What are the common doses used for intraventricular nicardipine for intracerebral vasospasm?

Comment by InpharmD Researcher

While studies evaluating intraventricular nicardipine for intracerebral vasospasm are mainly limited to retrospective studies and case series, the most commonly reported dose was 4 mg given at various intervals. In general, reported dosages and frequencies ranged from 2 to 4 mg every 6-12 hours, with more recent studies administering 4 mg nicardipine diluted in 2 mL of normal saline via external ventricular drain. Available studies typically report the concentration that was prepared, but a comprehensive literature search was unable to identify stability data related to sterile product preparation of concentration reported.

Background

A 2019 systematic review covered nicardipine injection dosing regimens, effects on cerebral blood flow, side effects, treatment risks, patient selection, and outcomes. The studies included in this review focused on the use of nicardipine injected via an external ventricular or cisternal drain in the treatment of cerebral vasospasm that was related to aneurysmal subarachnoid hemorrhage (aSAH). Reported dosages and frequencies ranged from 2 to 4 mg every 6-12 hours. Many of the early studies used 4 mg nicardipine diluted in 10 mL of normal saline administered via cisternal drain. Many of the more recent studies chose to use 4 mg nicardipine diluted in 2 mL of normal saline using intraventricular administration via external ventricular drain. A more concentrated formulation was used in one study by diluting 4 mg in 1.6 mL of normal saline and mixing with preservative-free 0.4 mL sodium chloride to yield a total volume of 2 mL. The smaller volume may have been used to decrease chemical irritation to the ependymal surface of the ventricles and to maximize delivery. There is a noticeable variation in the reported duration of therapy, ranging from one to two injections during maximal cerebral vasospasm to up to 10 days of treatment when administered in a prophylactic manner. [1]

Infection was a concern for many studies as the injection of drugs into the intraventricular space increases the risk for bacterial or chemical ventriculitis. The incidence of infection was found to be significantly different when the administration of intrathecal nicardipine was limited to patients who only had moderate to severe angiographic vasospasm or severely elevated transcranial doppler mean flow velocity. The risk of infection is minimized by using proper sterile techniques and protocols during extraventricular drain placement and intrathecal nicardipine delivery. Although this review demonstrated decreased angiographic vasospasm, decreased symptomatic vasospasm, and a reduction in mean flow velocity, more research is needed to demonstrate the efficacy of intraventricular nicardipine in the treatment of aSAH. The different primary outcome measures, dosing strategies, duration of therapy, and selection bias among published literature are all limitations to concluding efficacy. Stability data for the preparation of intrathecal nicardipine was not provided. [1]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What are the common doses used for intraventricular nicardipine for intracerebral vasospasm? Is there any stability information related to the sterile product preparation of the dose?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

