CASE REPORTS
`
`743
`
`Vervloet D, Camboulives J: Association between latex sensitization and repeated
`latex exposure in children. ANESTHESIOLOGY 1997; 86:599 – 602
`11. Brown RH, Shauble JF, Hamilton RG: Prevalence of latex allergy among
`anaesthesiologists: Identification of sensitized but asymptomatic individuals. AN-
`ESTHESIOLOGY 1998; 89:292–9
`12. Levy DA, Leynadier F: Latex allergy: Review of recent advances. Current
`Allergy Reports 2001; 1:32– 8
`13. Laxenaire MC, Mouton C, Frédéric, Viry-Babel F, Bouchon Y: Anaphylactic
`shock after tourniquet removal in orthopedic surgery. Ann Fr Anesth Reanim
`1996; 15:179 – 84
`14. Cardot E, Tillie-Leblond I, Jeannin P, Facon A, Breuil K, Patte F, Tonnel AB:
`Anaphylactic reaction to local administration of rifamycin SV. J Allergy Clin
`Immunol 1995; 95:1–7
`15. Jorrot JC, Mercier F, Pecquet C, Jacquinot P, Conseiller C: Perioperative
`anaphylactic shock caused by latex. Ann Fr Anesth Reanim 1989; 8:278 –9
`16. Péchinot M: Latex hypersensitivity after cesarean section. Ann Fr Anesth
`Reanim 1997; 16:79 – 80
`17. Seigne R: Allergies and anaesthesia (letter). Br J Anaesth 1997; 78:778
`
`18. Pecquet C: Risk factors for latex allergy: Diagnostic methods for aprotinin
`allergy. Ann Fr Anesth Reanim 2002; 21:123– 8
`19. Reche M, Pascual CY, Vicente J, Caballero T, Martin-Munoz F, Sanchez S,
`Martin-Esteban M: Tomato allergy in children and young adults: Cross-reactivity
`with latex and potato. Allergy 2001; 56:1197–201
`20. Moller M, Kayma M, Vieluf D, Paschke A, Steinhart H: Determination and
`characterization of cross-reacting allergens in latex, avocado, banana and kiwi
`fruit. Allergy 1998; 53:289 –96
`21. Garcia Ortiz JC, Moyano JC, Alvarez M, Bellido J: Latex allergy in fruit-
`allergic patients. Allergy 1998; 53:532– 6
`22. Chen Z, Posch A, Cremer R, Raulf-Heimsoth M, Baur X: Identification of
`hevein (Hev b 602) in hevea latex as a major cross-reacting allergen with avocado
`fruit in patients with latex allergy. J Allergy Clin Immunol 1998; 102:476 – 81
`23. Posch A, Wheeler CH, Chen Z, Flagge A, Dunn MJ, Papenfuss F, Raulf-
`Heimsoth M, Baur X: Class I endochitinase containing a hevein domain is the
`causative allergen in latex-associated avocado allergy. Clin Exp Allergy 1999;
`29:667–72
`
`Anesthesiology 2003; 99:743–4
`
`© 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
`
`Use of Inhaled Iloprost in a Case of Pulmonary Hypertension
`during Pediatric Congenital Heart Surgery
`Matthias Müller, M.D.,* Stefan Scholz, M.D.,* Myron Kwapisz, M.D.,† Hakan Akintürk, M.D.,‡ Josef Thul, M.D.,§
`Gunter Hempelmann, M.D.储
`
`IMPAIRED endothelium-dependent vasodilatation is
`present in children with high pulmonary flow and pres-
`sure which might be exacerbated by cardiopulmonary
`bypass (CPB).1,2 It has been reported that an increased
`pulmonary vascular resistance, either directly or as a
`surrogate of the systemic inflammatory response after
`cardiopulmonary bypass, has a significant effect on the
`postoperative recovery of infants after cardiac opera-
`tions.3 Iloprost is the stable carbacyclin derivative of
`prostaglandin I2. The use of aerosolized prostaglandin I2
`has shown to be safe in healthy lambs with regard to
`coagulation parameters, hemodynamics, and pulmonary
`toxicity.4,5 Inhaled iloprost has been used as a diagnostic
`tool to assess the vasodilator capacity of the pulmonary
`vascular bed in children with congenital heart disease
`and elevated pulmonary vascular resistance, as well as
`intensive care unit treatment of pulmonary hypertension
`in a small series of children after cardiac surgery.6 In
`adults, inhaled iloprost has been successfully used to
`control pulmonary hypertension after CPB.7 However,
`no data are available about the intraoperative use of
`inhaled iloprost in infants younger than 1 yr with pul-
`monary hypertension undergoing cardiac surgery.
