association between post-resuscitation partial pressure of arterial

DOI: 10.1161/CIRCULATIONAHA.112.000168

1

Association between Post-Resuscitation Partial Pressure of Arterial

Carbon Dioxide and Neurological Outcome in Patients with

Post-Cardiac Arrest Syndrome

Running title: Roberts et al.; PaCO2 after cardiac arrest

Brian W. Roberts, MD1; J. Hope Kilgannon, MD1; Michael E. Chansky, MD1;

Neil Mittal, MD1; Jonathan Wooden, MD1; Stephen Trzeciak, MD, MPH1,2

1Dept of Emergency Medicine; 2Dept of Medicine, Division of Critical Care Medicine, Cooper

University Hospital, Cooper Medical School of Rowan University, Camden, NJ

Address for Correspondence:

Brian W. Roberts, MD

Department of Emergency Medicine

Cooper University Hospital

One Cooper Plaza, K152

Camden, NJ 08103

Tel: 856-342-2351

Fax: 856-968-8272

E-mail: [email protected]

Journal Subject Codes: Treatment:[27] Other treatment, Treatment:[25] CPR and emergency cardiac care

Neil Mittal, MD1; Jonathan Wooden, MD1; Stephen Trzeciak, MD, MMPMPHHH1,2,22

11DeDeDeptptpt offf EmEmEmergegegenncncy Medicine; 2Dept of Mediciciinenene, Division of CrCC iticicalalal CCare Medicine, Cooper

Univverersssityyy HHosospipipitatall,l, CCCoooopepeper r MeMeM dicccalll Schohohool oooff f RoRoowwawann UUnUniviveeerssiitytyy,, CCaCamdmddenenn, NJNJNJ

AdAdddress ffor CCorrespo dndence:

by guest on March 24, 2018

http://circ.ahajournals.org/D

ownloaded from

by guest on M

arch 24, 2018http://circ.ahajournals.org/

Dow

nloaded from



ownloaded from

by guest on M

arch 24, 2018http://circ.ahajournals.org/

Dow

nloaded from

http://circ.ahajournals.org/





2

Abstract:

Background—Partial pressure of arterial CO2 (PaCO2) is a regulator of cerebral blood flow after

brain injury. Recent guidelines for management of cardiac arrest recommend maintaining

PaCO2 40-45mmHg after successful resuscitation; however, there is paucity of data on the

prevalence of PaCO2 derangements during the post-cardiac arrest period, and association with

outcome.

Methods and Results—We analyzed a prospectively compiled and maintained cardiac arrest

registry at a single academic medical center. Inclusion criteria: age 18, non-trauma arrest, and

comatose after return of spontaneous circulation (ROSC). We analyzed arterial blood gas data

during 0-24 hours after ROSC and determined whether patients had exposure to hypocapnia

and/or hypercapnia (defined as PaCO2 30mmHg and PaCO2 50mmHg, respectively, based on

previous literature). The primary outcome was poor neurological function at hospital discharge,

defined as Cerebral Performance Category 3. We used multivariable logistic regression, with

multiple sensitivity analyses, adjusted for factors known to predict poor outcome, to determine if

post-ROSC hypocapnia and/or hypercapnia were independent predictors of poor neurological

function. Of 193 patients, 52 (27%) had hypocapnia only, 63 (33%) had hypercapnia only, 18

(9%) had both hypocapnia and hypercapnia exposure, and 60 (31%) had no exposure; 74% of

patients had poor neurological outcome. Hypocapnia and hypercapnia were independently

associated with poor neurological function, odds ratio 2.43 (95% CI 1.04-5.65) and 2.20 (95% CI

1.03-4.71) respectively.

Conclusions—Hypocapnia and hypercapnia were common after cardiac arrest and

independently associated with poor neurological outcome. These data suggest PaCO2

derangements could be potentially harmful for post-cardiac arrest patients.

Key words: cardiac arrest, heart arrest, cardiopulmonary resuscitation, brain ischemia, resuscitation, hypocapnia, hypercapnia, anoxic brain injury, shock

yp p ( 2 g 2 g, p yy,

previous literature). The primary outcome was poor neurological function r at hosospippitatat l dididiscscschahahargrge,,

defined as Cerebral Performance Category 3. We used multivariable logistic regression, with

multipple sensitivityty analyses, adjusted for factors known to predict poor outcome, to determine if

popoosstst-R-R-ROSOSCCC hhyhypoocacapnpniaia aandnd/or r hyhypeperccapnin a wewerere innndeppenendedent pprereedddictotorsrs of popooror neuror lol gig cal

ffuunccctit on. Of 19199333 ppapatiitienentstts, 525252 (((2727%)%)%) hhadadd hypppooocappnniia ooonlnlly,y, 66333 (3(33%3%%) ) hahah dd hyhyypepeercrcapappnininiaa onononlylyly,, 18188

999%)%)%) hhada botototh hh hyhyyppopocacapnpnnia aandndnd hhypypperere ccaappnpniaia exxpxposossuurere,, anannd d 606060 ((3311%)%)%) haadad nnoo o exexxpoposusuurrere; 7444% % ofofof

patitienentsts hhadad poooor neneururologogicalal ooututcome. HHypypocacapniaa aandnd hhypypere cacapnpniaia wereree inindedependndenntltlyy

associated wwwititthh h popopoororr nnneueuuroroololologigig cacal ll fufuuncncctititionon, ododddsdsds rratata ioioio 222 44.4333 (9(9(95%5%5% CCCIII 111.040404 5-5-5 6.65)5)5) aandndnd 222.20 (9( 5% CCC



ownloaded from



3

Introduction

After successful resuscitation from cardiac arrest, the majority of patients go on to die in the

hospital or survive with severe neurological disability due to anoxic brain injury.1 With the

discovery that therapeutic hypothermia can reduce the degree of brain injury, it is now clear that

therapeutic interventions applied after return of spontaneous circulation (ROSC) can

substantially improve clinical outcomes from cardiac arrest.2, 3 However, even with therapeutic

hypothermia the mortality of post-cardiac arrest patients remains unacceptably high. Finding

new approaches to further attenuate brain injury after resuscitation is a high priority for

resuscitation science.

Partial pressure of arterial carbon dioxide (PaCO2) is a major regulator of cerebral blood

flow after brain injury, and derangements of PaCO2 have been thought to worsen clinical

outcomes after many forms of brain injury by altering cerebral blood flow and increasing

cerebral ischemia.4 Hypocapnia and hypercapnia have been previously demonstrated to be

associated with poor clinical outcomes in traumatic brain injury,5, 6 and pediatric post-cardiac

arrest.7 Hypocapnia has also been associated with poor clinical outcomes in mechanically

ventilated preterm neonates,8 and adult patients suffering stroke.9, 10 Although hyperventilation

during cardiopulmonary resuscitation (CPR) has been previously demonstrated to be common

and associated with poor outcome, presumably through increased intra-thoracic pressure with

subsequent decrease in venous return, cardiac output, and coronary perfusion pressure, thereby

lowering the chances of achieving ROSC, 11-16 it is unclear if PaCO2 derangements after ROSC

has been achieved could also potentially worsen neurological outcome. In 2010, the American

Heart Association Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency

Cardiovascular Care recommended that during the post-ROSC period, a PaCO2 of 40-45 mmHg

Partial pressure of arterial carbon dioxide (PaCO2) is a major regulator oof f f ceeerer brbrbralalal bbblololoood

flow after brain injury, and derangements of PaCO2 have been thought to worsen clinical

ouutctccomommeses aaaftftfteeer mmmaananyy forms of brain injury by alllteteteriinng cerebral blloooo d flflflowowow and increasing

ceereeebrb al ischeemimiiaa.44 HyHyH ppopocaccapnpnpniaia aaandndnd hhhypypperccapppniaa hhaavee e bbebeeenn pprereviviououslsllyyy ddedemomomonsnstrtrratata ededed ttto bebbe

asssososociciciatata eded wwwiitith h popopooror cccliinniniccal l ououutctctcomomomesess iin nn trtrtrauauaumamam ttticc brbrraiainnn inininjuuuryryr ,,5, 66 aaandndd pppededdiaiai trtrtricic pppooost--ccacardrdiaiaac

arrest.777 Hypopopocacacapnpnpniaiaia hhhasass alslslso o o bebeeenenen aaassss ococociaiaateteed d d wiwiw ththth pppooooo r r r clclclinininicici alalal oooututtcococomememess s ininin mmmececechahahaninin cac lly



ownloaded from



4

should be targeted in this population of brain injured patients.17 However, there is a paucity of

clinical data on the subject of hypocapnia and hypercapnia during the post-ROSC period in adult

patients. Specifically, it is unclear if exposure to hypocapnia and/or hypercapnia during the

initial post-ROSC period is common and associated with neurological outcome.

