Download Aminoglycosides use in patients over 75 years old

Age and Ageing 2014; 43: 676–681
doi: 10.1093/ageing/afu023
Published electronically 2 March 2014
© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society.
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Aminoglycosides use in patients over 75 years old
THIBAUT FRAISSE1, CLAUDINE GRAS AYGON1, MARC PACCALIN2, VIRGINIE VITRAT3, BENOIT DE WAZIERES4,
VERONIQUE BAUDOUX5, CATHERINE LECHICHE6, AURELIE VICENS7, ALBERT SOTTO6, LEONARDO PAGANI3,
JACQUES GAILLAT3, EMMANUEL FORESTIER8, GAËTAN GAVAZZI9
CH Ales – CSGA, 811 Av Dr Jean Goubert, Ales 30100, France
CHU Poitiers – Geriatric, Poitiers, France
3
CH Annecy – Infectious Disease, Annecy, France
4
CHU Caremeau – Geriatric, Nimes, France
5
CH Saumur – Geriatric, Saumur, France
6
CHU Caremeau – Infectious Disease, Nimes, France
7
CHU Strasbourg – Infectious Disease, Strasbourg, France
8
CH Chambéry – Infectious Disease, Chambéry, France
9
University Hospital of Grenoble – University Clinic of Geriatric Medicine, BP 217, Grenoble 38043, France
1
2
Address correspondence to: Thibaut Fraisse. Tel: +33 466783156 Fax: +33 466783356 Email: [email protected]
Abstract
Objective: to describe aminoglycoside use and nephrotoxicity in patients older than 75 years.
Design: retrospective multicenter study.
Setting: hospital department, rehabilitation, long-term care center.
Population: patients ≥75 years old treated by aminoglycosides.
Results: 184 patients, mean age: 84.4 years (range: 75–101). One hundred and twenty-seven patients received other nephrotoxic drug(s). Gentamicin (70%) and amikacin (30%) were used and the once-daily dosing was preferred (92%). Average treatment period was 2.75 (1–10) days for amikacin and 4.4 (1–30) for gentamicin with average dosage 13.5 and 3.5 mg/kg/day,
respectively. The monitoring of maximal plasmatic concentration (Cmax) was done in 37 patients, 9 of them had probabilistic
treatment. Only one had a Cmax fulfilling the objective of French recommendations (gentamicin >30 mg/l, amikacin >60 mg/l).
When infection was documented, the objective of Cmax >10 × minimal inhibitory concentration of the strain was reached for
27%. Minimal plasmatic concentration was checked in 38% of cases, with adequate value (gentamicin <0.5 mg/l, amikacin
<2.5 mg/l) for 37%. At the end of aminoglycoside course, 40 patients increased their serum creatinine >25% of the baseline
value. In multivariate analysis, this was associated with treatment length ≥3 days and concomitant use of nephrotoxic drugs.
Conclusion: aminoglycosides dosing used in elderly patients probably need therapeutic drug monitoring and dose adjustment.
Aminoglycosides are used to treat severe infections. One of the most important side effects is nephrotoxicity in oldest patients.
To minimise nephrotoxicity, short treatments are necessary and avoiding others nephrotoxic drugs could be relevant.
Keywords: aminoglycoside, oldest old, renal failure
Introduction
Aminoglycosides are intravenous bactericidal antibiotics whose
broad spectrum encompasses Gram-negative and Grampositive pathogens. They are mainly used in severe infections.
