Academiejaar 2013 – 2014 Nitroglycerin increases venous return but reduces CVP: a preload paradox? Ine WITTERS Promotor: Prof. dr. Stefan De Hert Co-promotor: dr. Stefaan Bouchez Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie-Reanimatie
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Nitroglycerin increases venous return but reduces CVP: a ... · afterload which reduces ventricular ejection or a decline in ventricular function. The LVEDV The LVEDV and other preload
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Academiejaar 2013 – 2014
Nitroglycerin increases venous return but reduces CVP: a preload paradox?
Ine WITTERS
Promotor: Prof. dr. Stefan De Hert
Co-promotor: dr. Stefaan Bouchez
Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie-Reanimatie
Academiejaar 2013 – 2014
Nitroglycerin increases venous return but reduces CVP: a preload paradox?
Ine WITTERS
Promotor: Prof. dr. Stefan De Hert
Co-promotor: dr. Stefaan Bouchez
Masterproef voorgedragen in de master in de specialistische geneeskunde Anesthesie-Reanimatie
De auteur en de promotor geven de toelating deze masterproef voor consultatie beschikbaar te stellen
en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van
het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden
bij het aanhalen van resultaten uit deze masterproef.
Datum
(handtekening ASO) (handtekening promotor)
Ine Witters Prof.dr. Stefan De Hert
(Naam ASO) (Naam promotor)
Voorwoord
Het hanteren van de cardiovasculaire dynamiek in peroperatieve en kritiek zieke patiënten
blijft in de klinische praktijk een evenwichtsoefening die soms moeilijk blijkt door nog deels
onopgehelderde fysiologische mechanismen. Maar de techniek staat niet stil en dit laat ons toe
verder onderzoek te voeren naar de mysteries van de lichaamscirculatie. Het blijft een
intrigerende materie die me boeit en bezighoudt.
Ik wil enkele mensen bedanken die me ondersteund hebben bij het opstellen van deze
masterproef. Vooreerst mijn co-promotor, dr. Stefaan Bouchez, die me het onderwerp
aanreikte. Door zijn interesse in het onderwerp enthousiasmeerde hij me. Hij onderzocht,
corrigeerde en vulde mijn werk aan. Hij spaarde tijd noch moeite om zijn expertise te delen
met mij en hielp me enorm ondanks mijn krappe tijdsschema.
Prof. dr. Stefan De Hert bedank ik om het promotorschap over mijn werk te willen
aanvaarden en mij vooruit te helpen middels zijn ruime kennis over wetenschappelijk werk.
Prof.dr. Patrick Wouters, diensthoofd Anesthesie-Reanimatie van UZ Gent, bedank ik om mij
vijf jaar te begeleiden, te evalueren, en bij te sturen tijdens mijn opleiding.
Mijn moeder en mijn vrienden hebben mijn pieken en dalen tijdens het opstellen van deze
masterproef van dichtbij meegemaakt. Ze ondersteunden me en stuwden me voort door hun
motivatie.
Table of contents
Abstract ………………………………………………………………………………….. 1
Introduction ……………………………………………………………………………… 2
Objective ………………………………………………………………………………… 9
Methods …………………………………………………………………………………. 9
Results …………………………………………………………………………………… 10
Discussion ………………………………………………………………………………. 12
References ………………………………………………………………………………. 14
Nederlandse samenvatting ……………………………………………………………… 15
1
Abstract
For many years, physicians have considered the heart as the principal actor in cardiovascular
physiology. In the twentieth century, Guyton elaborated the idea of the venous system as a
determining factor for cardiac output. The heart can only pump out that what it receives and
thus in steady state conditions, venous return equals cardiac output. Venous return is affected
by three elements: right atrial pressure, resistance to venous return and mean systemic filling
pressure. This last element can be used as a parameter for effective circulating blood volume.
The main problem with this parameter is that it cannot be easily measured in clinical practice,
but only in experimental stop-flow models. Based on the Guytonian concepts, a clinical
decision support system, the NavigatorTM
, was developed. This device integrates data from
conventional monitoring devices and calculates new variables such as the mean systemic
filling pressure analogue (Pmsa) and global heart performance (Eh). We used the NavigatorTM
to study the haemodynamic effects of nitroglycerin in cardiac surgery patients. We found that
nitroglycerin has, next to its ability to lower central venous pressure and arterial blood
pressure, a beneficial effect on global heart performance. Furthermore, we found that changes
in cardiac output after nitroglycerin administration were correlated to the change in pressure
gradient for venous return (Pmsa-CVP).
2
Introduction
Circulatory instability may be experienced in patients for a variety of reasons such as
perioperative ischaemia, heart failure or the effects of a critical illness. The use of
hemodynamic monitoring underpins the evaluation of the unstable cardiovascular system. In
1970 Swan and Ganz introduced the flotation catheter for the measurement of the pulmonary
artery wedge pressure and the assessment of the preload of the heart1. Since that time
clinicians have used the wedge pressure to evaluate patients’ volume status and to optimize
preload to improve cardiac output. It is reasoned that cardiac output ultimately depends on the
ejection of blood from the left ventricle and is based on the Frank-Starling relationship: the
better the filling of the left heart, the better cardiac output.
