The use of hemodynamic and cerebral monitoring to study pharmacodynamics in neonates
A. Smits 1, L. Thewissen 1,2, A. Dereymaeker 1,2, E. Dempsey 3,4, A. Caicedo 5,6, G. Naulaers 1,2
1 Neonatal intensive care unit, University Hospitals Leuven, Leuven, Belgium
2 Department of Development and Regeneration, KU Leuven, Leuven, Belgium
3 Department of Pediatrics and Child Health, Neonatal Intensive Care Unit, Wilton, Cork, Ireland
4 Irish Center for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland
5 Department of Electrical Engineering, STADIUS-ESAT, KU Leuven, Leuven, Belgium
6 iMinds Medical, Department Medical Information Technologies Leuven, Belgium
Corresponding author
Prof. Dr. Gunnar Naulaers Neonatal intensive care unit University Hospitals Leuven
Herestraat 49, 3000 Leuven, Belgium
Phone: +32 16 34 32 11, Email: gunnar.naulaers@uzleuven.be
Keywords: pharmacodynamics, neonate, monitoring, hemodynamics, cerebral activity
Word count structured abstract: 248
Word count main text (introduction –conclusion): 4363 4562
Number of tables: 0
Number of figures: 2
Graphical abstract: 1
References: 84 86
ABSTRACT
Background: Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical
responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates.
Methods: We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the
hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates.
Results: The use of blood pressure measurements, heart rate variability, functional echocardiography, near-
infrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the ‘brain circulation model’, the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools.
Conclusion: The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD
effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. However, since these tools mainly reflect short-term drug effects, long-term outcome of drug therapy in neonates also warrants attention.
1. INTRODUCTION
1.1. Developmental pharmacodynamics
Understanding drug (side)effects, requires integration of pharmacokinetic (PK, concentration/time relationship) and pharmacodynamic (PD, concentration/effect relationship) aspects of the drug, but also characteristics of the patient receiving the drug. Within the neonatal population, ontogeny (defined as age-related maturation) influences PK/PD processes (i.e. developmental pharmacology). The main PK processes are drug absorption, distribution, metabolism and excretion. While data on developmental PK are increasing over the last few decades, developmental PD is less well studied and relates to the number, affinity and type of receptors, the availability of natural ligands, and post-receptor effects [1, 2]. Drugs acting on the cardiovascular or central nervous system (CNS) body compartment are of specific interest to explore developmental PD due to often relatively fast clinical responses in neonates, which furthermore may differ from drug effects in older children and adults.
As described by Donovan et al, CNS-related PD differences between neonates and adults are divided in 3 groups: structure/connectivity, excitability and receptor activity/sensitivity [3]. These differences have to be considered in addition to, but independent from PK alterations. An example of PD variability based on difference in structure/connectivity is dexamethasone. Although the incidence of cerebral palsy in former preterm neonates treated with dexamethasone is higher compared to placebo treatment, the drug does not seem to affect cognition in adults [3]. The increased excitability of the newborn brain can be illustrated by the switch of γ-amino butyric acid (GABA) A receptors from an excitatory to inhibitory mode during early development. This can explain the occurrence of seizures in preterm neonates after benzodiazepine administration [4, 5]. An illustration of developmental PD of a vasoactive compound is dopamine, a catecholamine with peripheral as well as CNS effects, acting through a family of dopamine receptors with different subtypes (D1-D5). Dopamine increases renal blood flow, diuresis and sodium excretion via dopamine receptors in the kidney. Data of animal species observed a different PD response to low dopamine doses between mature (renal vasodilatation) and newborn (vasoconstriction due to α-adrenergic receptor stimulation) animals [6-8]. The natriuretic response to D1 agonists in the newborn seemed hereby blunted. Whether this is based on differences in receptor activity/affinity, receptor density, coupling to second messengers or intracellular mechanisms is unknown.
Although human studies indicate increased urine output in very low birth weight neonates receiving dopamine [7], further research on the mechanism of action and PD (side)effects are needed.
