Prophylactic or Early Selective Surfactant Combined With nCPAP in Very Preterm Infants
OBJECTIVE: Early surfactant followed by extubation to nasal continuous positive airway pressure (nCPAP) compared with later surfactant and mechanical ventilation (MV) reduce the need for MV, air leaks, and bronchopulmonary dysplasia. This randomized, controlled trial investigated whether prophylactic surfactant followed by nCPAP compared with early nCPAP application with early selective surfactant would reduce the need for MV in the first 5 days of life.
METHODS: A total of 208 inborn infants who were born at 25 to 28 weeks' gestation and were not intubated at birth were randomly assigned to prophylactic surfactant or nCPAP within 30 minutes of birth. Outcomes were assessed within the first 5 days of life and until death or discharge of the infants from hospital.
RESULTS: Thirty-three (31.4%) infants in the prophylactic surfactant group needed MV in the first 5 days of life compared with 34 (33.0%) in the nCPAP group (risk ratio: 0.95 [95% confidence interval: 0.64–1.41]; P = .80). Death and type of survival at 28 days of life and 36 weeks' postmenstrual age and incidence of main morbidities of prematurity (secondary outcomes) were similar in the 2 groups. A total of 78.1% of infants in the prophylactic surfactant group and 78.6% in the nCPAP group survived in room air at 36 weeks' postmenstrual age.
CONCLUSIONS: Prophylactic surfactant was not superior to nCPAP and early selective surfactant in decreasing the need for MV in the first 5 days of life and the incidence of main morbidities of prematurity in spontaneously breathing very preterm infants on nCPAP.
- preterm newborn
- respiratory distress syndrome
- mechanical ventilation
- bronchopulmonary dysplasia
WHAT'S KNOWN ON THIS SUBJECT:
Prophylactic surfactant and delivery room nCPAP are beneficial practices to reduce lung injury in preterm infants. A brief intubation for surfactant administration in preterm infants on nCPAP reduces the need for MV when used early in respiratory distress syndrome.
WHAT THIS STUDY ADDS:
In spontaneously breathing preterm newborns who are treated with nCPAP, prophylactic surfactant given within 30 minutes of birth is not superior to early selective surfactant in terms of requirement of MV in the first 5 days of life.
Respiratory distress syndrome contributes to mortality and morbidity in very preterm infants and with mechanical ventilation (MV) is a major determinant of bronchopulmonary dysplasia (BPD). Surfactant treatment changes the natural history of respiratory distress syndrome (RDS), resulting in a 30% to 65% relative reduction in risk for pneumothorax and up to a 40% relative reduction in neonatal mortality; adverse events are infrequent and long-term follow-up studies are reassuring.1 Randomized, controlled trials (RCTs) have demonstrated that prophylactic or early surfactant therapy compared with delayed rescue surfactant treatment results in improved outcomes for preterm infants at high risk.2
Nasal continuous positive airway pressure (nCPAP) is an important first-line form of respiratory support in newborns and is used as an alternative to intubation and MV in extremely preterm infants.3,4 Observational and cohort studies have shown that nCPAP followed by intubation, surfactant administration, and MV only if nCPAP failure criteria are reached reduce the need for MV. Furthermore, a reduced incidence of BPD without increased mortality has been reported.5,–,8 Few RCTs have compared intubation and MV with early nCPAP or different types of nCPAP and did not highlight significant differences.9,–,11
A brief intubation for surfactant administration in newborns on nCPAP, the intubation-surfactant-extubation (InSurE) method,12,13 has also been investigated and resulted in a reduced need for MV in the first week of life when used early in RDS14,–,17; however, the vast majority of these studies included a low number of extremely preterm infants. Prophylactic surfactant and delivery room nCPAP to maintain functional residual volume have been identified as potentially beneficial practices that, if adopted for extremely preterm infants, could reduce lung injury18; however, no RCTs have yet compared prophylactic surfactant with early nCPAP, especially in extremely preterm infants at high risk for developing RDS. In fact, the recently published Continuous Positive Airway Pressure or Intubation at Birth (COIN) trial compared the use of nCPAP shortly after birth with intubation and MV; in both groups, surfactant was given only to mechanically ventilated patients with high oxygen requirement, and there was no immediate extubation to nCPAP.11
An international randomized controlled trial to evaluate the efficacy of combining prophylactic surfactant and early nasal continuous positive airway pressure in very preterm infants (CURPAP study) was designed to compare the administration of prophylactic surfactant followed by nCPAP with early nCPAP followed by early selective surfactant. The primary end point was the need for MV in the first 5 days of life.
