Surviving Sepsis Guidelines 2021 update

Surviving Sepsis Guideline update 2021

Ideally these should be guidelines, from which clinicians can deviate when indicated, but they are often used as KPI targets instead (eg antibiotics within 1hr, 30ml/kg fluid bolus). This has caused issues in the past with some of the strong recommendations having weak evidence. The 2021 update is a bit more reasonable in some of the targets, but the evidence still leaves something to be desired.

TL:DR Key Points for ED:

  • Sepsis Screening programs are important
  • Promote dynamic measures (such as capillary refill time, passive leg raise and echo) to guide fluid resuscitation
  • Downgrade of 30ml/kg fluid bolus from ‘recommend’ to ‘suggest’
    • I strongly recommend thorough assessment and an individualised approach to fluid resuscitation
  • Recommend crystalloids as resuscitation fluid 
  • Albumin can be used eg in cirrhotic patients with sepsis
  • Recommend against using gelatins and starches
  • Septic shock recommend giving antibiotics asap, ideally <1hr
    • Always consider septic shock in unexplained hypotension
  • Sepsis/unwell without shock – investigate cause and aim to give antibiotics within 3 hours if concern for infection persists (rather than blanket <1hr antibiotics for all query sepsis)
  • Noradrenaline is recommended first line vasopressor and should be started peripherally if needed
  • Initial target MAP for septic shock remains 65mmHg 
  • Suggest invasive monitoring (art line) and expedious ICU admission for septic shock
  • Suggest use of high flow nasal cannula over NIV
  • Suggest iv steroids in those with septic shock and ongoing vasopressor requirement
  • Discuss goals of care

Let’s dive into the 2021 update!

Screening and early treatment

Screening for patients with sepsis and septic shock

Recommendation 1: For hospitals and health systems, we recommend using a performance improvement programme for sepsis, including sepsis screening for acutely ill, high-risk patients and standard operating procedures for treatment.
Strong recommendation, moderate quality of evidence for screening 
Strong recommendation, very low-quality evidence for standard operating procedures

This is fair. We should screen for sepsis as part of our SOP. We should be able to deviate when clinically indicated.

2. We recommend against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock.
Strong recommendation, moderate-quality evidence

None of these tools are perfect at identifying sepsis and predicting mortality or severe illness. SIRS was designed as a screening tool for sepsis and is sensitive in identifying possible sepsis but less useful in predicting mortality. NEWS and MEWS are both good at identifying deterioration and severe illness, and predicting disease severity in sepsis. qSOFA is described as predictor of severity in sepsis, as opposed to a screening tool for sepsis.
A hybrid approach is likely to have the best sensitivity and utility for sepsis, although I would be very happy if I saw either NEWS or MEWS being introduced as the defacto screening tool for ill or deteriorating patients in my hospital.

3. For adults suspected of having sepsis, we suggest measuring blood lactate.
Weak recommendation, very low-quality evidence

We routinely get lactate on the VBG. Lactate is better used as a mortality predictor, or possibly a marker of response to treatment than a screening tool.

Initial Resuscitation

4. Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately.
Best practice statement

5. For patients with sepsis-induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. 
Weak recommendation, low quality of evidence 
DOWNGRADE from strong recommendation, low quality of evidence.

This is a change from “recommended” due to low quality of evidence. There are no prospective interventional studies looking at different volumes for the initial resuscitation of those with sepsis or septic shock. A retrospective study including ED adult patients with sepsis or septic shock found failure to receive 30 mL/kg of crystalloids was associated with higher mortality but ignores important confounders.
Guidelines also cite the PROCESS, PROMISE, and ARISE trials (which are mainly famous for debunking EGDT), in which patients ended up recieving roughly 30ml/kg fluid initially.
Systematic review found no evidence to support this recommendation and rightly points out the need to properly assess the benefits and potential harms.

There are multiple potential harms from giving all patients at least 30ml/kg crystalloid in the first 3 hrs, and poor evidence to support this blanket approach. I’d suggest until we get better evidence that fluids should always be given in a measured and considered fashion individualised to the patient’s condition.

6. For adults with sepsis or septic shock, we suggest using dynamic measures to guide fluid resuscitation, over physical examination, or static parameters alone.
Weak recommendation, very low-quality evidence

For those of us in ED these dynamic measures typically would involve response to passive leg raise or fluid challenge using pulse pressure variation, echo (VTI) or possible capillary refill time. I think this is probably the future, but determining which measures, which cut-offs and doing the least necessary will probably be key.

7. For adults with sepsis or septic shock, we suggest guiding resuscitation to decrease serum lactate in patients with elevated lactate level, over not using serum lactate.
Weak recommendation, very low-quality evidence

Hmm, a combined and holistic approach may be best, rather than focusing too much on any one number.

