Journal of Critical Care xxx (2014) xxx–xxx

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Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: Retrospective study☆ D. Fernandes a, b,⁎, J. Gonçalves-Pereira b, S. Janeiro c, J. Silvestre b, L. Bento d, P. Póvoa b, e a

Infectious Disease and Tropical Medicine Department, Egas Moniz Hospital, CHLO, Lisbon, Portugal Polyvalent Intensive Care Unit, São Francisco Xavier Hospital, CHLO, Lisbon, Portugal Internal Medicine Department, Hospital de São Bernardo, CHS, Lisbon, Portugal d Medical Emergency Unit, São José Hospital, CHLC, Lisbon, Portugal e Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal b c

a r t i c l e

i n f o

a b s t r a c t

Keywords: Critically ill Bacterial meningitis Severe sepsis Outcome

Background: Bacterial meningitis constitutes a medical emergency. Its burden has driven from childhood to the elderly and the immunocompromised population. However, the admission of patients with bacterial meningitis to the intensive care unit (ICU) has been sparsely approached, as have the prognostic factors associated with an adverse clinical outcome. Methods: We performed a retrospective analysis during a 7-year period of patients older than 18 years admitted to 2 polyvalent ICUs. Clinical, demographic, and outcome data were collected to evaluate its clinical impact on the outcome of patients with acute bacterial meningitis. Results: We identified 65 patients with the diagnosis of acute bacterial meningitis (mean Acute Physiology and Chronic Health Evaluation II, 23; hospital mortality, 40%). Upon clinical presentation, their most frequent signs were fever (84%), seizures (21.5%), and a low Glasgow Coma Scale (GCS) score (GCS b 8; 58.4%). Fiftyfive patients (85%) required organ support. A definite microbiological diagnosis was achieved in 45 patients. An adverse clinical outcome was noted in 46 patients (71%). These patients were older (P = .005), had higher Physiology and Chronic Health Evaluation II score (P = .022), and had lower GCS (P = .022). In the multivariate analysis, older age (per year; adjusted odds ratio [aOR], 1.059) was associated with an adverse outcome, whereas a higher GCS (per point; aOR, 0.826) and presence of fever upon admission (aOR, 0.142) increase the chance of a good recovery. Conclusions: Patients with acute bacterial meningitis admitted to ICU had substantial morbidity and mortality. Those with low GCS or absence of fever have a particularly high risk of an adverse outcome. © 2013 Elsevier Inc. All rights reserved.

1. Introduction

advances in medical care, namely, vaccines, have shifted the burden of bacterial meningitis from the infant to the adult population [1,2]. Besides, the improvement in organ support techniques was counterbalanced by longer lifetime expectancy, frequent use of immunosuppressive therapy, and the growing number of neurosurgical procedures. As a result, the overall mortality rate of bacterial meningitis had remained stable [2-4]. Reasons for admission of patients with meningitis to an intensive care unit (ICU) are mostly related to acute changes in the level of consciousness and/or severe sepsis or septic shock with multipleorgan failure. In addition, some microorganisms responsible for meningitis, typically meningococci, are associated with very acute and rapidly progressive clinical syndromes with high mortality [3]. Nevertheless, the impact of meningitis in ICU is largely unknown. Few studies have evaluated the epidemiology and risk factors for adverse clinical outcomes of this population. The purpose of this study was to identify factors associated with in-hospital mortality and morbidity of critically ill adult patients with bacterial meningitis.

Bacterial meningitis constitutes a medical emergency with significant morbidity and mortality [1]. Over the last decades,

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; GCS, Glasgow Coma Scale; ICU, intensive care unit; CSF, cerebrospinal fluid; CNS, central nervous system. ☆ Competing interests: No financial or nonfinancial competing interest to declare related to the topic of this manuscript.Authors’ contributions: D.F., J.G.P., J.S., and P.P. designed the study. D.F. and J.G.P. performed the statistical analysis. D.F. and S.J. collected the data. D.F., S.J., J.G.P., J.S., L.B., and P.P. draft the manuscript. All authors read and approved the final manuscript. ⁎ Corresponding author. Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, EPE, Estrada do Forte do Alto do Duque, 1449-005 Lisboa, Portugal. Tel.: +351 21 043 2352. E-mail addresses: [email protected] (D. Fernandes), [email protected] (J. Gonçalves-Pereira), [email protected] (S. Janeiro), [email protected] (J. Silvestre), luisfi[email protected] (L. Bento), [email protected] (P. Póvoa). 0883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved.

