Inhaled Nitric Oxide Selectively Decreases Pulmonary Artery Pressure and Pulmonary Vascular Resistance Following Acute Massive Pulmonary Microembolism in Piglets

laboratory and animal investigations Inhaled Nitric Oxide Selectively Decreases Pulmonary Artery Pressure and Pulmonary Vascular Resistance Following Acute Massive Pulmonary Microembolism in Piglets* Bernd W. Bottiger, MD; Johann Motsch, MD; Joachim Dorsam, MD; Ulf Mieck, MD; Andre Gries, MD, Jorg Weimann, MD; and Eike Martin, MD

Acute massive pulmonary embolism increases pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which may lead to early right ventricular failure and subsequent cardiocirculatory deterioration. Inhaled nitric oxide (NO) selectively dilates pulmonary vessels in vivo. Thus, inhaled NO may be useful in preventing cardiocirculatory deterioration following pulmonary embolism. We investigated the effects of inhaled NO in the acute phase of massive pulmonary microembolism in 10 anesthetized and mechanically ventilated piglets (body weight, 18±2 kg). Microspheres of 300-pm diameter were injected IV in an amount sufficient to initially increase mean PAP to 45 mm Hg. Forty-five minutes after pulmonary embolization, the pretreatment control values were recorded. Thereafter, the piglets inhaled 40 ppm NO, and subsequently 80 ppm NO. When 40 ppm NO was inhaled, there was a significant decrease in systolic PAP (-10.3%; 44.5±2.2 to 39.9±2.4 mm Hg; p<0.05) and mean PAP (-9.4%; 32.9±1.3 to 29.8±1.3 mm Hg; p<0.05). PVR was changed by -13.6% (p=0.07). Administration of 80 ppm NO resulted in a significant decrease in systolic PAP (-12.6%; to 38.9± 1.9 mm Hg; p<0.05), mean PAP (-11.9%; to 29.0± 1.4 mm Hg; p<0.05), and PVR (-19.4%; p<0.05) compared with pretreatment values. Discontinuation of NO inhalation was associated with an immediate return to pretreatment values. Systemic hemodynamics and the arterial and mixed venous oxygen concentrations remained unchanged. We conclude that inhaled NO following acute massive pulmonary microembolism selectively decreases PAP and PVR without influencing systemic hemodynamics in piglets. (CHEST 1996; 110:1041-47) Key words: nitric oxide inhalation; pulmonary arterial hypertension; pulmonary embolism Abbreviations: CO=cardiacoutput; CVP=central venous pressure; DPAP=diastolicpulmonaryarterypressure; EtC02=endtidal concentration of carbon dioxide; Flo2=fraction of inspired oxygen concentration; HR=heart rate; MAP=mean systemic arterial pressure; MPAP=mean pulmonary artery pressure; Nz=nitrogen; NO=nitric oxide; N02=nitrogen dioxide; PCWP= pulmonary capillary wedge pressure; PE=pulmonary embolism; Pvo2=mixed venous oxygen tension; PVR=pulmonary vascular resistance; SPAP=systolic pulmonary artery pressure; SVR=systemic vascular resistance

pulmonary embolism (PE) is the sole cause of death in approximately 100,000 patients annually in the United States, and a contributing factor in another *From the Departments of Anesthesiology (Drs. Biittiger, Motsch, Mieck, Gries, Weimann, and Martin) arid Urology (ITr. Diirsam), University of Heidelberg, Germany. Presented in part at the Eighth European Congress of Intensive Care Medicine, Athens, Greece, October 19, 1995; and at the German Anesthesiologists" Annual Meeting, Hamburg, Gennany, March 22, 1995. Manuscript received June 16, 1995; revision accer.ted May 10, 1996. Reprint requests: Dr. Biittiger, Dept of Anesthesiology, Univ. of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidellierg, Germany

100,000 deaths. 1 Mortality in the early phase of fulminant PE is extremely high, with 45 to 90% of all deaths occurring within 2 h after the onset of symptoms. 2·3 Thus, a significant reduction in overall mortality can be expected only if adequate therapy is started immediately in the early phase. Right ventricular failure induced by the increase in right ventricular afterload and mean pulmonary artery pressure (MPAP) is the final cause of deterioration leading to circulatory failure in patients who die from fulminant PE. 4 Decreasing the right ventricular afterload thus remains the CHEST/110/4/0CTOBER,1996

