antihyperthermic treatment decreases perihematomal hypodensity · published ahead of print on march...

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Antihyperthermic treatment decreasesperihematomal hypodensityPablo Hervella PhD Manuel Rodrıguez-Yantildeez MD PhD Jose Manuel Pumar MD PhD

Paulo Avila-Gomez BSc Andres da Silva-Candal PhD Ignacio Lopez-Loureiro PhD

Elena Rodrıguez-Maqueda BSc Clara Correa-Paz PhD Jose Castillo MD PhD Tomas Sobrino PhD

Francisco Campos PhD and Ramon Iglesias-Rey PhD

Neurologyreg 2020941-11 doi101212WNL0000000000009288

Correspondence

Dr Hervella

pablohervellalorenzo

sergases

or Dr Iglesias-Rey

ramoniglesiasrey

sergases

AbstractObjectiveTo investigate the effect on perihematomal hypodensity and outcome of a decrease in bodytemperature in the first 24 hours in patients with intracerebral hemorrhage (ICH)

MethodsIn this retrospective study on a prospectively registered database among the 1100 patients 795met all the inclusion criteria Temperature variations in the first 24 hours and perihematomalhypodensity (PHHD) were recorded Patients ge375degC were treated with antihyperthermicdrugs for at least 48 hours The main objective was to determine the association amongtemperature variation PHHD and outcome at 3 months

ResultsThe decrease in temperature in the first 24 hours increased the possibility of good outcome11-fold Temperature decrease lower PHHD volume and a good outcome were observed in318 of the patients who received antihyperthermic treatment

ConclusionThe administration of early antihyperthermic treatment in patients with spontaneous ICHwitha basal axillary temperature ge375degC resulted in good outcome in a third of the treated patients

RELATED ARTICLE

EditorialHyperthermia cerebraledema and outcome inintracerebral hemorrhageToo darn hot

Page 687

From the Clinical Neurosciences Research Laboratory (LINC) (PH PA-G AdS-C IL-L ER-M C-CP JC TS FC RI-R) Health Research Institute of Santiago de Compostela(IDIS) and Stroke Unit Department of Neurology (MR-Y) and Department of Neuroradiology (JMP) Hospital Clınico Universitario Santiago de Compostela Spain

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by FIDIS

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Published Ahead of Print on March 27 2020 as 101212WNL0000000000009288

Spontaneous (nontraumatic) intracerebral hemorrhage(ICH) constitutes around 10ndash15 of strokes and is asso-ciated with poor outcome1 In the last decade mortality dueto ICH has decreased but unlike ischemic stroke bothmorbidity and dependence are increasing probably due to theabsence of effective treatments and to population aging23

ICH growth during the first hours is a critical factor for neu-rologic deterioration and poor outcome regardless of otherfactors that determine high mortality and poor outcome at thetime of ICH such as hematoma volume and intracranial hy-pertensionwith displacement of intracerebral structures45 Therelation between ICH growth in the first hours and poor out-come was recently confirmed in an extensive meta-analysis6

Clinical trials aimed at halting hematoma growth have failedto show efficacy so far7 and new therapeutic targets are beingsought now focusing on other secondary mechanisms asso-ciated with brain damage such as the perihematomal hypo-density (PHHD) volume8ndash10

Hyperthermia has been associated with poor outcome inICH11 and with the increase of PHHD volume12 especially byhypertensive mechanisms13 Hypothermia has been proposedas a treatment for ICH that is associated with a decrease inPHHD However this kind of treatment is not recommendedfor patients with ICH due to the highmorbidity andmortalityand more clinical trials are needed to verify its efficacy andsafety14ndash17

We analyzed the association between the clinical outcome at 3months and the decrease in body temperature in the first 24hours in patients with ICH Then we analyzed the associationbetween the PHHD and the decrease in temperature andfinally tested the hypothesis of treating patients with ICHwithantihyperthermic drugs for reducing PHHD and improvingthe clinical outcome

MethodsStudy designThis is a retrospective study performed on a prospectiveregister of patients in a databank approved by the GalicianEthics Committee Patients were treated in the emergencyservice of a single tertiary university hospital (UniversityClinical Hospital of Santiago de Compostela [Spain]) bytrained health personnel and later admitted to the stroke unitand treated by neurologists specialized in cerebrovasculartreatment according to a protocol based on Spanish and in-ternational clinical guidelines1819

Standard protocol approvals registrationsand patient consentsThis study was carried out in accordance with the HelsinkiDeclaration of the World Medical Association (2008) andapproved by the Clinical Research Ethics Committee ofGalicia Informed consent was obtained from patients or theirrelatives at the time of inclusion in the registry authorizing theanonymous use of data for further studies

Inclusion and exclusion criteriaFrom January 2008 to December 2018 1100 patients withspontaneous ICH were included in the data bank Exclusioncriteria were the following (1) latency time (from the onset ofsymptoms to hospital care) gt24 hours (n = 185) (2) previousmodified Rankin Scale (mRS) score gt1 (n = 193) (3) knownchronic inflammatory diseases (n = 26) (4) absence of at least 2neuroimaging studies in the first week (n = 208) (5) isolatedprimary intraventricular hemorrhage (n = 23) (6) loss of follow-up (face-to-face or telephone) for 3 months (n = 174) (7)patients undergoing surgical removal of hematoma (n = 38) Forthe purpose of this study 795 patients were considered valid

Clinical and analytical variablesThe variables analyzed in this study are shown in table 1 andtable-e1 (doiorg105061dryadnp5hqbzps) In particularaxillary temperature was recorded upon admission and every 6hours during the whole hospitalization time in the stroke unitFor this study we used the maximum temperature obtained inthe first 24 hours after admission to the stroke unit As the mainvariable we determined the difference between the axillarytemperature at admission and the temperature at 24 hours(differences gt0degC considered as increase and le0degC as decrease)

