Measurement of Mean Systemic Filling Pressure & Stressed Volume with CardioQ+® Oesophageal Doppler Measurement

Accurate assessment of the intravascular volume status of a hemodynamically
unstable patient at the bedside or in the operating theatre is challenging but,
if available, would be important for assessing the determinants of
cardiovascular insufficiency and response to therapy. Clinical symptoms, like
skin turgor, are notoriously unreliable to assess volume status. Static filling
pressure, like central venous pressure (CVP) and mean arterial pressure (MAP),
have not been of much help to the clinician either. Consequently, dynamic
parameters have become a focus of interest. Stroke volume variation (SVV) and
pulse pressure variation (PPV) perform much better. However, conditions that
frequently occur in the operating theatre and in the ICU (atrial fibrillation
or tidal volume ventilation below 8 ml/kg for instance) can make precise and
accurate measurement troublesome. Challenges with PEEP, passive leg raising or
a mini fluid challenge have been used as alternatives but often difficult to
execute in clinical practice. Moreover, reliability is often an issue. We are
still not able to define hypo-, hyper- or normovolaemia. We are still looking
for a gold standard parameter to indicate volume status or even define it.
Intravascular volume can be divided into unstressed volume (the volume that is
needed to fill the blood vessels, without creating a distending pressure) and
stressed volume (Vs, the volume that stresses the vascular walls, resulting in
a distending pressure). This distending pressure is referred to as mean
systemic filling pressure (MSFP). MSFP is the pressure to which all
intravascular pressures equilibrate during cardiac arrest and is the pressure
that is determined by both systemic vascular compliance (Csys) and Vs [Guyton].
MSFP itself is a major determinant of venous return (VR), because it defines
the upstream pressure, and relative to central venous pressure (CVP), is the
driving pressure for venous return and thus cardiac output (CO):

CO = VR = (MSFP * CVP) / Rv
(Rv is resistance to venous return).

Vs can be considered as reflecting the effective intravascular blood volume.
Estimation of Vs would thus help the clinician in the decision of whether to
choose volume resuscitation, diuresis, inotropic drugs, or vasoactive
medication. In combination with a cardiac function curve, measuring MSFP and Vs
should provide a powerful and basic tool to characterize the hemodynamic status
of patients.
In recent years, it has been shown to be possible to measure mean systemic
filling pressure in alive ICU patients at the bedside using multiple methods
amongst others employing respiratory holds of 12 seconds at incremental airway
pressures. When MSFP is measured before and after fluid administration, a
pressure-volume relationship can be constructed, in which Csys is the slope of
the relation (*volume/*MSFP). The measurement of MSFP has been repeated by
other groups. Consequently, physiological principles that were first described
by Arthur Guyton were used to estimate stressed volume in these patients:

Vs = Csys x MSFP

Using the inspiratory hold method to determine MSFP we can now determine total
Csys, Vs, and cardiac function curves at the bedside. This model was validated
earlier by Jansen and Vs values were found to be similar to those found by
Magder and De Varennes who measured Vs and MSFP in arrested patients (i.e. of
course the gold standard).
Vs has thus only been measured once in patients. In this study, we will use the
CardioQ to measure MSFP in an automated way, and determine Csys and Vs to
assess their reliability to assess fluid loading responsiveness to 500 mL fluid
in 42 patients during elective CABG surgery. No clinical application of this
useful parameter exists yet. This study can be the next step to make bedside
stressed volume determination possible for the use in the operating theatre. It
will allow us to directly determine an individual*s volume status.

Furthermore by comparing MSFP measured with inspiratory holds (MSFPhold) and
with the arm pressure method (MSFParm) we are able to compare those two
methods. The arm method is in theory applicable to a broad patient population.

Using the CardioQ, parameters of intrinsic cardiac contractility and afterload
can be measured at the bedside. Ejection fraction, the gold standard for
non-invasive contractility assessment, is proportional to mean blood flow
velocity measured in the descending thoracic aorta with the CardioQ.
Oesophageal doppler-derived indexes of blood flow velocity and acceleration, as
well as force and kinetic energy, can be derived and used for continuous
assessment of cardiac contractility at the bedside. Using oesophageal
doppler-derived parameters, the different components of afterload: inertia,
resistance and elastance, can also be individually determined.
The integration of these additional hemodynamic parameters can assist the
clinician in optimising and individualising the haemodynamics of unstable
patients in theatre and the ICU. However, these concepts remain largely
non-validated in patients (i.e. no *normal* values have been defined and no
knowledge of their real variation with common hemodynamic treatments is known).
The current observational study allows characterising baseline values in a
population of high risk surgical patients and study their variation in response
to a fluid challenge.

