als 713: prognostication in normothermia · dallas 2015 tfqo: clifton callaway (coi #214) evrevs:...

Dallas 2015

TFQO: Clifton Callaway (COI #214)

EVREVs: Claudio Sandroni (COI #134); Tobias Cronberg (COI #35)

Taskforce: ALS

ALS 713: Prognostication in Normothermia

Dallas 2015 COI Disclosure (specific to this systematic review)

Commercial/industry

Claudio Sandroni: none

Tobias Cronberg: none

Potential intellectual conflicts Claudio Sandroni: first author of two systematic reviews on prognostication after cardiac arrest and of the ERC-ESICM Advisory Statement on prognostication in comatose survivors of cardiac arrest

Tobias Cronberg: author of the ERC-ESICM Advisory Statement on

prognostication in comatose survivors of cardiac arrest

Dallas 2015

2010 CoSTR

ALS-PA-041A (Clinical Examination)

ALS-PA-051A (Electrophysiology)

ALS-PA-052A-B (Biomarkers)

ALS-PA-059 (Imaging)

Dallas 2015

2010 Clinical Examination

The following parameters predicted poor outcome (CPC 3 or 4, or death) with a false-positive rate (FPR) of 0%:

absent vestibulo-ocular reflexes at 24 h [(95%CI 0%-14%)] (LOE P1)

absence of pupillary light and corneal reflex at 72 h (95% CI 0% to 9%) (LOE P1)

GCS <5 at 48 h (95% CI 0% - 13%) (LOE P1) and on day 3 (95% CI 0% - 6%) (LOE P2)

a clinical examination score<15 on day 4 [(95%CI 0% -18%) (LOE P1)

However, in 1 study an absent motor response (GCS motor =1) at 72 h after cardiac arrest predicted poor outcome with a FPR of 5% [(95%CI 2% to 9%] (LOE P1)

The presence of myoclonus status in adults was strongly associated with poor outcome (LOE P1; LOE P3; LOE P4), but rare cases of good neurological recovery have been described and accurate diagnosis was problematic.

Dallas 2015


Treatment Recommendations There are no clinical neurologic signs that reliably predict poor outcome <24 hours after cardiac arrest.

In adult patients who are comatose after cardiac arrest, have not been treated with hypothermia and have no confounding factors (e.g., hypotension, sedatives or neuromuscular blockers), the absence of both pupillary light and corneal reflex at 72 hours reliably predicts poor outcome.

Absence of vestibulo-ocular reflexes at 24 hours and a GCS motor score of 2 or less at 72 hours are less reliable.

Other clinical signs, including myoclonus, are not recommended for predicting poor outcome

Dallas 2015


Knowledge Gaps

The reevaluation of prognostic indicators during therapeutic hypothermia and in the presence of other confounders needs to be completed to guide current post–cardiac arrest care.

Dallas 2015

2010 Electrophysiology

SEP measured between 4 h and 2 weeks after cardiac arrest were associated with poor outcome in 14 studies (LOE P1, P2, P3)

The absence of cortical N20 response to median nerve stimulation at 24 to 72 hours after cardiac arrest predicted poor outcome (CPC 3 or 4, or death) with a FPR of 0.7% (95% CI 0.1 -3.7) (LOE P1)

Electroencephalography predicted poor outcome in comatose survivors of cardiac arrest within 1 week after cardiac arrest in 12 studies (LOE P1, P3, P4, P5).

In a meta-analysis, EEG showing generalized suppression to less than 20 µV, burst-suppression pattern associated with generalized epileptic activity, or diffuse periodic complexes on a flat background 12 to 72 hours after sustained ROSC predicted a poor outcome (FPR of 3%, 95% CI 0.9% to 11%).

Dallas 2015


Treatment Recommendations No electrophysiological study reliably predicts outcome of comatose patient after cardiac arrest in the first 24 hours.

After 24 hours, bilateral absence of the N20 cortical response to median nerve stimulation predicts poor outcome in comatose cardiac arrest survivors not treated with therapeutic hypothermia.

In the absence of confounding circumstances, such as sedatives, hypotension, hypothermia, or hypoxemia, it is reasonable to use unprocessed EEG interpretation (specifically identifying generalized suppression to less than 20 µV, burst suppression pattern with generalized epileptic activity, or diffuse periodic complexes on a flat background) observed between 24 and 72 hours after sustained ROSC to assist the prediction of a poor outcome in comatose survivors of cardiac arrest not treated with hypothermia.