The Effect of Intraventricular Administration of Nicardipine on Mean Cerebral Blood Flow Velocity Measured by Transcranial Doppler in the Treatment of Vasospasm Following Aneurysmal Subarachnoid Hemorrhage
Design	Retrospective chart review N= 64
Objective	To report the effects of intraventricular administration of nicardipine on mean cerebral blood flow velocity (Vm) as measured by transcranial Doppler (TCD) in the treatment of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH)
Study Groups	All participants (N= 64)
Inclusion Criteria	Treated with intraventricular nicardipine for suspected vasospasm after aSAH
Exclusion Criteria	Excluded from the primary analysis of the effects on cerebral blood flow velocity: Lacked TCD windows; received only a single dose of intraventricular nicardipine; received intra-arterial therapy within 24 hours of initiating intraventricular nicardipine; did not have baseline TCD measurements prior to the administration of intraventricular nicardipine
Methods	The authors retrospectively identified and reviewed the charts of 64 patients treated with intraventricular nicardipine for suspected vasospasm after aSAH. The decision to initiate intraventricular nicardipine was based upon clinical suspicion of cerebral vasospasm determined by the following criteria: elevation of mean cerebral blood flow velocity during high-risk time for cerebral vasospasm, clinical deterioration suspicious for delayed cerebral ischemia, or radiographic evidence of cerebral vasospasm (computed tomography angiogram or catheter angiogram). All external ventricular drains (EVD) were already in place for clinical reasons relating to aSAH (hydrocephalus, intracranial pressure monitoring, intraventricular hemorrhage). In addition to clinically indicated hypertensive and hypervolemic therapy, all patients received oral nimodipine for 21 days. Nicardipine was administered at 4 mg mixed with 2 mL of preservative-free saline through the EVD every 8-12 hours. Intracranial pressure (ICP) data, recorded hourly as per unit protocol, was collected, and the maximum ICP over a 24-hour period was defined.
Duration	January 2006 to June 2007
Outcome Measures	Effects of intraventricular administration of nicardipine on mean cerebral blood flow velocity; elevated ICP; ventricular catheter-related infections (VRI)
Baseline Characteristics		All participants (N= 64)
	Median Age, years	51.6
	Smoker	33 (52%)
	Hypertension	35 (55%)
	Surgical clipping	29 (45%)
	Endovascular coiling	35 (55%)
	Mean doses nicardipine per patient	6.7
	Mean post bleed day nicardipine started (range)	7 (2–19)
	Mean duration of EVD, days	14.7
Results	Endpoint	Participants (N= 42)	p-value
	*Effects of intraventricular administration of nicardipine on mean cerebral blood flow velocity 24-h period prior to initiation of intraventricular nicardipine Aggregate Middle cerebral artery (MCA) Anterior cerebral artery (ACA) Before and after administration of intraventricular nicardipine Aggregate MCA ACA 24 hour period after initiation of intraventricular nicardipine Aggregate MCA ACA	- - +11.5 +27.9 +9.5 - -15.5 -26.3 -7.4 - -2.7 -2.9 -6.7	- - <0.001 <0.001 0.003 - <0.001 <0.001 <0.001 - 0.09 0.43 0.24
	**Mean maximum ICP, mmHg On the days prior to nicardipine administration (Days 1-3) On the days intraventricular nicardipine was administered (Days 4-6)	- 18.6 18.1
	**VRI Clinically definite Clinically possible	- 4 (6.3%) 7 (10.9%)
	Only 42 patients were included in the primary analysis *All 64 patients were included in the safety data Clinically definite VRI (strict definition) was defined as a positive CSF culture and CSF glucose <40 mg/dl (assuming absence of systemic hypoglycemia) or having persistently positive CSF cultures on serially collected samples. Clinically possible VRI (liberal definition) was defined as a positive CSF culture and CSF glucose >40 mg/dl or a negative CSF culture and CSF glucose <40 mg/dl on two consecutive samples prompting empiric antibiotic treatment and/or EVD removal or exchange.
Adverse Events	See results
Study Author Conclusions	Intraventricular nicardipine was associated with a significant and sustained reduction in mean cerebral blood flow velocity as measured by transcranial Doppler when used in the treatment of suspected cerebral vasospasm following aneurysmal subarachnoid hemorrhage. We do not find significant safety concerns related to elevations of intracranial pressure or ventricular catheter-related infections.
InpharmD Researcher Critique	The retrospective design and lack of a control group introduce the risk of many forms of bias. Clinical outcomes associated with change in surrogate markers are not further explored.

References:

Webb A, Kolenda J, Martin K, Wright W, Samuels O. The effect of intraventricular administration of nicardipine on mean cerebral blood flow velocity measured by transcranial doppler in the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2010;12(2):159-164.

