journal clum

1. Diuretics Versus Volume Expansion
in the Initial Management of Acute
Intermediate High‐Risk Pulmonary
Embolism
Ferrari E. Lung (2022); DOI:10.1007/s00408-022-00530-5

2. Clinical Question
● In adult patients with acute pulmonary embolism and right heart strain does a
strategy of volume expansion or early diuretic therapy result in a more rapid
resolution of troponin levels?

3. Background
● Acute pulmonary embolism (PE) is a common cause for hospital presentation
● Right heart strain is associated with an increased mortality in patient’s with PE
● Current ESC 2019 guidelines recommend consideration of ‘cautious fluid loading’
if CVP low
● Right ventricular (RV) dilatation may result in compression of the left ventricle and
further compromise cardiac output
● This may be ameliorated by diuretic therapy

4. Methods
● Multi-centre, unblinded parallel group randomised controlled trial (two hospitals in Cannes and Nice,
France, 2016 to 2019)
● 1:1 randomisation but remainder of randomization strategy not documented
● Written informed consent
● No information regarding allocation concealment
● Study powered to 90% to demonstrate ‘superiority of diuretics’ in the normalisation of troponin at 72
hours
○ 44 patient required, but to offset any study exits 60 recruited
○ No mention of anticipated effect sizes
● TTE performed at admission, 4 hours post treatment and then daily until normalisation or post ICU
discharge
○ All TTEs were checked by two blinded readers
● Troponin and BNP were measure on admission, then every 12 hours until normalization
● Maximum time delay from definitive diagnosis to randomization was 2 hours, and maximum time
from randomization to treatment was 1 hour
● All patients followed for at least 30 days

5. Population
● Inclusion: Patient presenting with acute pulmonary embolism confirmed on CT and all of:
○ RV Dilatation (measured by RV:LV ratio > 0.9 in apical view or >0.7 in parasternal long axis)
○ RV dysfunction tricuspid annular plane systolic excursion (TAPSE) < 16mm and RV lateral wall
velocity (RV S’) < 10mm/s
○ Troponin (Tn) 70ng/L and B-type natriuretic peptide (BNP) > 100 pg/mL
● Exclusion:
○ Cardiogenic shock
○ Need for thrombolysis
○ Need for catecholamine infusion
○ Cardiopulmonary resuscitation on admission.
○ Severe chronic renal disease (GFR , 30ml/min)
○ An IVC diameter < 21mm
○ Already received fluid or diuretic therapy in the prior 24 hours
○ Chronic diuretic use
● 181 patients assessed for eligibility
○ 121 excluded
■ Not meeting inclusion criteria (n=120)
■ Declined consent (n=1)
○ 60 randomized
■ 30 volume expansion
■ 30 diuretic therapy

6. Population
● Comparing baseline characteristics of intervention vs. control group
○ Very similar between the two groups (volume expansion vs diuretic therapy):
■ Median age: 75 vs 71
■ Male: 17% vs 20%
■ Baseline Vital Signs
■ Median SBP (mmHg): 138 vs 132
■ Median HR: 94 vs 91
■ SpO2: 95% vs 95%
■ Oxygen Rate: 3L/min v 3L/min
■ Biomarkers
■ Creatinine (μmol/L): 92 vs 89
■ Troponin (ng/mL): 456 vs 620
■ BNP (pg/mL): 384 vs 407
■ ECHO Parameters
■ RV:LV ratio on 4 chamber view: 1.15 vs 1.1
■ TAPSE (mm): 14 vs 13
■ RV S’ (mm/s): 9 vs 8
■ Systolic pulmonary artery pressure (mmHg) 54 vs 58

7. Intervention
● Volume expansion:
○ 500ml Saline infusion over 4 hours
○ Followed by a further 1000ml over 24 hours
● Diuretic therapy:
○ IV Furosemide bolus 40mg
○ Further 40mg bolus after four hours in urine output < 500ml in that time
period
Management common to both groups
● Immediate therapeutic anticoagulation
● Thrombolysis if indicated by hypotension of cardiogenic shock

8. Outcome
● Primary outcome:
○ No difference in time to normalization of Troponin concentrations (< 70 ng/L). 72 vs 76
hours (p = 0.74)
● Secondary outcomes:
○ Biomarkers
■ Longer time to normalization of BNP in volume expansion group 108 vs 56
hours (p = 0.05)
■ Time to 50% reduction in BNP shorter in diuretic group and greater proportion
(47% vs 13%) of participants in diuretic group had reduction in BNP at hour 12
○ ECHO Features
■ Significantly greater reduction in systolic pulmonary artery pressure at 4 hours
in diuretic group: 0 vs -7mmHg (p = 0.006)
■ This was not significant at 24 or 48 hours
■ Significantly greater reduction in IVC diameter at 4 hours: 0 vs -3 mm (p=
0.008)
■ This was not significant at 24 or 48 hours
■ No significant difference in any of the following parameters at 4, 24 or 48
hours:
■ TAPSE
■ RV S’

9. Authors’ Conclusions
● A single intravenous bolus of 40 mg furosemide was well-tolerated
● Compared with volume expansion, intravenous diuretic therapy modifies neither
Tn kinetics nor RV echocardiographic parameters but accelerates BNP
normalization, and reduction in sPAP and IVC diameter significantly
● These findings, which need to be confirmed in trials with clinical end points, may
translate to a rapid improvement in RV function using one-shot diuretic

10. Strengths
● Well designed phase 2 trial
● Addresses a challenging clinical question in which there is little guidance
● Detailed ECHO and biomarker data obtained
● No loss to follow up
● Good separation between groups with respect to urine output

11. Weaknesses
● Limited methodology provided in the manuscript makes assessing internal validity
hard
● This was a Phase 2 trial that can only be hypothesis generating and further
studies would be required prior to implementation in clinical practice
● Although the use of troponin or BNP at presentation has been used to risk stratify
patients, it may not follow that normalisation of these biomarkers equates to
improved prognosis
● The conclusion that RV function may be improved by the administration of
diuretics is not directly supported by the trial data
● There was no measurement of cardiac output which may have been informative

12. Final thoughts
● When performing ECHO routinely on patients with PE, right ventricular dysfunction is
present in a high proportion (33% in this study)
● Diuretics will likely reduce right atrial pressure and pulmonary artery pressure when
given to these patients but it is not clear this will change outcomes
● We will continue to aim to provide a tailored approach to maintain cardiac output in
patients with PE – this may include modifying pre-load with fluid or diuretics,
contractility with inodilators, and afterload with vasodilators and anticoagulants

13. References
Ferrari, E., Sartre, B., Labbaoui, M. et al. Diuretics Versus Volume Expansion in the Initial
Management of Acute Intermediate High-Risk Pulmonary Embolism. Lung 200, 179–
185 (2022). https://doi.org/10.1007/s00408-022-00530-5

14. Thank you