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The objective of this study was to investigate the short-term cardiovascular effects of intravenous (IV) medetomidine-midazolam-fentanyl (MMF) injections in the rabbit using vascular ultrasonography and echocardiography.
Anesthesia with MMF was induced intramuscularly (IM) in 8 female New Zealand White rabbits before 3 defined bolus injections of MMF were given IV. Before and for 10 min after each MMF injection the following vascular variables [at the left common carotid artery (ACC) after the first injection and at the abdominal aorta (AA) after the second injection]: vessel diameter (D), peak systolic, minimum diastolic, end-diastolic and average blood flow velocities (psBFV, mdBFV, edBFV, Vave), average volumetric flow (VFave), resistance index (RI) and pulsatility index (PI) and other clinical variables: mean arterial pressure (MAP), heart rate (HR), peripheral arterial oxygen saturation and end-tidal CO2 were recorded. Echocardiography was used after the third injection to investigate changes in cardiac parameters. Additionally, hemodynamic effects were observed at the ACC after complete subcutaneous antagonism of anesthesia by atipamezole-flumazenil-naloxone (AFN) until recovery of the animals.
Medetomidine-midazolam-fentanyl IV caused a significant decrease of blood flow velocity in both investigated vessels which was associated with a significant decrease of HR and cardiac performance indicated by the decrease of FS and average volumetric blood flow. Mean arterial pressure significantly increased after each MMF injection; whereas, it significantly decreased after AFN injection. Therefore, MMF and AFN should be carefully used in rabbits and may not be suitable in patients with ventricular dysfunction.
Notre objectif était d’étudier par ultrasonographie et échocardiographie les effets cardiovasculaires à court-terme d’injections intraveineuses (IV) de médétomidine-midazolam-fentanyl (MMF) chez le lapin.
L’anesthésie avec MMF a été induite par voie intramusculaire (IM) chez 8 lapines albinos de Nouvelle-Zélande avant d’administrer 3 bolus de MMF par voie IV. Avant, et pour 10 min après chaque injection de MMF, les données suivantes ont été enregistrées [au niveau de l’artère carotide commune gauche (ACC) après la première injection et au niveau de l’aorte abdominale (AA) après la seconde injection] : diamètre des vaisseaux (D), la vélocité du flot sanguin au pic de la systole (psBFV), au minimum de la diastole (mdBFV), à la fin de la diastole (edBFV) et le flot moyen (Vave), le flot volumétrique moyen (VFave), l’index de résistance (RI) et l’index de battement des vaisseaux (PI). D’autres variables cliniques ont également été enregistrées : la pression artérielle moyenne (MAP), le rythme cardiaque (HR), la saturation artérielle périphérique en oxygène et le CO2 télo-expiratoire. L’échocardiographie a été utilisée après la troisième injection afin d’étudier les changements dans les paramètres cardiaques. Également, les effets hémodynamiques ont été observés au niveau de l’ACC après un antagonisme sous-cutané complet de l’anesthésie par l’administration de la combinaison atipamézole-flumazil-naloxone (AFN) jusqu’au réveil des animaux.
L’administration de MMF par voie IV a causé une diminution significative de la vélocité du flot sanguin dans les deux vaisseaux étudiés et a été associée à une diminution significative du HR et de la performance cardiaque indiquée par la diminution de FS et du flot volumétrique moyen. La pression artérielle moyenne a augmenté de manière significative après chaque injection de MMF; alors qu’elle a diminué de manière significative après l’injection d’AFN. Ainsi, les combinaisons MMF et AFN devraient être utilisés prudemment chez les lapins et pourraient ne pas être indiqués chez des patients avec une dysfonction ventriculaire.
(Traduit par Docteur Serge Messier)
Anesthesia with the combination of medetomidine, midazolam, and fentanyl (MMF), each of which can be antagonized by specific antagonists, has been described as a useful anesthetic technique for rabbits (1,2). Obvious benefits of this drug combination relate to the competitive reversibility by specific antagonists for all components, which leads to an improvement to control anesthetic depth, a shorter recovery phase and less occurrence of hypothermia (2,3).
Medetomidine and its specific antagonist atipamezole react with α2-adrenoceptors, midazolam and its antagonist flumazenil bind on benzodiazepine receptors, and fentanyl and its antagonist naloxone act on opioid receptors. The degree of analgesia produced by medetomidine is insufficient for surgical procedures but in combination with a potent opioid like fentanyl and a α2-agonist surgical anesthesia may be produced in rabbits (1). The use of medetomidine and fentanyl, however, is associated with marked bradycardia and hypotension in rabbits (4–7). Midazolam complements the sedative-hypnotic effects of medetomidine with minor additional effects at therapeutic doses (8). Cardiovascular effects have been studied in long-term administration of the drug combination (2); however, there is little information available about the direct cardiovascular effects of intravenous MMF bolus injections. Ultrasound imaging technologies, including Doppler-based modes, can be used for the visualization of direct vascular effects of anesthetic drugs (9,10).
Our study, therefore, was designed to investigate and to visualize in vivo short-term cardiovascular effects of MMF and its reversal (AFN) in rabbits.
Eight female New Zealand White rabbits were used in the study. Mean ± standard deviation (s) body weight (BW) was 2.74 ± 0.28 kg, and rabbits were between 10 and 16 wk of age. Rabbits were obtained from a colony free of respiratory pathogens (Asamhof, Bad Kissingen, Germany). They were housed separately in cages on dust-free wooden shavings. Room temperature (19°C ± 2°C), relative humidity (50% and 60%), and a light cycle (12 h of light and 12 h of darkness) were maintained during acclimatization of at least 7 d in advance of the experiment. Rabbits were fed a commercial pelleted diet (Altromin, Lage, Germany); autoclaved hay and water were available ad libitum. Experiments were approved by the local animal care committee and were in accordance with the German Animal Welfare Act.
On the day of the experiment, each rabbit was weighed and clinically examined for behavior, respiration, and cardiovascular variables. Experiments were conducted between 9 and 12 am. Anesthesia was induced using medetomidine (Domitor; Pfizer GmbH, Karlsruhe, Germany), 0.2 mg/kg BW, midazolam (Dormicum; Hoffmann-La Roche, Grenzach Wyhlen, Germany), 1.0 mg/kg BW, and fentanyl (Fentanyl B. Braun 0.5 mg; B. Braun Melsungen AG, Melsungen, Germany), 0.02 mg/kg BW injected intramuscularly (IM) in 1 syringe. A stable anesthesia characterized by good muscle relaxation with stable baseline cardiovascular variables lasting approximately 30 min as observed from preliminary work was maintained with this dose. After the swallowing reflex was lost, the trachea was intubated (inner diameter of endotracheal tube, 2.5 to 3.0 mm) without direct laryngeal observation. A local anesthetic [Emla (lidocaine + pilocaine); Astra Zeneca GmbH, Wedel, Germany] was put on the skin of the left ear of each rabbit, and a catheter [Vasofix; 20 SWG (1.1 × 33 mm) B. Braun Melsungen AG, Germany] was inserted in the median auricular artery for arterial blood pressure measurements. Another catheter [Vasofix; 22 SWG (0.9 × 25 mm), B. Braun Melsungen AG] was inserted in the lateral auricular vein. Each rabbit was shaved in preparation for ultrasonographic measurements and body temperature was maintained between 37°C to 38°C by a heating pad.
Ultrasonographic measurements of the left common carotid artery (ACC) and 2-dimensional guided M-mode echocardiography were conducted with the rabbits positioned in dorsal recumbency. For ultrasonography of the abdominal aorta (AA), the rabbits were positioned in right lateral recumbency. Measurements were carried out after bolus injections of MMF IV (see experimental protocol).
Animals breathed spontaneously during anesthesia, but the inspired room air was supplemented by flow of oxygen in front of the endotracheal tube. Monitoring of mean arterial pressure (MAP), heart rate (HR), end-tidal CO2 (PET′CO2) and peripheral arterial oxygen saturation (SpO2) was conducted using a patient monitor [Datex Ohmeda S/5, type F-CM1.00, pressure transducers (Hellige type 4-327-I); GE Healthcare, Helsinki, Finland]. At the end of data collection, following the last bolus (1.5 h), MMF anesthesia was completely reversed by using atipamezole 1.0 mg/kg (Antisedan; Pfizer GmbH, Karlsruhe, Germany), flumazenil 0.1 mg/kg (Anexate; Hoffmann-La Roche, Grenzach Wyhlen, Germany), and naloxone 0.03 mg/kg (Narcanti Vet; Janssen Animal Health, Neuss, Germany) (AFN) subcutaneously (SC) in 1 syringe.
Three bolus injections (30, 50, and 70 min following initial IM anesthetic injection) of the combination of medetomidine 0.03 mg/kg, midazolam 0.16 mg/kg, and fentanyl 0.003 mg/kg (MMF, 1/6 of the induction dose) were given intravenously (IV). No other anesthetic or analgesic drug or surgical stimulation was applied during the experiment. Vascular and hemodynamic alterations induced by the first injection (30 min after induction of anaesthesia with MMF) were recorded by ultrasonography at the ACC. After the second MMF injection (20 minutes after the first bolus injection of MMF) ultrasonic indicators were measured at the AA. Finally, after the third injection (20 min after the second bolus injection of MMF) echocardiographic parameters of the heart were measured to investigate alterations of cardiac parameters. Additionally, the effects after antagonism of MMF were observed at the ACC after subcutaneous AFN injection (20 min after the third injection of MMF) until regain of righting reflex of the rabbits.
Baseline measurements were taken prior to each bolus injection once stable anesthesia was present (fluctuation of +/− 5% in all measurements for 5 min). Baseline ultrasound data were taken at different locations (ACC before the first injection and reversal; AA before the second injection; heart before the third injection). After each injection, vascular and echocardiographic images were recorded at 30 s, 1 min, and then at 1-minute intervals for up to 10 min. The injection volume was adjusted with sodium chloride solution (0.9%) to 0.6 mL per bolus and the injection speed per bolus was 20 s. Time (T) = 0 was taken as the time at the end of MMF injection. During ultrasonographic examinations of the ACC and AA, vessel images and velocity spectra were recorded for subsequent determination of vessel diameter, peak systolic blood flow velocity (psBFV), minimum diastolic blood flow velocity (mdBFV), end-diastolic blood flow velocity (edBFV), and time-average blood flow velocity (Vave).
The resistance index (RI) of the vessels, which was derived from psBFV and edBFV, is an important index that reflects the vascular resistance distal to the point of Doppler imaging. The RI was calculated by use of the following equation (11):
The pulsatility index (PI) was also used to characterize peripheral vascular resistance in accordance with the following equation (12):
Mean volumetric flow (VFave) in the abdominal aorta and left common carotid artery was calculated (13) as:
where: r is the vessel radius.
Echocardiographic investigation related to the third injection measured fractional shortening, which was calculated by use of the following equation (14):
where: LVEDD is left ventricular end-diastolic diameter and LVESD is left ventricular end-systolic diameter.
Clinical data, including HR, MAP, SpO2, PET′CO2, and the plethysmographic amplitude were recorded concurrently with the ultrasonographic examination.
Vascular imaging was conducted by a 10-MHz linear transducer (FLA 10-MHz 1A; GE Vingmed, Horten, Norway). For echocardiography, a 10-MHz sector transducer (FPA, 10-MHz 2A; GE Vingmed, Horten, Norway) was used. The transducers were in conjunction with an ultrasonographic system (A/S System FIVE/REM; GE Vingmed).
Vascular variables of the ACC and AA were measured in accordance with a method described elsewhere (10). Doppler evaluations were conducted in pulse-wave mode. Recorded velocity spectra were assessed for quality on the basis of clarity of the visual and audible signal and then stored for subsequent measurement of psBFV, mdBFV, edBFV, and Vave. From these variables, the RI, PI, and mean volumetric flow (VFave) were derived. Furthermore, 2-dimensional images of the vessel wall were assessed and stored for subsequent measurement of the luminal diameter between the leading edge of the innermost echogenic layer by cursor adjustment (15).
For the echocardiographic assessment, a right parasternal view was used. Two-dimensional M-mode short-axis views at the level of the chorda tendinae were recorded for measurement of ventricular dimensions (left ventricular end-systolic and end-diastolic diameters). Fractional shortening of the left ventricle was derived from these variables (14,16,17).
Mean ± s values were reported for all data. To attain a maximum of power in regard to limited sample size, statistical comparisons were considered as exploratory data analyses. Thus, no correction of α error rate was taken into account. However, a two-sided P-value < 0.05 was considered to outline statistical significance (rather as a standardized measure of distance and/or effect than as a formal proof of hypothesis) within each statistical comparison.
To evaluate overall patterns for variables of interest, linear mixed models (LMM) with monotonous (linear) or transient (quadratic) time effects were calculated. The LMM approach properly reflects the structure of repeated data and accounts for correlation between measurements within the same subjects. Autoregressive correlation structures (first order) as well as random effects for each rabbit were considered in the regression analysis. Effects of time were specified first by graphic assessment and verified by stepwise model derivation. Only if a significant effect of time was detected during LMM analysis, multiple post hoc Student t-tests for paired samples were used to assess differences between each time point during the examination period of 10 min and the baseline value. Furthermore, the Friedman test followed by Student t-tests for paired samples were used to separately compare related samples for equivalent time points after the first, second, and third bolus for the variables HR, MAP, SpO2, and PET′CO2. All statistical analyses were conducted with commercially available software (SPSS, Version 16.0; SPSS, Chicago, Illinois, USA).
Data for vascular ultrasonographic measurements of the ACC after injection of the first MMF bolus were determined (Table I).
The psBFV, RI, VFave, and PI significantly decreased immediately after injection and remained significantly decreased compared to baseline values for 1 to 5 min after the first bolus injection. Although the edBFV increased from minute 0.5 up to minute 3 and decreased again afterward, the post-hoc tests did not reveal any significant differences. Furthermore results of the linear mixed regression model indicated the vessel luminal diameter recorded at the ACC did not change significantly from baseline values.
Data for vascular ultrasonographic measurements of the AA after the second bolus injection of MMF were determined (Table II).
Luminal diameter of the AA was significantly increased after the injection compared to baseline values. In contrast, psBFV, edBFV, and VFave were significantly decreased after MMF injection compared to baseline values.
Additionally, according to the linear mixed regression model the RI increased after a temporal decrement to 0.5 min, but lacked statistical significance. Furthermore, results of the linear mixed regression model indicated the PI at the AA did not change significantly from baseline values.
Selected echocardiographic variables measured after injection of the third bolus of MMF were determined (Table III).
The LVESD significantly increased after the third bolus of MMF compared to baseline values. Additionally, FS significantly decreased at 0.5 until 2 min after injection compared to baseline values.
The MAP significantly increased immediately after each injection. In contrast, heart rate significantly decreased after each injection until the termination of measurements. Also PET′CO2 significantly decreased at 0.5 to 1 min after each injection, and then returned towards baseline values. Based on the mixed model regression SpO2 did not significantly change after MMF bolus injections.
When data at equivalent time points after the first, second, and third MMF bolus injections were compared with the Friedman test, no significant time-adjusted differences in HR, MAP, SpO2, and PET′CO2 were revealed between the injections.
Recorded plethysmographic amplitude (PA) revealed a reversible flattening immediately after the MMF bolus injections (data not shown).
After the AFN injection the luminal diameter of the ACC significantly decreased, whereas psBFV and PI at the ACC significantly increased at 1 to 5 min after AFN injection compared to baseline values. When data at equivalent time points after the first MMF bolus injections and the AFN bolus injection were compared with the Friedman test, a significant decrease of the vessel diameter and RI, and a significant increase of psBFV and edBFV at the ACC were measured after AFN injection.
Heart rate significantly increased and MAP significantly decreased after AFN injection compared to the corresponding baseline value. And finally, an increase of the amplitude of PA was recorded after antagonism.
When data at equivalent time points after the first MMF bolus injections were compared with values after the AFN injection, significant time-adjusted differences in HR and MAP were revealed between the MMF and the AFN injections.
The purpose of this work was to investigate some short-term cardiovascular effects of intravenous MMF injections using ultrasound measurements in anesthetized rabbits. In addition, the effects after complete reversal (AFN) were observed until regain of righting reflex of the animals.
In the present study, IM injection of the combination of medetomidine 0.2 mg/kg, midazolam 1.0 mg/kg, and fentanyl 0.02 mg/kg produced a stable anesthesia within 5 to 10 min, characterized by good muscle relaxation with stable baseline cardiovascular variables for approximately 30 min (18). Further prolongation of anesthesia with the present combination may be achieved by IV injection of medetomidine 0.03 mg/kg, midazolam 0.16 mg/kg, and fentanyl 0.003 mg/kg (1/6 of the induction dose) every 20 min. The short-term cardiovascular effects of those further intravenous MMF injections for prolongation of anesthesia were determined using Doppler ultrasonography, considered as a widely accepted, accurate, non-invasive method for evaluating blood flow in a variety of vessels, such as the extracranial carotid system and the abdominal aorta (19). Percutaneous sonographical examination allows an immediate visualization of vascular effects and is comparable with perivascular ultrasonic flow probes as a non-invasive method (20). In this study, vascular dimensions were measured using ultrasound at the common carotid artery and the abdominal aorta. The combination of Doppler-flow technology using high-resolution vessel images, with echocardiography and hemodynamic monitoring can provide extensive information about the cardiovascular effects of drugs. Furthermore, changes in peripheral vascular resistance within the distribution area of measured vessels can also be determined directly by measuring edBFV and indirectly by calculation of the RI and PI (11,12,21).
