Oxygen Does Not Hasten Resolution of Symptomatic Spontaneous Pneumothorax in Neonates

ORIGINAL ARTICLE Administration of 100% oxygen does not hasten resolution of symptomatic spontaneous pneumothorax in neonates

SD Clark1,2, F Saker1,2, MT Schneeberger1,2, E Park2,3, DW Sutton2,4 and Y Littner1,2

OBJECTIVE: To compare the effectiveness of 100% oxygen therapy vs oxygen treatment with targeted pulse oximetry in the management of symptomatic small to moderate spontaneous pneumothorax (SP). In total, 100% oxygen treatment for SP has been a common practice in neonatology, albeit there is little evidence to validate its efficacy. STUDY DESIGN: A retrospective chart review of 83 neonatal records with the diagnosis of pneumothorax was conducted. Infants o35 weeks gestation, those with large pneumothoraces requiring chest tube drainage and/or ventilatory support were excluded. Data gathered included demographics, vital signs, treatment information and clinical indicators of resolution of symptoms. RESULT: In total, 45 neonates with SP were included in the study. Groups were similar for gestational age, birth weight, Apgar scores, gravidity, parity, gender, race, pneumothorax size and location. Patients in the 100% oxygen therapy group received a significantly longer oxygen treatment (21.3 vs 8 h, Po0.001), required longer intravenous fluid treatment (48.6 ± 29.9 vs 31.3 ± 18.8 h, P = 0.03) and were delayed in reaching full feeds (44.1 ± 25.7 vs 29.5 ± 18.8 h, P = 0.03) compared with the oxygen-targeted treatment group. Time to first oral feeding, time to resolution of tachypnea and length of stay were similar in both groups. CONCLUSION: There are no clinically significant advantages to using 100% oxygen in the treatment of symptomatic small to moderate SP. In fact, it may result in longer exposure to unnecessary oxygen treatment and toxicity. Oxygen should be reserved for those who are hypoxic and adjusted to comply with accepted saturation levels in neonates. Journal of Perinatology (2014) 34, 528–531; doi:10.1038/jp.2014.55; published online 3 April 2014

INTRODUCTION a long-lasting effect particularly on neonates who lack adequate 6–10 Spontaneous pneumothorax (SP) occurs in 0.05 to 2% of all live- antioxidant capacities. born infants.1,2 Most infants remain asymptomatic and do not In our facility, both administration of 100% oxygen and supple- require any intervention. Symptomatic SP, is less common (0.05 to mental oxygen with targeted pulse oximetry (range of 92 to 95%) 1% of live births), and will often present within the first hours of are common practices for the treatment of SP. Treatment choice is life.2–4 Common clinical signs may include tachypnea, cyanosis, based solely on the preference of the attending neonatologist. tachycardia and changes in blood pressure. SP can be idiopathic Using this unique opportunity, we aimed to compare these or may be associated with transient tachypnea of the newborn, two philosophies of treatment in the management of small to respiratory distress syndrome, meconium aspiration syndrome, moderate SP in neonates. We hypothesized that 100% oxygen birth depression, birth trauma and difficult delivery. treatment will accelerate the resolution of SP in neonates. The treatment of SP varies and is determined by symptoms, size of the air leak, whether or not it is under tension and the custo- mary practice of the neonatology group. For small to moderate METHODS pneumothorax that is neither under tension nor causing hemo- Patients dynamic changes, conservative treatment options consist of close observation with symptomatic treatment vs use of 100% inspired We retrospectively reviewed the medical records of babies born at Hillcrest ‘ ’ Hospital, Cleveland, OH between 2008 and 2011. Patients were selected oxygen for nitrogen washout . Nitrogen washout hastens the using the ICD-9 code for pneumothorax. Diagnosis of pneumothorax was resolution of pneumothorax by increasing the gradient for suspected based on physical exam, clinical symptoms and confirmed by nitrogen absorption from the extra-pulmonary space. In 1971, chest X-ray. Inclusion criteria included: neonates admitted to the neonatal Northfield5 described accelerated resolution of pneumothoraces intensive care unit with confirmed pneumothorax on chest X-ray within