Pulmonary function in long-term survivors of hyaline membrane ...

Pulmonary Function in Long-termSurvivors of Hyaline Membrane Disease*James R. Shelter, M.D., EC.CP. A William D. Lucht, M.D.;tA. K. Goel, B.S.; James D. Snell, M.D., F.C.C.P,§and MildredT. Stahlman, M.D.\\In order to determine the long-term pulmonary consequencesof hyaline membrane disease (HMD), we measuredpulmonary function and airway responsiveness to methacholinein 22 survivors of HMD aged 18 to 22 years.Nineteen age-matched control subjects without a history oflung disease or asthma were also studied. There was nostatistically significant difference between the mean pulmonaryfunction test results of the control vs the HMDgroup. The mean N28 of the five HMD patients whorequired assisted ventilation was significantly different fromthat of the control group. Airway responsiveness to methacholine,as estimated by the dose of methacholine aerosolnecessary to provoke a 35 percent fall in SCaw did notdiffer between the control and HMD groups. In the absenceof prematurity, low birth weight (

Measurements of forced expiratory flow were made using acomputerized mass flow meter. Functional residual capacity (FRC)was measured by nitrogen washout. The single breath diffusingcapacity for carbon monoxide was determined. The slope of phase3 of the single breath oxygen test (the nitrogen delta) was obtainedusing standard methods. 12 The values are reported as the percentpredicted, in an effort to control for the effect of age, sex, andheight on pulmonary function. K!,fiMethacholine inhalation challenge was done by having subjectsinhale doubling concentrations of methacholine aerosol from abreath-activated dose-metering device connected to a nebulizerwhich aerosolized approximately 0.010 ml of solution per breath.Measurements of specific airway conductance (SGaw) were madein triplicate in a constant volume body plethysmograph beforemeasurements of forced expiratory flow were obtained. 1718 Fivebreaths of methacholine aerosol were inhaled from functionalresidual capacity during tidal breathing. Increasing concentrationsof methacholine were inhaled at five-minute intervals until theSGaw had fallen by 35 percent from baseline measurements, or thehighest concentration of methacholine had been achieved. If subjectsdid not have a significant fall at a concentration of 10 mg/ml,then ten breaths of this concentration were given, and this wasconsidered to be equivalent to a concentration of 20 mg/ml forpurposes of analysis. Airway responsiveness was expressed as thedose of methacholine (mg/ml) required to cause a 35 percent fall inSGaw (EDajSGaw) and was calculated by interpolation from theindividual log dose response curves. One patient had an FEV[ thatwas 53 percent of predicted, and the response to bronchodilatorswas measured instead of the response to methacholine. No subjectwas studied within six weeks of a viral upper respiratory tractinfection.Standard chest roentgenograms were made in the posterioranteriorand lateral views.Review of the nursery records was undertaken to provide birthweight, gestational age, duration of assisted ventilation, pulmonarycomplications, and the oxygen score. The oxygen score was calculatedby assigning one point for every hour spent at an FIo2 of .21to .39, two points .40 to .59, three points for .60 to .79, four pointsfor .8 to 1.0. 3 Eighteen of the 22 HMD subjects had pulmonaryfunction tests done at age 7 and/or ll. 5The study was approved by the Vanderbilt University Committeefor the Protection of Human Subjects.StatisticsDifferences between the control and HMD groups were testedfor by impaired one tailed Student's t-test or by Wilcoxon nonpairedrank sum test when the data were found to be nonnormal indistribution. A p

