Intensive Care Med (2005) 31:1029–1041
`DOI 10.1007/s00134-005-2675-4
`
`S P E C I A L A R T I C L E
`
`Inhaled nitric oxide therapy in adults:
`European expert recommendations
`
`Peter Germann
`Antonio Braschi
`Giorgio Della Rocca
`Anh Tuan Dinh-Xuan
`Konrad Falke
`Claes Frostell
`Lars E. Gustafsson
`Philippe HervØ
`Philippe Jolliet
`Udo Kaisers
`Hector Litvan
`Duncan J. Macrae
`Marco Maggiorini
`Nandor Marczin
`Bernd Mueller
`Didier Payen
`Marco Ranucci
`Dietmar Schranz
`Rainer Zimmermann
`Roman Ullrich
`
`Received: 8 November 2004
`Accepted: 24 May 2005
`Published online: 23 June 2005
` Springer-Verlag 2005
`
`Peter Germann, Roman Ullrich: Both autors
`contributed equally in preparing and editing
`the manuscript.
`This article refers to the article available at
`http://dx.doi.org/10.1007/s00134-005-
`2674-5
`This conference was supported by an un-
`restricted grant from INO-Therapeutics.
`P. Germann ()) · R. Ullrich
`Department of Anaesthesiology and
`General Intensive Care,
`Medical University of Vienna,
`Waehringerguertel 18–20, 1090 Vienna,
`Austria
`e-mail: peter.germann@meduniwien.ac.at
`Tel.: +43-1-404004181
`Fax: +43-1-404004183
`
`A. Braschi
`Department of Anaesthesia and Intensive
`Care,
`University of Pavia,
`IRCCS Policlinico S. Matteo,
`P.le Golgi 2, 27100 Pavia, Italy
`
`G. Della Rocca
`Policlinico Universita Udine,
`Via Colugna 50, 33100 Udine, Italy
`
`A. T. Dinh-Xuan
`Service de Physiologie-Explorations
`Fonctionnelles,
`Hôpital Cochin,
`27 rue du Faubourg Saint-Jacques,
`75679 Paris cedex 14, France
`
`K. Falke
`Department of Anaesthesiology and
`Intensive Care Medicine,
`CharitØ Campus Virchow Klinikum,
`University Medical Center,
`Augustenburger Platz 1, 13353 Berlin,
`Germany
`
`C. Frostell
`Department of Anaesthesia
`and Intensive Care,
`Karolinska Institutet, Danderyd Hospital,
`18288 Danderyd, Sweden
`
`L. E. Gustafsson
`Physiology and Pharmacology
`at Berzelius Lab,
`Karolinska Institutet,
`17177 Stockholm, Sweden
`
`P. HervØ
`Service d’Explorations Fonctionnelles,
`Centre Chirurgical Marie Lannelongue,
`133 avenue de la RØsistance-Le Plessis
`Robinson, 93350 Orsay, France
`
`P. Jolliet
`Division of Medical Intensive Care,
`University Hospital of Geneva,
`1211 Geneva 14, Switzerland
`
`U. Kaisers
`Department of Anaesthesiology
`and Intensive Care Medicine,
`CharitØ Campus Virchow Klinikum,
`University Medical Center,
`Augustenburger Platz 1, 13353 Berlin,
`Germany
`
`H. Litvan
`Cardiac Anestesia and
`Postoperative Intensive Care Unit,
`Hospital Santa Creu i Sant Pau,
`C/San Antoni Mª Claret 167,
`08025 Barcelona, Spain
`
`D. J. Macrae
`Paediatric Intensive Care,
`Royal Brompton Hospital,
`Sydney Street, London, SW3 6NP, UK
`
`M. Maggiorini
`Intensive Care Unit,
`Department of Internal Medicine,
`Universitätsspital,
`Ramistrasse 100, 8091 Zurich, Switzerland
`
`N. Marczin
`Heart Science Centre,
`Harefield Hospital,
`Harefield, UB9 6JH, UK
`
`B. Mueller
`Laboratory of Respiratory Cell Biology,
`Division of Pneumology,
`Philipps University,
`Baldingerstrasse, 35033 Marburg, Germany
`
`1029
`
`

`

`1030
`
`D. Payen
`DØpartement d’AnesthØsie-RØanimation
`Chirurgicale,
`Hôpital Lariboisi›re,
`2 Rue Ambroise ParØ,
`75475 Paris cedex 10, France
`
`M. Ranucci
`Department of Cardiothoracic
`Anaesthesia and Intensive Care,
`Istituto Policlinico S. Donato,
`Via Morandi 30, 20097 S. Donato
`Milanese, Italy
`
`D. Schranz · R. Zimmermann
`Abteilung Kinderkardiologie,
`Univ.-Kinderklinik Giessen,
`Klinikstrasse 36, 35392 Giessen, Germany
`
`Abstract Background: Inhaled nitric
`oxide (iNO) has been used for treat-
