First use of intraventricular nicardipine in a pediatric patient with vasospasm secondary to meningitis: illustrative case

Abstract

BACKGROUND

Cerebral vasospasm is commonly associated with adult aneurysmal subarachnoid hemorrhage but can develop in children. The standard vasospasm treatment includes induced hypertension, avoidance of hypovolemia, systemic use of the calcium channel blocker (CCB) nimodipine, and cerebral angiography for intraarterial therapy. Emerging treatments in adults, such as intraventricular CCB administration, have not been investigated in children. This study demonstrates the successful use of an intraventricular CCB in a pediatric patient with refractory vasospasm secondary to meningitis.

OBSERVATIONS

A 12-year-old female presented with Streptococcus pneumoniae meningitis and ventriculitis with refractory symptomatic cerebral vasospasm. She received a 5-day course of intrathecal nicardipine through an existing external ventricular drain. Her clinical status, transcranial Doppler studies, and radiography improved. Treatment was well tolerated.

LESSONS

Pediatric vasospasm is uncommon and potentially devastating. The management of vasospasm in adults occurs frequently. Principles of this management are adapted to pediatric care given the rarity of vasospasm in children. The use of intraventricular nicardipine has been reported in the care of adults with level 3 evidence. It has not been adequately reported in children with refractory vasospasm. Here, the first use of intraventricular nicardipine in treating pediatric cerebral vasospasm in the setting of meningitis is described and highlighted.

The incidence of meningitis in the United States in 2019 was 0.11 cases per 100,000 persons, most commonly in children under 1 year of age and in adolescents and adults from 16 to 23 years old.¹ The associated morbidity and mortality are high.^1,2 Cerebral vasospasm can occur in cases of meningitis with infection causing inflammation and irritation of the arterial supply to the brain.^3,4

Vasospasm, defined as >50% reduction in the size of an artery lumen, is typically associated with aneurysmal subarachnoid hemorrhage (aSAH). Vasospasm can cause cerebral ischemia and infarction, leading to a 20% morbidity and mortality rate in the setting of aSAH.^5–7 Mainstays of management include euvolemia and permissive or induced hypertension. Oral nimodipine for prophylaxis is associated with a reduction in delayed cerebral ischemia.^7,8 Although diagnostic cerebral angiography remains the gold standard, cerebral artery vasospasm can be detected with multiple imaging modalities including transcranial Doppler (TCD), computed tomography angiography (CTA), and magnetic resonance angiography (MRA). Table 1 shows the diagnostic testing accuracy of these modalities.^9–14 If clinically symptomatic vasospasm develops in the setting of maximal medical management strategies, endovascular treatment options include intraarterial nimodipine, intravenous milrinone or nicardipine, and balloon angioplasties.⁹

TABLE 1.

Diagnostic testing accuracy of imaging modalities for detecting cerebral artery vasospasm

Modality	Sensitivity	Specificity	Authors & Year
Transcranial Doppler	75%–90%	94%–100%	Heiserman, 200011
CTA	84%–85%	89%–98%	Grossen et al., 202215
MRA	56%	97%	Anderson et al., 200014

Some studies have demonstrated that intrathecal nicardipine decreases the rate of cerebral vasospasm, delays cerebral ischemia, and improves clinical outcomes in the adult population, although level 1 evidence is lacking.^15–17 Due to limited literature and a lower incidence of pediatric cerebral vasospasm, treatments for this patient population lag in volume and quality of supporting evidence.

We present the first report on the use of intraventricular nicardipine to treat refractory pediatric cerebral vasospasm due to meningitis. This case is highlighted to add to evolving treatment options for children with cerebral vasospasm and draw attention to the need for a practical pediatric-specific approach to cerebral vasospasm.