Intraventricular Nicardipine for Aneurysmal Subarachnoid Hemorrhage Related Vasospasm: Assessment of 90 Days Outcome
Design	Retrospective case-control study N= 28
Objective	To evaluate the safety and outcomes of intraventricular nicardipine (IVN) for vasospasm (VSP) in aneurysmal subarachnoid hemorrhage (aSAH) patients compared to a control population
Study Groups	IVN-treated (n= 14) Control (n= 14)
Inclusion Criteria	Age ≥ 18 years; aneurysmal or arteriovenous malformation (AVM)-related subarachnoid hemorrhage with computed tomography angiography (CTA) or digital subtraction angiogram (DSA) evidence of intracranial aneurysm or AVM; external ventricular drain (EVD) placed by clinical criteria; documented or abstracted modified Rankin Scale (mRS) and Glasgow Outcomes Scale (GOS) during admission and at 30 (or discharge) and 90 days
Exclusion Criteria	Treated with intraventricular antibiotics for bacterial meningitis-related VSP; no arterial bleeding subarachnoid hemorrhage (non-aneurysmal, non-AVM) or VSP due to another cause; pregnant
Methods	Retrospective chart review was conducted in 13 aSAH patients and one AVM-related SAH patient treated with IVN and 14 aSAH patients without IVN who served as controls. Aneurysmal SAH patients were either treated with coiling or clipping therapy upon admission. All patients received nimodipine to prevent VSP or hypertensive, hypervolemic, and hemodilution (triple H) therapy if symptomatic. Cerebral mean blood flow velocity (MFV) was measured daily by transcranial Doppler (TCD). Patients were initiated on IVN therapy based on the severity of MVF TCD (at least > 180 cm/s), or clinical measurable deficit, or via the attending neurosurgeon. Intraventricular nicardipine was mixed under sterile conditions from a nicardipine vial as a solution into sterile, preservative-free normal saline (0.9%), typically a 1 mg/ml solution. Isovolemic cerebrospinal fluid (CSF) aspiration and injection (e.g. the exact volume in mL to be injected of nicardipine and sterile saline flush had to be withdrawn first as CSF) were used under sterile conditions.
Duration	Follow-up: 30 days and 90 days after SAH
Outcome Measures	MFV of middle cerebral arteries (MCA), mRS (good outcome= 0–2; moderate outcome= 3–4; poor outcome= 5–6), and GOS (favorable outcome= 4–5; unfavorable outcome= 1–3)
Baseline Characteristics		IVN-treated (n= 14)	Control (n= 14)
	Age, years	44.5	45
	Female	12 (83%)	12 (83%)
	Fisher Score 3 4	3 (21%) 11 (79%)	6 (43%) 8 (57%)
	Right-sided aneurysms	9 (64%)	9 (64%)
	Received statins during hospital stay	5 (36%)	8 (57%)
	IV clazosentan		1 (7%)
	Fever during hospitalization	11 (79%)	11 (79%)
	Red blood cell transfusion*	14 (100%)	7 (50%)
	*Red blood cell transfusion given to the patient if their hemoglobin was ≤9 g/dL (except for one patient with a target hemoglobin >10 g/dL due to active ischemia in watershed areas) The median dose of nicardipine used was 4 mg (range 3-7 mg), with a median number of doses of 7 (range 1 to 17).
Results	Endpoint	Pre-IVN	Post-IVN	p-value
	Mean right MCA MFV (range), cm/s (n= 13)	120 (33 to 213)	82 (21 to 166)	0.041
	Mean left MCV MVF (range), cm/s (n= 12)	102 (33 to to 241)	73 (18 to 228)	0.206
	Endpoint	INV-treated (n= 14)	Control (n= 14)	p-value
	30 days mRS Good Moderate Poor 90 days mRS Good Moderate Poor	2 (14%) 3 (21%) 9 (64%) - 3 (21%) 4 (29%) 7 (50%)	5 (36%) 4 (29%) 5 (36%) - 7 (50%) 4 (29%) 3 (21%)	0.156 0.122
	30 days GOS Favorable Unfavorable 90 days GOS Favorable Unfavorable	3 (21%) 11 (79%) 4 (29%) 10 (71%)	5 (36%) 9 (64%) 8 (57%) 6 (43%)	0.443 0.153
Adverse Events	IVN was well tolerated in all 14 patients, and no adverse events were observed.
Study Author Conclusions	IVN appears relatively safe and effective in treating VSP by TCD, but there was no difference in clinical outcomes between nicardipine and control patients at 30 and 90 days. In the future, larger studies are needed to evaluate the clinical outcome with IVN.
InpharmD Researcher Critique	Despite the median dose being reported as 4 mg, patients received doses as high as 7 mg. Evaluation of the safety or efficacy of specific doses was not within the scope of this study.

