Survival but not severity of hypoxic-ischemic encephalopathy is associated with higher mean arterial blood pressure after cardiac arrest: a retrospective cohort study

doi:10.21203/rs.3.rs-2731294/v1

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Survival but not severity of hypoxic-ischemic encephalopathy is associated with higher mean arterial blood pressure after cardiac arrest: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-2731294/v1

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Background: To study the association between mean arterial blood pressure (MAP), vasopressor requirement, and severity of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA).

Methods: Between 2008 and 2017, we retrospectively analyzed the MAP 200 hours after CA and quantified vasopressor requirements using the cumulative vasopressor index (CVI). Using postmortem brain autopsy in non-survivors, the severity of HIE was histopathologically dichotomized into no/mild and severe HIE. In survivors, we dichotomized the HIE severity into no/mild - Cerebral Performance Category (CPC) 1 – and severe HIE (CPC 4). Regain of consciousness, death causes and five-day survival were investigated as hemodynamic confounders.

Results: Among 350 non-survivors, 117 had histopathologically severe HIE and 233 no/mild HIE without differences in MAP (73.1 vs 72.0 mmHg, p_group=0.639). Compared to non-survivors, 211 CPC 1 and 57 CPC 4 patients had higher MAPs that showed significant, but clinically non-relevant MAP differences (81.2 vs 82.3 mmHg, p_group<0.001). No/mild HIE non-survivors (n=54) regaining consciousness before death had higher MAPs compared to no/mild HIE non-survivors (n=179) who remained persistently comatose (74.7 vs 69.3 mmHg, p_group<0.001). No/mild HIE non-survivors regaining consciousness required less vasopressors (CVI 2.1 vs 3.6, p_group<0.001). Independently of HIE severity, survivors were faster weaned from vasopressors (CVI 1.0).

Conclusions: Higher MAP was associated with survival but not HIE severity in CA patients treated with a vasopressor-supported MAP target above 65 mmHg. Awakening from coma was associated with less vasopressor requirements. Our results provide no evidence for a MAP target above current guideline recommendations to decrease the severity of HIE.

Health sciences/Diseases/Neurological disorders/Hypoxic ischaemic encephalopathy

Health sciences/Neurology/Neurological disorders/Disorders of consciousness

Health sciences/Medical research/Outcomes research

cardiac arrest

brain autopsy

hypoxic-ischemic encephalopathy

mean arterial pressure

cumulative vasopressor index

prognosis

The severity of hypoxic-ischemic encephalopathy (HIE) mainly determines long-term outcome in comatose patients resuscitated from cardiac arrest (CA) (1–5). Hemodynamic instability contributes to increased mortality and secondary brain injury (6–8) Blood pressure management with vasopressors aims to maintain sufficient cerebral perfusion and avoid secondary ischemia as cerebral blood flow autoregulation is impaired following cerebral ischemia (9–11).

Current international guidelines recommend to avoid mean arterial blood pressures (MAP) below 65 mmHg. Vasopressors are recommended to counteract lower values, but evidence supporting a specific MAP target is lacking (11, 12). Hypotension and increased vasopressor requirements were previously found to be associated with increased mortality and poor neurological outcome (13, 14). However, interventional studies comparing different MAP targets failed to demonstrate improved outcome with a MAP above 65 mmHg (15–18). Importantly, extracerebral death causes are frequent in patients without severe HIE and confound studies with mortality as the primary outcome (1, 3).

Hence, we studied the association between MAP, vasopressors and severity of HIE evaluated by quantified histopathology and neurological status considering death causes.

