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
  • 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

Metadata

Summary author: Alastair Brown – @alastairbrown21
Summary date: 9th June 2022
Peer-review editor: George Walker

Picture by: Pexels

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