Association between elevated mean arterial blood pressure and neurological outcome after resuscitation from cardiac arrest: results

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Association between elevated mean arterial blood pressure and neurological outcome after resuscitation from cardiac arrest: results

from a multicenter prospective cohort study

Supplemental Material

Brian W. Roberts, MD, MSc¹; J. Hope Kilgannon, MD¹; Benton R. Hunter, MD³; Michael A.

Puskarich, MD⁴; Lisa Pierce, BA²; Michael Donnino, MD⁵; Christopher Jones, MD¹; Brian M.

Fuller, MD⁷; Jeffrey A. Kline, MD³; Alan E. Jones, MD⁴; Nathan I. Shapiro, MD, MPH⁵; Benjamin S. Abella, MD, MPhil⁶; Stephen Trzeciak, MD, MPH^1,2

1: The Department of Emergency Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey

2: The Department of Medicine, Division of Critical Care Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey

3: The Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, Indiana

4: The Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi

5: The Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

6: The Center for Resuscitation Science and Department of Emergency Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

7: Departments of Emergency Medicine and Anesthesiology, Division of Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri

For submission to Critical Care Medicine

Address for correspondence:

Brian W. Roberts, MD, MSc Cooper University Hospital One Cooper Plaza, K152 Camden, New Jersey 08103 Phone: (856) 342-2351

E-mail: [email protected]

Funding: National Heart, Lung, and Blood Institute (U.S.), R01HL112815 and K23HL126979

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Supplemental Methods

We entered the following candidate variables that were previously demonstrated to be strong predictors of poor outcome in post-cardiac arrest patients into the multivariable Poisson regression model: 1) age (decile); 2) initial cardiac rhythm [asystole or pulseless electrical activity (PEA) vs. ventricular fibrillation/ventricular tachycardia (VF/VT)]; 3) duration of CPR (min); and 4) arrest location (in-hospital vs. out-of-hospital). Given some patients may still have had exposure a MAP < 70 mmHg at some point during the initial six hours after ROSC, and the known association between hypotension exposure and neurological outcome,[1] we entered exposure to MAP < 70 mmHg into our model in order to ensure we were testing the association between elevated MAP and neurological outcome. To account for other potential confounders we entered additional candidate variables into the model if statistically different at p < 0.10 between mean MAP groups. We chose the conservative p < 0.10 for inclusion in the model to ensure we included all potential measured confounders. We performed stepwise elimination with a criterion for retention in the model of p < 0.05. Statistical interactions and collinearity were assessed. Goodness of fit of the model was evaluated with the Deviance test. The same

analyses were performed for the secondary outcomes.

For the primary outcome we performed multiple pre-planned subgroup analyses by vasopressor infusion (yes/no), location of cardiac arrest (in-hospital versus out-of-hospital), and initial cardiac rhythm (PEA/asystole versus VT/VF). In addition, patients with chronic hypertension can have changes in cerebral blood flow autoregulation, in which the lower limit of autoregulation is shifted towards higher MAPs, potentially diminishing tolerance to lower blood pressure.[2, 3]

Therefore, we performed a pre-planned stratified analysis by pre-arrest diagnosis of

hypertension (yes/no). We analyzed the association between mean MAP and good neurological outcome for each subgroup using separate multivariable Poisson regression models to calculate

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relative risks with 95% confidence intervals (CI) adjusting for candidate variables retained in the original model. We graphed the adjusted relative risks with 95% CIs.

To test if the dose of vasopressor administration modified the association between mean MAP and neurological outcome we performed a test of interaction in our original model to assess whether the association between mean MAP and neurological outcome differed as vasopressor dose increased. Unless there was evidence against the null hypothesis of homogeneity of effects (i.e., p < 0.1), the overall relative risk was regarded as the most reliable guide to the approximate relative risk. We chose a conservative p < 0.10 for testing the null hypothesis of homogeneity of effects to reduce the risk of type II error.

To further evaluate the relationship between higher MAP and neurological outcome we entered ascending ranges of mean MAP (i.e. 70-80, 81-90, 91-100, 101-110, and > 110 mmHg) into our constructed model with MAP 70-80 mmHg as the reference. To test for an association between the duration of exposure to MAP > 90 mmHg and neurological outcome, we also performed a post hoc analysis entering the number of hourly blood pressure measurements (0-6) with MAP

> 90 mmHg during the initial six hours after ROSC into our constructed model.

Finally, to determine if the association between mean MAP and neurological outcome was driven by mortality, we performed a post-hoc sensitivity analysis limited to only patients who survived to hospital discharge.

