Note: Descriptions are shown in the official language in which they were submitted.
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1
TREATVtENT OF ACUTE RESPI:RATOlE2Y DISTRESS SYNDRO~IIE
CROSS REFERENCE TO RELATED APPLICATION
100011 This application claims priority to U.S. Provisional Patent Application
No.
60/761,250, filed January 23, 2006, and to PCT[US2006/02423, fil.ed Janciary
23, 2006.
FIELD OF INVENTION
[00021 The present invention. relates to the treata.nent of a patient
sufferia3g from acute
lung injury (ALI) and/or acute respiratory distress syaadroine (ARDS) by
admi.nistering a
lung surfactant preparation to the patient.
BACKGROUND OF TFiE TNVENTION
[0003] Acute respiratory distress syndrome (ARDS) was originally termed the
adult
respircrtory distress syndrome because it resembled the clinical pictur.e of
infant
respiratory distress syridrome (IRDS), and botli exhibitea liyaline mexnbranes
at autopsy
(Lancet. 1.967;2:319-323, Claest. 1971; 60:233-239). Avery and Mead (.4 z. J.
Dis. Child.
1959:97:517-523) first reported that luiag surfactant quantity and activity
were abnormal
in infants with IRDS, and surfactant rcplac8ment l.ias subsequently beconie
standard
therapy f'or premattire infan.ts at risk for or l-iaving IRDS. Petty and
Ashbaug. (Chest.
1971; 60:233-239) described qualitative and quantitative surfactant
deficiencies in thei.r
initial description of ARDS, and the subsequent scientifc literatLire,
recent.ly reviewed by
Notter (Lurzg Sui;factants. New York, NY: Marcel Dekker, 2000), has supported
the role of
surfactant dysfunction in both ARDS and less severe acute ltmg iu~jury (ALI)
(,4xl2.
J. Reslbir=. Crit. Ca.re llfecz'. 1994;1.49:818-824).
[00041 Surfactant replacement in ARDS and ALI in hunians has bccn largely
urisuceessful. Tliree large prospective, randomized controlled clinica.l
trials of
surfactant replacement demonstrated little or iio benefit in adults wilb ARDS
or ALI
who were treated with aerosolized synthetic Exosurf (Btu-roughs Wellcome,
Kirkland,
Quebec)(1V. Etzgl. J.Afed. 1996;334: 1417-1421), instil.led, semisynthetic
Survanta
(Abbott Laboratories, Abbott Park, IL) (Atn. J. Respir. Crit. CrxreMcrl. 1997;
155:1.309-
1315), and instilled recombinant surfactant-speci.fic protein C-
based'VeiZticute (ALTANA
Ph.anna, Konstanz, Gerinany) (N. Lragl. J. Med. 2004;351:884-892).
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[00051 Surfactant preparations differ in phospholipids, neutral lipid, and
protein
eoniposition and the failure of previous trials may relate to these
differences. The
i,rnportan.ce of the hydrophobic surfactant apoprotein surfactant-specific
protein. B has
only recently been r.ecognized. (Pecliatr.Res. 1986;20:460-467).
(0006] Calfactant is a rnodifiQd natural surfactant with a ratio of
p.laosphol.ipids to
apoprotein SP-B sunilar to ttiat found in natural bovine surfactant (Expc:rt
Opin.
1'hcrrinacnther. 2001;2:1479-1493). Biophysical and biological testing
demonstrates
activity equal to natural surfactant (Am.Rev Respir. Dis. 1992;145;24-30) and
resistance to inhibition by plasma and other profeins associatod with lung
in}ury or
1U by cell wall. and lysophospholipids (Afn. J. Respir. C'rit Care Mer.i.
1998;158:28-35).
[0007] It was hypothesized that a natural surfactant coittaining high levels
of SP-B,
such as calfactant, naight prove effective in ARDS or ALI. A positive acute
response to
calfactant adna.inistration in. an open-label trial in. 29 children.
ventilated for ALI was
reported in I996(C'rit Care Med. 1996;24_1376-1322), and a subsequent
contxolled but
un-blinded st-udy of 42 patients replicated tlris acute improvement and
demonstrated a
shortened ven.tilator and intensive care unit course (Crit. Ccire.Med.
