Analysis of Risk Factors for Early-onset Ventilator-associated Pneumonia in a Neurosurgical Intensive Care Unit: A Single-center Retrospective Study

Abstract

Background:

Ventilator-associated pneumonia (VAP) is a severe infection among patients in the neurosurgery intensive care unit (NICU).

Methods:

We retrospectively evaluated risk factors for early-onset ventilator-associated pneumonia (EOVAP) from January 2019 to December 2019 at a NICU. A total of 89 NICU patients who were intubated within 48 hours of onset and whose mechanical ventilation time was longer than 7 days were enrolled. The enrolled patients had no history of chronic lung disease and no clinical manifestations of infection before intubation. Clinical data of patients were recorded, and the incidence of and risk factors for EOVAP were analyzed. Patients were also grouped by age (≥65 vs. <65 years) and whether they had received hypothermia treatment or not.

Results:

Among 89 mechanically ventilated patients (49 men and 40 women; median age 60.1±14.3 years), 40 patients (44.9%) developed EOVAP in 7 days and 14 patients (15.7%) had multidrug resistant bacteria. Binary logistic regression analysis indicated that older age (≥65years) (odds ratio [OR]: 0.267, 95% confidence interval [CI]: 0.101-0.709, P=0.008) and therapeutic hypothermia (OR: 0.235, CI: 0.075-0.738, p=0.013) were independent predictors of EOVAP. Levels of peripheral blood leukocytes, neutrophils and platelets were lower in the therapeutic hypothermia group than those that did not receive hypothermia treatment.

Conclusions:

This study found that older age (≥65years) and therapeutic hypothermia were independently associated with the risk of EOVAP in NICU patients.

Background

Ventilator-associated pneumonia (VAP) remains a common complication among neurosurgery intensive care unit (NICU) patients who require invasive mechanical ventilation. Several measures are available to decrease the incidence of VAP, such as elevation of the head of the bed, maintenance of tracheal cuff pressure, spontaneous awakening trials and starting enteral nutrition as early as possible [1, 2]. However, despite the application of these interventions, VAP is reported to affect 5–40% of patients receiving mechanical ventilation for more than 2 days[3, 4]. VAP results in a markedly prolonged hospital length of stay[5] and increased ventilator days in patients [6], with attributable mortality estimated to be approximately 13%.[7].

Patients with brain injury are highly susceptible to nosocomial pneumonia[8]; published studies have reported the incidence to range from 22% to 71%[9]. Hence, there is an urgent need to prevent VAP occurrence by early identification of risk factors in patients with brain injury requiring mechanical ventilation. In this context, we aimed to evaluate risk factors for early-onset ventilator-associated pneumonia (EOVAP) in NICU patients undergoing mechanical ventilation for 7 days.

Methods

Study population

This retrospective observational, single-center cohort study was conducted at Xuanwu Hospital Capital Medical University, China. Neurosurgery is a key specialty, with a total of 38 NICU beds in this hospital. From January to December 2019, we retrospectively analyzed clinical data of all NICU patients who fulfilled the following:

Inclusion criteria:

(1) Age≥18 years and intubation within 48 hours of onset; (2) no clinical symptoms or signs of infection at the time of intubation; and (3) mechanical ventilation time greater than 7 days, to minimize the effect of mechanical ventilation time and ICU stay time on EOVAP.

Exclusion criteria:

(1) Pre-existing chronic pulmonary diseases, such as chronic obstructive pulmonary disease, asthma, bronchiectasis, active tuberculosis, empyema and other diseases. (2) chest radiograph or CT examination before admission showing atelectasis or pneumonia. (3) patients with acute and chronic liver failure, kidney failure, cancer or severe immunodeficiency[10].

EOVAP Definitions

To maintain consistency with the literature, EOVAP was defined as pneumonia that occurred during the first 7 days after the onset of mechanical ventilation[8, 11].

VAP criteria were as follows: [12, 13] presence of new and/or progressive pulmonary infiltrates on a chest radiograph in a patient ventilated for more than 48 hours plus 2 or more of the following:

(1) Temperature > 38 °C; (2) leukocytosis (white blood cell count ≥ 12,000 cells/ mm3) or leukopenia (white blood cell count < 4,000 cells/mm3); (3) presence of purulent tracheal aspirate.

Microbiological Evaluation

EOVAP was diagnosed by noninvasive sampling and semiquantitative culture as recommended in the guidelines [14]. All patients admitted to the NICU and intubated will have received tracheobronchial aspiration (TBAS) through a closed-suction system. The TBAS was sent to the hospital's microbiology laboratories for the detection of bacteria and fungi. In the microbiology laboratory, the TBAS was plated on agar medium (3 days of culture for aerobic bacteria and 2 weeks for fungi) using a semi-quantitative culture method. Bacterial identification and antibiotic susceptibility tests using standard methods were performed for samples that showed positive growth, as recommended in CDC guidelines[15].