They exert their bactericidal effect against Gram-negative bacteria through a concentration-dependent activity, whereas the
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efficacy determinant against Gram-positive bacteria is mostly
the area under the curve over 24 h. Elimination is almost completely through renal clearance [1]. Aging of the population,
combined with the frequency of severe infections and increasing bacterial resistance, leads to widespread aminoglycoside use
in old patients. However, this population has an increased risk
of toxicity such as renal failure [2]. The physiological conditions
Aminoglycosides use in patients over 75 years old
of old patients also influence pharmacokinetic of aminoglycosides (PK) [2]. Some studies have been performed on PK of
aminoglycosides in older patients [3–5] but only few analysed
nephrotoxicity [4, 5]. In 2011, the Agence Française de Sécurite
Sanitaire des Produits de Santé and the French Infectious
Diseases Society (Société de Pathologie Infectieuse de Langue
Française, SPILF) published an update of guidelines on the use
of aminoglycosides [6]. The recommendations promote oncedaily use, short treatment and adequate dose, as efficacy
requires a plasmatic peak concentration (Cmax) as high as 8- to
10-fold the minimum inhibitory concentration (MIC) of the
target pathogen, while toxicity is mostly related to high-trough
(Cmin) concentration [1, 6, 7]. The aim of our study was first to
describe aminoglycosides use in current practice in older
patients (≥75 years old) and then to analyse nephrotoxicity.
Methods
A national multicenter retrospective observational study was
conducted on behalf of the SPILF and of Geriatric Medicine
society (Société Française de Gériatrie et Gérontologie,
SFGG). The inclusion criteria were patients 75 years and
older hospitalised for >24 h who received at least one dose
of aminoglycoside, after March 2011 (date of publication of
the French national guidelines for aminoglycoside use) and
discharged before the beginning of the study. Electronic
mailing lists of the two societies were used to recruit the investigator centers. Each participating center had to include
the last five consecutive patients fulfilling the inclusion criteria. A standardised data collection sheet were retrospectively filled in from the medical charts including: demographics
(sex, age), weight, serum creatinine and glomerular filtration
rate (GFR) estimated by the Modification of Diet in Renal
Disease (MDRD) formula [8], concomitant use of other
nephrotoxic drugs, type of infection, microbiological data, all
antibiotic drugs used, and for aminoglycosides, their plasmatic concentration monitoring, route of administration and
length of treatment. Follow-up data, such as survival and
renal function, were also evaluated. Physician should report
ototoxicity if patient complained of loss of audition or
dizziness. However, audiolgic or vestibular investigations
were not required. We analysed PK parameters according to
values compared with national recommendations [6]: Cmin of
≤0.5 mg/l for gentamicin and 2.5 mg/l for amikacin and
Cmax of 30–40 mg/l for gentamicin and 60–80 mg/l for
amikacin when aminoglycoside were used as empiric treatment (without documentation when Cmax was checked) and
a Cmax of >10 times the MIC of strain isolated in documented
infections.
Nephrotoxicity was defined by an increase of creatinine
level over 25% between admission and the last available
measure was used to define nephrotoxicity. We used the
National Kidney Foundation (NKF) guidelines for chronic
kidney diseases classification [9]: renal impairment was considered as patients who had worsened functional class.
Statistical analysis
Descriptive statistics were used to characterise the population. Discrete variables were expressed as counts with percentages and continuous data were expressed as mean ± SD.
Categorical data were compared using χ 2-test or Fisher’s
exact test, as appropriate, and continuous variables were
compared using the Student’s t-test. The Mann–Whitney
U-test and the Wilcoxon-rank test were used to compare
continuous non-normal distributed variables. A logistical regression was used to examine the contribution of factors for
renal failure in the univariate analysis. Multivariate logistic regression analysis was carried out for the factors associated
with the risk of renal failure by the univariate analysis
(P < 0.20). The threshold of significance was set at 5% for all
tests and pertinent statistical results were presented in the
format of odds ratio (OR) with 95% confidence interval
(CI). The risk factors of renal failure was defined by either an
increase of 25% of serum creatinine or an increase of 50% or
44 µmol/l of serum creatinine or worsening functional class
of chronic renal disease. The concordance of those risk
factors was checked by calculating the multi-judge kappa
concordance coefficient. It ranges between 0 and 1: the
closer to 1 the value, the higher the degree of concordance
is. All statistical analyses were performed with SAS software,
version 9.0 (SAS Institute, Inc, Cary, NC, USA).
