Impact of hypotension after return of spontaneous circulation on survival in patients of out-of-hospital cardiac arrest

Accepted Manuscript Impact of hypotension after return of spontaneous circulation on survival in patients of out-of-hospital cardiac arrest

Lui Chun Tat, Chiu Yu Koon, Tsui Kwok Leung PII: DOI: Reference:

S0735-6757(17)30547-8 doi: 10.1016/j.ajem.2017.07.019 YAJEM 56804

To appear in: Received date: Revised date: Accepted date:

10 May 2017 3 July 2017 4 July 2017

Please cite this article as: Lui Chun Tat, Chiu Yu Koon, Tsui Kwok Leung , Impact of hypotension after return of spontaneous circulation on survival in patients of out-ofhospital cardiac arrest, (2017), doi: 10.1016/j.ajem.2017.07.019

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Title page

Title:

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Impact of hypotension after return of spontaneous circulation on survival in

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patients of out-of-hospital cardiac arrest

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Post-ROSC hypotension and survival

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Authors

Qualification

Tsui Kwok Leung

Associate consultant, Tuen

Medicine)

Mun Hospital, Hong Kong

MBChB

Resident, Tuen Mun Hospital, Hong Kong

FRCSEd

Senior medical officer, Pok

FHKAM (Emergency

Oi Hospital, Hong Kong

Medicine)

* Corresponding author

Position and hospital

FHKAM (Emergency

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Lui Chun Tat *

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Authors

Chiu Yu Koon

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Short running title:

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Department of Accident and Emergency Medicine, G/F, Tuen Mun Hospital, 23 Tsing Chung Koon Road, Tuen Mun, N.T., HKSAR

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Tel: 852-24685200

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Fax: 852-24569186

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(e-mail: [email protected])

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Correspondence to: Dr CT Lui

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Abstract Objective:

To investigate the relationship between hypotension in the first 3 hours

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after return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac

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arrest.

Method: This retrospective cohort study occurred at two regional hospitals and

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included adult OHCA patients who experienced ROSC from July 1, 2014 to

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December 31, 2015. Hemodynamic and inotrope administration data were retrieved

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for 3 hours after ROSC. We calculated the hypotensive exposure index (HEI) as the

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surrogate marker of the exposure of hypotension. The area under the ROC curve and multivariate logistic regression models were performed to analyze the effect of HEI

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on survival. Mean arterial pressure (MAP) was explored in the surviving and

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non-surviving patient groups using repeated measures MANCOVA, adjusted for the use of inotropes and down time.

Results:

A total of 289 patients were included in the study, and 29 survived. The

median 1-hour HEI and 3-hour HEI were significantly lower in the survival group (p<0.001). The area under the ROC curve for 3-hour HEI was 0.861. The repeated

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measures MANCOVA indicated that an interaction existed between post-ROSC time and downtime [F(5,197)=2.31, p=0.046]. No significant change in the MAP was observed in the 3 hours after ROSC, except in the group with a prolonged down time.

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According to the tests examining the effects of the use of inotropes on the survival

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outcomes of the different subjects, the MAP was significantly higher in the surviving

Among the patients who experienced ROSC after OHCA, post-ROSC

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Conclusion:

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group [F(1,201)=4.11; p=0.044; ηp2=0.020].

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hypotension was an independent predictor of survival.

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Introduction Post-cardiac arrest syndrome is a unique and complex combination of pathophysiological processes, including post cardiac arrest brain injury, post cardiac

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arrest myocardial dysfunction, and systemic ischemia/reperfusion response. (1)

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Hypotension is common after cardiac arrest. In a large observational study, post-return

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of spontaneous circulation (ROSC) hypotension was present in 47% of patients within 1 hour of intensive care unit arrival. (2) Resuscitation guidelines provide

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recommendations for hypotension management in the post-ROSC period. The 2015

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American Heart Association Guidelines for post-cardiac arrest care recommend

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avoiding and immediately correcting hypotension (systolic blood pressure <90 mmHg

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and mean arterial pressure <65 mmHg) during post resuscitation care. (3) The European Resuscitation Council and European Society of Intensive Care Medicine

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Guidelines for Post-resuscitation Care 2015 suggest targeting the MAP to achieve an

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adequate urine output and normal or decreasing plasma lactate values. (4) All guidelines acknowledge that the current evidence for targeted blood pressure is weak, and it is unknown whether the use of an inotrope to achieve an ideal blood pressure is associated with optimal survival.