Sample Size calculation

We estimated our sample size calculation based on our prior work regarding the association between MAP and neurological outcome.[1] We estimated a 40% good neurological outcome rate for mean MAP > 90 mmHg and 20% good neurological outcome for mean MAP 70-

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90mmHg. We determined for 90% power at an α of 0.05 we would need 109 subjects per group and planned to enroll at least 110 subjects into each group.

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Supplemental Table 1: Post-cardiac arrest data for all subjects during the initial six hours after return of spontaneous circulation (ROSC).

*Mean MAP (mean arterial blood pressure) over the initial six hours after return of spontaneous circulation. ^†Defined as partial pressure of arterial oxygen (PaO2) < 60 mmHg on arterial blood gas during the initial six hours after ROSC;

‡Defined as PaO2 > 300 mmHg on arterial blood gas during the initial six hours after ROSC.

Epi, epinephrine; Norepi, norepinephrine; PCI, percutaneous coronary intervention; SOFA, Sequential Organ Failure Assessment.

Variables

All Subjects n = 269

Mean MAP*

70-90 mmHg n = 110

Mean MAP

> 90 mmHg n = 159

p - value

Mean MAP* [mmHg (SD)] 95 (15) 81 (6) 105 (11) < 0.001

Exposure to MAP < 70 mmHg [n (%)]

131 (49) 89 (81) 42 (26) < 0.001

Hypoxia^† [n (%)] 47 (17) 19 (17) 28 (18) 0.943

Hyperoxia^‡ [n (%)] 101 (38) 36 (33) 65 (41) 0.209

Plateau pressure (cmH2O) [median (IQR)]

20 (16-24) 21 (17-26) 20 (16-24) 0.479

Vasopressor infusion [n (%)] 138 (51) 79 (72) 59 (37) <0.001

Dopamine <5 µg/kg/min OR dobutamine (any dose)

11 (4) 6 (5) 5 (3) 0.347

Dopamine >5 µg/kg/min OR Epi/Norepi <0.1µg/kg/min

43 (16) 24 (22) 19 (12) 0.030

Dopamine >15 µg/kg/min OR

Epi/Norepi >0.1 µg/kg/min 85 (32) 50 (45) 35 (22) <0.001

PCI [n (%)] 31 (12) 9 (8) 22 (14) 0.153

Modified SOFA score [mean (IQR)] 5 (4-7) 6 (4-8) 5 (3-7) 0.110

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Supplemental Table 2: Multivariable Poisson regression model (using a log link) with good

neurological outcome [defined as modified Rankin Scale (mRS) ≥ 3 at hospital discharge] as the dependent variable.

Variables Relative Risk 95% CI p-value

Mean MAP > 90 mmHg 2.46 2.09 - 2.88 <0.001

VT/VF 2.38 1.78 - 3.17 <0.001

Age* 0.87 0.83 - 0.92 <0.001

CPR duration (min) 0.97 0.96 - 0.98 <0.001

*Calibrated for a rise of 10 years. CI, confidence interval; CPR, cardiopulmonary resuscitation;

MAP, mean arterial blood pressure; VT/VF, ventricular tachycardia/ventricular fibrillation.

Model has good fit: Deviance test p = 1

Removed for non-significance: vasopressor infusion (p = 0.508); Charlson comorbidity index (p

= 0.472); in-hospital cardiac arrest (p = 0.244); exposure to MAP < 70 mmHg during the initial six hours after return of spontaneous circulation (p = 0.150); malignancy (p = 0.138); congestive heart failure (p = 0.106).

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Supplemental Table 3: Multivariable Poisson regression model (using a log link) with survival

to hospital discharge as the dependent variable.

Mean MAP > 90 mmHg 1.90 1.64 - 2.20 <0.001

VT/VF 1.59 1.35 - 1.87 <0.001

Age* 0.93 0.89 - 0.97 0.001

CPR duration (min) 0.97 0.96 - 0.97 <0.001

In-hospital cardiac arrest 1.55 1.19 - 2.03 0.001 Charlson comorbidity index 0.89 0.80 - 1.00 0.048

Model has good fit: Deviance test p = 0.1

Removed for non-significance: malignancy (p = 0.867); congestive heart failure (p = 0.936);

vasopressor infusion (p = 0.154); exposure to MAP < 70 mmHg during the initial six hours after return of spontaneous circulation (p = 0.502).

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Supplemental Table 4: Multivariable Poisson regression model (using a log link) with the Full

Outline of UnResponsiveness (FOUR) score > 6 at 72 hours after ROSC as the dependent variable.

