World Neurosurgery: X 18 (2023) 100160

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World Neurosurgery: X
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Fine tuning of neurointensive care in aneurysmal subarachnoid hemorrhage:

From one-size-fits-all towards individualized care
Teodor Svedung Wettervik *, Anders Lew
en, Per Enblad
Department of Medical Sciences, Section of Neurosurgery, Uppsala University, SE-751 85, Uppsala, Sweden

A R T I C L E I N F O A B S T R A C T

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe type of acute brain injury with high mortality and
This work has not been previously presented.
burden of neurological sequelae. General management aims at early aneurysm occlusion to prevent re-bleeding,
cerebrospinal fluid drainage in case of increased intracranial pressure and/or acute hydrocephalus, and cerebral
Keywords:
blood flow augmentation in case of delayed ischemic neurological deficits. In addition, the brain is vulnerable to
Aneurysmal subarachnoid hemorrhage
Multimodal monitoring
physiological insults in the acute phase and neurointensive care (NIC) is important to optimize the cerebral
Neurointensive care physiology to avoid secondary brain injury. NIC has led to significantly better neurological recovery following
Precision medicine aSAH, but there is still great room for further improvements. First, current aSAH NIC management protocols are to
some extent extrapolated from those in traumatic brain injury, notwithstanding important disease-specific dif-
ferences. Second, the same NIC management protocols are applied to all aSAH patients, despite great patient
heterogeneity. Third, the main variables of interest, intracranial pressure and cerebral perfusion pressure, may be
too superficial to fully detect and treat several important pathomechanisms. Fourth, there is a lack of under-
standing not only regarding physiological, but also cellular and molecular pathomechanisms and there is a need to
better monitor and treat these processes. This narrative review aims to discuss current state-of-the-art NIC of
aSAH, knowledge gaps in the field, and future directions towards a more individualized care in the future.

1. Introduction state globally and focally may be questioned.7,8 The development of new
multimodality monitoring (MMM) tools to assess cerebral blood flow
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of (CBF; imaging and invasive probes), CBF autoregulation (e.g. pressure
acute brain injury that is treated in the neurointensive care (NIC) unit. reactivity index), brain tissue oxygenation (btO2 and jugular bulb), and
The mainstay of NIC is to monitor systemic and cerebral physiology and cerebral energy metabolism (microdialysis) have improved our under-
to prevent and treat avoidable factors that could otherwise induce sec- standing of disease pathophysiology and the cerebral effects of treat-
ondary brain injury.1,2 Since the initiation and development of NIC, ments, but their validity to guide management still remains unclear
clinical outcome has significantly improved for aSAH patients.2 How- considering their inherent temporal, spatial, and logistical constraints.
ever, several challenges still exist. Fourth, the focus of NIC has been directed towards systemic and cerebral
First, current aSAH gudielines3,4 and local management protocols5 of physiological optimization, but this does not address all pathomechan-
NIC variables such as intracranial pressure (ICP) and cerebral perfusion isms that occur on a cellular and molecular level such as neuro-
pressure (CPP) are either absent or to a great degree developed based on inflammation, neurodegeneration, and neurorepair.9,10 A better
those from severe traumatic brain injury (TBI), which stands as the understanding of this could potentially contribute to the development of
prototype disease in NIC. However, the same targets and threholds may appropriate pharmacological agents and administration of these in an
not apply in both diseases.6 Second, the same NIC targets are to a great optimal time window based on high-resolution bedside monitoring data.
extent applied for all aSAH patients under most circumstances, despite Consequently, although the development of NIC in aSAH has been a
inter- (demography, co-morbidities, extent of injury) and intraindividual success from a historical point of view,2 there is clearly room for further
(throughout the temporal course of the acute phase) differences. Third, improvement. The aim of this narrative review was to discuss the current
current NIC targets such as ICP and CPP are only surrogates of the ce- knowledge gaps, the limitation of extrapolation of TBI guidelines to
rebral environment, but their validity to predict the actual intracranial aSAH,3,4,11 and more particularly about fine tuning of NIC in aSAH to

* Corresponding author. Department of Medical Sciences, Section of Neurosurgery, Uppsala University, SE-751 85 Uppsala, Sweden.
E-mail address: teodor.svedung-wettervik@neuro.uu.se (T. Svedung Wettervik).

https://doi.org/10.1016/j.wnsx.2023.100160
Received 31 October 2022; Received in revised form 20 January 2023; Accepted 22 January 2023
2590-1397/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
T. Svedung Wettervik et al. World Neurosurgery: X 18 (2023) 100160

