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Effects of hypertonic saline on intracranial pressure variables in
subarachnoid haemorrhage patients
Gunnar Kristoffer Bentsen
Ph.D. thesis
Division of Anaesthesiology and Intensive Care Medicine Rikshospitalet University Hospital
University of Oslo Oslo, Norway
2009
© Gunnar Kristoffer Bentsen, 2009 Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 714 ISBN 978-82-8072-765-7 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AiT e-dit AS, Oslo, 2009. Produced in co-operation with Unipub AS. The thesis is produced by Unipub AS merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. Unipub AS is owned by The University Foundation for Student Life (SiO)
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”Following the intravenous injection of 30 per cent sodium chloride, the normal convexity of the brain in the trephine opening disappears soon after the injection is begun, so that the brain is seen to lie flat. As the intravenous injection of salt is continued, the brain falls away from the skull until the surface presented becomes concave. The maximum shrinkage has been observed usually in from fifteen to thirty minutes after the completion of the injection, when the brain lies flaccid, 3 to 4 mm below the inner table of the skull.”
LH Weed and PS McKibben, 1919.
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CONTENTS
Page Acknowledgements 6 Abbreviations 8 Publications included in the thesis 9 Introduction 10 Subarachnoid haemorrhage 10 Definitions, incidence, and outcome 10 Mechanisms of injury to the brain 11 Aspects of treatment 12 Osmotherapy 14 Context definition 14 Mechanisms 14 History 16 Mannitol 17 Hypertonic saline 18 Animal studies 20 Human studies 22 Intracranial pressure monitoring 24 Mean ICP 24 ICP waveform analysis 26 Aims of the thesis 28 Methods 29 Study design 29 Data collection 30 Statistical methods 31 Synopsis of results 33 Paper I 33 Paper II 34 Paper III 35 Discussion 37 The relevance of ICP and CPP 38 Different ICP variables 39 Effects of HSS on mean ICP and CPP in SAH patients 40 Temporal pattern of change 41 Study solution 43 Dose and practical use 44 Adverse effects 46 Effects of HSS on mean ICP wave amplitude in SAH patients 47 Future clinical research questions 49 Main conclusions 51 Implications for clinical practice 53 References 55 Papers I - III
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ACKNOWLEDGEMENTS
The present work has been carried out at the Division of Anaestesiology and Intensive Care
Medicine, Rikshospitalet University Hospital, which has also financed the work, and the
University of Oslo, Faculty of Medicine, during the period 2002 – 2008. During the whole
period I have been surrounded by generosity both at work and at home, and I want to express
my sincere gratitude to all who have helped and supported me these years.
First of all, Professor Audun Stubhaug, my principal supervisor, always supportive and
enthusiastic. Even though heavily tied up in work at all times, finding enough time to couch
me through all stages of this doctoral thesis in a exemplary way, lending me access to his vast
knowledge in research, statistics, and medicine. My sincerest thanks also to my two other
supervisors; Professor Harald Breivik, indeed a man of letters, contributing from his
overwhelming experience, and with his sharpened skills in manuscript preparation. Øyvind
Skraastad, now Head of our Division, former leader of our paediatric anaesthesia team,
supporting me all the way and helping me combine research with clinical work. The same
goes to Einar Hysing, former Head of our Division, now Hospital Medical Director, for
encouragement and preparing the ground for my combination of research and clinical work.
The principal building blocks of a thesis are of course the papers behind it. The great
involvement from all my co-authors has been a rewarding experience for me. I thank
Professor Tryggve Lundar and Per Kristian Eide from the Department of Neurosurgery for
their contribution. Per Kristian Eide has also developed the method for monitoring mean ICP
wave amplitude investigated in Paper III, and has introduced me to the fascinating world of
intracranial pressure waves. I also want to thank William Sorteberg for valuable input and
support.
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During the time I have worked with this thesis I have been fortunate to enjoy the
privilege of working full- or part-time at our paediatric anaesthesia team. I want to thank
Marius Asplin, Even Fagermoen, Bjørn Aage Feet, Torleiv Haugen, Sidsel Hetland, Bjarne
Morisbak, Roger Roscher, Gunn Kari Sangolt (late), Anne-Beate Solås, Sjur Sponheim, and
Kari Wagner for transfer of clinical skills and knowledge, for encouragement and bright days.
Our collegium as a whole is a group I am proud to be a part of, so many devoted and
skilled physicians working together in a relaxed atmosphere topped with solid portions of
humour and self-irony. Many have helped me recruit patients at all hours, I thank you all.
Sincere thanks also to the entire nursing staff at our intensive care units, which
faithfully and with a smile has included the extra load of work clinical studies carry, attitudes
truly worthy a university clinic.
For technical assistance, I am very grateful to Jan Olav Høgetveit who designed the
LabView application making harvesting of data to Paper I and II possible. Likewise had data
harvest to Paper III been impossible without Trond Stadheim.
Last but foremost, I thank my family, my most important source of help, joy, and
support. My fantastic wife, Elin, with whom I can share all my challenges and wins. My
equally fantastic kids, Hanna and Lars, unconditionally loving and a constant source of
happiness. Our dog, Mila, for not having eaten any important material.
May 2008. Gunnar Bentsen
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ABBREVIATIONS
ABP Arterial blood pressure
BBB Blood-brain-barrier
CBF
CBV
Cerebral blood flow
Cerebral blood volume
CDO2 Cerebral oxygen delivery
CI Cardiac index
CNS Central nervous system
CPM
CPP
Central pontine myelinolysis
Cerebral perfusion pressure (CPP = MAP – ICP)
CSF
CVP
DIND
ELWI
Cerebrospinal fluid
Central venous pressure
Delayed ischemic neurological deficit
Extravascular lung water index
EVD External ventricular drain
FFT Fast Fourier transformation
GCS Glasgow Coma Score
GOS Glasgow Outcome Score
HR Heart rate
HS Hypertonic saline
HSS 7.2% (72 mg/mL) saline in 6% (60 mg/mL) hydroxyethyl starch
200/0.5 (sodium content: 1.23 mmol/mL)
ICP Intracranial pressure
ICU Intensive care unit
ITBI Intrathorasic blood volume index
IVH Intraventricular haemorrhage
MAP Mean arterial pressure
NS Normal saline
SAH Subarachnoid haemorrhage
SpO2
TBI
Peripheral oxygen saturation
Traumatic brain injury
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PUBLICATIONS INCLUDED IN THE THESIS
The thesis is based on the following articles, which are referred to in the text by their roman
numerals:
I. Bentsen G, Breivik H, Lundar T, Stubhaug A. Predictable reduction of intracranial
hypertension with hypertonic saline hydroxyethyl starch: a prospective clinical trial in
critically ill patients with subarachnoid haemorrhage. Acta Anaesthesiol Scand 2004;
48: 1089-1095.
II. Bentsen G, Breivik H, Lundar T, Stubhaug A. Hypertonic saline (7.2%) in 6%
hydroxyethyl starch reduces intracranial pressure and improves hemodynamics in a
placebo-controlled study involving stable patients with subarachnoid hemorrhage. Crit
Care Med 2006; 34: 2912-7.
III. Bentsen G, Stubhaug A, Eide PK. Differential effects of osmotherapy on static and
pulsatile intracranial pressure (ICP). Crit Care Med; accepted for publication.
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INTRODUCTION
Subarachnoid haemorrhage
Definitions, incidence, and outcome
Subarachnoid haemorrhage (SAH) is characterized by the presence of blood in the
subarachnoid space; the space covering the central nervous system that normally only
contains cerebrospinal fluid. The bleeding can be either traumatic or spontaneous. This thesis
only deals with the spontaneous, non-traumatic bleedings, which in about 80 to 85% of the
cases are due to the rupture of a cerebrovascular aneurysm (van Gijn and Rinkel, 2001).
The overall incidence of spontaneous SAH is in meta-analyses reported to be
somewhere around 10:100,000 annually, but with variations from six to eight in USA and
most of Europe to around 20:100,000 in Finland and Japan (Linn et al., 1996; Teunissen et al.,
1996; Menghini et al., 1998; van Gijn and Rinkel, 2001). Women have a 1.6 times higher risk
than men (Linn et al., 1996), and black people twice the risk of whites (Broderick et al., 1992)
of experiencing a SAH. Smoking, hypertension, and alcohol abuse increase the risk for SAH
(Teunissen et al., 1996).
Case fatality rates are high in SAH compared with other forms of stroke, varying
between 32% and 67%, with a weighted average of 51%, but the fatality rate has decreased
over the last three to four decades by 0.5 to 1.0% annually (Hop et al., 1997; Johnston et al.,
1998; Koffijberg et al., 2008). Even though SAH accounts for only 3% of all strokes (Sudlow
and Warlow, 1997), 4.4% of cerebrovascular deaths are due to SAH (Johnston et al., 1998).
SAH also accounts for 27% of total years of potential life lost before age 65 due to
cerebrovascular disease (Johnston et al., 1998). This is due to the high fatality rate and the fact
that the population of SAH patients is younger than the populations with cerebral infarction
and intracerebral haemorrhages.
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About 50% of those who die, die within the first two days after the stroke (Stegmayr et
al., 2004). This represents a challenge to the acute management of these patients. Of vital
importance is prompt diagnosis, rapid transfer to a neurosurgical unit, early securing of the
aneurysm, and optimal intensive care (Bakke and Lindegaard, 2007).
Of the survivors, approximately one third need lifelong care (Hop et al., 1997), and
almost a half of the survivors suffer life-long cognitive impairment (Hackett and Anderson,
2000; Mayer et al., 2002). Hopefully, improved intensive care with avoidance of secondary
insults can help reduce also these figures.
Mechanisms of injury to the brain.
Brain injury after SAH is a biphasic event.
First there is the initial impact of the bleeding itself causing cerebral ischemia. A sharp
increase in intracranial pressure (ICP) leads to a dramatic reduction in cerebral perfusion
pressure (CPP) (Talacchi, 1993). But even after recovery of CPP, there is evidence of
prolonged hypoperfusion with flow measured in different studies at 20 – 80% of baseline
levels (Jackowski et al., 1990; Piepgras et al., 1995; Prunell et al., 2004). There is also
evidence of loss of autoregulation, disruption of the blood-brain-barrier (BBB), cellular
swelling leading to cerebral oedema, and initiation of apoptotic processes, but the
understanding of the underlying mechanisms and the ultimate relevance of these early
changes is still incomplete (Cahill et al., 2006; Mocco et al., 2007; Schubert and Thome,
2008).