1.2. The add-on value of monitoring tools
Besides the developmental/ontogeny-related aspect, also the extensive physiologic variability (weight, age, renal and metabolic maturation, specific diseases), the lack of robust drug dosing regimens, parameters influencing
distribution of drugs and/or their metabolites into different body compartments (e.g. drug protein binding, permeability of membranes), and the lack of information on PD responses make it difficult to predict neonatal drug effects. This makes clinical PD trials in neonates necessary, but challenging. The introduction of bedside monitoring tools in this unique population is of add-on value in the PD assessment of especially cardiovascular and neuroactive drugs. Besides basal vital signs (e.g. heart rate, blood pressure) and/or clinical scores (e.g.
sedation, relaxation), PD assessment now also involves new parameters introduced by these monitoring tools.
The study of cerebral PD for example incorporates the effects on the cerebral blood flow (CBF), cerebral oxygenation (rSO2, regional cerebral oxygen saturation) and cerebral metabolism (cFTOE, cerebral fractional tissue oxygen extraction). Most of the anesthetic agents have an effect on both CBF and cerebral metabolism.
This can be within the frame of blood flow metabolism coupling, but some agents like propofol, a short acting anesthetic, will cause a low systemic blood pressure by direct effect on the vasculature through vasodilatation.
First we provide an overview of frequently used bedside tools to monitor hemodynamic or cerebral PD effects in neonates., and Ssubsequently, available data on some examples of specific compounds will be summarized.
2. BEDSIDE TOOLS TO MONITOR PHARMACODYNAMIC EFECTS
2.1. Hemodynamic monitoring: heart rate and blood pressure
The most commonly monitored hemodynamic parameters are heart rate and systolic, mean and diastolic blood pressure (BP). In neonatal intensive care BP is often measured invasively using the umbilical, radial or tibial artery. In this way effects of drugs like dopamine or epinephrine, and also anesthetics like propofol or sevoflurane, can be immediately determined by alterations in heart rate and/or BP. However, whether a decrease in BP is clinically relevant, mainly depends on the effect of the medication on metabolism as will be discussed later. Another relevant discussion is the lack of consensus regarding the ‘ideal BP’ [9-12]. Although firm definitions and reference values are currently not available for (preterm) neonates, a mean arterial BP below the postmenstrual age (PMA, weeks) is often considered as hypotension in the first days of life. In addition, the occurrence of hypotension without clinical signs of shock and close observation without treatment (i.e. fluid bolus and/or inotropes) is referred to as ‘permissive hypotension’ and displays comparable outcome as normotensive patients [10]. Besides parameter values, also the measurement technique used, environmental (stress), patient-related factors (sleep/wake status) and concomitant medication can influence hemodynamic parameters trends.
2.2. Functional Echocardiography and Non-Invasive Cardiac Output Monitoring
Functional echocardiography has an important role in assessing the adequacy of circulatory status. The method is rational and non-invasive, and it provides accurate information about hemodynamic status such as measures of cardiac output (right ventricular output, left ventricular output and superior vena cava flow). More sophisticated measures of function include measures of right and left ventricular function including tissue doppler imaging and speckle tracking [13]. The problems with ultrasound are obvious; the necessary skill set is required, assessment takes some time and may lead to clinical instability, inter-rater variability, circulatory shunts complicate the measurement of systemic blood flow, and ultrasound is not a continuous monitoring tool. Despite these challenges echocardiography is now an very established monitoring tool within the neonatal intensive care unit (NICU). Multiple randomised studies addressed the effect of inotropes on measures of cardiac output. Roze [14]
Chatterjee [15] and Evans [16] evaluated dopamine compared to dobutamine in very preterm infants who were deemed to be hypotensive. The definitions differed from study to study, the number of infants enrolled varied (20 to 40 patients) as did the gestational age (GA). The findings were variable with two studies suggesting an increase in BP but a reduction in measures of cardiac output, including right and left ventricular output. Evans and colleagues evaluated the effects of dopamine and dobutamine on superior vena cava in neonates < 30 weeks and identified a reduction in superior vena cava (SVC) blood flow with dopamine but an increase with dobutamine. The same group also evaluated the effect of milrinone on SVC flow in preterm neonates at risk of low blood flow [17]. Milrinone was associated with an increase in heart rate but no reliable change in SVC blood flow.
More recently non-invasive cardiac output monitoring (NICOM) has been used as a hemodynamic assessment tool in newborns. This continuous assessment tool offers the possibility to study the effects of various drugs including inotropes/inodilators. El Khuffash et al compared NICOM measurements to cardiac ultrasound measurements and found an excellent correlation between these measurements [18]. Lien et al used non-invasive cardiac output to measure hemodynamic changes during surgical ligation of patent ductus arteriosus in very low birth weight infants [19]. This new tool offers great potential in the future PD study of specific therapies in newborns.
