Neural function is the essence of human existence. Thus, preventing the loss of any neural element is a major goal of perioperative anesthesia and critical care management. Intracranial pressure (ICP) can be a surrogate of secondary brain injury, as high ICP has been correlated with high mortality and poor neurological outcome.1 ICP monitoring and control have thus been the cornerstones of the neurocritical care management of brain-injured patients since the mid-20th century.2 However, interpretation of ICP is not straightforward as numerous disparate physiological processes may concurrently contribute to the observed numerical ICP value. Arguably, etiologic contributors to elevated ICP and its physiological consequences should be major factors in developing rational therapeutic strategies. Treatment strategies used in one cause of ICP elevation, for example hyperemia, may be ineffective or even harmful if applied in others, for example edema producing ischemia, or hydrocephalus. Although there are numerous published protocols and guidelines with respect to ICP management, they generally do not emphasize the multiple and dissimilar pathophysiological processes of intracranial hypertension which might enable a more individualized approach to its management.
This review outlines evidence for distinct conceptual subsets of intracranial hypertension with supportive data from published literature and invasive and noninvasive monitoring from the University of Pennsylvania Neurointensive Care Unit (neuroICU). The neuromonitoring modalities employed in the latter are summarized in the supplemental digital content (Supplemental Digital Content 1, http://links.lww.com/JNA/A129 Methods and IRB approval for neuromonitoring used in University of Pennsylvania neuroICU patients). We synthesize information from the literature and our patient-based observations in support of a conclusion that ICP elevations can have multiple distinct yet interacting pathophysiological subsets. Moreover, we suggest an unexplored and novel research area focused on examining outcomes of ICP management, based on consideration of disparate structural and physiological factors contributing to, and resulting from, elevated ICP.
PATHOPHYSIOLOGY OF INTRACRANIAL HYPERTENSION
More than 2 centuries ago, the Monro-Kellie doctrine characterized the cranial vault as a fixed space comprised of 3 components: blood, cerebrospinal fluid (CSF), and brain tissue. It defined that the sum of volumes of brain, CSF, and intracranial blood is constant and, therefore, that an increase in volume in one compartment results in a compensatory decrease in the volume of another. Initially, such volume increase results in only a small or imperceptible increase in ICP, likely due to compensatory mechanisms that include spinal dislocation of CSF or extracranial dislocation of cerebral venous blood. However, beyond a critical threshold of increased volume in any intracranial compartment, further small volume increases can result in an exponential increase in ICP, indicated on the steeper part of the pressure-volume curve (Supplemental Digital Content 2, http://links.lww.com/JNA/A130 Intracranial compliance curve). It is important to note that the proper physiological terminology for describing a change in pressure for a given change in volume is elastance, although compliance is the generally used term to describe intracranial dynamics, that is poor compliance indicating increased change in pressure for a given change in volume. Poor compliance is further manifest in changes in the ICP waveform (Supplemental Digital Content 3, http://links.lww.com/JNA/A131 ICP waveform changes with decrements in compliance).
Cerebral perfusion pressure (CPP) is the pressure gradient across the cerebrovascular bed that drives cerebral blood flow (CBF). It is generally calculated from the difference between mean arterial pressure (MAP) and ICP (or distal venous pressure if greater). Increases in ICP can decrease CPP, and therefore decrease CBF. If ICP increases to the level of critical closing pressure,3 CBF, ordinarily continuous throughout the cardiac cycle, becomes discontinuous and there is no flow during diastole. If ICP exceeds systolic blood pressure, intracranial circulatory arrest may occur4 (Supplemental Digital Content 4, http://links.lww.com/JNA/A132 Cerebral oligemia with decreased CPP). Moreover, ICP gradients can result in brain tissue shift or herniation, and arterial occlusion.
Pathophysiological Subsets of Intracranial Hypertension
Multiple disparate factors contribute to ICP elevations. This suggests that defining a taxonomy of ICP subsets may assist in framing the pathophysiology of ICP, and thus in focusing research efforts and devising appropriate therapy.
Abnormalities in ICP have a nonuniform genesis. In the context of abnormal intracranial compliance they are generally related to issues with cerebral blood volume, edema and masses, and CSF. The taxonomy of intracranial hypertension is summarized in Table 1. A more detailed description of this taxonomy (with an incomplete list of clinical examples) is provided below, and in subsequent sections of this review.
- Increased blood volume
- cerebral arterial hypervolemia
- ○ autoregulated active vasodilation
- ■ neural activation
- - rapid eye movement sleep
- - seizure
- - nociception
- - dysautonomia
- - fever
- - agitation/delirium
- ■ metabolic mediators
- - hypercapnia
- arterial hypercapnia
- - hypoglycemia
- - hypoxemia
- - anemia
- ■ decreasing blood pressure-related vasodilation
- ○ dysregulated passive arterial vasodilation
- ■ endothelial and blood-brain barrier injury (BBB)
- ■ liver failure
- ■ posterior reversible encephalopathysyndrome (PRES)
- ■ malignant hypertension
- ■ reperfusion hyperemia
- - postarteriovenous malformation resection
- - postcarotid endarterectomy or carotid stent
- - postendovascular thrombectomy
- - postglobal cerebral ischemia
- cerebral venous hypervolemia
- ○ starling resistor outflow obstruction
- ○ venous sinus obstruction
- ■ extrinsic compression
- ■ thrombosis
- ■ pseudotumor cerebri
- ○ very high extracranial venous pressure
- ■ very high intrathoracic pressure
- ■ superior vena cava syndrome
- ■ right heart failure or obstruction
- ■ digital jugular compression (Queckenstedtmaneuver)
- ■ Trendelenburg position
- Masses and edema
- brain tissue edema
- ○ vasogenic edema
- ■ trauma
- ■ unremitting hyperemia
- ■ tumors
- ■ BBB and blood-CSF barrier injury
- ■ inflammation
- ○ cytotoxic edema
- ■ postanoxic-ischemic disruption of ionic homeostasis
- ■ hyperammonemia
- ornithine transcarbamylase deficiency
- severe liver failure
- ■ reversal of osmolar gradients
- ■ idiogenic osmoles
- ■ inflammation
- ○ intracranial neoplasia
- ○ hematoma
- ■ intraparenchymal hemorrhage
- ■ subarachnoid hemorrhage
- ■ subdural hemorrhage
- ■ epidural hemorrhage
- Increased CSF volume
- ○ communicating
- ■ decreased CSF absorption
- ■ increased CSF production
- ○ noncommunicating
- ■ congenital abnormality
- ■ intraventicular hemorrhage
- ■ ventricular tumor or cyst
- ■ posterior fossa compression (tumor, edema, or hematoma)
- Idiopathic intracranial hypertension (IIH)
While these pathophysiological subsets provide a conceptual framework for approaching intracranial hypertension, it is important to be cognizant that the processes they describe seldom arise in isolation, but often in combination. For example, a hyperemic process may initially increase ICP but then contribute to subsequent edema or hemorrhage with further increases in ICP, but now with oligemia. A detailed description of these ICP subsets follows.
