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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5573_Библиотеки_им_академика_М_И_Перельмана.pdf
9 Extracorporeal Membrane Oxygenation
Lipophilicity is expressed as the logarithm of the ratio of unionized drug dispersed in octanol (lipid layer) to unionized drug dispersed in water (i.e., the partition coefcient or logP). A positive logP indicates lipophilicity (a drug with a logP
of 2 partitions 100 times more into octanol than into water), and a negative logP
indicates hydrophilicity (a drug with a logP of −2 partitions 100 times more into
water than octanol). Drugs with both high protein binding and high lipophilicity are
most likely to be sequestered in the ECMO circuit [59]. In general, a logP >2 is
considered to be “high” lipophilicity, and logP <1 is considered to be “low” lipophilicity (Patel etal. 2023). High-lipophilicity drugs will be attracted to and trapped in
the membrane oxygenator bers, while hydrophilic drugs will pass easily through
the membrane and be more attracted to the hydrophilic blood plasma.
Upon initiation of ECMO, large amounts of drug adsorb onto the new, “clean”
circuit. This results in a low concentration of drugs back to the body. Over time,
once the circuit components are fully saturated, the adsorbed drug will be released
back into circulation based on concentration gradients in the blood versus on the
membrane and will potentially contribute more to the therapeutic effect. This cycle
will repeat with each circuit change. In light of these pharmacokinetic changes with
the ECMO in addition to the changes seen in critically ill patients and with CRRT,
medication dosing in critically ill patients on ECMO (with and without CRRT) can
be quite complex. Details and considerations for dosage will be addressed in the
individual medication sections that follow.
241
9.6 Analgesia andSedation Considerations inECMO
9.6.1 Assessment ofPain andSedation
The provision of analgesia and sedation to patients undergoing ECMO support is a
standard of practice aimed at achieving various clinical goals. These goals include
ensuring adequate pain control, preventing and addressing agitation, enhancing
ventilator synchrony, optimizing ECMO ows, maintaining catheter positioning,
reducing metabolic demands, enabling effective patient communication, promoting
early liberation from ECMO, and ultimately improving long-term functional outcomes. Fundamental principles of managing pain and sedation should align with
those applied to other critically ill patients of equal severity of illness, in accordance
with international guidelines [43]. There are no specic sedation and analgesia
guidelines tailored to patients undergoing ECMO support, and therefore, deviations
from existing guidelines are anticipated in this complex patient population. For
example, contrary to guideline recommendations advocating for light sedation, the
initial 24–48hours following ECMO cannulation may often necessitate deeper levels of sedation, especially if coupled with neuromuscular blockade, to optimize
ECMO support and ventilatory support and prevent potential harm from cannula
dislodgement. Deeper levels of sedation beyond the initial cannulation period may
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S. Davis et al.
still be necessary to maintain appropriate ECMO support. Consequently, there is
often a heightened need for more frequent utilization of benzodiazepines and
increased doses of other analgesic and sedative medications compared to patients
with equal severity of illness not receiving ECMO support. Nonetheless, following
guideline-supported practices that advocate for targeting light levels of sedation and
avoiding benzodiazepines when clinically suitable plays a vital role in promoting
successful endotracheal extubation, preventing physical deconditioning, and
enabling regular neurological assessment in ECMO-supported patients [47].
Monitoring of pain and sedation is essential to ensure the effectiveness of treatment and minimize medication overuse. In line with guideline recommendations, it
is critical to dene, measure, and perform routine daily reassessments of pain and
sedation goals in order to adjust doses based on the individual needs of the patient
at different stages of critical illness. Clinical monitoring involves subjective bedside
assessment and objective evaluations using validated scoring instruments including
the Behavioral Pain Scale (BPS), Critical-Care Pain Observation Tool (CPOT), and
Richmond Agitation-Sedation Scale (RASS). In an international survey of 221 bedside clinicians caring for adult VV-ECMO patients, pain was primarily assessed
using CPOT (42%) and BPS (36%), and level of sedation was assessed using RASS
(90%). When clinical monitoring is unreliable in noncommunicative, deeply
sedated, and paralyzed patients, the use of electrophysiological techniques in the
form of electroencephalography (EEG), electromyography (EMG), and evoked
potential signals may be employed [60]. However, the validity and reliability of
these methods have not been investigated in ECMO patients [60].