individualize care both in terms of cerebral physiology and molecular techniques may provide a more accurate picture of the cerebral situation.
injury patterns. Altogether, MMM carries great potential, despite existing limitations
(Fig. 2). In the sections below, we discuss the different steps to optimize
2. Individualized therapy in neurointensive care – the role of cerebral energy metabolism divided into the CBF-, oxygenation-, and
multimodality monitoring nutrient-patways together with factors involved in energy metabolism
(Fig. 1).
There are several physiological steps that affect CBF and the cerebral
delivery of oxygen (CDO2) as well as nutrients (glucose and lactate; 3. Individualized therapy – physiological targets to optimize
CDGlc and CDLac) and there are many pathomechanisms that may cerebral energy metabolism
interfere (Fig. 1). Evovling secondary brain injury can be fairly detected
as a neurological deterioration, clinically assessed by repeated neuro- 3.1. Optimizing CBF
logical examinations, although this is more challenging in unconscious
patients that require intubation, mechanical ventilation, and sedation. In Fig. 1 describes the pathways to optimize cerebral energy meta-
classic NIC, ICP and CPP are monitored in unconscious aSAH patients and bolism. It is key to maintain a sufficiently high CBF to achieve adequate
treatment aims to avoid intracranial hypertension and to ensure suffi- CDO2 and CDGlc/CDLac. CBF disturbances are common in aSAH8 and
cient cerebral perfusion. However, even in case of normal ICP and CPP, may be attributed to several pathomechanisms, as discussed below.
disturbances in CBF, btO2, and cerebral energy metabolism are
frequent.8,12–14 For that reason, there has been a development of MMM 3.1.1. ICP-monitoring, thresholds, and treatments
tools to enable monitoring of the different steps to achieve cerebral en- During ictus, there is a rapid increase in ICP following the hemor-
ergy metabolism (Tables 1 and 2). Monitoring may then also include rhage from the ruptured intracranial aneurysm. Thereafter, secondary
cerebral pressure autoregulation (pressure reactivity index, mean flow ICP elevations may occur in both an acute (<24 h) and delayed (2–14
index), CBF (intraparenchymal probes, transcranial Doppler, and radio- days post-ictus) fashion due to e.g. re-bleeding, acute hydrocephalus,
logical imaging), brain tissue oxygenation (jugular bulb, btO2), and ce- intracerebral hemorraghe, subdural hematomas, diffuse global cerebral
rebral energy metabolism (microdialysis and radiological imaging). edema, and cerebral edema.17 High ICP may in turn induce compression
Ideally, a complete MMM setup enables earlier detection of impending of neural structures as well as lead to macro- and microvascular CBF
brain injury and diagnosis of the specific pathomechanisms, which in disturbances by lowering CPP and inducing capillary collapse.18
turn predispose for more cause-specific therapies. However, so far, the In an aSAH cohort study of patients with EVD-monitoring due to un-
implementation of MMM-based management has been limited to a few consciousness or hydrocephalus, ICP elevations were found to be very
research-oriented NIC units.15,16 A major reason for this is that contro- common. Around 80% of the patients exhibited at least one episode of ICP
versy remains regarding the validity to guide management based on above 20 mmHg for more than 5 min.19 Still, the role of ICP monitoring,
these MMM-tools. For example, the microdialysis only represents a small the definition of elevated ICP, and protocols for when ICP-lowering
brain region and the rationale to guide a global therapy such as treatments are warranted remain controversial. Currently, the Neuro-
CPP-levels is questionable considering the regional differences in cere- critical Care Society (NCC) has no recommendation on ICP-monitoring or
bral injury patterns and pathophysiology.7 At the same time, a global ICP-lowering treatments,4 whereas the American Heart Association (AHA)
measure such as jugular bulb oxygenation may be too insensitive to suggests cerebrospinal fluid (CSF) drainage with an EVD or a lumbar
detect small, but important, focal cerebral oxygen disturbances. Another drainage in case of acute hydrocephalus,3 but the role of ICP-monitoring,
problem is that some methods such as radiological imaging only gives per se, and ICP-lowering treatments are not stated. Due to the lack of
snap-shots of the cerebral status. However, even if no MMM tool is per- recommendations from aSAH guidelines, most centers, including ours,
fect, the combined analysis of the information obtained by the different have extrapolated the ICP-regime from TBI protocols.5,11,20

Fig. 1. Physiological pathways, pathomechanisms, and management options to optimize cerebral energy metabolism in aSAH.
The figure describes the different pathways to ensure cerebral energy metabolism. In the CBF pathway, MAP and ICP determine CPP, which together with the cerebral
autoregulation determine CBF. In the oxygenation pathway, pO2 and HgB determine the CaO2, which together with CBF constitute the CDO2. In the nutrient pathway,
CaGlc and CaLac are defined as the arterial content of these metabolites, which together with CBF determine CDGlc and CDLac. CDGlc, CDLac, and CDO2 are necessary
for the cerebral production of energy, which takes place in the cytosol and mitochondria of the brain cells. Several pathomechanisms may interfere with each step,
which can be addressed to some extent with specifically targeted management strategies, as suggested in the figure.
AR ¼ Autoregulation, aSAH ¼ Aneurysmal subarachnoid hemorrhage, CaGlc ¼ Arterial content of glucose, CaLac ¼ Arterial content of lactate, CaO2 ¼ Arterial content
of oxygen, CBF ¼ Cerebral blood flow, CDGlc ¼ Cerebral delivery of glucose, CDLac ¼ Cerebral delivery of lactate, CDO2 ¼ Cerebral delivery of oxygen, CSD ¼ Cortical
spreading depolarization, EP ¼ Epilepsy, FiO2 ¼ Fraction of inspired oxygen, Hgb ¼ Hemoglobin, HHH ¼ Hemodilution, hypertension, and hypervolemia, ICP ¼
Intracranial pressure, MAP ¼ Mean arterial blood pressure, pO2 ¼ Partial pressure of oxygen, RBCT ¼ Red blood cell transfusion.

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Table 1
Multimodality monitoring – a selection of methods and their benefits and limitations.
Physiological Monitoring method Advantage Limitations
variable

ICP EVD Both monitoring and treatment of Infections. Clotting of the EVD.
ICP by CSF drainage.
Intraparenchymal probe Less invasive than EVD. Does not offer ICP treatment with CSF drainage. Zero-drift.
CPP Any ICP monitor combined with Continuous global estimate of CBF. Spatial constraints; does not take into account differences in cerebral
arterial line for continuous systemic autoregulation or vasospasm.
ABP.
CBF autoregulation PRx (ICP and ABP) Measure of the global autoregulatory Requires ICP-monitor. Low signal-to-noise ratio. Spatial constraints;
status. insensitive to focal disturbances.
CPPopt (PRx and CPP) Global CBF surrogate that takes into Requires advanced software. Still insufficiently studied in aSAH. Spatial
account autoregulatory status. constraints; insensitive to focal disturbances.
Mx (TCD and CPP) Easy to use bedside. May detect User-dependent. Spatial constraints; limited global spatial validity, especially
regional autoregulatory differences. in the posterior circulation
Cerebral blood flow Radiology (Perfusion-CT, Xe-CT, PET, Both global and focal. Logistics; Difficult to transport unstable patients to the radiology department.
MRI) Time constraints; represents only a snapshot.
TCD Easy to use bedside. Measures velocity, not CBF. User-dependent. Spatial constraints; limited
global spatial validity, especially in the posterior circulation. Time
constraints; monitoring occurs in a limited time interval.
Intraparenchymal thermal diffusion Continuous CBF measure. Spatial constraints; limited global spatial validity.
probe
Brain tissue Jugular bulb catheter (SjvO2) Continuous and feasible global Spatial constraints; low sensitivity for focal ischemia.
oxygenation measure.
Intraparenchymal device (BtO2) Continuous and feasible focal Spatial constraints; limited global spatial validity, especially in the posterior
measure. circulation
NIRS Non-invasive. Spatial constraints; limited global spatial validity, especially in the posterior
circulation
Cerebral energy MD Feasible for continuous evaluation. Spatial constraints; limited global spatial validity.
metabolism PET Possible to investigate focal/global Logistics; Difficult to transport unstable patients to the radiology department.
complex aspects of energy Time constraints; represents only a snapshot.
metabolism.
EEG Helpful to diagnose cerebral Complexity; difficult to interpret bedside.
ischemia and NCSE

ABP ¼ Arterial blood pressure, CBF ¼ Cerebral blood flow, CSF ¼ Cerebrospinal fluid, EEG ¼ Electroencephalography, EVD ¼ external ventricular drain, ICP ¼
Intracranial pressure, MD ¼ Microdialysis, Mx ¼ Mean flow index, NCSE ¼ Non-convulsive status epilepticus, NIRS ¼ Near infrared spectroscopy, PET ¼ Positron
emission tomography, PRx ¼ Pressure reactivity index, TCD ¼ Transcranial Doppler, Xe-CT ¼ Xenon-enhanced computed tomography.

