- Email: [email protected]
Mechanical Ventilation during Acute Brain-Injury in Children
Accepted Manuscript Title: Mechanical Ventilation during Acute Brain-Injury in Children Author: Jordan S Rettig Elizabeth D Duncan Robert C Tasker PII: DOI: Reference:
S1526-0542(16)00006-3 http://dx.doi.org/doi:10.1016/j.prrv.2016.02.001 YPRRV 1117
To appear in:
YPRRV
Received date: Accepted date:
14-10-2015 10-2-2016
Please cite this article as: Rettig JS, Duncan ED, Tasker RC, Mechanical Ventilation during Acute Brain-Injury in Children, Paediatric Respiratory Reviews (2016), http://dx.doi.org/10.1016/j.prrv.2016.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mechanical Ventilation during Acute Brain-Injury in Children Jordan S Rettig,1 Elizabeth D Duncan,1 Robert C Tasker1,2 of Anesthesiology, Perioperative and Pain Medicine, Division of Critical
ip t
1Department
Care Medicine; 2Department of Neurology; Boston Children’s Hospital and Harvard
cr
Medical School, Boston, MA
Robert C Tasker MBBS, MD Division of Critical Care Medicine (Bader 621)
an
Boston Children’s Hospital
M
300 Longwood Avenue, Boston, Massachusetts 02115
us
Correspondence to:
0ffice 617-355-3508 fax 617-730-0453
pt
Word counts:
ed
[email protected]
156 words
Article:
3869 words
Ac ce
Abstract:
Page 1 of 29
Abstract Mechanical ventilation in the brain-injured pediatric patient requires many considerations, including the type and severity of lung and brain injury and how progression of such injury will develop. This review focuses on neurological
ip t
breathing patterns at presentation, the effect of brain injury on the lung,
developmental aspects of blood gas tensions on cerebral blood flow, and strategies
cr
used during mechanical ventilation in infants and children receiving neurological
intensive care. Taking these basic principles, our clinical approach is informed by
us
balancing the blood gas tension targets that follow from the ventilation support we choose and the intracranial consequences of these choices on vascular and hydrodynamic physiology. As such, we are left with two key decisions: a low tidal
an
volume strategy for the lung versus the consequence of hypercapnia on the brain; and the use of positive end expiratory pressure to optimize oxygenation versus the
M
consequence of impaired cerebral venous return from the brain and resultant
Key words:
ed
intracranial hypertension.
Brain injury; Acute lung injury; Neurogenic pulmonary edema; Permissive
Ac ce
pt
hypercapnia; Intracranial pressure; Pediatric
Page 2 of 29
Educational Aims: In this review, the reader will come to appreciate that: There are specific neurological breathing patterns in the brain-injured pediatric patient and that there is an organ-system interaction between the
ip t
brain and lungs that affect pulmonary function; There are developmental aspects to the effect of blood gas tensions on
cr
cerebral blood flow;
There are two clinical dilemmas during mechanical ventilation for acute lung
us
injury in brain-injured patients: a low tidal volume strategy optimal for the lung versus the detrimental consequence of hypercapnia on the brain; and the use of positive end expiratory pressure to optimize oxygenation versus
Ac ce
pt
ed
M
resultant intracranial hypertension.
an
the consequence of impaired cerebral venous return from the brain and
Page 3 of 29
Emergency endotracheal intubation and mechanical ventilation of the acutely brain-injured child needing respiratory support is central to patient resuscitation, stabilization and preventing progressive neurological decline. Such critically ill patients are at risk since even the process of patient positioning for
ip t
endotracheal intubation, inducing anesthesia, and laryngoscopy may provoke
rostrocaudal herniation (i.e., central syndrome) or compromise marginally perfused
cr
brain tissue. The Emergency Neurological Life Support suggested algorithm for initial airway management, mechanical ventilation, sedation and evaluation within the
us
first hour of care are beyond the scope of this review and readers are directed to standard texts and emergency department protocols.[1]
This review will focus on neurological breathing patterns, the effect of brain
an
injury on the lung, developmental aspects of blood gas tensions on the cerebral circulation, and strategies used during mechanical ventilation in infants and
M
children receiving neurological intensive care. This discussion takes examples from the clinical research literature covering the four common neuropathological processes, i.e., severe traumatic brain injury (TBI), refractory status epilepticus
ed
(RSE), central nervous system (CNS) infection, and any condition complicated by
pt
raised intracranial pressure (ICP).
Ac ce
Breathing patterns with brain injury Neural control of breathing depends on both conscious and automatic inputs integrated in respiratory centers within the pons and medulla. Automatic control of breathing is located in areas of the dorsolateral tegmentum of the pons as well as the medulla, specifically the nucleus tractus solitarius and retroambigualis. The descending pathways of the ventrolateral columns of the spinal cord also allow for conscious input from the cortex into this collection of nuclei. There are four classic descriptions of abnormal breathing with specific lesions in the brain seen in comatose patients with raised ICP during worsening stages of central syndrome.[2,3] Any of these breathing dysrhythmias may occur in
Page 4 of 29
emergency conditions such as acute hydrocephalus, TBI, cerebrovascular stroke, intracranial hemorrhage, and brain tumors. Cheyne-Stokes breathing is characterized by variable respiratory rate and tidal volume that has a regular cycle of crescendo-to-decrescendo pattern. This type of breathing is associated with
ip t
disruptions in the connections between the cortices of the two cerebral hemispheres and dysfunction of the medial forebrain structures. Apneustic
breathing is typified by a prolonged inspiratory pause and is associated with lesions
cr
of the lower tegmentum of the pons. Cluster breathing is irregular quick breaths
us
regularly separated by long pauses and is associated with lesions of the lower pons or medulla. Ataxic breathing is complete loss of rhythmicity of breathing with irregular breaths and variable tidal volumes, and is associated with lesions of the
an
medulla. More common than these classic patterns, however, is the pattern of central hyperventilation. This pattern results from diffuse cortical and subcortical
M
injury and is a consequence of eliminating the conscious input from the cortex to the brain stem centers for breathing. In this state, breathing is controlled almost entirely by automatic input originating from within the brain stem and, as such,
ed
there is decreased dependency on local brain stem sensing of arterial partial pressure of carbon dioxide (PaCO2) tension as the trigger to respiratory drive.[3]
pt
How should we use this information during mechanical ventilation strategies for brain-injured patients? Two issues are foremost in our considerations. First, an
Ac ce
abnormal pattern and depth of spontaneous breathing will lead to inadequate oxygenation. Second, the dissociation between PaCO2 and drive to breathing will lead to inadvertent hypo- or hypercapnia if spontaneous breathing is permitted.
The lung in brain injury Acutely brain-injured patients may exhibit altered pulmonary mechanics or lung injury with pulmonary edema. The causes include aspiration pneumonitis occurring before endotracheal intubation, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), transfusion-associated lung injury and neurogenic pulmonary
Page 5 of 29
edema (NPE). Out of all of these conditions, only NPE will be discussed in this review. Neurogenic pulmonary edema is the consequence of extravasation of proteinaceous fluid across the alveolar-capillary membrane.[4] The condition was
ip t
described in the literature over 100 years ago[5,6] and it has been reported in cases of cervical spine injury, TBI, RSE and anoxic brain damage from hanging. For
example, the risk of developing NPE after TBI is 20% in the adult population and it
cr
is related to the severity of injury[7] with more severe injuries being more likely to
us
result in the condition. The onset of NPE may be rapid after initial injury and its occurrence is strongly associated with injury of the central autonomic network and the nucleus of the tractus solitarius in the medulla.[7]
an
Historically, two primary physiologic mechanisms were thought to underlie the development of NPE. Firstly there appears to be a pulmonary hydrostatic
M
component to NPE.[8] Both pulmonary and systemic vasoconstriction may occur with raised ICP or excess sympathetic activity in RSE and TBI. Pulmonary vasoconstriction increases pulmonary capillary hydrostatic pressure, and systemic
ed
venoconstriction increases venous return, both of which result in pulmonary edema.[9-12] Recent studies have shown that left ventricular systolic function may be
pt
adversely affected as well, because of increased afterload from systemic arterial hypertension or excessive vagal tone, leading to possible left atrial hypertension.[13The second mechanism is increased pulmonary capillary permeability. Alpha-
Ac ce
15]
adrenergic agonists released in response to brain injury may directly increase permeability or cause release of secondary mediators, which then increase vascular permeability.[16] Rapid pulmonary vasoconstriction and increased venous return may then result in microvascular injury. More recently, another mechanism for NPE has been proposed which
suggests a role for a systemic inflammatory response leading to pulmonary infiltration of neutrophils, cytokine release, and endothelial dysfunction triggered by sympathetic discharge.[17] In support of this theory, we know that brain injury is directly associated with increased intracranial production of pro-inflammatory mediators, and subsequent release of these mediators into the systemic circulation
Page 6 of 29
results in lung injury.[18] For example, Mascia et al. showed in severe brain injury cases that an increased risk of ALI was associated with mechanical ventilation using higher tidal volumes.[19] We also know that ALI alone induces a systemic inflammatory response, which has the potential to increase circulating
ip t
concentrations of neuronal markers of damage (i.e., neuron specific enolase and the S100B protein).[20] Lastly, we also know that in experimental ALI, intracranial
hypertension worsens pre-existing lung damage and further increases cerebral
cr
edema, and there appears to be a reciprocal and synergistic interaction between
us
these two conditions.[21,22] Taking all of this information together, we should no longer consider the brain and lungs as separate entities in critical care. There is a potentially dangerous “cross-talk” between the lung and brain such that our
an
strategies for protective mechanical ventilation not only have the potential to
M
reduce ALI but brain injury as well.