9.6.2 Analgesic andSedative Agents
9.6.2.1 Opioids
Critical care analgesia and sedation guidelines support an analgesia-rst approach
(i.e., analgosedation) to minimize the use of sedatives, with opioids remaining as
the mainstay for pain management. For most mechanically ventilated ECMO
patients, parenteral opioids are the cornerstone for pain management and sedative
effects. Opioids are recommended to be used at the lowest effective dose with judicious titration as part of a multimodal analgesia regimen. The decision regarding
which opioid to use and frequency of dosing (e.g., intermittent vs. continuous infusion) varies based on clinical goals, anticipated pharmacokinetic alterations during
ECMO, and patient-specic factors such as hemodynamics and renal and hepatic
function. In two international surveys, fentanyl was the most frequently reported
opioid used by clinicians caring for VV-ECMO patients, followed by hydromorphone and morphine [25, 46].
Fentanyl, due to its rapid onset of action and ease of titration, is frequently utilized as the primary analgesic in critically ill patients. However, because fentanyl is
both highly lipophilic and extensively protein bound (Table 9.4), its use among
9 Extracorporeal Membrane Oxygenation
243
patients receiving ECMO support is less desirable due to the high probability of
being sequestered within the ECMO circuit. Ex vivo studies have shown that >70%
of the fentanyl dose is sequestered in the circuit as compared to ~20% of the hydromorphone dose [63, 126, 127]. To overcome this substantial loss, higher doses of
fentanyl may be required to provide adequate pain relief in ECMO patients, or alternatively, other opioids (e.g., hydromorphone) may be considered. A comparison of
hydromorphone or fentanyl-based sedation in 148 ECMO patients found a fourfold
greater utilization of fentanyl equivalents in the fentanyl-based group as a secondary outcome [79]. The primary outcome of delirium-free, coma-free days, however,
was also signicantly less in the fentanyl-based group. These results were also demonstrated in a study of 52 ECMO patients receiving either fentanyl or hydromorphone continuous infusions. Opioid requirements, dened as morphine milligram
equivalents, were signicantly lower in the hydromorphone-based group at 24 and
48hours with no change in pain or sedation scores or sedative use compared to the
fentanyl-based group [90].
Hydromorphone, a hydrophilic and low protein-bound opioid (Table9.4), may
be considered as the preferred agent in patients receiving ECMO or as a second-line
agent for patients who have inadequate pain control despite high doses of fentanyl
(≥400mcg/hour) [139]. Contrary to the increased fentanyl requirements seen in the
Landoff and Martin studies discussed above, Browder and colleagues found no difference in opioid requirements between fentanyl- and hydromorphone-based regimens in predominately VV-ECMO patients [21]. Limitations of this study included
clinician unfamiliarity with hydromorphone doses and titration and inclusion of
patients receiving hydromorphone only within 24hours of cannulation, which limits generalizability to patients who are switched to hydromorphone-based analgosedation after 24hours of cannulation due to inadequacy of pain control with fentanyl.
Morphine, a hydrophilic and moderately protein-bound opioid (Table9.4), has a
low propensity for sequestration within the ECMO circuit. An exvivo study evaluating morphine concentrations at 24hours following administration of a single dose
in blood-, crystalloid-, and albumin-primed ECMO circuits demonstrated no signicant loss compared to baseline [126, 127]. Although morphine displays favorable physicochemical properties, it has not been as widely studied in adult ECMO
Table 9.4 Physiochemical properties of select opioids and sedatives used in ECMO
Opioids/sedatives Protein binding LogP
Dexmedetomidine 94% 2.8
Fentanyl 80–85% 4.05
Hydromorphone 10–20% 1.06
Ketamine 27% 3.12
Midazolam 97% 2.73
Morphine 20–35% 0.87
Lorazepam 85–90% 2.39
Propofol 99% 3.79
LogP log of partition coefcient
Information adapted from Lexicomp and DrugBank Online
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S. Davis et al.
patients. Furthermore, the use of morphine in the ICU for analgosedation is limited
by risks of adverse effects that outweigh the benets in critically ill patients. These
adverse effects include hypotension associated with histamine release as well as
prolonged sedation and risk of neurotoxicity in patients with renal dysfunction.
