Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest—Results from the Prospective, Observational COMMUNICATE Trial
Abstract
1. Introduction
2. Methods
2.1. Study Setting Population
2.2. Data Collection
2.3. Outcomes
2.4. Statistical Analyses
3. Results
3.1. Baseline Characteristics
3.2. Subgroup Analysis
3.3. Secondary Endpoints
3.3.1. In-Hospital Mortality
3.3.2. Neurological Outcome (CPC) at Hospital Discharge
4. Discussion
5. Strengths and Limitations
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
Primary Endpoint: 90-Day Mortality | ||||
---|---|---|---|---|
(C) Adjusted for age, gender and cardiovascular risk factors | (D) Adjusted for age, gender and laboratory values (PCT, Lc, CRP) | |||
OR or Coefficient (95% CI) | p-value | OR or Coefficient (95% CI) | p-value | |
ADMA | 2.12 (0.94, 4.78) | 0.072 | 3.07 (1.19, 7.90) | 0.02 |
ADMA log | 1.56 (0.83, 2.92) | 0.167 | 2.03 (1.00, 4.10) | 0.049 |
ADMA per decile | 1.05 (0.96, 1.16) | 0.280 | 1.09 (0.99, 1.20) | 0.09 |
SDMA | 0.93 (0.74, 1.17) | 0.552 | 0.97 (0.76, 1.20) | 0.79 |
SDMA log | 1.14 (0.81, 1.61) | 0.459 | 1.24 (0.85, 1.80) | 0.26 |
SDMA per decile | 1.05 (0.96, 1.16) | 0.277 | 1.08 (0.97, 1.00) | 0.16 |
Arginin | 0.53 (0.30, 0.93) | 0.028 | 0.78 (0.43, 1.42) | 0.43 |
Arginin log | 0.49 (0.31, 0.77) | 0.002 | 0.62 (0.39, 0.98) | 0.04 |
Arginin per decile | 0.86 (0.78, 0.95) | 0.002 | 0.91 (0.82, 1.00) | 0.09 |
Ratio | 0.65 (0.47, 0.90) | 0.010 | 0.75 (0.55, 1.03) | 0.08 |
Ratio log | 0.42 (0.26, 0.66) | <0.001 | 0.49 (0.31, 0.70) | <0.01 |
Ratio per decile | 0.81 (0.73, 0.90) | <0.001 | 0.85 (0.76, 0.90) | <0.01 |
Secondary endpoint: In-hospital mortality | ||||
(C) Adjusted for age, gender and cardiovascular risk factors | (D) Adjusted for age, gender and laboratory values (PCT, Lc, CRP) | |||
OR or Coefficient (95% CI) | p-Value | OR or Coefficient (95% CI) | p-Value | |
ADMA | 2.06 (0.93, 4.57) | 0.074 | 2.75 (1.07, 7.08) | 0.04 |
ADMA log | 1.54 (0.83, 2.88) | 0.174 | 1.89 (0.92, 3.88) | 0.08 |
ADMA per decile | 1.05 (0.96, 1.15) | 0.285 | 1.08 (0.97, 1.21) | 0.14 |
SDMA | 0.94 (0.76, 1.17) | 0.59 | 0.91 (0.69, 1.2) | 0.48 |
SDMA log | 1.03 (0.74, 1.45) | 0.849 | 1.04 (0.72, 1.52) | 0.83 |
SDMA per decile | 1.02 (0.93, 1.12) | 0.676 | 1.02 (0.92, 1.13) | 0.72 |
Arginin | 0.67 (0.39, 1.16) | 0.157 | 1.11 (0.6, 2.04) | 0.74 |
Arginin log | 0.60 (0.40, 0.89) | 0.012 | 0.80 (0.51, 1.26) | 0.34 |
Arginin per decile | 0.89 (0.81, 0.98) | 0.018 | 0.97 (0.87, 1.08) | 0.56 |
Ratio | 0.75 (0.56, 1.02) | 0.066 | 0.90 (0.67, 1.21) | 0.49 |
Ratio log | 0.52 (0.35, 0.78) | <0.001 | 0.66 (0.43, 1.01) | 0.06 |
Ratio per decile | 0.86 (0.78, 0.94) | <0.001 | 0.92 (0.82, 1.02) | 0.11 |
Secondary endpoint: hospital discharge CPC | ||||
(C) Adjusted for age, gender and cardiovascular risk factors | (D) Adjusted for age, gender and laboratory values (PCT, Lc, CRP) | |||
