1. What immediate steps in management do you take when a patient with intracranial hemorrhage (ICH) exhibits signs of elevated intracranial pressure (ICP)?

The immediate steps in the management of intracranial hypertension (ICP >20 mmHg for 5 minutes) in the setting of ICH follow the mantra of emergency medicine and include an evaluation and intervention upon airway, breathing, and circulation. In some instances (e.g. major traumas, initial GCS ≤ 8, etc.), patients found to have ICH on head CT will have previously been intubated. However, in many situations this will not be the case. In such patients with rapidly declining neurological status, intubation is crucial to protect the airway and maintain adequate oxygenation and ventilation. When possible, a moment of pause should be taken at this point to perform a rapid (1 to 2 minutes) but detailed pre-sedation/pre-intubation neurologic exam, as outlined by the Emergency Neurological Life Support (ENLS) protocol on airway, ventilation, and sedation (Seder, 2012). While we sometimes forget this step, as it may not affect our management as emergency physicians it may critically influence later neurosurgical decision-making.

As a brief review, the four classic indications for intubation include failure of maintenance of airway protection, failure of oxygenation, failure of ventilation, and anticipated clinical deterioration. The latter is commonly the reason for intubation in ICH.

The chosen method of airway protection in the setting of intracranial hypertension is rapid sequence intubation (RSI) as it offers protection against reflex responses to laryngoscopy that raise ICP (Sagarin, 2005; Li, 1999; Sakles, 1998; Walls, 1993). Importantly, ENLS recommends the administration of the appropriate pretreatment and induction agents even in the presence of presumed coma, as laryngoscopy may still stimulate reflexes that raise ICP (Bedford, 1980). In terms of pretreatment medications, perhaps none is more controversial than lidocaine. Proponents of its use often highlight its safety profile and its ability to blunt the direct laryngeal reflex, which otherwise raises ICP (Salhi, 2007). Detractors, on the other hand, point out that there are no human trials showing benefit, only one trial evaluating its effect on ICP at the time of intubation, and that this study was in brain tumor patients rather than traumatic brain injury (TBI) patients (Vaillancourt, 2007). The debate is likely to continue, as it would be logistically very difficult to design an outcome study. Nonetheless, if chosen, the pretreatment lidocaine dose is 1.5 mg/kg three minutes before intubation. Other options include fentanyl 2-3 mcg/kg and esmolol 1-2 mg/kg, both of which blunt the reflex sympathetic response (increase in heart rate and blood pressure). However, caution is advised in hypotension. In terms of induction agents, etomidate has minimal hemodynamic effects. Propofol is also popular, although through its vasodilatory effects, can cause hypotension. Ketamine, on the other hand, despite previously being avoided, is gaining recognition, particularly for its hemodynamic profile. When weighing all of these options, it would be prudent to remember that in head trauma patients, a single systolic blood pressure (SBP) below 90 mmHg is associated with a 150% increase in mortality (Chesnut, 1993). The choice between depolarizing (e.g. succinylcholine) and non-depolarizing (e.g. rocuronium) neuromuscular blocking agents may be similarly difficult. Succinylcholine has a rapid onset and short duration of action, allowing for a more rapid full neurological reevaluation following intubation. These benefits must be compared with the risk of hyperkalemia in patients with immobility and chronic motor deficits. Additionally, if more than one intubation attempt is made, this may require a delay for succinylcholine re-dosing. In contrast, rocuronium has a longer duration of action, which affects the timing of repeat neurological exams, however, re-dosing it is not required on repeat intubation attempts and it avoids the risk of hyperkalemia. Once intubation is achieved, the head of the bed (HOB) should be raised to 30 degrees to improve venous return in aid the reduction of ICP (Winters, 2011; Feldman, 1992; Ng, 2004; Winkelman, 2000; Moraine, 2000).

