Functional Residual Capacity and Compliance of the Respiratory System After Surfactant Treatment in Premature Infants with Severe Respiratory Distress Syndrome

Eur J Pediatr (2002) 161: 485–490 DOI 10.1007/s00431-002-0989-6

ORIGINAL PAPER

Ju¨ rgen Dinger Æ Andreas To¨ pfer Æ Peter Schaller Roland Schwarze Functional residual capacity and compliance of the respiratory system after surfactant treatment in premature infants with severe respiratory distress syndrome

Received: 24 September 2001 / Accepted: 25 May 2002 / Published online: 12 July 2002 Springer-Verlag 2002

Abstract To understand the mechanisms behind im- Abbreviations a/A arterial/alveolar tension Æ CRS proved oxygenation after intratrachealsurfactant in- compliance of the respiratory system Æ FRC functional stillation, the immediate and late effects on lung volume residualcapacity Æ RDS respiratory distress syndrome Æ and compliance of the respiratory system (CRS) were SF6 sulphur hexafluoride analysed. Infants received modified porcine surfactant (Curosurf) or modified bovine surfactant (Alveofact). Introduction Measurements of functionalresidualcapacity (FRC) and CRS were successfully performed in 90 ventilated Surfactant replacement rapidly improves gas exchange preterm infants (birth weight 1264±435 g; gestational and results in early improvement in oxygen saturation age 28.2±2.5 weeks) with severe respiratory distress and reduction in mean airway pressure, decreases neo- syndrome. FRC and CRS were measured during me- natal mortality and incidence of pulmonary interstitial chanicalventilationprior to and 1, 3, 6, 24, 48, 72, 96, emphysema and pneumothorax [8, 9, 25, 40, 44]. Despite 120 and 168 h after surfactant replacement. Oxygen- the clinical improvement reports about changes in pul- ation rapidly improved. FRC increased significantly monary mechanics in neonates with respiratory distress from 7.64±1.58 ml/kg to 15.35±3.27 ml/kg (P<0.01) syndrome (RDS) have been less convincing [5, 11, 12, 14, at 1 h after surfactant instillation. CRS remained vir- 19, 23,24]. Many of the proposed physiological mecha- tually unchanged during the first hours after surfactant nisms thought to govern the effect of surfactant on gas replacement and a concomitant decrease in specific exchange remain either unconfirmed or inadequately compliance was seen. Conclusion: the changes in lung characterised in the ventilated human infant. Our un- function following surfactant treatment can only be ex- derstanding of physiological responses to surfactant plained by initial stabilisation of already aerated alveoli treatment in human infants is limited by difficulties in- followed by recruitment of new gas exchange units as volved in assessing pulmonary function, particularly in mechanisms involved in mediating the effect of surfac- the measurement of lung volume. tant on gas exchange. However, since no significant Although there are several studies describing the ef- correlation between changes in functional residual ca- fect of surfactant treatment on the mechanicalproperties pacity and improvement in arterial-to-alveolar oxygen of the lung in human infants [2, 3, 4, 5, 7, 12, 14, 15,31], tension ratio was seen, other effects of surfactant must the results of these studies had to be interpreted without be considered. These include local and/or systemic knowledge of change in lung volume. To our knowledge, changes in haemodynamics. there are only a few reports [11, 16, 19, 20, 24,39] describing the effect of surfactant treatment on lung vol- Keywords Functionalresidualcapacity Æ Gas ume only selective in a small number of mechanically exchange Æ Premature infant Æ Respiratory distress ventilated preterm human infants. syndrome Æ Surfactant To understand the mechanisms behind improved oxygenation after intratracheal surfactant instillation, the immediate and longitudinal effects on compliance of the J. Dinger (&) Æ A. To¨ pfer Æ P. Schaller Æ R. Schwarze respiratory system (CRS), functionalresidualcapacity Klinik fu¨ r Kinderheilkunde, Medizinische Fakulta¨ t, (FRC) and gas exchange were systematically analysed. In Technische Universita¨ t Dresden, Fetscherstrasse 74, this report we describe the changes in FRC, CRS and gas 01307 Dresden, Germany E-mail: [email protected] exchange immediately before and 1, 3, 6, 24, 48, 72, 96, Tel.: +49-351-4582341 120 and 168 h after administration of modified porcine Fax: +49-351-4584331 (Curosurf) or bovine (Alveofact) surfactant. 486

settings (PIP, PEEP, inspiratory and expiratory time, FiO2 ) were Patients and methods noted. From information on blood gases and ventilator settings the Patients following indices were calculated:

The patient group comprised 90 preterm infants with RDS treated 1. a/A ratio = PaO2/FiO2·(patm–pH20)–PaCO2 where patm = in the neonatalintensive care unit at Dresden University hospital atmospheric pressure and pH2O = water vapour pressure (Table 1). The inclusion criteria for surfactant instillation were [22]. clinical and radiological evidence of RDS, the need for endotrac- 2. Mean airway pressure = (PIP·Ti + PEEP·Te)/(Ti +Te) heal intubation for ventilation and an arterial/alveolar tension (a/ where Ti = inspiratory time and Te = expiratory time [21]. A) ratio of <0.2. The post-natalage at surfactant treatment ranged from 1 to 12 h (mean 2.5 h). None of the infants had a clinically significant infection or patent ductus arteriosus during this study. Pulmonary function testing Written informed parentalconsent was obtained. The study was approved by the hospitalethics committee. FRC was measured with a computerised multiple breath wash in/ washout technique [18,28], using sulphur hexafluoride (SF6), a nontoxic, insoluble tracer gas [27]. This method allows repeated measurements (each wash in/washout sequence takes about 1.5– Surfactant administration 2 min) without interfering with ventilator settings or the inspired oxygen concentration. For measurement, a heated pneumotach- The endotrachealtube was suctioned just prior to administration ograph and a fast mainstream infrared SF6 analyser were placed of surfactant. Modified porcine (Curosurf) or bovine (Alveofact) between the Y-piece of the ventilator circuit and the endotracheal surfactant was given in two separate boluses (initial dose of tube. Any constant flow ventilator can be used. Set-up of mea- 100 mg/kg), each one being injected over 20 s in the right and surement apparatus, measurement process and algorithms for cal- then in the left lateral position. The surfactant was administrated culation of FRC have been described in detail [17, 36, 37,41]. The intratracheally using a special endotracheal tube with a drug mainstream infrared SF6 analyser was built as a prototype by canal. After each administration, hand ventilation was performed Siemens-Elema, Sweden. SF6 concentration during wash in was with a Laerdalbag for 1 min. and then the ventilatorwas re- 0.8%–1%. Accuracy and reproducibility of the FRC measurement connected. Suctioning of the endotrachealtube was avoided for equipment has been tested in a mechanicallungmodel[37]. 4–6 h after completing the surfactant instillation, unless clinically CRS was measured according to the inflation method [17]. Flow indicated. Up to two retreatment doses (100 mg/kg in the was measured using a pneumotachograph [34] inserted between the Curosurf group and 50 mg/kg in the Alveofact group) were endotrachealtube and the ventilatorcircuit. Airway pressure administrated if the a/A ratio remained <0.2. changes were measured from the infant’s side of the pneumotachograph using a Validyne pressure transducer. Flow, volume and pressure were recorded simultaneously, compliance was calculated Ventilation and monitoring and displayed immediately by the computer. Measurement of CRS was tested with lung models (copper wool filled bottles) and found to All infants were given the same method of ventilation by a time have an error of +3% [37]. Compliance was related to the FRC on cycled pressure controlled ventilator (Bear Cub Model BP 2001, each occasion to give specific compliance (compliance/FRC). Medical Systems Inc., Riverside, Calif., USA). Ventilation was Measurements of FRC and compliance were made in triplicate under initially started with PEEP of 0.4 kPa and PIP of between 1.6 and steady state conditions 20 min after varying ventilator settings [41]. 2.5 kPa. The usualunit policywas to adjust FiO 2 and mean The coefficient of variation (range with median in parentheses) of airway pressure to maintain arterialoxygen between 6.0 kPa and repeated measurements was 0.29–4.16 (1.65%) for FRC and 0.67–5.2 8.0 kPa. Arterialcarbon dioxide was maintained between 5.0 kPa (2.44%) for compliance. and 8.0 kPa by adjusting PIP and ventilatory rate. The usual sequence employed in winding down the ventilator with improv- ing blood gases was: (1) reduction of FiO2; (2) reduction of Statistics ventilator rate; (3) reduction in PIP. If necessary, the infants were sedated but not paralysed with intravenous midazolam The Student’s t test for paired data was used to analyse differ- (0.2 mg/kg). ences in absolute values of FiO2, FRC, CRS, a/A ratio and Transcutaneous tpCO2, ECG, oxygen saturation and blood compliance/FRC. Regression analysis was used to determine pressure were continuously monitored. In addition to arterial blood whether quantitative changes in a/A ratio were related to changes gases determined for clinical purposes pH, PaCO2 and PaO2 were in FRC. Statisticalsignificance was accepted at P<0.05. Data measured immediately before surfactant instillation and also with are expressed as mean values ± SD when not otherwise indi- every determination of lung mechanics. At the same time respirator cated.