Study design and post-resuscitation care

The ethical committee of the Charité University Hospital approved the study (approval number: EA2/007/16, title: “Prognosis after cardiac arrest and resuscitation – Evaluation of prognostic parameters using brain autopsy”) on 5th of February 2016 and waived the need for patient consent. The study complied with the 1975 Helsinki Declaration and the study was written following the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. In a non-survivor cohort, we retrospectively included consecutively admitted patients with postmortem brain autopsies after initially successful resuscitation from all intensive care units (ICU) at the Charité University Hospital, Berlin, Germany, between January 2008 and May 2017. Treatment adhered to international guidelines of post-resuscitation care (10, 19) including hemodynamic management and targeted temperature management (TTM) in 93 patients (27 %) withbrain autopsy and 264 patients (99 %) withICU survival. We recorded demographics following the Utstein style (20), preexisting diseases, and temporary regain of consciousness (i.e. awake and communicating) before death. Clinical death causes were classified into cardiac cause, sepsis/multiorgan failure (MOF), brain injury and others (1). Neuroprognostication and withdrawal of life-sustaining therapy (WLST) followed international guidelines (10, 19). Treating physicians requested brain autopsies independently from the study. In a survivor cohort, we included patients with coma or unresponsive wakefulness syndrome – cerebral performance category (CPC) 4 – and no/mild neurological deficits (CPC 1) upon ICU discharge between January 2006 and December 2015.

Histopathological evaluation of postmortem brain autopsy

We histopathologically quantified neuronal death using the selective eosinophilic neuronal death (SEND) classification. Raters were blinded from clinical data as previously described (21–24). In short, neuronal death following cerebral reperfusion after resuscitation is visible as pyknotic, red neurons. In oxygen-sensitive (cortex, hippocampus and cerebellum) and less oxygen-sensitive regions (basal ganglia, mesencephalon, pons and medulla oblongata), we microscopically quantified selective eosinophilic neuronal death ranging from 0 % (SEN 0), below 30 % (SEN 1), 30–60 % (SEN 2), 60–90 % (SEN 3) and above 90 % (SEN 4). We dichotomized non-survivors histopathologically into no/mild HIE and severe HIE (24).

Hemodynamic monitoring

MAP was continuously monitored and stored in 30-minute-intervals. We calculated mean and interquartile ranges (IQR) hourly during the first 200 hours. To quantify vasopressor requirements, we determined the cumulative vasopressor index (CVI) hourly (25). The CVI numerically rates dosages of dopamine, epinephrine, norepinephrine, phenylephrine and vasopressin according to potency from 0–20 with higher values indicating higher vasopressor requirements (Supplementary Table 1). Stratifying histopathological and clinical HIE severity, we studied the association between MAP and CVI. To consider hemodynamic biases, we investigated regain of consciousness, death causes, selective histopathological damage patterns, and five-day survival.

Statistical analysis

Demographic variables were presented as median/mean and IQR, standard deviation (SD) or percentage, and tested for statistical significance (p < 0.05) using Chi-square test or Wilcoxon rank sum test. Histopathological results are illustrated as heatmaps. Continuous MAP and CVI data are presented as confidence plots and mutual dependence in scatter plots. We used a general linear model testing statistical significance between groups (denoted as p_group), time and interaction between group and time during the first 200 hours, between the first and second 100 hours, and day-wise intervals. We analyzed results of general linear model quantitatively, reviewed box plots, and provided descriptive statistics if suitable. Mutual MAP and CVI dependence was tested using a Welch two-sample t-test or a Mann-Whitney U test for independent samples. In multiple group comparison, we compared pairwise with p-value correction for multiple testing using a Mann-Whitney U test. Analyses were performed using MATLAB, release 2019b (MathWorks Inc), and R Project, released 2020 (The R Project for Statistical Computing).

Study population

We included 618 patients, 350 non-survivors with brain autopsy and 268 survivors. Table 1 illustrates demographics and Supplementary Table 2 preexisting diseases. In non-survivors, 233 and 117 patients showed no/mild and severe HIE, respectively. 54 (23%) of 233 no/mild HIE and 15 of 117 (13%, p = 0.031) severe HIE non-survivors initially regained consciousness. No/mild HIE non-survivors had more out-of-hospital CA (OHCA) (p < 0.001) and shorter resuscitations compared to severe HIE non-survivors (10 min, IQR 5–23, vs 15 min, 5–27, p = 0.017). Regain of consciousness in no/mild HIE non-survivors was associated with shorter resuscitations (5 min, 1–10, p < 0.001). Of 350 non-survivors, 85 had cardiac, 158 MOF and 41 CNS death causes (Supplementary Table 3, Supplementary Table 4). Cardiac death patients had more preexisting cardiac disease, whereas MOF was the primary death cause in no/mild HIE (p = 0.002). Figure 1 illustrates histopathological results and regional neuronal death stratified by death causes, HIE dichotomization and regain of consciousness. In the survivor cohort, we included 211 CPC 1 and 57 CPC 4 patients. CPC 4 patients had non-significantly longer resuscitations compared to CPC 1 patients (15 min, 10–24, vs 12 min, 8–20, p = 0.062). CPC 1 patients were younger (p = 0.010) and had more cardiac CA causes (p = 0.004), more shockable rhythms (p = 0.003), and shorter ICU durations (p < 0.001).

