Hyperventilation therapy for control of posttraumatic intracranial hypertension

Introduction

Intracranial hypertension [IH] is a common clinical problem in the intensive care unit [ICU], which requires immediate and urgent treatment. IH is the result of either primary central nervous system [CNS] lesion or a complication of co-existing systemic disease. It is caused by a variety of conditions divided into five main categories based on their pathological mechanism [Table 1]. Any condition affecting the CNS, defined as acute brain injury [ABI] [[e.g. traumatic brain injury [TBI]], has two components: primary brain injury that cannot be reversed and secondary brain injury [SBI]. SBI is defined as any physiological event that can occur within minutes, hours, or days after the initial injury and leads to further damage of nervous tissue. It can be detected through clinical examination and intracranial pressure [ICP] monitoring, as it is mostly due to increased ICP, and confirmed by imaging tests. Since there is a causal relationship between primary brain injury, IH, and SBI [Fig. 1], we focus on IH in this article. We conducted a literature search on MEDLINE/PubMed and Cochrane Library for studies completed in the last twenty years using the terms "intracranial hypertension" and "ICU management". We have also included guidelines from all established societies regarding IH in ABI [TBI, intracerebral hemorrhage [ICH], aneurysmal subarachnoid hemorrhage [SAH], ischemic stroke] and its management in ICU. The aim of this review article is to provide basic knowledge updated with what's new in the literature regarding the management of patient with IH.

Table 1 Causes of intracranial hypertension based on their pathological mechanism

Full size table

Fig. 1

Causal relationship between primary brain injury, intracranial hypertension and secondary brain injury

Full size image

Clinical presentation of IH

The clinical manifestations of IH are nonspecific and their severity does not correlate with the degree of IH [Table 2]. The comatose patient with ABI and possible IH should be clinically evaluated using routinely either the Glasgow coma scale [GCS] [combined with assessment of pupils] or the full outline of unresponsiveness [FOUR] score, as multimodality monitoring [MMM] consensus recommend [1]. Brain herniation is a potentially fatal complication of IH. There are six types of herniation, namely the uncal transtentorial, the central transtentorial, the subfalcine, the tonsilar, the ascending transtentorial and the transcalvarial herniation [Fig. 2].

Table 2 Clinical manifestations of intracranial hypertension

Full size table

Fig. 2

Types of brain herniation. ACA: Anterior cerebral artery, PCA: Posterior cerebral artery

Full size image

ICP monitoring

In clinical practice, invasive and non-invasive methods of ICP monitoring are used aiming to determine the optimal cerebral perfusion pressure [CPP].

Invasive ICP monitoring

IH is associated with poor outcome and particularly with increased mortality [2], so it seems reasonable to measure ICP. The latest guidelines [3] recommend management of severe TBI patients using information from ICP monitoring to reduce in-hospital and 2-week post-injury mortality. It is difficult to demonstrate a direct association between specific monitoring and outcome improvement. Indeed, in a randomized trial [4] involving patients with severe TBI, ICP-guided therapy was not shown to be superior to care based on imaging and clinical examination. Recent studies [5,6,7] have also yielded conflicting results. Invasive ICP measurement is performed by specific catheters, inserted into the intraventricular, intraparenchymal, epidural, subdural or subarachnoid space [8]. The ideal ICP monitoring device should be reliable, accurate, cost-effective and be associated with minimal morbidity. Today, the intraventricular catheter remains the most reliable method [gold standard] for ICP monitoring, as it measures global ICP, provided that no obstruction of CSF flow occurs. The main features of ICP monitoring catheters are shown in Table 3. Recently, the intraparenchymal catheters used for ICP monitoring have integrated a CSF drainage catheter and catheters that detect parameters, such as brain tissue O2 partial pressure [PbtO2] and cerebral blood flow [CBF]. Epidural, subdural and subarachnoid catheters are less accurate and are therefore rarely used.

Table 3 Main features of ICP monitoring catheters

Full size table

Non-invasive ICP monitoring

No method of non-invasive ICP monitoring can replace invasive monitoring, but may be useful either as a complementary tool or in deciding whether to initiate invasive monitoring.

