Download Prof.Dr. Amr Zaki Mansour Prof. Dr. Ashraf Mohamed Mohsen Dr

Prospective randomized study on the effect of
indomethacin on intracranial pressure during
craniotomy for patients with supratentorial
tumors
Thesis
Submitted for fulfillment of M.D. degree in anesthesiology
Faculty of medicine, Cairo University
By
Ahmed Ragab Abd El-Hakeim
M.B.B.Ch, M.Sc Anesthesia
Supervised by
Prof.Dr. Amr Zaki Mansour
Professor of Anesthesia, Faculty of Medicine
Cairo University
Prof. Dr. Ashraf Mohamed Mohsen
Professor of Anesthesia, Faculty of Medicine
Cairo University
Dr. Mohamed Waleed Awad
Assistant professor of Anesthesia, Faculty of Medicine
Cairo University
Dr. Sameh Nabil Abu-Alam
Lecturer of Anesthesia, Faculty of Medicine
Cairo University
Faculty of Medicine
Cairo University
2010
Dedication I dedicate this work to my family, whom without their sincere
emotional support, pushing me forward, this work would not have ever
been completed.
i
Acknowledgment First and foremost, thanks to God, the most kind and merciful.
Words will never be able to express my deepest gratitude to all those who
helped me during preparation of this study.
I gratefully acknowledge the sincere advice and guidance of Prof.
Dr. Amr Zaki Mansour and Dr. Ashraf Mohamed
Mohsen (Professors of anesthesiology, faculty of medicine, Cairo
University), for their constructive guidance and general help in
accomplishing this work
I am greatly honored to express my sincere appreciation to assistant
Prof. Dr. Mohamed Waleed Awad (Assistant Professor of
anesthesiology, faculty of medicine, Cairo University), for his continuous
support, direction and meticulous revision of this work
I owe a particular debt of gratitude to Dr. Sameh Nabil Abu-
Alam (Lecturer of anesthesiology, faculty of medicine, Cairo
University), for his valuable help, support and guidance.
ii
Abstract This study was carried out to evaluate the effects of
perioperative indomethacin
on
intracranial
pressure
(ICP). Forty
patients subjected to craniotomy for supratentorial cerebral tumors were
anesthetized with propofol, fentanyl and isoflurane. A PaCo2 level
averaging 35-40 mmHg was achieved. The patients were randomized
to
intravenous
indomethacin
50 mg as bolus then infusion by
0.3mg/kg/hr. till opening the dura in 20 patients
or
placebo
administrated in the other 20 patients . ICP was measured continuously
subdurally with ICP probe(Codman Micro Sensor, Johnson & Johnson
Medical Ltd)
A significant decrease in ICP from 9.5 to 2.6 mm Hg (median)
was found after indomethacin administration. In the indomethacin
group, dura was sufficiently relaxed and dura was opened without the
occurrence of cerebral
swelling. In
the placebo
group,
mannitol
supplemented with hypocapnia was applied in many patients. These
findings suggest that perioperative treatment with indomethacin is an
excellent treatment of intracranial hypertension during normocapnic
isoflurane anesthesia for craniotomy.
Key Words: Indomethacin—Intracranial pressure—Cerebral blood
flow—Cerebral metabolism—Neuroanesthesia.
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Contents Dedication ....................................................................................................i Acknowledgment ....................................................................................... ii Abstract ..................................................................................................... iii Contents .....................................................................................................iv List of Figures .............................................................................................v List of Tables .............................................................................................vi Abbreviations ........................................................................................... vii Introduction .................................................................................................1 Physiology of Cerebral blood flow and ICP ...............................................4 Indomethacin.............................................................................................27 Materials and Methods..............................................................................35 Results .......................................................................................................40 Discussion .................................................................................................49 Conclusion ................................................................................................53 Summary ...................................................................................................55 References .................................................................................................59 ‫ اﻟﻤﻠﺨﺺ اﻟﻌﺮﺑﻲ‬..............................................................................................76 iv
List of Figures Figure 1. The effect of temperature reduction on the cerebral metabolic
rate of oxygen .............................................................................................9 Figure 2. Changes in cerebral blood flow (CBF) caused by independent
alterations in PaCO2 , PaO2 , and mean arterial pressure (MAP) .............11 Figure 3. Intracranial pressure-volume relationship ................................23 Figure 4. Pathophysiology of intracranial hypertension .........................26 Figure 5. Pathways for the metabolism of arachidonic acid.............31 Figure 6. Intraoperative changes in intracranial pressure. .......................44 Figure 7. Intraoperative changes in mean arterial pressure (MAP) (mean
