Surviving Sepsis Campaign Guidelines

Blog Written by Dr Jose Chacko

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.

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 to confirm or exclude the diagnosis of sepsis. The most common reason for raised lactate levels 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 converts pyruvate to acetyl CoA. Instead, lactic dehydrogenase converts 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.

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.

The 2016 guidelines had recommended initial resuscitation aimed to target normal lactate levels. However, the 2021 guidelines have revised this recommendation and favour 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 is 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 strong. This recommendation in based on a retrospective study, 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.¹

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.² 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 continue to 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.

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 crystalloid.^3,4 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. 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 in 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.⁵

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-centred outcomes among patients who received monotherapy compared with combination antibiotic therapy in patients with severe sepsis.⁶

What should be the target mean arterial pressure (MAP)

The SSG recommends 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.⁷ 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.⁸  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 does 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).⁹ 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 wards¹⁰ or the emergency department¹¹ 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 identification of septic patients early and prioritize admission to ICU to optimize clinical outcomes.   

Summary – 

SSCG 2021 is a good guide for clinicians. However, clinicians should use a personalised approach in treating patients with sepsis and septic shock.