Synthetic vs Human Surfactants in the Treatment of Respiratory

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                                                                   Synthetic   vs Human Surfactants                                                                                                                           in
                                                                   the Treatment    of Respiratory
                                                                   Distress  Syndrome:    Radiographic

                                                                       . .   .

                                 Deborah    Levine1                   Exosurf,  a synthetic     surfactant,    was instilled    endotracheally      in 49 neonates      as treat-
                       David      K. Edwards      11112            ment for respiratory     distress syndrome.         The radiologic    courses of these neonates            were
                                 T. Allen Merritt2’3               compared    with the courses         of 18 neonates       previously    treated    with human      surfactant
                                                                   and of 18 untreated      neonates.       The radiologic    seventy of respiratory        distress syndrome
                                                                   decreased significantly       in neonates    treated with Exosurt compared            with that in untreated
                                                                   neonates.   Radiologic     improvement        in those treated with Exosurf was slightly delayed
                                                                   when compared        with the improvement           of age-matched        neonates     treated   with human
                                                                   surfactant.        Otherwise          no significant               difference             was      noted      between          Exosurf           and     human
                                                                   surfactant    in radiologic    severity of respiratory    distress    syndrome    or in the prevalence
                                                                   of pulmonary      interstitial emphysema,      pneumothorax,       and bronchopulmonary      dysplasia.
                                                                      These findings support the thesis that artificial surfactant            is an acceptable   substitute
                                                                   for surfactants     of biological   origin, with possible benefits of safety and ease of use.

                                                                      AJR        157:371-374,           August          1991

                                                                      The endotracheal                   application      of exogenous                           surfactants    is variably     effective  in
                                                                   treating respiratory                 distress     syndrome    (ADS)                         in preterm    neonates      [1 -4]. Exosurt
                                                                   Neonatal          (Burroughs           Wellcome,             Research               Triangle           Park, NC) is a synthetic surfac-
                                                                   tant that has                recently         been approved       by the United States                                Food and Drug
                                                                   Administration.              Because          it is a synthetic preparation, the difficulties                                          in purifying           and
                                                                   standardizing              lipid mixtures              extracted             from biological                  materials             are avoided.             The
                                                                   potential        risks of immunologic                       reactions               and     infectious             agents           that     are       possible
                                                                   with lung        extracts         and animal proteins are avoided also [5, 6].
                                                                                              and human
                                                                      The chest radiograph is useful and reliable in assessing the severity of RDS [7-
                                                                   9] and in evaluating the changes in ADS associated        with treatment with human
                                                                   [1 0] and bovine [1 i -i 3] surfactants.  We previously compared findings on chest
                                                                   radiographs   of neonates   with ADS who were treated with human surfactant     with
                                                                   findings on radiographs of similar neonates     treated with placebo [1 0]. We undertook
                                                                   the present study to evaluate    the hypothesis      that neonates  treated with synthetic
                                                                   surfactant         exhibit      radiologic            changes             similar     to those             reported         for neonates                treated
    Received    December      26, 1990; accepted          after    with human             surfactant.
revision March 12, 1991.
    1 Department of Radiology (H-756), University of
California,  San Diego, Medical Center, 225 Dickin-                Materials          and       Methods
son St., San Diego, CA 92103. Address reprint
requests to D. K. Edwards.                                            The patients            treated     with     Exosurf            were      consecutive              pretenm         neonates         (gestational           age,
    2 Department  of Pediatrics, University of Califor-            25-36         weeks)     born between                October         6, 1 989, and August                      7, 1990, in whom                      ADS was
nia, San Diego,    Medical    Center,   225 Dickinson       St.,   diagnosed         on the     basis     of clinical      criteria      (respiratory              distress     and      respiratory          failure     requiring
San Diego,     CA 92103.                                           ventilatory    assistance     with an a/Ao2 ratio < 0.22 2-24 hr after birth-the      a/Ao2 ratio is a
  3 Present address: University         of California,   Davis,    unitless ratio defined as the arterial carbon dioxide partial pressure divided by the dry fraction
Medical Center, 251 6 Stockton          Blvd., Sacramento,         of inspiratory     oxygen minus the arterial carbon dioxide partial pressure:     Paco2/[Fio2    (760 -
CA 95817.                                                          47) - Paco2]) and for whom parental informed consent was available.            Of these 51 patients,
0361-803X/91/1572-0371                                             the radiographs      of one were lost, and one had no films exposed after surfactant   administration;
C   American   Roentgen      Ray Society                           these two patients        were excluded.
372                                                                                                                         LEVINE            ET AL.                                                                             AJR:157, August 1991

