- Email: [email protected]
Is permissive hypercapnia helpful or harmful?
OCCASIONAL REVIEW
Is permissive hypercapnia helpful or harmful?
Physiologic effects of hypercapnia (Table 1) Hypercapnia and the immune system Hypercapnic acidosis alters the immune response. The effects are complex and whilst there is an inhibition of some inflammatory pathways the picture in vivo is mixed. Hypercapnic acidosis has been shown to inhibit the innate, as well as, adaptive immune response. Macrophages incubated with CO2 produce less tumour necrosis factor (TNF) and interleukin-1 (IL-1) in response to LPS compared to those incubated with helium. The response to lipopolysaccharide (LPS) stimulated cytokine release by peritoneal macrophages, possibly explains the lack of systemic reaction to laparoscopic surgery with CO2. Neutrophils respond to hypercapnia by decreasing intracellular oxidant and release of IL-8. Spreading is another function of neutrophils that is inhibited by an acidic pH, release superoxide during the spreading, generating an intracellular acid environment that is essential to microbicidal activity. Hypercapnia also inhibits neutrophil adherence. Conversely, extracellular acidosis may intensify acute inflammatory responses by inducing neutrophil activation, delaying spontaneous apoptosis and extending its functional lifespan. Acidosis also has a number of other effects on inflammatory mechanisms, including attenuating leucocyte superoxide formation, neuronal apoptosis, phosphodiesterese-A activity expression of cell adhesion molecules and neutrophils Naþ/Hþ exchange. Xanthine-oxidase, an enzyme that has an important role in reperfusion injury is inhibited by hypercapnic acidosis. During inflammation, hypercapnia and acidosis may tilt the balance towards cell salvage at the tissue level.
Catarina Silvestre Harish Vyas
Abstract Permissive hypercapnia (PHC) is a ventilatory strategy in which high levels of carbon dioxide (CO2) are tolerated as to avoid high tidal volumes, lung over-distention and ventilator induced lung injury. The decrease of mortality and morbidity in asthma, ARDS and neonatal chronic lung disease using lung protective strategies and permissive hypercapnia is described in several studies. In spite of the limitation in knowledge regarding the physiological effects of PHC, there are clinical data demonstrating its benefits in several clinical scenarios. This article describes the physiological effects of PHC, the use of PHC in clinical scenarios and the contraindications of PHC in neonates and children.
Keywords children; mechanical ventilation; permissive hypercapnia
Introduction Mechanical ventilation has traditionally been used with the aim of normalizing the blood gases. Historically this was used to achieve normal levels of oxygen as well as CO2. However, a major side effect of this technique is barotrauma and excessive mortality, cardiocirculatory failure, or pulmonary barotrauma, due to extremely high pressures used in overcoming the airway obstruction. The seminal work of Darioli and Perret in 1984 evaluated the role of permissive hypercapnia (PHC) in status asthamaticus. They observed that controlled mechanical hypoventilation appeared to be an effective way of treating life-threatening asthma with a reduction in barotrauma and fatal complications of mechanical ventilation. Bidani et al. observed that avoidance of alveolar over-distention, through pressure or volume limitation in patients with acute respiratory failure, had better outcome without deleterious effects of hypercapnia. Since then the use of PHC has become well established in the management of acute respiratory failure. Several studies have shown that mechanical ventilation using lung protective strategies with low tidal volumes and low minute volumes, resulting in PHC, had better outcomes not only in adults but also in children and neonates. The association between hypercapnia and adverse outcomes in diverse clinical situations including cardiac arrest, sepsis and neonatal asphyxia has been questioned. The level of CO2 tolerated in a given child is very variable.
Hypercapnia and the lung In experimental animal models of hypercapnic acidosis, lung compliance is enhanced by increase in surfactant secretion or activity. Hypercapnic acidosis increases the arterial oxygenation by improving the matching of ventilation and perfusion. PHC has two conflicting effects; it can, by direct dilatation of the small airway, decrease the airway resistance and bronchodilation and, by the stimulation of vagus nerve, increase the airway resistance of the large airways and cause bronchoconstriction. The stimulation of vagus nerve can also decrease diaphragmatic contractibility. This can be particularly deleterious on weaning from mechanical ventilation. Hypercapnia and the heart Hypercapnic acidosis directly reduces the contractibility of cardiac and vascular smooth muscle. However, this is counterbalanced by the effect of several other mechanisms which lead to increase of cardiac output. Hypercapnia increases arterial and tissue oxygenation by four mechanisms: first it potentiates hypoxic pulmonary vasoconstriction and increases local alveolar ventilation by inhibiting airway tone, improving the ventilation/perfusion (V/Q) matching and the arterial oxygenation. Second, it increases cardiac output through the release of catecholamines and their sympathoadrenal effects (an increase of PaCO2 of 1.3 kPa increases the cardiac index by 14% in ventilated patients). Third, CO2 shifts the dissociation curve of oxyhaemoglobin to the right, facilitating the release of O2 to the tissues. Fourth, hypercapnia promotes microvascular vasodilatation. Hypercapnia acidosis appears to
Catarina Silvestre MD is a Senior Fellow PICU in the PICU at Nottingham University Hospital, Nottingham, UK. Conflict of interest: none declared. Harish Vyas DM FRCP FRCPCH is Professor in PICU and Respiratory Medicine at the PICU at Nottingham University Hospital, Nottingham, UK. Conflict of interest: none declared.