Current studies have primarily relied on measurements taken in either the first hours

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after ICU arrival or the following day. (2, 5) Janet E. Bray et al. have explored the association of outcomes of out-of-hospital cardiac arrest (OHCA) patients and spot blood pressure measurements upon hospital arrival, which was on average 38 minutes

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post-ROSC. (5) The association between the trend and duration of hypotension and

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the clinical outcomes in earlier ROSC phases is unclear. The objective of the current

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study was to investigate the association between hypotension in the early hours after ROSC (with adjustments for other Utstein prognosticators) and the survival outcomes

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of OHCA patients.

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Methods Study design and setting This retrospective cohort study was conducted at two regional hospitals in Hong Kong.

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The emergency departments of the two hospitals provided emergency care for a

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population of more than one million. All out-of-hospital cardiac arrests were delivered

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to either center, unless there were obvious post-mortem changes. Prehospital resuscitation was provided by the emergency medical service (EMS), using a basic

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life support protocol and automatic external defibrillators. Resuscitation was

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continued in the emergency department upon arrival, with advanced cardiac life

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support protocol. If a patient had sustained ROSC, they were admitted to the intensive

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Data collection

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care unit (ICU) or other in-patient wards.

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Non-traumatic OHCA patients (18 years old and older) who achieved return of spontaneous circulation (ROSC) from July 1, 2014 to December 31, 2015 were included. Return of spontaneous circulation (ROSC) was defined (for all rhythms) as the restoration of a spontaneous circulation resulting in more than an occasional gasp, fleeting palpated pulse, or arterial waveform that continued for approximately more than 20 minutes, in accordance with the Utstein style. (6) Patients with post-mortem

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changes and cardiac arrest in the emergency department were excluded. Ethical approval was obtained from the local institutional review board (reference number

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NTWC/CREC/16038).

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Data were retrieved from the local cardiac arrest registry, in alignment with Utstein

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style. The patients’ demographic data and prehospital resuscitation and in-hospital resuscitation parameters were retrieved. The arrest to basic life support (BLS) time

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was defined as the time from the witnessed arrest to the EMS time of arrival at the

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patient’s side and the start of cardiopulmonary resuscitation. For unwitnessed arrests,

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the time of found arrest served as a surrogate. The arrest to ALS time was defined

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similarly, from the time of arrest to the arrival at the emergency department and the start of advanced life support. Down time was defined in a similar manner, as the time

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pressure.

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elapsed from the arrest time to the time of first documented measurable blood

The primary outcome was survival to hospital discharge. The survivors’ neurological outcomes were categorized using Cerebral Performance Categories (CPC), with CPC 1 and 2 regarded as favorable neurological outcomes.

Hemodynamic and administration of inotropes data were retrieved for 3 hours after

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ROSC. In the emergency department, post-resuscitation hemodynamic monitoring was performed using non-invasive blood pressure monitoring with oscillatory sphygmomanometers, and hemodynamic data were documented by the attending

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nurse every 3 minutes during the post-resuscitation phase. Data were documented in a

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standardized resuscitation chart. For patient admitted to the critical care unit, an

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arterial line was inserted for continuous hemodynamic monitoring. In the ward, blood pressure documentation was performed every 30 minutes, or whenever there was a

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major change in the patient’s hemodynamics. Data were retrieved from the in-patient

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medical records.

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Definitions

To quantify the exposure to hypotension during the post-ROSC period for each patient,

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the time-weighted average mean arterial pressure (TWA-MAP) and hypotensive

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exposure index (HEI) were defined. Both indices intended to incorporate the severity of hypotension and the duration of exposure to hypotension.

Time-weighted average mean arterial pressure (TWA-MAP) The time-weighted index in the 3 hours post-ROSC was defined using a method commonly adopted in epidemiological research. For each patient, the multiplicative

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product of the MAP and the duration of exposure to that MAP were obtained. The products were summed up and divided by the total duration of post-resuscitation

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observation time to obtain the TWA-MAP. The TWA-MAP equation for was

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TWA-MAP is a weighted measure of MAP, and a lower value implies more exposure

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to hypotension.

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Hypotensive exposure index (HEI)

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We defined HEI to quantify hypotension exposure. We defined hypotension as any

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measured mean arterial pressure (MAP) < 65 mmHg. After the patients experienced

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hypotension for a particular time interval, the hypotensive exposure value was calculated as the multiplicative product of (65-MAP) and duration (i.e., [65-MAP] x

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duration). The hypotensive exposure value was regarded as zero if the MAP was ≥ 65

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mmHg. For each patient, the HEI was defined as the sum of the hypotensive exposure values divided by the total length of exposure duration. The equation for HEI was .