The intensity of the neurologic deficit was determined by theNIH Stroke Scale (NIHSS) upon admission and every 6hours during the hospitalization in the stroke unit For thisstudy the NIHSS was assessed at admission The functionaldeficit was assessed by the mRS score at discharge and at 3months plusmn 15 days Both scales were evaluated by in-ternationally certified neurologists supervised by the sameneurologist (MR-Y)

Neuroimaging studiesAll of the patients included in the study underwent at least 2computerized CT scans the first one on admission and thenext one during the first 7 days The volumes were de-termined using the ABC2 method20 until 2016 and after-wards through the automated planimetric method21 ThePHHD volume was calculated by subtracting the hematomavolume from the total volume of the lesion (figure 1) ICHgrowth and PHHD volume were categorized as le6 mL vs gt6

GlossaryANOVA = analysis of variance CI = confidence interval ICH = intracerebral hemorrhage mRS = modified Rankin ScaleNIHSS = NIH Stroke Scale OR = odds ratio PHHD = perihematomal hypodensity

2 Neurology | Volume 94 Number 16 | April 21 2020 NeurologyorgN

mL due to its sensitivity and specificity according to theliterature622 All neuroimaging studies were reviewed by thesame neuroradiologist (JMP)

InterventionFollowing the hospital protocol all patients with a baselinetemperature ge375degC were treated with 1 g of paracetamolorally or 2 g of metamizole intravenously every 8 hours Thetreatment was maintained for at least 48 hours regardless of therecorded temperature We considered a positive response toantihyperthermic treatment when the maximum temperature inthe first 24 hours was lower than the temperature at admissionPatients were not subjected to other hypothermic procedures

Outcome endpointsThe main objective of the study was to determine the asso-ciation between the temperature decrease in the first 24 hoursand the clinical outcome at 3 months (mRS categorized le2good outcome vs gt2 poor outcome) Secondary objectiveswere (1) the association between the PHHD volume and theoutcome at 3 months and (2) the influence of the anti-hyperthermic treatment on the PHHD volume and its re-percussion on the outcome at 3 months

Table 1 Clinical variables biochemical measures andneuroimaging values by outcome groups at3 months

Goodoutcome(n = 348)

Pooroutcome(n = 447) p Value

Age y 711 plusmn 128 769 plusmn 116 lt00001

Women 417 459 0250

Latency time min 2427 plusmn 2078 2317 plusmn 2047 0489

Previous modified RankinScale score

0 (0 1) 1 (0 1) lt00001

Arterial hypertension 667 664 0504

Diabetes 193 233 0192

Smoking 135 78 0010

Alcoholism 161 145 0952

Dyslipidemia 425 365 0092

Ischemic heart disease 83 107 0278

Atrial fibrillation 158 251 0002

Heart failure 29 40 0441

Previous stroke 173 188 0514

Axillary temperature atadmission degC

365 plusmn 07 363 plusmn 09 lt00001

Temperature at admission2 at 24 hours degC

048 plusmn 032 001 plusmn 038 lt00001

Decrease in temperaturein 24 hours

962 548 lt00001

Antihyperthermictreatment

135 226 0001

Basal glycemia mgdL 1300 plusmn 454 1466 plusmn 502 lt00001

Leukocytes times103mL 71 plusmn 27 123 plusmn 68 0001

Platelets times103mL 2166 plusmn 837 1912 plusmn 880 0685

Fibrinogen mgdL 4252 plusmn 901 4533 plusmn 1101 0001

C-reactive protein mgL 43 plusmn 44 61 plusmn 58 lt00001

Glycosylatedhemoglobin

59 plusmn 08 59 plusmn 08 0148

LDL cholesterol mgdL 1152 plusmn 240 1002 plusmn 239 0105

HDL cholesterol mgdL 431 plusmn 144 391 plusmn 187 0734

Triglycerides mgdL 1027 plusmn 369 984 plusmn 490 0806

Microalbuminuriamg24 h

188 plusmn 351 223 plusmn 336 0403

Sedimentation rate mm 291 plusmn 199 438 plusmn 316 0004

ICH volume atadmission mL

209 plusmn 187 464 plusmn 409 lt00001

Growth of the ICH mL 121 plusmn 240 219 plusmn 356 lt00001

Growth of the ICH ge6 mL 236 468 lt00001

PHHD volume mL 76 plusmn 106 178 plusmn 217 lt00001

Table 1 Clinical variables biochemical measures andneuroimaging values by outcome groups at3 months (continued)



PHHD volume ge6 mL 279 626 lt00001

Leukoaraiosis 319 445 lt00001

NIHSS at admission 9 (5 13) 15 (11 19) lt00001

Modified Rankin Scalescore at 3 months

2 (0 2) 5 (3 6) lt00001

ICH topography 0133

Deep hemisphere 543 468

Lobar 388 452

Cerebellar 49 40

Brainstem 21 40

Hemorrhagiccontamination

149 253 lt00001

ICH diagnosis 0071

Hypertensive 514 450

Amyloid 109 161

Anticoagulants 124 215

Otherindeterminate 253 174

Abbreviations HDL = high-density lipoprotein ICH = intracerebral hemor-rhage LDL = low-density lipoprotein NIHSS = NIH Stroke Scale PHHD =perihematomal hypodensityValues are mean plusmn SD or

NeurologyorgN Neurology | Volume 94 Number 16 | April 21 2020 3

Statistical methodFirst an analysis was performed describing the sample Fre-quencies and percentages were calculated for categorical varia-bles while the continuous variables were expressed by meanvalues plusmn SD ormedian values and interquartile range dependingon their adjustment to normality Kolmogorov-Smirnov testwith Lilliefors correction was applied to assess normalityAnalysis of variance (ANOVA) and χ2 tests were performed todetermine differences in the variables between the groups(patients with good outcome vs patients with poor outcome)Bivariate correlations were performed using Spearman coef-ficients The logistic regression analysis was performed with theindependent variables selected by their statistical significance inthe bivariate analysis or by their clinical significance Theseresults were shown as odd ratios (ORs) with 95 confidenceintervals (CIs) A p value lt005 was considered to be statisticallysignificant All statistical analyses were conducted in SPSS 210(IBM Armonk NY)