INCREASED BLOOD VOLUME
In the normal state, physiological increases in cerebral blood volume do not increase ICP because of the compensatory capacitive mechanisms of the intracranial compartment (Supplemental Digital Content 2, http://links.lww.com/JNA/A130 Intracranial compliance curve) (Supplemental Digital Content 3, http://links.lww.com/JNA/A131 ICP waveform changes with decrements in compliance) (Supplemental Digital Content 4, http://links.lww.com/JNA/A132 Cerebral oligemia with decreased CPP). However, with disturbed intracranial compliance, compensatory mechanisms are diminished and further small increases in the volume of any intracranial compartment then produces significant increases in ICP. Increased intravascular blood volume can be related to cerebral arterial and cerebral venous hypervolemia.
Cerebral Arterial Hypervolemia
Autoregulated Active Vasodilation
Autoregulation of CBF refers to the property of the brain to maintain relatively constant blood flow and oxygen supply in the face of changes in CPP, dynamically accommodating changes in both nutrient supply and cerebral metabolic requirements.5 In normotensive adults with intact autoregulation, CBF is maintained at a constant rate of about 50 mL/min/100 g when CPP varies within a classically described range of 50 to 150 mmH g. Notably, Drummond6 presents evidence and opinion suggesting that a lower limit of autoregulation of 70 mm Hg in healthy humans may be more appropriate.
The key mechanism of myogenic autoregulation is change in cerebrovascular resistance by vasoconstriction and vasodilation in response to changes in CPP. With intact autoregulation, when a decrement in CPP approaches the lower limit of autoregulation vasodilation occurs to maintain CBF but, as CPP decreases below the lower limit of autoregulation, maximum cerebral vasodilation arises. This initially associates with a proportional CBF decrement as oxygen extraction increases to meet metabolic demand as a secondary compensation. However, further CBF decrease produces anaerobic cerebral ischemia and, ultimately, infarction. Conversely, elevated CPP within the autoregulatory range induces cerebral vasoconstriction (Supplemental Digital Content 5, http://links.lww.com/JNA/A133 Autoregulation of cerebral blood flow).7,8 When autoregulation is intact, an increase in CPP above its upper limit produces dysregulated elevated CBF; this is discussed in more detail below. The following are examples where physiological autoregulatory vasodilation or hyperemia may contribute to intracranial hypertension.
Neural Activation. CBF is normally coupled to brain metabolism to ensure adequate nutrient and oxygen supply to support neural activity. Conditions of abnormally increased metabolic demand can increase CBF, with an ICP elevation if compliance is abnormal. These include increased ICP in response to rapid eye movement sleep,9 seizure,10 noxious stimuli (eg, suctioning, endotracheal intubation, and neurological assessments),11 lung recruitment maneuvers,12 fever,13 and paroxysmal sympathetic hyperactivity.14 Examples are presented in the supplemental digital content of cerebral hyperemic responses to laryngoscopy and paroxysmal sympathetic activity (Supplemental Digital Content 6, http://links.lww.com/JNA/A134 Hyperemic intracranial hypertension produced by laryngoscopy) (Supplemental Digital Content 7, http://links.lww.com/JNA/A135 Hyperemic intracranial hypertension produced by sympathetic storm).
Metabolic Mediators. Hypercapnia,15 hypoxemia,15 hypoglycemia,16 and anemia,17,18 are all normally associated with hyperemic responses linked to maintenance of nutrient supply and removal of waste products from the brain. This is best illustrated in the well-known relationships between CBF and PaO2 and PaCO2 (Supplemental Digital Content 8, http://links.lww.com/JNA/A136 PaO2 and PaCO2 alter CBF). These physiological responses to metabolic mediators associated with hyperemia are normally well tolerated, but can increase ICP in certain circumstances. An example of retained CO2 leading to hyperemia in a neuroICU patient is shown in the supplementary digital content (Supplemental Digital Content 9, http://links.lww.com/JNA/A137 Increase in CBF and PbO2 with increased CO2). In this example, induction of moderately increased PaCO2 through a decrease in minute ventilation increased CBF and brain tissue oxygen partial pressure; ICP was low before the CO2 increase and thus capacitive mechanisms averted a significant increase in ICP. Drugs that mimic these conditions, such as acute intravenous acetazolamide-induced tissue respiratory acidosis in a noncompliant brain, may also increase CBF19 with consequent hyperemia-related increases in ICP20 (Supplemental Digital Content 10, http://links.lww.com/JNA/A138 Increased ICP after acetazolamide injection).
