Early in my training I had a few comatose meningitis patients. They were admitted, given antibiotics, and supported on a ventilator. They died. For a while, I believed that this condition was fairly hopeless.
Then I encountered a comatose young man with meningitis due to adjacent mastoiditis. His lumbar puncture opening pressure was ~50cm. Following mastoidectomy and temporary placement of a lumbar drain, he recovered. Since then, I have been increasingly aggressive about managing this. Some patients have responded surprisingly well.
Severe meningitis patients deserve neurocritical care
Patients judged to have severe meningitis should be admitted to neurointensive care units without delay for ICP monitoring and management according to modern neurointensive care principles – Edberg 2011
Patients with coma or stupor due to meningitis are ideal candidates for aggressive neurocritical care. They are often relatively young and previously healthy. Meningitis typically spares the brain tissue itself, allowing it to be highly reversible.
Nonetheless, meningitis patients typically fail to receive such care. Patients with severe bacterial meningitis in the United States usually receive less attention to intracranial pressure management than patients with cryptococcal meningitis treated in third-world countries.
Step #1: Steroids
Early steroid administration improves neurologic outcomes, particularly in pneumococcal meningitis (1). Nonetheless, adherence remains poor. When giving antibiotics for meningitis or possible meningitis, just give a dose of dexamethasone. The safety of steroid in critical illness has been explored here and here. Unless the patient has tuberculosis or a fungal infection, steroid is advisable.
Step #2: Drain CSF if ICP is elevated
The most common cause of death in severe meningitis is elevated intracranial pressure (Edeberg 2011). This is due to brain tissue edema and impaired re-absorption of CSF. In some cases, patients may slip into a death spiral of escalating intracranial pressure causing hypoperfusion.
CSF drainage serves two purposes. First, CSF removal will reduce the intracranial pressure (ICP). Second, CSF removal will drain purulent material from the subarachnoid space. Meningitis is a closed space infection, similar to empyema or purulent pericarcarditis. Drainage is a logical approach to a closed space infection.
Cryptococcal meningitis: A model for bacterial meningitis
This post is about bacterial meningitis. However, ICP elevation is better studied in patients with cryptococcal meningitis, where it occurs more frequently. Thus, cryptococcal meningitis may serve as a model to help us understand bacterial meningitis.
The most immediate determinant of outcome of cryptococcal meningoencephalitis is control of symptomatic increased intracranial pressure – Infectious Disease Society of America Guidelines
ICP management is recognized as a cornerstone of treating cryptoccal meningitis. The Infectious Disease Society of America recommends therapeutic drainage of CSF via lumbar puncture if the opening pressure is >25cm water and there are symptoms of elevated intracranial pressure. Subsequently, daily therapeutic lumbar puncture or placement of a lumbar or ventricular drain may be used. Studies of cryptococcal meningitis have correlated CSF removal with improved mortality (Rolfes 2014).
Evidence supporting CSF drainage in bacterial meningitis
Abulhasan 2013 performed a retrospective study of 37 patients admitted to a Canadian ICU with meningitis between 2000-2010. Lumbar drains were used as “salvage therapy,” so patients receiving drains were sicker. However, patients who received lumbar drains had better outcomes, including reduced mortality (0/11 vs. 4/26, p=0.0001). Although this is a retrospective correlational study, it is notable that patients with drains did better despite higher initial illness severity. Other studies of bacterial meningitis have also correlated CSF drainage with better outcomes (e.g. Glimaker 2014).
Indication for CSF drainage?
As discussed further below, the intracranial pressure (ICP) is equal to the opening pressure of the lumbar puncture. An opening pressure >27 cm water equates to an ICP >20mm mercury, which would merit intervention based on most neurocritical care standards. This is consistent with the guidelines for cryptococcal meningitis above (which recommend drainage if the opening pressure is >25 cm water) and available literature on bacterial meningitis (Glimaker 2014)(2).
Technique for CSF drainage
In the absence of comparative studies, a lumbar drain may be the safest approach. In addition to the study above, lumbar drains have been shown to be safe and effective in cryptococcal meningitis, even in resource-limited settings (Manosuthi 2008). The main advantage of a lumbar drain is that it is less invasive than a ventricular drain, which requires drilling through the skull and pushing a catheter through brain tissue. In contrast, placement of a lumbar drain consists of performing a lumbar puncture and then threading a tiny catheter into the subarachnoid space.