Partial pressure of carbon dioxide and oxygen
ed
Neurocritical care of children with brain injury focuses on management of ICP, cerebral blood flow (CBF), and avoidance of secondary brain injury through the
Ac ce
CBF.
pt
prevention of hypocapnia, hypercapnia and hypoxemia because of their effects on
A developmental perspective of PaCO2 and CBF PaCO2 is a strong modulator of CBF and small vessel tone. Hypercapnia increases CBF and causes intracranial hypertension through cerebral vasodilation. Hypocapnia decreases CBF and cerebral blood volume (CBV) with the consequent risk of cerebral ischemia. In 1948 Kety and Schmidt[23] described a curvilinear relationship between PaCO2 and CBF. A reduction of PaCO2 from 40 to 20 mm Hg (5.3 to 2.7 kPa) decreased CBF but not to the same extent as the increase in CBF when PaCO2 is increased from 40 to 60 mm Hg (5.3 to 8 kPa). In these studies cerebral metabolic rate for oxygen (CMRO2; Equation 1, Table 1) did not change
Page 7 of 29
during this degree of hypercapnia. The increase in CBF without any increase in CMRO2 resulted in a decrease in the arteriovenous oxygen difference in content (AVDO2), i.e., reduced oxygen extraction fraction (OEF; Equations 2 and 3, Table 1). The hypercapnia-induced increase in CBF is ~6% per mm Hg change in PaCO2, and
ip t
hypocapnia decreases CBF by ~3% per mm Hg change in PaCO2 (Figure 1). The relation between CBF and CBV (including arterial, capillary and venous blood
volume) during changes in PaCO2 has also been investigated in humans. Inspection
cr
of equations 4 and 5 (Table 1) show that change in CBF with change in CBV due to
us
hypercapnia, for example, is not linear; the increase in CBV during hypercapnia is less than what would be expected from the change in CBF and, the degree of decrease in CBV during hypocapnia, is also less than would be expected from a
an
change in CBF were the relationships linear (Table 1). These relationships are illustrated by Poiseuille’s law (Equation 6, Table 1), which predicts that CBV
M
increases proportionally to the square of the diameter, yielding the relation CBV = c x CBF0.5, which is in good agreement with the relationship observed during changes in PaCO2.
ed
The question of whether alteration in PaCO2 changes CBF equally in all brain regions is somewhat controversial; for example whether both gray and white matter
pt
behave the same. There appears to be a developmental difference in CBF response to PaCO2, although in all age groups CBF increases with increasing PaCO2. In both
Ac ce
fetus and newborn, gray matter CBF increases at PaCO2 greater than 40 mm Hg (5.3 kPa), but changes little at lower PaCO2 levels. Also, the change in CBF per mm Hg change in PaCO2 is higher in the newborn than in the fetus, and this suggests that the cerebrovascular response to PaCO2 is not completely developed at birth. This depressed CO2 response in the fetus may be correlated to a difference in CMRO2 (i.e., when CBF responses are normalized for CMRO2, the increase in CBF matches the developmental profile of CBF with the greatest change in newborns, smaller in adults and even smaller in fetuses). Hypocapnia does not alter the lower limit of cerebral autoregulation in mature animals, but it does lead to lower CBF per unit change in cerebral perfusion pressure (CPP, which is the difference between mean arterial blood pressure and
Page 8 of 29
mean ICP).[24] At lower mean blood pressure, below the level of cerebral autoregulation, there is an attenuation of the slope of the CBF-to-perfusion pressure graph (Figure 1), which suggests that the cerebral vascular response is attenuated with hypotension. CBF in preterm infants is dependent on PaCO2.[25] The cerebral
ip t
vascular response to PaCO2 is less in the first day of life and increases with gestational age. It is also attenuated, but not eliminated, in hypotensive infants. This reactivity is quite robust even in preterm infants; it is estimated to be ~4% per
cr
mmHg PCO2.[26] Interestingly, during anesthesia with sevoflurane this response is
us
also preserved in children (18 months to 7 years of age) and hence hypocapnia can result in cerebrovascular vasoconstriction and reduction of CBF.[27]
In preterm infants, even mild hypocapnia (PaCO2 <35 mm Hg [<4.7 kPa]) is
an
associated with cerebral palsy and cystic periventricular leucomalacia, and seizures are associated with rapid correction of hypocapnia – leading some to advocate
M
stepwise correction in low PaCO2.[28] In term infants with hypoxic-ischemic encephalopathy there is a positive association between subsequent neurocognitive
ed
outcome and hypocapnia.[29]
The cerebrovascular response to oxygen
pt
Hypoxia elevates CBF (Figure 2A). CBF does not change in response to small deviations in the arterial partial pressure of oxygen (PaO2) around normal levels.
Ac ce
Rather, when PaO2 falls to ~50 mm Hg (6.7 kPa) regional CBF begins to rise. As PaO2 is further reduced below this threshold CBF increases exponentially. It may reach over 400% of basal flow at PaO2 levels still compatible with life. There is no significant change in CMRO2 over the range of PaO2 23 to 100 mm Hg (3.1 to 13.3 kPa).
The responses of the cerebral circulation to hypoxia relate to hemoglobin
oxygen saturation (HbO2); at a PaO2 >70 mm Hg (9.3 kPa), HbO2 is 100%. However, when the PaO2 reaches ~50 mm Hg (6.7 kPa) HbO2 is 85%. Under conditions of reduced availability of oxygen, such as in anemia, the regional CBF/PaO2 curve is shifted to the right (Figure 2B). Hypoxic elevations in regional CBF are not associated with changes in metabolic rate. However, the vasodilation is additive
Page 9 of 29
with that produced by metabolic signals, particularly acidosis and hypercapnia. Figure 3 provides a summary of autoregulation and the changes in CBV and OEF around the lower limit of autoregulation when it is intact. Throughout childhood regional brain OEF is relatively constant; this feature reflects the coupling between
ip t
regional CMRO2 and regional CBF. In some circumstances CMRO2-to-CBF coupling may be disrupted, and the change in OEF will reflect the predominant abnormality. For example: ischemia is present when CMRO2 exceeds oxygen-delivery via CBF;
cr
hyperemia occurs when oxygen-delivery via CBF exceeds tissue requirement or
us
CMRO2. Figure 3B depicts four zones of physiology: I, a state of normal CBF and AVDO2 with reduced CBV due to increased cerebrovascular resistance (CVR); II, a state of normal CBF and AVDO2 with reduced CBV due to reduced CVR; III, a state of
an
falling CBF with raised CBV and AVDO2 at a time when cerebrovascular vasodilatation is maximal; and IV, a state of low CBF and CBV with raised AVDO2.
M
States III and IV have the potential for causing brain injury – it is a matter of duration and intensity of insult.[30] For example, how low can we let the patient’s hemoglobin fall (Figure 2B) before we should consider the detrimental effect of
ed
decreased oxygen content and a shift in the CBF/PaO2 curve to the right?
pt
PaCO2 target during mechanical ventilation In severe TBI, hyperventilation with PaCO2 <25 mm Hg (3.3 kPa) was previously
Ac ce
used as treatment for lowering ICP through vasoconstriction. We now target normal PaCO2 levels (35 to 40 mm Hg [4.7 to 5.3 kPa])[31] since even PaCO2 <30 mm Hg (4 kPa) may induce significant cerebral ischemia.[32] Hence, permitting spontaneous hyperventilation and the development of hypocapnia in brain-injured children may be counterproductive to outcome. The main issues to consider in regard to PaCO2-reactivity, hypocapnia and
CBF are duration of alteration in PaCO2 and whether there has been adaptation in the cerebrospinal fluid (CSF) concentration of bicarbonate ([HCO3]CSF). This change in the relationship between CBF and acute change in PaCO2 usually occurs within 6 to 12 hours after initiation of hypocapnia. For example, in diabetic ketoacidosis, hypocapnia develops over days in response to worsening metabolic acidosis.
Page 10 of 29
Despite this deterioration, CBF is preserved at normal levels because of an adaptation with falling [HCO3]CSF that parallels falling PaCO2[33] – rather like the adaptation occurring with ascent to altitude.[34] When such patients require mechanical ventilation we do not know what PaCO2 should be targeted, but using
ip t
neuromuscular blockade to stop spontaneous hyperventilation and permit immediate normalization of PaCO2, before there has been repair in [HCO3]CSF, is
potentially dangerous.[33,34] A similar cautious approach may be needed in cases of
cr
CNS infection presenting with spontaneous hyperventilation, which is the normal
us
response in most patients.[35] Like diabetic ketoacidosis, we do not know what level in PaCO2 should be targeted during initial mechanical ventilation in those in with baseline hypocapnia. Two studies in adults with acute bacterial meningitis have
an
demonstrated that short-term hyperventilation does not enhance regional abnormalities in CBF nor does it alter CMRO2.[36,37] These slowly developing
M
conditions should be contrasted with more acute neurological disease processes. In adults with cerebrovascular stroke, hypoxia results in cerebral vasodilation and increased CBF, which may elevate ICP and thus further compromise cerebral
ed
perfusion.[38-40] In children with severe TBI, hypocapnia (PaCO2 ≤35 mm Hg [≤4.7 kPa) on admission to an intensive care unit is associated with increased discharge
pt
mortality.[41]
Ac ce
PaO2 target during mechanical ventilation Arterial oxygen content is typically used as a proxy for assuring adequate oxygenation of the brain. There are no large studies that have systematically examined the role of different mechanical ventilation strategies on brain oxygenation. Most clinical strategies emphasize maximal oxygenation with adequate fractional inspired oxygen (FiO2) in order to maintain brain tissue oxygen partial pressure (PbtO2) tension. To date, no study has demonstrated benefit from the prophylactic use of high FiO2 in the setting of brain injury. In adults, PbtO2 monitors are used in combination with ICP and brain temperature monitoring. Normal PbtO2 is >20 mmHg (2.7 kPa) and levels <10 mmHg (1.3 kPa) indicate severe cerebral ischemia.[42] Figaji et al. showed that
Page 11 of 29
reduced PbtO2 is associated with poor outcome in pediatric patients with severe TBI.[43] The Brain Trauma Foundation guidelines in adults with severe TBI suggests avoiding PaO2 <60 mm Hg (8 kPa, or equivalent to arterial oxygen-hemoglobin saturation <90%) and targeting PbtO2 >15 mm Hg (2 kPa).[44] Manoeuvers affecting
ip t
ventilation, oxygen management, and ventilator strategies guided by PbtO2 are now frequently used in clinical practice in adults. Interventions that increase PbtO2 include increasing FiO2, increasing positive end expiratory pressure (PEEP),
cr
increasing minute ventilation, decreasing PaCO2 to lower ICP, using neuromuscular
us
blockade and deep sedation, augmenting blood pressure, and administering red blood cell transfusions.[45]
As an alternative to PbtO2 monitoring, cerebral near-infrared spectroscopy
an
(NIRS)[46,47] has been proposed for the noninvasive monitoring of cerebral tissue oxygenation and perfusion in infants and children. PbtO2 of 1 mm Hg is equivalent to
M
0.003 mL O2/100 g brain. Regional cerebral oxygen saturation (rScO2) is used to estimate cerebral oxygenation and perfusion (Figure 3B) and as a proxy of jugular bulb oxygen-hemoglobin saturation (SjvO2). Table 2 provides a typical algorithm
ed
that can be used in bedside monitoring. This modality has many promising components, but at this time there is insufficient evidence to recommend NIRS as a
Ac ce
injured patient.[48,49]
pt
sole monitoring modality for cerebral oxygenation and perfusion in the brain
Mechanical ventilation strategies in brain injury Guidelines for the management of ALI and the more severe ARDS are beyond the scope of this review. Most practitioners accept that a lung-protective-mechanicalventilation strategy should be used, which includes use of low tidal volumes (6mL/kg) with limited plateau pressure (<30 cm H2O).[50] In patients with acute brain injury who are mechanically ventilated there is often a bedside discussion of targets and goals, weighing-up what might be best for the brain against what is considered the best for the lungs. For example, one
Page 12 of 29
consequence of using the above lung protective mechanical ventilation strategy is the development and need to tolerate hypercapnia. However it may be that we should choose the brain over the lungs,[51] which as we have learned from recent studies is not straightforward because of the reciprocal “cross-talk” in pathology
ip t
between the lungs and the brain.[17,19-22] Permissive hypercapnia and brain injury
cr
In combined brain and lung injury we need to balance what is optimal for lung
us
protection using controlled hypoventilation, yet permitting hypercapnia, against targeting PaCO2 to a level that avoids worsening ICP control because of increasing CBF. In other words, how high can hypercapnia be?
