In this single centre, observational cohort study of 106 ICU patients with sepsis we demonstrated that analysis of the RVOT Doppler waveform and RV-PA coupling is feasible and holds interesting clinical hypotheses. Increased PVR and RV-PA uncoupling were present in a significant proportion of patients. There was a trend towards increased ICU and hospital mortality in those with non-invasive surrogates of increased PVR: PAATc and PAATc/PASP. This is in keeping with previous small studies that have demonstrated raised PVR is associated with increased mortality in sepsis (20,21). Vieillard Baron et al. have shown TAPSE does not discriminate RV failure in patients with sepsis(22). Zhang et al. found markers of RV systolic function fail to prognosticate in ARDS(23). RVD defined by reduced TAPSE or subjective assessment was not associated with increased mortality in our study and are supportive of these findings. Those with RV-PA uncoupling defined by TAPSE/PASP < 0.4mm/mmHg had a higher hospital mortality and were significantly more likely to have raised PVR. This is in keeping with studies in the non-critically ill (24). Our findings suggest increased PVR with RV-PA uncoupling is perhaps more prognostically significant than RVD assessed by TAPSE or subjective assessment in sepsis.
The incidence of RVD varied in this study depending on the definition used. This highlights issues that currently exist with heterogeneity and poorly defined diagnostic categories of RVD (25). A standardised assessment for RV studies as described by Huang et al. in the PRICES expert statement could help mitigate such issues in future prospective studies(26). Invasive measures of RV-PA uncoupling (pressure- volume loop-derived end-systolic elastance (Ees)/end-systolic to arterial elastances (Ea)) using right heart catheterisation (RHC) is considered gold standard. Solda et al. have shown that a TAPSE/PASP ratio of \(<\) 0.31mm/mmHg correlates with invasive Ees/Ea (17). TAPSE provides an estimate of RV contractility and PASP an estimate of RV afterload. When the RV fails to augment contractility with increased afterload RV dilation occurs via heterometric adaptation (27). Others have found cut off values of < 0.36 mm/mmHg to correlate with mortality and PVR in heart failure (28). A TAPSE/PASP < 0.635mm/mmHg was associated with increased mortality in COVID 19 ARDS(11). Lower Tricuspid annular systolic velocity/right ventricular systolic pressure (TASV/RVSP) ratios were associated with increased mortality in a large retrospective data set of 4259 patients in cardiac intensive care(10). Animal models have shown RV-PA uncoupling occurs as sepsis severity increases (29). Our study has shown RV-PA coupling is common in patients admitted to ICU with sepsis. A third of patients had a TAPSE/PASP cut off of < 0.4mm/mmHg that revealed an AUC of 0.7 for both ICU and hospital mortality. To our knowledge there are no prospective studies evaluating RV-PA coupling in sepsis.
RV-PA coupling may have a role in helping define RVD phenotypes and the therapeutic significance of RV-PA uncoupling in sepsis requires further investigation. It may be important to differentiate RVD subgroups into those with preserved and uncoupled RV-PA interaction as treatment strategies may vary. For example, in those with RV-PA uncoupling the use of pulmonary vasodilators could be of benefit to lower PVR and improve RV performance. Overall, the findings suggest that moving from an isolated RV assessment to evaluation that incorporates the inextricable linkage to the pulmonary vasculature could have greater prognostic utility. This hypothesis is of interest to inform future prospective study design.
Various cut off values of PAAT ranging from 90msec to 105msec to detect raised PVR and/or PH have been described in the non-critically ill (30). Tossavavinen et al. showed a PAAT less than 90msec had superior accuracy (83%) to other non-invasive measures in identifying patients with raised PVR of > 3 WU when compared to the gold standard right heart catheterisation (RHC). In our study, PAATc values of < 73msec were significantly associated with increased ICU and hospital mortality. The PAATc/PASP ratio has correlated with PVR (r = − 0.67, p 0.001) in previous studies, and a cut off PAATc/ PASP of < 2 had a positive and negative predictive value of 83% and 79% respectively to predicting PVR > 3WU in this study(14). In our study, lower PAATc/PASP ratios were associated with increased ICU and hospital mortality. A cut off value of < 1.1 revealed an AUC of 0.9. Although challenging, further validation studies using TTE measured PAAT, PASP, TAPSE/PASP and RV function against invasively measured PVR, PASP and RV ejection fraction with fast response PA catheters could be useful to further inform use of these parameters in our cohort.
TRVmax to estimate pulmonary pressures was unavailable in 24 (23%) patients where RVOT Doppler flow measurement of PAAT was available. This is an important finding in our patient group as a significant proportion of patients with pulmonary vascular dysfunction can be missed if pulmonary pressures are relied upon in isolation (15,31). Yared et al.(32) found a strong inverse correlation (r-0.95) between TTE measured PAAT and 4x TRVmax2 in the non-critically ill. In contrast, a weak-moderate inverse correlation was found in our study. These conflicting results may be accounted for by the vastly different patient populations studied. Critically ill patients have varying degrees of RVD, tricuspid regurgitation and often inadequate spectral Doppler traces, all of which may affect values of TRVmax for calculation of PASP. Further studies evaluating TTE PAAT measurement against TTE derived PASP taking into account the caveats mentioned could inform the lack of strong correlation in the critically ill.
In the presence of increased PVR, reflected waves propagate more rapidly, with less attenuation, arriving at the RVOT during systole and causing systolic notching (Fig. 1). Systolic notching can be categorised mid systolic (MSN) or late systolic notching (LSN). The presence of a pulmonary MSN is more likely to represent increased pulmonary vascular resistance and poor vascular compliance. Those with a MSN pattern have the most severe pulmonary vascular disease and worst RV function in some studies (16). Takathama et al. found signal notching, shortening of the mid-systolic deceleration time, and diminution of the late systolic flow velocity confer a higher mortality risk in those with PH(33). In our study, 14% of patients had evidence of RVOT flow notching, and this was mostly MSN, suggesting significantly raised PVR. Interestingly, in those with severe RVD by subjective assessment did not have notching, whereas those with RV-PA uncoupling were significantly more likely. Further prospective study of RVOT notching patterns in those with preserved RV-PA coupling versus RV-PA uncoupling in sepsis would be of interest, particularly with dedicated imaging optimisation for assessment of the RVOT Doppler profile.
Left heart dysfunction is common in sepsis(34) and those with PH secondary to left heart failure (isolated postcapillary PH) have normal PVR (below 3 WU) and raised LAP. It is unknown what haemodynamic subgroups of PH are more common in sepsis. We evaluated for raised LAP using a simplified approach previously reported by Brault et al. (19), where an E/A ratio > 1.5 in those with reduced EF of \(\le 45\%\) predicted raised LAP when correlated with pulmonary artery occlusion pressure. In those with ‘raised LAP’ the PAAT was not significantly shorter. This is hypothesis generating to suggest raised PVR in sepsis could have a significant pre-capillary component.