Abstract
OBJECTIVE:
We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter (CVC)-associated deep venous thrombosis (CADVT) in critically ill children.
DESIGN:
Post hoc analysis of a Bayesian phase 2b randomized clinical trial
SETTING:
7 pediatric intensive care units
PATIENTS:
Children <18 years old with newly inserted CVC
INTERVENTION:
Enoxaparin started <24 hours after insertion of CVC and adjusted to anti-Xa level of 0.2–0.5 IU/mL vs usual care
MEASUREMENTS AND MAIN RESULTS:
Of 51 children randomized, 24 were infants <1 year old. Risk ratios of CADVT with prophylaxis with enoxaparin were 0.98 (95% credible interval: 0.37, 2.44) in infants and 0.24 (95% credible interval: 0.04, 0.82) in older children ≥1 year old. Infants and older children achieved anti-Xa level ≥0.2 IU/mL at comparable times. While CVC was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% confidence interval: 8.78, 437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% confidence interval: 15.7%, 74.4%). Median minimum platelet count while CVC was in situ was higher in infants by 39 × 103/mm3 (interquartile range: 17, 61 × 103/mm3). CVC:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against CADVT at lower factor VIII activity and at higher platelet count.
CONCLUSION:
The relatively lesser contribution of thrombin generation on CVC-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.
CLINICALTRIALS.GOV IDENTIFIER:
Keywords: central venous catheter, deep venous thrombosis, infant, platelet, thrombin
INTRODUCTION
Pediatric venous thromboembolism (VTE), which is predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children (1). Critical illness and presence of central venous catheter (CVC) are the most important risk factors for VTE in children with each factor at least doubling the risk of DVT (2). Given that VTE is generally preventable in adults, national and hospital-based initiatives are being undertaken to reduce its incidence in children. Hospital-based initiatives recommend that pharmacologic prophylaxis be considered against CVC-associated DVT (CADVT) (3). Yet for children, the American College of Chest Physicians recommend against this practice while the American Society of Hematology did not address its prevention (4, 5). Recommendations are limited due to paucity of pediatric-specific evidence on the efficacy of pharmacologic prophylaxis against CADVT (6, 7).
We recently completed the Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Trial, a Bayesian phase 2b RCT, which was designed to obtain preliminary evidence on the efficacy of early prophylaxis against CADVT in critically ill children (8). Critically ill children with an untunneled CVC received prophylactic dose of enoxaparin adjusted to anti-Xa level of 0.2–0.5 IU/mL within 24 hours after insertion of the CVC or usual care. Randomization was stratified based on the age-dependent distribution of the risk of VTE in children (1). Compared with usual care, risk ratio of CADVT detected through surveillance ultrasonography with enoxaparin was 0.55 (95% credible interval, CrI: 0.24, 1.11) (8). We observed that the reduction in CADVT was limited to older children ≥1 year old with risk ratio of 0.24 (95% CrI: 0.04, 0.82) vs 0.98 (95% CrI: 0.37, 2.44) in infants <1 year old. In this post hoc analysis, we aimed to explore the age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children.
METHODS
Study Design and Oversight
The CRETE Trial was previously described (8). It was an open-label blinded endpoint Bayesian phase 2b RCT conducted in 7 pediatric intensive care units (ICU) in the United States from November 2017 to August 2019. Randomization to enoxaparin or usual care was 1:1 and stratified within ICU, then by age, i.e., <1 year, 1–13 years and >13 years (1). Yale Human Investigations Committee (HIC#1302011506) and local institutional review boards approved the CRETE Trial. Parental permission and assent, as appropriate, were obtained on enrollment.
Subjects
Children admitted to the pediatric ICU with <24 hours after insertion of an untunneled CVC in the internal jugular or femoral vein, with CVC required for ≥24 hours, >36 weeks corrected gestational age to <18 years old and with anticipated ICU stay ≥48 hours were enrolled (8). Excluded were those with coagulopathy, clinically relevant bleeding or at high risk of bleeding, on concomitant antithrombotic agent, DVT at site of insertion of the CVC in prior 6 weeks, allergy to heparin or history of heparin-induced thrombocytopenia.