Results
Thirty-eight centers participated among French hospitals
and geriatric care centers. There were 15 geriatric medicine
units, 12 infectious disease units, 2 rehabilitation centers, 2
long-term care departments, one nursing home and 7
various units such as internal medicine or intensive care
units. One hundred and eighty-four patients were included
(Table 1). One hundred and seventy-six (69%) received at
least one concomitant potentially nephrotoxic drug: loop diuretic (76 patients), angiotensin converting enzyme inhibitor
(ACEi) (38), angiotensin receptor Blocker (28), vancomycin
(21), iodine contrast product injection (20) and other drugs
(6). The infection’s sites were urinary tract (UT) (60 patients),
endocardium (36), lower respiratory tract (LRT) (25), bone
and joint (BJ) (15), skin and soft tissues (SST) (6), brain (2).
Thirty-one patients had isolated bacteremia, 2 febrile neutropenia and 7 fever of unknown origin (FUO). Infection was
documented for 153 patients (83%): 79 had Gram-positive
cocci (GPC) isolated, 68 Gram-negative bacilli (GNB) and 6
other. The most frequently isolated bacteria were: Staphylococcus
aureus (34 strains), Escherichia coli (31), Streptococcus sp. (21),
Enterococcus sp. (18) and P. aeruginosa (16).
Ninety-six patients received a first antibiotic before the
aminoglycoside, such as β-lactamin in 71cases, quinolone in
16, macrolide or lincosamide in 8 and cotrimoxazole in
6. The sites of infection were UT (22), endocardium (22),
LRT (18), bacteremia (15), BJ (8), FUO (5), SST (3), febrile
neutropenia (2) and brain abscess (1). Four patients received
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T. Fraisse et al.
Table 1. Description of the population studied: global data and according to unit of hospitalisation
Unit of hospitalisation
Total
Geriatric
Infectious disease
Medicine
Others
Number(n)
Mean age (years) (range)
Patients >85 years n (%)
Sex ratio: Male/female
Mean weight (kg) (range)
Mean body mass index (range)
Mean creatinaemia (µmol/l) (range)
Mean glomerular filtration rate
(MDRD) (ml/min) (range)
Mean albuminaemia (g/l) (range)
Mean length of stay (days) (range)
184
84.4 ± 5.3 (75–101.8)
85 (46%)
109/75
67 ± 15.8 (34–116)
25 ± 5.2 (14–41)
103 ± 50 (20–377)
49 ± 23 (10–311)
75
86.5 ± 5.4 (75–101.8)
48 (64%)
40/35
62.2 ± 14 (34–96)
23.4 ± 4.6 (17–37)
108 ± 42 (20–249)
65 ± 41 (22.5–311)
21
83.4 ± 4.9 (75.7–94.2)
8 (38%)
11/10
66 ± 15.6 (42–100)
25.4 ± 4.8 (18–37)
98 ± 62 (35–273)
78 ± 36 (15–164)
74
82.3 ± 4.3 (75.3–92)
21 (28%)
50/24
71.6 ± 14.8 (75–91)
25.8 ± 5.2 (15.9–36)
99 ± 46 (46–300)
74 ± 29.7 (18–147)
14
85.5 ± 5.5 (75–93)
8 (57%)
8/6
71.3 ± 20.8 (42–116)
27.2 ± 7 (14–41)
113 ± 85 (46–377)
72 ± 35 (10–144)
27 ± 6.5 (12–49)
24 ± 26 (2–150)
26 ± 6.4 (12–41)
27 ± 31 (2–150)
27 ± 5.2 (14–34)
17 ± 10 (3–45)
28 ± 7 (15–49)
24 ± 23 (2–141)
27 ± 5 (19–38)
....................................................................................