Please cite this article as: Fernandes D, et al, Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: Retrospective study, J Crit Care (2014),


D. Fernandes et al. / Journal of Critical Care xxx (2014) xxx–xxx

2. Materials and methods This was a retrospective study of data prospectively collected. All patients older than 18 years consecutively admitted between January 2005 and December 2011 to either the ICU of São Francisco Xavier Hospital (Centro Hospitalar de Lisboa Ocidental, EPE) or to the ICU of São José Hospital (Centro Hospitalar de Lisboa Central), both in Lisbon, Portugal, were included in our study. All patients with a diagnosis of acute community acquired bacterial meningitis were segregated for further analysis. The ethical committees of both hospitals approved this study. Data were retrieved from the medical records of the included patients. Bacterial meningitis was defined according to the Centers for Disease Control and Prevention (Atlanta, Ga) recommendations [5], as either a positive cerebrospinal fluid (CSF) culture or a suggestive clinical history (fever, headache, head stiffness) and one or more of the following criteria: CSF pleocytosis (N 10 cells/mL), positive blood culture, suggestive CSF Gram stain, or positive pneumococcal antigens detected by a latex agglutination method in CSF or urine. Meningitis was further classified as primary of the central nervous system or secondary to an infection in other organs. Demographic information and presence of comorbidities, namely, infection by the HIV, malignancy, asplenia, diabetes mellitus, longterm use of corticosteroids or other immunosuppressive medications, known dural fistula, or severe chronic alcoholism, were collected. In addition, Acute Physiology and Chronic Health Evaluation (APACHE II) [6] and the Glasgow Coma Scale (GCS) score at admission [7] were recorded, as well as the need for mechanical ventilation, renal replacement therapy, neuromonitoring devices, or vasopressor support. For study purposes, fever was considered when a central body temperature higher than 38.2ºC was registered within the first 24 hours upon ICU admission. Therapeutic data, in particular antibiotics, anticonvulsant, or antiedematous therapy, were also retrieved from medical records as well as laboratory data (from serum and CSF) and the results of imaging studies, especially head computed tomographic scan. For study purposes, corticosteroid adjuvant therapy was defined as the use of dexametasone, at least 0.15 mg/kg every 6 hours or equivalent, started within the first 24 hours of diagnosis of bacterial meningitis and maintained for at least 4 days. Neurologic impairment was defined as one or more of the following: presence of motor deficit, clinically detected hearing impairment, behavioral or language disturbance, or hydrocephalus. As proposed by other investigators, an adverse clinical outcome was defined as death during ICU stay or severe neurologic impairment at discharge from the ICU [8-10]. A comparative analysis between patients with an adverse and a favorable clinical outcome was performed.

Analysis was performed using SPSS Statistics for Windows, version 17.0 (SPSS Inc, Chicago, Ill). The tests were 2 tailed, with significance levels fixed at 5%. 4. Results and discussion We identified 65 patients with bacterial meningitis (age, 53 ± 15 years; 70.8% men) with an APACHE II score of 23 ± 9 admitted to the ICU during the study period. The majority (60%) was admitted from the hospital emergency department, whereas the others were transferred from other hospitals. In 50 patients, a diagnosis of primary meningitis was made. Meningitis was considered to be secondary in the remaining 15 (6 with pneumonia, 6 with endocarditis, 2 with otitis media, 1 with sinusitis). Most patients presented with at least 1 risk factor for infection: immunossupression, including infection with HIV (n = 4 patients), diabetes mellitus (n = 3), long-term corticosteroid therapy (n = 1), and severe chronic alcoholism (n = 3); dural fistula was present in 2 patients, and 3 other patients had a documented infection of the ear or head sinus. A head computed tomographic scan was performed in 59 patients within the first 24 hours of hospital admission. Twelve underwent an emergency neurosurgical procedure: 8 to treat a complication of meningitis (n = 5 hydrocephaly; n = 3 brain abscess) and 4 before admission to the ICU, as a result of head trauma. Clinical presentation included fever in 55 patients, generalized tonic-clonic seizures in 14, and acute depression of the level of consciousness (GCS b8) in 38. The organ support interventions are described in Table 1. Fifty-five patients required organ support, of which 25 had more than one organ failure at admission.