in 10 patients treated with oxygen. the first 12 h of life. A pediatric radiologist, blinded to the therapeutic Although there are no additional human studies that confirm approach, read all chest X-rays. Exclusion criteria included: neonates the efficacy or safety of this treatment, nitrogen washout became o35 weeks gestation, aggressive resuscitation and/or positive pressure a common practice in neonatology. On the other hand, there is a ventilation in the delivery room, any treatment of large pneumothorax growing body of literature about the potential detrimental effects with needle aspiration, chest tube and/or ventilatory support. We also excluded patients who expired or were transferred to a tertiary level of hyperoxia in newborns. Animal and human newborn studies center, and patients who crossed over treatment strategies. Discontinua- have demonstrated that hyperoxia-induced oxidative stress may tion of O2 therapy in the conventional oxygen therapy group was guided contribute to the pathogenesis of several disorders and may have by pulse oximetry readings, whereas in the nitrogen washout group O2

1Department of Neonatology, The Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, USA; 2Cleveland Clinic Lerner College of Medicine of Medicine of Case Western Reserve University, Cleveland, OH, USA; 3Department of Radiology, The Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, USA and 4Respiratory Therapy, The Cleveland Clinic Children's, Cleveland Clinic, Cleveland, OH, USA. Correspondence: Dr Y Littner, Department of Neonatology, Cleveland Clinic Children’s, The Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA. E-mail: [email protected] Received 19 November 2013; revised 17 February 2014; accepted 24 February 2014; published online 3 April 2014 Nitrogen washout treatment for SP SD Clark et al 529 therapy was stopped when pneumothorax on chest X-ray and/or Demographics and patient characteristics respiratory distress resolved. Groups were similar for gestational age, birth weight, gender, gravidity, parity, mode of delivery and Apgar scores. In both groups, the Data collection majority of patients were Caucasians (85% in the nitrogen washout After institutional review board approval was obtained, the history was group and 81% in the conventional therapy group). In addition, rate retrieved from the medical records of all participating patients. The of delivery complications, sepsis risk factors and SNAPPE-II scores following data were collected: demographics, maternal and perinatal were comparable between groups. Spontaneous pneumothorax history, delivery room details, neonatal vital signs (in the first 24 h of life), was more common in males than females (Table 1). clinical indicators of respiratory distress (e.g., tachypnea, grunting and retractions), respiratory support treatment (e.g., delivery method such as Vital signs oxygen hood or nasal cannula, FiO2 and the length of respiratory support), time to first introduction of oral feeding and time to achieve full feeding, Both groups remained hemodynamically stable during their length of intravenous fluid treatment, length of hospitalization, lab results hospitalization. Average heart rate, mean arterial pressure and and radiological findings. Scores for Neonatal Acute Physiology and urine output in the first 24 h of life were similar in both groups. Perinatal Extension II (SNAPPE-II) were determined on the first day of life fi 11 Average pulse pressures were signi cantly higher in the nitrogen for each patient. To evaluate the extent of oxygen exposure, an area washout group (29.3 ± 7.9 vs 25 ± 4.9 mm Hg, P = 0.03) (Table 2). under the curve analysis was performed. This method, quantifies the cumulative oxygen exposure as an integration of oxygen concentration ∑ − 12 over time ( (FiO2 0.21) × time (hours)). Respiratory status, laboratory values and treatment The groups did not differ in either pneumothorax size (small or Primary and secondary endpoints medium) or its location (right, left or bilateral) (Table 2). Pulse The primary endpoints of our study were the length of oxygen therapy and time to resolution of respiratory distress. Secondary endpoints included the time to first introduction of oral feeding, time to achieve full feeding and length of hospitalization. Table 1. Demographic, perinatal characteristics and SNAPPE-II scores in study groups