9.6.2.2 Ketamine
Ketamine, because of its -methyl-d-aspartate (NMDA) receptor-blocking properties, provides both sedative and analgesic effects and is recommended in guidelines
to be used at low doses as an adjunct to opioid therapy to improve wakefulness and
reduce hyperalgesia and opioid consumption [43]. Since ketamine is moderately
lipophilic but exhibits a low degree of protein binding (Table9.4), it remains uncertain whether high doses are required to attain adequate sedation and reduce total
opioid consumption in patients receiving ECMO.In a retrospective observational
study, Tellor and colleagues evaluated opioid and sedative requirements among 26
ECMO patients concomitantly receiving a ketamine infusion at a median starting
dose of 50mg/hour (max 150mg/hour). Within 2hours of ketamine initiation, a
meaningful reduction (dened as a change of at least dexmedetomidine 0.2mcg/kg/
hour, fentanyl 25mcg/hour, midazolam 1mg/hour, or propofol 10mcg/kg/min) in
sedative and opioid infusion doses was observed in more than a third of patients,
without a change in the median RASS score at 24hours [135]. Conversely, in a
small randomized trial involving 20 VV-ECMO patients with ARDS, low-dose ketamine infusion did not lead to a reduction but instead increased the need for opioids
or sedatives [45]. However, these ndings could potentially be attributed to the titration of opioid and sedative dosages based on parameters other than the sedation
goal, absence of a standardized sedation protocol, and inadequacy of ketamine dosing. There is limited data supporting changes in ketamine pharmacokinetic parameters during ECMO.In two case reports, ketamine administered at doses of 2mg/
kg/hour compared to 0.625mg/kg/hour reached sufcient mean steady-state plasma
concentrations, similar to critically ill patients not receiving ECMO support [50,
77]. Although the benets of ketamine among ECMO patients remain to be eluci-
dated, studies have not indicated signicant harm associated with its use. Initiating
ketamine at low-to-moderate doses as an adjunctive agent may be reasonable in
patients on ECMO failing to achieve target pain and sedation goals, despite the use
of opioids and other sedative agents.
Propofol
9.6.2.3
Propofol is a highly lipophilic and extensively protein-bound agent that possesses
sedative, hypnotic, and anxiolytic properties (Table 9.4). Propofol is a frequently
used sedative in the ICU owing to its immediate onset, ease of titration, and short
duration of action, much like fentanyl. Among patients receiving ECMO support,
concerns have been raised regarding the lipophilic nature of propofol and its
9 Extracorporeal Membrane Oxygenation
245
potential impact on adsorption and oxygenator failure. Several studies evaluating
propofol- based sedation strategies among ECMO patients found no difference in
the rate of oxygenator exchange in those receiving propofol versus those who did
not [21, 67, 78]. Not surprisingly, higher median daily doses of propofol were
required in patients who did not require oxygenator exchanges [67]. Despite evidence indicating that propofol likely does not increase oxygenator exchanges, the
loss of propofol in the ECMO circuit can be signicant. An exvivo study reported
a 70% decrease in propofol concentrations within only 30minutes of administration
[81]. In regard to dosing of propofol, a retrospective study showed that the use of
propofol to achieve light levels of sedation in predominantly VV-ECMO patients
with ARDS showed no signicant increases in median daily doses throughout the
duration of ECMO support [112]. On the contrary, propofol doses increased to peak
levels on day 3 of ECMO support in a cohort of VV-ECMO patients with ARDS
requiring deep sedation [37]. Most clinicians report using propofol when caring for
VV-ECMO patients requiring deep levels of sedation [46]. Since propofol is prone
to signicant circuit sequestration, higher than recommended doses may be necessary to achieve target sedation, especially deeper levels of sedation. Use of propofol
at high doses for a prolonged period of time may be limited by hypotension, propofol-related infusion syndrome, or hypertriglyceridemia [10, 132].
9.6.2.4 Benzodiazepines
While non-benzodiazepine sedatives are the preferred agents to improve short- and
long-term outcomes in mechanically ventilated critically ill patients, the use of benzodiazepines as an alternative or concomitant therapy may be necessary in ECMO
patients when sedation goals are unmet or deep sedation is desired. When targeting
deep sedation for VV-ECMO patients, 24% and 41% of clinicians reported using
benzodiazepines as a rst- and second-line agent, respectively. Benzodiazepines,
such as midazolam and lorazepam, are highly lipophilic and extensively proteinbound sedati
ves, which render them highly susceptible to sequestration within the
ECMO circuit (Table9.4).