The objectives of this study were to determine the prevalence of hypocapnia and

hypercapnia during the initial post-ROSC period, and their associations with neurological

outcome among adult patients resuscitated from cardiac arrest. We hypothesized that

hypocapnia and hypercapnia are common during the initial post-ROSC period and are both

independently associated with poor neurological outcome.

Methods

Setting

We analyzed a prospectively compiled and maintained cardiac arrest registry at a single

academic medical center, Cooper University Hospital in Camden, NJ.18 We have prospectively

collected data on all post-cardiac arrest patients at our institution since 2009. We collect data

pertaining to the index cardiac arrest event, and outcomes consistent with the Utstein style for

reporting cardiac arrest research, including all post-ROSC variables recommended for post-

resuscitation research.19, 20 In order to prospectively identify consecutive post-cardiac arrest

patients, we utilized a 24-hour per day, 7-day per week paging system. The paging system was

activated in one of two ways: a) a hospital wide “code blue” activation anytime a cardiac arrest

occurred in the hospital; b) ED unit secretaries were trained to activate a page when an out-of-

hospital cardiac arrest arrived in the ED (or a cardiac arrest occurred in the ED). In each case, an

on-call investigator received the page and responded to the cardiac arrest event to begin data

Methods

Seetttttinininggg

WeWe aanalyzed a a pprrooospepeectctivivivelelelyy y ccocompmpmpiililededd aaand mmmaainttaaiinneddd cccararddid aacac aaarrresest t rreeggiiststrryry aat t a aa sisiingngn lell

accadadademememicic mmmedeedicicaaal ccenennteter,r,r CCoooooopepeerrr UnUnU ivivvererrsisisitytyty HHHososo ppipitatat l l ininn CCCamamamdeded nn,n, NNNJ.J.118 WWWe e hahahaveve ppprrrospsppececctitivvevelylyy

collected datataa ooon n n alala ll l popopostss -cccararardidd acacac ararrrerer sttt pppatata ieieientntn s ss atata ooururu iinsnsnstitititutututitiiononon sininincecece 2220000009.9.9 WeWeWe cccololollel ct data



ownloaded from



5

entry. The Institutional Review Board approved this study with a waiver of written informed

consent.

Participants

We included both in- and out-of-hospital adult post-cardiac arrest patients who were comatose

after ROSC between 2009-2011. The inclusion criteria were: 1) age 18 years; 2) cardiac arrest,

defined as a documented absence of pulse and CPR initiated; 3) ROSC > 20 minutes; and 4)

neurological impairment after ROSC [defined as patient inability to follow commands (i.e.

Glasgow Coma Score motor less than 6) during the first hour after ROSC]. We excluded

patients with cardiac arrest related to trauma. We also excluded patients who died prior to an

arterial blood gas analysis being obtained.

Data Collection

We abstracted the following variables: demographics, comorbidities, all arterial blood gas

analyses recorded over the first 24 hours after ROSC, post-cardiac arrest interventions [e.g.

percutaneous coronary interventions (PCI) and therapeutic hypothermia (TH)], and neurological

status at hospital discharge [defined by the Cerebral Performance Category (CPC)]. We entered

all data into a dedicated Access database (Microsoft Corporation, Redmond, WA) and exported

to StatPlus version 2009 (AnalystSoft Inc., Alexandria, VA) for analysis.

Outcome measures

The primary outcome was poor neurological function at hospital discharge, defined as a Cerebral

Performance Category (CPC) 3. The CPC is a validated five-point scale of neurological

disability and historically the most commonly used outcome measure in post-cardiac arrest

research (1: good cerebral performance, 2: moderate cerebral disability, 3: severe cerebral

disability, 4: coma/vegetative state, 5: death).19, 21-23 The CPC was prospectively determined for

arterial blood gas analysis being obtained.

Data Collection

WeWee aaabsbsbsttrtracacacteteteddd thhhee e fofollowing variables: demograaapphphiiccs, comorbidiititiiese , alalalaaa ll l aarterial blood gas

annalallysy es recorrdededed ovveerer ttthehehe ffiririrsstst 22444 hhohouurursss aftteerr ROOOSSCC, popopostst--caarardidiaccc aarrrreeestt inintteterrvrvenenntitit oononss [eee.g.g..

pepercrcrcutututanana eoeooususus ccororronnnararyyy iinntetervvvenenntititionononss (P(PPCICICI))) aanand d d ththhererapapeueueutititicc c hyhyypopop ththererermimimia (T(T( HH)H)],]], aandndnd neueuuroroolologggiccacal

tatus at hospsppitititalala dddisisischchhararargegee [[[dedd fififinenened d d bybyy ttthehehe CCCererereeebrbrb alala PPererrfofoformrmrmananancecece CCCatatategegegororory y y (C(CCPCPCPC)])])]. . WWe enteredd



ownloaded from



6

each patient at the time of hospital discharge. Patients with a CPC of 1 or 2 had sufficient

cerebral function at discharge to live independently.

Data Analysis

We began the analysis with descriptive statistics. We displayed categorical data as counts and

proportions. We described continuous data as mean values and standard deviation (SD) or

median values and interquartile range (IQR), based on distribution of data. For the purposes of

analysis, we determined whether or not patients had exposure to hypocapnia and/or hypercapnia

during the first 24 hours after ROSC. We decided a priori to define exposure to hypocapnia as

one or more recorded PaCO2 30 mmHg and exposure to hypercapnia as one or more recorded

PaCO2 50 mmHg, based on previously published cutoffs in studies of traumatic brain injury

and pediatric post-cardiac arrest.5, 7 No exposure was defined as no recorded PaCO2 30 or 50

mmHg during the first 24 hours after ROSC. We graphed the proportion of poor neurological

outcome at hospital discharge for only hypocapnia exposure, only hypercapnia exposure, both

hypocapnia and hypercapnia exposure, and no exposure.

We calculated odds ratios using multivariable logistic regression analysis to determine if

hypocapnia exposure and hypercapnia exposure were independently associated with neurological

function at hospital discharge. We selected the following candidate variables for the regression

model that were previously demonstrated to be strong predictors of poor outcome in post-cardiac

arrest patients: initial cardiac rhythm [asystole or pulseless electrical activity (PEA) versus

ventricular fibrillation/ventricular tachycardia (VF/VT)] and prolonged duration of CPR (CPR

duration > 20 minutes).1, 24-28 In order to also adjust the model for the possibility that hypocapnia

represented a respiratory compensation for metabolic acidosis (which may be associated with

poor outcome), we also added presence of metabolic acidosis as a variable in the regression

PaCO2 50 mmHg, based on previously published cutoffs in studies of traumatiticcc brbrbraiiin nn inininjujujuryryr

and pediatric post-cardiac arrest.5, 7 No exposure was defined as no recorded PaCO2 30 or 50

mmmmmHgHgHg dddurururinininggg thhheee fifirst 24 hours after ROSC. WeWeWe ggrraphed the prooopopp rttioioionn n of poor neurological

outcccomo e at hosospipip taaal dididiscscchahahargrgrge e fofor r onononlylyy hhhypooocaaapniiaa eexpopoposusurre,, ononlyly hhypyperercacappnpniiaia eexpxxpoososurure,e,, bbbooothhh

hyhypopopocacacapnpnp iaiaa aaandnd hhypypypererrcacaapnpnp iaa eexpxpxposososuurure,e,, aaandndnd nnooo exexexpopoposusuurere..