Table 2. Prescription of aminoglycoside and data on plasmatic monitoring (Cmin: minimal concentration of aminoglycoside,
Cmax: maximal concentration of aminoglycoside)
Total
Amikacin
Gentamicin
184 (100%)
166 (90%)
56 (30%)
49 (87%)
128 (70%)
117 (91%)
169 (92%)
11 (6%)
4 (2%)
54 (97%)
2 (3%)
115 (90%)
9 (7%)
4 (3%)
175 (95%)
2 (1%)
7 (4%)
–
51 (91%)
1 (2%)
4 (7%)
2.75 ± 2 (1–10)
13.5 ± 4.4 (3.8–25)
10 (18%)
43.3 ± 15 (24–72)
2 (20%)
2 (22%)
14 (25%)
2.2 ± 1.5 (0.8–6.4)
10 (71%)
1 (25%)
124 (97%)
1 (0.8%)
3 (2.2%)
4.4 ± 5.2 (1–30)
3.5 ± 1.2 (0.4–7)
27 (21%)
9.4 ± 4.8 (3.2–24)
6 (28%)
14 (52%)
57 (44%)
1.66 ± 1.8 (0.2–7.8)
16 (28%)
10 (24%)
....................................................................................
n (%)
Senior
Number of administrations per day
1
2
3 and more
Route of administration
Intravenous
Intramuscular
Subcutaneous
Mean length of administration (days) (range)
Mean dose (mg/kg)
Cmax monitoring (n, %)
Mean Cmax (mg/l) (range)
Patient with correct Cmax n (%)
Dosage adaptation n (%)
Cmin monitoring (n, %)
Mean Cmin value (mg/l) (range)
Patient with correct Cmin
Interval adaptation (n, %)
37 (20%)
7 (19%)
16 (43%)
71 (38%)
26 (37%)
11 (24%)
aminoglycoside alone, whereas 138 patients were concomitantly given other antimicrobial and 42 patients 2 or more.
The two used aminoglycosides were gentamicin and amikacin (Table 2). Once-daily administration was used for 169
patients (92%) mostly intravenously. Thirty-seven patients
(20%) had a Cmax measured. Nine patients who received
aminoglycosides as empiric treatment had Cmax checked and
only 1 (11%) reached the objective recommended by national
guidelines [6]. Cmax control was used for 28 patients who had
documented infection. Only 22 isolated strains had an available MIC. Six out of 22 patients (27%) had a Cmax of >10
MIC. Median Cmax value was 8.4 mg/l for gentamicin and
45 mg/l for amikacin. Only 16 patients had a dosage adjustment reported. Patients with plasma Cmax monitoring had no
statistically different age, body mass index, severity of disease
or albuminaemia compared with other patients. Twenty-two
patients had only one Cmax dosage, 9 had 2 and 6 had ≥3
678
monitored Cmax. Cmin was monitored in 71 patients (38%).
Out of these 71 patients, 26 Cmin (36%) were correct (<2.5
mg/l for amikacin and <0.5 mg/l for gentamicin) [6]. Eleven
out of 45 patients (24%) who had Cmin above the recommended value had an adaptation of interval length between
administrations. No statistical difference was found for unit
of admission, albuminaemia, renal function and use of other
nephrotoxic drug between patient who had Cmin monitoring
and those who did not. Thirty-five patients had 1 Cmin
dosage, 14 had 2, 10 had 3 and 12 had ≥4 controlled Cmin
(up to 13 × Cmin dosages). Aminoglycosides were stopped in
47 patients (25%) before the end of treatment such as physician initially prescribed. Twenty-four had a GPC infection, 7
a GNB, 6 a polymicrobian infection and 10 did not have isolated pathogen. Site of infections were: endocardium (16),
UT (kidney 6, prostate 3), bacteremia (6), FUO (6), BJ (5),
LRT (4), febrile neutropenia (1). The causes of
Aminoglycosides use in patients over 75 years old
Table 3. Univariate analysis of risk factors associated with
renal impairment after aminoglycoside use
No renal
impairment
n (%)
Renal
impairment
n (%)
P-value
OR [95%
confident
interval]
........................................