This was a phase IV international, multicenter, open-label, RCT approved by independent ethics committees in accordance with requirements of each participating country. It was conducted in accordance with good clinical practice guidelines and all applicable regulatory rules under the guiding principles of the Declaration of Helsinki. Inborn infants with gestational ages (GAs) from 25 weeks 0 days and 28 weeks 6 days were included. Exclusion criteria were severe birth asphyxia or a 5-minute Apgar score <3, endotracheal intubation for resuscitation or insufficient respiratory drive, known genetic disorders, potentially life-threatening conditions unrelated to prematurity, and premature rupture of membranes for >3 weeks. Written informed consent was obtained before delivery.
Eligible infants were randomly assigned immediately after birth by using a central interactive voice response system. Randomization was stratified by GA at birth into 2 strata: 25 to 26 weeks and 27 to 28 weeks. Infants were assigned to 1 of 2 treatment groups within 1 of the 2 strata in a 1:1 ratio. The block size for the randomization within each stratum was 4. The randomization design ensured that, in the case of twins, both siblings were allocated to the same treatment group.
Positive pressure with the system in use in each delivery room (flow-dependent bag or T-piece system) was used to stabilize newborns in both groups after birth. When infants fulfilled all entry criteria, they were randomly assigned by using the interactive voice response system and the allocated treatment was begun within 30 minutes of birth.
Infants who were randomly assigned to prophylactic surfactant were intubated for administration of a dose of poractant alfa (Curosurf [Chiesi Farmaceutici, Parma, Italy]) of 200 mg/kg. The tube position was confirmed by auscultation. During surfactant administration, infants were manually ventilated to facilitate surfactant distribution and then extubated to nCPAP as soon as possible within 1 hour if respiratory drive was present. In the absence of good respiratory drive, MV was started. Infants who were extubated to nCPAP after surfactant were eligible for MV if nCPAP failure occurred (nCPAP failure criteria are defined in detail in the next section).
Infants who were assigned to nCPAP were stabilized on nCPAP alone. In the event of nCPAP failure and after obtaining a chest radiograph, early selective surfactant was administered in a dose of 200 mg/kg. Thereafter, infants were treated as in the prophylactic surfactant group.
During stabilization and transport to the NICU, any CPAP device was allowed according to the practice of each investigative site; in the NICU, nCPAP was given through nasal prongs/mask using a flow-dependent system (the Infant Flow System was preferred) with an initial pressure of 6 to 7 cmH2O, in both groups. A second dose and additional doses of surfactant of 100 mg/kg could be administered to infants who were on MV.
Continuous monitoring by pulse oximetry was performed; fraction of inspired oxygen (Fio2), clinical outcomes (usual complications of prematurity), nCPAP, and MV pressures were recorded at regular intervals. The clinical risk index for babies score19 was assessed. Concomitant medications were recorded for 5 days after initial treatment. Adverse events and clinical outcomes were assessed until the end of study, at death, or at discharge from hospital.
Definition of nCPAP Failure
Infants who met ≥1 of the following criteria were defined as nCPAP failures: Fio2 >0.4 on nCPAP to maintain oxygen saturation of 85% to 92% for at least 30 minutes unless rapid clinical deterioration occurred, apnea defined as >4 episodes of apnea per hour or >2 episodes of apnea per hour when ventilation with bag and mask was required, respiratory acidosis defined as Pco2 >65 mmHg (8.5 kPa), and pH <7.2 on arterial or capillary blood gas sample.
Indication for Termination of MV
The decision to extubate and place on nCPAP was considered when there was good respiratory drive, Fio2 requirement was <0.4 to maintain pulse oximetry readings (85%–92%), ventilator pressures were relatively low (ie, mean airways pressure ≤7 and ≤8 cmH2O in conventional mechanical and high-frequency oscillatory ventilation, respectively), capillary or arterial Pco2 was <65 mmHg (8.5 kPa), and pH was ≥7.2.
