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Impact of Altered Airway Pressure on Intracranial Pressure, Perfusion, and Oxygenation

A Narrative Review

Chen, Han, MD, PhD1,2,3,4,5; Menon, David K., MD, PhD6,7; Kavanagh, Brian P., MD1,2,3

doi: 10.1097/CCM.0000000000003558
Concise Definitive Review

Objectives: A narrative review of the pathophysiology linking altered airway pressure and intracranial pressure and cerebral oxygenation.

Data Sources: Online search of PubMed and manual review of articles (laboratory and patient studies) of the altered airway pressure on intracranial pressure, cerebral perfusion, or cerebral oxygenation.

Study Selection: Randomized trials, observational and physiologic studies.

Data Extraction: Our group determined by consensus which resources would best inform this review.

Data Synthesis: In the normal brain, positive-pressure ventilation does not significantly alter intracranial pressure, cerebral oxygenation, or perfusion. In injured brains, the impact of airway pressure on intracranial pressure is variable and determined by several factors; a cerebral venous Starling resistor explains much of the variability. Negative-pressure ventilation can improve cerebral perfusion and oxygenation and reduce intracranial pressure in experimental models, but data are limited, and mechanisms and clinical benefit remain uncertain.

Conclusions: The effects of airway pressure and ventilation on cerebral perfusion and oxygenation are increasingly understood, especially in the setting of brain injury. In the face of competing mechanisms and priorities, multimodal monitoring and individualized titration will increasingly be required to optimize care.

1Translational Medicine, The Research Institute, Hospital for Sick Children, Toronto, ON, Canada.

2Departments of Critical Care Medicine and Anesthesiology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

3Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.

4Fujian Provincial Clinical college, Fujian Medical University, Fuzhou, China.

5Surgical Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, China.

6Neurosciences Critical Care Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom.

7Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom.

Drs. Chen, Menon, and Kavanagh helped with conception and design, and drafting the article for important intellectual content.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by research funds (to Dr. Kavanagh) from the Canadian Institutes of Health Research.

Dr. Chen is supported by National Natural Science Foundation of China (Grant Number: 81701942). Dr. Menon received support for article research from National Institute for Health Research, United Kingdom. He is a Professorial Fellow, Queens’ College, Cambridge, United Kingdom, and a Senior Investigator, National Institute for Health Research, United Kingdom. Dr. Kavanagh disclosed that he has a patent pending for a device for mechanical ventilation. He holds the Dr Geoffrey Barker Chair in Critical Care Research.

For information regarding this article, E-mail:

Mechanical ventilation is a core management strategy in patients with acute intracranial hypertension; although the relationships among ventilation, PaCO2, and intracranial pressure (ICP) are well understood, the impact of altering airway pressure (Paw) is less well appreciated. It is often assumed that raising Paw will invariably elevate ICP, but recent data indicate that this is not always the case. The effect of altering Paw depends on several factors (e.g., respiratory mechanics, lung recruitability, baseline ICP), and the resulting ICP may be unchanged, increased, or decreased. Furthermore, the impact on cerebral oxygenation is often unknown. This “Review” considers the pathophysiology linking altered Paw and ICP, the impact of pleural and venous pressures, and the consequences for cerebral oxygenation. Data from patient (Table 1) and laboratory (Table 2) studies are synthesized, and the importance of titrating Paw against individual responses considered.





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Words used were “airway pressure, positive pressure ventilation, negative pressure ventilation, mechanical ventilation, PEEP, ICP, cerebral perfusion pressure (CPP), cerebral oxygenation, brain tissue oxygenation, cerebral blood flow.” References from articles were also searched to identify additional studies.

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The Monroe-Kellie doctrine dictates that the contents of the cranium consist of the combined volume of the brain, the blood, and the cerebrospinal fluid (CSF); because the skull is rigid (and its contents noncompressible), increases in the volume of the contents exponentially increases the ICP (Fig. 1). Because the components are noncompressible and the overall volume cannot be increased, an increase in intracranial mass (edema, hydrocephalus, tumor, hematoma, etc.) results in displacement of the fluid components (i.e., blood and CSF) out of the cranium (34). Once the capacity to displace CSF and blood volume is exhausted, additional increases in any of the intracranial contents are associated with precipitous increases in ICP (34).

