doi: 10.1136/jnnp.2008.156596March 16, 2009

2009 80: 916-920 originally published onlineJ Neurol Neurosurg Psychiatry M Oddo, J M Levine, S Frangos, et al. intracranial hypertensiontraumatic brain injury and refractorycerebral oxygenation in patients with severe Effect of mannitol and hypertonic saline on

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Effect of mannitol and hypertonic saline on cerebraloxygenation in patients with severe traumatic braininjury and refractory intracranial hypertension

M Oddo,1 J M Levine,1,2,3 S Frangos,1 E Carrera,4 E Maloney-Wilensky,1 J L Pascual,5

W A Kofke,1,3 S A Mayer,4 P D LeRoux1

1 Department of Neurosurgery,University of PennsylvaniaMedical Center, Philadelphia,Pennsylvania, USA;2 Department of Neurology,University of PennsylvaniaMedical Center, Philadelphia,Pennsylvania, USA;3 Department of Anesthesiologyand Critical Care, University ofPennsylvania Medical Center,Philadelphia, Pennsylvania, USA;4 Department of Neurology,Critical Care Division, ColumbiaUniversity Medical Center, NewYork, New York, USA;5 Department of Surgery,University of PennsylvaniaMedical Center, Philadelphia,Pennsylvania, USA

Correspondence to:P D LeRoux, Department ofNeurosurgery, Clinical ResearchDivision, University ofPennsylvania Medical Center,Philadelphia, Pennsylvania, USA;Peter.LeRoux@uphs.upenn.edu

This work was performed at theNeurointensive Care Unit,University of PennsylvaniaMedical Center, Philadelphia,Pennsylvania, USA.

Received 24 June 2008Revised 17 February 2009Accepted 26 February 2009Published Online First16 March 2009

ABSTRACTBackground: The impact of osmotic therapies on brainoxygen has not been extensively studied in humans. Weexamined the effects on brain tissue oxygen tension(PbtO2) of mannitol and hypertonic saline (HTS) in patientswith severe traumatic brain injury (TBI) and refractoryintracranial hypertension.Methods: 12 consecutive patients with severe TBI whounderwent intracranial pressure (ICP) and PbtO2 mon-itoring were studied. Patients were treated with mannitol(25%, 0.75 g/kg) for episodes of elevated ICP (.20 mmHg) or HTS (7.5%, 250 ml) if ICP was not controlled withmannitol. PbtO2, ICP, mean arterial pressure, cerebralperfusion pressure (CPP), central venous pressure andcardiac output were monitored continuously.Results: 42 episodes of intracranial hypertension, treatedwith mannitol (n = 28 boluses) or HTS (n = 14 boluses),were analysed. HTS treatment was associated with anincrease in PbtO2 (from baseline 28.3 (13.8) mm Hg to34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at60 min and 41.4 (17.7) mm Hg at 120 min; all p,0.01)while mannitol did not affect PbtO2 (baseline 30.4 (11.4)vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; allp.0.1). Compared with mannitol, HTS was associatedwith lower ICP and higher CPP and cardiac output.Conclusions: In patients with severe TBI and elevatedICP refractory to previous mannitol treatment, 7.5%hypertonic saline administered as second tier therapy isassociated with a significant increase in brain oxygena-tion, and improved cerebral and systemic haemody-namics.

Intracranial hypertension is common after severetraumatic brain injury (TBI) and may adverselyaffect outcome.1 2 Control of intracranial pressure(ICP) is therefore a mainstay of treatment aftersevere TBI. Osmotherapy is frequently used tocontrol ICP. Although no firm recommendationsexist, mannitol is more frequently used as a firsttier therapy for elevated ICP while hypertonicsaline (HTS) is given as a secondline therapy inpatients unresponsive to mannitol therapy.3 Thecomparative effects of these two agents on cerebralphysiology, rather than ICP alone, after severe TBIare only beginning to be elucidated. While someauthors report that mannitol and HTS have asimilar effect, at least when given in equimolardoses,4 others have demonstrated that HTS may bemore effective than mannitol in reducing elevatedICP in patients with severe TBI.5 6 In addition to itspotent osmotic effect, HTS has beneficial effectson vascular tone,7 and in animal models of TBI,

