Permissive Hypercapnia in Neonates: Specific Experience and Limitations

  • Gonzalo Mariani
  • J. Davin Miller
  • Waldemar A. CarloEmail author


Two decades ago, a consensus of experts on mechanical ventilation indicated that one of the potential strategies to reduce lung injury was to modify blood-gas targets to accept a higher-than-normal PaCO2 (Slutsky 1993). This approach to ventilator support has been called permissive hypercapnia, also termed controlled mechanical hypoventilation. In the past, many clinicians aimed to achieve PaCO2 levels of 40 mmHg or less in ventilated neonates. Experimental and clinical researches during the last two decades indicate that slightly higher PaCO2 levels may allow a reduction in ventilatory support and may reduce the risk for lung injury.


Lung Injury VLBW Infant Hypercapnic Acidosis Permissive Hypercapnia PaCO2 Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ammari A, Suri M, Milisavljevic V, Sahni R, Bateman D, Sanocka U et al (2005) Variables associated with the early failure of nasal CPAP in very low birth weight infants. J Pediatr 147:341–347PubMedCrossRefGoogle Scholar
  2. Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton RB et al (1987) Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 79:26–30PubMedGoogle Scholar
  3. Bagolan P, Casaccia G, Crescenzi F, Nahom A, Trucchi A, Giorlandino C (2004) Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg 39:313–318PubMedCrossRefGoogle Scholar
  4. Benjamin JT, Smith RJ, Halloran BA, Day TJ, Kelly DR, Prince LS (2007) FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by toll-like receptor activation. Am J Physiol Lung Cell Mol Physiol 292:L550–L558PubMedCrossRefGoogle Scholar
  5. Bohlin K, Jonsson B, Gustafsson AS, Blennow M (2008) Continuous positive airway pressure and surfactant. Neonatology 93:309–315PubMedCrossRefGoogle Scholar
  6. Boynton BR, Hammond MD (1994) Pulmonary gas exchange: basic principles and the effects of mechanical ventilation. In: Boynton BR, Carlo WA, Jobe AH (eds) New therapies for neonatal respiratory failure: a physiological approach. Cambridge University Press, Cambridge, pp 115–128Google Scholar
  7. Brogan TV, Robertson HT, Lamm WJ, Souders JE, Swenson ER (2004) Carbon dioxide added late in inspiration reduces ventilation-perfusion heterogeneity without causing respiratory acidosis. J Appl Physiol 96:1894–1898PubMedCrossRefGoogle Scholar
  8. Cardenas VJ Jr, Zwischenberger JB, Tao W, Nguyen PD, Schroeder T, Traber LD et al (1996) Correction of blood pH attenuates changes in hemodynamics and organ blood flow during permissive hypercapnia. Crit Care Med 24:827–834PubMedCrossRefGoogle Scholar
  9. Carlo WA (2007) Permissive hypercapnia and permissive hypoxemia in neonates. J Perinatol 27(Suppl 1s):S64–S70CrossRefGoogle Scholar
  10. Carlo WA, Stark AR, Wright LL, Tyson JE, Papile LA, Shankaran S et al (2002) Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr 141:370–374PubMedCrossRefGoogle Scholar
  11. Collins MP, Lorenz JM, Jetton J, Paneth N (2001) Hypocapnia and other ventilation-related risk factors for cerebral palsy in low birth weight infants. Pediatr Res 50:712–719PubMedCrossRefGoogle Scholar
  12. Das S, Du Z, Bassly S, Singer L, Vicencio AG (2009) Effects of chronic hypercapnia in the neonatal mouse lung and brain. Pediatr Pulmonol 44:176–182PubMedCrossRefGoogle Scholar
  13. Doerr CH, Gajic O, Berrios JC, Caples S, Abdel M, Lymp JF et al (2005) Hypercapnic acidosis impairs plasma membrane wound resealing in ventilator-injured lungs. Am J Respir Crit Care Med 171:1371–1377PubMedCentralPubMedCrossRefGoogle Scholar