Statistical analysis Conventional therapy Nitrogen washout P The Minitab statistical program (version 13.1) was utilized for statistical (n = 19) (n = 26) analyses (Minitab, State College, PA, USA). Continuous variables were compared using the Student's t-test for normally distributed variables. Gestational age (weeks) 38.9 ± 1.5 39.4 ± 1.5 NS The Mann–Whitney test was used for variables with skewed distribution. Birth weight (grams) 3295 ± 469 3359 ± 509 NS A P-value o0.05 was considered significant. Sex M:F 16:3 21:5 NS Gravidity (range) 2 (1–4) 2 (1–5) NS Parity (range) 1 (1–3) 1 (1–4) NS RESULTS Cesarean section % 32% 56% NS Apgar 1 min (range) 8 (2–9) 8 (4–9) NS We identified 83 neonates with the diagnosis of pneumothorax. A Apgar 5 min (range) 9 (8–9) 9 (7–9) NS total of 45 neonates met inclusion criteria and 38 were excluded. SNAPPE-II 0 (0–12) 0 (0–12) NS Twenty-six neonates received nitrogen washout, whereas 19 fi neonates received supplemental oxygen to maintain a pulse Abbreviations: NS, non signi cant; SNAPPE, Score for Neonatal Acute Physiology and Perinatal Extension II. oximetry range of 92 to 95% (conventional oxygen therapy) All data expressed as mean ± s.d., except Apgar scores, gravidity, parity and (Figure 1). Based on total of 11 412 deliveries during the study SNAPPE-II scores, which are expressed as median (range). period, our occurrence of SP was 0.39%.

Figure 1. Flow diagram of included and excluded patients.

© 2014 Nature America, Inc. Journal of Perinatology (2014), 528 – 531 Nitrogen washout treatment for SP SD Clark et al 530 guidelines for hemodynamically stable but symptomatic neonate Table 2. Hemodynamic, respiratory, laboratory and treatment is still lacking. Nitrogen washout therapy, first introduced by characteristics of study groups Ashmore13 in 1965, remains one of the common approaches used Conventional Nitrogen P today. It is performed by administering 100% oxygen and is therapy washout believed to accelerate the resolution of pneumothoraces. Both the (n = 19) (n = 26) American College of Chest Physicians and the British Thoracic Society recommend observation as the treatment of choice for Average HR in first 24 h (b.p.m.) 131 ± 9 133 ± 10 NS adults with small spontaneous pneumothoraces.14,15 The British Average MAP in first 24 h 48.6 ± 5.1 51.2 ± 6.2 NS Thoracic Society also advises that hospitalized patients will receive (mm Hg) fl fi ± ± supplemental high- ow oxygen when feasible. This recommenda- Average PP in rst 24 h 25.0 4.9 29.3 7.9 0.03 fi 5 (mm Hg) tion is established upon an early study by North eld, which Urine output in first 24 h (ml kg 1 ± 0.25 1.2 ± 0.34 NS described increased rate of gas absorption from a large per day) pneumothorax in 10 adult patients. Notably, Northfield did not Pneumothorax size 2:17 8:14 NS find any statistically significant differences of gas absorption in (medium:small) patients with small or moderate pneumothoraces.4 A literature Pneumothorax location 10:4:5 12:4:10 NS review yields a limited number of clinical observations describing (right:left:bilateral) the use of 100% oxygen for management of SP.16–18 Neither one Pulse oximetry prior to 95.2 ± 5.3 96.5 ± 3.8 NS of these studies confirmed the efficacy of this treatment, although therapy (%) both recognized the risk involved with oxygen therapy. Animal Length of O therapy (hours)* 7 (0–48) 21.3 (2–127) o0.001 2 studies using rabbits with total unilateral lung pneumothoraces Mean FiO2 0.29 ± 0.09 0.82 ± 0.13 o0.001 – o also tested the theory of accelerated nitrogen absorption with Cumulative O2 exposure score 61 (0 916) 1173 0.001 19–21 (630–3350) oxygen therapy. These studies showed improved rate of Time to resolution of 20 ± 26 37 ± 27 NS resolution of large pneumothorax with higher inspired oxygen tachypnea (hours) therapy. Nonetheless, it is important to recognize that this animal pH 7.36 ± 0.09 7.36 ± 0.06 NS model used total lung pneumothorax that would be fatal if left – – PaO2 (mm Hg)* 78 (46 353) 178 (62 461) 0.002 untreated in humans. PaCO2 (mm Hg) 39.8 ± 18.5 37.9 ± 8.5 NS - − 1 The other aspect of a treatment with 100% oxygen relate to its HCO3 (mEq l ) 19.8 ± 2.6 20.3 ± 5.2 NS − potential toxicity in the neonate. Prolonged