Table 1

**Patient characteristics.**¹Categorical variables were compared using Chi-square tests (χ²), non-normally distributed continuous variables were compared using Wilcoxon rank sum tests (W). HIE – hypoxic-ischemic encephalopathy, CPC – cerebral performance category, IQR – inter-quartile range, OHCA – out-of-hospital cardiac arrest, CA – cardiac arrest, tROSC – time from cardiac arrest to spontaneous circulation, ICU – intensive care unit, WLST – withdrawal of life-sustaining treatment, MOF – sepsis/multiorgan failure, CNS – clinically predicted severe brain injury, SEND – selective eosinophilic neuronal death.
Demographic characteristics	severe HIE non-survivors (n = 117)	no/mild HIE non-survivors (n = 233)	Statistical comparison severe HIE vs. no/mild HIE non-survivors, test statistic (p)¹	CPC 4 survivors (n = 57)	CPC 1 survivors (n = 211)	Statistical comparison CPC 4 vs. CPC 1 survivors, test statistic (p)¹
Gender, male (n, %)	69 (59)	145 (62)	χ² = 0.224 (p = 0.636)	35 (61)	163 (77)	χ² = 5.048 (p = 0.025)
Age, year (median, IQR)	68 (59–76)	69 (58–76)	W = 13482 (p = 0.969)	62 (51–72)	59 (49–67)	W = 5134 (p = 0.010)
OHCA, (n, %)	75 (64)	215 (92)	χ² = 41.56 (p < 0.001)	45 (79)	159 (75)	χ² = 2.390 (p = 0.122)
Cardiac cause of CA, (%)	36	31	χ² = 0.46 (p = 0.498)	58	78	χ² = 8.198 (p = 0.004)
Shockable initial rhythm, (%)	30	23	χ² = 1.16 (p = 0.281)	36	71	χ² = 8.949 (p = 0.003)
tROSC, min, (median, IQR)	15 (5–27)	10 (5–23)	W = 5718 (p = 0.017)	15 (10–24)	12 (8–20)	W = 4878.5 (p = 0.062)
Targeted temperature management, (n, %)	53 (45)	40 (17)	χ² = 30.17 (p < 0.001)	54 (95)	210 (100)	χ² = 4.123 (p = 0.042)
Second CA with resuscitation during ICU stay, (n, %)	49 (42)	108 (46)	χ² = 0.46 (p = 0.497)	not applicable	not applicable	-
Temporarily conscious during ICU stay, (n, %)	15 (13)	54 (23)	χ² = 4.64 (p = 0.031)	not applicable	not applicable	-
WLST, (n, %)	62 (53)	91 (39)	χ² = 5.59 (p = 0.018)	not applicable	not applicable	-
Length of ICU stay, day (median, IQR)	3 (1–8)	1 (0–8)	W = 11026 (p = 0.003)	29 (21–38)	13 (8–23)	W = 3037 (p < 0.001)
Death cause, cardiac, (n, %)	23 (20)	62 (27)	χ² = 1.686 (p = 0.194)	not applicable	not applicable	-
Death cause, MOF, (n, %)	39 (33)	119 (51)	χ² = 9.195 (p = 0.002)	not applicable	not applicable	-
Death cause, CNS, (n, %)	39 (33)	2 (1)	χ² = 76.317 (p < 0.001)	not applicable	not applicable	-
Death cause, others, (n, %)	16 (14)	50 (22)	χ² = 2.597 (p = 0.107)	not applicable	not applicable	-
Maximal SEND score (range 0–4), cortex, (median, IQR)	3 (2–4)	1 (1–1)	W = 1710 (p < 0.001)	not applicable	not applicable	-
Maximal SEND score (range 0–4), hippocampus, (median, IQR)	3.5 (2–4)	1 (1–1)	W = 3883.5 (p < 0.001)	not applicable	not applicable	-
Maximal SEND score (range 0–4), cerebellum, (median, IQR)	3 (1–4)	1 (0–1)	W = 3602.5 (p < 0.001)	not applicable	not applicable	-
Maximal SEND score (range 0–4), brainstem, (median, IQR)	1 (1–2)	1 (0–1)	W = 6338 (p < 0.001)	not applicable	not applicable	-