Figure 1

Figure 1

An increase in Paw increases pleural pressure (Ppl), which in turn elevates central (and jugular) venous pressure. Because increased jugular venous pressure impedes cerebral venous return, the cerebral blood volume (CBV)—and the ICP—increases (35). Raised ICP may occur because of greater intracranial blood volume due to greater arterial inflow or less venous outflow (36 , 37).

The effectiveness of the transmission of Paw to the pleural space and the intrathoracic veins depends on the relative compliance of the lung and chest wall (38); transmission of pressure from the thoracic veins to the neck and cranial veins can be impeded by head position, or by the effect of a cranial “Starling resistor” (21).

A Starling resistor is a collapsible tube on which the external pressure exceeds the outflow pressure (Fig. 2), and depending on that pressure difference, provides a “variable” resistor. The anatomic basis is the cranium (i.e., a sealed, rigid compartment that determines the external pressure), the noncollapsible cerebral artery (upstream), the noncollapsible superior sagittal sinus (downstream), and the intervening collapsible cerebral veins.

Figure 2

Figure 2

Evidence for this phenomenon comes from hemodynamic (21 , 22 , 40) and imaging (41) studies. In graded elevations in ICP, the Paw was altered (21 , 22) (Fig. 2) and an abrupt drop in venous pressure (a “resistor”) demonstrated by passing a catheter from the cerebral vein into the sagittal sinus (21). Raised ICP compressed the cerebral veins and decreased downstream venous pressure; thus, the increased pressure gradient between the cerebral vein and the sagittal sinus constitutes a vascular “waterfall” impeding the transmission of central venous pressure (CVP) into the cranium and regulating outflow. In this scenario, increases in Paw will be incompletely transmitted and will not (or only marginally) further increase ICP (21 , 22). However, if Paw exceeds a threshold, the CVP (and downstream venous pressure) exceeds the ICP; this opens the resistor and establishes a direct (venous) connection between the thorax and the cranium: here, elevating Paw raises ICP.

Finally, decreased venous return also lowers the cardiac output, which if it reduces systemic arterial pressure, will lower the CPP. If cerebral autoregulation is intact, cerebral blood flow (CBF) may be maintained despite a lower CPP, but if impaired, decreased CPP may lower CBF and CBV, and thereby decrease ICP. Brain injury raises the lower limit of CPP at which autoregulation is active (42–44), resulting in differential effects on ICP with reductions in CPP that depend on how much CPP has already been reduced. Above the (elevated) lower limit of autoregulation, reduced CPP will result in vasodilatation, which in a noncompliant intracranial cavity will increase ICP and further reduce CPP (and potentially CBF). Reduced CPP below the lower limit of autoregulation will not trigger autoregulatory vasodilatation—and regardless of ICP—will nonetheless reduce CBF. CBF appears not to be closely related to cardiac output (45). A conceptual framework of the integrated regulation of brain perfusion suggests that CBF is regulated by multiple factors including sympathetic activity, renin-angiotensin action, cardiac output, blood pressure, metabolic products, nitric oxide, etc (33).

The concept of intracranial compliance is important. Impaired compliance is not synonymous with elevated ICP. Although comparable in shape, individual patient ventricular volume-pressure curves may demonstrate important differences. A similar level of ICP might occur in the face of a higher versus a lower compensatory reserve. Measurement of intracranial compliance is performed (in experimental models) by injecting a known (small) amount of fluid into the CSF and noting the increment in ICP.

Thus, the two key determinants of the impact of elevating positive end-expiratory pressure (PEEP) are the intracranial compliance and the “net” change of CBV, which is determined by the relative inflow (regulated by preload, cerebral autoregulation, respiratory mechanics, CO2, etc.) and outflow (regulated by CVP, Starling resistor, etc.) (Fig. 1).