exposure to high Base excess (mmol l 1) − 4.2 ± 2.6 − 3.1 ± 6.1 NS − 1 ± ± levels of oxygen produces free radicals and has detrimental effects Lactate (mmol l ) 3.9 1.6 3.4 0.8 NS 22 Time to first introduction 18 ± 9.1 24.7 ± 16.4 NS on many organs and tissues. Exposure to high oxygen of oral feeding (hours) concentration has been linked to decreased pulmonary compli- Time to achieve full 29.5 ± 18.8 44.1 ± 25.7 0.03 ance and vital capacity, impaired diffusing capacity, and feeding (hours) abnormalities in small airway function.23 Neonates are parti- Length of intravenous 31.3 ± 18.8 48.6 ± 29.9 0.03 cularly sensitive to free radicals due to sub-optimal antioxidant fluid treatment (hours) defense systems.7 Expectedly, current neonatal practices advise Length of hospitalization 3.53 ± 1.68 4.35 ±1.96 NS judicious use of oxygen in the delivery room and during post-natal 22,24 Abbreviations: HR, heart rate; MAP, mean arterial pressure; NS, non life. significant; PP, pulse pressure. In the current study, we compared two different approaches All data expressed as mean ± s.d. except length of O2 therapy, cumulative for the treatment of symptomatic small to moderate SP in O2 exposure score and PaO2, which is expressed as median (range). neonates. The nitrogen washout group received 100% inspired oxygen, whereas the other was treated with conventional oxygen therapy (targeted oxygen saturation). Both groups oximetry readings prior to any respiratory support were similar in were similar in their demographic characteristics, delivery both groups. Arterial blood gas values on admission including: pH, − complications, risk factors and pneumothoraces size and location. PaCO2, HCO3, base excess and lactate were similar in both groups To exclude the possibility of biased results due to different (Table 2). The nitrogen washout group did have higher arterial severity of illness, we used the SNAPPE-II scores and found no fi PaO2 (178 vs 78 mm Hg, P = 0.002), received a signi cant longer differences between groups. Overall, most patients enrolled in this o oxygen treatment (21.3 vs 7 h, P 0.001) was exposed to higher study were affected by mild respiratory distress, received short- o mean FiO2 (0.82 vs 0.29, P 0.001) and cumulative O2 exposure term oxygen therapy and were discharged home at day of life 4 o score (1173 vs 61, P 0.001). There was no statistical dif- on average. ference between groups in the time for resolution of tachypnea − 1 Patients in both groups remained hemodynamically stable and (respiratory rate >60 min ) (37.1 ± 27.3 vs 24.8 ± 32.6 h, P = 0.181) did not differ in their vital signs. The higher pulse pressure in the (Table 2). nitrogen washout therapy group could be a result of prolonged use of intravenous fluids in these patients. From a respiratory Feeding, intravenous therapy and length of stay perspective, both groups had similar pulse oximetry readings on There was no difference in the time to first introduction of oral admission prior to any oxygen treatment. Groups also did not feedings. However, the nitrogen washout group did require longer differ in blood gas values (excluding PaO2). This further supports our observation of similar severity of illness in both groups. As time to achieve full feeds (44.1 ± 25.7 vs 29.5 ± 18.8 h, P = 0.03) and fi received intravenous fluid treatment for a longer period of time expected, the 100% oxygen therapy group had signi cantly higher mean FiO2, higher arterial PaO2. They also received (48.6 ± 29.9 vs 31.3 ± 18.8 h, P = 0.03), compared with the conven- fi tional group (Table 2). Length of stay was similar in both groups signi cantly longer oxygen treatment when compared with the (4.47 ± 0.35 vs 4.04 ± 0.41 days, P = 0.168) (Table 2). conventional group. Cumulative O2 exposure score, which estimates overall oxygen exposure (duration and concentration), was significantly higher in the 100% oxygen therapy group. Conceivably, these observations could be attributed to false DISCUSSION perception of illness in these patients. The lack of targeted pulse Spontaneous pneumothorax is a recognized cause of respiratory oximetry combined with 100% oxygen therapy, may have masked distress in the neonatal period. General agreement on treatment the ability of the caregiver to recognize clinical improvement.

