Infection is a common complication in patients admitted to the intensive care unit (ICU) after out-of-hospital cardiac arrest (OHCA),[1-4] and previous studies have determined that pneumonia was the most common infectious complication. [1,4,5] The lungs are prone to infection due to many factors, such as frequent mechanical complications in the upper airway and thorax after cardiac resuscitation,[6] unprotected airway, decreased mental status, emergent airway access, and prolonged mechanical ventilation.[7]

Therapeutic hypothermia can improve neurological outcomes and reduce mortality in resuscitated patients after OHCA[5,8,9] and is recommended for unconscious adult patients that are resuscitated after OHCA.[10] However, hypothermia can impair immune function by inhibiting the release of various inflammatory cytokines, suppressing leukocyte and phagocyte chemotaxis, and inducing insulin resistance and hyperglycemia.[10-12] A few studies have recently suggested that therapeutic hypothermia might increase infectious complications in OHCA patients. [3,13,14]

However, there is limited data on the impact of antibiotic prophylaxis during therapeutic hypothermia and the effect on infection in resuscitated patients. Although a recent study reported that prophylactic antibiotics were associated with a reduced incidence of pneumonia, there was a lack of information about the timing of pneumonia.[15] It is unclear whether prophylactic antibiotics actually reduce early-onset pneumonia in OHCA patients treated with therapeutic hypothermia.

Thus, we performed a retrospective cohort study to examine whether prophylactic antibiotics during therapeutic hypothermia can reduce episodes of early-onset pneumonia. The purpose of this study was to investigate the effect of prophylactic antibiotics on the development of early-onset pneumonia in OHCA patients treated with therapeutic hypothermia.

During the study period, 128 patients were admitted to the ICU for therapeutic hypothermia after cardiac arrest. In this cohort, 38 patients died within the first 72 hours, 17 patients exhibited pneumonia before hypothermia, and another 5 patients had missing data. Therefore, 68 patients were included in the analysis.

Table 1 shows the baseline characteristics of the 68 patients. The median age was 57 years, and 79.4% (n = 54) were male. Most of the OHCAs were related to cardiac etiology (n = 48, 70.6%), followed by asphyxiation (n = 12, 17.6%). Prophylactic antibiotics were initiated in 48 (70.6%) of 68 patients, and these patients were regarded as the prophylactic antibiotic group. Initial white blood cell count was higher in the prophylactic antibiotic group. There were no other significantly different baseline characteristics between the prophylactic antibiotic group and the control group.

Among the 68 patients analyzed in this study, early-onset pneumonia occurred in 29.4% (n = 20), and the in-hospital mortality rate was 16.2% (n = 11) (Table 2). Prophylactic antibiotics did not decrease the rate of early-onset pneumonia (prophylactic antibiotic group, 29.2%; control group, 30.0%; p = 0.945). The most commonly used antibiotic for prophylaxis was third-generation cephalosporin (n = 24, 35.3%), and the class of prophylactic antibiotics did not influence the occurrence of early-onset pneumonia (Table 3). Microbiological samples were collected within 5 days of admission in 35 patients. In general, clinicians ordered a microbiological examination when patients had new infiltrates on chest radiograph or fever after therapeutic hypothermia. Among the 20 of those patients with early-onset pneumonia, causative micro-organisms were detected in 3 patients. 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. Additionally, antibiotic prophylaxis did not influence the duration of mechanical ventilation (prophylactic antibiotic group, 10 days; control group, 8 days; p = 0.483) or the length of ICU stay (prophylactic antibiotic group, 12 days; control group, 10 days; p = 0.627). In-hospital mortality and poor neurological outcome were not significantly different between the 2 groups.

Factors associated with early-onset pneumonia were evaluated. We observed a trend towards a longer duration of hypothermia in patients with early-onset pneumonia (early-onset pneumonia, 1,456 [1,440-1,643] min; control, 1,440 [1,385-1,460] min, p = 0.054). A binary regression model showed that a hypothermia duration ≥ 24 hours might be associated with early-onset pneumonia, although this result was not statistically significant (odds ratio [OR], 3.400; 95% confidence interval [CI], 0.873-13.239 p = 0.078) (Table 4). Outcomes including duration of ICU stay and mechanical ventilator support, in-hospital mortality, and neurological outcome were not associated with development of early-onset pneumonia (Table 5).

In this study, prophylactic antibiotic therapy during hypothermia treatment in patients that survived after OHCA was not associated with reduced incidence of early–onset pneumonia. Additionally, it did not affect the duration of mechanical ventilation, the length of ICU stay, in-hospital mortality, or poor neurological outcome.[18]

Infectious complications are frequent after cardiac arrest and may be even more frequent after therapeutic hypothermia.[3] Pneumonia is the most common type of infection associated with therapeutic hypothermia.[19,20] Perbet et al.[13] reported that therapeutic hypothermia was the single independent risk factor that increased the risk of early-onset pneumonia (OR, 1.9; 95% CI, 1.28-2.80; p = 0.001). The incidence of early-onset pneumonia has been reported to range from 33% to 65%[3,13,21,22] given the extreme variability of the diagnostic criteria used for this complication. The incidence of early-onset pneumonia in this study was slightly lower than that reported previously. We excluded patients who presented with pneumonia after return of spontaneous circulation but before induction of therapeutic hypothermia, which might have contributed to the lower incidence of early-onset pneumonia.