        Exosurf          Neonatal           is a 1 3.5:1 .5:1 .0 mixture                      of dipalmitoyl-phospha-                           suggesting        bronchopulmonary                dysplasia           [14], and these results were
tidylcholine,             hexadecanol,               and tyloxapol.                For treatment,                the sunfactant                 compared       with      the     prevalence       of bronchopulmonary                 dysplasia     in the
was reconstituted                         with  water and administered
                                                    8 ml of distilled                                                                           previous study.
endotracheally       in a dose of 5 mg/kg body weight (54 mg/kg of                                                                                 Statistical methods               included      Student’s           t test and chi-square        test.
dipalmitoyl-phosphatidylcholine).   In order to promote   uniform distri-
bution,                                                         to
          half the dose was given with the patient turned 45#{176} the left                                                                     Results
and half with the patient similarly turned to the right. A second dose
was given 1 2 hr after the first dose.                                                                                                                Exosurf-treated               neonates       were significantly                older and larger
        The initial chest radiographs                              were a supine anteroposterior                                 and            than the        neonates             treated  with human surfactant                           and     the
horizontal-beam                    lateral       view       collimated           from        the chin       to the umbilicus;                   untreated       neonates             were [1 0]. The Exosurl-treated
subsequent films were anteroposterior                                             only, collimated to the chest.                                of less than 30 weeks’ gestation were not significantly differ-
Film was TML 1 (Kodak, Rochester,                                                NY) with a Lanex fine screen                                   ent from these patients. Characteristics    of the patients in
(Kodak)           with     film      factors        that      varied       with        the     patient’s         size    (approxi-
                                                                                                                                                these groups are shown in Table 2.
mately        2 mAs at 55 kVp). A 1 02-cm                                   focus-film            distance         on a mobile
                                                                                                                                                   The scores of the severity of ADS on radiographs for these
machine           (General            Electric,         Waukesha,                WI)     was      used,         with     exposure
                                                                                                                                                groups are presented in Figure 1 ; note that the time scale
timed   to the end-inspiration     phase                                  of the ventilator    or during                       quiet
breathing   for patients    not receiving                                 assisted  ventilation.   Films                       were
                                                                                                                                                begins at birth, whereas the statistical analyses of severity
exposed            only        as clinically         indicated.
                                                                                                                                                scores were performed with respect to time since surfactant
        All chest radiographs                      for each patient were evaluated                                      retrospec-              administration.                At no time          were          the        scores   of the groups
tively      by one of the authors                             and by a pediatric                     radiologist          working               treated with Exosurf and                         human surfactant significantly   dif-
concurrently               without           knowledge             of    the time of sunfactant administra-                                     ferent, and both showed                         significant improvement   (p < .025)
tion. Films were scored for the severity of ADS by using a previously                                                                           after surtactant treatment                      compared with untreated neonates.
described      method [1 0J that assigns    higher scores for more severe                                                                       However, the neonates                           of less than 30 weeks’ gestation
ADS (Table 1). Films were also examined           for evidence of air leaks.                                                                    treated      with      Exosurf        took      slightly        longer       to respond     to surlac-
     After the radiographs      were evaluated,      the times of surfactant
                                                                                                                                                tant than did the group treated with human surfactant. Com-
administration     were determined    from the medical     record. Films were
                                                                                                                                                pared with improvement        in the untreated group, the improve-
divided    into 0-5.9   hr, 6-1 1 .9 hr, 12-23.9     hr, and 24-48     hr after-
treatment groups, and radiologic severity scores were statistically
                                                                                                                                                ment in Exosurf-treated         neonates of less than 30 weeks’
analyzed by using films exposed during these periods after surfactant                                                                           gestation did not become statistically         significant   until 6.0-
administration. If more than one film was taken during a given period,                                                                          1 1 .9 hr after treatment    (p < .005), whereas those treated
the average time and score were treated as a single datum.                                                                                      with human surtactant       showed significant        improvement     by
        Comparison                was        made           with    1 8 neonates                  treated   with human                          5.9 hr after treatment (p < .025).
surfactant               and      with       1 8 neonates            treated with                 randomized     placebo                           Air leaks developed     in nine (i 8%) of the Exosurf-treated
(air)     reported             previously         [1 0]. These neonates were generally                                       similar            neonates; all nine had pulmonary interstitial emphysema,            and
to those             treated             with     Exosurf,   except for gestational age                                        (<30             two had pneumothorax        also. Of the 29 neonates of less than
weeks),           a more            stringent           clinical        definition           of ADS (a/Ao2                < 0.15),
                                                                                                                                                30 weeks’ gestation,      air leaks developed         in seven (24%),
and exclusion     of neonates      with suspected    sepsis.  Because    the
                                                                                                                                                which was not significantly different by chi-squane test from
previous   study included only neonates      of less than 30 weeks’ ges-
tation, the Exosurf-treated     neonates were considered     both as a total
                                                                                                                                                patients treated with human surfactant           (i i %) or untreated
group (49 neonates)         and as a subgroup     of less than 30 weeks’                                                                        control subjects (44%).
gestation   (29 neonates).                                                                                                                         Among all neonates        radiographed     by approximately       28
    The final radiographs                            of 1 1 Exosunf                     patients           who were           radio-            days after birth, changes suggesting bronchopulmonary              dys-
graphed            when           28 days           old or older                 were         examined            for changes                   plasia     were       seen       in all groups             (Table        2). These     did not differ

