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See the corresponding editorial in this issue, pp 891–892.

J Neurosurg 120:893–900, 2014

©AANS, 2014

Patient-specific thresholds of intracranial pressure in severe

traumatic brain injury

Clinical article
Christos Lazaridis, M.D.,1,2 Stacia M. DeSantis, Ph.D., 3 Peter Smielewski, Ph.D.,1
David K. Menon, M.D., Ph.D., F.Med.Sci., 4 Peter Hutchinson, F.R.C.S.(SN), Ph.D.,1
John D. Pickard, F.R.C.S., M.Chir., F.Med.Sci.,1 and Marek Czosnyka, Ph.D.1
Academic Neurosurgical Unit, University of Cambridge Clinical School, Cambridge; 2Department of
Neurology, Divisions of Neurocritical Care and Vascular Neurology, Baylor College of Medicine, Houston;
Division of Biostatistics, School of Public Health at Houston, University of Texas, Houston, Texas; and
University Department of Anaesthesia, Addenbrooke’s Hospital, University of Cambridge, United Kingdom

Object. Based on continuous monitoring of the pressure reactivity index (PRx), the authors defined individual-
ized intracranial pressure (ICP) thresholds by graphing the relationship between ICP and PRx. These investigators
hypothesized that an “ICP dose” based on individually assessed ICP thresholds would correlate more closely with
the 6-month outcome when compared with ICP doses derived by the recommended universal thresholds of 20 and
25 mm Hg.
Methods. This study was a retrospective analysis of prospectively collected data from 327 patients with severe
traumatic brain injury.
Results. Individualized thresholds were visually identified from graphs of PRx versus ICP; PRx > 0.2 was the
cutoff. Intracranial pressure doses were then computed as the cumulative area under the curve above the defined
thresholds in graphing ICP versus time. The term “Dose 20” (D20) was used to refer to an ICP threshold of 20 mm
Hg; the markers D25 and DPRx were calculated similarly. Separate logistic regression models were fit with death as
the outcome and each dose as the predictor, both alone and adjusted for covariates. The discriminative ability of each
dose for mortality was assessed by receiver operating characteristic AUC analysis in which 5-fold cross-validation
was used. A clearly identifiable PRx-based threshold was possible in 224 patients (68%). The DPRx (AUC 0.81, 95%
CI 0.74–0.87) was found to have the highest area under the curve (AUC) over both D20 (0.75, 95% CI 0.68–0.81)
and D25 (0.77, 95% CI 0.70–0.83); in the cross-validation model, DPRx remained the best discriminator of mortality
(DPRx: AUC 0.77 [95% CI 0.68–0.89]; D20: 0.72 [95% CI 0.66–0.81]; and D25: 0.65 [95% CI 0.56–0.73]).
Conclusions. The authors explored the importance of different ICP thresholds for outcome by calculating pa-
tient-specific ICP doses based on the continuous monitoring of cerebrovascular pressure reactivity. They found that
these individualized doses of intracranial hypertension were stronger predictors of death than doses derived from the
universal thresholds of 20 and 25 mm Hg. The PRx could offer a method that can be directed toward individualizing
the ICP threshold.

Key Words      •      intracranial pressure      •      cerebrovascular pressure reactivity      •     

neuromonitoring      •      clinical outcome      •      traumatic brain injury

ntracranial hypertension has been closely linked to ment thresholds. Data from observational studies and
adverse outcomes after traumatic brain injury (TBI); noncontrolled series have suggested thresholds ranging
nevertheless there have been no large randomized tri- from 15 to 25 mm Hg.2,11,20,25,28 The Brain Trauma Foun-
als that directly compare intracranial pressure (ICP) treat- dation’s (BTF’s) latest guideline5 has identified a lack
of Level I evidence and offered, as a Level II, the treat-
Abbreviations used in this paper: ABP = arterial blood pressure; ment threshold of 20 mm Hg, mainly based on the larg-
AUC = area under the curve; BTF = Brain Trauma Foundation; est available prospective observational study, which was
CPP = cerebral perfusion pressure; DECRA = decompressive cra- published by Marmarou et al.20 It is also recognized in
niectomy; D20, D25, DPRx = ICP doses based on thresholds of 20 the BTF guideline that rather than accepting a generic,
mm Hg, 25 mm Hg, and PRx > 0.2; GCS = Glasgow Coma Scale;
GOS = Glasgow Outcome Scale; ICP = intracranial pressure; MAP This article contains some figures that are displayed in color
= mean arterial pressure; PRx = pressure reactivity index; ROC = on­line but in black-and-white in the print edition.
receiver operating characteristic; TBI = traumatic brain injury.

