Expert Opinion on the Management of Intracerebroventricular (ICV) Drug Delivery

1. Expert Opinion on the Management of Intracerebroventricular (ICV) Drug Delivery
Irene Slavc1
, Jessica L. Cohen-Pfeffer2
, Sridharan Gururangan3
, Elaina Jurecki2
, Jeanne Krauser3
, Thomas Lester2
, Daniel Lim4
,
Marcos Maldaun5
, Christoph Schwering6
, Adam J. Shaywitz2
, Manfred Westphal6
1
Medical University of Vienna, Vienna, Austria; 2
BioMarin Pharmaceutical Inc., Novato, CA, USA; 3
Duke University Medical Center, Durham, NC, USA; 4
University of California, San Francisco, CA, USA;
5
IEP-Hospital Sírio-Libanês, São Paulo, Brazil; 6
University Medical Center Hamburg-Eppendorf, Hamburg, Germany
©2016 BioMarin Pharmaceutical Inc. All rights reserved.Presented at the 12th Annual WORLD Symposium: 29 February – 4 March, 2016, San Diego, CA
http://www.biomarin.com/pdf/WORLD2016p5.pdf
Results
Background
■■ The ICV route of administration has been used for many decades to treat pediatric
and adult patients with a broad range of central nervous system (CNS) disorders
to achieve therapeutic concentration of medications within the brain that may
otherwise not be possible due to the protective blood-brain barrier1
■■ A systematic literature review revealed that noninfectious complication rates per patient
may be as high as 33%2-7
, while infectious complication rates may reach 27%.8-17
Following stringent measures may significantly lower complication rates (< 5%)5
■■ There has been no consensus in management of ICV devices and associated rates
of reported complications are variable
Objectives
■■ Explore best practices in the management of ICV devices and drug delivery to
achieve lower complication rates
■■ Obtain expert guidance on care and prevention of complications related to ICV
devices and drug administration and identify resources needed to support these
patients in the clinic
Methods
■■ A global expert panel of seven healthcare professionals with experience in ICV
delivery was convened on September 17-18, 2015, to explore best practices for the
management of ICV devices in order to prevent complications
–– Specialties represented: neurosurgery (3), neuro-oncology (1), pediatric neuro-
oncology nurse (1), pediatric hematology oncology (1), pediatrics (1)
■■ Expert opinion and guidance was gathered from participant discussions and survey
that assessed the experience of each participant and standard practice for ICV
access of each participant’s respective institution
■■ All experts were experienced in implantation of ICV devices or access of devices
for chemotherapy administration
–– One expert was experienced in the administration of an investigational drug
administered through ICV infusion as part of an ongoing phase I/II study
Results
Table 1. ICV Management Experience of Expert Panel
Number of ICV Devices Implanted To Date By Respondent
Number of ICV devices Number of respondents
21-49 1
50+ 4
N/A – Unknown 2
Youngest Patient in Whom ICV Device Has Been Implanted By Respondent’s Institution
Age Number of respondents
Birth-6 months 4
26+ years 1
N/A – Unknown 2
Youngest Patient in Whom You Would Recommend Implantation of an ICV Device
Age Number of respondents
Birth-6 months 3
3-5 years 1
6-9 years 1
N/A – Unknown 2
Longest Period For Which An ICV Device Has Remained Implanted
Length of time Number of respondents
2-5 years 1
5-10 years 1
10+ years 4
N/A - Unknown 1
Site of ICV Device Access and Drug Delivery
Site Number of respondents
ICU (Per Clinical Trial Protocol) 1
Inpatient – step down unit 1
Inpatient – hospital room 1
Outpatient – day unit room 3
N/A 1
Maximum Number of Punctures A Device Is Able To Sustain
Number of Punctures Number of respondents
30-49 2
200-299 1
N/A - unknown 4
Presence of Policy/Protocol for Aseptic/Sterile Technique at Institution
Response Number of respondents
Yes 1
No 4
N/A - Unknown 2
Conclusions
■■ ICV drug delivery is an effective route of administration into the CNS, and can be done
safely when stringent measures are taken to prevent complications
■■ All experts agreed that by following strict aseptic techniques and limiting the accessing
of the device to a select group of well-trained personnel, the rate of infection for ICV
devices can be kept at a minimum
■■ Key expert recommendations include:
–– Taking extreme care to follow strict aseptic/sterile techniques in the management and
access of ICV device
–– Limiting personnel performing the access to those with the training and expertise in
the puncture and aseptic techniques
–– Proper implantation of device away from the incision
–– Waiting a minimum of 5 days after device implantation before first use of device to
allow proper wound healing and reduce the risk of backflow of the administered drug
through the catheter tract
–– All personnel/caregivers wear masks during the procedure
–– Skin disinfection 3-5 times with iodine or alcohol-based disinfectant and use sterile gloves
Figure 1: Best Practices – Preparation of Injection Site and Access of ICV Device
Funding:
BioMarin Pharmaceutical Inc. provided funding for the meeting, writing, editing, and poster production.
