Clinical experience in the use of inhaled nitric oxide in infants with pulmonary hypertension

In haled ni tric ox ide (iNO) is a po tent lo cal vaso di la tor. Nu mer ous case re ports de scribe its ef fi cacy in treat ing per sis tent pul mo nary hy per ten sion of the new born (PPHN). This re port de scribes ex pe ri ence at the authors’ in sti tu tion with iNO ther apy in 10 con secu tive in fants with PPHN of a number of eti olo gies. In fants re ceived iNO at doses of 0.2 to 80 ppm for 1 to 481 h. Five in fants were clas si fied as re spond ers (20 torr or greater rise in PaO2) and one as a par tial re sponder (PaO2 rise of 10 to 19 torr). The re main ing four did not re spond. Over all ob served mor tal ity was three of 10, with two of four of non re spond ers and the only par tial re sponder dy ing. Sur vi vors re quired ven ti la tion for 18±18 days and oxy gen for 29±30 days, and they re mained in hos pi tal 40±30 days (mean ± SD). Al though im prove ment in oxy gena tion with iNO was pri mar ily due to re duc tion in pul mo nary pres sure, in se lec tive pa tients, changes in ventilationperfusion re la tion ships could ac count for some of the in crease in oxy gena tion. The pres ence of sig nifi cant me the mo globi ne mia in two pa tients (7% and 4.5%) when the in fants’ iNO dose was in creased to 80 ppm high lights the im por tance of care ful moni tor ing for tox ic ity. Fur ther stud ies are needed to de fine the best dos age and du ra tion of iNO. While iNO shows great prom ise in the treat ment of PPHN, ran dom ized con trolled tri als are needed to de line ate in which in fants iNO use is in di cated.


Expé ri ence clin ique rela tive à l'u tili sa tion d'oxyde ni tri que en in ha la tion chez les nourris sons at te ints d'hy per ten sion pul mon aire
RÉS UMÉ : L'oxyde ni tri que en in ha la tion est un vaso dila ta teur lo cal puis sant.De nom bre uses études de cas dé crivent son ef ficacité dans le traite ment de l'hy per ten sion pul mon aire per sis tante du nouveau-né (HPPN).Le pré sent ar ti cle dé crit l'expé ri ence de l'établis se ment où pra tique l'au teur en ce qui con cerne l'u tili sation d'oxyde ni tri que en in ha la tion pour traiter une sé rie de 10 nouveau-nés souf frant d'HPPN d'é ti olo gies variées.Les nouveau-nés ont reçu de l'oxyde ni tri que en in ha la tion à des doses de 0,2 à 80 par ties/mil lion pen dant 1 à 481 heures.Cinq nour ris -N i tric ox ide is a po tent cel lu lar mes sen ger that plays a criti cal role in the modu la tion of vas cu lar tone throughout the body (1).An im por tant clini cal ap pli ca tion of this action is in the treat ment of per sis tent pul mo nary hy per ten sion of the new born (PPHN) (2)(3)(4)(5)(6)(7)(8)(9).In this pa per we de scribe all neo nates treated at our in sti tu tion from the time of in tro duction of ni tric ox ide as an in ves ti ga tional treat ment mo dal ity up to the start of our in volve ment in a large mul ti cen tre trial of in haled ni tric ox ide (iNO) for PPHN.Our ex pe ri ence thus far raises some in ter est ing points with re gard to iNO dos age and treat ment du ra tion, meas ures of re sponse and its po tential role in the treat ment of many types of neo na tal lung disease.Ul ti mately, the need for mul ti cen tre, ran dom ized tri als to as sess iNO is ap par ent.