References:

Lu N, Jackson D, Luke S, Festic E, Hanel RA, Freeman WD. Intraventricular nicardipine for aneurysmal subarachnoid hemorrhage related vasospasm: assessment of 90 days outcome. Neurocrit Care. 2012;16(3):368-375. doi:10.1007/s12028-011-9659-8

Acute effects of intraventricular nicardipine on cerebral hemodynamics: A preliminary finding
Design	Retrospective analysis N= 11
Objective	To examine the acute effects of intraventricular nicardipine (IVTN) on intracranial pressure (ICP), brain oxygen, cerebral blood flow, and brain metabolism using high-resolution multimodality monitoring (MMM) data
Study Groups	All participants (N= 11; 54 doses of IVTN)
Inclusion Criteria	Mechanically ventilated poor-grade subarachnoid hemorrhage (SAH) patients undergoing MMM and treated with IVTN for refractory vasospasm; moderate-to-severe angiographic vasospasm and delayed cerebral ischemia (DCI), defined as clinical deterioration, cerebral infarction, or both
Exclusion Criteria	Not specified
Methods	Patients charts were retrospectively analyzed to identify eligible patients and collect baseline and clinical data. Before IVTN administration, 3-4 ml of cerebrospinal fluid was withdrawn, and the same volume of nicardipine solution (1 mg/mL) was administered via an external ventricular drain (EVD). The usual dose used at the study center was 4 mg Q8H. After administration, EVD was clamped for approximately 1 h and then reopened. Physiological parameters, such as ICP, partial brain oxygen tension (P_btO₂), and cerebral perfusion pressure (CPP), were monitored before and after IVTN administration.
Duration	Enrollment period: June 2008 and December 2010 Follow-up: up to 6 h after IVTN injection
Outcome Measures	Physiologic variables associated with IVTN administration
Baseline Characteristics		All patients (N= 11)
	Age, years	46
	Female	73%
	Initiation of nicardipine after onset of SAH (interquartile range [IQR]), days	10 (7.5 to 11)
	Vasospasm Multiple vessels Bilateral intracranial arteries Refractory severe vasospasm after standard treatments	100% 73% 100%
	Global cerebral edema	100%
	modified Fisher Scale at 3 months 5 6	27.3% 72.7%
	Only one patient received IVTN 3 mg Q12H.
Results	Endpoint	All patients (N= 11)
	Mean ICP, mm Hg^* Baseline Absolute change at 20 min after IVTN p-value	16.2 ± 6.9 2.5 ± 0.9 <0.01
	Mean CCP, mm Hg Baseline Decrease at 20 min after IVTN Decrease at 20 min after IVTN p-value	102.8 ± 7.2 3.7 ± 1.8 3.8 ± 1.8 0.046 and 0.038
	^*Individual variation was high: two patients had an increased ICP by 10 mm Hg after IVTN. Other physiological parameters or autoregulation indices did not change significantly after IVTN administration compared to the baseline.
Adverse Events	Not disclosed
Study Author Conclusions	The vasodilatory effect of IVTN transiently increased ICP but did not significantly affect P_btO₂, cerebral blood flow, or oxidative glucose metabolism in the immediate phase after injection.
InpharmD Researcher Critique	The study was limited by its small sample size, lacks a comparator group, and mainly focuses on the assessment of surrogate endpoints. Clinical outcomes are not explicitly evaluated within the study, and thus long-term effects of IVTN in the setting of SAH-included vasospasm need further investigation.

References:

Ko SB, Choi HA, Helbok R, et al. Acute effects of intraventricular nicardipine on cerebral hemodynamics: A preliminary finding. Clin Neurol Neurosurg. 2016;144:48-52. doi:10.1016/j.clineuro.2016.02.037