`ment of acute respiratory failure and
`pulmonary hypertension since 1991
`in adult patients in the perioperative
`setting and in critical care. Methods:
`This contribution assesses evidence
`for the use of iNO in this population
`as presented to a expert group jointly
`organised by the European Society of
`Intensive Care Medicine and the Eu-
`ropean Association of Cardiothoracic
`Anaesthesiologists. Conclusions: Ex-
`pert recommendations on the use of
`iNO in adults were agreed on fol-
`
`Introduction
`
`Methods
`
`lowing presentation of the evidence
`at the expert meeting held in June
`2004.
`
`Keywords Inhaled nitric oxide ·
`Pulmonary hypertension · Acute
`respiratory distress syndrome ·
`Acute lung injury · Cardiac surgery ·
`Lung transplantation
`
`Inhaled nitric oxide (iNO) has been used in Europe for
`treatment of acute respiratory failure and pulmonary hy-
`pertension for several years, both in the operating room
`and the intensive care unit. In the middle 1980s Higen-
`botham and his group [1, 2] were the first to demonstrate
`that iNO selectively decreases pulmonary artery pressure
`(PAP) in a series of patients with primary pulmonary
`hypertension. Then it was demonstrated that iNO can
`selectively reverse experimental pulmonary arterial hy-
`pertension [3]. In the early 1990s it was shown that iNO
`selectively decreases pulmonary arterial hypertension and
`improves arterial oxygenation in patients with acute res-
`piratory distress syndrome (ARDS) [4, 5, 6, 7, 8, 9]. The
`rationale for the treatment of critically ill patients with
`iNO was based on these studies [1, 2, 3, 4, 5, 6, 7, 8, 9].
`However, subsequent randomised controlled trials (RCTs)
`failed to confirm an improvement in survival or morbidity
`in critically ill patients treated with iNO [10, 11, 12, 13,
`14, 15]. In addition, to date there is no drug approval for
`these indications in adults, although iNO is still exten-
`sively used as an off-label drug, and many clinicians
`consider it an important treatment, combining effective
`selective pulmonary vasodilatation with a favourable
`pharmacological profile [16]. iNO has been approved for
`treatment of term and near-term neonates with hypoxic
`respiratory failure. The provision of a pharmaceutical
`product has led to high drug costs and an increased need
`for justification of the clinical use of iNO in adults in
`daily practice. This suggested to our group that recom-
`mendations should be established on the use of iNO in
`adults covering all aspects of current and potential ap-
`plications based on expert opinion.
`
`An Advisory Board was established under the auspices of the Eu-
`ropean Society of Intensive Care Medicine and European Associ-
`ation of Cardiothoracic Anaesthesiologists to coordinate the sci-
`entific program of the meeting. The board consisted of experts with
`proven scientific or clinical expertise relevant to the clinical use of
`iNO. The board identified a further panel of experts who were
`invited to act as section leaders whose role was to review the lit-
`erature in their designated subject area, taking special care to ensure
`the presence of different opinions. Section leaders were asked to
`produce written summaries of their subject area, which were then
`circulated to delegates prior to the meeting and which formed the
`basis of the evidence presented to delegates at the expert meeting
`itself. A further panel of opinion leaders were invited to attend the
`meeting on the basis of their known interest in the use of iNO or
`their status as opinion leaders in the field of adult intensive care.
