American Journal of Emergency Medicine 32 (2014) 150–155
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Factors associated with pneumonia in post–cardiac arrest patients receiving therapeutic hypothermia☆ Jae-Hyug Woo, MD, Yong Su Lim, MD, PhD ⁎, Hyuk Jun Yang, MD, PhD, Won Bin Park, MD, Jin Seong Cho, MD, PhD, Jin Joo Kim, MD, PhD, Sung Youl Hyun, MD, PhD, Gun Lee, MD, PhD Department of Emergency Medicine, Gachon University Gil Medical Center, 1198, Guwol-dong, Namdong-gu, Incheon, 405-760, South Korea
a r t i c l e
i n f o
Article history: Received 26 August 2013 Received in revised form 11 October 2013 Accepted 14 October 2013
a b s t r a c t Aim: The aim of this study is to investigate risk factors associated with the development of pneumonia during the first 7 days of admission in survivors of cardiac arrest receiving therapeutic hypothermia. Methods: A total of 123 patients receiving therapeutic hypothermia after out-of-hospital cardiac arrest between January 2008 and December 2010 were enrolled. Study populations were categorized as “pneumonia present” [P (+)] and “pneumonia absent” [P (−)] contingent upon the development of pneumonia during the first 7 days of admission. Risk factors and outcomes related to development of pneumonia were determined. Results: Fifty-nine patients (48.0 %) developed pneumonia, and P (+) patients had lower Acute Physiology and Chronic Health Evaluation II score (22 vs 26); longer durations of central venous catheter (8.9 vs 5.1 days), nasogastric tube (11.1 vs 3.8 days), mechanical ventilation (MV) (9.3 vs 3.7 days), and intensive care unit stay (10.0 vs 5.0 days); and higher rates of nasogastric feeding (66.1% vs 35.9 %), tracheostomy (52.5% vs 17.2 %), and postanoxic seizure (62.7% vs 39.1 %). In multivariate analyses, the occurrence of postanoxic seizure (odds ratio, 2.75; 95% confidence interval, 1.06-7.14; P = .04) and the length of MV (odds ratio, 1.33; 95% confidence interval, 1.15-1.52; P b .001) were independently associated with the development of pneumonia. The development of pneumonia had no significant association with survival (log-rank test, P = .15). Conclusion: Postanoxic seizure and prolonged duration of MV are independently associated with development of pneumonia. It may be helpful that we give more attention to the development of pneumonia in patients with postanoxic seizure and provide prompt diagnosis and treatment of postanoxic seizure. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Out-of-hospital cardiac arrest (OHCA) survivors frequently have infectious complications. Some authors propose a hypothesis that it is because resuscitation is an extreme stress with a profound decrease of cell-mediated immunity and gastrointestinal ischemia-reperfusion injury in the setting of circulatory arrest may lead to bacterial translocation from the digestive tract into the bloodstream [1-4]. Among the complications, pneumonia is the most common infection [1]. Emergency airway and vascular access, unprotected airway, pulmonary contusion during cardiopulmonary resuscitation (CPR), decreased mental status, and prolonged invasive mechanical ventilation (MV) may increase the risk for pulmonary infection in OHCA survivors [1,5,6]. Recently, comprehensive post–cardiac arrest (CA) care and the implementation of therapeutic hypothermia (TH) as a proven standard therapy have reduced brain injury and improved neurologic
outcome in comatose survivors of OHCA [7]. However, prolonged hypothermia is known to decrease immune function by inhibiting the release of proinflammatory cytokines and by suppressing the chemotactic migration of leukocytes and phagocytosis [7,8]. Moreover, some studies have reported that the implementation of TH is associated with an increased incidence and risk of infection, with pneumonia being most common, especially early-onset pneumonia [5,6]. Although TH may increase the incidence of several complications including pneumonia, TH is standard care to reduce ischemic brain injury in OHCA survivors and has been used widely. Thus, this study is designed to investigate risk factors that are associated with the development of pneumonia during the first 7 days of admission in comatose survivors of OHCA patients receiving TH. 2. Methods 2.1. Study population
☆ Conflicts of interest: No conflict of interest. ⁎ Corresponding author. Tel.: +82 32 460 3015; fax: +82 32 460 3019. E-mail address: [email protected] (Y.S. Lim). 0735-6757/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajem.2013.10.035
The setting of the study was a university hospital emergency department (ED) located in Incheon City, South Korea, with an annual
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
patient volume of approximately 90 000. We conducted a singlecenter and retrospective cohort study between January 2008 and December 2010. This study was approved by the institutional review board of our hospital. The study population consisted of patients 18 years or older who were successfully resuscitated after nontraumatic OHCA and then treated with TH. Patients who died within the first 24 hours and with known pneumonia or other infection before CA were excluded from the analysis. Data were obtained from a prospective registry database including all patients treated in the ED after CA and medical records at our hospital and other hospitals. The collected baseline characteristic variables of patients were sex, age, location of CA, performance of bystander CPR, interval from collapse to basic life support (BLS), interval from collapse to advanced cardiovascular life support (ACLS), interval from BLS to ACLS, interval from collapse to return of spontaneous circulation (ROSC), initial cardiac rhythm, presumed etiology of CA, total dose of epinephrine, number of vasopressors for 48 hours, number of defibrillation events, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, initial lactate in ED, and factors associated with TH (target body temperature [BT], cooling method, initial BT on TH start, interval from TH start to target BT, and hypotension during induction of TH). 2.2. Therapeutic hypothermia
151
colony-forming unit/mL and 10 3 colony-forming unit /mL, respectively). Body temperature and white blood cell count were not considered, as they are affected by hypothermia. Despite a negative quantitative culture, the diagnosis was retained when the previous signs were present with associated purulent endotracheal aspirates and hypoxemia (PaO2/fraction of inspired oxygen b240) not explained by pulmonary edema, pulmonary embolism, or atelectasis [6]. All data were retrospectively reviewed by 2 investigators to diagnose pneumonia that developed during the first 7 days of admission. Each case of disagreement between prospective diagnosis and retrospective assessment was resolved by consensus between the investigators, with the help of a third expert if necessary. We divided the study population into 2 groups, “pneumonia present” [P (+)] and “pneumonia absent” [P (−)], contingent upon the development of pneumonia during the first 7 days of admission. We then compared risk factors associated with the development of pneumonia during the first 7 days of admission and outcome between the 2 groups. We collected the risk factors associated with pneumonia as reported in previous studies and other alleged factors [1,5-7,11-13]. The collected variables were number and duration of central venous catheter (CVC) placements, factors related to nasogastric tube (NG tube), nasogastric feeding, reintubation, tracheostomy, length of MV, length of ICU stay, duration of sedation, blood glucose levels, immunosuppression, age, APACHE II score on ICU admission, and postanoxic seizure. Factors related to CA, CPR, and TH were compared between the 2 groups.
If patients were unconscious with Glasgow Coma Scale less than 9 after ROSC, they were treated with TH, admitted to the intensive care unit (ICU), and treated with standard intensive care including invasive monitoring, hemodynamic support, MV, and analgesia sedation. The exclusion criteria of TH were shock despite the use of vasopressors (systolic blood pressure b 90 mm Hg), active bleeding, trauma, or possible causes of coma other than CA (head trauma or cerebrovascular accident). Therapeutic hypothermia was performed by surface (exovascular) or internal (endovascular) cooling techniques as soon as possible after ROSC. The surface cooling technique was performed by the application of a water-circulating hydrogel pad (Arctic Sun; Medivance, Inc, Louisville, CO), and the internal cooling technique was performed by insertion of an intravascular cooling catheter (CoolLine; Alsius Corporation, Irvine, CA) connected to a cooling device (CoolGard 3000; Alsius Corporation) into the right internal jugular vein. The core temperature was measured by rectal probe. The target temperature was 32°C to 34°C, and the duration of maintenance was 24 hours. The rewarming rate was 0.3°C per hour with the same device. Exovascular and endovascular techniques were alternately selected. Continuous midazolam and fentanyl were given for sedation analgesia, and vecuronium was administered to control shivering. Daily neurologic assessments including motor and brain stem reflex were performed. Portable electroencephalography (EEG) was checked within 7 days after admission at least once, and EEG were interpreted by certified electroencephalographers, at bedside and post hoc, with bipolar and monopolar montages. Postanoxic seizure was diagnosed in the presence of clinical, electrographic, or electroclinical abnormalities suggestive of postanoxic seizure [9,10].