If neurosurgical assistance is unavailable, an alternative is serial therapeutic lumbar punctures. This may be performed every 12-24 hours with a goal of achieving a closing pressure <20cm or <50% of the opening pressure in cases of severely elevated pressures (3). Unfortunately, serial LP allows for drainage of less CSF than an indwelling drain and ICP may rise between procedures, so it may be less effective (Macsween 2005). Serial lumbar puncture can be used temporarily as a bridge to drain placement.
Step #3: Defend the cerebral perfusion pressure
CPP = MAP – ICP
The cerebral perfusion pressure (CPP) is the mean arterial pressure (MAP) minus the intracranial pressure (ICP). This is the pressure driving blood flow through the brain. As such, the CPP is arguably more important than either the MAP or ICP taken in isolation.
Normally, arteries in the brain dilate or constrict to maintain a constant perfusion across a range of cerebral perfusion pressures (autoregulation). This often fails in meningitis, causing blood flow to vary directly in proportion to the CPP (Moller 2000). If CPP isn't maintained, perfusion may fall dangerously low. The ideal target for the CPP is debatable, but a reasonable target may be >60 mm (Kumar 2014)(4).
Know your patient's ICP & CPP
These patients will receive a head CT to exclude herniation or intracranial mass lesion. Presuming that these are absent, the pressure should be uniform throughout the subarachnoid space bathing the brain and spinal cord. Indeed, lumbar puncture has been shown to provide an accurate measurement of ICP under these conditions (Lenfeldt 2007, Kapadia 1996):
ICP in mm Hg = (0.7 mm Hg/cm water)(LP pressure in cm water)
This allows calculation of the CPP:
CPP = MAP – ICP
CPP = MAP – 0.7(LP pressure in cm water)
For patients with an elevated ICP, the MAP target must be increased to achieve an adequate CPP. The MAP target required to maintain a CPP >60 mm is estimated using the equation below (4). In comatose patients whose opening pressure has not yet been measured, it may be reasonable to assume an elevated ICP and target a higher MAP than usual.
Target MAP > [0.7(LP pressure in cm) + 60 mm]
CT scan findings (e.g. ventricular dilation) are insensitive for detection of acute elevations in intracranial pressure due to meningitis (Winkler 2002). Pressure may be increased evenly throughout the ventricles and subarachnoid space, without causing any tissue shift. Therefore, neurocritical care of these patients should be based on direct measurement of the ICP, rather than guessing its value from a neuroimaging study (5).
Defend the CPP using norepinephrine
The simplest and fastest way to improve the CPP is to increase the MAP using vasopressors. In one RCT of pediatric meningitis and encephalitis, a strategy of targeting CPP was more effective than targeting a normal ICP using primarily osmotherapy (Kumar 2014)(6).
Often phenylephrine is used for this purpose, but phenylephrine may reduce the cardiac output and cerebral perfusion. The best choice of vasopressor may be norepinephrine, which improves both MAP and cerebral oxygenation (Pfister 2008). Volume loading shouldn't be attempted unless there is true hypovolemia.
General measures for patients with elevated ICP include adequate sedation, head elevation, and maintenance of PaCO2 levels within a low-normal range. If patients are refractory to these measures as well as CSF drainage then further therapies may be considered (e.g. osmotherapy, barbiturate coma; Cuthbertson 2004). Some reports describe meningitis patients who received decompressive craniotomy with eventual recovery (Bordes 2011, Perin 2008).
Step #4: Control the temperature
Neurocritically ill patients generally don't do well with fever. This is especially true of patients with ICP elevation, which may be aggravated by fever.
There is no evidence regarding the utility of fever control in adult meningitis. Nonetheless, targeting normothermia seems reasonable, particularly in patients with ICP elevation. Scheduled acetaminophen may be the first step, but this is often ineffective (7). For refractory fever, adhesive external adaptive cooling systems (e.g. the Arctic Sun) set to target 36C are an effective way to achieve normothermia (Glimaker 2014).
An multi-center RCT found that therapeutic hypothermia to 33C increased mortality in meningitis (Mourvillier 2013)(8). This is consistent with numerous risks of hypothermia as discussed here. It remains possible that hypothermia could be beneficial in selected patients as salvage therapy for refractory ICP elevation (Popugaev 2014).
Step #5: Beware of seizures
Meningitis patients have a ~20% risk of seizure, with higher risk in sicker patients (Edberg 2011, Fernandes 2014). There is no evidence about seizure prophylaxis with levtiracetam. This might not be a bad idea for patients with coma, who are at the highest risk of seizure and in whom the diagnosis of seizure may be difficult. Regardless, there should be a high index of suspicion for noncovulsive status epilepticus with consideration for EEG monitoring.