Procedures
Children randomized to enoxaparin received the drug subcutaneously every 12 hours at 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for others (4). First dose was administered <24 hours after insertion of the CVC and targeted an anti-Xa level of 0.2–0.5 IU/mL. Anti-Xa level was measured locally 4–6 hours after every third dose until target was reached. Enoxaparin continued until end of study period, which was removal of CVC, or earlier upon discharge from ICU, radiologic diagnosis of CADVT, start of therapeutic anticoagulation or 28 days after insertion of CVC. Children randomized to usual care did not receive placebo. Blinded certified ultrasound technicians performed ultrasonography on the site of CVC within 24 hours of end of study. A committee of 3 pediatric radiologists blindly and independently diagnosed CADVT. For this post hoc analysis, the lead radiologist retrospectively measured in triplicate the diameter of the vein of insertion.
Blood was drawn from the CVC into citrated tubes (BD Vacutainer Plus Plastic Citrate Tubes, Becton and Dickinson Company, Franklin Lakes, NJ, USA) on the day of, day after and day 4 after insertion of the CVC, then processed locally for platelet poor plasma. Endogenous thrombin potential (ETP) was measured from plasma using Calibrated Automated Thrombogram (Thrombinoscope, Maastricht, the Netherlands) and 1 pM of tissue factor (PPP-Reagent LOW, Stago Diagnsotica, Parsippany, NJ, USA) per manufacturer’s protocol. Factor VIII activity and D-dimer level were measured using Siemens Factor VIII Chromogenic Assay and Stratus CS Acute Care DDMR Testpak (Siemens Healthcare Diagnostics Inc., Newark, DE), respectively.
Outcome Measures
Primary outcome was presence of CADVT, defined as DVT in the site of insertion of the CVC confirmed by ultrasonography. The committee of pediatric radiologists diagnosed CADVT if ≥2 of intravenous echogenic material adherent to the venous wall, non-compressibility of the vein or abnormal venous Doppler were present (9, 10). At least 2 concurring radiologists were needed to diagnose CADVT.
Statistical Considerations
Consistent with the primary analysis of the CRETE Trial, we used Bayesian inference to estimate the risk ratio of CADVT with prophylaxis with enoxaparin in infants <1 year old and older children ≥1 year old (8). We combined children 1–13 years old and >13 years old because the risks of CADVT in each trial arm were similar between age strata. We modeled the risk ratio of CADVT as log-binomial distribution with minimally informative prior, N(0, 100,000), on the log-risk ratio (11). Markov chain Monte Carlo methodology was used, with risk ratio presented as posterior median (equal tailed 95% CrI).
In the absence of pre-specified analyses and pertinent information, frequentist inference was used for the remaining analyses (12). Median times to first dose of enoxaparin and anti-Xa level ≥0.2 IU/mL among children randomized to enoxaparin were estimated using the Kaplan-Meier approach with log-rank test to determine statistical significance between infants and older children. We also compared between infants and older children severity of illness as expressed by Paediatric Index of Mortality 2, characteristics of the CVC, i.e., site of insertion, size and number of lumens, ratio (CVC:vein ratio) and difference (CVC:vein difference) in diameters of CVC and vein of insertion, and laboratory parameters, i.e., hemoglobin, international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelet count, ETP, factor VIII activity and D-dimer level (13). These variables were of interest because of potential effect on CVC-associated thrombus formation in critically ill children. Continuous variables were compared using Wilcoxon rank sum test, while categorical variables were compared using chi-squared or Fisher’s exact test, as appropriate. ETP, factor VIII activity and D-dimer level were compared using linear mixed effects model with sampling time entered as categorical variable and children as random intercepts. Variables were log-transformed as needed.