Journal of Perinatology (2014), 528 – 531 © 2014 Nature America, Inc. Nitrogen washout treatment for SP SD Clark et al 531 In addition, cessation of oxygen therapy usually occurred after a REFERENCES chest radiograph had confirmed resolution of the pneumothorax. 1 Davis C, Stevens G. Value of routine radiographic examination of the newborn, However, these X-rays were purposely taken infrequently to based on a study of 702 consecutive babies. Am J Obstet Gynecol 1930; 20: 73. minimize radiation exposure. 2 Chernick V, Avery ME. Spontaneous alveolar rupture at birth. Pediatrics 1963; 32: The wellbeing of neonates and the improvement in their 816–824. respiratory status are often associated with their ability to tolerate 3 Trevisanuto D, Doglioni N, Ferrarese P, Vedovato S, Cosmi E, Zanardo V. Neonatal pneumothorax: comparison between neonatal transfers and inborn infants. and advance feeding. Although the groups did not differ in timing 33 – of introduction of feeds, the 100% oxygen therapy group was J Perinat Med 2005; :449 454. 4 Steele RW, Metz JR, Bass JW, DuBois JJ. Pneumothorax and pneumomediastinum delayed in reaching full feeds and required longer intravenous in the newborn. Radiology 1971; 98:629–632. fluid therapy compared with the conventional therapy group. 5 Northfield TC. Oxygen therapy for spontaneous pneumothorax. Br Med J 1971; 4: However, these differences did not translate into changes in 86–88. length of hospitalization. 6 Maltepe E, Saugstad OD. Oxygen in health and disease: regulation of oxygen The main limitations of our study include a small sample homeostasis--clinical implications. Pediatr Res 2009; 65: 261–268. size and its retrospective design. A randomized controlled study 7 Saugstad OD. Oxygen toxicity in the neonatal period. Acta Paediatr Scand 1990; will possibly allow for better observation and data collection. 79: 881–892. 8 Saugstad OD, Sejersted Y, Solberg R, Wollen EJ, Bjørås M. Oxygenation of the However, we believe that many caregivers would be hesitant to 101 – participate in such a prospective trial given the overwhelming newborn: a molecular approach. Neonatology 2012; :315 325. 9 Saugstad OD. Resuscitation of newborn infants: from oxygen to room air. Lancet evidence of potential toxicity from 100% oxygen exposure. 2010; 376: 1970–1971. It is also uncertain whether caregivers can identify the exact 10 Shoji H, Koletzko B. Oxidative stress and antioxidant protection in the time of resolution of the pneumothorax to determine when to perinatal period. Curr Opin Clin Nutr Metab Care 2007; 10:324–328. stop the hyperoxic therapy. Lung ultrasound to monitor the 11 Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: Simplified size of a pneumothorax can be valuable, but is not always newborn illness severity and mortality risk scores. J Pediatr 2001; 138:92–100. available in the neonatal intensive care unit. Frequent chest X-rays 12 Stevens TP, Dylag A, Panthagani I, Pryhuber G, Halterman J. Effect of cumulative to assess resolution of pneumothoraces is impractical and would oxygen exposure on respiratory symptoms during infancy among VLBW infants 45 – subject the babies to significant and unwarranted radiation without bronchopulmonary dysplasia. Pediatr Pulmonol 2010; : 371 379. 