Treating hypoxemic COVID-19 "ARDS" patients with almitrine: The earlier the better?

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Treating hypoxemic COVID-19 "ARDS" patients with almitrine: The earlier the better?

BENDJELID, Karim, GIRAUD, Raphaël, VON DÜRING, Stephan

BENDJELID, Karim, GIRAUD, Raphaël, VON DÜRING, Stephan. Treating hypoxemic

COVID-19 "ARDS" patients with almitrine: The earlier the better? Anaesthesia, critical care &

pain medicine , 2020, vol. 39, no. 4, p. 451-452

PMID : 32653550

DOI : 10.1016/j.accpm.2020.07.003

Available at:

http://archive-ouverte.unige.ch/unige:142400

Disclaimer: layout of this document may differ from the published version.

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Editorial

Treating hypoxemic COVID-19 ‘‘ARDS’’ patients with almitrine:

The earlier the better?

COVID-19viralpneumonia(pneumonitis)isanacuterespira- tory illness associated with a new droplet-borne coronavirus (SARS-CoV-2). To this day, the pandemic has resulted in over 9millioninfectionsworldwidewithover470,000deaths,andis associated with a profound disruption of the world’s health systems and economy. Surprisingly, the majority of infected patients exhibit good thoraco-pulmonarycompliancewithpre- served lung mechanics following intubation and mechanical ventilation (MV) [1,2]. Nevertheless, the dominant respiratory featureisprofoundanddisproportionatehypoxemia[1].

InarecenteditorialpublishedintheJAMA,MariniandGattinoni arguethatdeepsedationandMVshouldbeimplementedearlyon inordertopreventCOVID-19patientsfromgeneratingspontane- ousinspiratoryefforts[3].Theauthorsstatethatintheearlyphase oflunginfection,thehightranspulmonarypressuresassociated withspontaneousvigorousinspiratoryeffortsmayprovokeself- inducedlunginjuries(P-SILI)[3].Evenifweagreewiththispresent opinion,itisdifficulttomakethedecisiontointubateandparalyse notvery symptomatic — butprofoundlyhypoxemic — patients whenthemaincauseofthisconditionisasevereintrapulmonary oxygenshunt[2,4].Indeed,itappearsthatthepresentSARS-CoV-2 pneumonitisinducesasignificantintrapulmonarycapillaryshunt resultingfromalossofhypoxicpulmonaryvasoconstriction(HPV, Euler-Liljestrandmechanism)[4–6].Whenrecalcitranthypoxemia ispresent,specificnon-ventilatorystrategieslikebodypositioning (proneandanti-Trendelenburg)andpharmacologicaltreatments, especially intravenous (IV) almitrine-bismesylate, may be of interest[4].

AlmitrineisascientificallyrecogniseddrugthatenhancesHPV by a vasoconstrictor effectspecific topulmonary arteries via a calciummediated action [7]. Inhypoxemic patients withacute respiratorydistresssyndrome (ARDS),this medicationhasbeen

usedwithsuccess[8,9].Inthisregard,inthisissueofAnaesthesia Critical CarePain Medicine,the readerwill find two interesting articles examining different, but converging prospects of IV almitrineadministrationonventilation-perfusioninequalitiesin COVID-19 ARDS patients. Both authors hypothesised that IV almitrine may restore some blood oxygenation,even partially, when associated with postural manoeuvres and/or nitricoxide (NO)inhalation.

Inalandmarkfirststudy,Losseretal.presentedaprospective smallcaseseriesof17COVID-19ARDSpatientsadmittedtotheICU forinvasiveMV[10].Afterinitialassessment,10patientsreceived IV almitrine in the early phase of severe ARDS. The dose was initially 4, then 12 mcg/kg/min, with measurements of lung mechanicsandoxygenationunder100%FiO2after45minutesof eachincreaseindose.WithaPEEPof10cmH2OandamedianVTof 425mlthroughout,respiratorycomplianceremainedat35.4ml/

cmH2O with a driving pressure of 12 cmH2O. PaO2/FiO2 ratios increasedfrom135to215mmHg(P<0.05),withanincreasein ScvO2(73,81,85%respectively,P<0.05).Cardiacindexandright atrialpressureswerenotaffectedbythemedication.Anabsenceof spontaneous PaO2 improvement, over eight hours, in a control group(7patients)wasalsoobserved.

Cardinaleetal.reportaretrospectiveanalysisof20consecutive prone patients in severe COVID-19ARDS (medianPaO2/FiO2 at 106mmHg)andalreadyonventilationforoneweek(latephaseof severeARDS)[11].TenpatientsweretreatedwithNOinhalation (between10to20ppm),13withalmitrineinfusion(loadingdose of0.5mg/Kgover30minutes),and7withacombinedtreatment.

Thechoicesoftreatmentsandventilatorsettingswerelefttothe discretionoftheclinicians.InitialmedianPEEPwasof16cmH20,a respiratory complianceof33.3ml/cmH2O anda mediandriving pressureof14cmH2O.ABGanalysiswasperformedbeforestarting anyofthetreatmentsandwasrepeatedonehourafterinhaledNO orimmediatelyafterthealmitrineinfusion.Themedianincreaseof PaO2/FiO2ratiowasmarginalunderNOandalmitrine,respective- ly,andunderthecombinedtreatment(P=NS).