Signicant sequestration of midazolam was observed in two exvivo ECMO circuitry experiments with losses at 24hours of 87% and 89% [81, 126, 127]. To corroborate these ndings of circuitry loss, Shekar and colleagues demonstrated a 10%
increase (average 18mg/day) in the daily dose of midazolam after ECMO cannulation to maintain deep sedation [126, 127]. Several observational studies in patients
receiving ECMO support for severe ARDS demonstrated high sedative requirements when a deep level of sedation is targeted. DeBacker and colleagues found a
need for high midazolam doses, with a median requirement of 202mg in the rst
48hours following ECMO cannulation (DeBacker etal. 2018). Similarly, a retrospective study of patients with ARDS managed with and without ECMO support
demonstrated a twofold increase in the maximum 6-hour sedative exposure in the
ECMO-supported group; however, an adjusted analysis found that the ECMO circuit did not have a signicant effect on the cumulative sedative doses administered
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S. Davis et al.
from the start of ECMO to the point at which the maximum 6-hour sedative exposure was achieved [41]. DeGrado and colleagues [39] reported signicantly lower
sedative requirements compared to previous trials in a mixed cohort of VV- and
VA-ECMO patients. Benzodiazepine continuous infusions were administered on
less than half of the ECMO days, with a median daily dose (expressed in midazolam
equivalents) of 24mg. Moreover, there were no increased requirements throughout
the duration of ECMO support. These reduced sedative requirements could be
attributed to lower sedation goals, use of non-benzodiazepine infusions, and variable ECMO indications.
Lorazepam, being comparatively less lipophilic than midazolam yet extensively
protein bound, is an appealing alternative agent that has demonstrated a lower
degree of loss within the ECMO circuit at 24hours compared to midazolam (59%
vs. 83%) [62]. However, routine use of lorazepam as a sedative in critically ill
patients with and without ECMO support is limited by the risk of propylene glycol
toxicity in parenteral and enteral solution forms of lorazepam that can result in
metabolic acidosis, seizures, respiratory depression, and renal insufciency. Only
18% of clinicians reported using lorazepam as the preferred benzodiazepine among
adult VV-ECMO patients in an international survey [25]. Although the superiority
of a specic benzodiazepine has not been established, midazolam has been subject
to more extensive invivo research and, as a result, may be the preferred choice as a
sedative.
9.6.2.5 Dexmedetomidine
Dexmedetomidine, a highly lipophilic and extensively protein-bound sedative, has
been associated with signicant losses in the ECMO circuit (Table9.4), as demonstrated in an invitro study observing 24-hour losses between 67% and 93% and
67% and 88% for new and old circuits, respectively [140]. This study also found no
difference in pre- and post-oxygenator concentrations, suggesting that the polyvinyl
chloride tubing contributes to dexmedetomidine loss. Dexmedetomidine’s mechanism of alpha-2 receptor agonism exerts sedative and anxiolytic effects without
inducing respiratory depression. Despite concerns of circuit sequestration, these
pharmacologic characteristics make dexmedetomidine an ideal sedative when aiming for lighter levels of sedation or when weaning midazolam or propofol. For
patients on VV-ECMO with lighter sedation goals (e.g., RASS 0 to −1), clinicians
often reported dexmedetomidine as their preferred choice for both initial and secondary sedation when aiming for a lighter level of sedation [46]. While limited
clinical data exists on the use of dexmedetomidine in ECMO patients, a small retrospective study of 26 ECMO patients reported 92% receiving dexmedetomidine at a
median dose of 0.7mcg/kg/hour. The authors observed no signicant increases in
median daily dose of dexmedetomidine throughout the duration of ECMO support [112].
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247
9.7 Infection Considerations inECMO
ELSO registry data reports nosocomial infection prevalence of up to 21% in adults
and a culture positivity rate of up to 65% with an associated increase in mortality [3,
16]. Bizzarro and colleagues reported that an indication of eCPR and VA cannula-
tion was associated with the highest rates of infection. Coagulase-negative staphylococci were the most common organisms, followed by Candida, Pseudomonas
aeruginosa, Staphylococcus aureus, and other gram-negative organisms [16]. In a
meta-analysis by Li and colleagues, the prevalence of nosocomial infections was
8.8–64% with a relative 32% increased risk of death compared to noninfected
ECMO patients [83]. Independent risk factors for infection included duration of
ECMO, high severity of illness score (e.g., sequential organ failure assessment),
age, time on ventilator prior to ECMO, and use of VV cannulation [83]. The most
common causative organisms were gram negative (Acinetobacter baumannii,
enteric bacilli, and Klebsiella pneumoniae); however, gram-positive and fungal
organisms were also reported [83]. Early infections in ECMO are usually the result
of gram-positive skin ora and gram-negative organisms found in the femoral cannulation site; late ECMO infections may result from these same pathogens or fungal
pathogens, particularly yeast [123]. Given the variety of potential organisms associated with nosocomial infections during ECMO, a broad-spectrum antimicrobial
strategy is often employed.