4.1. Microbiological data A definite microbiological diagnosis was achieved in 45 patients (69.2%; Table 2). Streptococcus pneumoniae was the most common identified microorganism (n = 23). Bacteria were isolated from CSF culture in 17 patients, blood cultures in 9 patients, and in both in 16 patients. In 3 patients, the microbiological identification was based on antigen detection test. In roughly one third of the patients, microbiological identification was not achieved. Most patients were treated with ceftriaxone in combination with another antibiotic (51 patients; 78.4%), including 5 receiving ampicillin and 19 vancomycin. Monotherapy was given to only 10 patients, according to the microbiological identification. One patient died before receiving any antibiotic. Thirty-four patients received adjuvant corticosteroid therapy within the first 24 hours of diagnosis.

3. Statistical methods Standard descriptive statistics were used. Data were presented as mean ± SD, unless otherwise stated. Association between categorical variables was assessed by Fisher exact test. Continuous variables were assessed by Wilcoxon rank sum test or Student t test according to data distribution. We performed a multivariate logistic regression analysis to determine the variables independently associated that best predicted an adverse outcome. We included in the model the variables statistically significant in the univariate analyses (P b .1). Multicolinearity among these variables was checked by computing the correlation coefficient (r) between them, taken 2 × 2. An r b 0.4 was considered low enough to exclude correlation between the variables. When colinearity was found, we selected the variable clinically more relevant. Results of the multivariate logistic regression model were reported as adjusted odds ratio (aOR) with 95% confidence interval (CI). Significance was accepted for P b .05.

Table 1 Patients demographic and clinical characteristics Total (n = 65) Male sex Age (y) Origin Emergency department Other APACHE II GCS on admission ICU length of stay (d), median (IQR) Organ support interventions Mechanical ventilation Vasopressor RRT ICU mortality Hospital mortality

46 (71) 54 ± 15 39 (60) 26 (40) 24 ± 9 8 ± 3.7 7.2 (3.3-19) 52 (80) 27 (41.5) 3 (4.6) 17 (26.2) 26 (40)

RRT indicates renal replacement therapy. Data presented as n (%) or mean ± SD, unless otherwise stated.

Please cite this article as: Fernandes D, et al, Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: Retrospective study, J Crit Care (2014),

D. Fernandes et al. / Journal of Critical Care xxx (2014) xxx–xxx


Table 3 Factors associated with an adverse clinical outcome

Age (y) Male, n Transferred from other hospital, n Fever, n Seizures, n Altered immune status, n GCS, mean APACHE II, mean Ventilatory support, n Vasopressor support, n Hemodialysis support, n WCC (cells/μL), mean CRP (mg/dL) CSF leukocyte count (cells/mm3), mean S pneumoniae, n Corticosteroid adjunctive therapy, n

Adverse clinical outcome (n = 46)

Favorable clinical outcome (n = 19)


56.9 33 (71.7%) 16 (34.8%)

45.8 13 (68.4%) 10 (52.6%)

.005 .793 .187

42 (91.3%) 9 (19.6%) 7 (15.2%) 7.6 25.3 40 (86.9%) 23 (50%) 2 (4.3%) 14474 18.5 1017

13 (68.4%) 5 (26.3%) 1 (5.2%) 9.8 19.3 12 (63.2%) 4 (21.1%) 1 (5.2%) 19005 17.9 1360

.020 .584 .274 .022 .022 .031 .022 .875 .63 .787 .779

17 (37%) 25 (54.3%)

6 (31.6%) 9 (47.4%)

.686 .762

CRP indicates C-reactive protein; WCC, white cell count.

Fig. 1. Distribution of mortality of patients in the ICU.