Whatdothesetwostudiesaddtowhatisalreadyknownonthis topic? First, thebenefit ofa combinationof NO inhalation and almitrine on PaO₂/FiO₂ ratios is more important in the early exudativephasethanintheproliferativephaseofsevereclassical ARDS [8,9,12].Thissame timeframecan befoundin COVID-19 ARDSandcanbeexplainedbythefactthat,intheearlyphase,lung injuryprobablyresultsfromthegassideofthealveolus(alveolar oedaema).TheevolutionoftheCOVID-19(latephase)appearsto AnaesthCritCarePainMedxxx(2020)xxx–xxx

ARTICLE INFO

Keywords:

Hypoxemia Capillaryshunt COVID-19 Almitrine GModel

ACCPM-702;No.ofPages2

Pleasecitethisarticleinpressas:BendjelidK,etal.TreatinghypoxemicCOVID-19‘‘ARDS’’patientswithalmitrine:Theearlierthe better?.AnaesthCritCarePainMed(2020),https://doi.org/10.1016/j.accpm.2020.07.003

https://doi.org/10.1016/j.accpm.2020.07.003

2352-5568/^C 2020Socie´te´ franc¸aised’anesthe´sieetdere´animation(Sfar).PublishedbyElsevierMassonSAS.Allrightsreserved.

includeanimportantendothelialinsultwithhistologicalevidence of endothelial dysfunction [13] that mandates an additional vascularandrheologicalapproach[3].Second,acombinationof gravitationalandpharmacologicalintervention(pronepositioning andalmitrine)improvePaO2/FiO2ratiosofsevereARDSpatients, principally in the early phase of ARDS [14]. The gravitational posturepotentiatesHPVinducedbyanalmitrineinfusion,which actstodivertpulmonarybloodflowawayfrompoorlyventilated alveolitowardwell-ventilatedareas.However,regrettablyinthe secondinvestigation[11],therewasinsufficientechocardiograph- icassessmentneededtoexcludeapatentforamenovale.Indeed, the haemodynamic effects of almitrine on pulmonary arterial pressureandrightventricularpressures[15]mayinduceanintra- cardiacshuntthatoffsetsandabolishesthebenefitofthedrugon bloodoxygenation.

Recently, Barthe´le´my et al. also completed a retrospective analysisof 19 severe COVID-19 ARDS patients treated withan almitrine infusion of 2 mcg/kg/min, as a rescue therapy for refractoryhypoxemia[16].ThemediantimefromICUadmission wasfourdays.PEEPwas10cmH2OandCrs32ml/cmH2O.Eighteen patientshadatleastonesessionofpronepositioningbeforethe almitrineinfusion,and15hadneuromuscularblockersandprone positioningatthetimeoftheinfusion.ThemedianPaO2/FiO2ratio increasedfrom79beforetheinfusionwasstarted,to117mmHg withinthefirst 6hours(P=0.001). Despite animprovement in oxygenation,the majority of patients under almitrine required additionalrescuetherapiesordied.

Whatcanbelearnedfromthepresentstudies?Readingthese articlesisstimulating tointensivistsand physiologists whoare currently facing the unprecedented challenge of treating and ventilating COVID-19 ARDS patients. As already stated above, severalfeatures of SARS-CoV-2pneumonitisdistinguishitfrom typicalARDS.First,patientsoftendisplayasilenthypoxemiawith very few clinical symptoms (dyspnoea) despite low PaO2/FiO2

ratios[4].Suchaconditionisprobablyrelatedtoanimpairmentof thecarotidbodysensors,whichphysiologicallysenseshypoxemia andincreasestherespiratorydrive.Second,theseverehypoxemia ismainlyduetoalarge intrapulmonarycapillary oxygenshunt linkedtolossofHPV.Atthispoint,weturnthequestionovertothe reader:howcanweusephysiologytotreatafailureofthebody’s homeostaticO2-sensingsystem,whichincludesboththepulmo- narycirculation and thecarotid body sensors [4]?The present question is crucial since the surest way to increase COVID-19 mortality is the liberal use of intubation and MV [1]. Indeed, althoughfrequentlylife-savingduringthreateninghypoxemia,MV isalsoassociatedwithvariouscomplications,someofthemlife- threateninginandofthemselves[4].Inthisregard,thekeyfactor thatcouldmakealmitrineadministrationofgreatimportancein COVID-19patientsisitsabilitytoavoidintubationandMV[17].

Finally,ifwerevisitrecentresultsintheexistingliterature,we maysaythatadministrationofIValmitrineintheearlyphaseof lunginjuryandARDSmaybeassociatedwithanimprovementin arterial blood oxygenation in COVID-19 ARDS patients. As previouslystatedinanothereditorial,theproposedpharmacolog- ical treatment seems justified as long as its aim is to prevent intubation and MV, or improve MV weaning, without further deteriorationofthepatient’sdangerousstate[4].

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

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1

aIntensiveCareDivision,GenevaUniversityHospitals,Geneva, Switzerland

bGenevaHaemodynamicResearchGroup,Geneva,Switzerland

cFacultyofMedicine,UniversityofGeneva,Geneva,Switzerland

dDepartmentofCriticalCareMedicine,SunnybrookHealthSciences Centre,Toronto,Ontario,Canada

*Correspondingauthorat:CardiovascularUnit,IntensiveCare Division,GenevaUniversityHospitals,Geneva,Switzerland E-mailaddress:karim.bendjelid@hcuge.ch(K.Bendjelid).

Availableonlinexxx Editorial/AnaesthCritCarePainMedxxx(2020)xxx–xxx

2 GModel

ACCPM-702;No.ofPages2

Pleasecitethisarticleinpressas:BendjelidK,etal.TreatinghypoxemicCOVID-19‘‘ARDS’’patientswithalmitrine:Theearlierthe better?.AnaesthCritCarePainMed(2020),https://doi.org/10.1016/j.accpm.2020.07.003