`
`* Consultant, † Resident, Department of Anaesthesiology, Intensive Care Med-
`icine, Pain Therapy, ‡ Consultant, Department of Cardiac and Pediatric Cardiac
`Surgery, § Consultant, Department of Pediatric Cardiology, and 储 Professor and
`Chairman, Department of Anaesthesiology, Intensive Care Medicine, Pain Ther-
`apy, University Hospital Giessen.
`
`Received from the Department of Anaesthesiology, Intensive Care Medicine,
`Pain Therapy, University Hospital Giessen, Giessen, Germany. Submitted for
`publication December 13, 2002. Accepted for publication March 11, 2003.
`Support was provided solely from departmental sources.
`
`Address reprint requests to Dr. med. Müller: Department of Anaesthesiology,
`Intensive Care Medicine, Pain Therapy, University Hospital Giessen, Rudolf-
`Buchheim-Str. 7, 35392 Giessen, Germany. Address electronic mail
`to:
`Matthias.F.Mueller@chiru.med.uni-giessen.de. Individual article reprints may be
`purchased through the Journal Web site, www.anesthesiology.org.
`
`Anesthesiology, V 99, No 3, Sep 2003
`
`Case Report
`
`A 6-month-old infant girl, weighing 3.66 kg, was scheduled for atrial
`and ventricular septal closure. The preoperative medical history in-
`cluded gestational age of 29 weeks at birth, trisomy 21, and broncho-
`pulmonary dysplasia. Preoperative cardiac catheterization revealed an
`unrestrictive ostium secundum type atrial septum defect and an unre-
`strictive perimembranous ventricular septal defect, resulting in pulmo-
`nary hypertension with a pulmonary-to-systemic perfusion ratio (Qp/
`Qs) of 1.4 and a pulmonary-to-systemic vascular resistance ratio (Rp/
`Rs) of 0.6. The preanesthetic medication consisted of aldactone,
`hydrochlorothiazide, digoxin, and antibiotics. In the operating room,
`general anesthesia was induced with fentanyl followed by pancuro-
`nium bromide and was maintained with fentanyl (total dose, 82 ␮g ⫻
`kg⫺1), isoflurane (maximum end-tidal concentration 0.4 vol%), and
`midazolam (total dose, 0.4 mg ⫻ kg⫺1) after starting CPB. CPB was
`performed using nonpulsatile flow (2.4 l ⫻ min⫺1 ⫻ m⫺2) with a
`membrane oxygenator in moderate hypothermia (rectal temperature
`⬎ 33°C). To maintain full CPB flow at acceptable systemic pressures,
`the ␣-adrenergic antagonist urapidil (total dose, 1.0 mg ⫻ kg⫺1) was
`administered to keep the mean systemic blood pressure below
`40 mmHg. Cold crystalloid cardioplegia (Bretschneider [histidine tryp-
`tophane ketoglutarate] solution, 110 ml) was given before clamping
`the aorta. The aortic clamping time was 65 min. During reperfusion of
`the heart, a loading dose of milrinone (50 ␮g ⫻ kg⫺1 over 60 min)
`followed by a continuous infusion of 0.5 ␮g ⫻ kg⫺1⫻ min⫺1was
`started. After a total CPB time of 112 min, weaning off CPB was
`successful at the first attempt. Inhaled iloprost (2.5 ␮g ⫻ kg⫺1 over
`20 min) was administered after weaning off CPB, because the mean
`pulmonary artery pressure/mean systemic blood pressure ratio (Pp/Ps)
`was increased to 0.72 and arterial oxygen saturation was 76%, despite
`hyperventilation (PaCO2, 30 –35 mmHg) with an inspired oxygen frac-
`tion of 1.0. Iloprost was prepared from a vial of Ilomedin 50 i.v.®
`(Schering AG, Berlin, Germany) containing iloprost 50 ␮g/2.5 ml and
`was diluted with isotonic saline to obtain a concentration of iloprost
`2 ␮g/ml. For inhalation, 4.5 ml of iloprost 2 ␮g/ml were administered
`using an ultrasonic nebulizer. Inhaled iloprost decreased the Pp/Ps to
`0.59 and increased the oxygen saturation to 90%. The hemodynamic
`parameters and oxygen saturation readings are summarized in table 1.
