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
• 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

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’

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