These preliminary results suggest that continuous EEG monitoring may be useful

for titrating midazolam infusions to achieve an adequate level of sedation and

guide appropriate weaning, while minimizing prolonged periods of deep or over-
sedation in patients with variable or impaired clearance of midazolam.
Midazolam Pharmacokinetics
Full data is available for 10 patients; mean study days, infusion days, and days
without continuous infusion were 8.9, 4.8, and 4.1 days, respectively (Table 1).
While on continuous infusion, mean midazolam concentration was
281 +/- 191 ng/mL (IQR 114-423 ng/mL) compared to 85.04 +/- 122.77 ng/mL
(IQR 19-100 ng/mL) with intermittent dosing (Table 1).
Mean clearance of midazolam, determined at steady-state (CL
ss
) while on
continuous infusion, was 454 +/- 481 mL/min (IQR 158-469 mL/min) (Table 2).
Although mean CL
ss
was comparable to healthy controls, there was wide inter-
and intrasubject variability (Figure 1, Table 2).
Terminal half-life (T) was prolonged in all patients as compared to previously
published normal values (Figure 2, Table 2).

Table 1: Midazolam Dosing and Mean
Concentration
Continuous
infusion
Intermittent
dosing*
Days 4.8 4.1
MDZ

281 (191) 85 (123)

*Bolus dosing following discontinuation of infusion;
Concentration is in ng/mL, and reported as mean (SD);

MDZ = midazolam ; (p<0.0001 for comparison)

Table 2: Pharmacokinetic Parameters in Study Participants and Healthy
Controls
PK Parameter
Study Patients Healthy Controls

Mean (SD) IQR (Range) Mean Range
CLss (mL/min) 454 (481) 158-469
(31-1157)
376 267-485
T (h) 15.5 (9.10) 9.0-17.7
(7.3-34.9)
3.2 1.0-4.0

Data from Ref. #2 & 5; CL

ss
= Clearance at steady-state; T

= Terminal half-life
Results
1. Pandharipande, P., et al. Lorazepam is an independent risk factor for transitioning
to delirium in intensive care unit patients. Anaesthesiology 2006; 104:21-6
2. Albrecht, S., et al. The effect of age on the pharmacokinetics and
pharmacodynamics of midazolam. Clin Pharm and Ther 1999;65:630-6
3. Spencer, E.M., et al. Continuous monitoring of depth of sedation by EEG spectral
analysis in patients requiring mechanical ventilation. Brit J. Anes. 1994;73:649-54
4. Savard, M., et al. Continuous EEG Monitoring in Severe Guillain-Barre Syndrome
Patients. J Clin Neurophysiol 2009;26:213
5. Malacrida R., et al. Pharmacokinetics of midazolam administered by continuous
intravenous infusion to intensive care unit patients. Crit Care Med. 1992;20:1123-
26.
6. Dresser, G.K., Coordinate induction of both cytochrome P4503A and MDR1 by St
Johns wort in healthy subjects. Clin Pharm Ther. 2003;73:41-50
The Effect of Critical Illness on the Pharmacokinetics
and Dose-Response Relationship of Midazolam
Daniel H. Ovakim MD, MSc
1,2
, Karen J. Bosma MD
2,3
, G. Bryan Young MD
2,4
, Mithu Sen MD
2,3
, Loretta Norton MSc
4
,

