From Emergency Department to Intensive Care Unit - ScienceDirect.com

ORIGINAL ARTICLE

Management of Severe Community-acquired Septic Meningitis in Adults: From Emergency Department to Intensive Care Unit Chia-Lin Hsu,1 Chia-Hsuin Chang,1 King-Nang Wong,2 Kuan-Yu Chen,1* Chong-Jen Yu,1 Pan-Chyr Yang1 Background/Purpose: To study the clinical features, diagnostic processes, timing of antibiotic administration and outcomes of patients with severe community-acquired septic meningitis at an emergency department (ED), who required intensive care unit (ICU) admission. Methods: From January 1993 to December 2005, the medical records of patients admitted to the ICU with a diagnosis of community-acquired septic meningitis were reviewed. The clinical characteristics, including causative pathogens, treatment course, and outcomes were collected and analyzed. Results: A total of 40 patients were included, with an overall inhospital mortality rate of 77.5%. The most common pathogen was Klebsiella pneumoniae (n = 20, 50%), followed by Streptococcus pneumoniae (n = 6, 15%), and Cryptococcus neoformans (n = 5, 12.5%). There was a mean duration of 8.9 hours between ED arrival and initiation of antibiotic therapy. Effective antibiotics were administered for a mean period of 23.8 hours after arrival. Time delay from ED arrival to ICU admission was correlated with time delay of effective antibiotics administration, head computed tomography, and cerebrospinal fluid study (r = 0.32, 0.47, and 0.53, respectively; p = 0.05, 0.006, and 0.001, respectively). Earlier ICU admission was demonstrated in survivors as compared with those who died (11.1 vs. 38.0 hours, p = 0.01). Conclusion: Severe septic meningitis remains a disease with high mortality and morbidity. Expeditious diagnostic processes with early appropriate antibiotic treatment and ICU admission at the ED are important in improving the quality of care and patient outcome. [J Formos Med Assoc 2009;108(2):112–118] Key Words: emergency department, intensive care unit, meningitis

delayed antibiotic therapy increase the risk of unfavorable outcomes.4–6 Streptococcus pneumoniae has been reported as the most common causative pathogen.3,5,7 Aside from bacteria, Cryptococcus neoformans is not a rare pathogen in community-acquired septic meningitis.8–10 The mortality rate of cryptococcal meningitis in patients without AIDS is about 16–31%, while these patients may have similar clinical

Community-acquired septic meningitis is one of the most severe infectious diseases, with high morbidity and mortality.1 Despite advances in diagnostic techniques and antibiotic treatment, community-acquired bacterial meningitis still results in a high mortality, ranging from 17% to 28%.2–5 Various factors, including age, systemic comorbidity, altered mental status, seizure, causative pathogens, no use of corticosteroids, and

©2009 Elsevier & Formosan Medical Association .

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Department of Internal Medicine, National Taiwan University Hospital, Taipei, and 2Department of Internal Medicine, Da-Chen General Hospital, Miaoli, Taiwan. Received: May 23, 2008 Revised: July 21, 2008 Accepted: August 5, 2008

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*Correspondence to: Dr Kuan-Yu Chen, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]

J Formos Med Assoc | 2009 • Vol 108 • No 2

Severe meningitis: from ED to ICU

presentations as bacterial meningitis.10–12 High titers of cryptococcal antigen and low consciousness levels are related to poor outcomes.10,12 The role of quick diagnosis and early antibiotic use for community-acquired septic meningitis, which may influence the outcome, has drawn more attention recently.4,12–14 However, there is a paucity of data about the timing of antibiotic administration, diagnostic processes, and outcomes of patients with community-acquired septic meningitis in the emergency department (ED) who require admission to the intensive care unit (ICU). The present study investigated the timing of diagnostic and therapeutic processes from the ED to ICU admission. Clinical characteristics and causative pathogens of these patients were also analyzed.