Secondly, given that the patient has survived the impact of the bleeding, there is a
more prolonged phase. Many patients experience bleeding into the ventricular system
affecting drainage of cerebrospinal fluid (CSF). This may lead to the development of
hydrocephalus and subsequent rise in ICP leading to ischemia within hours (Bakke and
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Lindegaard, 2007). Cellular swelling and disruption of the BBB induces cerebral oedema,
which also increases ICP. This process typically culminates after two to four days (Thiex and
Tsirka, 2007), but may cause distortion and displacement of brain tissue resulting in
compression of vital structures (“herniation” syndromes). Claassen et al. have reported the
presence of cerebral oedema to be associated with poor outcome. Global oedema was found at
admission in 8% of patients with an additional 12% developing delayed oedema (Claassen et
al., 2002). Reaching peak incidence at about a week, delayed vasospasm may also cause
seriously impaired cerebral blood flow (CBF) and ischemia. Radiographic evidence of
vasospasm can be found in more than 50% of patients, but only half of these experience
symptoms of delayed ischemic neurological deficits (DIND) (Keyrouz and Diringer, 2007).
Somewhere along the time line, there is also a periprocedural phase, where the source
of bleeding is secured either by surgical clipping or endovascular coiling. These procedures
also carry some risk. Complications may arise due to thrombosis, bleeding, induced
vasospasm, or excessive traumatisation of brain tissue (Bakke and Lindegaard, 2007).
Aspects of treatment
In short, the goals of treatment are; meeting the neuronal metabolic needs at all times,
avoiding secondary deterioration, and avoiding further bleeds.
The avoidance of re-bleeding is achieved by surgical clipping or endovascular coiling
of the aneurysm. The trend is to perform this intervention at an early stage. The risk of re-
bleeding is closely related to time and the occurrence of re-bleeding is strongly associated
with poor outcome (Ohkuma et al., 2001; Bakke and Lindegaard, 2007). The risk of re-
bleeding is highest during the first 24 hours after the initial bleeding and immediate
administration of tranexamic acid upon diagnosis of SAH may reduce the risk of early re-
bleeding (Hillman et al., 2002).
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Securing optimal oxygen and nutritional supply has many aspects. First, one important
measure is to reduce the oxygen need. This can be achieved by avoiding hyperthermia and
sedating the patient, in the final instance by inducing a pentobarbital coma. Sedation of the
patient may warrant securing the airway and the institution of mechanical ventilation.
Mechanical ventilation is often also needed because the patient is unconscious to begin with
or because pneumonia impairs gas exchange to the degree that the patient is hypoxemic. By
mechanical ventilation the oxygen supply and carbon dioxide removal can most often be well
controlled. For the oxygen taken up in the lungs to be delivered to the brain we must ensure
that the haemoglobin content is sufficient, and that the brain is perfused. This means that the
CPP has to be adequate, and the blood pressure and cardiac output can be controlled by
adequate volume supply and the use of vasoactive drugs when needed.
As is obvious from the previous section, raised ICP is often a threat to adequate
perfusion and cell function. Intracranial hypertension can be attenuated by sedation, head
elevation, and temperature control. For short time relief of increased ICP, reduction of arterial
CO2 content by hyperventilation can be very effective, but aggressive hyperventilation can
induce grave vasoconstriction leading to ischemia in itself. Especially in patients suffering
from acute hydrocephalus caused by intraventricular haemorrhage (IVH), external drainage of
cerebrospinal fluid (CSF), either by a ventricular catheter or by the lumbar route is very
helpful in rapidly decreasing the ICP. In extreme cases of cerebral swelling, the procedure of
decompressive hemicraniectomy can be life saving (Schirmer et al., 2007; Hutchinson et al.,
2007). This brings me to the subject of osmotherapy, which is the last of the commonly
applied strategies used to attenuate raised ICP.
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Osmotherapy
Context definition
The use of osmotically active solutions to reduce the volume of the intracranial content
(Paczynski, 1997).
Mechanisms
The water content of the brain approximates 80% (Bhardwaj, 2007). When we add that a
small 1.6% reduction in water content yields a 90 mL reduction in brain volume (Cascino et
al., 1983), we have the foundation for understanding osmotherapy.
The osmotic pressure of a solution is proportional to the number of particles in a given
volume (Rapoport, 1976), but osmotic effectiveness of solutions depends as much on the
properties of the membrane(s) separating the different compartments of solutions as their
respective molarities. This can be expressed as the membrane’s osmotic reflection coefficient
(�) for a given solute. Given a reflection coefficient of zero, the membrane is completely
permeable for that solute. On the other hand, if the membrane is impermeable, the value is
one (Zornow, 1996).
The properties of the BBB differ greatly from the properties of capillaries elsewhere in
the body. Unlike “ordinary capillaries”, the BBB is virtually impermeable to small solute
molecules like sodium and chloride. It is these compounds that regulate the water balance
across the BBB. The importance of the colloid osmotic pressure, known from the Starling
equation, is less in the uninjured brain; the flow of water is tightly controlled by the
crystalloid osmotic pressure.
Another important property of the BBB, is the relative impermeability of molecules of
water (Raichle et al., 1976). On 9 October 1991 the first water channel, Aquaporin-1, was
discovered (Preston et al., 1992). Subsequently other aquaporins have been identified, and
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Aquaporine-4 located in the brain may control most of the water transport across the BBB,
and represent a rate limiting factor for this process. However, the importance of Aquaporine-4
in human cerebral oedema is still undefined, but Aquaporine-4 has a potential for future
therapeutic interventions (Agre et al., 2002; Chen et al., 2007; Bloch and Manley, 2007).
The intravenous infusion of a hypertonic solution establishes an osmotic gradient
between the intravascular space and the extracellular volume of the brain. This gradient
provides a potent force to move water from the brain’s extra- and intracellular space into the
capillaries. In this way, the volume of the brain is reduced and thereby the ICP (Zornow,
1996).
There are other theories as to how the osmotherapeutics reduce ICP. There are several
variants of “haemodynamic” theories, all emphasizing the importance of dynamic changes in
cerebral blood volume (CBV) (Paczynski, 1997). Muizelaar et al. have reported, from a study
in cats, a rapid reduction in the diameter of arterioles and venules on the surface of the brain
immediately after an intravenous mannitol bolus of 1 g/kg given during 1 minute (Muizelaar
et al., 1983). Subsequently they reported how this effect on ICP was greater in patients with
intact autoregulation, than in patients without (Muizelaar et al., 1984). I must, however,
express methodological concerns regarding this last study as there seem to be repeated
measurements in some patients and inclusion of patients with ICP above the stated inclusion
criteria. The reduction in CBV was believed to be caused mainly by a vasoconstriction
induced by reduction in blood viscosity improving blood flow (Muizelaar et al., 1983). This
cerebral vasoconstriction has, however, been shown not to occur in other studies (Ravussin et
al., 1985; Auer and Haselsberger, 1987). Auer et al. gave mannitol during 15 minutes, which
is more in line with clinical practice than the one minute used by Muizelaar et al., and
Ravussin et al. found reduced ICP despite increased CBV.
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It seems reasonable to speculate that instant, haemodynamic changes may account for
some of the early (less than 15 minutes) effect seen on ICP after osmotherapy, whilst the
osmotic effect is slower in onset, gradually dehydrating the brain towards a peek effect at 15
to 30 minutes after administration of a hypertonic solution (Ziai et al., 2007).
History
The first description of osmotherapy applied to the central nervous system (CNS), is attributed
to Weed and McKibben in 1919 (Weed and McKibben, 1919a; Weed and McKibben, 1919b).
As research fellows in the Army Neurosurgical Laboratory at the Johns Hopkins Medical
School, they were attempting to measure the transport of sodium salts from the blood into the
CSF in cats. Upon intravenous injection of small volumes of 30% hypertonic saline (HS), they
measured a marked and sustained decrease in ICP (Weed and McKibben, 1919b). This they
found was due to shrinkage of the brain. They went on to describe how they through a
craniotomy defect could observe the brain shrink away after HS injection with maximum
effect 15 to 30 minutes after completion of the injection (Weed and McKibben, 1919a).
In 1927, intravenous delivery of osmotic agents for clinical practice was first
formalized by Fremont-Smith and Forbes (Fremont-Smith and Forbes, 1927). They first used
concentrated urea. 11 years later they were followed by Hughes et al. who demonstrated that
concentrated solutions of human plasma proteins could reduce raised ICP (Hughes et al.,
1938). The use of plasma proteins was however limited because of fear of allergic reactions
and high cost.
Wider attention was brought to the use of urea by Javid et al in the late 1950s (Javid
and Settlage, 1956; Javid, 1961). With its low molecular weight of 60 Daltons, slow
elimination from blood, and relatively slow BBB penetration (� = 0.48) (Qureshi and Suarez,
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2000), it was a potent osmotic agent. It had however a significant potential for rebound
cerebral oedema and side effects like phlebitis and haemolysis.
During early 1960s two other compounds replaced urea; mannitol and glycerol.
Glycerol, introduced in 1964 is a trivalent alchohol (1,2,3-propanetriol), partially metabolized
to CO2 and water (Cantore et al., 1964). With a reflection coefficient (�) of 0.59 (Qureshi and
Suarez, 2000), it has a significant potential for causing rebound cerebral oedema. Side effects
include haemolysis, haemoglobinuria, renal failure, and hyperosmolar coma (Bhardwaj,
2007). Possibly due to tradition, glycerol has been used quite frequently throughout Asia and
some centres in continental Europe, whereas mannitol has been the drug of choice in the UK
and the Americas (Paczynski, 1997). Mannitol has also been the preferred choice in the
Nordic countries. Only since late 80s has hypertonic saline, the compound that started it all,
gained renewed interest.
Mannitol
As mentioned previously, mannitol has been the osmotic agent of choice in clinical practice in
many countries for nearly five decades (Brain Trauma Foundation et al., 2007a). Mannitol has
a molecular weight of 182 Daltons, and is an alcohol derivate of the sugar mannose. As
opposed to urea, it has a short plasma half-life of 2 to 4 hours. The reflection coefficient (�) is
0.9 (Qureshi and Suarez, 2000), which is much better than those of urea and glycerol. It does,
however, leave the door open for rebound elevation of ICP upon repeated administrations.
This has been much debated during the last two decades, and has reduced its use at least for
repeated administrations (Garcia-Sola et al., 1991; Kaufmann and Cardoso, 1992; Kofke,
1993; Polderman et al., 2003). In a study by Rudehill et al. the level of mannitol in the CSF
increased after a single intravenous administration, and did not start to fall during the first
eight hours after administration (Rudehill et al., 1993). Other side effects are acute renal
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failure, particularly if serum osmolarity is > 320 mOsm/L combined with hypovolaemia
(Worthley et al., 1988; Bullock, 1995). Mannitol is also of course foremost a diuretic, and will
upon repeated administration lead to hypovolaemia if volume is not adequately substituted.
Hypertonic saline
After Velasco et al. in 1980 showed how bled dogs could be haemodynamically resuscitated
with 4 mL/kg of 7.0% saline (Velasco et al., 1980), HS was evaluated for rapid resuscitation
of patients with haemorrhagic shock during the 1980s and 90s. A small study by De Felippe Jr
et al. (de Felippe Jr et al., 1980) was followed by a series of large randomised studies
conducted in the pre-hospital setting (Holcroft et al., 1987; Vassar et al., 1991; Mattox et al.,
1991; Vassar et al., 1993a; Vassar et al., 1993b). In two of the studies by Vassar et al. (Vassar
et al., 1991; Vassar et al., 1993a), improved survival was reported after HS as compared to
isotonic resuscitation in patients suffering from traumatic brain injury (TBI); survival to
discharge being 32 versus 16% in the first study and 34 versus 12% in the second. This
boosted the wave of studies looking at HS and cerebral effects from the 1990s.