                                          TABLE             1: Radiographic                     Scoring         System         for the Severity            of Respiratory            Distress      Syndrome

                                                                                                                                                                     Cardiac        and
                                                  Score                            Granularity                              Air Bronchograms                        Diaphnagmatic                     Aeration

                                                        1               Faint,      requiring           close             None       beyond      center             Sharp                         Normal
                                                                           observation               to do-                  of chest
                                                        2               Easily       seen                                 Faint at the bases                        Sharp                         Normal
                                                        3               Prominent;              light and                 Obvious                                   Slightly     fuzzy            Normal         to
                                                                           dark         areas      of lung                                                                                           slightly         do-
                                                                           approximately                                                                                                             creased
                                                        4               Marked;           lungs    sub-                   Marked                                    Indistinct                    Decreased
                                                                           stantially           more
                                                                           light       than      dark
                                                        5               Lungs essentially                                 Sharp and distinct                        Indiscernible                 Impossible            to
                                                                           opaque                                            or absent                                                               assess

                                                Note-Reproduced                     with permission             from Edwards           et at. [10].
AJR:157,             August           1991                                                    SYNTHETIC                         VS     HUMAN            SUAFACTANTS               IN RDS                                                      373

 TABLE 2: Characteristics    of Exosurf Neonatal-Treated,                                                                             Human              intraventnicular     hemorrhage     (two). None of these                 deaths     were
 Surfactant-Treated,   and Untreated   Neonates
                                                                                                                                                         attributed     to surfactant   administration.
                                                              Exosurf-Treated                              Human
                                                                            <30 Weeks’                  Surfactant-              Untreated
                                                            Total             Gestation                   Treated                 (n = 18)
                                                        (n=49)                   (n=29)                   (n=18)                                         Discussion