Anemia (hemoglobin<9 g/dL) produces compensatory vasodilation and hyperemia in preclinical models as well as in humans (Supplemental Digital Content 11, http://links.lww.com/JNA/A139 Anemia induced cerebral hyperemia in rodents) (Supplemental Digital Content 12, http://links.lww.com/JNA/A140 Anemia induced cerebral hyperemia in humans),17,18 and has also been associated with increased ICP.21
Decreasing Blood Pressure-related Vasodilation. Lundberg22 monitored ICP in hundreds of patients, identifying characteristic pressure waves. One of these waves, termed A waves by Lundberg and later referred to as plateau waves (Supplemental Digital Content 13, http://links.lww.com/JNA/A141 Lundberg intracranial pressure waves) occurs when ICP abruptly increases to nearly systemic blood pressure levels for about 10 to 30 minutes, occasionally accompanied by neurological deterioration (Supplemental Digital Content 14, http://links.lww.com/JNA/A142 Plateau waves caused by decreased blood pressure). Rosner and Becker8 suggest that 2 concurrent conditions of exponential physiology produce plateau waves: (1) ICP at the steep portion of the exponential ICP-intracranial volume relationship (Supplemental Digital Content 2, http://links.lww.com/JNA/A130 Intracranial compliance curve), and (2) preserved autoregulation in some parts of the brain such that cerebral blood volume increases exponentially with CPP decrements (Supplemental Digital Content 15, http://links.lww.com/JNA/A143 Non-linear relationship of cerebral blood volume to blood pressure). This concurrent exponential physiology accounts for the abrupt and severe increase in ICP, which is characteristic of plateau waves. However, this “plateau wave physiology” likely also arises in less dramatic manner as an element of hypervolemic ICP elevation. We have observed this phenomenon of an apparent inverse relationship between MAP and ICP during continuous multimodality neuromonitoring in NeuroICU patients (Supplemental Digital Content 16, http://links.lww.com/JNA/A144 Plateau wave physiology in a neuroICU patient). Clearly, to develop plateau wave physiology there must be a significant portion of the brain with reactive vasculature, in the setting of an injured brain, with impaired compliance, as depicted in Figure 1 and the supplemental digital content (Supplemental Digital Content 17, http://links.lww.com/JNA/A145 Role of heterogeneous autoregulation in plateau wave and dysregulation physiology).
Dysregulated Passive Arterial Vasodilation
Primary CBF dysautoregulation with passive arterial vasodilation can arise secondary to a continuum of conditions associated with endothelial and BBB injury. Such conditions include significant brain injury (ischemic or traumatic),23 acute liver failure,24 hyperperfusion states such as malignant hypertension/PRES,25,26 arteriovenous malformation (AVM) resection with subsequent normal perfusion pressure breakthrough,27,28 and postcarotid endarterectomy29 or endovascular thrombectomy with successful restoration of CBF.30 In addition, secondary dysregulation can arise in extremes of hypercapnia, hypoxemia, anemia, hypotension, and hypoglycemia, by which brain edema may be exacerbated. In all of these cases of extreme vasodilation, CBF is expected to vary directly with systemic blood pressure.
Endothelial and BBB (and Blood-CSF) Injury. Endothelial damage and disrupted BBB can result in dilated poorly reactive vascular beds and capillary leakage, respectively. The endothelial dysfunction dysregulates CBF, which then varies in proportion to CPP with consequent increased blood volume and ICP31 (Supplemental Digital Content 18, http://links.lww.com/JNA/A146 ICP increases with hypertension in the injured brain) (Supplemental Digital Content 19, http://links.lww.com/JNA/A147 Loss of autoregulation with hyperemic intracranial hypertension). The injured BBB promotes hydrostatically driven perivascular and interstitial vasogenic brain edema,32 ultimately resulting in oligemia.32
Liver Failure. Aggarwal et al24 documented the time course of CBF and hyperemic ICP during the progression of liver failure from mild to severe. The natural history encompasses impaired autoregulation leading to an early phase of significant hyperemia, followed by brain hypoxia and cerebral edema.33 The latter can progress to cause malignant intracranial hypertension, oligemia, and eventually brain death. The root cause is believed to be dysregulated hyperemia, attenuation of which may delay or prevent consequent edema.34
PRES. The pathogenesis of PRES has not been fully elucidated but is believed to involve cerebral hyperemia due to dysregulated vasodilation as a result of blood pressure exceeding autoregulatory limits, as well as BBB dysfunction due to endothelial damage; both result in vasogenic edema.26 PRES has been associated with several conditions, most notably uncontrolled hypertension, eclampsia, and immunosuppressive therapy.26,35,36 The natural progression of PRES occasionally leads to severe diffuse brain edema with malignant intracranial hypertension, intracerebral hemorrhage, and death.36,37
Malignant Hypertension. The impact on the brain of malignant hypertension has been known for some time and is very similar to, or the same as, PRES. It likely represents the result of hypertension beyond the upper limit of autoregulation, the consequence of which is high pressure hyperemia.25 This can lead to pinocytotic fluid transfer, injury to the capillary bed, vasogenic edema, and intracranial hypertension,26 and, eventually, malignant cerebral edema and oligemia.25,38,39
Reperfusion Hyperemia. Several conditions of chronic or subacute ischemia or intracranial vascular hypotension with restoration of normal perfusion can produce a hyperemic state. This state can produce dysregulated vasodilation such that cerebral blood volume and ICP may vary directly with blood pressure. It can also create a potential for progression to BBB disruption, hemorrhage, intracranial hypertension and eventually, on a physiological continuum, to oligemia and ischemia. This clearly indicates the potential adverse effects of hyperemia in baseline normal brain, which is perhaps also relevant to hyperemia associated with liver failure, PRES, and malignant hypertension.