The reflection coefficient (�) across the BBB for NaCl is 1.0 (Rapoport, 1976;
Zornow, 1996; Qureshi and Suarez, 2000). In that respect, HS is an ideal osmotic agent. The
main effect on elevated ICP is due to the “dehydrating” effect on the brain (Qureshi and
Suarez, 2000; Ziai et al., 2007). The “dehydrating” effect of hypertonic saline (HS) has been
shown both in animal studies (Todd et al., 1985; Zornow et al., 1989; Bacher et al., 1998;
Toung et al., 2007; Chen et al., 2007) and in a MRI-study in humans (Saltarini et al., 2002).
Theoretically most of the effect would be found in uninjured parts of the brain. This is
supported by most studies (Zornow et al., 1989; Battistella and Wisner, 1991; Shackford et
al., 1992). Normal brain tissue is “dehydrated” to accommodate the increase in intracranial
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volume that results from oedema or haemorrhage. The effect in parts of the brain with injured
BBB is more unpredictable (Chen et al., 2007).
Cerebrovascular endothelial cells and red blood cells are also dehydrated, improving
CBF and oxygen delivery due to increased vessel diameter and reduced size of the blood cells
(Mazzoni et al., 1990; Shackford et al., 1992; Doyle et al., 2001). And like mannitol, HS
lowers blood viscosity which may induce vasoconstriction with reduced CBV (Burke et al.,
1981; Muizelaar et al., 1983).
Another advantage of HS is that it does not have the potentially detrimental diuretic
effect like mannitol, which may lead to hypovolaemia and impaired cerebral perfusion (Arai
et al., 1986; Worthley et al., 1988).
There are a number of additional effects attributed to HS that deserve a brief
mentioning even though most of the documentation is based on animal studies and has to date
uncertain clinical implication. HS may have positive neurochemical effects, as HS solutions
restore normal membrane resting potential by normalizing intracellular concentrations of
sodium and chloride (Nakayama et al., 1985). HS may also have positive immunomodulatory
effects on the inflammatory process generated by brain trauma, reducing leukocyte adherence
and migration to injured parts of the brain (Hartl et al., 1997b). Several animal studies indicate
a protective effect against bacterial infections (Coimbra et al., 1997; Shields et al., 2003; Chen
et al., 2006), but very limited conclusions can be drawn as to the effect in humans (Kolsen-
Petersen, 2004).
The saline concentration in the solutions that have been investigated ranges from 1.4 to
29.2%, and both solutions with and without the addition of a colloid have been used (Tables
1-2, page 21)(Table 3, page 23). The addition of a colloid, typically 6% dextrane or
hydroxyethyl starch, has in haemodynamic resuscitation studies prolonged the haemodynamic
effect compared with HS alone (Smith et al., 1985; Kramer et al., 1986; Velasco et al., 1989).
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For the attenuating effect on raised ICP, the addition of a colloid has not altered the effect
compared with HS alone (Vassar et al., 1993a). Other studies have shown that intravenous
infusion of 6% dextrane or hydroxyethyl starch solutions without HS do not reduce ICP
(Gunnar et al., 1986; Ducey et al., 1989). This fits well with what can be expected from
theoretical considerations based on the different properties of the BBB and capillaries
elsewhere in the body.
Animal studies
Todd et al. were among the first to re-examine the cerebral effects of hypertonic saline
solutions (Todd et al., 1985). They demonstrated in rabbits a decrease in brain water content,
a decrease in ICP, and an increase in cerebral blood flow (CBF) following infusion of
hypertonic Ringers’s solution (osmolality of 480 mOsm/kg). A number of animal studies
followed. Studies looking at the effect of HS on ICP, CBF, or cerebral oxygen delivery
(CDO2) are listed in Tables 1 and 2 (page 21).
Although there are indications of possible problems with rebound increase in ICP in
the material from Prough et al. from 1999 (Prough et al., 1999), the overall picture is that of
reliable reduction in ICP and improvement in CBF. The later findings by German groups of a
possible neuroprotective effect of HS is also encouraging (Heimann et al., 2003; Zausinger et
al., 2004; Bermueller et al., 2006). These findings are supported by other studies not looking
at effect on ICP (Hamaguchi and Ogata, 1995; Hamaguchi et al., 2002; Thomale et al., 2004).
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Table 1. Animal studies investigating cerebral effects of HS without cerebral trauma.
↓ ICP, ↑ CBF, ↑ CDO21,5% SL, RLSSPigSchmoker et al., 1991
↓ ICP, ↓ ICE6%S,6%HE,NS,WBSSPigDucey et al., 1989
↓ ICP after HS, ↓ CBF and CDO2both groups
7.5% S, RLSSDogPrough et al., 1986
� ICP after HS, ↑ICP after NS, D40
3%S, NS, 6%DSSDogGunnar et al., 1986
↓ ICP, � CBF and CDO27.5% S, RLSSDogPrough et al., 1985
↓ ICP, ↑CBF, cerebral dehydration1.6% S, NSNoneRabbitTodd et al., 1985
Results after HSStudy solutionsInjuryAnimal
↓ ICP, ↑ CBF, ↑ CDO21,5% SL, RLSSPigSchmoker et al., 1991
↓ ICP, ↓ ICE6%S,6%HE,NS,WBSSPigDucey et al., 1989
↓ ICP after HS, ↓ CBF and CDO2both groups
7.5% S, RLSSDogPrough et al., 1986
� ICP after HS, ↑ICP after NS, D40
3%S, NS, 6%DSSDogGunnar et al., 1986
↓ ICP, � CBF and CDO27.5% S, RLSSDogPrough et al., 1985
↓ ICP, ↑CBF, cerebral dehydration1.6% S, NSNoneRabbitTodd et al., 1985
Results after HSStudy solutionsInjuryAnimal
↓, decreased; ↑, increased; �, unchanged; SS, sirculatory shock induced by bleeding; HS, hypertonic saline; S, saline; NS, 0.9% saline, RL, lactated Ringers; SL, sodium lactate; D, Dextrane 40; HE, hetastarch; WB, whole blood; ICP, intracranial pressure; CBF, cerebral blood flow, CDO2, cerebral oxygen delivery; ICE, intracranial elastance
Table 2. Animal studies investigating cerebral effects of HS with cerebral trauma.
↓ICP, HSD also ↓morphological damage
HSD, 7,2%S/HES, M, NS
SAHRatBermueller et al., 2006
↓ICP, HSD also ↑ neurological recovery
HSD, 7.5%S, NSSAHRatZausinger et al., 2004
�CBF, ↓infarct size7.5%S/10%HES, 10%HES, NS
VORatHeimann et al., 2003
↓ICP, rebound ↑ ICP7.2%S, 7,2%S/20%HES, 20%HES, 0.8%S
SS, SBDogPrough et al., 1999
↓ICP, BWC equal7.5%S, RLH, CryoSheepAnderson et al., 1997
↓ICP, ↑ ScO27.5%S, RLSS, CryoPigletTaylor et al., 1996
↓ CDO2 for both3%S, 10%HEH, PFICatDeWitt et al., 1996
↓ICP, ↑ CBF, ↑ CDO2, ↓contralat BWC
1.5%SL, RLCryoPigShackford et al., 1992
↓ ICP, ↑ CBF7.2% S, 0.8% SSS, SBDogPrough et al., 1991
↓ ICP, ↑ CBFHSD, RLSS, CryoPigWalsh et al., 1991
↓ ICP, ↓ contralat BWC7.5%S, RLHT, CryoSheepBattistella and Wisner, 1991
Less ↑ ICP, ↓ contralat BWC1.4%RLHD, CryoRabbitZornow et al., 1989
↓ ICP, ↓BWC3%S, NS, 10%DSS, EBDogGunnar et al., 1988
Results after HSStudy solutionsInjuryAnimal
↓ICP, HSD also ↓morphological damage
HSD, 7,2%S/HES, M, NS
SAHRatBermueller et al., 2006
↓ICP, HSD also ↑ neurological recovery
HSD, 7.5%S, NSSAHRatZausinger et al., 2004
�CBF, ↓infarct size7.5%S/10%HES, 10%HES, NS
VORatHeimann et al., 2003
↓ICP, rebound ↑ ICP7.2%S, 7,2%S/20%HES, 20%HES, 0.8%S
SS, SBDogPrough et al., 1999
↓ICP, BWC equal7.5%S, RLH, CryoSheepAnderson et al., 1997
↓ICP, ↑ ScO27.5%S, RLSS, CryoPigletTaylor et al., 1996
↓ CDO2 for both3%S, 10%HEH, PFICatDeWitt et al., 1996
↓ICP, ↑ CBF, ↑ CDO2, ↓contralat BWC
1.5%SL, RLCryoPigShackford et al., 1992
↓ ICP, ↑ CBF7.2% S, 0.8% SSS, SBDogPrough et al., 1991
↓ ICP, ↑ CBFHSD, RLSS, CryoPigWalsh et al., 1991
↓ ICP, ↓ contralat BWC7.5%S, RLHT, CryoSheepBattistella and Wisner, 1991
Less ↑ ICP, ↓ contralat BWC1.4%RLHD, CryoRabbitZornow et al., 1989
↓ ICP, ↓BWC3%S, NS, 10%DSS, EBDogGunnar et al., 1988
Results after HSStudy solutionsInjuryAnimal
↓, decreased; ↑, increased; �, unchanged; SS, circulatory shock induced by bleeding; H, moderate haemorrhage; HD, hemodilusion; HT, hypotension; EB, epidural balloon; SB subdural balloon; Cryo, cryogenic lesion; PFI, fluid-percussion injury; VO, occlusion of cortical veins; SAH, subarachnoid haemorrhage; HS, hypertonic saline; S, saline; NS, 0.9% saline, RL, lactated Ringer; SL, sodium lactate; D, Dextrane 40; HSD, 7.5%S in 6%D;HE, hetastarch; HES, hydroxyethyl starch; M, 20% mannitol; ICP, intracranial pressure; CBF, cerebral blood flow, CDO2, cerebral oxygen delivery; BWC, brain water content ; ScO2, cerebrovascular oxygen saturation
22
Human studies
Several human studies have been performed looking at the effect of HS on ICP (Table
3, page 23). Most of these were published prior to the publication of the studies included in
this thesis, but also a handful during the time during completion of this thesis. I have included
all of these in Table 3 (page 23) for completeness.
The main finding in these reports is that of a reliable reduction in ICP after HS
administration. In studies comparing HS to mannitol, HS is either equal or superior to
mannitol. The magnitude of the maximum effect is described, but information about the time
course of the effect is most often lacking. When is maximum effect reached? How long does
the effect last, and is there rebound in patients with damaged BBB?
Only two retrospective studies from Baltimore report negative effects. Increased in-
hospital mortality was found in one study (Qureshi et al., 1999) and loss of effect on ICP after
3 – 4 days in another (Qureshi et al., 1998). Both these studies applied continuous infusion of
3% sodium chloride / sodium acetate during several days. The indication for HS was cerebral
oedema with or without intracranial hypertension. Mean ICP before initiation of HS was < 20
mmHg in these studies and infusion was continued regardless of ICP. There was also a greater
incidence of penetrating injury in the HS group in the study from 1999. My interpretation of
these studies is that without signs of intracranial hypertension or decreased intracranial
compliance, there is no clear indication for continuous infusion of HS.
Many of the studies are conducted with mixed patient populations, although there is a
majority of TBI patients. All together there are only ten SAH patients included in the
prospective studies. The effect of HS on ICP may very well differ between patient groups.
Patients with localized BBB disruption will most probably respond much better to
osmotherapy than those with generalized BBB disruption.
23
Table 3. Studies exploring the effect of hypertonic saline on ICP in humans.
Reversal of TTH in 75% of cases,�ICP
30-60 mL 23.4% S(bolus)
68(76)
Retrospective, cohort
8stroke, 29ICH, 16 SAH, 8 BT, 7other;TTH
Koenig et al.,2008
�ICP, �CPP, �PI300 mL 3% S, (daily bolus, 20 min. if ↑ ICP)
18(38)
Prospective, observational
TBI; ICP > 20mmHg
Huang et al., 2006
↓ ICP, equal reduction, but longer duration
23,4% S vs M (bolus, S after M)
13RetrospectiveTBI; ↑ICP resistant to conv. therapy
Ware et al., 2005
↓ICP, mean 57% vs 48% from baseline
HSH vs 15% M (1.4 vs 1.8mL/kg)
32Prospective, randomized
10TBI, 9SAH, 7CI, 4ICH, 2other; ICP > 20mmHg
Harutjunyan et al., 2005
↓ ICP, greater reduction and longer duration
100ml HSD vs. 200ml 20% M(bolus, 5 min.)
9Prospective, randomized,cross-over
TBI; ICP > 20mmHg
Battison et al., 2005
Less time with ↑ ICP, less clinical failure
7.5% S vs. 20% M 2 ml/kg
20Prospective, randomized
TBI; ↑ICP resistant to conv. Therapy
Vialet et al., 2003
↓ ICP, � CVP. M: ↓CVP
3% S vs. M(boluses, 3 days)
30Prospective, randomized
BT; surgeryDe Vivo et al., 2001
↓ ICP, no adverse effects, 3 dead due to ↑ ICP
3% S (cont. infusion)
68RetrospectiveTBI, childrenPeterson et al., 2000
↓ ICP, no adverse effects, peak serum sodium 157-187 mEq/L
3% S (cont. infusion 4 -18 days)
10Prospective, observational
TBI, children; ↑ICP resistant to conv. therapy
Khanna et al., 2000
↓ ICP, mean ~30% from baseline, ↑CPP, ↑ CO
1.5 mL/kg, 7,2%S (bolus, 15 min.)
14Prospective, observational
TBI; GCS < 13, ICP >15mmHg
Munar et al., 2000
↑ in-hospital mortality3% S vs. NS(infusjon)
36 46c
Retrospective case-control
TBIQureshi et al., 1999
↓ICP, mean 42% from baseline, mean duration 3 hours
2 mL/kg 7.5% S (bolus)
10(48)
Prospective, observational
6TBI, 4SAH; ↑ICP resistant to conv. therapy
Horn et al., 1999
Improved haemodynamics, no adverse effects
3% S (cont. infusion)
29RetrospectiveSAH with vasospasm and hyponatremia
Suarez et al., 1999
↓ ICP, ↓ventilator time, ↓RDS, ↑survivale
1,7% S vs. RL(cont. infusion)
32Prospective, randomized
TBI, childrenSimma et al., 1998
↓ICP, mean 62% from baseline, mean duration several hours.
30 mL 23,4%S (bolus)
8(20)
Retrospective5SAH, 3 other; ↑ICP resistant to conv. therapy
Suarez et al., 1998
↓ICP, mean 43% from baseline, mean duration 101min.
100mL 10% S(bolus, 5 min.)
6(42)
Prospective, observational
5TBI, 1SAH; ↑ICP, ↓CPP, no effect of M, THAM, Sorbitol
Schatzmann et al., 1998
mean ΔICP: HSH: -11 mmHg, M: -6 mmHg
100mL HSH, vs. 200mL, 20% M (bolus, 15 min.)
9(30)
Prospective, randomized,cross-over
Stroke; ↑ICP >25 mmHg or pupil dilatation
Schwarz et al., 1998
↓ ICP, ↓ oedema, rebound after 3-4 days
3%S(cont. infusion)
27(30)
Retrospective8TBI, 4BT, 1SAH, 8ICH, 6CI
Qureshi et al., 1998
Equally safe, HS group more severely ill
1.6%S vs. RL34Prospective, randomized
TBI – resuscitationShackford et al., 1998
↓ ICP, ↑ CPP, 5 survivedHSH (bolus)
6 (32)
Prospective, observational
TBI; ↑ICP resistant to conv. therapy
Hartl et al., 1997a
Immediate ↓ ICP 7.5% S (bolus)
1Case reportTBI; ↑ICP resistant to conv. therapy
Einhaus et al., 1996
↓ ICP 3% vs. 0.9%S (10mL/kg bolus)
18Prospective, rando-mized, cross-over
TBI, childrenFisher et al., 1992
Immediate ↓ ICP29.2% S (bolus)
2Case-seriesTBI; ↑ICP resistant to conv. therapy
Worthley et al., 1988
Results after HSStudy solutionsNStudy designPatient population
Reversal of TTH in 75% of cases,�ICP
30-60 mL 23.4% S(bolus)
68(76)
Retrospective, cohort
8stroke, 29ICH, 16 SAH, 8 BT, 7other;TTH
Koenig et al.,2008
�ICP, �CPP, �PI300 mL 3% S, (daily bolus, 20 min. if ↑ ICP)
18(38)
Prospective, observational
TBI; ICP > 20mmHg
Huang et al., 2006
↓ ICP, equal reduction, but longer duration
23,4% S vs M (bolus, S after M)
13RetrospectiveTBI; ↑ICP resistant to conv. therapy
Ware et al., 2005
↓ICP, mean 57% vs 48% from baseline
HSH vs 15% M (1.4 vs 1.8mL/kg)
32Prospective, randomized
10TBI, 9SAH, 7CI, 4ICH, 2other; ICP > 20mmHg
Harutjunyan et al., 2005
↓ ICP, greater reduction and longer duration
100ml HSD vs. 200ml 20% M(bolus, 5 min.)
9Prospective, randomized,cross-over
TBI; ICP > 20mmHg
Battison et al., 2005
Less time with ↑ ICP, less clinical failure
7.5% S vs. 20% M 2 ml/kg
20Prospective, randomized
TBI; ↑ICP resistant to conv. Therapy
Vialet et al., 2003
↓ ICP, � CVP. M: ↓CVP
3% S vs. M(boluses, 3 days)
30Prospective, randomized
BT; surgeryDe Vivo et al., 2001
↓ ICP, no adverse effects, 3 dead due to ↑ ICP
3% S (cont. infusion)
68RetrospectiveTBI, childrenPeterson et al., 2000
↓ ICP, no adverse effects, peak serum sodium 157-187 mEq/L
3% S (cont. infusion 4 -18 days)
10Prospective, observational
TBI, children; ↑ICP resistant to conv. therapy
Khanna et al., 2000
↓ ICP, mean ~30% from baseline, ↑CPP, ↑ CO
1.5 mL/kg, 7,2%S (bolus, 15 min.)
14Prospective, observational
TBI; GCS < 13, ICP >15mmHg
Munar et al., 2000
↑ in-hospital mortality3% S vs. NS(infusjon)
36 46c
Retrospective case-control
TBIQureshi et al., 1999
↓ICP, mean 42% from baseline, mean duration 3 hours
2 mL/kg 7.5% S (bolus)
10(48)
Prospective, observational
6TBI, 4SAH; ↑ICP resistant to conv. therapy
Horn et al., 1999
Improved haemodynamics, no adverse effects
3% S (cont. infusion)
29RetrospectiveSAH with vasospasm and hyponatremia
Suarez et al., 1999
↓ ICP, ↓ventilator time, ↓RDS, ↑survivale
1,7% S vs. RL(cont. infusion)
32Prospective, randomized
TBI, childrenSimma et al., 1998
↓ICP, mean 62% from baseline, mean duration several hours.
30 mL 23,4%S (bolus)
8(20)
Retrospective5SAH, 3 other; ↑ICP resistant to conv. therapy
Suarez et al., 1998
↓ICP, mean 43% from baseline, mean duration 101min.
100mL 10% S(bolus, 5 min.)
6(42)
Prospective, observational
5TBI, 1SAH; ↑ICP, ↓CPP, no effect of M, THAM, Sorbitol
Schatzmann et al., 1998
mean ΔICP: HSH: -11 mmHg, M: -6 mmHg
100mL HSH, vs. 200mL, 20% M (bolus, 15 min.)
9(30)
Prospective, randomized,cross-over
Stroke; ↑ICP >25 mmHg or pupil dilatation
Schwarz et al., 1998
↓ ICP, ↓ oedema, rebound after 3-4 days
3%S(cont. infusion)
27(30)
Retrospective8TBI, 4BT, 1SAH, 8ICH, 6CI
Qureshi et al., 1998
Equally safe, HS group more severely ill
1.6%S vs. RL34Prospective, randomized
TBI – resuscitationShackford et al., 1998
↓ ICP, ↑ CPP, 5 survivedHSH (bolus)
6 (32)
Prospective, observational
TBI; ↑ICP resistant to conv. therapy
Hartl et al., 1997a
Immediate ↓ ICP 7.5% S (bolus)
1Case reportTBI; ↑ICP resistant to conv. therapy
Einhaus et al., 1996
↓ ICP 3% vs. 0.9%S (10mL/kg bolus)
18Prospective, rando-mized, cross-over
TBI, childrenFisher et al., 1992
Immediate ↓ ICP29.2% S (bolus)
2Case-seriesTBI; ↑ICP resistant to conv. therapy
Worthley et al., 1988
Results after HSStudy solutionsNStudy designPatient population
↓, decreased; ↑, increased; �, unchanged; N, number of patients (interventions); ICP, intracranial pressure; CPP, cerebral perfusion pressure; PI, cerebrovascular pulsatility index; BO, brain oedema; TBI, traumatic brain injury; SAH, subarachnoid haemorrhage; PO, postoperative; BT, brain tumour; ICH, non-traumatic intracerebral haemorrhage; CI, cerebral infarction; TTH, transtentorial herniation; GCS, Glasgow coma score; CO, cardiac output; HS, hypertonic saline; S, saline; NS, 0.9% saline; HES, hydroxyethyl starch; RL, lactated Ringer; HSH, 7.2-7.5% HS in 6% HES; HSD, 7.5%S in 6%Dextran; M, mannitol; RDS, respiratory distress syndrome
24
Intracranial pressure monitoring
Mean ICP
Current state-of-art technology computes mean ICP during short time windows (e.g. 5 – 15 s
duration). ICP can be measured by a number of different techniques, unfortunately all
invasive. This means that measuring ICP must be weighed against the risks of infection and
haemorrhage (Ghajar, 1995). The measurement of ICP via an intraventricular catheter, is
internationally considered “the gold standard” (Guillaume and Janny, 1951; Lundberg, 1960;
Czosnyka and Pickard, 2004; Steiner and Andrews, 2006). The advantages of this technique
are the possibility of CSF drainage and the possibility to perform re-zeroing of the system, i.e.
re-calibration towards atmospheric pressure. This technique requires, however, meticulous
attention to adjustments of the zero level as the patient’s position is changed, and the
monitoring is of course lost if the drain is clotted. The alternative technique is the use of a
miniature, solid, intraparenchymal sensor. These allow continuous pressure monitoring at the
same time as CSF can be drained through a ventricular catheter. The main disadvantage of
most of the available systems is that they can not be re-calibrated once inserted, and that the
zero pressure level may drift (Morgalla et al., 2001; Piper et al., 2001). Other techniques like
subarachnoid or epidural probes, lumbar CSF pressure, tympanic membrane displacement, or
transcranial Doppler, have not shown sufficient reliability for clinical use (Steiner and
Andrews, 2006).