Brain computed tomography [CT]

CT evaluates rapidly the presence of specific findings that enhance the diagnosis of ΙΗ. These include mass effect, midline shift, cerebral edema, hydrocephalus, compression of basal cisterns and changes in grey-white matter differentiation.

Brain magnetic resonance imaging [MRI]

MRI shows in more detail soft tissue and cerebral parenchymal lesions, which may not have been detected on CT, e.g. diffuse axonal injury. However, the prolonged screening time and stay of the patient in the supine position, which may aggravate ICP, make its use limited to patients with suspected IH.

Transcranial Doppler [TCD] ultrasonography

TCD is a useful, bedside, non-invasive technique for detecting inadequate CBF and assessing cerebral autoregulation. It may indicate the need for invasive brain monitoring and direct treatment in a multifactorial multimodal neuromonitoring approach [9]. TCD detects blood flow velocity [FV] through the major intracranial vessels, most commonly the middle cerebral artery [MCA]. In cases of elevated ICP, the external pressure in the cerebral vessels increases, which is reflected by changes in FV. Detection of reduced FV indicates impediment to CBF and indirectly increased ICP. Besides the mean FV, pulsatility index [PI] and slopes of the TCD waveforms have been correlated with ICP [10,11,12,13]. It has been found that PI changes in the MCA are associated with changes in ICP, when the latter is between 5–40 mmHg. However, the accuracy of the technique depends on the experience of the operator and, in addition, 10–15% of the patients do not have adequate bone window.

Optic Nerve Sheath Diameter [ONSD]

The space between the optic nerve and its sheath is filled with CSF and therefore its pressure equals ICP. Thus, ONSD measured using a transocular ultrasound is increased in patients with IH. Several studies have shown that ONSD > 5 mm corresponds to ICP ≥ 20 mmHg [14, 15]. However, this association may be affected by conditions, such as tumors, inflammation, Grave’s disease and sarcoidosis, which may alter ONSD. The ONSD measurement technique is cheap, efficient and non-time consuming, but operator dependent [10].

Tympanic membrane displacement [TMD]

Because of the CSF and perilymph communication through the cochlear aqueduct, an increase in ICP is directly transmitted to the footplate of the stapes, displacing the tympanic membrane from its initial position. Inwards displacement indicates high, and outwards normal or low ICP [16]. However, this technique lacks accuracy and is an unreliable method of quantitative assessment of ICP in clinical practice.

Non-invasive methods of ICP monitoring and their basic characteristics are listed in Table 4.

Table 4 Non-invasive methods of ICP monitoring

Full size table

Additional tools in ICP monitoring

Advance in understanding the pathophysiology of ABI has led to the development of various diagnostic tools that provide additional information on the adequacy of cerebral perfusion and extent of injury.

Brain tissue O2 partial pressure [PbtO2]

Measurement of PbtO2 by inserting a microcatheter in the white matter allows to unmask reduced perfusion and insufficient oxygen supply [ 30 mmHg]. However, the measurement is regional, as only approximately 15 mm2 of tissue around the tip is sampled [8]. Current MMM consensus consider PbtO2 of less than 20 mmHg as threshold to consider intervention [1]. Studies have shown that low PbtO2 can be observed in combination with either high or low ICP [17], which enhances the value of brain oxygen monitoring. Thus, MMM consensus suggest its use to assist titration of medical and surgical therapies to guide ICP/CPP therapy, identify refractory IH and treatment thresholds, help manage delayed cerebral ischemia [DCI], and select patients for second-tier therapy [1]. Finally, a tendency to better outcomes with combined PbtO2 and ICP/CPP therapy compared to ICP/CPP therapy alone has been shown in severe TBI [18].

Jugular venous oxygen saturation [SjvO2]

Measurement of SjvO2 by a catheter placed in the jugular bulb could be used to estimate the balance between cerebral oxygen delivery and demand. SjvO2 differentiates insufficient oxygen supply due to impaired cerebral perfusion [SjvO2  80%]. Increased ICP is mainly associated with reduced SjvO2 [18]. It could be part of MMM or be used in conjunction with ICP monitoring. but it is more difficult to use and less reliable than PbtO2 monitoring [1]. Due to the inherent shortcomings of the method, it can only provide information about global metabolism and its use has been limited [8].