Dallas 2015


Knowledge Gaps More data are needed about the performance and timing of somatosensory evoked potentials and electroencephalography criteria for aiding prognostication in patients treated with induced hypothermia.

Dallas 2015

2010 Biomarkers

Serum neuronal-specific enolase (NSE) elevations are associated with poor outcome for comatose patients after cardiac arrest (LOE P1; LOE P2; LOE P3).

Although specific cutoff values with a FPR of 0% have been reported, clinical application is limited due to variability in the 0% FPR cutoff values reported among various studies.

Serum S100 elevations are associated with poor outcome for comatose patients after cardiac arrest (LOE P1; LOE P2; LOE P3)

Worse outcomes for comatose survivors of cardiac arrest are also associated with increased levels of cerebrospinal fluid (CSF)-CK (LOE P2), CKBB (LOE P1; LOE P2; LOE P3). However, 1 study found no relationship between cerebrospinal fluid-CKBB and prognosis (LOE P2).

Outcomes are also associated with increased cerebrospinal fluid levels of other markers including NSE (LOE P1; LOE P2; S100 (LOE P2); LDH, GOT (LOE P2); neurofilament (LOE P3); and acid phosphatase and lactate (LOE P2).

Dallas 2015

2010 Biomarkers

Treatment Recommendations Evidence does not support the use of serum or cerebrospinal fluid biomarkers alone as predictors of poor outcomes in comatose patients after cardiac arrest with or without treatment with therapeutic hypothermia.

Limitations included small numbers of patients and/or inconsistency in cutoff values for predicting poor outcome.

Dallas 2015

2010 Biomarkers

Knowledge Gaps Future studies should identify and resolve the heterogeneity of cutoff values used to predict poor outcome with a FPR of zero.

Studies also must account for confounders that may alter levels or predictive performance of various markers (eg, hypothermia, underlying disease, pregnancy, intra-aortic balloon pump, brain instrumentation, hemodialyisis, or other organ failure).

Studies examining whether biomarkers can be used to monitor ongoing injury and response to therapy may be useful.

Dallas 2015

2010 Imaging

MRI There are no LOE P1-P2-studies that support the use of MRI.

In 32 studies (P3-P5) the timing of MRI ranged from 1 day to 10 months after ROSC.

Overall these studies were limited by small sample sizes, variable time of imaging (many very late in the course of the event), lack of comparison with a standardized method of prognostication, often nonmodern MRI techniques, and early withdrawal of care.

Dallas 2015

2010 Imaging

CT There are no LOE P1-P2-studies that support the use of CT.

In 22 studies (P3-P5) the timing of MRI ranged from 1 h to 20 days after ROSC.

Overall these studies were limited by small sample sizes, variable time of imaging (many very late in the course of the event), lack of comparison with a standardized method of prognostication, and early withdrawal of care.

Dallas 2015

2010 Imaging

Treatment Recommendations There is insufficient evidence to recommend for or against the routine use of neuroimaging to predict outcome of adult cardiac arrest survivors.

Knowledge Gaps Adequately powered prospective studies are required to evaluate the accuracy of CT, MRI, or both in prognosticating outcome of comatose cardiac arrest survivors.

Outcome prediction should include a comparison with more conventional methods.

All studies should allow for sufficient time to realize patient recovery, avoiding the bias of self-fulfilling prophecy and premature withdrawal of care.

Dallas 2015

C2015 PICO

Population: Adults with ROSC who are not treated with targeted temperature management (TTM)

Intervention: any clinical variable when normal (e.g. 1. Clinical Exam, 2. EEG, 3. SSEP, 4. Imaging, 5. Other)

Comparison: any clinical variable when abnormal

Outcomes Survival with Favorable neurological or functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year

Dallas 2015 Inclusion/Exclusion & Articles Found

Inclusion: adult (≥16 years) pts, comatose (unconscious, unresponsive, or GCS≤8)

Exclusion: Studies including pts. in hypoxic coma from causes other than CA (e.g., respiratory arrest, CO poisoning) except when a subpopulation of cardiac arrest patients could be evaluated separately.