We ccalalalcucuulalaateteted d odododdsdss rrrataa iooos s s usussinii g g g mumumultltltivivivarara iaiaiablblble e e looogigigistststicicic rrregegegreeesssss ioioion n n anananalala ysysysisisis ttooo deded termine ifff



ownloaded from



7

model, defined as one or more recorded base deficit -6 (based on previously published

literature).29

In order to ensure the association between hypocapnia exposure and hypercapnia

exposure remained independently associated with poor neurological outcome, after adjusting for

additional candidate variables known to be predictors of poor outcome, we performed additional

sensitivity analyses. Additional candidate variables included: (1) hyperoxia (defined as a PaO2

300 mmHg on the first arterial blood gas analysis obtained after ROSC),30, 31 (2) arterial

hypotension (defined as systolic blood pressure < 100 mmHg during the first 24 hours after

ROSC,32, 33 and (3) a shorter duration of CPR to define prolonged downtime (CPR duration > 10

minutes). In order to adjust for the possibility that hypercapnia represented the presence of pre-

cardiac arrest pulmonary disease, we added presence of previously documented pre-cardiac

arrest pulmonary disease as a variable in the sensitivity analyses. In addition, to adjust for

potential heterogeneity in the number of PaCO2 values assessed we added the number of PaCO2

assessed as a variable in the sensitivity analyses. Finally, to ensure we did not exclude any

additional possible confounders, we performed two separate correlation matrixes to identify

possible correlations between hypocapnia exposure and baseline variables as well as hypercapnia

exposure and baseline variables that we did not adjust for in the multivariable logistic regression

models, and planned to do additional sensitivity analyses adjusting for any correlated variables.

Sample size calculation

To ensure adequate power to test five covariates in a multivariable model, we estimated the

necessary sample size, based on the following assumptions: a) a predicted survival with good

neurological function rate of 28%;1 and b) an estimated event (survival with good neurological

function) per covariate ratio of 10:1 necessary for multivariable modeling.34, 35 To accrue the

minutes). In order to adjust for the possibility that hypercapnia represented the pprrreseseenccce e ofofof ppprere-

cardiac arrest pulmonary disease, we added presence of previously documented pre-cardiac

arrrereeststst ppp lululmomom nnnaryyy dddisisease as a variable in the sensnsnsiitiivvity analyses. IIn adaddddiditit on, to adjust for

poteeenntial heterorogggenneneitiityy ininin ttthehehe nnnumummbebeber r ofoff PaCCCOOO2 vvalluuesss aasasseseesssseded wwe adadddededed d ththheee nunumbmbmberer of f f PPaPaCOCOCO2

asssesesesssssedede aass s a aa vavarririaabablele inn n ththe seses nsnsnsitititivivivitityy y anananalalalysysy eseses.. FFininaalallylyy,, tototo eeensnsn uurureee wewewe dddidid nnnotott eexcxcxclululudeee aaanyny

additional ppososssisisiblblb ee e cococ nfnfnfououndndnderee s,s,s, wwweee pperererfofoormrmrmededed ttwowowo sssepeparararatatate e e cococorrrrrreelalaatititiononon mmmatata ririxexexesss totoo iiided ntify



ownloaded from



8

necessary 50 survivors with good neurological function we estimated that a minimum of 179

total cases would be necessary.

Results

One hundred and ninety three patients met all inclusion and no exclusion criteria. Of these, 52

(27%) had exposure to only hypocapnia, 63 (33%) had exposure to only hypercapnia, and 60

(31%) had no exposure. Eighteen (9%) patients had exposure to both hypocapnia and

hypercapnia resulting in a total of 70/193 (36%) patients with any hypocapnia exposure and

81/193 (42%) with any hypercapnia exposure. The median (IQR) number of PaCO2 assessed per

patient was 2 (1-4)

Table 1 displays baseline data for all subjects in the cohort, as well as patients with only

hypocapnia exposure, only hypercapnia exposure, both hypocapnia and hypercapnia exposure,

and no exposure36. The majority of patients were in-hospital cardiac arrests with PEA/asystole

as the initial rhythm [128/193 (66%)], and few patients were out-of-hospital cardiac arrest

patients with pulseless VF/VT as the initial rhythm [6/193 (3%)]. One hundred percent of

patients were mechanically ventilated after ROSC. Therapeutic hypothermia was performed on

100% (6/6) of patients with out-of-hospital, VF/VT cardiac arrest [indicated population (i.e.

Class I recommendation)], and in 40% (77/193) of all patients. Percutaneous coronary

intervention (PCI) was performed in 3/6 (50%) of patients with out-of-hospital, VF/VT cardiac

arrest and 15/193 (8%) of all patients. The overall in-hospital mortality was 68%. Table 2

displays post-cardiac arrest data for all subjects.

Seventy four percent of all patients were found to have the primary outcome of poor

neurological function at hospital discharge [CPC 1, 43/193 (22%); CPC 2, 8/193 (4%); CPC 3,

patient was 2 (1-4)

Table 1 displays baseline data for all subjects in the cohort, as well as patients with only

hyhypopopocacacapnpniaiaia eexxposososuurure, only hypercapnia exposurerere,, bbboth hypocapniniia a anndd d hhhypercapnia exposure,

anndd d non exposururee363 .. TTheheh mmmaajajorororiitity y ofofof ppaaatiieentss wwweree innn-hohoosspspitittalal ccararrdidiacc aarrreeseststss wwwitith h PEPEPEAA/A/asssysystotot llle

ass ttthehehe iiininititialalal rrhyhyyttthmm m [[1[12288/1/193933 (((666666%)%)% ],], aandndnd fffeew w w papapatiieene ttsts wwweerere ououo ttt-ofofof-h-h-hooospipipitatalll cacaardrdiaiaiaccc arrrrerestst

patients with h pupupulslselelelesese sss VFVFV /V/V/VT TT asasas tthehehe inininititiialalal rhrhrhytyty hmhmhm [[[6/6 19199333 (3(3(3%)%)%)].].] OnOnOneee huhuhundndndrereed d d pepepercrcrcenee t of



ownloaded from



9

8/193 (4%); CPC 4, 4/193 (2%); CPC 5, 130/193 (68%)]. Figure 1 displays the poor

neurological function at hospital discharge in relation to only hypocapnia exposure, only

hypercapnia exposure, both hypocapnia and hypercapnia exposure, and no exposure, during the

first 24 hours after return of spontaneous circulation. Patients with only hypocapnia exposure,

only hypercapnia exposure, and both hypocapnia and hypercapnia had a higher prevalence of

poor neurological function at hospital discharge than patients with no exposure (83%, 78%, 89%,

57% respectively).

Table 3 displays the results of the multivariable logistic regression model with poor

neurological function at hospital discharge as the dependent variable. After adjusting for initial

cardiac rhythm, prolonged duration of CPR, and metabolic acidosis, both hypocapnia exposure

and hypercapnia exposure were found to be independent predictors of poor neurological function

at hospital discharge, odds ratio 2.43 (95% CI 1.04-5.65) and 2.20 (95% CI 1.03-4.71)

respectively. Table 4 displays sensitivity analyses. Both hypocapnia exposure and hypercapnia

exposure remained independently associated with poor neurological function at hospital

discharge after adjusted for additional variables known to be predictors of poor outcome (i.e.

hyperoxia, arterial hypotension, know pre-cardiac arrest pulmonary disease, and different

durations of CPR). Using correlation matrixes, the only additional baseline variable we found to

have a statistically significant correlation with hypocapnia or hypercapnia was between

hypercapnia and congestive heart failure (Online Data Supplement 1). Both hypocapnia

exposure and hypercapnia exposure remained independently associated with poor neurological

function at hospital discharge after adjusted for number of PaCO2 assessed and congestive heart

failure (Online Data Supplement 2).

cardiac rhythm, prolonged duration of CPR, and metabolic acidosis, both hypocaapapninin a exexpopoposususurere

and hypercapnia exposure were found to be independent predictors of poor neurological function

att hhhososospipipitatatalll dididissschahaargrgrgee, odds ratio 2.43 (95% CI 1.0004--5.65) and 2.20200 (955% % % CIC 1.03-4.71)

eespppece tively. TaTaTablle 444 ddisisisplplplayayaysss sesensnsnsititivvvittty annnaallyseees. BBootthth hhhypppococapppninia a exexexpoposususurere aandndnd hhhyyypeerercacaapnpnnia

exxpopoposususurere rremememaiainnedd d ininddedepepep ndnddenene tltltlyyy asaassosoociciiatatatededed wiwiwiththh pppooooor r neneneuururololologogogicicalalal fufuunccctitiononon aaat t hohohosspspittaal

discharge affteteerr r adadadjujujuststs ededed fororr aaadddddditititioioi nananal vavav riririababablelelesss knknknowowwn n tototo bbbe e e prprpredede iccctototorsrsrs ooof f f popop ororo oooutututcococomem (i.e.



ownloaded from



10

Discussion

In this study, we prospectively identified adult post-cardiac arrest patients, and determined the

prevalence of hypocapnia exposure and hypercapnia exposure during the first 24 hours after

ROSC. Our objective was to test whether post-ROSC exposure to hypocapnia and/or

hypercapnia was associated with poor neurological function at hospital discharge. We found that

36% of patients had any hypocapnia exposure and 42% had any hypercapnia exposure. Using

multivariable logistic regression, including multiple sensitivity analyses, we found that both

hypocapnia exposure and hypercapnia exposure after ROSC were independent predictors of poor

neurological function at hospital discharge. These findings suggest both hypocapnia and

hypercapnia are common during the initial post-ROSC period and are independently associated

with poor neurological outcome.