Primary and Secondary Outcomes
The primary outcome was need for MV within the first 5 days of life. Infants in both groups were considered to have reached the primary outcome when they could not be extubated within 1 hour after surfactant administration or when they met the nCPAP failure criteria after extubation. The secondary outcomes were death, survival in room air, survival with oxygen, and survival on respiratory support at 28 days of life and at 36 weeks' postmenstrual age; incidence of BPD by using criteria proposed by the National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute/Office of Rare Diseases Workshop20; air leaks; pulmonary hemorrhage; intraventricular hemorrhage21; patent ductus arteriosus defined echocardiographically; retinopathy of prematurity by stage of severity22; necrotizing enterocolitis defined as stage 2 or higher as per modified Bell criteria23; cystic periventricular leukomalacia24; sepsis defined as a positive blood culture or suggestive clinical and laboratory findings leading to treatment with antibiotics for at least 7 days despite absence of a positive blood culture; duration of hospitalization; total duration of MV; and use of systemic postnatal steroids. Requirement for surfactant (need for early selective in the nCPAP arm and additional doses in both groups) was also recorded. All outcomes were assessed until death or discharge from hospital.
By using data from participating centers, it was estimated that 50% of infants of 25 to 28 weeks' GA would require MV. We calculated a sample size on the basis that prophylactic surfactant would reduce this outcome to 30%. With 80% power and a 2-sided significance level of .05, 93 infants would be needed in each group. Assuming a dropout rate of 12%, 104 infants per group were needed, giving a total sample size of 208 participants, ignoring nonindependence of twins. The analysis was performed according to the intention-to-treat principle.
For the primary efficacy analysis, we used the Cochran-Mantel-Haenszel (CMH) test, which adjusts for stratification factors of GA and center. Risk ratios (RRs), 95% confidence intervals (CIs), and P values are reported. The influence of including twins in the primary analysis as independent observations was assessed by using 2 sensitivity analyses. The primary analysis was repeated when (1) 1 infant from each set of twins was removed at random from the analysis and (2) all twins were removed from the analysis population. A logistic regression analysis was performed on the primary analysis by using a number of covariates, including treatment, stratum, gender, race, type of delivery, birth weight, prenatal steroids, and twin birth.
For the secondary analyses, proportional data were analyzed by using the Cochran-Mantel-Haenszel test and continuous data by using an analysis of covariance. Overall differences between treatment groups and associated 95% CIs are reported. An analysis of normality of data was also performed, and for data not normally distributed, a suitable transformation was performed. When there were no suitable transformations, data were analyzed by using the Wilcoxon Rank-sum test and the median difference between treatments and associated P value are reported. RRs and 95% CIs are reported.
Figure 1 shows the number of newborns who were assessed for eligibility, the number of eligible newborns, and the number of newborns who were randomly assigned to each treatment group. A total of 208 newborns were enrolled between March 2007 and May 2008 in 24 European NICUs. The demographic and clinical characteristics were similar in the 2 groups (Table 1).
Thirty-three (31.4%) infants in the prophylactic surfactant group needed MV in the first 5 days compared with 34 (33.0%) in the nCPAP group (RR: 0.95 [95% CI: 0.64–1.41]; P = .80). The presence of twins did not influence the results. Primary outcome in the 2 GA strata was also similar (Table 2).
In the prophylactic surfactant group, 10 of 105 newborns could not be extubated after surfactant treatment compared with 19 of 50 infants who were intubated for selective surfactant in the nCPAP group; reintubation after extubation to nCPAP was required for 23 of 95 and for 15 of 31, respectively. The reasons for MV (>1 could be recorded) in the prophylactic surfactant group were Fio2 >0.4 in 6 of 33, apneic episodes or absence of respiratory drive in 23 of 33, and respiratory acidosis in 6 of 33. In the nCPAP group, these were Fio2 >0.4 in 25 of 34, apneic episodes or absence of respiratory drive in 19 of 34, and respiratory acidosis in 13 of 34. Exploratory logistic regression by using the primary outcome as a function of covariates showed that need for MV in the first 5 days was inversely related to birth weight (P = .001) and significantly greater in boys compared with girls (P = .046). These covariates were included in the final model via stepwise progression. The adjusted odds ratio for the treatment allocation was 1.02 (95% CI: 0.55–1.88; P = .95).