  14. Dudell GG, CDH Study Group (2006) Are permissive strategies now standard of care for neonates with congenital diaphragmatic hernia (CDH) [abstract]? In: Presented at: 2006 PAS annual meeting, San Francisco. E-PAS2006:59:453. Available at:
  15. Dunn MS, Reilly MC (2003) Approaches to the initial respiratory management of preterm neonates. Paediatr Respir Rev 4:2–8PubMedCrossRefGoogle Scholar
  16. Dunn MS, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D et al (2011) Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 128:e1069–e1076Google Scholar
  17. Fabres J, Carlo WA, Phillips V, Howard G, Ambalavanan N (2007) Both extremes of PaCO2 and the magnitude of fluctuations are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics 119:299–305PubMedCrossRefGoogle Scholar
  18. Feihl F, Eckert P, Brimioulle S, Jacobs O, Schaller MD, Mélot C et al (2000) Permissive hypercapnia impairs pulmonary gas exchange in the acute respiratory distress syndrome. Am J Respir Crit Care Med 162:209–215PubMedCrossRefGoogle Scholar
  19. Finer N (2006) To intubate or not–that is the question: continuous positive airway pressure versus surfactant and extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 91:F392–F394PubMedCentralPubMedCrossRefGoogle Scholar
  20. Finer NN, Carlo WA, Duara S, Fanaroff AA, Donovan EF, Wright LL et al (2004) Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics 114:651–657PubMedCrossRefGoogle Scholar
  21. Fischer HS, Bührer C (2013) Avoiding Endotracheal Ventilation to Prevent Bronchopulmonary Dysplasia: A Meta-analysis. Pediatrics 132;e1351–e1360Google Scholar
  22. Finer NN, Carlo WA, Duara S, Fanaroff AA, Donovan EF, Wright LL et al (2004) Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: a feasibility trial. Pediatrics 114:651–657Google Scholar
  23. Gullberg N, Winberg P, Selldén H (1999) Changes in stroke volume cause change in cardiac output in neonates and infants when mean airway pressure is altered. Acta Anaesthesiol Scand 43:999–1004PubMedCrossRefGoogle Scholar
  24. Gullberg N, Winberg P, Selldén H (2004) Changes in mean airway pressure during HFOV influences cardiac output in neonates and infants. Acta Anaesthesiol Scand 48:218–223PubMedCrossRefGoogle Scholar
  25. Hare GM, Kavanagh BP, Mazer CD, Hum KM, Kim SY, Coackley C et al (2003) Hypercapnia increases cerebral tissue oxygen tension in anesthetized rats. Can J Anaesth 50:1061–1068PubMedCrossRefGoogle Scholar
  26. Hino JK, Short BL, Rais-Bahrami K, Seale WR (2000) Cerebral blood flow and metabolism during and after prolonged hypercapnia in newborn lambs. Crit Care Med 28:3505–3510PubMedCrossRefGoogle Scholar
  27. Holmes JM, Zhang S, Leske DA, Lanier WL (1998) Carbon dioxide-induced retinopathy in the neonatal rat. Curr Eye Res 17:608–616PubMedCrossRefGoogle Scholar
  28. Jobe AH (1999) The new BPD. An arrest of lung development. Pediatr Res 46:641–643PubMedCrossRefGoogle Scholar
  29. Jobe AH (2003) Antenatal factors and development of bronchopulmonary dysplasia. Semin Neonatol 8:9–17PubMedCrossRefGoogle Scholar
  30. Kaiser J, Gauss CH, Williams DK (2005) The effects of hypercapnia on cerebral autoregulation in ventilated very low birth weight infants. Pediatr Res 58:931–935PubMedCentralPubMedCrossRefGoogle Scholar
  31. Kaiser JR, Gauss CH, Pont MM, Williams DK (2006) Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants. J Perinatol 26:279–285PubMedCrossRefGoogle Scholar
  32. Kamper J, Feilberg Jørgensen N, Jonsbo F, Pederson-Bjergaard L, Pryds O, Danish ETFOL Study Group (2004) The Danish national study in infants with extremely low gestational age and birth weight (the ETFOL study): respiratory morbidity and outcome. Acta Paediatr 93:225–232PubMedCrossRefGoogle Scholar
