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A comparison of transcutaneous Doppler corrected flow time, b-type natriuretic peptide and central venous pressure as predictors of fluid responsiveness in septic shock: a preliminary evaluation.

Intravenous fluid therapy is an important component of septic shock management. However, reliable prediction of the haemodynamic response to a fluid bolus continues to pose a challenge. Accurate evaluation is important to avoid unnecessary volume replacement which can be deleterious in critically ill patients (1). Clinical assessment of fluid status is hindered by limited sensitivity and specificity of clinical signs in the critically ill patient. Several laboratory and monitoring modalities have been evaluated independently as predictors of fluid responsiveness. Aortic flow time (FT) is the duration of blood flow during systole as measured by Doppler techniques. FT is heart rate dependent. However, correction for heart rate is achieved by dividing FT by the square root of the heart rate period. The result is flow time corrected (FTc), which has been shown to predict fluid responsiveness in critically ill ventilated patients (2) and in neurosurgical critical care (3). To our knowledge there are no published data on the utility of FTc as a predictor of fluid responsiveness specifically in septic shock. Furthermore, no study has previously evaluated non-invasive, transcutaneously measured FTc as a predictor of fluid responsiveness.

Another variable of interest is plasma B-type natriuretic peptide concentration (BNP). As a biochemical marker of heart failure (4), BNP might exclude a fluid responsive state (plateau of Frank Starling curve). However, the potential use of BNP as a predictor of fluid responsiveness in patients with sepsis has only been subject to one previous investigation. That study concluded that plasma BNP was not a reliable marker of fluid responsiveness (5), but the potential interaction between cardiac rhythm and BNP was not specifically addressed in that study. Cardiac dysrhythmia, particularly atrial fibrillation, is common in sepsis and is associated with increased BNP (6).

Given limited data on both these published variables and lack of any comparative studies, we undertook a pilot study to compare FTc, BNP and central venous pressure (CVP) as predictors of fluid responsiveness in septic shock patients without cardiac dysrhythmia. Though its performance as a predictor of fluid responsiveness is questionable (7), CVP was incorporated as a commonly used guide to clinical fluid therapy. An auxiliary aim was to determine the feasibility of transcutaneous Doppler FTc measurement in the setting of septic shock.

MATERIALS AND METHODS

The Uniting Care Health Human Research Ethics Committee (project 2007/36) and the Guardianship and Administration Tribunal of Queensland (project 2006/06) granted approval for this project prior to commencement.

Patients

This preliminary study recruited 10 consecutive adult septic shock patients treated in a multidisciplinary Australian tertiary adult intensive care unit (ICU) during a four-month period (September to December 2007). Eligibility was determined by the clinical decision to undertake intravenous fluid challenge in a patient with septic shock, defined according to the International Sepsis Definitions Conference (8). Exclusion criteria included a patient or legally authorised representative who declined participation, age less than 18 years, cardiac rhythm other than sinus and moderate to severe valvular heart disease. To minimise selection processes, spontaneously breathing patients were included; therefore variables dependent upon heart-lung interaction, such as stroke volume variation and pulse pressure variation, were not studied.

Study protocol

The timing of this study was determined by the clinical decision to administer an acute fluid load. In keeping with recent international consensus statement recommendations9, a 250 ml bolus of 4% albumin (Albumex 4 [40 g/l], CSL Ltd, Parkville, Vic.) was administered over 15 minutes by infusion pump. Doppler and other haemodynamic data was collected immediately before and five minutes after fluid loading. During the study period infusions (including sedation and vasopressors) remained constant and no additional medications were administered.

Transcutaneous Doppler

Non-invasive continuous wave Doppler was performed using a commercially available USCOM[R] device (USCOM Ltd, Sydney, NSW [Figure 1]). A recent comparison of this device with the pulmonary artery catheter in ICU, yielded bias [+ or -] precision of 0.06 l/min/[m.sup.2] [+ or -] 0.4 l/min/[m.sup.2} (10). Using USCOM methodology, measurements were performed via an aortic window, with the 2.2 MHz continuous wave Doppler probe placed in the suprasternal notch or above the clavicle and directed at the aortic valve. All USCOM data resulted from the mean of four consecutive measurements at each time point performed by a single experienced operator. Variables recorded included FTc, velocity time integral, stroke volume, stroke volume index, cardiac output and cardiac index. In the absence of alterations in medications that might affect afterload, FTc less than 350 ms was accepted as an index of hypovolaemia (11,12).

Plasma B-type natriuretic peptide concentration

Arterial blood was collected into EDTA tubes (BD Vacutainer, UK) concurrently with the initial haemodynamic assessment. Plasma BNP concentration was quantified using the ADIVA Centaur[R] CP system (sensitivity and assay range 2.0 to 5000 pg/ml). Elevation of BNP was defined by a threshold of 144 pg/ml, as previously reported as a strong predictor of cardiac dysfunction in ICU (13).

