Does anemia contribute to end-organ dysfunction in ICU patients Statistical Analysis

Does anemia contribute to end-organ dysfunction in ICU patients Statistical Analysis Xue Han, MPH and Matt Shotwell, PhD Department of Biostatistics Vanderbilt University School of Medicine March 14, 2014 Contents 1 Analysis 1: Transitional Model to model next day s effect 2 1.1 Outcome1: Daily Delirium...................................... 2 1.1.1 Descriptive Statistics..................................... 2 1.1.2 Multinomial logistic regression with Normal as the reference level for outcome variable Delirium........................................ 3 1.2 Outcome2: Daily troponin (greater than 0.1) as an index of cardiac dysfunction........ 7 1.2.1 Descriptive Statistics..................................... 7 1.2.2 Logistic regression. tro greater than 0.1 (Y/N)...................... 7 1.2.3 Linear regression. Continuous Response.......................... 8 1.3 Outcome3: Daily renal SOFA score 2.............................. 9 1.3.1 Descriptive Statistics..................................... 9 1.3.2 Logistic regression, Daily renal SOFA 2(Y/N)..................... 10 1.3.3 Proportional odds logistic regression regression, Ordinal response (0-4)......... 11 1.4 Outcome4: Daily resp SOFA score ( 2).............................. 12 1.4.1 Descriptive Statistics..................................... 12 1.4.2 Logistic regression, Daily RESP SOFA 2(Y/N)..................... 13 1.4.3 Proportional odds logistic regression, Ordinal response (0-4)............... 14 1.5 Outcome5: Daily Ventilator (Y/N) as a measure of success of extubation........... 15 1.5.1 Descriptive Statistics..................................... 15 1.5.2 Logistic regression (Daily Ventilation (Y/N))....................... 15 2 Analysis2: Hb during ICU stay and predicted outcomes 17 2.1 Outcome1: ICU mortality...................................... 17 2.1.1 Descriptive Statistics..................................... 17 2.1.2 Logistic regression for ICU.mortality (Y/N)........................ 17 2.1.3 Time dependent covariate survival analysis for Time to ICU.mortality......... 18 2.2 Outcome2: Cardiac dysfunction(tropnin greater than 0.1).................... 19 2.2.1 Correlated time dependent covariate survival analysis for Time to Tropnin greater than 0.1............................................... 19 2.3 Outcome3: Renal dysfunction.................................... 20 2.3.1 Outcome: Time to renal dysfunction Survival analysis with correlated time dependent covariate........................................... 20 2.4 Outcome4: Time to resolution of delirium............................. 20 2.5 Outcome5: Time to successful extubation............................. 20 1

1 Analysis 1: Transitional Model to model next day s effect 1.1 Outcome1: Daily Delirium 1.1.1 Descriptive Statistics Table 1: Descriptive by Icu.status 2 N Normal Discharged Delirious Comatose Deceased Combined Test Statistic N = 1976 N = 697 N = 1994 N = 1917 N = 127 N = 6711 icu.status.today 6711 χ 2 8 = 4326, P < 0.0011 Normal 73% (1451) 66% ( 462) 11% ( 217) 5% ( 88) 9% ( 11) 33% (2229) Delirious 21% ( 410) 28% ( 193) 61% (1210) 20% ( 380) 22% ( 28) 33% (2221) Comatose 6% ( 115) 6% ( 42) 28% ( 567) 76% (1449) 69% ( 88) 34% (2261) Age at enrollment 6711 50 60 70 51 61 71 54 64 73 52 62 70 54 63 73 52 62 71 F 4,6706 = 18, P < 0.001 2 ICU type 6711 Surgical 28% ( 552) 35% ( 242) 42% ( 844) 38% ( 736) 19% ( 24) 36% (2398) χ 2 4 = 112, P < 0.0011 APACHE APS at enrollment 6711 15 20 26 15 21 26 17 23 28 18 24 29 19 25 28 16 22 27 F 4,6706 = 43, P < 0.001 2 Charlson score 6711 1 2 4 1 2 4 1 2 4 1 2 3 1 2 4 1 2 4 F 4,6706 = 8, P < 0.001 2 Framingham stroke risk score 6711 6 9 14 6 10 15 7 11 15 5 9 13 4 9 13 6 10 14 F 4,6706 = 24, P < 0.001 2 Lowest mean arterial pressure, current 24h 6704 55 63 72 58 66 76 55 62 71 54 60 66 46 54 61 55 62 70 F 4,6699 = 51, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% (1976) 100% ( 697) 100% (1994) 100% (1917) 100% ( 127) 100% (6711) Study day 6711 3 7 14 3 5 11 3 7 13 2 5 10 3 6 14 3 6 12 F 4,6706 = 35, P < 0.001 2 Septic in the current 24h? 6703 Septic today 60% (1182) 49% ( 344) 67% (1330) 70% (1337) 73% ( 91) 64% (4284) χ 2 4 = 117, P < 0.0011 sevsepsis.l24 6703 Severely septic today 47% ( 926) 34% ( 240) 65% (1302) 69% (1323) 71% ( 89) 58% (3880) χ 2 4 = 406, P < 0.0011 Lowest hemoglobin, current 24h 5837 8.8 9.8 10.8 8.9 9.8 10.8 8.7 9.6 10.7 8.6 9.6 10.7 8.6 9.9 10.6 8.7 9.7 10.7 F 4,5832 = 4.4, P = 0.002 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test

1.1.2 Multinomial logistic regression with Normal as the reference level for outcome variable Delirium 3 Level Discharged vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal -2.092 0.559 0.000 0.123 0.041 0.369 icu.status.todaydelirious -0.913 0.888 0.304 0.401 0.070 2.287 icu.status.todaycomatose -0.801 0.984 0.416 0.449 0.065 3.086 age.enroll -0.006 0.006 0.254 0.994 0.983 1.005 icu.typesurgical 0.498 0.136 0.000 1.645 1.259 2.149 apache.aps 0.019 0.008 0.015 1.019 1.004 1.035 charlson.score -0.001 0.026 0.977 0.999 0.949 1.052 stroke.risk 0.017 0.013 0.196 1.017 0.991 1.043 map.low.icu 0.016 0.004 0.000 1.016 1.007 1.025 study.day -0.067 0.010 0.000 0.936 0.918 0.954 sepsis.l24septic today -0.366 0.127 0.004 0.694 0.541 0.889 hgb.icu 0.036 0.040 0.372 1.037 0.958 1.122 icu.status.todaydelirious:age.enroll -0.005 0.011 0.666 0.995 0.975 1.016 icu.status.todaycomatose:age.enroll 0.012 0.018 0.495 1.012 0.978 1.048 icu.status.todaydelirious:icu.typesurgical -0.236 0.239 0.323 0.790 0.495 1.261 icu.status.todaycomatose:icu.typesurgical -0.879 0.427 0.040 0.415 0.180 0.959 icu.status.todaydelirious:apache.aps -0.020 0.015 0.173 0.980 0.951 1.009 icu.status.todaycomatose:apache.aps -0.004 0.025 0.866 0.996 0.949 1.045 icu.status.todaydelirious:charlson.score 0.004 0.053 0.946 1.004 0.904 1.114 icu.status.todaycomatose:charlson.score -0.017 0.099 0.862 0.983 0.810 1.193 icu.status.todaydelirious:stroke.risk 0.027 0.025 0.284 1.027 0.978 1.078 icu.status.todaycomatose:stroke.risk -0.035 0.044 0.432 0.966 0.885 1.053 icu.status.todaydelirious:map.low.icu -0.010 0.009 0.257 0.990 0.974 1.007 icu.status.todaycomatose:map.low.icu 0.009 0.015 0.553 1.009 0.980 1.039 icu.status.todaydelirious:study.day 0.059 0.019 0.002 1.061 1.023 1.100 icu.status.todaycomatose:study.day 0.039 0.034 0.251 1.040 0.973 1.112 icu.status.todaydelirious:sepsis.l24septic today -0.095 0.237 0.688 0.909 0.572 1.446 icu.status.todaycomatose:sepsis.l24septic today 0.106 0.397 0.789 1.112 0.511 2.420 icu.status.todaydelirious:hgb.icu -0.016 0.073 0.821 0.984 0.853 1.134 icu.status.todaycomatose:hgb.icu -0.217 0.113 0.055 0.805 0.645 1.005 Level Delirious vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal -2.177 0.770 0.005 0.113 0.025 0.512