OR or Coefficient (95% CI) | p-Value | OR or Coefficient (95% CI) | p-Value | |
ADMA | 1.66 (0.76, 3.64) | 0.203 | 2.02 (0.78, 5.25) | 0.15 |
ADMA log | 1.23 (0.67, 2.28) | 0.506 | 1.38 (0.67, 2.84) | 0.38 |
ADMA per decile | 1.02 (0.93, 1.12) | 0.727 | 1.03 (0.92, 1.14) | 0.65 |
SDMA | 0.91 (0.73, 1.13) | 0.380 | 0.89 (0.67, 1.17) | 0.39 |
SDMA log | 0.86 (0.62, 1.20) | 0.371 | 0.87 (0.60, 1.25) | 0.45 |
SDMA per decile | 0.99 (0.90, 1.09) | 0.859 | 0.99 (0.89, 1.11) | 0.90 |
Arginin | 0.51 (0.29, 0.89) | 0.017 | 0.78 (0.42, 1.43) | 0.42 |
Arginin log | 0.48 (0.30, 0.75) | 0.001 | 0.63 (0.39, 1.01) | 0.06 |
Arginin per decile | 0.85 (0.78, 0.94) | 0.001 | 0.91 (0.82, 1.02) | 0.10 |
Ratio | 0.70 (0.52, 0.95) | <0.001 | 0.83 (0.61, 1.12) | 0.23 |
Ratio log | 0.46 (0.29, 0.71) | <0.001 | 0.58 (0.37, 0.92) | 0.02 |
Ratio per decile | 0.83 (0.76, 0.92) | <0.001 | 0.89 (0.80, 0.99) | 0.03 |
References
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Factor | All | Survivors | Non-Survivors | p-Value |
---|---|---|---|---|
Number (n) | 263 | 133 | 130 | |
Sociodemographics | ||||
Age, median (IQR) | 65 (57, 74) | 62 (53, 73) | 69 (61, 78) | <0.001 |
Male sex, n (%) | 193 (73.4%) | 111 (83.5%) | 82 (63.1%) | <0.001 |
Cause of cardiac arrest | ||||
Coronary artery disease, n (%) | 130 (49.6%) | 79 (59.8%) | 51 (39.2%) | <0.001 |
Arrhythmia, n (%) | 55 (21.0%) | 28 (21.2%) | 27 (20.8%) | 0.93 |
Other / unknown, n (%) | 77 (29.4%) | 25 (18.9%) | 52 (40.0%) | <0.001 |
Comorbidities | ||||
Chronic kidney disease, n (%) | 37 (14.1%) | 14 (10.6%) | 23 (17.7%) | 0.10 |
Chronic obstructive pulmonary disease, n (%) | 19 (7.3%) | 7 (5.3%) | 12 (9.2%) | 0.22 |
Congestive heart failure, n (%) | 38 (14.5%) | 16 (12.1%) | 22 (16.9%) | 0.27 |
Coronary artery disease, n (%) | 180 (68.7%) | 101 (76.5%) | 79 (60.8%) | <0.01 |
Cardiovascular risk factors | ||||
Positive smoking history, n (%) | 132 (61.1%) | 78 (66.7%) | 54 (54.5%) | 0.07 |
Hypertension, n (%) | 139 (53.1%) | 70 (53.0%) | 69 (53.1%) | 0.99 |
Positive family history, n (%) | 70 (35.2%) | 40 (37.4%) | 30 (32.6%) | 0.48 |
Hyperlipidemia, n (%) | 94 (42.5%) | 51 (44.7%) | 43 (40.2%) | 0.49 |
Diabetes mellitus, n (%) | 66 (25.2%) | 23 (17.4%) | 43 (33.1%) | <0.01 |
Resuscitation Information | ||||
Time to ROSC (min), median (IQR) | 20.5 (12, 32) | 15 (10, 25) | 29 (19, 40) | <0.001 |
Bystander CPR, n (%) | 170 (64.9%) | 99 (74.4%) | 71 (55.0%) | <0.01 |
Initial shockable rhythm, n (%) | 159 (63.3%) | 104 (81.9%) | 55 (44.4%) | <0.001 |
Use of epinephrine during CPR, n (%) | 159 (63.3%) | 61 (47.7%) | 98 (79.7%) | <0.001 |
Initial ICU treatment and status | ||||
Targeted temperature management (TTM), n (%) | 165 (63.0%) | 78 (59.1%) | 87 (66.9%) | 0.19 |
Intubation, n (%) | 225 (85.9%) | 99 (75.0%) | 126 (96.9%) | <0.001 |
Vasoactive drugs, n (%) | 186 (71.0%) | 83 (62.9%) | 103 (79.2%) | <0.01 |