`The patient was transferred with stable hemodynamic parameters to
`the pediatric intensive care unit. However, 120 min after terminating
`
`Downloaded From: http://anesthesiology.pubs.asahq.org/ on 06/19/2017
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1040, p. 1 of 5
`
`

`

`744
`
`CASE REPORTS
`
`Table 1. Changes in Hemodynamic Parameters and Arterial Oxygen Saturation
`
`Heart rate, beats/min
`Systemic blood pressure, mmHg
`Pulmonary artery pressure, mmHg
`Pp/Ps
`Arterial oxygen saturation, %
`
`Before II
`
`137
`73/58/45
`59/42/28
`0.72
`76
`
`End of II
`
`143
`73/54/41
`46/34/25
`0.63
`90
`
`60 min after II
`
`120 min after II
`
`142
`72/54/42
`43/32/22
`0.59
`90
`
`162
`62/43/35
`47/35/26
`0.81
`89
`
`II ⫽ inhaled iloprost; Pp/Ps ⫽ mean pulmonary artery pressure/mean systemic blood pressure ratio.
`
`inhalational therapy with iloprost, the Pp/Ps increased again to 0.81.
`The postoperative course was complicated by recurrent pulmonary
`hypertensive crises during recovery from anesthesia that required
`prolonged sedation, relaxation, and nonselective pulmonary vasodila-
`tors despite the application of inhaled nitric oxide (iNO). We speculate
`that this may be because of a higher sympathetic activation during
`recovery from anesthesia and/or a minor response to iNO. Inhaled
`iloprost, however, has not been used during mechanical ventilation in
`the pediatric intensive care unit. The patient was ventilated for 6
`postoperative days and was discharged to the referring hospital on the
`seventh postoperative day.
`
`Discussion
`
`This case report demonstrates that a single dose of
`inhaled iloprost (2.5 ␮g ⫻ kg⫺1 over 20 min) may be
`used to decrease Pp/Ps and to improve oxygen satura-
`tion in an infant after weaning off CPB; 120 min later the
`Pp/Ps returned to baseline. A documented hemody-
`namic effect for 1 to 2 h has previously been described.8
`The effective dose of inhaled iloprost in infants is not
`clear and seems to be dependent on the clinical setting.
`From previous applications, we speculate that a lower
`dose of inhaled iloprost is not very effective in infants
`after weaning off CPB, who were already hyperventi-
`lated with 100% oxygen.
`In accordance with Ri-
`mensberger et al.,6 we observed no decrease in systemic
`blood pressure even though we used a fivefold higher
`dose. This may be explained by our clinical setting (i.e.,
`immediately after weaning off CPB; intraoperative use of
`the systemic vasodilators urapidil and milrinone). Theo-
`retically, different characteristics of the aerosol spray
`may result in different intrapulmonary drug depletion
`characteristics, which could explain the lack of spillover
`into systemic circulation. However, we used a tested
`ultrasonic nebulizer (Optineb®; Nebu-Tec, Elsenfeld,
`Germany) that provided an aerosol with a mass median
`aerodynamic diameter of the droplets of 3.4 ␮m.
`Although iNO is widely used to decrease pulmonary
`vascular resistance in infants undergoing cardiac sur-
`gery, the effects of iNO vary among patients and cum-
`
`bersome devices are necessary to administer iNO safe-
`ly.9,10 Furthermore, rebound phenomena have been
`described with iNO withdrawal, bearing the risk of life-
`threatening pulmonary hypertensive crisis (e.g., during
`transportation to the intensive care unit).11 Inhaled ilo-
`prost may, therefore, be an alternative for selective pul-
`monary vasodilation in infants undergoing cardiac surgery
`because it is effective, easy to use, and long-acting. Further-
`more, from an economic point of view inhaled iloprost
`may be attractive because iNO became very expensive
`after approval by the Food and Drug Administration.