1999;27;188-795).
The positive restilts in those prelinlinary studies led to a multicenter,
blinded,
controlled trial of calfactant coinpared with placebo in infants, children,
and
adolescents with respi ra.tor.y faa.lure from ARDS or AI.,I.
SUMMARY OF THE INVEN'TION
[0008] The present invention is directed to a process for treating a patient
su.ffering
from lung disease that requires the use of mechanical ventilation to sustain
breathing. The
process coniprises the stop of adzninislering to the pati.en.t a
therapeuticail_y effective dosage
of a surfactant coniprising SP-B and phospholipid at a concentration of SP-B
relative to
concentrati.on of phospholipid that is sufficient to prodi.ice detectable SP-B
activity.
[00091 The preferred sLiTfacta-it is calfactant.
BRIEF DESCRIPTION OF THE DRAW INGS
[00010] Figure i is a chart depicting the enrolhment of patients rand.omly
assigned to
the cal.f:actant and placebo groups.
[000111 Figure 2 is a grapli coinpEuing the successfiil extubation of
calfactan.t and
placebo patients during the study.
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3
[00012] Figure 3 includes two graph.s of oxygenation index vs tin-ie for the
calfactant
a:tld placebo patient groups.
[000131 Figure 4 contains Tables 1, 2, a.nd 3, which are discussed in the
Detailed
Description of the Inventior.z.
DETAILED DESCRIPTION OF THE IN'VENTION
1000141 The present invention relates to a process for treating a patient
sufferi.ng frorn
acute respiratory distress syndrome (ARDS) or acute lung injury (ALI), as well
as other
patients suffering from 1tu1g discasc that i-cquires the use of inechan.ical
ventilation to
sustain breathing but does not meet either the X-ray and/or the severity
criteria for
ARDS or ALI. More specifically, the invention, is directed to the treatnzent
of a patient
selected frona. the group consisting of (a) patients suffering from acute lung
injury, who are
patients with acute respiratory failure requiring mechajaical ventilation,
witli severe bilateral
Iiui.g ederna/collapse by chest X-Ray, and havin.g a ratio of arterial oxygen
partial pressure,
Pa0?, to fractior.t of irlspire:d oxygen, FiO2,that is less t111n 300 (PaO-
)/Fi02 <300); (b)
patieats suffering from acute respiratory distress syndroine (ARDS) who are a
subset of ALI
patients in that their PaO2/FiO2 <200; and (c) patients suffering fronz lung
disease that
requires the use ofinechanical ventilation to sustai.n breathing but does ziot
r7ieet either llie
X-.ray and/or the severity criteria for ARDS or ALT.
[000151 The process comprises the step of administering to the patient a
t.herapeuticaliy
effective dosage of a surfactant coin.prisi.ng SP-B and phospholipid at a
concentration of SP-
B relative to concentration of phospholipid that is sufficient to produce
detectable SP-B
dependent activity, whereby the patient has an improved likelihood of stu-
vival relative to a
coinparable patient treated with a placebo.
1000161 With respect to this invention, thc teiin "SP-B" is understood to
refer either to
"apoprotein SP-B" or "a protein that ex:hi.lii.ts SP-B-Iike activity."
[00017} I:n a preferred etY7Tcodirric:nt of the invention, the surfactant is
admitzistered by
in.tratracheal insti.liati.on.
[000181 In another preferred embodiment of the invention, the therapeutically
effectivc dosage coniprises about 10 n1g phosphol.ipid/kg body weigllt to
about 200 ing
phospholipid /kg body rveiglit, which is equivalent to about 400 mg to about
8400 mg
plzosphol.ipid / m2 of body surface area, or about 1.1 ml to about 240 rnlhn2
of a suspension
containing pliospholipid in a concentrati.on of about 35 nzg/ml.
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[00019[ In another preferred enibodiment of the invention, the surfactant
comprises a
saline sitspensioil comprising about 25 mg/nil to about 100 mg/inl
ofphospholipid, plus
SP-B in an azzoii.nt of about 0.1 wt. % to about 4.0 wt.%, based oii. the
weight of
phospholipid.