`The European Society of Intensive Care Medicine and the Euro-
`pean Society of Cardiothoracic Anaesthesiologists were officially
`represented at the meeting. At the expert meeting each subject area
`was presented in summary by the section leader(s), following which
`open discussions led to the composition of draft expert recom-
`mendations statements. These were then edited and re-presented to
`delegates with further discussion and reading leading to final
`agreement on the individual recommendations.
`The first part of this program was built upon discussions among
`a core group of experts, and this led to draft recommendations
`covering areas such as clinical pharmacology, toxicity, dosing,
`administration and various indications supported by appropriate
`literature and clinical data analysis. These draft recommendations
`were made available to a wider group of physicians through a
`dedicated restricted website. Following discussions based upon
`these statements revisions were published online. A 2-day confer-
`ence was then organised, enabling 58 experts from different spe-
`cialties and coming from 14 European Union countries to openly
`discuss all related issues and jointly agree on recommendations.
`During this conference an Editorial Committee was formed to
`summarise expert recommendations. These statements were then
`published anew on the dedicated, restricted website for final review
`and comments by all participants. Following a last round of online
`discussions the Editorial Committee prepared the final article which
`is presented in this contribution. The cost of this project, including
`hotel and accommodation, travel, online conferencing facilities, IT
`support and website, expenses for preparation work, was approx.
`e218,000 (e20,000 for the first part and e198,000 for the second
`part of the program) which was supported through an unrestricted
`grant from INO Therapeutics. The process of producing the present
`
`1030
`
`

`

`expert recommendations was entirely independent of the sponsor-
`ing company, and the contributors specified their potential conflicts
`of interest. The sponsor has no authorship or editorial control over
`the content of the meetings or any subsequent publication. Most of
`the expense for this effort has been time by the Committee.
`
`Results
`
`Clinical pharmacology
`
`iNO acutely relaxes constricted vascular smooth muscle
`leading to vasodilatation of the pulmonary circulation
`with no measurable haemodynamic action outside the
`lung (‘selective pulmonary vasodilatation’). In addition,
`iNO potentially dilates constricted bronchial smooth
`muscle, and it may improve arterial oxygenation in hy-
`poxaemic patients by reducing the intrapulmonary shunt
`leading to enhanced matching of ventilation and perfu-
`sion. The selective pulmonary vasodilator action of iNO
`has been confirmed in various animal models [3], in a
`human model of acute alveolar hypoxia [17] and in pa-
`tients with pulmonary arterial hypertension resulting from
`pulmonary vascular constriction [1, 2, 18, 19]. However,
`due to its short half-life sustained vasodilatation requires
`the continuous delivery of iNO to the lungs. Sudden
`disruption of iNO therapy can therefore result in a severe
`withdrawal reaction with rebound and possibly severe
`vasoconstriction [20]. The bronchodilator effect of iNO is
`dose dependent
`in anaesthetised animals [21] and in
`volunteers or patients with active bronchoconstriction
`[22]. Even at the high doses of iNO used in these studies
`(80 ppm) the bronchodilator response of iNO was less
`effective than a subsequent inhalation of a standard b2-
`agonist [22].
`Several clinical studies have tested the use of iNO for
`treatment of acute pulmonary hypertension or hypox-
`aemia employing doses between 3 and 80 ppm. However,
`these acute physiological effects did not alter clinical
`outcome parameters, such as mortality or morbidity, and a
`high proportion of patients do not respond to iNO therapy
`(non-responders). There is some evidence from experi-
`mental and human studies for potential pharmacodynamic
`effects outside the pulmonary circulation, mainly on di-
`uresis and natriuresis [23, 24], platelet function [25, 26],
`and modulation of the immune response [27].
`
`Expert recommendations:
`
`– It has been conclusively demonstrated in human ex-
`perimentation and clinical studies that exposure to iNO
`causes a concentration-dependent and immediate se-
`lective pulmonary vasodilatation in the presence of
`pulmonary vasoconstriction in most patients.
`– Nitric oxide induces vasorelaxation in ventilated por-
`tions of the lung and redistributes pulmonary blood
`
`1031
`
`flow, thus reducing intrapulmonary shunting in most
`hypoxaemic patients, at concentrations ranging from
`0.1–10 ppm iNO. However, the optimum dose may
`vary over time and between different subjects.