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absolute ICP threshold, an attempt should be made to the Glasgow Coma Scale (GCS) score. The postresuscita-
individualize thresholds based on patient characteristics, tion GCS score was used in patients in whom sedation was
other critical parameters, and on a risk-benefit consider- discontinued immediately following hospital admission. In
ation of treating ICP values. patients who were deemed too unstable to undergo formal
Cerebrovascular pressure reactivity is defined as the neurological assessment on admission, the GCS score col-
ability of vascular smooth muscle to respond to chang- lected on scene was used. The clinical outcome was as-
es in transmural pressure, and represents one of the key sessed at 6 months by using the Glasgow Outcome Scale
mechanisms responsible for autoregulation of cerebral (GOS).16 All monitoring modalities recorded in the study
blood flow.22 Pressure reactivity can be determined by were part of standard clinical care.
observing the response of ICP to changes in mean arte-
rial pressure (MAP); if intact, a rise in MAP will lead Data Acquisition and Processing
within 5–15 seconds to vasoconstriction with reduction The ABP was monitored invasively through the radial
of cerebral blood volume, and ICP will decrease; if de- or femoral artery with the aid of a standard pressure moni-
fective, cerebral blood volume will increase passively toring kit (Baxter Healthcare, CardioVascular Group) and
and ICP will rise. The opposite applies to a reduction in was zeroed at the level of the right atrium. The ICP was
MAP.24 A computer-aided method has been developed at monitored using an intraparenchymal probe (Codman ICP
Cambridge to calculate and monitor the moving coher- MicroSensor, Codman & Shurtleff) inserted into the fron-
ence/correlation index between spontaneous slow waves tal cortex. All signals were digitized using an analog-to-
(20–200 seconds) of MAP and ICP.9,27 digital converter (DT9801, Data Translation), sampled at a
This method derives a pressure reactivity index (PRx) frequency of 100 Hz, and recorded using a laptop computer
that has values in the range between -1 and +1. A negative with ICM+ software (University of Cambridge, Cambridge
or zero value reflects a normally reactive vascular bed, Enterprise, Cambridge, UK,
whereas positive values reflect passive, nonreactive ves- The same software was later used for the
sels. Previous studies have established a significant cor- retrospective analysis of all stored signals. Time-averaged
relation between PRx and outcome after head injury, in- values of ICP, ABP, and CPP (CPP = ABP - ICP) were cal-
cluding a time-dependent element: if PRx persisted above culated using waveform time integration over 60-second
0.2 for more than 6 hours, this was usually associated with intervals. The PRx was calculated as a short-term moving
a fatal outcome.9,10,29 We defined patient-specific, pressure Pearson correlation coefficient between changes in 30 con-
reactivity–guided ICP thresholds by graphing the rela- secutive 10-second averages of ABP and corresponding
tionship between ICP and PRx over the total monitoring ICP signals (with 80% overlap of data). Averaging over 10
time. We hypothesized that an “ICP dose” based on a dis- seconds was used to suppress the influence of pulse and
turbed pressure-reactivity ICP threshold would correlate respiratory waves.
more closely with clinical outcome when compared with
The ICP Thresholds: Definitions and “Dose” Calculations
an ICP dose calculated using the generic, recommended
thresholds of 20 and 25 mm Hg. Our aim was to explore Based on the continuous measurement and monitor-
the predictive ability of individualized ICP thresholds ing of PRx we defined patient-specific, individualized
based on PRx, compared with ICP insults derived from ICP thresholds. These thresholds were visually identified
universal thresholds of 20 and 25 mm Hg. from graphs of PRx versus ICP over the total monitor-
ing time for each patient individually. The cutoff used
was PRx > 0.2; this was chosen based on previous work
Methods from the group demonstrating that at that level there is
Patient Population significant disturbance of pressure reactivity and an in-
creased mortality rate.9,29 The value for the ICP threshold
Monitoring of arterial blood pressure (ABP) and ICP was only accepted if the graph showed a distinct change
in patients following TBI has been an integral part of rou- of PRx values from < 0.2 to consistently > 0.2 (Fig. 1
tine clinical management. The computerized data storage shows 2 examples of individualized ICP threshold deter-
protocol was reviewed and approved by the local ethics mination). To quantify the physiological insult from in-
committee of Addenbrooke’s Hospital, Cambridge Univer- tracranial hypertension we used a method that accounts
sity, and the neurocritical care unit user’s group. All data for the cumulative extent and duration of these episodes.
were prospectively collected and stored. With individual The method computes a “dose” of secondary brain injury
consent from patient representatives, we retrospectively as the cumulative area under the curve above a defined
analyzed anonymized digital recordings of ABP and ICP threshold. The trapezoidal method was used to calculate
waveforms obtained in 327 consecutive patients with se- doses from graphs of ICP versus time; the ICP “dose” is
vere TBI who were admitted to the neurocritical care unit measured in mm Hg*hour.32 For an ICP threshold of 20
at Addenbrooke’s Hospital between 2003 and 2009. mm Hg we named the dose D20. Using the same method-
All patients were sedated, intubated, and received me- ology we calculated D25 and DPRx. For identification of
chanical ventilation during the recording period. A cere- ICP thresholds and calculation of doses the investigators
bral perfusion pressure (CPP)- and ICP-oriented protocol were blinded to clinical outcome.
for management of head injury was used, with CPP main-
tained at > 60 mm Hg and ICP < 20–25 mm Hg.21 Baseline Statistical Analysis
neurological status of each patient was determined using The data are presented as mean or median values