Fran Priestap MSc
2
, Rommel Tirona PhD
1
, Richard B. Kim MD
1
, and George K. Dresser MD, PhD
1
1
Division of Clinical Pharmacology,
2
Critical Care Western, Division of Critical Care Medicine &
3
Division of Respirology, Department of Medicine, University of Western Ontario
4
Department of Clinical Neurological Sciences, University of Western Ontario
Background
Critically ill patients require sedation to tolerate the invasive
monitoring devices and interventions necessary to facilitate
their care.
There is growing evidence that prolonged use of sedatives, such
as the benzodiazepine midazolam, is associated with delirium
and other complications that can prolong ICU stay and increase
mortality
1
.
The pharmacokinetics (PK) of midazolam in healthy populations
is well characterized, and pharmacodynamic (PD) studies
demonstrate a predictable dose-response relationship
2
.
Information on the effect of critical illness, however, on the PK
and PD of midazolam is less reported.
To investigate the effect of critical illness on the clearance and
terminal half-life of midazolam.
To determine if analysis of plasma midazolam concentration in
combination with continuous electroencephalography (EEG)
can be used to assess level of sedation.
Objectives
Patients
Patients with a diagnosis of sepsis and receiving a continuous
infusion of midazolam were screened for inclusion.
Sepsis was defined as the occurrence of 2 SIRS criteria in the
presence of a known or suspected infection.
Patients admitted to ICU with status epilepticus, or a primarily
neurological diagnosis were excluded.
Pharmacokinetic Analysis
Blood samples were collected daily for plasma midazolam
concentration analysis.
Midazolam levels were quantified using liquid chromatography
with tandem mass spectroscopy.
Phamacodynamic Analysis
Upon enrollment, a continuous subhairline EEG montage (four-
channel bipolar montage eight facial/one ground electrode)
was applied, and maintained throughout the study period.
EEG signal adequacy and electrode impedance was monitored
daily by an electrophysiologist.
Clinical and laboratory parameters were monitored daily.
In our study participants, midazolam clearance and half-life varied over a wider
range, among and within individuals, in comparison to healthy populations.
Midazolam concentrations while on continuous infusion were inversely
correlated to EEG SEF and clinical GCS assessment.
The lower plasma midazolam concentration associated with GCS 8 may be a
reflection of severity of illness, concomitant medication use, and variable or
impaired clearance during the course of illness.

Acknowledgements
References
Funding for this study was provided by a grant from the Lawson Health Research
Institute (GKD) and the Academic Development Fund (KJB).
The authors thank Tracey Bentall and Cameron Ross for
administrative and technical support
Midazolam Pharmacodynamics
Methodology
Discussion
0
5
10
15
20
25
30
35
40

T
1
/
2

(
h
o
u
r
s
)

0
200
400
600
800
1000
1200
1400
0 1 2 3 4 5 6 7 8 9 10
C
S
S

(
m
L
/
m
i
n
)

Patient ID
Figure 1: Observed intra- and intersubject variability in midazolam
clearance at steady-state: Blue dots represent clearance range of
healthy controls (Ref 2,5,6); C
ss
= Clearance at Steady State
Figure 2: Variability in terminal half-
life of midazolam among study
patients. T
1/2
= Terminal half-life
EEG Findings
Depth of sedation was assessed by EEG Spectral Edge Frequency (SEF)
4
, and
proportion of delta wave frequency ( 4 Hz) at the time of blood collection.
Plasma midazolam concentration was inversely correlated with EEG SEF
(Figure 3), with maximal slowing within the delta range (not shown).
Midazolam and Level of Consciousness (GCS)
Plasma midazolam concentration was inversely correlated with patient GCS
determination at the time of blood collection (Figure 3).
Mean plasma midazolam concentration associated with GCS 8 was
301.73 +/- 206.60 ng/mL, compared to 105.65 +/- 107.90 ng/mL for GCS >8
(p = 0.008), which is lower than previously published values of 598 119 ng/mL
and 431 +/- 422 ng/mL, respectively, in healthy volunteers
2
.
Conclusions and Future Directions
3
4
5
6
7
8
9
10
11
12
13
14
15
0
2
4
6
8
10
12
14
16
18
20
0 100 200 300 400 500 600 700 800
G
C
S

S
E
F
(
H
z
)

MidazolamPlasma Concentration (ng/mL)
SEF (Hz) GCS
p = 0.001 (Rho
S
)
Figure 3: Glasgow Coma Scale (GCS) and EEG Spectral Edge Frequency (SEF) vs. plasma midazolam
concentration. Spearmans rho for SEF and GCS =-0.565, (p=0.0002), 0.363 (p=0.001) respectively.
p = 0.0002 (Rho
S
)