4 icu.status.todaydelirious -0.327 0.585 0.576 0.721 0.229 2.268 icu.status.todaycomatose 0.522 0.679 0.442 1.686 0.445 6.385 age.enroll 0.005 0.008 0.531 1.005 0.990 1.021 icu.typesurgical 0.881 0.178 0.000 2.412 1.701 3.422 apache.aps 0.014 0.011 0.204 1.014 0.992 1.036 charlson.score -0.003 0.037 0.941 0.997 0.928 1.071 stroke.risk 0.041 0.017 0.018 1.042 1.007 1.078 map.low.icu -0.006 0.006 0.312 0.994 0.982 1.006 study.day -0.022 0.012 0.053 0.978 0.956 1.000 sepsis.l24septic today 0.447 0.180 0.013 1.564 1.099 2.226 hgb.icu -0.075 0.059 0.208 0.928 0.827 1.042 icu.status.todaydelirious:age.enroll 0.008 0.010 0.396 1.008 0.989 1.028 icu.status.todaycomatose:age.enroll 0.021 0.012 0.096 1.021 0.996 1.046 icu.status.todaydelirious:icu.typesurgical -0.784 0.220 0.000 0.456 0.297 0.702 icu.status.todaycomatose:icu.typesurgical -0.784 0.282 0.005 0.457 0.263 0.794 icu.status.todaydelirious:apache.aps -0.001 0.014 0.964 0.999 0.973 1.027 icu.status.todaycomatose:apache.aps 0.006 0.017 0.730 1.006 0.973 1.040 icu.status.todaydelirious:charlson.score 0.008 0.048 0.862 1.008 0.919 1.107 icu.status.todaycomatose:charlson.score -0.025 0.065 0.703 0.976 0.860 1.107 icu.status.todaydelirious:stroke.risk -0.029 0.022 0.197 0.972 0.930 1.015 icu.status.todaycomatose:stroke.risk -0.058 0.030 0.049 0.943 0.890 1.000 icu.status.todaydelirious:map.low.icu 0.005 0.008 0.491 1.005 0.990 1.021 icu.status.todaycomatose:map.low.icu 0.012 0.011 0.274 1.012 0.991 1.033 icu.status.todaydelirious:study.day 0.057 0.015 0.000 1.058 1.027 1.090 icu.status.todaycomatose:study.day 0.004 0.021 0.862 1.004 0.963 1.046 icu.status.todaydelirious:sepsis.l24septic today -0.267 0.225 0.234 0.765 0.493 1.189 icu.status.todaycomatose:sepsis.l24septic today -0.097 0.281 0.729 0.907 0.523 1.573 icu.status.todaydelirious:hgb.icu 0.053 0.072 0.462 1.054 0.916 1.213 icu.status.todaycomatose:hgb.icu -0.052 0.084 0.536 0.949 0.805 1.119 Level Comatose vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal -2.602 1.129 0.021 0.074 0.008 0.677 icu.status.todaydelirious -0.132 0.725 0.855 0.876 0.212 3.625 icu.status.todaycomatose 2.945 0.603 0.000 19.002 5.826 61.971 age.enroll 0.008 0.012 0.499 1.008 0.985 1.031 icu.typesurgical 0.816 0.275 0.003 2.261 1.320 3.873 apache.aps 0.009 0.017 0.569 1.009 0.977 1.043 charlson.score 0.006 0.054 0.905 1.006 0.906 1.118

5 stroke.risk -0.009 0.027 0.733 0.991 0.939 1.045 map.low.icu -0.021 0.009 0.021 0.979 0.961 0.997 study.day -0.078 0.021 0.000 0.925 0.888 0.963 sepsis.l24septic today 0.918 0.291 0.002 2.504 1.416 4.428 hgb.icu 0.029 0.085 0.733 1.029 0.872 1.215 icu.status.todaydelirious:age.enroll 0.017 0.014 0.219 1.017 0.990 1.045 icu.status.todaycomatose:age.enroll 0.019 0.015 0.205 1.019 0.990 1.048 icu.status.todaydelirious:icu.typesurgical -0.703 0.317 0.026 0.495 0.266 0.921 icu.status.todaycomatose:icu.typesurgical -0.939 0.344 0.006 0.391 0.199 0.767 icu.status.todaydelirious:apache.aps -0.010 0.019 0.624 0.991 0.954 1.029 icu.status.todaycomatose:apache.aps 0.023 0.021 0.259 1.024 0.983 1.066 icu.status.todaydelirious:charlson.score -0.045 0.066 0.492 0.956 0.840 1.087 icu.status.todaycomatose:charlson.score -0.081 0.074 0.273 0.923 0.799 1.066 icu.status.todaydelirious:stroke.risk -0.025 0.032 0.444 0.976 0.916 1.039 icu.status.todaycomatose:stroke.risk -0.061 0.035 0.084 0.941 0.878 1.008 icu.status.todaydelirious:map.low.icu 0.012 0.011 0.259 1.013 0.991 1.035 icu.status.todaycomatose:map.low.icu 0.011 0.012 0.356 1.011 0.987 1.036 icu.status.todaydelirious:study.day 0.081 0.024 0.001 1.084 1.034 1.137 icu.status.todaycomatose:study.day 0.046 0.027 0.083 1.047 0.994 1.103 icu.status.todaydelirious:sepsis.l24septic today -0.729 0.335 0.030 0.482 0.250 0.930 icu.status.todaycomatose:sepsis.l24septic today -0.485 0.354 0.171 0.615 0.307 1.233 icu.status.todaydelirious:hgb.icu -0.087 0.099 0.376 0.916 0.755 1.112 icu.status.todaycomatose:hgb.icu -0.162 0.101 0.108 0.850 0.697 1.036 Level Deceased vs. Level Normal betahat se pval RRR RRR.lo RRR.up icu.status.todaynormal -4.669 0.101 0.000 0.009 0.008 0.011 icu.status.todaydelirious -4.152 1.728 0.016 0.016 0.001 0.465 icu.status.todaycomatose 1.835 1.108 0.098 6.263 0.713 54.985 age.enroll 0.006 0.021 0.775 1.006 0.965 1.049 icu.typesurgical 0.134 0.548 0.807 1.143 0.391 3.346 apache.aps 0.008 0.030 0.791 1.008 0.950 1.069 charlson.score 0.132 0.079 0.095 1.141 0.977 1.332 stroke.risk -0.053 0.054 0.327 0.948 0.853 1.054 map.low.icu -0.011 0.016 0.504 0.989 0.958 1.021 study.day 0.011 0.028 0.704 1.011 0.957 1.068 sepsis.l24septic today 0.484 0.497 0.330 1.622 0.613 4.293 hgb.icu 0.035 0.119 0.771 1.035 0.820 1.308 icu.status.todaydelirious:age.enroll 0.003 0.030 0.911 1.003 0.946 1.064