`
`References
`
`1. Celermajer DS, Cullen S, Deanfield JE: Impairment of endothelium-depen-
`dent pulmonary artery relaxation in children with congenital heart disease and
`abnormal pulmonary hemodynamics. Circulation 1993; 87:440 – 6
`2. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ: Use of inhaled nitric
`oxide and acetylcholine in the evaluation of pulmonary hypertension and endo-
`thelial function after cardiopulmonary bypass. Circulation 1993; 88:2128 –38
`3. Schulze-Neick I, Li J, Penny DJ, Redington AN: Pulmonary vascular resis-
`tance after cardiopulmonary bypass in infants: Effect on postoperative recovery.
`J Thorac Cardiovasc Surg 2001; 121:1033–9
`4. Habler O, Kleen M, Takenaka S, Leiderer R, Pusch R, Welte M, Zwissler B,
`Messmer K: Eight hours’ inhalation of prostacyclin (PGI2) in healthy lambs:
`Effects on tracheal, bronchial, and alveolar morphology. Intensive Care Med
`1996; 22:1232– 8
`5. Habler O, Kleen M, Zwissler B, Pusch R, Welte M, Vogelmeier C, Kempter
`B, Krombach F, Messmer K: Inhalation of prostacyclin (PGI2) for 8 hours does
`not produce signs of acute pulmonary toxicity in healthy lambs. Intensive Care
`Med 1996; 22:426 –33
`6. Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli
`B, Beghetti M: Inhaled nitric oxide versus aerosolized iloprost in secondary
`pulmonary hypertension in children with congenital heart disease: Vasodilator
`capacity and cellular mechanisms. Circulation 2001; 103:544 – 8
`7. Theodoraki K, Rellia P, Thanopouos A, Tsourelis L, Zarkalis D, Sfyrakis P,
`Antoniou T: Inhaled iloprost controls pulmonary hypertension after cardiopul-
`monary bypass. Can J Anesth 2002; 49:963–7
`8. Hoeper MM, Olschewski H, Ghofrani HA, Wilkens H, Winkler J, Borst MM,
`Niedermeyer J, Fabel H, Seeger W: A comparison of the acute hemodynamic
`effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary
`hypertension. German PPH study group. J Am Coll Cardiol 2000; 35:176 – 82
`9. Atz AM, Wessel DL: Inhaled nitric oxide in the neonate with cardiac disease.
`Semin Perinatol 1997; 21:441–55
`10. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner
`GJ, Davis KJ, Hyers TM, Papadakos P: Effects of inhaled nitric oxide in patients
`with acute respiratory distress syndrome: Results of a randomized phase II trial.
`Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998; 26:15–23
`11. Atz AM, Adatia I, Wessel DL: Rebound pulmonary hypertension after
`inhalation of nitric oxide. Ann Thorac Surg 1996; 62:1759 – 64
`
`Anesthesiology, V 99, No 3, Sep 2003
`
`Downloaded From: http://anesthesiology.pubs.asahq.org/ on 06/19/2017
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1040, p. 2 of 5
`
`

`

`Anesthesiology 2003; 99:745–7
`
`© 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
`
`Intraoperative Management of Severe Pulmonary Hypertension
`during Cardiac Surgery with Inhaled Iloprost
`Steffen Rex, M.D.,* Thomas Busch, M.D.,† Manfred Vettelschoss, M.D.,‡ Lothar de Rossi, M.D.,§ Rolf Rossaint, M.D.,储
`Wolfgang Buhre, M.D.**
`
`745
`
`PULMONARY hypertension is an important risk factor
`for the development of acute right heart failure after
`cardiac surgery.1,2 Even with early and adequate therapy,
`right ventricular (RV) failure is associated with increased
`morbidity and mortality.1,3 We report the case of a pa-
`tient with severe pulmonary hypertension related to
`aortic valve stenosis and mitral valve insufficiency who
`underwent combined bivalvular surgery and coronary
`artery bypass grafting. Pulmonary vascular resistance
`(PVR) was effectively decreased after the administration
`of inhaled iloprost before cardiopulmonary bypass (CPB)
`and during weaning from CPB. RV failure could be
`avoided and the perioperative course was uneventful.