Sex
Female
53 (42.74)
Male
71 (57.26)
Age
<85 years
68 (54.84)
≥85 years
56 (45.16)
Nephrotoxic drug
No
41 (33.06)
Yes
83 (66.94)
Infection severity
Sepsis
84 (67.74)
Severe
40 (25.81)
sepsis
+choc
Aminoglycoside
Gentamicin
84 (67.74)
Amikacin
40 (32.26)
Prescription duration
<3 days
98 (79.03)
≥3 days
26 (20.97)
Number administration per day
1
115 (92.74)
>1
9 (7.26)
Monitoring residual level
No
79 (63.71)
Yes
45 (36.29)
8 (26.67)
22 (73.33)
17 (56.67)
13 (43.33)
3 (10.00)
27 (90.00)
22 (73.33)
8 (26.67)
0.11
1
2.1 [0.85–4.97]
0.86
0.02
1
4.5 [1.27–15.52]
0.59
25 (83.33)
5 (16.67)
0.09
14 (46.67)
16 (53.33)
<0.001
1
4.31 [1.86–9.95]
24 (80.00)
6 (20.00)
0.04
1
3.19 [1.04–9.82]
13 (43.33)
17 (56.67)
0.04
1
2.29 [1.02–5.16]
discontinuation were: adverse event (n = 13), difficult venous
access (n = 4), failure of treatment (n = 2) and not reported
(n = 28). At the end of hospitalisation, 117 patients were considered cured and 19 had a remaining infection. Forty-eight
patients (26%) died: 11 patients out of 25 (44%) who had
LRT infection died, 11 out of 31 (35%) with bacteremia, 12
out of 36 (33%) with endocarditis, 9 out of 60 (15%) with
UT infection and 5 among those who had other sites of infection. Death was attributed to infection in 28 cases. No
ototoxicity was reported. Forty patients (22%) had an increase in their serum creatinine level over 25% at the end of
hospitalisation. In univariate analysis, significant factors associated with increased serum creatinine were (Table 3) length
of treatment, concurrent nephrotoxic drug administration,
multiple daily dose and Cmin monitoring. In multivariate analysis, risk factors were treatment of >3 days (P = 0.003, OR:
5.25 [95% CI: 2.16–12.74]) and concomitant administration
of nephrotoxic drug (P = 0.0085, OR: 5.79 [95% CI: 1.57–
21.38]). We tested concordance between the definition of
renal failure that we have chosen (a 25% raise of serum creatinin) and three other definitions used in the literature: a raise
of 50% of serum creatinin, an increase of 44 µmol/l of
serum creatinin and an alteration of functional class of renal
failure (NKF). The kappa coefficient concordances were
0.815 [CI: 0.694–0.938], 0.769 [CI: 0.635–0938] and 0.76
[CI: 0.617–0.877], respectively.
Discussion
Aminoglycosides are bactericidal antibiotics with a remarkable efficacy and synergistic activity when used in combination regimens for severe infections or resistant bacteria
common in the elderly. However, the well-known nephrotoxicity of aminoglycosides limits their use in this frail population. Aminoglycosides have their best bactericidal activity as
concentration-dependent antimicrobials against GNB: that
is, the drug Cmax should at least be 8- to 10-fold the pathogen MIC. Based on the latest European Committee
Antimicrobial Susceptibility testing [10], the French recommendations and also some recent data [6, 11, 12] proposed to
increase the target concentration for a real therapeutic use of
this antimicrobial class. Higher dosages (15–20 mg/kg/day
of amikacin, 3–8 mg/kg/day of gentamicin) have therefore
been proposed to reach this goal. It is clear that microbiological and clinical susceptibilities do not always match:
indeed, even if from a microbiological point of view amikacin
is considered as a therapeutic choice up to MIC = 16 mg/l,
according to CLSI standards, such a strain would really
require amikacin target concentration at 160 mg/l, which
becomes an impossible threshold.