8. For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. 
Weak recommendation, low quality of evidence, NEW

This needs to be taken in context of underlying physiological state and ongoing therapy but is simple and repeatable, and along with skin mottling can be a useful marker of low cardiac output. I’m all for increased emphasis on clinical assessment if it is shown to be valuable. 

The ANDROMEDA SHOCK trial evaluated resuscitation guided by capillary refill time (CRT) vs lactate clearance and although it showed a trend towards reduced mortality in the CRT arm, this was not statistically significant (p=0.06). The trial was significantly underpowered and it is possible that a hybrid or refined approach might help us guide fluid resuscitation better in the future.

Mean arterial pressure

9. For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. 
Strong recommendation, moderate-quality evidence.

Again, an individualised approach may be most appropriate, but we need more evidence on how to determine these targets based on different patient factors. An RCT evaluating patients in septic shock randomized to MAP targets of 65-70 mm Hg versus 80-85 mm Hg found no difference in mortality. There was reduced risk of renal replacement therapy in patients with chronic hypertension and higher rates of atrial fibrillation in the group randomized to the higher MAP target group.
Several trials have looked at lower MAP and suggest lower targets may be permissible but quality evidence is lacking.

10. For adults with sepsis or septic shock who require ICU admission, we suggest admitting the patients to the ICU within 6 hours.
Weak recommendation, low-quality evidence

Multiple observational studies have shown that prolonged ED stays and delay in admission of ill patients significantly increases patient mortality. Timely transfer out of ED also keeps ED staff happy and has multiple positive knock on effects for flow and care of other patients 🙂

Infection

Diagnosis of infection

11. For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected
Best practice statement

Common sense.

Time to antibiotics

12. For adults with possible septic shock or a high likelihood for sepsis, we recommend administering antimicrobials immediately, ideally within 1 hour of recognition.
Strong recommendation, low quality evidence (SEPTIC SHOCK)
Strong recommendation, very low quality evidence (sepsis without shock)

Sick patients with shock (unexplained hypotension) should always be strongly considered for sepsis, and treatment sooner rather than later is likely to be beneficial. Note however that there is very little good evidence here. Most of the trials showing benefit for early antibiotics in sepsis were retrospective, and many prospective trials (and RCT) do not conclude that early antibiotics improve survival.

The evidence in possibly septic patients without shock is weaker still, and I do not think we should be blindly prescribing broad spectrum antibiotics to all comers ‘just in case’. A more considered approach seems far more sensible.

13. For adults with possible sepsis without shock, we recommend rapid assessment of the likelihood of infectious versus noninfectious causes of acute illness.
Best practice statement

They say – rapid assessment includes history and clinical examination, tests for both 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 3 h of presentation so that a decision can be made as to the likelihood of an infectious cause of the patient’s presentation and timely antimicrobial therapy provided if the likelihood of sepsis is thought to be high.
I say – sure.

14. For adults with possible sepsis without shock, we suggest a time-limited course of rapid investigation and if concern for infection persists, the administration of antimicrobials within 3 hours from the time when sepsis was first recognized.
Weak recommendation, very low quality evidence

This is confusing. They say 3 hrs from presentation, then 3 hrs from when sepsis was first recognised. I’m sure at the M+M someone will say sepsis could have been diagnosed earlier and retrospectively start the 3hr timer ticking from then.

15. For adults with a low likelihood of infection and without shock, we suggest deferring antimicrobials while continuing to closely monitor the patient.
Weak recommendation, very low quality evidence

Yep.

Haemodynamic management

Fluid management

32. For adults with sepsis or septic shock, we recommend using crystalloids as first line fluid for resuscitation
Strong recommendation, moderate quality of evidence 

33. For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. 
Weak recommendation, low quality of evidence

There is no evidence of benefit from colloids and multiple possible harms. Crystalloids are also cheaper and widespread. 

Normal saline may result in hyperchloremic metabolic acidosis and the SMART and SALT-ED trials support the use of balanced crystalloids, however the more recent and much larger BaSICS trial showed no difference in 90 day mortality between 0.9% NaCl and balanced crystalloids. There was a significant increase in mortality for patients with TBI receiving balanced crystalloids and although this is a secondary outcome it would be reasonable to use 0.9% saline in patients with a head injury.

34. For adults with sepsis or septic shock, we suggest using albumin in patients who received large volumes of crystalloids over using crystalloids alone
Weak recommendation, moderate quality of evidence

There is some evidence for the use of albumin particularly in cirrhotic patients with sepsis.

35. For adults with sepsis or septic shock, we recommend against using starches for resuscitation
Strong recommendation, high quality of evidence

Good evidence of harm (renal failure).

36. For adults with sepsis and septic shock, we suggest against using gelatin for resuscitation
Weak recommendation, moderate quality evidence

There is no evidence of mortality benefit from gelofusine, but potentially increased risk of renal injury, anaphylaxis and coagulation issues.