Methods This was a retrospective, single-center, cohort study from January 1993 to December 2005. The study site was an 1800-bed tertiary medical center with a 32-bed ICU. The study was granted approval from the Institutional Review Board. From January 1993 to December 2005, all patients admitted to the ICU from the ED, with a diagnosis of acute community-acquired septic meningitis, were included. The diagnosis was established if the patient had a compatible clinical picture and definite identification of an etiologic agent by at least one of three criteria: (1) positive cerebrospinal fluid (CSF) Gram, Ziehl-Neelsen or India ink staining; (2) positive CSF culture; and (3) negative CSF culture with neutrophilic pleocytosis and positive blood culture or positive CSF cryptococcal antigen test. An episode of septic meningitis was considered as community-acquired if a patient had not been previously treated in a hospital or had been discharged over 2 weeks ago. Those patients with meningitis who required ICU admission after ED arrival were defined as having severe septic meningitis. Patients were excluded if they were under 18 years of age, with human immunodeficiency virus infection or viral meningitis. J Formos Med Assoc | 2009 • Vol 108 • No 2

If the patient had more than one episode of community-acquired meningitis in the study period, only the first episode was analyzed. Concurrent pneumonia upon admission was defined if the patient had new or increased infiltrates upon chest radiography, with at least one of the following: (1) cough with purulent sputum or a change in the character of sputum, and the presence of rales, rhonchi, or bronchial sounds suggestive of pneumonia; (2) body temperature above 38°C; and (3) white blood cell (WBC) count > 10 × 109/L or < 4.0 × 109/L, even while the diagnosis of meningitis was established. Effective antibiotics were defined as those to which the causative pathogens were susceptible in vitro and that penetrated the CSF. Patient outcome when discharged was evaluated according to the Glasgow Outcome Scale.15 Patients who survived to discharge were defined as the survival group and the others were the nonsurvival group. Information on the clinical characteristics, including age, gender, coexisting disease, presenting symptoms, consciousness level, ventilator use, complications in the ICU, and outcomes were recorded. Consciousness level was evaluated by the Glasgow Coma Scale (GCS).16 The durations from ED arrival to head computed tomography (CT), CSF study, initiation of antibiotic therapy, effective antibiotic use, and ICU admission were recorded. Laboratory data were collected, including WBC count, platelet count, biochemistry, C-reactive protein (CRP), CSF cell count, and microorganisms isolated from CSF and blood. All continuous data were presented as the mean ± standard deviation. Correlations between the survival and nonsurvival groups with respect to time from ED arrival to antibiotic treatment, to effective antibiotic administration, to head CT and lumbar puncture, and to ICU admission were analyzed by nonparametric Spearman’s rank correlation. Clinical features, laboratory results, and management processes were also compared using Fisher’s exact test for categorical variables, and the nonparametric Mann–Whitney U test for continuous variables. A value of p ≤ 0.05 was considered statistically significant. 113

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Results Demographic data and causative organisms From January 1993 to December 2005, there were a total of 117 patients with 122 episodes of community-acquired septic meningitis. There were 77 patients not admitted to the ICU. Thus, they were excluded because their meningitis did not fit the definition of severe septic meningitis. A total of 40 patients admitted to the ICU were included. The mean age was 60 years (range, 24–87 years) with male predominance (62.5%, Table 1). The most common comorbidity was diabetes mellitus (57.5%), followed by malignancy (15.0%), liver cirrhosis (15.0%), and end-stage renal disease (12.5%). Over one fifth (12.5%) were on steroids. The causative pathogens are listed in Table 2. Gram-negative bacteria accounted for more than half (n = 22, 55%), especially Klebsiella pneumoniae (n = 20, 50%). Among the 13 patients with Gram-positive bacterial pathogens, S. pneumoniae was the most common (n = 6, 15%). Five patients (12.5%) had cryptococcal meningitis.

Clinical course and outcome Deterioration in consciousness was the most common clinical presentation (100%), followed by fever (92.5%), neck stiffness (77%), and headache (42.5%) (Table 3). The mean GCS was 7.25

(range, 3–13). More than half of the patients (n = 21, 52.5%) had a diagnosis of pneumonia simultaneously in the ED, and most of them (92.5%) required mechanical ventilation. Thirtyfour patients underwent head CT, and the most common finding was cerebral edema, followed by hydrocephalus, cerebral infarction, and meningeal enhancement (Table 4). All of the patients were admitted via the ED. The first antibiotic was given within a mean duration of 8.9 hours after arrival (Table 5). However, effective antibiotic therapy was delayed for a mean 23.8 hours after arrival. The mean duration from

Table 2. Causative pathogens of communityacquired septic meningitis in 40 patients admitted to the intensive care unit* Gram-negative bacteria Klebsiella pneumoniae Escherichia coli Acinetobacter baumannii

22 (55.0) 20 (50.0) 1 (2.5) 1 (2.5)

Gram-positive bacteria Streptococcus pneumoniae Streptococcus spp. Staphylococcus aureus Enterococcus avium

13 (32.5) 6 (15.0) 3 (7.5) 3 (7.5) 1 (2.5)

Fungus Cryptococcus neoformans

5 (12.5) 5 (12.5)

*Data presented as n (%).