`– iNO is believed to have other pulmonary and extra-
`pulmonary effects. Their clinical relevance and con-
`centration-response relationships remain to be inves-
`tigated.
`
`Synergistic effects
`
`The rationale for combining iNO with other therapeutics,
`either pharmacological or nonpharmacological, is to ob-
`tain a synergistic or additive effect on pulmonary vascular
`tone in patients with pulmonary arterial hypertension or
`hypoxaemia. Most proposed synergistic drugs are effec-
`tive in influencing only one or the other of these two
`potential therapeutic aims. For example, prostacyclin [28]
`and adenosine [29] directly stimulate the synthesis of
`cyclic adenosine monophosphate (cAMP) whereas phos-
`phodiesterases inhibitors inhibit the breakdown of cAMP
`and cyclic guanosine monophosphate (cGMP), thereby
`effecting pulmonary vascular
`relaxation through sig-
`nalling pathways that are different from those which are
`directly brought about by NO.
`
`Expert recommendations:
`
`– The rationale for combining iNO with other drugs is to
`obtain an additive (or synergistic) effect and to induce
`an additional reduction in pulmonary vascular tone
`and/or further optimisation of pulmonary gas exchange
`than is obtained by use of iNO alone.
`– There are clinical reports of the co-administration of
`‘synergistic’ drugs with iNO. The majority of syner-
`gistic drugs are effective in influencing only one or
`another of these desired therapeutic aims [30, 31, 32,
`33, 34, 35, 36, 37].
`– Only the association of iNO and inhaled nebulised
`prostacyclin has shown, in a limited number of pa-
`tients, positive effects on both pulmonary hypertension
`and gas exchange [36]. The therapeutic benefit of this
`synergistic response has yet to be determined.
`– Published studies on the use of potentially synergistic
`drugs in association with iNO report effects on small
`populations or are methodologically inadequate.
`– Dose-response studies with both iNO and the associ-
`ated drugs are incompletely defined.
`– The underlying molecular mechanisms of interaction
`between NO and potentially synergistic drugs and the
`cross-talk pathways of the two drugs acting together
`are only partially understood.
`– The interpretation of clinical data in individual patients
`and from small published experiences must therefore
`be made with caution.
`
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`
`

`

`1032
`
`– On the basis of current evidence the clinical use of
`synergistic drugs in adults in association with iNO
`cannot be recommended outside the confines of clin-
`ical trials.
`
`Toxicology, monitoring, delivery, transport
`
`Over the course of the past decade iNO has been ad-
`ministered to numerous patients without any apparent
`major side effect [10, 11, 12, 13, 14, 15]. Although the
`use of iNO is considered to be safe, and there is no evi-
`dence of direct NO toxicity at clinically relevant doses,
`precautions and safety regulations must be taken into
`account, especially the risk of exposure to higher oxides
`of NO (i.e. nitric dioxide). Therefore care should be taken
`to use iNO in humans that has been manufactured ac-
`cording to agreed good manufacturing practice standards
`(medical grade iNO). These issues have been reviewed in
`detail previously,
`including toxicology, monitoring of
`iNO therapy, delivery and procedures for transport of
`patients on iNO together with environmental issues and
`considerations on staff training [38].
`
`Toxicology and monitoring
`
`Expert recommendations:
`
`– There is no evidence of direct NO toxicity at clinically
`relevant doses.
`– Methaemoglobin should be measured 4 h after com-
`mencing iNO and daily thereafter.
`– Clinically significant levels of methaemoglobin are
`unlikely to result unless iNO concentrations over
`20 ppm are administered.
`– Administration of iNO is associated with NO2 forma-
`tion which is potentially toxic.
`– Environmental exposure limits exposure to NO2 to a 2-
`ppm 8 h time-weighted average in non-intubated pa-
`tients and staff.
`– Clinically significant levels of NO2 are unlikely to
`occur when iNO is delivered by an efficient delivery
`system at concentrations of 20 ppm or less.