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Table 1-Time Schedule of the Experimental Protocol and Time Points of Measurements Time Schedule Animal preparation Pretreatment steady state (30 min) Pulmonary embolization (5 min) Stabilization phase postembohzation (45 min) NO inhalation 40 ppm (10 min) NO inhalation 80 ppm (10 min)

Time Points and Description 0, Immediately prior to embolization PE, 3 min after embolization Con 1, 45 min after embolization (pretreatment control value) NO 40, 5 min after 40 ppm NO NO 80, 5 min after 80 ppm NO Con2, 10 min after discontinuation of N0 (posttreatment control value)

central therapeutic strategy in treating acute lifethreatening PE. 5•6 Thrombolysis or pulmonary embolectomy, however, usually requires an accurate cliagnosis because of the potential major side effects involved. 6·7 Therefore, most patients suffering from massive PE do not receive specific treatment for recanalization during this important early phase. 5 An alternative therapeutic approach in the acute phase is pulmonary vasoclilation with a subsequent decrease in right ventricular afterload, which might be beneficial in preventing deterioration. 5 •8•9 The clinical value ofiV administered vasoclilators such as nitroglycerin, sodium nitroprusside, calcium channel blockers, and prostaglanclin analogues, however, is limited by their nonselectivity. This may result in dose-dependent systemic vasoclilation with severe hypotension and thus in a reinforcement of right ventricular ischemia in patients suffering from massive PE. 5·8-11 In contrast to IV administered vasoclilators, inhaled nitric oxide (NO) has shown selective pulmonary vasoclilatory effects in various conditions associated with pulmonary hypertension.12-17 The objective of the present study was to investigate the effects of inhaled NO on the hemodynamic system in a porcine model of acute massive pulmonary microembolism.

lungs were mechanically ventilated at a rate of 20/min using a ventilator (Servo 900 C Ventilator; Siemens Elema AB; Solna, Sweden) that was modified for administration of inhaled N 0. 19 The tidal volume was adjusted to ensure a PaC02 between 35 and 40 mm Hg within a period of more than 30 min before the start of each experiment. The fraction of inspired oxygen concentration (Fio 2) was set at 0.3. This ventilatory regimen was maintained throughout the study period. The end-tidal concentration of carbon dioxide (EtC02) was analyzed continuously (Normocap; Datex; Helsinki, Finland). Rectal temperatures of all animals were maintained at a constant level between 35.5°C ;mel 37.0°C using a warming pad. Using local cut-down procedures, all animals underwent placement of a right femoral arterial catheter (Leader Cath 20G; Laboratoires Pharmaceutiques Vygon; Ecouen, France), a right femoral vein 5.5F thermistor-tipped flow-directed pulmonary artery thermodilution catheter (93-63l-5.5F; Baxter Healthcare Corp; Irl'ine, Calif), and a left internal jugular vein central venous line (Arrow Central Vein Catheterization Set 14G; Arrow International Inc; Reading, Pa). The tip of the pulmonary artery catheter was placed in the pulmonary artery, and the correct placement was verified by measuring the pulmonary artery wedge pressure. The position of the catheter tip was corrected during the study period whenever necessary. Nonheparinized 0.9% saline solution (2 mUh) was used to maintain line patency. Each catheter line was connected to a pressure transducer (Uniflow Pressure Monitoring Kit; Baxter Healthcare Corp) that was leveled to midheart. The transducer output was displayed continuously on an oscillograph (Vicom SMU-612; Hellige; Freiburg, Germany) and recorded continuously on a multichannel recorder (Vicom SMR-821; Hellige). Measurements included mean systemic arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), systolic pulmonary artery pressure (SPAP), MPAP, diastolic pulmonary artery pressure (DPAP), and pulmonary capillaty wedge pressure (PCWP). All hemodynamic measurements were taken at end-expiration. At predicted time points (Table 1), the cardiac output (CO) was determined by thermodilution using a CO computer (Vicom SMU-612 Dilu; Hellige). To achieve CO measurements, 5-mL boluses of ice-cold saline solution were injected at end-expiration via the injection port of the pulmonary artery catheter. The thermodilution curve was inspected for accurate measurement, and the mean value obtained from three consecutive measurements was recorded. By drav.oing blood from the pulmonary artery and the femoral artery, the mixed venous oxygen tension (Pvo2 ) and the Pa02 were detern1ined, respectively, using a blood gas analyzer (ABL 300; Radiometer; Copenhagen, Denmark). The hemodynamic parameters derived were calculated using standard formulas: pulmonary vascular resistance (PVR)~(MPAP-PCWP)xC0- 1 x79.9; and systemic vascular resistance (SVR)~(MAP-CVP) xco- 1 x79.9.