6 icu.status.todaycomatose:age.enroll 0.026 0.026 0.325 1.026 0.975 1.080 icu.status.todaydelirious:icu.typesurgical 0.031 0.688 0.965 1.031 0.267 3.975 icu.status.todaycomatose:icu.typesurgical -1.127 0.661 0.088 0.324 0.089 1.185 icu.status.todaydelirious:apache.aps 0.018 0.040 0.645 1.018 0.942 1.101 icu.status.todaycomatose:apache.aps 0.023 0.036 0.517 1.024 0.954 1.098 icu.status.todaydelirious:charlson.score -0.038 0.122 0.754 0.962 0.758 1.223 icu.status.todaycomatose:charlson.score -0.083 0.110 0.450 0.921 0.743 1.141 icu.status.todaydelirious:stroke.risk 0.077 0.071 0.277 1.080 0.940 1.241 icu.status.todaycomatose:stroke.risk -0.021 0.066 0.746 0.979 0.861 1.113 icu.status.todaydelirious:map.low.icu -0.022 0.022 0.331 0.978 0.936 1.022 icu.status.todaycomatose:map.low.icu -0.030 0.021 0.151 0.970 0.931 1.011 icu.status.todaydelirious:study.day 0.024 0.041 0.551 1.025 0.946 1.110 icu.status.todaycomatose:study.day -0.025 0.039 0.524 0.976 0.904 1.053 icu.status.todaydelirious:sepsis.l24septic today 0.073 0.692 0.916 1.076 0.277 4.177 icu.status.todaycomatose:sepsis.l24septic today -0.042 0.604 0.945 0.959 0.293 3.134 icu.status.todaydelirious:hgb.icu 0.076 0.146 0.602 1.079 0.811 1.436 icu.status.todaycomatose:hgb.icu -0.226 0.151 0.135 0.797 0.593 1.073

1.2 Outcome2: Daily troponin (greater than 0.1) as an index of cardiac dysfunction 1.2.1 Descriptive Statistics Table 2: Descriptive by Troponin ( greater than 0.1) 7 N No Yes Combined Test Statistic N = 5710 N = 137 N = 5847 tro.imp.cat 6704 χ 2 1 = 369, P < 0.0011 Yes 5% ( 271) 43% ( 59) 6% ( 330) Highest troponin, current 24h (missing = <0.1) 6704 0.026 0.053 0.080 0.052 0.096 0.920 0.026 0.053 0.080 F 1,5840 = 80, P < 0.001 2 trop.tomo 5847 0.025 0.050 0.076 0.230 0.726 2.110 0.026 0.051 0.078 F 1,5845 = 431, P < 0.001 2 Age at enrollment 6711 52 62 71 54 68 71 52 62 71 F 1,5845 = 3.6, P = 0.057 2 ICU type 6711 Surgical 36% (2067) 36% ( 49) 36% (2116) χ 2 1 = 0.01, P = 0.921 APACHE APS at enrollment 6711 16 22 27 19 23 29 16 22 27 F 1,5845 = 3.5, P = 0.061 2 Charlson score 6711 1 2 4 1 3 4 1 2 4 F 1,5845 = 4.8, P = 0.029 2 Framingham stroke risk score 6711 6 9 14 7 11 15 6 10 14 F 1,5845 = 8.1, P = 0.004 2 Lowest mean arterial pressure, current 24h 6704 55 62 70 49 57 66 55 62 70 F 1,5840 = 18, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% (5710) 100% ( 137) 100% (5847) Septic in the current 24h? 6703 Septic today 65% (3732) 65% ( 89) 65% (3821) χ 2 1 = 0.01, P = 0.911 sevsepsis.l24 6703 Severely septic today 60% (3443) 60% ( 82) 60% (3525) χ 2 1 = 0.01, P = 0.911 Lowest hemoglobin, current 24h 5837 8.7 9.6 10.7 8.9 9.8 10.9 8.7 9.7 10.7 F 1,5157 = 2.1, P = 0.14 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test 1.2.2 Logistic regression. tro greater than 0.1 (Y/N) Table 3: Outcome:Tropnin (greater than 0.1).. P-values less than 0.05 are in red. tro.imp.cat=yes 3.559 1.930 35.146 ( 0.800, 1543.883) 0.065 age.enroll 0.003 0.012 1.003 ( 0.980, 1.027) 0.811 icu.type=surgical -0.016 0.253 0.984 ( 0.599, 1.617) 0.949 apache.aps 0.014 0.015 1.015 ( 0.985, 1.045) 0.337 charlson.score 0.056 0.054 1.058 ( 0.952, 1.175) 0.297 stroke.risk 0.060 0.025 1.062 ( 1.011, 1.116) 0.017 map.low.icu -0.017 0.010 0.983 ( 0.965, 1.002) 0.081 study.day -0.043 0.021 0.958 ( 0.918, 0.999) 0.043 sepsis.l24=septic today -0.048 0.251 0.953 ( 0.583, 1.558) 0.847 hgb.icu -0.021 0.081 0.979 ( 0.836, 1.148) 0.797 tro.imp.cat=yes * age.enroll -0.017 0.020 0.983 ( 0.945, 1.023) 0.404