an
In laboratory research, with different levels of hypercapnia (PaCO2 60 to 80 mm Hg [8 to 10.7 kPa], 80 to 100 mm Hg [10.7 to 13.3 kPa], and 100 to 120 mm Hg
M
[13.3 to 16 kPa]) after experimental transient global cerebral ischemia-reperfusion injury a level 80 to 100 mm Hg (10.7 to 13.3 kPa) was associated with the best neurological deficit scores and least histopathological changes.[52] Unfortunately,
ed
there are few such studies identifying optimal PaCO2 thresholds for optimal outcomes in brain-injured patients – and it is debatable that any such studies would
pt
be acceptable to clinicians and ethicists. Hence we need to rely on detailed clinical observational studies, which are at risk of reflecting bias because of patient
Ac ce
selection. For example, two studies indicate a detrimental effect of permissive hypercapnia. In neonates, permissive hypercapnia was associated with more severe injury from intracranial hemorrhage,[53] although a recent study suggests that acidosis is of more consequence.[54] In children with severe TBI hypercapnia (PaCO2 ≥46 mm Hg [≥6.1 kPa]) on admission to an intensive care unit was associated with increased discharged mortality.[41] In contrast, a recent study in 12 adults with subarachnoid hemorrhage and ARDS showed the opposite effect. A lung protective strategy (i.e., tidal volume 5 to 8 mL/kg) with permissive hypercapnia (PaCO2 50 to 60 mm Hg [6.7 to 8 kPa]) did not result in increased ICP.[55] The clinical guidelines for severe TBI do not address the strategy of tolerating hypercapnia during management of ALI and ARDS;[31] the topic of
Page 13 of 29
combined lung and brain injury lacks Class I and II clinical data. That said, the approach we have taken when having to balance lung with brain management is to try and individualize the PaCO2 target to cerebral oxygenation.[56] In a patient with combined meningococcal septicemia, meningitis, cerebral edema and ARDS, we
ip t
identified the upper limit of "tolerable" hypercapnia as the level that would not result in significant cerebral hyperemia based on SjvO2 levels. Initially, cautious
induction of pH 7.32 and PaCO2 <45 mm Hg (<6 kPa) was tolerated; subsequent
cr
metabolic compensation meant that higher levels of PaCO2 could be permitted. In
us
similar cerebral-versus-pulmonary circumstances we suggest that this approach warrants consideration. An alternative to invasive monitoring of SjvO2 could be
an
NIRS. PEEP and ICP
M
PEEP may affect both CBF/CPP and ICP: PEEP increases intrathoracic pressure and jugular venous pressure; and, decreases venous return, mean blood pressure, and cardiac output. Raised ICP may occur because increased jugular venous pressure
ed
causes increased CBV, particularly when intracerebral compliance is decreased. Reduced CPP may occur because of the effect of PEEP on venous return and cardiac
pt
output: with intact autoregulation decreased CPP is compensated by cerebral vasodilation, and leads to raised ICP; with impaired autoregulation decreased CPP
Ac ce
leads to ischemia.
In ALI/ARDS, hypoxemia is managed by applying PEEP and increasing the
FiO2 with the goal of maintaining pulse oximetry oxygen-hemoglobin saturation (SpO2) above 88%.[57] In the brain-injured patient, the clinician is left with deciding optimal ventilator settings for the oxygenation target while avoiding the potential increase in ICP associated with using PEEP. Before discussing the clinical studies that help in this decision, one simple manoeuver that aids venous return from the head is to keep the head of the bed elevated at 30°, which maintains cerebral venous drainage via the vertebral veins not affected by PEEP.[58] A number of studies in adults with severe TBI or subarachnoid hemorrhage support the practice of using PEEP.[17] The conclusion from these studies is that
Page 14 of 29
optimal oxygenation can be achieved by using adequate FiO2 and by applying PEEP. PEEP may, however, affect the cerebral circulation by hemodynamic- and PaCO2mediated mechanisms and these effects should be monitored and used to titrate PEEP. For example, a recent study in 21 pediatric postoperative neurosurgery
ip t
patients examined a number of hemodynamic and intracranial parameters after applying increasing levels of PEEP (0, 4 and 8 cm H2O).[59] PEEP significantly
increased compliance of the respiratory system without affecting ICP. There were
cr
no significant variations in values of arterial pressure, CPP, and middle cerebral
us
artery CBF-velocity (using transcranial Doppler). However, CVP significantly
increased as PEEP was raised from 0 to 8 cm H2O. The authors concluded that PEEP values up to 8 cm H2O could be applied in such patients in order to restore lung
an
recruitment without any consequence on level of ICP.
M
Conclusions
Mechanical ventilation in the brain-injured pediatric patient requires many considerations, including the type and severity of lung and brain injury and how
ed
progression of such injury will interact. Based on current literature, there is a brainlung interaction, which must be elucidated further in order to provide optimal
pt
therapy for the patient with combined lung and brain injury. Currently, the basic principles of our clinical approach are based on an understanding of how blood gas
Ac ce
tensions and our ventilation support competes in their influence on intracranial vascular and hydrodynamic physiology:[60] a low tidal volume strategy for the lung versus the consequence of hypercapnia on the brain; and, the use of PEEP to optimize oxygenation versus the consequence of impaired cerebral venous return from the brain and resultant raised ICP. As such, any changes in blood gas tensions away from normal should occur slowly over hours so as to permit central compensation and attenuate any adverse side effects.
Page 15 of 29
Future directions for research: The development of bedside clinical tools that allow us to better assess and monitor changes in CBF.
ip t
The development of biomarkers of brain injury that can be used in clinical
care so as to assess when lung injury, or our mechanical ventilation strategy,
cr
is detrimental to the brain.
The development of biomarkers of lung injury that can be used in clinical
Ac ce
pt
ed
M
an
us
care so as to assess when brain injury is adversely affecting the lung.
Page 16 of 29
References 1.
Seder DB, Jagoda A, Riggs B. Emergency neurological life support: airway, ventilation and sedation. Neurocrit Care 2015; 23 Suppl 2:S5-S22. Plum F, Posner LB. The diagnosis of stupor and coma. Philadelphia: FA Davis,
ip t
2.
1980. 3.
Bolton CF, Chen R, Wijdicks EFM, Zifko UA. Neurology of breathing.
Berthiaume Y, Broaddus VC, Gropper M, et al. Alveolar liquid and protein
us
4.
cr
Philadelphia: Elsevier, 2004.
clearance from normal dog lungs. J Appl Physiol 1988; 65:585-93. 5.
Moutier F. Hypertension et mort par oedema pulmonaire aigu, chez les
an
blesses cranio-encephaliques. Presse Med 1918; 26:108-9.
Shanahan WT. Pulmonary oedema in epilepsy. NY Med J 1908; 37:54-6.
7.
Bratton SL, Davis RL. Acute lung injury in isolated traumatic brain injury.
M
6.
Neurosurgery 1997; 40:707-12. 8.
Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human
9.
ed
neurogenic pulmonary edema. Chest 1997; 111:1326-33. Maron MB, Dawson CA. Pulmonary venoconstriction caused by elevated
pt
cerebrospinal fluid pressure in the dog. J Appl Physiol Respir Environ Exerc Physiology 1980; 49:73-8.
Hoff JT, Nishimura M, Garcia-Uria J, Miranda S. Experimental Neurogenic
Ac ce
10.
pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg
1981; 54:627-31.
11.
Sedy J, Zicha J, Nedvikova J, Kunes J. The role of sympathetic nervous system in the development of neurogenic pulmonary edema in spinal cord-injured rats. J Appl Physiol (1985) 2012; 112:1-8.
12.
Sedy J, Kunes J, Zicha J. Pathogenetic mechanisms of neurogenic pulmonary edema. J Neurotrauma 2015 [Epub ahead of print, PMID 25496372].
13.
Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med 2002; 28:1012-23.
Page 17 of 29
14.
Bahloul M, Chaari AN, Kallel H, et al. Neurogenic pulmonary edema due to traumatic brain injury: evidence of cardiac dysfunction. Am J Crit Care 2006; 15:462-70.
15.
Mayer SA, Lin J, Homma S, et al. Myocardial Injury and left ventricular
16.
ip t
performance after subarachnoid hemorrhage. Stroke 1999; 30:780-6. Colice GL, Matthay MA, Bass E, Matthay RA. Neurogenic pulmonary edema. Am Rev Respir Dis 1984; 130:941-8.
Mascia L. Acute lung injury in patients with severe brain injury: a double hit
cr
17. 18.
us
model. Neurocrit Care 2009; 11:417-26.
Hutchinson PJ, O’Connell MT, Rothwell NJ, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta and their
19.
an
endogenous inhibitor IL-1ra. J Neurotrauma 2007; 24:1545-57. Mascia L, Zavala E, Bosma K, et al. High tidal volume is associated with the
M
development of acute lung injury after severe brain injury: an international observational study. Crit Care Med 2007; 35:1815-20. 20.
Bickenbach J, Zoremba N, Fries M, et al. Low tidal volume ventilation in a
ed
porcine model of acute lung injury improves cerebral tissue oxygenation. Anesth Analg 2009; 109:847-55.
Holland MC, Mackersie RC, Morabito D, et al. The development of acute lung
pt
21.
injury is associated with worse neurologic outcome in patients with severe 22.
Ac ce
traumatic brain injury. J Trauma 2003; 55:106-11.
Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj 2006; 20:263-71.
23.
Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide
and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948; 27:484-92.
24.
Artru AA, Katz RA, Colley PS. Autoregulation of cerebral blood flow during normocapnia and hypocapnia in dogs. Anesthesiology 1989; 70:288-92.
25.
Vanderhaegen J, Naulaers G, Vanhole C, et al. The effect of changes in tPCO2 on the fractional tissue oxygen extraction – as measured by near-infrared
Page 18 of 29
spectroscopy – in neonates during the first days of life. Eur J Paediatr Neurol 2009; 13:128-34. 26.
Pryds O, Andersen GE, Friis-Hansen B. Cerebral blood flow reactivity in spontaneously breathing, preterm infants shortly after birth. Acta Paediatr
27.
ip t
Scand 1990; 79:391-6. Rowney DA, Fairgrieve R, Bissonnette B. Cerebrovascular carbon dioxide reactivity in children anaesthetized with sevoflurane. Br J Anaesth 2002;
Collins MP, Lorenz JM, Jetton JR, Paneth N. Hypocapnia and other ventilation-
us
28.
cr
88:357-61.
related risk factors for cerebral palsy in low birth weight infants. Pediatr Res 2001; 50:712-9.