MATERIALS AND METHODS

Animal Preparation

NO Delivery System

After the study had been approved by the Governmental Animal Care Committee, 10 German Landrace piglets (body weight, 18±2 kg) were investigated. All animals were handled according to the Guiding Principles published by the National Institutes of Health and the Council of the American Physiologic Society. 15 Follmving overnight fasting and premedication vl'ith azaperone (Stresnil; Janssen; Neuss, Germany; 1 mglkg IM), the animals were anesthetized using IV administered midazolam (Dormicum; HoffmannLaRoche; Grenzach-Wyhlen, Germany; 1 mglkg) and piritramide (Dipidolor; Janssen; 0.8 mglkg), and paralyzed with pancuronium bromide (Organon Teknika; Eppelheim, Germany; 0.3 mglkg). Ringer's solution was administered during the entire study period at an infusion rate of 3 l)1Vkglh. After endotracheal intubation, the

NO was obtained as a mixture of 800 ppm NO in pure nitrogen (N2) (Messer Griesheim; Ludwigshafen, Germany). NO in N2, air, and oxygen were mixed with a gas blender and delivered to the low-pressure gas inlet of the ventilator as previously described (Fig 1) 19 The oxygen concentration was continuously measured distally to the NO/N2 inlet. Concentrations of NO and nitrogen dioxide (N02) were analyzed continuously at the proximal end of the inspiratory limb using chemiluminescence (N 0/NOyN Ox-analyzer CLD 700 AL; Zellweger Ecco-System GmbH; Munich, Germany). The analyzer was calibrated at the beginning of each experiment using standard gas concentrations according to the manufacturer's instructions. A volume-controlled mode of ventilation was used and the expiratory minute volume was closely monitored. 19 The Fio2

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Laboratory and Animal investigations

Low-pressure Inlet ~ Ventilator Servo™ 900C

NOINOx- Analyzer

Animal

FIGURE l. Diagram of the NO administration circuit. NO in pure Nz, air, and 02 were mixed with a gas blender and delivered to the low-pressure gas inlet of the ventilator. Concentrations of NO and N 02 were analyzed continuously at the proximal end of the inspiratory limb using chemiluminescence. To minimize formation o~ possibly toxic NOz, a sodalime absorber was introduced into the inspiratory limb of the tubing system 19

was kept constant by adjusting the oxygen admixture. To minimize fonnation of possibly toxic N02, a sodalime absorber containing a mixture ofCa(OH)z and NaOH (Grace SA; Epemon, France) was introduced into the inspiratory limb of the tubing system. Using the described equipment (Fig 1), the concentrations of N0 2 measured at the proximal end of the respirator limb were always below L'5 ppm.l9

Experimental Protocol After tennination of the preparation period, the experimental animals were allowed to stabilize for 30 min. All variables were then determined under steady-state conditions (time point 0; Table 1). Thereafter, acute massive PE was induced by stepwise injection of 300-pm microspheres (Sephadex C.'50 coarse; Pharmacia Biotech; Freiburg, Germany) into the superior vena cava over a period of 5 min. Pilot experiments demonstrated an enormous variation in the requirement of the microsphere dosage over time to induce adequate pulmonary hypertension. Fixed dosage schemes resulted in a relevant mortality associated with the injection of microspheres. Therefore, the amount of rnicrospheres administered was individually adjusted to be sufficient to induce an initial increase in MPAP to 45 mm Hg. Three minutes after embolization (time point PE; Table 1), a further set of measurements was taken. In accordance with observations in PE models using clifferent experimental settings, 9 ·20·22 we observed a spontaneous decrease in MPAP and an increase in MAP following experimentally induced PE in pilot investigations using this animal model. For this reason, we did not initiate specific treatment with NO until the hemodynamic parameters were stable at a steady-state level, which was reached in 4.'5 min after PE. This is in close agreement with investigations in other animal models using emboli of different origin.9,20-22 Following a further set of measurements after this minimum