Intraventricular Nicardipine for Refractory Cerebral Vasospasm after Subarachnoid Hemorrhage
Design	Case series N= 8
Objective	To report clinical experience with intraventricular nicardipine for refractory vasospasm in eight patients in whom conventional therapies were ineffective, contraindicated, or technically not feasible
Methods	A case series describes the use of intraventricular nicardipine for refractory vasospasm in eight patients with delayed ischemic neurological deficit (DIND) following subarachnoid hemorrhage (SAH) who did not respond to hypertensive, hypervolemic, and hemodilution (triple H) therapy. Additional conventional therapies that were attempted included transluminal angioplasty and calcium channel antagonists. Intraventricular nicardipine 4 mg injection diluted in 8 mL of preservative-free saline every 12 h was injected via the ventriculostomy port and the proximal port was clamped for 1 h, after which it was opened to the baseline drainage level. The nicardipine was continued through post-SAH day 14 or until symptoms resolve. All efforts were made to withdraw 8 mL of cerebrospinal fluid (CSF) prior to administration of the drug to prevent increase in intracranial pressure. Intracranial pressure (ICP) was measured every 15 minutes during the infusion period and CSF was sampled three times weekly for infections.
Baseline Characteristics	Patient	Age/Sex	Aneurysm type	Vasospasm location	DIND onset
	1	45/F	Middle cerebral artery	Bilateral anterior cerebral; left posterior cerebral arteries	Day 5
	2	45/F	Anterior cerebral artery (A1)	Bilateral internal carotid; bilateral middle cerebral; left anterior cerebral arteries	Day 9
	3	40/F	Postero-inferior cerebellar artery	Bilateral internal carotids, anterior cerebral (A1); middle cerebral (M2); right posterior communicating arteries	Day 13
	4	63/F	Anterior cerebral artery (A2)	Bilateral anterior cerebral; middle cerebral arteries	Day 10
	5	76/F	Anterior communicating artery	Diffuse, small vessel vasospasm	Day 9
	6	38/F	Anterior cerebral artery (A1)	Bilateral middle cerebral; inferior cerebral arteries	Day 6
	7	38/F	Anterior communicating artery	Anterior cerebral artery (A2)	Day 7
	8	59/M	Anterior communicating artery	Bilateral anterior cerebral (A1 & A2); middle cerebral arteries (M1 & M2)	Day 5
Results	Patient	Nicardipine start	Reason for nicardipine	Outcome	Treatment length
	1	Day 5	Cardiovascular compromise	Discharged to home; RS 3; F/U CT scan no new ischemic lesions	10 days
	2	Day 9	Poor response to standard therapy; distal location not amenable to angioplasty; cardiovascular compromise	Care withdrawn	17 days
	3	Day 13	Poor response to standard therapy; distal location not amenable to angioplasty	Discharged to home; RS 3; F/U MRI no new ischemic lesions	11 days
	4	Day 11	Poor response to standard therapy (including intra-arterial verapamil)	Discharged to home; RS 2; F/U CT scan no new ischemic lesions	8 days
	5	Day 9	Neuro-interventional radiologist unavailable; severe pulmonary edema and atrial fibrillation with triple H	Discharged to home; RS 2; F/U CT scan no new ischemic lesions	9 days
	6	Day 7	Poor response to standard therapy (including intra-arterial verapamil)	Discharged to home; RS 2; F/U CT scan no new ischemic lesions	8 days
	7	Day 8	Poor response to standard therapy; distal location not amenable to angioplasty	Discharged to home; RS 2; F/U CT scan no new ischemic lesions	5 days
	8	Day 7	Poor response to standard therapy; distal location not amenable to angioplasty	Discharged to rehab; RS 3; F/U CT scan no new ischemic lesions	8 days
	RS: Rankin scale
Adverse Events	Intraventricular nicardipine was generally well tolerated with minimal side effects (of note, no ventriculitis or seizures were observed). One patient experienced nausea and headache, subsequently relieved by the removal of CSF prior to the administration of intraventricular nicardipine.
	Seven patients had mild to moderate disability with six being discharged to home and one discharged to a rehabilitation center.
	One patient with malignant cerebral edema died.
Study Author Conclusions	These preliminary observations suggest that intraventricular nicardipine could be considered as a safe and effective treatment modality to treat vasospasm refractory to conventional management.

References:

Goodson K, Lapointe M, Monroe T, Chalela JA. Intraventricular nicardipine for refractory cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care. 2008;8(2):247-252. doi:10.1007/s12028-007-9017-z