Table 1. Demographic data and comorbidity in community-acquired septic meningitis patients admitted to the intensive care unit*

Age (yr) Sex (M/F) Diabetes mellitus Malignancy Nasopharyngeal carcinoma ESRD Liver cirrhosis Steroid use COPD Head injury history

Total (n = 40)

Survival (n = 9)

Nonsurvival (n = 31)

p

60.0 ± 15.0 25/15 23 (57.5) 6 (15.0) 3 (7.5) 5 (12.5) 6 (15.0) 5 (12.5) 3 (7.5) 1 (2.5)

59.6 ± 1 9.1 5/4 6 (66.7) 2 (22.2) 1 (11.1) 2 (22.2) 0 (0.0) 2 (22.2) 2 (22.2) 0 (0.0)

60.2 ± 14.0 20/11 17 (54.8) 4 (12.9) 2 (6.5) 3 (9.7) 6 (19.4) 3 (9.7) 1 (3.2) 1 (3.2)

0.95 0.71 0.71 0.60 0.55 0.31 0.31 0.31 0.12 0.99

*Data presented as mean ± standard deviation or n or n (%). ESRD = end-stage renal disease; COPD = chronic obstructive pulmonary disease.

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Table 3. Initial clinical presentations and laboratory data of 40 community-acquired septic meningitis patients admitted to the intensive care unit* Total (n = 40)

Survival (n = 9)


p

Fever

37 (92.5)

9 (100.0)

28 (90.3)

0.99

Headache

17 (42.5)

3 (33.3)

14 (45.2)

0.71

Deterioration of consciousness

40 (100.0)

9 (100.0)

31 (100.0)

0.99

Neck stiffness

31 (77.5)

6 (66.7)

25 (80.6)

0.39

GCS score

7.25 ± 3.28

7.33 ± 3.24

7.23 ± 3.34

0.95

Seizure

8 (20.0)

2 (22.2)

6 (19.4)

0.99

Focal signs

8 (20.0)

1 (11.1)

7 (22.6)

0.66

Shock

17 (42.5)

5 (55.6)

12 (38.7)

0.46

Concurrent pneumonia on admission

21 (52.5)

6 (66.7)

15 (48.4)

0.46

Positive blood culture

27 (67.5)

7 (77.8)

20 (64.5)

0.69

312.5 ± 168.2 (n = 19) 7998 ± 16,794 (n = 28) 0.84 ± 1.21 (n = 19) 42.2 ± 45.4 (n = 26)

282.5 ± 147.7 (n = 8) 11,239 ± 17,913 (n = 7) 0.53 ± 0.37 (n = 5) 49.4 ± 58.1 (n = 7)

334.4 ± 185.5 (n = 11) 6917 ± 16,722 (n = 21) 0.95 ± 1.38 (n = 14) 39.5 ± 41.3 (n = 19)

0.72 0.47 0.96 0.95

19.8 ± 11.1 (n = 17) 2.34 ± 2.58

12.2 ± 8.9 (n = 7) 3.18 ± 4.84

25.1 ± 9.5 (n = 10) 2.09 ± 1.45

0.02 0.52

CSF study Open pressure (mmH2O) WBC count (μL) Total protein (g/dL) Glucose (mg/dL) Blood chemistry CRP (mg/dL) Creatinine (mg/dL)

*Data presented as n (%) or mean ± standard deviation. GCS = Glasgow Coma Scale; CSF = cerebrospinal fluid; WBC = white blood cell; CRP = C-reactive protein.

Table 4. Head computed tomography findings in community-acquired septic meningitis patients admitted to the intensive care unit* Total (n = 34)

Survival (n = 8)


p

4 (11.8) 13 (37.1) 14 (40.0) 6 (17.1) 6 (17.1)

2 (25.0) 2 (25.0) 2 (25.0) 1 (12.5) 1 (12.5)

2 (7.7) 11 (40.7) 12 (44.4) 5 (18.5) 5 (18.5)

0.23 0.68 0.43 0.99 0.99

Normal Hydrocephalus Cerebral edema Cerebral infarction Meningeal enhancement *Data presented as n (%).

Table 5. Time delay of antibiotic use, cerebrospinal fluid (CSF) study, and head computed tomography (CT) in the emergency department (ED) in patients with severe community-acquired septic meningitis*

ED to antibiotic use (hr) ED to effective antibiotic use (hr) ED to CSF study (hr) ED to head CT (hr) ED to ICU admission (hr)

Total (n = 40)

Survival (n = 9)


p

8.85 ± 13.99 23.82 ± 33.52 32.05 ± 37.10 30.89 ± 54.90 31.93 ± 33.85

4.88 ± 4.45 22.15 ± 28.34 21.14 ± 17.48 23.77 ± 40.14 11.11 ± 10.59

10.00 ± 15.59 24.33 ± 35.35 35.33 ± 40.88 33.17 ± 59.38 37.98 ± 35.94

0.68 0.81 0.64 0.79 0.01

*Data presented as mean ± standard deviation.


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Table 6. Treatment course and complications of community-acquired septic meningitis patients admitted to the intensive care unit*

Steroid use Mechanical ventilation Gastrointestinal bleeding Acute renal failure Subsequent shock

Total (n = 40)

Survival (n = 9)


p

10 (25.0) 37 (92.5) 26 (65.0) 23 (57.5) 35 (87.5)

3 (33.3) 8 (88.9) 4 (44.4) 3 (33.3) 5 (55.6)

7 (22.6) 29 (93.5) 22 (71.0) 20 (64.5) 30 (96.8)

0.67 0.55 0.23 0.13 < 0.01

*Data presented as n (%).

arrival at the ED to head CT and CSF study was 30.9 and 32.1 hours, respectively. Time from ED to ICU admission was strongly correlated with the time to effective antibiotic use, head CT, and lumbar puncture (r = 0.32, 0.47, and 0.53, respectively; p = 0.05, 0.006, and 0.001, respectively). Among the 40 patients admitted to the ICU, 31 died in the hospital (77.5%). There were no significant differences between the survival and nonsurvival groups in terms of clinical characteristics. Shorter duration from the ED to ICU admission was noted in the survival group than the nonsurvival group (11.1 vs. 38.0 hours, p = 0.01). No significant differences in CSF data and hemograms were found between the two patient groups. Among the 17 patients with available CRP data, a significantly higher level was noted in the nonsurvival group (25.1 ± 9.5 vs. 12.2 ± 8.9, p = 0.02). After ICU admission, 33.3% and 22.6% in the survival and nonsurvival groups, respectively, received steroid treatment (Table 6). A significantly higher proportion of patients developed subsequent shock in the ICU among those who died as compared with those who survived (96.8% vs. 55.6%, p < 0.01). There were more patients in the nonsurvival group than the survival group with gastrointestinal bleeding (71.0% vs. 44.4%) and acute renal failure (64.5% vs. 33.3%). For patients who were discharged alive, the discharge conditions were: vegetative (n = 1), severe disability (n = 4), moderate disability (n = 3), and mild or no disability (n = 1), based on the Glasgow Outcome Scale evaluation. 116

Discussion We demonstrated that, in patients with community-acquired septic meningitis who required ICU admission, approximately 60% had diabetes mellitus, and K. pneumoniae was the most common causative pathogen. They had poor prognosis, with a 77.5% inhospital mortality, which is substantially higher than that reported previously (10.9–25%).17–19 This might be related to several factors, including different geographic distribution of causative pathogens, as well as delayed appropriate antibiotic treatment and ICU admission. Prior studies in the United States and Europe have shown that S. pneumoniae is the most common pathogen in community-acquired bacterial meningitis, whereas the most common Gramnegative pathogen is Neisseria meningitidis followed by Haemophilus influenzae.5,7 In the present study, S. pneumoniae only accounted for 15.0% of the patients and the most common causative pathogens were Gram-negative bacteria, especially K. pneumoniae. A high prevalence of K. pneumoniae infection, especially in diabetic patients, has also been reported in some areas of Asia.20–23 Previous studies have observed that the mortality rate of bacterial meningitis (mostly caused by K. pneumoniae) is as high as 34–44%.22,23 Increasing evidence suggests that a certain genotype, such as capsular serotype K1 or K2, plays an important role in determining virulence and metastatic complications in K. pneumoniae infection.24,25 However, the relationship among K. pneumoniae infection, diabetes mellitus, and high mortality rate still needs to be elucidated. J Formos Med Assoc | 2009 • Vol 108 • No 2


