“Sepsis Code to Resus 1.” Your charge nurse comes out of her office, “Doc, you know that’s the cardiac arrest patient right? They’re not febrile. Why are we ordering antibiotics?”
Despite all the hoopla and controversy surrounding mandated CMS guidelines surrounding the Surviving Sepsis Campaign, there’s limited evidence that antibiotics may be beneficial for those with severe sepsis.[1,2]
However, what about your undifferentiated cardiac arrest patient? Is there a role for antibiotics? Let’s take a look.
Post-arrest Syndrome: What is it?
Patients who have a return of spontaneous circulation (ROSC) are sick. We know this. The medical term for the post-arrest, Sick as Shit (SAS), intubated patient on multiple pressors has been defined as the post-arrest syndrome. Negovsky first described this syndrome almost 50 years ago as “post-resuscitation disease,” later to be renamed post-arrest syndrome to emphasize that resuscitation does not end at ROSC.[3,4] Appropriately, post-arrest care is emphasized in the AHA/ILCOR 2020 updated chain of survival.[5]
Chain of survival [5]
Post-arrest SIRS?
Post-arrest syndrome and sepsis have overlap. Systemic ischemia of cardiac arrest results in a shock state in which tissues are provided with less oxygen. This decreased oxygen delivery to tissue, also known as oxygen debt, leads to an inflammatory cascade similar to sepsis.[4,6,7]
So, if post-arrest syndrome and sepsis result in similar inflammatory states, and if antibiotics are beneficial in sepsis, shouldn’t antibiotics help treat post-arrest syndrome?
To answer this question, let’s go back to medical school. At some point in medical school, you were probably asked to memorize the SIRS criteria. For review:
SIRS criteria (MDCalc)
Having taken care of post-ROSC patients, we know they have abnormal labs and vitals, and most will meet SIRS criteria. However, hopefully, you were also taught that SIRS does not equal sepsis. Sepsis requires a bacterial source. Antibiotics are only helpful in treating sepsis if a bacterial source is underlying the inflammatory state.
This then begs the question: How many patients with ROSC have an underlying bacterial infection?
What’s the incidence of bacteremia in OHCA?
A prospective, observational study including 173 patients presenting to the ED with out-of-hospital cardiac arrest (OHCA) found the incidence of bacteremia to be 38%.[8] Those with bacteremia were found to have a statistically significant decrease in survival to hospital admission (25% vs 40%), however, mortality was unchanged at 30 days (93.8% vs 92.6%).[8]
This study still leaves us with two important questions;
First, did these patients die of bacteremia or die with bacteremia? Cardiac arrest patients are the sickest of the sick. The presence of bacteremia does not mean these patients died of bacteremia. Perhaps bacteremia was a result of the post-cardiac arrest state itself.
Put another way, perhaps bacteremia indicated a sicker cohort of OCHA patients. Of the cohort that survived to admission, 94% of bacteremic patients required pressors compared to just 74.4% of non-bacteremic patients. The bacteremic patients also had higher lactate and lower pH.[8] While these findings are thought-provoking, we should be careful about over-analyzing such a small cohort, which is underpowered to draw meaningful conclusions. Additionally, this was an observational study which is prone to selection bias and decreases the certainty of these findings.
Secondly, and more importantly, do antibiotics help in this population? We know that patients with bacteremia benefit from antibiotics.[9] However, do bacteremic patients presenting to the ED with OHCA benefit from antibiotics? This is really the question we want to ask.
Can antibiotics prevent post-arrest pneumonia?
Cardiac arrest survivors are at increased risk of developing pneumonia.[10] Risk factors for developing pneumonia include aspiration during CPR, decreased secretion clearance, and impaired neutrophil function from therapeutic hypothermia.[11] (Whether or not therapeutic hypothermia actually increases the risk of pneumonia and sepsis is not clear, with a 2014 systematic review initially showing increased risk of sepsis and pneumonia, however, a more recent large RCT showed no statistically significant increase in these adverse events.[12,13]) So, knowing this, would it make sense to give prophylactic antibiotics to post-arrest patients?
The 2019 Anthartic study was a well-designed study aimed to address this question.[14] This multi-center, double-blind trial, randomized 198 adults undergoing targeted temperature management after shockable out-of-hospital cardiac arrest to a 1-day course of amoxicillin-clavulanate or placebo. The primary outcome was ventilator-associated pneumonia within seven days, and investigators found a decreased incidence in the antibiotic group: 19% vs 34% (HR 0.53, 95% CI: 0.3 to 0.95). Secondary outcomes found no difference in ventilator-free days, ICU length of stay, mortality, or safety.
While technically a positive study, does this trial examine any patient-oriented outcomes? Patient-oriented outcomes are outcomes that patients (and families) care about: mortality, morbidity, cost, etc. If an intervention does not change patient-oriented outcomes (outcomes which we should also care about), does it matter? While interesting (and not surprising) that a short course of antibiotics may decrease the rate of early ventilator pneumonia, I’m not convinced that this study provides sufficient evidence for giving antibiotics to all cardiac arrest patients. Keep in mind, this study only included patients with shockable rhythms and we, therefore, cannot extend the findings to patients with non-shockable cardiac arrest. Additionally, while there was no difference in secondary outcomes, we cannot definitively rule out the possibility of benefit as the trial was underpowered for these outcomes. The takeaway should be that there is inadequate evidence that prophylactic antibiotics administered to patients with cardiac arrest will improve patient-oriented outcomes.