Data availabilityAll data are available within the text of the article Furtheranonymized data could be made available to qualified inves-tigators upon reasonable request

ResultsIn this study 795 patients with ICH were included and 305were excluded Some differences were found between theincluded and excluded groups The included patients wereolder and more hypertensive and hyperlipemic with moreatrial fibrillation and higher basal temperature Regardingthe ICH diagnosis there were more amyloid and anticoag-ulant cases and less indeterminate and primary in-traventricular hemorrhages in the included group (75 vs0 p lt 00001) The rest of the variables studied that couldbe determined in the excluded group were similar in the 2groups A description of the clinical and analytical variablesof the included patients is provided in table e-1 (doiorg105061dryadnp5hqbzps)

Main objective the effect of temperaturedecrease on the outcome at 3 monthsAn analysis was carried out to study the variables that in-fluence the outcome at 3 months At 3 months (plusmn15 days)348 patients (438) presented good outcome while 447(522) showed poor outcome The variables associated withthe outcome are listed in table 1 Regarding body tempera-ture it can be seen that the temperature at admission washigher in patients with good outcome (365 plusmn 07degC vs 363 plusmn09degC p lt 00001) although in both groups the averagetemperature was below 37degC However the decrease intemperature in the first 24 hours was significantly higher inpatients with good outcome (048 plusmn 032 vs 001 plusmn 038 p lt00001) and the percentage of patients with temperaturedecrease was also higher in the good outcome group (962vs 548 p lt 00001) In addition we observed a relationship(ANOVA test p lt 00001) between variations in axillarytemperature in the first 24 hours and the mRS values with thepatients with high temperature decrease being the ones withlower mRS (figure 2)

In the logistic regression model (table 2) the temperaturedecrease in the first 24 hours was independently associatedwith good outcome at 3 months (adjusted OR 1128 95CI469ndash2701 p lt 00001) Therefore the decrease in temper-ature in the first 24 hours multiplies by 11 the possibility ofgood outcome while the hematoma growth multiplies by 5the possibility of poor outcome (adjusted OR 555 95 CI263ndash1111 p lt 00001)

Secondary objectives

Influence of PHHDvolumeon the outcomeat 3monthsThe average PHHD volume measured in the second CTneuroimage was 133 plusmn 1820 mL in the whole sample 373patients presented a PHHD volume ge6 mL and 418 patientslt6 mL PHHD volume was directly related to worse mRSscores at 3 months (figure 3) A descriptive analysis (tablee-2 doiorg105061dryadnp5hqbzps) categorizing thepatients according to the PHHD volume showed that goodoutcome is more frequent in the group of patients with

Figure 1 Example of CT scan

CT scan obtained during the first week after admission The perihematomalhypodensity volume is calculated by subtracting the hematoma volume(region inside the black dashes) from the total volume of the lesion (whitedashes)


a PHHD volume lt6 mL (721 vs 279 p lt 00001) Agefrequency of arterial hypertension temperature at admis-sion leukocytes fibrinogen microalbuminuria C-reactiveprotein and sedimentation rate showed lower values inpatients with a PHHD volume lt6 mL The ICH volume andthe NIHSS at admission also showed lower values in patientswith PHHD lt6 mL

The logistic regression analysis (table 2) showed that goodoutcome is 023 times more frequent in patients with a PHHDvolume ge6 mL (OR 023 95 CI 017ndash031 p lt 00001)although we did not observe an association between outcomeand PHHD volume after adjusting with ICH growth

Regarding temperature PHHD volume was lower in patientswith a decrease in temperature in the first 24 hours (figure 4)The temperature decrease in the first 24 hours was morefrequent in patients with a PHHD volume lt6 mL (916 vs642 p lt 00001) In another adjusted logistic regressionmodel (table e-3 doiorg105061dryadnp5hqbzps) thedecrease in temperature was found to be 17 times more fre-quent in patients with a PHHD volume lt6 mL (adjusted OR1687 95 CI 375ndash7584 p lt 00001)

Influence of the antihyperthermic treatment on PHHDvolume and its repercussion on the outcome at 3monthsAmong the 795 patients included in the study 148 receivedantihyperthermic treatment according to the hospital pro-tocol (their clinical and biological variables are listed in table 3)Body temperature was reduced in 65 patients (439) whilein 83 (561) the treatment did not cause a reduction of the

temperature Interestingly among the 647 patients who didnot receive treatment 529 showed a decrease in body tem-perature (846)

The average decrease in temperature was significantly differ-ent in the 3 groups of patients responders nonrespondersand not treated with antihyperthermic drugs (086 plusmn 045degC vsminus009 plusmn 025degC vs 021 plusmn 039degC p lt 00001) (figure 5A)likewise PHHD volume was lower in the group of patientswith a positive response to treatment compared with patientswho responded negatively and those with no treatment (19 plusmn28 mL vs 366 plusmn 234 mL vs 112 plusmn 158 mL p lt 00001)(figure 5B)

A goodoutcome at 3monthswas observed in 723of responderpatients to antihyperthermic drugs while none of the patientswith a negative response experienced good outcome at 3 months(plt 00001) (table e-4 doiorg105061dryadnp5hqbzps) Thepositive response to antihyperthermic treatment was also asso-ciated with good outcome as shown in the logistic regressionanalysis of table 2 (OR 300 95 CI 171ndash528 p lt 00001adjusted OR 167 95 CI 118ndash787 p = 0022)

