Indirect CT venography of the lower extremities: impact of scan delay and patient factors on contrast enhancement and examination quality

The study was approved by the Regional Committee for medical and health research ethics of South-Eastern Norway and Akershus University Hospital data protection officer. Written informed consent was obtained from all patients. The study was not registered at clinicaltrials.​gov.

Between 2017 and 2020, patients with clinical suspicion of DVT and clinical mimics of DVT were prospectively enrolled in this study. Exclusion criteria were age < 18 years, pregnancy, previous allergic reaction to CM and renal impairment. A flowchart of patients eligible for indirect lower limb CTV during the study period and the % excluded with the reason of exclusion is shown in Fig. 1.

Descriptive statistics are reported using mean (SD) or number (%), as appropriate. The time-density curves for the popliteal veins were illustrated using a boxplot (median, 25% and 75% percentiles).

Objective evaluation of popliteal CE was performed by estimating the proportion of examinations exceeding predefined cut-offs of 70, 80, 90 and 100 HU at scan delays between 90 and 210 s. For standardisation, only patients with a complete set of measurements at scan delays between 90 and 210 s were included.

Differences between scan delays in proportions exceeding the cut-offs were tested with a logistic mixed model trained on binary endpoints with patient identity as a random effect and time as a fixed effect. The binary endpoint was whether the popliteal CE exceeded the given threshold.

We also estimated the peak CE defined as the highest attenuation value for each patient, and the TPCE defined as the scan delay at which the highest attenuation was achieved.

The subjective rating of examination quality according to scan delay was reported as the percentage of adequate examinations between 90 and 210 s. The inter-rater agreement (%) and Cohen’s kappa score were estimated [31]. The strength of agreement was rated as poor, slight, fair, moderate, substantial or almost perfect according to the Kappa statistic scores < 0.00, 0.00–0.20, 0.21–0.40, 0.41–0.60, 0.61–0.80 and 0.81–1.00 respectively [32]. Differences between scan delays in the proportions of adequate examinations were tested with a logistic mixed model trained on the subjective ratings by the raters, using patient and rater identity as random effects and time as a fixed effect.

A Bayesian mixed-effects non-linear spline regression model was used to model the variation of CE and subjective rating of examination quality with time [33]. We used fixed effects in the form of an I-spline basis of degree three and knots at 90 s and 150 s, and random effects of a constant and linear term for each individual and a constant term for rater identity for subjective ratings [34]. The I-spline fixed effects provide a basis for six monotonic functions that can capture the global non-linearity in the relationship between the outcome variable and time, while the random effects allow for variation in scale between individuals and raters. The I-spline basis is shown in Fig. 3a. A Gaussian likelihood was used for the CE measurements and a logistic likelihood for the binary subjective ratings.

The trained mixed-effects spline model allows for estimation of the time at which the latent variables underlying the models reach a plateau: for the Gaussian likelihood, this can be interpreted as a smoothed value of the contrast enhancement, while for the logistic likelihood the latent variable can be interpreted as the log odds ratio of the rating being judged acceptable.

For both CE and subjective rating, we defined the plateau threshold as the maximum of the model latent variable mean across scan delays minus half the predicted standard deviation, with the prediction including all fixed and random effects. The time until the plateau was reached was defined as the minimum time point at which the predicted mean value is greater than the plateau threshold.

A linear mixed-effects model was used to evaluate associations between patient factors and the TPCE. A significance level of 0.05 was chosen for the analysis.

Patients with missing data on heart rate (6%), systolic blood pressure (8%) or CO (6%) were excluded from the analyses of baseline characteristics and predictors of TPCE.

Patients with missing attenuation measurements (19%) (due to thrombus at one or both sides (n = 3) or missing image acquisitions at any scan delay (n = 7)) were excluded from the cut-off analyses to archive a complete set of data for comparison.

Statistical analyses were performed with R version 4.1.0 (R Foundation for Statistical Computing) using the libraries brms and lme4, or Stata version 15.1 (StataCorp) [35].

The CE increased with increasing scan delay after CM injection and reached a plateau from 120 to 210 s (Fig. 2).

The mixed-effects model using the I-spline basis was fitted successfully, with the basis shown in Fig. 3a and CE model predictions in Fig. 3b. For the CE models, the plateau was reached between scan delays of 90 s and 120 s (at 97 s). At this point, the median predicted plateau height was 122 HU, with first and third quartiles of 115 HU and 132 HU, incorporating the variation between individuals and epistemic uncertainty.