Table 3: (continued) tro.imp.cat=yes * icu.type=surgical 0.852 0.421 2.343 ( 1.027, 5.348) 0.043 tro.imp.cat=yes * apache.aps -0.020 0.025 0.980 ( 0.933, 1.030) 0.424 tro.imp.cat=yes * charlson.score -0.071 0.092 0.932 ( 0.778, 1.116) 0.442 tro.imp.cat=yes * stroke.risk -0.090 0.044 0.914 ( 0.839, 0.996) 0.040 tro.imp.cat=yes * map.low.icu -0.009 0.016 0.991 ( 0.960, 1.023) 0.563 tro.imp.cat=yes * study.day 0.051 0.037 1.052 ( 0.978, 1.132) 0.172 tro.imp.cat=yes * sepsis.l24=septic today 0.559 0.420 1.749 ( 0.767, 3.986) 0.183 tro.imp.cat=yes * hgb.icu 0.135 0.128 1.145 ( 0.891, 1.472) 0.290 1.2.3 Linear regression. Continuous Response Table 4: Outcome:Tropnin. Multiple linear regression (OLS) results. P-values less than 0.05 are in red. 8 Parameter Est P-value Coef SE 95% Confidence Interval p-value tro.imp -0.358 0.054 (-0.465, -0.251) <0.001 age.enroll 0.000 0.003 (-0.005, 0.005) 0.925 icu.type=surgical -0.023 0.057 (-0.134, 0.088) 0.683 apache.aps -0.001 0.003 (-0.007, 0.006) 0.840 charlson.score 0.017 0.013 (-0.009, 0.043) 0.195 stroke.risk 0.000 0.006 (-0.012, 0.012) 0.953 map.low.icu 0.003 0.002 (-0.001, 0.007) 0.172 study.day -0.010 0.004 (-0.018, -0.002) 0.013 sepsis.l24=septic today -0.055 0.058 (-0.169, 0.059) 0.347 hgb.icu -0.038 0.018 (-0.073, -0.003) 0.034 tro.imp * age.enroll 0.012 0.001 ( 0.011, 0.013) <0.001 tro.imp * icu.type=surgical 0.030 0.027 (-0.022, 0.083) 0.255 tro.imp * apache.aps 0.001 0.001 ( 0.000, 0.003) 0.130 tro.imp * charlson.score -0.009 0.002 (-0.014, -0.004) <0.001 tro.imp * stroke.risk -0.023 0.001 (-0.025, -0.021) <0.001 tro.imp * map.low.icu -0.017 0.001 (-0.018, -0.016) <0.001 tro.imp * study.day 0.065 0.004 ( 0.056, 0.073) <0.001 tro.imp * sepsis.l24=septic today -0.060 0.012 (-0.083, -0.037) <0.001 tro.imp * hgb.icu 0.083 0.004 ( 0.076, 0.090) <0.001

1.3 Outcome3: Daily renal SOFA score 2 1.3.1 Descriptive Statistics Table 5: Descriptive by next day s Renal SOFA score 2 9 N No Yes Combined Test Statistic N = 4319 N = 1528 N = 5847 sofa.renal.cat 6704 χ 2 1 = 4270, P < 0.0011 Yes 4% ( 185) 90% (1380) 27% (1565) SOFA renal component score 6704 0 69% (2971) 1% ( 11) 51% (2982) χ 2 4 = 4375, P < 0.0011 1 27% (1161) 9% ( 134) 22% (1295) 2 4% ( 172) 48% ( 726) 15% ( 898) 3 0% ( 6) 21% ( 317) 6% ( 323) 4 0% ( 7) 22% ( 337) 6% ( 344) renal.tomo 5847 0 71% (3061) 0% ( 0) 52% (3061) χ 2 4 = 5847, P < 0.0011 1 29% (1258) 0% ( 0) 22% (1258) 2 0% ( 0) 58% ( 886) 15% ( 886) 3 0% ( 0) 20% ( 303) 5% ( 303) 4 0% ( 0) 22% ( 339) 6% ( 339) Age at enrollment 6711 51 61 71 55 64 71 52 62 71 F 1,5845 = 22, P < 0.001 2 ICU type 6711 Surgical 39% (1668) 29% ( 448) 36% (2116) χ 2 1 = 42, P < 0.0011 APACHE APS at enrollment 6711 16 21 26 19 25 31 16 22 27 F 1,5845 = 158, P < 0.001 2 Charlson score 6711 1 2 3 2 3 4 1 2 4 F 1,5845 = 307, P < 0.001 2 Framingham stroke risk score 6711 6 9 14 6 10 15 6 10 14 F 1,5845 = 20, P < 0.001 2 Lowest mean arterial pressure, current 24h 6704 56 63 71 51 58 65 55 62 70 F 1,5840 = 213, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% (4319) 100% (1528) 100% (5847) Septic in the current 24h? 6703 Septic today 65% (2823) 65% ( 998) 65% (3821) χ 2 1 = 0, P = 0.971 sevsepsis.l24 6703 Severely septic today 59% (2533) 65% ( 992) 60% (3525) χ 2 1 = 19, P < 0.0011 Lowest hemoglobin, current 24h 5837 8.8 9.7 10.8 8.6 9.4 10.5 8.7 9.7 10.7 F 1,5157 = 34, P < 0.001 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test Table 6: Descriptive by next day s Renal SOFA score (0-4) N 0 1 2 3 4 Combined Test Statistic N = 3061 N = 1258 N = 886 N = 303 N = 339 N = 5847 sofa.renal.cat 6704 χ 2 4 = 4379, P < 0.0011 Yes 0% ( 12) 14% ( 173) 85% ( 756) 98% ( 295) 97% ( 329) 27% (1565) a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test