DiscussionSpontaneous ICH constitutes a progressive cause ofmortality and morbidity that until now could be consid-ered a therapeutically orphan disease Neither the surgicalapproach nor procoagulant drugs has shown safety orefficacy723ndash25 Thus new therapeutic approaches havebeen explored focusing on more reachable objectives In

Figure 2 Temperature and modified Rankin Scale (mRS) score

Decrease in temperature during the first 24 hours inrelation to the mRS score at 3 months plusmn 15 days CI =confidence interval


recent years PHHD has been identified as an attractivepossibility

PHHD mechanisms are complex and not completely un-derstood and therefore we prefer to use the descriptive nameperihematomal hypodensity instead of perihematomal edemafrequently cited in the literature Undoubtedly many events ofa large PHHD are associated with inflammatory mechanisms26

and have been linked to the appearance of a cytotoxic edema inthe first hours and with a vasogenic edema in later phases92728

However other mechanisms should not be ruled out such asischemic necrosis or neurotoxicity associated with coagulationmechanisms2930 A novel and promising hypothesis associatedthe presence and progression of PHHD with the existence ofspreading depressions and isoelectric spreading depolariza-tions although its association with episodes of metabolic de-rangement and ischemic lesions remains speculative31 It hasalso been postulated that upregulated microRNA-23a-3p inpatients with ICH promotes the apoptosis of cerebral vascularendothelial cells by downregulating ZO-1 thus participating inthe formation of PHHD after ICH32

The prognostic role of PHHD in ICH has been widely de-bated in the literature with contradictory results10 The

latest prospective studies showed a strong relationship be-tween PHHD volume and higher mortality andmorbidity8933ndash36 This prognostic capacity is higher duringthe first 24 hours progressively decreasing its value duringthe subacute phase of ICH9 Although the prognostic ca-pacity of the PHHD volume over the clinical outcome wasnot the main objective of our study we initially showed thatPHHD volume was significantly higher in patients witha worse outcome at 3 months and a PHHD volume lt6 mLwas 4 times more frequent in patients with a good outcomeHowever the association between PHHD and clinical out-come was not observed after including other relevant vari-ables in the model such as ICH volume and temperatureMoreover high levels of significant prognostic factors ofpoor outcome at 3 months (such as fibrinogen or tempera-ture) were also found in patients with low volumes ofPHHD pointing out the weak association between PHHDand clinical outcome

PHHD has been the target of different treatments for ICH1516

Corticosteroids could be effective in late phases in which vaso-genic edema may predominate however they have not shownutility and cause a greater number of complications37 Similarlyhypertonic solutions did not affect the outcome at 3 months38

Table 2 Multivariate analysis

Independent variables OR not adjusted 95 CI p Value OR adjusted 95 CI p Value

Decrease in temperature in 24 hours 2078 1278ndash3377 lt00001 1128 469ndash2701 lt00001

PHHD volume ge6 mLa 023 017ndash031 lt00001 061 037ndash102 0058

Positive antihyperthermic treatment 300 171ndash528 lt00001 167 118ndash787 0022

Growth of the ICH ge6 mL 035 026ndash048 lt00001 018 009ndash038 lt00001

NIHSS at admission 079 076ndash081 lt00001 083 078ndash087 lt00001

Age 096 095ndash097 lt00001 097 094ndash099 0007

Glycemia 099 099ndash099 lt00001 099 098ndash099 0028

Axillary temperature at admission 058 049ndash068 lt00001 114 080ndash162 0464

ICH volume at admission 096 094ndash097 lt00001 099 098ndash100 0143

Previous modified Rankin Scale score 066 057ndash077 lt00001 072 050ndash104 0080

Smoking 161 110ndash237 0014 127 054ndash303 0583

Atrial fibrillation 051 037ndash071 lt00001 082 043ndash1532 0527

Leukocytes 094 090ndash097 0001 098 089ndash107 0621

Fibrinogen 099 099ndash099 lt00001 099 099ndash100 0063

C-reactive protein 093 090ndash095 lt00001 101 095ndash108 0704

Sedimentation rate 099 098ndash099 lt00001 099 098ndash101 0732

Leukoaraiosis 058 045ndash075 lt00001 080 039ndash163 0545

Hemorrhagic contamination 044 033ndash061 lt00001 063 035ndash114 0124

Abbreviations CI = confidence interval ICH = intracerebral hemorrhage NIHSS = NIH Stroke Scale OR = odds ratio PHHD = perihematomal hypodensityDependent variable good outcome at 3 months plusmn 15 daysa Adjusted only for patients with growth of the ICH lt6 mL


There is a clear relation between hyperthermia evenmoderate and a poor outcome of nontraumatic ICH1139ndash42

In our experience an axillary temperature at admissionge375degC multiplies by 4 the risk of a poor outcome at 3months11 Preclinical trials aiming for hypothermic

temperatures of 35degC confirmed the association betweenhypothermia and a decrease in PHHD along with a betteroutcome17 with evidence that supports the translationalityto human clinical practice43ndash45 especially if hypothermia isestablished early14 However this therapeutic procedure is

Figure 3 Perihematomal hypodensity (PHHD) and modified Rankin Scale (mRS) score

PHHD volume in each score of themRS evaluated at3 months plusmn 15 days ANOVA = analysis of varianceCI = confidence interval

Figure 4 Perihematomal hypodensity (PHHD) volume

Scatterplot of decrease in body temperature at24 hours and the PHHD volume The decrease intemperature is associated with a lower PHHDvolume


still not safe and has not been proven in clinical trials forpatients with ICH

Based on this evidence in this study we aimed to investigate theefficacy of a moderate decrease in temperature (in our series thechange in temperature in the first 24 hours with or withoutantihyperthermic treatment) since it is incorporated into theclinical practice guidelines for ischemic stroke management4647

We have verified that a decrease in body temperature multipliedby 11 the association with a good outcome The variation in bodytemperature is proportional to the changes in PHHDvolume andthis association is independent of other variables