HEI is an exposure index to hypotension, and a higher value implies more exposure to hypotension. HEI was calculated for the initial hour after ROSC (1-hour HEI) to indicate early hypotensive exposure. Similarly, a 3-hour HEI was calculated for

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hypotensive exposure in first 3 hours after ROSC.

Statistical analysis

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SPSS version 22 for Windows ( IBM SPSS Statistics for Windows, Version 22.0,

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released 2013, IBM Corp., Armonk, NY, USA) was used for data analysis. A 5% level

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of significance was adopted, and p<0.05 indicated statistical significance. TWA-MAP, 3-hour HEI and 1-hour HEI were calculated, according to the previously given

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definitions. Baseline characteristics were presented and contrasted for the surviving

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and non-surviving groups.

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Univariate and multivariate logistic regression models were performed to predict survival. The model was controlled for confounding variables and prognosticators,

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using the forward stepwise method, with likelihood ratios (table 2). Model calibration

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was assessed with the Hosmer-and-Lemeshow test. Model discrimination was explored with the area under the receiver operating characteristic curve for predicted probabilities.

The discriminatory capacities of the hypotensive indices were explored. The area under the ROC curve was calculated to predict survival by 3-hour HEI, 1-hour HEI

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and TWA-MAP. A pairwise comparison of the area under the ROC curves was performed using a non-parametric method (7). The best cut-off for the indices was

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obtained with Youden’s J statistics.

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The MAP was explored in the surviving and non-surviving group, with repeated

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measure multivariate analysis of covariance (MANCOVA), adjusted for the use of inotropes and total down time. Mauchly’s test of sphericity was used to check the

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sphericity assumption. If the sphericity assumption was violated, within-subject

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effects (post-ROSC MAP trends) were interpreted through univariate analysis and the

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Greenhouse-Geisser correction. Multivariate tests were interpreted with Wilks’

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Lambda. Box’s M test was used to assess for homogeneity.

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Sample size was calculated with NCSS PASS 2011 software, assuming 80% power

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and 5% level of significance. With a 9.6% baseline probability of survival to discharge for the ROSC (8), to obtain an independent predictor of survival in a logistic regression with an odds ratio of 2.5, 207 patients would be required.

Results

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During the study period, 919 OHCAs were recorded in the cardiac arrest registry, and 299 patients sustained ROSC. A total of 289 patients were included, with 10 cases excluded because of incomplete data. Of the 289 included patients, 29 (10%) patients

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survived to hospital discharge. The characteristics of the surviving versus

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non-survivng group are contrasted in Table 1.

For the post-ROSC hemodynamics, the median 1-hour HEI was 0 mmHg in the

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surviving group, which implied that most survivors did not have post-ROSC

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hypotension. In contrast, the 1-hour HEI was 281.8 mmHg (IQR 56.1-793.2) in the

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non-surviving group. Similarly, the median 3-hour HEI was 0 mmHg in the surviving

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group and 487.1 mmHg (IQR 131.7-1488) in the non-surviving group. The TWA-MAP in the survival group (102.1 mmHg) was significantly higher than that in

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the non-surviving group (72.3 mmHg, p<0.001). Infusions of inotropes were less

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prevalent in the surviving group (41.4%). However, most patients in the non-surviving group required inotropic support (93.8%). The mean arterial pressure and systolic blood pressure were higher in the surviving group at all time points in 3 hours after ROSC (Figure 1). There was no significant difference in the pulse rates of the surviving and non-surviving groups.

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A multivariate logistic regression model was used to adjust for confounding variables. It demonstrated that total downtime (OR=0.941, 95% CI, 0.890-0.995, p=0.034), post-ROSC ICU care (OR=12.985, 95% CI, 3.412-49.411, p<0.001) and 3-hour HEI

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(OR=0.998, 95% CI, 0.997-1.000, p=0.039) were independent predictors of survival

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(Table 2). The model demonstrated satisfactory goodness-of-fit (Hosmer-Lemeshow

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test, p=0.686) and good model discrimination (area under the ROC curve for

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predicted probabilities, 0.934, 95% CI, 0.878-0.990).

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Figure 2 shows the ROC curve for the post-ROSC hemodynamic parameters

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predicting survival or death. The area under the ROC curve was 0.871 for TWA-MAP

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(95% CI, 0.827-0.908), 0.861 for the 3-hour HEI (95% CI 0.816-0.899), and 0.841 for the 1-hour HEI (95% CI 0.794-0.882). Pairwise comparison of the area under ROC

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curve did not demonstrated ant significant differences (TWA-MAP vs 1-hour HEI,

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p=0.419; TWA-MAP vs 3-hours HEI, p=0.775; 1-hour HEI vs 3-hours HEI, p=0.248). The cut-off for the best balance between sensitivity and specificity for the 3-hour HEI was 100, according to Youden’s J statistic.