Pappas A, Shankaran S, Laptook AR, et al. Hypocarbia and adverse outcome
an
29.
in neonatal hypoxic-ischemic encephalopathy. J Pediatr 2011; 158:752-8 e1. Hou X, Ding H, Teng Y, et al. Research on the relationship between brain
M
30.
anoxia at different regional oxygen saturations and brain damage using nearinfrared spectroscopy. Physiol Meas 2007; 28:1251-65. Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical
ed
31.
management of severe traumatic brain injury in infants, children, and
pt
adolescents—second edition: Chapter 13. Hyperventilation. Pediatr Crit Care Med 2012; 13 Suppl 1:S58-S60. Skippen P, Seear M, Poskitt K, et al. Effect of hyperventilation on regional
Ac ce
32.
cerebral blood flow in head-injured children. Crit Care Med 1997; 25:1402-9.
33.
Tasker RC, Lutman D, Peters MJ. Hyperventilation in severe diabetic ketoacidosis. Pediatr Crit Care Med 2005; 6:405-11.
34.
Tasker RC, Lutman D, Peters MJ. Cerebrospinal Fluid Ion and Acid-Base Balance. Pediatr Crit Care Med 2006; 7:94-7.
35.
Hansen EL, Kristensen HS, Brodersen P, et al. Acid-base pattern of cerebrospinal fluid and arterial blood in bacterial meningitis and in encephalitis. Acta Med Scand 1974; 196:431–7.
Page 19 of 29
36.
Moller K, Hogh P, Larsen FS, et al. Regional cerebral blood flow during hyperventilation in patients with acute bacterial meningitis. Clin Physiol 2000; 20:399-410.
37.
Moller K, Strauss GI, Thomsen G, et al. Cerebral blood flow, oxidative
ip t
metabolism and cerebrovascular carbon dioxide reactivity in patients with acute bacterial meningitis. Acta Anaesthesiol Scand 2002; 46:567-78. 38.
Steiner LA AJ, Gupta AK, Menon DK. Cerebral oxygen vasoreactivity and
Roach ES, Golomb MR, Adams R, et al. Management of Stroke in Infants and
us
39.
cr
cerebral tissue oxygen reactivity. Br J Anaesth 2003; 90: 774-86.
Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on 40.
an
Cardiovascular Disease in the Young. Stroke 2008; 39:2644-91. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of
M
patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870–947.
Ramaiah VK, Sharma D, Ma L, et al. Admission oxygenation and ventilation
ed
41.
parameters associated with discharge survival in severe pediatric traumatic 42.
pt
brain injury. Childs Nerv Syst 2013; 29:629-34. Narotam PK, Burjonrappa SC, Raynor SC, Rao M, Taylon C. Cerebral
Ac ce
oxygenation in major pediatric trauma: its relevance to trauma severity and outcome. J Pediatr Surg 2006; 41:505-13.
43.
Figaji AA, Fieggen AG, Argent AC, Leroux PD, Peter JC. Does adherence to treatment targets in children with severe traumatic brain injury avoid brain hypoxia? A brain tissue oxygenation study. Neurosurgery 2008; 63:83-91.
44.
Bratton SL, Chestnut RM, Ghajar J, et al. Brain Trauma Foundation guidelines for the management of severe traumatic brain injury: X. Brain oxygen monitoring and thresholds. J Neurotrauma 2007; 24 S1: S65-70.
45.
Pascual JL, Georgoff P, Horan A, et al. Reduced brain tissue oxygen in traumatic brain injury: are most commonly used interventions successful? J Trauma 2011; 70:535-46.
Page 20 of 29
46.
Van Bel F, Lemmers PM, Naulaers G. Monitoring neonatal cerebral oxygen saturation in clinical practice: value and pitfalls. Neonatology 2008; 94:237– 44.
47.
Budohoski KP, Zweifel C, Kasprowicz M, et al. What comes first? The
ip t
dynamics of cerebral oxygenation and blood flow in response to changes in arterial pressure and intracranial pressure after head injury. Br J Anaesth 2012; 108: 89–99.
Rosenthal G, Furmanov A, Itshayek E, Shoshan Y, Singh, V. Assessment of a
cr
48.
brain injury. J Neurosurg 2014; 120:901–7. 49.
us
noninvasive cerebral oxygenation monitor in patients with severe traumatic Davies DJ, Su Z, Clancy MT, et al. Near-Infrared Spectroscopy in the
an
Monitoring of Adult Traumatic Brain Injury: A Review. J Neurotrauma 2015 32:1–9.
The Acute Respiratory Distress Syndrome Network. Ventilation with lower
M
50.
tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 51.
ed
342:1301-8.
Golan E, Fan E. Choosing brain over lungs: who wins? Crit Care Med 2011;
52.
pt
39:1595-6.
Zhou Q, Cao B, Niu L, et al. Effects of permissive hypercapnia on transient
Ac ce
global cerebral ischemia-reperfusion injury in rats. Anesthesiology 2010; 112:288-97.
53.
Hagen EW, Sadek-Badawi M, Carlton DP, Palta M. Permissive hypercapnia and risk for brain injury and developmental impairment. Pediatrics 2008; 122:e583-9.
54.
Zayek MM, Alrifai W, Whitehurst RM, et al. Acidemia versus hypercapnia and risk for intraventricular hemorrhage. Am J Perinatol 2014; 31:345-52.
55.
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 2010; 152:2143-5.
Page 21 of 29
56.
Tasker RC, Peters MJ. Combined lung injury, meningitis and cerebral edema: how permissive can hypercapnia be? Intensive Care Med 1998; 24:616-9.
57.
Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilator protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir
58.
ip t
Crit Care Med 2007; 176:761-7. Feldman Z, Kanter MJ, Robertson CS, et al. Effect of head elevation on head-injured patients. J Neurosurg 1992; 76:207-11.
Pulitano S, Mancino A, Pietrini D, et al. Effects of positive end expiratory
us
59.
cr
intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in
pressure (PEEP) on intracranial and cerebral perfusion pressure in pediatric neurosurgical patients. J Neurosurg Anesthesiol 2013; 25:330-4.
an
Tasker RC. Intracranial pressure and cerebrovascular autoregulation in
pt
ed
M
pediatric critical illness. Semin Pediatr Neurol 2014; 21:255-62.
Ac ce
60.
Page 22 of 29
Legends Table 1. Equations describing the pathway for blood and oxygen in the brain
ip t
Table 2. Algorithm for NIRS with baseline 55% to 75%
cr
Figure 1. CBF changes with PaCO2. Graph showing the change in CBF with hypercapnia and hypocapnia in the normotensive and hypotensive states. In
us
hypotension there is attenuation in the PaCO2 to CBF relationship.
an
Figure 2. CBF changes with PaO2. 2A: Acute rise in CBF with fall in PaO2, with threshold for “hypoxia” at ~50 mm Hg (6.7 kPa). 2B: Shift in curve to the right with
M
anemia, and a higher (closer to normal) threshold for “hypoxia”. Figure 3. Cerebral autoregulation curve. 3A: Autoregulatory plateau where UL and
ed
LL indicate upper and lower limits, respectively. 3B: Changes in oxygen OEF, CBV
Ac ce
pt
and CBF as perfusion pressure falls (see text for details).
Page 23 of 29
Table 1. Equations describing the pathway for blood and oxygen in the brain
ip t
Equations
cr
[1] CMRO2 = (CBF CaO2) – (CBF CvO2) – CiO2 [2] OEF = (SaO2 – SjvO2) ÷ SaO2
us
[3] OEF = CMRO2 ÷ (CBF × 1.34 × [Hb] × SaO2) [4] CBF = CBV ÷ t`
an
[5] CBV = 1.09 CBF0.29
M
[6] Q = ( r4 P) ÷ (8 L)
Ac ce
pt
ed
Key: CaO2 is the oxygen content of arterial blood; CBF is the cerebral blood flow; CBV is the cerebral blood volume; CiO2 is the oxygen content of brain tissue; CMRO2 is the cerebral metabolic rate for oxygen; CvO2 is the oxygen content of venous blood; [Hb] is the hemoglobin concentration; is blood viscosity; L is vessel length; OEF is oxygen extraction fraction of brain; P is the pressure gradient between inflow and outflow; Q is flow; R is resistance to flow; r is vessel radius; SaO2 is oxygen-hemoglobin saturation of arterial blood; SjvO2 is oxygen-hemoglobin saturation of jugular venous blood; t` is mean transit time of blood
Page 24 of 29
Table 2. Algorithm for NIRS with baseline 55% to 75% Position of probe Probe may be poorly placed or there may be neck venous or arterial occlusion from catheters Check NIRS probe position Inspect head and neck for occlusion by positioning or catheters Blood pressure Review normal value for age and state
an
SpO2 Review target range for age and state
Correct positioning
Treat hypotension If SpO2 low: increase FiO2 and find cause Correct hypoventilation
[Hb] Review target range for age and state
Consider transfusion if [Hb] <7g/dL
Systemic hemodynamics Review cardiac function and SvO2
Optimize cardiac function
CMRO2 Review possible change from baseline Assess change in temperature Assess underlying seizure activity
Control fever, hyperthermia and seizures
pt
ed
M
PaCO2 Review target range for age and state Assess EtCO2 and/or PaCO2
Ac ce
Increase from 75% upwards
ip t
Action
cr
Reduction from baseline state ≥%15
Assessment Sequence
us
Derangement
Intracranial hydrodynamics Review neurology Assess for features of raised ICP Assess for pre-infarction cerebral ischemia
Consider cerebral imaging and treat as global/focal ischemia and edema
Position of probe Probe may be poorly placed Check NIRS probe position
Correct
Cerebral hyperemia or hypometabolism OEF may be decreased because Hypothermia or anesthesia Hypercapnia and acidosis Postictal state Postoperative neurovascular hyperperfusion Brain tissue infarction
Correct each cause
Page 25 of 29
Figure 1. CBF changes with PaCO2. Graph showing the change in CBF with hypercapnia and hypocapnia in the normotensive and hypotensive states. In
Ac ce
pt
ed
M
an
us
cr
ip t
hypotension there is attenuation in the PaCO2 to CBF relationship.
Page 26 of 29
ip t cr us an M ed pt Ac ce Figure 2. CBF changes with PaO2. 2A: Acute rise in CBF with fall in PaO2, with threshold for “hypoxia” at ~50 mm Hg (6.7 kPa). 2B: Shift in curve to the right with anemia, and a higher (closer to normal) threshold for “hypoxia”.
Page 27 of 29
ip t cr us an M ed pt Ac ce Figure 3. Cerebral autoregulation curve. 3A: Autoregulatory plateau where UL and LL indicate upper and lower limits, respectively. 3B: Changes in oxygen OEF, CBV and CBF as perfusion pressure falls (see text for details).