A questionable aspect of our findings is the limited effectivenessof antihyperthermic treatment since it only managed to reducethe temperature in fewer than half of the patients who pre-sented an axillary temperature ge375degC on admission This isprobably due to the multiple mechanisms that can conditionthe temperature increase in ICH and the type of hemorrhage is

Table 3 Clinical variables biochemical measures andneuroimaging values categorized in patientswitha negative and positive response toantihyperthermic treatment


p ValueNo (n = 647) Yes (n = 148)

Age y 733 plusmn 131 736 plusmn 134 0738

Women 444 380 0146

Latency time min 2317 plusmn2089

2277 plusmn 1876 0840


1 (0 1) 1 (0 1) 0599

Arterial hypertension 580 773 lt00001

Diabetes 191 276 0015

Smoking 106 117 0681










021 plusmn 039 029 plusmn 058 0034

Decrease in temperature in24 hours

761 589 lt00001

Basal glycemia mgdL 137 plusmn 47 1498 plusmn 531 00004

Leukocytes times103mL 85 plusmn 31 106 plusmn 38 lt00001


Fibrinogen mgdL 4356 plusmn1007

4759 plusmn 999 lt00001


Glycosylated hemoglobin 58 plusmn 09 59 plusmn 10 035




Microalbuminuria mg24 h 153 plusmn 301 275 plusmn 275 0008

Sedimentation rate mm 226 plusmn 205 469 plusmn 259 lt00001


369 plusmn 379 612 plusmn 541 lt00001

Growth of the ICH mL 111 plusmn 266 52 plusmn 144 0009

Growth of the ICH ge6 mL 391 257 0002


Table 3 Clinical variables biochemical measures andneuroimaging values categorized in patients witha negative and positive response toantihyperthermic treatment (continued)


p ValueNo (n = 647) Yes (n = 148)

PHHD volume ge6 mL 541 459 0083

Leukoaraiosis 313 307 0927


Modified Rankin Scale scoreat 3 months

3 (1 6) 6 (2 6) lt00001

Good outcome at 3 months 465 317 lt00001

ICH topography 0264


Lobar 418 382

Cerebellar 50 28

Brainstem 35 49


208 245 0301

ICH diagnosis lt00001


Amyloid 107 86





undoubtedly one of these variables13 In our series the thera-peutic response was positive in only 311 of hypertensiveICH in 429 of amyloid ICH in 250 associated withantiplateletsanticoagulants and in 742 of indeterminatecases (p lt 00001 data not shown in the Results) The overallbenefit (determined as good outcome at 3 months) of patientswho received antihyperthermic treatment was 318

Despite the fact that only 318 of patients who receivedantihyperthermic treatment benefited from a moderate

decrease in temperature associated with a decrease in PHHDvolume (paracetamol andmetamizole do not have remarkableantiinflammatory effects raising other mechanisms) theseresults could encourage the consideration of a prospective andmulticentric study since the design of our study does notallow for the evaluation of a possible benefit of anti-hyperthermic treatment in normothermic patients

Our study shows the weakness of its retrospective nature suchas the lack of a blind assignation of patients to

Figure 5 Therapeutic response

(A) Decrease in body temperature at 24 hours inthe antihyperthermic treated group (without andwith a therapeutic response) and the nontreatedgroup (B) Perihematomal hypodensity (PHHD)volume in the 3 groups according to the thera-peutic response CI = confidence interval


antihyperthermic treatments that could bias the sampleNevertheless the influence of the temperature variation overthe different mRS has the same trend independent on theantihyperthermic treatment Also due to the retrospectivenature of the study we could rule out any inclusion bias

The administration of early antihyperthermic treatment inpatients with a spontaneous ICH with a basal axillary tem-perature ge375degC is associated with a moderate decrease intemperature in the first 24 hours and with a better prognosis at3 months in one-third of the treated patients

Study fundingThis study was partially supported by grants from the SpanishMinistry of Economy and Competitiveness (SAF2014-56336-Rand SAF2017-84267-R) Xunta de Galicia (Consellerıa Educa-cion GRC2014027 and IN607A20183) Instituto de SaludCarlos III (PIE1300024 and PI1701103) Spanish ResearchNetwork on Cerebrovascular Diseases RETICS-INVICTUSPLUS (RD160019) and by the European Union FEDERprogram T Sobrino (CPII1700027) and F Campos(CP1400154) are recipients of research contracts from theMiguel Servet Program of Instituto de Salud Carlos III Thesponsors did not participate in the study design collectionanalysis or interpretation of the data in writing the reportor in the decision to submit the paper for publication

DisclosureThe authors report no relevant disclosures Go toNeurologyorgN for full disclosures

Publication historyReceived by Neurology June 3 2019 Accepted in final formNovember 21 2019

References1 Feigin VL Krishnamurtly RV Parmar P et al Update on the global burden of

ischemic and hemorrhagic stroke in 1990-2013 the GBD 2013 study Neuro-epidemiology 201545161ndash176

2 Rodrıguez-Castro E Lopez-Dequidt I Santamarıa-Cadavid M et al Trends in strokeoutcomes in the last ten years in a European tertiary hospital BMCNeurol 201818164

3 Keep RF Hua Y Xi G Intracerebral haemorrhage mechanisms of injury and ther-apeutic targets Lancet Neurol 201211720ndash731

4 Tuhrim S Horowitz DR Scacher M et al Comparison of model predicting survivalfollowing intracerebral hemorrhage Crit Care Med 199523950ndash954

5 Leira R Davalos A Silva Y et al Early neurologic deterioration in intracerebralhemorrhage predictors and associated factors Neurology 200463461ndash467

6 Salman RA Frantzias J Lee R et al Absolute risk and predictors of the growth ofacute spontaneous intracerebral haemorrhage a systematic review and meta-analysisof individual patient data Lancet Neurol 201817885ndash894