[00020] In another preferred embodiment of the invention, the surfactant i s a
li.ang
surfactant.
[00021] h1 a particularly prefe:rred ernbodirnent of the invention, the
surfactant is
calfactanL.
[00022] The activity of SP-B can be measured as biophysical activity or
biologic
act:ivity. Biophysical activity is determined by observing i:iia.t the surface
ttension ofan
inverted air "bubble" in the suspension under consider.ation reaches < i
nliNlnl at mininltzm
bubble volunze within 5 nzinutes when oscillated in a Pulsating Bubble
Surfactoineter
(Electronetics, Anzherst, NY) at 20 cycles/rninute as described in Wang et a1.
(Arrz JPdzysiol
Lung C'ell.Mol Physiol 2002; 283: I,$97). Biologic activity is detennin.ed by
observing
restoration to n.on.-nal of the deflation pressure-volume curve in an excised
or in situ
surfactant deficient aiiimai liing using the method of Bermel (Lun.g 1984; 162-
99-17 3) or
Mizuno (Peiliatr Res 1.995, 37.271-276).
[00023] In another embodiment, the present invention is drawn. to the
supplement.atiolz of the conapositions of the invention with exogenous SP-B or
SP-C,
alotie cir in combination, and particularly to the supplementation with
exogenous SP-B.
For example, the results of the present invention are counterintuitive in that
ARDS/ALI
is not readily characterized as a surfactaiit deficient state, a ten-n which
would be most
appropriately used to describe the situation that prevails in the lungs of a
premature
infarit. Insteaci, while not wishing to be bound by any particular theory, the
results
obtained herein suggest that it might be most appropriate to .refer to
ARDS/ALI as a
surfactant dysfuinctional state, where nornia.7 surfactant fiinction is
disitiipted by, for
example, pr.oteins and other materials resulting from lung damage.
[000241 Again while not wishing to be bound by a.ny particular theory, the
results
obtained herein are st7ongl.y suggestive of the protective aspects of
surfactants in such
situations of surfactant dysfunction, and also strongly suggest that the
presence of SP-B
and/or SP-C, but particularly SP-B, in added surfactant znay confer an
advantageoLis
effect on a patie7lt suffering from ARDS/ALI, particularly in terzns of
red:uction of
patient mortality for suc1.1 ARDS/ALT patients.
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[000251 Thi.i.s in light of the above, an ernbodiment of the present invention
is based
on the supplenient.ation of the surfactants of the invention, i:ncluding, but
not linai.ted to
the calf-lung based surfactants of the invention, with exogenous SP-B or SP-C.
.For
exan-iple, the surfactants of the invention may be supplemented with SP-B or
SP-C
5 obtained as described i.n United States Patents No. 6,020,307 or 6,458,759,
herein
incorporated in their entirctics by refercnce. Such compositions inay exhibit
further
advantageous properties as described above or in addition to the above. Assays
for these
properties will include cliidcal studies as well as physical and.
biochetn.ical assays for
lung function such as desci-ibed elsewhere herein. Assays will also include
aniinal
models wliich znodel the presence ofvarious conipotulds in the lulzgs in
ART)S/Ai..I
cases that nlay result in surfactant dysfitnction, such that any p'rotective
effects surfactant
containing exogenously provid.ed SP-B or SP-C alone or in combination may be
assayed.
[000261 In the above embodimetit of the invention, SP-B may be added in an
anloun.t
such that the total amount of SP-B in the surfactan.t (i.e., endogenous plus
exogenous) is
about 0,1 wt. % to about 4.0 wt.%, based on the weiglit of pliospliolipids,
and more
preferably in an arziount such that the total aniount of SP-B in the
surfactant is about 0.7
wt fo, 0.8 wt "/o, 0.9 wt Jo, 1.0 wt %, 1.1 wt Jo, 1.2 wt %, 1.3 wt %, 1.4
wt ofo, 1.5 wt %,
1.6 wt %, 1.7 wt %, 1.8 wt %, 1.9 wt /u, 2.0 wt %, 2.1 wt `%, 2.2 wt %, 2.3
wt /u, 2_4 wt
%,2,5wt%,2.fiw't%,2.7wt%,.2.4wt%,2.9wt%,3.0wt%,3.1 Wt"/o,3.2wt%,3.3
wt%, 3.4wt0110,3.5wt 1o,3.6wt%,3.7wt.%,3.8 wt%,3.9wt%,or4.Owt%,and
most preferably greater than about 0.7 wt % based on the weight of
phospholipids. SP-C
may be added in similar aniounts,
[00027] Tl:ie following description is illustrative of the process of the
present
invention.. Those skilled iri the arL will recognize that scope of the
invention is not
limited by the specific exan-iples and treatment protocols d.escribed herein.