Table 6: (continued) 10 N 0 1 2 3 4 Combined Test Statistic N = 3061 N = 1258 N = 886 N = 303 N = 339 N = 5847 SOFA renal component score 6704 χ 2 16 = 11626, P < 0.0011 0 92% (2820) 12% ( 151) 1% ( 7) 1% ( 2) 1% ( 2) 51% (2982) 1 7% ( 227) 74% ( 934) 14% ( 122) 2% ( 5) 2% ( 7) 22% (1295) 2 0% ( 7) 13% ( 165) 73% ( 642) 22% ( 66) 5% ( 18) 15% ( 898) 3 0% ( 2) 0% ( 4) 10% ( 88) 59% ( 179) 15% ( 50) 6% ( 323) 4 0% ( 3) 0% ( 4) 3% ( 26) 17% ( 50) 77% ( 261) 6% ( 344) Age at enrollment 6711 51 60 70 52 63 72 56 64 71 60 66 72 47 60 66 52 62 71 F 4,5842 = 22, P < 0.001 2 ICU type 6711 Surgical 40% (1215) 36% ( 453) 35% ( 310) 22% ( 68) 21% ( 70) 36% (2116) χ 2 4 = 77, P < 0.0011 APACHE APS at enrollment 6711 16 21 26 17 22 27 19 24 30 20 27 33 17 23 29 16 22 27 F 4,5842 = 52, P < 0.001 2 Charlson score 6711 1.0 2.0 3.0 1.0 2.0 3.0 2.0 3.0 4.0 2.0 3.0 5.0 2.0 3.0 5.5 1.0 2.0 4.0 F 4,5842 = 93, P < 0.001 2 Framingham stroke risk score 6711 5 9 14 6 10 15 6 10 15 7 12 16 5 8 14 6 10 14 F 4,5842 = 19, P < 0.001 2 Lowest mean arterial pressure, current 24h 6704 57 64 72 53 60 67 51 58 65 52 60 66 50 58 67 55 62 70 F 4,5837 = 84, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% (3061) 100% (1258) 100% ( 886) 100% ( 303) 100% ( 339) 100% (5847) Septic in the current 24h? 6703 Septic today 66% (2032) 63% ( 791) 67% ( 589) 61% ( 184) 67% ( 225) 65% (3821) χ 2 4 = 8.4, P = 0.0791 sevsepsis.l24 6703 Severely septic today 58% (1781) 60% ( 752) 66% ( 583) 61% ( 184) 67% ( 225) 60% (3525) χ 2 4 = 23, P < 0.0011 Lowest hemoglobin, current 24h 5837 8.8 9.8 10.8 8.7 9.6 10.7 8.6 9.5 10.5 8.8 9.5 10.5 8.4 9.2 10.4 8.7 9.7 10.7 F 4,5154 = 11, P < 0.001 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test 1.3.2 Logistic regression, Daily renal SOFA 2(Y/N) Table 7: Outcome:Daily renal SOFA =2.. P-values less than 0.05 are in red. sofa.renal.cat=yes 2.2096 1.106 9.112 ( 1.043, 79.622) 0.046 age.enroll 0.0090 0.009 1.009 ( 0.992, 1.026) 0.303 icu.type=surgical -0.3035 0.190 0.738 ( 0.509, 1.071) 0.110 apache.aps 0.0233 0.011 1.024 ( 1.001, 1.047) 0.044 charlson.score 0.0955 0.039 1.100 ( 1.018, 1.189) 0.015 stroke.risk -0.0311 0.021 0.969 ( 0.930, 1.010) 0.141 map.low.icu -0.0371 0.007 0.964 ( 0.950, 0.977) <0.001 study.day -0.0007 0.013 0.999 ( 0.974, 1.026) 0.956 sepsis.l24=septic today 0.0100 0.192 1.010 ( 0.694, 1.470) 0.959 hgb.icu -0.0450 0.059 0.956 ( 0.852, 1.073) 0.446 sofa.renal.cat=yes * age.enroll 0.0008 0.012 1.001 ( 0.978, 1.024) 0.942 sofa.renal.cat=yes * icu.type=surgical 0.0618 0.257 1.064 ( 0.642, 1.762) 0.810 sofa.renal.cat=yes * apache.aps -0.0146 0.015 0.986 ( 0.957, 1.015) 0.332 sofa.renal.cat=yes * charlson.score 0.0113 0.056 1.011 ( 0.905, 1.129) 0.841 sofa.renal.cat=yes * stroke.risk 0.0381 0.028 1.039 ( 0.984, 1.097) 0.166 sofa.renal.cat=yes * map.low.icu 0.0385 0.010 1.039 ( 1.020, 1.059) <0.001

Table 7: (continued) sofa.renal.cat=yes * study.day 0.0212 0.019 1.021 ( 0.984, 1.060) 0.262 sofa.renal.cat=yes * sepsis.l24=septic today 0.2890 0.257 1.335 ( 0.806, 2.211) 0.262 sofa.renal.cat=yes * hgb.icu 0.0101 0.082 1.010 ( 0.861, 1.185) 0.901 1.3.3 Proportional odds logistic regression regression, Ordinal response (0-4) Table 8: Outcome:Daily renal SOFA (0-4).. P-values less than 0.05 are in red. 11 sofa.renal 3.038 0.314 20.871 (11.276, 38.628) <0.001 age.enroll 0.009 0.005 1.010 ( 0.999, 1.020) 0.079 icu.type=surgical -0.157 0.119 0.855 ( 0.677, 1.078) 0.185 apache.aps 0.022 0.007 1.022 ( 1.008, 1.037) 0.002 charlson.score 0.060 0.026 1.062 ( 1.009, 1.119) 0.022 stroke.risk -0.011 0.013 0.989 ( 0.964, 1.014) 0.385 map.low.icu -0.027 0.005 0.974 ( 0.965, 0.983) <0.001 study.day -0.007 0.009 0.993 ( 0.977, 1.010) 0.419 sepsis.l24=septic today 0.048 0.120 1.049 ( 0.829, 1.328) 0.691 hgb.icu -0.005 0.036 0.995 ( 0.928, 1.067) 0.895 sofa.renal * age.enroll -0.003 0.003 0.997 ( 0.991, 1.003) 0.370 sofa.renal * icu.type=surgical -0.002 0.074 0.998 ( 0.863, 1.153) 0.974 sofa.renal * apache.aps -0.011 0.004 0.989 ( 0.981, 0.997) 0.006 sofa.renal * charlson.score -0.011 0.015 0.989 ( 0.961, 1.019) 0.481 sofa.renal * stroke.risk 0.004 0.007 1.004 ( 0.990, 1.019) 0.550 sofa.renal * map.low.icu 0.010 0.003 1.010 ( 1.004, 1.015) <0.001 sofa.renal * study.day 0.008 0.005 1.008 ( 0.998, 1.019) 0.111 sofa.renal * sepsis.l24=septic today -0.012 0.071 0.989 ( 0.860, 1.136) 0.871 sofa.renal * hgb.icu 0.011 0.022 1.011 ( 0.968, 1.056) 0.618

1.4 Outcome4: Daily resp SOFA score ( 2) 1.4.1 Descriptive Statistics Table 9: Descriptive by next day s RESP SOFA score ( 2) 12 N No Yes Combined Test Statistic N = 276 N = 5571 N = 5847 sofa.resp.cat 6704 χ 2 1 = 2576, P < 0.0011 Yes 39% ( 107) 99% (5510) 96% (5617) SOFA respiratory component score 6704 0 0% ( 0) 0% ( 9) 0% ( 9) χ 2 4 = 2717, P < 0.0011 1 61% ( 169) 1% ( 47) 4% ( 216) 2 34% ( 95) 51% (2852) 50% (2947) 3 4% ( 12) 45% (2505) 43% (2517) 4 0% ( 0) 3% ( 153) 3% ( 153) resp.tomo 5847 0 3% ( 8) 0% ( 0) 0% ( 8) χ 2 4 = 5847, P < 0.0011 1 97% ( 268) 0% ( 0) 5% ( 268) 2 0% ( 0) 57% (3152) 54% (3152) 3 0% ( 0) 41% (2285) 39% (2285) 4 0% ( 0) 2% ( 134) 2% ( 134) Age at enrollment 6711 53 62 70 52 62 71 52 62 71 F 1,5845 = 0.13, P = 0.72 2 ICU type 6711 Surgical 23% ( 64) 37% (2052) 36% (2116) χ 2 1 = 21, P < 0.0011 APACHE APS at enrollment 6711 11 19 26 17 22 27 16 22 27 F 1,5845 = 33, P < 0.001 2 Charlson score 6711 0 2 4 1 2 4 1 2 4 F 1,5845 = 0.71, P = 0.4 2 Framingham stroke risk score 6711 6 9 13 6 10 14 6 10 14 F 1,5845 = 2.4, P = 0.12 2 Lowest mean arterial pressure, current 24h 6704 55 64 73 55 62 70 55 62 70 F 1,5840 = 9.6, P = 0.002 2 Was patient in ICU today? 6711 1 ICU 100% ( 276) 100% (5571) 100% (5847) Septic in the current 24h? 6703 Septic today 30% ( 84) 67% (3737) 65% (3821) χ 2 1 = 157, P < 0.0011 sevsepsis.l24 6703 Severely septic today 22% ( 61) 62% (3464) 60% (3525) χ 2 1 = 177, P < 0.0011 Lowest hemoglobin, current 24h 5837 9.4 10.4 11.3 8.7 9.6 10.7 8.7 9.7 10.7 F 1,5157 = 38, P < 0.001 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test Table 10: Descriptive by next day s RESP SOFA score (0-4) N 0 1 2 3 4 Combined Test Statistic N = 8 N = 268 N = 3152 N = 2285 N = 134 N = 5847 sofa.resp.cat 6704 χ 2 4 = 2633, P < 0.0011 Yes 88% ( 7) 37% ( 100) 99% (3102) 100% (2275) 99% ( 133) 96% (5617) a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test