9.7.1 Aminoglycosides
As a class, aminoglycosides are minimally protein bound and hydrophilic
(Table9.5). The effect of the ECMO circuit sequestration on this class is expected
to be minimal, though increased Vd in critically ill patients, with or without ECMO,
may result in the need for higher aminoglycoside doses. An observational, casecontrol study of 46 ECMO patients showed no signicant difference in peak concentrations of amikacin compared to non-ECMO critically ill patients [56]. There
was also no difference in the prevalence of subtherapeutic, therapeutic, and supratherapeutic levels between the groups; however, 50% of ECMO patients and 64% of
non-ECMO patients had amikacin levels outside of the therapeutic range. A prospective, observational study of 44 ECMO patients found that in eight patients
receiving aminoglycosides, gentamicin, and tobramycin, therapeutic peaks were
achieved in all patients, but only 37.5% of amikacin peak levels were therapeutic
[18]. Therapeutic drug monitoring (TDM) is routinely performed for aminoglycosides, and this data emphasizes the importance of TDM in critically ill patients,
especially in those on either ECMO, CRRT, or both.
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S. Davis et al.
9.7.2 Beta-Lactams
Beta-lactams with or without beta-lactamase inhibitors generally have low protein
binding and low logP across the class, with the exception of ceftriaxone being
85–90% protein bound (Table9.5). Given these characteristics, these agents do not
bind signicantly to the ECMO circuit and are cleared with the same frequency as a
non-ECMO patient. In a study of 105 ECMO patients (majority VV) receiving either
piperacillin, ceftazidime, meropenem, or linezolid, there was no difference in total
serum concentrations of ceftazidime and high-dose (6g/day) meropenem compared
to non-ECMO patients [76]. Serum concentrations of piperacillin/tazobactam and
standard-dose (3g/day) meropenem were signicantly reduced in patients on ECMO;
however, all median values met therapeutic targets. There was also an association
between increased ceftazidime and meropenem concentrations with prolonged use
of the same ECMO circuit membrane, indicating that once the membrane is saturated, sequestration subsides and serum concentrations increase [76]. Other studies
have shown 80–100% of therapeutic level attainment with ceftolozane/tazobactam,
cefepime, ceftazidime, meropenem, and piperacillin/tazobactam [5, 18, 61]. Overall,
ECMO does not have a signicant effect on the pharmacokinetics and pharmacodynamic proles of beta-lactam antibiotics. Use of continuous-infusion antimicrobials
has been shown to improve cure rates and mortality in critically ill patients and
should be utilized, along with TDM when possible, to optimize antimicrobial
efcacy.
Table 9.5 Physiochemical properties of select antibiotics used in ECMO
Antibiotic Protein binding LogP
Amikacin 10% −3.2
Ceftaroline 20% −0.79
Ceftolozane/tazobactam 20%/30% −6.17/−1.8
Ceftriaxone 85–90% −1.7
Cefepime 20% −0.37
Daptomycin 84–93% −0.47
Gentamicin <30% −3.1
Imipenem/cilastatin 20%/40% −0.19/−0.29
Linezolid 31% 0.9
Meropenem 2% −0.6
Piperacillin/tazobactam 30%/30% 0.3/−1.8
Tobramycin <30% −5.8
Vancomycin 55% −3.1
LogP log of partition coefcient
Information adapted from Lexicomp and DrugBank Online
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249
9.7.3 Glycopeptides, Lipopeptides, andOxazolidinones
Daptomycin, linezolid, and vancomycin exhibit variable protein binding but relatively low lipophilicity (Table 9.5). Data for daptomycin in ECMO is limited to
exvivo studies, which demonstrate no signicant decrease in daptomycin concentrations or sequestration in the circuit [30, 70]. In a case report of three patients on
ECMO who received standard-dose linezolid (1200mg/day), adequate concentrations were achieved if the MIC was ≤1 for methicillin-resistant Staphylococcus
aureus pneumonia [38]. Ex vivo studies demonstrate minimal sequestration of van-
comycin in the ECMO circuit [94, 126, 127]. An observational study of 11 ECMO
patients (55% VV) matched with 11 control patients demonstrated similar vancomycin concentrations between ECMO and non-ECMO patients when administered
as a loading dose over 4 hours followed by a daily continuous infusion [44].