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Pressure reactivity-based individualized ICP thresholds

Fig. 1.  Examples of individualized ICP threshold determination based on PRx > 0.2 for 2 patients.  A: A distinct change is
shown from PRx < 0.2 to PRx > 0.2 at an ICP of 12 mm Hg.  B: Tracings from a different patient in whom the ICP threshold
is 56 mm Hg (PRx changes from < 0.2 to > 0.2 at a range of 54–58 mm Hg). Both patients subsequently developed refractory
intracranial hypertension.

with their standard deviation or range, where appropri- idated AUC and the 5th and 95th percentiles, and provide
ate. The nonparametric Wilcoxon rank-sum test was used an estimate of how well the different ICP doses would
to compare each measure by GOS status. Nonparametric predict death in a new data set. Statistical analyses were
Spearman correlations and associated p values were used performed using SAS version 9.3 and R 2.14.2 software.
to correlate ICP and PRx. For outcome analysis, 1 mean
value of the variables PRx, CPP, and ICP was calculated
for each patient. The predictive ability of each marker on Results
death was assessed. Logistic regression was performed Descriptive Statistics
for each binary outcome and for each marker in the study.
For each analysis, receiver operating characteristic (ROC) The database population included 327 patients (246
curves were calculated and the area under the curve males, 75%), ranging in age from 15 to 87 years (median
(AUC) was used as a measure of discriminative ability age 36 years). The median baseline GCS score was 6 and
and after adjusting for baseline GCS score, age, and sex. ranged from 3 to 15; 25% of patients had a baseline GCS
Because observed AUCs are “over fit” to the data, to de- score > 8, but their condition subsequently deteriorated,
termine how well the ICP doses would perform in terms requiring critical care and warranting invasive monitor-
of prediction, 5-fold cross-validation of each covariate- ing. The GOS score was missing in 5 patients (1.5%).
adjusted model was performed. For this procedure, the Outcomes were grouped as follows: good recovery in 51
logistic regression model was iteratively fit to four-fifths (16%); moderate disability in 82 (25%); severe disability
of the data, and a predicted AUC was calculated on the in 105 (32%); persistent vegetative state in 9 (3%); and
remaining one-fifth of the data; the 5 AUCs were then av- death in 75 (23%). Patients in persistent vegetative state
eraged. Cross-validated results are presented as cross-val- were excluded from further outcome analysis because