PATIENTS AND METHODS
Ten in fants ad mit ted to the neo na tal in ten sive care unit, Win ni peg Chil dren's Hos pi tal, Win ni peg, Mani toba between Sep tem ber 1993 and March 1994 re ceived iNO.All had clini cal evi dence of pri mary or sec on dary pul mo nary hyper ten sion as dem on strated by hy poxe mia and a sig nifi cant dif fer ence be tween pre-and post duc tal oxy gen satu ra tions.All pa tients were in tu bated and me chani cally ven ti lated with oxy gen re quire ments in ex cess of 80% for at least 8 h de spite con ven tional ther apy, con sist ing of as sisted ven ti la tion, bicar bon ate ad mini stra tion (to main tain pH above 7.50), paraly sis (pan cu ronium) and se da tion (fen tanyl or mor phine), sons ont été clas si fiés comme « répon dants » (aug men ta tion de la PaO 2 égale ou supé rieure à 20 torr) et un nour ris son comme « répon dant par tiel » (aug men ta tion de la PaO 2 de 10 à 19 torr).Les quatre autres nour ris sons n'ont pas répondu au traite ment.La mortal ité globale ob servée était de trois sur 10 nour ris sons, dont deux des quatre nour ris sons n'ay ant pas répondu au traite ment ainsi que le seul nour ris son ay ant répondu par tiel le ment.Les sur vivants ont reçu une ven ti la tion ar ti fi cielle pen dant 18±18 jours et de l'oxygène pen dant 29±30 jours; ils sont restés hos pi tal isés pen dant 40±30 jours (moy enne ± écart-type).Bien qu'une amé lio ra tion dans l'oxygé na tion avec de l'oxyde ni tri que en in ha la tion était princi pa le ment at tribu able à une réduc tion de la pres sion de l'ar tère pulmon aire, chez cer tains pa tients, les change ments ob servés dans le rap port ventilation-perfusion pour raient ex pliquer une par tie de l'aug men ta tion de l'oxygé na tion.La pré sence d'une méthémoglobi némie sig ni fi ca tive chez deux nour ris sons (7 % et 4,5 %) quand la dose d'oxyde ni tri que en in ha la tion ad min is trée at teignait 80 par ties/mil lion démontre l'im por tance d'un moni to r age rig oureux pour préve nir la tox ic ité.Il est né ces saire de me ner d'autres études pour définir un dos age et une pé ri ode d'ad min istra tion op ti maux de l'oxyde ni tri que en in ha la tion.Si l'oxyde nitri que en in ha la tion ap paraît comme un traite ment promet teur dans l'HPPN, il est in dis pen sa ble de me ner d'autres es sais com paratifs ran domisés pour pré ciser chez quels nour ris sons l'u tili sa tion de l'oxyde ni tri que en in ha la tion est in diquée.and ino tropic sup port (do pa mine, dobu ta mine and/or noradrena line).Sur fac tant was used at the dis cre tion of the attend ing neo na tolo gist.One in fant with dia phrag matic her nia was treated with high fre quency jet ven ti la tion (Bun nell Life Pulse, Bun nell Inc, Utah).Pa tient char ac ter is tics are de tailed in Ta ble 1. Pa tients with nontreat able, life-threatening malfor ma tions were ex cluded.
In fants with any in crease in PaO 2 were per mit ted to remain on iNO to al low for pos si ble late re sponse.Pa tients were weaned from iNO as soon as they were clini cally sta ble.Dose was se quen tially re duced as long as ven ti la tor rate, pres sures or oxy gen con cen tra tion did not in crease more than 25% to com pen sate for any de te rio ra tion in oxy gena tion (ie, satu ra tions be low 90%).
In fants had post duc tal ar te rial lines in place and un derwent de tailed echo car dio graphic ex ami na tions be fore starting iNO to as sess car diac per form ance and con firm nor mal car diac anat omy and the pres ence, mag ni tude and di rec tion of con tinu ous or in ter mit tent shunt ing via a pat ent duc tus arte rio sus.In ad di tion to se rial ar te rial blood gases, pre-and post duc tal oxy gen satu ra tions were con tinu ally meas ured to as sess the de gree of shunt ing at the level of the duc tus as well as the re sponse to iNO.In fants were clas si fied as re spond ers when the PaO 2 rose by 20 torr or more and as par tial re sponders if the PaO 2 rose 10 to 19 torr whitin half an hour of ini tiation of iNO.To quan tify fur ther the longer term re sponse, the oxy gena tion in dex (OI) was also meas ured.The OI (OI = [mean air way pres sure x frac tion of in spired oxy gen x 100]/PaO 2 ) cor rects for changes in ven ti la tion over time.For term in fants, treat ment was ini ti ated at a con cen tra tion of 20 ppm for 30 mins, and was in creased to 80 ppm for an ad ditional 30 mins if the pa tient did not ex pe ri ence an im provement in PaO 2 of at least 20 torr above base line on the same ven ti la tor set tings and frac tion of in spired oxy gen, and as long as there were no side ef fects (eg, hy poten sion).Pre mature in fants were started on 5 ppm and were not in creased fur -ther be cause of con cern of al tered plate let func tion and the po ten tial ef fect on in tra ven tricu lar hem or rhage.