PAEDIATRICS AND CHILD HEALTH 25:4
192
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
to be more neuroprotective then higher PaCO2 (more than 9.3 kPa). Hypercapnia may contribute to the pathogenesis of retinopathy of prematurity due to the increase retinal vasodilation and increase oxygen delivery.
Effects of hypercapnic acidosis in different systems Immune system Inhibit the innate and adaptive immune functions: C Y Neutrophil function C Y Phagocyte function C Y Production of free radicals of O2 C Y Decrease xanthine-oxidase formation C Y Cell adhesion molecules Lung C [ Lung compliance C [ Surfactant secretion/activity C [ Matching of V/Q C Dilatation of small airways C Constriction large airway (vagal stimulation) C Y Diaphragmatic function Heart C Y Contractibility of cardiac and vascular smooth muscle C [ Pulmonary vasoconstriction C [ Cardiac output C [ Release of catecholamines C [ Release of O2 by Bohr effect C [ Microvascular vasodilatation C [ NO production Brain Has potent vasodilator effect with: C [ Cerebral tissue oxygenation C [ Cerebral blood flow C [ Intracranial Pressure C [ Cerebral cortex apoptosis C [ Retinopathy of prematurity Other organs C Hepatocytes apoptosis C Action on renal cortical tubes
Other organs: acidosis has effects on other organs including the liver and kidney. In experimental models, the hepatocytes exposed to acidosis had delayed cell death when subject to anoxia or hypoxia. The renal cortical tubes, when exposed to anoxia have greater ATP levels on re-oxygenation at acidotic pH.
Clinical scenarios (Table 2) Acute respiratory distress syndrome ARDS is one of the most challenging clinical syndromes in critical care. A lung protective ventilation strategy using 6 ml/kg tidal volume has been associated with lower mortality and fewer ventilator days. Kregenow et al. demonstrated that hypercapnic acidosis had a protective effect against ventilator-associated lung injury. There is however no evidence relating mortality and the levels of PaCO2. Severe asthma PHC and controlled hypoventilation are a well established strategy in asthma, 1984 PHC and controlled hypoventilation are a well established strategy in asthma, first described in 1984 by Darioli and Perrret. The objective of this form of ventilation is to avoid excessive airway pressure and minimize lung hyperinflation. This ventilatory strategy is associated with a low incidence of barotrauma and reduced mortality in patients admitted with life-threating asthma. Hypercapnia and acidosis are well tolerated in the absence of contra-indications like intracranial hypertension. Sepsis The effect of hypercapnia in sepsis is still unclear. Severe sepsis of pulmonary or systemic origin induces organ failure. Sepsis with ARDS has been associated with higher mortality rates. Evidence suggests that 40 % of patients with sepsis develop ARDS and that infection complicates 45% of critical ill patients. The role of hypercapnic acidosis in the immune response in sepsis is still unclear. Immunocompetence is essential to an effective host response and CO2 and acidosis can modulate this interaction by several mechanisms resulting in a suppression of the immune
Table 1
protect the heart from ischaemia-reperfusion injury. Both hypercapnia and acidosis have been shown to reduce cardiac infarct size in animal models. Due to PHC-associated increase in cardiac output, regional (including mesenteric) blood flow is also increased. Hypercapnia and the brain Cerebral perfusion and oxygenation are dependent on PaCO2. Hypocapnia decreases oxygen delivery to the brain through cerebral vasoconstriction. Severe hypocapnia can be associated with poor neurologic outcome, with increased risk of intracranial haemorrhage, periventricular leukomalacia and cerebral palsy. Hypercapnia appears to be neuro-protective in hypoxic state through its potent vasodilatation effect. It also leads to increase in intracranial pressure with adverse consequences, especially in the presence of cerebral oedema and raised intracranial pressure. Animal studies showed that hypercapnia is associated with increased cerebral cortex apoptosis. Although increased cerebral flow associated with severe hypercapnia is detrimental to the preterm brain, controlled permissive hypercapnia has not been associated with adverse neurological outcomes. On the developing brain, mild to moderate hypercapnia (5.3e7.3 kPa) seems
PAEDIATRICS AND CHILD HEALTH 25:4
Indications and contraindications of PHC Indications
Relative contraindications
ARDS
Raised intracranial pressure Raised pulmonary pressure
Asthma Sepsis Neonatal RDS Congenital diaphragmatic hernia Congenital heart disease PPHN Table 2
193
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
scenario continuous monitoring of intracranial pressure may be necessary. A retrospective study in patients with subarachnoid haemorrhage showed that a PHC between 6.6 and 8.0 kPa did not affect the intracranial pressure. The paediatric use of this approach has been described in a child with meningococcal sepsis with meningitis and ARDS.