7 Qureshi AI Mendelow AD Hanley DF Intracerebral haemorrhage Lancet 20093731632ndash1644

8 Grunwald Z Beslow LA Urday S et al Perihematomal edema expansion rates and patientoutcomes in deep and lobar intracerebral hemorrhage Neurocrit Care 201726205ndash212

9 Wu TY Sharma G Strbian D et al Natural history of perihematomal edema andimpact on outcome after intracerebral hemorrhage Stroke 201748873ndash879

10 Yu Z Zheng J You C Prognostic role of perihematomal edema in intracerebralhemorrhage a systematic review Turk Neurosurg 201828511ndash522

11 Campos F Sobrino T Vietes-Prado A et al Hyperthermia in human ischemic andhemorrhagic stroke similar outcome different mechanisms PLoS One 20138e78429

12 Mehdiratta M Kumar S Hackney D et al Serum ferritin level and perihematomaedema volume in patients with spontaneous intracerebral hemorrhage Stroke 2008391165ndash1170

13 Iglesias-Rey Rodrıguez-Yantildeez M Arias S et al Inflammation edema and poor out-come are associated with hyperthermia in hypertensive intracerebral hemorrhage EurJ Neurol 2018251161ndash1168

14 Volbers B Herrmann S Willfarth W et al Impact of hypothermia and duration onperihemorrhagic edema evolution after intracerebral hemorrhage Stroke 2016472249ndash2255

15 Leasure A Kimberly WT Sansing LH et al Treatment of edema associated withintracerebral hemorrhage Curr Treat Options Neurol 2016189

16 KimH Edwards NJ Choi HA et al Treatment strategies to attenuate perihematomaledema in patients with intracerebral hemorrhage World Neurosurg 20169432ndash41

Appendix Authors

Name Location Contribution

PabloHervellaPhD

Health Research Instituteof Santiago de Compostela(IDIS) Santiago deCompostela Spain

Designed andconceptualized the studyanalyzed the data wrotethe manuscript

ManuelRodrıguez-Yantildeez MDPhD


Major role in theacquisition of dataneuroimaging studyinterpreted the datarevised the manuscript

Jose ManuelPumar MDPhD

Clinical UniversityHospital Santiago deCompostela Spain


Paulo AvilaBSc


Acquired and interpretedthe data critical revision ofthe manuscript

Andres daSilva-Candal PhD



Appendix (continued)


IgnacioLopez-LoureiroBSc



ElenaRodrıguez-MaquedaBSc



ClaraCorrea BSc



Jose CastilloMD PhD



TomasSobrinoPhD


Interpreted the datacritical revision of themanuscript

FranciscoCamposPhD



RamonIglesias-ReyPhD




17 Melmed KR Lyden PDMeta-analysis of pre-clinical trials of therapeutic hypothermiafor intracerebral hemorrhage Ther Hypothermia Temp Manag 20177141ndash146

18 Rodrıguez-Yantildeez M Castellanos M Freijo MM et al Clinical practice guidelines inintracerebral haemorrhage Neurologıa 201328236ndash249

19 Broderick J Connolly S Feldmann E et al Guidelines for the management ofspontaneous intracerebral hemorrhage in adults 2007 update a guideline from theAmerican Heart AssociationAmerican Stroke Association Stroke Council HighBlood Pressure Research Council and the Quality of Care and Outcomes in ResearchInterdisciplinary Working Group Stroke 2007382001ndash2023

20 Sims JR Gharai LR Sahaefer P et al ABC2 rapid clinical estimate of infarct per-fusion and mismatch volumes Neurology 2009722104ndash2110

21 Krishnan K Muktar SF Lingard J et al Performance characteristics of methods forquantifying spontaneous intracerebral haemorrhage data from the Efficacy of NitricOxide in Stroke (ENOS) trial J Neurol Neurosurg Psychiatry 2015861258ndash1266

22 Dowlatshani D Demchuck AM Flaherty ML et al Defining hematoma expansion inintracerebral hemorrhage relationship with patient outcome Neurology 2011761238ndash1244

23 Veltkamp R Purrucker J Management of spontaneous intracerebral hemorrhageCurr Neurol Neurosci Rep 20171780

24 Kim JY Bae HJ Spontaneous intracerebral hemorrhage management J Stroke 20171928ndash39

25 Salman RA Law ZK Bath PM et al Haemostatic therapies for acute spontaneousintracerebral haemorrhage Cochrane Database Syst Rev 20184CD005951

26 Gusdon AM Gialdini G Kone G et al Neutrophil-lymphocyte ratio and peri-hematomal edema growth in intracerebral hemorrhage Stroke 2017482589ndash2592

27 Urday S Kimberly WY Beslow LA et al Targeting secondary injury in intracerebralhaemorrhage-peri-haematomal oedema Nat Rev Neurol 201511111ndash122

28 Majidi S Rahim B Gilani SI et al CT evolution of hematoma and surroundinghypodensity in a cadaveric model of intracerebral hemorrhage J Neuroimaging 201626346ndash350

29 Castillo J Davalos A Alvarez-Sabın J et al Molecular signatures of brain injury afterintracerebral hemorrhage Neurology 200258624ndash629

30 Buletko AB Thacker T Cho SM et al Cerebral ischemia and deterioration with lowerblood pressure target in intracerebral hemorrhage Neurology 201891e1058ndashe1066

31 Helbok R Schiefecker AJ Friberg C et al Spreading depolarizations in patients withspontaneous intracerebral hemorrhage association with perihematomal edema pro-gression J Cereb Blood Flow Metab 2017371871ndash1882

32 Hu YL Wang H Huang Q et al MicroRNA-23a-3p promotes the perihematomaledema formation after intracerebral hemorrhage via ZO-1 Eu RevMed Pharmacol Sci2018222809ndash2816

33 Urday S Beslow LA Dai F et al Rate of peri-hematomal edema expansion predictsoutcome after intracerebral hemorrhage Crit Care Med 201644790ndash797