Illustrative Case

Presentation

A previously healthy 12-year-old female presented with 3 days of flu-like symptoms and 1 day of altered mental status and bilateral ophthalmoparesis. Physical examination noted bilateral abducens nerve palsies and left trochlear nerve palsy. She was intubated because of a declining mental status. Lumbar puncture opening pressure was high at 44 cm H₂O. The cerebrospinal fluid (CSF) profile was significant for 436 mg/dL protein, <2 mg/dL glucose, 4,818 white blood cells, and gram-positive cocci in pairs. Magnetic resonance imaging (MRI) showed right-sided pan-sinusitis and ventriculitis with ventriculomegaly, along with findings consistent with infection such as diffuse meningeal enhancement and punctate foci of diffusion restriction scattered in multiple sulci. There was no epidural abscess or subdural empyema. External ventricular drainage was performed to address high intracranial pressure in the setting of declining clinical status with fulminant central nervous system infection. Ventricular CSF was cloudy with purulent sediment. The pediatric otolaryngology service performed an endoscopic washout for sinusitis.

Empirical intravenous (IV) ceftriaxone, vancomycin, and metronidazole were given until speciation from CSF cultures with Streptococcus pneumoniae. With that information, the antimicrobial plan was tailored to a course of 4 weeks of IV ceftriaxone and metronidazole. The patient remained in the critical care setting for treatment of meningitis and ventriculitis from acute sinusitis. She developed seizures and vasospasm.

Vasospasm Management and Hospital Course

The patient experienced the acute onset of left upper-extremity (LUE) motor and sensory deficits, left-sided vision loss, dysarthria, and confusion with a Pediatric National Institutes of Health Stroke Scale score of 25 on her 2nd hospital day. MRI and MRA showed a right middle cerebral artery (MCA) vasospasm, without ischemic stroke changes (Fig. 1). Figure 2 demonstrates the TCD velocity and Lindegaard ratio over time. TCD studies showed a velocity of 193.1 cm/s in the proximal right MCA and 131.5 cm/s in the proximal left MCA. The Lindegaard ratio for the right and left sides were 2.6 and 4.4, respectively. Hyperdynamic therapy with norepinephrine, epinephrine, and vasopressin achieved systolic blood pressure (SBP) goals of 160 to 180 mm Hg, which correlated with clinical improvement with a return of spontaneous LUE movement. Oral nimodipine was dosed at a frequency to avoid observed hypotension side effects. The SBP goals of 160 to 180 mm Hg were challenging to maintain in this patient, requiring high intravenous titration of three pressors over multiple days. Additional options were discussed in an interdisciplinary manner: serial endovascular intraarterial verapamil therapy or other adjunctive measures. With multidisciplinary consideration of the complex care, intraventricular calcium channel blocker (CCB) was initiated using the existing external ventricular drain (EVD). The risks, benefits, and alternatives were weighed carefully. The benefits include treating vasospasm and mitigating the development of ischemic stroke, which could produce devastating lifelong deficits and consequences. Risks reported in the literature include up to a 7% risk of meningitis from EVD access for intrathecal dosing: in this scenario, the risk was considered in context, as the patient was already on IV antibiotics for severe intracranial infection.^18,19 The dosing of the intrathecal nicardipine was developed based on published protocols.^39–42

FIG. 1.

Sagittal (A), coronal (B), and axial (C) MRA on presentation. Sagittal (D), coronal (E), and axial (F) MRA at the time of a change in the neurological examination on hospital day 2.

FIG. 2.

Line graph comparing proximal left MCA blood flow velocities as measured by TCD and Lindegaard ratios over time, in hours since the onset of vasospasm. TCD in cm/s is represented in blue, initial value 131.5 cm/s. Lindegaard ratios are represented in pink, initial value 4.4. Vasospasm threshold is represented with a dashed line, at 120 cm/s for TCD and 3 for Lindegaard ratios. The timing of vasospasm treatment is indicated by arrows on the x-axis. Although the patient’s Lindegaard ratio decreased to <3 after IV or oral nimodipine standard of care (SOC) initiation, her blood flow velocity remained elevated >120 cm/s at hour 12 of vasospasm. Initiation of intrathecal nicardipine (ITN) began shortly after, and blood flow velocity decreased to 94 cm/s within 12 hours. ITN continued through hour 168, and velocities and Lindegaard ratios remained below vasospasm thresholds.

Four milligrams of intraventricular nicardipine diluted with 0.9% normal saline solution was administered every 8 hours for a total course of 5 days. There was no recurrence of the LUE weakness. TCD trends improved, with the left Lindegaard ratio improving from 4.4 to 1.2 (Fig. 2). Repeat MRA at the end of the 5-day course showed improved blood flow in the patient’s right MCA, now symmetric with the left MCA. The patient developed nonocclusive thrombi in the left straight and sigmoid dural venous sinus, which was treated with anticoagulation. Critical care was de-escalated after resolution of the vasospasm.