response. The net effect depends on the site of infection and if the acidosis is buffered or not. Although hypercapnia appears to protect the lung from injury, the outcome appears to be worse in prolonged pneumonia due to the imunossupression and yet associated with better outcomes in systemic sepsis due to reduced lung damage. Pre-clinical studies indicate that hypercapnia acidosis may be protective in systemic sepsis and early phase of pneumonia induced sepsis.
Increase pulmonary vascular resistance The clinical situations that can lead to pulmonary hypertension should be considered as a relative contra-indication to PHC. A rational approach would be using PHC but monitor pulmonary pressures and the presence of right ventricular failure, tricuspid regurgitation and right to left shunt.
Neonatal respiratory distress syndrome (RDS) PHC is one of the ventilator goals in neonates with RDS. Acceptance of PaCO2 of 6.0e9.3 kPa and pH >7.2, as a strategy for managing patients on mechanical ventilation avoids high tidal volumes and over-distention. In a large multicentre study of PHC and dexamethasone in extremely low birth weight infants, only 1% of the babies in the PHC group required ventilation at 36 weeks of gestational age compared with 16% of the normocapnic group ( p < 0.01). Kamper et al. reported a national multicentre study showing that the use of nasal continuous positive pressure and PHC decreases the incidence of chronic lung disease. Use of smaller tidal volumes and PHC appears to be safe and reduces lung injury in preterm babies. However the safe level of paCO2 has not yet been determined.
Buffering of acidosis There are concerns that buffering the acidosis may worsen the clinical situation by cutting the protective effects of hypercapnia. There is evidence that this protective effect is related to acidosis rather than high PaCO2. Buffering with bicarbonate raises systemic CO2 and worsens intracellular acidosis. An alternative option is tromethamine (Tham) in situations when buffering acidosis is indicated. Safe limits of hypercapnia There is no consensus on the upper limit of hypercapnia. Most physicians avoid PaCO2 above 13 kPa. The major concerns about severe hypercapnia are related to cerebral vasodilatation and cerebral oedema, as several case reports associate severe hypercapnia with subarachnoid haemorrhage and cerebral oedema. However, in asthamaticus patients, extreme hypercapnia between 20 and 25 kPa was tolerated for several hours without adverse outcomes. In many studies of patients undergoing PHC, a pH as low as 7.2 appears to be have been well tolerated.
Congenital diaphramatic hernia (CDH) Management of infants with CDH involves early intubation, appropriate ventilator management, treatment of pulmonary hypertension and surgical correction. Historically, the strategy involved aggressive ventilation with high inspiratory pressures, hyperoxygenation and hyperventilation with administration of bicarbonate. That approach was associated with significant morbidity and mortality. The new approach based on PHC (PaCO2 up to 8 kPa) and gentle ventilation has significantly reduced mortality and decreased the use of ECMO.
Conclusions Protective ventilatory strategies that involve hypoventilation with low tidal volumes result in PHC. The potential benefits are not only related to the reduced lung stretch, but with the physiological effects of CO2 in the lungs, brain, cardiovascular and immune system. There are “in vitro” studies that demonstrate the beneficial effect of PHC, and raise the possibility of an induced hypercapnia for therapeutic effects. There are clinical evidences of the role of PHC in ARDS, asthma and sepsis. However, there are still concerns regarding the potential deleterious effects of PHC especially in patients with CNS pathologies with raised ICP. A
Persistent pulmonary hypertension of the newborn (PPNH) Aggressive hyperventilation with hypocapnia is known to be a significant risk factor for hearing impairment in PPHN survivors. Both conventional and high-frequency ventilation can be used in the management. In severe PPHN most centres prefer HFOV as it usually supresses patient’s spontaneous breathing. “Gentle” ventilation strategies with optimal PEEP, relatively low PIP and PHC ensure adequate lung expansion without barotrauma. Congenital heart disease (CHD) The ventilation of infants with CHD has changed from a hyperventilation strategy to a hypoventilation and PHC strategy. Hypercapnea improves the oxygenation of the brain and other organs. This is particularly relevant in neonates with congenital heart defects where low cerebral blood flow is associated with adverse neurological outcome.