[FIGURE 1 OMITTED]

Haemodynamics

All patients had central venous catheters for clinical monitoring. Marquette Solar 9500 clinical monitors (Marquette Medical Systems/GE Healthcare) were used. Pulmonary artery catheters were not used.

Fluid responsiveness

A variable was regarded as a predictor of fluid responsiveness if its baseline value correlated with the change in stroke volume associated with fluid challenge (1). A favourable response to fluid challenge was defined by an increase in stroke volume of [greater than or equal to] 15%; these patients were regarded as responders.

Statistics

Analysis was performed using SPSS, version 14.0 for Windows (SPSS Inc., Chicago, IL, USA). Correlation between variables was assessed using Spearman's rank correlation coefficient. Two-tailed Fisher's exact probability test was used to assess differences between responders and non-responders with regard to baseline variables. Significance was determined as P <0.05.

RESULTS

Patient characteristics are presented in Table 1. Mean [+ or -] SD Acute Physiological and Chronic Health Evaluation II score was 21.8[+ or -]12.7. All participants remained in sinus rhythm throughout the study. Fluid loading was undertaken during resuscitation of hypotensive patients (60%) or in an attempt to optimise fluid status and reduce vasopressor dose (40%). Mortality in ICU was 40% and in hospital was 60%. Trans-aortic USCOM measurements were satisfactorily achieved on all patients at each study time point.

Prediction of fluid responsiveness

Table 2 presents baseline variables and subsequent change in stroke volume for each participant. Percent change in stroke volume following fluid challenge correlated with FTc (r=-0.81, P=0.004) (Figure 2). No correlation was observed with BNP (r=-0.3, P=0.4) (Figure 3) or CVP (r=-0.4, P=0.2) (Figure 4). Four out of five patients with FTc less than 350 ms responded to fluid challenge, while all participants with FTc greater than 350 ms were non-responders (P=0.047). BNP was not significantly different between responders and non-responders (P=1). Furthermore, three out of seven patients with elevated BNP (greater than 144 pg/ml) demonstrated an increase in stroke volume [greater than or equal to] 15%. Two patients demonstrated a decrement in stroke volume following fluid challenge.

Relationships between variables

FTc correlated with baseline values of velocity time integral (r=0.83, P=0.003), stroke volume (r=0.85, P=0.001), stroke volume index (r=0.78, P=0.008), cardiac output (r=0.9, P=0.0003), cardiac index (r=0.88, P=0.0007) and BNP (r=0.636, P=0.047). BNP correlated with baseline values of velocity time integral (r=0.66, P=0.04), stroke volume (r=0.75, P=0.01), stroke volume index (r=0.68, P=0.03), cardiac output (r=0.72, P=0.02) and cardiac index (r=0.72, P=0.02). No correlation was observed between BNP and CVP (r=0.4, P=0.2).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

DISCUSSION

The cardinal finding of this study is that FTc emerged as a better predictor of change in Dopplerderived stroke volume following fluid challenge (fluid responsiveness) than BNP or CVP. To the best of our knowledge, this report represents the first specific evaluation of FTc as a predictor of fluid responsiveness in septic shock. It is also the first reported comparison between FTc, BNP and CVP. In addition, we are unaware of any previous data evaluating transcutaneously measured FTc as a predictor of fluid responsiveness and have confirmed the feasibility of this technique in septic shock. Moreover, our study is the first to demonstrate FTc as a predictor of fluid responsiveness in a cohort that includes spontaneously breathing patients.

Using oesophageal Doppler, FTc has been shown to be a predictor of fluid responsiveness in mechanically ventilated critically ill2 and anaesthetised neurosurgical (3) patients. Previously, an FTc less than 350 ms has been proposed as an indicator of hypovolaemia (11,12). In our study, this threshold allowed discrimination between responders and non-responders. Four out of five patients with FTc less than 350 ms in our study responded to fluid challenge, while all participants with FTc greater than 350 ms were non-responders.

BNP is generally released by cardiac myocytes in response to ventricular strain (14). It follows that by diagnosing ventricular failure (plateau of Frank Starling curve), elevated BNP should exclude a fluid responsive state. There are scant data addressing this possibility in critical care (5,15). Our data confirm that BNP does not appear to be useful in septic shock, even when the potential confounding influence of cardiac dysrhythmia is excluded. Although BNP greater than 144 pg/ml has previously been posed as a strong predictor of cardiac dysfunction in ICU (13), 42% of patients with BNP above this threshold responded to fluid challenge. This data confirms that reported by Pirracchio (5) and strengthens assertions by Rudiger and colleagues, that elevated BNP should not be an indication to withhold fluid loading in septic shock (16). BNP has previously demonstrated variable correlation with cardiac index in critically ill patients (17,18), including patients with septic shock (19).