However, in a study of 20 patients (55% VA), 95% were found to require a dose
increase after initial non-steady-state trough levels were obtained on standard dosing (mean 16mg/kg q12h) [111]. It is important to note that patients in this study
did not receive a loading dose of vancomycin, and the low initial trough results are
likely due to the increased Vd of vancomycin in critically ill ECMO patients and
lack of a loading dose rather than due to ECMO circuit sequestration of vancomycin. A recent study of 116 patients on ECMO (61% VA) treated with vancomycin
(25mg/kg load followed by 15mg/kg q12h) found that only 18% of patients had
>50% of levels in the therapeutic range (Marella etal. 2020). The highest proportion
of subtherapeutic levels was noted in patients on ECMO for <6days, and levels for
patients on ECMO for 6–13days were signicantly more likely to be therapeutic.
Conversely, patients on CRRT were more likely to have supratherapeutic levels.
While physiochemical properties have shown that vancomycin is not prone to circuit sequestration, the conicting data with invivo studies underlines the importance of TDM monitoring for vancomycin in critically ill ECMO patients.
9.7.4 Antifungals
Azole derivatives have moderate-to-high protein binding and high lipophilicity,
with the exception of uconazole, and therefore would be more likely to sequester
into the ECMO circuit components (Table9.6). In a study of 85 patients on ECMO,
of the 10 who received uconazole, 9 had adequate serum concentrations [125].
Eighty percent of the uconazole patients were on concomitant RRT, including the
one patient who had concentrations below target. In a retrospective study of 132
patients receiving voriconazole, rst trough concentrations were signicantly lower
in the ECMO group compared to non-ECMO patients. The ECMO patients were
signicantly younger and had a higher SOFA score at baseline. This study found the
use of ECMO to be an independent risk factor of below target voriconazole exposure [147]. Another retrospective study of 69 patients (74% VV-ECMO) did not nd
250
Table 9.6 Physiochemical properties of select antifungals used in ECMO
Antifungal Protein binding LogP
Caspofungin 97% 0.17
Fluconazole 12% 0.5
Isavuconazole >98% 3.46
Micafungin >99% −1.5
Posaconazole >99% 5.5
Voriconazole 58% 1.65
LogP log of partition coefcient
Information adapted from Lexicomp and DrugBank Online
S. Davis et al.
a difference in median trough concentrations on ECMO versus non-ECMO days;
however, 48% of all samples were subtherapeutic despite a median trough concentration within the goal range [137, 138].
Contrary to what the physiochemical properties might predict, isavuconazole and
posaconazole pharmacokinetics show minimal changes during ECMO.A prospective
study of seven ECMO patients (86% VV) receiving isavuconazole for aspergillosis
prophylaxis found no difference between serum, pre-oxygenator, or post-oxygenator
levels. Target plasma levels were obtained within 24hours and maintained for the
duration of the study utilizing standard doses. No breakthrough fungal infections
were observed [74]. In a study of six ECMO patients (100% VV) receiving posaconazole, all trough levels achieved the target range for prophylaxis (≥0.7mg/L), and
69% achieved the target for treatment (≥1mg/dL) [137, 138]. Since these studies are
small, robust conclusions cannot be made, and further exvivo studies will elucidate
the true effect of the ECMO circuit on isavuconazole and posaconazole. It is hypothesized that since the Vd of the agents in critically ill patients is large at baseline, further increases in Vd from the ECMO circuit may not have a clinically meaningful
effect [137, 138]. Based on these results, empiric dose changes may not be warranted
with the use of azole antifungals in ECMO patients; however, TDM should be implemented when possible, especially if treating invasive fungal infections.
Echinocandins as a class have a very high degree of protein binding (>90%) and
low lipophilicity (Table 9.6). An observational, prospective study in 12 ECMO
patients receiving micafungin for prophylaxis found no difference in micafungin
concentrations pre- and post-oxygenator membrane. No breakthrough fungal infections were observed [85]. Studies and case reports have also found no effect of
ECMO on anidulafungin and caspofungin [87]. No studies have yet evaluated the
effect of ECMO on rezafungin. No empiric dose adjustments seem to be necessary
with the use of echinocandin agents on ECMO.
9.8 Fluid Management Considerations inECMO
As mentioned in the prior section on uid management, maintaining euvolemia
with adequate perfusion in the setting of ECMO can be very challenging. Euvolemia
can be achieved through the use of loop diuretics with or without additional agents