  33. Kantores C, McNamara PJ, Teixeira L, Engelberts D, Murthy P, Kavanagh BP et al (2006) Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat. Am J Physiol Lung Cell Mol Physiol 291:L912–L922PubMedCrossRefGoogle Scholar
  34. Kondo T, Kumagai M, Ohta Y, Bishop B (2000) Ventilatory responses to hypercapnia and hypoxia following chronic hypercapnia in the rat. Respir Physiol 122:35–43PubMedCrossRefGoogle Scholar
  35. Kraybill EN, Runyun DK, Bose CL, Khan JH (1989) Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams. J Pediatr 115:115–120PubMedCrossRefGoogle Scholar
  36. Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill–too little of a good thing? Lancet 354:1283–1286PubMedCrossRefGoogle Scholar
  37. Laffey JG, Tanaka M, Engelberts D, Luo X, Yuan S, Tanswell K et al (2000) Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 162:2287–2294PubMedCrossRefGoogle Scholar
  38. Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P (2004) Hypercapnic acidosis attenuates endotoxin induced acute lung injury. Am J Respir Crit Care Med 169:46–56PubMedCrossRefGoogle Scholar
  39. Lang JD Jr, Chumley P, Eiserich JP, Estevez A, Bamberg T, Adhami A et al (2000) Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway. Am J Physiol Lung Cell Mol Physiol 279:L994–L1002PubMedGoogle Scholar
  40. Lang CJ, Dong P, Hosszu EK, Doyle IR (2005a) Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 289:L96–L103PubMedCrossRefGoogle Scholar
  41. Lang JD, Figueroa M, Sanders KD, Aslan M, Liu Y, Chumley P et al (2005b) Hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharide-induced lung injury. Am J Respir Crit Care Med 171:147–157PubMedCrossRefGoogle Scholar
  42. Leduc M, Dermorvant-Duchemin E, Checchin D, Sennlaub F, Sirinyan M, Kooli A et al (2006) Hypercapnia- and trans-arachidonic acid-induced retinal microvascular degeneration: implications in the genesis of retinopathy of prematurity. Semin Perinatol 30:129–138PubMedCrossRefGoogle Scholar
  43. Li G, Zhou D, Vicencio AG, Ryu J, Xue J, Kanaan A et al (2006) Effect of carbon dioxide on neonatal mouse lung: a genomic approach. J Appl Physiol 101:1556–1564PubMedCrossRefGoogle Scholar
  44. Mariani G, Cifuentes J, Carlo WA (1999) Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 104:1082–1088PubMedCrossRefGoogle Scholar
  45. Masood A, Yi M, Lau M, Belcastro R, Shek S, Pan J et al (2009) Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats. Am J Physiol Lung Cell Mol Physiol 297:L920–L930PubMedCrossRefGoogle Scholar
  46. McKee LA, Fabres J, Howard G, Peralta-Carcelen M, Carlo WA, Ambalavanan N (2009) PaCO2 and neurodevelopment in extremely low birth weight infants. J Pediatr 155:217–221PubMedCrossRefGoogle Scholar
  47. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB (2008) Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 358:700–708PubMedCrossRefGoogle Scholar
  48. Nichol AD, O’Cronin DF, Howell K, Naughton F, O’Brien S, Boylan J et al (2009) Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis. Crit Care Med 37:2953–2961PubMedCrossRefGoogle Scholar
  49. Northway WH Jr, Rosan RC, Porter DY (1967) Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 276:357–368PubMedCrossRefGoogle Scholar
  50. O’Croinin D, Ni Chonghaile M, Higgins B, Laffey JG (2005) Bench-to-bedside review: permissive hypercapnia. Crit Care 9:51–59PubMedCrossRefGoogle Scholar
  51. Payne NR, LaCorte M, Sun S, Karna P, Lewis-Hunstiger M, Goldsmith JP, Breathsavers Group (2006a) Evaluation and development of potentially better practices to reduce bronchopulmonary dysplasia in very low birth weight infants. Pediatrics 118(Suppl 2):S65–S72PubMedCrossRefGoogle Scholar