Page 28 of 29
Page 29 of 29
ed
pt
Ac ce us
an
M
cr
ip t
S1526-0542(16)00006-3 http://dx.doi.org/doi:10.1016/j.prrv.2016.02.001 YPRRV 1117
To appear in:
YPRRV
Received date: Accepted date:
14-10-2015 10-2-2016
Please cite this article as: Rettig JS, Duncan ED, Tasker RC, Mechanical Ventilation during Acute Brain-Injury in Children, Paediatric Respiratory Reviews (2016), http://dx.doi.org/10.1016/j.prrv.2016.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Mechanical Ventilation during Acute Brain-Injury in Children Jordan S Rettig,1 Elizabeth D Duncan,1 Robert C Tasker1,2 of Anesthesiology, Perioperative and Pain Medicine, Division of Critical
ip t
1Department
Care Medicine; 2Department of Neurology; Boston Children’s Hospital and Harvard
cr
Medical School, Boston, MA
Robert C Tasker MBBS, MD Division of Critical Care Medicine (Bader 621)
an
Boston Children’s Hospital
M
300 Longwood Avenue, Boston, Massachusetts 02115
us
Correspondence to:
0ffice 617-355-3508 fax 617-730-0453
pt
Word counts:
ed
[email protected]
156 words
Article:
3869 words
Ac ce
Abstract:
Page 1 of 29
Abstract Mechanical ventilation in the brain-injured pediatric patient requires many considerations, including the type and severity of lung and brain injury and how progression of such injury will develop. This review focuses on neurological
ip t
breathing patterns at presentation, the effect of brain injury on the lung,
developmental aspects of blood gas tensions on cerebral blood flow, and strategies
cr
used during mechanical ventilation in infants and children receiving neurological
intensive care. Taking these basic principles, our clinical approach is informed by
us
balancing the blood gas tension targets that follow from the ventilation support we choose and the intracranial consequences of these choices on vascular and hydrodynamic physiology. As such, we are left with two key decisions: a low tidal
an
volume strategy for the lung versus the consequence of hypercapnia on the brain; and the use of positive end expiratory pressure to optimize oxygenation versus the
M
consequence of impaired cerebral venous return from the brain and resultant
Key words:
ed
intracranial hypertension.
Brain injury; Acute lung injury; Neurogenic pulmonary edema; Permissive
Ac ce
pt
hypercapnia; Intracranial pressure; Pediatric
Page 2 of 29
Educational Aims: In this review, the reader will come to appreciate that: There are specific neurological breathing patterns in the brain-injured pediatric patient and that there is an organ-system interaction between the
ip t
brain and lungs that affect pulmonary function; There are developmental aspects to the effect of blood gas tensions on
cr
cerebral blood flow;
There are two clinical dilemmas during mechanical ventilation for acute lung
us
injury in brain-injured patients: a low tidal volume strategy optimal for the lung versus the detrimental consequence of hypercapnia on the brain; and the use of positive end expiratory pressure to optimize oxygenation versus
Ac ce
pt
ed
M
resultant intracranial hypertension.
an
the consequence of impaired cerebral venous return from the brain and
Page 3 of 29
Emergency endotracheal intubation and mechanical ventilation of the acutely brain-injured child needing respiratory support is central to patient resuscitation, stabilization and preventing progressive neurological decline. Such critically ill patients are at risk since even the process of patient positioning for
ip t
endotracheal intubation, inducing anesthesia, and laryngoscopy may provoke
rostrocaudal herniation (i.e., central syndrome) or compromise marginally perfused
cr
brain tissue. The Emergency Neurological Life Support suggested algorithm for initial airway management, mechanical ventilation, sedation and evaluation within the
us
first hour of care are beyond the scope of this review and readers are directed to standard texts and emergency department protocols.[1]
This review will focus on neurological breathing patterns, the effect of brain
an
injury on the lung, developmental aspects of blood gas tensions on the cerebral circulation, and strategies used during mechanical ventilation in infants and
M
children receiving neurological intensive care. This discussion takes examples from the clinical research literature covering the four common neuropathological processes, i.e., severe traumatic brain injury (TBI), refractory status epilepticus
ed
(RSE), central nervous system (CNS) infection, and any condition complicated by
pt
raised intracranial pressure (ICP).
Ac ce
Breathing patterns with brain injury Neural control of breathing depends on both conscious and automatic inputs integrated in respiratory centers within the pons and medulla. Automatic control of breathing is located in areas of the dorsolateral tegmentum of the pons as well as the medulla, specifically the nucleus tractus solitarius and retroambigualis. The descending pathways of the ventrolateral columns of the spinal cord also allow for conscious input from the cortex into this collection of nuclei. There are four classic descriptions of abnormal breathing with specific lesions in the brain seen in comatose patients with raised ICP during worsening stages of central syndrome.[2,3] Any of these breathing dysrhythmias may occur in
Page 4 of 29
emergency conditions such as acute hydrocephalus, TBI, cerebrovascular stroke, intracranial hemorrhage, and brain tumors. Cheyne-Stokes breathing is characterized by variable respiratory rate and tidal volume that has a regular cycle of crescendo-to-decrescendo pattern. This type of breathing is associated with
ip t
disruptions in the connections between the cortices of the two cerebral hemispheres and dysfunction of the medial forebrain structures. Apneustic
breathing is typified by a prolonged inspiratory pause and is associated with lesions
cr
of the lower tegmentum of the pons. Cluster breathing is irregular quick breaths
us
regularly separated by long pauses and is associated with lesions of the lower pons or medulla. Ataxic breathing is complete loss of rhythmicity of breathing with irregular breaths and variable tidal volumes, and is associated with lesions of the
an
medulla. More common than these classic patterns, however, is the pattern of central hyperventilation. This pattern results from diffuse cortical and subcortical
M
injury and is a consequence of eliminating the conscious input from the cortex to the brain stem centers for breathing. In this state, breathing is controlled almost entirely by automatic input originating from within the brain stem and, as such,
ed
there is decreased dependency on local brain stem sensing of arterial partial pressure of carbon dioxide (PaCO2) tension as the trigger to respiratory drive.[3]
pt
How should we use this information during mechanical ventilation strategies for brain-injured patients? Two issues are foremost in our considerations. First, an
Ac ce
abnormal pattern and depth of spontaneous breathing will lead to inadequate oxygenation. Second, the dissociation between PaCO2 and drive to breathing will lead to inadvertent hypo- or hypercapnia if spontaneous breathing is permitted.
The lung in brain injury Acutely brain-injured patients may exhibit altered pulmonary mechanics or lung injury with pulmonary edema. The causes include aspiration pneumonitis occurring before endotracheal intubation, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), transfusion-associated lung injury and neurogenic pulmonary
Page 5 of 29
edema (NPE). Out of all of these conditions, only NPE will be discussed in this review. Neurogenic pulmonary edema is the consequence of extravasation of proteinaceous fluid across the alveolar-capillary membrane.[4] The condition was
ip t
described in the literature over 100 years ago[5,6] and it has been reported in cases of cervical spine injury, TBI, RSE and anoxic brain damage from hanging. For
example, the risk of developing NPE after TBI is 20% in the adult population and it
cr
is related to the severity of injury[7] with more severe injuries being more likely to
us
result in the condition. The onset of NPE may be rapid after initial injury and its occurrence is strongly associated with injury of the central autonomic network and the nucleus of the tractus solitarius in the medulla.[7]
an
Historically, two primary physiologic mechanisms were thought to underlie the development of NPE. Firstly there appears to be a pulmonary hydrostatic
M
component to NPE.[8] Both pulmonary and systemic vasoconstriction may occur with raised ICP or excess sympathetic activity in RSE and TBI. Pulmonary vasoconstriction increases pulmonary capillary hydrostatic pressure, and systemic
ed
venoconstriction increases venous return, both of which result in pulmonary edema.[9-12] Recent studies have shown that left ventricular systolic function may be
pt
adversely affected as well, because of increased afterload from systemic arterial hypertension or excessive vagal tone, leading to possible left atrial hypertension.[13The second mechanism is increased pulmonary capillary permeability. Alpha-
Ac ce
15]
adrenergic agonists released in response to brain injury may directly increase permeability or cause release of secondary mediators, which then increase vascular permeability.[16] Rapid pulmonary vasoconstriction and increased venous return may then result in microvascular injury. More recently, another mechanism for NPE has been proposed which
suggests a role for a systemic inflammatory response leading to pulmonary infiltration of neutrophils, cytokine release, and endothelial dysfunction triggered by sympathetic discharge.[17] In support of this theory, we know that brain injury is directly associated with increased intracranial production of pro-inflammatory mediators, and subsequent release of these mediators into the systemic circulation
Page 6 of 29
results in lung injury.[18] For example, Mascia et al. showed in severe brain injury cases that an increased risk of ALI was associated with mechanical ventilation using higher tidal volumes.[19] We also know that ALI alone induces a systemic inflammatory response, which has the potential to increase circulating
ip t
concentrations of neuronal markers of damage (i.e., neuron specific enolase and the S100B protein).[20] Lastly, we also know that in experimental ALI, intracranial
hypertension worsens pre-existing lung damage and further increases cerebral
cr
edema, and there appears to be a reciprocal and synergistic interaction between
us
these two conditions.[21,22] Taking all of this information together, we should no longer consider the brain and lungs as separate entities in critical care. There is a potentially dangerous “cross-talk” between the lung and brain such that our
an
strategies for protective mechanical ventilation not only have the potential to
M
reduce ALI but brain injury as well.