Table 10: (continued) 13 N 0 1 2 3 4 Combined Test Statistic N = 8 N = 268 N = 3152 N = 2285 N = 134 N = 5847 SOFA respiratory component score 6704 χ 2 16 = 5156, P < 0.0011 0 0% ( 0) 0% ( 0) 0% ( 7) 0% ( 2) 0% ( 0) 0% ( 9) 1 12% ( 1) 63% ( 168) 1% ( 40) 0% ( 6) 1% ( 1) 4% ( 216) 2 38% ( 3) 34% ( 92) 76% (2404) 19% ( 435) 10% ( 13) 50% (2947) 3 50% ( 4) 3% ( 8) 22% ( 685) 76% (1744) 57% ( 76) 43% (2517) 4 0% ( 0) 0% ( 0) 0% ( 13) 4% ( 96) 33% ( 44) 3% ( 153) renal.tomo 5847 0 75% ( 6) 44% ( 119) 55% (1718) 51% (1158) 45% ( 60) 52% (3061) χ 2 16 = 101, P < 0.0011 1 0% ( 0) 16% ( 44) 20% ( 644) 23% ( 534) 27% ( 36) 22% (1258) 2 25% ( 2) 15% ( 40) 14% ( 441) 17% ( 380) 17% ( 23) 15% ( 886) 3 0% ( 0) 7% ( 19) 6% ( 182) 4% ( 95) 5% ( 7) 5% ( 303) 4 0% ( 0) 17% ( 46) 5% ( 167) 5% ( 118) 6% ( 8) 6% ( 339) Age at enrollment 6711 56 63 77 53 62 70 53 62 71 51 61 70 44 56 66 52 62 71 F 4,5842 = 11, P < 0.001 2 ICU type 6711 Surgical 75% ( 6) 22% ( 58) 37% (1177) 37% ( 841) 25% ( 34) 36% (2116) χ 2 4 = 39, P < 0.0011 APACHE APS at enrollment 6711 20 24 29 11 19 26 17 22 28 16 22 27 13 22 26 16 22 27 F 4,5842 = 11, P < 0.001 2 Charlson score 6711 0.0 0.5 4.5 0.0 2.0 4.0 1.0 2.0 4.0 1.0 2.0 3.0 0.0 2.0 3.0 1.0 2.0 4.0 F 4,5842 = 6.4, P < 0.001 2 Framingham stroke risk score 6711 9.8 11.0 15.5 6.0 9.0 13.0 6.0 10.0 15.0 6.0 9.0 14.0 3.0 7.0 10.0 6.0 10.0 14.0 F 4,5842 = 11, P < 0.001 2 Lowest mean arterial pressure, current 24h 6704 58 64 68 55 64 74 55 62 70 54 61 68 52 60 70 55 62 70 F 4,5837 = 8.9, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% ( 8) 100% ( 268) 100% (3152) 100% (2285) 100% ( 134) 100% (5847) Septic in the current 24h? 6703 Septic today 75% ( 6) 29% ( 78) 64% (2024) 71% (1611) 76% ( 102) 65% (3821) χ 2 4 = 192, P < 0.0011 sevsepsis.l24 6703 Severely septic today 62% ( 5) 21% ( 56) 60% (1876) 66% (1505) 62% ( 83) 60% (3525) χ 2 4 = 205, P < 0.0011 Lowest hemoglobin, current 24h 5837 9.0 9.7 11.4 9.4 10.4 11.3 8.8 9.7 10.7 8.6 9.5 10.6 9.0 9.8 10.6 8.7 9.7 10.7 F 4,5154 = 12, P < 0.001 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Kruskal-Wallis test 1.4.2 Logistic regression, Daily RESP SOFA 2(Y/N) Table 11: Outcome:Daily resp SOFA 2..P valueslessthan0.05areinred. sofa.resp.cat=yes 4.8893 1.458 132.864 ( 7.630, 2313.720) <0.001 age.enroll -0.0078 0.020 0.992 ( 0.955, 1.031) 0.691 icu.type=surgical 0.8227 0.403 2.276 ( 1.034, 5.013) 0.041 apache.aps 0.0325 0.021 1.033 ( 0.992, 1.076) 0.116 charlson.score -0.0803 0.071 0.923 ( 0.803, 1.061) 0.259 stroke.risk 0.0509 0.038 1.052 ( 0.977, 1.134) 0.181 map.low.icu -0.0231 0.011 0.977 ( 0.957, 0.998) 0.029 study.day -0.0460 0.027 0.955 ( 0.905, 1.008) 0.093 sepsis.l24=septic today 0.6974 0.354 2.009 ( 1.003, 4.023) 0.049 sofa.resp.cat=yes * age.enroll -0.0009 0.022 0.999 ( 0.957, 1.043) 0.966