`
`Case Report
`
`A 78-yr-old female patient (height, 1.75 m; weight, 74 kg) presented
`with a history of syncope and congestive heart
`failure. Cardiac
`catheterization revealed severe aortic valve stenosis (aortic valve area,
`0.49 cm2; mean pressure gradient 58 mmHg), mitral valve insufficiency
`(degree II), critical stenosis of the left main coronary artery, impaired
`left ventricular function, and hypokinesia of the anterior and apical left
`inferior wall. Furthermore, severe pulmonary hypertension was diag-
`nosed (pulmonary artery pressure, 80/30 mmHg; mean pulmonary
`artery pressure, 65 mmHg; pulmonary artery occlusion pressure,
`45 mmHg).
`After the induction of anesthesia with sufentanil and midazolam,
`anesthesia was maintained with isoflurane and sufentanil. Hemody-
`namic monitoring consisted of arterial, central venous, and pulmonary
`artery catheterization. Hemodynamic parameters are presented in table
`1. In addition, transesophageal echocardiography (Omniplane II T6210
`probe; Sonos 5500, Philips Medical Systems, Best, The Netherlands)
`was performed intraoperatively. Before CPB, transesophageal echocar-
`diography confirmed the diagnoses obtained by cardiac catheterization
`and revealed severe RV dysfunction. Detailed echocardiographic data
`are listed in table 2.
`After the induction of anesthesia, nitroglycerin was administered
`intravenously to decrease PVR; however, the nitroglycerin was not
`effective (table 1). After sternotomy, PVR increased, probably because
`
`* Resident, § Staff Anesthesiologist, 储 Professor and Chairman, ** Associate Pro-
`fessor, Department of Anesthesiology, University Hospital, Technical University
`Aachen.
`† Associate Professor, ‡ Staff Surgeon, Department of Thoracic and
`Cardiovascular Surgery, University Hospital.
`
`Received from the Department of Anesthesiology, University Hospital, Tech-
`nical University Aachen, Aachen, Germany. Submitted for publication January 7,
`2003. Accepted for publication May 1, 2003. Support was provided solely from
`institutional and departmental sources.
`
`Address reprint requests to Dr. Rex: Klinik für Anästhesiologie, Univer-
`sitätsklinikum der RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany.
`Address electronic mail to: srex@ukaachen.de. Individual article reprints may be
`purchased through the Journal Web site, www.anesthesiology.org.
`
`Anesthesiology, V 99, No 3, Sep 2003
`
`of increased RV preload caused by the reduction in intrathoracic
`pressure. Therefore, we administered 12.5 ␮g aerosolized iloprost
`(Ilomedin®; Schering Deutschland GmbH, Berlin, Germany) over 15
`min via a commercially available nebulizer (Aeroneb® Pro; Aerogen
`Inc., Mountain View, CA) connected to the inspiratory limb of the
`ventilator circuit. The administration of iloprost significantly decreased
`pulmonary artery pressure and PVR and was accompanied by an
`increase in cardiac output. CPB was performed using moderate hypo-
`thermia (30°C), and cardioplegic arrest was instituted with 2 l of
`crystalloid cardioplegia. The patient underwent aortic valve replace-
`ment, mitral valve repair, and aorto-coronary bypass grafting to the left
`anterior descending and circumflex arteries. The duration of ischemia
`was 140 min. After 80 min of reperfusion, 12.5 ␮g inhaled iloprost
`were again administered over 15 min. Weaning from CPB was com-
`pleted after a reperfusion time of 97 min. Moderate doses of vasoactive
`agents were administered to achieve adequate hemodynamic parame-
`ters. Transesophageal echocardiography showed an improvement in
`RV-function parameters after CPB: the RV-fractional area change in-
`creased from 18% (pre-CPB) to 38% (post-CPB). The patient was trans-
`ferred to the intensive care unit, and endotracheal extubation was
`performed 13 h postoperatively.