There were no significant differences between groups for any secondary outcome, even when the 2 GA strata were analyzed separately (Tables 3 and 4). Median (range) days of hospitalization were 68 (2–212) in the prophylactic surfactant group and 71 (1–202) in the nCPAP group (P = .66); median (range) hours of mechanical ventilation were 128.8 (1–1466) and 132.8 (1–2698) in the 2 study groups, respectively (P = .33).
Fifty (48.5%) infants in the nCPAP group needed early selective surfactant at a median age of 240 minutes (range: 10–5728 minutes). Fourteen (13.3%) infants in the prophylactic surfactant group needed a second dose of surfactant compared with 11 (10.6%) in the nCPAP group (RR: 1.25 [95% CI: 0.59–2.62]; P = .56). Three or more doses of surfactant were given to 3 (2.8%) infants in the prophylactic surfactant group and to 3 (2.9%) infants in the nCPAP group.
Early nCPAP, surfactant treatment, and MV are established interventions for treatment of neonatal RDS. These methods complement each other, although the optimal strategy remains to be confirmed. Our study shows that, in spontaneously breathing preterm newborns who were treated with nCPAP, prophylactic surfactant given within 30 minutes of birth was not superior to early selective surfactant in terms of requirement of MV in the first 5 days of life. Prophylactic surfactant treatment within 15 minutes of birth reduced mortality compared with later selective surfactant treatment25; however, these trials were performed when prenatal steroid use was very low (∼20%) compared with 96% to 98% in our study. The increased use of prenatal steroids may be 1 of the reasons for not finding a difference between our 2 study groups. Less likely, the protective effect of surfactant may have been masked by the period of MV within 1 hour after the surfactant administration.26 Although, according to the protocol, extubation was recommended as soon as possible after surfactant administration, the precise duration of intubation was not recorded. Conversely, the limit of 1 hour to perform the surfactant administration procedure in these very preterm newborns seemed a good compromise between speed and safety and reflects standard clinical practice.27
A systematic review of studies that compared InSurE with later selective surfactant treatment followed by MV showed a reduced need for MV in newborns who were treated with the former approach.27 The authors concluded that RCTs of prophylactic surfactant administration with rapid extubation compared with later, selective surfactant therapy were needed. A recent retrospective study showed that the majority of infants who were <28 weeks' GA and were initially intubated, given surfactant, and thereafter placed on nCPAP could be maintained on nCPAP alone.28
We considered that prophylactic InSurE needed a randomized trial to determine whether it offers additional advantage over the early selective InSurE. Our findings suggest that in spontaneously breathing newborns of 25 to 28 weeks' GA, it is possible to initiate nCPAP and treat with surfactant later only when they show signs of RDS, which in our population occurred in 48.5% of cases. The not statistically significant trend toward a higher requirement of MV in infants who received prophylactic surfactant compared with those who received early selective treatment in the lower GA stratum confirms the validity of this approach also in the more preterm infants.
Nearly one-third of infants in our study required MV in the first 5 days of life, in both study groups. This rate is lower than the estimated 50% at the time our trial began and is also lower compared with the COIN trial,11 which reported a need for endotracheal intubation and MV in 46% of infants who were of 25 to 28 weeks' GA and randomly assigned to receive nCPAP at birth; however, in that study and in the CURPAP participating centers in the pretrial period, extubation after surfactant instillation was not planned or standardized. Actually, in the CURPAP trial, 50 (48.5%) of 103 infants in the nCPAP group were intubated to receive surfactant, but MV was required only in 34 (33%) of 103 because 16 (15.5%) of 103 were successfully extubated and avoided MV within 5 days of life. In summary, our results show that nearly one-third of infants who were intubated for surfactant administration can be successfully extubated to nCPAP at these low GAs.
The main reasons for MV were increasing oxygen requirement and apnea. In this study, MV after surfactant instillation was started when Fio2 requirement was >0.4. Some NICUs use a more conservative approach, starting MV at an Fio2 value of >0.6. Moreover, other, recent ventilatory strategies, such as nasal intermittent positive pressure ventilation or bilevel CPAP, were not allowed in this study. Whether these approaches could have further reduced the need for MV in our group of infants of 25 to 28 weeks' GA remains an open issue that needs additional investigation.