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C. Lazaridis et al.

this group is disproportionally smaller than other out-

come groups, leaving 313 patients for outcome analysis.
Duration of data recording ranged between 1 and 28 days
per patient, with a mean of 4 days. Descriptive statistics
and p values for GCS score, age, MAP, ICP, CPP, and PRx
according to GOS group are reported in Table 1. Age,
GCS score, ICP, CPP, and PRx were significantly differ-
ent based on GOS status (p < 0.05).
The ICP Thresholds and ROC Analysis
Patient-specific ICP thresholds were visually identi-
fied from graphs of PRx versus mean ICP. A clearly iden-
tifiable threshold based on the set criteria was possible
in 224 patients (68%). The mean, median, interquartile
range, and SD values for the ICP threshold based on PRx
were 25, 24, 20–32, and 10, respectively. Figure 2 depicts
the ICP threshold distribution for PRx > 0.2 for the whole
cohort. Separate logistic regression models with death as
the outcome and dose as the predictor (both alone and Fig. 2.  The x axis shows ICP in mm Hg. The ICP threshold distribu-
adjusted for the covariates GCS score, age, and sex) were tion for the whole cohort, as defined by patient-specific, individualized
fit. To assess the discriminative ability of each dose for thresholds for PRx > 0.2. The median value of 24 mm Hg is depicted.
mortality, an ROC analysis was performed and the AUC The mean, interquartile range, and SD were 25, 20–32, and 10, re-
was reported (Table 2). spectively.
In the covariate-adjusted logistic regression model,
all the doses calculated were significantly associated with evated ICP > 30 mm Hg without immediate neurological
death (p < 0.0001 for D20, D25, and DPRx). Furthermore, compromise.4 In contrast, patients with severe TBI are
DPRx (0.81, 95% CI 0.74–0.87) was found to have the thought to have an increased mortality rate after an ICP
highest AUC over both D20 (0.75, 95% CI 0.68–0.81) and threshold that lies between 20 and 25 mm Hg. This can
D25 (0.77, 95% CI 0.70–0.83), indicating that it has the best be attributed to an acute, unaccounted for impairment of
discriminative ability. Cross-validation confirmed the re- free CSF communication; a mechanism serving to equili-
sults of the observed AUCs; in the cross-validated model, brate any detrimental pressure gradients within the cra-
DPRx was still the best predictor of death (DPRx AUC niospinal space (Pascal’s law).
0.77 [95% CI 0.68–0.89], D20 0.72 [95% CI 0.66–0.81], We explored the predictive ability of individual-
and D25 0.65 [95% CI 0.56–0.73]). Figure 3 depicts the ized ICP thresholds based on the PRx, as compared with
resulting observed ROC curves for DPRx versus D20, both “standard” fixed ICP thresholds. We found that the ICP
unadjusted and adjusted for covariates. The larger area un- doses derived from an index describing the status of cere-
der the ROC curve indicates that inclusion of these covari- brovascular pressure reactivity were stronger predictors
ates improves the discriminative ability of the marker. of the 6-month mortality rate compared with doses calcu-
lated based on the “suggested” ICP threshold of 20 mm
Hg and also from a second fixed threshold of 25 mm Hg.
Discussion The most recent version of the BTF guidelines has rec-
Raised ICP is detrimental across different neurologi- ognized the lack of Level I evidence as it pertains to ICP
cal conditions. Different management thresholds apply thresholds.5 The guidelines concluded with proposals, as
depending on the clinical scenario. Patients with chronic key issues for future investigation, to explore methods for
hydrocephalus withstand, without adverse effects, an identifying critical ICP or “herniation pressure,” and for
ICP rise up to 40 mm Hg during infusion studies.18 In identifying physiological parameters that would comple-
pseudotumor cerebri, patients often have chronically el- ment measurements of absolute ICP, in an effort to better
TABLE 1: Patient demographics, clinical variables, and outcome in 322 patients with severe TBI*