The 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation

and Emergency Cardiovascular Care recommend that ventilation should be titrated to achieve a

PaCO2 of 40-45 mmHg during the post-ROSC period.17 However, at the present time we are

unaware of any prior clinical research studies on the subject of hypocapnia and hypercapnia

during the post-ROSC period in adult patients. Specifically, it has been unclear if exposure to

hypocapnia and/or hypercapnia during the initial post-ROSC period is common and

independently associated with neurological outcome. To our knowledge this is the first report

that both hypocapnia and hypercapnia during the post-ROSC period could be potentially harmful

in adult patients resuscitated from cardiac arrest.

PaCO2 is a major regulator of cerebral blood flow after brain injury. Although

hyperventilation during CPR has been previously found to be associated with poor outcome, it is

thought to be more related to increased intra-thoracic pressure with subsequent decrease in

hypercapnia are common during the initial post-ROSC period and are independeentnntlylyy aasssssococociaiaiatetedd

with poor neurological outcome.

ThThThee e 20202 1000 AAAmmerican Heart Association GuGuGuidddelines for Cardrddiopupuulmlmlmonary Resuscitation

anndd d EmE ergenccy y CaCaCardddioioi vvavascscsculululaarar CCarararee e rreecccommmmeend thhhat vvveenentitiilaaatitiononn ssshohoululu d d bebe ttitittrtratatededed tttoo acaca hihihievevvee a

PaPaCOCOCO222 ooff 404040-4-455 mmmmmHHHg dduru ininng gg thththeee ppoposstst-RRROSOSOSCCC pepepeririododo ..177 HHoHowewewevvever,r,r aaat t tttheee prprresese enene t t tititimmeme wwee ararre

unaware of aanynyny pppriririororo cccliliinin cacacalll rresesseaeae rcrcrch h stststudududieieies s s onono tthehehe ssububbjjjececect t t ofoff hhhypypypocococapapapnininia a a anannd d d hyhyhypepepercrr apnia



ownloaded from



11

venous return and cardiac output, and decreased coronary perfusion pressure during CPR,

thereby lowering the chances of achieving ROSC, as opposed to an effect of hypocapnia itself.11-

16 Hypocapnia has been postulated to be detrimental during the post-ROSC period secondary to

hypocapnia-induced cerebral vasoconstriction resulting in decreased cerebral blood flow and

increased cerebral ischemia potentially exacerbating anoxic brain injury.4, 37, 38 Cerebral blood

flow has been demonstrated to decrease approximately 3% for every 1 mmHg decrease in PaCO2

in patients with traumatic brain injury.39 Although it has been suggested that this degree of

reactivity to PaCO2 may be blunted during this initial post-ROSC period,40-42 recent literature

suggests it remains intact.4, 43, 44 Hypocapnia has also been suggested to worsen

ischemic/reperfusion injury by increasing cerebral oxygen demand through increased neural

excitability, and increasing cerebral oxygen demand could be deleterious in anoxic brain

injury.45, 46

Hypocapnia has been demonstrated to be associated with poor clinical outcomes in

traumatic brain injury patients,5, 6 mechanically ventilated preterm neonates,8 and pediatric post-

cardiac arrest patients.7 In a post-cardiac arrest animal model, cerebral blood flow promotion,

through induced hypertension, mild hemodilution, and normocapnia, along with therapeutic

hypothermia was shown to improve neurological outcome compared to combined hypocapnia,

normotension, and normothermia.44 Also, in a recent clinical study, ventilation titrated to

maintain PaCO2 37.6 – 45.1 mmHg, as a part of a bundle with multiple other goals (including

hypothermia, arterial oxygen saturation optimization, and blood pressure goals), was associated

with increased survival in post-cardiac patients.47 However, the independent effects of PaCO2

control itself cannot be determined from these two studies.

Conversely, hypercapnia has been demonstrated to decrease cerebrovascular resistance

schemic/reperfusion injury by increasing cerebral oxygen demand through increeaaasedede nnneuueurararalll

excitability, and increasing cerebral oxygen demand could be deleterious in anoxic brain

nnjujuuryryry..45,45,45, 464646

Hypocacappnniia hhhaaas bbbeeeeeenn n deddemomomonnsnsttrraatted ttto be aaassssoccciaiaateteddd wwiwiththh pppooor r ccliininiccacall l ououtctctcoomomeees iiinn

rrauauumamamatiticc brbrbraiaain n iinnjujuuryryy ppatata ieientntnts,ss 5, 5,5 66 mmmecechahahanininicacacallllyyy veveenntntillatata ededed pppreeetetet rrmrm nnneoeoonanaatetes,s,8 aaandndd pppeeediiaatrrricic pppososst-t

cardiac arrestst pppatata ieieientntn s.s..777 Innn aaa pppososst-t-t cacaardrr iaiaiac c c arararrerereststst aaanininimamam l momomodededel,l,, ccceree ebebebrararal l l blblblooooood d flflflowowow ppproror motion,



ownloaded from



12

and increase blood flow, suggesting a potential benefit in patients suffering from ischemic brain

injury;4, 48 however, studies of traumatic brain injury and pediatric post-cardiac arrest syndrome

have demonstrated hypercapnia to be association with poor clinical outcomes.5, 7 The association

between hypercapnia and poor outcome has been suggested to be secondary to hypercapnia-

induced cerebral vasodilation and increased intracranial volume resulting in increased

intracranial pressure and decreased cerebral perfusion.49, 50

We sought to perform this study because we believe if titrating ventilation to maintain an

ideal PaCO2 during the post-ROSC period is shown to improve patient neurological outcome,

this would potentially allow for a simple therapeutic approach to help attenuate the brain injury

associated with post-cardiac arrest syndrome. In this observational study we showed both

hypocapnia and hypercapnia exposure were common and were independently associated with

poor neurological function at hospital discharge. Our findings suggest that post-ROSC PaCO2

derangements may be harmful, and provide scientific rationale for further research to determine

the optimal target PaCO2 range during the initial post-ROSC period.

We acknowledge that this study has important limitations to consider. First, we did not

measure cerebral blood flow in patients, and therefore were unable to determine the direct effects

of PaCO2 derangements on cerebral blood flow during the post-ROSC period. Second, although

we used multivariable logistic regression analyses to adjust for cardiac arrest characteristics

known to predict in-hospital mortality, there still exists the potential of unmeasured confounders.

Of note, we did not find hyperoxia to have a statistically significant association with poor

neurological outcome in our cohort. This may be secondary to the fact that this study had a

much smaller sample size compared to previous hyperoxia studies30 (n = 193 vs. n = 6326) and

thus was not powered to identify such an association. Third, this study was limited to one center

associated with post-cardiac arrest syndrome. In this observational study we shoowewewedd boboboththth

hypocapnia and hypercapnia exposure were common and were independently associated with

pooororor nnneeueuroorololologggicaaall l fufuf nction at hospital dischargee. OOOur findings suguguggeststt ttthhahat post-ROSC PaCO2

ddederaaangn ementss mmayayy bbe e hahaarmrmmfufuful,ll, aandndnd pprroovvvide scccientttifffic rrratattioionnanalele ffforor ffururththt eeer rreeseseaearcrcch h h totot dddettterermmim nnne ff

hhe e e opopoptitit mamall l tatatargrgeeet PPPaCaCCOOO222 rrannngegeg dddurururiining g thhhee e inininitttiiialala pppoosost---ROROOSSCSC pppererrioiood.d.d.