As outlined by ENLS, hyperventilation is one of a series of steps taken to acutely lower ICP and prevent infarction of neuronal tissues (Seder, 2012). Lowering the PCO₂ causes alkalosis of the cerebrospinal fluid, which in turn leads to cerebral vasoconstriction. The typical goal PCO₂ is 28-35 mmHg (20 breaths per minute), and end-tidal CO₂ monitoring is recommended (Swadron, 2012). It is extremely important to note that hyperventilation is meant as a bridge to more definitive therapy to reduce ICP, as it reduces cerebral blood flow and can lead to additional ischemia. Furthermore, following prolonged hyperventilation, the local pH normalizes through pH buffering mechanisms. Once this occurs, it triggers vasodilation, which can cause cerebral edema. In effect, except in the event of acute brain herniation, the PCO₂ goal should be between 35-45 mmHg (or end-tidal CO₂ to 30-40 mmHg) (Seder, 2012).

Hyperosmolar therapy with either mannitol or hypertonic saline (HTS) is another important step in intracranial hypertension. Mannitol (20% solution, 0.25-1 g/kg IV via rapid IV infusion) works by two mechanisms (Bratton, 2007). The first, which occurs within minutes, is plasma volume expansion, which lowers the blood viscosity and improves cerebral blood flow and oxygenation. The second, and perhaps more well-known, takes 15-30 minutes, and is the creation of an osmotic gradient that drives water out of neuronal cells and into the plasma, followed by rapid diuresis. This latter effect is critical, as it may precipitate hypotension in the absence of concomitant IV fluid administration. Most experts also recommend Foley placement for careful control of volume status. HTS (in various concentrations but often 3%, 150 mL IV over 10 minutes), in contrast, is believed not to produce rapid hypotension, which may be a reason for its increasing popularity in recent years. It also creates a higher osmolality in the vasculature, and draws fluid out of the cerebrum (Bratton, 2007). While there are proponents for the selective use of either agent, there are no head-to-head trials evaluating the relative efficacy of mannitol and HTS, and both are considered appropriate therapies (Swadron, 2012).

Although much of the above literature derives from ICH as the result of trauma, the management of ICH in the non-traumatic setting, at least acutely, is generally the same.

2. In which patients with ICH do you push for invasive neurosurgical intervention?

Following ICH, the decision of whether or not to pursue surgical intervention is reliant upon the patient’s neurological exam as well as head CT findings. The most widely accepted evidence-based recommendations are the Brain Trauma Foundation Guidelines for the Surgical Management of Traumatic Brain Injury, and there are several criteria upon which they rely (Bullock, 2006a; Bullock, 2006b; Bullock, 2006c; Bullock, 2006d). While there are many niche indications for operative intervention, practically speaking, since neurosurgery is likely to be consulted in any case of ICH, it would be helpful to remember the following clear indications for surgery:

• GCS ≤ 8 + large mass lesion
• Any GCS + extra-axial hematoma (epidural or subdural hematoma) ≥ 1cm thick
• Any GCS + extra-axial hematoma (epidural or subdural hematoma) ≥ 5mm midline shift
• Intracranial hematomas >3cm in diameter (especially with mass effect)

When there is any form of deterioration on repeat examinations, a focal neurologic deficit, or pupillary changes such as anisocoria or fixation/dilation, surgery should be expedited (Swadron, 2012). Nearly all neurosurgeons agree that intervention is prudent in posterior fossa lesions given the confined space compared to supratentorial lesions. Beyond this, there is still considerable variation worldwide in surgical intervention. The STICH II trial looked at a randomized sample of patients with spontaneous, superficial supratentorial ICH, comparing early surgery with early medical management (with possible surgery after 12h). The investigators found no increase in death or disability at six months in the early surgery group, and a small survival advantage (Mendelow, 2013). A similar trial in traumatic ICH is ongoing. Importantly, while severe coagulopathy is a relative contraindication to surgery, it can be corrected intraoperatively and should not delay the patient’s course to the operating room.