The percentages of examinations achieving enhancement above cut-offs across all thresholds from 70 to 100 HU were significantly higher at 90 s compared to 60 s and at 120 s compared to 90 s. After 120 s, there were no statistically significant differences across scan delays for any thresholds (Table 2). From this, we might reasonably claim that a plateau is reached somewhere between 90 and 120 s.

Mean TPCE was 157 s (SD 45), and mean peak CE was 157 HU (SD 36). In the linear mixed-effects model including both popliteal veins, no patient factors showed a significant effect on TPCE (Table 3).

The mixed-effects model using the I-spline basis was fitted successfully, with the spline basis shown in Fig. 3a and subjective rating model log odds ratio predictions in Fig. 3c.

The model showed that the subjective examination quality reached a plateau between scan delays of 90 and 120 s (at 105 s).

The percentage of examinations rated as acceptable was significantly higher at 120 s compared to 90 s. After 120 s, there were no statistically significant differences across scan delays (Table 4).

The inter-observer agreement was consistently above 80% with one exception for scan delays between 90 and 210 s (Table 4). The kappa was substantial (0.67) at 90 s scan delay, but poor-slight (between −0.52 and 0.35) at scan delays between 120 and 210 s.

Our time-density curves showed that CE increased with time until a plateau was reached from 120 to 210 s after CM injection, which corresponds with the findings of Szapiro et al [16]. The CE variation between 120 and 210 s was small and I-spline modelling indicated that this variation of CE was within the range of noise and that a peak CE could not be identified within the plateau.

According to previous studies, CE above 70 HU in the popliteal veins is sufficient to distinguish a thrombus from surrounding CE and soft tissues, since most thrombi are below 70 HU [16, 22‐25]. Hence, 70 HU, 80 HU, 90 HU and 100 HU were chosen as cut-offs in our subgroup analyses. We found that the percentage of examinations achieving CE above cut-off was higher at 120 s compared to 90 s, but after 120 s, there were no differences across scan delays for any thresholds, which is consistent with the I-spline model.

In the linear mixed-effect model, no patient factors were associated with TPCE. Hence, we found no evidence to support tailoring scan delay to age, sex, body weight, systolic blood pressure, heart rate, CO or presence of DVT.

The results of the subjective rating of examination quality were consistent with the objective measurements. However, differences between raters suggest that other factors in addition to venous CE were addressed. The inter-observer agreement was consistently above 80% with one exception, but low kappa values between −0.52 and 0.35 were seen at scan delays 120 to 210 s. The kappa calculation is considered a more robust measure than just measuring the proportion of agreements since kappa adjusts for agreements occurring by chance. However, in this case, the proportions of inadequate examinations were low resulting in a high probability of agreement by chance. In cases like ours where the distribution of ratings between categories is highly skewed, the kappa may be paradoxically low even though %-agreement is high. In this situation, the expected agreement may be high, close to the observed agreement, explaining a low kappa [36, 37]. Furthermore, as the raters were not blinded to the scan delay, a rater with a preference for a specific scan delay may have biased the results.

The strength of the present study is that data was collected prospectively and it addresses an almost 20-year-old topic to a newer CT scanner technology. Both objective and subjective measurements of quality were analysed. In addition, data on patient factors were collected to analyse possible associations with TPCE to evaluate if a patient-tailored scan delay may be preferable to a fixed scan delay.

There are several limitations in our study. All our imaging data were acquired at the level of the proximal popliteal veins which may limit the validity of our results at the more proximal and distal anatomical levels. Also, we only included a limited number of patients that consented and that could be examined during daytime. Furthermore, patients with missing data on patient factors and missing imaging data were excluded from the analyses as part of standardization, making the sample size smaller. This weakened the statistical strength when analysing possible associations between patient factors and TPCE. Finally, the Nexfin device used to measure CO is non-invasive and has been reported to be a valid method compared to thermodilution, FloTrac/vigileo and echocardiography [29, 30, 38]. However, others have questioned the validity of the same device in certain groups of patients [39‐41]. The baseline values of heart rate and CO were relatively high for patients at rest in our study, which may be explained by the stress associated with the examination, but this might also be explained by measurement uncertainties related to the Nexfin. The strength of the Nexfin measurement lies in its ability to detect variations accurately, such as in follow up of patients, but may be less accurate as an absolute value measurement [42].

In conclusion, we found that no patient factors were associated with the TPCE in CTV and that a scan delay of 120–210 s yielded the best examination quality.