Our study showed a very good respiratory outcome in the whole population: 78% to 79% of infants, in both arms, survived without any supplemental oxygen or respiratory support at 36 weeks' postmenstrual age. The incidences of moderate/severe BPD were 14.3% and 11.7%, respectively, in the prophylactic surfactant and nCPAP groups; that is lower than the 30% incidence reported in other studies.29,30 The need for oxygen treatment among survivors was also lower than in the COIN trial of a comparable population treated with a very similar approach11; however, that study differed from ours in a number of ways. First, in the nCPAP group, surfactant was given to infants who were intubated for MV when they needed >60% rather than 40% oxygen. Second, there was no immediate extubation to nCPAP. Third, surfactant was not administered to all intubated infants, and the proportion of infants who were treated with surfactant was lower than in our nCPAP group (38% vs 48.5%); therefore, the respiratory management used in our study combining extensive use of nCPAP with either prophylactic or early selective surfactant seems to be both safe and efficacious in spontaneously breathing infants of 25 to 28 weeks' GA.
Previous studies reported an increased incidence of pneumothorax in nCPAP-treated compared with MV-treated newborns or no treatment.11,31 The use of prophylactic or early surfactant therapy has been associated with a decreased risk for pneumothorax.27 In our study, the combination of nCPAP with prophylactic or early surfactant treatment resulted in an overall incidence of pneumothorax of 3.8%; 6 of the 8 infants who developed pneumothorax were on MV at the time of pneumothorax diagnosis. This incidence is lower than that reported in other studies.11,32 In newborns who were allocated to receive nCPAP in the delivery room, the COIN trial11 reported an incidence of pneumothorax of 9.1% compared with 1.0% in the CURPAP trial. The earlier administration of surfactant and the lower rate of mechanically ventilated infants in the CURPAP compared with the COIN trial could explain this difference. In fact, in the CURPAP trial, the median age for surfactant administration in the nCPAP group was 4.0 hours compared with 6.6 hours for intubation in the COIN trial, and the rate of mechanically ventilated newborns was 33% compared with 46%.
Infants who were treated with prophylactic surfactant tended to have a higher rate of pneumothorax compared with the nCPAP group (6.7% vs 1.0%), although this difference was not statistically significant. A recent study that investigated risk factors for pneumothorax concluded that only factors that were present on the day of pulmonary air leak were independently associated with this outcome.32 In our population, only 2 infants developed a pneumothorax on the day of randomization, suggesting that treatment allocation did not influence this outcome; however, we cannot exclude that in some infants who were in the prophylactic surfactant group and had more compliant lungs, the administration of surfactant coupled with positive pressure ventilation through an endotracheal tube may have induced pulmonary damage, eventually leading to air leaks.
The incidences of other complications related to prematurity were not significantly different between the 2 treatment groups and did not differ substantially from those of the COIN trial.11 The relatively high frequency of sepsis in our population could be attributed to the broad criteria used to define it. The durations of MV and hospitalization were almost identical in the 2 study groups and in line with previous results.11 Also, the use of additional doses of surfactant after the first prophylactic or early selective dose did not differ significantly between the groups.
The main implication for clinical practice of this study is that nCPAP should be started soon after birth in spontaneously breathing infants of 25 to 28 weeks' GA and early selective surfactant should be given once signs of respiratory distress have developed. With this strategy, >50% of infants will need only nCPAP, 48.5% will need intubation and surfactant, and nearly one-third will need MV in the first 5 days of life. These results are particularly reliable, because nearly 85% of eligible newborns were randomly assigned.
These conclusions can be applied to a population of infants who are born between GAs of 25 weeks 0 days and 28 weeks 6 days and do not require intubation at birth, representing the majority of infants who were assessed for eligibility in our study. Moreover, the use of prenatal steroids was very high in our study, and it is possible that in other settings the results might be different.
This study was funded by Chiesi Farmaceutici SpA (Parma, Italy).
