S., Levy, M.M., Marshall, J.C., Martin, G.S., Opal, S.M., Rubenfeld, G.D., van der Poll, T., Vincent, J.-L., Angus, D.C., 2016. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801.
Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022;386(25):2387-2398.
Bloos F, Held J, Kluge S, et al. (1→3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial. Intensive Care Med. 2022;48(7):865-875. doi:10.1007/s00134-022-06733-x
Meyhoff TS, Hjortrup PB, Wetterslev J, et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. New England Journal of Medicine. 2022;386(26):2459-2470.
O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Critical Care Medicine. 2008;36(4):1330.
Morelli A, Ertmer C, Westphal M, et al. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691. doi:10.1001/jama.2013.278477
Cheng MP, Stenstrom R, Paquette K, et al. Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis. Ann Intern Med. 2019;171(8):547-554. doi:10.7326/M19-1696
Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020;323(5):423. doi:10.1001/jama.2019.22176
Fowler AA III, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261-1270. doi:10.1001/jama.2019.11825
Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-664. doi:10.1001/jama.2019.0071
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. New England Journal of Medicine. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716
Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. New England Journal of Medicine. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835
Sprung CL, Annane D, Keh D, et al. Hydrocortisone Therapy for Patients with Septic Shock. N Engl J Med. 2008;358(2):111-124. doi:10.1056/NEJMoa071366
Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. CHEST. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036
Maitland K, Kiguli S, Opoka RO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. New England Journal of Medicine. 2011;364(26):2483-2495. doi:10.1056/NEJMoa1101549
Goal-Directed Resuscitation for Patients with Early Septic Shock. New England Journal of Medicine. 2014;371(16):1496-1506. doi:10.1056/NEJMoa1404380
Dünser MW, Dankl D, Petros S, Mer M. Clinical Examination Skills in the Adult Critically Ill Patient. Springer International Publishing; 2018.