Copyright @ 2010 by the Shock Society. Unauthorized reproduction of this article is prohibited.

ASSOCIATION OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION WITHELEVATED NTYPRO-BNP IN GENERAL INTENSIVE CARE UNIT PATIENTSWITH PRESERVED EJECTION FRACTION: A COMPLEMENTARY ROLE

OF TISSUE DOPPLER IMAGING PARAMETERS AND NTYPRO-BNPLEVELS FOR ADVERSE OUTCOME

Ignatios Ikonomidis,* Maria Nikolaou,* Ioanna Dimopoulou,† IoannisParaskevaidis,* John Lekakis,* Irini Mavrou,† Marinella Tzanela,‡ Petros

Kopterides,† Iraklis Tsangaris,† Apostolos Armaganidis,†

and Dimitrios T.H. Kremastinos**Second Department of Cardiology and †Second Department of Critical Care Medicine, Attikon Hospital,

Medical School, University of Athens, and ‡Department of Endocrinology, EvangelismosHospital, Athens, Greece

Received 6 Apr 2009; first review completed 21 Apr 2009; accepted in final form 5 May 2009

ABSTRACT—The mechanisms of the N-terminalYproYbrain natriuretic peptide (NTYpro-BNP) release in intensive careunit (ICU) patients with preserved ejection fraction (EF) are unclear. We investigated whether left ventricular (LV)dysfunction, as assessed by tissue Doppler imaging (TDI), is related to NTYpro-BNP levels in ICU patients with preservedEF and has a complementary value to NTYpro-BNP in the determination of in-hospital mortality. We examined 58mechanically ventilated patients with no history of heart failure (age, 60 T 18 years; EF, 63% T 7%). The systolic (S) andearly diastolic (E¶) velocity of the mitral annulus by TDI and the E/E¶ as well as NTYpro-BNP, troponin, lactate acid, bloodoxygen (PO2/FIO2), sepsis, and ICU mortality were assessed. Systolic, E¶, and E/E¶ correlated with age, PO2/FIO2, lactateacid, NTYpro-BNP, troponin, history of arterial hypertension, and diabetes (P G 0.05). By multivariate analysis, thedeterminants of NTYpro-BNP were S (P = 0.024), E/E¶ (P = 0.017), and sepsis (P = 0.015). An NTYpro-BNP greater than941 pg/mL was a reliable predictor of LV diastolic dysfunction defined as a composite of E¶ less than or equal to 8 cm/sand/or mean E/E greater than or equal to 13 (area under the curve, 75%; P = 0.03). Patients with combined NTYpro-BNPgreater than 941 pg/mL and abnormal TDI markers had increased creatinine levels and a lower MAP, PO2/FIO2, andsurvival rate than those with abnormal TDI or NTYpro-BNP alone or patients with normal TDI markers and NTYpro-BNP(25%, 60%, 70%, and 84%, respectively; P G 0.05). The addition of abnormal TDI in a model including NTYpro-BNP andsepsis increased the model’s value for in-hospital mortality (P for change = 0.01). In ICU patients with preserved EF, LVdiastolic dysfunction and sepsis determine NTYpro-BNP levels. Tissue Doppler imaging markers and NTYpro-BNP have acomplementary value for in-hospital mortality.

KEYWORDS—Tissue Doppler imaging, diastolic dysfunction, NTYpro-BNP, natriuretic peptides, prognosis, intensive careunit

INTRODUCTION

Several studies have investigated the use of various clinical

and biochemical markers to assess outcome in critically ill

patients (1, 2).

Recently, the use of natriuretic peptides as prognostic

indicators in critical illness has aroused great interest (1Y8).

Brain natriuretic peptide (BNP) is a polypeptide neuro-

hormone, which is mainly produced and secreted by cardio-

myocytes. The main stimuli for its synthesis and release is

myocyte stretch because of elevated cardiac pressure and/or

volume (2). Thus, increased myocardial wall stress because of

hypertension, diabetes and myocardial ischemia, structural

myocardial disease such as left ventricular (LV) hypertrophy,

and excessive intravascular volume causing myocardial

stretch and cardiac dilatation may increase BNP (2, 9).

However, inflammation (10), neurohumoral activation, angio-

tensine II, stress hormones (2, 11), and hypoxia (12), as well

as treatment with inotropic agents and fluids (11), are also

considered as triggering factors for BNP production in

critically ill patients. The pharmacologic effect of BNP at

the cellular level is mediated by increases in cyclic guanosine

monophosphate, which lead to relaxation of vascular smooth

muscle (2). Brain natriuretic peptide induces vasodilation;

inhibits renin, aldosterone, and angiotensin production;

increases diuresis; and is thus an important regulator of fluid

homeostasis (2). Studies have postulated that the vasodilatory

effects of BNP may cause hypotension and impairment of

renal function in septic patients (13) or patients with systolic

heart failure (14Y16). Brain natriuretic peptide is secreted into

the blood as a prohormone, where it is cleaved into active

BNP and inactive metabolite N-terminalYpro-BNP (NTYpro-

BNP) (2). Brain natriuretic peptide and NTYpro-BNP are

produced in equimolar amounts but are removed from the

circulation by different mechanisms at different time rates,

making the plasma concentration unequal (2). N-TerminalYpro-BNP is mainly excreted by the kidneys, has a longer half-

life time, and a better in vitro stability than BNP, which is

cleared by specific clearance cell receptors and enzyme

141

SHOCK, Vol. 33, No. 2, pp. 141Y148, 2010

Address reprint requests to Ignatios Ikonomidis, MD, FESC, University of

Athens, Attikon Hospital, Perikleous 19, N. Chalkidona, Athens 14343, Greece.