Table 1. Characteristics of the 90 infants studied Porcine surfactant Bovine surfactant Number (n)5040 Male 23 (46%) 22 (55%) Birth weight (g) 1264±435 1243±467 Gestationalage (weeks) 28.2±2.51 28.7±2.9 Age at start of study (h) 2.5 (1–12) 2.6 (1–12) a a FiO2 82±13.6 82.8±14.1 a/A ratio 0.104±0.025a 0.102±0.024a Peak inspiratory pressure (kPa) 2.21±0.29a 2.38±0.35a Mean airway pressure (kPa) 1.26±0.31a 1.41±1.1a Positive end expiratory pressure (kPa) 0.4±0a 0.4±0a Ventilatory rate (bpm) 58.4±5.1a 59.4±5.7a

aBefore surfactant replacement 487 Changes observed over the first days Results The most important finding was that statisticalanalysis The determination of FRC and pulmonary mechanics revealed significant changes in CRS at 3 h after treat- was successfully performed before and after surfactant ment with porcine surfactant (P<0.01) and at 24 h after instillation in all 90 patients. A group of 50 infants was treatment with bovine surfactant (P<0.01). In addition treated with porcine and 40 patients with bovine sur- we found a persistent improvement of oxygenation and factant (Table 1). Some 62 patients received a single FRC over time following surfactant therapy (Fig. 1) dose of surfactant (27 in the Alveofact group; 35 in the (Table 2). Curosurf group), 24 patients two (11 patients in the Alveofact group and 13 in the Curosurf group) and four infants (two patients of each group) three doses of sur- Discussion factant. Only the changes after last surfactant administration are reported here. The results from the present study regarding FRC and CRS in infants with severe RDS are comparable to those reported previously [11, 16, 19, 20, 24, 39]. Our data Immediate effects of surfactant confirm that infants with severe RDS have non-com- pliant [18,43], low volume lungs [24, 26, 32,43]. Infants A summary of results is given in Table 2. Immediately with severe RDS have a FRC of approximately 25% of after surfactant instillation, oxygenation improved rap- normal[26,35]. idly. FiO2 decreased from 82.3% to 30.9% 1 h after Very few patients have been studied with measure- surfactant instillation (P<0.01). The a/A ratio and FRC ments of FRC and compliance after surfactant treat- increased significantly 1 h after surfactant treatment ment, as summarised in Table 3. The infants in this (P<0.01) (Table 2). There was no evidence that the study treated with naturalsurfactant preparations re- change in a/A ratio for a given change in FRC was sponded with improved oxygenation accompanied by an different for the two naturalsurfactant preparations increase in FRC. According to the literature, onset and (P>0.5). Improvement in oxygenation was paralleled by magnitude of the improvement in oxygenation and of an increase in FRC, however, no significant correlation the increase in FRC are different in the published studies was found between a change in a/A ratio and a change [11, 16, 19, 20, 24,39]. The differences in the results of in FRC for both naturalsurfactant preparations various studies could be due to differences in the infants (P>0.2). (birth weight, gestationalage, acidosis, PaO before FRC increased in all patients 1 h after surfactant 2 treatment, FiO2 and age at time of treatment) investi- treatment by 28% to 381% (median 101%) from gated, the use of different measurement techniques for 7.64±1.58 to 15.35±3.27 ml/kg (Table 2), while no si- FRC and different surfactant preparations [8, 11, 19, multaneous changes in compliance were observed. 20,24]. Furthermore the biophysicalactivity of surfac- Therefore, the specific lung compliance tended to be tant may be inhibited by protein leaked into airways. reduced immediately after surfactant treatment from Nevertheless, immediately after replacement of natural 0.380±0.110 to 0.200±0.057 (P<0.01) (Table 2). surfactant in all studies in human neonates oxygenation

Table 2. Eﬀect of surfactant on lung function and gas exchange 1, 3, 6 and 24 h after surfactant instillation. Results given as mean ± SD Before surfactant 1 h after surfactant 3 h after surfactant 6 h after surfactant 24 h after surfactant