Objectives

1. To assess the sensitivity, specificity, negative and positive predictive
value of Vs to predict fluid loading responsiveness (>12% increase in
CO after 500 ml of fluids).

2. To assess the accuracy of Vs to follow a 500 mL increase in stressed volume.

3. To assess the sensitivity, specificity, negative and positive predictive
value of HR, CO, CVP, MSFP, MAP, SV, SVV and PPV to predict fluid
loading responsiveness.

4. To assess the reliability of the measurement of stressed volume with
the arm method (MSFParm) compared to the inspiratory hold method (MSFPhold)

5. To determine the effect of a standardised fluid loading on parameters of
intrinsic contractility and afterload.




Research hypothesis

1. Bedside-determined stressed volume using MSFP, Csys and CO measured with
CardioQ+ can predict fluid responsiveness (>12% increase in CO) by at least 90%
sensitivity and specificity.

2. Bedside-determined stressed volume pre- and post 500 mL infusion will
correlate within 95% of the infused volume.

42 patients planned for elective CABG surgery, will be studied postoperatively
at the Intensive Care Unit after approval by the university medical ethics
committee and patient*s informed consent is obtained.

Anaesthesia:
Anaesthesia is induced with propofol, sufentanil and rocuronium. Anaesthesia is
maintained with sufentanil, sevoflurane and rocuronium over a peripheral venous
cannula (18, 16 or 14G). Patients are treated in line with routine CABG
anaesthesia care, i.e. a radial artery line is introduced prior to induction,
and a central line is placed immediately after induction. Patients are
ventilated in a volume controlled ventilation mode adjusted to achieve
normocapnia (etCO2 between 35 and 50 mmHg) with tidal volumes of 6*8 mL·kg-1
IBW and a respiratory rate of 12*14 breaths·min-1. Fraction of inspired oxygen
(FiO2) is 0.4 and a positive end-expiratory pressure (PEEP) of 5 cmH2O will be
applied. Relative hemodynamic stability is achieved using fluids and
catecholamines at the discretion of the treating anaesthesiologist. At the end
of the surgery the standard transoesophageal echocardiography (TOE) probe is
removed and replaced by a smaller CardioQ transoesophageal doppler probe (ODM).
This ODM probe is fixed to the mouth and remains in situ for measurements at
the ICU.

Measurements:
Patient age, height, weight, and gender is recorded. Arterial blood pressure
(Prad) is monitored via a 20G, 3.8-cm long radial arterial catheter inserted by
Seldinger technique (Arrow AK-04220, Teleflex Incorporated, Wayne, PA, United
States of America) and connected to a pressure transducer. A central venous
line is introduced thourgh a side port in the right inertnal jugular vein. The
Prad and CVP transducer is referenced to the intersection of the anterior
axillary line and the fifth intercostal space. The arterial blood pressure is
looped to the CardioQ+ device (Deltex Medical, Chichester, United Kingdom) and
MAP, CVP, SBP, DBP, PPV, SV, SVV, CO and CI are registered. Standard
electrocardiogram leads are used to monitor heart rate. SpO2 is monitored with
pulse oximetry on the index finger of either right or left hand. Beat-to-beat
CO, SV and SVV is also obtained by CardioQ+ via the oesophageal Doppler probe.
The probe inserted orally according to device guidelines. The signal is
optimized and the probe is fixed to the mouth with tape consequently.

Experimental Protocol:
MAP must be at least 55 mmHg and CI above 1.5 L·min-1 to allow start of the
study measurements. Central temperature is kept between 35.5 and 37.5 ºC.After
the surgery,when the patient is in the Intensive Care Unit (ICU), when the
above conditions are met and there is no contra-indication for fluid
administration, the rapid cuff inflator is attached around the upper arm and
study measurements are performed. These measurements are performed in the first
hour postoperatively. According to standard care anaesthesia is maintained for
at least the first 2,5 hours after surgery, so the patient will be sedated and
mechanically ventilated. First, a baseline measurement is performed (MAP, SBP,
CVP, DBP, PPV, SV, SVV, COdoppler, COpulsecontour, HR, core temperature. Hb
levels will be measured using arterial blood gas analysis.Radial artery
pressure and COdoppler are logged on the Deltex CardioQ+ device at a sample
frequency of 100 Hz and 0.2 mmHg resolution. From the steady-state over the
final three seconds of a set of four 12-second inspiratory-hold manoeuvres at
Pvent plateau pressures of 5, 15, 25 and 35 cmH2O, mean arterial pressure and
cardiac output are recorded. From these values cardiac output is extrapolated
to zero and the concomitant MAP is calculated. This value is equal to MSFP. The
hold procedures are marked in the CardioQ device to allow post-hoc analysis,
and to allow a new algorithm to be created for the device to automate this
procedure. The inspiratory-hold manoeuvres are separated by one-minute
intervals to re-establish the initial hemodynamic steady state. When Pvent
increases, CO and MAP decrease with a delay of three-four beats, reaching a
steady state between 7 and 12 seconds after start of inflation.