MAP and HIE severity

In non-survivors, there was no difference in MAP between severe and no/mild HIE (73.1 vs 72.0 mmHg, p_group =0.639) but a significant change over time (p < 0.001) with MAP drops below 60 mmHg in the first 48 hours (Fig. 2A). Compared to non-survivors, CPC 1 and CPC 4 patients had higher MAPs that differed (81.2 vs 82.3 mmHg, p_group<0.001) and increased over time (p < 0.001) (Fig. 2C). In CPC 1 patients, mean MAP was 76.4 mmHg (80.5 mmHg in CPC 4) in the first 24 hours, lowest with 72.6 mmHg (73.8 mmHg in CPC 4) between 24–48 hours, and increased to a stable mean of 86.4 mmHg (86.5 mmHg in CPC 4) during the last 100 hours. Except from the first 24 hours, MAP differences were not larger than 2 mmHg. No/mild HIE non-survivors who regained consciousness had higher MAPs compared to those with persistent coma (74.7 mmHg vs 69.3 mmHg, p_group<0.001) in whom MAPs significantly increase over time (p < 0.001) (Fig. 2B). In group comparison, CPC 1 and CPC 4 patients had the highest mean MAP of 81.2 and 82.3 mmHg, respectively, followed by no/mild HIE non-survivors who regained consciousness (mean MAP 74.7 mmHg, p < 0.001) during the 200 hours.

Vasopressor therapy and HIE severity

Vasopressor requirements differed between no/mild HIE and severe HIE non-survivors (p_group<0.001) and time (p < 0.001) with a significant decrease (p = 0.01) of severe HIE non-survivors between 72–96 hours and consequently higher CVI in no/mild HIE patients (Fig. 3A). In no/mild HIE non-survivors, regaining consciousness (n = 54) was associated with lower (p_group<0.001) and faster decrease (p < 0.001) of vasopressors (Fig. 3B). CVI of CPC 1 and CPC 4 patients both significantly decreased (p < 0.001) over time without group difference (p_group=0.28) (Fig. 3C). In group comparison, CPC 1 and CPC 4 patients had the lowest CVI (both mean 1.0), followed by no/mild HIE non-survivors with regain of consciousness (mean CVI 2.1).

Association between MAP and vasopressor therapy

Severe HIE non-survivors required less vasopressors (CVI 2.3 vs 2.7, p < 0.001) to achieve higher MAPs (mean of 73.1 vs 72.0 mmHg, p = 0.001) compared to no/mild HIE non-survivors (Supplementary Fig. 1A). In no/mild HIE non-survivors, regain of consciousness was associated with higher MAPs (mean of 74.7 vs 69.3 mmHg, p < 0.001) and less vasopressors (CVI 2.1 vs 3.6, p < 0.001) (Supplementary Fig. 1B). CPC 1 and CPC 4 patients needed the same vasopressor dosages (CVI 1.0) to achieve similar MAPs (mean of 81.2 vs 82.3 mmHg, p = 0.10) (Supplementary Fig. 1C). Supplementary Fig. 2 and Supplementary Results shows the influence of five-day survival. Notably, no/mild HIE non-survivors with persistent coma had higher mean MAPs during the first 100 hours in case of five-day survival (71.1 vs 67.1 mmHg).