In the analysis of within-subject effects of post-ROSC MAP trends with repeated measure MANCOVA, Mauchly’s sphericity test indicated a violation of the

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assumption of sphericity. (p=0.003). Univariate analysis with the Greenhouse-Geisser correction was adopted: post-ROSC time [F(2.33, 468.91) = 2.21; p=0.102; ηp2=0.011]; interaction between post-ROSC time and down time [F(2.33, 468.91) =

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2.97; p=0.04; ηp2=0.015]; surviving group [F(2.33, 468.91) = 1.39; p=0.250;

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ηp2=0.007]; and post-ROSC inotropes [F(2.33, 468.91) = 1.71; p=0.176; ηp2=0.008].

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Box’s M test indicated homogeneity (p=0.064). Multivariate tests were analyzed: post-ROSC time [F(5,197) = 1.24; p=0.290; ηp2=0.031]; interaction between

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post-ROSC time and downtime [F(5,197) = 2.31; p=0.046; ηp2=0.055]; surviving

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group [F(5,197) = 1.72; p=0.131; ηp2=0.042]; and post-ROSC inotropes [F(5,197) =

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0.707; p=0.619; ηp2=0.018]. Both univariate and multivariate analyses suggested that

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there was no significant change in the MAP within the 3 hours after ROSC within

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subjects, except for the group with prolonged down times.

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For the tests examining the between-subject effects of the use of inotropes and survival outcomes, infusion of inotropes [F(1,201) = 4.82; p=0.029; ηp2=0.023]; down time [F(1,201) = 3.069; p=0.081; ηp2=0.015]; survival [F(1,201) = 4.11; p=0.044; ηp2=0.020]; and for the interaction between inotropes and survival, [F(1,201) = 0.99; p=0.320; ηp2=0.005]. The results demonstrated that the patients administered inotropes had higher MAPs after ROSC, the surviving patients had higher post-ROSC

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MAPs, independent of the infusion of inotropes, and there was no significant relationship between inotropes, survival and MAP.

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Discussion

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Current studies investigating the relationship between post cardiac arrest hypotension

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and clinical outcomes are using different methods to quantify hypotension. One common definition is SBP <90 mmHg or MAP <60 mmHg sustained for more than 60

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minutes and requiring vasopressor support after fluid resuscitation within the first 24

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hours of ROSC. (2, 9) J. Hope Kilgannon et al. have defined hypotension exposure as

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two or more SBP measurements of <100 mmHg within 6 hours after ROSC. (10)

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Marie E. Beylin et al. have examined the MAP at 1, 6, 12, and 24 hours post-ROSC. (11) We used HEI to quantify hypotension exposure. The index integrated the effect of

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the duration of hypotension exposure together with the magnitude of the hypotension

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episode. We believed that this index could better reflect the exact effect of hypotension. A commonly observed phenomenon is the surge of blood pressure immediately after ROSC, likely due to intense vasoconstriction in the arrest state and the effect of adrenaline. (12) The value of TWA-MAP would theoretically be a less accurate reflection of hypotensive exposure since hypertensive exposure would

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balance out the effect. Therefore, we had adopted HEI as the quantifying index of hypotension in our study.

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In our study, the area under the ROC curves for the three indices predicting survival

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indicated there was no major difference between TWA-MAP and HEI. The areas

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under the ROC curve were 0.861 and 0.841 for HEI at 3 hours and 1 hour, respectively. The minor difference indicated that hypotensive exposure during the first

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hour in the early phase was already highly predictive of outcomes. Further

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observation of later hypotension did not provide much additional yield in predicting

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survival.

For the trend of MAP in the post-ROSC period, our study demonstrated that there

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were no major changes in the MAP in the first 3 hours after ROSC, except in the

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group of patients with prolonged down times, as demonstrated by the significant interaction between post-ROSC time and total down time in the MANCOVA. This finding appears to be logical because down time is a strong independent predictor of survival itself. Most patients with prolonged down times will deteriorate in the post-ROSC period, with poor outcomes.

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In this study, we showed that in patients with ROSC after OHCA, post-ROSC hypotension was an independent predictor of survival. Similar results have been reported in previous studies. (5, 10, 13) However, the causal relationship between

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post-ROSC hypotension and outcome is still not well established, and it remains

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controversial. It is debatable whether post-ROSC hypotension is the cause of poor

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outcomes, or conversely, that hypotension is a phenomenon in patients with poor outcomes. Patients with poor outcomes are likely to suffer more severe ischemia and

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reperfusion injury, and, thus, more cardiovascular and neurological damage, resulting

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in more profound hypotension. To date, there is no direct evidence demonstrating that

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artificial correction and avoidance of hypotension with inotropes during the

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post-ROSC period could result in better outcomes. There have been advocates for goal-directed hemodynamic optimization in the post-cardiac arrest syndrome.