`
`Discussion
`
`Impaired RV function is associated with a poor out-
`come in the surgical and nonsurgical settings.1,4 The
`mortality of patients with combined arterial hypotension
`and severe RV dysfunction after CPB (defined as RV-
`fractional area change ⬍ 35%) can reach 86%.3
`Adequate treatment of RV failure consists of different
`strategies. The main goal is to decrease RV afterload by
`using vasodilating agents. The use of intravenously ap-
`plied vasodilators is limited, as they are not selective to
`the pulmonary circulation and often cause arterial hypo-
`tension. Therefore, the administration of selective pul-
`monary vasodilators such as inhaled nitric oxide and
`prostacyclin may be beneficial.5,6 Inhaled prostacyclin
`seems to be the more favorable agent because of its lack
`of toxicity, ease of application, and reduced costs.5 Ilo-
`prost is the stable carbacyclin derivative of prostacyclin
`and can be administered intermittently, as the hemody-
`namic effects of a single dose are sustained for approx-
`imately 60 –120 min.7 Although the plasma half-life time
`of intravenously administered iloprost is known (20 –30
`min), no pharmacokinetic data are available concerning
`the plasma half-life time and the bioavailability after
`administration of inhaled iloprost.8
`Similar to inhaled prostacyclin, inhaled iloprost causes
`a more pronounced increase in cardiac output and a
`
`Downloaded From: http://anesthesiology.pubs.asahq.org/ on 06/19/2017
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1040, p. 3 of 5
`
`

`

`746
`
`Table 1. Hemodynamic Data
`
`MAP, mmHg
`CVP, mmHg
`MPAP, mmHg
`PAOP, mmHg
`TPG, mmHg
`HR, min⫺1
`CO, l/min
`SV, ml
`SVR, dyne 䡠 s 䡠 cm⫺5
`PVR, dyne 䡠 s 䡠 cm⫺5
`PVR/SVR ratio
`Epinephrine, ␮g 䡠 kg⫺1 䡠 min⫺1
`Norepinephrine, ␮g 䡠 kg⫺1 䡠 min⫺1
`Nitroglycerin, ␮g 䡠 kg⫺1 䡠 min⫺1
`Milrinone, ␮g 䡠 kg⫺1 䡠 min⫺1
`
`CASE REPORTS
`
`Pre-CPB
`
`Post-CPB†
`
`Preoperativeⴱ
`
`After Anesthesia
`Induction
`
`Chest
`Open
`
`After 12.5 ␮g Inhaled
`Iloprost
`
`100
`10
`65
`45
`20
`80
`3.5
`32
`2,057
`457
`0.22
`
`78
`15
`43
`30
`13
`60
`2.5
`41
`2,016
`416
`0.21
`
`72
`11
`42
`23
`19
`77
`2.5
`32
`1,952
`608
`0.31
`
`62
`8
`21
`14
`7
`66
`5.2
`78
`830
`107
`0.13
`
`1
`
`1
`
`Chest
`Open
`
`66
`13
`33
`17
`15
`87
`5.7
`65
`743
`224
`0.30
`0.07
`0.05
`
`0.5
`
`Chest
`Closed
`
`57
`13
`29
`14
`15
`83
`5.0
`60
`704
`240
`0.34
`0.07
`0.05
`
`0.25
`
`* Data obtained by cardiac catheterization. † After 12.5 ␮g of inhaled iloprost.
`CO ⫽ cardiac output; CPB ⫽ cardiopulmonary bypass; CVP ⫽ central venous pressure; HR ⫽ heart rate; MAP ⫽ mean arterial pressure; MPAP ⫽ mean
`pulmonary artery pressure; PAOP ⫽ pulmonary artery occlusion pressure; PVR ⫽ pulmonary vascular resistance; SV ⫽ stroke volume; SVR ⫽ systemic vascular
`resistance; TPG ⫽ transpulmonary gradient (MAP ⫺ PAOP).