Argument for: No one dies without “Vanc and Pip/Tazo”
Let’s return to our initial question: which cardiac arrest patients should receive antibiotics? Clearly, a patient with evidence of a bacterial source of infection should receive antibiotics. For example, evidence of chest infiltrates (perhaps pre-covid) consistent with bacterial pneumonia may justify antibiotics. Additionally, if a family member reports recent symptoms suggestive of bacterial infection (e.g. a family member reports that the patient was complaining of fever and dysuria and the UA is consistent with cystitis), it is certainly reasonable to administer antibiotics.
Even without history or exam findings consistent with bacterial infection, you can make the argument for administering antibiotics. For the sick patient on pressors after arrest without an attributable cause (ECG without evidence of occlusion MI, CTA without pulmonary embolism, etc) it is reasonable to consider pan-culturing the patient and administering broad-spectrum antibiotics. This is the “kitchen-sink” argument. For the sickest patient in the room without an attributable cause, why not administer antibiotics if there is a possibility that they may benefit the patient?
Argument against: “Do no harm”
On the contrary, to the above argument, one may ask: Why should we administer systemic antibiotics if a patient has no evidence of bacterial infection and evidence suggests that prophylactic antibiotics demonstrate no benefit in patient-oriented outcomes?
If that’s not enough, the 2020 ILCOR update recommends “not using prophylactic antibiotics in patients after ROSC.” [15] ILCOR cites the above Anthartic study demonstrating no benefit to patient-oriented outcomes as well as a 2019 systematic review demonstrating no benefit for prophylactic antibiotics.[16]
Lastly, antibiotics are not without harm. Aside from the known adverse events associated with antibiotic use (C. difficile infection, allergic reaction, acute kidney injury), antibiotic resistance is of growing concern.
Takeaways:
- 1. Post-arrest syndrome and sepsis have overlap in presentation
- 2. Bacteremic cardiac arrest patients may have worse outcomes
- 3. Antibiotics may decrease the rate of early ventilator-associated pneumonia
- 4. No studies of prophylactic antibiotics have demonstrated favorable, patient-oriented outcomes
References:
[1] Santistevan J. Sepsis CMS Core Measure (SEP-1) Highlights. ACEP Quality Improvement and Safety Section. Available at: https://www.acep.org/how-we-serve/sections/quality-improvement–patient-safety/newsletters/march-2016/sepsis-cms-core-measure-sep-1-highlights/
[2] Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010;38(4):1045-1053. doi:10.1097/CCM.0b013e3181cc4824
[3] Negovsky VA. The second step in resuscitation–the treatment of the ‘post-resuscitation disease’. Resuscitation. 1972;1(1):1-7. doi:10.1016/0300-9572(72)90058-5
[4] Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation. 2008;118(23):2452-2483. doi:10.1161/CIRCULATIONAHA.108.190652
[5] Merchant RM, Topjian AA, Panchal AR, et al. Part 1: Executive Summary: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S337-S357. doi:10.1161/CIR.0000000000000918
[6] Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation: biology and clinical implications. Intensive Care Med. 2001;27(1):19-31. doi:10.1007/s001340000790
[7] Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome?. Curr Opin Crit Care. 2004;10(3):208-212. doi:10.1097/01.ccx.0000126090.06275.fe
[8] Coba V, Jaehne AK, Suarez A, et al. The incidence and significance of bacteremia in out of hospital cardiac arrest. Resuscitation. 2014;85(2):196-202. doi:10.1016/j.resuscitation.2013.09.022
[9] Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244(5):379-386. doi:10.1046/j.1365-2796.1998.00379.x
[10] Perbet S, Mongardon N, Dumas F, et al. Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis. Am J Respir Crit Care Med. 2011;184(9):1048-1054. doi:10.1164/rccm.201102-0331OC
[11] Farkas J. PulmCrit Wee – Prophylactic antibiotics after cardiac arrest? PulmCrit blog. Available at: https://emcrit.org/pulmcrit/anthartic/
[12] Geurts M, Macleod MR, Kollmar R, Kremer PH, van der Worp HB. Therapeutic hypothermia and the risk of infection: a systematic review and meta-analysis. Crit Care Med. 2014;42(2):231-242. doi:10.1097/CCM.0b013e3182a276e8
[13] Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-2294. doi:10.1056/NEJMoa2100591
[14] François B, Cariou A, Clere-Jehl R, et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. N Engl J Med. 2019;381(19):1831-1842. doi:10.1056/NEJMoa1812379
[15] Nolan JP, Maconochie I, Soar J, et al. Executive Summary 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Resuscitation. 2020;156:A1-A22. doi:10.1016/j.resuscitation.2020.09.009
[16] Couper K, Laloo R, Field R, Perkins GD, Thomas M, Yeung J. Prophylactic antibiotic use following cardiac arrest: A systematic review and meta-analysis. Resuscitation. 2019;141:166-173. doi:10.1016/j.resuscitation.2019.04.047
Robby
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