In separate models for each variable that was statistically different between infants and older children, the variable was interacted with trial arm using Poisson regression with robust error variance to model the risk of CADVT and to estimate risk ratios directly (14). Regression coefficient of the interaction term represented the additional change in log-risk ratio of CADVT due to prophylaxis with enoxaparin for every unit increase in the variable (15). Statistically significant interaction terms identified variables that modified the efficacy of prophylaxis with enoxaparin, i.e., efficacy of prophylaxis with enoxaparin differed depending on the level of the variable. The effect of infants vs older children was not included in the models because it was not statistically significant when added to the model.
Data was presented as count (percentage), median (interquartile range, IQR) and regression coefficient of interaction term (95% confidence interval, CI). P values <0.05 were considered statistically significant. Statistical analyses were conducted using Stata 16.1 (StataCorp, College Station, TX).
RESULTS
Subjects
The CRETE Trial randomized 51 children with 24 infants (Table). Median age was 4 months (IQR: 3, 8 months) for infants and 8.2 years (IQR: 3.5, 12.3 years) for older children. CADVT was determined in 47 children because ultrasonography was not performed in 2 infants and 2 older children randomized to enoxaparin mainly due to impending deaths (8). Among infants, 5 (50.0%) of 10 randomized to enoxaparin and 6 (50.0%) of 12 randomized to usual care developed CADVT for a risk ratio of 0.98 (95% CrI: 0.37, 2.44; Figure 1). Among older children, 2 (15.4%) of 13 randomized to enoxaparin and 7 (58.3%) of 12 randomized to usual care developed CADVT for a risk ratio of 0.24 (95% CrI: 0.04, 0.82).
Table.
Characteristics and laboratory parameters of critically ill children enrolled in the CRETE Trial.
| Characteristics | Infants (n=24) |
Older Children (n=27) |
P value |
|---|---|---|---|
| Enoxaparin arm | 12 (50.0) | 15 (55.6) | 0.69 |
| Age (in years) | 0.3 (0.2, 0.7) | 8.2 (3.5, 12.3) | <0.001 |
| Weight (in kg) | 6.4 (4.1, 8.1) | 23.5 (14.4, 55.3) | <0.001 |
| Height (in m) | 0.60 (0.52, 0.63) | 1.16 (0.93, 1.49) | <0.001 |
| Pediatric Index of Mortality 2 | 0.014 (0.005, 0.139) | 0.031 (0.010, 0.101) | 0.19 |
| Female sex | 13 (54.2) | 15 (55.6) | 0.92 |
| Race and ethnicity | 0.28 | ||
| Non-Hispanic white | 12 (50.0) | 19 (70.4) | |
| Non-Hispanic black | 6 (25.0) | 3 (11.1) | |
| Non-Hispanic mixed | 1 (4.2) | 0 (0.0) | |
| Hispanic | 5 (20.8) | 5 (18.5) | |
| Presence of cancer | 0 (0.0) | 1 (3.7) | 0.34 |
| Presence of infection | 12 (50.0) | 18 (66.7) | 0.23 |
| Presence of congenital heart disease | 3 (12.5) | 1 (3.7) | 0.24 |
| Presence of permanent immobility | 1 (4.2) | 4 (14.8) | 0.20 |
| Presence of recent surgery | 2 (8.3) | 0 (0.0) | 0.13 |
| Personal history of VTE | 0 (0.0) | 1 (3.7) | 0.34 |
| Number of lumens | 0.01 | ||
| 1 | 2 (8.3) | 0 (0.0) | |
| 2 | 16 (66.7) | 11 (40.7) | |
| 3 | 6 (25.0) | 16 (59.3) | |
| Size of CVC (in Fr) | <0.001 | ||
| 3 | 2 (8.3) | 0 (0.0) | |