HTS improves systemic haemodynamics,8 9 cere-bral blood flow (CBF)9–11 and may enhance cerebralmicrocirculation by reducing the adhesion ofpolymorphonuclear cells12 13 and by stimulatinglocal release of nitric oxide.14

Although ICP and cerebral perfusion pressure(CPP) traditionally are the major targets of TBItreatment, the interstitial partial pressure ofoxygen in brain tissue (PbtO2) is emerging as anadditional complementary therapeutic target.Specialised sensors placed directly into brainparenchyma allow for continuous bedside assess-ment of PbtO2 and for the quantification ofsecondary hypoxic events that occur after theinitial brain insult.15 Observational clinical studiesdemonstrate a relationship between reduced PbtO2

and poor outcome16 17 and suggest that PbtO2

targeted therapy may improve clinical outcomes.18

It is therefore important to understand howvarious treatments options impact on PbtO2.

There has been limited study on the effect ofdifferent osmotic therapies on PbtO2 in braininjured patients and the results vary. For example,in patients with TBI with elevated ICP, mannitoldoes not consistently improve PbtO2.12 19 In con-trast, in patients with intracranial hypertensionafter subarachnoid haemorrhage, HTS mayincrease CBF20 21 and PbtO2.22 However, little isknown about the impact of HTS on PbtO2 inpatients with severe TBI and intracranial hyper-tension, and in particular those with elevated ICPrefractory to mannitol. In this study, we examinedhow mannitol and HTS, used to treat recurrentepisodes of elevated ICP, influenced brain oxygenin patients with severe TBI.

CLINICAL MATERIAL AND METHODS

Patient populationConsecutive patients with severe TBI admitted tothe Hospital of the University of Pennsylvania, alevel I trauma centre, and who underwent PbtO2

monitoring in the neurointensive care unit wereretrospectively identified from a prospective obser-vational database (the Brain Oxygen MonitoringOutcome study) over a 2 year period (2005–2006).Severe TBI was defined by (1) a history of trauma,(2) a post-resuscitation admission Glasgow ComaScale score (8 and (3) clinical and radiographicexclusion of alternate causes of coma. Patients whoreceived osmotherapy with both mannitol andHTS to treat refractory intracranial hypertension(defined as the occurrence of recurrent episodes of

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ICP .20 mm Hg for more than 10 min despite initial medicalmanagement) were included in the analysis. Patients who hadbilateral fixed and dilated pupils at admission were excluded fromthe study. Our Institutional Review Board approved the study.

Intracranial and systemic monitorsICP, brain temperature and PbtO2 were continuously monitoredusing commercially available products (Licox, IntegraNeuroscience, Plainsboro, New Jersey, USA). Intracranialmonitors were inserted at the bedside in the neurointensivecare unit through a burr hole into the frontal lobe and securedwith a triple lumen bolt. The monitors were placed into whitematter that appeared normal on head CT and on the side ofmaximal pathology. When there was no asymmetry in brainpathology on CT, the probes were placed in the right frontalregion. If the patient had undergone a craniotomy, the probeswere placed on the same side as the injury if the craniotomy flappermitted. Follow-up head CT scans were performed in allpatients within 24 h of admission to confirm correct placementof the various monitors (eg, not in a contusion or infarct). Probefunction and stability was confirmed by an appropriate PbtO2

increase following an oxygen challenge (inspired O2 fraction(FiO2) 1.0 for 5 min). PbtO2 measurements were corrected forbrain temperature fluctuations. To allow for probe equilibra-tion, data from the first 6 h after PbtO2 monitor insertion werediscarded.

Each patient had an indwelling arterial (radial artery)catheter. Heart rate, blood pressure (through the arterial line)and arterial oxygen saturation (SaO2) were recorded continu-ously in all patients. CPP was calculated from the measuredparameters (CPP = MAP–ICP (corrected for ICP and arterialcatheter position)). Patients had a pulmonary artery catheter,and central venous pressure and cardiac output (thermodilu-tion) were recorded. As part of routine care, FiO2, SaO2,respiratory rate and ventilator settings (eg, ventilator mode,tidal volume, minute ventilation and positive end expiratorypressure) were recorded in the ICU flowsheet every 15 min.Arterial blood gas analysis was usually performed at 08:00 and20:00 each day while the patient was ventilated and if there wasany significant cardiopulmonary change or at the discretion ofthe neuro-intensivist. Arterial samples were analysed forhaemoglobin, arterial oxygen (PaO2) and carbon dioxide(PaCO2) tension and pH.