Our study is one of the first focusing on aminoglycosides
practical use in the oldest patients. The French network of
the geriatric and infectious disease societies led to a large
number of patients included. We decided to include only five
consecutive patients per center to limit center bias. Low
value of mean serum albumin is an illustration of both intensity of inflammation and also mild-to-moderate malnutrition.
Most of the patients had a chronic renal failure with an
average GFR of 49 ml/min/1.73 m2. Nevertheless, renal
impairment could also be due to the sepsis related injury,
pre-existing risk factors, dehydration and other nephrotoxic
treatments [13]. The high number of patients receiving loop
diuretics and ACEi or angiotensin receptor blockers also
reflects the burden of comorbidities in the studied population. Concurrent presence of multiple comorbidities and severity of infections could explain the length of stay (24 days)
and mortality rate (26%). Few patients received subcutaneous
or intramuscular injections. Subcutaneous route is not routinely recommended for aminoglycosides because of the risk
of skin necrosis [6, 14]. No such side-effect was reported in
our study. Treatment duration was associated with renal impairment and could be reduced in most of cases except
endocarditis. Bactericidal and synergic effect of aminoglycosides are the most important at the beginning of the treatment in order to quickly reduce inoculums and withdraw
therefore the administration as soon as possible [1, 6]. This
can be particularly true for geriatric patients who seem to
have significant renal function impairment after 3 days. The
single daily dose was associated with less risk of renal impairment in univariate analysis but this was not significant in
the multivariate model. The average dose was lower than
recommended for amikacin (mean: 13.5 mg/kg/day) and in
the lower range for gentamicin (mean: 3.5 mg/kg/day).
Aminoglycosides exert their best activity with a Cmax/MIC
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T. Fraisse et al.
ratio of ≥8–10 [1, 6, 11]. To achieve the target concentration,
a high dose of aminoglycoside should be delivered. The low
administered dose recorded in the present study could
explain that only few patients reached the targeted Cmax. It
may also be related to treatment failure and infection-related
mortality. Indeed, even if the extension in the aminoglycoside
administration could afford to obtain therapeutic levels, it is
still difficult to accept full single dose in case of renal impairment. As a matter of facts, Cmax monitoring seems absolutely
advisable in the presence of high MIC or difficult-to-treat
infections, whereas Cmin monitoring would drive the timing
between one and another injection, while avoiding drug toxicity. Aminoglycoside Therapeutic Drug Monitoring (TDM)
was not routinely used in our study. We did not find any
factors statistically associated with aminoglycoside TDM. PK
data were also difficult to obtain with few patients achieving
the recommended plasmatic concentration values.
Beside the high number of inadequate plasma concentration
of aminoglycoside, it is interesting to note that there was little adjustment of aminoglycoside dose or interval schemes. A part of
explanation may be the delay needed to obtain the PK results.
In our study, renal failure was defined by a rise of >25%
of serum creatinine. There is no consensual definition of
renal failure in studies on aminoglycosides. We compared
with different published definitions and found that the risk
factors associated in the multivariate analysis were similar.
We also compared with a definition of renal failure using the
classification of NKF [9]. It also had a good correlation with
the results found with our definition. The two most important factors associated with the aminoglycosides renal toxicity
were treatment duration (≥3 days) and concomitant use of
nephrotoxic drug such ACEi or loop diuretic.
Conclusion
Aminoglycoside are commonly used in the elderly with
impaired conditions and usually severe disease. When prescribing aminoglycoside, it is important to use the highest
dose and the shortest as possible (<3 days). Limiting concomitant prescription of other nephrotoxic drugs could be
also relevant to prevent nephrotoxicity. PK monitoring is
helpful in order to adapt aminoglycoside dose and interval
schemes according to the good practice recommendations,
especially if the patient has renal impairment risk factors.
