Download Sedation during extracorporeal membrane oxygenation—why more

Correspondence
Sedation during extracorporeal membrane
oxygenation—why more is less
Patients on extracorporeal membrane oxygenation
(ECMO) often have increased sedation requirements1.
Given the expanding scope of ECMO2 and increasing
awareness of the morbidity associated with excessive
sedation in the intensive care unit3, it is important that
the mechanisms behind such altered sedation needs
are further investigated. To that end, we measured
the plasma concentrations of morphine, midazolam
and their clinically relevant metabolites prior to and
after the commencement of ECMO in a patient with
preserved hepatic and renal function in order to
highlight the independent effect ECMO may have
on the pharmacokinetics of these compounds. Prior
ethics approval was obtained from the local Human
Research Ethics Committee (HREC/11/QPCH/121).
A 30-year-old man (admission weight 85 kg)
with severe respiratory failure was referred to the
Prince Charles Hospital, Brisbane, Queensland,
for consideration for venovenous ECMO as a
bridge to recovery or lung transplantation. He had
been ventilated for 20 days for a biopsy-proven
Anaesthesia and Intensive Care, Vol. 40, No. 6, November 2012
1067
cryptogenic organising pneumonia that was not
responsive to immunosuppression. Sedation prior
to and after commencement of ECMO was titrated
to a Richmond Agitation Sedation Scale of -3 to -4
and a bispectral index of 40–45. The patient also
received neuromuscular paralysis with vecuronium
(0.5 mg/hour, titrated to 1–2 twitches on train-offour monitoring) to optimise ECMO flows and
ventilation. Pre-ECMO sedation comprised of
propofol 100 mg/hour, morphine 20 mg/hour and
midazolam 20 mg/hour. Percutaneous cannulation
was performed using a 25 Fr multistage cannula and a
22 Fr single stage cannula (Bio-Medicus®, Medtronic,
Minneapolis, MN, USA) in the left and right femoral
veins for access and return, respectively. The circuit
consisted of bioline tubing, a centrifugal pump and
a polymethyl pentene oxygenator (Jostra Rotaflow™
& Quadrox D™, Maquet, Germany). Serial blood
samples (1 ml) from a radial arterial line were
collected over a 90-minute period prior to and 12
hours after commencing ECMO for measurement of
the plasma concentrations of morphine, midazolam
and their major metabolites. Samples were analysed
using a validated robotic solid phase extraction liquid
chromatography-tandem mass spectrometry method.
In the first three hours after commencement of
ECMO, the propofol infusion regimen was increased
to 200 mg/hour (P=0.4), and the morphine and
midazolam infusion regimens were each increased
to 50 mg/hour (P <0.001) to achieve pre-ECMO
sedation levels (Figure 1A). In addition, propofol was
also administered as repeated boluses (30–50 mg, up
to total of 300 mg in the first hour). The escalation
in morphine and midazolam doses correlated with a
decrement in plasma concentrations of these drugs
and their active metabolites. There was a significant
reduction in the plasma morphine (20%), midazolam
(11%), 1-hydroxy midazolam (17%), morphine-3glucuronide (36%) and morphine-6-glucuronide
(35%) concentrations on commencement of ECMO,
compared to pre-ECMO levels which increased
consistently with the marked increase in administered
drug doses (Figures 1B and 1C). The increased
requirement for sedation persisted for the entire
duration of ECMO (19 days). Tracheotomy performed
on day 7 did not lead to a significant reduction in
sedative doses.
Despite studies showing heightened sedation
requirements during ECMO1, the mechanisms
underpinning this clinical observation are not adequately defined. Pharmacokinetics studies in neonates have reported increased volumes of distribution
and decreased drug elimination during ECMO4.
Correspondence
1068
In vitro circuit studies using neonatal circuits show
significant sequestration of sedative and analgesic
drugs in the ECMO circuit4. However, this pharmacokinetics data cannot be extrapolated to adults due
to physiological and technical differences between the
two populations. More detailed reviews of the sparse
data on altered pharmacokinetics during ECMO can
be found elsewhere4.
The altered sedation requirements in this cohort1
is concerning as excessive sedative drug use may add
to intensive care unit morbidity5. However, achieving
optimal levels of sedation to promote comfort,
A)
200
100
Dose (mg/h)
[ Bispectral index ]
80
150
60
100
40
50
0
20
0
5
10
15
Propofol
Bispectral index
Morphine
Midazolam
Acknowledgements
0
Time since ECMO commenced( h)
ECMO commenced
B)
100
1500
60
1000
40
500
0
Morphine dose
80
Dose, mg/h
Concentration, ng/ml
2000
Morphine
M3G
M6G
20
0
60
120
180
240
0
300
Time, min
J. A. Roberts
S. Ghassabian
80
60
1000
40
500
Dose, mg/h
Concentration, ng/ml
1500
0
Midazolam dose
Midazolam
1-OH-midazolam
4-OH-midazolam
20
0
60
This work was supported, in part, by funding
provided by the National Health and Medical
Research Council, the Australian and New Zealand
College of Anaesthetists, the Intensive Care
Foundation and the Prince Charles Hospital
Foundation. This work utilised infrastructure purchased with Queensland Government Smart State
Research Facilities Investment Funds and Australian
Government Education Investment Super Science
Funds as part of the Therapeutic Innovation
Australia—Queensland Node project. We would like
to acknowledge Ms Rachel Buschel for her assistance
with data collection and Associate Professor Adrian
Barnett for performing the statistical analysis. Dr J. A.
Roberts is funded by a National Health and Medical
Research Council of Australian Training Research
Fellowship (409931).
K. Shekar
ECMO commenced
C)
relieve stress, maximise ECMO flows and minimise
oxygen consumption, while preventing accidental
dislodgement of life-sustaining equipment, can be
a difficult balancing act in the setting of altered
pharmacokinetics during ECMO. Although the
use of minimal sedation and early tracheotomy and
ambulation in selected patients has been reported5,
this is not always possible.
This report provides preliminary mechanistic
explanation for altered sedation requirements in
these patients on ECMO. It also highlights important
clinical issues such as sedation targets during ECMO,
utility of bispectral index monitoring and the timing
of tracheotomy in critically ill patients receiving
ECMO. Systematic research using ex vivo animal6
and clinical pharmacokinetic studies is required to
improve sedative and analgesic drug prescription
during ECMO.
120
180
240
0
300
Time, min
Figure 1: Escalating morphine and midazolam dosing requirements
(A) upon commencement of extracorporeal membrane
oxygenation correlated with the decreased plasma levels of these
drugs and their active metabolites (B, C). BIS=bispectral index,
ECMO=extracorporeal membrane oxygenation.
D. V. Mullany
M. Ziegenfuss
M. T. Smith
Y. L. Fung
J. F. Fraser
Brisbane, Queensland
References
1. Shekar K, Roberts JA, Mullany DV, Corley A, Fisquet S, Bull
TN et al. Increased sedation requirements in patients receiving
extracorporeal membrane oxygenation for respiratory and
cardiorespiratory failure. Anaesth Intensive Care 2012; 40:648655.
Anaesthesia and Intensive Care, Vol. 40, No. 6, November 2012
Correspondence
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Anestesiol 2012; 76:534-540.
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ventilated patient. Am J Respir Crit Care Med 2012; 185:486497.
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changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 2012 [Epub ahead of print].
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life support in the new era. Intensive Care Med 2012; 38:210220.
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Dunster KR et al. Development of simulated and ovine models
of extracorporeal life support to improve understanding of
circuit-host interactions. Crit Care Resusc 2012; 14:105-111.
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