General patient managementAll patients were managed in the neurointensive care unitaccording to a local algorithm based on the Brain Trauma

Foundation TBI guidelines.3 This included early evacuation ofspace occupying mass lesions in the operating room. Eachpatient was fully resuscitated according to Advanced TraumaLife Support guidelines from the American College of Surgeons,intubated and mechanically ventilated with the head of the bedinitially elevated ,20–30u. FiO2 and minute ventilation wereadjusted to maintain SaO2 .93%, PaO2 between 90 and100 mm Hg and PaCO2 between 34 and 38 mm Hg. Volumeresuscitation was achieved with 0.9% normal saline andalbumin for a target central venous pressure (CVP) of 6–10 cm H2O. After adequate fluid resuscitation, CPP was keptabove 60 mmHg, using vasopressors if required. Vasopressors(mainly phenylephrine) were only used to ensure adequate CPP,and patients who received vasopressors for cardio-circulatoryfailure were excluded from the present study.

Management of elevated ICPA standard stair step approach was used to treat intracranialhypertension. Therapeutic targets were adjusted to maintainICP ,20 mm Hg and CPP .60 mm Hg. Initial managementconsisted of head of bed elevation, sedation (lorazepam),analgesia (fentanyl), muscle paralysis (vecuronium) and inter-mittent cerebrospinal fluid drainage using an external ventri-cular drain. Optimised moderate hyperventilation (PaCO2 30–35 mm Hg) was used selectively to control ICP provided PbtO2

did not decrease during this intervention.

OsmotherapyIf ICP remained .20 mm Hg for more than 10 min despite theinitial management, osmotherapy was started, provided thatserum osmolarity was ,320 mosmol and serum sodium,155 mmol/l. In all 12 patients, mannitol (25%, 0.75 g/kg,412 mosmol/dose, infused over 20 min) was administered asfirstline treatment of intracranial hypertension. HTS (7.5%solution, 250 ml, 641 mosmol/dose, infused over 30 min) wasused as a secondline therapy to control ICP. The decision toinfuse HTS was made at the discretion of the treating neuro-intensivist and based on each patient’s overall therapeuticintensity. However, according to our management protocol,HTS could only be used if a patient had already receivedmannitol for a previous episode of increased ICP or had a MAP(90 mm Hg. HTS was contraindicated if CVP was .

15 mm Hg, or the patient had chronic hyponatraemia, heartfailure or diabetes insipidus.

Data collection and analysisAll physiological variables (ICP, brain temperature, MAP, CPP,CVP, SaO2 and PbtO2) were recorded continuously using abedside monitor (Component Monitoring System M1046-9090C; Hewlett Packard, Andover, Massachusetts, USA).These variables and respiratory rate, FiO2, ventilator settings(ie, ventilatory mode, tidal volume, minute ventilation andpositive end expiratory pressure) and cardiac output wererecorded in the intensive care unit flowsheet every 30 min.Cardiac output was measured with the use of a pulmonaryartery catheter. Serum sodium and osmolarity before and aftertreatment were also measured. As the duration of ICP reductionusually is maintained for 60–120 min after bolus administrationof both mannitol23 and HTS,7 24 ICP and other physiologicalvariables were averaged at 30, 60 and 120 min after each bolusadministration. Treatment baseline was defined as the average

Table 1 Patient clinical characteristics

Characteristic

n 12

Age (years) 36 (16)

Sex (women/men) 3/9

Injury type (n)

Diffuse injury 6

Subdural haematoma 6

Admission Glasgow Coma Scale (median (range)) 3 (3–8)

Time from admission to initiation of PbtO2 monitoring (hours) 8 (7)

Total duration of PbtO2 monitoring (days) 8 (3)

Hospital length of stay (days) 20 (13)

Mortality (n (%)) 4/12 (33)

Data are expressed as mean (SD) unless otherwise indicated.PbtO2, brain tissue oxygen pressure.

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of all values obtained during the 120 min before a bolus wasadministered. At each time point, means for each variable weremeasured for each bolus of mannitol and HTS.