`– If long-term iNO treatment is to be undertaken, at-
`tempts should be made to reduce the concentration of
`iNO to 10 ppm or less to further reduce exposure to
`potentially toxic NO2.
`– Use of iNO is associated with accumulation of nitrate
`and nitrite. The significance of these increases is un-
`certain.
`– There are no long-term follow-up studies from which
`freedom from late adverse effects following iNO
`therapy can be ascertained.
`
`Delivery
`
`Expert recommendations:
`
`– INO should be delivered by a system approved for
`clinical use, conforming to appropriate CE standards
`and capable of meeting the following specifications.
`– It should be able to deliver a constant concentration of
`iNO to the patient.
`– The design should minimise the generation of NO2 and
`should have continuous monitoring and alarms for
`inspired NO, NO2 and O2.
`– A backup system for hand ventilation should be im-
`mediately available to ensure continuous iNO delivery
`in the case of delivery device malfunction.
`– The delivery device should be compatible with the
`type(s) of ventilator(s) in use, which at present does
`not include closed-circuit, rebreathing systems during
`anaesthesia.
`
`Transport
`
`Expert recommendations:
`
`– iNO therapy must be delivered without interruption
`when patients are transferred within or between hos-
`pitals.
`– An iNO delivery and monitoring system which is of
`low weight and is designed and approved for use
`during transport in road and air ambulances is urgently
`needed.
`
`Contraindication
`
`– Methaemoglobin reductase deficiency (congenital or
`acquired)
`
`Diagnostic assessment
`
`Heart failure
`
`The frequently elevated PVR in patients with chronic left
`ventricular failure may be a result of dysregulation of
`vascular smooth muscle tone and structural remodelling
`[39]. There is growing evidence that the dysregulation of
`pulmonary vascular tone in disease states, such as chronic
`heart failure involves vascular endothelial dysfunction
`with impaired endogenous NO availability in the pul-
`monary circulation. Endothelial cell dysfunction predis-
`poses the vessel wall to vasoconstriction, leucocyte ad-
`herence, platelet activation, mitogenesis,
`thrombosis,
`impaired coagulation and vascular inflammation [40]. In
`addition, endothelial function testing may serve as a
`
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`
`

`

`1033
`
`useful biomarker of pulmonary circulatory function [41].
`Bocchi and colleagues [42] reported sudden development
`of pulmonary oedema in patients with severe congestive
`heart failure treated with iNO, which was most probably
`due to a sudden increase in left atrial filling caused by
`pulmonary vasodilatation rather than a direct negative
`inotropic effect of iNO [43]. iNO may be used as a test for
`pulmonary vasoreactivity before cardiac transplantation.
`
`Expert recommendations:
`
`– Response to iNO treatment may identify patients still
`suitable for heart or heart/lung transplantation or to
`help to identify patients with congenital heart disease
`suitable for further intervention.
`– iNO decreases PVR but potentially increases left
`ventricular preload which may be dangerous in left
`ventricular dysfunction. In the presence of left heart
`dysfunction it
`is increasingly recognised that
`iNO
`testing should be performed only after optimising heart
`failure therapy immediately prior to testing.
`– iNO testing is useful to demonstrate the remaining
`reactivity of the precapillary component of postcapil-
`lary pulmonary hypertension. Reduction in PAP/PVR
`shown by iNO testing does not imply that long-term
`iNO therapy should be instituted
`
`Pulmonary arterial hypertension
`
`Pulmonary arterial hypertension, previously known as
`primary pulmonary hypertension, is a rapidly progressive
`disease of the pulmonary vasculature with consecutive
`right heart failure [44]. Prognosis may be improved in
`adult patients responding to calcium channel blocker and/
`or anticoagulation [45] and in patients treated with con-
`tinuous prostacyclin [46]. The response to acute vasodi-
`lator testing has important
`implications both for the
`choice of therapy and for prognosis [28, 47, 48]. For
`example, only patients with a positive response to acute
`vasodilator testing remain suitable for long-term treat-
`ment with calcium channel blocker. Those who do not are
`treated with long-term intravenous epoprostenol. Today
`intravenous epoprostenol adenosine or iNO is recom-
`mended for acute vasodilator testing in adults, defined as
`a decrease in the mean PAP of at least 10 mmHg to less
`than 40 mmHg with an increased or unchanged cardiac
`output [49]. iNO has been shown to be superior to pros-
`tacyclin for this use [50] whereas aerosolised iloprost is
`more effective in improving oxygenation and haemody-
`namics in patients with primary pulmonary hypertension
`[51]. Combining oxygen and iNO can identify a greater
`number of appropriate candidates for corrective cardiac
`surgery or transplantation during preoperative testing
`[52].