Table 2-Effects of Pulmonary Embolization* Time Point Parameter

0

PE

SPAP, mm Jig MPAP, mm Hg DPAP, mm Hg PVR, dynesls·cm-.5 MAP, mm Hg SVR, d:nesls·cm-·5 CO, Umin HR, bpm CVP, mm Hg PCWP, mm Hg Pa02, mm Hg Pvo 2 , mm Hg PaC0 2 , mm Hg EtC02, mm Hg

23.8:!:0.9 16.6:!: l.l 11.6:+:1.2 199:!:28 86.2:!:2.8 2,202:!:241 3.3:!:0.4 92:!:7 .5.6:!:2.0 9.3:!:0.9 13.5:!:6 41:!:1 38:!:1 39:!:1

60.5:!:2.7 1 43.0:+: l.l I 32.2:!:1.2 1 1,024:!:861 73.7:!:5.6 1 1,853:!:211 2.9:!:0.4 125:!:11 I 10.1:!:1.31 8.5:!:1.3 60:!:3 1 31:+:2 1 44:!:2 1 34:!:2 1

*Sequential changes in SPAP, MPAP, and DPAP; PVR; MAP; SVR; CO; HR; CVP; PCWP; Pa02; Pvo2; PaC0 2; and EtC02. Time points of measurements were at baseline immecliately before embolization (0) and 3 min after embolization (PE). Data are mcan:!:SEM. 1p<0.05 vs time point 0. stabilization interval of4.'5 min (time point Con 1 ; Table 1), we started NO administration at an inspired concentration of 40 ppm. Measurements were repeated5 min after initiation of NO therapy (time point NO 40; Table 1). Follmving 10 min of 40 ppm NO, the concentration of inhaled NO was increased to 80 ppm, and a further set of measurements was taken .'5 min later (time point NO 80; Table 1). A final set of measurements was taken 10 min after CHEST I 110 I 4 I OCTOBER, 1996

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Systolic pulmonary artery pressure [mmHg) 46 44

42 40 38 36

*

35

Statistical Analysis of Data

* p<0.05

~----+-----~----~-----+~--~

Con 1

NO 40

NO 80

Mean pulmonary artery pressure [mmHg]

~----~----~--~~----~--~~

33 31 -

5

* p<0.05 Con 1

NO 40

NO 80

Pulmonary vascular resistance [change in%]

.-----~--------------~-,,-----,

0 -5 -10 -15 -20 -25 -30

90

* Con 1

NO 40

* p<0.05

NO 80

Mean systemic blood pressure [mmHg]

85

80

75 70

65 60+-----+-----~----~----~--~

Con 1

NO 40

NO 80

Cardiac output [L/min] 3.9 3.7 3.5 3.3

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To obtain an initial MPAP of 45 mm Hg by pulmonary embolization, the microspheres had to be administered in doses between 75 and 800 mg (median, 167 mg). No mortality was associated with the administration of microspheres in the animals investigated. The acute effects of pulmonary embolization are summarized in Table 2. The pretreatment control data (Con 1) obtained after the postembolic stabilization phase 45 min after PE are presented in Figure 2 and in Tables 3 and 4. With the administration of inhaled NO (40 ppm), a decrease in SPAP (-10.3% vs Conr; p<0.05) and MPAP (-9.4% vs Con1; p<0.05) was observed, while the changes in DPAP (-7.2%) and PVR (-13.6%) did not reach statistical significance. MAP, SVR, and all the other parameters obtained, including Pa02, Pvo2, and CO remained unchanged (Fig 2; Tables 3 and 4). The subsequent increase in inhaled N 0 concentration to 80 ppm led to a decrease in SPAP (-12.6% vs Con 1; p<0.05), MPAP (-11.9% vs Con1; p<0.05), and PVR (-19.4% vs Con1; p<0.05), without significant changes in any of the other parameters obtained (Fig 2; Tables 3 and 4). Data obtained 10 min after discontinuation of inhaled NO treatment (Con2) were not different from pretreatment control values (time point Con 1; Fig 2; Tables 3 and 4). The postmortem examination excluded intracardiac shunt connections in all animals. DISCUSSION