| 4 | 17 (70.8) | 7 (25.9) | |
| 5 | 5 (20.8) | 15 (55.6) | |
| 7 | 0 (0.0) | 5 (18.5) | |
| Ratio of diameters of CVC and vein (in mm/mm) | 0.33 (0.27, 0.40) | 0.26 (0.23, 0.34) | 0.12 |
| Difference in diameters of CVC and vein (in mm) | 2.7 (1.9, 3.7) | 4.5 (3.0, 5.2) | 0.01 |
| Site of insertion of the CVC | 0.93 | ||
| Left femoral | 4 (16.7) | 4 (14.8) | |
| Right internal jugular | 14 (58.3) | 14 (51.9) | |
| Right femoral | 6 (25.0) | 9 (33.3) | |
| Hemoglobin (in g/dL) | |||
| On day of insertion of CVC | 9.4 (8.7, 10.9) | 10.4 (9.3, 11.9) | 0.07 |
| Minimum while CVC was in situ | 8.3 (7.6, 9.0) | 9.5 (8.4, 10.5) | <0.001 |
| Maximum while CVC was in situ | 10.7 (9.3, 12.0) | 11.9 (10.1, 13.3) | 0.02 |
| Platelet count (in 103/mm3) | |||
| On day of insertion of CVC | 285 (249, 350) | 222 (167, 291) | 0.04 |
| Minimum while CVC was in situ | 243 (178, 298) | 204 (109, 234) | 0.04 |
| Maximum while CVC was in situ | 348 (285, 423) | 255 (170, 380) | 0.07 |
| International normalized ratio | |||
| On day of insertion of CVC | 1.12 (1.05, 1.29) | 1.21 (1.13, 1.40) | 0.07 |
| Maximum while CVC was in situ | 1.10 (1.04, 1.29) | 1.21 (1.13, 1.40) | 0.053 |
| Activated partial thromboplastin time (in sec) | |||
| On day of insertion of CVC | 33.3 (31.5, 38.0) | 31.8 (27.7, 37.3) | 0.25 |
| Maximum while CVC was in situ | 33.3 (31.5, 37.0) | 33.8 (27.8, 37.7) | 0.85 |
| Endogenous thrombin potential (in Nm.min) | 0.04 | ||
| On day of insertion of CVC | 800.22 (282.05, 1086.09) | 1049.41 (919.70, 1455.05) | |
| On day after insertion of CVC | 746.00 (478.30, 935.54) | 1013.33 (657.37, 1314.90) | |
| On day 4 after insertion of CVC | 835.90 (0.00, 1211.68) | 1011.03 (231.25, 1229.33) | |
| Factor VIII activity (in %) | 0.003 | ||
| On day of insertion of CVC | 103.6 (70.2, 161.0) | 134.4 (108.5, 188.3) | |
| On day after insertion of CVC | 104.2 (78.4, 166.5) | 136.8 (116.0, 193.9) | |
| On day 4 after insertion of CVC | 88.0 (69.5, 156.5) | 169.9 (126.4, 235.9) | |
| D-dimer level (in mg/L) | 0.25 | ||
| On day of insertion of CVC | 1.44 (0.69, 4.39) | 2.38 (1.40, 4.10) | |
| On day after insertion of CVC | 1.48 (0.72, 2.75) | 1.63 (1.12, 3.14) | |
| On day 4 after insertion of CVC | 1.55 (1.06, 3.30) | 1.68 (1.02, 4.88) |
CVC – central venous catheter. Data is presented as count (percentage) or median (interquartile range).
Figure 1.
Posterior distributions of the risk ratio of central venous catheter-associated deep venous thrombosis (CADVT) with prophylaxis with enoxaparin in critically ill infants and older children. The vertical line represents the posterior median of the probability distribution of the risk ratio. CrI – credible interval.
First dose of enoxaparin was administered at comparable times in infants (median: 21.0 hours after insertion of the CVC; IQR: 13.5, 23.5 hours) and older children (median: 21.1 hours; IQR: 15.3, 23.4 hours; p=0.68; Figure 2). Time to anti-Xa level ≥0.2 IU/mL was also comparable between infants (median: 52.5 hours after insertion of the CVC; IQR: 51.3, 88.3 hours) and older children (median: 48.0 hours; IQR: 40.1, 88.6 hours; p=0.32).