`Expert recommendations:
`
`– iNO is a potent selective pulmonary vasodilator which
`used alone or in combination with other vasodilators
`may be useful in revealing the extent of reversibility (if
`any) in selected patients with pulmonary arterial hy-
`pertension.
`– iNO clearly identifies responders suitable for long-
`term treatment with calcium channel blockers.
`– iNO dose recommended for acute vasodilator testing
`should be 10–20 ppm. iNO does not have relevant
`adverse effects during short-term acute testing.
`– iNO combined with additional O2 may lead to further
`pulmonary vasodilatation.
`– There is insufficient data to recommend iNO for long-
`term therapy of pulmonary arterial hypertension.
`
`Medical conditions complicated
`by pulmonary arterial hypertension
`
`Thromboembolism
`
`iNO, which decreases PAP [2], is likely to unload the
`right ventricle in pulmonary embolism and chronic
`thromboembolic pulmonary hypertension. Furthermore,
`its platelet anti-aggregate property could prove beneficial
`[53, 54]. iNO for severe pulmonary embolism or chronic
`thromboembolic pulmonary hypertension has not been
`investigated in randomised controlled trials. Animal
`studies have shown that iNO decreases PVR [55] and
`platelet aggregation [54]. Use of iNO has been reported in
`case reports from patients with massive pulmonary em-
`bolism leading to cardiogenic shock. iNO decreased right
`ventricular afterload, improved cardiac output (CO) and
`increased arterial oxygen content [56, 57, 58]. After
`thrombendarterectomy iNO significantly improved arte-
`rial oxygenation but had a negligible effect on PAP. In
`one case postoperative hypotension progressively re-
`versed with iNO [59].
`
`Expert recommendations:
`
`– There are no controlled trials which support the routine
`use of iNO in patients with thromboembolic disease.
`– iNO might be of benefit
`in selected patients with
`thromboembolic disease who have severe right ven-
`tricular failure and/or severe hypoxaemia.
`
`Sickle-cell disease
`
`Stiffened red blood cells lead to impaired blood flow in
`the microcirculation, veno-occlusive phenomena,
`in-
`flammation and haemolysis [60]. Given the depletion of
`endogenous NO by cell-free haemoglobin iNO may re-
`store endothelial homeostasis by enhancing pulmonary
`vasodilatation and inactivation of cell-free haemoglobin.
`
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`
`

`

`1034
`
`In transgenic sickle-cell mice iNO protects from hypoxia/
`reoxygenation induced lung injury, attenuates inflamma-
`tory response, modulates genes involved in ischaemic/
`reperfusion injury and improves survival [61]. Case re-
`ports in the acute chest syndrome have shown an im-
`proved oxygenation and decreased PAPm with iNO [62,
`63]. A small prospective, double-blind, randomised, pla-
`cebo-controlled paediatric study has shown that iNO is
`associated with a greater reduction in pain and less use of
`morphine over the first 6 h but not duration of hospital-
`isation [64].
`
`Expert recommendations:
`
`– There is limited clinical experience suggesting that
`iNO improves oxygenation and decreases PVR in
`some patients with acute chest syndrome.
`– A single randomised, placebo-controlled trial in severe
`vaso-occlusive disease suggests that use of iNO is
`associated with improved pain control.
`– At present there are insufficient data to recommend the
`routine use of iNO to manage complications of sickle
`cell disease.