Included: 46 articles

Dallas 2015 2015 Proposed Treatment Recommendations

Clinical Examination - 1

We recommend using the absence of pupillary reflex to light (or the combined absence of both pupillary and corneal reflexes) at ≥72h from ROSC to predict poor outcome.

We suggest against using an absent or extensor motor response to pain (M≤2) alone to predict poor outcome, given its high false positive rate. However, due to its high sensitivity, this sign may be used to identify the population with poor neurological status needing prognostication or to predict poor outcome in combination with other more robust predictors.



We suggest using the presence of a status myoclonus within 72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome.

We suggest prolonging the observation of clinical signs when interference from residual sedation or paralysis is suspected, so that the possibility of obtaining false positive results is minimized.


Electrophysiology

We recommend using bilateral absence of N20 SSEP wave at ≥24h after ROSC to predict poor outcome.

We suggest using the presence of burst-suppression on EEG at 72h from ROSC in combination with other predictors for prognosticating a poor neurological outcome.

We suggest against using EEG grades due to the inconsistencies in their definitions.

We also do not suggest using low-voltage EEG given the potential interferences of technical factors on EEG amplitude.


Biomarkers

We suggest using high serum values of NSE at 24-72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome. However, no threshold enabling prediction with zero FPR can be recommended.

We suggest using utmost care and preferably sampling at multiple time-points when assessing NSE, to avoid false positive results due to hemolysis.


Imaging

We suggest using the presence of a marked reduction of the GM/WM ratio on brain CT within 48 h after ROSC or the presence of extensive reduction in diffusion on brain MRI at 2-6 days after ROSC in combination with other predictors for prognosticating a poor neurological outcome.

We suggest using brain imaging studies for prognostication only in centers where specific experience is available.

Dallas 2015

Risk of Bias in studies

Author, year Index Blinding (treating

team)

Blinding (index or outcome

evaluators)

Excludes sedation

or paralysis

Best CPC

Excludes previous neurol.

diseases

Interobserv. agreement assessed

Length of follow-up

Index test used for

WLST Overall

Bassetti 1996 SSEP No no N/A no yes no 1 year No serious

Bassetti, 1996 EEG, BR No no no no yes no 1 year No serious

Bauer, 2003 SEP N70 No no N/A no no no 1 year No serious

Berkhoff, 2000 EEG, SSEP No no yes no no no 1 year Not reported Very serious

Bertini, 1989 PLR No no no no yes no discharge Not reported very serious

Brunko, 1987 SSEP No no N/A no no no 30 days Not reported very serious

Chockroverty, 1975

EEG No no no no no no 30 days Not reported very serious

Choi, 2008 CT No no N/A no no yes discharge Not reported very serious

Choi, 2010 MRI No no N/A no no no 90 days No serious

Earnest 1979 PLR, MR No no no no yes no discharge Not reported very serious

Edgren 1987 PLR, CR, MR No no yes no yes no 180 days Yes Very serious

Edgren, 1987 EEG No yes yes no yes no 180 days No Serious

Els, 2004 MRI No yes N/A yes no no 180 days Not reported very serious

Fischer, 2006 GCS No no yes yes no no 1 year Not reported very serious

Gendo 2001 SEP N70 No no N/A no no no 180 days Not reported very serious

Grindal 1977 EEG No no no no no no 60 days Not reported very serious

Dallas 2015



team)


evaluators)