The poor correlation between BNP and subsequent change in stroke volume is most likely explained by the existence of confounders. Extremely high BNP concentrations have been reported in septic patients, even in the presence of preserved left ventricular systolic function (20). The precise cause of this is unclear but may be due to several potential confounders, including inflammation (21,22), impaired clearance (5) and commonly employed therapies such as altered intrathoracic pressures/ mechanical ventilation (23) and the use of vasoactive and inotropic drugs (24). In keeping with previous data, static values of CVP did not predict haemodynamic response to fluid challenge (7).

Two patients demonstrated a decrement in stroke volume following fluid loading. Though this might be exaggerated by test-retest variability, the magnitude of the change ([greater than or equal to] 10%) supports the possibility that excess volume loading has compromised left ventricular stroke volume, either via ventricular interaction (25) or overdistension of the ventricle in diastole (26).

Limitations

We have undertaken a preliminary study in a small sample of patients with septic shock. A larger sample should be studied to permit sensitivity, specificity and receiver operating characteristic curve calculations. The inclusion of spontaneously breathing patients contributes to the clinical interest of this study but prevented evaluation of dynamic indices of ventricular filling based on heart-lung interactions (1). Haemodynamic response to passive leg raising was not undertaken in this preliminary study. Stroke volume and related measurements were performed using a non-invasive, transcutaneous Doppler device, USCOM. This device is an accurate and safe alternative to the pulmonary artery catheter in ICU (10). Although not specifically validated in septic shock, the principles of Doppler determination of stroke volume are widely accepted (27). The possibility of inaccuracies relating to angle of insonation and algorithmic estimation of aortic valve cross-sectional area were minimised by recording four repeated measures at each time point by a single, experienced operator and by defining fluid responsiveness in terms of percentage change in stroke volume from baseline. Pulmonary artery catheterisation was not performed on any patient in this study. This is consistent with our usual practice and recent recommendations regarding management of septic shock (9,28).

Mathematical coupling must be considered when a relationship is demonstrated between two variables sharing a common component and measured at the same time. In such a case an error in the measurement of the shared component could influence both variables in the same direction and thus could force the correlation between them (29). We do not believe this is the case in our study, where a correlation has been demonstrated between FTc before fluid loading and the percent change in stroke volume after fluid loading. Evaluation of FTc as a predictor of fluid responsiveness using an independent method for determining change in stroke volume/cardiac output is warranted.

CONCLUSIONS

Data from this preliminary study support FTc as a better predictor of fluid responsiveness than either BNP nor CVP in septic shock. Transcutaneous aortic Doppler FTc offers promise as a simple, completely non-invasive predictor of fluid responsiveness and should be evaluated further in larger studies.

ACKNOWLEDGEMENTS

This study was conducted with the support of grants from the Australian and New Zealand College of Anaesthetists and the PA Foundation (Princess Alexandra Hospital, Brisbane, Qld). We thank USCOM Ltd, who kindly loaned the USCOM device used in this study.

Accepted for publication on August 13, 2009.

REFERENCES

(1.) Sturgess DJ, Joyce CJ, Marwick TH, Venkatesh B. A Clinician's Guide to Predicting Fluid Responsiveness in Critical Illness: Applied Physiology and Research Methodology. Anaesth Intensive Care 2007; 35:669-678.

(2.) Monnet X, Rienzo M, Osman D, Anguel N, Richard C, Pinsky MR et al. Esophageal Doppler monitoring predicts fluid responsiveness in critically ill ventilated patients. Intensive Care Med 2005; 31:1195-1201.

(3.) Lee JH, Kim JT, Yoon SZ, Lim YJ, Jeon Y, Bahk JH et al. Evaluation of corrected flow time in oesophageal Doppler as a predictor of fluid responsiveness. Br J Anaesth 2007; 99:343-348.

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(6.) Knudsen CW, Omland T, Clopton P, Westheim A, Abraham WT, Storrow AB et al. Diagnostic value of B-Type natriuretic peptide and chest radiographic findings in patients with acute dyspnea. Am J Med 2004; 116:363-368.

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(11.) Sinclair S, James S, Singer M. Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture: randomised controlled trial. BMJ 1997; 315:909-912.

(12.) Conway DH, Mayall R, Abdul-Latif MS, Gilligan S, Tackaberry C, Randomised controlled trial investigating the influence of intravenous fluid titration using oesophageal Doppler monitoring during bowel surgery. Anaesthesia 2002; 57:845-849.