The ad mini stra tion of iNO was ac com plished by the setup shown in Fig ure 1. Gas from a tank of ni tric ox ide (1000 ppm) in bal ance with ni tro gen (Mathe son Gas Prod ucts Canada) was de liv ered via a flow me ter (# 603, Mathe son Gas Prod ucts) into the in spi ra tory limb of a pressure-limited, time-cycled in fant ven ti la tor (100B, Sechrist In dus tries Inc, Cali for nia) 60 cm proxi mal to the hu midi fier and 210 cm proxi mal to the pa ti ent's en do tra cheal tube con nec tor.The con cen tra tion of iNO was meas ured by a chemi lu mi nes cent ni tro gen ox ides ana lyzer (Model 8940, Moni tor Labs, Lear Sie gler Meas ure ment Corp, Colo rado) from gas sam pled just proxi mal to the hu midi fier.Ex haust gases were scav enged from the ex pi ra tory limb to pre vent en vi ron mental con tamina tion.
Po ten tial tox ic ity from iNO was moni tored by regu lar meas ure ment of blood lev els of me the mo glo bin (metHb) with a co-oximeter (Ra di ome ter, Co pen ha gen, Den mark) and meas ures of ni tro gen di ox ide in ex pired air by an elec trochemi cal sen sor (4584 NO 2 Ana lyzer, Exi dyne In stru ment Tech nolo gies, Penn syl va nia).Pa ren tal in formed con sent was ob tained be fore ad mini stra tion of iNO, and the pro to col was ap proved by the Hu man Eth ics Com mit tee of The Uni ver sity of Mani toba.

RESULTS
Pa tient re sults are de tailed in Ta ble 2. Be fore the ini tia tion of iNO, pa tients had a pre-to post duc tal satu ra tion dif fer ence of 34±14%.In fants re ceived iNO of 0.2 to 80 ppm for between 1 and 481 h.Ad min istra tion of iNO led to in creases in PaO 2 of greater than 20 torr in five of 10 pa tients (re sponders), an in crease of 10 to 19 torr in one pa tient (par tial responder) and a rise of less than 10 torr in four pa tients (non re spond ers) within the first hour of ini ti at ing iNO.Respond ers tended to have a lower ini tial OI (23±17 ver sus  63±53) and had iNO ini ti ated later in life than par tial and non re spond ers (27±11 h ver sus 19±8 h, mean ± SD), suggest ing that par tial and non re spond ers had a more se vere disease pro cess.Fur ther ex ami na tion of OI data for the ini tial 24 h of iNO re vealed two re spond ers who had some de te rio ration be tween 2 and 8 h pos ton set of iNO (Fig ure 2).Only two in fants, both re spond ers, showed pro gres sive im prove ment in OIs in the first 24 h.The maxi mum con cen tra tion of ni tro gen di ox ide de tected in any pa tient was 0.4 ppm.Eight pa tients had maxi mum meas ured metHb be low 2.9%.In the re main ing two cases, metHb rose to 7% and 4.5% when the in fants' iNO dose was in creased to 80 ppm.It rap idly re turned to 2.8% and 2.6% when their re spec tive doses were re duced to 30 and 20 ppm.Only one pa tient (#10) suf fered de te rio ra tion in sys temic blood pres sure with ini tia tion of iNO.How ever, this is likely to have been co in ci den tal be cause this in fant was ex tremely un sta ble he mo dy nami cally for his en tire hos pi tal course un til death, soon af ter iNO was dis con tin ued.
Among the 10 pa tients, three died, of whom two were non re spond ers and one a par tial re sponder.Four pa tients received sur fac tant: two with me co nium as pi ra tion and two pre ma ture in fants with res pi ra tory dis tress syn drome.Sur vivors re quired ven ti la tion for 18±18 days, oxy gen for 29±30 days and re mained in hos pi tal 40±30 days.