Consequently, a 100 mL fluid bolus is given in 30 seconds via the peripheral
venous cannula using a 50 mL Syringe (Baxter Nederland BV, Utrecht, the
Netherlands). MSFP (2) is measured again. Hereafter, 500 mL of fluid is
administered within 10 minutes. A second round of overall measurements is done
(MAP, CVP, SBP, DBP, PPV, SV, SVV, COdoppler, COpulsecontour, HR, central
temperature). MSFP (3) is measured, a 100 mL fluid bolus is given after two
minutes within 30 seconds. During the last round of measurements, MSFP (4) is
measured again. The total duration of the measurements will be around 30
minutes. After the study measurements the CardioQ oesophageal doppler monitor
probe (ODM) will be removed.

Compliance, Stressed Volume, and Fluid Responsiveness:
Compliance is calculated from the change in MSFP after the 100 mL fluid bolus.
Csys = (*volume/*MSFP). Stressed volume is calculated as Vs = Csys x MSFP.
Consequently Vs is described per kg body weight to correct for inter-individual
differences. Fluid loading responsiveness is defined as an increase of >12% in
cardiac output to a 500 mL fluid administration.

Potential study-associated side effects that can occur would be related to:

The total of 700 mL of fluid that is administered for study purposes. As 2000
to 4000 mL fluid is standard to be administred within the first 24 hours
postoperatively, complications like decompensated heart failure seem very
unlikely.

The introduction of the oesophageal probe for cardiac output measurement could
theoretically lead to laceration of the oropharynx or oesophagus. This 4.8 - 7
mm probe is inserted orally. Reports of complications are rare despite its
widespread use for this type of surgery in peri-operative goal-directed therapy
protocols that are national standards in the UK, USA and France.

The inspiratory hold procedure will encompass a number of 12-second
mechanical-breath holds at incremental pressures of 5, 15 and 25 cmH2O. These
pressures are, however, within the normal airway pressure limits set for
routine ventilation. The last inspiratory hold will be at 35 cmH2O. This airway
pressure is above the standard ventilation pressures but well within the range
of what is acceptable in clinical care. Earlier studies by Jansen et al. have
used similar pressures and have not found any deleterious effects in their
patients. During previous research on this topic in critically ill patients we
did not encounter any pulmonary complications. We do not expect any
complications during this study but to increase safety further we have ruled
out inclusion of patients with lung emphysema and with right sided cardiac
failure.

The use of the rapid cuff inflator (blood pressure cuff) will not lead to any
additional risks for patients.

The measurements will be performed in the first postoperatively at the ICU.
This implies that patients in this study will not receive additional
anaesthesia since patients after a CABG are kept sedated and mechanically
ventilated until at least 2,5 hours postoperatively.

To determine Kinetic Energy we will measure Hb levels. Since only a clinical
indication for an arterial line will allow patients to participate in the
study, drawing blood will be performed from the arterial line (i.e. no
additional stabbing). We will use a closed arterial-line system as is the
standard in our institution. This guarantees no loss of blood outside the blood
needed for analysis. We will require to draw 4 ml of blood per participating
subject for the study in total. This represents only a minute quantity of blood
(approximately 0.01% of total blood volume of an adult) and will not cause harm
to the patient.

The expected advantage from the development of this technique for future
patients is large, as there is a demand for a sound method to measure
intravascular volume status and response tot fluid loading in all
hemodynamically compromised patients in the operating theatre and intensive
care. There is considerable morbidity and mortality associated with hypovolemia
and hypervolemia in these patients.

Risks and burdens for the study patients are minimal. The expected advantage of
the development of a better method to ascertain volume status of patients
outweighs the burden and risks for our study patients in our opinion. No
advantage is expected for the study subjects.