Chronically hypotensive territories adjacent to AVMs sustain leftward shift of the normal cerebral autoregulation curve. Resumption of normal perfusion pressure after AVM resection is therefore believed to exceed the upper limit of autoregulation. This is commonly called normal perfusion pressure breakthrough and is analogous to the physiology of hypertensive hyperemia, leading to vasogenic edema and intraparenchymal hemorrhage.27,28,40
In patients with chronic carotid arterial stenosis, CBF is maintained by maximal distal arteriolar vasodilation. During carotid endarterectomy, immediately after unclamping the repaired artery, regional hyperemia can overwhelm autoregulatory mechanisms in areas of reduced vasoreactivity, which may lead to BBB disruption and protracted hyperemia with edema and hemorrhage.29 This pathophysiology is supported by reports of attenuation of reperfusion-associated complications through strict control of arterial blood pressure during carotid surgery.29
In the context of acute stroke with ischemic compromise to the BBB and endothelium, reperfusion hyperemia and microvascular injury can occur after interventions to restore perfusion. The consequence is an increased risk of hemorrhagic transformation and cerebral edema, contributing to ICP elevation. Notably, lower blood pressure in a population study is associated with less hyperemia and intraparenchymal hemorrhage, although increased risk of ischemia,30 whereas high blood pressure is associated with more intraparenchymal hemorrhage and worse functional outcomes.41 An example of an immediate hyperemic response during endovascular thrombectomy is shown in the supplemental digital content (Supplemental Digital Content 20, http://links.lww.com/JNA/A148 Hyperemia with reperfusion after endovascular thrombectomy).
In summary, multiple reports clearly highlight that both regulated and dysregulated hyperemia can increase ICP. It thus appears that, depending on specific pathophysiology, both increasing and decreasing blood pressure can increase ICP in the appropriate clinical setting (Fig. 2) (Supplemental Digital Content 21, http://links.lww.com/JNA/A149 Hypervolemic intracranial hypertension with high and low blood pressure). In patients with both types of blood pressure-related hyperemia, this suggests the presence of an optimal CPP23 which might be considered as an element of hypervolemic ICP management strategy (Supplemental Digital Content 22, http://links.lww.com/JNA/A150 Bimodal ICP response to blood pressure).
Cerebral Venous Hypervolemia
Cerebral venous physiology is complex and incompletely understood. Nevertheless, an accepted notion is that increased cerebral venous or dural venous sinus pressures may increase brain tissue hydrostatic pressure and thereby contribute to vasogenic edema. Primary factors contributing to increased cerebral venous volume include functional Starling resistor type venous outflow obstruction, mechanical outflow obstruction, such as with venous thrombosis and very high extracranial venous pressure.
Starling Resistor Outflow Obstruction. The Starling resistor concept, sometimes referred to as vascular waterfall phenomenon or hydraulic hypothesis, describes the situation where external tissue pressure is greater than internal vascular pressure. In such a situation hollow tubes such as blood vessels collapse and flow then becomes dependent on the difference between proximal upstream pressure and distal external extravascular pressure at the point of constriction.
As suggested by Grande et al42 and Huseby et al,43 increased ICP, from whatever etiology, can also produce a direct Starling resistor (vascular waterfall) type of constriction of venous outflow at the level of the cerebral veins proximal to the dural sinuses. This venous obstruction produces an increase in internal venous pressure, which maintains vein patency such that flow continues. However, it also increases tissue hydrostatic pressure, which then presents the potential to produce or exacerbate cerebral edema which further increases ICP with a positive feedback cycle thus produced (Fig. 3) (Supplemental Digital Content 23, http://links.lww.com/JNA/A151 Mechanism of vasogenic edema from elevated ICP producing a venous outflow obstruction).42,44 This venous Starling resistor removes the effect on perfusion of distal downstream pressure (eg, sagittal sinus), as long as outflow internal vascular pressure remains less than (or equal to) external tissue pressure (or ICP).45–48 Notably, sagittal sinus pressure is thought to be generally unaffected by ICP because of the unyielding walls of the sinus, whereas the thin-walled cerebral veins and lacunae are affected by ICP.47
This presents 3 conceptual situations relating venous outflow and ICP as follows (Pcv, cerebral venous pressure; Pss, sagittal sinus pressure; →, vascular waterfall):
- Normal ICP-MAP>Pcv>ICP>Pss. There is no tissue compression of cerebral veins and perfusion pressure driving CBF is determined by MAP-Pss (Figs. 4A, 5A) (Supplemental Digital Content 24, http://links.lww.com/JNA/A152 Oligemic intracranial hypertension) (Supplemental Digital Content 25, http://links.lww.com/JNA/A153 Vasogenic edema from arterial and venous causes).
- Elevated ICP-MAP>Pcv=ICP→Pss. This arises in the Lund model42 where increased ICP and external tissue pressure increase Pcv to a level equivalent to ICP. This permits continued flow but at higher Pcv, with consequent increased tissue hydrostatic pressure. In this case, perfusion pressure driving CBF is MAP-ICP (or Pcv). Pss, consequent to the vascular waterfall, is removed from the equation (Figs. 3, 5C) (Supplemental Digital Content 23, http://links.lww.com/JNA/A151 Mechanism of vasogenic edema from elevated ICP producing a venous outflow obstruction) (Supplemental Digital Content 25, http://links.lww.com/JNA/A153 Vasogenic edema from arterial and venous causes).
- Infarction/brain death: MAP=Pcv=ICP→Pss. There is no pressure gradient to support perfusion and Pss consequent to the vascular waterfall is removed from the equation (Fig. 4B) (Supplemental Digital Content 24, http://links.lww.com/JNA/A152 Oligemic intracranial hypertension).