Excludes sedation

or paralysis

Best CPC


diseases


Length of follow-up

Index test used for

WLST Overall

Hachimi-Idrissi, 2002

S-100B Yes yes N/A yes no N/A discharge No No

Kaplan, 1999 EEG No no no no no No discharge Not reported very serious

Krumholz, 1988 Myoclonus No no no no yes No 180 days Not reported Very serious

Madl 2000 SEP N70 No no N/A no no No 180 days Not reported very serious

Mlynash, 2010 MRI No yes N/A yes no Yes 180 days Not reported very serious

Morimoto, 1993 CT no no N/A no no No discharge Not reported very serious

Mussack, 2002 S-100B no no N/A no no N/A 1 year Not reported very serious

Nakabayashi 2001 SEPs no no N/A no no No 1 year Not reported Very serious

Pfeifer 2005 GCS no no yes no yes No 30 days Not reported Very serious

Reisinger, 2007 NSE No no N/A no no N/A 180 days No Serious

Rosen, 1998 S-100B no no N/A no no N/A discharge Not reported very serious

Rosen, 2001 NSE, S-100B no no N/A no no N/A 1 year Not reported very serious

Rothstein, 1991 EEG no no no no no No 60 days Not reported very serious

Rothstein, 2000 SSEP no no N/A no no No 30 days No Serious

Samaniego, 2011 NSE no no N/A no no N/A 90 days Not reported very serious

Scollo-Lavizzari 1987

EEG no no no no no No discharge Not reported very serious

Steffen, 2010 NSE no no N/A no no N/A discharge no serious

Stelzl, 1995 SSEP, NSE no no N/A no no No discharge Not reported very serious

Dallas 2015



team)


evaluators)

Excludes sedation

or paralysis

Best CPC


diseases


Length of follow-up

Index test used for

WLST Overall

Thomke, 2005 Myoclonus no no yes no no No 1 year no serious

Tiainen, 2003 NSE, S-100B no no N/A no no N/A 180 days Not reported very serious

Tianen, 2005 SSEP No no N/A no no No 180 days no serious

Topcuoglu 2009 GCS no yes no no no No 90 days no serious

Topcuoglu, 2009 MRI yes yes N/A no no No 90 days no No

Torbey, 2004 CT no no N/A no no No discharge Not reported very serious

Vignaendra, 1974 EEG no no no no no No discharge Not reported very serious

Wijdicks, 1994 Myoclonus no no no yes yes No 180 days no Serious

Wijdicks, 2001 MRI no yes N/A no no No discharge Not reported very serious

Wijman, 2009 MRI limited yes N/A yes no No 180 days No Serious

Wu, 2009 MRI No no N/A no no No 180 days Not reported very serious

Young 2005 SSEP No no N/A no yes No 90 days Not reported very serious

Young 2005 PLR, CR, OVR No no yes no yes No 90 days Not reported very serious

Zanatta, 2012 SSEPs No no N/A no no No 90 days Not reported very serious

Zandbergen, 2006a

PLR, CR, MR, myoclonus, EEG

no no yes no yes No 1 year Yes (PLR, MR) very serious

Zandbergen 2006a NSE, S-100B Yes no N/A no yes No 1 year No No

Zandbergen 2006a SSEPs Limited no N/A no no No 1 year Yes Very serious

Zandbergen 2006b SEP N70 Limited no N/A no no No 1 year No Serious

Dallas 2015



team)


evaluators)

Excludes sedation

or paralysis

Best CPC


diseases


Length of follow-up

Index test used for

WLST Overall

Zhang, 2011 EEG no yes yes no no No 180 days Not reported very serious

Zhang, 2011 SSEP no yes N/A no no No 180 days Not reported very serious

Zingler, 2003 SSEP no no N/A no no No 90 days Not reported very serious

Zingler, 2003 NSE, S-100B no no N/A no no No 90 days Not reported very serious

Dallas 2015

For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified 4 studies on brainstem reflexes, motor response, or myoclonus (650 patients, low or very low QOE)

For the critical outcome of survival with unfavorable neurological status or death at one year, we identified 2 studies on brainstem reflexes, motor response, GCS, or myoclonus (172 patients, very low QOE)


Dallas 2015


For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified two studies on pupillary reflex and motor response or oculocephalic reflex (151 patients, very low QOE)

For the critical outcome of survival with unfavorable neurological status or death at 30 days, we identified one study on GCS (97 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified two studies on corneal reflex, pupillary reflex, motor response, oculovestibular reflex, GCS, or myoclonus (97 patients, very low QOE).

Dallas 2015

Evidence profile table

Predictor

(studies) Timing

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Corneal

reflex (3) At 24h

Very

serious No Serious

Very

serious Very low 157 12 268 60 37 [32-42] 17 [9-27] 2 [1-4]

Corneal

reflex (2) At 48h

Very

serious No Serious

Very

serious Very low 97 3 231 38 30 [25-35] 7 [2-20] 3 [1-8]

Pupillary

reflex (3) At 24h

Very

serious No No

Very

serious very low 88 7 331 70 21 [17-25] 9 [4-18] 3 [1-5]

Pupillary

reflex (3) At 48h

Very

serious No No

Very

serious very low 65 2 281 55 19 [15-23] 4 [0-12] 4 [1-14]