FURTHER READING 1 Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984; 129: 385e7. 2 Curley G, Hayes M, Laffey JG. Can “permissive” hypercapnia modulate the severity of sepsis-induced ALI/ARDS? Crit Care 2011; 15: 212. http://dx.doi.org/10.1186/cc9994. 3 Rogovik A, Goldman R. Permissive hypercapnia. Emerg Med Clin North Am 2008; 26: 941e52. http://dx.doi.org/10.1016/j.emc.2008. 08.002. viii-ix. 4 Curley GF, Laffey JG, Kavanagh BP. CrossTalk proposal: there is added benefit to providing permissive hypercapnia in the treatment of
Areas of controversies Raised intracranial pressure The effects of hypercapnia in cerebral blood flow auto-regulation in situations of raised intracranial pressures have been a concern. In ARDS with raised intracranial pressures, hypercapnia should be a relative rather than an absolute contra-indication. In this
PAEDIATRICS AND CHILD HEALTH 25:4
194
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
5
6
7
8
9
10
11
ARDS. J Physiol 2013; 591(Pt 11): 2763e5. http://dx.doi.org/10.1113/ jphysiol.2013.252601. Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. Semin Fetal Neonatal Med 2009; 14: 21e7. http://dx.doi.org/10.1016/j.siny.2008.08.005. Curley G, Contreras M, Nichol AD, Higgins BD, Laffey JG. Hypercapnia and acidosis in sepsis: a double-edged sword? Anesthesiology 2010; 112: 462e72. http://dx.doi.org/10.1097/ALN.0b013e3181ca361f. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301e8. http://dx.doi.org/10. 1056/NEJM200005043421801. Oddo M, Feihl F, Schaller M-D, Perret C. Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med 2006; 32: 501e10. Carlo WA, Stark AR, Wright LL, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr 2002; 141: 370e4. Kamper J, Feilberg Jørgensen N, Jonsbo F, Pedersen-Bjergaard L, Pryds O, Danish ETFOL Study Group. The Danish national study in infants with extremely low gestational age and birth weight (the ETFOL study): respiratory morbidity and outcome. Acta Paediatr 2004; 93: 225e32. Guidry CA, Hranjec T, Rodgers BM, Kane B, McGahren ED. Permissive hypercapnia in the management of congenital diaphragmatic hernia: our institutional experience. J Am Coll Surg 2012; 214: 640e5. http:// dx.doi.org/10.1016/j.jamcollsurg.2011.12.036. 647.e1; discussion 646e647.
PAEDIATRICS AND CHILD HEALTH 25:4
12 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol 2014; 38: 78e91. http://dx.doi.org/10. 1053/j.semperi.2013.11.004. 13 Petridis AK, Doukas A, Kienke S, et al. The effect of lung-protective permissive hypercapnia in intracerebral pressure in patients with subarachnoid haemorrhage and ARDS. A retrospective study. Acta Neurochir (Wien) 2010; 152: 2143e5. http://dx.doi.org/10.1007/ s00701-010-0761-z. 14 Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP. Permissive hypercapniaerole in protective lung ventilatory strategies. Intensive Care Med 2004; 30: 347e56. http://dx.doi.org/10.1007/ s00134-003-2051-1. 15 Higgins BD, Costello JF, Laffey JG. Permissive hypercapnia in protective lung ventilatory strategies. Paediatr Child Heath 2007; 17-3: 94e103.
Practice points C C C
C
C
195
PHC is a consequence of lung protective ventilatory strategies PHC reduces inflammation and oxidant-induced injury PHC improves blood flow, oxygenation and is a potent vasodilator agent PHC is a gold standard strategy in ARDS and Asthma, and can be beneficial in other clinical situations like sepsis, CDH, PPNH and congenital heart diseases. PHC is not recommended in situations with raised ICP
Ó 2014 Elsevier Ltd. All rights reserved.
Is permissive hypercapnia helpful or harmful?