Venous Sinus Obstruction. One form of cerebral venous obstruction is believed to contribute to pseudotumor cerebri, or IIH. This is likely a mechanical venous constriction thought to contribute to the below-noted pathophysiology to increase ICP.49,50 IIH likely has other contributing factors and is described in more detail subsequently.
The other primary factor in venous sinus obstruction is thrombosis. Cerebral venous sinus thrombosis is the collective term for thrombosis of the cerebral dural sinuses and cerebral veins,51,52 and it can play a key role in the pathophysiology of intracranial hypertension. The physiology is complex and at least 4 interacting processes can be identified:
- Given that CSF reabsorption occurs at arachnoid granulations in the cerebral venous sinuses, thrombosis of dural sinuses can impair CSF reabsorption resulting in increased CSF volume. This can cause communicating hydrocephalus and increased ICP.
- Cerebral venous sinus thrombosis is believed to produce an increase in local venular and capillary pressures from venous outflow obstruction. This produces or exacerbates BBB disruption with consequent vasogenic edema and oligemia/ischemia.53,54
- Venular and capillary disruption can also result in intraparenchymal hemorrhage to increase ICP. If the hemorrhage includes the ventricular system, the process may be further complicated by noncommunicating hydrocephalus.
- Vasogenic edema with worsened intracranial hypertension can result in further venous outflow obstruction by a Starling resistor effect, further exacerbating the pathophysiological process.
Very High Extracranial Venous Pressure. Anything that increases venous pressure sufficient to fall within the range of ICP at the level of the cranium carries a theoretical risk of increased intracranial venous volume (Fig. 3) (Supplemental Digital Content 23, http://links.lww.com/JNA/A151 Mechanism of vasogenic edema from elevated ICP producing a venous outflow obstruction). Such situations may include high airway pressure, acute superior vena cava syndrome, right heart failure or obstruction, or Trendelenburg head-down position. The concept is dramatically demonstrated at the bedside where digital jugular compression (Queckenstedt maneuver) transiently increases ICP.55 A systematic overview of venous effects on ICP is provided by Wilson.56
Positive-end expiratory pressure (PEEP) has been reported to increase ICP57 and this effect is often presumed to be related to venous outflow obstruction secondary to PEEP-related increased intrathoracic pressure. However, hydrostatically this can only arise when PEEP is very high and pulmonary compliance is sufficiently high to allow transmission of the PEEP to the intrathoracic vasculature.58 Moreover, the increase in extracranial venous pressure must exceed ICP in order to impact intracranial venous outflow. Thus, an ICP of 20 mm Hg would mandate a PEEP-mediated increase in extracranial venous pressure of >20 mm Hg (~26 cm H2O) in order to impact on ICP. Such high levels of PEEP are typically used only in the context of very low pulmonary compliance, in which case the airway pressure is not fully transmitted to the intrathoracic vasculature.58 Further, the general situation of head-of-bed elevation would mandate even higher venous pressure in the thorax in order to affect intracranial venous blood volume. Thus, simple hydrostatic considerations suggest a minimal effect of PEEP when ICP is low, and a negligible effect when ICP is high, reflecting the notion that PEEP-mediated increase in extracranial venous outflow pressure must exceed ICP in order to increase ICP.43 Nonetheless ICP has been noted to increase with application of PEEP in clinical situations.57 A synthesis of the literature leads to the conclusion that this is most likely a plateau wave type physiology, wherein PEEP produces a decrement in blood pressure which then produces compensatory cerebral arterial dilation in normally autoregulating cerebral vasculature (Supplemental Digital Content 14, http://links.lww.com/JNA/A142 Plateau waves caused by decreased blood pressure) (Supplemental Digital Content 15, http://links.lww.com/JNA/A143 Non-linear relationship of cerebral blood volume to blood pressure) (Supplemental Digital Content 16, http://links.lww.com/JNA/A144 Plateau wave physiology in a neuroICU patient).
MASSES AND EDEMA
Increased intracranial tissue or extravascular blood volume are important causes of intracranial hypertension. In contrast to increased intravascular blood volume subsets of elevated ICP, masses and edema can directly produce oligemic intracranial hypertension and have immediate deleterious effects. The continuum of progressively decreased CPP from mass or edema producing oligemia observed with transcranial Doppler is illustrated in the supplemental digital content (Supplemental Digital Content 4, http://links.lww.com/JNA/A132 Cerebral oligemia with decreased CPP). The 3 major causes of this situation are edema, and masses due to neoplasia or hemorrhage.
Brain Tissue Edema
Diffuse brain tissue edema is an important cause of intracranial hypertension and is commonly entwined with other causes of increased ICP. Brain tissue edema can produce severe oligemia as depicted in neuroICU patient neuromonitoring data, where a progressive rise in ICP postischemia is accompanied by a decrease in CBF in progression to brain death (Fig. 4) (Supplemental Digital Content 24, http://links.lww.com/JNA/A152 Oligemic intracranial hypertension) (Supplemental Digital Content 26, http://links.lww.com/JNA/A154 Oligemic intracranial hypertension progressing to brain death). Brain edema is an abnormal accumulation of fluid within the brain parenchyma and is subdivided into 2 major categories—vasogenic and cytotoxic edema.59–61 Notably, both types of edema may arise concurrently.