Table 2—Pulmonary Function Test Results in Selected Individual HMD Patients*BirthWeight,0,FEV]/FEFSubjectGScore FVC FEV,FVC25-75 Vmax 50% Vmax 25% TLC N2oDeoIt 1,687 1,824 82t 58+ Tit 28t 31t 18+ 75t 2,9t 74+2+ 2,665 519 92 94 105 96 99 98 76t 1.2t 80+3? 1,205 463 86t 85t 99 91 118 68 74t .8 934t 2,155 466 112 108 93 78 71 57 114 5,8f 996+ 4,196 85 94 83t 85f 55t 51+ 47 90 .8 877 1,106 320 98 102 106 117 123 97 84 1,9+ 1048 2,438 277 102 107 108 99 99 85 84 1,2+ 1109 2,381 241 108 107 108 96 97 80 94 4.2+ 9710 1,984 200 100 107 107 116 112 107 82t .6 9911 2,601 217 125 107 88t 71 70 66 105 .7 9612 2,438 108 119 106 94 76 75 48 103 .6 127Control 91 87 89 70 67 48 83 .9 80limit•Values are expressed as percent predicted except for N28, which is expressed as %N/500ml.Underlined values are those outside the 95 percent confidence limits of Knudson et al.""+Values outside the control values. The control limit was calculated: Mean ± 1.729 SD of the values of the 19 control subjects.iPatients who underwent assisted ventilation.terenol with no improvement in flow The third HMDpatient had a recent viral upper respiratory tractinfection and was unavailable for further testing. Therewas no correlation between the oxygen score or birthweight and the degree of airway responsiveness tomethacholine. The HMD and control subjects werestudied over a period of three years, but there was nocorrelation between the time of year in which theywere studied and the ED^ SGawWheezing was reported by six of the 19 HMDLog E D 3 5SGaw(mg/ml)>1.31.20,80.40-0.4-0,8OOOOOOOO° o°°°ooo0 0oCONTROL•••••HMDFIGURE 1. Log estimated dose of methacholine (mg/ml) required tocause a fall in SGaw of 35 percent from baseline values in control(open circles) and HMD patients (closed circles). Each pointrepresents the value obtained in a single subject. There was nodifference between the log EDjsSGaw of the control and HMDgroups.patients undergoing methacholine challenge and threeof 19 control subjects, but this increase in the reportingof wheeze was not statistically significant (p = 0,47 byFisher's exact test). Only one HMD patient had beengiven a diagnosis of asthma and had taken bronchodilatorsin the past. Four HMD survivors reported ahistory of asthma in parents or siblings. Two of thesefour responded to methacholine. Four of the controlsubjects had a parent or sibling with asthma, and threeof these four responded to methacholine.Of the 16 chest roentgenograms, one showed asevere pectus deformity that has since been surgicallycorrected; patient 1 had evidence of hyperinflation,and two others had a suggestion of very mild interstitialdisease.DISCUSSIONOur study shows that long-term survivors of HMDwho were not premature and who were treated onlywith oxygen and/or negative pressure ventilation havefew detectable abnormalities in pulmonary function.There was no difference in the mean test resultsbetween the HMD and the control group. However,the five patients with the most severe disease whorequired assisted ventilation had a mean N28 that wassignificantly different from the control group.Patient 1 had the highest oxygen score in the HMDgroup (1824) and had been identified in previousfollow-up studies as having symptomatic respiratoryimpairment. His current tests suggest both restrictiveand obstructive lung disease. This patient, how­1,5ever, had normal spirometry at age 7, and had normalvolumes and diffusion at age 11, with only an FEVjthat was low He has a history of recurrent acutebronchitis and is a cigarette smoker. He requirednegative pressure ventilation, and for a time, was736 Long-term Survivors of Hyaline Membrane Disease (Shelter et al)Downloaded From: http://publications.chestnet.org/ on 03/29/2014

intubated and ventilated with positive pressure. Likewise,patient 2 had a high 0 2 score (519), with normalspirometry at age 11. He had surgical repair of apectus deformity at age 19. His current pulmonaryfunction test results indicate mild restrictive lungdisease. He received negative pressure ventilation.Patient 4, who also received negative pressure ventilation,had findings consistent with mild restrictivelung disease; his prior testing had shown only adecreased FVC at age 7, with normal spirometry atage 11. Patient 3 had tests consistent with airflowobstruction. She was the daughter of a diabetic motherand had mild to moderate HMD. She had a familyhistory of asthma and began to smoke cigarettes at age14. Her tests of lung volumes and spirometry at age11 were normal. The failure to discover more abnormalitiesin