We aackckcknonon wlwlwledededgegeg thahahat t t thhhisisis sstututudydyy hhhasasas iimpmpmpororo tatat ntntn llimimimitititatatatioioonsnsns to o o cococonsnsnsidididerere . FFFiririrststt,,, weww did not



ownloaded from



13

and it is possible that a study of larger scope could have found different results. Fourth, this was

an analysis of a prospectively compiled and maintained cardiac arrest registry; therefore, there

was no predefined protocol for obtaining arterial blood gases potentially resulting in

heterogeneity in timing and number of arterial blood gases obtained for each patient. Fifth,

although we believe the association between hypercapnia and poor neurological outcome is

secondary to increased intracranial pressure, there exists the possibility that hypercapnia is a

reflection of lung injury and poor pulmonary compliance, which may be associated with poor

outcome. Sixth, we defined hypocapnia as PaCO2 30 mmHg and hypercapnia as PaCO2 50

mmHg based on PaCO2 levels from previously published studies,5, 7 thus the exact PaCO2 levels

associated with potential harm are unknown. Lastly, this was an observational study and thus we

can only report association rather than infer causation.

Conclusions

In this sample of adult patients resuscitated from cardiac arrest, we found that both hypocapnia

and hypercapnia exposure after ROSC were common and were independently associated with

poor neurological function at hospital discharge. These data suggest PaCO2 derangements could

be potentially harmful in patients resuscitated from cardiac arrest. Future research to determine

the optimal target PaCO2 range after ROSC is warranted.

Conflict of Interest Disclosures: None.

References: 1. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, Nichol G, Lane-Truitt T, Potts J, Ornato JP, Berg RA. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295:50-57.

associated with potential harm are unknown. Lastly, this was an observational ssttutudydydy aaandndnd ttthuhuhuss we

can only report association rather than infer causation.

CCConncnclusions

nn ttthihihisss sasampmpmplelele ooff f aaddulultt papapatitiennntsts rrresesesusuuscicitatat tetetedd d frfromomom ccaarardidiiaccc aaarrrrresesst,t,t wwweee fofof uuunddd ththhatatat bbbototth h h hyhypopopocacappnpniiaa

and hypercapappninin a a a exexexpopoposususure aaaftftfterer RRROSOSOSC C wewewererere cccomomommomomon n n anannd d d wewewererere iiindndndepepepenenendededentntntlylyy aaassssssococociaiai ted with



ownloaded from



14

2. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563. 3. Hypothermia after cardiac arrest (HACA) study group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556. 4. Buunk G, van der Hoeven JG, Meinders AE. Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke. 1997;28:1569-1573. 5. Davis DP, Idris AH, Sise MJ, Kennedy F, Eastman AB, Velky T, Vilke GM, Hoyt DB. Early ventilation and outcome in patients with moderate to severe traumatic brain injury. Crit Care Med. 2006;34:1202-1208. 6. Muizelaar JP, Marmarou A, Ward JD, Kontos HA, Choi SC, Becker DP, Gruemer H, Young HF. Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. J Neurosurg. 1991;75:731-739. 7. Del Castillo J, Lopez-Herce J, Matamoros M, Canadas S, Rodriguez-Calvo A, Cechetti C, Rodriguez-Nunez A, Alvarez AC. Hyperoxia, hypocapnia and hypercapnia as outcome factors after cardiac arrest in children. Resuscitation. 2012; 83:1456-61. 8. Greisen G, Munck H, Lou H. Severe hypocarbia in preterm infants and neurodevelopmental deficit. Acta Paediatr Scand. 1987;76:401-404. 9. Plum F. Hyperpnea, hyperventilation, and brain dysfunction. Ann Intern Med. 1972;76:328. 10. Rout MW, Lane DJ, Wollner L. Prognosis in acute cerebrovascular accidents in relation to respiratory pattern and blood gas tensions. Br Med J. 1971;3:7-9. 11. Aufderheide TP, Lurie KG. Death by hyperventilation: A common and life-threatening problem during cardiopulmonary resuscitation. Crit Care Med. 2004;32:S345-351. 12. Aufderheide TP, Sigurdsson G, Pirrallo RG, Yannopoulos D, McKnite S, von Briesen C, Sparks CW, Conrad CJ, Provo TA, Lurie KG. Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation. 2004;109:1960-1965. 13. O'Neill JF, Deakin CD. Do we hyperventilate cardiac arrest patients? Resuscitation. 2007;73:82-85. 14. Cheifetz IM, Craig DM, Quick G, McGovern JJ, Cannon ML, Ungerleider RM, Smith PK, Meliones JN. Increasing tidal volumes and pulmonary overdistention adversely affect pulmonary vascular mechanics and cardiac output in a pediatric swine model. Crit Care Med. 1998;26:710-716. 15. Karlsson T, Stjernstrom EL, Stjernstrom H, Norlen K, Wiklund L. Central and regional blood

7. Del Castillo J, Lopez-Herce J, Matamoros M, Canadas S, Rodriguez-Calvo AA, , CeCeechchheetettititi CCC, , Rodriguez-Nunez A, Alvarez AC. Hyperoxia, hypocapnia and hypercapnia as oututcococomememe fffacacactootorssrs after cardiac arrest in children. Resuscitation. 2012; 83:1456-61.

8.. GGGrerereisisisenenn GGG,, MuMuunncnck H, Lou H. Severe hypocarrbbibiaa in preterm infffanaa tss aaanndnd neurodevelopmentaldedeefificcicit.t Actata PPPaeaedididiatatr r ScScScananandd. . 19199878787;7;7; 6:6:40401-1-40404.4.

9.9.. PPlulum F. HHypyy eerrpppneaa,, hhhypepeervrvvenentit laaatitit oonn,, anddd bbbrainnn dydysfsffunununctctctiooon. AnAnAnn Innnteeernrn MMMeded. 111977272;;766:32228..

10. RoRo tut MMW,W, LLanne e DDJ, WoW llllnener r L.L Progngnososisis iinn acuutete ccerrebebrorovaascsculularar acccciddenentsts in rerelatitionon tooespiratory papapattttt erere n n n anana d d d blbb oooood d d gagaas ss tetet nsnsn iooonsnsns.. BrBrBr MMMededed JJJ. 1999717171;3;3;3:7:77-9-99..JJJ



ownloaded from



15

flow during hyperventilation. An experimental study in the pig. Acta Anaesthesiol Scand. 1994;38:180-186. 16. Yannopoulos D, Tang W, Roussos C, Aufderheide TP, Idris AH, Lurie KG. Reducing ventilation frequency during cardiopulmonary resuscitation in a porcine model of cardiac arrest. Respir Care. 2005;50:628-635. 17. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R, Vanden Hoek TL, Kronick SL. Part 9: Post-cardiac arrest care: 2010 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122:S768-786. 18. Roberts BW, Kilgannon JH, Chansky ME, Mittal N, Wooden J, Parrillo JE, Trzeciak S. Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome. Crit Care Med. 2013 Mar 15. [Epub ahead of print]. 19. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D'Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zideman D. Cardiac arrest and cardiopulmonary resuscitation outcome reports: Update and simplification of the utstein templates for resuscitation registries: A statement for healthcare professionals from a task force of the international liaison committee on resuscitation (american heart association, european resuscitation council, australian resuscitation council, new zealand resuscitation council, heart and stroke foundation of canada, interamerican heart foundation, resuscitation councils of southern africa). Circulation. 2004;110:3385-3397. 20. Langhelle A, Nolan J, Herlitz J, Castren M, Wenzel V, Soreide E, Engdahl J, Steen PA. Recommended guidelines for reviewing, reporting, and conducting research on post-resuscitation care: The utstein style. Resuscitation. 2005;66:271-283. 21. Brain resuscitation clinical trial II study group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med. 1991;324:1225-1231. 22. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1:480-484. 23. Trzeciak S, Jones AE, Kilgannon JH, Fuller BM, Roberts BW, Parrillo JE, Farrar JT. Outcome measures utilized in clinical trials of interventions for post-cardiac arrest syndrome: A systematic review. Resuscitation. 2009;80:617-623. 24. Gaul GB, Gruska M, Titscher G, Blazek G, Havelec L, Marktl W, Muellner W, Kaff A. Prediction of survival after out-of-hospital cardiac arrest: Results of a community-based study in vienna. Resuscitation. 1996;32:169-176.

K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkinn GGGL,L,L MManancicinin ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolollannn J,, , OkOkOkadadada a K,K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zidememananan DDD. CaCaCardrdrdiaiaiacc arrest and cardiopulmonary resuscitation outcome reports: Update and simplification of the utstein tempplates for resuscitation registries: A statement for healthcare pprofessionals from a taskfoorcrccee e ofofof ttthehehe iiinnntererrnananatit onal liaison committee on rereesususscitation (ameeririr can n heheheart association, eueuuroooppean ressuuuscicitatatatitionon cccououuncncn ilil,,, aaaususu trtralaliaian n reresususcscitittatttion n cococounununcil,l,, nnneewew zzeaeaalalal ndd rresesesususu cicitatatitionono coouununcil, heart aanndn strtrooko ee e fofofounununddadatitiononon ooff cccanaadaaa, inntteerrammmeerericicanann hheeearrtrt fofounuundadatitiiononn,, rereesusuuscscitii atatatiioionnn cocooununncils of sosouthhherrn aaffriica)).. CCCirccullatata iooonn. 2000444;1110:33383885-5-5-3333339997.