GOS Group No. of Pts Age (yrs)† M/F GCS Score† MAP ICP† CPP† PRx†
death 75 45 ± 18 60:15 6±3 95 ± 9 22 ± 11 73 ± 12 0.09 ± 0.2
PVS 9 — — — — — — —
severe disability 105 38 ± 15 78:27 6±3 94 ± 6 16 ± 4 78 ± 6 0.02 ± 0.16
moderate disability 82 32 ± 14 67:15 8±4 93 ± 7 16 ± 5 78 ± 7 0.01 ± 0.14
good recovery 51 34 ± 17 32:19 7±3 94 ± 6 15 ± 4 78 ± 7 −0.01 ± 0.13
total 322 237:85 17.5 ± 7 0.03 ± 0.17

*  Values are expressed as the mean ± SD. The MAP, ICP, CPP, and PRx values were averaged in each patient over the whole monitoring period. Pts =
patients; PVS = persistent vegetative state; — = excluded from further analysis.
†  Significant difference (p < 0.05, ANOVA) between GOS groups.

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TABLE 2: Logistic regression for ICP doses and ROC analysis of predictive power for mortality in patients with severe TBI

Univariate Covariate- Covariate-Adjusted

ICP Dose p Value AUC 95% CI Adjusted p Value* AUC 95% CI Cross-Validated AUC* 95% CI
D20 <0.0011 0.63 0.55–0.70 <0.0001 0.75 0.68–0.81 0.72 0.66–0.81
D25 0.0001 0.65 0.57–0.73 <0.0001 0.77 0.70–0.83 0.65 0.56–0.73
DPRx <0.0001 0.72 0.63–0.80 <0.0001 0.81 0.74–0.87 0.77 0.68–0.89

*  Adjusted for baseline GCS score, age, and sex.

quantify the impact of intracranial hypertension on sec- ized controlled trial of ICP monitoring in severe TBI by
ondary brain injury and neurological outcome. We found Chesnut et al.7 This was the first such trial to compare man-
highly significant correlations of increased mean ICP and agement of intracranial hypertension based on monitoring
ICP dose with mortality rates. Intracranial hypertension and treatment of ICP above the fixed threshold of 20 mm
is commonly encountered in patients with severe TBI Hg, versus a protocol based on clinical examination and
and, although not universally, is widely accepted to cor- neuroimaging. This trial found no benefit of one protocol
relate strongly with neurological outcome.12,23 over the other. It is beyond our scope to discuss this study
Nevertheless, recent publications have challenged the in detail; nevertheless and in conjunction with the afore-
traditional understanding on monitoring and treatment mentioned DECRA trial, we believe that an important as-
of high ICP. Shafi et al.26 analyzed the National Trauma pect in interpreting the results should be the limitation of
Data Bank for the period 1994–2001, comparing patients using fixed, universal ICP thresholds and thus disregarding
who underwent ICP monitoring with those who were patient-specific injury patterns, individual pathophysiol-
not monitored. After adjustment for multiple confound- ogy, and response to treatment interventions.
ing factors, including admission GCS score, age, blood We chose to quantify secondary brain injury caused
pressure, and injury severity score, ICP monitoring was by intracranial hypertension by using a method that ac-
associated with a 45% lower rate of survival. The authors counts for the cumulative extent and duration of these
interpreted this result as a failure of BTF criteria to iden- episodes. This method computes a “dose” of intracrani-
tify the patients who were most likely to benefit from ICP al hypertension as the cumulative area under the curve
monitoring. Further possible explanations include the above a defined threshold. This approach may more accu-
idea that intracranial hypertension is a surrogate for se- rately reflect the impact of secondary brain insults on out-
verity of brain injury, and that treatment interventions are come than did previous methods (for example, tradition-
either ineffective or even potentially harmful. ally taking into account only the mean ICP or the time
In discussing interventions, the recent decompressive spent above a given threshold), because it accounts for
craniectomy (DECRA) trial showed that this intervention, both the degree and the duration of ICP elevation.3,13,17,32
despite effectively reducing ICP, did not translate into im- An additional advantage, as pointed out by Vik et al.,32 is
proved neurological outcomes.8 It is of relevance that the that the predictive power of doses for different thresholds
issue of an appropriate ICP threshold was highlighted as can be explored.
one of the critiques and main differentiating features of the In this study we explored different thresholds by cal-
DECRA trial from the ongoing RESCUEicp (Randomized culating doses based on pressure reactivity and compar-
Evaluation of Surgery with Craniectomy for Uncontrolla- ing them against doses derived from the conventionally
ble Elevation of ICP) study.15 Our findings become further accepted threshold of 20 mm Hg, and from a second fixed
pertinent in view of the recent publication of the random- threshold of 25 mm Hg, because this is the recommended
range in the BTF guidelines. To our knowledge this is
the first report attempting the determination of individu-
alized patient-specific ICP thresholds in patients with se-
vere TBI, using these thresholds to quantify ICP dose per
patient, and comparing these doses to the ones derived
from the currently accepted generic thresholds of 20–25
mm Hg. Although not undertaken in the present work,
similar methodology could be applied in the evaluation
of different CPP thresholds; furthermore, the relative
contribution to secondary brain injury of ICP versus CPP
insults could be explored. Cerebrovascular pressure re-
activity is an intrinsic underlying mechanism of cerebral
blood flow regulation. The status of pressure reactivity
has been shown to be important in bridging CPP with
Fig. 3.  The ROC curves for DPRx versus D20, both unadjusted and
ICP-targeted approaches.14 In the current analysis, as in
adjusted for covariates. The larger area under the ROC curve indicates prior data from our group, the PRx is strongly correlated
superiority of DPRx over D20; also, inclusion of covariates improves the with death (Table 1).
discriminative ability of the markers. Steiner et al.29 and more recently Aries et al.1 have