Currently, there is insufficient data to support the use of prophylactic antibiotic therapy after OHCA, although it is frequently used in practice. In the study performed by Perbet et al.,[13] prophylactic antibiotics, defined as antimicrobial therapy prescribed in the first 12 hours in the absence of pneumonia, were administered to 176 (27%) of patients, and 78% were treated with therapeutic hypothermia. In that study, the incidence of early-onset pneumonia in patients with and without antibiotic prophylaxis was 68.2% (120/176) and 64.3% (299/465), respectively. However, antibiotic prophylaxis did not influence the incidence of early-onset pneumonia in that study (OR, 1.30; 95% CI, 0.88-1.92, p = 0.18). In contrast, another retrospective cohort study reported that prophylactic antibiotics were associated with a reduced incidence of pneumonia in cardiac arrest survivors treated with therapeutic hypothermia.[15] Prophylactic antibiotics were prescribed in 33% of patients, and pneumonia developed in 12.6% of patients with prophylactic antibiotics and 54.9% of patients without (p < 0.001). However, early- and late-onset pneumonia were not distinguished in that study. Thus, the efficacy of prophylactic antibiotics for early-onset pneumonia remains unclear.

Perbet et al.[13] reported that therapeutic hypothermia was the single factor associated with early-onset pneumonia, but that the duration of hypothermia did not affect the development of early-onset pneumonia. Conversely, another study reported higher risk of pneumonia when therapeutic hypothermia was used over a longer period of time (≥ 48-72 hours).[23] Polderman[24] reported that nosocomial infection appeared to be closely linked to a longer duration of hypothermia, especially hypothermia that persisted for > 24 hours. In the current study, patients with early-onset pneumonia were likely to have a longer duration of hypothermia, although this result was not statistically significant. Because the duration of hypothermia could be a confounder of early-onset pneumonia, we performed subgroup analysis with patients whose duration of hypothermia was ≤ 24 hours. Among 38 patients with a duration of hypothermia ≤ 24 hours, the prophylactic antibiotics group showed fewer cases of early-onset pneumonia, although this result was not statistically significant (prophylactic antibiotics group, 21.4%; control group, 30.0%; p = 0.673). Therefore, additional study will be needed to analyze the effect of prophylactic antibiotics on the development of early-onset pneumonia with controlled duration of hypothermia in a large study population.

A previous study performed by Woo et al.[22] showed that postanoxic seizure developed in 48.8% (60/123) of patients treated with therapeutic hypothermia. They reported that postanoxic seizure was an independent risk factor of pneumonia after therapeutic hypothermia, and that aspiration during seizure triggered the occurrence of this complication. The mechanism of early-onset pneumonia after OHCA may be primarily a consequence of the combination of aspiration pneumonitis and aspiration pneumonia.[18] In our study, the incidence of seizure in patients with early-onset pneumonia was higher than in those without, but the difference was not statistically significant. The incidence of seizure in our study was lower than that in the previous study by Woo et al., which might have affected the results.

The present study is the first to specifically evaluate the association of prophylactic antibiotic use during hypothermia and the development of early-onset pneumonia within 5 days of admission. Our data suggest that prophylactic antibiotic therapy during hypothermia treatment in patients that survive OHCA does not reduce development of pneumonia. Additionally, because the etiology of arrest might affect the outcome, we performed subgroup analysis after excluding patients with cardiac arrest of noncardiac etiology. Among 48 patients with cardiac etiologies, the proportion of patients that developed early-onset pneumonia was not statistically different between the prophylactic antibiotics group and the control group (prophylactic antibiotics group, 24.2%; control group, 26.7%; p = 0.857).

However, there were several limitations to our study. First, it was a single-center retrospective study with only 68 patients, which could account for the lack of statistical power. Next, the definition of early-onset pneumonia is currently debated, and diagnosis of early-onset pneumonia after OHCA can be difficult due to confounding factors, such as sepsis-like syndrome after cardiopulmonary resuscitation and influences of therapeutic hypothermia.[25] In this study, early-onset pneumonia was defined based on the timing of onset in relation to cardiac arrest, with a previous study classifying early-onset pneumonia as pneumonia that develops within 3 to 5 days after cardiac arrest.[18] Because there is not currently a diagnostic consensus, we modified our study to adhere to the previously used definition.[18,26] However, our findings are still limited because our analysis was not restricted to bacteriologically-proven infection. Further studies to evaluate the effect of prophylactic antibiotics on early-onset pneumonia based on a microbiologically-confirmed diagnosis are needed. Third, selection bias may have occurred. Prophylactic antibiotics were more likely to be administered in patients who had leukocytosis, which is affected by hypothermia as well as infection or inflammatory processes. Finally, we could not evaluate aspiration of oro-pharyngeal or gastric contents, which has been considered a mechanism of early-onset pneumonia after OHCA. [18]

In conclusion, prophylactic antibiotic therapy during hypothermia treatment in patients admitted to the ICU after OHCA did not reduce the incidence of early-onset pneumonia. Because of the limitations to this study, additional well-designed prospective studies are needed to further evaluate the influence of prophylactic antibiotics on early-onset pneumonia.