Table 11: (continued) sofa.resp.cat=yes * icu.type=surgical -0.5844 0.457 0.557 ( 0.228, 1.364) 0.201 sofa.resp.cat=yes * apache.aps -0.0110 0.024 0.989 ( 0.943, 1.037) 0.649 sofa.resp.cat=yes * charlson.score 0.0092 0.082 1.009 ( 0.859, 1.186) 0.911 sofa.resp.cat=yes * stroke.risk -0.0309 0.044 0.970 ( 0.890, 1.056) 0.480 sofa.resp.cat=yes * map.low.icu 0.0014 0.013 1.001 ( 0.976, 1.027) 0.915 sofa.resp.cat=yes * study.day 0.0427 0.031 1.044 ( 0.982, 1.109) 0.169 sofa.resp.cat=yes * sepsis.l24=septic today 0.2926 0.407 1.340 ( 0.603, 2.978) 0.473 1.4.3 Proportional odds logistic regression, Ordinal response (0-4) Table 12: Outcome:Daily resp SOFA (0-4).. P-values less than 0.05 are in red. 14 sofa.resp 2.116 0.484 8.297 ( 3.210, 21.447) <0.001 age.enroll -0.011 0.013 0.989 ( 0.965, 1.014) 0.372 icu.type=surgical 1.730 0.293 5.639 ( 3.175, 10.016) <0.001 apache.aps 0.031 0.016 1.032 ( 1.000, 1.064) 0.049 charlson.score -0.038 0.063 0.963 ( 0.851, 1.090) 0.550 stroke.risk 0.101 0.030 1.106 ( 1.042, 1.173) <0.001 map.low.icu -0.023 0.010 0.978 ( 0.958, 0.998) 0.029 study.day -0.046 0.021 0.955 ( 0.917, 0.995) 0.027 sepsis.l24=septic today 1.513 0.291 4.539 ( 2.568, 8.023) <0.001 hgb.icu -0.326 0.091 0.722 ( 0.604, 0.862) <0.001 sofa.resp * age.enroll 0.005 0.005 1.005 ( 0.995, 1.014) 0.330 sofa.resp * icu.type=surgical -0.675 0.113 0.509 ( 0.408, 0.635) <0.001 sofa.resp * apache.aps -0.015 0.006 0.986 ( 0.974, 0.997) 0.017 sofa.resp * charlson.score -0.010 0.025 0.990 ( 0.942, 1.040) 0.686 sofa.resp * stroke.risk -0.040 0.011 0.961 ( 0.940, 0.983) <0.001 sofa.resp * map.low.icu 0.005 0.004 1.006 ( 0.998, 1.014) 0.175 sofa.resp * study.day 0.017 0.008 1.017 ( 1.001, 1.033) 0.041 sofa.resp * sepsis.l24=septic today -0.476 0.112 0.621 ( 0.498, 0.774) <0.001 sofa.resp * hgb.icu 0.111 0.034 1.118 ( 1.046, 1.195) 0.001

1.5 Outcome5: Daily Ventilator (Y/N) as a measure of success of extubation 1.5.1 Descriptive Statistics Table 13: Descriptive by ventilator (Y/N) 15 N No Yes Combined Test Statistic N = 1580 N = 4269 N = 5849 on.vent.l24 6711 χ 2 1 = 3661, P < 0.0011 Yes 25% ( 399) 98% (4198) 79% (4597) Age at enrollment 6711 51 61 70 52 63 71 52 62 71 F 1,5847 = 8.7, P = 0.003 2 ICU type 6711 Surgical 32% ( 500) 38% (1616) 36% (2116) χ 2 1 = 19, P < 0.0011 APACHE APS at enrollment 6711 14 20 26 18 22 28 16 22 27 F 1,5847 = 110, P < 0.001 2 Charlson score 6711 1 2 4 1 2 4 1 2 4 F 1,5847 = 16, P < 0.001 2 Framingham stroke risk score 6711 6 9 14 6 10 14 6 10 14 F 1,5847 = 0.06, P = 0.81 2 Lowest mean arterial pressure, current 24h 6704 56 65 74 54 61 68 55 62 70 F 1,5842 = 83, P < 0.001 2 Was patient in ICU today? 6711 1 ICU 100% (1580) 100% (4269) 100% (5849) Septic in the current 24h? 6703 Septic today 54% ( 858) 69% (2963) 65% (3821) χ 2 1 = 116, P < 0.0011 sevsepsis.l24 6703 Severely septic today 37% ( 587) 69% (2938) 60% (3525) χ 2 1 = 483, P < 0.0011 Lowest hemoglobin, current 24h 5837 8.9 9.8 10.9 8.7 9.6 10.6 8.7 9.7 10.7 F 1,5157 = 29, P < 0.001 2 a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Pearson test; 2 Wilcoxon test 1.5.2 Logistic regression (Daily Ventilation (Y/N)) Table 14: Outcome:Daily ventilation (Y/N).. P-values less than 0.05 are in red. on.vent.l24=yes 8.135 1.330 3412.469 ( 251.938, 46221.401) <0.001 age.enroll 0.004 0.014 1.004 ( 0.978, 1.031) 0.765 icu.type=surgical 0.629 0.281 1.876 ( 1.082, 3.250) 0.025 apache.aps 0.009 0.016 1.009 ( 0.977, 1.042) 0.581 charlson.score 0.020 0.061 1.020 ( 0.904, 1.151) 0.749 stroke.risk -0.007 0.029 0.993 ( 0.939, 1.051) 0.817 map.low.icu -0.003 0.010 0.997 ( 0.979, 1.016) 0.775 study.day -0.026 0.021 0.974 ( 0.935, 1.015) 0.209 sepsis.l24=septic today 0.540 0.283 1.716 ( 0.985, 2.986) 0.056 hgb.icu 0.073 0.087 1.076 ( 0.907, 1.277) 0.401 on.vent.l24=yes * age.enroll 0.003 0.015 1.003 ( 0.975, 1.032) 0.838 on.vent.l24=yes * icu.type=surgical -0.857 0.304 0.424 ( 0.234, 0.770) 0.005 on.vent.l24=yes * apache.aps 0.001 0.018 1.001 ( 0.967, 1.037) 0.952

Table 14: (continued) on.vent.l24=yes * charlson.score -0.077 0.066 0.926 ( 0.813, 1.054) 0.245 on.vent.l24=yes * stroke.risk -0.014 0.031 0.986 ( 0.927, 1.048) 0.648 on.vent.l24=yes * map.low.icu -0.027 0.011 0.973 ( 0.953, 0.993) 0.010 on.vent.l24=yes * study.day 0.057 0.023 1.059 ( 1.012, 1.108) 0.013 on.vent.l24=yes * sepsis.l24=septic today -0.155 0.306 0.856 ( 0.470, 1.560) 0.612 on.vent.l24=yes * hgb.icu -0.127 0.094 0.881 ( 0.732, 1.059) 0.176 16