Partial pressure of carbon dioxide and oxygen
ed
Neurocritical care of children with brain injury focuses on management of ICP, cerebral blood flow (CBF), and avoidance of secondary brain injury through the
Ac ce
CBF.
pt
prevention of hypocapnia, hypercapnia and hypoxemia because of their effects on
A developmental perspective of PaCO2 and CBF PaCO2 is a strong modulator of CBF and small vessel tone. Hypercapnia increases CBF and causes intracranial hypertension through cerebral vasodilation. Hypocapnia decreases CBF and cerebral blood volume (CBV) with the consequent risk of cerebral ischemia. In 1948 Kety and Schmidt[23] described a curvilinear relationship between PaCO2 and CBF. A reduction of PaCO2 from 40 to 20 mm Hg (5.3 to 2.7 kPa) decreased CBF but not to the same extent as the increase in CBF when PaCO2 is increased from 40 to 60 mm Hg (5.3 to 8 kPa). In these studies cerebral metabolic rate for oxygen (CMRO2; Equation 1, Table 1) did not change
Page 7 of 29
during this degree of hypercapnia. The increase in CBF without any increase in CMRO2 resulted in a decrease in the arteriovenous oxygen difference in content (AVDO2), i.e., reduced oxygen extraction fraction (OEF; Equations 2 and 3, Table 1). The hypercapnia-induced increase in CBF is ~6% per mm Hg change in PaCO2, and
ip t
hypocapnia decreases CBF by ~3% per mm Hg change in PaCO2 (Figure 1). The relation between CBF and CBV (including arterial, capillary and venous blood
volume) during changes in PaCO2 has also been investigated in humans. Inspection
cr
of equations 4 and 5 (Table 1) show that change in CBF with change in CBV due to
us
hypercapnia, for example, is not linear; the increase in CBV during hypercapnia is less than what would be expected from the change in CBF and, the degree of decrease in CBV during hypocapnia, is also less than would be expected from a
an
change in CBF were the relationships linear (Table 1). These relationships are illustrated by Poiseuille’s law (Equation 6, Table 1), which predicts that CBV
M
increases proportionally to the square of the diameter, yielding the relation CBV = c x CBF0.5, which is in good agreement with the relationship observed during changes in PaCO2.
ed
The question of whether alteration in PaCO2 changes CBF equally in all brain regions is somewhat controversial; for example whether both gray and white matter
pt
behave the same. There appears to be a developmental difference in CBF response to PaCO2, although in all age groups CBF increases with increasing PaCO2. In both
Ac ce
fetus and newborn, gray matter CBF increases at PaCO2 greater than 40 mm Hg (5.3 kPa), but changes little at lower PaCO2 levels. Also, the change in CBF per mm Hg change in PaCO2 is higher in the newborn than in the fetus, and this suggests that the cerebrovascular response to PaCO2 is not completely developed at birth. This depressed CO2 response in the fetus may be correlated to a difference in CMRO2 (i.e., when CBF responses are normalized for CMRO2, the increase in CBF matches the developmental profile of CBF with the greatest change in newborns, smaller in adults and even smaller in fetuses). Hypocapnia does not alter the lower limit of cerebral autoregulation in mature animals, but it does lead to lower CBF per unit change in cerebral perfusion pressure (CPP, which is the difference between mean arterial blood pressure and
Page 8 of 29
mean ICP).[24] At lower mean blood pressure, below the level of cerebral autoregulation, there is an attenuation of the slope of the CBF-to-perfusion pressure graph (Figure 1), which suggests that the cerebral vascular response is attenuated with hypotension. CBF in preterm infants is dependent on PaCO2.[25] The cerebral
ip t
vascular response to PaCO2 is less in the first day of life and increases with gestational age. It is also attenuated, but not eliminated, in hypotensive infants. This reactivity is quite robust even in preterm infants; it is estimated to be ~4% per
cr
mmHg PCO2.[26] Interestingly, during anesthesia with sevoflurane this response is
us
also preserved in children (18 months to 7 years of age) and hence hypocapnia can result in cerebrovascular vasoconstriction and reduction of CBF.[27]
In preterm infants, even mild hypocapnia (PaCO2 <35 mm Hg [<4.7 kPa]) is
an
associated with cerebral palsy and cystic periventricular leucomalacia, and seizures are associated with rapid correction of hypocapnia – leading some to advocate
M
stepwise correction in low PaCO2.[28] In term infants with hypoxic-ischemic encephalopathy there is a positive association between subsequent neurocognitive
ed
outcome and hypocapnia.[29]
The cerebrovascular response to oxygen
pt
Hypoxia elevates CBF (Figure 2A). CBF does not change in response to small deviations in the arterial partial pressure of oxygen (PaO2) around normal levels.
Ac ce
Rather, when PaO2 falls to ~50 mm Hg (6.7 kPa) regional CBF begins to rise. As PaO2 is further reduced below this threshold CBF increases exponentially. It may reach over 400% of basal flow at PaO2 levels still compatible with life. There is no significant change in CMRO2 over the range of PaO2 23 to 100 mm Hg (3.1 to 13.3 kPa).
The responses of the cerebral circulation to hypoxia relate to hemoglobin
oxygen saturation (HbO2); at a PaO2 >70 mm Hg (9.3 kPa), HbO2 is 100%. However, when the PaO2 reaches ~50 mm Hg (6.7 kPa) HbO2 is 85%. Under conditions of reduced availability of oxygen, such as in anemia, the regional CBF/PaO2 curve is shifted to the right (Figure 2B). Hypoxic elevations in regional CBF are not associated with changes in metabolic rate. However, the vasodilation is additive
Page 9 of 29
with that produced by metabolic signals, particularly acidosis and hypercapnia. Figure 3 provides a summary of autoregulation and the changes in CBV and OEF around the lower limit of autoregulation when it is intact. Throughout childhood regional brain OEF is relatively constant; this feature reflects the coupling between
ip t
regional CMRO2 and regional CBF. In some circumstances CMRO2-to-CBF coupling may be disrupted, and the change in OEF will reflect the predominant abnormality. For example: ischemia is present when CMRO2 exceeds oxygen-delivery via CBF;
cr
hyperemia occurs when oxygen-delivery via CBF exceeds tissue requirement or
us
CMRO2. Figure 3B depicts four zones of physiology: I, a state of normal CBF and AVDO2 with reduced CBV due to increased cerebrovascular resistance (CVR); II, a state of normal CBF and AVDO2 with reduced CBV due to reduced CVR; III, a state of
an
falling CBF with raised CBV and AVDO2 at a time when cerebrovascular vasodilatation is maximal; and IV, a state of low CBF and CBV with raised AVDO2.
M
States III and IV have the potential for causing brain injury – it is a matter of duration and intensity of insult.[30] For example, how low can we let the patient’s hemoglobin fall (Figure 2B) before we should consider the detrimental effect of
ed
decreased oxygen content and a shift in the CBF/PaO2 curve to the right?
pt
PaCO2 target during mechanical ventilation In severe TBI, hyperventilation with PaCO2 <25 mm Hg (3.3 kPa) was previously
Ac ce
used as treatment for lowering ICP through vasoconstriction. We now target normal PaCO2 levels (35 to 40 mm Hg [4.7 to 5.3 kPa])[31] since even PaCO2 <30 mm Hg (4 kPa) may induce significant cerebral ischemia.[32] Hence, permitting spontaneous hyperventilation and the development of hypocapnia in brain-injured children may be counterproductive to outcome. The main issues to consider in regard to PaCO2-reactivity, hypocapnia and
CBF are duration of alteration in PaCO2 and whether there has been adaptation in the cerebrospinal fluid (CSF) concentration of bicarbonate ([HCO3]CSF). This change in the relationship between CBF and acute change in PaCO2 usually occurs within 6 to 12 hours after initiation of hypocapnia. For example, in diabetic ketoacidosis, hypocapnia develops over days in response to worsening metabolic acidosis.
Page 10 of 29
Despite this deterioration, CBF is preserved at normal levels because of an adaptation with falling [HCO3]CSF that parallels falling PaCO2[33] – rather like the adaptation occurring with ascent to altitude.[34] When such patients require mechanical ventilation we do not know what PaCO2 should be targeted, but using
ip t
neuromuscular blockade to stop spontaneous hyperventilation and permit immediate normalization of PaCO2, before there has been repair in [HCO3]CSF, is
potentially dangerous.[33,34] A similar cautious approach may be needed in cases of
cr
CNS infection presenting with spontaneous hyperventilation, which is the normal
us
response in most patients.[35] Like diabetic ketoacidosis, we do not know what level in PaCO2 should be targeted during initial mechanical ventilation in those in with baseline hypocapnia. Two studies in adults with acute bacterial meningitis have
an
demonstrated that short-term hyperventilation does not enhance regional abnormalities in CBF nor does it alter CMRO2.[36,37] These slowly developing
M
conditions should be contrasted with more acute neurological disease processes. In adults with cerebrovascular stroke, hypoxia results in cerebral vasodilation and increased CBF, which may elevate ICP and thus further compromise cerebral
ed
perfusion.[38-40] In children with severe TBI, hypocapnia (PaCO2 ≤35 mm Hg [≤4.7 kPa) on admission to an intensive care unit is associated with increased discharge
pt
mortality.[41]
Ac ce
PaO2 target during mechanical ventilation Arterial oxygen content is typically used as a proxy for assuring adequate oxygenation of the brain. There are no large studies that have systematically examined the role of different mechanical ventilation strategies on brain oxygenation. Most clinical strategies emphasize maximal oxygenation with adequate fractional inspired oxygen (FiO2) in order to maintain brain tissue oxygen partial pressure (PbtO2) tension. To date, no study has demonstrated benefit from the prophylactic use of high FiO2 in the setting of brain injury. In adults, PbtO2 monitors are used in combination with ICP and brain temperature monitoring. Normal PbtO2 is >20 mmHg (2.7 kPa) and levels <10 mmHg (1.3 kPa) indicate severe cerebral ischemia.[42] Figaji et al. showed that
Page 11 of 29
reduced PbtO2 is associated with poor outcome in pediatric patients with severe TBI.[43] The Brain Trauma Foundation guidelines in adults with severe TBI suggests avoiding PaO2 <60 mm Hg (8 kPa, or equivalent to arterial oxygen-hemoglobin saturation <90%) and targeting PbtO2 >15 mm Hg (2 kPa).[44] Manoeuvers affecting
ip t
ventilation, oxygen management, and ventilator strategies guided by PbtO2 are now frequently used in clinical practice in adults. Interventions that increase PbtO2 include increasing FiO2, increasing positive end expiratory pressure (PEEP),
cr
increasing minute ventilation, decreasing PaCO2 to lower ICP, using neuromuscular
us
blockade and deep sedation, augmenting blood pressure, and administering red blood cell transfusions.[45]
As an alternative to PbtO2 monitoring, cerebral near-infrared spectroscopy
an
(NIRS)[46,47] has been proposed for the noninvasive monitoring of cerebral tissue oxygenation and perfusion in infants and children. PbtO2 of 1 mm Hg is equivalent to
M
0.003 mL O2/100 g brain. Regional cerebral oxygen saturation (rScO2) is used to estimate cerebral oxygenation and perfusion (Figure 3B) and as a proxy of jugular bulb oxygen-hemoglobin saturation (SjvO2). Table 2 provides a typical algorithm
ed
that can be used in bedside monitoring. This modality has many promising components, but at this time there is insufficient evidence to recommend NIRS as a
Ac ce
injured patient.[48,49]
pt
sole monitoring modality for cerebral oxygenation and perfusion in the brain
Mechanical ventilation strategies in brain injury Guidelines for the management of ALI and the more severe ARDS are beyond the scope of this review. Most practitioners accept that a lung-protective-mechanicalventilation strategy should be used, which includes use of low tidal volumes (6mL/kg) with limited plateau pressure (<30 cm H2O).[50] In patients with acute brain injury who are mechanically ventilated there is often a bedside discussion of targets and goals, weighing-up what might be best for the brain against what is considered the best for the lungs. For example, one
Page 12 of 29
consequence of using the above lung protective mechanical ventilation strategy is the development and need to tolerate hypercapnia. However it may be that we should choose the brain over the lungs,[51] which as we have learned from recent studies is not straightforward because of the reciprocal “cross-talk” in pathology
ip t
between the lungs and the brain.[17,19-22] Permissive hypercapnia and brain injury
cr
In combined brain and lung injury we need to balance what is optimal for lung
us
protection using controlled hypoventilation, yet permitting hypercapnia, against targeting PaCO2 to a level that avoids worsening ICP control because of increasing CBF. In other words, how high can hypercapnia be?