`
`Chronic obstructive pulmonary disease
`
`In chronic obstructive pulmonary disease pulmonary hy-
`pertension responds poorly to oxygen therapy and has an
`adverse impact on prognosis. Pathophysiological studies
`in stable patients have consistently documented that iNO
`lowers PAPm and PVR [65]. Studies report both an im-
`provement [65] and a worsening in arterial oxygenation
`[66]. The concomitant administration of O2 either pre-
`vents a decrease in [67] or increases PaO2 [33]. In intu-
`bated and mechanically ventilated patients neither arterial
`oxygenation nor cardiac function are influenced by iNO
`[68]. A recent prospective randomised trial comparing O2
`alone and O2 plus iNO over a 3-month period in stable
`patients demonstrated a reduction in PAPm and PVR and
`an increase in cardiac output at the end of the trial period
`in the O2 plus iNO group only [69]. No study to date has
`explored the impact of either acute or chronic iNO on
`patient outcome.
`
`Expert recommendations:
`
`– There is no evidence that iNO therapy is of clinical
`benefit in patients with chronic obstructive pulmonary
`disease.
`
`Cardiac surgery
`
`Perioperative pulmonary hypertension
`in adult cardiac surgery
`
`Several strategies have been employed to avoid postop-
`erative pulmonary hypertension, including pharmacolog-
`ical inhibitors of inflammation, improved cardioplegic
`solutions, and new surgical techniques avoiding the use of
`CPB. Treatment strategies include the use of iNO, pros-
`taglandins and ultimately ventricular assist devices.
`CPB has been shown to reduce NO production within
`the pulmonary vasculature, and replacement of endoge-
`nous NO by treatment with iNO lowers the increased
`vascular resistance [70] and reduces markers of CPB-in-
`duced inflammatory activation [71]. iNO was more ef-
`fective than milrinone in lowering PVR in 45 adult car-
`diac surgery patients [72]. iNO is equally effective as
`standard intravenous vasodilators, without altering sys-
`temic haemodynamics [73]. Doses greater than 20 ppm
`offer no advantage [73, 74], and patients with a high
`preoperative PVR have a greater response to iNO [75].
`Similar data have been reported for treatment of pulmo-
`nary hypertension in high-risk cardiac surgery patients
`[19], patients undergoing heart transplantation [76, 77]
`and insertion of left ventricular assist devices [78, 79].
`
`Expert recommendations:
`
`– There are no randomised, placebo-controlled clinical
`trials that show that iNO improves clinical outcomes in
`adults with perioperative acute right ventricular dys-
`function and elevated PVR
`in patients with
`– Clinical experience suggests that
`confirmed acute right ventricular dysfunction and el-
`evated PVR, use of iNO may result in haemodynamic
`improvement when used during or after cardiac sur-
`gery
`– Prior to iNO administration right ventricular function
`should be optimised with conventional
`treatment
`(specifically, ensuring optimal ventilation,
`thoracic
`decompression, preload optimisation, attempting to
`lower PVR with standard measures, increasing sys-
`temic perfusion pressure to increase coronary perfu-
`sion, and reduction in myocardial oxygen consump-
`tion).
`
`Left ventricular assist devices
`
`Ventricular assist devices (VAD) can dramatically im-
`prove survival and morbidity of patients with severe acute
`or chronic heart failure, either as a bridge to transplan-
`tation, as a bridge to recovery or as a permanent therapy
`[80]. In the presence of pulmonary hypertension filling of
`the left-sided VAD is impaired and the right ventricle
`
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`
`

`

`1035
`
`ical trials determining the role of iNO for the treatment of
`pulmonary hypertension in cardiac transplant patients.
`However, iNO therapy is considered to be a part of a
`multimodal treatment strategy by expert opinion, includ-
`ing iNO, optimising right ventricular filling, increasing
`heart rate and reducing PVR [76].
`
`Expert recommendations:
`
`– Several institutions with extensive experience in car-
`diac transplantation use and recommend iNO as a part
`of standard therapy for all cardiac transplant proce-
`dures associated with increased PVR.
`– Following weaning from the ventilator iNO therapy
`may be discontinued and be replaced by intravenous
`vasodilators.