± SD). Error bars represent ±1 SD. ...........................................................45 Figure 8. Surgeon satisfaction rates with brain condition .......................46 Figure 9. Visual analogue scale (VAS) in the postoperative period .......47 v
List of Tables Table 1. Normal cerebral physiologic values............................................5 Table 2. Demographic data of study groups ............................................41 Table 3. Presenting symptoms .................................................................42 Table 4. Duration of surgery and postoperative complications ...............43 Table 5. ICP measures recorded throughout observation period .............43 Table 6. PaCO2 in ABG before induction, at skin incision, at dura
incision and after extubation ....................................................................45 Table 7. Time to eye opening and obeying verbal commands after
discontinue of GA .....................................................................................46 Table 8. Postoperative analgesic requirements ........................................48 vi
Abbreviations BBB
Blood-Brain Barrier
CBF
Cerebral Blood Flow
CBV
Cerebral Blood Volume
CMR
Cerebral Metabolic Rate
CMRO2
Cerebral Metabolic Rate of Oxygen
CPP
Cerebral Perfusion Pressure
CSF
Cerebrospinal Fluid
CVR
Cerebral Venous Resistance
EEG
Electroencephalogram
ICP
Intracranial Tension
LA
Local Anaesthetics
MAC
Minimal Alveolar Concentration
MAP
Mean Arterial Pressure
N2O
Nitrous Oxide
NO
Nitric Oxide
NSAID
Non-Steroidal Anti-Inflammatory Drug
VIP
Vasoactive Intestinal Peptide
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Introduction Introduction Intracranial pressure is the pressure inside the cranial vault relative to
atmospheric pressure; it measures normally less than 10 mmHg. The rigid
cranium surrounding the brain creates a unique protective space. As brain
tissue is nearly incompressible, any rise in pressure will cause
cerebrospinal fluid (CSF) and blood to be expressed out of the cranium.
Thus change in volume of one compartment is accompanied by a
reciprocal change in another compartment (1).
Increased intracranial tension may lead to cerebral swelling
which may jeopardize cerebral circulation and surgical access. Hence,
high ICP must be decreased to reduce potential problems of ischemia and
optimization of the surgical field (1).
The intracranial contents can be divided into four compartments:
Solid material 10%; Tissue water 75%; CSF (150 ml) 10%; Blood (50—
75 ml) 5%.The blood compartment is the compartment that receives the
anesthesiologist's greatest attention because it is the most amenable to
rapid alteration. The blood compartment should be considered two
separate components: venous and arterial. Venous compartment is
reduced by avoiding Obstruction of cerebral venous drainage by extremes
of head position or circumferential pressure (Philadelphia collars,
endotracheal tube ties) or anything that causes increased intra-thoracic
pressure can result in obstruction of cerebral venous drainage. Arterial
compartment is reduced by the effect of anesthetic drugs and techniques
1
Introduction affecting cerebral blood flow (CBF); normally CBF represents 12% to
15% of cardiac output (50ml/100g/min.).Many factors can affect CBF
such as cerebral autoregulation; respiratory gases especially PaCo2,
blood viscosity, temperature, anesthetic agents and inotropes (pressors,
vasodilators). The general approach to decrease ICP is to select
anesthetics and control the physiologic parameters in a manner that
avoids unnecessary increases in CBF, cerebral blood volume (CBV) and
thus decrease ICP (2).
Indomethacin has been suggested as a therapeutic option to
manage increased intracranial pressure (ICP) in patients undergoing brain
surgery (3). Indomethacin is a non-steroidal anti-inflammatory drug
(NSAID) that exhibits anti-inflammatory, analgesic and antipyretic
activity via a reversible inhibition of cyclo-oxygenase enzyme.
Indomethacin is available in oral, rectal and intravenous (i.v.)
formulations (4). Peak plasma concentration of indomethacin is usually
achieved within 5 minutes after i.v. injection, whereas after oral
administration, peak plasma concentration is attained within 30 - 120
minutes (4). The indomethacin can induce a decrease in ICP within few
seconds after an I.V. bolus dose (50mg) and may last for 10-20 min (5).
More over with continuous indomethacin infusion (0.3mg/kg/hr), the
otherwise intractable intracranial hypertension can be controlled (6).
Many studies have demonstrated that indomethacin can decrease
CBF in rats, rabbits, cats, dogs, goats, and pigs (7-10), other studies
demonstrated same effect in humans after traumatic head injuries (11,
12). Theories whereby indomethacin produces its effect on CBF are
thought to include; a decrease in production of cerebral vasodilating
2
Introduction prostaglandins (via cyclo-oxygenase inhibition), mild hyperventilation
(decreasing PaCO2), direct vasoconstriction of cerebral blood vessels
(13), and decreasing CSF production by potentiating the inhibitory effect
of endothelin on CSF production by the choroid plexus(14). In addition
Indomethacin may be considered a neuroprotective drug by lowering
cerebral temperature and therefore ICP through preventing hyperpyrexia
(15).