Mean arterial pressure (mmHg), median (IQR) | 82 (70, 93) | 84 (71.5, 93) | 80 (70, 93) | 0.19 |
Systolic blood pressure (mmHg), median (IQR) | 116 (101, 130) | 117 (101, 128.5) | 116 (101, 130) | 0.82 |
Diastolic blood pressure (mmHg), median (IQR) | 67 (55, 77) | 70 (58, 79) | 64.5 (51, 77) | 0.04 |
Heartrate (bpm), median (IQR) | 85 (74, 99) | 81 (69.5, 94.5) | 88.5 (76, 102) | 0.02 |
Respiratory rate, median (IQR) | 17 (14, 20) | 17 (14, 20) | 16 (14, 20) | 0.90 |
Initial laboratory parameters | ||||
pH, median (IQR) | 7.27 (7.2, 7.3) | 7.28 (7.2, 7.3) | 7.24 (7.1, 7.3) | 0.01 |
Lactate (mmol/l), median (IQR) | 6.2 (3.6, 9) | 4.8 (2.8, 6.9) | 7.6 (5.2, 10) | <0.001 |
Creatinine (µmol/l), median (IQR) | 99 (78, 122) | 92.5 (78, 108) | 109 (76, 144) | <0.01 |
PCT (ng/mL), median (IQR) | 0.52 (0.15, 2.14) | 0.19 (0.1, 0.84) | 1.26 (0.4, 3.91) | <0.001 |
WBC (g/l), median (IQR) | 14 (10.3, 18.9) | 13 (9.64, 16.2) | 15.4 (11, 20.3) | <0.01 |
CRP (mg/dl), median (IQR) | 5.9 (1.5, 20.7) | 3 (1.25, 10.8) | 12.2 (2.6, 33.3) | <0.001 |
Primary Endpoint: 90-Day Mortality | ||||||
---|---|---|---|---|---|---|
Survivors (n = 133) | Non-Survivors (n = 130) | p-Value | OR or Coefficient (95% CI) | p-Value | AUC | |
ADMA (µmol/L) | 0.63 (0.50, 0.79) | 0.67 (0.51, 0.88) | 0.09 | 2.35 (1.08, 5.11) | 0.03 | 0.56 |
ADMA log | 1.75 (0.98, 3.11) | 0.06 | ||||
ADMA per decile | 1.07 (0.99, 1.17) | 0.10 | ||||
SDMA (µmol/L) | 0.85 (0.50, 1.13) | 1.02 (0.58, 1.56) | 0.03 | 1.06 (0.87, 1.29) | 0.59 | 0.58 |
SDMA log | 1.34 (0.99, 1.82) | 0.06 | ||||
SDMA per decile | 1.10 (1.01, 1.20) | 0.03 | ||||
Arginine (µmol/L) | 82 (52.3, 119) | 58.1 (41.7, 99.8) | <0.01 | 0.57 (0.34, 0.96) | 0.03 | 0.61 |
Arginine log | 0.51 (0.34, 0.76) | <0.01 | ||||
Arginine per decile | 0.87 (0.80, 0.95) | <0.01 | ||||
Ratio | 134 (99, 183) | 91 (64, 134) | <0.001 | 0.64 (0.47, 0.88) | <0.01 | 0.67 |
Ratio log | 0.40 (0.26, 0.61) | <0.001 | ||||
Ratio per decile | 0.80 (0.73, 0.88) | <0.001 | ||||
Secondary endpoint: in-hospital mortality | ||||||
Survivors (n = 145) | Non-Survivors (n = 118) | p-Value | OR or Coefficient (95% CI) | p-Value | AUC | |
ADMA (µmol/L) | 0.63 (0.50, 0.79) | 0.67 (0.50, 0.88) | 0.14 | 2.13 (1.01, 4.50) | 0.047 | 0.55 |
ADMA log | 1.64 (0.92, 2.91) | 0.09 | ||||
ADMA per decile | 1.06 (0.98, 1.16) | 0.16 | ||||
SDMA (µmol/L) | 0.89 (0.51, 1.15) | 0.97 (0.55, 1.56) | 0.18 | 1.03 (0.85, 1.25) | 0.76 | 0.55 |
SDMA log | 1.20 (0.89, 1.63) | 0.23 | ||||
SDMA per decile | 1.06 (0.98, 1.16) | 0.15 | ||||
Arginine (µmol/L) | 77.5 (51.4, 117) | 58.2 (41.8, 110) | 0.02 | 0.71 (0.43, 1.18) | 0.19 | 0.59 |
Arginine log | 0.60 (0.42, 0.87) | <0.01 | ||||
Arginine per decile | 0.90 (0.83, 0.98) | 0.02 | ||||
Ratio | 130 (95, 181) | 92 (65, 138) | <0.001 | 0.75 (0.55, 1.01) | 0.06 | 0.63 |
Ratio log | 0.50 (0.34, 0.74) | <0.001 | ||||