Patients
1000281 In accordance with the present inventivn, a patient undergoing
treatnlent
is preferably post-neonatal, i.e., after 40 weeks post-conceptual age, and one
wcclc
3o or more after birth,
[00029] Twenty-o.ne pediatric inten.si.ve care units (PICUs) across the
Pediatric Acute
Lung liajLrry and Sepsis Investigator network enrolled patients over a 3-year
period from
July 2000 to :3'uly 2003. Institutional review boards at eacll institution
approved
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the study protocol. Tnfornied consent was obtained from a parent or guardian
prior to
enrollz.nent. Demographie infonm.ationobtained included age, sex, and raee/
ethnicity
(white, black, Hispanic, or other), determined from the nzedical record..
[00030E En.try criteria included age I weelc to 21 years; respiratory failure
d.ue to
radiograpliically eviclent bilateral parenchymal lung disease; enrolli-nent
within 24 hours of
initiation of niechanical ventilation (extended to 48 hours after the in.itial
50 patients);
and an oxygenation index higher than 7[oxygenation. index=(fraction of
inspirecl
oxygen) X (mean airway pressure) X l00/PaOz].
[00031] Exclu.sion criteria included prematurity (corrected gestational age
<37
weeks); status asthmaticus; head injury with Glasgow Coma Scale of <$; chronic
luiag
disease defined by home oxygen or diuretic use; brain death, do not
resuscitate orders,
ongoing cardiopulmonary resuscitation, or limitation of life support;
siViificant airway
disease that might delay extubation; uncorrected congenital heart disease,
preexisting myocardial dysfi.inction, or cardiogenic pulmonary ede.ina.
[00032] Randoni:ization was sti-ati.Ced to bala-nce the severity of lting
injury
between groups at stttdy entry. Stratification was based on evidence of
increllsed
nlortality in. patients with an oxygenation index of 13 or high.er (fast
entry) compared
with an oxygenation index hi.ghcr than 7 but less than 13 (slow entry) within
6 hours
of th.e initiation of mechanical ventilation.
Study Protocol
[00033] Patients were randomized to receive in(ratracheal instillation of 2
doses of 80
mL/rr.mz calfactant (35 mg/rnL of phospholipid suspension in saline) or an
equal
volume of air placebo. For infants weighing less than 10 kg, the equivalent
newborn
dose of calfactant was 3 mL/kg. Treatment was administered in 4 equal aliquots
instilled intratracheally via a srnall catheter. 1'ai:ient positions were
changed between.
aliquots (left decubitus, head up tl=ieti down; right decubitus, head up then
down) and
sedation and neuron-iuscular blockade were given for the procedure. Gas
exchange was
inaintarned by manual ventilation with 100% oxygen using pressures comparable
with.
those previously used on mechanical ventilation. By protocol, a second
intervention was
performed a mean (SD) of 12 (2) hours later if the oxygenation index rernained
higlzcr
than 7.
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[00034] To niaintain blinding, a pharn-iacist drew the next (opaque) envelope
frorn
the appropriate fast entry or slow entry file previou.sly randomized centrally
in bloclcs
of 2 and 4 and seut the syringes of calfactant oz placebo to the PICU in an
opaque
container. A respiratory therapist not otherwise involved with the care of the
pati.ent placed opaque tape on the endotracheal tube an.dperformed the
intervention_
Physicians, investigators, and nurses caring for the patient reinained
blinded. to
treatment assignmen.t th.roughout the study.
1000351 Participating physicians agreed to follo~v ventilator guidelines
limiting tidal
volume of less than 8 mL/kg; fraction of inspired oxygen of less than 0.6;
peak inspiratory
pressure of less than 40 nzrn Hg; ancl ;['UC02 of greater than 40 a.nd less
than 60 nim I Ig.