20. LaLanghehelll e A,A NNololaan JJ, HeHerlrlititz z J,J Castrtrenen MM, WeW nznzelel VV, SoSorer iddee E,E, EEnggdadahlhl JJ, Steeeen PAPA..Recommendedeed d d guguguidididelelinininese fffororor revevevieiei wiww ngngng,, rererepopoportrtrtininng,g,g, aaandnd ccconononduduductctctinini g g g rereresesesearararchchch ooon n n popopoststs -r-resuscitatioonncacarere:: ThThee ututststeieinn ststylylee ReResususcscititatatioionn 20200505;6;66:6:272711-282833



ownloaded from



16

25. Langhelle A, Tyvold SS, Lexow K, Hapnes SA, Sunde K, Steen PA. In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in norway. Resuscitation. 2003;56:247-263. 26. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, Berg RA, Nichol G, Lane-Trultt T. Cardiopulmonary resuscitation of adults in the hospital: A report of 14720 cardiac arrests from the national registry of cardiopulmonary resuscitation. Resuscitation. 2003;58:297-308. 27. Hajbaghery MA, Mousavi G, Akbari H. Factors influencing survival after in-hospital cardiopulmonary resuscitation. Resuscitation. 2005;66:317-321. 28. Tok D, Keles GT, Toprak V, Topcu I. Assessment of in-hospital cardiopulmonary resuscitation using utstein template in a university hospital. Tohoku J Exp Med. 2004;202:265-273. 29. Hodgman EI, Morse BC, Dente CJ, Mina MJ, Shaz BH, Nicholas JM, Wyrzykowski AD, Salomone JP, Rozycki GS, Feliciano DV. Base deficit as a marker of survival after traumatic injury: Consistent across changing patient populations and resuscitation paradigms. J Trauma Acute Care Surg. 2012;72:844-851. 30. Kilgannon JH, Jones AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, Parrillo JE, Trzeciak S. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA. 2010;303:2165-2171. 31. Kilgannon JH, Jones AE, Parrillo JE, Dellinger RP, Milcarek B, Hunter K, Shapiro NI, Trzeciak S. Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. Circulation. 2011;123:2717-2722. 32. Kilgannon JH, Roberts BW, Reihl LR, Chansky ME, Jones AE, Dellinger RP, Parrillo JE, Trzeciak S. Early arterial hypotension is common in the post-cardiac arrest syndrome and associated with increased in-hospital mortality. Resuscitation. 2008;79:410-416. 33. Trzeciak S, Jones AE, Kilgannon JH, Milcarek B, Hunter K, Shapiro NI, Hollenberg SM, Dellinger P, Parrillo JE. Significance of arterial hypotension after resuscitation from cardiac arrest. Crit Care Med. 2009;37:2895-2903; quiz 2904. 34. Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. Ii. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995;48:1503-1510. 35. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49:1373-1379. 36. Murray SB, Bates DW, Ngo L, Ufberg JW, Shapiro NI. Charlson index is associated with

Salomone JP, Rozycki GS, Feliciano DV. Base deficit as a marker of survival afteer r r trtrtrauaumamatitic cnjury: Consistent across changing patient populations and resuscitation paradiggmmms.. JJ TrTrTrauauaumamam

Acute Care Surg. 2012;72:844-851.

30. Kilggannon JH, , JoJ nes AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, Parrillo JE, Trrzezezeciciciakakak SSS.. AsAA sooociciciata ion between arterial hyperoxoxoxiaia following ressuuuscittatatatioioion from cardiac arrest anannd d iinin-hospipiitatatal momomortrtalalititity.y.y. JAJAJAMAMAA.. 20202 1010;3;3; 0303:2:216165-5-212171.

3311. KKiK lgannoon n JHHH,, Jonnnesss AEAEE, PPParrr illlolol JJEEE, Deeellllingeerer RRP,P,P, MMMilili caarekkk BBB, HHunununteterrr KK,K, Shahaappipiroroo NNNI, TrTrzezezeciciciakaka SS.. ReReR lalaattioononshshhippp bbettwewew enenen sssuupuprraranononormrmrmalalal ooxyxxygegeg nnn tetetensnsnsiooon n n aanand dd ououo tttcoomome ee afafafteter r r rereesuusscscititi atatiioionnn fromm ccardidiaca aarrrrest.t. CiCircululatioionn. 202011;112323:2:271717-7-272 2222.

3232 KiKilglganannononn JHJH RoRobebertrtss BWBW ReReihihll LRLR ChChananskskyy MEME JoJoneness AEAE DeDelllliningegerr RPRP PaParrrrilillolo JJEE



ownloaded from



17

one-year mortality in emergency department patients with suspected infection. Acad Emerg Med. 2006;13:530-536. 37. Ausina A, Baguena M, Nadal M, Manrique S, Ferrer A, Sahuquillo J, Garnacho A. Cerebral hemodynamic changes during sustained hypocapnia in severe head injury: Can hyperventilation cause cerebral ischemia? Acta Neurochir Suppl. 1998;71:1-4. 38. Yundt KD, Diringer MN. The use of hyperventilation and its impact on cerebral ischemia in the treatment of traumatic brain injury. Crit Care Clin. 1997;13:163-184. 39. Cold GE. Cerebral blood flow in acute head injury. The regulation of cerebral blood flow and metabolism during the acute phase of head injury, and its significance for therapy. ActaNeurochir Suppl (Wien). 1990;49:1-64. 40. Krep H, Brinker G, Pillekamp F, Hossmann KA. Treatment with an endothelin type a receptor-antagonist after cardiac arrest and resuscitation improves cerebral hemodynamic and functional recovery in rats. Crit Care Med. 2000;28:2866-2872. 41. Krep H, Brinker G, Schwindt W, Hossmann KA. Endothelin type a-antagonist improves long-term neurological recovery after cardiac arrest in rats. Crit Care Med. 2000;28:2873-2880. 42. Nemoto EM, Snyder JV, Carroll RG, Morita H. Global ischemia in dogs: Cerebrovascular co2 reactivity and autoregulation. Stroke. 1975;6:425-431. 43. Kagstrom E, Smith ML, Siesjo BK. Cerebral circulatory responses to hypercapnia and hypoxia in the recovery period following complete and incomplete cerebral ischemia in the rat. Acta Physiol Scand. 1983;118:281-291. 44. Safar P, Xiao F, Radovsky A, Tanigawa K, Ebmeyer U, Bircher N, Alexander H, Stezoski SW. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke. 1996;27:105-113. 45. Bergsholm P, Gran L, Bleie H. Seizure duration in unilateral electroconvulsive therapy. The effect of hypocapnia induced by hyperventilation and the effect of ventilation with oxygen. ActaPsychiatr Scand. 1984;69:121-128. 46. Huttunen J, Tolvanen H, Heinonen E, Voipio J, Wikstrom H, Ilmoniemi RJ, Hari R, Kaila K. Effects of voluntary hyperventilation on cortical sensory responses. Electroencephalographic and magnetoencephalographic studies. Exp Brain Res. 1999;125:248-254. 47. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, Draegni T, Steen PA. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation. 2007;73:29-39. 48. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An experimental study in the immature rat.

41. Krep H, Brinker G, Schwindt W, Hossmann KA. Endothelin type a-antagonnisisst imimi prprprovovoveseses ong-term neurological recovery after cardiac arrest in rats. Crit Care Med. 20000;2;228:8:8:282828737373-22-2888888000.

42. Nemoto EM,, SSnyder JV, Carroll RG, Morita H. Global ischemia in dogs: Cerebrovascular coo222 rerereaacactititivivivitytyty andndnd aautu oregulation. Stroke. 1975;666:4:4: 2225-431.

4433. KKagstrom EE, , SSmmitiith h MLMLML,, SiSiSiesesjojoo BBBKKK. CCerrebebbral cciirrcuuulalaatotorryry rresesppoponsnseses tooo hyhyypeppercrcapapapninin a a annnddd hyhyhypopooxia in tthehe reeecoooverrry peririiododd folo looowwiwingngg comommplettte aandndd iiinncncomomompletetee cerrebbrbraall iisschchemmmiaa iinn tthe rararatt. AcActatata PPPhyhyhysisiiololol SScacaanddd. 119988383;1; 181818:2:22818181-2-2-291911.