DISCUSSION
Ni tric ox ide is a po tent smooth mus cle re lax ant pro duced endoge nously in en do the lial cells, and be cause of rapid metabo lism ex erts its ac tion lo cally in the pul mo nary bed only (1).This se lec tiv ity dif fers greatly from that of other vaso dila tor agents pre vi ously used to treat PPHN (10).To date, pub lished case re ports have ad dressed treat ment suc cess in se lected pa tients treated with iNO, while the over all ex pe rience of in di vid ual cen tres re mains largely un known (2)(3)(4)(5)(6)(7)(8)(9).Al though we have treated only a small number of new borns with iNO, our ex pe ri ence thus far raises some in ter est ing points with re gard to iNO use in the ther apy of PPHN.
Echo car di ogra phy has been widely used to as sess iNO's ef fect on duc tal shunt ing, an in di ca tor of the pres ence and degree of pul mo nary hy per ten sion (5).In our 10 pa tients, neither the di rec tion of duc tal shunt ing on ini tial echo car di ogra phy nor the change in shunt ing af ter ini ti at ing iNO was cor re lated with, and there fore pre dic tive of, the degree of im prove ment in oxy gena tion.This may be a re flection of the limi ta tions of echo car di ogra phy in es ti mat ing ac tual pul mo nary ar tery pres sure (11) and its abil ity to provide only a 'sna pshot' of the con tinu ally chang ing re la tionship be tween pul mo nary and sys temic ar te rial pres sures.Con versely, the poor cor re la tion be tween echo car dio graphic find ings and changes in oxy gena tion due to iNO may re flect the pres ence of con comi tant al tered ventilation-perfusion (V/Q) re la tion ships.In deed, ni tric ox ide is known to have im por tant ef fects on V/Q mis match ing (12,13), which can be quan ti fied clini cally by com par ing the in creases in pre-and post duc tal PaO 2 with ini tia tion of iNO.In two of our pa tients (#1 and #4) where both ar te rial lines were placed, larger improve ments in PaO 2 were seen pre duc tally (190 and 63 torr) than post duc tally (149 and 31 torr), in di cat ing that im proved V/Q re la tion ships were par tially re spon si ble for the re sponse with iNO.Con se quently, the re sponse to iNO in any pa tient must be re lated to over all clini cal im prove ment in hy poxemia and not just to iso lated echo car dio graphi cally de termined al tera tions in shunt ing.
How ever, the ex pres sion of clini cal im prove ment in oxygena tion is also sus cep ti ble to mis in ter pre ta tion.Al though only five in fants were clas si fied as re spond ers due to changes in PaO 2 , nine of 10 pa tients showed some im prove ment in the OI within the 24 h fol low ing iNO ad mini stra tion.Because OI re flects changes in both oxy gena tion and the patients' ven ti la tor set tings, one must be care ful in at trib ut ing a pa ti ent's im prove ment to iNO alone when ex am in ing OI data.In deed, de pend ing on the 'wi ndow' of time one wishes to ex am ine, an im prove ment in the OI while on iNO is seen in all of our pa tients, de spite over all mor tal ity of 30%.The deter mi na tion of cause and ef fect is es pe cially dif fi cult in any in fant clas si fied as a 'late re sponder' where im prove ment may have lit tle to do with iNO.More im por tant, large changes in OI may cor re spond to clini cally in sig nifi cant improve ments in PaO 2 when in fants are pro foundly hy poxic.For ex am ple, al though our ninth pa ti ent's OI dropped by 43 within 1 h of in sti tu tion of iNO (Fig ure 2), PaO 2 in creased by only 6 torr.Thus, there is a need for a ran dom ized con trolled trial to truly de line ate in fants who will bene fit from iNO.
We note that all three of our con geni tal dia phrag matic hernia (CDH) pa tients were suc cess fully treated for their PPHN with iNO, which was ad min is tered con tinu ously dur ing their op era tive re pairs, usu ally a pe riod of in sta bil ity (14).As a group, in fants with CDH have one of the poor est out comes in the neo na tal ex tra cor po real mem brane oxy gena tion (ECMO) reg is try, de spite this ex tremely ag gres sive form of ther apy (15).There is no re li able means of pre dict ing which in fants with CDH will sur vive be fore treat ment is ini ti ated (16)(17)(18)(19).We specu late that only in fants with CDH who have lesser degrees of pul mo nary hy popla sia will re spond to iNO, and that the re main der will con tinue to re quire ECMO.Thus, iNO should re duce the over all need for ECMO in CDH pa tients.