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demonstrated the value of using the PRx in identifying an used in assessing ICP thresholds with the current meth-
optimal CPP, under and above which outcome worsens. odology. Possible explanations for these patterns relate to
In fact, this work has been recognized and incorporated an insufficient number of data sets either because of in-
in the BTF guidelines as a method of optimizing cerebral adequate recording time or, less likely, because of a high
perfusion.6,19 In addition, we have observed that continu- rate of artifacts (artifacts were minimized mainly because
ous bedside monitoring of PRx in certain circumstances patients were under heavy sedation and neuromuscular
can serve as a physiological alarm before the occurrence blockade). It should be also kept in mind that the calcu-
of refractory intracranial hypertension (Fig. 4, recording lation of PRx requires the presence of spontaneous fluc-
from a patient in our database). Finally, we report here tuations in ABP. Although such fluctuations are present in
that an ICP dose as calculated by a patient-specific ICP the majority of patients following TBI, the magnitude may
threshold corresponding to PRx > 0.2 was the best dis- be insufficient to produce significant ICP changes. In such
criminator of mortality in our cohort and as compared cases the value of PRx will be unreliable.
with doses derived from “fixed” thresholds of 20 and 25 Apart from representing technical limitations, these
mm Hg. patterns could be physiologically interpreted as states of
dissociation between cerebrovascular pressure reactivity
Limitations of the Study and mean ICP. One should also consider that the influ-
Intracranial pressure thresholds were identified ret- ence of treatment targets on the relationship between ICP
rospectively from recordings of the whole period of ICP thresholds and neurological outcomes is unknown. How-
monitoring. The findings, therefore, are not necessarily ever, this bias is inevitable because this is a retrospective
applicable to real-time data collected in the ICU. Thresh- review of patients from 2003 to 2009, who were treated
old determination was done by visual inspection of ICP according to best available contemporary evidence, and
versus PRx graphs; the next step to improve this meth- institutional and international guidelines. Last, in this
odology would include an algorithm for objective and study we did not investigate markers of brain tissue oxy-
automated identification of a patient-specific threshold. genation and metabolism that have been used in attempts
To limit bias, both threshold identification and dose cal- to characterize the physiological burden of intracranial
culation were done by investigators who were blinded to hypertension and to correlate these markers to neurologi-
clinical outcome. cal outcomes.30,31 The interplay between cerebrovascular
We were able to identify a PRx-based ICP threshold in pressure reactivity, tissue oxygenation, tissue metabolism,
two-thirds of our patients; frequent reasons that prevented and ICP is complex and not fully understood. It is plau-
us from identifying a specific threshold are depicted in Fig. sible that information from multimodality monitoring
5. Three patterns emerge: one of disturbed PRx throughout will provide a more complete description of the physi-
the ICP range; a second reverse pattern where PRx remains ological consequences of ICP insults at the tissue level. In
consistently preserved; and a third pattern where PRx var- addition, these multimodality data could potentially serve
ies randomly with ICP. In these situations, PRx cannot be in tailoring treatment thresholds and interventions away

Fig. 4.  An episode of refractory intracranial hypertension is depicted. At time point A, PRx is noted to increase progressively;
shortly thereafter ICP is noted to rise. Time point B is characterized by a precipitous ICP increase.