34 Murthy SB Moradiya Y Dawson J et al Perihematomal edema and functionaloutcome in intracerebral hemorrhage influence of the hematoma volume and loca-tion Stroke 2015463088ndash3092

35 Volbers B Willfarth W Kuramatsu JB et al Impact of perihemorrhagic edema onshort-term outcome after intrace4rebral hemorrhage Neurocrit Care 201624404ndash412

36 Yang J Arima H Wu G et al Prognostic significance of perihematomal edema inacute intracerebral hemorrhage pooled analysis from the intensive blood pres-sure reduction in acute cerebral hemorrhage trial studies Stroke 2015461009ndash1013

37 Poungvarin N Bhoopat W Viriyavejakul A et al Effects of dexamethasone in primaryintracerebral hemorrhage N Eng J Med 19873161229ndash1223

38 Wang X Arima H Yang Y et al Mannitol and outcome in intracerebral hemorrhagepropensity score and multivariable intensive blood pressure reduction in acute ce-rebral hemorrhage trial 2 results Stroke 2015462762ndash2767

39 Mehdiratta M Kumar S Hackney D et al Association between serum ferritin leveland perihematomal edema volume in patients with spontaneous intracerebral hem-orrhage Stroke 2008391165ndash1170

40 Rincon F Mayer SA The epidemiology of intracerebral hemorrhage in the UnitedStates from 1979 to 2008 Neurocrit Care 20131995ndash2008

41 Lord AS Gilmon E Choi HA et al Time course and predictors of neurologicaldeterioration after intracerebral hemorrhage Stroke 201546647ndash652

42 Liang T Chen Q Li Q et al 5-HT1a activation in POAH area induces therapeutichypothermia in a rat model of intracerebral hemorrhage Oncotarget 2017873613ndash73626

43 Kollmn R Staykov D Dorfler A et al Hypothermia reduces perihemorrhagic edemaafter intracerebral hemorrhage Stroke 2010411684ndash1689

44 Staykov D Schwab S Dorfler A et al Hypothermia reduces perihemorrhagic edemaafter intracerebral hemorrhage but does it influence function at outcome and mor-tality Ther Hypothermia Temp Manag 20111105ndash106

45 Staykov D Mild prolonged hypothermia for large intracerebral hemorrhage Neu-rocrit Care 201318178ndash183

46 Powerr WJ Derdeyn CP Biller J et al 2015 American Heart AssociationAmericanStroke Association focused update on the 2013 guidelines for the early managementof patients with acute ischemic stroke regarding endovascular treatment a guidelinefor healthcare professionals from the American Heart AssociationAmerican StrokeAssociation Stroke 2015463020ndash3035

47 Alonso M Egido JA Casado I et al Guıa para el tratamiento del infarto cerebralagudo Neurologıa 201429102ndash122


DOI 101212WNL0000000000009288 published online March 27 2020Neurology

Pablo Hervella Manuel Rodriacuteguez-Yaacutentildeez Joseacute Manuel Pumar et al Antihyperthermic treatment decreases perihematomal hypodensity

This information is current as of March 27 2020

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ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2020 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

Spontaneous (nontraumatic) intracerebral hemorrhage(ICH) constitutes around 10ndash15 of strokes and is asso-ciated with poor outcome1 In the last decade mortality dueto ICH has decreased but unlike ischemic stroke bothmorbidity and dependence are increasing probably due to theabsence of effective treatments and to population aging23

ICH growth during the first hours is a critical factor for neu-rologic deterioration and poor outcome regardless of otherfactors that determine high mortality and poor outcome at thetime of ICH such as hematoma volume and intracranial hy-pertensionwith displacement of intracerebral structures45 Therelation between ICH growth in the first hours and poor out-come was recently confirmed in an extensive meta-analysis6

Clinical trials aimed at halting hematoma growth have failedto show efficacy so far7 and new therapeutic targets are beingsought now focusing on other secondary mechanisms asso-ciated with brain damage such as the perihematomal hypo-density (PHHD) volume8ndash10

Hyperthermia has been associated with poor outcome inICH11 and with the increase of PHHD volume12 especially byhypertensive mechanisms13 Hypothermia has been proposedas a treatment for ICH that is associated with a decrease inPHHD However this kind of treatment is not recommendedfor patients with ICH due to the highmorbidity andmortalityand more clinical trials are needed to verify its efficacy andsafety14ndash17

We analyzed the association between the clinical outcome at 3months and the decrease in body temperature in the first 24hours in patients with ICH Then we analyzed the associationbetween the PHHD and the decrease in temperature andfinally tested the hypothesis of treating patients with ICHwithantihyperthermic drugs for reducing PHHD and improvingthe clinical outcome

MethodsStudy designThis is a retrospective study performed on a prospectiveregister of patients in a databank approved by the GalicianEthics Committee Patients were treated in the emergencyservice of a single tertiary university hospital (UniversityClinical Hospital of Santiago de Compostela [Spain]) bytrained health personnel and later admitted to the stroke unitand treated by neurologists specialized in cerebrovasculartreatment according to a protocol based on Spanish and in-ternational clinical guidelines1819

Standard protocol approvals registrationsand patient consentsThis study was carried out in accordance with the HelsinkiDeclaration of the World Medical Association (2008) andapproved by the Clinical Research Ethics Committee ofGalicia Informed consent was obtained from patients or theirrelatives at the time of inclusion in the registry authorizing theanonymous use of data for further studies

Inclusion and exclusion criteriaFrom January 2008 to December 2018 1100 patients withspontaneous ICH were included in the data bank Exclusioncriteria were the following (1) latency time (from the onset ofsymptoms to hospital care) gt24 hours (n = 185) (2) previousmodified Rankin Scale (mRS) score gt1 (n = 193) (3) knownchronic inflammatory diseases (n = 26) (4) absence of at least 2neuroimaging studies in the first week (n = 208) (5) isolatedprimary intraventricular hemorrhage (n = 23) (6) loss of follow-up (face-to-face or telephone) for 3 months (n = 174) (7)patients undergoing surgical removal of hematoma (n = 38) Forthe purpose of this study 795 patients were considered valid