Vasogenic edema encompasses conditions associated with BBB breakdown, allowing movement of intravascular proteins, solutes, and water through the damaged microvascular endothelial cells into the extracellular space. Etiologies of vasogenic edema are numerous and include traumatic brain injury, brain tumor, radiation necrosis, acute demyelination, dysregulated hyperemia, venous obstruction, and inflammatory/infectious processes (Fig. 5) (Supplemental Digital Content 25, http://links.lww.com/JNA/A153 Vasogenic edema from arterial and venous causes). In addition, vasogenic edema arises with increased blood pressure in the context of BBB and vascular injury. Moreover, as discussed above, intracranial hypertension from any cause with associated venous obstruction and increased tissue hydrostatic pressure promotes yet another type of vasogenic edema (Fig. 5) (Supplemental Digital Content 25, http://links.lww.com/JNA/A153 Vasogenic edema from arterial and venous causes). When brain edema overcomes the compensatory mechanisms, ICP, following an exponential relationship with volume of an intracranial compartment, can increase dramatically resulting in compromise of CBF with widespread ischemia or in herniation4,62,63 (Fig. 4) (Supplemental Digital Content 24, http://links.lww.com/JNA/A152 Oligemic intracranial hypertension) (Supplemental Digital Content 26, http://links.lww.com/JNA/A154 Oligemic intracranial hypertension progressing to brain death).
Causes of cytotoxic edema include hypoxic-ischemic brain injury, traumatic brain injury, central nervous system infections, drug overdoses, renal and liver failure, spreading depolarization,64 ornithine transcarbamylase deficiency,65 and osmolar gradient syndromes as may be seen with hyperglycemia and hyponatremia. In such insults, processes arise to cause intracellular fluid translocation. In the case of hypoxia-ischemia, a primary insult leads to failure of ATP-dependent sodium-potassium and calcium pumps resulting in intracellular sodium (or other metabolite) accumulation, an osmotic gradient, fluid shift from extracellular to intracellular compartments, and eventual cellular swelling. Other syndromes may increase different intracellular osmoles to produce the same effect. Calcium can also accumulate within the cell, triggering an inflammatory cascade that recruits microglia and leads to free radical formation that ultimately results in the destruction of the BBB and concurrent vasogenic edema.59–61
Pathologic intracranial masses can increase ICP, eventually culminating in oligemia. Masses can be in the form of hematoma or neoplasm and, in both instances, the more rapid the growth of said mass, the more acute and profound the rise in ICP. Several types of hematomas can arise: intraparenchymal, subarachnoid, subdural, and epidural. Each hematoma and tumor type has unique characteristics, a detailed description of which is beyond the scope of this review.
INCREASED CSF VOLUME
Over a century ago, Dandy proposed the classic hypothesis of CSF hydrodynamics.66,67 In brief, CSF is produced mainly by epithelial cells of the choroid plexus lining the cerebral ventricles using active transport, largely dependent on the enzyme carbonic anhydrase. CSF then circulates unidirectionally through the ventricular system, from the lateral ventricles to the foramen of Monro, into the third ventricle, aqueduct of Sylvius, the fourth ventricle, and finally exiting into the spinal subarachnoid space through the foramina of Luschka and Magendie. The spinal subarachnoid space is in direct communication with the intracranial subarachnoid space from where CSF is passively absorbed down a pressure gradient through the arachnoid villi of dural venous sinuses into venous sinuses. In order for this process to occur, CSF pressure must exceed sagittal sinus venous pressure.68,69 From the venous sinuses, CSF eventually enters into the systemic venous circulation. This classic description of CSF dynamics has recently been enhanced to incorporate the glymphatic system, a perivascular intraparenchymal pathway for CSF egress from the brain.70
Hydrocephalus is a disruption of CSF formation, flow, or absorption characterized by excessive accumulation of CSF within the cerebral ventricular system and/or subarachnoid space. Regardless of cause, this can result in ventriculomegaly and intracranial hypertension. Hydrocephalus was historically classified by Dandy into 2 types-communicating and noncommunicating (Supplemental Digital Content 27, http://links.lww.com/JNA/A155 Hydrocephalus). Communicating hydrocephalus occurs due to excess CSF production or, more commonly, ineffective CSF absorption. For example, it can be a result of scarring or fibrosis in the subarachnoid space after infection, inflammation, or hemorrhage. Noncommunicating hydrocephalus, on the other hand, occurs from obstruction of CSF flow within the ventricular system or its outlets, resulting in dilation of the ventricular system proximal to the point of obstruction.71 A role for the glymphatic system has been proposed for normal pressure hydrocephalus,70 but any role in other hydrocephalus types is not yet established.
The exact pathophysiology of intracranial hypertension in IIH remains unknown. Hence it does not fit neatly into the taxonomic categories described above, although many aspects of IIH cut across them. Proposed mechanisms include excess CSF production, reduced CSF absorption, CSF outflow obstruction, increased brain tissue water content, and abnormalities of vitamin A metabolism.72 It is also proposed that any mechanistic theory for IIH must account for its epidemiologic predilection for obese young females. Cerebral venous sinus stenosis is identified in a majority of IIH patients, raising the possibility of a causal contribution.49,50 Given the limited understanding of its pathophysiology, management strategies for IIH focus on treatment of raised ICP with carbonic anhydrase inhibitors, alleviation of symptoms of raised ICP such as headaches and vision loss, and targeting potential contributing factors such as obesity. Although there is no unifying hypothesis for IIH, future clinical trials will hopefully add to the existing knowledge of its pathophysiology.
CONCLUSIONS: SUBSET ORIENTED TREATMENT OF INTRACRANIAL HYPERTENSION
In this review we describe a physiological taxonomy of intracranial hypertension and thereby illuminate the notion of several physiological subsets contributing to raised ICP. Our review creates a tempting speculation that consideration of these various etiologies of intracranial hypertension may support focused and individualized diagnostic and therapeutic maneuvers which otherwise might not be considered. Some examples can be entertained. Diagnosis of intracranial hypertension with autoregulated hyperemia would support the use of hyperventilation, whereas dysregulated hyperemia would support aggressive blood pressure management. Oligemia as the cause of raised ICP would support osmotherapy or surgical decompression, but increased CSF volume warrants treatment with CSF diversion by ventriculostomy. We suggest that future research in ICP management should incorporate these concepts of ICP subsets to thereby decrease patient heterogeneity and lessen the likelihood of inconclusive results.