`
`Thoracic surgery
`
`One-lung ventilation
`
`Hypoxaemia frequently occurs during one-lung ventila-
`tion (OLV) and is due mainly to an increased pulmonary
`blood flow to the non-ventilated lung (intrapulmonary
`shunt) [86, 87]. High inspired oxygen concentrations,
`intermittent
`two-lung ventilation, continuous positive
`airway pressure and high frequency jet ventilation to the
`ventilated, dependent lung are common interventions to
`improve arterial oxygenation. Two studies suggest that in
`the absence of arterial hypoxaemia or pulmonary hyper-
`tension iNO does not modify oxygenation or pulmonary
`artery pressure [88, 89]. In theory iNO should increase
`pulmonary blood flow to the ventilated, dependent lung
`by dilating the pulmonary vasculature [90]. However,
`Fradj et al. [91] reported that iNO at 20 ppm was not
`superior to nitrogen in the treatment of arterial hypox-
`aemia during OLV. In another study iNO administration
`was effective only in a subgroup of patients with severe
`hypoxaemia, high intrapulmonary shunt and pulmonary
`hypertension during OLV [92].
`Almitrine combined with iNO can attenuate arterial
`hypoxaemia during OLV or in patients with ARDS [30,
`31, 34, 93, 94, 95]. However, as iNO during OLV is
`seldom effective when used alone, the role of iNO to
`improve the effects of almitrine has yet to be confirmed
`[94]. Therefore the expert panel cannot make any rec-
`ommendations on the use of a combination of iNO with
`intravenous almitrine, taking also into consideration the
`long half-life time of the drug, its potential for systemic
`toxicity and its limited availability in most countries.
`
`cannot be unloaded further worsening the right ventricular
`dysfunction. This situation may necessitate the implant of
`a biventricular assist device. The development of right
`ventricular dysfunction remains a serious clinical problem
`being associated with a high transfusion rate, multiple
`organ failure, increased length of stay and a high mor-
`tality rate [80]. Recent studies ranging from case reports,
`observational studies and RCTs have demonstrated ben-
`eficial effects of iNO therapy in such patients [43, 81, 82].
`However, there are no data to suggest that this transient
`action of iNO has any lasting effect that favourably in-
`fluences clinical outcomes. The doses used in theses
`studies varied between 10–40 ppm. Potential concerns
`arise from the possibility of abrupt rebound pulmonary
`hypertension from withdrawal of iNO, and sudden in-
`creases in left atrial filling, similar to the mechanisms
`occurring in patients with acute heart failure [43]. Cur-
`rently the role of iNO in the treatment of heart failure
`patients undergoing left-sided VAD insertion is tested in
`an ongoing large, multicentre trial.
`
`Expert recommendations:
`
`– There is a high prevalence of right ventricular dys-
`function refractory to conventional clinical measures
`in patients in whom insertion of a left ventricular assist
`device is required
`– The expert panel believe that iNO therapy is effective
`in providing favourable pulmonary haemodynamics
`leading to improved right ventricular and left-sided
`VAD assisted cardiac output in patients with pulmo-
`nary hypertension and inadequate left-sided VAD flow
`refractory to conventional manoeuvres. On the basis of
`these improved critical physiological variables the
`expert panel recommend that it is reasonable to con-
`sider the use of iNO in this clinical situation among
`other vasodilator therapies.
`– Further studies are required to better define the indi-
`cations for iNO in cardiac surgical patients and in
`particular to elucidate its effects on clinical outcomes.
`
`Heart transplantation
`
`Cardiac transplantation remains the surgical option for
`treatment of end-stage heart disease. In many cases severe
`pulmonary hypertension is present at time of transplan-
`tation, contributing to life-threatening right heart failure, a
`significant predictor of early postoperative mortality [83].
`iNO reduced elevated pulmonary resistance in adult car-
`diac transplantation [84], was more effective in reducing
`PVR than intravenous prostaglandin E1 [85], reduced the
`occurrence of right ventricular failure [76] and increased
`survival irrespective of the preoperative condition in a
`large case series of patients undergoing cardiac trans-
`plantation [77]. Until now there are no randomised clin-
`
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`Expert recommendations:
`
`ARDS/ALI
`
`– There is no evidence to support the routine use of iNO
`for the prevention or reversal of hypoxaemia during
`OLV.
`– Some patients who develop very severe