In intracranial hemorrhage, much of the damage occurs through secondary injury over time. The development of intracranial hypertension is associated with an increase in mortality (Bratton, 2007). As such, the 2007 Brain Trauma Foundation Guidelines recommend (level II) ICP monitoring in the following settings:

• GCS ≤ 8 (but salvageable) + abnormal head CT*
• GCS ≤ 8 (but salvageable) + normal head CT + 2 of the following:
  • Age > 40 years
  • SBP < 90 mmHg
  • Motor posturing

*hematomas, contusions, swelling, herniation, compressed basal cisterns

Part of the reason this has been suggested is that diagnosing intracranial hypertension based on clinical exam alone is challenging. Furthermore, ventriculostomy (placement of an external ventricular drain, EVD) has not only diagnostic but also therapeutic potential through CSF drainage. Very recently, however, the utility of ICP monitoring has been put into question. The first randomized, controlled trial of TBI patients with and without ICP monitors was published, showing no difference in six-month clinical outcomes between the two groups (Chesnut, 2012). Importantly, intracranial hypertension (either via ICP monitoring or clinical exam and imaging) was acted upon in both groups, so this study does not address whether interventions targeting ICP lead to outcome differences.

3. What interventions do you initiate in patients with ICH on antiplatelet medications?

There are varied practices in this setting, as outcome data are highly variable. Theoretically, the use of antiplatelet therapy (e.g. aspirin, clopidogrel) leads to hematoma expansion and increased mortality, as has been found in several observational studies (Roquer, 2005; Saloheimo, 2006; Naidech, 2009; Toyoda, 2005). However, despite this being a logical conclusion, there are numerous studies, which have failed to show a clinical outcome difference between ICH patients taking antiplatelet agents and those that are not (Caso, 2007; Foerch, 2006; Sansing, 2009). In light of these conflicting results, some believe it is important to pursue antiplatelet reversal until more definitive data emerges (Campbell, 2010). However, even if it is accepted that antiplatelet therapy leads to hematoma expansion and worsened clinical outcomes, it cannot be presumed that platelet transfusion, the most common antiplatelet reversal strategy, is beneficial. None of the observational trials comparing patients taking aspirin and clopidogrel have shown a favorable impact. Further, platelet transfusion carries with it the risk of infection, transfusion-related acute lung injury, and allergic reactions.

Another option is desmopressin (DDAVP, 0.3 mcg/kg IV), which triggers the release of von Willebrand factor and factor VIII. It has been shown to reverse uremic as well as aspirin- and clopidogrel-induced platelet dysfunction (Flordal, 1993; Reiter, 2003; Leithauser, 2008). It is a popular alternative or adjunct to platelet transfusion and is considered to have a favorable side effect profile – particularly in comparison to the associated risks of platelet transfusion described above.

Overall, pending further investigation, it appears that the use of platelets and/or DDAVP at this stage is largely dependent on institutional practices.

4. What agent(s) do you use for warfarin reversal in the setting of ICH? What about other oral anticoagulants?

In the setting of ICH, the four agents considered for warfarin reversal include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), and recombinant activated factor VII (rFVIIa). There is also no clear evidence on the most appropriate target INRs, though many groups aim for INRs of 1.2-1.5.

In a review of the literature, Goodnough and Shander demonstrated that among guidelines for anticoagulant reversal in ICH, consensus is strongest for the use of vitamin K, which promotes hepatic synthesis of clotting factors II, VII, IX, and X (2011).  Its onset of action is between 2-6 hours but requires up to 24 hours to have full effect. As seen in the table below, it is typically given in doses of 5-10 mg IV. Vitamin K is often given alongside other agents, which have shorter half-lives.

FFP contains all of the coagulation factors and is the most common method of factor replacement in the United States (Dentali, 2006). However, as the amount of vitamin K-dependent factors per unit of FFP is variable, it is often difficult to predict the degree of INR correction that will accompany a given amount of FFP. A rough estimation for the amount of FFP required to correct a coagulopathy involves calculating the difference in the factor activity (%) between the goal INR and the current INR (readily available in chart format) and noting that each unit of FFP roughly increases the factor activity by 2.5%. Practically, for patients taking warfarin in the therapeutic range (INR 2-3), 2-4 units (10-12 ml/kg) of FFP are often needed. While FFP is commonly used for warfarin reversal in ICH, difficulty arises in patients with cardiac, renal, and hepatic disease who cannot tolerate large fluid loads. Additionally, the INR of FFP is around 1.5, which limits the ultimate reversal nadir.

