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5 Neuropharmacology in the ICU: Monitoring the Therapeutic Response…
89
respiratory depression and systemic hypotension when dosed aggressively or
administered as continuous infusions. The ICP can be indirectly elevated from
benzodiazepine administration due to hypercarbia (acidity causing cerebral vasodilation) in patients with respiratory depression. Midazolam is typically used to
control elevated ICP in patients with hemodynamic instability over propofol, as it
does not have as much of an effect on reducing systemic blood pressure. However,
due to the potential for tachyphylaxis, higher doses of midazolam infusion may be
required to adequately control ICP [39]. Midazolam has high lipid content and can
accumulate in tissues causing prolonged sedation but has a relatively short halflife (1 hour) [40]. Additionally, diazepam and lorazepam containing propylene
glycol, which can reduce blood pressure with rapid administration and monitoring
for signs of propylene glycol toxicity (e.g., high anion gap metabolic acidosis,
osmolar gap, and a sepsis-like picture), are recommended with prolonged therapy
[41, 42].
5.2.2.2 Barbiturates
Barbiturates (i.e., pentobarbital, phenobarbital, and thiopental) are also GABAA
agonists and can also cause respiratory depression and hypotension. Studies have
shown a direct effect of reduction in ICP in patients with severe head injury and
refractory elevated ICPs; however, hypotension was also observed in some of the
patients [43, 44]. Intravenous formulations of phenobarbital and pentobarbital also
contain propylene glycol, and therefore, one should monitor for toxicity and may
require vasopressor support during continuous infusion therapy [45]. Barbiturates
are typically used as adjunctive therapy to reduce ICP, and in a select group of
patients for the treatment of refractory status epilepticus [1, 45].
5.2.2.3 Opioids
Opioids are Mu receptor agonists, and are commonly used for analgesia. In one
study of patients with severe closed-head injuries, both morphine and fentanyl were
shown to signicantly increase ICP without any signicant change in CBF based on
TCD measurements, regardless of whether or not cerebral autoregulation was preserved. A decrease in systemic MAP and hypotension was also observed [46].
Another common side effect of opioids is respiratory depression, producing a rise in
(hypercarbia), and increased ICP [38, 45, 47]. The effect on ICP was noted
PaCO
2
to be transient after boluses of fentanyl, sufentanil, and alfentanil in head trauma
patients [47]. In patients who are hemodynamically unstable, morphine would not
be recommended as it causes histamine release and subsequent vasodilation/hypotension [46]. Fentanyl, however, has a fast onset of action and is easily titratable and
is commonly used as analgosedation in patients with neurological injury [45].
Fentanyl is less expensive than remifentanil, a shorter acting agent that is metabolized by plasma esterases and most commonly used in the operating room versus
90
R. Fillmore and G. M. Brophy
intensive care unit. Remifentanil may also reduce CBF, similar to intravenous anesthetics [7, 48]. Also keep in mind that opioids’ concentrations and effects are inuenced by hepatic and renal dysfunction (refer to section below on drug clearance
and metabolism).
5.2.2.4 Anticonvulsant Medications
Apart from the previously mentioned benzodiazepines and barbiturates, there is not
much literature on the relationship between antiseizure drugs and cerebral vasculature. A common side effect of anticonvulsant agents is sedation and systemic hypotension [42].
Levetiracetam (proposed MOA: binds SV2A synaptic vesicle glycoprotein) and
lacosamide (proposed MOA: inhibits sodium channels) did not have a signicant
effect on systemic vasculature. However, phenytoin (which blocks voltage-gated
sodium channels) was shown to cause systemic hypotension [49]. Recall that
changes in systemic blood pressure can effect ICP via cerebral autoregulation.
Medications that effect the systemic pH can also have an effect on cerebral vasculature. Topiramate (proposed MOA: acts on multiple cellular targets including inhibiting carbonic anhydrase) was shown to increase cerebral blood ow velocities on
TCDs in the MCA and PCA in one study as it causes a metabolic acidosis leading
to cerebral vasodilation [50]. Drugs with similar mechanisms of action, such as
zonisamide, should also be monitored for these effects.
5.2.2.5 Other Sedatives/Anesthetics
The MOA of propofol is not completely understood, but it appears to be an agonist
at the GABA receptor, making it useful for sedation and seizure control. One of the
major adverse effects of propofol is systemic hypotension, especially with bolus
dosing or large titrations. It may also increase ICP as a result of this systemic hypotensive effect due to compensatory cerebral vasodilation, but decreased ICP and
CBF can be observed in patients with impaired cerebral autoregulation [1]. In one
study comparing propofol, pentobarbital, and isourane, all three were shown to
increase both CBF and CBV; however, the greatest effect was seen with isourane.
Remember that acute changes in ICP are determined primarily by CBV [3, 7].