Clinical and analytical variablesThe variables analyzed in this study are shown in table 1 andtable-e1 (doiorg105061dryadnp5hqbzps) In particularaxillary temperature was recorded upon admission and every 6hours during the whole hospitalization time in the stroke unitFor this study we used the maximum temperature obtained inthe first 24 hours after admission to the stroke unit As the mainvariable we determined the difference between the axillarytemperature at admission and the temperature at 24 hours(differences gt0degC considered as increase and le0degC as decrease)

The intensity of the neurologic deficit was determined by theNIH Stroke Scale (NIHSS) upon admission and every 6hours during the hospitalization in the stroke unit For thisstudy the NIHSS was assessed at admission The functionaldeficit was assessed by the mRS score at discharge and at 3months plusmn 15 days Both scales were evaluated by in-ternationally certified neurologists supervised by the sameneurologist (MR-Y)

Neuroimaging studiesAll of the patients included in the study underwent at least 2computerized CT scans the first one on admission and thenext one during the first 7 days The volumes were de-termined using the ABC2 method20 until 2016 and after-wards through the automated planimetric method21 ThePHHD volume was calculated by subtracting the hematomavolume from the total volume of the lesion (figure 1) ICHgrowth and PHHD volume were categorized as le6 mL vs gt6

GlossaryANOVA = analysis of variance CI = confidence interval ICH = intracerebral hemorrhage mRS = modified Rankin ScaleNIHSS = NIH Stroke Scale OR = odds ratio PHHD = perihematomal hypodensity









Women 417 459 0250



0 (0 1) 1 (0 1) lt00001


Diabetes 193 233 0192

Smoking 135 78 0010










048 plusmn 032 001 plusmn 038 lt00001


962 548 lt00001


135 226 0001












188 plusmn 351 223 plusmn 336 0403



209 plusmn 187 464 plusmn 409 lt00001











2 (0 2) 5 (3 6) lt00001

ICH topography 0133


Lobar 388 452

Cerebellar 49 40

Brainstem 21 40


149 253 lt00001

ICH diagnosis 0071


Amyloid 109 161






































































p ValueNo (n = 647) Yes (n = 148)


Women 444 380 0146


2277 plusmn 1876 0840


1 (0 1) 1 (0 1) 0599


Diabetes 191 276 0015

Smoking 106 117 0681










021 plusmn 039 029 plusmn 058 0034


761 589 lt00001





4759 plusmn 999 lt00001









369 plusmn 379 612 plusmn 541 lt00001






p ValueNo (n = 647) Yes (n = 148)





3 (1 6) 6 (2 6) lt00001


ICH topography 0264


Lobar 418 382

Cerebellar 50 28

Brainstem 35 49


208 245 0301



Amyloid 107 86


































Appendix Authors


PabloHervellaPhD









Paulo AvilaBSc














ClaraCorrea BSc



Jose CastilloMD PhD



TomasSobrinoPhD



FranciscoCamposPhD












































Citations









Reprints











Women 417 459 0250



0 (0 1) 1 (0 1) lt00001


Diabetes 193 233 0192

Smoking 135 78 0010










048 plusmn 032 001 plusmn 038 lt00001


962 548 lt00001


135 226 0001












188 plusmn 351 223 plusmn 336 0403



209 plusmn 187 464 plusmn 409 lt00001











2 (0 2) 5 (3 6) lt00001

ICH topography 0133


Lobar 388 452

Cerebellar 49 40

Brainstem 21 40


149 253 lt00001

ICH diagnosis 0071


Amyloid 109 161






































































p ValueNo (n = 647) Yes (n = 148)


Women 444 380 0146


2277 plusmn 1876 0840


1 (0 1) 1 (0 1) 0599


Diabetes 191 276 0015

Smoking 106 117 0681










021 plusmn 039 029 plusmn 058 0034


761 589 lt00001





4759 plusmn 999 lt00001









369 plusmn 379 612 plusmn 541 lt00001






p ValueNo (n = 647) Yes (n = 148)





3 (1 6) 6 (2 6) lt00001


ICH topography 0264


Lobar 418 382

Cerebellar 50 28

Brainstem 35 49


208 245 0301



Amyloid 107 86


































Appendix Authors


PabloHervellaPhD









Paulo AvilaBSc














ClaraCorrea BSc



Jose CastilloMD PhD



TomasSobrinoPhD



FranciscoCamposPhD












































Citations









Reprints





































































p ValueNo (n = 647) Yes (n = 148)


Women 444 380 0146


2277 plusmn 1876 0840


1 (0 1) 1 (0 1) 0599


Diabetes 191 276 0015

Smoking 106 117 0681










021 plusmn 039 029 plusmn 058 0034


761 589 lt00001





4759 plusmn 999 lt00001









369 plusmn 379 612 plusmn 541 lt00001






p ValueNo (n = 647) Yes (n = 148)





3 (1 6) 6 (2 6) lt00001


ICH topography 0264


Lobar 418 382

Cerebellar 50 28

Brainstem 35 49


208 245 0301



Amyloid 107 86


































Appendix Authors


PabloHervellaPhD









Paulo AvilaBSc














ClaraCorrea BSc



Jose CastilloMD PhD



TomasSobrinoPhD



FranciscoCamposPhD












































Citations









Reprints

































Appendix Authors


PabloHervellaPhD









Paulo AvilaBSc














ClaraCorrea BSc



Jose CastilloMD PhD



TomasSobrinoPhD



FranciscoCamposPhD












































Citations









Reprints









































Citations









Reprints




antihyperthermic treatment decreases perihematomal hypodensity · published ahead of print on march...

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