An im por tant, and largely un an swered, is sue is the po tential long and short term tox ic ity of iNO.Ni tric ox ide re acts with he mo glo bin and is then oxi dized to metHb (10).Although it nor mally con sti tutes less than 3% of the to tal he moglo bin pres ent (20), metHb is sig nifi cantly ele vated by in creas ing doses of iNO, which may pro duce hy poxia.Similarly, iNO in the pres ence of oxy gen re acts di rectly to produce higher ox ides of ni tro gen, which are toxic in high con cen tra tions (21).Be cause the for ma tion of metHb and higher ox ides of ni tro gen is dose-dependent, re duc ing iNO to the low est pos si ble ef fi ca cious lev els should re duce po ten tial tox ic ity (22).Case re ports have de scribed us ing iNO at 2 ppm in chil dren with pul mo nary hy per ten sion af ter car diac sur gery (23) and 0.1 ppm for adults with adult res pi ra tory dis tress syn drome (ARDS) (24).We ob served re sponses to iNO as low as 0.2 ppm in two of our pa tients with CDH, which we be lieve are the low est doses thus far re ported in neo nates.Al though such doses are small, they are 100 times higher than the con cen tra tion of ni tric ox ide ex haled by healthy hu mans (25).
In gen eral, the du ra tion of iNO ad mini stra tion has been restricted to less than 72 h (2-7).Al though there is a re port of its use at 20 ppm for 23 days, this pa tient ul ti mately died while still on iNO (8).Ros saint et al (13) de scribed ad mini stra tion of iNO for 53 days in pa tients with ARDS.In two of our patients with CDH, iNO was given for nine and 20 days be fore suc cess ful dis con tinua tion.We be lieve these to be the longest iNO ad mini stra tions with suc cess ful out come re ported in the neo na tal lit era ture.The need for pro longed ad mini stration of iNO high lights the re frac tory na ture of PPHN and the pro pen sity for con tin ued V/Q mis match ing in some pa tients.Sur pris ingly, one of our pre vi ously men tioned pa tients with CDH mani fested the larg est ini tial in creases in PaO 2 of all our pa tients, sug gest ing that the mag ni tude of the ini tial response is in de pend ent of the du ra tion of ther apy re quired.
Al though ex pe ri ence in the use of iNO in in fants with PPHN is lim ited, the po ten tial value of iNO in the ther apy of this con di tion is read ily ap par ent.Our small pa tient number lim its our abil ity to dis cern which pa tients will re spond to iNO.In deed, many ques tions re main con cern ing the use of iNO, in clud ing pos si ble long term tox ic ity and op ti mal dosage level and du ra tion of ther apy.The ul ti mate clari fi ca tion of iNO's fu ture thera peu tic role awaits the re sults of mul ticen tre con trolled tri als, to which we have now con cen trated our ef forts.

Fig ure 1 )
Fig ure1) Cir cuit used to de liver ni tric ox ide to pa tients

Fig ure 2 )
Fig ure2) Changes in oxy gena tion in dex (OI, de fined as mean air way pres sure × frac tion of in spired oxy gen × 100)/PaO 2 ) for re spond ers (left) and par tial and non re spond ers (right) dur ing ini tial 24 h of in haled ni tric ox ide (iNO) ad mini stra tion.Only two re spond ers showed a pro gres sive re duc tion in OI (Pa tients #3 and #4).Two other re spond ers mani fested tran sient in creases in OI be tween 2 and 8 h af ter start ing iNO (Pa tients #2 and #5).In pa tients #9 and #10, large changes in OIs cor re sponded to small changes in PaO 2 de spite con stant ven ti la tor settings

TABLE 2 Characteristics of iNO treatment, with infants listed by decreasing postductal PaO 2 rise with iNO initiation
CL Duc tus closed; iNO In haled ni tric ox ide; metHb Me the mo glo bin; n/a Pa tient died be fore echo car di ogra phy