Physiologic effects of hypercapnia (Table 1) Hypercapnia and the immune system Hypercapnic acidosis alters the immune response. The effects are complex and whilst there is an inhibition of some inflammatory pathways the picture in vivo is mixed. Hypercapnic acidosis has been shown to inhibit the innate, as well as, adaptive immune response. Macrophages incubated with CO2 produce less tumour necrosis factor (TNF) and interleukin-1 (IL-1) in response to LPS compared to those incubated with helium. The response to lipopolysaccharide (LPS) stimulated cytokine release by peritoneal macrophages, possibly explains the lack of systemic reaction to laparoscopic surgery with CO2. Neutrophils respond to hypercapnia by decreasing intracellular oxidant and release of IL-8. Spreading is another function of neutrophils that is inhibited by an acidic pH, release superoxide during the spreading, generating an intracellular acid environment that is essential to microbicidal activity. Hypercapnia also inhibits neutrophil adherence. Conversely, extracellular acidosis may intensify acute inflammatory responses by inducing neutrophil activation, delaying spontaneous apoptosis and extending its functional lifespan. Acidosis also has a number of other effects on inflammatory mechanisms, including attenuating leucocyte superoxide formation, neuronal apoptosis, phosphodiesterese-A activity expression of cell adhesion molecules and neutrophils Naþ/Hþ exchange. Xanthine-oxidase, an enzyme that has an important role in reperfusion injury is inhibited by hypercapnic acidosis. During inflammation, hypercapnia and acidosis may tilt the balance towards cell salvage at the tissue level.
Catarina Silvestre Harish Vyas
Abstract Permissive hypercapnia (PHC) is a ventilatory strategy in which high levels of carbon dioxide (CO2) are tolerated as to avoid high tidal volumes, lung over-distention and ventilator induced lung injury. The decrease of mortality and morbidity in asthma, ARDS and neonatal chronic lung disease using lung protective strategies and permissive hypercapnia is described in several studies. In spite of the limitation in knowledge regarding the physiological effects of PHC, there are clinical data demonstrating its benefits in several clinical scenarios. This article describes the physiological effects of PHC, the use of PHC in clinical scenarios and the contraindications of PHC in neonates and children.
Keywords children; mechanical ventilation; permissive hypercapnia
Introduction Mechanical ventilation has traditionally been used with the aim of normalizing the blood gases. Historically this was used to achieve normal levels of oxygen as well as CO2. However, a major side effect of this technique is barotrauma and excessive mortality, cardiocirculatory failure, or pulmonary barotrauma, due to extremely high pressures used in overcoming the airway obstruction. The seminal work of Darioli and Perret in 1984 evaluated the role of permissive hypercapnia (PHC) in status asthamaticus. They observed that controlled mechanical hypoventilation appeared to be an effective way of treating life-threatening asthma with a reduction in barotrauma and fatal complications of mechanical ventilation. Bidani et al. observed that avoidance of alveolar over-distention, through pressure or volume limitation in patients with acute respiratory failure, had better outcome without deleterious effects of hypercapnia. Since then the use of PHC has become well established in the management of acute respiratory failure. Several studies have shown that mechanical ventilation using lung protective strategies with low tidal volumes and low minute volumes, resulting in PHC, had better outcomes not only in adults but also in children and neonates. The association between hypercapnia and adverse outcomes in diverse clinical situations including cardiac arrest, sepsis and neonatal asphyxia has been questioned. The level of CO2 tolerated in a given child is very variable.
Hypercapnia and the lung In experimental animal models of hypercapnic acidosis, lung compliance is enhanced by increase in surfactant secretion or activity. Hypercapnic acidosis increases the arterial oxygenation by improving the matching of ventilation and perfusion. PHC has two conflicting effects; it can, by direct dilatation of the small airway, decrease the airway resistance and bronchodilation and, by the stimulation of vagus nerve, increase the airway resistance of the large airways and cause bronchoconstriction. The stimulation of vagus nerve can also decrease diaphragmatic contractibility. This can be particularly deleterious on weaning from mechanical ventilation. Hypercapnia and the heart Hypercapnic acidosis directly reduces the contractibility of cardiac and vascular smooth muscle. However, this is counterbalanced by the effect of several other mechanisms which lead to increase of cardiac output. Hypercapnia increases arterial and tissue oxygenation by four mechanisms: first it potentiates hypoxic pulmonary vasoconstriction and increases local alveolar ventilation by inhibiting airway tone, improving the ventilation/perfusion (V/Q) matching and the arterial oxygenation. Second, it increases cardiac output through the release of catecholamines and their sympathoadrenal effects (an increase of PaCO2 of 1.3 kPa increases the cardiac index by 14% in ventilated patients). Third, CO2 shifts the dissociation curve of oxyhaemoglobin to the right, facilitating the release of O2 to the tissues. Fourth, hypercapnia promotes microvascular vasodilatation. Hypercapnia acidosis appears to
Catarina Silvestre MD is a Senior Fellow PICU in the PICU at Nottingham University Hospital, Nottingham, UK. Conflict of interest: none declared. Harish Vyas DM FRCP FRCPCH is Professor in PICU and Respiratory Medicine at the PICU at Nottingham University Hospital, Nottingham, UK. Conflict of interest: none declared.