To our knowledge, this is the first study to demonstrate that inhaled N 0 selectively decreases pulmonary

3.1-

2.9 2.7

Statistical analysis was performed using analysis of variance and Student's t test with Bonferroni correction. Because the data determined 45 min after PE (time point Conr) served as pretreatment control values for assessing the specific effects of N 0 therapy, all measurements of ensuing time points were compared with time point Conr. Student's paired t test was used to evaluate the acute effects of pulmonary embolization. All data are expressed as mean::'::SEM. A probability value of less than 0.05 was considered significant. RESULTS

29

27

discontinuation of NO administration (time point Con2; Table 1). No attempts were made to correct any hemodynamic changes observed during the entire study period with fluid administration or inotropic agents. After completion of the protocol, all animals were killed with potassium chloride, and subsequent postmortem examinations were carried out to exclude intracardiac shunt connections.

Con 1

NO 40

NO 80

FIGURE 2. At left: effect of inhaled nitric oxide (NO) on (from top in descending order) SPAP; MPAP; PVR; mean systemic BP; and CO. Time points of measurements were as follows: immediately before administration of NO (45 min after embolization; Conr); 5 min after 40 ppm NO (NO 40); 5 min after 80 ppm NO (NO 80); and lO min after cessation of inhaled NO (Con2l- Data are mean::'::SEM (asterisk indicates p<0.05 vs Con 1).

Laboratory and Animal Investigations

Table 3-Effect of Inhaled NO After Pulmonary Embolization on Hemodynamic Parameters* Time Point Parameter

Con 1

N040

N080

Con2

HR, bpm CVP, mm Hg PCWP, mm Hg SVR, dynesls·cm-·5

113±11 8.7±1.4 9.8±1.4 1,722±148

113±10 7.4±0.6 8.9±1.3 1,690±157

110±8 7.6±0.7 8.6±1.3 1,640±124

106±8 7.8±0.5 9.2±1.2 1,760±151

*Sequential ch;mges in HR, CVP, PCWP, and SVR. Time points of measurements were immediately before administration of NO (45 min after embolization; Con 1), 5 min after40 ppm NO (NO 40), 5 min after 80 ppm NO (NO 80), and 10 min after cessation of inhaled NO administration (Con2). Data are mean±SEM.

hypertension without causing systemic vasodilation in an animal model of acute massive pulmonary microembolism. This effect was reached within minutes using an inspiratory concentration of 40 ppm NO. A subsequent increase to 80 ppm NO led to a decrease in SPAP, MPAP, and PVR. The decrease in MPAP without significant changes in CO indicates that the changes observed in pulmonary artery pressures and PVR were specific and not dependent on changes in C0. 22 NO administration caused neither systemic arterial hypotension nor a decrease in Pa02 or Pvoz, both of which may be deleterious during the acute phase of massive PE. This contrasts with various IV vasodilating agents that have been used in several experimental settings to treat acute pulmonary hypertension of various etiology. 5·8·23·24 However, inhaled NO did not lead to an increase in PaOz or Pvoz, despite the observation in ARDS that inhaled NO is capable of decreasing intrapulmonary shunting. 12 This may possibly reflect special circumstances in the present model of pulmonary microembolization. In the present model, pulmonary vascular changes may be caused predominantly by mechanical vascular obstruction rather than by any relevant concomitant pulmonary vasoconstriction. The distribution of vascular obstruction and the local effects of microspheres may be different from those of blood clots. 5 It is well known that a significant portion of the pulmonary hypertension that immediately follows blood clot embolization is mediated by vasoconstrictive influences, which are mainly induced by platelet-derived mediators related to platelets coating the emboli. 5·25·26 It may