2 Analysis2: Hb during ICU stay and predicted outcomes 2.1 Outcome1: ICU mortality 2.1.1 Descriptive Statistics Table 15: Descriptive by Mortality (Y/N) unique subject) N No Yes Combined Test Statistic N = 685 N = 128 N = 813 Age at enrollment 813 50 61 70 54 63 74 51 61 71 F 1,811 = 4.3, P = 0.038 1 ICU type 813 Surgical 35% (238) 19% ( 24) 32% (262) χ 2 1 = 13, P < 0.0012 APACHE APS at enrollment 813 15 20 26 20 25 29 15 21 26 F 1,811 = 22, P < 0.001 1 Charlson score 813 1.0 2.0 4.0 1.0 2.5 4.0 1.0 2.0 4.0 F 1,811 = 6.5, P = 0.011 1 Framingham stroke risk score 813 6.0 10.0 15.0 4.8 9.0 13.2 6.0 9.0 14.0 F 1,811 = 1.9, P = 0.17 1 lowest.hgb.icu 803 7.9 8.9 10.3 7.7 8.5 9.7 7.9 8.9 10.2 F 1,801 = 4.8, P = 0.029 1 auc.hgb.icu 813 22 43 95 24 51 103 23 45 97 F 1,811 = 0.57, P = 0.45 1 mean.sofa 813 5.6 7.0 9.0 8.2 10.8 13.4 5.8 7.5 9.9 F 1,811 = 134, P < 0.001 1 duration.sepsis 813 0.0 2.0 6.0 1.0 4.0 8.2 0.0 3.0 7.0 F 1,811 = 12, P < 0.001 1 max.sofa.renal 813 0 42% (285) 15% ( 19) 37% (304) χ 2 4 = 44, P < 0.0012 1 24% (163) 23% ( 30) 24% (193) 2 19% (132) 37% ( 47) 22% (179) 3 6% ( 39) 12% ( 16) 7% ( 55) 4 10% ( 66) 12% ( 16) 10% ( 82) a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. N is the number of non missing values. Numbers after percents are frequencies. Tests used: 1 Wilcoxon test; 2 Pearson test 2.1.2 Logistic regression for ICU.mortality (Y/N) Two different functional forms of hemoglobin during ICU was considered in the below analysis (two different models) Table 16: Outcome:Mortality.. P-values less than 0.05 are in red. lowest.hgb.icu -0.004 0.077 0.996 (0.857, 1.157) 0.953 age.enroll 0.041 0.011 1.042 (1.019, 1.065) <0.001 icu.type=surgical -0.993 0.273 0.371 (0.217, 0.633) <0.001 apache.aps -0.007 0.015 0.993 (0.964, 1.024) 0.666 charlson.score -0.014 0.051 0.986 (0.892, 1.090) 0.781 stroke.risk -0.049 0.025 0.952 (0.907, 1.000) 0.051 mean.sofa 0.425 0.045 1.530 (1.401, 1.670) <0.001 duration.sepsis 0.021 0.020 1.022 (0.982, 1.063) 0.287 Table 17: Outcome:Mortality.. P-values less than 0.05 are in red. auc.hgb.icu -0.002 0.003 0.998 (0.991, 1.004) 0.452 age.enroll 0.041 0.011 1.042 (1.020, 1.065) <0.001 icu.type=surgical -0.963 0.275 0.382 (0.223, 0.655) <0.001 apache.aps -0.006 0.015 0.994 (0.964, 1.024) 0.672 charlson.score -0.009 0.051 0.991 (0.897, 1.094) 0.858 stroke.risk -0.051 0.025 0.951 (0.905, 0.998) 0.042 mean.sofa 0.428 0.044 1.534 (1.407, 1.674) <0.001 duration.sepsis 0.043 0.033 1.044 (0.978, 1.114) 0.194 17

2.1.3 Time dependent covariate survival analysis for Time to ICU.mortality Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Age.enroll, icu.type, apache.aps, Call: coxph(formula = Surv(time1, time2, mortality.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) coef exp(coef) se(coef) robust se z p hgb.icu 0.0621 1.064 0.0815 0.0746 0.833 4.0e-01 age.enroll 0.0189 1.019 0.0127 0.0104 1.815 7.0e-02 icu.typesurgical -1.0109 0.364 0.3231 0.3094-3.268 1.1e-03 apache.aps 0.0135 1.014 0.0188 0.0159 0.850 4.0e-01 charlson.score 0.1090 1.115 0.0638 0.0650 1.678 9.3e-02 stroke.risk -0.0634 0.939 0.0304 0.0278-2.276 2.3e-02 daily.sofa 0.2553 1.291 0.0422 0.0392 6.504 7.8e-11 sevsepsis.l24severely septic today 0.0903 1.095 0.3161 0.2928 0.309 7.6e-01 Likelihood ratio test=78.3 on 8 df, p=1.05e-13 n= 5848, number of events= 84 (876 observations deleted due to missingness) 18

2.2 Outcome2: Cardiac dysfunction(tropnin greater than 0.1) 2.2.1 Correlated time dependent covariate survival analysis for Time to Tropnin greater than 0.1 Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Call: coxph(formula = Surv(time1, time2, tropnin.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) Age.enroll, icu.type, apache.aps, coef exp(coef) se(coef) robust se z p hgb.icu 0.04474 1.046 0.0546 0.0508 0.8806 0.38000 age.enroll -0.00258 0.997 0.0105 0.0102-0.2537 0.80000 icu.typesurgical -0.02246 0.978 0.2179 0.2860-0.0785 0.94000 apache.aps 0.02061 1.021 0.0140 0.0172 1.1961 0.23000 charlson.score -0.02259 0.978 0.0435 0.0443-0.5095 0.61000 stroke.risk 0.08141 1.085 0.0236 0.0267 3.0440 0.00230 daily.sofa 0.11588 1.123 0.0316 0.0338 3.4259 0.00061 sevsepsis.l24severely septic today 0.06074 1.063 0.2185 0.2141 0.2837 0.78000 Likelihood ratio test=33.4 on 8 df, p=0.0000532 n= 5848, number of events= 129 (876 observations deleted due to missingness) 19

2.3 Outcome3: Renal dysfunction 2.3.1 Outcome: Time to renal dysfunction Survival analysis with correlated time dependent covariate Variable hgb.icu, daily.sofa, severe sepsis were time variang covariates. charlson.score,stroke.risk did not change over time. Call: coxph(formula = Surv(time1, time2, renal.censor) ~ hgb.icu + age.enroll + icu.type + apache.aps + charlson.score + stroke.risk + daily.sofa + sevsepsis.l24 + cluster(id), data = brain.dailyobs) Age.enroll, icu.type, apache.aps, coef exp(coef) se(coef) robust se z p hgb.icu -0.08317 0.920 0.03608 0.05370-1.549 0.12000 age.enroll 0.00604 1.006 0.00500 0.00942 0.641 0.52000 icu.typesurgical -0.78254 0.457 0.12800 0.31420-2.491 0.01300 apache.aps 0.02102 1.021 0.00728 0.01526 1.377 0.17000 charlson.score 0.15526 1.168 0.02410 0.04094 3.792 0.00015 stroke.risk 0.01747 1.018 0.01148 0.02274 0.768 0.44000 daily.sofa 0.27420 1.315 0.01691 0.03085 8.889 0.00000 sevsepsis.l24severely septic today -0.28192 0.754 0.11774 0.17140-1.645 0.10000 Likelihood ratio test=508 on 8 df, p=0 n= 5848, number of events= 557 (876 observations deleted due to missingness) 2.4 Outcome4: Time to resolution of delirium To be continue 2.5 Outcome5: Time to successful extubation To be continue 20