PAEDIATRICS AND CHILD HEALTH 25:4
192
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
to be more neuroprotective then higher PaCO2 (more than 9.3 kPa). Hypercapnia may contribute to the pathogenesis of retinopathy of prematurity due to the increase retinal vasodilation and increase oxygen delivery.
Effects of hypercapnic acidosis in different systems Immune system Inhibit the innate and adaptive immune functions: C Y Neutrophil function C Y Phagocyte function C Y Production of free radicals of O2 C Y Decrease xanthine-oxidase formation C Y Cell adhesion molecules Lung C [ Lung compliance C [ Surfactant secretion/activity C [ Matching of V/Q C Dilatation of small airways C Constriction large airway (vagal stimulation) C Y Diaphragmatic function Heart C Y Contractibility of cardiac and vascular smooth muscle C [ Pulmonary vasoconstriction C [ Cardiac output C [ Release of catecholamines C [ Release of O2 by Bohr effect C [ Microvascular vasodilatation C [ NO production Brain Has potent vasodilator effect with: C [ Cerebral tissue oxygenation C [ Cerebral blood flow C [ Intracranial Pressure C [ Cerebral cortex apoptosis C [ Retinopathy of prematurity Other organs C Hepatocytes apoptosis C Action on renal cortical tubes
Other organs: acidosis has effects on other organs including the liver and kidney. In experimental models, the hepatocytes exposed to acidosis had delayed cell death when subject to anoxia or hypoxia. The renal cortical tubes, when exposed to anoxia have greater ATP levels on re-oxygenation at acidotic pH.
Clinical scenarios (Table 2) Acute respiratory distress syndrome ARDS is one of the most challenging clinical syndromes in critical care. A lung protective ventilation strategy using 6 ml/kg tidal volume has been associated with lower mortality and fewer ventilator days. Kregenow et al. demonstrated that hypercapnic acidosis had a protective effect against ventilator-associated lung injury. There is however no evidence relating mortality and the levels of PaCO2. Severe asthma PHC and controlled hypoventilation are a well established strategy in asthma, 1984 PHC and controlled hypoventilation are a well established strategy in asthma, first described in 1984 by Darioli and Perrret. The objective of this form of ventilation is to avoid excessive airway pressure and minimize lung hyperinflation. This ventilatory strategy is associated with a low incidence of barotrauma and reduced mortality in patients admitted with life-threating asthma. Hypercapnia and acidosis are well tolerated in the absence of contra-indications like intracranial hypertension. Sepsis The effect of hypercapnia in sepsis is still unclear. Severe sepsis of pulmonary or systemic origin induces organ failure. Sepsis with ARDS has been associated with higher mortality rates. Evidence suggests that 40 % of patients with sepsis develop ARDS and that infection complicates 45% of critical ill patients. The role of hypercapnic acidosis in the immune response in sepsis is still unclear. Immunocompetence is essential to an effective host response and CO2 and acidosis can modulate this interaction by several mechanisms resulting in a suppression of the immune
Table 1
protect the heart from ischaemia-reperfusion injury. Both hypercapnia and acidosis have been shown to reduce cardiac infarct size in animal models. Due to PHC-associated increase in cardiac output, regional (including mesenteric) blood flow is also increased. Hypercapnia and the brain Cerebral perfusion and oxygenation are dependent on PaCO2. Hypocapnia decreases oxygen delivery to the brain through cerebral vasoconstriction. Severe hypocapnia can be associated with poor neurologic outcome, with increased risk of intracranial haemorrhage, periventricular leukomalacia and cerebral palsy. Hypercapnia appears to be neuro-protective in hypoxic state through its potent vasodilatation effect. It also leads to increase in intracranial pressure with adverse consequences, especially in the presence of cerebral oedema and raised intracranial pressure. Animal studies showed that hypercapnia is associated with increased cerebral cortex apoptosis. Although increased cerebral flow associated with severe hypercapnia is detrimental to the preterm brain, controlled permissive hypercapnia has not been associated with adverse neurological outcomes. On the developing brain, mild to moderate hypercapnia (5.3e7.3 kPa) seems
PAEDIATRICS AND CHILD HEALTH 25:4
Indications and contraindications of PHC Indications
Relative contraindications
ARDS
Raised intracranial pressure Raised pulmonary pressure
Asthma Sepsis Neonatal RDS Congenital diaphragmatic hernia Congenital heart disease PPHN Table 2
193
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
scenario continuous monitoring of intracranial pressure may be necessary. A retrospective study in patients with subarachnoid haemorrhage showed that a PHC between 6.6 and 8.0 kPa did not affect the intracranial pressure. The paediatric use of this approach has been described in a child with meningococcal sepsis with meningitis and ARDS.