an
In laboratory research, with different levels of hypercapnia (PaCO2 60 to 80 mm Hg [8 to 10.7 kPa], 80 to 100 mm Hg [10.7 to 13.3 kPa], and 100 to 120 mm Hg
M
[13.3 to 16 kPa]) after experimental transient global cerebral ischemia-reperfusion injury a level 80 to 100 mm Hg (10.7 to 13.3 kPa) was associated with the best neurological deficit scores and least histopathological changes.[52] Unfortunately,
ed
there are few such studies identifying optimal PaCO2 thresholds for optimal outcomes in brain-injured patients – and it is debatable that any such studies would
pt
be acceptable to clinicians and ethicists. Hence we need to rely on detailed clinical observational studies, which are at risk of reflecting bias because of patient
Ac ce
selection. For example, two studies indicate a detrimental effect of permissive hypercapnia. In neonates, permissive hypercapnia was associated with more severe injury from intracranial hemorrhage,[53] although a recent study suggests that acidosis is of more consequence.[54] In children with severe TBI hypercapnia (PaCO2 ≥46 mm Hg [≥6.1 kPa]) on admission to an intensive care unit was associated with increased discharged mortality.[41] In contrast, a recent study in 12 adults with subarachnoid hemorrhage and ARDS showed the opposite effect. A lung protective strategy (i.e., tidal volume 5 to 8 mL/kg) with permissive hypercapnia (PaCO2 50 to 60 mm Hg [6.7 to 8 kPa]) did not result in increased ICP.[55] The clinical guidelines for severe TBI do not address the strategy of tolerating hypercapnia during management of ALI and ARDS;[31] the topic of
Page 13 of 29
combined lung and brain injury lacks Class I and II clinical data. That said, the approach we have taken when having to balance lung with brain management is to try and individualize the PaCO2 target to cerebral oxygenation.[56] In a patient with combined meningococcal septicemia, meningitis, cerebral edema and ARDS, we
ip t
identified the upper limit of "tolerable" hypercapnia as the level that would not result in significant cerebral hyperemia based on SjvO2 levels. Initially, cautious
induction of pH 7.32 and PaCO2 <45 mm Hg (<6 kPa) was tolerated; subsequent
cr
metabolic compensation meant that higher levels of PaCO2 could be permitted. In
us
similar cerebral-versus-pulmonary circumstances we suggest that this approach warrants consideration. An alternative to invasive monitoring of SjvO2 could be
an
NIRS. PEEP and ICP
M
PEEP may affect both CBF/CPP and ICP: PEEP increases intrathoracic pressure and jugular venous pressure; and, decreases venous return, mean blood pressure, and cardiac output. Raised ICP may occur because increased jugular venous pressure
ed
causes increased CBV, particularly when intracerebral compliance is decreased. Reduced CPP may occur because of the effect of PEEP on venous return and cardiac
pt
output: with intact autoregulation decreased CPP is compensated by cerebral vasodilation, and leads to raised ICP; with impaired autoregulation decreased CPP
Ac ce
leads to ischemia.
In ALI/ARDS, hypoxemia is managed by applying PEEP and increasing the
FiO2 with the goal of maintaining pulse oximetry oxygen-hemoglobin saturation (SpO2) above 88%.[57] In the brain-injured patient, the clinician is left with deciding optimal ventilator settings for the oxygenation target while avoiding the potential increase in ICP associated with using PEEP. Before discussing the clinical studies that help in this decision, one simple manoeuver that aids venous return from the head is to keep the head of the bed elevated at 30°, which maintains cerebral venous drainage via the vertebral veins not affected by PEEP.[58] A number of studies in adults with severe TBI or subarachnoid hemorrhage support the practice of using PEEP.[17] The conclusion from these studies is that
Page 14 of 29
optimal oxygenation can be achieved by using adequate FiO2 and by applying PEEP. PEEP may, however, affect the cerebral circulation by hemodynamic- and PaCO2mediated mechanisms and these effects should be monitored and used to titrate PEEP. For example, a recent study in 21 pediatric postoperative neurosurgery
ip t
patients examined a number of hemodynamic and intracranial parameters after applying increasing levels of PEEP (0, 4 and 8 cm H2O).[59] PEEP significantly
increased compliance of the respiratory system without affecting ICP. There were
cr
no significant variations in values of arterial pressure, CPP, and middle cerebral
us
artery CBF-velocity (using transcranial Doppler). However, CVP significantly
increased as PEEP was raised from 0 to 8 cm H2O. The authors concluded that PEEP values up to 8 cm H2O could be applied in such patients in order to restore lung
an
recruitment without any consequence on level of ICP.
M
Conclusions
Mechanical ventilation in the brain-injured pediatric patient requires many considerations, including the type and severity of lung and brain injury and how
ed
progression of such injury will interact. Based on current literature, there is a brainlung interaction, which must be elucidated further in order to provide optimal
pt
therapy for the patient with combined lung and brain injury. Currently, the basic principles of our clinical approach are based on an understanding of how blood gas
Ac ce
tensions and our ventilation support competes in their influence on intracranial vascular and hydrodynamic physiology:[60] a low tidal volume strategy for the lung versus the consequence of hypercapnia on the brain; and, the use of PEEP to optimize oxygenation versus the consequence of impaired cerebral venous return from the brain and resultant raised ICP. As such, any changes in blood gas tensions away from normal should occur slowly over hours so as to permit central compensation and attenuate any adverse side effects.
Page 15 of 29
Future directions for research: The development of bedside clinical tools that allow us to better assess and monitor changes in CBF.
ip t
The development of biomarkers of brain injury that can be used in clinical
care so as to assess when lung injury, or our mechanical ventilation strategy,
cr
is detrimental to the brain.
The development of biomarkers of lung injury that can be used in clinical
Ac ce
pt
ed
M
an
us
care so as to assess when brain injury is adversely affecting the lung.
Page 16 of 29
References 1.
Seder DB, Jagoda A, Riggs B. Emergency neurological life support: airway, ventilation and sedation. Neurocrit Care 2015; 23 Suppl 2:S5-S22. Plum F, Posner LB. The diagnosis of stupor and coma. Philadelphia: FA Davis,
ip t
2.
1980. 3.
Bolton CF, Chen R, Wijdicks EFM, Zifko UA. Neurology of breathing.
Berthiaume Y, Broaddus VC, Gropper M, et al. Alveolar liquid and protein
us
4.
cr
Philadelphia: Elsevier, 2004.
clearance from normal dog lungs. J Appl Physiol 1988; 65:585-93. 5.
Moutier F. Hypertension et mort par oedema pulmonaire aigu, chez les
an
blesses cranio-encephaliques. Presse Med 1918; 26:108-9.
Shanahan WT. Pulmonary oedema in epilepsy. NY Med J 1908; 37:54-6.
7.
Bratton SL, Davis RL. Acute lung injury in isolated traumatic brain injury.
M
6.
Neurosurgery 1997; 40:707-12. 8.
Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human
9.
ed
neurogenic pulmonary edema. Chest 1997; 111:1326-33. Maron MB, Dawson CA. Pulmonary venoconstriction caused by elevated
pt
cerebrospinal fluid pressure in the dog. J Appl Physiol Respir Environ Exerc Physiology 1980; 49:73-8.
Hoff JT, Nishimura M, Garcia-Uria J, Miranda S. Experimental Neurogenic
Ac ce
10.
pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg
1981; 54:627-31.
11.
Sedy J, Zicha J, Nedvikova J, Kunes J. The role of sympathetic nervous system in the development of neurogenic pulmonary edema in spinal cord-injured rats. J Appl Physiol (1985) 2012; 112:1-8.
12.
Sedy J, Kunes J, Zicha J. Pathogenetic mechanisms of neurogenic pulmonary edema. J Neurotrauma 2015 [Epub ahead of print, PMID 25496372].
13.
Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med 2002; 28:1012-23.
Page 17 of 29
14.
Bahloul M, Chaari AN, Kallel H, et al. Neurogenic pulmonary edema due to traumatic brain injury: evidence of cardiac dysfunction. Am J Crit Care 2006; 15:462-70.
15.
Mayer SA, Lin J, Homma S, et al. Myocardial Injury and left ventricular
16.
ip t
performance after subarachnoid hemorrhage. Stroke 1999; 30:780-6. Colice GL, Matthay MA, Bass E, Matthay RA. Neurogenic pulmonary edema. Am Rev Respir Dis 1984; 130:941-8.
Mascia L. Acute lung injury in patients with severe brain injury: a double hit
cr
17. 18.
us
model. Neurocrit Care 2009; 11:417-26.
Hutchinson PJ, O’Connell MT, Rothwell NJ, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta and their
19.
an
endogenous inhibitor IL-1ra. J Neurotrauma 2007; 24:1545-57. Mascia L, Zavala E, Bosma K, et al. High tidal volume is associated with the
M
development of acute lung injury after severe brain injury: an international observational study. Crit Care Med 2007; 35:1815-20. 20.
Bickenbach J, Zoremba N, Fries M, et al. Low tidal volume ventilation in a
ed
porcine model of acute lung injury improves cerebral tissue oxygenation. Anesth Analg 2009; 109:847-55.
Holland MC, Mackersie RC, Morabito D, et al. The development of acute lung
pt
21.
injury is associated with worse neurologic outcome in patients with severe 22.
Ac ce
traumatic brain injury. J Trauma 2003; 55:106-11.
Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj 2006; 20:263-71.
23.
Kety SS, Schmidt CF. The effects of altered arterial tensions of carbon dioxide
and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948; 27:484-92.
24.
Artru AA, Katz RA, Colley PS. Autoregulation of cerebral blood flow during normocapnia and hypocapnia in dogs. Anesthesiology 1989; 70:288-92.
25.
Vanderhaegen J, Naulaers G, Vanhole C, et al. The effect of changes in tPCO2 on the fractional tissue oxygen extraction – as measured by near-infrared
Page 18 of 29
spectroscopy – in neonates during the first days of life. Eur J Paediatr Neurol 2009; 13:128-34. 26.
Pryds O, Andersen GE, Friis-Hansen B. Cerebral blood flow reactivity in spontaneously breathing, preterm infants shortly after birth. Acta Paediatr
27.
ip t
Scand 1990; 79:391-6. Rowney DA, Fairgrieve R, Bissonnette B. Cerebrovascular carbon dioxide reactivity in children anaesthetized with sevoflurane. Br J Anaesth 2002;
Collins MP, Lorenz JM, Jetton JR, Paneth N. Hypocapnia and other ventilation-
us
28.
cr
88:357-61.
related risk factors for cerebral palsy in low birth weight infants. Pediatr Res 2001; 50:712-9.