(13.) McLean AS, Tang B, Nalos M, Huang SJ, Stewart DE. Increased B-type natriuretic peptide (BNP) level is a strong predictor for cardiac dysfunction in intensive care unit patients. Anaesth Intensive Care 2003; 31:21-27.

(14.) Sturgess DJ, Marwick TH, Joyce CJ, Venkatesh B. B-type natriuretic peptide concentrations and myocardial dysfunction in critical illness. Anaesth Intensive Care 2006; 34:151-163.

(15.) Mekontso-Dessap A, Tual L, Kirsch M, D'Honneur G, Loisance D, Brochard L et al. B-type natriuretic peptide to assess haemodynamic status after cardiac surgery. Br J Anaesth 2006; 97:777-782.

(16.) Rudiger A, Gasser S, Fischler M, Hornemann T, von Eckardstein A, Maggiorini M. Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure. Crit Care Med 2006; 34:2140-2144.

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(23.) Shirakami G, Magaribuchi T, Shingu K, Suga S, Tamai S, Nakao K et al. Positive end-expiratory pressure ventilation decreases plasma atrial and brain natriuretic peptide levels in humans. Anesth Analg 1993; 77:1116-1121.

(24.) Hanford DS, Glembotski CC. Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: potential roles for protein kinase C and mitogen-activated protein kinase. Mol Endocrinol 1996; 10:1719-1727.

(25.) Elzinga G, van Grondelle R, Westerhof N, van den Bos GC. Ventricular interference. Am J Physiol 1974; 226:941-947.

(26.) Patterson SW, Piper H, Starling EH. The regulation of the heart beat. J Physiol 1914; 48:465-513.

(27.) Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15:167-184.

(28.) Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296-327.

(29.) Monnet X, Pinsky M, Teboul JL. FTc is not an accurate predictor of fluid responsiveness. Intensive Care Med 2006; 32:1090-1091.

D. J. STURGESS *, R. L. S. PASCOE [[dagger]], G. SCALIA [[double dagger]], B. VENKATESH [[section]]

Department of Intensive Care, The Wesley Hospital, Brisbane, Queensland, Australia

* M.B., B.S., F.A.N.Z.C.A., F.R.A.C.G.P., Lecturer, University of Queensland, Princess Alexandra Hospital.

[[dagger]] M.B., B.S., F.A.N.Z.C.A., F.J.F.I.C.M., Director.

[[double dagger]] M.B., B.S., F.R.A.C.P., Cardiologist, Heart Care Partners.

[[section]] M.D., F.R.C.A., F.J.F.I.C.M., Deputy Director.

Address for correspondence: Dr D. J. Sturgess, Intensive Care Fellow, Department of Intensive Care, The Wesley Hospital, Brisbane, Qld 4066.
Table 1
Patient characteristics

Patient   Age (years)   Gender          Diagnosis

1         80            Female          Community acquired pneumonia
2         67            Male            Urological sepsis
3         68            Male            Community acquired pneumonia
4         75            Female          Enteritis
5         72            Male            Hospital acquired pneumonia
6         40            Male            Hospital acquired pneumonia
7         43            Female          Peritonitis
8         64            Female          Catheter related sepsis
9         68            Female          Ascending cholangitis
10        42            Male            Peritonitis

Patient   APACHE II     Mechanical      Vasopressor
                        ventilation *

1         23            Yes             Yes
2         51            No              Yes
3         24            No              No
4         14            Yes             Yes
5         20            Yes             No
6         13            Yes             Yes
7         9             Yes             No
8         31            No              No
9         8             Yes             Yes
10        25            No              Yes

Patients are numbered sequentially by date and time of enrolment.
* Mechanically ventilated patients were treated with synchronised
intermittent mandatory ventilation. APACHE II score represents severity
of illness determined during the first 24 hours of intensive care
unit admission, not necessarily at the time of study. APACHE=Acute
Physiological and Chronic Health Evaluation.

Table 2
Baseline variables and subsequent change in stroke volume

Patient   BNP (pg/ml)   FTc (ms)   CVP (mmHg)   [DELTA]SV %

1         407           377        7            0
2         167           509        6            -11
3         264           314        16           16 *
4         227           280        2            27 *
5         157           258        4            22 *
6         7             239        3            17 *
7         386           393        11           -10
8         2757          416        11           4
9         57            308        12           2
10        77            352        1            11

BNP=plasma B-type natriuretic peptide concentration,
FTc=Doppler corrected flow time, CVP = central venous
pressure, [DELTA]SV %=percent change in stroke volume following
fluid challenge. * responders (stroke volume increase >15%).


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Author:Sturgess, D.J.; Pascoe, R.L.S.; Scalia, G.; Venkatesh, B.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8AUST
Date:Mar 1, 2010
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