Ratio per decile | 0.85 (0.78, 0.93) | <0.001 | ||||
Secondary endpoint: Neurological outcome (CPC) at hospital discharge | ||||||
Good Neurological Outcome (n = 122) | Poor Neurological Outcome (n = 141) | p-Value | OR or Coefficient (95%CI) | p-Value | AUC | |
ADMA (µmol/L) | 0.65 (0.51, 0.80) | 0.65 (0.49, 0.83) | 0.53 | 1.73 (0.82, 3.64) | 0.15 | 0.52 |
ADMA log | 1.33 (0.75, 2.33) | 0.33 | ||||
ADMA per decile | 1.03 (0.94, 1.12) | 0.52 | ||||
SDMA (µmol/L) | 0.91 (0.52, 1.18) | 0.91 (0.54, 1.46) | 0.54 | 0.99 (0.82, 1.21) | 0.96 | 0.52 |
SDMA log | 1.02 (0.76, 1.37) | 0.89 | ||||
SDMA per decile | 1.03 (0.95, 1.12) | 0.45 | ||||
Arginine (µmol/L) | 83.2 (52.5, 119) | 58.6 (41.8, 108) | <0.01 | 0.57 (0.34, 0.96) | 0.03 | 0.61 |
Arginine log | 0.51 (0.34, 0.77) | <0.01 | ||||
Arginine per decile | 0.87 (0.80, 0.95) | <0.01 | ||||
Ratio | 131 (98, 184) | 100 (64, 139) | <0.001 | 0.73 (0.54, 0.97) | 0.03 | 0.65 |
Ratio log | 0.47 (0.31, 0.70) | <0.001 | ||||
Ratio per decile | 0.83 (0.76, 0.91) | <0.001 |
Primary Endpoint: 90-Day Mortality | ||||
---|---|---|---|---|
(A) Adjusted for Age, Sex and Comorbidities | (B) Adjusted for Age, Sex and Resuscitation Circumstances | |||
OR or Coefficient (95% CI) | p-Value | OR or Coefficient (95% CI) | p-Value | |
ADMA | 2.44 (1.09, 5.45) | 0.03 | 3.58 (1.25, 10.24) | 0.017 |
ADMA log | 1.72 (0.93, 3.21) | 0.09 | 2.36 (1.10, 5.08) | 0.028 |
ADMA per decile | 1.07 (0.97, 1.17) | 0.17 | 1.11 (0.99, 1.24) | 0.07 |
SDMA | 0.99 (0.80, 1.22) | 0.90 | 1.01 (0.80, 1.28) | 0.912 |
SDMA log | 1.17 (0.84, 1.65) | 0.36 | 1.47 (1.00, 2.15) | 0.048 |
SDMA per decile | 1.07 (0.97, 1.17) | 0.18 | 1.14 (1.02, 1.28) | 0.018 |
Arginine | 0.54 (0.31, 0.94) | 0.03 | 0.45 (0.24, 0.85) | 0.014 |
Arginine log | 0.47 (0.31, 0.73) | <0.01 | 0.45 (0.27, 0.76) | <0.01 |
Arginine per decile | 0.85 (0.77, 0.94) | <0.01 | 0.88 (0.80, 0.98) | <0.01 |
Ratio | 0.64 (0.46, 0.88) | <0.01 | 0.55 (0.39, 0.78) | 0.001 |
Ratio log | 0.40 (0.25, 0.62) | <0.001 | 0.32 (0.18, 0.54) | <0.001 |
Ratio per decile | 0.80 (0.72, 0.88) | <0.001 | 0.77 (0.69, 0.87) | <0.001 |
Secondary endpoint: In-hospital mortality | ||||
(A) Adjusted for age, sex and comorbidities | (B) Adjusted for age, sex and resuscitation circumstances | |||
OR or Coefficient (95% CI) | p-Value | OR or Coefficient (95% CI) | p-Value | |
ADMA | 1.98 (0.90, 4.36) | 0.09 | 3.00 (1.06, 8.52) | 0.039 |
ADMA log | 1.46 (0.78, 2.72) | 0.23 | 2.17 (1.00, 4.69) | 0.049 |
ADMA per decile | 1.04 (0.94, 1.14) | 0.45 | 1.09 (0.98, 1.22) | 0.113 |
SDMA | 1.00 (0.81, 1.24) | 0.97 | 0.97 (0.78, 1.22) | 0.81 |
SDMA log | 1.10 (0.78, 1.54) | 0.59 | 1.26 (0.87, 1.83) | 0.224 |
SDMA per decile | 1.04 (0.94, 1.14) | 0.44 | 1.09 (0.97, 1.21) | 0.136 |
Arginine | 0.63 (0.36, 1.09) | 0.10 | 0.62 (0.33, 1.17) | 0.142 |
Arginine log | 0.55 (0.36, 0.83) | <0.01 | 0.60 (0.37, 0.96) | 0.034 |