Key points
• Aminoglycoside are commonly used in oldest old patients
with impaired conditions and usually severe disease.
• When prescribing aminoglycoside, it is important to use
the right high dose for as short as possible (<3 days).
• Whenever it’s possible, limiting concomitant prescription
of other nephrotoxic drugs could prevent aminoglycoside
nephrotoxicity.
680
Acknowledgements
All the physicians that participated to data collection: A
Barrel (Ch durecu), S Bayle (CH Avignon), V Berard (CH St
Marcellin), C Clement (CH L’estran), D Croisier Bertin
(CHU Dijon), M Debray (CH annecy), JF Desson (CH de
Bayeux), a Dinh (CHU R Poincare Garches), D Entrecanale
(Ch Leopold Bellan), B Fougere (CH Lomme), M Guillet
(CHU Nantes), C Jarry (CH Angouleme), S Kripciak (Chu
H Montdor), L Legout (Ch Alpes Leman), AL Lecapitaine
(CH Mantes LA Jolie), G Lefalher (CH Beziers), A Makinson
(clinique Beausoleil), J Marchal Fenninger (CH Bischwiller), F
Mechai (Chu Avicennes), D Patial Delon (Chu Rennes), C
Peng (GH Sainte Perrine), D Phardin (CH Dreux), E piet
(Hopital Sud Leman), G Puigserver (CH Aix), K Repesse
(Hospital A Pare), D Rioux (GH Bichat), I Rouannet (CHU
Nîmes), JL Schmit (CHU Amiens), P Suel (CH Dieppe), JP
Stahl (CHU Grenoble).
Conflicts of interest
None declared.
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© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society.
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Abnormal levels of brain metabolites may
mediate cognitive impairment in stroke-free
patients with cerebrovascular risk factors
DONG SUN1, JUNJIAN ZHANG1, YUANTENG FAN1, XUAN LIU1, YONGZHE GAO1, GUANGYAO WU2, YATAO YAN1,
JUNJIE ZENG2
1
Department of Neurology, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Hubei 430071, China
Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
2
Address correspondence to: J. Zhang. Tel: +(86) 027 67813086; Fax: +(86) 02768758670. Email: [email protected]
Abstract
Objective: conventional vascular risk factors (VRFs) are associated with cognitive impairment independent of stroke and
detectable cerebral lesions. We used proton magnetic resonance spectroscopy (1H MRS) to examine the hypotheses that abnormal levels of brain metabolites may mediate the relationship between VRFs and cognitive impairment.
Methods: a group of 54 stroke-free subjects with various VRFs underwent comprehensive cognitive assessments and 1H
MRS scan of the left hippocampus and prefrontal cortex. We indirectly measured the concentrations of N-acetylaspartate
(NAA), choline, inositol, creatine (Cr) and total concentrations of glutamate plus glutamine (Glx). VRFs were quantified by
Framingham stroke risk profile (FSRP) score. Subjects were divided into low- (<10%), medium- (10–20%) and high-risk
(>20%) groups according to their FSRP scores. Pearson and partial correlation analysis were used to investigate the correlation
between FSRP scores and cognitive performance along with the brain metabolism.
Results: compared with subjects in low-risk group, high-risk group subjects had significantly poor performances on the tasks
of working memory, delayed recall and executive function. In high-risk group, hippocampal Glx/Cr ratios and prefrontal
NAA/Cr ratios were significantly lower than those in low-risk group. Lower prefrontal NAA/Cr ratios were associated with
executive dysfunction, and lower hippocampal Glx/Cr ratios were associated with impaired delayed recall.
Conclusion: abnormal concentrations of brain metabolites and decreased glutamate plus glutamine concentration may play an
important role in the pathophysiology of VRF-associated cognitive impairment. Brain metabolites detected by 1H MRS may
serve as important markers for monitoring VRFs burden.
Keywords: brain metabolites, cognitive impairment, Framingham stroke risk profile
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