44. Safar P, XXXiaiaiaoo F,F,F, RRRadadadovvvsksksky yy A,A,A, TTTanana igiggawawawaa a K,K,K, EbEbEbmememeyeyeerr r U,U,U BBBiririrchchc ererer NNN,, AlAlAlexexexananndededer r r H,H,H, StezoskiSWSW ImImprprovoveded ccererebebrarall reresususcscititatatioionn frfromom ccarardidiacac aarrrresestt inin ddogogss wiwithth mmilildd hyhypopoththerermimiaa plplusus



ownloaded from



18

Pediatrics. 1995;95:868-874.

49. Brian JE, Jr. Carbon dioxide and the cerebral circulation. Anesthesiology. 1998;88:1365-1386. 50. Falkenbach P, Kamarainen A, Makela A, Kurola J, Varpula T, Ala-Kokko T, Perttila J, Tenhunen J. Incidence of iatrogenic dyscarbia during mild therapeutic hypothermia after successful resuscitation from out-of-hospital cardiac arrest. Resuscitation. 2009;80:990-993.



ownloaded from



19

Table 1. Baseline data for all subjects at the time of cardiac arrest.

All Subjects n = 193

Only Hypocapnia Exposure

n = 52

Only Hypercapnia Exposure

n = 63

Both* n = 18

No Exposure n = 60

Age [years (SD)] 64 (18) 63 (19) 61 (17) 66 (15) 66 (15) Female gender [n (%)] 83 (43) 30 (58) 28 (44) 5 (28) 20 (33) Pre-existing comorbidities [n (%)] Diabetes 79 (41) 21 (40) 29 (46) 5 (28) 24 (40) Known coronary artery disease 40 (21) 13 (25) 10 (16) 2 (11) 15 (25) Hypertension 99 (51) 23 (44) 26 (41) 11 (61) 39 (65) Malignancy 35 (18) 12 (23) 5 (8) 5 (28) 13 (22) Renal insufficiency 50 (26) 15 (29) 15 (24) 4 (23) 16 (26) Pulmonary disease 45 (23) 8 (15) 25 (40) 3 (17) 9 (15) Cerebral vascular disease 11 (6) 3 (6) 4 (6) 1 (6) 3 (5) Congestive heart failure 34 (18) 10 (19) 7 (11) 1 (6) 16 (27) Charleson comorbidity score36 (SD) 2.8 (2.3) 2.7 (1.8) 3.0 (2.7) 2.9 (2.1) 2.7 (2.3) Arrest location [n (%)] Out-of-hospital 33 (17) 10 (19) 12 (19) 4 (22) 7 (12) In-hospital 160 (83) 42 (81) 51 (81) 14 (78) 53 (88) Initial arrest rhythm [n (%)] PEA/asystole 154 (80) 40 (77) 58 (92) 13 (72) 43 (72) VF/VT 38 (19) 12 (23) 5 (8) 5 (28) 16 (27) Unknown 1 (1) 0 0 0 1 (1) CPR duration > 10 minutes [n (%)] 81 (42) 23 (44) 26 (41) 9 (50) 23 (38) CPR duration > 20 minutes [n (%)] 19 (10) 5 (10) 4 (6) 4 (22) 6 (10) *Exposure to both hypocapnia and hypercapnia during the first 24 hours after return of spontaneous circulation; CPR, cardiopulmonary resuscitation; PEA, pulseless electrical activity; VF, ventricular fibrillation; VT ventricular tachycardia

abetes 79 (41) 21 (40) 29 (46) 5 (28)) 2424 ((4040) nown coronary artery disease 40 (21) 13 (25) 10 (16) 2 ((11111))) 51515 (((252525)ypertension 99 (51) 23 (44) 26 (41) 11 (( 16161))) 393939 ((656565))alignancy 35 (18) 12 (23) 5 (8) 5 (28) 13 (22) enal insufficiency 50 (26) 15 (29) 15 (24) 4 (23) 16 (26) ulmonanaryry ddiseaasese 45 (23) 8 8 (1(1( 5)5 25 (40) 3 (17) 9 (15) errebebbrarar l l vavav scululularaa dddis aeaeasesese 11 (6) 333 66( ) 4 4 (6( ) 1 (6) 3 (5) onnongegeststs ivi e heartt fafafailurure e 3434 ((1818)) 01010 (191 ) 77 7 1(1( 1)) 11 (((6)6) 1166 (2(2( 7)7 eesoon nn comorbidity y scscscoro eee 636 (((SDSDS ))) 2.22 8 (2(2 3.3. ) 2.7 77 11( .8) .3.3 0 0 (2(2.7.7)) ) 2.2.2.99 2(2(2.1.1. ))) 22.2.777 22(2.3. )ttt l ccocation [n (%)] tutut-o-- f-f-f-hoh spspital 3333 (((1717)) 0010 (1919) ) 211 ((19) ) 44 (2(22))2) 77 ((( 2212)

--hhospspspititi lalal 16166000 (8(83)3)3) 44422 2 (8(8(81)1)1 55111 (8(8(81)1)1 111444 (7(7(78)8)8) 555333 (8(8( 8)8)8) ll ararrerestst rrhyhyyththmm [[[nn (%(%( )])])]

EA/asystole 11154544 ((8000))) 40400 (((777777)) ) 585858 ((929292) ) 131313 (((727272))) 43 (72)F/F/VTVT 3838 ((1919)) 1212 ((2323)) 55 (8(8)) 55 (2(28)8) 1166 (2(27)7)



ownloaded from



20

Table 2. Post-cardiac arrest data for all subjects.

All Subjects n = 193

Only Hypocapnia Exposure

n = 52

Only Hypercapnia Exposure

n = 63

Both* n = 18

No Exposure n = 60

Metabolic acidosis* [n (%)] 132 (68) 48 (92) 43 (68) 12 (67) 29 (48) Hyperoxia† [n (%)] 46 (24) 18 (35) 12 (19) 2 (11) 14 (23) Arterial hypotension‡ [n (%)] 173 (90) 47 (90) 56 (89) 16 (89) 54 (90) *Defined as a base deficit -6 during the first 24 hours after return of spontaneous circulation; †Defined as a PaO2 300 mmHg on the first arterial blood gas analysis obtained after return of spontaneous circulation; ‡Defined as systolic blood pressure < 100 mmHg during the first 24 hours after return of spontaneous circulation.

Table 3. Multivariate logistic regression model with poor neurological outcome [defined as Cerebral Performance Category (CPC) 3 at hospital discharge] as the dependent variable. Variable Beta Standard Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 0.89 0.43 2.43 1.04 5.65 0.040 Hypercapnia† 0.79 0.39 2.20 1.03 4.71 0.042 Metabolic acidosis‡ 1.05 0.38 2.85 1.35 5.99 0.006 PEA/asystole initial rhythm 0.78 0.44 2.17 0.91 5.18 0.080 CPR > 20 minutes 1.32 0.81 3.74 0.76 18.46 0.105 *Defined as exposure to a partial pressure of arterial CO2 30 mmHg during the first 24 hours after return of spontaneous circulation; †Defined as exposure to a partial pressure of arterial CO2 50 mmHg during the first 24 hours after return of spontaneous circulation; ‡Defined as a base deficit -6 during the first 24 hours after return of spontaneous circulation; CPR, cardiopulmonary resuscitation; LCI, lower confidence interval; PEA, pulseless electrical activity; UCI, upper confidence interval.

ned as a base deficit 6 during the first 24 hours after return of spontaneous circulation; Defined as a PaO2 300 mmHg on tthehe ffirirstst aartere ial l blblooo d gis obtained after return of spontaneous circulation; ‡Defined as systolic blood pressure < 100 mmHg during the first 24 hourss afafafteteter r r reretuuturnrn ooof ff spspspononontat ne

ation.

e 3. MuMuMultltltivivivararariaiaiatetete l gogisisi tiitic c regression model with poor neurologigigicac l l outcome [defined as Ceererr brbrb al Performance Category (CPCspipiitatat l l didid scs hargrge]e]e as tthehe ddepependent variable.

aba eele BBBeteta a StStananandad rdrr EErroroo ddOd sdsd Ratatatioioi 99 %5%5% LLCIC 999 %5%5% UUCCIC p v-v-v lalueu cacc nnpniai * 0.00 89 0 4.4. 33 .22 434 111 0.044 5.65 0 0.. 044rcrcapapapnininiaaa†† 000.7.799 0.3939 22.20 0 1.11 3030 444.7.711 0.0. 4042 2bob liic c cacacidididosososisisi ‡‡‡ 111 0.0055 0.0 83838 222.8.8855 11.353535 555 99.9999 00.0.0000006 66 asasasysysystototolelele iiinininitititialalal rrrhyhyhythththmmm 000.787878 000 44.4444 222.171717 000 99.9111 555.181818 000 00.0808080 > 20 minutes 111.3.3222 0.818181 333.77.74 44 0.0.0 6676 118.8.8 464646 0.105

dd t tii ll ff t ii ll CO 30 H dd ii hth fifi t 24 hh fft t ff t ii ll iti ††D fifi dd



ownloaded from



21

Table 4. Results of sensitivity analyses: Multivariate logistic regression models with poor neurological outcome [defined as Cerebral Performance Category (CPC) 3 at hospital discharge] as the dependent variable.