When the original ICP protocols are transferred from TBI there are Altogether, despite that ICP-elevations are frequent and escalated
some important aSAH-related issues that need to be considered. First, treatments protocols are warranted, there is currently a lack of high-
regarding indication, ICP-monitoring is chiefly considered in TBI patiens quality studies as well as guideline recommendations in this area for
with Glasgow coma scale score 8. In aSAH patients, ICP-monitoring is aSAH. There is some support that many aspects of the TBI protocols may
applied more liberally also in less unconscious patients since ICP may be be extrapolated to aSAH,12,21 but there are many pertinent
increased due to CSF disturbances also before ventricular dilatation ap- disease-specific differences that need to be further elucidated regarding
pears. CSF treatment may even be used in drowsy but conscious aSAH optimal ICP-treatment thresholds and optimal treatment options and
patients in case of symptomatic acute hydrocephalus. Second, regarding their order of escalation. MMM tools may carry a role to determine when
ICP monitors, the EVD, with the possibility to drain CSF, is consistently cerebral decompensation occurs due to high ICP and to evaluate suc-
used in aSAH, since CSF disturbances and acute hydrocephalus are such cessful effects of treatments, but the evidence to support this approach is
prominent etiologies for ICP elevations. Third, the ICP-thresholds that very limited.
warrant treatment are not as investigated in aSAH as in TBI. There are
some studies that have demonstrated that aSAH patients with longer 3.1.2. Carbon dioxide management: a balance between intracranial pressure
monitoring episodes of ICP above 20–25 mmHg exhibit an increased risk and cerebral blood flow optimization
of clinical deterioration,5 worse cerebral energy metabolism,12 unfa- Several studies of aSAH support normo- and even hypercapnia in order
vorable outcome,6,21 and mortality.19 These thresholds would be in to counteract ischemic CBF,32 increase brain tissue oxygenation,32 reduce
accordance with those established in TBI.11,22 Fourth, regarding DCI,33 and improve clinical outcome.33–35 However, the literature is not
ICP-lowering treatments, aSAH patients may benefit much more from completely consistent, as others have rather found that mild hyperventi-
CSF-drainage with an EVD than in TBI, considering that the dominating lation (pCO2 4.0–5.1 kPa) may be the optimal balance to avoid last-tier ICP
reason for increased ICP is CSF disturbances and acute hydrocephalus. treatments, DCI, and poor outcome.36 Particularly, one fear with too
Hyperventilation is used in TBI to lower ICP by cerebral vasoconstric- generous hypercapnia is steal phenomemen, i.e. CBF augmentation only in
tion,23 which may be more dangerous in aSAH due to the high incidence pCO2-reactive brain regions that were already non-ischemic, while vaso-
of concurrent vasospasm (see 3.1.2). Barbiturates and decompressive spastic and ischemic brain regions with lost pCO2-reactivity instead exhibit
craniectomy (DC) are occasionally last-tier life-saving treatments in a CBF decrease.37 On balance, a pCO2 between 4.5 and 5.5 kPa may be an
aSAH, but there is no clear evidence if they improve clinical outcome in adequate balance among high ICP, low CBF, and the risk of steal. Radio-
aSAH.17,24,25 Both barbiturates and DC have more established roles as logical imaging such as xenon-enhanced computed tomography38–40 and
last-tier ICP-treatments in TBI,11,26,27 although the role of DC has been MMM-tools including btO2/jugular bulb and microdialysis may be of value
challenged also in TBI.28,29 Lastly, in TBI, there are some studies that to better determine the cerebral net effects of therapy changes in pCO2--
support the use of individualized ICP-thresholds, defined as the ICP-level ventilation, although spatial constraints to focal brain regions may limit
when cerebral autoregulation becomes severely deranged,30,31 but this the sensitivity of btO2 or mircrodialysis to detect the any potential negative
remains to be investigated in aSAH. steal effect in distant, vulnerable brain regions.

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T. Svedung Wettervik et al. World Neurosurgery: X 18 (2023) 100160

Table 2
Monitoring variables, target intervals, and treatments in aSAH – international guidelines (AHA, NCC), local practices (Uppsala), and comparison with TBI (BTF).
Variable Target interval Treatment
3
ICP AHA: CSF drainage with an EVD or a lumbar drainage in case of acute hydrocephalus Head elevation
NCC: None4 Hematoma evacuation
Uppsala: ICP 20 mm Hg5 Hyperventilation
BTF: ICP 22 mm Hg11 CSF drainage
Sedation
Barbiturates
Decompressive craniectomy
ABP/CPP i) before aneurysm AHA: i) avoiding systolic bood pressure (sBP) above 160 mmHg. ii) euvolemia, no strict ABP-/CPP- ICP control (above)
occlusion target3 Intravenous fluids
ii) after aneurysm occlusion NCC: i) avoding MAP above 110 mmHg. ii) euvolemia, no strict ABP-/CPP-target4 Vasopressors
Uppsala: i) sBP 120–160 mmHg and CPP 60 mmHg. ii) CPP 60 mmHg5 Antihypertensives
BTF: i) and ii) not applicable. ii) CPP between 60 and 70 mm Hg11
CBF pressure autoregulation AHA: No target3 CPP optimum
NCC: No target4
Uppsala: No target5
BTF: No target11
CBF AHA: No target3 CPP-, pCO2-, and autoregulation
NCC: No target4 management
Uppsala: No target20
BTF: No target11
Arterial oxygenation AHA: RBCT may be beneficial for aSAH patients at risk of cerebral ischemia. No specific HgB or Respiratory optimization
pO2 target3 Minimize blood loss
NCC: HgB above 8–10 g/dL. No specific pO2 target4 Red blood cell traunsfusion
Uppsala: Hgb >10 g/dL and pO2  12 kPa5
BTF: No target11
Arterial glucose AHA: No specific target, but avoid hypoglycemia3 Intravenous glucose
NCC: 4.4–11.1 mM4 Insulin injection/infusion
Uppsala: 5–10 mM5
BTF: No target11
Tight glycemic control: 4.4–6.1 mM81
Cerebral oxygenation AHA: No target3 CBF and arterial oxygenation management
NCC: No target4
Uppsala: No target5
BTF: No target11
Cerebral glucose AHA: No target3 CBF and arterial glucose management
NCC: No target4
Uppsala: No target, but clinical evaluation if cerebral glucose <0.5 mM (MD)153
BTF: No target11
MD consensus meeting 2014: Cerebral glucose >0.2–0.8 mM92
Cerebral energy metabolism AHA: No target3 Optimize the variables above.
NCC: No target4
Uppsala: No target, but clinical evaluation if cerebral LPR >40 (MD)153
BTF: No target11
MD consensus meeting 2014: Cerebral LPR <25–4092

