Title of Thesis
ASSESSMENT OF CAROTID DOPPLER INDICES AND EtCO­₂ AS A SURROGATE OF FLUID RESPONSIVENess FOLLOWING PASSIVE LEG RAISE MANEOUVRE 
Introduction:
Fluid resuscitation is a challenging task. On one hand, the severity of the disease incites one to initiate treatment rapidly and massively. In line with this, the pivotal study by Rivers et al. [1] showed that massive fluid administration during the first 6 h of resuscitation of patients with severe sepsis and septic shock was associated with improved outcome. On the other hand, it has now been clearly demonstrated that fluid overload has detrimental consequences. Fluid overload prolongs mechanical ventilation and increases the mortality of critically ill patients in general and, more specifically, in patients with sepsis [2–4], acute respiratory distress syndrome (ARDS) [5–7], intra-abdominal hypertension [8] and acute kidney injury [9, 10]. The potential benefit of volume expansion, related to an increase in cardiac output and oxygen delivery, must be balanced by the risk of aggravating lung and tissue oedema [11]. 
The response to a fluid challenge is complicated by cardiovascular physiology [12]. Due to varying shapes that the Frank–Starling curve could take depending on the ventricular systolic function, a fluid challenge could lead to either a significant or a negligible increase in stroke volume and cardiac output. If no attempts are made to predict the response of cardiac output to volume expansion, “fluid responsiveness” occurs in only half the patients [13]. For this prediction, the method that has been used for decades, namely central venous pressure (CVP), has been demonstrated to be unreliable. Conversely, a number of “dynamic” methods have been developed to test preload responsiveness [14, 15]. 

Passive leg raising (PLR) has been used for decades by rescuers as a first-line measure in patients with dizziness and syncope. Its interest in critical care has emerged after a study demonstrating that it induces significant changes in right and left cardiac preload [25]. In the subsequent years it showed that PLR could be used as a reliable provocative test to detect preload responsiveness [26]. The major advantage of PLR tests is that it is a reversible “preload challenge” of around 300 to 500 mL of blood [27] that can be repeated as frequently asrequired without infusing a drop of fluid and prevents overloading the patient.
 
Since 2006, many studies have confirmed the reliability of the PLR test with a remarkable consistency. Two meta-analyses of these studies have been recently published [28, 29]. In almost 1000 adult patients included in 21 studies, the author’s team found that the pooled sensitivity was 85% and the pooled specificity was 91% [29]. The mean threshold that simultaneously provided the best sensitivity and specificity was a PLR-induced increase in cardiac output of 10% or more [29] (Table 1). The robust reliability of this test has likely contributed to its popularity and widespread application.The PLR test has been included in the last update of the recommendations of the Surviving Sepsis Campaign [30] and in a consensus conference of the European Society of Intensive Care Medicine.
The most important aspects of performing PLR is that its effects must be assessed by the direct measurement of cardiac output. It is important to recognise that changes in arterial pressure do not allow the assessment of the PLR haemodynamic effects with reliability; this has been confirmed by the recent meta-analyses [28, 29]. When the PLR-induced changes in arterial pulse pressure are used, the specificity remains very good, but the sensitivity of the test is much poorer. Moreover, cardiac output must be measured continuously and in real time. This does not imply that the PLR test necessarily requires invasive monitoring. Many studies have used non-invasive or minimally invasive techniques to estimate the PLR-induced changes in cardiac output [28,
29]. 
At present, there is no non-invasive method that can reliably and accurately identify fluid responsiveness. Echocardiography, with measurements of the PLR induced changes in the velocity time integral of the left ventricular outflow tract, has been used in many studies. Even the PLR-induced changes in the peak velocity of the carotid [31] arteries seem to be reliable indicators of the response of cardiac output to PLR. The totally non-invasive estimation of cardiac output by pulse wave transit time may be also suitable for the PLR test. 
Another original and totally non-invasive method is to measure the PLR-induced increase in end-tidal carbon dioxide (CO2) [32-34]. This technique requires that the patient has perfectly stable mechanical ventilation, in order to be sure that the changes in end-tidal CO2 are only related to changes in cardiac output. A recent study showed that the changes in end-tidal CO2 were able to detect the changes in cardiac output during PLR. Thus, PETCO2 has been suggested as a non-invasive alternative for continuous assessment of CO in different shock states [35].
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Cardiac output, however, has been challenging to measure at the bedside. The traditional reference standard for measuring CO requires theinsertion of a pulmonary artery catheter [36, 37] which is invasive, associated with a risk for serious complications [38], and its use may offer no clinical benefits [11–15]. Newer non-invasive devices using bioreactance parameters have mixed evidence in their accuracy and reliability [44–48], and require a dedicated machine that may not be readily available. Lastly, estimations of CO using echocardiography have been suggested as a bedside measure. However, its use may not be feasible due to high training requirements [49]. However, there are studies which show strong correlation with the esCCO (Estimated continuous cardiac output) by Pulse wave transit time method and echocardiography for measuring CO, and change in CO after fluid infusion in ICU patients (50).
In the quest to identify feasible, non-invasive, and reproducible bedside estimates of CO, carotid Doppler imaging shows promise. In particular, two carotid measurements have emerged as candidate markers of CO: corrected carotid flow time (CFT) and carotid blood flow (CBF). CFT is the carotid systole time, with heart rate correction applied. This measure is easy to perform and may correlate with intravascular volume [51]. CBF is the integral of blood volume that is ejected through the carotid artery with each cardiac cycle. This measure has been shown to be feasible to perform at the bedside [52, 53]. Studies to date have shown that corrected CFT increases in response to fluid administration or consumption [54, 55], and decreases in response to volume removal in dialysis [51] and blood donation [56]. However, none of these studies correlated corrected CFT with CO. CBF has been less extensively studied. However, in one study of 34 patients, a change in CBF in response to PLR was found to correlate significantly with a change in stroke volume index, measured by bioreactance [57]. Despite these promising studies, neither measure has been correlated directly with any non-invasive reference standard for measuring CO. 
Hence it will be our endeavour to correlate the changes in Carotid Doppler indices (corrected CFT, CBF, Vmax) and EtCO₂with that of esCCO as a surrogate of fluid responsiveness following passive leg raise manoeuvre. To the best of our knowledge this study has not been conducted in our institution before. 

HYPOTHESIS

We hypothesised that changes in Cardiac Output (CO) of fluid responder (∆CO > 15%) will reflect as changes in carotid doppler indices (Carotid blood flow, Corrected carotid flow time, Peak Systolic Velocity or Vmax) and etCO2 following Passive Leg Raise (PLR) manoeuvre