The 2021 Surviving Sepsis Campaign guidelines for the management of sepsis and septic shock have been published.1 The guidelines continue to emphasize the importance of rapidity and appropriateness in the recognition and care of patients suspected to have sepsis. The recommendations represent an important guidepost for the busy bedside clinician in providing optimal care and incorporate the best contemporaneous evidence. However, clinical situations are unique and a flexible approach may often involve deviation from general recommendations.
What is new and what may be the contentious in the current iteration of the Surviving Sepsis Guidelines (SSG) that may call for a deviation from the general recommendations?
Screening and early treatment
Recommendation against qSOFA
The qSOFA screening parameters include a systolic BP <100 mm Hg, respiratory rate >22, and a GCS <15. The presence of 2 or more criteria denotes a positive qSOFA.
The SSG make a strong recommendation against the use of qSOFA as a single screening tool, compared to the National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), or the systemic inflammatory response syndrome (SIRS) considering its poor sensitivity for the diagnosis of sepsis. This recommendation is mainly based on systematic reviews that have shown that qSOFA has a high specificity and predictor of poor outcomes, but low sensitivity for the diagnosis of sepsis.2,3
Lactate measurement and lactate-guided resuscitation
The SSG make a weak recommendation for the measurement of lactate levels among patients suspected of sepsis. This is largely based on a good correlation between raised lactate levels and the likelihood of sepsis. However, the lactate level must be interpreted based on the clinical situation; it is neither sensitive nor specific enough to confirm or exclude the diagnosis of sepsis. The most common reason for raised lactate levels in sepsis is probably due to adrenergic stimulation and stimulation of cAMP leading to increased aerobic glycolysis and activation of Na+–K+ATPase pump. This leads to a rise in pyruvate levels which overwhelms the capacity of pyruvate dehydrogenase that coverts pyruvate to acetyl CoA. Instead, lactic dehydrogenase converts the excess pyruvate to lactate. Lactate levels may also rise due to hepatic dysfunction, release from the lung in the presence of acute respiratory distress syndrome, and epinephrine administration to support the circulation.4 Although hyperlactatemia is a marker of adverse outcomes, raised lactate levels in sepsis is usually not due to reduced oxygen delivery with triggering of anaerobic metabolism. In fact, lactate may be an important substrate for the heart and the brain for aerobic energy production.5
The 2016 guidelines had recommended initial resuscitation aimed to target normal lactate levels. However, the 2021 guidelines have revised this recommendation and favor the guidance of resuscitation aimed to decrease (not normalize) lactate levels. This is based on the realization that normal lactate levels may not be achievable in many septic patients during the early phase of resuscitation.
Fluid resuscitation
How much fluid as part of initial resuscitation?
The 2021 guidelines continue to recommend fluid resuscitation with 30 ml/kg of a balanced crystalloid solution over the first 3 hours. The level of recommendation has been upgraded from weak to a strong. This recommendation in based on a retrospective study,6 and the mean volume of resuscitation fluid administered prior to randomization of patients in the ARISE, PROCESS, and PROMISE trials that evaluated early goal-directed therapy in sepsis. The mean volume of initial resuscitation in these trials was 27 ml/kg.7
The requirement of volume resuscitation is likely to be highly variable in septic patients. Although 30 ml/kg may be reasonable to begin with, a fixed volume is clearly not optimal in all settings.
In the three-armed FEAST trial, children with evidence of hypoperfusion related to sepsis were randomized to receive a bolus of normal saline, 5% albumin, or no fluid. The 48-hour and 4-week mortality were significantly higher among children who received either fluid bolus compared to those who received no bolus fluid.8 In a randomized control trial of septic patients in Zambia, patients received protocolized resuscitation including intravenous fluids, blood transfusions for a hemoglobin level of <7 g/dl, and vasopressors for a target mean arterial pressure (MAP) ≥65 mm Hg or usual care. The median volume of fluid administered was 3.5 L (IQR, 2.7-4.0 L) in the protocolized care group compared to 2.0 L (IQR, 1.0-2.5 L) in the usual care group. In-hospital mortality, the primary outcome, was significantly higher in the protocol-based care group that received a higher volume of intravenous fluids (48.1% vs. 33%; RR: 1.46, 95% CI: 1.04-2.05). These studies suggest that overzealous, fixed volume fluid resuscitation during the initial phase of sepsis may lead to adverse clinical outcomes.