Pupillary

reflex (2) At 72h

Very

serious No Serious Serious Very low 64 0 283 35 18 [15-23] 0 [0-8] 10 [1-71]

Dallas 2015


Predictor

(studies) Timing

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Absent CR

and PLR At 24h

Very

serious No -

Very

serious Very low 48 2 297 39 14 [10-18] 5 [1-17] 3 [1-11]

Absent CR

and PLR At 48h

Very

serious No -

Very

serious Very low 40 1 267 30 13 [9-17] 3 [0-17] 4 [1-26]

Absent CR

and PLR At 72h

Very

serious No -

Very

serious Very low 37 0 233 19 14 [10-18] 0 [0-15] 6 [0,4-87]

MR ≤2 (2) At 24h Very


MR ≤2 (2) At 72h Very

serious No Serious

Very

serious very low 218 7 78 19 39 [33-44] 15 [5-31] 3 [1-7]



We recommend using the absence of pupillary reflex to light (or the combined absence of both pupillary and corneal reflexes) at ≥72h from ROSC to predict poor outcome (strong recommendation, QOE very low).

We suggest against using an absent or extensor motor response to pain (M≤2) alone to predict poor outcome, given its high false positive rate (weak recommendation, QOE very low). However, due to its high sensitivity, this sign may be used to identify the population with poor neurological status needing prognostication or to predict poor outcome in combination with other more robust predictors.

Dallas 2015


Predictor

(studies) Timing

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Myoclonus Admission Serious No - Very

serious Very low 40 0 47 20 46 [35-57] 0 [0-14] 19 [1-302]

Myoclonus At 24h Very

serious No - Serious Very low 19 0 1 55 95 [75-100] 0 [0-5] 10 [7-1646]

Status

myoclonus At 36-48h

Very


Status

myoclonus At 72h

Very

serious No

Very

serious Very low 5 0 275 20 2 [1-4] 0 [0-14] 1 [0,1-14]



We suggest using the presence of a status myoclonus within 72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome (weak recommendation, QOE very low).

We suggest prolonging the observation of clinical signs when interference from residual sedation or paralysis is suspected, so that the possibility of obtaining false positive results is minimized.

Dallas 2015

Knowledge Gaps

Prospective studies are needed to investigate:

the pharmacokinetics of sedative and NMB drugs

the reproducibility of clinical signs used to predict

outcome.

There is no universally accepted definition of status myoclonus

Recently proposed definition = generalised myoclonus persisting for ≥30 minutes.

Dallas 2015

Electrophysiology - 1

For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified 2 studies on short-latency somatosensory evoked potentials (SSEP) (63 patients, very low QOE) and 3 studies on EEG (46 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 30 days, we identified 2 studies on SSEP (80 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 60 days we identified 2 studies on EEG (54 patients, very low QOE).

Dallas 2015

Electrophysiology - 2

For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified 2 studies on SSEP or EEG (102 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified 6 studies on SSEP, SEP or EEG (733 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 1 year, we identified 6 studies on SSEP or EEG (829 patients, low or very low QOE).

Dallas 2015


Predictor

(studies) Timing

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Absent N20

SSEP (4) At 24h

very

serious no serious no very low 156 0 206 92 43 [38-48] 0 [0-3] 24 [6-93]

Absent N20

SSEP (4) At 48h

very

serious no serious serious very low 125 0 145 58 46 [40-52] 0 [0-5] 11 [3-43]

Absent N20

SSEP (2) At 72h serious no serious serious very low 120 0 140 33 46 [40-52] 0 [0-9] 18 [3-122]

Absent N20

SSEP (3) At 12-72h

very

serious no serious serious very low 138 1 170 99 45 [39-51] 1 [0-5] 17 [4-65]

Dallas 2015


Predictor

(studies) Timing

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

EEG Grade 3-5 24 h Serious Serious Very

serious very low 5 0 9 12 36 [13-65] 0 [0-22] 10 [1-156]

EEG Grade 3-5 48 h Serious Serious Very

serious very low 4 0 7 11 36[11-69] 0 [0-24] 9 [1-150]

EEG Grade 4-5

(3) serious Serious no no Serious Very low 43 0 55 27 44[33-54] 0 [0-11] 7 [1-33]