BTF ¼ Brain Trauma Foundation, CBF ¼ Cerebral blood flow, CPP ¼ Cerebral perfusion pressure, CPPopt ¼ Optimal CPP, CSF ¼ Cerebrospinal fluid, ICP ¼ Intracranial
pressure, LPR ¼ Lactate-/pyruvate ratio, MD ¼ Microdialysis.

Fig. 2. Illustration of a multimodality monitoring case in an aSAH patient.

The figure shows an example of multimodality monitoring in aSAH at our center. This aSAH patients was unconscious, intubated, and mechanically ventilated and had
therefore received an EVD (*) for ICP monitoring and cerebral microdialysis (**) for energy metabolic monitoring. Xe-CT imaging was conducted during NIC to
estimate global and focal CBF. In addition, CDO2 could be calculated based on CBF and the concurrent CaO2. This type of MMM setup can be used to diagnose the
specific cause for imminent cerebral energy metabolic failure, by evaluating concurrent global/focal cerebral ischemia and CDO2. As illustrated, there is significant
regional CBF variation, which limits the global validity of focal monitors such as the microdialysis.
aSAH ¼ Aneurysmal subarachnoid hemorrhage, CBF ¼ Cerebral blood flow, CaO2 ¼ Arterial content of oxygen, CDO2 ¼ Cerebral delivery of oxygen, EVD ¼ External
ventricular drainage, MMM ¼ Multimodality monitoring, NIC ¼ Neurointensive care, Xe-CT ¼ Xenon-enhanced computed tomography.

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3.1.3. ABP-,CPP-, and cerebral autoregeulation monitoring, thresholds, and oxygen reactivity index (ORx).44 Particularly, when PRx is plotted
treatments against CPP, an autoregulation curve with the optimal plateau phase of
ABP- and, in the aSAH cases with an EVD, CPP-monitoring are very stable CBF can oftentimes be estimated (denoted as CPPopt). CPPopt as a
important during NIC.41 In aSAH care, there is a biphasic approach to treatment target has shown promising results in TBI studies,45 in which
target ABP and CPP. Re-bleeding is a severe early complication and the CPP close to CPPopt has been associated with optimal btO2,46 cerebral
highest risk is estimated to occur within the first 24 h post-ictus.42 energy metabolism,47 and clinical outcome.47–51 However, the evidence
Elevated ABP is thought to be an important risk factor for re-bleeding, to support CPPopt in aSAH is less clear. Some studies have found that CPP
although more aggressive ABP-lowering management has not shown below CPPopt is associated with lower CBF8,52 and precedes DCI,53
any definite outcome benefit.43 Currently, AHA recommends avoiding whereas CPP above CPPopt seems to provoke hyperemia and seizures,54
systolic bood pressure (sBP) above 160 mmHg3 and NCC recommends but it does not correlate with cerebral energy metabolism12 or unfavor-
that mean arterial blood pressure (MAP) above 110 mmHg should be able outcome.21
avoided until aneurysm occlusion.4 Altogether, several retrospective studies support that aSAH patients
After a successful aneurysm occlusion, the risk/benefit ratio of high may benefit from much higher CPP-targets closer to 70–90 mmHg, but
ABP/CPP changes, since the re-bleeding risk is almost obviated, whereas there is a need for prospective studies to validate this and determine the
there is a gradual increase in the risk of cerebral vasospasm, delayed best methods to reach these targets, e.g. ABP augmentation by fluids and
cerebral ischemia (DCI), and brain infarctions during the following vasopressors and/or different methods of ICP-lowering. There are pre-
10–14 days. Both AHA and the NCC recommend to maintain euvolemia liminary reports of individualized autoregulatory CPP-targets, but their
to prevent cerebral ischemia and to induce arterial hypertension in case role in aSAH remains to be determined.
of DCI, but without any strict ABP-/CPP-threshold.3,4 Due to the lack of
strict guideline recommendations in ABP-/CPP-targets,3,4 many centers
extrapolate the CPP-targets from TBI protocols and keep the lower 3.2. Oxygenation – arterial content, cerebral delivery, and cerebral tissue
threshold target at 60 mmHg.5,11 However, current evidence support that oxygenation
much higher CPP-targets may be warranted in aSAH (Fig. 3). Findings
from retrospective studies by our as well as other groups have demon- Previous sections have focused on CBF and this section will discuss
strated that CPP closer to 70–90 mmHg is associated with better brain the variables responsible for the arterial oxygen content (CaO2), with the
tissue oxygenation,14 cerebreal energy metabolism,12,14 and favorable ultimate goal to optimize CDO2. The hemoglobin (HgB) level is the main
outcome6,21 in aSAH. contributing factor for CaO2 in case of near maximal oxygen saturation
However, the role of fixed CPP-targets for all patients has also been (SaO2), whereas the freely dissolved oxygen only make up a small pro-
questioned, due to differences in cerebral autoregulation between pa- portion of the CaO2. Anemia therefore drastically reduces CDO2. At the
tients and throughout the temporal course in the acute phase (Fig. 4). For same time, hemodilution is one of the components in HHH-therapy to
example, many aSAH patients exhibit co-morbidities such as chronic improve blood rheology and increase CBF,8 although the net benefit on
arterial hypertension, leading to a chronic right-shifted autregulation CDO2 could be questioned.8 The definition of anemia and the threshold
curve. This means that the lower and upper limit of autoregulation are for red blood cell transfusion (RBCT) during NIC, the net cerebral effects
pushed towards higher baseline ABP-/CPP-values, predisposing for of hemodilution, and the role of arterial hyperoxia have received great
greater susceptibility for cerebral ischemia at ABP-/CPP-values that interest in acute brain injuries in general as well as in aSAH, as discussed
healthier patients would tolerate.44 Additionally, aSAH patients exhibit below.
various degrees of cerebral vasopasm thoughout the vascular tree, which
may also vary over time in the acute phase. The importance of an indi- 3.2.1. The role of hemoglobin
vidual and temporally dynamic cerebral pressure autoregulatory status Regarding the definition of significant anemia in aSAH, several
has encouraged the development of MMM tools to assess this function, retrospective studies demonstrate an increased risk of developing brain
including pressure reactivity index (PRx), mean flow index (Mx), and tissue hypoxia,55,56 cerebral energy metabolic disturbances,55,56 and
poor neurological outcome57 when HgB falls below 9–10 g/dL. However,

Fig. 3. CPP in relation to clinical outcome in TBI and SAH.