After initial resuscitation, the guidelines recommend further administration of fluid based on dynamic parameters. A Scandinavian multicentric randomized controlled trial evaluated this question among 151 patients. In the standard care group, patients could receive continued fluid boluses if the hemodynamic variables improved based on dynamic or static indices. In the fluid-restrictive arm, additional boluses were administered only if the lactate level was >4 mmol/l, the MAP was <50, skin mottling was present below the knee, or the patient was oliguric in the first 2 hours after randomization. This pilot study demonstrated that a restrictive protocol resulted in a significant reduction in the resuscitation volume. Although not powered to evaluate clinical outcomes, the use of a restrictive strategy resulted in a significantly lower incidence of worsening of acute kidney injury during the 90-day follow-up period. There was no significant difference in the incidence of ischemic events, days alive without ventilator support, or renal replacement therapy.9
The question remains unanswered if an arbitrary volume of bolus fluid is administered within a fixed period as part of a general approach, would this lead to iatrogenic fluid overload in a significant number of patients?
What type of fluid?
A balanced crystalloid is preferred over normal saline during the initial resuscitation phase. This recommendation is based on the SALT-ED and the SMART randomized controlled trials that demonstrated worse clinical outcomes with the use of normal saline compared to a balanced crystalloid.10,11 The recently published BaSICS trial compared plasmalyte to normal saline in critically ill patients who required fluid resuscitation in 75 ICUs in Brazil. No difference was noted in the 90-day mortality, the primary outcome of the study. Besides, the incidence of acute kidney injury requiring renal replacement therapy was also not different between groups.12 Further research regarding the resuscitation fluid is warranted, considering these contrasting reports.
Antibiotics
How soon should antibiotics be administered?
The SSG recommend antibiotic administration with an hour in patients presenting with septic shock and within 3 hours in patients with sepsis without shock. This is a departure from the previous guideline that recommended a 1-hour time frame in both situations. There is no argument that timely administration of antibiotics in septic patients is crucial to improving outcomes. However, setting a short, rigid timeframe may likely lead to logistical problems and overtreatment with antibiotics among patients who may not have an infective illness, considering the limited time available to arrive at a definitive diagnosis in a busy emergency department.
Alam et al. compared the effect of antibiotic administration by ambulance personnel with usual care involving antibiotic administration in the emergency department in patients with sepsis. In the early administration group, the median time to antibiotic administration was 26 min before presentation at the emergency department; in the usual care group, it was 70 minutes after arrival. There was no difference in the primary outcome of 28-day mortality between groups, regardless of the severity of illness.13
Monotherapy vs. combined therapy
The new guidelines recommend empiric therapy with two antimicrobials in situations with a high risk for multidrug-resistant organisms and monotherapy if the risk is low. Both are categorized as weak recommendations with a very low quality of evidence. Therapy should be scaled down to a single antibiotic once sensitivity reports are available. Although a rational recommendation, there is scant evidence to support the use of combination therapy in septic patients. A meta-analysis of randomized controlled trials revealed no difference in mortality or other patient-centered outcomes among patients who received monotherapy compared with combination antibiotic therapy in patients with severe sepsis.14
What should be the target mean arterial pressure (MAP)
The SSG recommend a target MAP of 65 mm Hg over higher targets for septic patients receiving vasopressors. This recommendation is based on the study by Lamontagne et al. with titration of vasopressors to a target MAP of 60–65 mm Hg, compared to usual care in patients with vasodilatory shock. There was no difference in the 90-day mortality between groups; exposure to vasopressors was significantly lower when a lower MAP of 60–65 mm Hg was targeted.15 However, in the SEPSISPAM trial, a target MAP of 80-85 compared to 65–70 mm Hg resulted in a significantly lower requirement for renal replacement therapy among patients with chronic hypertension, although there was no difference in the 28- and 90-day mortality.16 Assiduous adherence to fixed targets of MAP may not be appropriate; a flexible approach with a focus on measures of perfusion is likely to be more optimal.