1. Miller JD, Becker DP, Ward JD, et al. Significance of intracranial hypertension in severe head injury. J Neurosurg. 1977;47:503–516.
2. Schnitzer MS, Aschoff AA, Hacke WHacke W, Hanley DF, Einhaupl KM. Intracranial pressure
monitoring. Neurocritical Care. Berlin, Heidelberg: Springer; 1994:90–97.
3. Dewey R, Pieper H, Hunt W. Experimental cerebral hemodynamics. Vasomotor tone, critical closing pressure, and vascular bed resistance. J Neurosurg. 1974;41:597–606.
4. Hassler W, Steinmetz H, Gawlowski J. Transcranial Doppler ultrasonography in raised intracranial pressure
and in intracranial circulatory arrest. J Neurosurg. 1988;68:745–751.
5. Aaslid R, Lindegaard KF, Sorteberg W, et al. Cerebral autoregulation
dynamics in humans. Stroke. 1989;20:45–52.
6. Drummond JC. The lower limit of autoregulation: time to revise our thinking? Anesthesiology. 1997;86:1431–1433.
7. Risberg J, Lundberg N, Ingvar DH. Regional cerebral blood volume
during acute transient rises of the intracranial pressure
(plateau waves). J Neurosurg. 1969;31:303–310.
8. Rosner MJ, Becker DP. Origin and evolution of plateau waves. Experimental observations and a theoretical model. J Neurosurg. 1984;60:312–324.
9. Pierre Kahn A, Gabersek V, Hirsch JF. Intracranial pressure
and rapid eye movement sleep in hydrocephalus
. Child’s Brain. 1976;2:156–166.
10. Solheim O, Vik A, Gulati S, et al. Rapid and severe rise in static and pulsatile intracranial pressures during a generalized epileptic seizure. Seizure. 2008;17:740–743.
11. Burney RG, Winn R. Increased cerebrospinal fluid pressure during laryngoscopy and intubation for induction of anesthesia. Anesth Anal. 1975;54:687–690.
12. Bein T, Kuhr LP, Bele S, et al. Lung recruitment maneuver in patients with cerebral injury: effects on intracranial pressure
and cerebral metabolism. Intensive Care Med. 2002;28:554–558.
13. Nyholm L, Howells T, Lewén A, et al. The influence of hyperthermia on intracranial pressure
, cerebral oximetry and cerebral metabolism in traumatic brain injury. Upsala J Med Sci. 2017;122:177–184.
14. Klug N, Hoffmann O, Zierski J, et al. Decerebrate rigidity and vegetative signs in the acute midbrain syndrome with special regard to motor activity and intracranial pressure
. Acta Neurochir. 1984;72:219–233.
15. Sakabe T, SiesjÖ BK. The effect of indomethacin on the blood flow—metabolism couple in the brain under normal, hypercapnic and hypoxic conditions. Acta Physiol Scand. 1979;107:283–284.
16. Arbeláez AM, Su Y, Thomas JB, et al. Comparison of regional cerebral blood flow
responses to hypoglycemia using pulsed arterial spin labeling and positron emission tomography. PLoS One. 2013;8:e60085.
17. Borgstrom L, Johannsson H, Siesjo B. The influence of acute normovolemic anemia on cerebral blood flow
and oxygen consumption of anesthetized rats. Acta Physiol Scand. 1975;93:505–514.
18. Floyd T, McGarvey M, Ochroch E, et al. Perioperative changes in cerebral blood flow
after cardiac surgery: influence of anemia and aging. Ann Thoracic Surg. 2003;76:2037–2042.
19. Pindzola RR, Balzer JR, Nemoto EM, et al. Cerebrovascular reserve in patients with carotid occlusive disease assessed by stable xenon-enhanced ct cerebral blood flow
and transcranial Doppler. Stroke. 2001;32:1811–1817.
20. Holl K, Heissler HE, Nemati N, et al. Effect of acetazolamide-induced endogenous volume pressure testing of the cerebrospinal system on intracranial pressure
. Effect of Diamox® on intracranial pressure
(ICP). Neurochirurgia. 1990;33:29–36.
21. Mollan SP, Ball AK, Sinclair AJ, et al. Idiopathic intracranial hypertension associated with iron deficiency anaemia: a lesson for management. Eur Neurol. 2009;62:105–108.
22. Lundberg N. Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Acta Psychiatr Scand Suppl. 1960;36:1–193.
23. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med. 2002;30:733–738.
24. Aggarwal S, Obrist W, Yonas H, et al. Cerebral hemodynamic and metabolic profiles in fulminant hepatic failure: relationship to outcome. Liver Transpl. 2005;11:1353–1360.
25. Skinhoj E. On the pathogenesis of hypertensive encephalopathy as revealed by cerebral blood flow
studies in man. Prog Brain Res. 1977;47:235–243.
26. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29:1043–1049.
27. Batjer HH, Devous MD Sr, Meyer YJ, et al. Cerebrovascular hemodynamics in arteriovenous malformation complicated by normal perfusion pressure breakthrough. Neurosurgery. 1988;22:503–509.
28. Spetzler R, Wilson C, Weinstein P, et al. Normal perfusion pressure breakthrough theory. Clin Neurosurg. 1978;25:651–672.
29. Bouri S, Thapar A, Shalhoub J, et al. Hypertension and the post-carotid endarterectomy cerebral hyperperfusion syndrome. Eur J Vasc Endovasc Surg. 2011;41:229–237.
30. Goyal N, Tsivgoulis G, Pandhi A, et al. Blood pressure levels post mechanical thrombectomy and outcomes in large vessel occlusion strokes. Neurology. 2017;89:540–547.
31. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation
. Cerebrovasc Brain Metab Rev. 1990;2:161–192.