response. The net effect depends on the site of infection and if the acidosis is buffered or not. Although hypercapnia appears to protect the lung from injury, the outcome appears to be worse in prolonged pneumonia due to the imunossupression and yet associated with better outcomes in systemic sepsis due to reduced lung damage. Pre-clinical studies indicate that hypercapnia acidosis may be protective in systemic sepsis and early phase of pneumonia induced sepsis.
Increase pulmonary vascular resistance The clinical situations that can lead to pulmonary hypertension should be considered as a relative contra-indication to PHC. A rational approach would be using PHC but monitor pulmonary pressures and the presence of right ventricular failure, tricuspid regurgitation and right to left shunt.
Neonatal respiratory distress syndrome (RDS) PHC is one of the ventilator goals in neonates with RDS. Acceptance of PaCO2 of 6.0e9.3 kPa and pH >7.2, as a strategy for managing patients on mechanical ventilation avoids high tidal volumes and over-distention. In a large multicentre study of PHC and dexamethasone in extremely low birth weight infants, only 1% of the babies in the PHC group required ventilation at 36 weeks of gestational age compared with 16% of the normocapnic group ( p < 0.01). Kamper et al. reported a national multicentre study showing that the use of nasal continuous positive pressure and PHC decreases the incidence of chronic lung disease. Use of smaller tidal volumes and PHC appears to be safe and reduces lung injury in preterm babies. However the safe level of paCO2 has not yet been determined.
Buffering of acidosis There are concerns that buffering the acidosis may worsen the clinical situation by cutting the protective effects of hypercapnia. There is evidence that this protective effect is related to acidosis rather than high PaCO2. Buffering with bicarbonate raises systemic CO2 and worsens intracellular acidosis. An alternative option is tromethamine (Tham) in situations when buffering acidosis is indicated. Safe limits of hypercapnia There is no consensus on the upper limit of hypercapnia. Most physicians avoid PaCO2 above 13 kPa. The major concerns about severe hypercapnia are related to cerebral vasodilatation and cerebral oedema, as several case reports associate severe hypercapnia with subarachnoid haemorrhage and cerebral oedema. However, in asthamaticus patients, extreme hypercapnia between 20 and 25 kPa was tolerated for several hours without adverse outcomes. In many studies of patients undergoing PHC, a pH as low as 7.2 appears to be have been well tolerated.
Congenital diaphramatic hernia (CDH) Management of infants with CDH involves early intubation, appropriate ventilator management, treatment of pulmonary hypertension and surgical correction. Historically, the strategy involved aggressive ventilation with high inspiratory pressures, hyperoxygenation and hyperventilation with administration of bicarbonate. That approach was associated with significant morbidity and mortality. The new approach based on PHC (PaCO2 up to 8 kPa) and gentle ventilation has significantly reduced mortality and decreased the use of ECMO.
Conclusions Protective ventilatory strategies that involve hypoventilation with low tidal volumes result in PHC. The potential benefits are not only related to the reduced lung stretch, but with the physiological effects of CO2 in the lungs, brain, cardiovascular and immune system. There are “in vitro” studies that demonstrate the beneficial effect of PHC, and raise the possibility of an induced hypercapnia for therapeutic effects. There are clinical evidences of the role of PHC in ARDS, asthma and sepsis. However, there are still concerns regarding the potential deleterious effects of PHC especially in patients with CNS pathologies with raised ICP. A
Persistent pulmonary hypertension of the newborn (PPNH) Aggressive hyperventilation with hypocapnia is known to be a significant risk factor for hearing impairment in PPHN survivors. Both conventional and high-frequency ventilation can be used in the management. In severe PPHN most centres prefer HFOV as it usually supresses patient’s spontaneous breathing. “Gentle” ventilation strategies with optimal PEEP, relatively low PIP and PHC ensure adequate lung expansion without barotrauma. Congenital heart disease (CHD) The ventilation of infants with CHD has changed from a hyperventilation strategy to a hypoventilation and PHC strategy. Hypercapnea improves the oxygenation of the brain and other organs. This is particularly relevant in neonates with congenital heart defects where low cerebral blood flow is associated with adverse neurological outcome.