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This can be divided into two components: static (i.e., PEEP or continuous positive airway pressure) and dynamic (i.e., the changes with each tidal volume); an increase in either will increase mean Paw but can have different hemodynamic consequences (46). Increased “static” pressure causes a proportionate decrease in cardiac output, whereas increased dynamic pressure has minimal impact on cardiac output until a threshold is reached. Elevated static pressure elevates systemic venous pressure, whereas increased dynamic pressure can lower it (46). Nonetheless, most studies focus on the effects of static Paw (usually PEEP) on ICP, cerebral perfusion, and oxygenation. ICP elevation (variable, not sustained) may accompany elevation of peak Paw (1).

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Normal Brain

Few data exist describing the influence of Paw on ICP in patients without intracranial pathology (unsurprising—ICP not ordinarily be monitored). Using noninvasive assessment of ICP (e.g., transcranial Doppler [TCD], optic nerve sheath diameter) in patients undergoing elective surgery, PEEP of 8 cm H2O (Paw increase ≈4 cm H2O) has minimal impact on ICP (47 , 48).

The impact Paw on cerebral perfusion and oxygenation has been examined in patients without brain injury during elective surgery (47–53). The most common noninvasive assessment of cerebral perfusion is TCD ultrasound (49 , 54–56), whereas cerebral oxygenation is estimated using near-infrared spectroscopy (NIRS) (48 , 50–53 , 57). Increased Paw can increase (58), decrease (59), or not alter (60) CBF velocity; however, even if velocity is altered, regional oxygenation is usually maintained (61).

To accurately measure CBF using TCD, the diameter of the imaged artery must be constant (62). In the setting of intact autoregulation (no brain injury), the cerebral artery may constrict (or dilate) to maintain constant CBF (63) because the cardiac output fluctuates with Paw. However, although the middle cerebral artery diameter is sensitive to exercise (64), PaCO2 (65 , 66), and hypoxemia (67), it is unknown if it responds to altered Paw.

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Injured Brain: ICP

In patients with brain injury, ICP may be normal (or normalized by medical management) or elevated. The responses of ICP to increases in Paw are not predictable based on its initial level (7 , 8). Some studies report that increased PEEP may have no impact on ICP if not initially elevated, but may have impact if initially elevated (8). However, the opposite has also been reported: raised Paw had no impact on already elevated ICP, but increased it if initially normal (7). Finally, increased Paw may decrease ICP (68).

In attempting to reconcile these disparate reports, three issues are key. First, the ability to perform interventional testing in patients with intracranial hypertension is limited, as such patients are vulnerable. Second, assessment is confounded by analgesics, sedatives, anesthetics, and anticonvulsants, as well as deliberate control of blood pressure, blood gases, acid-base status, plasma osmolality, glucose, and temperature (69–72). Third, intracranial veins can behave as either veins in series without threshold flow characteristics (73) or as a “Starling Resistor” (21 , 22). If intrathoracic pressures are transmitted into the intracranial veins, this can increase the volume of intracranial blood (even if only slightly). If an incremental increase in the volume of the intracranial contents exceeds the “compensatory reserve,” ICP will rise precipitously (34). In summary, modest levels of positive Paw can potentially increase ICP but, alternatively, may have no significant effects.

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Injured Brain: Cerebral Perfusion and Oxygenation

There are few reports of the effects of altered Paw on cerebral perfusion or oxygenation, likely in part, because accurate noninvasive assessment is not generally available. The most widely used noninvasive assessment of CBF is TCD and, as with ICP, results are variable (5 , 15 , 18). Although widely used in patients without brain injury, noninvasive assessment of cerebral oxygenation (e.g., NIRS) has not been well investigated.

