Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Evans L, Rhodes A, Alhazzani W, Antonelli M, et al. Intensive Care Med. 2021 Nov;47(11):1181-1247.
The Surviving Sepsis Campaign (SSC) guidelines, first elaborated in 2004 and subsequently revised in 2008, 2012, and 2017, have now been updated for 2021. The rationale for each of the 93 specific recommendations from 6 workgroups is well-presented in Table 1 of the full paper, and the executive summary is approachable and concise. By way of providing an ultra-executive level summary, the notable updates contained in the 2021 guidelines can be broken down into three areas:
New concepts and significant changes in the current guidelines: Development of institutional “standard operating procedures” for management of patients who are acutely ill and at high risk of sepsis. Use of capillary refill time as an adjunct to guide resuscitation. Initiation of vasopressors peripherally when needed, as opposed to waiting for central venous access. Use of high-flow nasal cannula as first line (as opposed to non-invasive ventilation) for sepsis-related hypoxemic respiratory failure. Recommendations against normal saline and gelatin-based colloids in fluid resuscitation, and against levosimendan as a primary vasopressor. Recommendations against polymyxin B hemoperfusion, as well as against intravenous Vitamin C, as adjunctive therapies for sepsis and septic shock. A new best practice guideline recommending post-discharge follow-up for long-term sequelae of critical illness in sepsis survivors.
Major concepts from prior guidelines that remain unchanged: The previous recommendation for 30 mL/kg of crystalloid fluid administration within 3 hours remains - although this has been downgraded from a strong to a weak recommendation. The previous weak recommendations to guide resuscitation based on serial lactate levels remain unchanged. (These are two of the most frequently debated previous recommendations.) Norepinephrine remains the recommended first-line vasopressor, with serial addition of vasopressin followed by epinephrine if needed to meet hemodynamic goals. ARDSnet principles continue to predominate in recommendations for mechanical ventilation.
Modifications to prior guidelines: The previous strong recommendation for empiric antimicrobial administration within one hour of recognition of sepsis or septic shock has been subdivided into three specific strata: a strong recommendation for antimicrobials “ideally” within 1 hour for patients with possible septic shock or a high likelihood for sepsis; a weak recommendation for antimicrobials within 3 hours for patients with possible sepsis without shock; and a weak recommendation for deferring empiric antimicrobials in patients with a low likelihood of infection and without shock. (The previous time-based antibiotic recommendations were also frequently debated.) Prior guidelines were also clarified to strongly recommend methicillin-resistant staph aureus (MRSA) coverage and weakly recommend fungal coverage in patients at high risk (but weakly recommend against such coverage in patients at low risk) of MRSA and fungal infection, respectively. They weakly recommend for corticosteroids in septic shock with ongoing vasopressor requirements, eliminating language which only recommended steroids if hemodynamic targets could not be reached with fluids and vasopressors.
Clinicians should be familiar with the SSC guidelines as they are nationally national prominent, highly visible, and frequently incorporated into institutional metrics; however, they are by no means uncontested. Three previous guidelines that generated notable debate include the recommendations for 30mL/kg of intravenous fluid within 3 hours as initial resuscitation, time-specific delivery of empiric antibiotics, and the use of initial lactate and its clearance as a fluid resuscitation metric. Elements of these prior guidelines were previously integrated into a 3- and 6-hour resuscitation bundle (referred to as SEP-1), and compliance with this bundle began to be tracked publicly and nationally. In response, concern was voiced that the SSC guidelines extended beyond the evidence base, were operationally taxing, and that their rigid wholesale adoption could be potentially harmful, as articulated in several published critiques and alternative recommendations. While the 2021 update to the SSC guidelines mitigate these concerns somewhat, their core remains relatively specific and prescriptive. Overall, as the authors specifically acknowledge, these guidelines “cannot replace the clinician’s decision-making capacity when presented with a unique patient”.
Effect of vasopressin and methylprednisolone vs placebo on return of spontaneous circulation in patients with in-hospital cardiac arrest: A randomized clinical trial. Andersen LW, Isbye D, Kjaergaard J, Kristensen CM, et al. JAMA. 2021 Oct 26;326(16):1586-1594.
Optimal resuscitation practices for in-hospital cardiac arrest are not well-characterized. Although the etiology, time to recognition, and time to definitive therapy are known to differ between in- and out-of-hospital arrests, much of our emergency management of in-hospital cardiac arrest is based largely on extrapolation from out-of-hospital arrest studies. Of the scant existing evidence, two previous relatively small randomized trials reported benefits to the addition of vasopressin (20 IU for each parallel dose of epinephrine) and glucocorticoids (40 mg of methylprednisolone) vs placebo in the management of in-hospital arrest. However, these were relatively smaller and more geographically homogenous studies, and pending additional support these interventions have not been widely integrated into practice.
This article by Drs. Andersen and colleagues describes a multicenter randomized placebo-controlled trial of the addition of vasopressin and methylprednisolone vs. placebo to standard protocols for in-hospital cardiac arrest management, performed in ten hospitals in Denmark. Of 501 patients with in-hospital arrest who received at least one dose of epinephrine, 237 received the study intervention (40 mg methylprednisolone and 20 IU vasopressin, with up to 4 further doses of vasopressin given after each additional epinephrine dose) and 264 received placebo (normal saline). The groups were well-matched at baseline. The primary outcome of return of spontaneous circulation (ROSC) occurred in 42% of the intervention group compared to 33% of the placebo group, with a risk ratio of 1.3 (95% confidence interval 1.03 – 1.63, p=0.03). Neither secondary outcomes (survival and favorable neurological outcome at 30 and 90 days) nor safety outcomes (hyperglycemia, hypernatremia, and gastrointestinal bleeding) differed between groups. Prespecified subgroup analyses suggested that benefit may be particular to non-shockable initial rhythm, witnessed arrest, younger patients, and earlier drug delivery.
The increased incidence of ROSC in the methylprednisolone/vasopressin group matched the result of prior studies, although with a more modest effect size compared to the previously reported odds ratio of 2.98. However, the survival and favorable neurological outcome benefit seen in prior studies was not reproduced here. This may be related to differences between study populations, differences in the use of continued steroids post-arrest, and/or under-powering for these two specific outcomes. While this result may seem underwhelming, by comparison, data from the PARAMEDIC2 study supporting epinephrine for out-of-hospital cardiac arrest did not show an increase in survival with a favorable neurologic outcome either – and yet epinephrine remains a mainstay of Advance Cardiac Life Support. Thus the 9.6% absolute increase in the incidence of ROSC remains an important result. Overall, while this trial alone may not cement a role for vasopressin and methylprednisolone for in-hospital cardiac arrest, these data certainly provide equipoise for further study and may sway expert opinion in future guideline development.