Association of death cause with vasopressor therapy and MAP

In no/mild HIE non-survivors with cardiac death (Supplementary Fig. 3), persistent coma (n = 50) was associated with higher CVI (5.3 vs 3.4, p < 0.001) and lower MAPs (mean 64.8 vs 69.8 mmHg, p < 0.001). Conversely, regain of consciousness (n = 12) was associated with lower CVI (1.4 vs 2.3, p < 0.001) and lower MAPs (mean 72.3 vs 75.2 mmHg, p < 0.001). In all groups, MOF death cause was associated with higher vasopressors requirements (CVI ranging from 2.5–3.6), even in 30 no/mild HIE non-survivors regaining consciousness (CVI 2.5 vs 1.6, p < 0.001). In 39 severe HIE non-survivors suffering MOF death, MAP was lower compared to other death causes (mean 68.6 vs 75.1 mmHg, p < 0.001).

Association of selected histopathological neuronal death and clinically predicted brain injury on vasopressor therapy and MAP

In 39 severe HIE non-survivors with clinically predicted brain injury as death cause, MAP was higher (mean 69.2 vs 77.2 mmHg, p < 0.001) and CVI lower (1.8 vs 2.8, p < 0.001) compared to cardiac or MOF death causes (Fig. 4A). To study selective cortical brain injury, we compared non-survivors without brainstem neuronal death showing at least 30% (n = 10) and no cortical neuronal death (n = 31) (Fig. 4B). MAPs were indifferent (p = 0.57) whereas CVI was higher in patients without cortical and brainstem neuronal death (CVI 2.4 vs 1.5, p < 0.001). In non-survivors with more than 90% cortical neuronal death (n = 42) (Fig. 4C), CVI was also lower (CVI 2.1 vs 2.5, p < 0.001) and MAP higher (76.6 vs 73.9 mmHg, p < 0.001) compared to 53 patients without cortical neuronal death. Comparing non-survivors without (n = 107) and more than 30% brainstem neuronal death (n = 43), we found no difference in MAP (p = 0.12) but a lower CVI (2.5 vs 2.7, p = 0.005) (Fig. 4D). In group comparison, non-survivors with more than 90% cortical neuronal death had the highest MAP (mean 76.6 mmHg) meeting significant difference compared to all other five groups; and non-survivors with at least 30% cortical neuronal death with brainstem sparing had the lowest CVI with 1.5.

Our study is the hitherto largest on the association between MAP, and vasopressors, and HIE evaluated by brain autopsy in non-survivors and two survivor cohorts unbiased by extracerebral death causes. Our main findings are: (1) Using histopathological and clinical outcomes, all cohorts with severe and no/mild HIE had mean MAPs above the guideline recommended threshold of 65 mmHg. (2) Non-survivors with postmortem autopsy had lower mean MAPs (73.1 and 72.0 mmHg) than CPC 1 or CPC 4 survivors (81.2 and 82.3 mmHg). (3) Evaluated by histopathology, there was no difference in MAP of severe and no/mild HIE non-survivors. (4) Regain of consciousness in no/mild HIE was associated with higher MAP (74.7 vs 69.3 mmHg) compared to persistent coma before death. (5) Coma awakening led to less and faster weaning of vasopressors independently of HIE severity. (6) We found higher vasopressor requirements and lower MAPs in absence of cortical neuronal death, whereas brainstem neuronal death was associated with higher vasopressor requirements.

In a systematic review (14), higher blood pressure was associated with improved outcome and lower mortality with MAP between 65–90 mmHg (13, 26, 27). Higher MAPs may counteract the post-ischemically impaired cerebral autoregulation and thereby avoid secondary ischemia (9, 28, 29). However, interventional studies targeting higher MAPs of 72–100 mmHg compared to 65 mmHg failed to improve outcome (15–18). Importantly, clinical outcome was the primary endpoint in these studies and death (i.e. CPC 5) mainly contributed to poor outcome. In non-survivors, absence of severe HIE and extracerebral death causes are frequent (1, 3). To bypass this limitation, we evaluated the HIE severity using histopathology and clinical absence (CPC 1) and presence of HIE (CPC 4). Surprisingly, there was no MAP difference between severe and no/mild HIE non-survivors. Both non-survivor groups showed a reversible MAP decrease during the first 48 hours similar to previous studies(30–32) where poor outcome correlated with early hypotension.(31, 33–35)