  52. Payne NR, LaCorte M, Karna P, Chen S, Finkelstein M, Goldsmith JP et al (2006b) Reduction of bronchopulmonary dysplasia after participation in the breathsavers group of the Vermont oxford network neonatal intensive care quality improvement collaborative. Pediatrics 118(Suppl 2):S73–S77PubMedCrossRefGoogle Scholar
  53. Petrucci N, Iacovelli W (2004) Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome. The Cochrane Database Syst Rev (1):CD003844. doi: 10.1002/14651858.CD003844
  54. Prince LS, Dieperink HI, Okoh VO, Fierro-Perez GA, Lallone RL (2005) Toll-like receptor signaling inhibits structural development of the distal fetal mouse lung. Dev Dyn 233:553–561PubMedCrossRefGoogle Scholar
  55. Rai S, Engelberts D, Laffey JG, Frevert C, Kajikawa O, Martin TR et al (2004) Therapeutic hypercapnia is not protective in the in vivo surfactant-depleted rabbit lung. Pediatr Res 55:42–49PubMedCrossRefGoogle Scholar
  56. Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA et al (2009) Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 123:137–142PubMedCrossRefGoogle Scholar
  57. Rojas-Reyes MX, Morley CJ, Soll R (2012) Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev (3): CD000510. doi:  10.1002/14651858.CD000510.pub2. Available at:
  58. Rotta AT, Steinhorn DM (2006) Is permissive hypercapnia a beneficial strategy for pediatric acute lung injury? Respir Care Clin N Am 12:371–387PubMedGoogle Scholar
  59. Ryu J, Heldt GP, Nguyen M, Gavrialov O, Haddad GG (2010) Chronic hypercapnia alters lung matrix composition in mouse pups. J Appl Physiol 109:203–210PubMedCentralPubMedCrossRefGoogle Scholar
  60. Sandri F, Ancora G, Lanzoni A, Tagliabue P, Colnaghi M, Ventura ML et al (2004) Prophylactic nasal continuous positive airways pressure in newborns of 28-31 weeks gestation: multicentre randomised controlled clinical trial. Arch Dis Child Fetal Neonatal Ed 89:F394–F398PubMedCentralPubMedCrossRefGoogle Scholar
  61. Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S et al (2010) Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 125:e1402–e1409PubMedCrossRefGoogle Scholar
  62. Schmölzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung PY (2013) Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 347:f5980Google Scholar
  63. Sinclair SE, Kregenow DA, Lamm WJ, Starr IR, Chi EY, Hlastala MP (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166:403–408PubMedCrossRefGoogle Scholar
  64. Sinclair SE, Kregenow DA, Starr I, Schimmel C, Lamm WJ, Hlastala MP et al (2006) Therapeutic hypercapnia and ventilation-perfusion matching in acute lung injury: low minute ventilation vs inspired CO2. Chest 130:85–92PubMedCrossRefGoogle Scholar
  65. Slutsky AS (1993) Mechanical ventilation. American College of Chest Physicians’ Consensus Conference. Chest 104:1833–1859PubMedCrossRefGoogle Scholar
  66. Søvik S, Lossius K (2004) Development of ventilatory response to transient hypercapnia and hypercapnic hypoxia in term neonates. Pediatr Res 55:302–309PubMedCrossRefGoogle Scholar
  67. Stevens TP, Blennow M, Myers EH, Soll R (2007) Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev (4):CD003063. doi: 10.1002/14651858.CD003063.pub3
  68. Strand M, Ikegami M, Jobe AH (2003) Effects of high PCO2 on ventilated preterm lamb lungs. Pediatr Res 53:468–472PubMedCrossRefGoogle Scholar
  69. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR et al (2010) Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 362:1970–1979, Erratum in: N Engl J Med. 2010;362:2235PubMedCrossRefGoogle Scholar