E-mail: ignoik@otenet.gr.

DOI: 10.1097/SHK.0b013e3181ad31f8

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neutral endopeptidase (2). Brain natriuretic peptide and

NTYpro-BNP have been widely used as excellent markers in

the diagnosis of LV and prognosis of heart failure patients

(5Y7). In critically ill patients, NTYpro-BNP production may

be triggered by 1) LV dysfunction either preexisting, because

of cardiac disease (9), or acquired, because of hypoxia,

hypoperfusion, and toxic effects of inflammation (11, 12); 2)

renal dysfunction (3); 3) inflammatory mediators released

during infection and/or sepsis (10, 11); 4) elevation of stress

hormones and neurohumoral activation (2, 11) and thus may

be a predictor of adverse outcome.

Traditionally, natriuretic peptides have been used in the

diagnosis and prognosis of systolic and/or diastolic heart

failure (9). Elevated levels of these biomarkers have also been

recognized in noncardiac diseases such as pulmonary embo-

lism, sepsis, chronic obstructive pulmonary disease, and renal

insufficiency (17). The previously discussed noncardiac

causes of elevated NTYpro-BNP are often present in critically

ill patients admitted in a general intensive care unit (ICU).

Tissue Doppler imaging (TDI) indices are able to detect LV

diastolic and/or systolic dysfunction (18Y23) and have been

associated with elevated natriuretic peptide levels during

exercise (24) in patients with suspected diastolic heart failure

despite the presence of a normal ejection fraction (EF).

Furthermore, studies have shown that TDI markers of LV

function bear a prognostic impact on patients with cardiovas-

cular disease (25).

N-TerminalYpro-BNP levels are related with LV diastolic

dysfunction in patients with cardiovascular risk factors such

as hypertension and diabetes or overt cardiac disease (9, 10).

However, the association of LV diastolic dysfunction and

NTYpro-BNP levels in critically ill patients with preserved

EF, no history of chronic heart failure, and a high incidence of

noncardiac causes of elevated NTYpro-BNP during hospital-

ization in a general ICU has not been clearly defined.

In agreement with other investigators, we have previously

shown (3) that nonsurvivors have higher aminoterminal part

of BNP (NTYpro-BNP) levels on admission in ICU than

survivors, and that NTYpro-BNP is an independent predictor

of ICU mortality (3Y8). Furthermore, we have previously

shown that the use of inotropes, renal impairment, sepsis, and

age accounted for nearly 50% of the NTYpro-BNP variation in

ICU patients. However, in our previous study, we did not

investigate whether LV diastolic dysfunction, as assessed by

tissue Doppler echocardiography, is an additional determinant

of elevated NTYpro-BNP levels and whether TDI markers of

LV diastolic dysfunction have an independent and incremen-

tal value to NTYpro-BNP levels in the assessment of the in-

hospital mortality. Thus, in the present study, we hypothesized

that LV diastolic dysfunction is an additional determinant of

increased NTYpro-BNP levels in critically ill patients with

preserved ejection function and no history of heart failure

admitted in a general ICU, and thus, NTYpro-BNP may be a

reliable marker of LV diastolic dysfunction in these patients.

We also hypothesized that elevated NTYpro-BNP and abnor-

mal indices of LV function as assessed by TDI may have a

complementary value in the determination of in-hospital

mortality.

The aim of our study was 1) to investigate whether

NTYpro-BNP levels are independently related to LV diastolic

dysfunction as assessed by TDI in critically ill patients with

preserved ejection function and no history of heart failure

admitted in a general ICU and 2) to examine whether TDI

markers of LV diastolic function and NTYpro-BNP levels

have complementary value in the determination of the in-

hospital mortality in these patients. We have chosen to study

patients with preserved ejection as an association between

systolic cardiac dysfunction, BNP levels, and in-hospital

mortality has been demonstrated in critically ill patients (26).

PATIENTS AND METHODS

PatientsThis prospective single-center study included serial recruitment of

critically ill patients, aged older than 18 years, requiring support withmechanical ventilation, admitted in our general ICU during a 12-monthperiod. The study was approved by the hospital’s ethics committee, andinformed consent was obtained from patients’ relatives. Exclusion criteriaincluded chronic heart failure, defined by known history of hospitalization dueto heart failure decompensation and/or an LV ejection fraction (LVEF) of lessthan 45% on admission echocardiography, atrial fibrillation, and preexistentrenal insufficiency (history of serum creatinine 91.8 mg/dL before ICU entry).Patients’ clinical information included age, sex, reason for admission, diseaseseverity according to the Acute Physiology and Chronic Health Evaluation IIscore, degree of organ dysfunction quantified by the Sequential Organ FailureAssessment (SOFA) score, the presence of sepsis by using widely acceptedguidelines (27), requirement for inotropic agents (norepinephrine, dobut-amine, or dopamine), MAP, and central venous pressure (CVP). Blood gasanalysis, including partial pressure of oxygen (PO2), carbon dioxide (PCO2),and lactate acid, was also available. The ratio of partial pressure of oxygenin blood to the oxygen concentration given during mechanical ventilation(PO2/FIO2) was used as a marker of oxygenation. In-hospital outcome wasdefined as mortality during hospitalization.

EchocardiographyTransthoracic echocardiography was performed on admission using a

Vivid 4 (GE Medical Systems, Horten, Norway) phased array system. Studieswere digitally stored and analyzed by two observers (I.I., M.N.) blinded toclinical and laboratory data using a computerized station (Echopac GE). Allpatients had adequate images for analysis. For the analysis of segmental wallmotion abnormalities, a 16-segment protocol was used (28). Each segmentwas scored as follows: 1 indicates normal; 2, hypokinetic; 3, akinetic; and 4,dyskinetic. A total wall motion score was calculated as the sum of all16 segments. The wall motion score index was defined as the ratio of thenumber of segments with wall motion abnormalities divided by the total of all16 segments (normal value, 1). Patients with wall motion score index greaterthan or equal to 1.125 (corresponding to wall motion abnormalities in at leasttwo segments) were considered to present segmental wall motion abnormal-ities (28). However, none of our patients showed evidence of segmental wallmotion abnormalities. The following parameters were measured from cross-sectional echocardiographic images of the LV: 1) end-diastolic (LVEDD) andend-systolic diameter (in millimeters); 2) interventricular septal (IVS),posterior wall (PW) thickness (in millimeters); 3) relative wall thickness(RWT) as the sum of the IVS and PW thickness divided by the LVEDD; 4)fractional shortening and EF (percentage); and 5) left atrium dimension (inmillimeters). Transmitral pulsed wave Doppler velocities were recorded in thefour-chamber view with the sample volume at the tip of mitral valve leaflets.E and A wave velocities and deceleration time of early transmitral flowvelocity were measured. Myocardial velocities were recorded using color TDIto record low-velocity, high-intensity myocardial signals at a high frame rate(120 MHz). A 5-mm sample volume was placed in septal and lateral corner ofthe mitral annulus in the apical four-chamber views to record the systolicvelocity (S¶), early diastolic velocity (E¶), and late diastolic velocity (A¶). Themean value of the S¶, E¶, and A¶ in the septal and lateral corner was used foranalysis. The ratio of E wave of the mitral inflow measured by pulsed waveDoppler to the E¶ was calculated as an index of LV diastolic filling pressures.All Doppler markers were measured at the end-expiration (29). Interobserverand intraobserver variability of these measurements was 3% and 1.7%,respectively. Patients were stratified into those with or without a composite ofabnormal TDI indices of LV diastolic dysfunction. The composite wasdefined as mean E¶ less than or equal to 8 cm/s and/or septal E¶ younger than

142 SHOCK VOL. 33, NO. 2 IKONOMIDIS ET AL.

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40 years less than 9 cm/s, septal E¶ 40 to 60 years less than 7 cm/s, E¶ olderthan 60 years less than 6 cm/s, E/E¶ greater than 12 for the lateral corner, E/E¶greater than 15 for the septal corner of the mitral annulus, mean E/E¶ greaterthan or equal to 13 using previously published cutoff values (9, 18Y23)Furthermore, the patients were also stratified into those with an S less than orequal to 8 cm/s and those with higher S values, suggesting a normal systoliclongitudinal function of the LV (19).

Laboratory measurementsBlood samples were drawn on admission to determine NTYpro-BNP. The

blood was centrifuged and stored at j70-C until assayed. N-TerminalYpro-BNP was measured by the same study-assigned laboratory using commer-cially available kits (NTYpro-BNP; Elecsys 2010, Roche Diagnostics,Mannheim, Germany). The interassay coefficient of variance is less than3.0%. The analytic range is from 20 to 35,000 pg/mL. Patients’ hematologicaland biochemical profile included hemoglobin, white blood cells, platelets,INR creatinine, electrolytes, albumin, bilirubin, and troponin T.

Statistical analysisAll data were tested for normal distribution by the Kolmogorov-Smirnov

test. Results are presented as medians and ranges for parameters with non-normal distribution or mean values and SDs. Group comparisons wereperformed by Mann-Whitney and chi-square tests. Pearson and Spearmancorrelation coefficient assessed the associations between variables. Thelogarithm of the variables with a skewed distribution underwent logarithmictransformation for analysis. By receiver operator characteristic analysis, weassessed the predictive value of NTYpro-BNP for the presence of LV diastolicdysfunction. The area under the receiver operator characteristic curve andcorresponding confidence intervals (CIs), as well as the correspondingsensitivity and specificity, were calculated. Patients’ cohort was also stratifiedas patients with a composite of normal versus abnormal diastolic TDI indices(as previously defined), and the corresponding survival curves were comparedby the log-rank test. The combination of elevated NTYpro-BNP and abnormaldiastolic TDI markers for ICU mortality was also examined by survivalcurves. Univariate Cox regression analysis was used to calculate the relativerisk and CIs of the examined variables for in-hospital mortality. MultivariateCox regression analysis was used to assess the incremental value of thecomposite of abnormal TDI indices over other prognostic factors. The changeof -2LogLikelihood after addition of the composite of abnormal TDI in the

multivariable model was used to assess statistical significance. A P G 0.05was considered statistically significant in all analyses.

RESULTS

Of 75 patients fulfilling the inclusion criteria, 5 had in-

adequate echo image quality due to severe chronic obstructive

pulmonary disease, 5 died on ICU admission and thus did not

have an echo study, and 7 had extensive chest trauma

excluding the feasibility of a transthoracic echo study. Thus,

58 patients (39 men) with a mean age of 60 T 18 years (range,

18Y85 years) under mechanical ventilation were finally

included in the study. Admitting diagnosis was related to

medical (n = 35), surgical (n = 20), or multiple trauma (n = 3)

critical states. Additionally, 39 of 58 patients were diagnosed

to have sepsis, and 5 more had evidence of infection. Of 58

patients, 22 died during hospitalization, yielding an in-

hospital mortality rate of 38%. All patients had preserved

LVEF, with a mean value of 63% T 7%. Echocardiographic

findings are shown in Table 1.

TDI parameters

S, E¶, and E/E¶ correlated with age, NTYpro-BNP, myocar-

dial damage as assessed by troponin levels, PO2/FIO2, lactate

acid, history of hypertension, and RWT (P G 0.05; for all

correlations). Additionally, E¶ and E/E¶ were related with

history of diabetes (P G 0.05) and E¶ with presence of sepsis

(P = 0.04). As assessed by TDI markers, 27 patients (46%)

had a composite of abnormal TDI indices of LV diastolic

function. Of those, 18 patients also had an S less than 8 cm/s.

Patients with a composite of abnormal indices of LV diastolic

function had higher NTYpro-BNP, troponin, lactate acid

levels, incidence of history of hypertension and diabetes,

RWT than patients with normal TDI (P G 0.05; Table 2).

Interestingly, patients with abnormal TDI markers a lower

PO2/FIO2 than patients with normal TDI, suggesting that

elevated LV filling pressures may have caused pulmonary

congestion contributing to hypoxia (P G 0.05; Table 2). MAP

and CVP were similar between patients with abnormal and

normal TDI markers (P = not significant).

TABLE 1. Patients’ baseline echocardiographic evaluation

Mean value T SD

2D

EF, % 63 T 7

LVEDD, mm 49.0 T 5.2

LVESD, mm 31.4 T 6.0

IVS, mm 10.1 T 1.7

PW, mm 9.7 T 1.6

LA ,mm 38.9 T 5.3

RWT 0.41 T 0.07

Doppler

E, m/s 0.89 T 0.27

A, m/s 0.81 T 0.24

DT, ms 200 T 64

Tissue Doppler

S ,cm/s 9.5 T 3.0

E¶, cm/s 10.1 T 4.3

A¶, cm/s 10.9 T 4.5

E/E¶, mean 12 T 4.9

E/E¶, lat 11 T 4.4

E/E¶, IVS 12 T 4.9

A indicates late diastolic velocity of the mitral inflow; DT, decelerationtime of the early Doppler mitral inflow waveform; E, early diastolicvelocity of the mitral inflow; LVESD, LV end systolic diameter; IVS,interventricular septum; LA, left atrium.

TABLE 2. Differences between patients with or without LV diastolicdysfunction as assessed by TDI

LV diastolic dysfunction

Determinants of LVfunction No. (n = 31) Yes (n = 27) P

NTYpro-BNP 925 (106Y13,422) 2,449 (138Y35,000) 0.002

Troponin 0.04 T 0.05 0.23 T 0.2 0.02

Lactate acid 1.4 (0.8Y2.15) 2.0 (1.4Y4.6) 0.04

PO2/Fio2 284 T 154 210 T 121 0.03

History ofhypertension

7 (22%) 11 (40%) 0.02

History of diabetes 3 (11%) 5 (20%) 0.025

RWT 0.38 T 0.05 0.43 T 0.07 0.014

LV diastolic dysfunction was defined as a composite of E¶ e 8 cm/s, orE/E¶ 9 12 for the lateral corner, or E/E¶ 9 15 for the septal corner of themitral annulus or mean E/E¶ Q 13.

SHOCK FEBRUARY 2010 TDI, NTYPRO-BNP, AND OUTCOME IN ICU PATIENTS 143

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N-TerminalYproYbrain natriuretic neptide

In addition to TDI markers, NTYpro-BNP was also as-

sociated with age, myocardial damage as assessed by troponin

levels, RWT, presence of sepsis, inotrope infusion, SOFA

score, and tissue oxygenation as assessed by PO2/FIO2

(P G 0.05 for all correlations) and renal function as assessed

by creatinine levels (regression coefficient b, 0.44; P = 0.02).

In a multivariate linear regression model, including TDI

indices, and univariate determinants of NTYpro-BNP levels

with P less than 0.05 (troponin, age, creatinine, RWT,

presence of sepsis, inotrope infusion, SOFA score, PO2/FIO2)

the most important determinants of NTYpro-BNP levels were

S (regression coefficient b, -0.33; P = 0.024,), E/E¶ ratio

(regression coefficient b, 0.36; P = 0.017), and presence of

sepsis (regression coefficient b, 0.35; P = 0.012). By receiver

operating analysis, an NTYpro-BNP greater than 941 pg/mL

predicted a composite of abnormal TDI markers of LV

diastolic function with 73% sensitivity and 70% specificity

(area under the curve,75%; 95% CI, 68Y94; P = 0.03).

Interestingly, patients with an NTYpro-BNP greater than

941 pg/mL had lower MAP and similar CVP than patients

with lower levels (75 T 11 vs. 84 T 14 mmHg [P = 0.03] and

10.8 T 3.5 vs. 10.9 T 4.0 mmHg [P = 0.83], respectively),

suggesting the presence of a lower BP in the presence of

similar preload or at least similar right atrial Bstretch[ in

patients with increased NTYpro-BNP levels compared with

those with lower levels. Additionally, patients with an

NTYpro-BNP greater than 941 pg/mL had higher creatinine

levels than those with lower levels (1.75 T 1.1 vs. 1.04 T0.5 mg/L; P = 0.03).

Outcome

Of 58 patients, 22 died during hospitalization (59.0 T35 days), yielding a mortality rate of 38%. Survivors had

lower Acute Physiology and Chronic Health Evaluation II

score, troponin, and NTYpro-BNP levels, as well as higher

PO2/FIO2, incidence of sepsis, and higher TDI velocities (P G0.05 for all comparisons). By Kaplan-Meier curve analysis,

patients with a composite of abnormal TDI indices for LV

diastolic function had an increased mortality (survival rate,

37%) compared with patients with normal TDI markers

(survival rate, 83%; log-rank, 11,1; P = 0.001; Fig. 1, A).

The patients with a combination of abnormal TDI markers of

LV diastolic function and NTYpro-BNP greater than or equal

to 941 pg/mL had higher hospital mortality (survival rate,

25%) compared with patients with only abnormal TDI

(survival rate, 60%), only BNP greater than 941pg/mL

(survival rate, 70%), or a combination of normal TDI markers

and NTYpro-BNP less than 941 pg/mL (survival rate, 84%;

log-rank, 11,9; P = 0.007; Fig. 1, B). By Cox regression

analysis, presence of sepsis, NTYpro-BNP levels, and the

composite of abnormal TDI indices of diastolic LV function

were found significant univariate predictors of in-hospital

mortality among all the previously examined variables. The

corresponding relative risk of mortality was 4.6 (95% CI,

1.6Y12; P = 0.003) for the composite of abnormal TDI

markers, 3.1 (95% CI, 1.01Y10.7; P = 0.035) for sepsis, and

2.9 (95% CI, 1.07Y7.9; P = 0.03) for NTYpro-BNP, respecti-

vely. By multivariable Cox regression analysis, the addition

of the composite of abnormal TDI markers of LV diastolic

function, in a model including NTYpro-BNP and sepsis,

significantly increased the prognostic value of the model for

ICU mortality (j2LogLikelihood from j143.8 to j133.6; Pfor change = 0.01, respectively).

Interestingly, patients with a combination of abnormal TDI

markers of LV diastolic function and NTYpro-BNP greater

than or equal to 941 pg/mL had the lowest MAP compared

with patients with only abnormal TDI, only BNP greater than

941 pg/mL, or a combination of normal TDI markers and

NTYpro-BNP less than 941 pg/mL (72 T 8 vs. 79 T 7 vs. 75 T10 vs. 86 T 15 mmHg; F = 3.8; P = 0.014) in the presence of

similar CVP (11.0 T 3.8 vs. 12.7 T 3.2 vs. 11.7 T 4.3 vs. 10.1 T3.5 mmHg; F = 1.07; P = 0.37) as well as the lowest PO2/FIO2

(127 T 98 vs. 198 T 86 vs. 248 T 100 vs. 298 T 122 mmHg/%;

F = 3.8; P = 0.014) and elevated creatinine levels (1.7 T0.5 vs. 1.1 T 0.6 vs. 1.9 T 1.2 vs. 1.1 T 0.7. mg/L; F = 3.9;

FIG. 1. A, Kaplan-Meier curves for the prediction of in-hospital mortality in patients with a composite of abnormal TDI indices of LV function versusthose with normal TDI indices. B, Kaplan-Meier plots for the prediction of in-hospital mortality in patients with 1) normal TDI and NTYpro-BNP less than 941pg/mL, 2) normal TDI and NTYpro-BNP greater than 941 pg/mL, 3) abnormal TDI and NTYpro-BNP less than 941 pg/mL, and 4) abnormal TDI and NTYpro-BNPgreater than 941 pg/mL.

144 SHOCK VOL. 33, NO. 2 IKONOMIDIS ET AL.

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P = 0.01). Thus, patients with a combination of abnormal TDI

markers and NTYpro-BNP greater than or equal to 941 pg/mL

had the lowest PO2/FIO2 and MAP compared with the

remaining patients, suggesting a greater degree of reduced

blood oxygenation and tissue hypoperfusion.

DISCUSSION

In the present study, we have shown that approximately

half of critically ill patients with Bnormal[ EF and no history

of heart failure had evidence of LV diastolic dysfunction, as

assessed by TDI, and one third of them showed evidence of

impaired longitudinal systolic function. Moreover, this is the

first study that demonstrates the independent association of

elevated NTYpro-BNP levels with LV diastolic dysfunction in

mechanically ventilated, critically ill patients with preserved

EF. Furthermore, we have shown that TDI markers of LV

function and NTYpro-BNP levels are complementary predic-

tors of in-hospital mortality in patients with preserved EF on

admission to a general ICU.

LV diastolic dysfunction in ICU patients

Tissue Doppler imaging of the systolic mitral annulus

motion permits an early detection of the longitudinal systolic

dysfunction even if EF remains Bnormal[ (20, 22, 23).

Furthermore, the advantage of the E¶ over the mitral inflow

Doppler markers of diastolic function is that it behaves as

a relatively preload independent index of LV relaxation

(18, 22). E/E¶ is a widely used marker to assess simply and

accurately LV filling pressures (9, 23). Recently, transthoracic

estimation of the E/E¶ ratio at the end-expiration has been

shown to correlate closely with pulmonary artery occlusion

pressure in mechanically ventilated ICU patients (29). The

reduced TDI velocities of the mitral annulus (S, E¶, E/E¶) have

been shown to predict mortality or cardiovascular events

in patients with heart failure, myocardial infarction, or

hypertension (25).In the present study, we have shown that approximately

half of mechanically ventilated, critically ill patients with

Bnormal[ EF and no history of heart failure have evidence of

LV diastolic dysfunction, as assessed by TDI. Additionally,

31% showed evidence of impaired longitudinal systolic

function as assessed by an S¶less than 8 cm/s in addition to

LV diastolic dysfunction despite the presence of a preserved

EF. A reduced early systolic velocity (S) of the mitral annulus

by TDI has been described in patients with preserved EF and

LV diastolic dysfunction such as patients with hypertension,

coronary artery disease, diabetes, or cardiomyopathies (20).

This finding is thought to reflect an impairment of the LV

longitudinal systolic performance caused by dysfunction of

subendocardial myocardial layers on the ground of hyper-

trophy, fibrosis, elevated filling pressures, and subendocardial

ischemia (20). In our study, there was a close association

between TDI indices of LV diastolic function and age, history

of hypertension or diabetes, and relative wall thickness. It is

known that aging, arterial hypertension, diabetes mellitus, and

increased wall thickness may impair the diastolic properties in

the left ventricle (20Y22, 30). Additionally, in our study,

impaired TDI markers were also related with presence of

sepsis and increased levels of lactate acid. This finding

suggests that acidosis and/or inflammation may play an

additional role in myocardial depression in ICU patients

causing LV diastolic dysfunction. Studies have shown that

lactate acidosis (31) and inflammation (32, 33) are associated

with cardiac systolic or diastolic dysfunction. Therefore, we

may hypothesize that each one of the previously discussed

factors or their combination may worsen the myocardial

diastolic properties and longitudinal systolic function, as

assessed by TDI in critically ill patients with preserved EF.

In support of this hypothesis, TDI markers of LV function

were related with troponin levels, confirming that LV

diastolic dysfunction is related with a new-onset myocardial

damage in critically ill patients with preserved EF on

admission to ICU.In conclusion, LV diastolic dysfunction and impaired

longitudinal systolic function in our ICU patients with

preserved EF may originate from a preexisting increased wall

stress on the grounds of hypertension, diabetes, and increased

wall thickness (9), or may be caused from direct effects of

hypoxia, acidosis, and the release of toxic inflammatory

mediators during infection and/or sepsis on myocardium

(11, 22, 31Y33).

Determinants of NTYpro-BNP levels in ICU

Most studies in ICU patients have focused on LV systolic

dysfunction as assessed by means of an impaired EF and its

impact on natriuretic peptides and mortality (6Y8). The

independent association between NTYpro-BNP and TDI

markers of LV diastolic function found in the present study

suggests that LV diastolic dysfunction is a major determinant

of elevated NTYpro-BNP levels in ICU patients with

preserved EF. Studies have shown that myocyte stretch

because of elevated LV filling pressures may cause BNP

production (2). A further stimulus of NTYpro-BNP release is

tissue hypoxia (12). Thus, reduced blood oxygenation

because of pulmonary congestion on the grounds of LV

diastolic dysfunction may contribute to BNP production. In

our study, an NTYpro-BNP greater than 941 pg/mL was a

reliable predictor of LV diastolic dysfunction with 73%

sensitivity and 70% specificity. In ICU patients, the

myocyte stretch leading to elevated NTYpro-BNP may

originate from the LV filling pressures on the basis of

hypertension, diabetes, and increased wall thickness (9,

24, 34). Supporting this hypothesis, studies have shown that

LV stroke work, as well as pulmonary artery occlusion

pressure assessed after cardiac catheterization, correlated

with NTYpro-BNP in ICU patients (29, 34). However,

increased NTYpro-BNP production may be triggered from

the direct effect of inflammatory mediators during sepsis (10,

11, 13), elevated levels of stress hormones (2, 11), renal

dysfunction (2), or from overtreatment with fluids, vaso-

active medications (11), and positive pressure ventilation in

critically ill patients. Sepsis is associated with high cardiac

output, and therapy includes administration of fluids. It is

possible that cardiac distension occurs, with preserved sys-

tolic function causing elevation of BNP secretion (11, 35). In

agreement with other investigators (4Y8, 10), we have shown

SHOCK FEBRUARY 2010 TDI, NTYPRO-BNP, AND OUTCOME IN ICU PATIENTS 145

Copyright @ 2010 by the Shock Society. Unauthorized reproduction of this article is prohibited.

in the present study that NTYpro-BNP also correlated with

age, creatinine levels, inotrope infusion, presence of sepsis,

and hypoxia. Furthermore, the independent association, by

multivariate analysis, of NTYpro-BNP levels with S, E/E¶,

and presence of sepsis supports the hypothesis that sepsis

may cause NTYpro-BNP release in critically ill patients in

addition to diastolic LV dysfunction. The interrelation

between sepsis, TDI markers of LV function, and

NTYpro-BNP in our study suggests that the inflammatory

processes and release of inflammatory mediators in septic

conditions may cause LV diastolic dysfunction (10Y22),

leading to elevated NTYpro-BNP levels in ICU patients.

However, sepsis may cause elevated NTYpro-BNP levels

through mechanisms other than myocardial damage such

as renal impairment, increased stress hormones, and

elevated levels of inflammatory cytokines (11) or coex-

istent noncardiac causes of elevated NTYpro-BNP (10). In

summary, elevated NTYpro-BNP may be a marker of

preexisting LV diastolic dysfunction on the grounds of

hypertension diabetes and LV hypertrophy; of acquired LV

diastolic dysfunction because of sepsis, inflammation,

hypoxia, and acidosis; or of the systemic inflammatory

response during infection or sepsis in our critically ill

patients.

Determinants of ICU mortality

In our previous study (3), we have shown that NTYpro-BNP

levels are independent predictors of outcome in a large mixed

ICU population. In the present study, we have demonstrated

that LV diastolic dysfunction may determine NTYpro-BNP

levels in addition to other comorbidities. Furthermore, we

have shown that LV diastolic dysfunction as assessed by TDI

is a prognostic marker for ICU mortality in patients with

preserved EF in addition to elevated NTYpro-BNP levels and

presence of sepsis. In our study, patients with a composite of

abnormal TDI markers of diastolic LV function had a 4-fold

risk of death during hospitalization. Furthermore, the addition

of the composite of abnormal TDI markers of LV diastolic

function, in a model including NTYpro-BNP and sepsis,

significantly increased the prognostic value of the model for

ICU mortality. This finding suggests that in the presence of

low NTYpro-BNP levels or sepsis, TDI markers become

particularly useful in distinguishing patients at a substantially

lower or higher risk of an adverse event.

Additionally, the combination of normal TDI markers and

low NTYpro-BNP was associated with a survival rate of 84%,

whereas the combination of abnormal TDI markers and BNP

has a survival rate of 25%. Thus, the combination of NTYpro-

BNP levels with the TDI parameters of LV function could

discriminate those with an excellent compared with those with

a poor prognosis during ICU hospitalization.

Patients with the combination abnormal TDI markers and

high NTYpro-BNP levels had a lower survival rate compared

with patients with abnormal TDI or NTYpro-BNP alone or to

patients with normal TDI markers and low BNP levels.

Thus, abnormal TDI markers provided additional prognos-

tic information in patients with high NTYpro-BNP levels and

vice versa.

Our results suggest that TDI markers and NTYpro-BNP

levels may be complementary predictors of ICU mortality in

patients in critically ill patients with preserved EF and are in

line with studies demonstrating the independent and incre-

mental prognostic value of TDI markers in cardiovascular

disease (25).

Considering the causal relation of LV diastolic dysfunction

with outcome, LV diastolic dysfunction raises the left atrial

and pulmonary vein pressure (9, 22Y25) and thus causes

pulmonary congestion contributing to reduced blood oxygen-

ation and, consequently, to tissue hypoxia, acidosis, and

multiple organ failure. Indeed, in our study, patients with

LV diastolic dysfunction had a reduced PO2/FIO2 and

increased lactic acid. Additionally, LV diastolic dysfunction

may not permit an adequate increase of stroke volume in the

presence of excessive peripheral vasodilation during sepsis or

under conditions of low output, leading to tissue hypoperfu-

sion (11). In critically ill patients, elevated NTYpro-BNP may

be a cumulative marker of 1) LV diastolic dysfunction either

preexisting, because of cardiac disease, or acquired, because

of hypoxia, hypoperfusion, and toxic effects of inflammation;

2) renal dysfunction, 3) inflammatory process and tissue

hypoxia during infection and/or sepsis; 4) elevation of stress

hormones and neurohumoral activation and thus may be a

valid predictor of adverse outcome (2, 10Y17).

However, BNP is an active hormone that increases the

cellular production of cyclic guanosine monophosphate, lead-

ing to relaxation of vascular smooth muscle cells and renin

inhibition (2). Thus, elevated NTYpro-BNP may cause inap-

propriate vasodilation, especially in septic conditions, leading

to reduced MAP and thus may aggravate tissue hypoperfusion,

renal dysfunction, and multiple organ failure. Brain natriuretic

peptide antagonizes angiotensin IIYinduced efferent arteriolar

vasoconstriction and thus reduces glomerular filtration rate,

leading to increases in creatinine levels (15).

In agreement with this hypothesis, treatment with nesiritide,

a synthetic form of BNP, has been associated with adverse

outcome in patients with heart failure because of hypotension

and deterioration of renal function (14Y16). In the present

study, we have shown that patients with NTYpro-BNP greater

than 941 pg/mL had lower MAP and serum creatinine than

patients with lower NTYpro-BNP. Thus, through these

mechanisms, NTYpro-BNP levels may have a causal associ-

ation with outcome in our critically ill patients. Furthermore,

patients with combination of elevated NTYpro-BNP and

impaired TDI indices had the lowest MAP and PO2/FIO2 in

addition to elevated serum creatinine compared with the

remaining patients. Thus, pulmonary congestion and/or

inadequate increase of stroke volume under conditions of

peripheral vasodilation, because of LV diastolic dysfunction,

combined with a low MAP, because of the vasodilatory

effects of increased BNP, may contribute to reduced blood

oxygenation, tissue hypoperfusion, hypoxia, and further

deterioration of renal function. The previously discussed

mechanisms may at least partially explain the complementary

role of LV diastolic dysfunction and increased NTYpro-BNP

levels in the prediction of adverse outcome in our cohort of

critically ill patients.

146 SHOCK VOL. 33, NO. 2 IKONOMIDIS ET AL.

Copyright @ 2010 by the Shock Society. Unauthorized reproduction of this article is prohibited.

Study limitations

One of the limitations of our study was the absence of

hemodynamic evaluation of LV filling pressures with a Swan-

Ganz catheter even if the safety and use of these catheters

have been questioned. Furthermore, several studies have

shown a close correlation between elevated E/E¶ and inva-

sively assessed LV filling pressures (9, 18). The relatively

small sample of our patient cohort should also be acknowl-

edged. However, in our study, we have shown that TDI

indices of LV function are a useful prognostic tool, which are

easily performed and readily available by the bedside of

critically ill patients and may discriminate subtle diastolic

abnormalities of the cardiac wall, leading to increased

NTYpro-BNP levels and adverse outcome. Thus, the assess-

ment of TDI velocities of the mitral annulus is a useful tool to

rule out the origin of elevated NTYpro-BNP levels (LV

dysfunction or noncardiac factors) in critically patients with

preserved EF and to stratify more accurately the risk of

adverse outcome on patients’ admission to ICU.

Because patients are admitted into the ICU at varying time

points in the progression of their illness, serial assessment of

TDI markers and NTYpro-BNP over time may be more useful

in the determination of prognosis and the effects of treatment.

In our study, nonsurvivors had reduced oxygenation, a

higher level of acidosis, a higher incidence of sepsis, and

impaired indices of LV diastolic function than survivors. The

close link between adverse outcome and LV diastolic

dysfunction, reduced oxygenation, acidosis, and sepsis in our

study suggests that preexisting diastolic dysfunction may

generate a more Bvulnerable[ myocardium to toxic effects of

hypoxia, acidosis, and sepsis. It should be further investigated

whether prompt treatment of these factors may reverse at least

partly LV diastolic function and, consequently, patients’

prognosis of during ICU hospitalization. In patients with

impaired TDI indices and elevated NTYpro-BNP implying

elevated LV filling pressures, initiation of diuresis, ultra-

filtration, and/or inotropes should be considered individually

according to a patient’s underlying disease, clinical condition,

blood pressure, loading conditions as assessed by CVP, renal

function, and hourly urine volume. However, LV diastolic

dysfunction may also be a marker of increased severity of

illness and thus may not respond to these interventions.

CONCLUSION

In the present study, we have shown that LV diastolic

dysfunction, as assessed by TDI and sepsis, determine

NTYpro-BNP levels in critically ill patients with preserved

EF. Moreover, abnormal TDI indices of LV function and

NTYpro-BNP have a complementary value for in-hospital

mortality.

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