Burst

suppression ≤48h

Very

serious no

Very

serious very low 22 1 31 18 42 [28-56] 5 [0-26] 8 [1-55]

Burst

suppression 72 h

Very

serious no

Very

serious very low 22 0 228 27 9 [6-12] 0 [0-11] 5 [0,3-81]

EEG ≤20 µV ≤48 h Very

serious no

Very

serious very low 8 0 45 19 15 [7-28] 0 [0-15] 6 [0,4-104]

EEG ≤21 µV 72 h Sery

serious no

Very

serious very low 79 0 177 27 31 [25-37] 0 [0-11] 17 [1-272]


Electrophysiology

We recommend using bilateral absence of N20 SSEP wave at ≥24h after ROSC to predict poor outcome (strong recommendation, QOE very low).

We suggest using the presence of burst-suppression on EEG at 72h from ROSC in combination with other predictors for prognosticating a poor neurological outcome (weak recommendation, QOE very low).

We suggest against using EEG grades due to the inconsistencies in their definitions (weak recommendation, QOE very low).

We also do not suggest using low-voltage EEG, given the potential interferences of technical factors on EEG amplitude (weak recommendation, QOE very low).

Dallas 2015

Knowledge Gaps

In most prognostication studies on TTM-treated patients, SSEPs have been used as a criterion for WLST

Blinded studies are needed to assess the relevance of self-fulfilling prophecy for SSEPs.

Definitions of EEG-based predictors are inconsistent among prognostication studies.

Future studies should comply with recently recommended definitions (e.g. Hirsch and coll., 2013).

Dallas 2015

Biomarkers

For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified 2 studies on S-100B (99 patients, low or very low QOE) and 1 study on NSE (73 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified 1 study on NSE (32 patients, very low QOE) and 1 study on S-100B (27 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified 3 studies on NSE or S-100B (618 patients; moderate, low or very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at one year, we identified 2 studies on NSE or S-100B (86 patients, very low QOE)

Dallas 2015


Predictor,

timing

(studies)

Th

resh

old

(mcg

L-1) Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

NSE 24 h

(3)

13,3 Very

serious no -

Very

serious very low 10 0 7 16 59 [33-82] 0 [0-17] 20 [1-313]

33 no no - Serious moderate 114 0 122 36 48 [42-55] 0 [0-8] 36 [2-563]

47.6 Very

serious no -

Very

serious very low 9 0 8 10 53 [28-77] 0 [0-26] 12 [1-180]

NSE 48 h

(4)

8,8 very

serious no

very

serious very low 12 0 4 16 75 [48-93] 0 [0-17] 25 [2-389]

≥ 25 very

serious no

very

serious very low 14 0 24 23 37 [22-54] 0 [0-12] 18 [1-286]

43 very

serious no

very

serious very low 15 0 2 10 88 [64-99] 0 [0-26] 19 [1-286]

80 serious no no serious 34 0 19 104 64 [50-77] 0 [0-3] 89 [6-1447]

Dallas 2015


Predictor,

timing,

(studies)

Th

resh

old

(mcg

L-1)

Risk of

bias

In

dire

ctn

ess

In

co

nsis

ten

cy

Im

pre

cis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

NSE 72h

(5)

15 Very

serious No -

Very

serious Very low 30 0 12 23 71[55-84] 0 [0-12] 34 [2-532]

22.4 Serious No - Very

serious Very low 89 3 14 27 86 [78-92] 10 [2-27] 9 [3-25]

33 Very

serious No Serious

Very

serious Very low 101 1 82 37 55[-48-63] 3 [0-14] 9 [0-292]

90.9 Very

serious no

Very

serious Very low 13 0 4 10 76 [50-93] 0 [0-26] 17 [1-251]


Biomarkers

We suggest using high serum values of NSE at 24-72 h from ROSC in combination with other predictors for prognosticating a poor neurological outcome. However, no threshold enabling prediction with zero FPR can be recommended (weak recommendation, QOE very low).

We suggest using utmost care and preferably sampling at multiple time-points when assessing NSE, to avoid false positive results due to hemolysis.

Dallas 2015

Knowledge Gaps

There is a need for standardisation of the measuring techniques for NSE and S-100 in cardiac arrest patients.

Little information is available on the kinetics of the blood concentrations of biomarkers in the first few days after cardiac arrest.