Data were analyzed using SPSS (SPSS version 17.0; SPSS, Inc, Chicago, IL). Continuous data are presented as the median and interquartile range or mean and SD as appropriate. Univariate analysis was performed by using the Mann-Whitney U test or the Student t test for continuous variables or the χ 2 test for categorical variables. All variables found to be significant by univariate analysis (with selected P b .10 in the factor analysis), then underwent multivariate logistic regression analysis by the backward stepwise method. Survival curves were determined by the Kaplan-Meier method, and the log-rank test was used to compare curves. All statistical tests were 2 sided, and P b .05 was considered statistically significant.
2.3. Pneumonia analysis
3. Results
According to commonly used criteria, a diagnosis of pneumonia was retained in the presence of clinically compatible findings at auscultation and a new or progressive pulmonary infiltrate on chest x-ray (persistent for at least 48 hours) associated with a positive quantitative culture of distal pulmonary secretion samples. The specimens were obtained from endotracheal aspirates or with a blind protective specimen catheter (significant thresholds: 10 6
3.1. Baseline characteristics of study populations
2.4. Assessment of neurologic outcome At 1 month after the CA, we assessed the clinical neurologic outcome of patients using Cerebral Performance Category (CPC). The performance categories were defined as follows: CPC1, “conscious and alert with normal neurologic function or only slight cerebral disability”; CPC2, “conscious with moderate cerebral disability for part-time work in sheltered environment or independent existence”; CPC3, “conscious with severe cerebral disability precluding independent existence”; CPC4, “comatose or in a persistent vegetative state”; and CPC5, “brain dead or death.” The patients were then classified into 2 groups based on neurologic outcomes: the “good neurologic outcome” group (CPC1 and CPC2) and the “poor neurologic outcome” group (CPC3-CPC5). 2.5. Statistical analysis
During the study period, 175 patients were admitted to ICU. Of these 175 patients, 133 patients received TH. Two patients who died within the first 24 hours and 8 patients who already had pneumonia before CA were excluded. Consequently, the remaining 123 patients were enrolled in this study (Fig. 1). Of these patients, 59 patients
152
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
133 patients treated with therapeutic hypothermia
Exclusion; 2 deaths within the first 24h of admission 8 proved pneumonia prior to OHCA
123 enrolled patients
59 with pneumonia; 8 within the first 2 days after admission 32 within 3~4 days after admission 19 within 5~7 days after admission
64 without pneumonia
Fig. 1. Flow chart of patient enrollment and exclusion.
(48.0%) developed pneumonia [P (+)] during the first 7 days of admission. Pneumonia developed in 32 patients (54%) within 3 to 4 days after admission, in 8 patients (14%) in the first 2 days after admission, and in 19 patients (32%) within 5 to 7 days after admission. Baseline characteristics of P (+) and P (−) patients are summarized in Table 1. P (+) and P (−) patient groups had a median age of 50.0 (37.0-61.5) and 51.5 (44.5-62.0) years, and 34 (57.6%) and 47 (73.4%) were men, respectively. Higher APACHE II score in P (−) patients was the only significant difference (26.0 vs 22.0; P = .04). No other variables associated with CA, CPR, and TH had a significant difference between the 2 groups. 3.2. Microbiologic findings Among the 59 patients with pneumonia, 54 cases (91.5%) had microbiological confirmation by specimen cultures. The organisms isolated were methicillin-sensitive Staphylococcus aureus (15 cases, 27.8%), methicillin-resistant S aureus (12 cases, 22.2%), Klebsiella pneumoniae (10 cases, 18.5%), Pseudomonas aeruginosa (7 cases, 13.0%), Acinetobacter baumannii (3 cases, 5.6%), Haemophilus influenzae (2 cases, 3.7%), Serratia marcescens (2 cases, 3.7%), Streptococcus species (1 case, 1.9%), Escherichia coli (1 case, 1.9%), and Burkholderia cepacia (1 case, 1.9%). 3.3. Univariate analysis of factors associated with pneumonia Factors potentially associated with pneumonia in the univariate analysis are shown in Table 2. Between the 2 groups, the numbers of CVC were not different, but the P (+) group had a longer duration of the CVC (8.9 vs 5.1 days, P b .001). Most patients had an NG tube for drainage, but more patients were fed via NG tube (39 [66.1%] vs 23 [35.9%]; P = .001) in the P (+) group and they had the NG tube for longer periods (11.1 vs 3.8 days; P b .001). The time intervals associated with NG tube insertion and feeding were not significantly different.
The P (+) group received tracheostomy more frequently (31 [52.5%] vs 11 [17.2%]; P b .001) and had longer duration of MV (9.3 vs 3.7 days; P b .001) and ICU stay (10.0 vs 5.0 days; P b .001).
Table 1 Baseline characteristics of study population (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
Sex (male), n (%) Age (y) Location of arrest (residence), n (%) Bystander CPR, n (%) Interval from collapse to BLS (min) Interval from collapse to ACLS (min) Interval from BLS to ACLS (min) Interval from collapse to ROSC (min) Initial cardiac rhythm, n (%) VF/VT Non-VF/VT Asystole PEA Cardiac cause of arrest, n (%) Total dose of epinephrine (mg) No. of vasopressors for 48 h, n (%) No. of defibrillation, n (%) APACHE II score SOFA score Initial lactate in ED (mmol/L) Target BT, n (%) 32°C 33°C 34°C Cooling method (internal), n (%) Initial BT on TH start(°C) Interval from TH start to target BT (h) Hypotension during induction of TH, n (%)
47 51.5 28 10 7.0 16.0 9.0 35.0
34 50.0 30 6 6.0 17.0 10.0 31.0
(73.4) (44.5-62.0) (43.8) (15.6) (2.5-10.0) (10.0-25.0) (0.5-13.5) (18.5-48.5)
22 (34.4)
(57.6) (37.0-61.5) (50.8) (10.2) (4.0-9.0) (12.0-22.0) (4.0-14.5) (21.0-44.5)
P .09 .28 .47 .43 .65 .97 .38 .84 .51
17 (28.8)
37 5 39 3.0 2.0 1.0 26.0 10.0 8.7
(57.8) 28 (47.5) (7.8) 14 (23.7) (60.9) 35 (59.3) 1.00 (1.0-6.5) 3.0 (2.0-6.5) .69 (1.0-3.0) 2.0 (1.0-3.0) .86 (0.0-4.0) 1.0 (0.0-3.0) .80 (21.0-30.0) 22.0 (20.0-26.5) .04 (7.5-12.0) 9.0 (7.0-11.0) .08 (6.1-12.9) 8.7 (6.7-11.1) .91
8 50 6 34 36.1 1.8 37
(12.5) 6 (9.4) (78.1) 43 (72.9) (10.2) 10 (16.9) (53.1) 36 (61.0) (35.0-36.6) 36.0 (34.7-36.7) (1.0-4.0) 2.3 (1.2-4.6) (57.8) 31 (52.5)
.45 .47 .70 .35 .59
Values are expressed as number (percentage) and median (interquartile range), as appropriate. Abbreviations: VF/VT, ventricular fibrillation/pulseless ventricular tachycardia; PEA, pulseless electrical activity.