All patients (n=90) a/A ratio 0.103±0.024 0.345±0.120* 0.356±0.112* 0.346±0.095* 0.324±0.112* FiO2 82.3±13.8 30.9±9.1* 30.1±7.9* 30±8* 29.9±6.4* FRC (ml/kg) 7.64±1.58 15.35±3.27* 15.1±2.61* 14.95±2.41* 14.8±3.14* CRS (ml/kPa · kg) 2.78±0.66 2.99±0.73 3.11±0.75 3.22±0.72* 3.53±0.96* CRS/FRC 0.380±0.110 0.200±0.057* 0.211±0.055* 0.222±0.064* 0.250±0.087* Curosurf (n=50) a/A ratio 0.102±0.024 0.367±0.123* 0.375±0.114* 0.362±0.094* 0.353±0.119* FiO2 82±13.6 30.4±9.1* 29.1±7.2* 28.7±7.7* 28.5±6.5* FRC (ml/kg) 7.62±1.44 15.36±2.94* 15.46±2.72* 15.14±2.41* 14.93± 3.3* CRS (ml/kPa · kg) 2.66±0.59 2.9±0.69 3.15±0.79* 3.26±0.69* 3.63±1* CRS/FRC 0.360±0.100 0.195±0.060* 0.209±0.050* 0.223±0.060* 0.250±0.085* Alveofact (n=40) a/A ratio 0.102±0.024 0.337±0.114* 0.329±0.107* 0.327±0.096* 0.284±0.091* FiO2 82.8±14.1 31.4±9.1* 31.4±8.5* 31.8±8.3* 31.7±5.9* FRC (ml/kg) 7.43±1.75 15.33±3.69* 14.64±2.42* 14.76±2.7* 14.53±2.96* CRS (ml/kPa · kg) 2.93±0.71 3.10±0.76 3.07±0.74 3.17±0.76 3.41± 0.9* CRS/FRC 0.410±0.120 0.209±0.050* 0.214±0.057* 0.220±0.070* 0.250±0.090*

*P<0.01, compared with baseline value prior surfactant instillation 488 rapidly improved and FRC increased. These results perfused alveoli because the surface area for gas diffu- document the great importance of FRC changes in the sion is decreased. Furthermore, FRC acts as a buffer mechanism of improved oxygenation after surfactant volume of gas, permitting ongoing gas exchange and treatment in infants with RDS [6]. There are several stable PaO2 and PaCO2 between the phases of respira- possible mechanisms by which this may occur. Lungs tory cycles. Consequently, an improvement in FRC with diminished FRC, such as those in surfactant- would augment the surface area for gas exchange, in- deficiency states, have low ventilation relative to crease ventilation relative to perfusion and increase the buffering capacity of the respiratory system, resulting in improved gas exchange [13]. In contrast to animalstudies [1, 33, 42], those in human neonates have failed to demonstrate early improvement of compliance [4, 7, 11, 14, 15, 19, 20, 24]. Also in this study, statistical improvement in CRS was not found immediately after surfactant replacement. Improvement was measured at 3 h in the Curosurf- treated infants and at 24 h in the Alveofact-treated patients. Interpretation of changes in lung compliance after surfactant treatment must be done with caution. Many factors may influence compliance measurements in this and other studies. Age of the infant [2, 14, 19], prior course of ventilation [11, 19], volume history of the lung [3, 11, 12, 15], lung water content [2, 4, 15], pressures and rate of ventilation [6, 7, 29, 30], the infants spontaneous ventilatory effort (i.e. sedation and/or relaxation) [10, 11, 19] and methodological aspects [3, 7, 11, 14, 29, 30, 31] are only a few of the factors that should be considered interpreting measurements. Nevertheless, all studies measuring FRC and compliance in human infants with RDS after surfactant treatment have failed to show improvement in compliance immediately after surfactant instillation. Only improvement in oxygenation and increase in FRC were found. This improvement in oxygenation and the increase in FRC do not necessarily imply the recruitment of new gas exchange units. Based on theoreticaland experimentalanimalstudies, it is likelythat an increase Fig.1. Course of FRC, a/A ratio and CRS in infants with severe RDS during the 1st week after surfactant treatment (open bars in FRC after surfactant treatment represents either (1) Curosurf-treated infants, solid bars Alveofact-treated infants) the recruitment of new gas exchange units, or (2) the

Table 3. Reported changes in lung mechanics and lung volume after surfactant treatment in infants with severe RDS Reference Year Surfactant Number of Age Lung mechanics Lung volume patients (n)

[19] 1990 Human surfactant 4 15 min Unchanged C dyn Increase in FRC (20%–120%) (N2 washout) [24] 1991 Calf lung surfactant 7 2 h Unchanged C dyn Increase in FRC extract (Infasurf) (56%–330%) (He dilution) [39] 1992 Porcine surfactant 8 24 h Increased CRS Increase in FRC (Curosurf) (SF6 washout) [11] 1993 Bovine (Survanta) and 17 0.5–6 h Unchanged C dyn Increase in FRC (N2 synthetic (Exosurf) washout) surfactant [20] 1995 Porcine (Curosurf) and 12 1 h Unchanged C dyn Increase in FRC synthetic (Exosurf) (14%–163%) (He dilution) surfactant [16] 1997 Synthetic surfactant 14 24–48 h Increased CRS Increase in FRC (Exosurf) (2%–236%) (He dilution) Present study 2002 Porcine (Curosurf) and 90 1–168 h Unchanged CRS Increase in FRC (28%– bovine (Alveofact) (1 and 3 h), 381%) (SF6 washout) surfactant increased CRS (24 h) 489 increased distension of already aerated alveoli, or (3) the between two surfactant preparations. 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