`
`greater degree of PVR-reduction when compared with
`inhaled nitric oxide.7 Inhaled iloprost has been success-
`fully used in the long-term therapy of pulmonary hyper-
`tension and in the testing of pulmonary vascular respon-
`siveness.9,10 To our knowledge, only three reports are
`available concerning the use of inhaled iloprost during
`cardiac surgery, two of them in patients awaiting or
`having undergone heart transplantation.11–13
`In the present case, we used inhaled iloprost as part of
`a stepwise approach to prevent RV failure in a patient
`with severe pulmonary hypertension undergoing com-
`bined valve surgery and coronary artery bypass grafting.
`
`Table 2. Intraoperative Changes for Hemodynamic Data
`Obtained by Transesophageal Echocardiography
`
`Pre-CPB*
`
`Post-CPB†
`
`LV-EDA, cm2
`LV-ESA, cm2
`LV-FAC, %
`LVVD, ml
`LVVS, ml
`LVEF, %
`LVIDD, cm
`LVIDS, cm
`FS, %
`RV-EDA, cm2
`RV-ESA, cm2
`RV-FAC, %
`
`32.3
`24.0
`25.70
`118
`63.3
`46.36
`5.00
`3.01
`39.80
`18.7
`15.3
`18.18
`
`27.0
`21.6
`20
`86.5
`60.7
`29.83
`5.26
`3.74
`28.90
`7.74
`4.83
`37.60
`
`Mid-esophageal four-chamber view and the short axis of transgastric view
`were evaluated.
`* Closed chest, before administration of iloprost. † Closed chest, after ad-
`ministration of 12.5 ␮g inhaled iloprost.
`CPB ⫽ cardiopulmonary bypass; EDA ⫽ end-diastolic area; EF ⫽ ejection
`fraction (determined by “Simpson’s rule”); ESA ⫽ end-systolic area; FAC ⫽
`fractional area change; FS ⫽ fractional shortening; IDD ⫽ end-diastolic inner
`diameter; IDS ⫽ end-systolic inner diameter; LV ⫽ left ventricular; RV ⫽ right
`ventricular; VD ⫽ end-diastolic volume; VS ⫽ end-systolic volume.
`
`Anesthesiology, V 99, No 3, Sep 2003
`
`Administration of inhaled iloprost before CPB showed
`that the substance acted as an effective pulmonary vaso-
`dilator in our patient. Despite a concomitant decrease in
`mean arterial pressure and systemic vascular resistance
`(SVR), iloprost led to a more pronounced reduction of
`pulmonary artery pressure and PVR, so that the PVR/SVR
`ratio was remarkably decreased before CPB. During
`reperfusion, iloprost was again administered. PVR and
`pulmonary artery pressure were significantly decreased
`when compared with the preoperative values. However,
`the PVR/SVR ratio was increased after CPB, which can
`be attributed to an increase of PVR due to CPB-induced
`pulmonary vascular injury and to a decrease in SVR.
`Reduction of SVR after CPB is a well-known phenome-
`non mainly caused by hemodilution and activation of
`inflammatory mechanisms by extracorporal circulation.
`The additional use of milrinone contributed to the de-
`crease in SVR.
`We used inhaled iloprost during weaning from CPB as
`an integral part of the therapy and not as a rescue
`medication. This is in contrast to other case reports, in
`which inhaled nitric oxide, prostacyclin, or iloprost
`were used after RV failure had already occurred.14,15 The
`most effective dose and the best time for the administra-
`tion of iloprost are still unknown. We used a dose of
`iloprost that is within the range described in the litera-
`ture,7,11 and we administered the second dose before
`starting the weaning from CPB. Thus, an effective RV
`unloading could be expected in the immediate post-CPB
`period. RV failure with the need for an excessive dosage
`of catecholamines or even for reinstitution of CPB could
`be avoided. Despite the use of positive inotropic sub-
`stances and surgical correction of valvular disease, echo-
`cardiographic parameters indicated a significant impair-
`
`Downloaded From: http://anesthesiology.pubs.asahq.org/ on 06/19/2017
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1040, p. 4 of 5
`
`

`

`CASE REPORTS
`
`747
`
`function after CPB, most
`left ventricular
`ment of
`probably caused by severe myocardial stunning. Thus, it
`seems unlikely that improvement of RV function was
`caused solely by the surgical procedure.