Dallas 2015

Imaging

For the critical outcome of survival with unfavorable neurological status or death at discharge, we identified 3 studies on CT (113 patients, very low QOE) and 2 studies on MRI (40 patients, very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 90 days, we identified 2 studies on MRI (61 patients, low or very low QOE).

For the critical outcome of survival with unfavorable neurological status or death at 180 days, we identified 3 studies on MRI (34 patients, very low QOE).

Dallas 2015


CT Index

Timing

from

ROSC

Risk of

bias

Ind

irectn

ess

Inco

nsis

ten

cy

Imp

recis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

GWR<1.22 BG <24 h Very

serious No

Very

serious Very low 12 0 7 9 63 [38-84] 0 [0-45] 13 [1-190]

GWR<1.18 BG <48 h Very

serious No

Very

serious Very low 13 1 13 5 50 [30-70] 17 [0-64] 3 [0,5-19]

Brain swelling 72 h very

serious no

very

serious very low 25 0 23 5 52 [37-67] 0 [0-45] 6 [0,4-90]

Dallas 2015


MRI Index

Timing

from

ROSC

Risk of

bias

Ind

irectn

ess

Inco

nsis

ten

cy

Imp

recis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Extensive DWI

changes 4-32 h

Very

serious Serious

Very

serious Very low 7 0 0 5 100 [65-100] 0 [0-45] 11 [1-161]

Diffuse DWI –

FLAIR cortical

changes 80h

(IQR

55-117)

Very

serious No

Very

serious Very low 4 0 1 7 80 [28-99] 0 [0-35] 12 [1-183]

DWI changes

in BG

Very

serious No

Very

serious Very low 5 3 0 4 100 [55-100] 43 [10-82] 2 [1-5]

Dallas 2015


MRI Index

Timing

from

ROSC

Risk of

bias

Ind

irectn

ess

Inco

nsis

ten

cy

Imp

recis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Whole-brain

ADC<665 x10-6

mm2/sec

2 (0-10)

days

very

serious serious

very

serious very low 27 0 40 13 40 [28-53] 0 [0-21] 11 [1-175]

ADC < 650 ▪ 10-6

mm2/sec in >10%

of brain volume

49-108

h Serious No

Very

serious Very low 7 0 1 2 88 [47-100] 0 [0-78] 5 [0,4-64]

Occipital cortex

ADC < 740 x 10-6

mm2/sec

<120 h

serious serious Very

serious Very low 13 0 1 8 93 [66-100] 0 [0-31] 16 [1-241]

Putamen ADC <

590 x 10-6 mm2/sec serious serious

Very

serious Very low 13 0 1 8 93 [66-100] 0 [0-31] 16 [1-241]

Thalamus ADC <

647 x 10-6 mm2/sec serious serious

Very

serious Very low 12 0 2 8 86 [57-98] 0 [0-31] 15 [1-224]

Dallas 2015


MRI Index

Timing

from

ROSC

Risk of

bias

Ind

irectn

ess

Inco

nsis

ten

cy

Imp

recis

ion

QOE

TP FP FN TN

Sensitivity

[95%CI]

FPR

[95%CI]

LR+

[95%CI]

Extensive global

FLAIR changes ≤7d

very

serious no

very

serious very low 6 0 0 2 100 [61-100] 0 [0-78] 6 [0,4-71]

Extensive cortical

DWI and FLAIR

changes

≤7d no no very

serious low 13 0 1 2 93 [66-100] 0 [0-78] 5 [0,4-68]


Imaging

We suggest using the presence of a marked reduction of the GM/WM ratio on brain CT within 48 h after ROSC or the presence of extensive reduction in diffusion on brain MRI at 2-6 days after ROSC in combination with other predictors for prognosticating a poor neurological outcome (weak recommendation, QOE very low).

We suggest using brain imaging studies for prognostication only in centers where specific experience is available.

Dallas 2015

Knowledge Gaps

Prospective studies in unselected patient populations and including inter-rater agreement are needed for evaluating the prognostic accuracy of imaging studies in comatose patients resuscitated from cardiac arrest.

Dallas 2015

Next Steps

Consideration of interim statement

Person responsible

Due date

als 713: prognostication in normothermia · dallas 2015 tfqo: clifton callaway (coi #214) evrevs:...

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