Statistical analysisAs patients received a variable number of boluses of mannitoland HTS, one grand average of treatment was calculated foreach individual patient. For each variable, differences betweenmannitol and HTS treatments at all time points were thenanalysed with ANOVA for repeated measures. The JMP startersoftware (SAS Institute Inc, Cary, North Carolina, USA) wasused for data analysis. For all analyses a p value ,0.05 wasconsidered to be statistically significant.

RESULTS

Patient characteristicsTwelve consecutive patients with severe TBI (nine men andthree women, mean age 36 (16) years, median admission GCSscore 3 (range 3–8)) were studied. Baseline clinical anddemographic characteristics are shown in table 1. One-third ofpatients died.

Effect of osmotherapy on PbtO2

A total of 42 episodes of intracranial hypertension treated withmannitol (n = 28 boluses) or HTS (n = 14 boluses) wereanalysed. The median number of boluses analysed per patientwas 2 (range 1–4) for mannitol and 1 (1–2) for HTS. Themedian time interval between mannitol and HTS administra-tion was 8.6 (interquartile range 4.3–16.7) h. Effect of HTS andmannitol on brain oxygen is shown in fig 1. After HTS, PbtO2

increased from a mean pretreatment value of 28.3(13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0(17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min(all p,0.01). In contrast, mannitol was associated with a non-significant decrease in PbtO2 from the pretreatment value (30.4(11.4) mm Hg) at 30 min (28.7 (13.5) mm Hg), 60 min (28.4(10.6) mm Hg) and 120 min (27.5 (9.9) mm Hg). Comparedwith mannitol, HTS treatment was associated with higherlevels of PbtO2 at all times analysed. In particular, brain tissueoxygen after HTS was significantly greater at 60 and 120 minthan after mannitol (see fig 1).

Effect of osmotherapy on other cerebral and systemic variablesMean pretreatment values for ICP, MAP, CPP, CVP and cardiacoutput were similar for mannitol and HTS treatments. Baselineand post-osmotherapy PaO2/FiO2 ratio, respiratory rate andventilator settings (including FiO2) were similar in the twotreatment groups. Arterial blood gas analysis was not performedduring osmotherapy: however, SaO2, FiO2 and ventilatorsettings were stable during all interventions.

Mannitol and HTS were both associated with a significantICP reduction. However, at 60 and 120 min, HTS treatmentwas associated with lower ICP and higher CPP than mannitol(table 2). The decrease in ICP and PbtO2 increase did notdemonstrate a significant correlation. In addition, HTS bolusadministration was associated with an increase in cardiacoutput that was more significant than mannitol at all timepoints analysed. MAP and CVP did not differ significantlybetween treatment groups at each time point.

Baseline serum sodium and osmolarity were similar beforemannitol or HTS administration. At the end of the studyperiod, HTS treatment was associated with higher serumsodium (141 (6) before vs 149 (6) mmol/l after; p,0.01).Osmolarity did not differ significantly between the twotreatments. After HTS treatment, hypernatraemia (serumsodium .155 mmol/l) was observed in three patients. No othercomplications (eg, pulmonary oedema, renal failure) associatedwith osmotherapy were observed.

DISCUSSIONWe analysed 12 consecutive patients who received osmotherapywith both mannitol (28 treatments) and HTS (14 treatments)for refractory intracranial hypertension after severe TBI. We

Figure 1 Line graph illustrating mean (SD) brain tissue oxygen pressure(PbtO2) at baseline (time 0) and at 30, 60 and 120 min after hypertonicsaline and mannitol bolus administration. *p,0.05, **p,0.01 forcomparisons between the two treatments.