Accordingly, CPC 1 and 4 survivors had higher MAPs without critical MAP drops compared to non-survivors. Hypotension during the dying process may explain the MAP differences between our non-survivor and survivor cohorts. CPC 4 survivors had significantly higher MAPs compared to CPC 1 survivors, but except from the first 24 hours, differences were not larger than 2 mmHg. Due to clinically proven severe HIE, CPC 4 survivors enable us to study – unbiased by death – the association between MAP and brain injury.

Considering death as a confounder of HIE evaluation and based on neurological status of survivors, our results failed to show an association between MAP and brain injury. Otherwise, we would have found higher MAPs in CPC 1 compared to CPC 4 survivors and in no/mild HIE non-survivors. Importantly, the initial resuscitation time mainly impacts HIE severity reflecting that CPC 4 and severe HIE non-survivors had the longest times compared to CPC 1 and no/mild HIE non-survivors regaining consciousness. An animal study (36) corroborated that resuscitation time determines histopathological HIE severity in identical MAP regimes.

Extracerebral complications can cause prolonged coma and death despite absent HIE. To study this cohort, we dichotomized no/mild HIE non-survivors into regain of consciousness and persistent coma before death. No/mild HIE non-survivors who regained consciousness showed stabile blood pressures with a mean MAP of 74.7 mmHg. This corroborates previous studies in which even an hour of hypotension exposure was associated with higher mortality(30) and MAP stability during the first 48 hours with higher survival but without better neurological outcome. (37) Our mean MAP of 74.7 mmHg is higher compared to previous studies in which 70 mmHg and 65 mmHg, respectively, was the lower MAP threshold for good neurological outcome (26) and survival (13). Unlike previous studies, we analyzed MAP during the first 200 hours and found higher and stable MAP after 100 hours, which may be explained by increased sympathetic tone during the awakening from coma. (38, 39) Guided by near-infrared spectroscopy, intracranial pressure and oxygen saturation, two small studies found MAPs of 89 mmHg (40) and 87–101 mmHg (29) to avoid secondary brain injury. In our study, persistently comatose non-survivors with histopathological no/mild HIE had a mean MAP of 69.3 mmHg potentially supporting higher optimal MAPs. However, we cannot exclude regain of consciousness in case of long-term survival.

Importantly, the association between MAP and HIE cannot be studied without considering vasopressors. The CVI is an established tool to quantify vasopressor requirements (25) unaffected by TTM. (41–43) Increased vasopressor requirement was associated with higher mortality. (13, 32, 44) Accordingly, non-survivors had higher CVIs than CPC 1 and CPC 4 survivors; and mean CVIs similar to previous studies. (41, 45) In no/mild HIE non-survivors, regain of consciousness was associated with lower CVI without complete vasopressor weaning. Good outcome was previously more likely in patients with MAP above 70 mmHg with vasopressor requirements similar to our CPC 1 and CPC 4 patients.(26) However, excluding death as a HIE confounder, vasopressor requirement of CPC 1 survivors was not different from CPC 4 survivors. Hence, our results contradict that increased vasopressor requirements per se indicate poor outcome in survivors with MAP above 70 mmHg.

The incomplete vasopressor weaning in no/mild HIE is possibly explained by extracerebral complications causing hemodynamic instability, prolonged vasopressor requirement and death (1). Hence, our non-survivors suffering MOF death had higher CVI independently of histopathological HIE severity (41, 46) and five-day survival was associated with narrower CVI ranges indicating hemodynamic stability.

In no/mild HIE non-survivors regaining consciousness, we found less vasopressor requirements with higher MAPs reflecting the physiological response during coma awakening critically underlying brainstem control. (38, 39) Accordingly, selective brainstem neuronal death above 30 % was asociated with higher CVIs with unchanged MAPs compared to histopathologically intact brainstem. Selective cortical neuronal death was associated with less vasopressor requirements independently of additional brainstem injury. This corroborates results of unresponsive wakefulness syndrome survivors showing less hemodynamic response and MAP stability to external stimuli. (47, 48) Importantly, our results argue against that selective cortical brain injury cause increased vasopressor requirements. By contrast, we found higher CVIs if the cortex showed histopathologically no neuronal death.