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
153
Table 2 Comparison of risk factors related to pneumonia (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
No. of CVC, n (%) 1 37 (57.8) 35 (59.3) 2 27 (42.2) 24 (40.7) Duration of CVC (d) 5.1 (2.9-8.9) 8.9 (6.0-14.4) Insertion of NG tube, n (%) 62 (96.9) 58 (98.3) Nasogastric feeding, n (%) 23 (35.9) 39 (66.1) Duration of NG tube (d) 3.8 (2.3-9.0) 11.1 (6.1-24.8) Interval from collapse to NG 3.2 (1.4-5.4) 3.4 (1.4-8.9) tube insertion (hour) Interval from collapse to 5.0 (3.8-6.4) 5.8 (4.1-7.3) nasogastric feeding (d) Reintubation, n (%) 3 (4.7) 8 (13.6) Tracheostomy, n (%) 11 (17.2) 31 (52.5) Length of MV (d) 3.7 (2.3-6.9) 9.3 (6.3-14.0) Length of ICU stay (d) 5.0 (3.1-9.4) 10.0 (6.8-17.7) Duration of sedation (d) 1.5 (1.4-1.7) 1.6 (1.5-1.7) Blood glucose level (mg/dL) At 0 h 208.0 (155.0-290.0) 236.0 (181.0-302.5) At 12 h 171.0 (130.5-224.5) 195.0 (144.5-269.5) At 24 h 146.0 (108.0-207.5) 162.0 (130.0-221.0) Immunosuppression, n (%) 3 (4.7) 0 (0.0) Postanoxic seizure, n (%) 25 (39.1) 37 (62.7)
P 1.00
b.001 1.00 .001 b.001 .60 .18 .12 b.001 b.001 b.001 .34 .15 .09 .13 .25 .01
Values are expressed as number (percentage) and median (interquartile range), as appropriate.
In the P (+) group, more patients had postanoxic seizure (37 [62.7%] vs 25 [39.1%]; P = .01). Reintubation; blood glucose level at 0, 12, and 24 hours after ROSC; and immunosuppression were not significantly different between the 2 groups. 3.4. Outcomes of TH patients Death at 1 month and discharge were not statistically different between the 2 groups (Table 3). However, the P (+) group had more patients with bad CPC at 1 month than the P (−) group (48 [81.4%] vs 41 [64.1%]; P = .03). Kaplan-Meier survival analysis after 30 days revealed no significant difference between the 2 groups (log-rank test, P = .15) (Fig. 2). 3.5. Multivariate logistic regression analyses The variables found to be significant by univariate analysis (with selected P b .10 in the factor analysis) were sex, age, APACHE II, SOFA, the duration of CVC, nasogastric feeding, duration of NG tube, tracheostomy, length of MV, length of ICU stay, blood glucose level at 12 hours after ROSC, the occurrence of postanoxic seizure, survival time (max 90 days), and bad CPC at 1 month. The multivariate logistic regressions analyses by development of pneumonia are shown in Table 4. In multivariate analyses, the occurrence of postanoxic seizure (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.06-7.14; P = .04) and the length of MV (OR, 1.33; 95% CI, 1.15-1.52; P b .001) were significantly related to the development of pneumonia.
Fig. 2. Kaplan-Meier survival analysis of both groups. The dashed line, pneumonia (−) group; the solid line, pneumonia (+) group. A 30-day period was analyzed in follow-up time. The difference between the 2 groups was not significant (log-rank test, P = .15).
4. Discussion In this study, pneumonia was a frequent complication in OHCA patients receiving TH. Notably, postanoxic seizure was a risk factor for pneumonia in TH patients as was the length of MV. However, the development of pneumonia within 7 days after ROSC did not influence mortality. In previous studies, pneumonia was a frequent complication in TH patients with a prevalence of 29% to 70%; the most common pathogen was S aureus [5,6,14-16]. Similarly, 48% of patients in our study had pneumonia, and S aureus (27 cases) was the most frequently isolated organism of pneumonia. Therapeutic hypothermia had been suspected of increasing the risk of infectious pulmonary complications [5,17]. A clinical study by Perbet et al [6] demonstrated that TH was an independent risk factor for early onset pneumonia. Thus, the factors associated with TH were suspicious. However, in our study, there was no relationship between the development of pneumonia and factors associated with TH (target BT, cooling method, initial BT on TH start, interval from TH start to target BT, hypotension during induction of TH). Further studies are needed to determine whether TH influences the development of pneumonia alone or whether other factors related to TH influence the development of pneumonia. In a previous study, the independent risk factors for ventilatorassociated pneumonia by multivariate analysis were tracheostomy, multiple CVC insertions, reintubation, length of ICU stay, enteral feeding, and length of MV [12]. Similarly, prolonged duration of CVC,
Table 4 Multivariate analysis of factors related to the development of pneumonia Variables
Table 3 Comparison of outcome according to the development of pneumonia (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
P
Death at 1 mo, n (%) Death at discharge, n (%) Survival time (max. 90 d) Bad CPC at 1 mo, n (%) Bad CPC at discharge, n (%)
29 27 90.0 41 41
21 (35.6) 21 (35.6) 90.0 (13.5-90.0) 48 (81.4) 45 (76.3)
.27 .45 .07 .03 .14
(45.3) (42.2) (6.0-90.0) (64.1) (64.1)
Values are expressed as number (percentage) and median (interquartile range), as appropriate.
Sex (female) Nasogastric feeding (yes) Blood glucose level at 12 h (mg/dL) APACHE II Postanoxic seizure (yes) Length of MV (d)
OR
1.74 0.54 1.00 0.93 2.75 1.33
95% CI for OR Lower
Upper
0.67 0.18 1.00 0.85 1.06 1.15
4.59 1.63 1.00 1.02 7.14 1.52
P
.26 .28 .27 .11 .04 b.001
Odds ratios were calculated using a backward stepwise logistic regression analysis. Variables included in analysis were sex, age, APACHE II, SOFA, duration of central venous catheter, nasogastric feeding, duration of NG tube, tracheostomy, length of MV, length of ICU stay, blood glucose level at 12 hour after ROSC, occurrence of postanoxic seizure, survival time, and bad CPC at 1 month.
154
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
MV, ICU stay and NG tube, nasogastric feeding, and tracheostomy were associated with the development of pneumonia in our univariate analysis. However, in multivariate logistic regression analyses, only the prolonged duration of MV increased the risk of pneumonia in TH patients. However, longer duration of NG tube and more nasogastric feeding in the P (+) group are problematic. In this study, they did not increase the risk of pneumonia in multivariate logistic regression analyses, but they were certainly related to pneumonia in univariate analysis. In previous studies, a semirecumbent position during feeding for intubated patients and continuous aspiration of subglottic secretions through the use of a specially designed endotracheal tube reduced the incidence of early onset ventilator-associated pneumonia [13]. Furthermore, early enteral feeding (day 1 of intubation) was associated with a higher risk for pneumonia than late enteral feeding (day 5 of intubation), whereas postpyloric feeding was associated with a significant reduction in ventilator-associated pneumonia. These methods may help to decrease aspiration of gastric contents and development of pneumonia during NG tube maintenance and nasogastric feeding. Immunosuppression, reintubation, and continuous sedation were predicted risk factors of pneumonia. However, because the populations of immunosuppression and reintubation were so small, they might not influence the occurrence of pneumonia. A study by Rello et al [18] demonstrated that continuous sedation increased the risk of pneumonia 4-fold. In our study, because sedation continued similarly for all of patients until the hypothermia was stopped, there is no additional information gained as to whether sedation influences the development of pneumonia. Surprisingly, in our study, postanoxic seizure was an independent risk factor for pneumonia in TH patients. Furthermore, the occurrence of pneumonia increased more than 2-fold when postanoxic seizure developed. In previous studies, patients with seizure or chronic epilepsy had increased risk for pneumonia, and pneumonia due to seizure increased the mortality [19-21]. The authors presumed that aspiration during seizure triggered the occurrence of pneumonia. Increased oral secretions, impaired swallowing mechanisms, and difficulty in attaining adequate patient positioning during seizure significantly increased the risk of aspiration, and despite intubation, it was difficult to completely prevent secretions from invading the airway through the space around the cuff of the endotracheal tube [20,22]. For these reasons, postanoxic seizure in TH patients might also contribute to the development of pneumonia in spite of intubation. The occurrence of postanoxic seizure may cause poor recovery of consciousness and increase the use of sedative and antiepileptic drugs, consequently prolonging the length of MV and ICU stay, which may also contribute to the development of pneumonia. In this study, patients with postanoxic seizure had a longer duration of MV (7.1 vs 5.2; P = .02) and ICU stay (7.9 vs 6.5; P = .06) than patients without seizure. On the other hand, it may be that changes in the immune system or defense mechanisms during postanoxic seizure trigger the occurrence of pneumonia in TH patients. In other studies, chronic epilepsy may lead to relative suppression of the immune system with a subsequent increased risk of infections such as pneumonia [23]. However, there is still no evidence that a 1-time seizure event or continuous seizures during a short period leads to lower the immunity. Further study for immunologic changes during postanoxic seizure in TH patients is needed. Postanoxic seizure occurs in 18% to 45% of post-CA survivors and has been considered a strong predictor of poor outcome, especially if occurring early after CA [9,10,16,24-27]. Prolonged seizures may contribute to secondary brain injury caused by activation of excitotoxic cascades such as extracellular glutamate and neural lipid peroxidation, leading to cell death [28,29]. Peberdy et al [7] and Sunde
et al [30] reported that CA patients' seizures should be controlled promptly because prolonged, untreated seizures were detrimental to the brain. Therefore, we should treat postanoxic seizures promptly by appropriate methods to obtain good neurologic outcomes and to decrease the occurrence of pneumonia in TH patients. In our outcome analysis, pneumonia was associated with poor neurologic outcome in univariate analysis. However, after adjustment for potential confounding factors, there was no significant association. Survival analysis revealed no significant difference according to the development of pneumonia. We therefore suggest that the development of pneumonia did not influence survival and neurologic outcome. Some limitations of our study should be acknowledged. First, this is a retrospective, single-center study with a small study population. Second, because there is debate in clinical and microbiological diagnosis of pneumonia, we chose to adhere to recently used definitions [6]. In a previous study, a somewhat loose definition revealed the highest incidence of early-onset pneumonia. In our study, just 5 in 59 patients were diagnosed with pneumonia despite negative culture of distal pulmonary samples. Third, because continuous EEG was not checked, nonconvulsive seizure could not be included, and incidence of postanoxic seizure might be underestimated in this study. Fourth, we could not evaluate individual therapies that could influence the development of pneumonia such as semirecumbent positioning, oral care, and interval of change for ventilator units and so on. 5. Conclusions Pneumonia is a frequent infection in survivors of OHCA receiving TH during the first 7 days of admission. As it is known, prolonged duration of MV is independently associated with the development of pneumonia, and notably, postanoxic seizure is also an independent risk factor of the development of pneumonia in survivors of OHCA receiving TH during the first 7 days of admission. Although further study for mechanisms of how postanoxic seizure influences pneumonia is needed, it may be helpful that we give more attention to the development of pneumonia in patients with postanoxic seizure as well as provide prompt diagnosis and treatment of postanoxic seizure. References [1] Gajic O, Festic E, Afessa B. Infectious complications in survivors of cardiac arrest admitted to the medical intensive care unit. Resuscitation 2004;60:65–9. [2] Soppi E, Lindroos M, Nikoskelainen J, et al. Effect of cardiopulmonary resuscitation-induced stress on cell-mediated immunity. Intensive Care Med 1984;10: 287–92. [3] Cerchiari EL, Safar P, Klein E, et al. Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral postresuscitation syndrome. Resuscitation 1993;25:119–36. [4] Gaussorgues P, Gueugniaud PY, Vedrinne JM, et al. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 1988;14:575–7. [5] Mongardon N, Perbet S, Lemiale V, et al. Infectious complications in out-ofhospital cardiac arrest patients in the therapeutic hypothermia era. Crit Care Med 2011;39:1359–64. [6] 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;184:1048–54. [7] Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–86. [8] Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence. Intensive Care Med 2004;30:556–75. [9] Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an independent outcome predictor after cerebral anoxia. Neurology 2007;69:255–60. [10] Rossetti AO, Oddo M, Liaudet L, et al. Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia. Neurology 2009;72:744–9. [11] Ibrahim EH, Tracy L, Hill C, et al. The occurrence of ventilator-associated pneumonia in a community hospital: Risk factors and clinical outcomes. Chest 2001;120:555–61. [12] Joseph NM, Sistla S, Dutta TK, et al. Ventilator-associated pneumonia: a review. Eur J Intern Med 2010;21:360–8.
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155 [13] The ATS. Board of Directors and the IDSA Guideline Committee: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [14] Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–34. [15] Sagalyn E, Band RA, Gaieski DF, et al. Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences. Crit Care Med 2009;37:S223–6. [16] Nielsen N, Sunde K, Hovdenes J, et al. Hypothermia network. Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Crit Care Med 2011;39:57–64. [17] Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998;39:61–6. [18] Rello J, Diaz E, Roque M, et al. Risk factors for developing pneumonia within 48 hours of intubation. Am J Respir Crit Care Med 1999;159:1742–6. [19] Marrie TJ. Pneumococcal pneumonia: epidemiology and clinical features. Semin Respir Crit Care Med 1999;14:227–36. [20] DeToledo JC, Lowe MR, Gonzalez J, et al. Risk of aspiration pneumonia after an epileptic seizure: a retrospective analysis of 1634 adult patients. Epilepsy Behav 2004;5:593–5. [21] Forsgren L, Hauser WA, Olafsson E, et al. Mortality of epilepsy in developed countries: a review. Epilepsia 2005;46(Suppl 11):18–27.
155
[22] Young PJ, Rollinson M, Downward G, et al. Leakage of fluid past the tracheal tube cuff in a benchtop model. Br J Anaesth 1997;78:557–62. [23] Neligan A, Bell GS, Johnson AL, et al. The long-term risk of premature mortality in people with epilepsy. Brain 2011;134:388–95. [24] Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994;35:239–43. [25] Snyder BD, Hauser WA, Loewenson RB, et al. Neurologic prognosis after cardiopulmonary arrest: III. Seizure activity. Neurology 1980;30:1292. [26] Zandbergen EG, Hijdra A, Koelman JH, et al. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66:62–8. [27] Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–10. [28] van Landingham KE, Lothman EW. Self-sustaining limbic status epilepticus. I. Acute and chronic cerebral metabolic studies: limbic hypermetabolism and cortical hypometabolism. Neurology 1991;41:1942–9. [29] Vespa P, Martin NA, Nenov V, et al. Delayed increase in extracellular glycerol with post-traumatic electrographic seizure activity: support for the theory that seizures induce secondary injury. Acta Neurochir Suppl 2002;81: 355–7. [30] Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardized treatment protocol for post resuscitation care after out of hospital cardiac arrest. Resuscitation 2007;73:29–39.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Factors associated with pneumonia in post–cardiac arrest patients receiving therapeutic hypothermia☆ Jae-Hyug Woo, MD, Yong Su Lim, MD, PhD ⁎, Hyuk Jun Yang, MD, PhD, Won Bin Park, MD, Jin Seong Cho, MD, PhD, Jin Joo Kim, MD, PhD, Sung Youl Hyun, MD, PhD, Gun Lee, MD, PhD Department of Emergency Medicine, Gachon University Gil Medical Center, 1198, Guwol-dong, Namdong-gu, Incheon, 405-760, South Korea
a r t i c l e
i n f o
Article history: Received 26 August 2013 Received in revised form 11 October 2013 Accepted 14 October 2013
a b s t r a c t Aim: The aim of this study is to investigate risk factors associated with the development of pneumonia during the first 7 days of admission in survivors of cardiac arrest receiving therapeutic hypothermia. Methods: A total of 123 patients receiving therapeutic hypothermia after out-of-hospital cardiac arrest between January 2008 and December 2010 were enrolled. Study populations were categorized as “pneumonia present” [P (+)] and “pneumonia absent” [P (−)] contingent upon the development of pneumonia during the first 7 days of admission. Risk factors and outcomes related to development of pneumonia were determined. Results: Fifty-nine patients (48.0 %) developed pneumonia, and P (+) patients had lower Acute Physiology and Chronic Health Evaluation II score (22 vs 26); longer durations of central venous catheter (8.9 vs 5.1 days), nasogastric tube (11.1 vs 3.8 days), mechanical ventilation (MV) (9.3 vs 3.7 days), and intensive care unit stay (10.0 vs 5.0 days); and higher rates of nasogastric feeding (66.1% vs 35.9 %), tracheostomy (52.5% vs 17.2 %), and postanoxic seizure (62.7% vs 39.1 %). In multivariate analyses, the occurrence of postanoxic seizure (odds ratio, 2.75; 95% confidence interval, 1.06-7.14; P = .04) and the length of MV (odds ratio, 1.33; 95% confidence interval, 1.15-1.52; P b .001) were independently associated with the development of pneumonia. The development of pneumonia had no significant association with survival (log-rank test, P = .15). Conclusion: Postanoxic seizure and prolonged duration of MV are independently associated with development of pneumonia. It may be helpful that we give more attention to the development of pneumonia in patients with postanoxic seizure and provide prompt diagnosis and treatment of postanoxic seizure. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Out-of-hospital cardiac arrest (OHCA) survivors frequently have infectious complications. Some authors propose a hypothesis that it is because resuscitation is an extreme stress with a profound decrease of cell-mediated immunity and gastrointestinal ischemia-reperfusion injury in the setting of circulatory arrest may lead to bacterial translocation from the digestive tract into the bloodstream [1-4]. Among the complications, pneumonia is the most common infection [1]. Emergency airway and vascular access, unprotected airway, pulmonary contusion during cardiopulmonary resuscitation (CPR), decreased mental status, and prolonged invasive mechanical ventilation (MV) may increase the risk for pulmonary infection in OHCA survivors [1,5,6]. Recently, comprehensive post–cardiac arrest (CA) care and the implementation of therapeutic hypothermia (TH) as a proven standard therapy have reduced brain injury and improved neurologic
outcome in comatose survivors of OHCA [7]. However, prolonged hypothermia is known to decrease immune function by inhibiting the release of proinflammatory cytokines and by suppressing the chemotactic migration of leukocytes and phagocytosis [7,8]. Moreover, some studies have reported that the implementation of TH is associated with an increased incidence and risk of infection, with pneumonia being most common, especially early-onset pneumonia [5,6]. Although TH may increase the incidence of several complications including pneumonia, TH is standard care to reduce ischemic brain injury in OHCA survivors and has been used widely. Thus, this study is designed to investigate risk factors that are associated with the development of pneumonia during the first 7 days of admission in comatose survivors of OHCA patients receiving TH. 2. Methods 2.1. Study population
☆ Conflicts of interest: No conflict of interest. ⁎ Corresponding author. Tel.: +82 32 460 3015; fax: +82 32 460 3019. E-mail address: [email protected] (Y.S. Lim). 0735-6757/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajem.2013.10.035
The setting of the study was a university hospital emergency department (ED) located in Incheon City, South Korea, with an annual
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
patient volume of approximately 90 000. We conducted a singlecenter and retrospective cohort study between January 2008 and December 2010. This study was approved by the institutional review board of our hospital. The study population consisted of patients 18 years or older who were successfully resuscitated after nontraumatic OHCA and then treated with TH. Patients who died within the first 24 hours and with known pneumonia or other infection before CA were excluded from the analysis. Data were obtained from a prospective registry database including all patients treated in the ED after CA and medical records at our hospital and other hospitals. The collected baseline characteristic variables of patients were sex, age, location of CA, performance of bystander CPR, interval from collapse to basic life support (BLS), interval from collapse to advanced cardiovascular life support (ACLS), interval from BLS to ACLS, interval from collapse to return of spontaneous circulation (ROSC), initial cardiac rhythm, presumed etiology of CA, total dose of epinephrine, number of vasopressors for 48 hours, number of defibrillation events, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, initial lactate in ED, and factors associated with TH (target body temperature [BT], cooling method, initial BT on TH start, interval from TH start to target BT, and hypotension during induction of TH). 2.2. Therapeutic hypothermia
151
colony-forming unit/mL and 10 3 colony-forming unit /mL, respectively). Body temperature and white blood cell count were not considered, as they are affected by hypothermia. Despite a negative quantitative culture, the diagnosis was retained when the previous signs were present with associated purulent endotracheal aspirates and hypoxemia (PaO2/fraction of inspired oxygen b240) not explained by pulmonary edema, pulmonary embolism, or atelectasis [6]. All data were retrospectively reviewed by 2 investigators to diagnose pneumonia that developed during the first 7 days of admission. Each case of disagreement between prospective diagnosis and retrospective assessment was resolved by consensus between the investigators, with the help of a third expert if necessary. We divided the study population into 2 groups, “pneumonia present” [P (+)] and “pneumonia absent” [P (−)], contingent upon the development of pneumonia during the first 7 days of admission. We then compared risk factors associated with the development of pneumonia during the first 7 days of admission and outcome between the 2 groups. We collected the risk factors associated with pneumonia as reported in previous studies and other alleged factors [1,5-7,11-13]. The collected variables were number and duration of central venous catheter (CVC) placements, factors related to nasogastric tube (NG tube), nasogastric feeding, reintubation, tracheostomy, length of MV, length of ICU stay, duration of sedation, blood glucose levels, immunosuppression, age, APACHE II score on ICU admission, and postanoxic seizure. Factors related to CA, CPR, and TH were compared between the 2 groups.
If patients were unconscious with Glasgow Coma Scale less than 9 after ROSC, they were treated with TH, admitted to the intensive care unit (ICU), and treated with standard intensive care including invasive monitoring, hemodynamic support, MV, and analgesia sedation. The exclusion criteria of TH were shock despite the use of vasopressors (systolic blood pressure b 90 mm Hg), active bleeding, trauma, or possible causes of coma other than CA (head trauma or cerebrovascular accident). Therapeutic hypothermia was performed by surface (exovascular) or internal (endovascular) cooling techniques as soon as possible after ROSC. The surface cooling technique was performed by the application of a water-circulating hydrogel pad (Arctic Sun; Medivance, Inc, Louisville, CO), and the internal cooling technique was performed by insertion of an intravascular cooling catheter (CoolLine; Alsius Corporation, Irvine, CA) connected to a cooling device (CoolGard 3000; Alsius Corporation) into the right internal jugular vein. The core temperature was measured by rectal probe. The target temperature was 32°C to 34°C, and the duration of maintenance was 24 hours. The rewarming rate was 0.3°C per hour with the same device. Exovascular and endovascular techniques were alternately selected. Continuous midazolam and fentanyl were given for sedation analgesia, and vecuronium was administered to control shivering. Daily neurologic assessments including motor and brain stem reflex were performed. Portable electroencephalography (EEG) was checked within 7 days after admission at least once, and EEG were interpreted by certified electroencephalographers, at bedside and post hoc, with bipolar and monopolar montages. Postanoxic seizure was diagnosed in the presence of clinical, electrographic, or electroclinical abnormalities suggestive of postanoxic seizure [9,10].
Data were analyzed using SPSS (SPSS version 17.0; SPSS, Inc, Chicago, IL). Continuous data are presented as the median and interquartile range or mean and SD as appropriate. Univariate analysis was performed by using the Mann-Whitney U test or the Student t test for continuous variables or the χ 2 test for categorical variables. All variables found to be significant by univariate analysis (with selected P b .10 in the factor analysis), then underwent multivariate logistic regression analysis by the backward stepwise method. Survival curves were determined by the Kaplan-Meier method, and the log-rank test was used to compare curves. All statistical tests were 2 sided, and P b .05 was considered statistically significant.
2.3. Pneumonia analysis
3. Results
According to commonly used criteria, a diagnosis of pneumonia was retained in the presence of clinically compatible findings at auscultation and a new or progressive pulmonary infiltrate on chest x-ray (persistent for at least 48 hours) associated with a positive quantitative culture of distal pulmonary secretion samples. The specimens were obtained from endotracheal aspirates or with a blind protective specimen catheter (significant thresholds: 10 6
3.1. Baseline characteristics of study populations
2.4. Assessment of neurologic outcome At 1 month after the CA, we assessed the clinical neurologic outcome of patients using Cerebral Performance Category (CPC). The performance categories were defined as follows: CPC1, “conscious and alert with normal neurologic function or only slight cerebral disability”; CPC2, “conscious with moderate cerebral disability for part-time work in sheltered environment or independent existence”; CPC3, “conscious with severe cerebral disability precluding independent existence”; CPC4, “comatose or in a persistent vegetative state”; and CPC5, “brain dead or death.” The patients were then classified into 2 groups based on neurologic outcomes: the “good neurologic outcome” group (CPC1 and CPC2) and the “poor neurologic outcome” group (CPC3-CPC5). 2.5. Statistical analysis
During the study period, 175 patients were admitted to ICU. Of these 175 patients, 133 patients received TH. Two patients who died within the first 24 hours and 8 patients who already had pneumonia before CA were excluded. Consequently, the remaining 123 patients were enrolled in this study (Fig. 1). Of these patients, 59 patients
152
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
133 patients treated with therapeutic hypothermia
Exclusion; 2 deaths within the first 24h of admission 8 proved pneumonia prior to OHCA
123 enrolled patients
59 with pneumonia; 8 within the first 2 days after admission 32 within 3~4 days after admission 19 within 5~7 days after admission
64 without pneumonia
Fig. 1. Flow chart of patient enrollment and exclusion.
(48.0%) developed pneumonia [P (+)] during the first 7 days of admission. Pneumonia developed in 32 patients (54%) within 3 to 4 days after admission, in 8 patients (14%) in the first 2 days after admission, and in 19 patients (32%) within 5 to 7 days after admission. Baseline characteristics of P (+) and P (−) patients are summarized in Table 1. P (+) and P (−) patient groups had a median age of 50.0 (37.0-61.5) and 51.5 (44.5-62.0) years, and 34 (57.6%) and 47 (73.4%) were men, respectively. Higher APACHE II score in P (−) patients was the only significant difference (26.0 vs 22.0; P = .04). No other variables associated with CA, CPR, and TH had a significant difference between the 2 groups. 3.2. Microbiologic findings Among the 59 patients with pneumonia, 54 cases (91.5%) had microbiological confirmation by specimen cultures. The organisms isolated were methicillin-sensitive Staphylococcus aureus (15 cases, 27.8%), methicillin-resistant S aureus (12 cases, 22.2%), Klebsiella pneumoniae (10 cases, 18.5%), Pseudomonas aeruginosa (7 cases, 13.0%), Acinetobacter baumannii (3 cases, 5.6%), Haemophilus influenzae (2 cases, 3.7%), Serratia marcescens (2 cases, 3.7%), Streptococcus species (1 case, 1.9%), Escherichia coli (1 case, 1.9%), and Burkholderia cepacia (1 case, 1.9%). 3.3. Univariate analysis of factors associated with pneumonia Factors potentially associated with pneumonia in the univariate analysis are shown in Table 2. Between the 2 groups, the numbers of CVC were not different, but the P (+) group had a longer duration of the CVC (8.9 vs 5.1 days, P b .001). Most patients had an NG tube for drainage, but more patients were fed via NG tube (39 [66.1%] vs 23 [35.9%]; P = .001) in the P (+) group and they had the NG tube for longer periods (11.1 vs 3.8 days; P b .001). The time intervals associated with NG tube insertion and feeding were not significantly different.
The P (+) group received tracheostomy more frequently (31 [52.5%] vs 11 [17.2%]; P b .001) and had longer duration of MV (9.3 vs 3.7 days; P b .001) and ICU stay (10.0 vs 5.0 days; P b .001).
Table 1 Baseline characteristics of study population (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
Sex (male), n (%) Age (y) Location of arrest (residence), n (%) Bystander CPR, n (%) Interval from collapse to BLS (min) Interval from collapse to ACLS (min) Interval from BLS to ACLS (min) Interval from collapse to ROSC (min) Initial cardiac rhythm, n (%) VF/VT Non-VF/VT Asystole PEA Cardiac cause of arrest, n (%) Total dose of epinephrine (mg) No. of vasopressors for 48 h, n (%) No. of defibrillation, n (%) APACHE II score SOFA score Initial lactate in ED (mmol/L) Target BT, n (%) 32°C 33°C 34°C Cooling method (internal), n (%) Initial BT on TH start(°C) Interval from TH start to target BT (h) Hypotension during induction of TH, n (%)
47 51.5 28 10 7.0 16.0 9.0 35.0
34 50.0 30 6 6.0 17.0 10.0 31.0
(73.4) (44.5-62.0) (43.8) (15.6) (2.5-10.0) (10.0-25.0) (0.5-13.5) (18.5-48.5)
22 (34.4)
(57.6) (37.0-61.5) (50.8) (10.2) (4.0-9.0) (12.0-22.0) (4.0-14.5) (21.0-44.5)
P .09 .28 .47 .43 .65 .97 .38 .84 .51
17 (28.8)
37 5 39 3.0 2.0 1.0 26.0 10.0 8.7
(57.8) 28 (47.5) (7.8) 14 (23.7) (60.9) 35 (59.3) 1.00 (1.0-6.5) 3.0 (2.0-6.5) .69 (1.0-3.0) 2.0 (1.0-3.0) .86 (0.0-4.0) 1.0 (0.0-3.0) .80 (21.0-30.0) 22.0 (20.0-26.5) .04 (7.5-12.0) 9.0 (7.0-11.0) .08 (6.1-12.9) 8.7 (6.7-11.1) .91
8 50 6 34 36.1 1.8 37
(12.5) 6 (9.4) (78.1) 43 (72.9) (10.2) 10 (16.9) (53.1) 36 (61.0) (35.0-36.6) 36.0 (34.7-36.7) (1.0-4.0) 2.3 (1.2-4.6) (57.8) 31 (52.5)
.45 .47 .70 .35 .59
Values are expressed as number (percentage) and median (interquartile range), as appropriate. Abbreviations: VF/VT, ventricular fibrillation/pulseless ventricular tachycardia; PEA, pulseless electrical activity.
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
153
Table 2 Comparison of risk factors related to pneumonia (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
No. of CVC, n (%) 1 37 (57.8) 35 (59.3) 2 27 (42.2) 24 (40.7) Duration of CVC (d) 5.1 (2.9-8.9) 8.9 (6.0-14.4) Insertion of NG tube, n (%) 62 (96.9) 58 (98.3) Nasogastric feeding, n (%) 23 (35.9) 39 (66.1) Duration of NG tube (d) 3.8 (2.3-9.0) 11.1 (6.1-24.8) Interval from collapse to NG 3.2 (1.4-5.4) 3.4 (1.4-8.9) tube insertion (hour) Interval from collapse to 5.0 (3.8-6.4) 5.8 (4.1-7.3) nasogastric feeding (d) Reintubation, n (%) 3 (4.7) 8 (13.6) Tracheostomy, n (%) 11 (17.2) 31 (52.5) Length of MV (d) 3.7 (2.3-6.9) 9.3 (6.3-14.0) Length of ICU stay (d) 5.0 (3.1-9.4) 10.0 (6.8-17.7) Duration of sedation (d) 1.5 (1.4-1.7) 1.6 (1.5-1.7) Blood glucose level (mg/dL) At 0 h 208.0 (155.0-290.0) 236.0 (181.0-302.5) At 12 h 171.0 (130.5-224.5) 195.0 (144.5-269.5) At 24 h 146.0 (108.0-207.5) 162.0 (130.0-221.0) Immunosuppression, n (%) 3 (4.7) 0 (0.0) Postanoxic seizure, n (%) 25 (39.1) 37 (62.7)
P 1.00
b.001 1.00 .001 b.001 .60 .18 .12 b.001 b.001 b.001 .34 .15 .09 .13 .25 .01
Values are expressed as number (percentage) and median (interquartile range), as appropriate.
In the P (+) group, more patients had postanoxic seizure (37 [62.7%] vs 25 [39.1%]; P = .01). Reintubation; blood glucose level at 0, 12, and 24 hours after ROSC; and immunosuppression were not significantly different between the 2 groups. 3.4. Outcomes of TH patients Death at 1 month and discharge were not statistically different between the 2 groups (Table 3). However, the P (+) group had more patients with bad CPC at 1 month than the P (−) group (48 [81.4%] vs 41 [64.1%]; P = .03). Kaplan-Meier survival analysis after 30 days revealed no significant difference between the 2 groups (log-rank test, P = .15) (Fig. 2). 3.5. Multivariate logistic regression analyses The variables found to be significant by univariate analysis (with selected P b .10 in the factor analysis) were sex, age, APACHE II, SOFA, the duration of CVC, nasogastric feeding, duration of NG tube, tracheostomy, length of MV, length of ICU stay, blood glucose level at 12 hours after ROSC, the occurrence of postanoxic seizure, survival time (max 90 days), and bad CPC at 1 month. The multivariate logistic regressions analyses by development of pneumonia are shown in Table 4. In multivariate analyses, the occurrence of postanoxic seizure (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.06-7.14; P = .04) and the length of MV (OR, 1.33; 95% CI, 1.15-1.52; P b .001) were significantly related to the development of pneumonia.
Fig. 2. Kaplan-Meier survival analysis of both groups. The dashed line, pneumonia (−) group; the solid line, pneumonia (+) group. A 30-day period was analyzed in follow-up time. The difference between the 2 groups was not significant (log-rank test, P = .15).
4. Discussion In this study, pneumonia was a frequent complication in OHCA patients receiving TH. Notably, postanoxic seizure was a risk factor for pneumonia in TH patients as was the length of MV. However, the development of pneumonia within 7 days after ROSC did not influence mortality. In previous studies, pneumonia was a frequent complication in TH patients with a prevalence of 29% to 70%; the most common pathogen was S aureus [5,6,14-16]. Similarly, 48% of patients in our study had pneumonia, and S aureus (27 cases) was the most frequently isolated organism of pneumonia. Therapeutic hypothermia had been suspected of increasing the risk of infectious pulmonary complications [5,17]. A clinical study by Perbet et al [6] demonstrated that TH was an independent risk factor for early onset pneumonia. Thus, the factors associated with TH were suspicious. However, in our study, there was no relationship between the development of pneumonia and factors associated with TH (target BT, cooling method, initial BT on TH start, interval from TH start to target BT, hypotension during induction of TH). Further studies are needed to determine whether TH influences the development of pneumonia alone or whether other factors related to TH influence the development of pneumonia. In a previous study, the independent risk factors for ventilatorassociated pneumonia by multivariate analysis were tracheostomy, multiple CVC insertions, reintubation, length of ICU stay, enteral feeding, and length of MV [12]. Similarly, prolonged duration of CVC,
Table 4 Multivariate analysis of factors related to the development of pneumonia Variables
Table 3 Comparison of outcome according to the development of pneumonia (N = 123) Variables
Pneumonia (−) (n = 64)
Pneumonia (+) (n = 59)
P
Death at 1 mo, n (%) Death at discharge, n (%) Survival time (max. 90 d) Bad CPC at 1 mo, n (%) Bad CPC at discharge, n (%)
29 27 90.0 41 41
21 (35.6) 21 (35.6) 90.0 (13.5-90.0) 48 (81.4) 45 (76.3)
.27 .45 .07 .03 .14
(45.3) (42.2) (6.0-90.0) (64.1) (64.1)
Values are expressed as number (percentage) and median (interquartile range), as appropriate.
Sex (female) Nasogastric feeding (yes) Blood glucose level at 12 h (mg/dL) APACHE II Postanoxic seizure (yes) Length of MV (d)
OR
1.74 0.54 1.00 0.93 2.75 1.33
95% CI for OR Lower
Upper
0.67 0.18 1.00 0.85 1.06 1.15
4.59 1.63 1.00 1.02 7.14 1.52
P
.26 .28 .27 .11 .04 b.001
Odds ratios were calculated using a backward stepwise logistic regression analysis. Variables included in analysis were sex, age, APACHE II, SOFA, duration of central venous catheter, nasogastric feeding, duration of NG tube, tracheostomy, length of MV, length of ICU stay, blood glucose level at 12 hour after ROSC, occurrence of postanoxic seizure, survival time, and bad CPC at 1 month.