Blood gases and ventilator settings were evaltiated through study day 14.
[00036] Treatment with other surfactants was pirohiUited and the clinical care
teaii
determined all other aspects of the patient's care. All data were collected
prospectively.
Study Dr
{00037J Calfactant (1i:i.fasurfproduced by NY Ine, Amherst, NY) is a
nlodified
natural lung surfactant approved by the Food and Brnxg Acia-ninistTation for
:I1ZDS and
produced by extracting the phospholipids, neutral lipids, and hydrophobic
apoproteins
SP-B and SP-C fion3 bovine lung st.irfa.ctant obtained by saline lavage of
newbon2 calf lungs.
studv Out.conze
[000381 The priniaiy efficacy outcome was the duration of respiratory failure
as
measured by ventilator-free days in the 28 days following study entry. A
ventilator-free
day is a coixiposite ozi.lcoine Chat i.ncoi-porates both moi-tality an.d
dtration. of n-ieclianical
ventilati.on. Tn. the analysis, deatlz or the need for extracorporeal
tne.tnbranc oxygcnation are
equivalent to unresolved respiratory fai.lure at 28 days and equal to zlo
ventilator-free days.
Death was prospectively identified as tlie nlost irsiportant oulcUme and was
eareful.ly
i-tionitored for sa.fety reasons. Based ota niortality differences in.
preliminary studies, the
stlidy was not expected to identify a mort2lity benefit (CYit Care Nlecl.
1.996;24:131 U-1322).
[00039] Additional efficacy outconic mcasurements included PICU and hospital
lengths of stay, hospital charges, duratkozl of supplemental oxygen therapy,
and. failure of
conven.tional nzechanical ventilation (defined a priori by the use of high-
frequ.ency
oscillatory ventilation, nitric oxide, or extracorporeal membrane
oxygenation).
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[000401 The acute effects of surfactant therapy were evaluated by comparing
the
oxygenation index in the treatment aiad placebo groups over the 24 hours after
treatment. Vital signs and oxirnetry were monitored continuously and recorded
at 5-
min.ute intervals for 30 minutes after the intervention. Com.plicat7on.s at
the time of study
intcrvention included any si~,mi:C.cant change in vital signs (e.g.,
bradycardia,
hypotension) oi- sustained (>30 seconds) oxygeti saturation of less than 80%.
Safety
outcornes included mortality, pulmonary complications (air leaks, pulnionary
hen7orrli.age, atad nosuc;orriidl plreLtmo:nia), and any unexpected adverse
events.
Manczgemerr.t o,f Zhe St. ud~
[00041] T12e original study design called for enrol.linent of 300 patients and
completion in 2 years. Sarnple size calculation based on pilot study data
(Crit. Ctzre
Meci. 1999;27:188-195) suggested a 25% reduction in the 13-day average
ventilator
cour.se for pediatric respiratory failure would require 274 patients with an a
level of 05
and a j3l.evel of .10. Af-ter the f:rst year, it becarne apparent that
participating centers were
ezirolling fewer patients than expected. The data arid safety monitoring board
endorsed
a 1-year study extension and closure of the study at the end of that year
regardless of
enrollment. The data and safety rrzonitoiing board conducted an interim safety
analysis
when 1(}0 patients had beeri enrolled. No significant differences in adverse
events or
deaths were found. However, mortality was higher thai in the previous two
studies
(Crit Care Mecl. 1996;24:1316-1322, Crit. Care Med. 1999;27:188-195),
proixlptiitg a
blinded review of all deaths by the board. The board concluded that tl7e
increase in
deaths was due to the inclusion of immunoconzpromised.- children in the
current
study. At the di.rection of the Food arid Drug Adrninistration, the board
continued to
revicw the findings with each additional 10 d.eaths. The study was stopped at
the
predetem-l:i.ned 3-year limit and was not stopped because of mortality
differences. 'i'he
znortality diffcrcncc we found was not discovered until after tl-1e study was
closed.
Stc.7tistica.l ~.na.lt>sis
[000421 xz tests vver-e used to cuinpare groups w:ith respect to categorical
outcomes.