13 Ashmore PG. Spontaneous pneumothorax in the newborn. Can Med Assoc J 1965; exposure. 92 – fi :309 311. To the best of our knowledge, our study is the rst to compare 14 Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J et al. AACP Pneu- the efficacy of 100% oxygen therapy to an oxygen saturation- mothorax Consensus Group Management of spontaneous pneumothorax: an targeted approach for the treatment of symptomatic small to American College of Chest Physicians Delphi consensus statement. Chest 2001; moderate SP in neonates. Our work did not study the effect of 119:590–602. oxygen on large pneumothoraces. One hundred percent oxygen 15 Henry M, Arnold T, Harvey JPleural Diseases Group. Standards of Care Committee, therapy, allegedly believed to hasten pneumothoraces resolution, British Thoracic Society. BTS guidelines for the management of spontaneous promoted prolonged intravenous fluid therapy, delayed feeding pneumothorax. Thorax 2003; 58:39–52. advancement, did not facilitate clinical improvement and did not 16 Al Tawil K, Abu-Ekteish FM, Tamimi O, Al Hathal MM, Al Hathlol K, Abu Laimun B. reduce the length of hospitalization. Furthermore, the excessive Symptomatic spontaneous pneumothorax in term newborn infants. Pediatr Pulmonol 2004; 37:443–446. exposure to hyperoxia carries substantial risk of toxicity in this 17 Yu VY, Liew SW, Robertson NR. Pneumothorax in the newborn. Changing pattern. population. Although oxygen may increase recovery rates of a Arch Dis Child. 1975; 50:449–453. large pneumothorax, the limited evidence of its benefits does not 18 Butler DA, Orlowski JP. Nitrogen washout therapy for pneumothorax. Cleve Clin Q outweigh the short-term disadvantages and potential long-term 1983; 50:311–315. toxicities. Based on our observations, and contrary to our hypo- 19 England GJ, Hill RC, Timberlake GA, Harrah JD, Hill JF, Shahan YA et al. Resolution thesis, we conclude that 100% oxygen therapy does not offer any of experimental pneumothorax in rabbits by graded oxygen therapy. J Trama significant advantages compared with oxygen saturation-targeted 1998; 45:333–334. therapy for the treatment of symptomatic small to moderate 20 Hill RC, DeCarlo DPJr, Hill JF, Beamer KC, Hill ML, Timberlake GA. Resolution of spontaneous pneumothoraces in neonates. Supplemental experimental pneumothorax in rabbits by oxygen therapy. Ann Thorac Surg 1995; 59:825–827. oxygen should be reserved for those patients who are hypoxic 21 Zierold D, Lee SL, Subramanian S, DuBois JJ. Supplemental oxygen improves and adjusted to comply with accepted saturation levels in resolution of injury-induced pneumothorax. J Pediatr Surg 2000; 35: 998–1001. neonates. 22 Vento M, Sastre J, Asensi MA, Viña J. Room-air resuscitation causes less damage to heart and kidney than 100% oxygen. Am J Respir Crit Care Med 2005; 172: 1393–1398. 23 Jackson RM. Pulmonary oxygen toxicity. Chest 1985; 88:900–905. CONFLICT OF INTEREST 24 Vento M, Escobar J, Cernada M, Escrig R, Aguar M. The use and misuse of oxygen The authors declare no conflict of interest. during the neonatal period. Clin Perinatol 2012; 39:165–176.