Results of the present study indicated that after application of the induction dose of MMF, additional bolus injections (1/6 of the induction dose) caused a significant decrease (0.5 to 4 min after injection) of psBFV by a maximum of 36.4% in the ACC and by a maximum of 37.6% in the AA. In accordance with these findings VFave was significantly decreased after the MMF bolus injections in both vessels compared with respective baseline values indicating a significant decrease of average volumetric blood flow in the investigated vessels.
Furthermore, edBFV, in particular, decreased (significantly at the AA) immediately after MMF injections compared to baseline values. Correspondingly, the PI slightly increased at the AA. These findings indicated that bolus injections of MMF had a vasoconstrictive effect on the peripheral vessels particularly in the distribution area of the abdominal aorta. Our results are supported by findings in another study (22) in which the administration of medetomidine initially appeared to exert a vasoconstrictive effect mediated through a direct effect on α2-adroceptors of the smooth muscle of resistance vessels. Medetomidine not only causes peripheral vasoconstriction at arterial and venous vessels but also a central vasodilatation and a reversible centralization of circulation with increased perfusion of parenchymatous organs (23,24). Fentanyl has nearly the same effect at central vessels by decreasing the sympathetic tone (25).
In the present study, however, we found a significant decrease of RI and PI in the ACC after the first bolus injection; indicating in contrast to the measurements at the AA a decrease of peripheral vascular resistance in the distribution area of the carotid artery. This might be due to a local variation of the distribution of α2-adroceptors and resistance vessels in the different vascular territories (3,26).
Changes in plethysmographic amplitude were also recorded in the present study. Plethysmography has been used to measure changes in tissue blood volume. During the cardiac cycle, perfused tissue initially expands as the blood flow into the arterioles exceeds that into the capillary beds. Later in the cardiac cycle, accumulated blood drains into the venous system, allowing the tissue blood volume to return to its presystolic value. Specific changes of PA and specific features of the waveform can be used to distinguish healthy perfusion patterns from abnormal patterns in the peripheral vasculature (27). Peripheral vasoconstriction is reportedly associated with a decrease of the PA (28). In the present study, we detected this phenomenon after each MMF injection, corresponding to the significant decrease of edBFV within the distribution area of the abdominal aorta.
Furthermore, bolus injection of MMF induced an initial significant increase of MAP within the first minutes compared to baseline values, which is probably due to the initial peripheral vasoconstrictive properties of medetomidine. However, comparing the values at equivalent time points after the first, second, and third MMF bolus injections, MAP was well-preserved during the whole investigation period. These findings contrast with data from Vainio (22) who stated that in dogs approximately 30 min after medetomidine injection the activation of the central nervous system diminished the sympathetic outflow from the central nervous system, resulting in a decrease in blood pressure. Hellebrekers et al (4) explained this difference with a decreased sensitivity of peripheral vessel to α2-vasoreactivity in rabbits.
In accordance with Vainio (22) and Dhasmana et al (5) medetomidine and fentanyl are both associated with bradycardia which was also evident in the present study after each MMF bolus injection. Regarding medetomidine, bradycardia is thought to have at least 3 origins: baroreceptor-mediated increased vagal tone in response to hypertension decreasing the beat frequency; diminished central outflow and a direct suppressive effect on the cardiac presynaptic α2-adroceptors. The mechanism of opioid-induced bradycardia is not fully understood, but a centrally mediated increase in parasympathetic tone, direct negative chronotropic action at the sinus node, potentiation of vagally released acetylcholine at the sinus node, and reduction in sympathetic activity have all been implicated (29,30).