these patients at ages 7 and 11 may haveresulted from a wider range of normal values in thoseage groups. An alternative explanation is that thepulmonary disease of these patients may have progressed.Fourteen of the remaining HMD group hadnormal spirometry measured at their 11 year followup.Six HMD survivors had a single breath oxygen testthat was outside the 95 percent confidence range ofour normal control subjects, suggesting that HMDsurvivors may have subtle abnormalities in the distributionof ventilation, perhaps related to small airwaysdisease. However, the degree of impairment of thedistribution of ventilation alone did not appear to affectsymptoms.It appears that some HMD patients manifest abnormalitiesof pulmonary function in adult life. There isthe possibility that these abnormalities may haveprogressed since childhood, perhaps in response tothe deleterious effects of environmental lung injuries,such as cigarette smoking, viral upper respiratory tractinfections, or air pollution. It will be important tocontinue to follow the pulmonary function of at leastthose individuals with identifiable abnormalities.Unlike the studies by Bertrand et al and Mac-9Luskey et al our study did not reveal an increased10incidence of airway responsiveness in our group ofHMD survivors. However, there are differences inmethodology and in patient population between ourstudy and that of Bertrand and of MacLuskey Weused the ED 3 5 SGaw to quantify airway responsivenessinstead of the FEV: used by others. The SGaw is amore sensitive index of airway change during inhalationchallenge than is the FEVX, but may not discriminatebetween subjects with atopy and those withasthma. In the study of Bertrand et al, eight of 112123 9HMD subjects responded to inhaled histamine with afall in FEV, of 20 percent or more; 30 of 46 patientsstudied by MacLuskey et al responded to methacholine.If our HMD patients were similar, we 10 shouldhave found an even greater proportion of respondersby using measurements of SGaw However, only nineof 19 HMD patients tested responded to methacholine.It might be argued that our small control groupcontained an inordinate number of hyperreactivesubjects. We do not believe this to be the case, becausein 22 mild asthmatic subjects receiving no long-termmedications who responded to an identical challengeprotocol in our laboratory with a 20 percent or greaterfall in FEV,, the mean ED 3 5 SGaw was 3.3±5.1,which is significantly less than that of the 11 respondersinourcontrolgroup(10.5±6.0, p0.8).Rather, we believe that the difference in our findingsand those of Bertrand et al and Macluskey et al lies9 10in the populations studied. Our subjects were older atthe time of the study, and therefore, reflect a differentage and management approach at the time of theirinitial illness. They were treated with oxygen and/orassisted ventilation. Infants received negative pressureventilation only when oxygen therapy had failed andwere intubated and ventilated by hand using ananesthesia circle respirator when negative pressureventilation had failed and the patient was in extremis.The mean birth weights of our patients was242,244 ± 734 g (mean±SD), which is larger than thatreported by Bertrand et al (1,900 ±615) or Mac­9Luskey et al (1,166 ±193). Likewise, the oxygen10scores of the patients in our study were slightly lowerthan those of Bertrand et al (365 ±352 vs 554), and9only four of our 22 HMD subjects had a gestationalage of 32 weeks or less. Positive pressure ventilationwas not routinely used in our neonatal intensive careunit in the treatment of HMD at the time this cohortof patients was born. Thus, it may still be true thatHMD patients receiving positive pressure ventilationor other newer modes of intensive supportive therapyand infants of very low birth weight (