There are other problems with the measurement of mean ICP in addition to the
technical aspects. We see in clinical practice how mean ICP changes abruptly when the
patient’s position is changed. If an intraparenchymal probe is inserted on the right side, and
the patients head is turned from resting on the left side to the right side, measured mean ICP
might increase as much as 10 mmHg. Looking at trend plots of mean ICP, we regularly see
25
these different ICP levels directly relating to patient position. This can be explained by the
simple fact that mean ICP is influenced by the weight of the brain above the point of
measurement. Eide demonstrated in a small study how mean ICP measurements recorded
simultaneously from two different intraparynchamal sensors differed considerably (Eide,
2006b). A difference of above 5 mmHg was recorded 13% of the time and above 10 mmHg
6% of the time. He describes how one sensor showed mean ICP > 20 mmHg while the other
showed < 15 mmHg. Such a difference might have direct implications on patient treatment, no
matter what the cause of the difference is.
Another problem is deciding on what level of mean ICP should bring about an
intervention to decrease ICP. What is a normal ICP? In young healthy volunteers lying down,
average mean ICP was 11 mmHg (range 7 to 15 mmHg) (Albeck et al., 1991). In the upright
position mean ICP was found to be in the range of -5 to +5 mmHg (Chapman et al., 1990).
Starting measurements from the supine position, the decrease to this level was found to occur
when elevating the head to about 45°, not changing much thereafter. In evaluating different
mean ICP levels to outcome, one should therefore pay close attention to the degree of head
elevation in order to be able to compare results.
Although there is no definite agreement on the threshold for treatment, the guidelines
from the Brain Trauma Foundation recommend treatment of mean ICP > 20 – 25 mmHg in
traumatic brain injury (TBI) patients (Brain Trauma Foundation et al., 2007b). The decision in
an individual patient is of course taken looking at ICP together with other variables like CPP,
transcranial Doppler, clinical status, and radiological findings. It is not within the scope of this
thesis to go into all these considerations, but at this point only to emphasise the need for
further research that can improve the predictive power of our intracranial pressure
measurements.
26
ICP waveform analysis
One path that might prove worth while is looking at the intracranial pressure wave and
intracranial compliance. Intracranial compliance relates to the changes in ICP subsequent to
changes in intracranial volume at different pressure levels. When ICP is low and compliance
is high, a small increase in volume only causes a small increase in pressure. If, however, the
pressure is high and the compliance is low, this same increase in volume yields a far greater
increase in pressure. It has been shown that this intracranial pressure-volume relationship is
better described by a pulsatile than a static ICP (Avezaat et al., 1979; Gonzalez-Darder and
Barcia-Salorio, 1989).
A method for direct monitoring of brain compliance has been implemented in the
Spiegelberg Brain Compliance monitor. This method relies on the evaluation of the pressure
response to known small volume additions by inflating and deflating a balloon inserted within
the cerebrospinal space. Initial trials indicate its usefulness, but implication for outcome
remains to be demonstrated (Piper et al., 1999; Yau et al., 2002).
A lot of work has been done by a group in Cambridge, UK, looking at waveform
analysis of ICP (pulsatile ICP) (Czosnyka and Pickard, 2004). The ICP waveform consists of
several components, but it is especially the amplitude of the component with a frequency
equal to the heart rate that has gained most focus, the intracranial pulse pressure or ICP
amplitude. The Cambridge group has described two ICP derived indexes (Czosnyka and
Pickard, 2004). The first is called RAP (correlation coefficient (R) between AMP amplitude
(A) and mean pressure (P); index of compensatory reserve). When RAP is close to +1, the
amplitude varies directly with ICP, indicating a low intracranial compensatory reserve. The
second index is a pressure-reactivity index called PRx. A positive index is correlated with
poor autoregulation. Abnormal values have been demonstrated to predict poor outcome after
head injury (Steiner et al., 2002).
27
The magnitude of “slow ICP waves” (frequency ½ - 3 per minute) has also been
shown to correlate with outcome, a greater magnitude indicating favourable outcome
(Lundberg, 1960; Balestreri et al., 2004).
My curiosity about waveform analysis and its possible use in clinical practice was
awakened by the work performed at our institution by Eide and co-workers. He has developed
at method of actually continuously measuring the heartbeat to heartbeat intracranial pulse
pressure and displaying this in real time at the bed side (Eide, 2006a). Previously, information
about single ICP waves has been derived from spectral analysis using fast Fourier
transformation (FFT) (Christensen and Borgesen, 1989). FFT does, however, not include an
algorithm for identification of the single ICP waves. The intracranial pulse pressure recorded
using the new method is called “mean ICP wave amplitude”, and it was found to relate
significantly to both the acute clinical state (Glasgow Coma Score, GCS) and the final clinical
outcome (Glasgow Outcome Score, GOS) in SAH patients. This relationship could in that
study not be demonstrated for mean ICP and mean CPP (Eide and Sorteberg, 2006).
Moreover, a case report showed how a long-standing bad clinical state of a SAH patient was
rapidly changed by turning management from being guided by static ICP (mean ICP) to being
pulsatility (or waveform) guided according to the mean ICP wave amplitude (Eide et al.,
2007c). It was also reported how a reduction in intracranial pulsatility could be achieved by
increased drainage of cerebro-spinal fluid (CSF) via an external ventricular drain (EVD) (Eide
et al., 2007c). Given the positive indications that mean ICP wave amplitude could predict
outcome, I found it important to investigate whether a medical intervention with HS could
decrease mean ICP wave amplitude. An additional incentive for contributing research results
regarding this new variable is all the technical and practical difficulties related to mean ICP
that I have mentioned earlier.
28
AIMS OF THE THESIS
1. Describe the effects of bolus infusion of 7.2% (72 mg/mL) saline in 6% (60 mg/mL)
hydroxyethyl starch 200/0.5 solution (HSS) on the intracranial pressure (ICP)
variables, mean ICP and mean ICP wave amplitude, and cerebral perfusion pressure
(CPP) in patients with subarachnoid haemorrhage (SAH).
2. Describe the time course of these effects, including time to maximum effect.
3. Describe the magnitude of these effects.
4. Describe the changes in serum sodium concentration, and how serum sodium is related
to ICP during the study period.
5. Describe haemodynamic effects.
6. Describe how mean ICP and mean ICP wave amplitude are related.
7. Compare the effect of HSS on mean ICP with the effect on mean ICP wave amplitude
(intracranial pulse pressure).
8. Compare the effect on intracranial pulse pressure with the effect on systemic arterial
pulse pressure.
29
METHODS All data in the three studies have been collected from patients suffering from acute, non-
traumatic subarachnoid haemorrhage (SAH) admitted to the Intensive Care Unit at
Rikshospitalet University Hospital.
All patients included were unconscious due to the nature of their disease and could not
give their informed consent to participation. Possible risks and benefits were therefore given
thorough evaluation. The protocols were approved by the Regional Ethics Committee for
Medical Research and the Norwegian Medicines Agency. Close relatives were given oral and
written information in accordance with the terms for approval by the Ethics Committee.
Study design
A common denominator of the studies was the effort taken to ensure as laboratory-like
conditions as possible, given a clinical setting. The first measure to achieve this was of course
to only include SAH patients, the second measure was to only include patients which were
relatively stable before intervention, and the third was to make sure that nothing was done
with the patient during the study period unless dictated by the rescue treatment protocol.
In both Study I and II we looked at effects of HSS on mean ICP, CPP, and
haemodynamics during a 210 minutes study period. In Study I relevant patients with mean
ICP > 20 mmHg were included. This being an observational study, Study II was given a
randomised, single-blinded, placebo-controlled design including patients with mean ICP < 20
mmHg. Judged together, these two studies would then give sound evidence of an effect (Study
II), magnitude of effect (Study I), and time course of the effect (Study I and II). Study III
utilized data collected in a still ongoing prospective study looking at different ICP variables
and their association to outcome. Instances where known doses of HSS were administered at
30
known times were selected from a large database of pressure recordings, and before and after
values were analysed.
All data were recorded prospectively. In Study I and II they were analysed according
to the predetermined plan drawn up in the protocols. In Study III, the data were prospectively
collected as part of a different study still ongoing. The protocol for Study III was designed
after data collection had started.
Data collection
Intracranial pressure was measured via a solid ICP sensor (Codman MicroSensor™, Codman,
Raynham, MA) coupled to a Codman® pressure transducer (Codman ICP Express™,
Codman, Raynham, MA). For the continuous arterial blood pressure (ABP) monitoring, an
arterial cannula was placed in a radial or femoral artery and connected to a Baxter fluid sensor
(Baxter, Deerfield, IL). Arterial blood pressure was zeroed at the level of the heart. Both
signals together with heart rate (HR), central venous pressure (CVP), and peripheral oxygen
saturation (SpO2) were coupled to a vital signs Siemens 9000XL Series Monitor (Siemens
AG, Munich, Germany). Cardiac index (CI), intrathoracic blood volume index (ITBI), and
extravascular lung water index (ELWI) were measured by use of the PiCCO system (Pulsion
Medical Systems, Munich, Germany). Arterial blood gases, pH, haemoglobin, and sodium
were analysed with the ABL 725 (Radiometer, Denmark).
In study I and II, values from the Siemens monitor and the PiCCO system were
registered electronically on a bed side computer every 30 seconds (LabView, National
Instruments, Austin, TX). False blood pressure values due to blood sampling were removed
manually before analysis.
