The median ventilation duration was less than a day (23.5 hours) in 4192 ventilated patients. The study population had a median age of 59 years, 2404 were males and 1788 were females. The median ICU length of stay was 2.84 days while the median hospital stay was 7.48 days. 746 subjects expired in the hospital wards and 588 expired in the ICU. The median survival duration was 40.2 days for all expired patients, and 2.45 days for those who expired during ICU stay. Other relevant demographic characteristics are listed in Table 1.
Thromboprophylaxis use and Survival plot for ventilated patients
Of the 4192 ventilated patients, 111 patients were diagnosed with DVT and related conditions, and 70 were recorded as pulmonary embolism related categories in ICD-9. Congestive heart failure was present in 296 ventilated patients, atrial fibrillation in 669, coronary artery disease in 422, renal disorders in 280, liver diseases in 302 and 42 had Chronic Obstructive Pulmonary Disease. 829 had malignancies, 1518 had respiratory failure, one patient had endocarditis, 68 patients had Acute Respiratory Distress Syndrome, and 650 had pneumonia. Among those who received either oral or parenteral thromboprophylaxis, 2408 of the ventilated patients received Heparin or its derivatives. 250 patients received Warfarin; 220 patients received Enoxaparin while 653 patients received Aspirin. Platelets transfusions were given to 157 patients. Clopidogrel was given to 93 patients, while four patients received Fondaparinux. Clopidogrel, Fondaparinux and Dipyridamole-Aspirin combination were excluded from further analysis due to the small sample size. 61.5 percentage (n = 2580 patients) of the ventilated patients received Heparin, Warfarin and Enoxaparin, either alone or in combination. Among the 4192 patients, 225 were tested for D-dimer levels, 25 of them showed D-dimer levels within the normal range (< 500 units). D-dimers levels rapidly increase to higher levels (in thousands) in patients with thromboembolism. Thirty patients had D-dimer levels of 1000–2000 units, while in 170 patients, the levels were more than 2000 units. 288 of the ventilated patients had history of long-term use of anticoagulants prior to ICU admission, which included one or more of the oral anticoagulants (Warfarin and Aspirin).
SOFA scores at ICU admission and the duration of ventilation were positively associated with cumulative hazard (Fig. 1). The survival probability curve showed sharp decreases in the first week and continued decreasing for 10 days of ICU stay, then remained low afterwards (Fig. 1a). Based on the survival curves (Fig. 1a &b), SOFA scores were calculated at the 4th, 7th and 10th day of admission, and changes in the SOFA scores were analyzed relative to use of thromboprophylaxis. The effect of the blood thinners on SOFA score changes (delta SOFA) were also analyzed (Table 4). Cumulative plots showed mortality rates rising stepwise with SOFA scores at ICU admission (Fig. 2). Predicted cumulative probabilities showed higher SOFA scores having higher predictive values for overall hospital mortality (Fig. 2). DVTs were more likely treated with Warfarin (OR 4.19, 2.52–6.97) while pulmonary embolism patients were more likely to receive both Warfarin (OR 5.06, 2.75–9.3) and Enoxaparin (OR 3.8, 2-7.14) during the hospital stay (Table 2).
Hazard ratios for survival durations, ventilator durations and thromboembolic events
Aspirin was not significant in any of the outcomes calculated, except for the reduction of ICU stay duration (Tables 2, 3 & 4). Hazard ratio calculations included all ICU stay expired, in-patient stay expired, and discharged patients using regression analysis of data using proportional hazards model. For ICU length of stay, Heparin, Warfarin, Enoxaparin and Aspirin had hazard ratios of 0.59 (p < 0.01), 0.81(p < 0.01), 0.65(p < 0.01) and 0.88 (p < 0.01) respectively. For hospital length of stay, Heparin, Warfarin, Enoxaparin and Aspirin had hazard ratios of 0.7 (p < 0.01), 0.82(p < 0.01), 0.62(p < 0.01) and 0.96(p = 0.38) respectively (Table 3). For ventilation duration, Heparin, Warfarin, Enoxaparin and Aspirin had hazard ratios of 0.66 (p < 0.01), 0.87(p = 0.13), 0.64(p < 0.01) and 0.98(p = 0.59) respectively (Table 3). When data was analyzed for occurrence of major thromboembolic events for each of the blood thinners, none of the blood thinners showed statistically significant reduction in occurrences of pulmonary embolism and deep venous thrombosis, suggesting equivocal effects among Heparin, Warfarin, Enoxaparin and Aspirin (Table 3).
Adjusted odds ratios for ICU mortality, overall hospital mortality, platelets transfusion events and delta SOFAs at day 4, 7 & 10
The main objective of this study is ICU-stay related outcomes (e.g. mortality), hence, confounders for mortality were adjusted (Results, section Confounders adjusted outcomes, Table 4). The occurrence of thromboembolic episodes, such as PE and DVT, had insufficient case rates in the study population so they were not included as secondary objectives. The confounders used in the study were adopted from a publication on ICU mortality [12]. The analysis was adjusted for confounders age, gender, malignancy, smoking, chronic alcoholism, SOFA score at admission, night shift admissions, night shift deaths, weekend admission and weekend deaths (Table 4) [12]. Except Aspirin, all thromboprophylactic agents showed statistically significant reduction on ICU mortality (Table 4). Heparin, Warfarin and Enoxaparin had adjusted Odds ratios of 0.59(p < 0.01, 0.47–0.77), 0.23(p < 0.05, 0.1–0.57) and 0.36(P < 0.05, 0.16–0.83) for ICU mortality (Table 4). Heparin, Warfarin and Enoxaparin had adjusted Odds ratios of 0.51(p < 0.01, 0.38–0.68), 0.19(p < 0.01, 0.06–0.59) and 0.42(P = 0.06, 0.17–1.05) for overall ventilated patient hospital mortality, including after transfers to the inpatient ward. Only Heparin (P < 0.05, OR 1.52(1.07–2.15)) was associated with serious thrombocytopenia episodes, which required platelets transfusion (Table 4). Only Heparin had mild effect on improvement in sequential organ failure assessment (delta SOFA) scores at 7 and 10 day after ICU admission (P < 0.05, OR 1.17 (1.03–1.32) (Table 4).