Direct measurement of CBF using intracranial flow probes (4), radioactive microspheres (29 , 32), or arterial flow probes (23) suggests decreased (23) or unchanged (4 , 29 , 32) ICP following increases in Paw. However, in patients with subarachnoid hemorrhage, increases in PEEP (5–20 cm H2O) that are sufficient to decrease mean arterial pressure (MAP), reduce regional CBF and brain tissue oxygenation (PtiO2) (4). More recent multimodal monitoring that incorporates ICP, cerebral perfusion, and cerebral oxygenation may provide better insight (74 , 75). In summary, altered Paw may change cerebral perfusion or oxygenation before any change in ICP can be observed; such effects have not been extensively investigated and, at the bedside, are likely underrecognized. Ultimately, the focus must be on identifying vulnerable regions and determining the impact on perfusion or oxygenation in these areas.

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Compliance of the Lung and the Chest Wall

Understanding the relationships between respiratory mechanics and vascular physiology may help predict how changes in Paw will influence ICP (2 , 15 , 76).

Increases in Paw are transmitted to the pleural space and raise the Ppl, which in turn raises the CVP. The elevation in CVP reflects a reduced venous return, and the lowered cardiac output can initiate autoregulatory cerebral vasodilation and increase ICP. Elevated CVP can also directly increase ICP by decreasing jugular venous outflow or, in the presence a Starling resistor, open the resistor, increase outflow, and lower ICP (46 , 77).

The first link is the impact of Paw on Ppl. The transmission of changes in Paw to the pleural space depends on the relative compliance of the lung and the chest wall. If the lung compliance is high and the chest wall compliance is low, then the transmission is highly “efficient” (38). This can be conceptualized as an elevation in Paw maximally extending through the highly compliant lung to the pleural space, but because expansion of the pleural space is prevented by a noncompliant chest wall, the Ppl rises in close approximation to the Paw. By contrast, if the lung is noncompliant, the transmission of a change in Paw is poor; furthermore, even if Paw transmission is efficient, a highly compliant chest wall can dissipate swings in Ppl (Fig. 3).

Figure 3

Figure 3

The local static pressure in any part of the pleural space (Ppl) depends on the body position, the contents of the thorax and abdomen, and the distance between the dependent and nondependent thoracic margins (78). In normal lung, a “swing” in Ppl (e.g., inspiratory or expiratory effort) is transmitted—almost instantaneously—to all parts of the pleural space; this reflects normal or “fluid like” lung behavior (79). However, if injury or atelectasis is present, the transmission of swings in Ppl through abnormal areas may be impaired; this reflects “solid like” lung behavior (80). Thus, with dependent atelectasis, a deflection in Ppl near the diaphragm caused by spontaneous inspiratory effort will be poorly transmitted to the rest of the pleural space (81). In contrast, with positive-pressure ventilation and dependent atelectasis, dynamic changes in Paw will be greatest in the pleura around ventilated regions, but will not be effectively dissipated and not impact on venous pressure as effectively as with normal lungs.

The second link, Ppl is contiguous with the pericardial space (82); thus, an increase in Ppl increases CVP. Increased PEEP raises the mean systemic and the right atrial pressures to the same extent, thereby maintain an unchanged gradient for venous return (83). However, cyclic positive pressure reduces venous return, notwithstanding an unchanged mean Paw (84).

The third link, transmission of CVP to the internal jugular vein, is direct (85), but the vein can collapse and regulate an abrupt decrease in downstream pressure (CVP) from an accompanying increase in the gradient between CVP and the pressure in the internal jugular vein (e.g., negative-pressure ventilation, vigorous spontaneous breathing). By contrast, an increase in CVP can be transmitted to the internal jugular vein without being impeded by such an extracranial “waterfall” (85), provided any intracranial resistor is overcome (21 , 22).

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Impact of Concomitant Medical Management

A stepwise approach to escalating treatment intensity has evolved (86 , 87) and may impact the effects of mechanical ventilation. For example, sedation or barbiturate coma can induce a redistribution of intravascular volume and increase the risk of arterial hypotension due to vasodilatation. Hyperosmolar agents (e.g., mannitol) acutely increase intravascular volume, but subsequent diuresis causes hypovolemia, which can amplify the depressant effects of positive-pressure ventilation on hemodynamics and cerebral perfusion (88).