Data collection

The following data were obtained: age (categorized as ≥65 and <65 years), sex, smoking, body mass index (BMI), pre-existing comorbidities (coronary artery disease, hypertension, diabetes), intubation time (hospital admission or prehospital intubation), Acute Physiology and Chronic Health Evaluation II (APACHE II), The Glasgow Coma Scale/Score(GCS). Laboratory data and medications administered were also obtained, which included: albumin, C-reactive protein (CRP), procalcitonin (PCT), full blood count, alanine aminotransferase (ALT), serum creatinine (Scr), chest X-ray, norepinephrine, glucocorticoid, barbiturates, mannitol, therapeutic hypothermia, antibiotics administered after the intubation and 28-day mortality.

Statistical Analysis

All statistical analyses were performed using SPSS statistical software version 19.0. Continuous data were presented as mean ± standard deviation or median and interquartile range (IQR; 25th–75th percentile) for those that were not normally distributed. Independent-Samples T-Test or Mann-Whitney non-parametric test was used to compare differences in continuous variables. Chi-square test was used to compare categorical data. Binary multivariable logistic regression analysis was performed for parameters with p<0.10 on univariate analysis and the odds ratio (OR) with 95% confidence interval (95% CI) were calculated. All tests were two-tailed, with the significance level set at p<0.05.

Results

Patient characteristics

During a 12-month period, 615 mechanically ventilated patients were admitted to the NICU at our hospital. After an initial medical record review, the following records were removed from the analysis: 434 records for either extubation or death within 7days; 63 records for intubation performed more than 48 hours after admission; and 29 records for infection or chronic lung disease before intubation. A total of 89 patients who underwent mechanical ventilation satisfied the inclusion criteria. Among 89 mechanically ventilated patients (49 men and 40 women; median age 60.1±14.3 years), APACHE II was 13.8±3.8 and the GCS was 7.8 ± 2.2. A total of 40 patients (44.9%) developed EOVAP in 7 days (Fig 1).

Antibiotic use andmultidrug-resistant bacteria(MDRB)

All 89 patients were treated with prophylactic antibiotics (including 33 cases with cefminox, 32 cases with piperacillin tazobactam and 24 cases with ceftriaxone) within 24 hours after intubation. Antibiotics were continuously administered and adjusted according to the results of the bacterial culture. Within 7 days of intubation, 12 patients were administered carbapenem for more than 3 days. The sputum culture results within 7 days in 14 patients (accounting for 15.7%) showed MDRB (Table 1). However, statistical results showed no correlation between the administration of carbapenem antibiotics and the appearance of Gram-negative MDRB in the short term.

Risk factors for EOVAP

All 89 patients had no infection or underlying lung diseases on presentation. They were intubated within 48 hours of the onset of cerebrovascular disease and mechanical ventilation was maintained for more than 7 days. Within 2 days after intubation, all patients were provided with gastrointestinal nutritional support, acid inhibitors and blood glucose monitoring. The univariate analysis between the EOVAP group and the non-EOVAP group showed that only the proportion of patients aged ≥65years was statistically significantly different between the groups. There were no significant differences between the two groups in the use of glucocorticoids, MDRB, routine blood-based markers, inflammatory markers and 28-day mortality (Table 2).

Three factors with P<0.1 in univariate analysis results: ≥65 years, therapeutic hypothermia and CRP (7 days after intubation) were included in the binary multivariable logistic regression analysis. Logistic regression analyses showed that older age (≥65years) (odds ratio [OR]: 0.267, 95% confidence interval [CI]: 0.101-0.709, P=0.008) and therapeutic hypothermia (OR: 0.235, CI: 0.075-0.738, p=0.013), were independent predictors of EOVAP (Table 3).

Older age (≥65years) and therapeutic hypothermia

Patients were grouped by age (≥65 vs. <65 years) and whether they had received hypothermia treatment or not and differences in clinical characteristics between these groups were compared. Underlying diseases, inflammatory indicators, drug use and mortality, were not significantly different between the two age groups. However, levels of peripheral blood leukocytes, neutrophils and platelets were lower in the therapeutic hypothermia group than the that did not receive hypothermia treatment, with no significant differences in other indicators, including measures of inflammation (Table 4).

Discussion

With the aging of the population, there is an associated increase in cerebrovascular diseases, which is a global health burden. VAP is one of the most common complications in the management of patients with severe cerebrovascular disease. Therefore, there is important clinical value in the early identification of risk factors for EOVAP in patients with cerebrovascular disease.

Despite the fact that the majority of MDRB are isolated from patients with late-onset VAP, accumulating evidence shows that drug resistance is also a problem in patients who develop early-onset VAP[16]. In this study, NICU patients with no history of antibiotic use prior to admission had a 15.7% (14/89) incidence of MDRB during 7-day mechanical ventilation. The 3 cases of gram-positive MDRB were all Staphylococcus aureus. Burkholderia cepacia, Klebsiella pneumoniae and Acinetobacter were the main Gram-negative MDRB identified; no drug-resistant Pseudomonas aeruginosa was identified. There was no correlation between the administration of carbapenem antibiotics in the short term and the emergence of Gram-negative MDRB. It is speculated that MDRB may originate from exogenous sources such as contaminated respiratory instruments, infected aerosols from the ICU environment and contaminated hands and apparel of healthcare workers[11, 17].