32. Kinoshita K. Traumatic brain injury: pathophysiology for neurocritical care. J Intensive Care. 2016;4:29.
33. Larsen FS, Knudsen GM, Hansen BA. Pathophysiological changes in cerebral circulation, oxidative metabolism and blood-brain barrier in patients with acute liver failure: tailored cerebral oxygen utilization. J Hepatol. 1997;27:231–238.
34. Larsen FS, Wendon J. Brain edema
in liver failure: basic physiologic principles and management. Liver Transpl. 2002;8:983–989.
35. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. New Engl J Med. 1996;334:494–500.
36. Facchini A, Magnoni S, Civelli V, et al. Refractory intracranial hypertension in posterior reversible encephalopathy syndrome. Neurocrit Care. 2013;19:376–380.
37. Liman TG, Bohner G, Heuschmann PU, et al. The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES study. J Neurol. 2012;259:155–164.
38. Katsumata Y, Maehara T, Noda M, et al. Hypertensive encephalopathy: reversible CT and MR appearance. Radiat Med. 1993;11:160–163.
39. Skinhoj E, Strandgaard S. Pathogenesis of hypertensive encephalopathy. Lancet. 1973;1:461–462.
40. Ogasawara K, Yoshida K, Otawara Y, et al. Cerebral blood flow
imaging in arteriovenous malformation complicated by normal perfusion pressure breakthrough. Surg Neurol. 2001;56:380–384.
41. Mistry EA, Mistry AM, Nakawah MO, et al. Systolic blood pressure within 24 hours after thrombectomy for acute ischemic stroke correlates with outcome. J Am Heart Assoc. 2017. Doi: 10.1161/JAHA.117.006167.
42. Grande P, Asgeirsson B, Nordstrom C. Volume-targeted therapy of increased intracranial pressure
: the Lund concept unifies surgical and non-surgical treatments. Acta Anaesth Scand. 2002;46:929–941.
43. Huseby J, Luce J, Cary J, et al. Effects of positive end-expiratory pressure on intracranial pressure
in dogs with intracranial hypertension. J Neurosurg. 1981;55:704–705.
44. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513–538.
45. Permutt S, Riley RL. Hemodynamics of collapsible vessels with tone: the vascular waterfall. J Appl Physiol. 1963;18:924–932.
46. Ursino M, Lodi CA. A simple mathematical model of the interaction between intracranial pressure
and cerebral hemodynamics. J Appl Physiol. 1997;82:1256–1259.
47. Schaller B. Physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. Brain Res Rev. 2004;46:243–260.
48. Luce JM, Huseby J, Kirk W, et al. A Starling resistor regulates cerebral venous outflow in dogs. J Appl Physiol. 1982;53:1496–1503.
49. Owler BK, Parker G, Halmagyi GM, et al. Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg. 2003;98:1045–1055.
50. Stienen A, Weinzierl M, Ludolph A, et al. Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension. Eur J Neurol. 2008;15:1416–1418.
51. Ferro JM, Canhao P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664–670.
52. Saposnik G, Barinagarrementeria F, Brown RD Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158–1192.
53. Piazza G. Cerebral venous thrombosis. Circulation. 2012;125:1704–1709.
54. Itrat A, Shoukat S, Kamal AK. Pathophysiology of cerebral venous thrombosis—an overview. J Pak Med Assoc. 2006;56:506–508.
55. Pearce JMS. Queckenstedt’s manoeuvre. J Neurol Neurosurg Psychiatry. 2006;77:728.
56. Wilson MH. Monro-Kellie 2.0: The dynamic vascular and venous pathophysiological components of intracranial pressure
. J Cereb Blood Flow Metab. 2016;36:1338–1350.
57. Shapiro H, Marshall L. Intracranial pressure
responses to PEEP in head-injured patients. J Trauma. 1978;18:254–256.
58. Suter PM, Fairley HB, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. New Engl J Med. 1975;292:284–289.
59. Unterberg AW, Stover J, Kress B, et al. Edema and brain trauma. Neuroscience. 2004;129:1021–1029.
60. Klatzo I. Pathophysiological aspects of brain edema
. Acta Neuropathol. 1987;72:236–239.
61. Klatzo I. Evolution of brain edema
concepts. Acta Neruochir. 1994;60:3–6.
62. Schnitzer MS, Aschoff AA, Hacke W. Intracranial Pressure
Monitoring. Berlin Heidelberg: Springer; 1994.
63. Jha SK. Cerebral edema and its management. Med J Armed Forces India. 2003;59:326–331.
64. Dreier JP, Lemale CL, Kola V, et al. Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology. 2018;134:189–207.
65. Wendell LC, Khan A, Raser J, et al. Successful management of refractory intracranial hypertension from acute hyperammonemic encephalopathy in a woman with ornithine transcarbamylase deficiency. Neurocrit Care. 2010;13:113–117.
66. Dandy WE, Blackfan KD. An experimental and clinical study of internal hydrocephalus
. J Am Med Assoc. 1913;61:2216–2217.
67. Cushing H. Studies on the cerebrospinal fluid. J Med Res. 1914;31:1–19.
68. Weed LH. Forces concerned in the absorption of the cerebrospinal fluid. Am J Physiol. 1935;114:40–45.
69. Oreskovic D, Klarica M. The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations. Brain Res Rev. 2010;64:241–262.
70. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018;17:1016–1024.
71. Oreskovic D, Klarica M. Development of hydrocephalus
and classical hypothesis of cerebrospinal fluid hydrodynamics: facts and illusions. Prog Neurobiol. 2011;94:238–258.
72. Tabassi A, Salmasi AH, Jalali M. Serum and CSF vitamin A concentrations in idiopathic intracranial hypertension. Neurology. 2005;64:1893–1896.