This meta-analysis and systematic review disclosed prophylactic antibiotic administration had no effect on clinically-important outcomes with a low evidence quality, such as the incidence of pneumonia (including early-onset pneumonia), mortality, CPC1-2 and ICU LOS.
The main outcome of this trial was the incidence of pneumonia, and no differences could be demonstrated when applied prophylactic antibiotic. Several trials have revealed that infectious complications were common in survivors of cardiac arrest, as expected, pneumonia was the most common type of infection [19–20]. The risk of pneumonia after OHCA is increased by aspiration of gastric contents, post-resuscitation immune paralysis, high blood endotoxin concentration, intestinal mucosal disruption due to ischemic-reperfusion injury, mechanical ventilation, pulmonary contusions and chest wall dysfunction from rib and sternal fractures [21, 22, 23]. Emesis was documented in 32% of patients suffering non-traumatic OHCA, implying a high risk of aspiration [24]. In a RCT investigated benefits of prophylactic antibiotics in comatose survivors of OHCA, tracheobronchial aspiration was reported in 23 patients (28%) [16]. Immediate bronchoscopic airway cleaning together with prophylactic antibiotic administration might be efficient if aspiration is detected. Regrettably, there were only 2 trials excluding patients with aspiration [7, 16] in this meta-analysis, leading a bias to the incidence of pneumonia.
This ambiguity can be further complicated by TTM, as it was deemed to be an increased risk of early-onset pneumonia [25]. Paradoxically, results from a meta-analysis drawn a conclusion that no significant difference was found in pneumonia events [26]. The discrepancy could be explained when concerning the level and the period of TTM. Studies reported higher risk of pneumonia when TTM was used over a longer period of time (≥ 48–72 hours) and at a temperature of 33 ℃ when compared with 36 ℃ [27, 28]. All the patients included in this meta-analysis were treated with TTM, however, none of the trial detailed the level and the period.
Because of confounding factors, an accurate early diagnosis of pneumonia after OHCA remains a challenge. First of all, the post-cardiac arrest state which is characterized by high levels of circulating cytokines and adhesion molecules, the presence of plasma endotoxin and dysregulated leukocyte production of cytokines, recall the immunological profile found in patients with sepsis [29, 30]. In the post-hoc analysis of TTM-trial [31], Josef and co-workers recorded prospective data on infectious complications and considered the diagnostic value of both C-reactive protein and procalcitonin as low during the first three days after cardiac arrest as they were shown to be non-discriminatory for patients with infections and OHCA. The introduction of TTM complicates the diagnosis of infection. During the temperature-controlled period, body temperature changes and the presence of fever cannot be easily employed. All that which has been discussed above confuses the diagnosis of pneumonia and ulteriorly contributes the bias of trials recruited in the meta-analysis.
In post-hoc analysis of the TTM cohort, Harmon and colleagues found that pathogens isolated after OHCA comprised of both gram-negative (61.1%) and gram-positive (38.2%) micro-organisms, with most of the pathogens isolated in patients with pneumonia was Staphylococcus (23%) [14]. Gajic [20] had similar results with their most reported pathogens being Staphylococcus aureus (31%). Taken together, Harmon recommended a cephalosporin of 2nd or 3rd generation as a reasonable empiric approach [14].
Mortensen [33] reported that 95% of in-hospital cardiac arrest (IHCA) and 82% of OHCA patients received antimicrobial treatment in the post-cardiac arrest period. The risk of resistance occurring as a negative consequence of antibiotic prophylaxis use need to be weighed against the benefits. Hoth and colleagues [34] retrospectively reviewed patients contracted nosocomial pneumonia and revealed that when receiving prolonged (༞48h) prophylactic antibiotics, the causative organisms were more likely to be resistant or Gram-negative bacteria, and the incidence of antibiotic complications were two times greater than for patients who did not receive extended antibiotic prophylaxis. In line with this, Kroupa [35] disclosed that initial antibiotic therapy was changed in 52.8% of OHCA patients, alarming an increasing frequency of multi-resistant strains of pathogens. Contrarily, a recent RCT [7] comparing intravenous amoxicillin–clavulanate with placebo in patients suffering OHCA identified no increase in resistant bacteria. In trial of Kim [8], Methicillin-resistant Staphylococcus aureus was found in 2 patients in the prophylactic antibiotic group, and Klebsiella pneumoniae was found in 1 patient in the control group.
Couper and co-workers presented a meta-analysis concerning prophylactic antibiotic use in patients suffering cardiac arrest (including in-hospital and out-of-hospital cardiac arrest). Inpatients are likely to have pre-existing infections and/ or already be on antibiotics at the time of their cardiac arrest. The response time from trained personnel would be significantly shorter, as would the time to intubation, thereby potentially reducing the chance of aspiration [18]. Taken together, we only exam the association between prophylactic antibiotic administration and OHCA.
Limitations
This meta-analysis had several weaknesses that should be noted. Firstly, only 2 RCTs were recruited in this meta-analysis, of which one is under high risk. Secondly, the initiation and the treatment course of intervention group varied from trials. The missing data handling remained major limitations for this paper. We look forward to the publication of the full results of Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT) trial [36] to clarify the effect furtherly.