The high mortality rate in patients with seizures warrants a low threshold for starting anticonvulsant therapy in those with prior seizure or clinical suspicion of a seizure –Zoons 2008
Step #6: Consider an MRI
Meningitis patients will usually receive a noncontrasted head CT, but MRI may be required to detect associated findings such as infarction, brain abscess, or subdural empyema (Hazany 2014). For example, about 10% of patients with pneumococcal meningitis may develop sinus vein thrombosis, an indication for anticoagulation (Kastenbauer 2003). Although these findings aren't particularly common, they may alter management substantially.
- Severe meningitis is an emergency requiring neurocritical care, with careful attention to intracranial pressure (ICP) and cerebral perfusion pressure (CPP).
- The pressure transduced from a lumbar puncture is equal to the intracranial pressure. Measuring opening pressure allows for prompt identification of patients with elevated intracranial pressure.
- Drainage of CSF reduces the ICP. Because meningitis is a closed space infection, drainage might also speed resolution of the infection. This may be accomplished by a variety of methods (therapeutic lumbar puncture, indwelling lumbar drain, or external ventricular drain).
- The cerebral perfusion pressure (CPP = MAP – ICP) is the pressure gradient driving brain perfusion. The CPP should be supported aggressively, for example with norepinephrine.
- Because meningitis typically spares the brain tissue, these patients can experience dramatic improvement. However, this depends on rapid and meticulous care.
Coauthored with Ryan Clouser (@Neurocritguy), neurointensivist and partner in crime.
- One study in Malawi failed to detect benefit, possibly because 90% of patients had HIV. However, the benefit of early steroid in high-income countries has been confirmed by Cochrane meta-analysis and is recommended by the Infectious Disease Society of America guidelines.
- Whether patients with lower opening pressures might also benefit from drainage is unknown. It is possible that all patients with meningitis and altered mental status might benefit from drainage of purulent material. However, in the absence of clear evidence, it seems most justifiable to perform drainage in patients who have impaired mental status and a dangerously elevated ICP.
- This description of therapeutic LP is based on the Infectious Disease Society of America's guidelines for cryptococcal meningitis. There may be a concern that lumbar puncture may cause herniation. However, in the absence of a mass lesion, this should not occur. The safety of performing diagnostic and therapeutic LP in patients with meningitis and elevated ICP is well established (Glimaker 2014).
- Like any hemodynamic target, it is unclear exactly what the CPP should be, or whether we should be individualizing the goal. This formula is only intended as a rough guide towards getting the blood pressure into the appropriate range.
- Rarely a mass lesion may render LP unsafe (e.g. brain abscess with threatened herniation). In this situation the only way to measure ICP would be to insert a monitor into the brain (e.g. an external ventricular drain). However, in the great majority of meningitis cases, lumbar puncture is a convenient and safe way to determine the ICP.
- In this study, CSF drainage wasn't utilized, because it was a pediatric study which utilized intra-parenchymal ICP monitoring. Patients in the ICP-targeted therapy group received more hyperventilation, which may have also affected results. As such this study may not directly apply to adults with meningitis, but it does support the concept of CPP-targeted therapy (Kumar 2014).
- Pelkonen 2011 performed an RCT investigating the utility of acetaminophen in children with meningitis. Perhaps the most notable aspect of this study was that acetaminophen was quite ineffective in temperature control. Acetaminophen also appears to be relatively ineffective in fever due to subarachnoid hemorrhage, which like meningitis involves inflammation of the subarachnoid space.
- This study was stopped prematurely due to possible harm. The increase in mortality from hypothermia was on the border of statistical significance (51% vs. 31%, p=0.04). Given that prematurely terminating a study may increase the likelihood of obtaining aberrant statistical results, it remains unclear whether hypothermia increases mortality.
- Vancomycin +/- ampicillin should also be given, but the first priority is delivering dexamethasone, ceftriaxone, and acyclovir. Ampicillin is indicated in patients at risk for Listeria, but this is rare. Vancomycin is recommended for coverage of highly cephalosporin-resistant strains of pneumococci, but these strains are rare and it is unclear that vancomycin is actually needed to treat them (Lynch 2009). Ordering five drugs simultaneously often causes the most important drugs to be delayed. Thus, it may be best to push hard for dexamethasone, ceftriaxone, and acyclovir immediately, and then give the vancomycin and ampicillin.
Image credits: Opening image: Sleeping Beauty by Henry Meynell Rheam.
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