The figure illustrates the combined effect of “insult” duration and intensity on clinical outcome.6 Red and blue color indicate unfavorable and favorable clinical
outcome, respectively, in a subset of TBI (n ¼ 441) and aSAH (n ¼ 449) patients treated at our center. The patients were managed with similar treatment targets (CPP
60 mmHg) and the graphs illustrate that aSAH patients may benefit from much higher CPP-targets than TBI patients.
aSAH ¼ aneurysmal subarachnoid hemorrhage. CPP ¼ Cerebral perfusion pressure. TBI ¼ Traumatic brain injury.

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Fig. 4. A–B. Key concepts in cerebral pressure autoregulation and autoregulatory-oriented therapy.
Fig. 4A illustrates four examples of different cerebral pressure autoregulatory status. The blue curve shows the classic “Lassen curve” with a plateau of stable CBF over a
broad range of CPPs. Cerebral ischemia occurs at the lower end of autoregulation when the cerebral vessels are already maximally dilated and then become pressure
passive below this CPP-value. Similarly, cerebral hyperemia occurs as CPP surpasses the upper end of the autoregulatory plateau, when the capacity for further
cerebral vasoconstriction is exceeded, and CBF again follows CPP passively. The yellow curve shows a right-shifted curve with preserved plateau range, which could be
the case for patients with pre-ictal chronic arterial hypertension. The green curve illustrates a case with right-shifted and narrowed plateau, which may occur with
cerebral vasospasm with increased vasoconstriction and reduced capacity for vasodilation. Hence, both the yellow and green curves illustrate two cases with increased
susceptibility for cerebral ischemia despite “normal” CPP. The red curve illustrates a case with totally lost capacity to autoregulate, where CBF completely depends on
CPP. Fig. 4B illustrates how the capacity for cerebral pressure autoregulation curve may be continuously monitored with PRx plotted against CPP for the last 4 h, in
order to detect CPPopt. CPPopt reflects the plateau phase of CBF, i.e. the nadir of the U-shaped PRx/CPP curve. However, in cases with lost capacity to autoregulate,
e.g. with high PRx and without the U-shaped curve, CPPopt cannot be detected.
CBF ¼ Cerebral blood flow, CPP ¼ Cerebral perfusion pressure, CPPopt ¼ Optimal CPP, PRx ¼ Pressure reactivity index.

general management to avoid and when to treat anemia remains and even favorable at least in general ICU patients.63 However, it has
controversial. NCC recommends at first hand to minimize all necessary been questioned if this is valid for aSAH since these patients exhibit a
blood loss (e.g. from lab tests) and at second hand to give RBCT to keep reduced reserve for any CBF and CDO2 deterioration, predisposing for a
HgB above 8–10 g/dL and that patients with DCI might benefit from even lower tolerance for low HgB-levels. Thus, MMM-tools could then be
higher levels.4 AHA is more vague and states that RBCT may be beneficial useful to determine when cerebral decompensation occurs and when
for aSAH patients at risk of cerebral ischemia, although any threshold for higher HgB by means of RBCT could be warranted to individualize care.
treatment is not defined.3 Hence, the most crucial question has remained For example, RBCT might be beneficial for subnormal HgB with con-
if and when aSAH patients benefit from RBCT. Similar to the current brain tissue hypoxia, but not in case of normal brain tissue
anemia-threshold, RBCT seems to improve cerebral oxygenation and oxygenation. Otherwise, as a solution to any potential negative effect of
energy metabolism and clinical outcome when HgB has fallen below RBCT, other oxygen-carrying agents (e.g. SANGUINATE) have been
9–10 g/dL,57,58 but not in all studies.59 One important concern has been suggested as treatments to improve cerebral oxygenation in aSAH.64
if the potential improvement in cerebral oxygenation from RBCT, in ef- Interestingly, hemodilution, which is part of HHH-therapy, may seem
fect, outweighs the treatment risks. The potential negative effects of contradictory to the RBCT-approach. The idea of hemodilution is CBF
RBCT are not fully understood, but may include a worsening in cerebral augmentation to improve CDO2, but it occurs at the expense of a lower
pressure autoregulation,60 increased inflammatory response, as well as CaO2, and from a mechanistic point of view it is not fully clear if the CBF
cardiac and respiratory dysfunction.61,62 The risks of RBCT have led to augmentation occurs due to improved blood rheology or is a partial
explorations of “restricted” (HgB 7 g/dL) rather than “liberal” (10 g/dL) compensation to counteract an increased tissue hypoxia.65 Most aSAH
thresholds for RBCT, where the more restricted approach appears safe studies have confirmed that hemodilution leads to higher CBF, but that it