References:
1. Cook A, Mieure,K, Owen R et al. Intracerebroventricular Administration of Drugs. Pharmacotherapy 2009;29(7):832–845. 2. Brouwer AJ, Groenendaal F, van den Hoogen A, de Vos JE, de Vries LS. Ventricular reser-
voir punctures performed by nurses: an improvement in quality of care. Neonatal Netw 2010;29:243-8. 3. Bruinsma N, Stobberingh EE, Herpers MJ, Vles JS, Weber BJ, Gavilanes DA. Subcutaneous ventricular catheter
reservoir and ventriculoperitoneal drain-related infections in preterm infants and young children. Clin Microbiol Infect 2000;6:202-6. 4. Levy ML, Masri LS, McComb JG. Outcome for preterm infants with germinal matrix
hemorrhage and progressive hydrocephalus. Neurosurgery 1997;41:1111-7. 5. Peyrl A, Chocholous M, Azizi AA, et al. Safety of Ommaya reservoirs in children with brain tumors: a 20-year experience with 5472 intraven-
tricular drug administrations in 98 patients. J Neurooncol 2014;120:139-45. 6. Pompe R, Von Bueren A, Von Hoff K, et al. Feasibility and toxicity of intraventricular methotrexate for primary therapy of patients with childhood
medulloblastoma treated within the hit 2000 trial. Neuro-Oncology 2012;14:i97-i. 7. Richard E, Cinalli G, Assis D, Pierre-Kahn A, Lacaze-Masmonteil T. Treatment of post-haemorrhage ventricular dilatation with an Omma-
ya’s reservoir: management and outcome of 64 preterm infants. Childs Nerv Syst 2001;17:334-40. 8. Chamberlain MC, Kormanik PA, Barba D. Complications associated with intraventricular chemotherapy in patients with
leptomeningeal metastases. J Neurosurg 1997;87:694-9. 9. Cramond T, Stuart G. Intraventricular morphine for intractable pain of advanced cancer. J Pain Symptom Manage 1993;8:465-73. 10. Gwak HS, Lee CH, Yang
HS, et al. Chemoport with a non-collapsible chamber as a replacement for an Ommaya reservoir in the treatment of leptomeningeal carcinomatosis. Acta Neurochir (Wien ) 2011;153:1971-8. 11. Kim DK, Uttley D, Bell BA,
Marsh HT, Moore AJ. Comparison of rates of infection of two methods of emergency ventricular drainage. J Neurol Neurosurg Psychiatry 1995;58:444-6. 12. Kramer K, Smith M, Souweidane MM. Safety profile of long-term
intraventricular access devices in pediatric patients receiving radioimmunotherapy for central nervous system malignancies. Pediatr Blood Cancer 2014;61:1590-2. 13. Lishner M, Perrin RG, Feld R, et al. Complications
associated with Ommaya reservoirs in patients with cancer. The Princess Margaret Hospital experience and a review of the literature. Arch Intern Med 1990;150:173-6.14. Mead PA, Safdieh JE, Nizza P, Tuma S, Sepkowitz
KA. Ommaya reservoir infections: a 16-year retrospective analysis. J Infect 2014;68:225-30. 15. Perrin RG, Lishner M, Guha A, Curtis J, Feld R, Messner H. Experience with Ommaya reservoir in 120 consecutive patients
with meningeal malignancy. Can J Neurol Sci 1990;17:190-2. 16. Sampath R, Wadhwa R, Tawfik T, Nanda A, Guthikonda B. Stereotactic placement of ventricular catheters: does it affect proximal malfunction rates? Ste-
reotact Funct Neurosurg 2012;90:97-103. 17. Szvalb AD, Raad II, Weinberg JS, Suki D, Mayer R, Viola GM. Ommaya reservoir-related infections: clinical manifestations and treatment outcomes. J Infect 2014;68:216-24.