Mean MAP > 90 mmHg 1.36 1.17 - 1.58 <0.001

VT/VF 1.68 1.47 - 1.91 <0.001

Malignancy 0.70 0.51 - 0.94 0.019

CPR duration (min) 0.98 0.97 - 0.99 0.002

In-hospital cardiac arrest 1.59 1.36 - 1.85 <0.001 Charlson comorbidity index 1.05 1.01 - 1.10 0.015 CI, confidence interval; CPR, cardiopulmonary resuscitation; MAP, mean arterial blood pressure; VT/VF, ventricular tachycardia/ventricular fibrillation.

Model has good fit: Deviance test p = 1

Removed for non-significance: congestive heart failure (p = 0.725); exposure to MAP < 70 mmHg during the initial six hours after return of spontaneous circulation (p = 0.481);

vasopressor infusion (p = 0.443); age (p = 0.285).

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neurological outcome [defined as modified Rankin Scale (mRS) ≤ 3 at hospital discharge] as the dependent variable, entering interaction term between mean MAP (mean arterial blood

pressure) and vasopressor dose (coded as: 0, no vasopressor; 1, dopamine < 5 µg/kg/min or dobutamine (any dose); 2, dopamine > 5 µg/kg/min or epinephrine/norepinephrine <

0.1µg/kg/min; 3, dopamine > 15 µg/kg/min or epinephrine/norepinephrine >0.1 µg/kg/min).

Mean MAP > 90 mmHg 2.62 1.60 - 4.30 <0.001

Vasopressor dose 1.01 0.76 - 1.35 0.920

Interaction:

Mean MAP and Vasopressor dose

0.94 0.80 - 1.11 0.471

VT/VF 2.35 1.81 - 3.05 <0.001

Age* 0.88 0.82 - 0.94 <0.001

CPR duration (min) 0.97 0.95 - 0.99 <0.001

VT/VF, ventricular tachycardia/ventricular fibrillation.

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Supplemental Table 6: Multivariable Poisson regression model (using a log link) with mean

MAP (mean arterial blood pressure) entered as a categorical variable and good neurological outcome [defined as modified Rankin Scale (mRS) ≤ 3 at hospital discharge] at hospital discharge as the dependent variable.

Mean MAP (mmHg)

70-80 Reference

81-90 1.31 0.65 - 2.64 0.445

91 -100 2.80 2.15 - 3.66 <0.001

101-110 2.92 1.66 - 5.15 <0.001

> 110 2.97 1.86 - 4.76 <0.001

VT/VF 2.34 1.79 - 3.05 <0.001

Age* 0.87 0.83 - 0.91 <0.001

CPR duration (min) 0.97 0.96 - 0.98 <0.001

VT/VF, ventricular tachycardia/ventricular fibrillation.

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Supplemental Table 7: Multivariable Poisson regression model (using a log link) entering the

duration of exposure to MAP > 90 mmHg [i.e. number of hourly blood pressure measurements (0-6) with MAP > 90 mmHg] during the initial six hours after ROSC as an independent variable and good neurological outcome [defined as modified Rankin Scale (mRS) ≤ 3 at hospital discharge] at hospital discharge as the dependent variable.

Duration MAP > 90 mmHg 1.15 1.11 - 1.18 <0.001

VT/VF 2.38 1.87 - 3.02 <0.001

Age* 0.87 0.82 - 0.92 <0.001

CPR duration (min) 0.97 0.95 - 0.98 <0.001

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neurological outcome [defined as modified Rankin Scale (mRS) ≥ 3 at hospital discharge] as the dependent variable among survivors to hospital discharge (n = 122).

Mean MAP > 90 mmHg 1.36 1.08 - 1.72 0.010

VT/VF 1.51 1.05 - 2.17 0.025

Age* 0.95 0.89 - 1.01 0.092

CPR duration (min) 1.00 0.99 - 1.02 0.597

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References

1. Kilgannon JH, Roberts BW, Jones AE, Mittal N, Cohen E, Mitchell J, Chansky ME, Trzeciak S, (2014) Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest*. Crit Care Med 42: 2083-2091

2. Strandgaard S, Paulson OB, (1989) Cerebral blood flow and its pathophysiology in hypertension. Am J Hypertens 2: 486-492

3. Jones JV, Fitch W, MacKenzie ET, Strandgaard S, Harper AM, (1976) Lower limit of cerebral blood flow autoregulation in experimental renovascular hypertension in the baboon. Circ Res 39: 555-557