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

pulse contour cardiac output (and thus venous return, since cardiac output equals venous

return in steady state conditions). Hence, they could construct venous return curves and

determine Pmsf. Moreover, the derived parameters can also be calculated, namely resistance to

venous return, systemic compliance and stressed volume.

Despite being an elegant method to measure Pmsf, it excludes a great portion of patients

considering that far from all patients are sedated and fully mechanically ventilated.

Consequently, they also experimented with stop-flow conditions in the arm (assuming that the

arm is representative of the entire circulation, and that a stop-flow in the arm will soon (20-30

seconds) lead to a pressure approximating Pmsf) and demonstrated that the results of Parm and

Pmsf are interchangeable.

Eh:

Developed by Parkin6, the dimensionless variable Eh is a measure that can be used to describe

global heart performance. Eh is influenced by rate, rhythm, inotropic and lusotropic

determinants, in addition to mechanical factors (e.g. raised intrathoracic pressure, pericardial

tamponade).

6

Eh =

0 ≤ Eh ≤ 1

When CVP is equal to zero and Eh equals 1, the heart is working at maximum efficiency. As

Pra rises and both (Pmsf-CVP) and Eh are decreasing, venous return and cardiac output will fall

accordingly.

Measures of resistance:

The third element to control in circulation after volume and the heart is resistance. Resistance

is the impediment the blood flow encounters in a vessel, but it cannot be measured by any

direct means. Instead, resistance must be calculated from measurements of blood flow and

pressure. Resistance is expressed as peripheral resistance unit (PRU) or as dyne sec/cm5. In

the systemic circulation, about two thirds of the total systemic resistance is arteriolar

resistance in the small arterioles. The resistance to venous return can be explained as the

resistance encountered by the blood in the return to the heart and depends upon the

distribution of the circulatory compliance. Resistance to venous return is affected by both

arterial and venous resistances. For example, a fall in arterial resistance decreases blood

pressure and increases cardiac output while a fall in venous resistance increases both cardiac

output and blood pressure. Changes in the venous component of resistance are not easily

measurable. It is the arteriolar resistance, quantified as the systemic vascular resistance, that is

usually the object of therapeutic vasoactive control. The arterial resistance and RVR are

predominantly influenced by tissue oxygenation and are prime determinants of the venous

return and cardiac output.

Navigator:

NavigatorTM

(Applied Physiology Pty Ltd, Sydney Australia) is a clinical decision support

system that puts all these parameters together. The approach underpinning the Navigator®

monitoring system is to use an analogue for the mean systemic filling pressure and not any

preload measure like wedge pressure, to define the volume state. Together with central

venous pressure, this analogue for mean systemic filling pressure also permits a novel

definition of global heart performance Eh. The device acquires raw data every five seconds

7

from connected monitors and graphs it on the monitor display. A touchscreen enables the

clinician to enter target ranges for blood pressure, cardiac output and oxygen delivery.

Patient’s age, height and weight are also required.

On the right hand side of the display are the current values of the connected monitors, targets

and the anthropometrical data of the patient. On the left hand side, the monitor displays the

patient’s position on x (resistance, SVR) and y (volumetric, Pmsa) axes. A vertical axis that

runs parallel to the Pmsa axis shows the value of the heart performance (Eh). These two parallel

axes move independently from one another. The target zone is graphically delineated by

isoflow and isobar lines, defining a trapezoid zone in the center of the screen. The patient’s

current position is shown as a red dot in a yellow arrow. The direction of the arrow reflects

the suggested change in therapy in order for the patient position to reach the target zone.

Figure 2: Navigator display

NavigatorTM

uses a software algorithm to calculate an analogue of Pmsf (Pmsa) using the

following equation, developed by Parkin6:

8

Pmsa = a x CVP + b x MAP + c x CO

where a is 0.96, b is 0.04 and c is a factor with the dimensions of resistance dependent on the

patient’s anthropometric data: c =

.

For example, in a patient that has a CVP of 0, MAP of 100, CO of 6 and c= 0.5, this means

that Pmsa = 0.96 x 0 + 0.04 x 100 + 0.5 x 6 = 7.

This equation was stipulated by Parkin in 1999 and he tested the clinical validity in patients

receiving continuous venovenous haemodiafiltration7.

Although Maas et al found in their study that there was a poor agreement between Pmsf and

Pmsa, they also stipulated that Pmsa is an effective parameter to detect changes in effective

circulating blood volume (full concordance between ΔPmsf and ΔPmsa). They suggest a

calibration factor of 1.42 to adjust the Pmsa to match the Pmsf value8.

Cecconi et al. used the Navigator to assess the effects of a fluid challenge and fluid

responsiveness in intensive care patients. None of the parameters proved to be a good

predictor for fluid responsiveness, but they can distinguish the responders from the non-

responders. Pmsa increased in both fluid responders and non-responders, the CVP rises along

with Pmsa in non-responders. The change in Eh situated the patient on the Frank-Starling

curve: a decrease in Eh after fluid challenge showed that the heart was approaching the flat

part of the Frank-Starling curve and CVP rised correspondingly to limit venous return9.

Nitrates:

Nitrates and more specifically nitroglycerin (glyceryl trinitrate, GTN) are routinely used in

the treatment of heart failure, angina pectoris, acute treatment of hypertension and also in the

perioperative setting in patients undergoing cardiac surgery. It is known to have a significant

first-pass effect and necessitates parenteral (intravenous, sublingual) administration.

Denitration of nitroglycerine produces free nitrite (NO2-) which is converted to NO

10. NO

then activates guanylate cyclase that catalyses the conversion of GTP to cyclic GMP, which

relaxes smooth muscle of the vasculature. It works through vasodilation with a preference

towards the venous capacitance vessels and the large and medium-sized coronary arteries. It

produces a reduction in ventricular filling pressures, systemic and pulmonary vascular

9

resistance and systemic arterial pressure. Nitroglycerin theoretically has more than one action.

Venous compliance will increase, while resistance to venous return will decrease. The arterial

tone will decrease depending on the dose and will cause a dose-dependent effect on mean

arterial pressure. The net effect will be a modest decrease in blood pressure and a variable

response in cardiac output depending on the state of the circulatory system when nitroglycerin

is administered.

Figure 3: Structure of glyceryl trinitrate (nitroglycerin)

Objective

In clinical practice, during cardiac surgery, cardiac output often increases. In order to explain

the physiological mechanism reponsible for the changes in cardiac output during the

administration of nitroglycerine in cardiac surgical patients, NavigatorTM

was used. A feature

of the Navigator® is the ability to observe the influence of nitroglycerine on the circulatory

system using Pmsa and Eh in addition to the traditonal haemodynamic variables. The aim of the

study was to evaluate the circulatory effects of nitroglycerin in cardiac sugery patients

(coronary artery bypass graft patients).

Methods

The study was approved by the Ethics Committee of the University Hospital of Ghent.

Thirteen patients undergoing cardiac surgery, more particularly coronary artery bypass

surgery, were selected and included in the study. Written informed consent was obtained

before surgery. After induction of general anaesthesia and before surgical incision,

hemodynamic data were collected (standard monitoring, a radial artery catheter and cardiac

10

output by means of a Swan-Ganz catheter). Concurrently, data gathered by the NavigatorTM

device were noted. These data include Pmsa (analogue for mean systemic filling pressure), Eh

(heart performance) and SVR (systemic vascular resistance). Measurements were done in

supine position. Then nitroglycerin (NTG) infusion (0,5 mcg/kg/min) was started and after

hemodynamic stabilization (approximately after ten minutes), the same parameters were

collected and noted. Next, we compared the baseline hemodynamic data with those under

NTG administration. Data before and after administration of NTG were compared using

paired Student’s t test. The Pearson correlation test was calculated to assess the relation

between changes in the Pmsa-CVP gradient and the changes in CO.

Results

CVP decreased after the administration of GTN from 10 ± 3 to 6 ± 2 mm Hg (p = 0,001).

Figure 4: Central venous pressure at baseline and with nitroglycerin administration

Cardiac output did not change significantly after nitroglycerin infusion.

11

Figure 5: Cardiac output at baseline and with nitroglycerin administration

Systemic vascular resistance (SVR) decreased from 1397 ± 388 to 1181 ± 286 dyne.sec/cm5.

This was not significant (p = 4,1).

Figure 6 Systemic vascular resistance at baseline and with nitroglycerin infusion

Mean arterial blood pressure dropped from 80 ± 14 mm Hg to 62 ± 8 mm Hg (p = 0,016).

Pmsa decreased from 15,8 ± 2,8 mm Hg to 11,2 ± 2,0 mm Hg (p < 0,001). At the same time Eh

increased from 0.39 ± 0.10 to 0.50 ± 0.10 (p = 0.001).

There was a positive correlation between the change in gradient Pmsa - CVP (the driving

pressure for venous return) and the change in cardiac output (Figure).

12

Figure 7: ΔPmsa-CVP versus ΔCO. ΔPmsa-CVP = the change in gradient between Pmsa-CVP (baseline-GTN) and ΔCO = the change in CO (baseline-GTN).

Discussion

An essential step in forming a consistent numerical relationship between measured data and

therapy is to resolve measured circulatory variables such as cardiac output, MAP and CVP

into volume, resistive and cardiac states. The use of Pmsa in cardiovascular physiology

provides the true object of control of volume therapy and the parameter Eh provides a measure

of global performance of the heart and illustrates how VR regulates CO.

In our study we’ve noticed first of all a decrease in MAP, caused by a decrease in arterial tone

during the administration of GTN. Also Pmsa and CVP decreased as GTN increased the

venous compliance and decreased venous resistance.

Interestingly, we found that with the administration of GTN there was a better heart

performance as illustrated by an increase in Eh.

Changes in venous return and cardiac output after GTN infusion were not related to the

change in CVP but to the change in gradient between Pmsa and the CVP, the driving pressure

for venous return. The functional role of the heart may be seen as emptying the right atrium as

it is filled by the venous return, thus keeping the CVP well below Pmsf and maintaining

venous return. Changing this gradient will impact venous return and at the same time cardiac

output.

13

The reduction of CVP by nitroglycerin does not always implement a decrease in cardiac

output. The driving pressure of cardiac output depends on the gradient between Pmsf and CVP

and a rise in this gradient causes an increase in venous return (paradoxical). In our selected

group of patients, this phenomenon appears in several cases.

The development of new haemodynamic monitoring devices such as NavigatorTM

, which

applies the Guytonian concepts of the circulation, can help us to understand the

cardiovascular dynamics of patients in a more detailed manner and can lead to more

appropriate clinical decision making. If this will also result in better outcome for the patient,

has yet to be determined. But aside from allowing us to better understand the patient’s

physiology, it can also help us to further explore in depth the hemodynamic effects of

cardiovascular medication e.g. nitroglycerin.

14

References:

1. Swan HJ, Ganz W, Forrester J, et al. Catheterization of the heart in man with use of a

flow-directed balloon-tipped catheter. N Engl J Med 1970; 283:447–51.

2. Guyton AC, Coleman TG, Granger HJ: Circulation: overall regulation. Annu. Rev.

Physiol. 1972; 34:13–46, 1972.

3. Hall JE, Guyton AC. Textbook of Medical Physiology. Twelfth edition. Saunders

Elsevier, 2011.

4. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B

et al. Comparison of two fluid-management strategies in acute lung injuries. N Engl J

Med 2006; 354:2564-2575.

5. Maas JJ, Geerts BF, van den Berg PC et al. Assessment of venous return curve and

mean systemic filling pressure in postoperative cardiac surgery patients. Crit Care

Med 2009; 37:912-918.