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does not translate into any CDO2 improvement.8,66 Consequently, he- likely off-set by the corresponding increase in hypoglycemic events from
modilution does not benefit cerebral oxygenation, but there are perhaps IIT.90 Systemic continuous glucose monitoring could facilitate IIT by
other advantages of the CBF augmentation.67 Specifically, higher CBF earlier detection of imminent hypoglycemia, but the reliability of these
may increase CDGlc and in theory also clearance of cerebral waste continuous monitors has been questioned.91 In addition, as a way to
products. individualize care, it has been suggested to guide arterial glucose man-
To conclude, controversy remains regarding how to optimize CaO2 in agement based on microdialysis monitoring of cerebral glucose, e.g. by
aSAH. Both RBCT and hemodilution remain two apparanetly contradic- administration of intravenous glucose infusion in cases of low MD-glu-
tory treatment approaches for DCI. However, in theory, it may be that cose.92 However, this has not been sufficiently studied to implement in
RBCT is beneficial in case of brain tissue hypoxia to improve CDO2, clinical practice.
whereas the CBF augmentation may be more relevant when the pre- Currently, a more loose and less intense arterial glucose management
dominant pathomechanism is mitochondrial dysfunction in order to is generally favored, as NCC recommends to keep it between 4.4 and
drive anerobic energy metabolism. MMM-protocols could then be of 11.1 mM and possibly to adjust this based on low microdialysis-levels,4
value to further diagnose the cause of energy metabolic disturbance in whereas AHA generally recommends avoiding hypoglycemia.3 A com-
order to individualize CBF- and CaO2-oritented treatments. bination of a more reliable technique to continuously measure systemic
glucose combined with cerebral microdialysis-glucose monitoring could
3.2.2. Arterial oxygenation perhaps further refine arterial glucose management.
As already outlined, changes in the partial pressure of oxygen (pO2)
has a great influence on CaO2 when the SaO2 is low, but not under normal 3.3.2. Arterial lactate
settings with near full saturation. Otherwise, the effects of supranormal The role of lactate as a cerebral fuel has gradually gained acceptance
pO2 on the freely dissolved oxygen content is neglible for CaO2. Although and interest. Lactate is transported via monocarboxylate transporters into
NCC and AHA do not provide any guidelines for pO2,3,4 most centers aim endothelial cells and astrocytes via MCAT1 and into neurons via
for normoxia.5,35 There has also been an interest in normobaric hyper- MCAT2.93 In the astrocyte-neuron-lactate-shuttle (ANLS), astrocytes
oxia as a way to compensate for cerebral ischemia and diffusion limita- metabolize glucose into lactate, which is shuttled to neurons and is there
tions to improve cerebral oxygenation and aerobic energy metabolism. In used for oxidative phosphorylation.93–97 Under normal conditions, the
effect, increasing FiO2 to hyperoxic levels in order to treat low btO2 has arterial contribution to cerebral lactate is low around 10%, but increases
shown promise in TBI,68,69 however hyperoxic pO2-levels may also exert to 60% at 5 mM.98 However, the cerebral lactate uptake can be upre-
adverse effects including cerebral vasoconstriction70,71 and induction of gulated following acute brain injury.97 As the cerebral lactate increases,
reactive oxygen species.72 In aSAH, the negative effects of hyperoxia more is used as cerebral energy fuel, which spares glucose.95,99,100 Still,
seem to predominate, as hyperoxia has been associated with cerebral the use of exogenous lactate as a supplementary cerebral energy fuel
vasospasm,73 DCI,74,75 and unfavorable outcome.74–76 Altogether, nor- remains exploratory at the moment. However, it is worth mentioning that
moxia around 12 kPa with near maximal oxygen saturation seems most lactate solutions may exert additional cerebral effects. High arterial
beneficial. However, it remains to be determined if hyperoxia is only lactate may induce cerebral vasodilation and augment CBF,99,101
negative or may be beneficial in certain clinical states of e.g. diffusion although possibly at the expense of a worse pressure autoregulation.35,102
limitations due to edema or to overcome mitochondrial dysfunction, Furthermore, lactate in hypertonic solutions may be beneficial to reduce
based on MMM-analysis. brain edema and thereby reduce ICP.95 Altogether, further MMM studies
are needed to better determine the role of exogenous lactate infusions on
3.3. Cerebral delivery of nutrients cerebral physiology.

The content of the arterial nutrients glucose and lactate together with 3.4. Cerebral energy metabolism
CBF determine the CDGlc and CDLac. In this section, optimization of the
arterial content of glucose and lactate are discussed in detail. CaO2, CaGlc, CaLac, and CBF are important variables to optimize the
cerebral energy metabolic supply for neuronal survival. However, there
3.3.1. Arterial glucose thresholds and management are several additional variables that interfere with the capacity to
The arterial glucose content is under normal conditions regulated generate energy as well as the requirements of energy metabolic turn-
within a narrow interval, but aSAH typically induces an acute and often over, as described below.
persistent elevation in arterial glucose post-ictus due to activation of the
hypothalamic-pituitary-adrenal (HPA)-axis, hypothalamic damage/ 3.4.1. Hypo- and hyperthermia – temperature management
dysfunction, and systemic inflammation.35,77–79 Stress-induced hyper- The body has under normal conditions a tightly regulated set-
glycemia may compensate for eventual low CBF in order to attenuate temperature around 37  C. There is controversy over the exact defini-
neuroglucpoenia, but hyperglycemia may also exert several negative tions of hypo-, normo-, and hyperthermia in the literature, however,
systemic and cerebral effects. Particularly, hyperglycemia increases the T < 36  C, 36  C  T  38, and T > 38  C would be one example applied
risk of systemic complications including infections, disturbed wound by our institution.21,103 In addition, systemic and brain temperature are
healing, and respiratory dysfunction.77,80,81 In addition, hyperglycemia usually highly correlated, but brain temperature may be up to 1–2  C
is associated with disturbed cerebral energy metabolism82 and develop- higher following acute brain injury,104 secondary to elevated heat pro-
ment of DCI,82–84 possibly due to more vasospasm, microvascular duction from increased energy metabolism.
thrombi, increased systemic inflammation, and excacerbated reperfusion The natural course of body temperature follows a biphasic pattern
injury.77 Several studies have also established an association between after aSAH. Particularly in poor-grade cases with transient global
hyperglycemia and unfavorable clinical outcome in aSAH.35,79,82,83 ischemia, body temperature initially falls, possibly as a neuroprotective
Consequently, optimizing arterial glucose is of great importance and this mechanism, the first hours and then hyperthermia usually gradually
subject has received much interest and also led to great controversy both develops.105 Major drivers of hyperthermia are infectious complications
in general intensive care unit populations80,81 as well as after acute brain during NIC and neurogenic mechanisms. Neurogenic fever is common in
injury85–88 including aSAH.89,90 Specifically, intensive insulin therapy poor-grade cases with a greater burden of SAH and IVH106 and the un-
(IIT) to keep arterial glucose within a tight interval (e.g. 4.4–6.1 mM) derlying explanation is a change in temperature set point due to toxic and
leads to a significant reduction in mean arterial glucose-levels, but also inflammatory effects of the SAH/IVH and/or ischemic complications in
increases the incidence of hypoglycemia.90 Patients with aSAH are very the brainstem and hypothalamus.107
vulnerable to hypoglycemia and the gain in avoiding hyperglycemia is Several previous studies demonstrate an association between

