Effect of thoracic epidural anesthesia (TEA) on right ventricular function and ventricular-pulmonary coupling

Thoracic epidural anesthesia (TEA) is considered to be the gold standard
anesthetic approach in lung surgery and also widely applied in patients
undergoing cardiac surgery. TEA provides excellent analgesia, decreases
postoperative pulmonary complications [1,2], and may have a positive effect on
the immunologic and coagulation system [3,4]. Furthermore, experimental studies
have shown that TEA may provide cardiac protection for ischemia-reperfusion
injury [5] and avoid vasoconstriction of atherosclerotic coronary arteries and
plaque rupture [6,7]. Especially in the elderly population these risk
reductions are highly relevant. Regional anesthesia, in particular TEA, was
shown to be associated with reduced postoperative morbidity and mortality
compared with general anesthesia [8,9,10]. The reduced cardiac morbidity and
mortality is presumably related to the fact that stress following surgical
trauma typically increases adrenergic nervous activity and catecholamine
levels, which puts patients with coronary heart disease at increased risk for
ischemia and myocardial infarction.

However, blockade of the cardiac sympathetic fibres by TEA may affect right
ventricular function and interfere with the coupling between the right
ventricular function and right ventricular afterload. A possible negative
effect of TEA on the regulation of right ventricular contractility could be
highly relevant in surgical patients, particularly those with already depressed
right ventricular function and in conditions of pulmonary hypertension. The
interaction between TEA and the regulation of right ventricular function has
been investigated in experimental animal studies but data are partly
conflicting [11-16]. Studies investigating this effect in humans are not yet
performed.

Experimental studies have shown that increased afterload leads to enhanced
right ventricular systolic function which enables the right ventricle to
maintain stroke volume without having to invoke the Frank-Starling mechanism
[17-19]. This reflex mechanism is referred to as homeometric autoregulation and
was suggested to result from stimulation of stretch-activated calcium channels
[20], release of positive inotropic substances from the endocardial endothelium
[21] and/or from an elevated sympathetic tone [8,22].

Recently, Rex and colleagues [8] demonstrated that in pigs TEA strongly
inhibited the positive inotropic response to acute pulmonary hypertension,
suggesting an important role for sympathetic nervous system. If this phenomenon
is confirmed in humans, it is highly relevant for daily practice in
cardiothoracic surgery because pulmonary hypertension is frequently encountered
and right ventricular function is an important determinant of early and late
outcome [23-25].

Therefore, we aim to investigate this mechanism in patients subjected to lung
resection surgery. This intervention, obviously, increases right ventricular
afterload and cardiac function was previously shown to be a determinant of
outcome [26].

Right ventricular function will be assessed by invasive pressure-volume loop
analysis using combined pressure-conductance catheters [27,28]. The response of
right ventricular function to increased afterload, induced by brief, partial
clamping of the pulmonary artery, will be tested before and after induction of
TEA.

Right ventricular function will be assessed by invasive pressure-volume loop
analysis using combined pressure-conductance catheters [27,28]. The response of
right ventricular function to increased afterload, induced by brief, partial
clamping of the pulmonary artery, will be tested before and after induction of
TEA

3.1 Overall study design and flow chart

Ten (10) patients will be included in this open, single-centre study. Before
inclusion, the patients will be screened for eligibility according to the
inclusion and exclusion criteria and give their signed informed consent before
start of the study.
At the screening visit, a routine physical examination will be performed. An
ECG will be done and pulse and blood pressure will be measured for baseline
registrations.

On the day before surgery, a pregnancy test will be performed in women of
childbearing age. Patients will receive premedication and an epidural catheter.
A test dose of 3 ml lidocaine 2% will be injected through the catheter. Correct
position of the catheter is verified by assessment of sensory blockade. Lack of
sensory blockade 15 minutes after injection of the test dose will results in
exclusion of the patient from the trial. On completion of the epidural
procedure patients will return to the ward.
On the day of surgery, patients will receive standardized premedication and
standardized anesthesia induction. After induction of anesthesia a Swan-Ganz
pacing Pulmonary Artery Catheter (PAC) and a Pressure-Volume catheter (PV
catheter) will be inserted in the internal.jugular vein. Correct position of
the PV catheter in the right ventricle will be guided by online pressure and
volume signals and confirmed by transoesophageal echo (TEE). The insertion of
the PAC and the PV catheter will be performed by an experiences
anesthesiologist who works as a cardiothoracic anesthesiologist.