6. Parkin WG, Leaning MS. Therapeutic control of the circulation. J Clin Monit Comput

2008; 22:391-400.

7. Parkin WG, Wright C, Bellomo R, Boyce N. Use of a mean systemic filling pressure

analogue during the closed-loop control of fluid replacement in continuous

hemodiafiltration. J Crit Care 1994; 9:124-133.

8. Maas JJ, Pinsky MR, Geerts BF, de Wilde RB, Jansen JR. Estimation of mean

systemic filling pressure in postoperative cardiac sugery patients with three methods.

Intensive Care Med 2012; 38(9):1452-1460.

9. Cecconi M, Aya HD, Geisen M, Ebm C, Fletcher N, Grounds RM, Rhodes A.

Changes in the mean systemic filling pressure during a fluid challenge in postsurgical

intensive care patients. Intensive Care Med 2013; 39:1299-1305.

10. Valchanov KP, Arrowsmith JE. The role of venodilators in the perioperative

management of heart failure. Eur J Anaesth 2012: 29:121-127.

15

Nederlandse samenvatting

Het is een moeilijk evenwicht om bij een hemodynamisch instabiele patient een treffende

inschatting te maken van de cardiovasculaire status omdat courante parameters zoals

bloeddruk en cardiac output geen exact idee geven over de hartfunctie en/of intravasculair

circulerend bloedvolume. Daarnaast bestaat al eeuwen het idee dat het hart het centrum van de

cardiovasculaire fysiologie is, terwijl het perifere en dan voornamelijk veneuze partim van de

circulatie lang verwaarloosd werd. In de tweede helft van de 20ste

eeuw werkte Guyton de

experimenten van Bayliss en Starr verder uit en poneerde hij de stelling dat de cardiac output

in normale omstandigheden volledig bepaald wordt door de veneuze terugkeer. Enkel bij

hartfalen wordt het hart een limiterende factor voor cardiac output. De veneuze retour wordt

door drie elementen bepaald: rechter-atriumdruk, weerstand tegen veneuze retour, en

gemiddelde systemische vullingsdruk. Deze laatste is een parameter die gebruikt kan worden

als maat voor effectief circulerend bloedvolume. Hoewel dit een interessante parameter is om

te gebruiken in de klinische setting, bleek deze in de praktijk moeilijk meetbaar. Enkel

wanneer de circulatie tijdelijk werd gestopt (vb. inductie van ventrikelfibrillatie bij het testen

van ICD-toestellen), equilibreerde het vaatstelsel zich tot de gemiddelde systemische

vullingsdruk. Recent echter ontwikkelde een onderzoeksgroep een methode om deze druk te

meten bij geventileerde patiënten. Daarnaast werd een apparaat ontwikkeld op basis van de

berekeningen en formules van Parkin, de NavigatorTM

, dat de data van de huidige monitoring

(arteriële bloeddruk, cardiac output, antropometrische gegevens) gebruikt en deze integreert

om een analoog te berekenen van de gemiddelde systemische vullingsdruk en ook een nieuwe

parameter introduceert, nl. de globale hartperformantie.

Wij gebruikten de NavigatorTM

bij cardiochirurgische patiënten om uit te zoeken wat het

effect van nitroglycerine-toediening is op de cardiovasculaire parameters van de patiënt.

Hiervoor selecteerden we 13 patiënten waarvan we de baseline parameters noteerden en

daarna onderzochten we in welke mate deze parameters veranderden bij een toediening van

0,5 mcg/kg/min.

We stelden vast dat de toediening van nitroglycerine bij onze patiënten leidde tot een

verhoogde globale hartperformantie. Daarnaast stelden we ook vast dat er een correlatie

bestaat tussen het verschil in cardiac output (zonder en met nitroglycerine) en het verschil in

de drukgradiënt tussen de gemiddelde systemische vullingsdruk en de centraal veneuze druk

(de aandrijvingsdruk voor veneuze retour).