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However, there no clinical trial has supported that goal-directed hemodynamic

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support in the post-ROSC phase could result in better outcomes. (14)

We acknowledge that our study has several limitations. As a retrospective study, the study design did not allow us to record blood pressure in a fixed time interval. Undocumented hypotensive episodes may be present. This limitation may result in less accurate calculations of the hypotensive indices. Noninvasive blood pressure

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monitoring (i.e., cuff blood pressure) was used in the emergency department and general ward. A different measuring site (i.e., upper limb versus lower limb) might have provided different blood pressure readings. Arterial blood pressure provides a

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more reliable reading, however, it is not available in most cases. Moreover, the doses

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of inotrope infusion were not controlled in this study, therefore, the interaction

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between hemodynamic parameters and outcomes was not fully explored.

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Conclusion

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Our study demonstrated that for patients with ROSC after OHCA, post-ROSC

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hypotension was an independent predictor of survival. The surviving patients had

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Conflicts of interest

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None.

Funding None.

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higher post-ROSC MAPs, independent of the use of inotropes.

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ACCEPTED MANUSCRIPT Figure 1.

Trend of mean arterial pressure, systolic blood pressure and pulse rate in first 3

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hours after ROSC in survived and death groups

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ROC curve of post-ROSC hemodynamic markers predicting outcome

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Figure 2.

ACCEPTED MANUSCRIPT Table 1. Baseline characteristics, hemodynamic indices and outcome of the cohort All (n=289)

Survived (n=29)

Death (n=260)

p value

Age #

77 (61–85)

64 (58–76)

78 (61–86)

<0.001

Gender, male

163 (56.2%)

25 (86.2%)

138 (53.1%)

0.001

Witnessed

164 (56.6%)

23 (79.3%)

141 (54.2%)

0.010

Bystander CPR

70 (24.1%)

7 (24.1%)

63 (24.2%)

0.982

Defibrillation delivered

81 (27.9%)

18 (62.1%)

63 (24.2%)

<0.001

Prehospital

48 (16.6%)

17 (58.6%)

31 (11.9%)

<0.001

In ED

44 (15.2%)

3 (10.3%)

41 (15.8%)

0.590

53 (18.3%)

22 (75.9%)

31 (11.9%)

<0.001

8 (6–11)

7 (4.3–8.8)

9 (6–11)

0.034

27 (22–31)

26.5 (24–30)

40 (33–50)

27.5 (25.3–37.8)

376.3 (88.6–1380.9)

0 (0–9)

237.8 (32.4–718.4)

0 (0–9)

TWA-MAP, mmHg #

73 (59.8–88.3)

Inotropes infusion

Arrest to ALS time, min

#

Down time, min # 3-hours HEI, mmHg #

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Arrest to BLS time, min #

27 (22–31)

0.744

40 (34–50)

<0.001

SC

ICU admission

PT

Parameters

<0.001

281.8 (56.1–793.2)

<0.001

102.1 (94–109.9)

72.3 (58.7–84.5)

<0.001

256 (88.3%)

12 (41.4%)

244 (93.8%)

<0.001

Survival to discharge

29 (10%)

--

--

--

CPC on discharge

--

--

--

1 (1–2)

<0.001

MA

1-hour HEI, mmHg

19 (65.5%)

1 or 2

10 (34.5%)

Hospital length of stay, days

#

1 (1–3)

AC

CE

PT E

Shown in median and interquartile range

D

3 or 4

#

NU

487.1 (131.7–1488)

#

21.5 (9.8–33.8)

ACCEPTED MANUSCRIPT Table 2. Logistic regression predicting survival to discharge Predictors

Odds ratio

95% CI

p value

Down time #

0.941

0.890 – 0.995

0.034

0.998

0.997 – 1.000

0.039

12.985

3.412 – 49.411

<0.001

Age

0.987

0.929 – 1.050

0.538

Witnessed

2.238

0.464 – 10.796

0.325

Defibrillation

1.949

0.420 – 9.04

0.731

Arrest to BLS time

1.154

0.994 – 1.340

0.068

3-hours HEI #

CE

PT E

D

MA

NU

SC

RI

Included in the final model

AC

#

PT

Post-ROSC ICU care

#