This study had limitations. Due to the retrospective design, non-survivors with postmortem autopsies were limited and heterogeneous with a long inclusion period. We cannot rule out selection biases for obtaining autopsies and generalizability remains hence unknown. Furthermore, post-CA protocols have changed during the period. The SEND classification relies on a specific histopathological aspect of HIE using one staining. We recommend additional staining for synaptic damage and other cell types in future studies. We followed international guidelines avoiding hypotension below 65 mmHg without comparing to higher MAP targets. Histopathological validation of comparing MAP targets requires a prospective interventional trial. Finally, our study focused on MAP, but e.g. blood gases, volume status, and microcirculation are other important hemodynamic parameters.

In a large retrospective study, we found lower MAPs in non-survivors with postmortem brain autopsies compared to CPC 1 or CPC 4 survivors; however, all groups had MAPs above 65 mmHg. Based on histopathological evaluation, there was no difference of MAP in non-survivors with severe or no/mild HIE, but regain of consciousness was associated with higher MAP (74.7 vs 69.3 mmHg) in no/mild HIE non-survivors compared to persistent coma before death. We found lower requirement and faster weaning of vasopressors in coma awakening independently of HIE severity. Our results provide no evidence for elevating MAP targets above current guideline recommendations to improve neurological outcome after CA.

HIE

hypoxic-ischemic encephalopathy

cardiac arrest

MAP

mean arterial blood pressures

ICU

intensive care units

TTM

targeted temperature management

MOF

multiorgan failure

WLST

withdrawal of life-sustaining therapy

CPC

cerebral performance category

SEND

selective eosinophilic neuronal death

IQR

interquartile ranges

CVI

cumulative vasopressor index

standard deviation

OHCA

out-of-hospital cardiac arrest

Acknowledgements

We thank the Laerdal Foundation and the Berlin Institute of Health (BIH) at the Charité Universitätsmedizin Berlin for the research support.

Author contributions

SP - Study concept, data acquisition, data analysis, interpretation, drafting of the manuscript; JM - Data acquisition, data analysis, interpretation, drafting of the manuscript; WS - Data acquisition, critical revision of the manuscript; SM - Data acquisition, critical revision of the manuscript; CJP - Data analysis, interpretation, critical revision of the manuscript; CS - Study concept, data acquisition, data analysis, interpretation, drafting of the manuscript; JN - Study concept, data acquisition, data analysis, interpretation, drafting of the manuscript; CL - Funding, study concept, data acquisition, data analysis, interpretation, drafting of the manuscript; CE - Funding, study concept, data acquisition, data analysis, interpretation, drafting of the manuscript.

Funding

The Laerdal Foundation supported the project with a research fellowship grant for CE to conduct the study. CL was further supported by a clinical fellowship from the Berlin Institute of Health (BIH) at the Charité Universitätsmedizin Berlin. The research grants had no role in study concept, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Consent for publication

Not applicable.

Conflicts of interest

CL reports institutional fees from Bard Medical, Pfizer and Zoll; and personal fees from Edwards Lifesciences, outside the submitted work. CL is further supported by a clinical fellowship from the Berlin Institute of Health (BIH) at the Charité Universitätsmedizin Berlin. CE received a research fellowship grant from the Lærdal Foundation. However, the research grants had no role in study concept, data collection and analysis, decision to publish, or preparation of the manuscript. The other authors have no potential conflicts of interest.

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Survival but not severity of hypoxic-ischemic encephalopathy is associated with higher mean arterial blood pressure after cardiac arrest: a retrospective cohort study

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Abstract

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Background

Methods

Study design and post-resuscitation care

Histopathological evaluation of postmortem brain autopsy

Hemodynamic monitoring

Statistical analysis

Results

Study population

MAP and HIE severity

Vasopressor therapy and HIE severity

Association between MAP and vasopressor therapy

Association of death cause with vasopressor therapy and MAP

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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