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Pressure reactivity-based individualized ICP thresholds

Fig. 5.  Examples in which PRx cannot be used in assessing ICP thresholds. Three patterns emerge: one of disturbed PRx
(> 0.2) throughout the ICP range (A); a second reverse pattern in which PRx remains consistently preserved throughout the ICP
range (B); and a third pattern in which PRx varies randomly with ICP (C).

from fixed, generic ICP values, and toward dynamic and Senior Investigator award. Mr. Pickard is an NIHR senior investiga-
patient-specific cerebral physiology. tor awardee and a principal investigator within the NIHR Biomedical
Research Centre (Cambridge University Hospital Foundation Trust)
and lead principal investigator for the MRC “Acute Brain Injury
Conclusions Programme” grant. The remaining authors have not disclosed any
potential conflict of interest.
The predictive ability of individualized ICP thresh- Author contributions to the study and manuscript preparation
olds based on the continuous monitoring of cerebrovascu- include the following. Conception and design: Lazaridis, Czosnyka.
lar pressure reactivity was stronger than fixed thresholds Analysis and interpretation of data: Lazaridis, DeSantis, Smielewski,
of 20 and 25 mm Hg, in a large single-center database of Czosnyka. Drafting the article: Lazaridis, Czosnyka. Critically revis-
ing the article: Lazaridis, Smielewski, Menon, Hutchinson, Pickard,
patients with severe TBI. Monitoring of the PRx could Czosnyka. Reviewed submitted version of manuscript: Smielewski,
supplement ICP monitoring by offering patient-specific Menon, Hutchinson, Pickard, Czosnyka. Approved the final ver-
pathophysiological information. sion of the manuscript on behalf of all authors: Lazaridis. Statistical
analysis: DeSantis. Study supervision: Czosnyka.
We acknowledge great support from Addenbrooke’s Hospital
Neurocritical Care Unit staff and Academic Neurosurgical Unit   1.  Aries MJ, Czosnyka M, Budohoski KP, Steiner LA, Lavinio
registrars, without whose help the collection of computerized data A, Kolias AG, et al: Continuous determination of optimal ce-
would never have succeeded. We also thank Emma Vought, M.S., rebral perfusion pressure in traumatic brain injury. Crit Care
for assistance with figure reproduction. Med 40:2456–2463, 2012
  2.  Balestreri M, Czosnyka M, Hutchinson P, Steiner LA, Hiler
Disclosure M, Smielewski P, et al: Impact of intracranial pressure and
cerebral perfusion pressure on severe disability and mortality
The software for brain monitoring ICM+ (http://www.neuro after head injury. Neurocrit Care 4:8–13, 2006 is licensed by the University of Cambridge   3.  Barton CW, Hemphill JC, Morabito D, Manley G: A novel
(Cambridge Enterprise Ltd.). Mr. Czosnyka and Mr. Smielewski method of evaluating the impact of secondary brain insults on
have a financial interest in a part of the licensing fee. Mr. Hutchinson functional outcomes in traumatic brain-injured patients. Acad
is supported by an Academy of Medical Sciences/Health Foundation Emerg Med 12:1–6, 2005
Senior Scientist Fellowship and grants from the Medical Research   4.  Biousse V, Bruce BB, Newman NJ: Update on the pathophysi-
Council (MRC)/National Institute for Health Research (NIHR). He ology and management of idiopathic intracranial hyperten-
has also received a lecture honorarium from Codman and is a pat- sion. J Neurol Neurosurg Psychiatry 83:488–494, 2012
ent holder in Technicam. Mr. Menon is supported by funding from   5.  Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond
the MRC, the NIHR Cambridge Biomedical Centre, and an NIHR FF, Harris OA, Hartl R, et al: Guidelines for the management

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