Table 2 Physiological variables before and after a mannitol orhypertonic saline bolus for elevated intracranial pressure

Variable MannitolHypertonicsaline p Value

ICP (mm Hg)

Baseline 29 (8) 27 (8) 0.40

30 min 21 (8) 17 (7) 0.15

60 min 23 (12) 15 (6) ,0.001

120 min 24 (9) 15 (5) ,0.001

MAP (mm Hg)

Baseline 87 (15) 90 (12) 0.52

30 min 85 (23) 93 (16) 0.18

60 min 84 (25) 89 (14) 0.26

120 min 88 (13) 90 (14) 0.27

CPP (mm Hg)

Baseline 60 (17) 63 (15) 0.56

30 min 71 (16) 78 (18) 0.32

60 min 67 (20) 76 (16) 0.05

120 min 65 (19) 76 (17) 0.02

CVP (cm H2O)

Baseline 7 (3) 7 (4) 0.86

30 min 6 (3) 8 (5) 0.21

60 min 6 (2) 7 (4) 0.33

120 min 6 (3) 7 (4) 0.79

Cardiac output (l/min)

Baseline 6.7 (1.5) 6.4 (1.8) 0.76

30 min 6.3 (0.9) 7.5 (1.4) 0.003

60 min 6.6 (1.2) 7.8 (1.7) 0.007

120 min 6.1 (1.0) 7.5 (1.4) 0.002

Data are expressed as mean (SD).CPP, cerebral perfusion pressure; CVP, central venous pressure; ICP, intracranialpressure; MAP, mean arterial pressure.

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observed that: (1) HTS was associated with a significantimprovement in PbtO2; (2) HTS treatment was also associatedwith both an effective reduction of ICP and a significantimprovement in cardiac output; and (3) compared withmannitol, HTS had a more favourable effect on PbtO2, ICP,CPP and cardiac output.

Hypertonic saline and PbtO2

The positive impact of HTS on PbtO2 was observed within30 min and was statistically significant at 60 and 120 min.Hypertonic saline solutions may improve PbtO2 by increasingCBF, through multiple complementary mechanisms involvingthe cerebral macro- and/or microcirculation. Firstly, CBF mayincrease as ICP decreases, thereby increasing CPP. Consistentwith this, the increase in PbtO2 was significant at 60 and120 min when the beneficial effect of HTS on ICP and CPPlevels were most notable. In addition, as the PbtO2 probe is inwhite matter that appears ‘‘normal’’ on CT it is possible thatautoregulation is altered. However, we did not measure CBF orautoregulation and this will need future study. Anotherpossibility is that HTS improved PbtO2 through a relativeaugmentation of cardiac output which, in turn, may havecaused an increase in oxygen delivery and CBF. The effect ofHTS on cardiac output has previously been documented in non-neurological25 and neurological critically ill patients.26 Forreasons that are poorly understood, intracranial hypertensionis associated with reduced systolic function.27 28 It is thereforeplausible after severe TBI that HTS augments cardiac outputnot only by directly increasing cardiac preload but alsoindirectly by lowering ICP. This hypothesis warrants furtherstudy. A final possibility is that HTS improves PbtO2 byimproving flow in the cerebral microcirculation, by reducingserum viscosity, by improving endothelial function12 29 and/orthrough anti-inflammatory and antiapoptotic properties,30 all ofwhich improve CBF and brain oxygen delivery.11 20 21 31 Ourfindings are consistent with others in patients with acute braininjury22 and suggest that hypertonic saline solutions may havebeneficial effects on brain oxygenation in patients with severeTBI and intracranial hypertension.

Hypertonic saline and ICPAlthough the potential beneficial effects of HTS on brainpathophysiology were first observed in 1919, mannitol isfrequently administered as firstline osmotherapy for intracranialhypertension. However, in recent years, there has beenresurgent interest in the use of HTS. Recent small clinical seriessuggest that HTS is an effective agent to treat cerebral oedemaand elevated ICP.5 6 Our results are consistent with thesefindings.

Comparison between HTS and mannitolFew clinical studies have compared HTS with mannitol andthere is currently insufficient data to support the use of one overthe other. In experimental intracerebral haemorrhage, Qureshiet al found that none of these treatments had a significantinfluence on CBF or cerebral metabolism.23 Recent clinicalstudies in TBI patients showed that mannitol and HTS hadsimilar effects on elevated ICP and brain oxygen, at least whengiven in parallel and in equimolar doses.4 In contrast with theseclinical observations, other studies found HTS to be superior tomannitol in reducing ICP in patients with severe TBI.5 6 32 33

Furthermore, in animal models of intracranial hypertension,HTS also appears to provide better neuroprotection than

mannitol.30 34–36 Therefore, whether HTS may be superior tomannitol for control of intracranial hypertension is still acontroversial issue. As we did not compare mannitol and HTSin a parallel or randomised fashion, and the treatments were notadministered in equimolar doses, our study cannot provide adefinitive answer to this question. Rather, our results suggestthat HTS may have a more favourable effect on PbtO2 andcerebral and systemic haemodynamics than mannitol whenadministered as a second tier therapy for elevated ICP refractoryto mannitol in patients with severe TBI. Our data are alsoconsistent with previous observations in patients with severeTBI that suggest that mannitol has a limited effect on PbtO2

12 19

but this warrants further clinical investigation.