Oxygenation targets
Considering the lack of robust evidence, the SSG do not make any recommendation regarding oxygenation on sepsis-induced respiratory failure. Several randomized controlled trials have addressed this question. The ICU-ROX study randomized critically ill patients to a conservative SaO2 target of 91–96% compared to usual care, with SaO2 maintained between 91–100%. No difference was noted between groups in the number of ventilator-free days at day-28, and mortality at 90 and 180 days. However, a post hoc analysis revealed a trend towards improved survival at 90 days among septic patients who received usual care (higher SaO2).17 This hypothesis needs to be tested in future controlled trials.
Time to ICU admission
A 6-hour window is suggested for admission to the ICU in patients suspected to have sepsis. There is strong evidence that delay in ICU admission from the wards18 or the emergency department19 leads to adverse outcomes in septic patients. The 6-hour timeline recognizes time and space constraints, especially in lower and middle-income countries. Although a 6-hour timeframe is suggested, it is important to emphasize the early identification of septic patients and prioritized admission to ICU to optimize clinical outcomes.
The bottom line
No set of rigid guidelines can replace rational clinical judgement by the bedside clinician in the face of complex clinical scenarios. The SSG strongly emphasize this important caveat. The guidelines reflect general recommendations based on updated evidence. Clinicians will frequently need to deviate from guidelines when such divergence is meant to improve patient outcomes. No guidelines are cast in stone and context-based modifications in management are expected from the astute clinician. On the other hand, obsessive adherence to guidelines is likely to result in harm. Furthermore, modification of management options need to be incorporated into practice with the emergence of new evidence.
References
1. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. Published online October 2, 2021. doi:10.1007/s00134-021-06506-y
2. Serafim R, Gomes JA, Salluh J, Póvoa P. A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis. Chest. 2018;153(3):646-655. doi:10.1016/j.chest.2017.12.015
3. Fernando SM, Tran A, Taljaard M, et al. Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis. Ann Intern Med. 2018;168(4):266-275. doi:10.7326/M17-2820
4. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18(5):503. doi:10.1186/s13054-014-0503-3
5. Revelly J-P, Tappy L, Martinez A, et al. Lactate and glucose metabolism in severe sepsis and cardiogenic shock. Crit Care Med. 2005;33(10):2235-2240. doi:10.1097/01.ccm.0000181525.99295.8f
6. Kuttab HI, Lykins JD, Hughes MD, et al. Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock. Crit Care Med. 2019;47(11):1582-1590. doi:10.1097/CCM.0000000000003960
7. PRISM Investigators, Rowan KM, Angus DC, et al. Early, Goal-Directed Therapy for Septic Shock – A Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223-2234. doi:10.1056/NEJMoa1701380
8. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495. doi:10.1056/NEJMoa1101549
9. The CLASSIC Trial Group, The Scandinavian Critical Care Trials Group, Hjortrup PB, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42(11):1695-1705. doi:10.1007/s00134-016-4500-7
10. Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584
11. Self WH, Semler MW, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018;378(9):819-828. doi:10.1056/NEJMoa1711586
12. Zampieri FG, Machado FR, Biondi RS, et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. Published online August 10, 2021. doi:10.1001/jama.2021.11684
13. 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
14. Sjövall F, Perner A, Hylander Møller M. Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis – A systematic review with meta-analysis and trial sequential analysis. J Infect. 2017;74(4):331-344. doi:10.1016/j.jinf.2016.11.013
15. Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial. JAMA. 2020;323(10):938-949. doi:10.1001/jama.2020.0930
16. Asfar P, Meziani F, Hamel J-F, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173
17. Young P, Mackle D, Bellomo R, et al. Conservative oxygen therapy for mechanically ventilated adults with sepsis: a post hoc analysis of data from the intensive care unit randomized trial comparing two approaches to oxygen therapy (ICU-ROX). Intensive Care Med. 2020;46(1):17-26. doi:10.1007/s00134-019-05857-x
18. Harris S, Singer M, Sanderson C, Grieve R, Harrison D, Rowan K. Impact on mortality of prompt admission to critical care for deteriorating ward patients: an instrumental variable analysis using critical care bed strain. Intensive Care Med. 2018;44(5):606-615. doi:10.1007/s00134-018-5148-2
19. Chalfin DB, Trzeciak S, Likourezos A, Baumann BM, Dellinger RP, DELAY-ED study group. Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit. Crit Care Med. 2007;35(6):1477-1483. doi:10.1097/01.CCM.0000266585.74905.5A