She progressed with therapies and was subsequently discharged to home on hospital day 24 with significant improvement compared to admission. She was oriented and conversant with independent ambulation and symmetric strength in her upper and lower extremities. She remained on antiepileptics for seizures, anticoagulation for venous sinus thromboses, and a 4-week course of antibiotics.

Outpatient Follow-Up

By the 3-month outpatient follow-up, the patient had no deficits on detailed neurological examination. She had reintegrated back into school at her expected grade level. Levetiracetam was discontinued after completing a 6-month course. MRI and magnetic resonance venography at follow-up showed normalization of the ventricle size, no evidence of enhancement, no ischemic damage, and no evidence of occlusive venous sinus thrombosis.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

Pediatric cerebral vasospasm is a devastating condition with various etiologies and no clear treatment guidelines. Cerebral vasospasm, defined by a 50% reduction in vessel diameter, secondary to meningitis has been well documented.^20–24 Vasospasm is associated with significant morbidity and mortality, and patients are at risk for permanent neurological deficits and death secondary to anoxic brain injury due to hypoperfusion.^22,25–27

The pathophysiology of cerebral vasospasm has yet to be fully elucidated; multifactorial contributions involve autoregulatory dysfunction, inflammation, cortical spreading depression, and genetics.^28–30 The inflammation hypothesis primarily centers on the infiltration of macrophages and neutrophils into the subarachnoid space in response to a triggering event, wherein their retention occurs because of the absence of lymphatics and compromised CSF flow. These cells release endothelins and reactive oxygen species as they die, leading to arterial narrowing and vasospasm.²⁹ Certain individuals exhibit an increased genetic predisposition to an inflammatory response, thereby explaining some of the observed variations in the development and response to vasospasm.

There is no consensus on vasospasm treatment in children. Case reports and single-institution reviews have described varied treatments ranging from CCBs (oral, IV, or intraarterial) and milrinone to angioplasties and bypasses.^22,31–34 The treatments for vasospasm in the adult population are also variable with a range of reported efficacies (Table 2).^15,35–37 Oral nimodipine has been shown to improve functional outcomes after aSAH in adult patients, though it has not shown a concordant effect on radiographic vasospasm.^32,38,39 Similarly, it has demonstrated improved functional outcomes without a reduced incidence of vasospasm in pediatric patients, though with side effects, notably significant hypotension.³⁶ Heffren et al.³² found that within a cohort of 12 children, 75% required either medical interventions or dose adjustments of nimodipine to manage hypotension.

TABLE 2.

Cerebral vasospasm treatment strategy efficacy

Treatment	Drug	Favorable Outcome OR (95% CI)	Authors & Year
Triple H therapy	—	0.58 (0.06–4.4)	Lakhal et al., 202136
Hypervolemia	—	1.3 (0.46–4.0)	Lakhal et al., 202136
Calcium channel blocker	Nimodipine	1.6 (1.00–2.4)	Lakhal et al., 202136
	Nicardipine	0.96 (0.73–1.3)	Lakhal et al., 202136
	NPRI	8.5 (1.60–57)	Lakhal et al., 202136
	Fasudil	1.5 (0.32–7.6)	Lakhal et al., 202136
PDE-3 inhibitor	Milrinone	0.28 (0.10–0.77)*	Carlson et al., 202037
	Cilostazol	3.6 (2.00–6.5)	Lakhal et al., 202136
Anticoagulant	Enoxaparin	0.79 (0.40–1.5)	Lakhal et al., 202136
Anticholesterol	High-dose statin	0.74 (0.40–1.4)	Lakhal et al., 202136
	Statin	1.0 (0.81–1.3)	Lakhal et al., 202136
Other	Clazosentan	0.96 (0.72–1.3)	Lakhal et al., 202136
	Erythropoietin	1.2 (0.38–4.1)	Lakhal et al., 202136
	MgSO4	1.6 (1.00–2.4)	Lakhal et al., 202136
Intrathecal vs oral	Nimodipine	1.10 (0.69–1.75)	Pickard et al., 198939
Lumbar drain	—	2.42 (1.39–4.21)	Hafeez & Grandhi, 201916
TPA + EVD	TPA	1.47 (0.61–3.57)	Hafeez & Grandhi, 201916
Cisternal MgSO4	MgSO4	2.45 (0.27–22.37)	Hafeez & Grandhi, 201916

ETA = endothelin receptor antagonist; MgSO4 = magnesium sulfate; NPRI = nicardipine prolonged-release implant; PDE-3 = phosphodiesterase-3 inhibitor; TPA = tissue plasminogen activator.