Cerebral microdialysis

Cerebral microdialysis allows for semi-continuous measurement at the bedside of numerous parameters including glucose, glutamate, lactate, pyruvate, and glycerol concentrations. Metabolic changes of these parameters may occur before the usual cerebral physiological or pathophysiological changes [19], namely when ICP is normal. These changes may precede the clinical features of DCI and IH [20], allowing earlier therapeutic adjustments. In addition, derangements in cerebral metabolism detected by microdialysis can reveal the extent of the deleterious effect of IH on the brain [20]. However, microdialysis cannot be widely implemented yet due to its time-consuming maintenance and additional costs.

Near infrared spectroscopy [NIRS]

NIRS is a noninvasive tool that measures cerebral oxygenation by detecting oxygenated to deoxygenated hemoglobin concentrations. However, its use is limited in clinical practice since to date there are no studies to establish an absolute threshold for cerebral hypoxia and conditions such as scalp swelling and epidural/subdural hematomas lead to unreliable measurements [21].

Continuous electroencephalography [cEEG]

The use of cEEG is indicated in detection of convulsive and non‑convulsive seizures and prognosis of coma. Moreover, cEEG can be used in cases of increased ICP, as it is affected by changes in cerebral metabolism [22]. EEG patterns associated with elevated ICP include focal slowing of underlying rhythms or global EEG suppression progressing to burst suppression or flat EEG [23]. At the same time cEEG is a remarkably sensitive tool for detection of cerebral ischemia since it can reveal changes in neuronal function before structural damage. This is due to its high sensitivity to detect changes in CBF [24, 25]. Finally, cEEG can help predict outcome and titrate treatments such as barbiturates [26].

Management of IH

Progress in monitoring and understanding the pathophysiological mechanisms of IH allows the implementation of targeted interventions in order to improve the outcome of these patients. In the ICU all efforts should focus on preventing SBI although management of the primary cause of IH is the basic initial approach.

Prevention, detection and treatment of SBI are priorities of paramount importance for the clinical outcomes of patients. Several molecular and cellular pathways [27, 28] are activated in SBI. Thus, changes in ionic permeability, release of excitatory neurotransmitters and increased free radical accumulation cause mitochondrial dysfunction, which further triggers energy defects and processes of necrosis and apoptosis. These molecular and cellular changes could lead to the development of cytotoxic or vasogenic brain edema and disturbed autoregulation, resulting in an increase in the volume of intracranial components due to vasodilation or water accumulation, or both [29]. SBI is predictable and treatable and may be the result of extracranial [e.g. hypoxia, hypercapnia, arterial hypotension, fever] or intracranial [e.g. hematomas, contusions, seizures] factors [Table 5]. Indeed, hypoxia and arterial hypotension trigger the systemic inflammatory response syndrome [SIRS], which may further aggravate the development of secondary damage [30]. Trauma affects the blood–brain barrier [BBB] directly, with increased permeability, favoring vasogenic edema formation and activation of a proinflammatory state [31]. Seizures may aggravate the imbalance between energy expenditure and supply [32]. The control of all these variables has been shown to improve both neurological and functional outcomes of patients [33].

Table 5 Causes of secondary brain injury

Full size table

Pathophysiologically, the management of raised ICP focuses on four main axes:

• control and manipulation of vasoreactivity, CBF and flow-metabolism coupling

• managing the blood/brain osmotic gradient

• reducing the metabolic rate of oxygen consumption of cerebral tissue

• physical/surgical modalities which affect intracranial compliance

According to the last guidelines for TBI [3], the primary goal of IH treatment is to maintain ICP below 22 mmHg and CPP above 60 mmHg. Achieving these goals could be life-saving for brain's viability. The therapeutic measures for IH are distinguished in general prophylactic measures and those applied in the acute phase, in order to urgently reduce ICP and optimize CPP. All these interventions should be applied with a staircase approach tailored for each patient, as detailed below [Fig. 3].