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hyperthermia and negative outcomes in aSAH, including worse cerebral turnover leading to neuronal cell death.127 Both AHA and NCC state that
energy metabolism,108 development of DCI,106,109 and poor neurological short-term seizure prophylaxis may be considered in the acute phase,3,4
recovery.21,106,109,110 One explanation is that hyperthermia, per se, in- although NCC points out that phenytoin has been associated with
duces negative cerebral effects including increased cerebral energy worsened long-term outcome and should be avoided.4 NCC also suggests
metabolism, cerebral hyperemia, blood–brain-barrier disruption and the use of continuous EEG to assess for non-convulsive seizures in pa-
cerebral edema, intracranial hypertension, and excitotoxicity.111 How- tients who fail to improve.4
ever, the direction of the association between hyperthermia and poor A distinct, but akin neuroelectric phenomenom is cortical spreading
aSAH outcomes is not always clear and hyperthermia is to a great extent depolarization (CSD), characterized by a moving gradient of cortical
also an epiphenomenon of a worse primary and secondary brain injury. membrane depolarization with subsequent electrical depression and
Current guidelines recommend avoiding hyperthermia, although the associated CBF disturbances (inverse neurovascular coupling).127–129
treatment threshold and therapeutic approaches remain largely varied This may ultimately result in disturbed cerebral energy metabolism and
among guidelines and centers. AHA provides a recommendation to avoid cell death. There are currently no specific treatments for CSD, but it has
hyperthermia in general by using standard treatments, without any generally been suggested beneficial to optimize systemic and cerebral
further specifications.3 NCC recommends avoiding hyperthermia physiology. Furthermore, glutamate seems to be a major contributor to
(without any strict threshold), particularly in the vasospasm phase, by CSD and various pharmacological agents targeting glutamate synthesis
using acetaminophen and NSAIDs at first hand and surface cooling and and receptor-antagonists have also been suggested.127
intravascular devices at second hand, while avoiding shivering.4 The In conclusion, this is an emerging areas of NIC, studies of CSD, and the
level of evidence for these treatments is low. Specifically, among the role of the newer generation of antiepileptic agents with better tolerance
pharmacological agents, NSAIDs may reduce fever, but could simulta- profiles are much warranted.
neously induce cerebral vasoconstriction, and worsen CPP and btO2,
predisposing for negative net effects on the brain, in addition to risks of 3.4.3. Mitochondrial dysfunction
systemic complications (kidney injury).112 Among the various cooling Energy is produced via anaerobic glycolysis and aerobic oxidative
techniques, intravascular cooling shows some promise at least in TBI, as phosphorylation, in which the former only generates a small proportion
initiation of cooling improves cerebral energy metabolism.113 A major of the total energy production. Functioning mitochondrias are therefore
concern with this approach is the risk of inflicting stress and shivering, key for energy production. In recent years, the understanding of mito-
which may rather worsen cerebral physiology.114 Furthermore, thera- chondrial dysfunction as a pathophysiological mechanism in acute brain
peutic hypothermia has received great interest as a potential neuro- injuries including aSAH has gained increased understanding and inter-
protective treatment in acute brain injuries, however, so far, any true est.67,130,131 Microdialysis studies indicate that mitochondrial dysfunc-
benefit on outcome remains unclear in general as well as in aSAH. Spe- tion is common after aSAH67,132 and is associated with poor clinical
cifically, in aSAH, therapeutic hypothermia has been mostly studied as an outcome.133 It has been speculated if arterial hyperoxia could improve
intraoperative neuroprotective adjunct during surgery for ruptured oxidative aerobic energy metabolism in the mitochondria.134 Pharma-
intracranial aneurysms, which was shown to be safe, but did not improve cological agents such as cyclosporin have been tried as potential neuro-
neurological outcomes.115,116 AHA does currently not recommend it on a protective agents to ameliorate this pathological energy metabolic state
general basis, but holds it as an option.3 Otherwise therapeutic hypo- in TBI studies,135 but there are otherwise no current available therapies
thermia has been used to treat DCI117 and elevated ICP118 in case series, during NIC. This is also an emerging field that needs better under-
but without any conclusive evidence for its use. Similarly, although standing and therapeutic agents.
therapeutic hypothermia initially seemed promising in TBI,119 recent
studies have shown that hypothermia neither improves outcome if used 4. Cellular and molecular injury processes and the role of
to reduce intracranial hypertension prophylactically120 or therapeuti- neuroprotective agents
cally.121 Similarly, after cardiac arrest, initial studies found promising
neurological results with therapeutic hypothermia,122 whereas more Cerebral physiology as well as cellular and molecular injury patterns
recent studies indicate that this treatment does not improve functional compromise a very complex area that currently remains insufficiently
outcomes.123 understood. There have been several attempts to develop and implement
Altogether, hyperthermia is common during the late acute phase of neuroprotective agents in aSAH, but with limit success, similar to the
aSAH and is associated with negative outcomes, but the causality remains case in severe TBI. Some explanations for the disappointing results may
obscure. Currently, hyperthermia is chiefly treated on a symptomatic be animal/patient heterogeneity and differences in therapeutic windows
physiological basis. Particularly in non-infectious, neurogenic hyper- between animal models and human trials. A deeper understanding of the
thermia, the underlying mechanism is not addressed. It is possible that cellular and molecular injury patterns together with MMM-tools to
more granular studies based on protein biomarkers from CSF-/MD- monitor these processes bedside could potentially solve this problem, as
samples9,10 may provide a better understanding of underlying processes discussed below.
such as neuroinflammation and may provide a mechanistic basis for
future treatments. 4.1. Neuroprotective agents

3.4.2. Seizures and cortical spreading depolarizations There are a number of clinical trials that have evaluated different
Epileptic activity is common following acute brain injures in general pharmacological agents to address various aspects of aSAH pathophysi-
as well as after aSAH. This may manifest as focal or generalized ology.136 First, nimodipine is a calcium-channel blocker, which reduces
convulsive and non-convulsive seizures. Seizures occasionally occur DCI and improves outcome, and is the only neuroprotective agent that is
immediately after ictus or re-bleeding and in case of cerebral ischemia integrated in current management guidelines.3,4,137 The mechanism of
and brain herniation.124 Convulsive seizures are typically easy to iden- action was initially thought to counteract cerebral vasospasm, which
tify, whereas non-convulsive seizures are rather detected with electro- proved not to be the case,137 and other important but less understood
encephalography (EEG) in patients in a poor neurological condition mechanisms may be more important. Second, endothelin-receptor an-
without any other clear explanation.125 The rate of seizures based on tagonists have proven to counteract cerebral vasospasm, but without any
clinical criteria has been estimated to occur in between 4 and 26% of the benefit on clinical outcome, possibly as a consequence of associated
cases,124 whereas the rate of epileptic activity may be much higher as adverse effects such as anemia, arterial hypotension, and respiratory
evaluated with EEG and in particular with the more sensitive method failure.138 Third, other agents with a potential beneficial effect on cere-
electrocorticography.126 Seizures may increase ICP and energy metabolic bral vasospasm and DCI include statins139,140 and magnesium

