Ferrari
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
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?
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
Design
- Multi-centre, unblinded parallel group randomised controlled trial
- 1:1 randomisation but remainder of randomisation 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 normalisation
- Maximum time delay from definitive diagnosis to randomisation was 2 hours, and maximum time from randomisation to treatment was 1 hour
- All patients followed for at least 30 days
- Registered on clinical trials.gov (NCT02531581)
Setting
- Multi-centre study but number of centres not reported
- The authors were from two hospitals in Cannes and Nice
- January 2016 – December 2019
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 randomised
- 30 volume expansion
- 30 diuretic therapy
- 121 excluded
- 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
- Very similar between the two groups (volume expansion vs diuretic therapy):
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
Outcome
- Primary outcome:
- No difference in time to normalisation of Troponin concentrations (< 70 ng/L). 72 vs 76 hours (p = 0.74)
- Secondary outcomes:
- Biomarkers
- Longer time to normalisation 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’
- Significantly greater reduction in systolic pulmonary artery pressure at 4 hours in diuretic group: 0 vs -7mmHg (p = 0.006)
- Biomarkers
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
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
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
The Bottom Line
- 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
- I 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
External Links
- Article: Diuretics vs Volume Expansion
- Further Reading: 2019 ESC Guidelines
- Related Reading: TBL PE Summaries
Metadata
Summary author: Alastair Brown – @alastairbrown21
Summary date: 9th June 2022
Peer-review editor: George Walker
Picture by: Pexels