The Wilcoxon rank swn test was used to compare groups witb quantitative
outcomes.
Cure-rate models were used to compare time with successful ex.tubation (Lung
1984;
162:99-1). Repeated measures models were used to coni.pare the oxygenation
index
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9
within subjects over time. In post hoc analyses, logistic regression niodels
were used
to assess treatr.n,ent effects otz r:nortality, which were adjusted for fast
or slow entry
stratification factor; study site (sites with < 10 patients enrolled were
treated as one site);
age category (<t year, 1-5 years, 6-13 years, >13 years); and immune status
(immunoco ipronzised. vs no .conipromised). All variables and the subset of
variables
found to be significant were thcn tcstcd in rnultivariate models that included
the
treatnient group. We used statistical software to fit the cure rate nzodels
(GAUSS, Aptech
Systerns, Keiit, Wash) ai-id for other analyses (SAS version 8.2, SA.S
Institute, Cary, NTC).
Statistical signi.ficance was considered to be P<.05.
IO
Results
[00043] A total of 153 patients provided conseixt, but a parent withdrew
consent
prior to treatment. Seven.ty-seven patients were randomized to the calfactant
group,
and 75 patients were randoniized to the placebo group (Ftc.,'(ynt; 1). All
data were
included in an inten.tion-to-txeat analysi.s.
[00044] At study entry, 91 /a of patients nzet ARDS criteria and all patients
met ALI
criteria (Am. JRespir. Cria. Cure Mecl. 1994;149:818-824). There were no
significant
differences between groups in demographic profile, severity of illness at
randomization,
or coexisting diagnoses o-i- co-morbidities (TABLE 1). Although not
statFst]cally significant,
th.ere were five additional bone rnarrow transplant patietits in the placebo
group and
three additional near-drowriingpatients in the surfaetant arm; both groups had
I.iigh
baselin.e mortality. Eight protocol violations were identified: six patients
(tl-iree placebo
and three calfactant) had an initial oxygenation index of less than 7 but met
all other
entry crileri<<, and two patients (one placebo and one calfactarlt) received
nonprotoeol
surfactant adnlin:istration after the study interventifln. Adherence to tlxe
ventilator
guid.elines was comparable between groups. Fraction of inspired oxygen and
pea.l.c
pressures were within guidel'uies more than. 90% of the titne and PaC02 was
higher lhan
40 nuii. Hg more th.an. 80% of the tinie.
[000451 Unexpectedly, mortality was significantly greater in the placebo group
compared with the calfactant group (27/75 vs 15/77; odds ratio [OR], 2.32 [95%
confidence interval {CI}, 1.15-4.85]) when all deaths were considered and was
still
significant when death without recovery from respi.ratory failure was
considered
(Tasr.,.E2). Respiratory failure was given as the priniary cause of death in
40% of patients
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and as a major contributor of death in 43% of patients. Calfactant patients
averaged a
mean (SD) of 13.2 (10) ventilator-free days at 28 days, while placebo patients
averaged 11.5 (10.5) ventilator-free days (P= .21). The cumulative percentages
of
ext2ibated patients in each group over the first 28 days appear in rIGI.;~R.E
2.
5 f 00046] Oxygenation as measured. by oxygenatio.n index significantly
improved with
both doses ofcalfactan.t (FIGURI:3). Inaprovement after the first intervention
was not
adequate to precl.ude retreatment in most patients, however, as most
calfactant (70%) and
placebo patients (79 so) received a secon.d intet-vention per the study
protocol becal.I.se
their oxygenation index remained greater than 7,
10 [000471 Znfants younger than 12 nlontlzs constituted 26% of the population.
Mortality
in th:is su.bgroup of placebo patients was more than three tirn.es tllat of
calfactant-treated
patients (9/19 vs 3/21; P=.02). Ventilator-free days were also statistically
fewer in
placebo patients (na.ean [SD], 7.0 [9.9] vs. 15.2 [10.3]; P=.01).
(00048] Table 2 reports other clinical otttcomes. M.ore placebo patients did
not
respond to convcntional mechanical ventilation after the study intervention.