Figure 2.
Kaplan-Meier curves of the probabilities of receiving enoxaparin (A) and achieving anti-Xa level ≥0.2 IU/mL (B) between critically ill infants and older children.
Variables that Differentiated Infants from Older Children
Infants had proportionately more double and fewer triple lumen CVC than older children (Table). Median CVC:vein ratio was not statistically different although it was numerically larger in infants. Median CVC:vein difference was smaller in infants (2.7 mm; IQR: 1.9, 3.7 mm) than in older children (4.5 mm; IQR: 3.0, 5.2 mm). Median hemoglobin on day of insertion of the CVC and minimum and maximum hemoglobin while CVC was in situ were lower in infants by 1.1 g/dL (IQR: 0.6, 1.5 g/dL), 1.3 g/dL (IQR: 1.0, 1.5 g/dL) and 1.2 g/dL (IQR: 0.6, 1.8 g/dL), respectively. Corresponding parameters for platelet count were higher in infants by 63 × 103/mm3 (IQR: 41, 85 × 103/mm3), 39 × 103/mm3 (IQR: 17, 61 × 103/mm3) and 93 × 103/mm3 (IQR: 58, 128 × 103/mm3), respectively. ETP was lower in infants by 223.21 nM.min (95% CI: 8.78, 437.64 nM.min) and factor VIII activity by 45.1% (95% confidence interval: 15.7%, 74.4%; Figure 3). D-dimer levels were numerically lower in infants.
Figure 3.
Endogenous thrombin potential (ETP; A), factor VIII activity (B) and D-dimer level (C) across different sampling times in critically ill infants and older children.
Variables that Modified the Efficacy of Prophylaxis with Enoxaparin
In these analyses, higher risk ratios of CADVT with prophylaxis with enoxaparin, i.e., risk ratios that approached 1, indicated minimal reductions in risk of CADVT with prophylaxis with enoxaparin and less efficacy. Conversely, lower risk ratios, i.e., risk ratios that approached 0, indicated significant reductions in risk of CADVT with prophylaxis with enoxaparin and greater efficacy. Higher platelet count on day of insertion of the CVC (regression coefficient per 103/mm3 increase: 0.007; 95% CI: 0.002, 0.01) and higher minimum platelet count while CVC was in situ (regression coefficient per 103/mm3 increase: 0.007; 95% CI: 0.002, 0.01) were associated with higher risk ratios of CADVT (Figure 4 and Supplemental Table). Similar, though not statistically significant, association was observed for maximum platelet count (regression coefficient per 103/mm3 increase: 0.003; 95% CI: −0.0007, 0.007; p=0.11). These indicated that, in general, prophylaxis with enoxaparin was less efficacious in reducing the risk of CADVT when platelet count was high. Lower factor VIII activity while CVC was in situ was associated with higher risk ratio of CADVT (regression coefficient per 1% increase: −0.01; 95% CI: −0.02, −0.002). This indicated that prophylaxis with enoxaparin was less efficacious in reducing the risk of CADVT when factor VIII activity was low. Smaller CVC:vein difference was marginally associated with higher risk ratio of CADVT (regression coefficient per 10% increase: −0.10; 95% CI: −0.21, 0.01; p=0.07). ETP and hemoglobin did not modify the risk ratio of CADVT.
Figure 4.
Effect of factor VIII activity (A) and platelet count (B and C) on the risk ratio of CVC-associated DVT (CADVT) with prophylaxis with enoxaparin. Higher risk ratios of CADVT with prophylaxis with enoxaparin, i.e., risk ratios that approached 1, indicated minimal reductions in the risk of CADVT with prophylaxis with enoxaparin and less efficacy. Conversely, lower risk ratios, i.e., risk ratios that approached 0, indicated significant reductions in the risk of CADVT with prophylaxis with enoxaparin and greater efficacy.