In our study, PCT and CRP did not reliably distinguish patients with EOVAP from patients without EOVAP, a finding consistent with other studies[29-32]. However, older age (≥65years) and hypothermia therapy were independent predictors of EOVAP. A European multicenter cohort study reported that VAP was not increased among the elderly, but the associated mortality in these patients was higher[18]. This is contrary to our findings. Our evaluation of 89 patients with no history of chronic lung disease, no infection before intubation and the same duration of mechanical ventilation after intubation showed that age ≥ 65 years was an independent predictor of EOVAP. The reason for the divergent findings between the two studies may be attributed to the stringent patient inclusion criteria adopted in our study. The high incidence of EOVAP in the elderly (≥65 years) may be due to the gradual decline in respiratory function with age, the gradual atrophy of respiratory muscles, the decline in lung elasticity and the decline in the ability to expel sputum. At the same time, the respiratory mucosa of the elderly shrinks, the mucosal function decreases and the local defense function of the respiratory tract decreases, leading to an increase in the incidence of VAP.

Several published reports have indicated that hypothermia therapy is one of the most important risk factors for early-onset pneumonia. Esnault reported that the incidence of EOVAP after severe traumatic brain injury was more than 61% and that hypothermia was one of the major risk factors for EOVAP[19]. Sébastien reported that after out-of-hospital cardiac arrest, therapeutic hypothermia was associated with an increased risk of early-onset pneumonia[20]. Our findings further corroborate these observations. Hypothermia impairs immune functions by inhibiting the secretion of proinflammatory cytokines and suppressing leukocyte migration and phagocytosis [21]. Hypothermia-induced insulin resistance and hyperglycemia may further increase infection risk[20], leading to an increase in the incidence of VAP.

Bro-Jeppesen and Dufner reported that hypothermia treatment could lead to a decrease in the number of white blood cells and neutrophils[22, 23], which is consistent with the results of our study. However, the relationship between hypothermia and platelet count is controversial. Nielsen reported that thrombocytopenia occurred after therapeutic hypothermia in patients with cardiac arrest[24, 25]. But Takashi reported that therapeutic hypothermia had no significant effect on platelet counts in patients with severe traumatic brain injury. Our study found that after 7 days of mechanical ventilation, the platelet count of patients treated with hypothermia was significantly reduced, and it was associated with 28-day mortality (P= 0.006). The cause of thrombocytopenia caused by hypothermia is still unclear. Some studies have shown that hypothermia enhances shear-induced platelet aggregation[26] and decline in platelet function[27]. These results suggest that the monitoring of platelets in patients with hypothermia is essential. Further evaluation is needed when clinicians detect thrombocytopenia in hypothermic patients.

Conclusion

We retrospectively analyzed the clinical data of 89 NICU patients who received mechanical ventilation between January and December 2019. All 89 patients had no infection or underlying lung diseases. The study found that older age (≥65years) and therapeutic hypothermia were independently associated with the risk of EOVAP in NICU patients.

Declarations

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We thank all of the investigators and members of the Department of Neurosurgery, Xuanwu Hospital, Capital Medical University for their efforts .

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University

Guojie Teng, Xiuhong Nie, Lin Zhang

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University,

China International Neuroscience Institute (China-INI)

Ning Wang

Department of Evidence-based Medicine, Xuanwu Hospital Capital Medical University

Hongjun Liu

Contributions

Teng GJ performed the conception and design. Wang L acquired the data. Teng GJ and Zhang L contributed to manuscript drafting; Teng GJ and Liu HJ was responsible for the statistics of article. Nie XH was responsible for the revision of the manuscript for intellectual content. All authors issued final approval for the version to be submitted.

Corresponding author

Correspondence to Guojie Teng.

Ethics declarations

Ethics approval and consent to participate

All procedures performed in studies involving human participants were following the Ethics Committee of Xuanwu Hospital Research Ethics Committee (Approved No. of ethic committee: [2020]018). Due to the non-interventional and retrospective nature of the study, all patient data were analyzed anonymously, a waiver of informed consent was granted by the Institutional Review Board. All methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

VAP: Ventilator-associated pneumonia

NICU: Neurosurgery intensive care unit

EOVAP: Early-onset ventilator-associated pneumonia

TBAS: Tracheobronchial aspiration

BMI: Body mass index

APACHE II: Acute Physiology and Chronic Health Evaluation,

GCS: Glasgow Coma Scale/Score

CRP: C-reactive protein

PCT: Procalcitonin

ALT: Alanine aminotransferase

Scr: Serum creatinine

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Tables

Table 1. Types of multidrug resistant bacteria

Table 2 Characteristics of NICU patients comparing EOVAP vs. non-EOVAP groups

Table 3 Results of binary multivariable logistic regression analysis showing risk factors for EOVAP in NICU patients

Table 4 Characteristics of NICU patients comparing hypothermia therapy vs. non-hypothermia therapy groups

* The platelet count (7 days after intubation): death group vs. alive group P= 0.006