About one hundred years ago, Frank and Starling enunciated their “law of the heart”: the idea
that the more the left ventricle is filled in diastole, the greater the stroke volume of the
following systole. Control of the blood volume since that time has focussed on the ‘Starling’
idea of providing the heart with adequate preload or diastolic filling. If we consider the left
ventricular end-diastolic volume (LVEDV) as the traditional preload measure , it’s clear that
an increase in LVEDV could be caused by an increase in the blood volume, an increase in
afterload which reduces ventricular ejection or a decline in ventricular function. The LVEDV
and other preload measures do not measure the volume state of the body.
Another way of thinking about Starling’s law is to consider it the property of the heart to
cause the cardiac output to equilibrate with the venous return. Normally these two are in
equilibrium. If venous return increases, the inflow to the heart exceeds the outflow, the heart
fills causing a rise in stroke volume and cardiac output. This process continues until both
equilibrate. Control of the cardiac output is therefore about control of the venous return.
In the nineteenth century, Bayliss and Starling described the importance of the venous
circulation in their experiments with dogs. In the second half of the twentieth century, Arthur
Guyton further elaborated this new concept of cardiovascular physiology. According to
Guyton, the real role of the heart in regulating cardiac output is to lower right atrial pressure
and allow blood to drain back to the heart (venous return) so it can be pumped out again2. The
heart only pumps out the amount of blood it receives from the venous system. Only in heart
failure, the pump function becomes a limiting factor. Thus, in steady state, venous return
equals cardiac output. Guyton also suggested that the mean circulatory filling pressure was
3
the first measurable quantity that allows one to relate blood volume mathematically to control
of cardiac output and arterial blood pressure3.
Not seldom, it proves to be difficult to assess the intravascular volume status in an unstable
patient and hence, fluid resuscitation is walking a tightrope. We know that excessive fluid
loading can have detrimental effects on the patient, e.g. in acute lung injury4. Therefore, the
development of an accurate and readily usable parameter to evaluate intravascular volume
status remained a challenge for a long time.
Venous return:
When we assume that cardiac output is controlled by venous return, this means that various
factors of the peripheral circulation that affect flow of blood into the heart from the veins,
called the venous return, are the primary controllers.
Venous return is affected by three principal factors:
1. Right atrial pressure (Pra)
2. Resistance to venous return
3. Mean systemic filling pressure (Pmsf)
In clinical practice, we use the central venous pressure (CVP) as a surrogate for Pra.
The resistance to venous return is defined as the resistance encountered by the blood in
returning to the heart. It comes for the greater part from the veins (two thirds), and to a lesser
extent from the arterioles and small arteries (one third). A common cause of increase in
venous resistance is the venoconstriction in hypovolemia.
Venous return can only occur when there is a pressure gradient. The CVP produces a
backward force on the veins that impedes blood flow into the right atrium. Guyton showed in
his experiments that venous return diminishes with rising CVP. When CVP rises to equal Pmsf,
flow into the right atrium drops to zero (figure 1). There is also a plateau in venous return
when CVP falls below -4mm Hg. This is due to the collapse of the large veins entering the
chest.
4
Figure 1: Venous return curve. Redrawn from Guyton.
The slope of the venous return curve is reciprocal to the resistance to venous return.
Venous return can be calculated through the following formula:
VR =
in which VR is venous return, Pmsf is mean systemic filling pressure and RVR is resistance to
venous return.
dVR = Pmsf - CVP
where dVR is the pressure gradient of venous return2.
Mean systemic filling pressure:
The mean systemic filling pressure is the mean pressure in the entire systemic circulation and
does not depend on the operation of the heart. In humans this pressure is close to 7 mmHg. It
can be measured in the vessels when all circulation is stopped and both arterial and venous
pressures have reached equilibrium. This technique was used by Guyton during his
experiments in dogs, where he used total circulatory arrest with induced fibrillation to
measure Pmsf. Occasionally Pmsf is observed in the intensive care unit or the operating room,
following cessation of ventilation in the brain dead patient or with pacemaker failure. Pmsf is a
measure of effective intravascular volume and it depends on the stressed or “vessel-
distending” pressure. Total intravascular volume consists of both the stressed and unstressed
5
volume. The unstressed volume (60-70% of the total blood volume) is the quantity of blood
volume that does not stretch the vessels and thus is not a part of pressure buildup. It acts as a
blood reservoir. Meanwhile, the stressed volume (30-40% of total blood volume) is the
volume that distends the elastic wall of the vessels and that is hemodynamically active. The
stressed volume can be enlarged when fluid is administered of when unstressed volume is
being recruited through vasopressors.
Although it seemed a promising parameter, Pmsf didn’t prove to be a readily measurable
variable. All experiments assessing Pmsf had been done in stop-flow conditions, and thus
impracticable in the clinical field. The non-complete determination of cardiovascular volume
status in patients continued to deliver difficulties in terms of adequately treating the critically
ill or perioperative patients.
Recently, Maas et al.5 developed a bedside method for determining the Pmsf. They selected
postcardiac surgery patients who were mechanically ventilated and performed 12-second
inspiratory hold maneuvers at different ventilator plateau pressures (5, 15, 25 and 35cm H2O).
During these maneuvers they measured central venous pressure (as a surrogate for Pra), and