Significant changes of echocardiographic variables were detected in the present study. The LVESD significantly increased after the third bolus of MMF compared to baseline values. Additionally, FS significantly decreased at 0.5 until 2 min after injection compared to baseline values which might indicate (combined with the significant reduction of average volumetric flow in the ACC and AA) a significant reduction of cardiac output. Cardiac output is related to heart rate and stroke volume which is the difference between the ventricular end-diastolic volume (EDV) and end-systolic volume (ESV). Three primary mechanisms regulate SV through effects on EDV and ESV: preload, afterload, and inotropy. Although cardiac output is determined by heart rate and SV, changes in heart rate are quantitatively more important because heart rate inversely affects stroke volume.
Negative-inotropic effects of fentanyl in high doses are described by Strauer (31). Also a direct negative-chronotropic effect of fentanyl due to a high central vagotone was observed by Dhasmana et al (5). Medetomidine, in contrast, exerts no direct influence on inotropy of the heart, but induces, as already described, a significant bradycardia and therewith a decrease of contractility and cardiac output (32).
The effects after complete reversal of MMF with the injection of the antagonists (AFN) were observed by Doppler-sonography at the ACC until regain of righting reflex of the animals (5 to 8 min after subcutaneous injection).
After the AFN injection the luminal diameter of the ACC significantly decreased, whereas psBFV and PI significantly increased indicating a central and a slight peripheral vasoconstrictive effect of AFN. Heart rate was significantly increased after injection of AFN which might indicate, in accordance with literature (33–36), that all 3 antagonistic components, therefore, return the negative-chronotropic effect of the anesthetics. In contrast, the decreased MAP that was observed in the present study, probably caused by atipamezole (22), could not be balanced by the potential blood pressure increasing effect of flumazenil and naloxone (35,36). However, according to a study by Vainio (21) the decrease of MAP in dogs is usually transient and only short-lasting. In this study, it was observed for 5 min, but further measurements were not carried out.
In the present study, noncardiovascular reflexes were not measured during anesthesia because it was important to maintain the position of the ultrasound probe, a task complicated by reflexive movement in the rabbits. We examined the effects of injecting 1 to 2 mL of saline solution on vascular volume by use of ultrasonographic evaluation of the ACC and AA, and conspicuous changes were not detected. Therefore, we did not take steps to account for the possible effect of 0.6 mL injection volume per bolus when analyzing our findings.
One limitation of the present study is that ultrasound measurements were not obtained simultaneously at the various locations. Cumulative effects, therefore, had to be assumed when data were compared among the different sections of the study. Clinical variables, however, were simultaneously recorded during the different MMF bolus injections. When changes in variables such as HR, MAP, SpO2, and PET′CO2 after the first injection were compared with those of the second and the third injections, only minor differences were evident, implying that repeated MMF injections are associated with minor cumulative effects on hemodynamic function. Another limitation is in obtaining repeated measurements at the abdominal aorta and at the heart at a defined probe position. We did not measure these values at the beginning of anesthesia, before the first bolus of MMF was injected; therefore, possible cumulative effects on the baseline values at these 2 positions cannot be excluded.
Multiple post hoc Student t-tests for paired samples were used to assess differences between the value for each time point during the 10 min after MMF injection and the baseline value. Because the probability of detecting false significant differences (differences by chance) increases with number of tests conducted, adjustment of P-values for the number of comparison made would have increased confidence in the results. Nevertheless, any correction method would have increased the likelihood of a type II error and a considerably larger sample size would have been necessary to yield sufficient power for a detailed analysis. For that reason, we decided to use non-adjusted P-values as statistical measures of importance, and we consider our results explorative.
In conclusion, MMF bolus injections in rabbits in the present study caused a significant decrease of blood flow velocity in the vessels investigated. This is associated with a significant decrease of heart rate and cardiac performance indicated by the decrease of FS and VFave. Increase in peripheral vascular resistance (edBFV) was significant particularly in the distribution area of the AA after the second MMF bolus injection. Accordingly, MAP did significantly increase after injections and stayed well-preserved during the investigation period. After AFN injection HR increased significantly, but MAP significantly decreased compared to baseline values and the equivalent values after the first MMF injection. Because of these findings, MMF may not be suitable in patients with ventricular dysfunction, including those with low cardiovascular reserve and an elevated sensitivity to alteration of loading conditions, such as dilated cardiomyopathy, mitral and/or tricuspid regurgitation (37).
The authors are grateful for the contributions of Dr. Nikolaus Poth.