In Study III a different setup for electronic data harvest was used. By means of the
Siemens Infinity Gateway Software, the continuous ICP and ABP signals were transferred on
31
line via the hospital network to a computer server and stored as raw data files with sampling
rates of 100 Hz. These data were analysed retrospectively using an algorithm implemented in
the software SM NeuroWave Version 2.0 (Eide, 2006a). Information on the time and amount
of hypertonic saline administered was collected from the patient charts.
Statistical methods
All patients included in the studies were reported according to the principle of intention-to-
treat. Study I and II are very similar in design. Repeated measurements of continuous data
were collected from different individuals. While Study I was an observational study of ten
interventions in seven patients, Study II was a placebo-controlled comparison of two groups,
total 22 patients. Mean values of measured variables for each patient from a 5 min period just
prior to infusion of study drug served as baseline. For data acquired electronically every 30
seconds, the mean value of all 5 minute periods throughout the 210 minute study period were
calculated and used for analysis.
In Study I comparisons of values at the time of maximum effect and at the end of the
study were compared with baseline values applying Wilcoxon’s test for paired samples. Even
though the changes were highly significant, we chose to display the graphs of mean ICP and
CPP for the ten individual cases. Since the number of cases was so low, we found this to be
the best way to convey the results truthfully to the reader.
In Study II baseline values were also calculated as the mean of a 5-minute period prior
to infusion of HSS, and mean values for each 5-minute interval throughout the study period
were used for analysis like in Study I. Differences between the groups were assessed by un-
paired Student’s t-test with Welch correction when there were unequal variance. For analysis
of demographic data, Mann-Whitney and chi-square tests were also used. The number of
patients was equal to the number of cases. In this study we did not only compare maximum
32
effect to baseline levels, we calculated the area under the curve for the different variables and
standardized by the length of the study to get the mean change for the whole period. This is a
recommended approach to statistical analysis of serial measurements (Matthews et al., 1990).
In Study III we had a total of 52 registrations from 20 patients, ranging from one to six
per patient. Due to possible bias because of repeated measurements, only the first registration
in each patient was included in the main results. This is in accordance with the statistical
recommendations that the sampling unit, or the “unit of analysis”, must be the patient in
studies like this one (Altman and Bland, 1997). We did however include information also
about calculations based on the total material of 52 registrations. A paired t-test was applied
comparing values before and after intervention for each variable, correlation was calculated
according to Pearson, and standard linear and multiple regression analyses were applied. P-
values <0.05/number of comparisons (Bonferroni correction) were considered significant.
33
SYNOPSIS OF RESULTS
Paper I
This study was designed to document the short term effects of 7.2% (72 mg/mL) saline in 6%
(60 mg/mL) hydroxyethyl starch 200/0.5 solution (HyperHAES®) (HSS) on intracranial
hypertension after subarachnoid haemorrhage (SAH). Primary outcome variables were
changes in mean intracranial pressure (ICP), changes in cerebral perfusion pressure (CPP),
and number of treatment failures, here defined as not reaching mean ICP < 20 mmHg and
CPP > 60 mmHg during the study period. Secondary outcome variables were changes in
cardiac index (CI), intrathoracic blood volume index (ITBI), and extravascular lung water
index (ELWI).
Ten interventions in seven patients were included. All patients suffered from
spontaneous SAH, their source of bleeding had been secured, and they had raised mean ICP >
20 mmHg. A bolus of 2 mL/kg of HSS was infused during 20 minutes, and registrations
continued for a total of 210 minutes. A laboratory like setting was pursued.
All interventions resulted in decreased mean ICP < 20 mmHg and elevation of CPP >
60 mmHg, i.e. zero treatment failures. The mean value for maximum mean ICP decrease in
percent of baseline was 58%, a mean decrease of 14.3 mmHg from a baseline of 25 mmHg.
Maximum effect was reached at 40 minutes after start of infusion. The mean peak increase in
CPP was 26%. In the eight cases recorded for 210 minutes, the mean ICP was still 35% below
baseline values at the end of the study. The time course of changes in ICP and CPP is
displayed in Figure 1B (page 38). We could also demonstrate an inverse relationship between
mean ICP and serum sodium levels. The maximum mean serum sodium increase was 6.6
mmol/L. There were no statistically significant changes to the secondary outcome variables
(measured in only five cases), only a trend towards increase in CI (p = 0.06) and ITBI (p =
0.06).
34
We concluded that the infusion of 2 mL/kg of HSS had a predictable and clinically
significant beneficial effect on mean ICP and CPP.
Paper II
Study I being an observational study, this study was designed to strengthen those results. A
group given 2 mL/kg of HSS was compared with a placebo group receiving 2 mL/kg of
normal saline (NS). In order to do that, the inclusion criterion as to intracranial pressure was
mean ICP between 10 and 20 mmHg. The design apart from this was very similar to Study I
with almost the same outcome variables. Changes in mean ICP and CPP were however
primarily analysed as the changes in mean values for the entire study period, not only
maximum change and change at the end of the study period.
In the placebo-group, there were no changes in any variables indicating that the study
design was valid. In the HSS group we found a significant reduction in mean ICP and increase
in CPP. Mean difference between the groups (HSS – NS) in average �ICP was -3.0 mmHg
and �CPP was 5.4 mmHg. Mean maximal change in mean ICP was -5.6 mmHg in the HSS
group. No rebound increase in ICP was found during the study period. The temporal change
was very similar to the one found in Study I (Figure 2, page 42). In addition, we demonstrated
a significant increase in cardiac output in the HSS group. The changes in serum sodium found
in the HSS group was quite similar to the findings in Study I, mean maximum increase of 5.6
mmol/L measured at 30 minutes, and a level 3.3 mmol/L above baseline at the end of the
study.
We concluded that HSS reduce mean ICP and increase CPP in SAH patients, and that
positive haemodynamic effects can be found. Judged together with Study I we concluded that
HSS attenuates increased mean ICP in SAH patients with a maximum effect reached at 20-30
35
minutes after the completition of the infusion. The magnitude of the effect would be expected
to be in the range demonstrated in Study I.
Paper III
In this study we compared the effect of HSS on mean ICP with the effect on mean ICP wave
amplitude in SAH patients. Mean ICP wave amplitude is the intracranial pulse pressure
recorded according to the algorithm developed by Eide; each cardiac beat-induced single
pressure wave is automatically identified, and the pressure variables are calculated for
consecutive 6-second time windows (Eide, 2006a). We also compared the effect on mean ICP
wave amplitude with the effect on systemic arterial pulse pressure.
The study included 52 interventions with different amounts of HSS in 20 SAH
patients. Only the first intervention in each patient was included in the main results due to
statistical reasons. It was found that both mean ICP and mean ICP wave amplitude were
attenuated by HSS. A correlation was found between change in mean ICP and mean ICP wave
amplitude, but no correlation was found between baseline values of mean ICP and mean ICP
wave amplitude. There was also a difference as to whether the treatment goal was reached.
The goals were defined as mean ICP < 15 mmHg and mean ICP wave amplitude < 5 mmHg.
The goal was reached in 65% of cases for mean ICP, while only in 30% of cases for mean ICP
wave amplitude. The study also documented that there was no correlation between systemic
arterial pulse pressure and intracranial pulse pressure, indicating that the intracranial pulse
pressure is no reflection of systemic pressure changes but represents the response to the
intracranial volume changes with each heartbeat.
In conclusion, the study documents for the first time that a drug, in this case HSS, has
an attenuating effect on pulsatile ICP. The low percentage of target achievement for mean ICP
wave amplitude indicates, however, that the intracranial compliance state was less favourable
36
than expected in a majority of these SAH patients with mean ICP and mean CPP values
within normal ranges. The results also showed that the value of mean ICP wave amplitude
could not be deduced from the value of mean ICP or vice versa in any given individual
patient.
37
DISCUSSION
All three studies included in this thesis are about the effect of 7.2% (72 mg/mL) saline in 6%
(60 mg/mL) hydroxyethyl starch 200/0.5 solution (HSS) on intracranial pressure (ICP) in
patients suffering from acute, spontaneous, subarachnoid haemorrhage (SAH). There are,
however, thematically two different trails that are relevant to separate. Study I and II on one
hand, are documenting effects on the well known and much investigated variables mean ICP
and cerebral perfusion pressure (CPP). Study III on the other hand, is more on the edge to less
well described territory, contributing a piece of evidence concerning the newly described
intracranial pressure variable; mean ICP wave amplitude.
To put the perspective right, the findings in this thesis can tell nothing about whether
the use of HSS had any bearing on neurological outcome in the patients studied. But being
based on clinical studies, the results can, judged together with available literature, have direct
implications for our current practice treating these patients. I hope to supply the fundament for
an educated answer to whether clinical practice can be modified based on the findings in this
thesis.
Before continuing, I would like to make a small pause, and close a 85 years long loop
between the initial findings in 1919 by Capt. Lewis H. Weed and 1st Lt. Paul S. McKibben at
The Army Neuro-Surgical Laboratory, Johns Hopkins Medical School, their extensive
research in cats, and our own findings in patients admitted to our intensive care unit at the
beginning of the following century. The point is to visually illustrate the similarities between
an ICP curve from one of their publications (Weed and McKibben, 1919b) (Figure 1A, page
38) with our ICP curve from Study I (Figure 1B, page 38).
During the time I have worked with this thesis, it has remained a mystery to me why
hypertonic saline was not re-discovered before, as an osmotic agent in the context of
38
intracranial hypertension. HS is cheap and has a much higher blood brain barrier (BBB)
reflection coefficient than the other drugs studied throughout the 20th century.
A B
Figure 1. A: ICP curve from cat no. 1271 after IV infusion of 12 mL of 30% saline (Weed and McKibben, 1919b). B: Mean change in ICP and CPP after IV infusion of 2 mL/kg of 7.2% saline in 6% hydroxyethyl starch 200/0.5 solution in SAH patients, n = 10 (Paper I). ICP, intracranial pressure; CPP, cerebral perfusion pressure; IV, intravenous. Figure 1A used with the permission from The American Physiological Society.
The relevance of ICP and CPP
A fundamental assumption for the use of osmotherapy to reduce ICP is that raised ICP
correlates with bad outcome. Even though there is no single study that beyond doubt proves
that monitoring of ICP improves outcome as opposed to not monitoring ICP, there are strong
indications that support its value.
With data from 428 traumatic brain injury (TBI) patients, Marmarou et al. found that
the proportion of hourly ICP readings greater than 20 mmHg was highly significant in
explaining outcome (Marmarou et al., 1991). Several other authors have also demonstrated
worsened outcome in patients with increased ICP (Marshall et al., 1979; Narayan et al., 1981;
Fearnside et al., 1993). However, Resnick et al. failed to demonstrate such a correlation for
ICP > 20 mmHg measured more than 96 hours after injury (Resnick et al., 1997). In 1999,
Robertson et al. published a randomised study in 189 patients with severe head injury,
39
demonstrating that secondary ischaemic insults could be prevented with the implementation
of a target management protocol based on ICP and CPP (Robertson et al., 1999). Patel and co-
workers have published an abstract showing a mortality rate twice as high among patients
treated in non-neurosurgical units compared with patients treated in neurosurgical units (Patel
et al., 2003). The availability of ICP monitoring is of course only one out of many factors
differing between the groups in this study. All of these studies refer to TBI patients, and
Treggiari et al. have summarised evidence in a recent review (Treggiari et al., 2007).