Pappas A, Shankaran S, Laptook AR, et al. Hypocarbia and adverse outcome
an
29.
in neonatal hypoxic-ischemic encephalopathy. J Pediatr 2011; 158:752-8 e1. Hou X, Ding H, Teng Y, et al. Research on the relationship between brain
M
30.
anoxia at different regional oxygen saturations and brain damage using nearinfrared spectroscopy. Physiol Meas 2007; 28:1251-65. Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical
ed
31.
management of severe traumatic brain injury in infants, children, and
pt
adolescents—second edition: Chapter 13. Hyperventilation. Pediatr Crit Care Med 2012; 13 Suppl 1:S58-S60. Skippen P, Seear M, Poskitt K, et al. Effect of hyperventilation on regional
Ac ce
32.
cerebral blood flow in head-injured children. Crit Care Med 1997; 25:1402-9.
33.
Tasker RC, Lutman D, Peters MJ. Hyperventilation in severe diabetic ketoacidosis. Pediatr Crit Care Med 2005; 6:405-11.
34.
Tasker RC, Lutman D, Peters MJ. Cerebrospinal Fluid Ion and Acid-Base Balance. Pediatr Crit Care Med 2006; 7:94-7.
35.
Hansen EL, Kristensen HS, Brodersen P, et al. Acid-base pattern of cerebrospinal fluid and arterial blood in bacterial meningitis and in encephalitis. Acta Med Scand 1974; 196:431–7.
Page 19 of 29
36.
Moller K, Hogh P, Larsen FS, et al. Regional cerebral blood flow during hyperventilation in patients with acute bacterial meningitis. Clin Physiol 2000; 20:399-410.
37.
Moller K, Strauss GI, Thomsen G, et al. Cerebral blood flow, oxidative
ip t
metabolism and cerebrovascular carbon dioxide reactivity in patients with acute bacterial meningitis. Acta Anaesthesiol Scand 2002; 46:567-78. 38.
Steiner LA AJ, Gupta AK, Menon DK. Cerebral oxygen vasoreactivity and
Roach ES, Golomb MR, Adams R, et al. Management of Stroke in Infants and
us
39.
cr
cerebral tissue oxygen reactivity. Br J Anaesth 2003; 90: 774-86.
Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on 40.
an
Cardiovascular Disease in the Young. Stroke 2008; 39:2644-91. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of
M
patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:870–947.
Ramaiah VK, Sharma D, Ma L, et al. Admission oxygenation and ventilation
ed
41.
parameters associated with discharge survival in severe pediatric traumatic 42.
pt
brain injury. Childs Nerv Syst 2013; 29:629-34. Narotam PK, Burjonrappa SC, Raynor SC, Rao M, Taylon C. Cerebral
Ac ce
oxygenation in major pediatric trauma: its relevance to trauma severity and outcome. J Pediatr Surg 2006; 41:505-13.
43.
Figaji AA, Fieggen AG, Argent AC, Leroux PD, Peter JC. Does adherence to treatment targets in children with severe traumatic brain injury avoid brain hypoxia? A brain tissue oxygenation study. Neurosurgery 2008; 63:83-91.
44.
Bratton SL, Chestnut RM, Ghajar J, et al. Brain Trauma Foundation guidelines for the management of severe traumatic brain injury: X. Brain oxygen monitoring and thresholds. J Neurotrauma 2007; 24 S1: S65-70.
45.
Pascual JL, Georgoff P, Horan A, et al. Reduced brain tissue oxygen in traumatic brain injury: are most commonly used interventions successful? J Trauma 2011; 70:535-46.
Page 20 of 29
46.
Van Bel F, Lemmers PM, Naulaers G. Monitoring neonatal cerebral oxygen saturation in clinical practice: value and pitfalls. Neonatology 2008; 94:237– 44.
47.
Budohoski KP, Zweifel C, Kasprowicz M, et al. What comes first? The
ip t
dynamics of cerebral oxygenation and blood flow in response to changes in arterial pressure and intracranial pressure after head injury. Br J Anaesth 2012; 108: 89–99.
Rosenthal G, Furmanov A, Itshayek E, Shoshan Y, Singh, V. Assessment of a
cr
48.
brain injury. J Neurosurg 2014; 120:901–7. 49.
us
noninvasive cerebral oxygenation monitor in patients with severe traumatic Davies DJ, Su Z, Clancy MT, et al. Near-Infrared Spectroscopy in the
an
Monitoring of Adult Traumatic Brain Injury: A Review. J Neurotrauma 2015 32:1–9.
The Acute Respiratory Distress Syndrome Network. Ventilation with lower
M
50.
tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 51.
ed
342:1301-8.
Golan E, Fan E. Choosing brain over lungs: who wins? Crit Care Med 2011;
52.
pt
39:1595-6.
Zhou Q, Cao B, Niu L, et al. Effects of permissive hypercapnia on transient
Ac ce
global cerebral ischemia-reperfusion injury in rats. Anesthesiology 2010; 112:288-97.
53.
Hagen EW, Sadek-Badawi M, Carlton DP, Palta M. Permissive hypercapnia and risk for brain injury and developmental impairment. Pediatrics 2008; 122:e583-9.
54.
Zayek MM, Alrifai W, Whitehurst RM, et al. Acidemia versus hypercapnia and risk for intraventricular hemorrhage. Am J Perinatol 2014; 31:345-52.
55.
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 2010; 152:2143-5.
Page 21 of 29
56.
Tasker RC, Peters MJ. Combined lung injury, meningitis and cerebral edema: how permissive can hypercapnia be? Intensive Care Med 1998; 24:616-9.
57.
Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilator protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir
58.
ip t
Crit Care Med 2007; 176:761-7. Feldman Z, Kanter MJ, Robertson CS, et al. Effect of head elevation on head-injured patients. J Neurosurg 1992; 76:207-11.
Pulitano S, Mancino A, Pietrini D, et al. Effects of positive end expiratory
us
59.
cr
intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in
pressure (PEEP) on intracranial and cerebral perfusion pressure in pediatric neurosurgical patients. J Neurosurg Anesthesiol 2013; 25:330-4.
an
Tasker RC. Intracranial pressure and cerebrovascular autoregulation in
pt
ed
M
pediatric critical illness. Semin Pediatr Neurol 2014; 21:255-62.
Ac ce
60.
Page 22 of 29
Legends Table 1. Equations describing the pathway for blood and oxygen in the brain
ip t
Table 2. Algorithm for NIRS with baseline 55% to 75%
cr
Figure 1. CBF changes with PaCO2. Graph showing the change in CBF with hypercapnia and hypocapnia in the normotensive and hypotensive states. In
us
hypotension there is attenuation in the PaCO2 to CBF relationship.
an
Figure 2. CBF changes with PaO2. 2A: Acute rise in CBF with fall in PaO2, with threshold for “hypoxia” at ~50 mm Hg (6.7 kPa). 2B: Shift in curve to the right with
M
anemia, and a higher (closer to normal) threshold for “hypoxia”. Figure 3. Cerebral autoregulation curve. 3A: Autoregulatory plateau where UL and
ed
LL indicate upper and lower limits, respectively. 3B: Changes in oxygen OEF, CBV
Ac ce
pt
and CBF as perfusion pressure falls (see text for details).
Page 23 of 29
Table 1. Equations describing the pathway for blood and oxygen in the brain
ip t
Equations
cr
[1] CMRO2 = (CBF CaO2) – (CBF CvO2) – CiO2 [2] OEF = (SaO2 – SjvO2) ÷ SaO2
us
[3] OEF = CMRO2 ÷ (CBF × 1.34 × [Hb] × SaO2) [4] CBF = CBV ÷ t`
an
[5] CBV = 1.09 CBF0.29
M
[6] Q = ( r4 P) ÷ (8 L)
Ac ce
pt
ed
Key: CaO2 is the oxygen content of arterial blood; CBF is the cerebral blood flow; CBV is the cerebral blood volume; CiO2 is the oxygen content of brain tissue; CMRO2 is the cerebral metabolic rate for oxygen; CvO2 is the oxygen content of venous blood; [Hb] is the hemoglobin concentration; is blood viscosity; L is vessel length; OEF is oxygen extraction fraction of brain; P is the pressure gradient between inflow and outflow; Q is flow; R is resistance to flow; r is vessel radius; SaO2 is oxygen-hemoglobin saturation of arterial blood; SjvO2 is oxygen-hemoglobin saturation of jugular venous blood; t` is mean transit time of blood
Page 24 of 29
Table 2. Algorithm for NIRS with baseline 55% to 75% Position of probe Probe may be poorly placed or there may be neck venous or arterial occlusion from catheters Check NIRS probe position Inspect head and neck for occlusion by positioning or catheters Blood pressure Review normal value for age and state
an
SpO2 Review target range for age and state
Correct positioning
Treat hypotension If SpO2 low: increase FiO2 and find cause Correct hypoventilation
[Hb] Review target range for age and state
Consider transfusion if [Hb] <7g/dL
Systemic hemodynamics Review cardiac function and SvO2
Optimize cardiac function
CMRO2 Review possible change from baseline Assess change in temperature Assess underlying seizure activity
Control fever, hyperthermia and seizures
pt
ed
M
PaCO2 Review target range for age and state Assess EtCO2 and/or PaCO2
Ac ce
Increase from 75% upwards
ip t
Action
cr
Reduction from baseline state ≥%15
Assessment Sequence
us
Derangement
Intracranial hydrodynamics Review neurology Assess for features of raised ICP Assess for pre-infarction cerebral ischemia
Consider cerebral imaging and treat as global/focal ischemia and edema
Position of probe Probe may be poorly placed Check NIRS probe position
Correct
Cerebral hyperemia or hypometabolism OEF may be decreased because Hypothermia or anesthesia Hypercapnia and acidosis Postictal state Postoperative neurovascular hyperperfusion Brain tissue infarction
Correct each cause
Page 25 of 29
Figure 1. CBF changes with PaCO2. Graph showing the change in CBF with hypercapnia and hypocapnia in the normotensive and hypotensive states. In
Ac ce
pt
ed
M
an
us
cr
ip t
hypotension there is attenuation in the PaCO2 to CBF relationship.
Page 26 of 29
ip t cr us an M ed pt Ac ce Figure 2. CBF changes with PaO2. 2A: Acute rise in CBF with fall in PaO2, with threshold for “hypoxia” at ~50 mm Hg (6.7 kPa). 2B: Shift in curve to the right with anemia, and a higher (closer to normal) threshold for “hypoxia”.
Page 27 of 29
ip t cr us an M ed pt Ac ce Figure 3. Cerebral autoregulation curve. 3A: Autoregulatory plateau where UL and LL indicate upper and lower limits, respectively. 3B: Changes in oxygen OEF, CBV and CBF as perfusion pressure falls (see text for details).
Page 28 of 29
Page 29 of 29
ed
pt
Ac ce us
an
M
cr
ip t