sive support may exhibit abnormal lung function inchildhood.ACKNOWLEDGMENTS: The authors thank Dr. Ryszard Dworskifor use of unpublished observations, Dr. William Vaughn for helpwith statistical analysis, Dr. Dan Lindstroni for data analysis,Marguerite Douglas and Sherry Taylor for expert technical assistance,and Carol Cauthron and Regina Stanley for secretarialassistance.REFERENCES1 Stahiman M, Hedvall G, Dolanski E, Faxelius G, Burko H,Kirk V A six year follow-up of clinical hyaline membrane disease.Ped Clin N A 1973; 20:422-462 Lamarre A, Linsao L, Reilly BJ, Sawyer PR, Levison H. Residualpulmonary abnormalities in survivors of idiopathic respiratorydistress syndrome. Am Rev Respir Dis 1973;108:56-613 Coates AL, Desmond K, Willis D, Nogrady B. Oxygen therapyand long-term pulmonary outcome of respiratory distress syndromein newborns. Am J Dis Child 1982; 136:892-954 Heldt CP, Mcllroy MB, Hansen TN, Tooley WH. Exerciseperformance of the survivors of hyaline membrane disease.J Pediatr 1980; 96:995-995 Stahiman M, Hedvall G, Lindstrom D, Snell J. Role of hyalinemembrane disease in production of later childhood lung abnormalities.Pediatrics 1982; 69:572-766 Smyth JA, Tabchnik E, Duncan WJ, Reilly BJ, Levison H.Pulmonary function and bronchial hyperreactivity in long-termsurvivors of bronchopulmonary dysplasia. Pediatrics 1982;68:336-407 O'Brodovich HM, Mellins RB. State of the art: bronchopulmonarydysplasia: unresolved neonatal acute lung injury. Am RevRespir Dis 1985; 132:694-7098 Northway WH Jr, Rosan RC, Porter DY. Pulmonary diseasefollowing respiratory therapy of hyaline-membrane disease,N Engl J Med 1967;"276:357-689 Bertrand J-M, Riley SP, Popkin J, Coates AL. The long-termpulmonary sequelae of prematurity: the role of familial airwayhyperreactivity and the respiratory distress syndrome. N EnglJ Med 1985; 312:742-4510 MacLusky IB, Stringer D, Zarfen J, Smallhorn J, Levison H.Cardiorespiratory status in long-term survivors of prematurity,with and without hyaline membrane disease. Pediatr Pulmonol1986; 2:94-10211 Nickerson BG, Taussig LM. Family history of asthma in infantswith bronchopulmonary dysplasia. Pediatrics 1980; 65:1140-4412 Buist AS, VanFleet DI, Ross BB. Quantitative analysis of thealveolar plateau in the diagnosis of early airflow obstruction. AmRev Respir Dis 1973; 107:735-4313 Goldman HI, Becklake MR. Respiratory function tests: normalvalues at median altitudes and the prediction of normal results.Am Rev Tuberc 1959; 79:457-6714 Burrows B, Kasik JE, Niden AH, Barclay WR. Clinical usefulnessof the single breath pulmonary diffusing capacity test. AmRev Respir Dis 1961; 84:789-80615 Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximalexpiratory flow volume-curve: normal standards, variability, andeffects of age. Am Rev Respir Dis 1976; 113:587-60016 Knudson RJ, Lebowitz MD. Maxima! mid-expiratory flow(FEFavsw): normal limits and assessment of severity. Am RevRespir Dis 1978; 117:609-1017 DuBois AB, Botelho SY, Bedell GN, Marshall R, Comroe J. Arapid plethysmographic method for measuring thoracic gasvolume. J Clin Invest 1956; 35:322-2618 DuBois AB, Botehlo SY, Comroe JH. A new method formeasuring airway resistance in man using a body plethysmograph.J Clin Invest 1956; 35:327-3519 Steel RGD, Torrie JH. Principles and procedures of statistics.New York: McGraw-Hill Book Co, 1980:113-1820 Zar JH. Biostatistical analysis. Englewood Cliffs, NJ: Prentice-Hall, Inc, 1974:413.21 Fish JE, Rosenthal RR, Batra G, Menkes H, Summer W,Permutt S, et al. Airway responses to methacholine in allergicand nonallergic subjects. Am Rev Respir Dis 1977; 113:579-8622 OrehekJ, Nicoli MM, Delpierre S, Beaupre A. Influence of theprevious deep inspiration on the spirometrie measurement ofprovoked bronchoconstriction in asthma. Am Rev Respir Dis1981; 123:269-7223 Michoud MC, Ghezzo H, Amyot R. A comparison of pulmonaryfunction tests used for bronchial challenges. Bull Eur PhysiopatholRespir 1982; 18:609-2124 Stahiman MT, Malan AF, Shephard FM, Blankenship WJ, YoungWC, Gray J. Negative pressure assisted ventilation in infantswith hyaline membrane disease. J Pediatr 1970; 76:174-8225 Galdes-Sebaldt M, Sheller JR, Grogaard J, Stahiman MT.Extreme prematurity, not hyaline membrane disease (HMD), islinked with increased airway responsiveness and abnormalpulmonary function at 10 to 13 years of age. Pediatr Res 1987;21:501.738 Long-term Survivors of Hyaline Membrane Disease (Sheller et al)Downloaded From: http://publications.chestnet.org/ on 03/29/2014