Fig. 3

Staircase therapeutic approach of intracranial hypertension. An optimal therapeutic strategy is considered the step-by-step escalation of available interventions [29, 129], tailored for each patient. The primary goal is to maintain ICP below 22 mmHg and CPP above 60 mmHg [3]. Initially, general prophylactic measures should be applied immediately to all patients with suspected IH. Based on specific indications and conditions, surgical resection of mass lesions [48] and CSF drainage [3, 48, 69] should be considered as an initial treatment for lowering ICP. The following steps in turn include hyperosmolar therapy [mannitol or hypertonic saline] [3], which represents the cornerstone of medical treatment of acute IH, hyperventilation and therapeutic hypothermia [107, 108]. Τo control elevated ICP refractory to maximum standard medical and surgical treatment, at first, high-dose barbiturate administration [3] and then decompressive craniectomy [3, 48, 69] as a last step are recommended. This staircase therapeutic approach is based mainly on clinical experience rather than on strong published evidence. ICP: Intracranial pressure, CPP: Cerebral pressure perfusion, IH: Intracranial hypertension, CSF: Cerebrospinal fluid, BP: Blood pressure

Full size image

General prophylactic measures

General prophylactic measures aimed at optimizing various parameters [34] are an important part of the therapeutic approach of IH and are listed in Table 6.

Table 6 Effect of general prophylactic measures and acute interventions on outcome

Full size table

Intubation and mechanical ventilation

Early and rapid intubation and mechanical ventilation should be applied in comatose patients. This will help in controlling factors that may aggravate ICP, such as seizures and agitation. During intubation, adequate depth of sedation and elimination of reflexes such as cough and vomiting should be achieved.

Mechanical ventilation should aim at avoiding hypoxemia, hypercapnia and hypocapnia. Hypoxemia and hypercapnia should be avoided because of linear increase in CBF and hence ICP. Conversely, hypocapnia leads to an increased risk of ischemia by inducing cerebral vasoconstriction and reducing CBF. Consequently, PCO2 should be maintained at values between 35 and 40 mmHg.

The use of positive end-expiratory pressure [PEEP] during mechanical ventilation in patients with ABI has the risk of ICP elevation and CPP reduction [35] due to increased intrathoracic pressure and decreased cerebral venous drainage from the superior vena cava. However, in clinical trials, these effects occurred only when applying PEEP > 15 cmH2O in hypovolemic patients [36, 37]. Caricato et al. [38] concluded that the level of applied PEEP had no effect on the intracranial system in patients with low respiratory system compliance. Also, there are data [39, 40] claiming that the effect of PEEP on ICP depends on whether it causes alveolar hyperinflation or recruitment. In particular, if PEEP does not achieve effective alveolar recruitment but causes hyperinflation, it results in a significant increase in ICP due to impediment of cerebral venous return [40].

Blood pressure [BP] – CPP optimization

During BP monitoring hypotension should be avoided because it is an independent risk factor for poor outcome in patients with ABI [41]. The consequences of low BP are determined by the state of cerebral autoregulation. In patients with intact autoregulation, hypotension triggers reflex cerebral vasodilation and increases cerebral blood volume [CBV]. In contrast, in patients with impaired autoregulation, hypotension leads to cerebral ischemia due to CPP reduction. Nearly all patients with severe TBI exhibit hypotension, even in the absence of hemorrhage. This is regarded as a result of both administration of sedation / analgesia and severe SIRS. SIRS is induced by trauma and increases endothelial permeability, favoring volume shift and volume loss into the "third space" [42]. This hypovolemia may lead to inadequate CPP and subsequent ICP increase [43].

According to a large retrospective study of 15,733 patients with isolated moderate to severe TBI, patients with systolic blood pressure [SBP]  70 years old to decrease mortality and improve outcomes.

Strict monitoring of fluid balance is necessary in order to prevent hypovolemia – hypotension. Isotonic fluids should only be used and hypotonic fluids, such as 5% dextrose or 0.45% saline, should be strictly avoided. Systemic hypoosmolality [ 110 mmHg and ICP > 20 mmHg, systemic BP should be carefully lowered in order not to decrease CPP significantly. Therefore, it is suggested to use short-acting titratable agents, such as labetalol and nicardipine [47]. The guidelines for ICH [48] recommend the use of antihypertensive drugs if SBP is > 150 mmHg as it has been associated with improvement in functional outcome, namely significantly better functional recovery based on the modified Rankin scale [mRS] and better physical and mental health–related quality of life based on the EQ-5D scale.