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T. Svedung Wettervik et al. World Neurosurgery: X 18 (2023) 100160

sulphate,141 which, so far, are promising but need further validation.3,4 inherent limitations of MMM tools and proceed with methodo-
Fourth, mitochondrial dysfunction is common after aSAH67 and as out- logical innovation. Artificial intelligence may prove to be benefi-
lined above, cyclosporin has been used to treat this condition in TBI,135 cial in this attempt.
but it remains to be tested in aSAH. Fifth, there are several emerging iv) A major step towards MMM development and individualized
agents such as cilostazol that may exert broad-spectrum beneficial neu- treatments is to go from the physiological to the cellular and
roprotective effects that need to be further explored in future randomized molecular level of cerebral injury mechanisms. Large-pore cere-
controlled trials.140 Sixth, although tranexamic acid is not directly neu- bral microdialysis with bedside online measurements of bio-
roprotective, it could be viewed as that in one sense, since administration markers related to neuroinflammation, neurodegeneration, and
after ictus until aneurysm occlusion may reduce the rate of re-bleedings neurorepair may be one solution in this direction. Specifically, this
and thereby secondary brain injury. However, concerns have also been may be of great importance in order to optimize the indication and
raised regarding increased risk of thromboembolic complications with time window for future neuroprotective pharmacological agents.
this treatment136,142,143 and with modern management including early
aneurysm occlusion it does not seem to add any benefit on long-term
outcome.142 Declaration of competing interest

4.2. Online bedside monitoring of molecular injury patterns – the next step The authors declare no conflict of interest.
in precision medicine?
Acknowledgement
The development of large-pore microdialysis catheters has paved the
way to monitor and analyze complex molecular cascades in the inter- The study was supported by the Department of Medical sciences,
stitial tissue of the brain bedside.144–148 Together with the newly Uppsala University.
developed technique proximity extension assay (PEA),9,10,149 which is a
very sensitive tool to detect small quantities of protein while using only References
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131. Svedung Wettervik T, Hånell A, Howells T, et al. Females exhibit better cerebral https://doi.org/10.1016/j.celrep.2015.12.021.
pressure autoregulation, less mitochondrial dysfunction, and reduced excitotoxicity
after severe traumatic brain injury. J Neurotrauma. 2022. https://doi.org/10.1089/
neu.2022.0097. Abbreviatipons
132. Wettervik TS, Howells T, Hånell A, et al. Intracranial pressure variability: a new
potential metric of cerebral ischemia and energy metabolic dysfunction in
ABP ¼: Arterial blood pressure
aneurysmal subarachnoid hemorrhage? J Neurosurg Anesthesiol. 2022. https://
AHA ¼: American Heart Association
doi.org/10.1097/ANA.0000000000000816. ePub ahead of print.
ANLS ¼: Astrocyte-neuron-lactate-shuttle
133. Kofler M, Gaasch M, Rass V, et al. The importance of probe location for the
aSAH ¼: Aneurysmal SAH
interpretation of cerebral microdialysis data in subarachnoid hemorrhage patients.
BtO2 ¼: Brain tissue oxygenation
Neurocritical Care. 2020;32(1):135–144. https://doi.org/10.1007/s12028-019-
CaO2 ¼: Arterial oxygen content
00713-8.
CBF ¼: Cerebral blood flow
134. Diringer MN, Zazulia AR, Powers WJ. Does ischemia contribute to energy failure in
CDGlc ¼: Cerebral delivery of glucose
severe TBI? Translational stroke research. 2011;2(4):517–523. https://doi.org/
CDLac ¼: Cerebral delivery of lactate
10.1007/s12975-011-0119-8.
CDO2 ¼: Cerebral delivery of oxygen
135. Kelsen J, Karlsson M, Hansson MJ, et al. Copenhagen head injury ciclosporin study:
CPP ¼: Cerebral perfusion pressure
a phase IIa safety, pharmacokinetics, and biomarker study of ciclosporin in severe
CPPopt ¼: The optimal CPP, i.e. with the most optimal autoregulatory status (lowest PRx)
traumatic brain injury patients. J Neurotrauma. 2019;36(23):3253–3263. https://
CSD ¼: Cortical spreading depolarization
doi.org/10.1089/neu.2018.6369.
CSF ¼: Cerebrospinal fluid
136. Young AM, Karri SK, Helmy A, et al. Pharmacologic management of subarachnoid
DC ¼: Decompressive craniectomy
hemorrhage. World neurosurgery. 2015;84(1):28–35. https://doi.org/10.1016/
DCI ¼: Delayed cerebral ischemia
j.wneu.2015.02.004.
EEG ¼: Electroencephalography
137. Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral
EVD ¼: External ventricular drainage
infarction and outcome after subarachnoid haemorrhage: British aneurysm
Hgb ¼: Hemoglobin
nimodipine trial. BMJ (Clinical research ed). 1989;298(6674):636–642. https://
HHH ¼: Hypervolemia, hemodilution, and hypertension
doi.org/10.1136/bmj.298.6674.636.
HPA ¼: Hypothalamic-pituitary-adrenal
138. Macdonald RL, Higashida RT, Keller E, et al. Clazosentan, an endothelin receptor
ICH ¼: Intracerebral hemorrhage
antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing
ICP ¼: Intracranial pressure
surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial
IIT ¼: Intensive insulin therapy
(CONSCIOUS-2). Lancet Neurol. 2011;10(7):618–625. https://doi.org/10.1016/
IMPACT ¼: International mission for prognosis and analysis of clinical trials in TBI
s1474-4422(11)70108-9.

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T. Svedung Wettervik et al. World Neurosurgery: X 18 (2023) 100160

IVH ¼: Intraventricular hemorrhage PRx ¼: Pressure reactivity index

MMM ¼: Multimodality monitoring RBCT ¼: Red blood cell transfusion
NCC ¼: Neurocritical Care Society SAH ¼: Subarachnoid hemorrhage
NIC ¼: Neurointensive care SaO2 ¼: Arterial oxygen saturation
NSAID ¼: Non-steroidal anti-inflammatory drugs sBP ¼: Systolic blood pressure
PEA ¼: Proximity extension assay TBI ¼: Traumatic brain injury

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