3
Physiology of Cerebral blood flow and ICP Physiology of CBF and ICP REGULATION OF CEREBRAL BLOOD FLOW
The adult human brain weighs approximately 1350 gm and therefore
represents about 2% of total-body weight. However, it receives 12% to
15% of cardiac output. This high flow rate is a reflection of the brain's
high metabolic rate. At rest, the brain consumes oxygen at an average rate
of approximately 3.5 mL of oxygen per 100 gm of brain tissue per
minute. Whole-brain O2 consumption (13.5 × 3.5 = 47 mL/min)
represents about 20% of total-body oxygen utilization. Normal values for
CBF, CMR, and other physiologic variables are provided in (Table 1).
Table 1. Normal cerebral physiologic values (16)
Global CBF
45–55 mL/100 g/min
Cortical CBF (mostly gray matter)
75–80 mL/100 g/min
Subcortical CBF (mostly white matter)
‫׽‬20 mL/100 g/min
CMRO2
3–3.5 mL/100 g/min
Cerebral venous PO2
32–44 mm Hg
Cerebral venous SO2
55%–70%
ICP (supine)
8–12 mm Hg
.
Approximately 60% of the brain's energy consumption is used to
support electrophysiologic function. The depolarization-repolarization
activity that occurs and is reflected in the EEG requires energy
expenditure for the maintenance and restoration of ionic gradients and for
the synthesis, transport, and reuptake of neurotransmitters. The remainder
of the energy consumed by the brain is involved in cellular homeostatic
activities. Local CBF and local CMR within the brain are very
heterogeneous, and both are approximately four times greater in gray
5
Physiology of CBF and ICP matter than white matter. The cell population of the brain is also
heterogeneous in its oxygen requirements. Glial cells make up about half
the brain's volume and require less energy than neurons (16).
The brain's substantial demand for substrate must be met by
adequate delivery of oxygen and glucose. However, the space constraints
imposed by the noncompliant cranium and meninges require that blood
flow not be excessive. Not surprisingly, there are elaborate mechanisms
for the regulation of CBF. These mechanisms include chemical,
myogenic, and neurogenic factors. The precise mechanisms of these
effects are not well understood. However, a substantial volume of largely
recent research indicates that modulation of the arginine-nitric oxide
(NO)-cyclic guanosine monophosphate system(17) is central to the
changes in cerebral vascular tone caused by several processes, including
hypercapnia,(18)increased
CMR,(19)
volatile
anesthetics,(20)and
neurogenic mechanisms(21,22)
A‐ Chemical Regulation Several factors cause changes in the cerebral biochemical environment
that result in adjustments in CBF, including changes in CMR, PaCO2, and
PaO2.
1‐ Cerebral Metabolic Rate Increased neuronal activity results in increased local brain metabolism,
and this increase in CMR is associated with a well-matched, proportional
change in CBF(23). Regional CBF and CMR measurements performed
during maneuvers designed to activate specific brain regions provide
evidence of the strict local "coupling" of CMR and CBF(24,25).
Although the precise mechanisms that mediate flow-metabolism coupling
have not been defined, the available data implicate local by-products of
6
Physiology of CBF and ICP metabolism (K+ , H+ , lactate, adenosine). Glutamate, released with
increased neuronal activity, results in the synthesis and release of NO.
NO is a potent cerebral vasodilator that plays an important role in flow
and metabolism coupling(19).
More recent data have highlighted the role of glia in flowmetabolism coupling. Uptake of glutamate, released from neurons, by
glia triggers increased glial metabolism and lactate production. Glial
processes make contact with neurons and capillaries, and hence glia may
serve as a conduit for the coupling of increased neuronal activity with
increased glucose consumption and regional blood flow(26). Nerves that
innervate cerebral vessels release peptide neurotransmitters such as
vasoactive intestinal peptide (VIP), neuropeptide Y, substance P, and
calcitonin gene-related peptide. These neurotransmitters may also be
potentially involved in neurovascular coupling. Flow and metabolism
coupling within the brain is a complex physiologic process that is
regulated not by a single mechanism, but by a combination of metabolic,
glial, neural, and vascular factors.
CMR is influenced by several phenomena in the neurosurgical
environment, including the functional state of the nervous system,
anesthetics, and temperature.
• FUNCTIONAL STATE. CMR decreases during sleep and increases during sensory stimulation,
mental tasks, or arousal of any cause. During epileptic activity, CMR
increases may be extreme, whereas in coma, CMR may be substantially
reduced.
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