5. Conclusions

4.2. Outcome An adverse clinical outcome was noted in 46 patients (70.8%). These included 19 patients with a neurologic deficit upon hospital discharge and the 25 who died (17 in the ICU and 9 still in the hospital—Table 1). Overall, the mean time between ICU admission and death was 9.8 days but with a large interpatient variability (median, 3.7; interquartile range, 16.3). Intensive care unit mortality showed a bimodal distribution, with 53% of patients dying within the first 2 days of ICU stay. A later mortality peak was identified between days 10 and 20 (Fig. 1). Patients with an adverse clinical outcome (Table 3) were older (P = .005), had higher APACHE II score (P = .022), and had lower GCS (P = .022). Moreover, this subgroup more commonly needed ventilatory (P = .029) or vasopressor support (P = .022). A higher mortality was also found in the subgroup of patients older than 65 years (64% vs 31%, P = .016). In this study, we found no significant benefit from the adjunctive corticosteroid therapy in the outcome of patients with S pneumoniae meningitis (P = .867). In the multivariate analysis, age, presence of fever, GCS, and the APACHE II were considered. Older age (aOR per year, 1.059; 95% CI, 1.012-1.109) remained independently associated with an adverse clinical outcome (Table 4). On opposite, a higher GCS (aOR per point 0.826; 95% CI, 0.691-0.988) and the presence of fever (N38.2°C) upon admission (aOR, 0.142; 95% CI, 0.029-0.702) were found to be protective. Table 2 Isolated microorganisms Isolated bacteria Gram-positive bacteria S pneumoniae Streptococcus spp Listeria monocytogenes Staphylococcus aureus Enterococcus spp Streptococcus bovis Gram-negative bacteria Neisseria meningitidis Pseudomonas aeruginosa Klebsiella pneumoniae Escherichia coli

n (%) 23 (35.4) 2 (3.1) 2 (3.1) 6 (9.2) 4 (6.2) 1 (1.5) 2 (3.1) 2 (3.1) 2 (3.1) 1 (1.5)

In this study, we evaluated patients with acute bacterial meningitis admitted to the ICUs of 2 tertiary hospitals. The need for organ support, especially ventilatory (80%) and vasopressor (41.5%), was the most common reason for admission. We found high hospital mortality (40%), and in addition, 19 other patients had clinically relevant neurologic sequelae at hospital discharge. Older age, lower GCS, and absence of fever at ICU admission were all found to be independently associated with adverse clinical outcomes (either death or neurologic sequelae). This mortality rate was much higher than previously described. However, few studies addressed specifically the ICU population. In an observational study, Santos et al [11] reported an ICU mortality of 17%, also in a Portuguese population. However, this study also included patients with encephalitis or brain abscesses. Other series also reported lower mortality rates (ranging between 10% and 30%) [3,8,12]. On the contrary, one study similar to ours [2] that included only critically ill patients with bacterial meningitis found a similar mortality rate, 44%. The authors postulate that this high mortality might be related to the severity of the disease and/or postponed admission to the ICU [2]. In our cohort, the overall mortality was correctly predicted by the APACHE II score, which supports the hypothesis that this poor survival is mainly a consequence of disease severity at admission. The bimodal pattern of mortality distribution during UCI stay in our cohort has not been previously described. One might speculate that the early mortality could be attributed to the severity of the disease secondary to the hyperinflamatory stage. Some of the patients who survived the first days died late during the ICU course, which could be associated with refractory multiple-organ failure, failure to Table 4 Multivariate analysis of factors associated with an adverse clinical outcome Variable

Age (per year) GCS (per point) Fever (N38.2°C)

P (Wald)


.014 .036 .017

1.059 0.826 0.142

95% CI Lower


1.012 0.691 0.029

1.109 0.988 0.702

APACHE II was excluded from the final model (P = .405). Hosmer and Lemeshow goodness-of-fit test, P = .68.

Please cite this article as: Fernandes D, et al, Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: Retrospective study, J Crit Care (2014),