FURTHER READING 1 Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984; 129: 385e7. 2 Curley G, Hayes M, Laffey JG. Can “permissive” hypercapnia modulate the severity of sepsis-induced ALI/ARDS? Crit Care 2011; 15: 212. http://dx.doi.org/10.1186/cc9994. 3 Rogovik A, Goldman R. Permissive hypercapnia. Emerg Med Clin North Am 2008; 26: 941e52. http://dx.doi.org/10.1016/j.emc.2008. 08.002. viii-ix. 4 Curley GF, Laffey JG, Kavanagh BP. CrossTalk proposal: there is added benefit to providing permissive hypercapnia in the treatment of
Areas of controversies Raised intracranial pressure The effects of hypercapnia in cerebral blood flow auto-regulation in situations of raised intracranial pressures have been a concern. In ARDS with raised intracranial pressures, hypercapnia should be a relative rather than an absolute contra-indication. In this
PAEDIATRICS AND CHILD HEALTH 25:4
194
Ó 2014 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
5
6
7
8
9
10
11
ARDS. J Physiol 2013; 591(Pt 11): 2763e5. http://dx.doi.org/10.1113/ jphysiol.2013.252601. Thome UH, Ambalavanan N. Permissive hypercapnia to decrease lung injury in ventilated preterm neonates. Semin Fetal Neonatal Med 2009; 14: 21e7. http://dx.doi.org/10.1016/j.siny.2008.08.005. Curley G, Contreras M, Nichol AD, Higgins BD, Laffey JG. Hypercapnia and acidosis in sepsis: a double-edged sword? Anesthesiology 2010; 112: 462e72. http://dx.doi.org/10.1097/ALN.0b013e3181ca361f. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342: 1301e8. http://dx.doi.org/10. 1056/NEJM200005043421801. Oddo M, Feihl F, Schaller M-D, Perret C. Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med 2006; 32: 501e10. Carlo WA, Stark AR, Wright LL, et al. Minimal ventilation to prevent bronchopulmonary dysplasia in extremely-low-birth-weight infants. J Pediatr 2002; 141: 370e4. Kamper J, Feilberg Jørgensen N, Jonsbo F, Pedersen-Bjergaard L, Pryds O, Danish ETFOL Study Group. The Danish national study in infants with extremely low gestational age and birth weight (the ETFOL study): respiratory morbidity and outcome. Acta Paediatr 2004; 93: 225e32. Guidry CA, Hranjec T, Rodgers BM, Kane B, McGahren ED. Permissive hypercapnia in the management of congenital diaphragmatic hernia: our institutional experience. J Am Coll Surg 2012; 214: 640e5. http:// dx.doi.org/10.1016/j.jamcollsurg.2011.12.036. 647.e1; discussion 646e647.
PAEDIATRICS AND CHILD HEALTH 25:4
12 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Semin Perinatol 2014; 38: 78e91. http://dx.doi.org/10. 1053/j.semperi.2013.11.004. 13 Petridis AK, Doukas A, Kienke S, et al. The effect of lung-protective permissive hypercapnia in intracerebral pressure in patients with subarachnoid haemorrhage and ARDS. A retrospective study. Acta Neurochir (Wien) 2010; 152: 2143e5. http://dx.doi.org/10.1007/ s00701-010-0761-z. 14 Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP. Permissive hypercapniaerole in protective lung ventilatory strategies. Intensive Care Med 2004; 30: 347e56. http://dx.doi.org/10.1007/ s00134-003-2051-1. 15 Higgins BD, Costello JF, Laffey JG. Permissive hypercapnia in protective lung ventilatory strategies. Paediatr Child Heath 2007; 17-3: 94e103.
Practice points C C C
C
C
195
PHC is a consequence of lung protective ventilatory strategies PHC reduces inflammation and oxidant-induced injury PHC improves blood flow, oxygenation and is a potent vasodilator agent PHC is a gold standard strategy in ARDS and Asthma, and can be beneficial in other clinical situations like sepsis, CDH, PPNH and congenital heart diseases. PHC is not recommended in situations with raised ICP
Ó 2014 Elsevier Ltd. All rights reserved.