2.3 Near-Infrared Spectroscopy: cerebral oxygenation
Near-infrared spectroscopy (NIRS) can be used to monitor the cerebral oxygenation and circulation non- invasively. Near-infrared light (700-1000 nm) is transparent for biological tissue and is absorbed by oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (HHb) in the cerebral blood vessels. Absorption changes in near-infrared light can be converted into concentration changes in HbO2 and HHb, which are subsequently used
to determine rScO2. The transducer, containing the light emitting diode and distant sensors, is placed on the fronto-parietal left side of the neonatal skull to monitor rScO2. For more detailed technical information we refer to the separate references [20, 21].
With near-infrared spectroscopy the absorption of near-infrared light by oxy- and deoxy- hemoglobin is used to compute the rSO2 (HbO2/( HbO2+ HHb)). Last years, new monitors and neonatal probes make it possible to measure the cerebral oxygenation non-invasively even in very preterm infants. Recently, rSO2 reference values for preterms were proposed [21]. The cerebral oxygenation reflects mainly the venous cerebral oxygenation.
More sophisticated NIRS instruments will also provide measurements of HbO2, HHb, differences in hemoglobin concentration (HbD) and total hemoglobin (HbT), allowing to obtain details concerning CBF and cerebral blood volume.
2.4. (Amplitude integrated) Electroencephalography: cerebral function
Amplitude-integrated electroencephalography (aEEG) is a processed single-channel EEG for which at least 3 needle or adhesive scalp electrodes are needed. The electrical activity recorded is filtered for frequency, time- compressed and smoothed [22]. Based on the lower and upper margin amplitude of the activity band, different background patterns are distinguished. In addition, seizure activity and sleep-wake cycles can be observed [22].
Bedside amplitude-integrated electroencephalography (aEEG), and, complementary to this, multichannel video- EEG, is used more frequently to achieve insight in neurological well-being of the vulnerable (pre)term neonate.
Moreover, it can be used to study PD and reflects the underlying metabolic state of the brain (e.g. latent and secondary phase after perinatal asphyxia) [232]. Drug effects on neonatal cortical activity as measured with (a)EEG should be interpreted in relation to the level of brain maturation and thus the post menstrual age (PMA) of the baby. The quality and quantity of early brain activity (also called spontaneous activity transients or more common ‘burst activity’) is related to proper connectivity and the development of brain networks. Current research is focusing on the impact of routinely used drugs (e.g. morphine, fentanyl, caffeine, doxapram, theophylline) on the intrinsic characteristics of these very age-specific, intermittent brain activity as well as the organization of state [243-287], with the most pertinent question whether these drugs modulate only an acute and/or more sustained (developmental) effect on the maturing brain [298, 3029]. A recent systematic review documented that (a)EEG recorded early in life in preterms, may have potential as a marker for neurodevelopmental outcome later in life [31]. However, to assess the long-term PD and developmental effects of (CNS acting) drugs, monitoring tools have to be used in addition to clinical assessment tools (e.g. general movements, Bayley scales).
Additionally, there is increasing interest for targeted neuroprotective strategies with novel neuro-protective drugs such as melatonin, erythropoietin and allopurinol which require timely and quantifiable identification of infants at high risk. The implementation of continuous (a)EEG-monitoring in neonates suspected for encephalopathy and seizures has already shown to be of add-on value in the diagnosis as well as targeted treatment of seizures [320, 331]. Continuous multichannel video-EEG is therefore considered necessary to measure the efficacy of antiepileptic drugs [342-364]. However, one of the most elusive questions remains the identification of appropriate pharmacotherapy for neonatal seizures. We hereby highlight the urgent need for multicenter trials using quantifiable outcome measures to overcome age-specific pharmacodynamics and to identify optimal treatment regimens for both preterm and term neonates [375, 386].
3. THE BRAIN CIRCULATION MODEL
To provide a systematic overview of the hemodynamic effects on the brain, we propose an adapted scheme of
‘the brain circ model’ as first published by Banaji et al [397]. Basically, 3 important processes and 3 different mechanisms (autoregulation, blood flow metabolism coupling and cerebral oxygen balance) can be distinguished (Figure 1). A description of the processes and mechanisms involved is provided below.
3.1. Blood processes
The biochemistry and oxygenation of the blood will, in part, determine the oxygenation of the brain. This can be assessed by NIRS, which measures both cerebral oxygenation and cerebral blood volume. Administration of additional fluid boluses is one of the approaches to decrease viscosity and increase the cerebral blood volume.
Studies investigating the effect of additional fluid volumes in preterm neonates are highly relevant. As described by Lundstrom et al, administration of an extra volume of 20 ml/kg sodium chloride 0.9% in hypovolemia increases the blood pressure and the left ventricular output, however without a changes in cerebral blood flow [4038]. On the other hand, alterations in blood viscosity due to partial exchange transfusion in case of polycythemia changes both blood flow and oxygenation [4139-431].
Cerebral oxygenation is primarily dependent on the arterial oxygen saturation (SaO2) as described by Petrova et al [442]. Since changes in the oxygenation of the blood are mainly achieved by increasing FiO2 [453], a good correlation has been described between increase in FiO2 and the cerebral oxygenation. The recent SafeBbooscC
II trial highlighted adjustments in FiO2 as the most common intervention when the cerebral oxygenation value was low [464].
3.2. Vascular Smooth Muscle Processes
The vascular smooth muscles mainly regulate the blood flow to the brain by vasoconstriction and vasodilation.
Importantly, when the blood content (oxygen content, hemoglobin) remains stable, this will also lead to an increase or decrease in cerebral oxygenation as oxygen delivery will change.
Two important regulators are constantly influencing this process. First, chemically, a decrease in pH will cause vasodilation as documented in hypercapnia and acidosis. Hypocapnia will cause vasocontriction as described in different studies [475-5149] leading to cerebral ischemia and periventricular leukomalacia. Second, physically, a decrease in BP, within specific BP limits, will lead to vasodilation in case of good autoregulation.
Studying autoregulation can provide insight in the effect of drugs on BP and CBF. Anesthetics like sevoflurane are known to alter autoregulation in young infants [520-564]. The effect of inotropes like dopamine, dobutamine, epinephrine and milrinone on both BP and CBF will be discussed in one of the next paragraphs.
3.3. Tissue Processes
Cerebral metabolism plays a major role in the cerebral oxygenation of the brain. The brain blood flow metabolism coupling describes that blood flow and blood cerebral metabolism are coupled. The decrease in blood flow when anesthetics or sedatives are administered is thus mainly caused as a natural coupling with the decrease in metabolism. Studying the effect of sedative or anaesthetic drugs on CBF without taking into account the cerebral activity may result in incorrect interpretations. Doppler studies describe a decrease in blood flow when midazolam is administered , but whether this is harmful or just a reflection of the decrease in metabolism needs further investigation with monitoring tools like NIRS and EEG [575-597]. When considering CBF and cerebral oxygenation, we still need to take cerebral metabolism into account. In available neonatal clinical pharmacology reports, EEG is usually not performed concomitantly with hemodynamic measurements.
Nevertheless, many drugs do have a (in)direct effect on the cerebral metabolism. The use of (a)EEG in future PD research therefore needs to be promoted.
3.4. Mechanism I: Cerebral autoregulation
Cerebral autoregulation is the mechanism that keeps CBF constant within a certain BP range. Since the optimal BP in preterm neonates is currently unknown, measuring cerebral autoregulation can help to identify the lowest
and highest safe mean arterial blood pressure (MABP) in this population. At present, Although there is no universal autoregulation curve for the preterm neonate., Since ‘permissive hypotension’ can be accepted [10], it is unknown where the lower end of the autoregulation curve is located, and when treatment should be initiated to increase blood pressure. The add-on value of cerebral oxygenation, measured by NIRS, might hereby be of relevance. Hypotension with rScO2 within the normal range, is rather reassuring for the clinician. we assume that the lower border might be a MABP with a value equal to the PMA (i.e. 25 mmHg for a PMA of 25 weeks), however Furthermore, alterations in PCO2 and postnatal age (PNA) can influence the curve [6058-620]. New methods to describe autoregulation in preterm neonates using NIRS are recently published by our group and by use of CarMon (Cerebral autoregulation Monitor) we aim to study autoregulation in a very direct way. CarMon is a software program that effectively decouples the influences of SaO2 from the NIRS measurements, and subsequently calculates the different indicators of autoregulation, namely correlation, coherence, gain and phase between the blood pressure signal and rScO2 [631, 642]. This tool will mainly contribute to identify whether an increase in BP e.g. due to inotropes can be beneficial (resulting in a normal CBF), or harmful (by increasing the blood flow too much resulting in intraventricular haemorrhage as described by Alderliesten et al) [653]. This will be further explained in the inotropes paragraph.
3.5. Mechanism II: Cerebral Oxygen Balance
The cerebral oxygenation is determined by the cerebral oxygen delivery and cerebral oxygen demand. The oxygen delivery is dependent on the CBF and the blood oxygen content (which is dependent on hemoglobin and the peripheral oxygen saturation, SaO2). When SaO2 and brain metabolism are stable, the change in CBF will cause alterations in cerebral oxygenation. NIRS measures mainly the venous cerebral oxygenation. Since the arterial cerebral oxygenation (by measuring the oxygen saturation) is known, the cerebral fractional tissue oxygen extraction (cFTOE) can be calculated using the formula: cFTOE = (SaO2 – rSO2)/ SaO2 [664]. This will provide an estimation of the fractional oxygen extraction or the amount of oxygen taken from the blood by the brain. Changes in oxygen delivery can only be interpreted when the oxygen demand remains stable at the same time. This is one of the main problems in investigating drug effects since often oxygen delivery as well as oxygen demand are influenced. Importantly, when the venous saturation and fractional oxygen extraction remain stable, a drug can theoretically be considered as ‘safe’ for the brain.
3.6. Mechanism III: Blood flow metabolism coupling.
Blood flow metabolism coupling is well described in human and animal studies [675]. By using both EEG and NIRS, neurovascular coupling can be measured. Recently our group described different methods to look at neurovascular coupling [686, 697]. At present it is unknown whether a good neurovascular coupling is always present in (pre)term neonates. Since different compounds may influence neurovascular coupling [7068-720], this will certainly become a new area within the PD research.
The processes and mechanisms described are acting at the same time in the brain. Drugs can influence these processes and mechanisms, making it difficult to interpret and/or predict the final PD effects in a population, as well as in an individual patient. Besides drug efficacy, also safety require attention. Both the cerebral venous saturation and fractional oxygen extraction can be used as a (short term) safety guide, since they describe the endpoint of the oxygen balance. The next paragraphs focus on specific drugs and their effect on the brain. We will hereby mainly report the PD effects using the aforementioned monitoring tools and not the impact on the cellular level since this is outside the scope of the review.
4. THE EFFECT OF ANESTHETICS AND SEDATIVES ON THE NEONATAL BRAIN
Recently we documented the PD effects of an intravenous propofol bolus, administered as premedication for invasive procedures in(pre)term neonates [731, 742]. Propofol is a short-acting, highly lipophilic anesthetic which undergoes metabolisation through glucuronidation and hydroxylation. Taking into account the different processes and mechanisms, propofol seems to influence both metabolism and the vascular smooth muscle processes. The compound causes an immediate decrease in cerebral metabolism, which can be measured by (a)EEG. At the same time it can also decrease the MABP resulting in (permissive) hypotension, attributed to peripheral vasodilation. Significant hypotension might lead to a decrease in CBF and subsequently a decrease in cerebral oxygenation. However cerebral oxygenation remained stable during propofol bolus administration. This can mainly be explained by the decrease in cerebral metabolism. The decrease in oxygen demand is balancing the decrease in CBF. This was well documented by Vanderhaegen et al [742] in the subgroup of neonates with PNA > 10 days, receiving a propofol bolus. In this cohort a BP decrease was observed with a stable cerebral oxygenation during the first minutes. However, after 5-10 minutes cerebral oxygenation decreased. This was in contrast with the neonates with PNA ≤ 10 days, in which cerebral oxygenation remained stable. This difference is most likely explained by the fact that propofol clearance is higher with concomitant increase in cerebral
activity in cases with PNA > 10 days, while the blood pressure and CBF remained low. Balance between oxygen demand (increasing) and oxygen delivery (remaining low) was disturbed resulting in a lower venous saturation and higher fractional oxygen extraction in the older cases. In a second study, we combined a propofol dose- finding study in neonates with the assessment of clinical PD effects and vital sign trends after a bolus administration prior to endotracheal intubation (NEOPROP study) [731]. Besides confirming the feasibility of continuously monitoring PD effects in a NICU setting, the overall vital sign and cerebral parameter trends of the study population are provided in Figure 2. For the age-based trends (PMA and PNA based subgroups) we refer to the original paper [731]. The impact of propofol on aEEG measurement is currently under investigation as part of the NEOPROP study.
Sevoflurane is a preferred agent for inhalation induction of anesthesia in children. Reinsfeld et al described an
intrinsic cerebral vasodilatory effect of sevoflurane during cardiac surgery in adults when administered in doses causing burst-suppression on EEG. This vasodilation impairs the autoregulation and also causes a CBF in excess relative to oxygen demand, indicating a partial loss of cerebral blood flow-metabolism coupling [531]. In children < 2 years old an important decrease in BP has been described resulting in a decrease in CBF when BP was below 38 mmHg [542]. Wong et al described a preservation of autoregulation as long as the sevoflurane dose is below 1.5 minimal alveolar concentration (MAC, used to express anaesthetic vapour potency) [564].
Further studies investigating the effect of sevoflurane on CBF , cerebral oxygenation and metabolism are certainly needed. Investigation of brain activity during general anesthesia (sevoflurane and fentanyl and/or caudal block) in children (from neonates up to 2 years) revealed alterations in EEG parameters dependent on the concentration of anesthesia from the age of 3-5 months, while the neonatal EEG showed little anesthesia- dependent change under sevoflurane concentrations between 0.5% and 2% [753]. Recently, Poorun et al documented that premature-born children displayed altered patterns of background levels of EEG activity (i.e.
significantly lower alpha and beta power) during sevoflurane monoanesthesia compared to age-matched term- born children at mean age 4.9 years [764]. Since electrophysiological tools like EEG are increasingly used to determine anesthetic depth, these PD results are of relevance when considering titration of sevoflurane doses [764].
The benzodiazepine midazolam is a short-acting sedative, often used in neonates. The main mechanism of action is through γ-aminobutyric acid receptor interaction in the CNS. Midazolam is metabolized by cytochrome P450 3A, which displays a decreased activity in early life resulting in reduced midazolam clearance in neonates. Since
the drug can cause hypotension, CBF might decrease after administration of midazolam. However, meanwhile cerebral metabolism will also be low so the oxygen balance might still be normal. A decrease in HbD (as a surrogate for CBF) and BP was indeed described in different reports [575, 597, 775], however some authors finally considered midazolam as a harmful while others as a safe drug. This illustrates the differences and difficulties in interpretation of drug effects. Midazolam is also known to be able to suppress EEG activity and induce burst suppression or even seizures [786]. However, although depression of the aEEG background pattern occured after add-on administration of midazolam for refractory seizures in asphyxiate full-term neonates [797], the main type of background pattern did not change considerably. As summarized by Hellstrom-Westas, midazolam therefore does not seem to impair interpretation of the severity of brain injury [797, 8078]. Further investigation is needed in order to determine whether the decrease in metabolism is in balance with the decrease in CBF.
5. THE EFFECT OF INOTROPES ON THE NEONATAL BRAIN
In most cases an immediate effect is seen on heart rate and BP following administration of inotropes. Dopamine and epinephrine are the 2 main compounds resulting in an immediate BP increase when given in the appropriate dose. As mentioned previously, a MABP above the PMA is aimed for in preterm neonates. If we look at the autoregulation curve we might see that a lower BP will cause a decrease in CBF leading to ischemia while a high BP might cause an increase in blood flow with subsequent intraventricular hemorrhage [6159]. However, there is still a lot of debate regarding the use of inotropes in neonates and whether it is beneficial or harmful [11]. In the Hypotension in Preterm infants (HIP trial, ClinicalTrials.gov NCT01482559, randomization between dopamine and placebo to treat hypotension) this will be further evaluated [8179]. Wong et al described a promotion of the cerebral blood flow metabolism coupling after the use of dopamine in preterm neonates [820] and Pellicer et al described an increase in CBF in low birth weight infants after the use of dopamine or epinephrine in adequate doses [831]. However, in this study CBF decreased in some patients after inotropes were started. Importantly, cerebral oxygenation balance and metabolism was not measured in these patients so further research on this topic is certainly needed. In a report investigating the relation between aEEG continuity and amplitude with hemodynamic parameters in the first 48 hours of life in 92 preterm neonates (gestational age below 29 weeks), Shah et al documented that cases receiving inotropes for management of low blood pressure or poor perfusion before the age of 12h had significantly lower aEEG amplitude and continuity at 12, 24 and 48h compared to
neonates who did not require inotrope treatment. Interestingly, the differences persisted even in those neonates whose cardiovascular parameters were normalized at 12h [842]. The authors considered the use of inotropes as a marker for early poor perfusion (which might be associated with hypoxia/ischemia and/or impaired autoregulation), although a direct effect of inotropes on CBF or cerebral activity cannot be ruled out [842].
6. FUTURE CHALLENGES
The introduction of new tools for PD assessment in NICUs requires the need for validated age-appropriate reference values and end-points [853]. Furthermore, the researcher has to be aware that parameters measured by monitoring tools reflect the sum of multiple actions that might occur within the same time frame (e.g.
administration of propofol, performance of laryngoscopy and intubation and administration of surfactant during the INSURE procedure) [864]. Extraction of the compound-specific PD effects from these measurements is currently not yet feasible. In addition, it remains challenging to study new monitoring tools in a rapidly changing NICU setting (e.g. evolution to less invasive surfactant administration, the use of new modes in noninvasive respiratory support avoiding mechanical ventilation, the raised awareness on the relevance of kangaroo care). All these shifts in neonatal care need to be taken into account when performing and comparing PK/PD studies. In daily clinical care, the add-on value of multimodal monitoring tools is clear e.g. continuous vital signs measurement for early detection of heart rate variability indicating sepsis, and (a)EEG for detection of subclinical seizures and the effect of anti-epileptics. Therefore, we encourage the development of neonatal clinical pharmacology studies with the use of multimodal monitoring tools, towards an integrated PK/PD approach. Finally, current monitoring tools mainly reflect short-term drug effects, while also long-term (developmental) effects of drugs therapy in neonates warrant further attention.
7. CONCLUSIONS
Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of add-on value in the PD assessment in neonates. We provided an overview of tools to evaluate drug effects on
the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism, and illustrated their application on some specific anesthetics, sedatives and inotropes in neonates. We highlight the need to integrate these monitoring tools in future PD research. However, since they mainly reflect short-term drug effects, long-term outcome of drug therapy in neonates also warrants attention.
LIST OF ABBREVIATIONS
aEEG Amplitude-integrated electroencephalography
BP Blood pressure
CarMon Cerebral autoregulation monitor
CBF Cerebral blood flow
CNS Central nervous system
cFTOE Cerebral fractional tissue oxygen extraction
EEG Electroencephalography
GA Gestational age
GABA γ-amino butyric acid
HbO2 Oxygenated hemoglobin
HbD Differences in hemoglobin concentration
HbT Total hemoglobin
HHb Deoxygenated hemoglobin
MABP Mean arterial blood pressure MAC Minimal alveolar concentration
NaCl Natriumchloride
NICOM Non-invasive cardiac output monitoring NICU Neonatal intensive care unit
NIRS Near-infrared spectroscopy
PD Pharmacodynamics
PK Pharmacokinetics
PMA Postmenstrual age
PNA Postnatal age
rSO2 Regional cerebral oxygen saturation SaO2 Peripheral oxygen saturation
SVC Superior vena cava
ACKNOWLEDGEMENTS
A.Caicedo is a postdoctoral fellow of the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen).
Prof. Dempsey is supported by a Science Foundation Ireland Research Centre Award (INFANT-12/RC/2272).
The research is further facilitated by the agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT/SBO 130033).
CONFLICT OF INTEREST
The authors have no conflicts of interest to declare.
FIGURE LEGENDS
Figure 1: The adapted brain circulation model: Overview of the hemodynamic effects on the brain. Interaction
between the 3 processes (blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are indicated as well as value of the appropriate monitoring tools.
Figure 2: Median trend lines with interquartile range (grey zone) of the vital signs of the NEOPROP study
population [71]. For MABP, data of patients with invasive monitoring (n = 38) were included, for the other variables, data of 47 patients were included up to 240 minutes after propofol bolus administration with subsequent endotracheal intubation. MABP: mean arterial blood pressure, rScO2: regional cerebral oxygen saturation, FTOE: fractional tissue oxygen extraction, HR: heart rate, RR: respiration rate, SaO2: peripheral oxygen saturation. nu: numerical units.
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