    Mean birth weight (g)                               1 481                    1 071                     1 029                     1074                    Radiologic   improvement    of neonates     with ADS after admin-
    Mean gestational  age                                  29.7                     27.7                      27.7                      28.5             istration   of human and bovine surfactant          has been well doc-
    Male/female ratio                                         27/22                  1 7/1 2                         9/9                   10/8
                                                                                                                                                         umented in the literature    [1 0-i 3]. Similar improvement         occurs
    Mean age at first                                          7.7                     6.0                           6.1               -
                                                                                                                                                         with Exosurt,     which is a completely     synthetic   surfactant.    The
         treatment                   (hr)                                                                                                                slight     lag (approximately          6 hr) in response       to Exosurf         seen in
    Numberdied                                                    9                      8                           0                      4            neonates   of less than 30 weeks’ gestation            is consistent     with
    Number with air leaks                                      9                     7                           2                          8
                                                                                                                                                         findings showing        that Exosurf   has physiochemical        properties
    Number radiographed                                       11                    11                          12                         12
        28 days after                                                                                                                                    that approach      but do not equal those of purified natural lung
          birth                                                                                                                                          surfactant   [6]. This lag time could be clinically            important       if
      Abnormalities                     sug-                      9                      9                           6                      9            pulmonary    interstitial    emphysema       on other complications       that
          gesting           BPD                                                                                                                          would increase morbidity         or mortality    rates developed      during
       Radiologically                   mild                      4                      4                           4                      3
                                                                                                                                                         this     time.
       Radiologically                   mod-                      3                      3                           2                      2               The lack of difference     in radiologic severity between the
         orate BPD                                                                                                                                       entire Exosurf-treated    group and patients treated with human
       Radiologically                   so-                       2                      2                           0                      4            surfactant  may be related to the fact that some of the more
         vere BPD
                                                                                                                                                         mature Exosunf-treated      patients may have had relatively mild
       Radiologically                   nor-                      2                      2                           6                      2
          mal chest                                                                                                                                      RDS; the criterion for Exosurf therapy (a/Ao2                        <     0.22) was
                                                                                                                                                         less stringent than the one for human surfactant                          therapy (a/
       Note.-BPD                 =     bronch opulmonary                     dysplasia.                                                                  Ao2 < 0.i 5). Neonates        with relatively    mature lungs would be
                                                                                                                                                         expected     to improve more rapidly than less mature neonates,
                                                                                                                                                         regardless     of treatment.    This speculation      is supported   by the
significantly     between groups in either prevalence     or radiologic                                                                                  fact that bronchopulmonary          dysplasia,    which is generally con-
severity.     Bronchopulmonary     dysplasia    did not develop in any                                                                                   sidered    to be a multifactorial        complication      of oxygen    and
of the 20 Exosurf-treated       neonates     of more than 30 weeks’                                                                                      ventilator   therapy,    did not develop in any of the more mature
gestation.                                                                                                                                               Exosurl-treated          patients.
   Causes of death in the Exosurf-treated             neonates were                                                                                          Number    of deaths among the Exosurl-treated            population
sepsis (three cases), disseminated       intravascular coagulopathy                                                                                      (nine) were not significantly      different   from the number          of
(one), exsanguination      after central venous catheter placement                                                                                       deaths in the human surfactant-treated          (zero) and untreated
at the referring institution (one), respiratory failure (two), and                                                                                       (four) populations,    probably   in part because         of the small
                                                                                                                                                         numbers    of patients studied. A contributing       reason may have
                                                                                                                                                         been that the human surfactant       study excluded      neonates with
                                                                                                                                                         signs of sepsis, whereas      the Exosurf    study did not; three of
                       ?   1st       Dose          of   Surfactant                                                                                       the Exosurf-treated    neonates   died of sepsis.
                                                                                                                                                           A major source of morbidity and mortality in neonates with
              4                                                                                                                                          ADS is intracranial hemorrhage.  The prevalence of this dis-
                                                                                                                                                         order      in our patients      was not examined          in this study      because
                                                                                                                                                         it appears well established in many trials that the administra-
              3                                                                                                                                          tion of surfactant does not influence its prevalence [15].
                                                                                                                                                                      patients treated with human surfactant,
                                                                                                                                                                In three                                                 a transient
 0                                                                                                                                                       interstitial       disease developed
                                                                                                                                                                           lung                      [1 0]; this was not observed
                                                                                                                                                         after administration      of Exosurl,    nor were findings      suggestive
                       U   Control                                                                                                                       of asymmetric      surfactant   deposition.
              1        #{149}
                          Human                 Surfactant                                                                                                  The validity      of comparing      Exosurl-treated      patients     with
                       A   Exosurf               Neonatal                                                                                                neonates          treated 5 years earlier may be questioned.                However,
                       0   Exosurf               Neonatal             30    weeks        gestatlonal           age                                       other than the composition     of the exogenous                    surtactant,   no
                                                                                                                                                         major changes   in the treatment     of neonates                  with ADS have
               0       2         4          6       8        10       12    14      16       18    20     22         24    26     28        30
                                                                                                                                                         taken place in our nursery. Also, the pediatric                   principal inves-
                                                                  PatIent         Age        (hours)
                                                                                                                                                         tigaton and the primary              pediatric   radiologist    were the same in
       Fig.        1.-Scores                of the radiologic                    severity         of respiratory            distress             syn-    both      studies.
drome (RDS) in neonates treated with Exosurf Neonatal, human surfactant,                                                                                   Our results suggest that Exosurf, by radiologic criteria, is
and placebo. Higher scores reflect radiologically more severe RDS. Arrows
indicate average times of surfactant administration. Bars indicate standard                                                                              nearly as effective as human surfactant in ameliorating  ADS.
error of mean.                                                                                                                                           The availability, ease of preparation, and minimal expected
374                                                                                                    LEVINE       ET AL.                                                                 AJR:157,   August   1991

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                                                                                                                         classifications of infants with the respiratory distress syndrome. Eur J
treatment          of ADS.                                                                                                Pediatr       1979;130:271-278
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                                                                                                                         the idiopathic respiratory distress syndrome: a radiologicaland pathological
                                                                                                                          correlation       study.        1976;27:65-75
                                                                                                                                                     Clin Radiol
                                                                                                                      9. Weller MH. The roentgenographic          course and complications    of hyaline
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