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Impact on Clinical Outcomes

Although associations between intermediate (patho)physiologic endpoints (e.g., ICP, CBF, PtiO2) and clinical outcomes (e.g., mortality, disability) have been shown (72 , 89), the impact of altered Paw on clinical outcomes is rarely investigated, probably because mechanical ventilation is a “support” rather than a therapy. In respiratory failure, mechanical ventilation is seen as a central modality, and studies in respiratory failure generally exclude patients with brain injury. However, a ventilation strategy that improves intermediate endpoints may facilitate optimal brain recovery and improve outcome.

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Management of Concomitant Acute Respiratory Distress Syndrome and Intracranial Hypertension

Favorable effects of PEEP must be balanced with impact on hemodynamics and cerebral perfusion. The impact of PEEP on ICP is lessened if lung compliance is low (Fig. 3). However, “trade off” of lung protection (permitting some hypercapnia) and brain protection (avoiding abrupt hypercapnia, sometimes rapidly inducing hypocapnia) need to be considered (Fig. S1, Supplemental Digital Content 1,; and legend, Supplemental Digital Content 2, With elevated PEEP, individual titration may be essential.

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Monitoring and Individualization

The effect of positive-pressure ventilation on ICP (and probably on cerebral perfusion and oxygenation) is determined by several factors including the nature of the lesion (e.g., traumatic brain injury, subarachnoid hemorrhage, thrombotic stroke) and concomitant conditions (e.g., coexisting acute respiratory distress syndrome [ARDS], septic shock), and adjunct therapies (Fig. S1, Supplemental Digital Content 1,; and legend, Supplemental Digital Content 2, Because of the “interdependence” among these parameters, no single value can be considered in isolation, and the net impact may be difficult to predict. Thus, individualized monitoring and titration is key.

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Negative-Pressure Ventilation

Negative intrathoracic pressure decreases the impedance to venous return, which may in turn decrease ICP. The increased venous return may increase cardiac output and potentially increase MAP, and the latter may increase cerebral perfusion (90–94).

Two types of negative thoracic pressure devices are described: the intrathoracic pressure regulator and the inspiratory impedance threshold device. These can decrease ICP in brain injury following experimental cardiac arrest (90–92). The regulator decreases ICP in an experimental brain injury (93) and in patients (94). However, the effect of negative thoracic pressure on cerebral oxygenation is unknown (94). Continuous negative abdominal pressure (CNAP) has been reported as an adjunct to conventional ventilation for intra-abdominal hypertension (95–97). Subsequently, different forms of CNAP have been shown to selectively recruit basal atelectasis, increase end-expiratory lung volume, and improve oxygenation (80 , 98–100). Although CNAP can decrease intra-abdominal and intrathoracic pressure, the overall impact of CNAP on ICP, and cerebral perfusion or oxygenation is not well studied. In experimental intra-abdominal hypertension, CNAP reduced both intra-abdominal pressure and ICP (97). Negative-pressure ventilation is not widely used, and experience is limited.

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Although the effect of positive Paw on ICP has been widely studied, it is poorly understood, especially in terms of regional cerebral oxygenation. Negative-pressure ventilation may decrease ICP and possibly increase cerebral perfusion and oxygenation, but the impact and determinants need to be better understood. Finally, the effects of Paw on the brain in patients with different mechanisms of (and therapies for) brain injury need individual design and assessment of long-term impact.

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The effect of Paw on ICP is determined by several factors, and the net impact may be unpredictable. In the face of competing mechanisms and a spectrum of priorities, individualized titration is required to optimize care, especially in patients with severe respiratory failure (e.g., ARDS).

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                                          cerebral oxygenation; cerebral perfusion; intracranial pressure; mechanical ventilation; negative-pressure ventilation; positive-pressure ventilation

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