The survival patient group had earlier head CT examination, CSF examination, antibiotic therapy and ICU admission after ED arrival. Previous studies have demonstrated that delayed antibiotic treatment can cause adverse outcomes.4,14,22 The time duration between arrival in hospital and antibiotic treatment was nearly 9 hours, which was much longer than previously reported (4 hours) and guideline suggestions (30 minutes).4,14,26,27 The duration of first effective antibiotic use from ED arrival was obviously prolonged (23.8 hours). Delayed adequate antibiotic therapy might be a factor for the high mortality rates in this study. Reasons for delayed antibiotic treatment included: (1) failure to consider the diagnosis; (2) ignorance of the importance of rapid antibiotic administration for suspected septic meningitis; (3) absence of classic meningitis triad; and (4) waiting for diagnostic-treatment sequence: head CT followed by lumbar puncture for CSF study, and then antibiotics.14,26 In the present study, only 10 patients followed the diagnostic-treatment sequence, with a trend towards earlier antibiotic use than in the other patients (5.8 vs. 9.9 hours, p = 0.43), which suggests that waiting for the diagnostic-treatment sequence was not the major cause of delayed treatment. Instead, there might have been a failure to consider the diagnosis in atypical patients, which led to delayed treatment. More than half of the patients were diagnosed with pneumonia after arriving at the ED, where second generation cephalosporins were prescribed as the initial empirical treatment. A diagnosis of septic meningitis was not made among these patients until they had seizures or focal neurologic deficits that necessitated brain imaging studies and lumbar puncture. This finding indicated that physicians in the ED are more vigilant with patients with atypical presentations and perform prompt diagnostic work-up when necessary. Diagnosing septic meningitis according to clinical manifestations, especially in the elderly, is still a major challenge.28 A low incidence of the clinical triad of fever, neck stiffness and consciousness change (21–51%) in bacterial meningitis J Formos Med Assoc | 2009 • Vol 108 • No 2

has been noted in several studies.5,29,30 Meningeal signs such as Kernig’s sign, Brudzinski’s sign, and nuchal rigidity have only low sensitivity (5–30%) in patients with suspected meningitis.31 However, most patients present with at least one element of the classic triad, or two of the symptoms and signs including headache, fever, neck stiffness and altered mental state.3,5 Clinicians should be alert when only one or two of the above symptoms/signs are present. Waiting for the classic triad in the ED may unnecessarily delay diagnosis and adequate treatment. Early ICU admission may be beneficial for patients with severe septic meningitis. Previous reports have suggested that patients who present with altered mental state or neurologic deficit, especially in those with GCS < 12, require ICU admission.18,19 In our study, patients in the survival group were admitted to the ICU earlier than the nonsurvival patients. They also received effective antibiotic administration, brain imaging and lumbar puncture much earlier. Nevertheless, our patients had a poor state of consciousness when admitted to the ICU, with a mean GCS of 7. In addition to appropriate antibiotic therapy, intensive monitoring, prompt life support, and aggressive treatment in the ICU might be necessary for these patients with poor consciousness, whether mechanical ventilation is required or not. There are several limitations to the present study that need to be considered. First, the requirement of definite identification of an etiologic agent in the inclusion criteria resulted in a small case number. Second, the study suggested a survival benefit among patients with early antibiotic administration and ICU admission. However, we could not exclude the possibility of imbalanced distribution of important prognostic factors between patients of early and delayed ICU admission caused by the nonexperimental design and lack of standardized treatment protocols. Third, the results from this study conducted at a tertiary care center need to be interpreted cautiously when positing broad generalizations for other settings. In conclusion, severe septic meningitis is still a serious disease with high mortality and morbidity. 117

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Hastening diagnostic processes, early appropriate antibiotic therapy and ICU admission in the ED are important to improve the quality of care and patient outcome.

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