Arginine per decile | 0.88 (0.80, 0.96) | <0.01 | 0.90 (0.81, 1.00) | 0.057 |
Ratio | 0.72 (0.53, 0.98) | 0.03 | 0.67 (0.48, 0.92) | 0.013 |
Ratio log | 0.50 (0.33, 0.75) | <0.001 | 0.46 (0.28, 0.76) | 0.002 |
Ratio per decile | 0.85 (0.77, 0.93) | <0.001 | 0.83 (0.75, 0.93) | 0.001 |
Secondary endpoint: Neurological Outcome (CPC) at hospital discharge | ||||
(A) Adjusted for age, sex and comorbidities | (B) Adjusted for age, sex and resuscitation circumstances | |||
OR or Coefficient (95% CI) | p-Value | OR or Coefficient (95% CI) | p-Value | |
ADMA | 1.64 (0.76, 3.55) | 0.21 | 2.42 (0.82, 7.16) | 0.109 |
ADMA log | 1.18 (0.64, 2.18) | 0.59 | 1.61 (0.72, 3.57) | 0.246 |
ADMA per decile | 1.01 (0.92, 1.10) | 0.91 | 1.04 (0.93, 1.17) | 0.491 |
SDMA | 0.91 (0.74, 1.13) | 0.41 | 0.93 (0.74, 1.17) | 0.524 |
SDMA log | 0.84 (0.60, 1.16) | 0.29 | 1.01 (0.68, 1.50) | 0.953 |
SDMA per decile | 0.99 (0.90, 1.08) | 0.77 | 1.05 (0.93, 1.17) | 0.451 |
Arginine | 0.53 (0.31, 0.93) | 0.03 | 0.43 (0.21, 0.86) | 0.018 |
Arginine log | 0.48 (0.31, 0.75) | <0.01 | 0.44 (0.25, 0.77) | 0.004 |
Arginine per decile | 0.85 (0.77, 0.94) | <0.01 | 0.85 (0.75, 0.96) | 0.007 |
Ratio | 0.72 (0.54, 0.97) | 0.03 | 0.58 (0.41, 0.81) | 0.001 |
Ratio log | 0.47 (0.31, 0.72) | <0.01 | 0.36 (0.20, 0.63) | <0.001 |
Ratio per decile | 0.83 (0.76, 0.92) | <0.001 | 0.81 (0.71, 0.91) | <0.001 |
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Keller, A.; Becker, C.; Nienhaus, K.; Beck, K.; Vincent, A.; Sutter, R.; Tisljar, K.; Schuetz, P.; Bernasconi, L.; Neyer, P.; et al. Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest—Results from the Prospective, Observational COMMUNICATE Trial. J. Clin. Med. 2020, 9, 3815. https://doi.org/10.3390/jcm9123815
Keller A, Becker C, Nienhaus K, Beck K, Vincent A, Sutter R, Tisljar K, Schuetz P, Bernasconi L, Neyer P, et al. Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest—Results from the Prospective, Observational COMMUNICATE Trial. Journal of Clinical Medicine. 2020; 9(12):3815. https://doi.org/10.3390/jcm9123815
Chicago/Turabian StyleKeller, Annalena, Christoph Becker, Katharina Nienhaus, Katharina Beck, Alessia Vincent, Raoul Sutter, Kai Tisljar, Philipp Schuetz, Luca Bernasconi, Peter Neyer, and et al. 2020. "Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest—Results from the Prospective, Observational COMMUNICATE Trial" Journal of Clinical Medicine 9, no. 12: 3815. https://doi.org/10.3390/jcm9123815
APA StyleKeller, A., Becker, C., Nienhaus, K., Beck, K., Vincent, A., Sutter, R., Tisljar, K., Schuetz, P., Bernasconi, L., Neyer, P., Pargger, H., Marsch, S., & Hunziker, S. (2020). Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest—Results from the Prospective, Observational COMMUNICATE Trial. Journal of Clinical Medicine, 9(12), 3815. https://doi.org/10.3390/jcm9123815