  70. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R et al (2013) European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2013 Update. Neonatology 103:353–368Google Scholar
  71. Swenson ER, Robertson HT, Hlastala MP (1994) Effects of inspired carbon dioxide on ventilation-perfusion matching in normoxia, hypoxia, and hyperoxia. Am J Respir Crit Care Med 149:1563–1569PubMedCrossRefGoogle Scholar
  72. Takeshita K, Suzuki Y, Nishio K, Takeuchi O, Toda K, Kudo H et al (2003) Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation. Am J Respir Cell Mol Biol 29:124–132PubMedCrossRefGoogle Scholar
  73. Tapia JL, Urzua MS, Bancalari A, Meritano J, Torres G, Fabres J et al (2012) Randomized Trial of Early Bubble Continuous Positive Airway Pressure for Very Low Birth Weight Infants. J Pediatr 161:75–80Google Scholar
  74. Thome UH, Carroll W, Wu TJ, Johnson RB, Roane C, Young D et al (2006) Outcome of extremely preterm infants randomized at birth to different PaCO2 targets during the first seven days of life. Biol Neonate 90:218–225PubMedCrossRefGoogle Scholar
  75. Van Marter LJ, Allred EN, Pagano M, Sanocka U, Parad R, Moore M et al (2000) Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network. Pediatrics 105:1194–1201PubMedCrossRefGoogle Scholar
  76. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM (1995) Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 95:868–874PubMedGoogle Scholar
  77. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrøm K et al (1994) Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish-Swedish Multicenter Study Group. N Engl J Med 331:1051–1055PubMedCrossRefGoogle Scholar
  78. Verder H, Albertsen P, Ebbesen F, Greisen G, Robertson B, Bertelsen A et al (1999) Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks’ gestation. Pediatrics 103:E24PubMedCrossRefGoogle Scholar
  79. Verder H, Bohlin K, Kamper J, Lindwall R, Jonsson B (2009) Nasal CPAP and surfactant for treatment of respiratory distress syndrome and prevention of bronchopulmonary dysplasia. Acta Paediatr 98:1400–1408PubMedCrossRefGoogle Scholar
  80. Walley KR, Lewis TH, Wood LD (1990) Acute respiratory acidosis decreases left ventricular contractility but increases cardiac output in dogs. Circ Res 67:628–635PubMedCrossRefGoogle Scholar
  81. Watterberg KL, Demers LM, Scott SM, Murphy S (1996) Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97:210–215PubMedGoogle Scholar
  82. Weber T, Tschernich H, Sitzwohl C, Ullrich R, Germann P, Zimpfer M et al (2000) Tromethamine buffer modifies the depressant effect of permissive hypercapnia on myocardial contractility in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 162:1361–1365PubMedCrossRefGoogle Scholar
  83. Weiner JH, Chatburn RL, Carlo WA (1987) Ventilation and hemodynamic effects of high-frequency jet ventilation following cardiac surgery. Respir Care 32:332–338Google Scholar
  84. Woodgate PG, Davies MW (2001) Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants. Cochrane Database Syst Rev (2):CD002061. doi: 10.1002/14651858.CD002061
  85. Wung JT, James LS, Kilchevsky E, James E (1985) Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 76:488–494PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Gonzalo Mariani
    • 1
  • J. Davin Miller
    • 2
  • Waldemar A. Carlo
    • 3
    Email author
  1. 1.Division of NeonatologyInstituto Universitario, Hospital Italiano de Buenos AiresBuenos AiresArgentina
  2. 2.Neonatology Associates of AtlantaAtlantaUSA
  3. 3.Division of Neonatology, Newborn NurseriesUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations