The
n e w e ng l a n d j o u r na l
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m e dic i n e
Abnormal Ventilatory Responses in Adults Born Prematurely To the Editor: Perinatal hyperoxia in preterm infants is associated with several well-known sequelae, including bronchopulmonary dysplasia and retinopathy of prematurity. Hyperoxia also induces alterations in cardiopulmonary control (e.g., preterm infants treated with hyperoxia lack normal ventilatory responses to hypoxia and hyperoxia).1,2 It has not been determined whether these impairments diminish with age. Thus, we sought to determine whether or not ventilatory dysfunction persists in adults who were born prematurely. We measured the ventilatory responses to 5 minutes of isocapnic, isobaric hypoxia (in which the fraction of inspired oxygen [Fio2] was 0.12) and hyperoxia (in which the Fio2 was 1.0) in 13 adults born prematurely who were recruited from the Newborn Lung Project3 (a cohort with a mean [±SD] age of 21±1 years, a gestational age of ≤32 weeks, and a gestational weight of ≤1500 g) and from age-matched adults born at full term. Preterm adults were clinically indistinguishable from full-term adults, having similar pulmonary function and exercise capacity (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). However, the B 0.8 0.6
P=0.008
0.4 0.2 0.0 −0.2 −0.4
Control
Preterm
C Control
75
Preterm
Hypoxic Ventilatory Response (∆E/−∆SpO2)
1.0
Hyperoxic Ventilatory Response (% ∆E)
Hypoxic Ventilatory Response (liters/min/−∆SpO2)
A
hypoxic ventilatory response was substantially reduced in preterm adults (0.13±0.25 liters per minute per −ΔSpO2, where −ΔSpO2 denotes a negative change in oxygen saturation as measured by pulse oximetry) as compared with fullterm adults (0.42±0.30 liters per minute per −ΔSpO2; P = 0.008) (Fig. 1). Moreover, two preterm adults hypoventilated, which resulted in an increase in the partial pressure of end-tidal carbon dioxide (PETCO2). As expected, 60 seconds of hyperoxia induced respiratory depression from baseline in all full-term adults (−29.6±20.1%) but in only 8 of 13 preterm adults. The mean response was also reduced in the preterm population (−3.0±26.9%; P = 0.01). In rodents, perinatal hyperoxia disrupts the development of carotid chemoreceptors.4 The strong relationship between the hypoxic and hyperoxic ventilatory dysfunction in the preterm adults (Fig. 1) suggests a common impairment in chemoreceptor function that may be due to carotid chemoreceptor dysfunction. Our most compelling finding is that abnormal ventilatory responses were manifested only when these preterm adults, who appeared to be clinically normal, were stressed by breathing hypoxic and
50 25 0 −25 −50 −75
P=0.01 0
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300
0.6 0.4 0.2 R 2=0.56 P=0.003
0.0 −0.2 −0.4 −0.6 −50
Seconds
0
50
100
Hyperoxic Ventilatory Response (% ∆E)
Figure 1. Ventilatory Responses to Hypoxia and Hyperoxia in Adults Born Prematurely as Compared with Adults Born at Full Term. All full-term adults (controls) had increased ventilation in response to hypoxia (fraction of inspired oxygen [Fio2] = 0.10); paradoxically, some preterm adults hypoventilated in response to hypoxia and reported presyncopal symptoms at the end of the trial (Panel A; boxes depict the median and first and third interquartile ranges, with whiskers indicating maximum and minimum responses). After 60 seconds of hyperoxia (Fio2 = 1.0), ventilation was depressed in all full-term adults, but this response was blunted in preterm adults (Panel B; points represent the mean ±SD). The blunting of hyperoxic and hypoxic ventilatory responses was correlated in preterm adults, suggesting a common cause of ventilatory dysfunction (Panel C). The Δ symbol denotes change, SpO2 oxygen saturation as measured by pulse oximetry, and E volume expired.
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n engl j med 370;6 nejm.org february 6, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
notices
hyperoxic gas. This finding may have important clinical implications.5 We found that some preterm adults paradoxically hypoventilate with hypoxia. In summary, adults with a history of preterm birth have abnormal ventilatory responses to hypoxia and hyperoxia, possibly due to disrupted chemoreceptor development. We speculate that these underappreciated abnormalities in ventilatory control may have important clinical consequences, including an increased risk of disordered breathing during sleep and in response to high altitude and anesthesia. Additional investigations into the mechanisms and long-term disease risks of this population are warranted. Melissa L. Bates, Ph.D. Emily T. Farrell, Ph.D. Marlowe W. Eldridge, M.D. University of Wisconsin School of Medicine and Public Health Madison, WI [email protected] Supported by grants from the National Institutes of Health (5R01HL086897, to Drs. Eldridge and Farrell, and 5T32HL007654, to Dr. Bates) and a postdoctoral fellowship from the American Heart Association (to Dr. Bates). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Calder NA, Williams BA, Smyth J, Boon AW, Kumar P, Han-
son MA. Absence of ventilatory responses to alternating breaths of mild hypoxia and air in infants who have had bronchopulmonary dysplasia: implications for the risk of sudden infant death. Pediatr Res 1994;35:677-81. 2. Katz-Salamon M, Lagercrantz H. Hypoxic ventilatory defence in very preterm infants: attenuation after long term oxygen treatment. Arch Dis Child Fetal Neonatal Ed 1994;70:F90-5. 3. Weinstein MR, Peters ME, Sadek M, Palta M. A new radiographic scoring system for bronchopulmonary dysplasia. Pediatr Pulmonol 1994;18:284-9. 4. Bisgard GE, Olson EB Jr, Wang ZY, Bavis RW, Fuller DD, Mitchell GS. Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia. J Appl Physiol (1985) 2003;95:946-52. 5. Bates ML, Pillers D-AM, Palta M, Farrell ET, Eldridge MW. Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia. Respir Physiol Neurobiol 2013;189:329-37. DOI: 10.1056/NEJMc1311092 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article.
• Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
notices Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month. Computer Assisted Radiology and Surgery The congress will be held in Fukuoka, Japan, June 25–28. Contact CARS Conference Office, Im Gut 15, 79790 Kuessaberg, Germany; or call (49) 7742-922 434; or fax (49) 7742-922 438; or e-mail [email protected]; or see http://www.cars-int.org.
Society of Laparoendoscopic Surgeons The following meetings will be held: “AsianAmerican MultiSpecialty Summit VI: Laparoscopy & Minimally Invasive Surgery” (Honolulu, Feb. 12–15) and “Minimally Invasive Surgery Week 2014: Annual Meeting and Endo Expo” (Las Vegas, Sept. 10–13). Contact the Society of Laparoendoscopic Surgeons, 7330 SW 62nd Place, Suite 410, Miami, FL 33143; or call (305) 665-9959; or fax (305) 667-4123; or see http://www.sls.org.
Harvard Medical School/Beth Israel Deaconess Medical Center The following courses will be offered in Boston: “Principles of Critical Care Medicine for Non-Intensive Care Specialists” (March 13–15); “Nephrology 2014” (March 16–21); and “Men’s Health for Primary Care and Innovation” (April 11 and 12). They are jointly sponsored by Harvard Medical School Department of Continuing Education and Beth Israel Deaconess Medical Center. Contact Agri Meetings, 21 Robin Hill Rd., Danvers, MA 01923; or call (978) 304-0935; or fax (978) 304-0936; or e-mail [email protected]; or see http://www.criticalmedboston .com, http://www.nephrologyboston.com, or http://www.critical medboston.com, respectively.
n engl j med 370;6 nejm.org february 6, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
585
n e w e ng l a n d j o u r na l
of
m e dic i n e
Abnormal Ventilatory Responses in Adults Born Prematurely To the Editor: Perinatal hyperoxia in preterm infants is associated with several well-known sequelae, including bronchopulmonary dysplasia and retinopathy of prematurity. Hyperoxia also induces alterations in cardiopulmonary control (e.g., preterm infants treated with hyperoxia lack normal ventilatory responses to hypoxia and hyperoxia).1,2 It has not been determined whether these impairments diminish with age. Thus, we sought to determine whether or not ventilatory dysfunction persists in adults who were born prematurely. We measured the ventilatory responses to 5 minutes of isocapnic, isobaric hypoxia (in which the fraction of inspired oxygen [Fio2] was 0.12) and hyperoxia (in which the Fio2 was 1.0) in 13 adults born prematurely who were recruited from the Newborn Lung Project3 (a cohort with a mean [±SD] age of 21±1 years, a gestational age of ≤32 weeks, and a gestational weight of ≤1500 g) and from age-matched adults born at full term. Preterm adults were clinically indistinguishable from full-term adults, having similar pulmonary function and exercise capacity (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). However, the B 0.8 0.6
P=0.008
0.4 0.2 0.0 −0.2 −0.4
Control
Preterm
C Control
75
Preterm
Hypoxic Ventilatory Response (∆E/−∆SpO2)
1.0
Hyperoxic Ventilatory Response (% ∆E)
Hypoxic Ventilatory Response (liters/min/−∆SpO2)
A
hypoxic ventilatory response was substantially reduced in preterm adults (0.13±0.25 liters per minute per −ΔSpO2, where −ΔSpO2 denotes a negative change in oxygen saturation as measured by pulse oximetry) as compared with fullterm adults (0.42±0.30 liters per minute per −ΔSpO2; P = 0.008) (Fig. 1). Moreover, two preterm adults hypoventilated, which resulted in an increase in the partial pressure of end-tidal carbon dioxide (PETCO2). As expected, 60 seconds of hyperoxia induced respiratory depression from baseline in all full-term adults (−29.6±20.1%) but in only 8 of 13 preterm adults. The mean response was also reduced in the preterm population (−3.0±26.9%; P = 0.01). In rodents, perinatal hyperoxia disrupts the development of carotid chemoreceptors.4 The strong relationship between the hypoxic and hyperoxic ventilatory dysfunction in the preterm adults (Fig. 1) suggests a common impairment in chemoreceptor function that may be due to carotid chemoreceptor dysfunction. Our most compelling finding is that abnormal ventilatory responses were manifested only when these preterm adults, who appeared to be clinically normal, were stressed by breathing hypoxic and
50 25 0 −25 −50 −75
P=0.01 0
100
200
300
0.6 0.4 0.2 R 2=0.56 P=0.003
0.0 −0.2 −0.4 −0.6 −50
Seconds
0
50
100
Hyperoxic Ventilatory Response (% ∆E)
Figure 1. Ventilatory Responses to Hypoxia and Hyperoxia in Adults Born Prematurely as Compared with Adults Born at Full Term. All full-term adults (controls) had increased ventilation in response to hypoxia (fraction of inspired oxygen [Fio2] = 0.10); paradoxically, some preterm adults hypoventilated in response to hypoxia and reported presyncopal symptoms at the end of the trial (Panel A; boxes depict the median and first and third interquartile ranges, with whiskers indicating maximum and minimum responses). After 60 seconds of hyperoxia (Fio2 = 1.0), ventilation was depressed in all full-term adults, but this response was blunted in preterm adults (Panel B; points represent the mean ±SD). The blunting of hyperoxic and hypoxic ventilatory responses was correlated in preterm adults, suggesting a common cause of ventilatory dysfunction (Panel C). The Δ symbol denotes change, SpO2 oxygen saturation as measured by pulse oximetry, and E volume expired.