Citerio et al. have published a survey looking at the treatment of 350 SAH patients in
Italian neurosurgical centres, and found high intracranial pressure to be an independent factor
related to unfavourable outcome (Citerio et al., 2007). Two groups have found outcome to be
related to mean ICP and pulsatility in SAH patients (Eide and Sorteberg, 2006; Soehle et al.,
2007). Finally, Zanier et al. have documented the clinical advantages of monitoring ICP via a
computerised system over manual recordings (Zanier et al., 2007). Based on all this I find it
safe to conclude that monitoring of ICP and CPP is valuable to the patients suffering from
severe head injury and severe SAH.
Different ICP variables
As pointed out earlier, the first two papers are concerned with mean ICP, and the last also
with mean ICP wave amplitude. We have in the last paper referred to the two ICP variables
respectively as static and pulsatile ICP. The pulsatile ICP reflects the difference between
systolic and diastolic ICP, the static ICP (mean ICP) however, does not carry any information
about the shape of the ICP curve. The static ICP is influenced by a number of factors besides
pathological processes within the skull. Methodological factors such as the point of
measurement and baseline pressure level determined by zero calibration and drift, greatly
impacts the final measurement and has been discussed previously.
40
Pulsatile ICP (mean ICP wave amplitude) or intracranial pulse pressure is however in
many respects a more robust variable. It describes the dynamic pressure response evoked by
each cardiac beat. It does not need a correct zero calibration and is not influenced by drift of
the zero level (Eide, 2006b). Further, it is not influenced by alterations in head position like
described for mean ICP. In the study by Eide, while mean ICP differed considerably between
two sensors, the differences in single pressure wave amplitude were marginal (Eide, 2006b).
A difference of > 1 mmHg was found in only 0.8% of the time windows registered. Also, the
intracranial compliance is better described by the pulsatile than the static ICP (Avezaat et al.,
1979; Gonzalez-Darder and Barcia-Salorio, 1989; Eide et al., 2007a). With the availability of
pulsatile ICP at the bed-side in real time, I find this variable worth investigating as a
supplement to current standard neuromonitoring.
Effects of HSS on mean ICP and CPP in SAH patients
In Table 3 (page 23) I have listed the clinical studies looking at different concentrations of HS
used with the intention of controlling raised ICP. There are few SAH patients included in
these studies, and there are no studies with only SAH patients. There is also little information
about the time course of the effect. Inspired by this lack of knowledge, the two first studies
were designed to determine the short time effects on mean ICP and CPP of a HSS infusion in
SAH patients only. The reason that there is two and not one study is that I wanted to carry out
this research in a fashion as controlled as possible given a clinical setting, including a placebo
control. A placebo control group could not be justified including patients with mean ICP > 20
mmHg, which is the group of patients that is relevant to look at. Two quite similar studies
were therefore designed, one observational where all patients had mean ICP > 20 mmHg, and
one placebo-controlled where the patients had mean ICP 10 – 20 mmHg. An observational
study can never prove that an intervention was the cause of changes documented. The changes
41
could be due to natural courses or the effect of other interventions even if everything is kept
unaltered. The thought was that if the findings were similar in the two studies, the placebo-
controlled study would strengthen the findings from the observational study. The magnitude
of the effect of HSS would be reflected in the observational study where the inclusion criteria
for osmotherapy were relevant. In both studies we paid much attention to keeping all other
things that might affect ICP constant during the study period. No sudden increase in ICP
should lead to inclusion and a five minute period prior to infusion of HSS supplied baseline
values. During the 210 minute study period, the patients were not stimulated, their position
were unchanged, likewise ventilation, infusion rates for vasopressors, sedatives, and fluids.
The level of resistance towards CSF drainage was kept unaltered.
The results in the group that received HSS in Study II did closely mimic those of
Study I with a fall in mean ICP and rise in CPP, though with less absolute change as expected,
as the patients included in Study II had far lower ICP at inclusion. There was no change in the
placebo group (Figure 2, page 42). This indicated that the study design was valid, and that we
managed to control other variables that might have affected ICP. We therefore concluded that
HSS attenuates mean ICP and increases CPP in SAH patients.
Temporal pattern of change
The curves in Figure 2 (page 42) and Figure 1B (page 38) illustrates another important aspect;
i.e. the temporal pattern of the effect. Maximum effect is not reached immediately, as it is
when arterial CO2 partial pressure is reduced by hyperventilation. In our studies it took about
twice the infusion time before the maximum effect was reached. In Weed and McKibben’s
study it took 25-30 minutes after the end of the bolus (given during five minutes) (Figure 1A,
page 38). I have found only two clinical studies that contain such information. The first is a
report of two TBI patients given 250 and 100 mmol of NaCl during 10 minutes respectively
42
Figure 2. Changes in intracranial pressure (ICP) (top panel), and cerebral perfusion pressure (CPP) (bottom panel), after infusion of 2 mL/kg of study solution. HSS, 7.2% saline in 6% hydroxyethyl starch; NS, normal saline.
43
(Worthley et al., 1988). Maximum effect was reached about 20 minutes after the end of the
infusions deduced from graphs included in the paper. The second report is in a study by
Battison et al. including six TBI and three SAH patients, where HS was infused during 5
minutes. The paper includes a time-series plot from one patient, where the time to maximum
effect seems to be 20 – 30 minutes (Battison et al., 2005). In our studies I and II, average time
to maximum effect from start of infusion was 40 and 60 minutes respectively, the infusion
times being 20 and 30 minutes.
This is important information both for the practitioner and the scientist. For the
scientist, this indicates that the major effect of HS in the brain is due to removal of water, not
mainly due to haemodynamic effects that would be expected to display an immediate effect. It
may also say something about the properties of Aquaporine-4, if it is correct that these
channels represent a rate-limiting step for water flux across the blood-brain-barrier (BBB).
For the practitioner using HS in clinical practice, it is very important to know when maximum
effect of the intervention can be expected.
Study solution
Our choice of HS solution should be commented on. We chose a commercially available
solution (HyperHAES®) containing 7.2% (72 mg/mL) saline in 6% (60 mg/mL) hydroxyethyl
starch 200/0.5 (HSS). Converted to mmol, the sodium content is 1.23 mmol/mL. This solution
was chosen for several reasons. The combination of 7.2 to 7.5% saline in either hydroxyethyl
starch or dextrane has been extensively used in clinical research (Holcroft et al., 1987; Vassar
et al., 1991; Mattox et al., 1991; Vassar et al., 1993a; Vassar et al., 1993b), and is as such
known to be safe. We wanted our findings to be readily transferable to clinical practice, and
using a solution that is available seemed sensible. 3% saline is quite frequently used in
publications from the United States, but is seldom in stock in Norwegian hospitals. For the
44
reasons mentioned, and for issues related to the use of new drugs in medical research, we did
not want to prepare our own solution for these studies. All our patients were sedated and had a
central venous catheter in place, so the hypertonicity was not a problem. In acute, pre-hospital
settings, the solution can also be given in a peripheral vein. Using a less concentrated solution
would also have yielded a higher volume load which could become a problem in some
patients with cardiac and/or renal impairments.
As mentioned previously under Introduction (page 19), the addition of 6%
hydroxyethyl starch or dextrane to HS has been shown to prolong a positive haemodynamic
effect, but not influence the effect on ICP. I therefore find it justified to attribute the
intracranial pressure effects documented in our three studies to the HS component of the HSS
solution.
Dose and practical use
The dose used in the first two studies was 2 mL/kg of 7.2% saline in 6% hydroxyethyl starch
(HSS) (2.46 mmol Na+/kg). This is half of the conventional dose used in small-volume
haemodynamic resuscitation research, but we had found 2 mL/kg to be sufficient in pilots
prior to the studies. The idea was to not use a higher dose than necessary and thereby not
increase serum sodium more than necessary, so that the treatment could be repeated if the
clinical state indicates that. As discussed in Paper II, the findings from these studies indicate
that a standard dose might be lowered from 2 mL/kg, as the maximum reduction in mean ICP
in Paper I was > 50%. We now recommend a dose of 1 – 2 mL/kg. In practical use this has
evolved into a standard dose of 100 mL of HSS during 10-15 minutes in the average 60 – 90
kg adult. However, a proper dose-finding study should be made.
Are bolus doses the optimal way of administering HS as osmotherapy? There is no
definite answer to that. Most of the clinical studies listed in Table 3 (page 23) report only
45
single or repeated boluses, but some have used continuous infusion. Simma et al. randomised
children with TBI to an infusion of lactated Ringer’s solution (sodium 131 mmol/L) or HS
(sodium 268 mmol/L) with the goal of a serum sodium of 145-150 mmol/L during three days
in the HS group. An increase in serum sodium correlated with lower ICP and higher CPP.
They also reported fewer interventions, fewer complications, and shorter ICU stay in the HS
group (Simma et al., 1998). Qureshi et al. on the other hand reported increased in-hospital
mortality in a group of TBI-patients receiving a 3% HS-infusion as compared to normal saline
in a retrospective study (Qureshi et al., 1999). The infusion was targeted at a serum sodium
level of 145 – 155 mmol/L. There was, however, more penetrating injury in the HS group and
the infusion was continued even when mean ICP was normal. There are two studies on
children with TBI from San Diego applying a different approach (Khanna et al., 2000;
Peterson et al., 2000). In these studies, HS is infused on a sliding scale to achieve a target
serum sodium level that would maintain mean ICP < 20 mmHg. The results in these studies
were promising with good effect on ICP and CPP, and they also reported very high serum
sodium levels without adverse effects, mean highest level in the study by Khanna et al. was
170.7 mEq/L (range, 157 – 187 mEq/L).
I find the sliding scale approach logic, that the dose of HS should be dictated by the
need, here defined by the level of mean ICP, instead of targeting a predefined level for serum
sodium. It also underlines the need to pay attention to the serum sodium level at all times, not
allowing it to drift. However, in clinical practice there is often a need for a bolus intervention
in order to treat an increased ICP. Mere adjustments of a continuous infusion would not take
effect rapidly enough. I would therefore recommend to give a bolus of HS as described
previously when ICP > 20 mmHg and osmotherapy is indicated, followed by a continuous
infusion to maintain the serum sodium level achieved after the bolus. When needed, a new
46
bolus can be administered, and the infusion continued to maintain the new sodium level. This
can be pictured as a “stair-case approach” with respect to the serum sodium level.