The optimal value—target for CPP is a matter of debate. The minimum CPP value required to prevent cerebral ischemia is generally acceptable at 50–60 mmHg [49]. However, two distinct approaches have developed with differing views on whether CPP should be maintained at a higher or lower level. The Rosner concept [50] advocates an increased MAP, aiming at a higher CPP value in order to maintain adequate CBF. In contrast, the Lund concept [51] advocates reducing intravascular resistance and hydrostatic pressure and reducing CBV, thereby increasing CBF and making a lower CPP acceptable. According to the last guidelines for TBI [3], the recommended target CPP value is between 60 and 70 mmHg, as it has been associated with improved survival and favorable outcomes. However, whether 60 or 70 mmHg is the minimum optimal CPP threshold is unclear and may depend upon the patient’s autoregulatory status. At the same time, aggressive efforts to maintain CPP > 70 mmHg with fluids and vasopressors should be avoided because of the risk of acute respiratory distress syndrome [ARDS]. Moreover, excessive elevation of CPP favors edema formation by increasing capillary hydrostatic pressure across the BBB [52]. Therefore, it is worth noting that the optimal CPP depends on the particularities of each patient and should be individualized based on MMM. Advanced monitoring techniques such as PbtO2 and SjvO2 measurement, EEG and microdialysis may eventually allow clinicians to optimize CPP based on specific physiological circumstances in a particular patient at any given point in time.

Body positioning

The head of the bed should be elevated to 30° and the patient's head face midline so that internal jugular vein is not compressed and cerebral venous drainage is facilitated. Head elevation may reduce ICP without adversely affecting either CBF or CPP [53]. However, head elevation in excess of 45° should generally be avoided because paradoxical increases in ICP may occur in response to the excessive CPP reduction [54]. Important maneuvers that protect against ICP increases include reducing excessive flexion or rotation of the neck, avoiding restrictive neck taping, and minimizing stimuli that could induce cough and Valsalva responses, such as endotracheal suctioning [45].

Temperature control

The bundle of prophylactic measures to treat IH includes fever control. As it is known, elevated temperature affects ICP, by increasing cerebral metabolic demands and CBF [55]. It has been shown that patients with ICH, who develop a body temperature > 37.5 °C within the first 72 h, have significantly worse outcomes determined as Glasgow outcome scale [GOS] 1 or 2 [56]. In addition, in a later study of 110 TBI patients Stocchetti et al. demonstrated that fever within the first week was associated with increased ICP, significant neurologic impairment and prolonged ICU stay [57]. Due to the harmful effect of increased temperature on the cerebral parenchyma, it is recommended that it should not exceed 37 °C. To this end, early aggressive measures to control temperature in the patient with ABI should be implemented. These include intravenous and enteral antipyretic medications, control of room temperature, and cooling blankets or pads. A French study involving patients with septic shock showed that fever control using external cooling was safe and decreased vasopressor requirements and early mortality [58]. Regarding early hypothermia induction as a primary neuroprotective strategy in severe TBI patients, two recent randomized, multicenter clinical trials [59, 60] did not confirm its usefulness, given that prophylactic hypothermia was associated with poor outcomes [no difference on GOS at 6 months]. Thus, the TBI guidelines [3] do not recommend early [within 2.5 h], short-term [48 h post-injury] prophylactic hypothermia to improve outcomes in patients with diffuse brain injury.

Glycemic control

Hyperglycemia is associated with increased mortality in patients with ABI [61, 62]. However, it remains unclear what are the optimal blood glucose [BG] values. Initially, van den Berghe et al. [63] showed that normal BG levels between 80 and 110 mg/dL were associated with decreased morbidity and mortality, decreased hospitalization and cost-effectiveness. However, these results were not confirmed in later studies [64,65,66]. Thus, the guidelines for the treatment of hyperglycemia in critically ill patients [67] suggest that BG