Comparison. of duration of oxygen therapy, hospital and PrCLr lengths of stay,
and
hospital chxrges revealed no statistical differences betweeia groups.
[00049] Inlmediate connplicat:i.ons associated with instillation were more
frequent
in calfactant patients and were similar to the acute responses ofnew-horns to
surfactant
instillation. (Pedictty-ics. 1997;100:31-38). Hypotension was seen in 9% of
calfactaiit
instillations compared with 1% of placebo instillations (P=.005). All patients
with
hypotensio,ri responded to volume infctsion. Transient hypoxia occurred in 12%
of
calfactant instillations cotnpared with 3% of placebo instillations (P=.008),
but resolved
wlzen the calfactant instillation was slowed and/or the positive-pressure
ventilation
was transiently increased.. No patient was removed froni. the study because of
treatment complications. The incidence of air leaks was 13% in the calfactant
group
and 16% in the placcbo group (P=.65). Nosocomial. pneumonia was seen in 6% of
calf'actant patients and 11% of placebo patients (P=.40). No systemic
c=onzplications
were ascribed to tlio iriter vention in either group. The ORs an.d associated
95% CIs
of the treatment effect on mortality adjusted factors identified a priori
(fast vs. slow
entry, center) or a posteriori (age, immune status, enrollment nun~ber) are
shown in
TABLE 3. Although treatnient group is not significant in all models,
particularly
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those that adjust for ilnn:runoconipromised status, the OR associated with the
treatment was at least 2.1 for all models listed in TABL:E 3.
j00050j Infants, childreti, and adolescents with AL T who received calfactant
in this
naulticenter study had. decreased mortality, more rapid. improvement in
oxygenation
index, arrd were moi-e likely to respond to conventional mechanical
ventilation. The
prirnary outcome variable, ventilator-free days, was not significantly
different between
groups. Transient hypoxia and hypotension were nlore common with calfactant
treatinc;rrt, bul these effects were mil.d and did not necessitate withdrawal
from tlae study.
The acute positive effect of calfactant on ventilation in this trial is
consistcnt with
previous studies of calfactant in ch.i.[dren(Crit C,are Med. 1996;24:1316-
1322, Crit Care
Med. 1999;27:1. 8 8-195).
[00051] Infant respiratory distress syndrome results from quantitative
de~ficiency
of surfactant .leading to respiratory failure from progressive atelectasis.
Surfactant is also
deficient in ARDS and ALI, but is al.so inhibited by inila.i7umatory
mediators, plasma
proteins, and cellular debn's that are seeping into the airspace.
Consequently, the chal-
lenges for successful surfactant replacement therapy in ARDS and ALi are more
complex than for ll2DS (Biotnetrics. 2001;57:282-286). Two surfactants
effective in
IRDS had disappointing results when tested in large cliilical trials in ARDS
and ALX (N.
Eragl. .T. Mee 1996;334: 1417-1421, flrri. J. Resl.7it: Crit. Care Itileci;
1997; 155:1309-1315).
[000521 `f`lie previously observed acute benefits of calfactant on lun.g
function were
replicated herein (C'rit Care Med. 1996;24:1316-1322, Crit. Care Med.
1999;27:188-195).
Both doses of calfactant improved oxygenation, demonstrating that it caz.-i
fonn a
funetioning film in the injured lung. Calfactant did not, however, restore
lung fttnction
to norrrial nor did all of the patients respond positively. Only 55% of
calfactant patients
(vs. 33% of placebo patients) had a 25% or greater improvement in oxygenation
indcx by
12 hou.rs after the first intervention.
[00053] The duration of respiratoay failure was not irnproved with calfactant
as it was
in a pilot study(CYit. Care Med. 1999;27:188-195). The average duration of
ventilation
In calfactant compared with placebo patients was similar (11.3 vs. 10.8 days),
as
were lengths of stay and hospital chargcs. Thc absence of beneftt in these
param.eters may
be a consequence of the unexpected clisproportiol-tate survival of calfactant-
treated
patien.ts. As was observed with the introduction of surfactant therapy in
prernature
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12
infants, increased survival n-iay actually increase the need for prolonged
supportive
care (J. Clin. .fnvest. 1991 ;88:1976-1981).