DISCUSSION
In this post hoc analysis of a Bayesian phase 2b RCT, we showed that the risk of CADVT without prophylaxis was comparable between critically ill infants and older children. However, the risk ratio of CADVT with prophylaxis with enoxaparin was 0.98 in infants and 0.24 in older children despite initiating enoxaparin and achieving anti-Xa level ≥0.2 IU/mL at comparable times. Infants had lower factor VIII activity and ETP, but higher platelet count, than older children. Among all children, lower factor VIII activity and higher platelet count, in general, were associated with less efficacy of prophylaxis with enoxaparin against CADVT. Our findings provide insights into the age-dependent differences in the mechanism of CVC-associated thrombus formation in critically ill children. It should be emphasized that our analyses were not pre-specified, had small sample size and were primarily meant to generate hypotheses (16).
Artificial surface thrombosis, e.g., CADVT, is a complex interplay of protein adsorption, cell adhesion, activation of the contact system, thrombin generation and complement activation (17). We were able to evaluate thrombin generation, platelets and red blood cells. Given the comparable risks of CADVT between infants and older children without enoxaparin, we assumed that the summative effects of these mechanisms were comparable. However, we hypothesize that their relative contributions were different, potentially explaining the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against CADVT.
Our findings suggest that in infants, thrombin generation contributes relatively less to CVC-associated thrombus formation than in older children. Factor VIII, together with factor IX, amplifies the activation of factor X, which is essential to thrombin generation, and is, thus, a driver of thrombin generation (18). ETP measures thrombin generation over time (19). The lower factor VIII activity and ETP in infants than in older children does not seem to reflect normative values. Factor VIII activity does not change with age in healthy children (20). Similarly, healthy infants and older children have comparable ETP with the method we used (21). The difference may reflect the immaturity of the hemostatic system’s inflammatory response at younger ages (22, 23). For example, in severe sepsis, infants had lower levels of pro-coagulant factors than older children (22). The difference in ETP may also reflect the greater effect of alpha-2-macroglobulin, an acute phase reactant, on inhibition of thrombin generation in infants (21, 24). Infants having numerically lower D-dimer levels, a marker of thrombin generation, also support less thrombin generation in infants (25). Platelets seem to contribute relatively more to thrombus formation in infants. Age-dependent serum levels of thrombopoietin may explain the higher incidence of reactive thrombocytosis in infants (26).
The modifying effects of factor VIII activity and platelet count on the efficacy of prophylaxis with enoxaparin further support our hypothesis. Prophylaxis with enoxaparin was less efficacious against CADVT when factor VIII activity was low. This likely reflected the inhibitory action of enoxaparin on thrombin generation (4, 19). Lower factor VIII activity, e.g., in infants, suggested less thrombin generation for enoxaparin to inhibit and less efficacy against CADVT. Unlike factor VIII activity, enoxaparin reduces ETP (27, 28). Therefore, we anticipated that prophylaxis with enoxaparin would be more efficacious against CADVT at lower levels of ETP to reflect the effect of enoxaparin on ETP. We did not find this association. The reduction in ETP in infants may have been insufficient to demonstrate the modifying effect of ETP. Prophylaxis with enoxaparin was, in general, less efficacious against CADVT when platelet count was high, e.g., in infants. The contribution of platelets on thrombus formation may have been accentuated with reduction in thrombin generation with enoxaparin. In critically injured adults, normalization of clotting time with enoxaparin increased maximum clot strength, which was correlated with platelet count (29, 30). Hemoglobin did not modify the efficacy of prophylaxis with enoxaparin. It was not sufficiently abnormal to affect blood viscosity (31).