In such situations, there may be a role for PCC, which contains four  factors in higher concentrations than FFP, and requires a much smaller volume than FFP to achieve coagulopathy reversal. A September 2013 trial, published in Circulation found 4-factor PCC to be similarly effective (based on clinical and lab endpoints) and as safe as FFP (Sarode, 2013). Another reason for using PCC may be speed. In a number of small prospective and retrospective studies, PCC have demonstrated significantly more rapid reversal of coagulopathy in ICH than FFP (Cartmill, 2000; Huttner, 2006). Interestingly, while previous guidelines from the American College of Chest Physicians recommended the use of vitamin K with any of the more rapidly acting agents (PCC, FFP, or rFVIIa), the newest guidelines specifically recommend 4-factor PCC over FFP to accompany vitamin K (Ansell, 2008; Holbrook, 2012). In some institutions, PCC are given as a fixed dose of 25-50 international units/kg, while at others it is an INR-based dose (Andrews, 2012). A word of mention should be made about the cost of PCC. It has been estimated to cost $2,000 to reverse an INR of 3.0 in a patient with ICH. This is in contrast to FFP, which is between $200 and $400 (Steiner, 2006). Finally, while studies have shown a rapid correction of INR with PCC administration, no study has demonstrated decreased mortality.

rFVIIa promotes factor X activation and thrombin generation on platelets at sites of injury. In recent years, it has garnered much attention for its widespread off-label uses as a hemostatic agent. One major criticism, however, is that while rFVIIa has been shown to rapidly correct supratherapeutic INRs, it may not have a true clinical benefit (Nishijima, 2010; Mayer, 2008; Ilyas, 2008). Additionally, given its short, 4-hour half-life, vitamin K and FFP are often concurrently given. One of the greatest concerns with rFVIIa is its higher risk of arterial thromboembolic events (myocardial infarctions, cerebral infarctions), which was demonstrated in a randomized trial (Mayer, 2008). Like PCC, rFVIIa has a significant price tag. For reversal of an ICH patient with an INR of 3.0, its approximate cost is $5,000 to $15,000 (Steiner, 2006). At the time of this writing there are trials underway to see if rFVIIa changes outcomes in patients with ICH and active extravasation on CT angiography.

In terms of the newer anticoagulants on the market, dabigatran is a direct thrombin inhibitor that is used to prevent arterial and venous thromboembolism. In many cases of minor bleeding, simply holding the next dose and providing supportive care is adequate, as the half-life is between 14 and 17 hours with normal renal function. However, trouble arises in the setting of ICH because there is no accepted monitoring strategy or reversal agent (Watanabe, 2012). While dabigatran does have a prolonging effect on the PT and PTT, these are only valuable as rough guides to the degree of anticoagulant activity. It has been suggested that PCC and rFVIIa may be used for reversal but their benefit has yet to be demonstrated clinically (Alberts, 2012). Hemodialysis remains another option, although it may be difficult to rapidly initiate and has shown limited benefit in case reports only.

Rivaroxaban, another new agent, is a Xa inhibitor commonly employed for stroke prevention in patients with atrial fibrillation. Similar to dabigatran, while there is no specific antidote, its half-life is also short (five to nine hours). The theoretical possibility of reversal with rFVIIa and PCC exists, though this has not been shown. Presently, the best human data has been done on non-bleeding volunteers taking rivaroxaban who showed improved PTs after receiving 4-factor PCC (Eerenberg, 2011).

Thank you to Drs. Natalie Kreitzer and Opeolu Adeoye of the University of Cincinnati Department of Emergency Medicine and the Neurosciences ICU for their expert advice on these “answers.” Please also see their excellent, recent publication on the topic “An update on surgical and medical management strategies for intracerebral hemorrhage.”