Variable Beta Standard Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 0.90 0.42 2.45 1.08 5.56 0.032 Hypercapnia† 0.77 0.38 2.16 1.03 4.52 0.041 Metabolic acidosis‡ 1.05 0.37 2.85 1.38 5.86 0.004 PEA/asystole initial rhythm 0.57 0.43 1.77 0.77 4.10 0.182 Hyperoxia§ 0.05 0.43 1.05 0.45 2.42 0.911

Variable Beta Standard Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 1.25 0.42 3.49 1.54 7.90 0.003 Hypercapnia† 1.00 0.40 2.73 1.25 5.95 0.011 Arterial HypotensionII 1.37 0.58 3.92 1.26 12.14 0.018 Pulmonary Disease# 0.38 0.46 1.46 0.59 3.62 0.410 CPR > 20 minutes 1.26 0.79 3.52 0.75 16.53 0.110

Variable Beta Standard Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 1.22 0.42 3.40 1.51 7.68 0.003 Hypercapnia† 1.03 0.40 2.80 1.28 6.15 0.010 Arterial HypotensionII 1.38 0.57 3.96 1.29 12.12 0.016 Pulmonary Disease# 0.34 0.46 1.40 0.57 3.47 0.466 CPR > 10 minutes 0.12 0.36 1.12 0.55 2.29 0.748 *Defined as exposure to a partial pressure of arterial CO2 30 mmHg during the first 24 hours after return of spontaneous circulation; †Defined as exposure to a partial pressure of arterial CO2 50 mmHg during the first 24 hours after return of spontaneous circulation; ‡Defined as a base deficit -6 during the first 24 hours after return of spontaneous circulation; §Defined as a PaO2 300 mmHg on the first arterial blood gas analysis obtained after return of spontaneous circulation IIDefined as systolic blood pressure < 100 mmHg during the first 24 hours after return of spontaneous circulation; #Documented pre-cardiac arrest chronic obstructive pulmonary disease or asthma; CPR, cardiopulmonary resuscitation; LCI, lower confidence interval; UCI, upper confidence interval.

roxia§ 0.05 0.43 1.05 0.45 2.42 00.9.9111

able Beta Standard Error Odds Ratio 95% LCI 95% CUCUCI I p-pp-vavallulueeecapnia* 1.25 0.42 3.49 1.54 7.90 0.003 rcapnia† 1.00 0.40 2.73 1.25 5.95 0.011 ial HHypypypotototenenensisisionnonIII 1.37 0.58 3.3 92 1.26 12.14 0.018 ononnaraa y y y DiDiseasasee## 0.3838 00.46 6 1.1 46 000.5.5.59 3.3 626 0.410>>> 0020 mminutes 1.1.1 2626 000.7.79 9 9 3.3 522 00 7.77555 161616 5.5.53 3 0.0.11111 0

babable BBBetaa StS ananndadardrd E rrroro OO ddddss RaRaRatititioo 95%%% LCL I 5595% % CCUCI -p-vavalul e cacapnpnpn aiaia** 1.1.1 2222 00.4.4222 3.33 0040 11 5.5111 7.7.7 68688 000.003030 rcapapniniaa††† 1.0303 0 4.400 2.8080 1.2288 6.6 1515 00.0100 ial HypotensionnIIII 1.1 3888 0.5557 7 3.3..969 111.299 12121 1.1.12 2 2 0.016 ononararyy DiDiseseasasee## 00.3434 00 4.466 11.4040 00 5.577 33.4747 00 4.46666



ownloaded from



22

Figure Legend:

Figure 1. Proportion of patients with poor neurological function at hospital discharge [defined

as a Cerebral Performance Category (CPC) 3] in relation to no exposure, only hypercapnia

exposure, only hypocapnia exposure, and both hypocapnia and hypercapnia exposure during the

first 24 hours after return of spontaneous circulation.



ownloaded from


* Exposure to both hypocapnia and hypercapnia during the first 24 hours after return of spontaneous circulation.

Figure 1



ownloaded from


Stephen TrzeciakBrian W. Roberts, J. Hope Kilgannon, Michael E. Chansky, Neil Mittal, Jonathan Wooden and

Neurological Outcome in Patients with Post-Cardiac Arrest SyndromeAssociation between Post-Resuscitation Partial Pressure of Arterial Carbon Dioxide and

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online April 23, 2013;Circulation.

http://circ.ahajournals.org/content/early/2013/04/23/CIRCULATIONAHA.112.000168World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org/content/suppl/2013/04/23/CIRCULATIONAHA.112.000168.DC1Data Supplement (unedited) at:

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer available in the

Permissions in the middle column of the Web page under Services. Further information about this process isOnce the online version of the published article for which permission is being requested is located, click Request

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Circulation Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



ownloaded from

http://circ.ahajournals.org/content/early/2013/04/23/CIRCULATIONAHA.112.000168

http://circ.ahajournals.org/content/suppl/2013/04/23/CIRCULATIONAHA.112.000168.DC1

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/


CIRCULATIONAHA/2012/000168/R3

SUPPLEMENTAL MATERIAL

Online Data Supplement 1: Correlations between hypocapnia exposure and

hypercapnia exposure, and baseline variables.

Hypocapnia Hypercapnia

Age Correlation Coefficient

0.022 -0.091

p-value 0.764 0.210

Female Gender Correlation Coefficient

0.104 -0.034

p-value 0.153 0.642 Charleson Comorbidity score36

Correlation Coefficient

-0.020 0.067

p-value 0.784 0.356

Diabetes Correlation Coefficient

-0.062 0.023

p-value 0.396 0.749 Coronary artery disease


0.011 -0.121

p-value 0.879 0.093

Hypertension Correlation Coefficient

-0.045 -0.090

p-value 0.532 0.215

Malignancy Correlation Coefficient

0.119 -0.125

p-value 0.101 0.083 Renal insufficiency


0.019 -0.044

p-value 0.794 0.543 Cerebral vascular disease


0.000 0.019

p-value 0.995 0.794 Congestive heart failure


-0.040 -0.171

p-value 0.586 0.018 In-hospital cardiac arrest


-0.056 -0.063

p-value 0.437 0.385

CIRCULATIONAHA/2012/000168/R3

Online Data Supplement 2: Results of sensitivity analyses: Multivariate logistic

regression models with poor neurological outcome [defined as Cerebral Performance

Category (CPC) ≥ 3 at hospital discharge] as the dependent variable.

Variable Beta Standard

Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 1.16 0.40 3.19 1.44 7.05 0.004 Hypercapnia† 0.85 0.38 2.33 1.10 4.92 0.027 Number of PaCO2 assessed 0.04 0.07 1.04 0.90 1.19 0.612

Variable Beta Standard

Error Odds Ratio 95% LCI 95% UCI p-value Hypocapnia* 0.98 0.37 2.66 1.28 5.52 0.009 Hypercapnia† 1.23 0.40 3.43 1.56 7.55 0.002 Congestive heart failure 0.47 0.47 1.60 0.64 3.98 0.313

*Defined as exposure to a partial pressure of arterial CO2 ≤ 30 mmHg during the first 24

hours after return of spontaneous circulation; †Defined as exposure to a partial pressure

of arterial CO2 ≥ 50 mmHg during the first 24 hours after return of spontaneous

circulation; PaCO2, partial pressure of arterial carbon dioxide

association between post-resuscitation partial pressure of arterial

Documents