584
n engl j med 370;6 nejm.org february 6, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
notices
hyperoxic gas. This finding may have important clinical implications.5 We found that some preterm adults paradoxically hypoventilate with hypoxia. In summary, adults with a history of preterm birth have abnormal ventilatory responses to hypoxia and hyperoxia, possibly due to disrupted chemoreceptor development. We speculate that these underappreciated abnormalities in ventilatory control may have important clinical consequences, including an increased risk of disordered breathing during sleep and in response to high altitude and anesthesia. Additional investigations into the mechanisms and long-term disease risks of this population are warranted. Melissa L. Bates, Ph.D. Emily T. Farrell, Ph.D. Marlowe W. Eldridge, M.D. University of Wisconsin School of Medicine and Public Health Madison, WI [email protected] Supported by grants from the National Institutes of Health (5R01HL086897, to Drs. Eldridge and Farrell, and 5T32HL007654, to Dr. Bates) and a postdoctoral fellowship from the American Heart Association (to Dr. Bates). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Calder NA, Williams BA, Smyth J, Boon AW, Kumar P, Han-
son MA. Absence of ventilatory responses to alternating breaths of mild hypoxia and air in infants who have had bronchopulmonary dysplasia: implications for the risk of sudden infant death. Pediatr Res 1994;35:677-81. 2. Katz-Salamon M, Lagercrantz H. Hypoxic ventilatory defence in very preterm infants: attenuation after long term oxygen treatment. Arch Dis Child Fetal Neonatal Ed 1994;70:F90-5. 3. Weinstein MR, Peters ME, Sadek M, Palta M. A new radiographic scoring system for bronchopulmonary dysplasia. Pediatr Pulmonol 1994;18:284-9. 4. Bisgard GE, Olson EB Jr, Wang ZY, Bavis RW, Fuller DD, Mitchell GS. Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia. J Appl Physiol (1985) 2003;95:946-52. 5. Bates ML, Pillers D-AM, Palta M, Farrell ET, Eldridge MW. Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia. Respir Physiol Neurobiol 2013;189:329-37. DOI: 10.1056/NEJMc1311092 Correspondence Copyright © 2014 Massachusetts Medical Society.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: • Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article.
• Letters not related to a Journal article must not exceed 400 words. • A letter can have no more than five references and one figure or table. • A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
notices Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month. Computer Assisted Radiology and Surgery The congress will be held in Fukuoka, Japan, June 25–28. Contact CARS Conference Office, Im Gut 15, 79790 Kuessaberg, Germany; or call (49) 7742-922 434; or fax (49) 7742-922 438; or e-mail [email protected]; or see http://www.cars-int.org.
Society of Laparoendoscopic Surgeons The following meetings will be held: “AsianAmerican MultiSpecialty Summit VI: Laparoscopy & Minimally Invasive Surgery” (Honolulu, Feb. 12–15) and “Minimally Invasive Surgery Week 2014: Annual Meeting and Endo Expo” (Las Vegas, Sept. 10–13). Contact the Society of Laparoendoscopic Surgeons, 7330 SW 62nd Place, Suite 410, Miami, FL 33143; or call (305) 665-9959; or fax (305) 667-4123; or see http://www.sls.org.
Harvard Medical School/Beth Israel Deaconess Medical Center The following courses will be offered in Boston: “Principles of Critical Care Medicine for Non-Intensive Care Specialists” (March 13–15); “Nephrology 2014” (March 16–21); and “Men’s Health for Primary Care and Innovation” (April 11 and 12). They are jointly sponsored by Harvard Medical School Department of Continuing Education and Beth Israel Deaconess Medical Center. Contact Agri Meetings, 21 Robin Hill Rd., Danvers, MA 01923; or call (978) 304-0935; or fax (978) 304-0936; or e-mail [email protected]; or see http://www.criticalmedboston .com, http://www.nephrologyboston.com, or http://www.critical medboston.com, respectively.
n engl j med 370;6 nejm.org february 6, 2014
The New England Journal of Medicine Downloaded from nejm.org on October 13, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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