[00054] Severity of initial lung injury was expected to influence stlrvival.
Mortality
rate was i-iideed higher in fast (37%) cornpztred with slow entry (20%)
subgroups.
Mortality was lower in both strata for calfactant patients (26% calfactant vs.
46%
placebo for fast entry and 14 % vs. 26% for slow entry, respectively).
Unresolved
respiratory failure was given as the primazy cause or a niajor contributor i1-
1 83% of
deaths, and lack of iinproven-ient in oxygenafion after the intervention was
strorigly
associated witli mortality. In-lprovenlent in lung function offers a plausible
mechanislzz
whereby calfactant treatment might increase survival. because respiratoiy
failure was
a significant cause of death in this trial.
[00055] Overall mortality in. this study was higher than in the pilot study
(Crit. Care
Med. 1999;27:188-195) (14% in pilot stttdy vs. 28% herein), att.ribtitable to
the inclusion
of the previously excluded imnlunoconzpromised patients whose mortality rate
(56%)
was four times that of i..mnlunocompctcnt paticnts (13%). Mortality rates were
lower for
calfactant patients in hoth the i.lnmunocompromised (50% vs. 60%) and
iinrn'L1iloi;olTlpetCllt (7% v5. 20%) subgroups. The nunlerically greater
izumbe.r. of
immunocompromised patients in the placebo group (30 in the placebo group vs.
22 in
the calfactant group; P=.17) influenced the observed overall m.ortality
difference
between the groups. The ORs for mortality with placebo treatinent approached
but did
not z-each statistical significance (P=.08) after post hoc adjustr.nen.t for
inzinune status
(TABLE 3). This study was not powered sufficiertltly to detect effects in
specific
patien.t subgroups.
[00056] There may be naultiple reasons for the failure of ather surfiicLanls
in the lhr.ee
large ARDS trials (N. Engl. J. Med. 1996; 334: 1417-1421, Am. J. Respir. Crit
Care ItIecl.
1997; 155:1309-137.5, N. Engi. J. M,ecl. 2004; 351:884-892), but none of these
trials used a
lung surfactant preparat:ion contai~iing a sufficient ar.nount of SP-B, which.
is the essential
factor for ful.l surfacfar-t activity and resista.r.ice of a. surfactant to
inlubiti.on by blood and
inflammatory protein rltolecules present in Lhe alveoli in ARDS/ALI (J. Clin.
Invest. 1991;
88:1976-1981, A.m. J. Respir. Crit. Ccire Med. 1996;153:176-184). Congenital
absence of
SP-B in humans causes lethal neonatal respiratoiy distress syndrome (J. Clin_
Invest.
1994;93:1860-1863), and mice who are bred deficient of SP-B die at birth of
respiratory
failure (Proc. Natl. Acad. Sci. USA. 1995;92: 7794-7798). The SP-B pivtein by
itself
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13
confers ftill biophysical. and biological activity on surfactant phospholipids
(JLipid.Res.
1996;37:1749-1760) The surfactant used in the study has the higllest level of
resistance to
inactivation, as deterxnined by in vitro and, in vivo experimental testing,
due to its high
ratio of SP-B to phospholipids (Expert Opin.. Pharrnacother. 2001;2:1479-7
493, Arrr. Rev
Respir. Dis. 1992?145:24-30, Eur. Respir,I. 1993:6:971-977). It has greater
stu-face activity
a.nd physiological activity in animal lungs than Exosurf or Surva7lta, wl-iich
arc two
surfactants previousty used to treat ART)S in ad.i.i.l.ts (Gliern.. Phys.
Lipids, 2002; 114:21-34).
Additioaially, th.e aixzount of calfactarxt adrn.inistered in this lrial was
more than three tirnes
the estimated normal lung surfactant content of 20mg/kg {LuYZg Su~factants.
New York,
NY: Marcel Dekker, 2000).
j0a0571 In this multicenter, raaldomized., blinded trial., calfactant
adrninistration carly
in the course of pediatric acute respiratary fail ure resulted in acute
i.mproveinent in
oxygeii.atioa.i and unexpectedly produced lower mortality. Adverse effects of
the therapy were
m.inimal.