thus be the case that there is only a small and limited chance of reducing PVR in the present model of acute PE. In the light of the fact that low doses of inhaled NO may have a beneficial effect on oxygenation in ARDS, 27 low doses of inhaled NO may also be taken into consideration. However, to induce a hemodynamic response in pulmonary circulation to inhaled NO, higher doses are required, as are usually used in patients with ARDS with severe pulmonary vascular hypertension. 27 Overall, the insights gained from the present model of pulmonary microembolization could be relevant for clinical PE, because postmortem autopsy studies in patients who had undergone surgery demonstrated that more than 40% of PEs are, in fact, pulmonary microembolisms. 28 The administration of NO after PE was postponed in the present experimental setting to allow for postembolic hemodynamic stabilization in a steady state. 9·20-22 This reflects the clinical situation in which patients would not receive NO therapy immediately, but rather after some delay. Therefore, we did not study the immediate early postembolic effects of inhaled NO. The concept of selective pulmonary vasodilation to treat acute massive microembolism or macroembolism seems to be appropriate. Acute PE results in an immediate increase in PVR and right ventricular afterload, which may in tum lead to impairment of right ventricular function, increases in right ventricular volume and pressure, and subsequent right ventricular ischemia. 4·5·29·30 A decrease in CO with a decrease in MAP may exacerbate this vicious circle by

Table 4-Effect of Inhaled NO After Pulmonary Embolization on Blood Gas and Respiratory Parameters* Time Point Parameter

Con 1

N040

NO 80

Conz

Pa02, mm Hg Pvo2, mm Hg PaCOz, mm Hg EtC02 , mm Hg

60±3 34±2 51±2 38±2

64±3 34±2 50±2 38±2

61±4 33±2 51±2 39±2

64±4 35±1 51±2 39±2

*Sequential changes in Pa02, Pvoz, PaC0 2, and EtC02. Time points of measurements were immediately before administration of NO (45 min after embolization; ConJ), 5 min after 40 ppm NO (NO 40), 5 min after 80 ppm NO (NO 80), and 10 min after cessation of inhaled NO administration (Conz). Data are mean±SEM. CHEST I 110 I 4 I OCTOBER, 1996

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further impairing coronary blood flow to the right and left ventricles. 20 In the experimental setting, right ventricular failure following acute massive PE could be prevented by acutely decreasing right ventricular afterload and/or by maintaining right coronary artery blood flow. 20·29 ··31 Even a moderate but acute decrease in right ventricular afterload is known to prevent incipient right ventricular deterioration after acute PE. 1 Therefore, a decrease in PVR and MPAP induced by vasodilation may be helpful. The use of IV vasodilators for the treatment of pulmonary hypertension, however, may lead to dose-dependent systemic arterial vasodilation with critical hypotension and further impairment of coronary blood flow. 32 In addition, echocardiography has demonstrated a patent foramen ovale in up to 40% of patients with massive PE, 33 and systemic hypotension may increase right-to-left shunting and thus aggravate hypoxemia through the foramen ovale due to the increase in right atrial pressure to above left atrial pressure. 34 Thus, vasodilation of the pulmonary vessels may be beneficial if it occurs \vithout an increase in ventilation-to-perfusion mismatch, but systemic hypotension may be fatal during the acute phase of massive PE. 5 Recently observed inhibitory effects of inhaled NO on blood coagulation and platelet aggregabili!Y r;;ight be of additional benefit following acute PE?'-3 ' In conclusion, the present data demonstrate a specific effect of inhaled NO in reducing the pulmonary hypertension follmving acute massive pulmonary microembolism in piglets. This was not accompanied by systemic arterial hypotension or a decrease in arterial oxygen saturation. Thus, administration of inhaled NO might be a useful therapeutic approach in the acute phase of PE. ACKNOWLEDGMENTS: Our thanks are due to Professor G. Staebler, MD, <:;hairman of the Department of Urology, University of Heidelberg, for his kind support in allowing us to carry out the animal investigations in his experimental laboratories. In addition, we would like to thank H. Bauer, MD, Department of Anesthesiology, University of Heidelberg, for st~tistical analysis, and J. Jakobi, Depmiment of Vrology, University of Heidelberg, for technical and laboratory assistance.

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