Dexmedetomidine and clonidine (presynaptic alpha
receptor agonists) cause bra-
2
dycardia and hypotension but did not signicantly effect ICP in swine animal models [51]. Therefore, bolus dosing and large dosage titrations commonly cause these
effects and should be avoided [51]. Ketamine (a noncompetitive NMDA receptor
antagonist) is ideal for nonintubated patients as it does not affect respiratory drive
[1]. Contrary to other sedatives, ketamine has been shown to cause systemic hypertension, and preservation of the MAP.Earlier studies of ketamine suggested that it
caused an increased ICP [52]. However, based on more current data, ketamine was
not found to increase ICP when compared with opioids [53]. Ketamine was shown
to increase CBF, decrease ICP by 92.7%, and decrease the occurrence of DCI in a
5 Neuropharmacology in the ICU: Monitoring the Therapeutic Response…
cohort study of patients with aneurysmal subarachnoid hemorrhage being treated
with sedation (in addition to ketamine) [54].
91
5.2.3 Hemodynamic Agents
The use of agents that increase the systemic circulating volume (e.g., normal saline
and lactated ringers) can increase ICP acutely. The use of diuretics may have the
opposite effect. Large uctuations in volume status can effect cerebral vasculature;
however, central mechanisms usually preserve CPP and, ultimately, the ICP may
not change [55–57]. In patients with impaired cerebral autoregulation, changes in
volume status have variable affects on ICP which can impact TCD measurements.
Therefore, it is important to monitor intake and output (I/Os) and use noninvasive
methods (e.g., ultrasound) to evaluate if a patient’s volume status is adequate.
5.3 Drug Clearance andMetabolism: Disease Effects
Different disease states can change a drug’s metabolism, which may augment or
depress its effect. This is particularly true in patients with hepatic or renal dysfunction
as many medications are metabolized in these organs [58]. Ultimately, medications
that are not cleared as quickly due to hepatic or renal failure could cause more
enhanced side effects, such as hypotension and respiratory depression, which can alter
cerebral hemodynamics and possibly increased ICP [59]. Patients with fulminant liver
failure tend to have higher ICPs at baseline, which must be taken into consideration
when using medications that are hepatically cleared that could increase the ICP [60].
Disease states that change intravascular volume, such as chronic renal failure/volume
overload, heart failure, or sepsis, can alter a medication’s metabolism as well. Drug
metabolism is also affected by temperature, and decreases in metabolism are observed
with each degree the core temperature drops below 37°C, especially when utilizing
targeted temperature management and therapeutic hypothermia [1, 57, 61].
5.4 Conclusion
The use of noninvasive techniques, such as transcranial Doppler (TCD/TCCS), can
serve as a tool for determining the therapeutic response of pharmacological treatments in neurocritical care patients. However, one must keep in mind the complexities of different disease pathologies, volume status, acute changes in pH, and the
relationship between systemic vasculature and cerebral hemodynamics by using a
multivariable approach to management. It is recommended to avoid abrupt large
dosage adjustments to prevent large uctuations in systemic blood pressure, intracranial pressure, and cerebral blood ow.
92
INTENSIVE CARE UNIT
AM
Algorithm
R. Fillmore and G. M. Brophy
EMERGENCY DEPARTMENT(ED)
Clinical Status of the Patient
ABCD
Level of Consciousness (GCS)
Bilateral Pupillary reactivity?
Hemodynamic stability?
Oxygenation?
Mechanical Ventilation?
Subarachnoid Hemorrhage (SAH)Ischemic Stroke Traumatic Brain Injury (TBI)
CNS infection (Meningitis/Encephalitis) Intracerebral Hemorrhage (ICH) Non-Convulsive Status Epilepticus (NCSE)
Brain Tumors Post-Cardiac Arrest Neurosurgery Peri-operative complication
MONITOR Vasoactives Drugs MONITOR
Acute / Chronic Comorbidities
PK / PD
MONITOR Avoid Increase in ICP MONITOR (Systemic)
)
ABD (PaCO
2
End-Tidal CO
2
Estimated Cerebral Perfu-
-sion Pressure (eCPP)
Transtemporal Window Transtemporal Window Transtemporal Window Transtemporal Window
MCA–ACA–PCA MCA–ACA–PCA MC
Low Frequency Probe
MONITOR
Variation over-time Low Frequency Probe Dynamic CA
Dynamic CA?
Autoregulation Index (ARI)
Cerebral Blood Flow
Velocities(CBFV)
Submandibular Window
ICA–ECA
MONITOR
Spectral Doppler Waveform
MFV–EDV–PSV
Velocity [Variation over-time]
Lindegaard ratio
a) Drug indication
b) Drug dose
c) AED plasma concentrations
d) Drug-drug interactions
e) Organ function
f) Patient temperature
Multimodal Monitoring (MMM)
Impaired Cerebral Autoregulation (CAR)?
Cerebral Blood Flow velocities?
Intracranial Pressure (ICP)?
Cerebral Oxygenation?