Study limitationsOur study has several potential limitations. First, HTS wasadministered after mannitol in all patients. Therefore, our dataonly suggest that HTS improves PbtO2 and systemic haemo-dynamics when administered as a secondline osmotherapy inpatients with severe TBI and recurrent episodes of intracranialhypertension. In this context (ie, after mannitol), HTS hadmore favourable effects on brain oxygen and ICP than theprevious mannitol treatment. Second, the observed physiologi-cal changes after HTS administration may represent thecumulative effect of mannitol and HTS rather than HTS alone.However, pretreatment serum osmolarity and serum sodiumwere similar in the mannitol and HTS groups, and the timeinterval between each treatment was relatively long (median8.6 h), suggesting that a cumulative effect is less likely. Third,mannitol and hypertonic saline were not given at equimolardoses, and we cannot exclude the fact that the higherosmolarity of HTS may, at least in part, explain some of theobserved benefits on brain oxygen. Additional studies areneeded to analyse whether mannitol and HTS may havecomparable beneficial effects when administered in equimolardoses.4 Fourth, data were obtained from only 12 patients andtherefore the results should be considered preliminary.However, a total of 42 episodes of elevated ICP were analysedand the effects of 28 boluses of mannitol and 14 boluses of HTSwere studied. Fifth, the retrospective nature of the analysis mayhave introduced bias. However, patients were treated in astandardised fashion and the data were collected prospectively.Sixth, patients were examined at different time points after theinitial injury, and variations in CBF and PbtO2 may thereforehave occurred over time. Each patient however served as his/herown internal control, and this may have partially reduced thepotential influence of time. Seventh, given that MAP wascomparable between mannitol and HTS therapy, a possibleadditional explanation for the observed HTS associated increasein cardiac output may be a decrease in peripheral resistance or,alternatively, a difference in vasopressor dose between mannitoland HTS. These data were not available in our dataset, and weare unable to more precisely address these issues. However, wewish to point out that vasopressors were only used at low doseto maintain adequate CPP and none of the patients included inthe study had low cardiac output (cardiac output ranged from,6 to 8 l/min) or circulatory shock requiring vasopressors.Finally, we examined the effect of only a single dose of 7.5%HTS and so could not observe any dose dependent effect toconfirm our findings.

Despite these study limitations, our findings suggest thathypertonic saline solutions may significantly improve brainoxygen and systemic haemodynamics in patients with intra-cranial hypertension after severe TBI. Randomised clinical

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studies are needed to confirm our findings and to examinewhether hypertonic saline may be superior to mannitol for thetreatment of elevated ICP when both treatments are given inequimolar doses and weight adapted.

CONCLUSIONSOur data suggest that osmotherapy with 7.5% hypertonicsaline, when given as a second tier therapy for elevated ICP, isassociated with a significant improvement in brain oxygen, CPPand cardiac output in patients with severe TBI and intracranialhypertension refractory to previous mannitol administration. Inthis context, hypertonic saline also appears to have a morebeneficial effect on cerebral and systemic haemodynamics thanmannitol.

Acknowledgements: The authors thank Professor Francois Feihl for the carefulreview of statistical analysis.

Funding: Supported by Research Grants from the SICPA Foundation, Switzerland (toMO and EC), the Swiss National Science Foundation, Grant PBLAB-119620 (EC), theIntegra Foundation (PDL) and the Mary Elisabeth Groff Surgical and Medical ResearchTrust (PDL).

Competing interests: None.

Ethics approval: The study was approved by the Institutional Review Board, Hospitalof the University of Pennsylvania, Philadelphia, USA.

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Research paper

920 J Neurol Neurosurg Psychiatry 2009;80:916–920. doi:10.1136/jnnp.2008.156596

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