* Adjusted OR for lower likelihood of functional disability after 6 months.

Milrinone is a selective phosphodiesterase-3 inhibitor with both inotropic effects on the cardiovascular system and vasodilatory effects in the cerebral circulation.³⁹ It shows some success in the adult population, demonstrating improved long-term neurological outcomes.^36,40 Isola et al.³¹ reported on continuous IV milrinone in 80 pediatric patients, demonstrating improvement in 93% of them.

Intraarterial nimodipine has been used for the treatment of cerebral vasospasm; however, the intraventricular administration of CCBs may demonstrate a prolonged half-life in CSF due to the avoidance of first-pass metabolism.^16,19 Considering the presence of a previously placed EVD, the critical condition of our patient, and concerns regarding transport as well as the patient’s ability to tolerate an invasive procedure, intraventricular therapy was chosen over intraarterial therapy. This allowed for the rapid administration of nicardipine in the setting of an insufficient therapeutic response to standard of care interventions in a patient at high risk for ischemic stroke.

Intraventricular nicardipine has also been investigated in adult patients with cerebral vasospasm after aSAH.^41–45 In a cohort of 422 patients, Sadan et al.⁴⁴ demonstrated that those receiving intraventricular nicardipine showed significantly decreased daily cerebral blood flow velocities as measured by TCD and improved functional outcomes. An example of typical reported dosing is 4 mg of nicardipine diluted with 0.9% normal saline with clamping of the EVD for 30 to 60 minutes,^39–42 once every 8 to 12 hours.^41,42 The duration of treatment has not been widely standardized in these published series. Goodson et al.⁴² have been the only ones to report on a cohort with a standardized duration of continuing therapy until postbleed day 14. Webb et al.⁴³ reported the use of intraventricular nicardipine for an average of 2 to 3 days per patient, whereas Sadan et al.⁴⁴ administered it for an average of 8 days.

Intraventricular nicardipine administration requires patients to have an EVD or other ventricular access devices, introducing the possibility of infection. Some published reports have described CSF testing such as three times per week for screening for an EVD-related infection.^40–42 EVD-related infections were not found to be significantly different in those treated with intraventricular nicardipine compared to those in patients with EVDs used solely for CSF drainage,^16,44 although these studies did not include pediatric patients.

Intraventricular nicardipine administration can be considered in patients with vasospasm refractory to traditional therapy. Indications include the presence of an EVD with an intracranial pressure (ICP) <25 mm Hg. Contraindications include patients with a high infection risk or an ICP >25 mm Hg. This technique requires clamping of the EVD for 1 hour after administration; patients unable to tolerate clamping are not appropriate candidates.

A limitation of the current case presentation includes the inability to isolate the effect of intraventricular nicardipine as it followed standard care interventions. Intraventricular nicardipine can be used safely; however, more research is necessary to determine therapeutic efficacy.

Lessons

This is the first case describing the use of intraventricular nicardipine for treating vasospasm secondary to meningitis in a pediatric patient. A 12-year-old female with refractory cerebral vasospasm secondary to Streptococcus pneumoniae meningitis and ventriculitis was treated with intraventricular nicardipine, and the clinical scenario and the rationale based on the literature is explored. Given the morbidity and mortality associated with cerebral vasospasm, clinicians need a diverse and efficacious armamentarium for treatment.

Author Contributions

Conception and design: Lam, LoPresti. Acquisition of data: Horak, Abdelmageed, LoPresti. Analysis and interpretation of data: Horak, Patel, Scoville, LoPresti. Drafting the article: Horak, Patel, Abdelmageed, LoPresti. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Lam. Administrative/technical/material support: Lam, Horak. Study supervision: Lam.