Cerebral Perfusion Pressure? (CPP)
PHARMACOLOGICAL TREATMENT
Anesthetics / Sedatives Systemic / Cerebral
Antiepileptic Drugs (AEDs)
OPTIMAL DOSE
Avoid Adverse Effects
Avoid Negative Impact on CPP
Avoid decrease in Cerebral Oxygenation
Transcranial Doppler (TCD)
Transcranial Color-Coded duplex Sonography (TCCS)
REASSESS
(ICU)
DIAGNOSIS
Vasoconstriction Effects
Hemodynamic Patterns
Cerebral Autoregulation
(CAR)
Low Frequency Probe Low Frequency Probe
MONITOR MONITOR
Autoregulation Index (ARI) Pulsatility Index (PI)
Intracranial Pressure
CA–ACA–PCA
Spectral Doppler Waveform
Pupilar Ultrasound / PLR
[ Variation over time]
Vasodilation Effects
SBP (MAP)
(ICP)
ONSD
ABCD airway– breath – circulation- disturbances, ABD acid-base disturbance, MFV mean ow
velocity, EDV end-diastolic velocity, PSV peak ow velocity, ONSD optic nerve sheath diameter,
PLR pupilar light reex, SBP systolic blood pressure, MAP mean arterial pressure, CA cerebral
autoregulation
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95
Part II
Neurosonology: Basic Principles
Chapter 6
Transcranial Doppler Ultrasound: Physical
Principles
DavidH.Evans
Key Points
1. Ultrasound is a valuable noninvasive technique for studying the brain. It is, how-
ever, subject to a number of physical limitations which need to be appreciated in
order to ensure the correct interpretation of its results.
2. Because the skull causes rapid attenuation of ultrasound, it is necessary to use
relatively low transmitted ultrasound frequencies in transcranial applications
which limits spatial resolution in comparison to that achievable in soft tissue
imaging. The complex structure of the skull distorts ultrasound beams, further
degrading spatial resolution.
3. Doppler ultrasound is a powerful method for measuring blood ow velocities
and changes in velocity; however, because the sizes of cerebral vessel cannot be
measured accurately, it is not possible to convert velocity into ow. Furthermore,
because vessel sizes may change with time, it cannot reliably be assumed that
velocity changes are proportional to ow changes.
4. Doppler ultrasound is a powerful technique for detecting cerebral emboli.
5. While ultrasound is usually considered to be completely safe, users need to be
aware that it does have a potential to cause tissue damage, and strive to keep
exposure as low as compatible with obtaining good clinical results. It should be
remembered that transcranial Doppler employs relatively high intensities in
order to penetrate the skull bone, and may be used for lengthy periods of time in
monitoring applications.
D. H. Evans (*)
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
e-mail: dhe@le.ac.uk
C. N. Rodríguez et al. (eds.), Neurosonology in Critical Care,
https://doi.org/10.1007/978-3-030-81419-9_6
99© Springer Nature Switzerland AG 2022
100
D. H. Evans
6.1 Introduction
Ultrasound is an important technique for studying neurovascular physiology and
pathology. As with any measurement or imaging technique, it has strengths and
weaknesses, and there are a number of potential pitfalls for those interpreting its
results. This chapter describes the basic physics and instrumentation behind both
imaging and Doppler ultrasound techniques, with a special emphasis on their application to the cerebral circulation.
Medical ultrasound is used to image the body in much the same way as radar is
used to detect the range and speed of an aircraft, except that instead of using radio
waves, pulses of high-frequency sound are used. A transducer transmits a very short
pulse of ultrasound (often lasting much less than one-millionth of a second) into the
body, and then receives any reected ultrasound. Once a sufcient time has elapsed
for all the reections to return from the tissue of interest, another pulse is emitted
and the process repeated. The position of any structure producing a reection can be
calculated from the direction in which the pulse has been transmitted and received,
and from the delay between the transmission of the pulse and the reception of the
reection. Further information about the characteristics of the structure can be
determined from the size of the echo, and information about the movement of the
structure (particularly important for echoes from blood) can be extracted from slight
changes in the ultrasound phase between successive pulses (the so-called Doppler
effect). Ultrasound is an ideal technique for imaging soft tissue but cannot penetrate
gas, and is distorted and rapidly attenuated by bone.
6.2 Ultrasound andIts Propagation Through Tissue
Ultrasound is generally taken to mean any sound that has a frequency above the
limit of human hearing (about 20 kHz or 20,000 cycles per second). In medical
diagnostic applications, however, the frequencies used are approximately 100 to
1000 times greater than this, that is, in the range of 2MHz to 20MHz. The reason
for this is that spatial resolution is limited by the wavelength, which is inversely
related to the frequency. Ultrasonic waves in soft tissue, like audible sound waves,
are compressional wave produced by the push-pull action of the sources on the
propagating media. These waves are known as ‘longitudinal’ waves, since the oscillatory motion of the particles in the tissue is parallel to the direction of propagation.
Other modes of vibration such as ‘shear’ or ‘transverse’ waves can occur in bone,
but are not usually of great importance.