`
`References
`
`1. Kaul TK, Fields BL: Postoperative acute refractory right ventricular failure:
`Incidence, pathogenesis, management and prognosis. Cardiovasc Surg 2000;
`8:1–9
`2. Zwissler B: Acute right heart failure: Etiology—pathophysiology— diagno-
`sis—therapy. Anaesthesist 2000; 49:788 – 808
`3. Reichert CL, Visser CA, van den Brink RB, Koolen JJ, van Wezel HB, Moulijn
`AC, Dunning AJ: Prognostic value of biventricular function in hypotensive pa-
`tients after cardiac surgery as assessed by transesophageal echocardiography.
`J Cardiothorac Vasc Anesth 1992; 6:429 –32
`4. Bueno H, Lopez-Palop R, Bermejo J, Lopez-Sendon JL, Delcan JL: In-hospital
`outcome of elderly patients with acute inferior myocardial infarction and right
`ventricular involvement. Circulation 1997; 96:436 – 41
`5. Lowson SM: Inhaled alternatives to nitric oxide. ANESTHESIOLOGY 2002; 96:
`1504 –13
`6. Zwissler B: Inhaled vasodilators. Anaesthesist 2002; 51:603–24
`7. Hoeper MM, Olschewski H, Ghofrani HA, Wilkens H, Winkler J, Borst MM,
`Niedermeyer J, Fabel H, Seeger W: A comparison of the acute hemodynamic
`effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary
`hypertension. German PPH study group. J Am Coll Cardiol 2000; 35:176 – 82
`
`8. Grant SM, Goa KL: Iloprost: A review of its pharmacodynamic and pharma-
`cokinetic properties, and therapeutic potential in peripheral vascular disease,
`myocardial ischaemia and extracorporeal circulation procedures. Drugs 1992;
`43:889 –924
`9. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ,
`Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani
`HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez
`M, Siedentop H, Seeger W: Inhaled iloprost for severe pulmonary hypertension.
`N Engl J Med 2002; 347:322–9
`10. Sablotzki A, Czeslick E, Schubert S, Friedrich I, Muhling J, Dehne MG,
`Grond S, Hentschel T: L’iloprost ameliore l’hemodynamique chez des malades
`souffrant d’insuffisance cardiaque chronique et d’hypertension arterielle pulmo-
`naire [Iloprost improves hemodynamics in patients with severe chronic cardiac
`failure and secondary pulmonary hypertension]. Can J Anaesth 2002;
`49:1076 – 80
`11. Theodoraki K, Rellia P, Thanopoulos A, Tsourelis L, Zarkalis D, Sfyrakis P,
`Antoniou T: Inhaled iloprost controls pulmonary hypertension after cardiopul-
`monary bypass. Can J Anaesth 2002; 49:963–7
`12. Langer F, Wendler O, Wilhelm W, Tscholl D, Schafers HJ: Treatment of a
`case of acute right heart failure by inhalation of iloprost, a long-acting prostacy-
`clin analogue. Eur J Anaesthesiol 2001; 18:770 –3
`13. Wittwer T, Pethig K, Struber M, Hoeper M, Harringer W, Haverich A,
`Franke U, Wahlers T: Aerosolized iloprost for severe pulmonary hypertension as
`a bridge to heart transplantation. Ann Thorac Surg 2001; 71:1004 – 6
`14. Lowson SM, Doctor A, Walsh BK, Doorley PA: Inhaled prostacyclin for the
`treatment of pulmonary hypertension after cardiac surgery. Crit Care Med 2002;
`30:2762– 4
`15. Schroeder RA, Wood GL, Plotkin JS, Kuo PC: Intraoperative use of inhaled
`PGI(2) for acute pulmonary hypertension and right ventricular failure. Anesth
`Analg 2000; 91:291–5
`
`Anesthesiology, V 99, No 3, Sep 2003
`
`Downloaded From: http://anesthesiology.pubs.asahq.org/ on 06/19/2017
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1040, p. 5 of 5
`
`