Adverse effects
The classic adverse effect described in patients with rapidly increased serum sodium is central
pontine myelinolysis (CPM). This has typically been described after rapid correction of pre-
existing chronic hyponatraemia (Sterns et al., 1986; Vassar et al., 1990; Qureshi and Suarez,
2000; Verbalis, 2006). CPM has never been reported after elevation of a normal serum
sodium level (Qureshi and Suarez, 2000; Himmelseher, 2007), but breakdown of the BBB
followed by myelinolysis can occur if serum osmolality reaches 370 – 380 mOsm/kg (Soupart
et al., 1996). Intracranial haemorrhages have been reported in small children and cats after
abrupt changes in serum sodium (Finberg, 1967), but does not seem to be an issue in the
context of adult neurointensive care. However, we have in our institution implemented safety
precautions implying that one should avoid increasing serum sodium more than 15
mmol/L/day. We found in Study I and II mean maximum increase in serum sodium well
within this limit; 6.6 and 5.6 mmol/L after 2 mL/kg of HSS.
Even though the reflection coefficient (�) across intact BBB for NaCl is 1.0, one has to
be aware of possible rebound increase in ICP. Since one can imagine all degrees of damage to
the BBB, NaCl might leek into brain tissue in injured areas, later contributing to rebound
increase in ICP. One has also to be aware of the transport of organic osmolytes, e.g.
myoinositol, glutamine, glutamate, taurine, and urea into the brain, gradually compensating
for the acute hyperosmolar state created intravascularely after HS. (Lien et al., 1990; Sterns
and Silver, 2006; Verbalis, 2006). This means, that after culmination of the intracerebral
hypertension, one has to carefully and in a controlled manner reduce the serum sodium level
back toward normal levels, allowing the brain to lose the accumulated organic osmolytes
47
again. Fortunately, the loss of osmolytes is more rapid than the uptake (Verbalis, 2006), but
we recommend a reduction of serum sodium of no more than 10 mmol/L/day. I think that
caution in tapering of the hypernatremic state can eliminate some problems that can be
misconceived as rebound phenomena.
We do also advise caution in patients with unsecured aneurysms. A substantial
intracranial volume and pressure reduction might precipitate re-bleeding. I have however
never seen figures relating re-bleeding to the application of osmotherapy, but the general risk
of very early re-bleeding (first 24 hours) is as high as 15% when no antifibrinolytic drugs are
given (Hillman et al., 2002).
When using HS one has also always to be aware of the acute volume load that is
introduced to the circulation, paying special attention to patients with pre-existing heart
failure. We have, however, not encountered problems with this using 1 – 2 mL/kg of HSS.
Neither have we been able to attribute special clinical problems to the inevitable
hyperchloremic acidosis induced by the continuous and/or repeated administration of NaCl.
A significant risk of acute renal failure exists when mannitol is administered in large
doses, especially when serum osmolarity is > 320 mmol/L (Bullock, 1995) and the patient is
hypovolemic. This does not seem to be a problem to the same extent with HS, and a serum
osmolality > 320 mmol/L is not considered a contraindication to its use (Qureshi and Suarez,
2000). And as opposed to mannitol, repeated administration of HS would contribute to
correction of a hypovolemic state, rather than contributing to it.
Effects of HSS on mean ICP wave amplitude in SAH patients
Bed-side measurement of single wave intracranial pulse pressure is available based on a
method developed by Per Kristian Eide at our institution (Eide, 2006a). This is an interesting
variable, given the methodological problems with mean ICP discussed previously, and the
48
emerging documentation that mean ICP wave amplitude (intracranial pulse pressure) is better
correlated with outcome than mean ICP (Eide and Sorteberg, 2006; Eide, 2006c; Eide et al.,
2007b).
The measurement of intracranial pulse pressure is not a new thing. The fundamental
difference in the new algorithm is that mean ICP wave amplitude is calculated based on exact
measurements of single waves generated by each cardiac beat. Previous technologies have
either only measured maximum and minimum ICP during a given time frame, e.g. 15 – 20
seconds, the results thus “contaminated” by e.g. the effects of the respiratory cycle on the ICP
curve, or calculated on the basis of Fast Fourier transformation.
One important finding in Study III is that there is no correlation between the amplitude
of ICP and the amplitude of systemic arterial blood pressure (ABP). We can therefore
conclude that mean ICP wave amplitude is an independent variable reflecting the response to
intracranial volume changes induced by each cardiac beat, i.e. a reflection of the intracranial
compliance.
The main finding of Study III was that mean ICP wave amplitude was attenuated by
HSS. This has to my knowledge not been demonstrated before. However, the effect on mean
ICP wave amplitude was not directly comparable to the effect on mean ICP. First, there was
not a good agreement between the two measurements, signifying that the value of one of them
can not be deduced from the other. Secondly, there was a great discrepancy in target
achievement between the two variables. “Normal” mean ICP wave amplitude was only
achieved in a minority of cases while “normal” mean ICP was achieved in a majority of cases.
This suggests that the intracranial compliance state was less favourable than expected from
mean ICP in a majority of these patients. This is in concordance with the clinical perception
we have from our clinical day to day practice in the ICU, that a mean ICP of < 15 mmHg is
not “good enough” for a number of our SAH patients. For example, the mean ICP may be
49
normal, but the patient does not wake up. Only upon further reduction in mean ICP e.g by
increasing CSF drainage, does the patient wake up. This is illustrated by a case report by Eide
et al. where a SAH patient with normal mean ICP still was not waking up after 44 days (Eide
et al., 2007c). Only after changing to an ICP-wave guided management which brought about
increased CSF drainage, did the patient wake up. The notion that increased mean ICP wave
amplitude is indicative of an unfavourable state, is also supported by another case report by
Eide et al. that showed how increased amplitude was associated with increased levels of brain
metabolites indicative of ischemia (Eide et al., 2007a). All this challenges the thought that
“normal” mean ICP has the same implications in the injured and non-injured brain. These are
interesting aspects deserving further attention in the future.
A positive spin-off effect of measuring mean ICP wave amplitude with an online
display of the actual ICP curve drawn on the basis of measurements at 100 Hz, is that one has
a useful tool for judging whether the ICP measurement is valid. The diagnosis of a partly
dislodged catheter can readily be made just by looking at the curve. And in addition the
system will classify the measurements as invalid. This is information not supplied by mere
mean ICP.
Future clinical research questions
Reporting short time effects of hypertonic saline (HS) on intracranial pressure (ICP) variables
in subarachnoid haemorrhage (SAH) patients is important, but to link the use of HS or
measurements of increased mean ICP wave amplitude to effects on outcome; that is the real
challenge.
• Further studies are needed to better enlighten many aspects related to the use of
hypertonic saline in SAH patients with intracranial hypertension:
50
o Optimal dose
o Bolus, continuous infusion, or a combination
o Rebound phenomenon
o Timing related to time since injury
o Safety issues related to serum sodium levels and adverse effects
• Interesting and valuable knowledge would presumably emerge from studies
combining metabolic changes measured with micro dialysis, cerebral water content
and cerebral blood flow derived from MRI-investigations, and intracranial pressure
variables during administration of hypertonic saline.
• There is an immediate need for more data relating mean ICP and mean ICP wave
amplitude to neurological outcome.
51
MAIN CONCLUSIONS
All conclusions relate to patients suffering from acute spontaneous subarachnoid haemorrhage
(SAH) investigated in the intensive care setting.
1. Intravenous bolus infusion of 7.2% (72 mg/mL) saline in 6% (60 mg/mL)
hydroxyethyl starch 200/0.5 solution (HSS) during 20 – 30 minutes reduced
intracranial pressure (ICP), both mean ICP and mean ICP wave amplitude, and
increased cerebral perfusion pressure (CPP).
2. Intravenous bolus infusion of normal saline (single blind placebo) had no effect on
mean ICP or CPP, verifying stable study conditions.
3. When HSS was infused as a bolus during 20 to 30 minutes, the reduction in mean ICP
started almost immediately, but reached its maximum 20 to 30 minutes after the end of
the infusion, thereafter tapering off, but without a rebound within 3 hours.
4. When mean ICP was above 20 mmHg, 2 mL/kg of HSS (2.46 mmol Na+/kg) reduced
mean ICP in average by more than 50% at time of maximum effect, and mean ICP
remained below baseline three hours later.
5. Changes in mean ICP were inversely related to changes in serum sodium levels, and
mean maximum increase in serum sodium was about 6 mmol/L after 2 mL/kg of HSS .
6. A bolus infusion of 2 mL/kg of HSS increased cardiac output in our patients.
7. There was poor agreement between mean ICP and mean ICP wave amplitude, so the
level of one variable cannot be deduced from the other for any given individual
patient.
8. When the target level for mean ICP was reached after HSS infusion, the target for
mean ICP wave amplitude was reached only in a few patients. This suggests that the
52
intracranial compliance may be less favourable than expected in many SAH patients
with normal mean ICP and CPP.
9. There was no correlation between mean ICP wave amplitude (intracranial pulse
pressure) and systemic arterial pulse pressure. This supports the view that mean ICP
wave amplitude is reflecting the pressure response to intracranial volume changes
induced by each cardiac beat, i.e. intracranial compliance.
53
IMPLICATIONS FOR CLINICAL PRACTICE
The studies included in this thesis have documented that intravenous infusion of HSS has a
reliable effect on increased mean ICP in SAH patients. Mean ICP is lowered and as a
consequence of that, CPP is increased. Based on the findings of this thesis, which are
supported by other published studies, I now find there is enough evidence to recommend the
use of HS for osmotherapy in SAH patients, as an alternative to or a supplement to mannitol.
In clinical practice, the mode of administration could preferably be modified compared
with the regime presented in this thesis. The findings from study I indicates that a bolus dose
could be reduced from the 2 mL/kg of HSS used in the study, and in clinical practice, an
infusion time of 20 to 30 minutes would be perceived as too long. Further, our studies show
how the positive effects on the ICP variables are gradually reduced as serum sodium returns
to pre-infusion levels. I would therefore recommend to give a bolus of HS, e.g. NaCl 1 – 2
mmol/kg during 5 – 15 minutes, when ICP > 20 mmHg and osmotherapy is indicated,
followed by a continuous infusion to maintain the serum sodium level achieved after the
bolus. When needed, a new bolus can be administered, and the infusion continued to maintain
the new sodium level. Since serum sodium in our studies increased by about 6 mmol/L after
2.5 mmol/kg, there is room for repeated boluses per day without increasing serum sodium
more than 15 mmol/L/day. The inverse relationship between serum sodium and mean ICP,
also teaches us that a careful tapering of a hypernatremic state is important and necessary to
avoid rebound increase in mean ICP.
In our patients, cardiac output increased after HSS. This is in most cases clearly
beneficial, as many of these patients require vasopressors to achieve a satisfactory
haemodynamic situation. HSS may therefore reduce the need for such drugs.
54
It was not within the scope of this thesis to define the role of mean ICP wave
amplitude in clinical practice. More research is needed, but the findings from Study III have
taught us that the intracranial compliance situation is not necessarily good even though mean
ICP and CPP is normal. So at least in the cases where the radiology findings are fine, mean
ICP and CPP are fine, but the clinical state of the patient is not fine, these results lend support
to actively try to improve intracranial compliance e.g by infusion of HS or by increasing CSF
drainage.
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