Safety initiatives recommend limiting CVC:vein ratio to reduce the risk of CADVT (32). Although numerically larger in infants, we did not find the ratio to be statistically different from older children. However, we found CVC:vein difference to be significantly smaller in infants. We also found a marginally significant modifying effect of this difference on the efficacy of prophylaxis with enoxaparin. More severe venous occlusion in infants could have led to increased formation of large von Willebrand multimers from shear stress resulting in greater platelet activation and limited efficacy of enoxaparin (33). If validated, recommendations should perhaps limit the CVC:vein difference rather than the ratio.
Our findings have implications on potential strategies to reduce the risk of CADVT in critically ill infants. To compensate for the relatively lesser contribution of thrombin generation in infants, we hypothesize that therapeutic dose of enoxaparin with target anti-Xa level >0.5–1.0 IU/mL is necessary to reduce their risk of CADVT (34). Therapeutic dose should provide greater reduction in thrombin generation than prophylactic dose. But it should be balanced with the risk of bleeding. In the CRETE Trial, an infant randomized to enoxaparin had a clinically relevant bleed (8). In an observational study of hospitalized children with risk of CADVT seemingly lower with therapeutic than prophylactic dose, risk of bleeding was similar between doses (35). Alternatively, to address the relatively greater contribution of platelets in infants, anti-platelet therapy may be efficacious against CADVT in critically ill infants (17). Aspirin is used in children with palliated congenital heart disease to prevent VTE (36). Unlike other types of CVC, limiting the size of the untunneled CVC may not be feasible. This type is typically inserted for resuscitation when the largest CVC and with the greatest number of lumens is preferred.
Our post hoc analysis has limitations. Sample size was small, which resulted in uncertainty in our findings and potentially missed associations. The amount of plasma limited the biomarkers we measured. Our simplistic model of CVC-associated thrombus formation did not account for protein adsorption, activation of the contact system and complement activation. Analysis of platelets was limited to platelet count. Platelet function should be studied. There are no accurate methods to ascertain the number of venous punctures during insertion of CVC. We assumed that multiple attempts were uncommon because of common use of ultrasonography (32). Lastly, difficulties in measuring the vein may have led to measurement errors.
CONCLUSIONS
In this post hoc analysis of a Bayesian phase 2b RCT of early prophylaxis against CADVT in critically ill children, we showed that the reduction in risk of CADVT with prophylaxis with enoxaparin was limited to older children despite initiating enoxaparin and achieving anti-Xa level ≥0.2 IU/mL at comparable times. Our findings suggest that the relatively lesser contribution of thrombin generation on CVC-associated thrombus formation in infants, compared with older children, potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin. Consequently, therapeutic dose of enoxaparin may be needed to reduce the risk of CADVT in critically ill infants. These hypotheses should be tested in adequately powered studies.
Supplementary Material
FUNDING INFORMATION:
EVSF and PCS received funding from the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development to conduct the trial (R21HD089131). EVSF received funding from the American Heart Association to conduct the trial (16RNT31180018). VS received funding through the Clinical and Translational Science Award (CTSA) Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research.
Footnotes
CONFLICT OF INTEREST: EVSF and PCS received funding to conduct the CRETE Trial. The rest of the authors have no real or perceived conflict of interest.
Copyright form disclosure: Dr. Faustino’s institution received funding from National Institutes of Health (NIH and the American Heart Association. Drs. Faustino, Hanson, Pinto, Shabanova, and McPartland received support for article research from the NIH. Drs. Faustino, Raffini, Hanson, Kandil, McPartland, and Spinella disclosed off-label product use of enoxaparin (IND approval from the FDA was received). Dr. Raffini received funding from Bayer, Genetech, Xa-Tek, and HemaBiologics. Dr. Hanson’s institution received funding from the NIH. Dr. Kandil received funding from Children’s Hospital Collaborative, Improving Pediatric Sepsis Outcomes. Dr. Shabanova’s institution received funding from Prevention of Central Venous Catheter-Associated Thrombosis in Critically Ill Children NICHD: R21HD089131. The remaining authors have disclosed that they do not have any potential conflicts of interest.
ARTICLE TWEET: The relatively lesser contribution of thrombin generation on catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.
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