Critical Appraisal of Surviving Sepsis Guidelines

Written by – Dr Jose Chacko

“Bundled” care in sepsis

The 2018 surviving sepsis guidelines combined the previous 3- and 6-h bundles into a single 1-h bundle that included

• Estimation of lactate levels; repeat if level > 2 mmol/l (weak recommendation; low-quality evidence)
• Blood culture, followed by broad-spectrum antibiotics (best practice statement)
• Intravenous crystalloid at 30 ml/kg for hypotension or lactate ≥ 4 mmol/l (strong recommendation; low-quality evidence)
• Vasopressors if the patient remains hypotensive during or after fluid resuscitation for MAP ≥ 65 mm Hg (strong recommendation; moderate-quality)

Bundled vs. physician-judgement based approach

Kaukonen et al. showed that mortality with severe sepsis decreased significantly over a 12-year period in ANZ, though the conventional guidelines were not followed. This was a 12-year, retrospective, observational study from 2000 to 2012 including 101, 064 patients with severe sepsis from 171 ICUs in Australia and New Zealand. There was an absolute reduction in mortality by 16.7%, although bundled care was neither endorsed nor followed.¹

Intravenous fluids

A bolus dose of 30 ml/kg (more than 2.0 litres) within a 1-h window may be inappropriate in most subjects, especially if the diagnosis of sepsis is uncertain. For instance, a patient with cardiac failure may present with clinical and radiological features that suggest pneumonia (difficult to distinguish considering the short time window available) and maybe administered an inappropriately large volume of fluid.

Andrews et al. studied patients with sepsis and hypotension presenting to the emergency department of a 1500-bed referral hospital in Zambia between 2012-2013.² Patients were randomized to receive an early resuscitation protocol that included IV fluids with CVP monitoring, respiratory rate, and SaO2 and treatment with vasopressors for a MAP of more than 65 mm Hg. This group of patients were compared with patients who were managed based on clinician judgement. Patients in the protocolized care group received 3.5 litres in the first 6 hours after presentation to the emergency department, compared to 2.0 litres in the group in which fluids were administered based on clinician judgement. In-hospital mortality was higher among patients who received protocolized resuscitation compared to those who received resuscitation based on physician judgement. Although conducted in resource-constrained settings, among patients with a high incidence of HIV infection, an early resuscitation protocol with the administration of intravenous fluids and vasopressors increased in-hospital mortality in this study.

Lactate levels

There is definitive evidence to support the association between high lactate levels and mortality. However, it is unclear if lactate levels alone may be appropriate as a resuscitation target as the guidelines suggest.

Early antibiotics

The Centers for Medicare & Medicaid Services (CMS) in the US had recommended a Quality Measure for the initial management of community-acquired pneumonia, with antibiotic administration within 4 h of emergency department triage. This led to widespread, inappropriate antibiotic use to comply with the time frame mentioned in the guideline leading to downstream harmful effects with antibiotic resistance and C. difficile infection.³ 

The 2005 retrospective study by Kumar et al. suggested an increase in mortality by 7.6% for every 1-hour delay in septic shock.⁴ This was added to the guidelines in 2008 to include all patients with severe sepsis.

Needless to say, antibiotics must be administered as early as possible in patients who are septic, once the diagnosis is clear. However, setting a tight time frame may lead to unnecessary antibiotic administration to many who may not have an underlying infectious etiology.

Evidence on the timing of antibiotics

The only component of the bundle that may contribute to improved survival may be early antibiotics. Seymour et al. conducted a retrospective study involving 49,337 patients with severe sepsis or septic shock in New York city.⁵ They specifically evaluated the adherence to:

The 3-hour bundle

Blood cultures before antibiotics

Measurement of lactate

Administration of broad-spectrum antibiotics

The 6-hour bundle

30ml/kg fluid bolus in patients with hypotension or a lactate >4meq/l

Vasopressors for refractory hypotension

Re-measurement of lactate within 6 hours of starting protocol

They observed that a long time to the administration of antibiotics increased in-hospital mortality; however, a longer time to completion bolus intravenous did not. Besides, the improved in-hospital survival was observed only in patients who were in septic shock.

More recently, The PHANTASi (Prehospital ANTbiotics Against Sepsis) trial (Alam et al.) was conducted by the Emergency Medical Services in the Netherlands.⁶  They compared the effects of early administration of antibiotics in the ambulance with usual care. Patients in the group in which EMS personnel administered antibiotics, received the antibiotic dose 26 min prior to arrival at the emergency department. The time to administration of antibiotics was 70 min after arrival to the emergency department in the control group.  There was no difference in 28-d mortality with delayed antibiotic administration in this study.

Arbitrary time frames

Triage, evaluation and diagnosis is often not realistic within an hour. Physicians may be forced to comply with the bundle even when the diagnosis is unclear, to meet the guideline requirements. This type of a bundled approach might, paradoxically, lead to harm due to excessive use of interventions including fluids and antibiotics in patients who may not be septic or in septic shock. 

References

1. Kaukonen K-M, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308-1316. doi:10.1001/jama.2014.2637

2. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233-1240. doi:10.1001/jama.2017.10913

3. Pines JM, Isserman JA, Hinfey PB. The measurement of time to first antibiotic dose for pneumonia in the emergency department: a white paper and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med. 2009;37(3):335-340. doi:10.1016/j.jemermed.2009.06.127

4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. doi:10.1097/01.CCM.0000217961.75225.E9

5. Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017;376(23):2235-2244. doi:10.1056/NEJMoa1703058

6. Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open-label, randomised trial. Lancet Respir Med. 2018;6(1):40-50. doi:10.1016/S2213-2600(17)30469-1