154
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155
MV, ICU stay and NG tube, nasogastric feeding, and tracheostomy were associated with the development of pneumonia in our univariate analysis. However, in multivariate logistic regression analyses, only the prolonged duration of MV increased the risk of pneumonia in TH patients. However, longer duration of NG tube and more nasogastric feeding in the P (+) group are problematic. In this study, they did not increase the risk of pneumonia in multivariate logistic regression analyses, but they were certainly related to pneumonia in univariate analysis. In previous studies, a semirecumbent position during feeding for intubated patients and continuous aspiration of subglottic secretions through the use of a specially designed endotracheal tube reduced the incidence of early onset ventilator-associated pneumonia [13]. Furthermore, early enteral feeding (day 1 of intubation) was associated with a higher risk for pneumonia than late enteral feeding (day 5 of intubation), whereas postpyloric feeding was associated with a significant reduction in ventilator-associated pneumonia. These methods may help to decrease aspiration of gastric contents and development of pneumonia during NG tube maintenance and nasogastric feeding. Immunosuppression, reintubation, and continuous sedation were predicted risk factors of pneumonia. However, because the populations of immunosuppression and reintubation were so small, they might not influence the occurrence of pneumonia. A study by Rello et al [18] demonstrated that continuous sedation increased the risk of pneumonia 4-fold. In our study, because sedation continued similarly for all of patients until the hypothermia was stopped, there is no additional information gained as to whether sedation influences the development of pneumonia. Surprisingly, in our study, postanoxic seizure was an independent risk factor for pneumonia in TH patients. Furthermore, the occurrence of pneumonia increased more than 2-fold when postanoxic seizure developed. In previous studies, patients with seizure or chronic epilepsy had increased risk for pneumonia, and pneumonia due to seizure increased the mortality [19-21]. The authors presumed that aspiration during seizure triggered the occurrence of pneumonia. Increased oral secretions, impaired swallowing mechanisms, and difficulty in attaining adequate patient positioning during seizure significantly increased the risk of aspiration, and despite intubation, it was difficult to completely prevent secretions from invading the airway through the space around the cuff of the endotracheal tube [20,22]. For these reasons, postanoxic seizure in TH patients might also contribute to the development of pneumonia in spite of intubation. The occurrence of postanoxic seizure may cause poor recovery of consciousness and increase the use of sedative and antiepileptic drugs, consequently prolonging the length of MV and ICU stay, which may also contribute to the development of pneumonia. In this study, patients with postanoxic seizure had a longer duration of MV (7.1 vs 5.2; P = .02) and ICU stay (7.9 vs 6.5; P = .06) than patients without seizure. On the other hand, it may be that changes in the immune system or defense mechanisms during postanoxic seizure trigger the occurrence of pneumonia in TH patients. In other studies, chronic epilepsy may lead to relative suppression of the immune system with a subsequent increased risk of infections such as pneumonia [23]. However, there is still no evidence that a 1-time seizure event or continuous seizures during a short period leads to lower the immunity. Further study for immunologic changes during postanoxic seizure in TH patients is needed. Postanoxic seizure occurs in 18% to 45% of post-CA survivors and has been considered a strong predictor of poor outcome, especially if occurring early after CA [9,10,16,24-27]. Prolonged seizures may contribute to secondary brain injury caused by activation of excitotoxic cascades such as extracellular glutamate and neural lipid peroxidation, leading to cell death [28,29]. Peberdy et al [7] and Sunde
et al [30] reported that CA patients' seizures should be controlled promptly because prolonged, untreated seizures were detrimental to the brain. Therefore, we should treat postanoxic seizures promptly by appropriate methods to obtain good neurologic outcomes and to decrease the occurrence of pneumonia in TH patients. In our outcome analysis, pneumonia was associated with poor neurologic outcome in univariate analysis. However, after adjustment for potential confounding factors, there was no significant association. Survival analysis revealed no significant difference according to the development of pneumonia. We therefore suggest that the development of pneumonia did not influence survival and neurologic outcome. Some limitations of our study should be acknowledged. First, this is a retrospective, single-center study with a small study population. Second, because there is debate in clinical and microbiological diagnosis of pneumonia, we chose to adhere to recently used definitions [6]. In a previous study, a somewhat loose definition revealed the highest incidence of early-onset pneumonia. In our study, just 5 in 59 patients were diagnosed with pneumonia despite negative culture of distal pulmonary samples. Third, because continuous EEG was not checked, nonconvulsive seizure could not be included, and incidence of postanoxic seizure might be underestimated in this study. Fourth, we could not evaluate individual therapies that could influence the development of pneumonia such as semirecumbent positioning, oral care, and interval of change for ventilator units and so on. 5. Conclusions Pneumonia is a frequent infection in survivors of OHCA receiving TH during the first 7 days of admission. As it is known, prolonged duration of MV is independently associated with the development of pneumonia, and notably, postanoxic seizure is also an independent risk factor of the development of pneumonia in survivors of OHCA receiving TH during the first 7 days of admission. Although further study for mechanisms of how postanoxic seizure influences pneumonia is needed, it may be helpful that we give more attention to the development of pneumonia in patients with postanoxic seizure as well as provide prompt diagnosis and treatment of postanoxic seizure. References [1] Gajic O, Festic E, Afessa B. Infectious complications in survivors of cardiac arrest admitted to the medical intensive care unit. Resuscitation 2004;60:65–9. [2] Soppi E, Lindroos M, Nikoskelainen J, et al. Effect of cardiopulmonary resuscitation-induced stress on cell-mediated immunity. Intensive Care Med 1984;10: 287–92. [3] Cerchiari EL, Safar P, Klein E, et al. Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral postresuscitation syndrome. Resuscitation 1993;25:119–36. [4] Gaussorgues P, Gueugniaud PY, Vedrinne JM, et al. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med 1988;14:575–7. [5] Mongardon N, Perbet S, Lemiale V, et al. Infectious complications in out-ofhospital cardiac arrest patients in the therapeutic hypothermia era. Crit Care Med 2011;39:1359–64. [6] 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;184:1048–54. [7] Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–86. [8] Polderman KH. Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: indications and evidence. Intensive Care Med 2004;30:556–75. [9] Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an independent outcome predictor after cerebral anoxia. Neurology 2007;69:255–60. [10] Rossetti AO, Oddo M, Liaudet L, et al. Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia. Neurology 2009;72:744–9. [11] Ibrahim EH, Tracy L, Hill C, et al. The occurrence of ventilator-associated pneumonia in a community hospital: Risk factors and clinical outcomes. Chest 2001;120:555–61. [12] Joseph NM, Sistla S, Dutta TK, et al. Ventilator-associated pneumonia: a review. Eur J Intern Med 2010;21:360–8.
J-H. Woo et al. / American Journal of Emergency Medicine 32 (2014) 150–155 [13] The ATS. Board of Directors and the IDSA Guideline Committee: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [14] Nielsen N, Hovdenes J, Nilsson F, et al. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–34. [15] Sagalyn E, Band RA, Gaieski DF, et al. Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences. Crit Care Med 2009;37:S223–6. [16] Nielsen N, Sunde K, Hovdenes J, et al. Hypothermia network. Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Crit Care Med 2011;39:57–64. [17] Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998;39:61–6. [18] Rello J, Diaz E, Roque M, et al. Risk factors for developing pneumonia within 48 hours of intubation. Am J Respir Crit Care Med 1999;159:1742–6. [19] Marrie TJ. Pneumococcal pneumonia: epidemiology and clinical features. Semin Respir Crit Care Med 1999;14:227–36. [20] DeToledo JC, Lowe MR, Gonzalez J, et al. Risk of aspiration pneumonia after an epileptic seizure: a retrospective analysis of 1634 adult patients. Epilepsy Behav 2004;5:593–5. [21] Forsgren L, Hauser WA, Olafsson E, et al. Mortality of epilepsy in developed countries: a review. Epilepsia 2005;46(Suppl 11):18–27.
155
[22] Young PJ, Rollinson M, Downward G, et al. Leakage of fluid past the tracheal tube cuff in a benchtop model. Br J Anaesth 1997;78:557–62. [23] Neligan A, Bell GS, Johnson AL, et al. The long-term risk of premature mortality in people with epilepsy. Brain 2011;134:388–95. [24] Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994;35:239–43. [25] Snyder BD, Hauser WA, Loewenson RB, et al. Neurologic prognosis after cardiopulmonary arrest: III. Seizure activity. Neurology 1980;30:1292. [26] Zandbergen EG, Hijdra A, Koelman JH, et al. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66:62–8. [27] Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–10. [28] van Landingham KE, Lothman EW. Self-sustaining limbic status epilepticus. I. Acute and chronic cerebral metabolic studies: limbic hypermetabolism and cortical hypometabolism. Neurology 1991;41:1942–9. [29] Vespa P, Martin NA, Nenov V, et al. Delayed increase in extracellular glycerol with post-traumatic electrographic seizure activity: support for the theory that seizures induce secondary injury. Acta Neurochir Suppl 2002;81: 355–7. [30] Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardized treatment protocol for post resuscitation care after out of hospital cardiac arrest. Resuscitation 2007;73:29–39.