Vasoactive agents

37. For adults with septic shock, we recommend using norepinephrine as the first-line agent over other vasopressors.
Strong recommendation, low to high evidence depending on comparison vasopressor

Standard.

38. For adults with septic shock on norepinephrine with inadequate MAP levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine
Weak recommendation, moderate-quality evidence

They say – In our practice, vasopressin is usually started when the dose of norepinephrine is in the range of 0.25–0.5 μg/kg/min

39. For adults with septic shock and inadequate MAP levels despite norepinephrine and vasopressin, we suggest adding epinephrine
Weak recommendation, low-quality evidence

41. For adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure, we suggest either adding dobutamine to norepinephrine or using epinephrine alone
Weak recommendation, low quality of evidence

This (dobutamine in particular) is not well supported by their own provided rationale or evidence.

Echo and thorough clinical assessment should help guide treatment. Noradrenaline + adrenaline may be an option if vasodilation is an issue with dobutamine. 

43. For adults with septic shock, we suggest using invasive monitoring of arterial blood pressure over  non‑invasive monitoring, as soon as practical and if resources are available
Weak recommendation, very low quality of evidence

Useful, and helps us get in the critical care mindset for this patient.

44. For adults with septic shock, we suggest starting vasopressors peripherally to restore MAP rather than delaying initiation until a central venous access is secured
Weak recommendation, very low quality of evidence

It is safe and should be standard to use peripheral vasopressors in ED if needed.

45. There is insufficient evidence to make a recommendation on the use of restrictive versus liberal fluid strategies in the first 24 h of resuscitation in patients with sepsis and septic shock who still have signs of hypoperfusion and volume depletion after initial resuscitation

Trials ongoing (CLOVERS and CLASSIC).

47. For adults with sepsis‑induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen over non‑invasive ventilation
Weak recommendation, very low quality of evidence

I don’t think they are interchangeable, but hi-flow can certainly be part of the escalation of care.

58. For adults with septic shock and an ongoing requirement for vasopressor therapy we suggest using IV corticosteroids
Weak recommendation; moderate quality of evidence

Three new RCTs since 2016 (ADRENAL, APROCCHSS, VANISH) showing corticosteroids accelerating resolution of shock, but increasing neuromuscular weakness without an effect on overall mortality.

69. For adults with sepsis or septic shock, we recommend initiating insulin therapy at a glucose level of ≥ 180 mg/dL (10 mmol/L)
Strong recommendation; moderate quality of evidence

Unclear ideal glucose target, but increased risk of hypoglycaemia with tighter BSL control.

70. For adults with sepsis or septic shock, we suggest against using IV vitamin C
Weak recommendation, low quality of evidence

No evidence for metabolic cocktail.

71. For adults with septic shock and hypoperfusion‑induced lactic acidemia, we suggest against using sodium bicarbonate therapy to improve haemodynamics or to reduce vasopressor requirements
Weak recommendation, low quality of evidence

BICAR-ICU trial showed no mortality benefit for bicarb in all-cause metabolic acidosis, but may be beneficial in those with acute kidney injury.

74. For adults with sepsis or septic shock, we recommend discussing goals of care and prognosis with patients and families over no such discussion
Best Practice Statement

A very important part of our standard care.

Phew!! That was a lot to go through, and I left out a lot of the recommendations such as ventilation, discharge planning and feeding that are less relevant to us in the ED. Again, go here to read the whole document.

Once again the take home messages:

  • Sepsis Screening programs are important
  • Promote dynamic measures (such as capillary refill time, passive leg raise and echo) to guide fluid resuscitation
  • Downgrade of 30ml/kg fluid bolus from ‘recommend’ to ‘suggest’
    • I strongly recommend thorough assessment and an individualised approach to fluid resuscitation
  • Recommend crystalloids as resuscitation fluid 
  • Albumin can be used eg in cirrhotic patients with sepsis
  • Recommend against using gelatins and starches
  • Septic shock recommend giving antibiotics asap, ideally <1hr
    • Always consider septic shock in unexplained hypotension
  • Sepsis/unwell without shock – investigate cause and aim to give antibiotics within 3 hours if concern for infection persists (rather than blanket <1hr antibiotics for all query sepsis)
  • Noradrenaline is recommended first line vasopressor and should be started peripherally if needed
  • Initial target MAP for septic shock remains 65mmHg 
  • Suggest invasive monitoring (art line) and expedious ICU admission for septic shock
  • Suggest use of high flow nasal cannula over NIV
  • Suggest iv steroids in those with septic shock and ongoing vasopressor requirement
  • Discuss goals of care

I certainly look forward to discussing our hospital sepsis guidelines to prioritise rapid recognition and treatment of the severely ill, whilst giving us a bit of time to work out what is going on with those who are less unwell.

What are your thoughts on the new guidelines? Consider reading the full document here, and please feel free to discuss below!

Cheers!

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