Participating investigators and study centers are listed according to the number of infants they assessed: Maternity Hospital, Podoli, Prague, Czech Republic: Z. Stranak, I. Berka, J. Melichar, A. Pešulová, J. Semberová, H. Slavíková; General Faculty Hospital, Prague, Czech Republic: R. Plavka, J. Burkertova, M. Dokoupilová, L. Pazderová; Fakultni Nemocnice, Ostrava, Czech Republic: H. Podešvová, R. Kolářová, P. Kordoš, H. Wierdermanová; Teaching Hospital Hradec Králové, Hradec Králové, Czech Republic: Z. Kokstein, P. Bašek, J. Maly, E. Ticha; Ospedale Niguarda Ca Granda, U.O. Neonatologia e Terapia Intensiva Neonatale, Milan, Italy: S. Martinelli, R. Restelli; Faculty Hospital, Brno, Czech Republic: T. Juren, H. FukovFučíková, M. Kučera; Hospital of Bata, Zlin, Czech Republic: J. Macko, V. Rajchlová, B. Tesařová, S. Vyoralova; Ospedale Generale San Giovanni Calibita Fatebenefratelli Isola Tiberina, Rome, Italy: C. Gizzi, R. Agostino; Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena-Fondazione IRCCS-Università di Milano, Milan, Italy: F.A. Mosca, M.R. Colnaghi, V. Condó, P.G. Matassa; Fakultní Nemocnice, Olomouc, Czech Republic: L. Kantor, S. Šuláková, I. Vránová; Assistance Publique, Hôpitaux de Marseille, Marseille, France: U. Simeoni, V. Andres, F. Arnaud, F. Boubred, C. Grosse, V. Lacroze, I. Ligi, V. Millet; Ospedale S. Gerardo, Monza, Italy: P. Tagliabue, M.L. Ventura, F. Furlan; Ospedale Civile Maggiore-Azienda Ospedaliera, Verona, Italy: P. Biban, M. Soffiati, P. Santuz; Faculty Hospital, Prague, Czech Republic: M. Cerny, R. Brabec, B. Fišárková, L. Hícová, V. Kozák, J. Zunová; Hospital 12 de Octubre, Servicio de Neonatologia de Madrid, Madrid, Spain: C. Barrio, S. Caserío Carbonero, C. Alonso Díaz, J. Rodríguez López, M.T. Moral Pumarega; Hospital Central de Asturias, Servicio de Neonatologia, Oviedo, Spain: J. López Sastre, R.P. Arias, B. Fernández, B. Fernández Colomer, G. Coto, A. Ibáñez, A. Ramos, J. Santiago, A. Calvo; Ospedale Maggiore, Bologna, Italy: F. Sandri, F. Demaria, G. Mescoli; Ospedale S. Orsola Malpighi, Bologna, Italy: G. Faldella, G. Ancora, E. Maranella; Centre Hospitalier Universitaire Clocheville, Tours, France: E. Saliba, S. Chantepie-Bigot, A. Chemin, A. Favreau, C. Follet-Bouhamed, A. Henrot; Maternidade Julio Dinis, Oporto, Portugal: A. Areias, J. Pombeiro; Maternidade Dr Alfredo Da Costa, Servicio de Pediatria, Lisbon, Portugal: A. Valido, O. Nascimento, J. Nona, I. Santos; Hospital de Sant Joan de Deu, Servicio de Neonatologia, Esplugues De Llobregat, Spain: A. Riverola, J. Alvarez, M. Camprubi, N. Conde, I. Iglesias Platas; Ospedali Riuniti, Foggia, Italy: G. Rinaldi, G. Maffei, R. Magaldi, G. Popolo, M. Rinaldi; Hôpital Robert Debré, Paris, France: Y. Aujard, M. Arsac, O. Baud, I. Bauvin, C. Farnoux.
- Accepted January 25, 2010.
- Address correspondence to Fabrizio Sandri, MD, Ospedale Maggiore, Via Dell'Ospedale 2, 40100 Bologna, Italy. E-mail:
FINANCIAL DISCLOSURE: Dr Fabbri is the head of the Neonatology Clinical Department of and Dr Halliday has served as a consultant to Chiesi Farmaceutici; the other authors have no financial relationships relevant to this article to disclose.
- MV =
- mechanical ventilation •
- BPD =
- bronchopulmonary dysplasia •
- RDS =
- respiratory distress syndrome •
- RCT =
- randomized, controlled trial •
- nCPAP =
- nasal continuous positive airway pressure •
- InSurE =
- intubation-surfactant-extubation •
- GA =
- gestational age •
- Fio2 =
- fraction of inspired oxygen •
- RR =
- risk ratio •
- CI =
- confidence interval
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