D. Fernandes et al. / Journal of Critical Care xxx (2014) xxx–xxx

clear the initial infection, or secondary superinfections, resulting from the hypothetical immunosupression of late sepsis stage. Older age is classically considered a risk factor for a bad outcome in bacterial meningitis. However, few studies have evaluated its impact on the prognosis of critically ill patients with meningitis. In our study, the older population (N65 years) had much higher hospital mortality (64% in patients N65 years old). Similarly, Hoen et al [9] unveiled an association between age above 45 years and an adverse clinical outcome in pneumococcal meningitis, whereas Thigpen et al [4] described a linear increase of mortality with increasing age. Lai et al. [13] specifically studied bacterial meningitis in adults older than 65 years admitted to a tertiary center. They found both a higher incidence of meningitis and a higher mortality rate in this subgroup (34.8% and 39%, respectively). Fever is also frequently described in bacterial meningitis [1] as a clinical feature upon hospital admission. However, no study associated fever with an adverse clinical outcome [3,12,13]. In our cohort, the absence of fever was found to be associated with a dismal prognosis, maybe translating an inadequate host immune response. Moreover, the presence of fever is usually associated with more rapid infection recognition and treatment, and its suppression may lead to a worsening the outcome [14]. Altered level of consciousness is probably related to the extension of cerebral involvement by the infectious disease process and, therefore, is directly related to clinical outcome, as described by Flores-Cordero et al [3]. Accordingly, in our study, a relationship between a lower GCS and a worse outcome was found. Patients presenting with bacterial meningitis often have chronic medical conditions (including alcohol consumption) [2,8,12,13], which were also prevalent in our population, although they were not statistically associated with an adverse clinical outcome. However, we recognize that our series is underpowered to unveil such an association. As described in other cohorts [2-4], S pneumoniae was the most common isolated pathogen (35.4%). Antibiotic resistance is not common among invasive S pneumoniae in Portugal [15]. In fact, we did not find any antibiotic resistance in our patients. Still, one might speculate that a delayed institution of antibiotic therapy contributed to the high mortality described. Similarly to others [13], several patients presented with secondary meningitis (18.4%). We did not note any difference in adverse clinical outcomes between patients with primary and patients with secondary meningitis. We believe that our study contributes to the increasing knowledge on patients with severe bacterial meningitis. In fact, we included all patients with acute bacterial meningitis admitted to 2 adult ICUs during a 7-year period and were able to collect data on risk factors, microbiological documentation, antibiotics, and outcome.

However, we acknowledge several limitations of the study: the relatively low number of patients, the absence of a standardized treatment protocol, the absence of information regarding time from door to antibiotic therapy, or long-term mortality. Although the relatively long study period may be seen as a limitation, no major modifications in the standard of care of meningitis occurred in between. In conclusion, our findings corroborate that critically ill patients with severe acute bacterial meningitis remain associated with high morbidity and mortality. In our cohort, patients with low GCS and the absence of fever on admission as well as older age were at high risk for worst outcomes. References [1] Bhimraj A. Acute community-acquired bacterial meningitis in adults: an evidencebased review. Cleve Clin J Med 2012;79(6):393–400. [2] Edberg M, Furebring M, Sjolin J, Enblad P. Neurointensive care of patients with severe community-acquired meningitis. Acta Anaesthesiol Scand 2011;55(6): 732–9. [3] Flores-Cordero JM, Amaya-Villar R, Rincon-Ferrari MD, Leal-Noval SR, GarnachoMontero J, Llanos-Rodriguez AC, et al. Acute community-acquired bacterial meningitis in adults admitted to the intensive care unit: clinical manifestations, management and prognostic factors. Intensive Care Med 2003;29(11):1967–73. [4] Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011;364(21): 2016–25. [5] Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008;36(5):309–32. [6] Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13(10):818–29. [7] Jennett B, Teasdale G. Aspects of coma after severe head injury. Lancet 1977;1(8017):878–81. [8] Auburtin M, Porcher R, Bruneel F, Scanvic A, Trouillet JL, Bedos JP, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit Care Med 2002;165(5):713–7. [9] Hoen B, Viel JF, Gerard A, Dureux JB, Canton P. Mortality in pneumococcal meningitis: a multivariate analysis of prognostic factors. Eur J Med 1993;2(1): 28–32. [10] Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998;129(11):862–9. [11] Santos L, Soares M, Faustino A, Alves CL, Figueiro P, Sarmento A. Neurologic emergencies of infectious etiology—experience of the intensive care unit of infectious diseases. Infecção e Sépsis 2012;2:44–9. [12] Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol 2006;5(2):123–9. [13] Lai WA, Chen SF, Tsai NW, Chang CC, Chang WN, Lu CH, et al. Clinical characteristics and prognosis of acute bacterial meningitis in elderly patients over 65: a hospital-based study. BMC Geriatr 2011;11:91. [14] Launey Y, Nesseler N, Malledant Y, Seguin P. Clinical review: fever in septic ICU patients—friend or foe? Crit Care 2011;15(3):222. [15] Aguiar SI, Serrano I, Pinto FR, Melo-Cristino J, Ramirez M. Changes in Streptococcus pneumoniae serotypes causing invasive disease with non-universal vaccination coverage of the seven-valent conjugate vaccine. Clin Microbiol Infect 2008;14(9): 835–43.

Please cite this article as: Fernandes D, et al, Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: Retrospective study, J Crit Care (2014),

Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: retrospective study.

Bacterial meningitis constitutes a medical emergency. Its burden has driven from childhood to the elderly and the immunocompromised population. Howeve...
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