Starting at induction of anesthesia an electrolyte solution (NaCl 0.9%) will be
administered at a rate of 5 ml.kg-1.hr-1. and maintained until the end of this
study. Lungs will be ventilated with an FiO2 of 0.40 and ventilation will be
adjusted to maintain normocapnia and normoxia. After achievement of hemodynamic
(HD) steady state, measurements will be performed in baseline with the
ventilation temporarily (~15 sec) suspended at end expiration. The left or
right pulmonary artery will be briefly clamped for 2-3 minutes. After
unclamping the pulmonary artery and achievement of hemodynamic (HD) steady
state, 9 mL of lidocaine 2% will be injected through the epidural catheter. A
second set of hemodynamic measurements will start 15 minutes after epidural
injection and will follow the same protocol as the baseline measurements. After
completing the measurements, surgery will continue and anesthetic management
will be according to the judgment of the responsible anesthesiologist.

Adverse events (AE) will be recorded from the injection of the epidural test
dose until patient is dismissed from the post anesthesia care unit (PACU).

Study Design:

- Premedication & induction anesthesia
- Instrumentation under TEE guidance
PAC
PV catheter, tip in RV apex
Check signals (PAC, PV, pacing)
- Reposition patient
- Check signals
- Thoracotomy and isolation/preparation of left/right PA
- Hemodynamic measurements at baseline and during epidural block
(Semi) continuous display and recording of :
- CO (FlowTrac), RV PV-loops, ECG, PA pressure, arterial pressure
Time line of study design is presented in appendix 1.
Time line of measurements is presented in appendix 2..

Measurement protocol:

Baseline:
- start RA pacing at 80 bpm (or 10 bpm above SR)
- record stable CO reading, with single bolus thermodilution measurement
- record steady state PV loops during 15 s suspected respiration
- record PV loops during positive/negative Trendelenburg maneuver (during
suspended respiration)
- back to normal position
- record steady state PV loops during 15 s suspected respiration
- (partial) clamping of pulmonary artery aimed at increase in RV pressure > 20
mmHg (during continuous recording of PV loops
- record steady state PV loops (at increased afterload) during 15 s suspected
respiration
- record PV loops during positive/negative Trendelenburg maneuver (during
suspended respiration)
- back to normal position
- unclamp pulmonary artery
- record stable CO reading with single bolus thermodilution measurement
- record PV loops during hypertonic saline injection (10% saline, 5 ml bolus,
proximal injection port PAC), repeat 3x (preferably during suspended
respiration) to determine parallel conductance [29]

TEA
- epidural injection (9 ml, 2% lidocaine):
- wait 15 min to reach sensory blockade and stable hemodynamics
- repeat all measurements (except for hypertonic saline injections)
- remove PV catheter
- PAC will be left in place and used as a central line, which is normal routine

Time schedule (specific for *additional* time):

- Instrumentation of the catheters: 20 min ?
- Surgical preparation: 5 min
- Baseline measurements: 12 min
- Start epidural: 15 min
- Blocked measurements: 8 min

3.2 Discussion of study design, including choice of control groups

The primary objective of this study is to evaluate the inhibitory effect of
thoracic epidural anesthesia (TEA) on the native positive inotropic response of
the right ventricle to increased afterload. To increase statistical power and
for ethical reasons (and to limits costs) we have chosen for a study design in
which each individual serves as his or her own control (comparing baseline vs.
blocked condition) rather than a placebo-controlled design.

Patients receive their epidural catheter the day before surgery to make sure it
is positioned well without the consequence of a test dose having influence on
measurements. In our clinic we are familiar with the routine of giving an
epidural catheter to patients one day before surgery, as is the case with
patients for isolated lung perfusion.

8.1 RISKS AND ALTERATIONS VS. ROUTINE

- Additional instrumentation (PAC, PV catheter): The acquisition of venous
access for both the central venous catheter and the PAC is associated with
similar complications (id est arterial puncture, bleeding at the injection
site, pneumothorax, air- or thrombo-embolism, arrhythmias, infections[30].
Catheterization with a PAC may lead to more specific complications like mild
tricuspid insufficiency, pulmonary artery rupture and pulmonary infarction[30].
In a general ICU population the beneficial effects of the monitoring
characteristics of the PAC is upset by its complications. Several
subpopulations, however, have shown to have improved survival due to the
monitoring capabilities of the PAC, for example high-risk cardiac surgery [31].
A recent studies by Ranu et al. [32] and Hoeper et al. [33] showed that
insertion of a PAC is quick, safe and well-tolerated. PAC-insertion is not
associated with an increased risk of pneumothorax or other complications when
performed by an experienced operator.

- Longer procedure (20 min instrumentation before surgery, 35 min measurements
during surgery
- Hypertonic saline (10%) injections: 3x 5 ml bolus.
- (Partial) PA clamping (2x ~2 minutes)
- Epidural line will not be positioned on the day of surgery but the day before
surgery. This way there will not be interference of the epidural test dose
with the studt measurements
- Start surgery without use of epidural analgesia. Patients receive iv opiods
as analgesic regimen until the study is finished, where after the epidural
catheter can be used according to the normal routine. For postoperative
analgesia patients receive a patient controlled epidural analgesia system
according to the daily routine