18. FDA Safety Communications: Information about Huber Needles [press release]. Silver Spring, MD: U.S. Food and Drug Administration; May 12, 2015. http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/
ucm198719.htm. Accessed on February 1, 2016. 19. Obwegeser A, Seiwald M, Stickhammer, G. Intraventricular Chemotherapy. J Neurosurg 1998; 89:172-173.
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Considerations with Implantation of ICV Device
■■ ICV device implantation is a common procedure that is performed using
stereotactic aides in most facilities for precision
–– It is important to follow strict aseptic technique throughout the procedure and implant
the device away from the incision to minimize the risk of complications
–– Use of a neuro-navigation system may be helpful in the precise placement of the
catheter tip in smaller size ventricles
–– Immediate post-operative imaging (CT/MRI) is strongly recommended to ensure
precise placement of catheter within the appropriate ventricular holes and to correct
improper positioning
■■ Wait a minimum of 5 days after device implantation before first use to allow
proper wound healing and reduce the risk of backflow of the administered drug
through the catheter tract19
■■ CSF flow is the hallmark test to confirm if device and catheter are in the correct location
–– Intraoperative or post-operative imaging is recommended after ICV device implantation
to confirm appropriate placement
Preparation (Figure 1)
Disinfection
■■ Rigorous cleaning of puncture site and surrounding area with iodine or alcohol-
based solution is a crucial aspect of aseptic technique
■■ Although commonly used to clean with 3 swabs, some recommend using 5 swabs
with good outcomes
■■ Some recommend the use of chlorhexidine shampoo the night prior or morning of
the infusion
Hair removal
■■ Several experts stated they perform hair removal before every drug administration,
while others reported that it was based on physician’s preference or when necessary
■■ Experts agreed that if hair removal was performed, it should be done with caution
not to cause skin abrasions
■■ Recommended methods of hair removal included depilatory cream and electric
clippers; razor may be used with great care only by select experienced personnel
ICV Device Access (Figure 1)
Device Access
■■ Some experts recommend use of local anesthetic cream on the site of the puncture
■■ Butterfly needles are used for short bolus infusions. Port-a-cath needles
(non-coring Huber needles18
) were recommended for longer infusions due to better
fit and fixation
■■ Experts recommend puncturing the device in the center of the dome without
perforating the bottom of the reservoir
■■ Immediately after puncture, withdraw CSF (1-10ml): 1) to check patency
of catheter 2) for CSF analysis (optional) 3) for isovolumetric drug delivery
especially with larger volumes >5-10ml
■■ If there is no CSF return, recommendation is to consult directly with neurosurgeon
(without proceeding with the drug delivery)
■■ Expert opinion was evenly split regarding routine CSF analysis (collected prior to
drug administration)
–– The frequency of CSF analysis was reported as follows:
ŸŸ When infection is suspected
ŸŸ Every drug administration
ŸŸ Every time ICV device is accessed
■■ Limit the traffic in and out of the area when performing the access of the device - all
personnel/caregivers must wear masks during the procedure
Drug Administration
■■ All experts recommend flushing (e.g. CSF, artificial CSF or preservative-free saline)
the tubing, reservoir and internal cannula to ensure complete delivery of the drug
■■ Drug administration by bolus over 10-15 minutes or by slow infusion is adequate to
achieve sufficient flow and pressure and is postulated to result in proper distribution
throughout CSF cavities
Follow-up (Figure 1)
Post-administration Procedure
■■ Remove needle and cover injection site with sterile gauze while applying gentle
pressure, followed by sterile patch
■■ Most experts recommend to avoid pumping of reservoir
Patient Counseling
■■ Majority of experts indicated that they provided instructions to patients/caregivers
regarding home care of their ICV device, including:
–– Leaving the dressing in place for 24-48 hours especially for prolonged infusions
–– Watch for signs of infection (i.e. swelling, pain, discharge, fever); if signs of infection or
changes in mental status seek immediate medical care
–– Avoid direct trauma to the reservoir
–– Wash daily with neutral shampoo
–– Regularly wash the hair before intrathecal therapy and avoid touching or scratching the
skin over device location
Complications
■■ Though ICV device complications varied, the most commonly reported complication
was infection
–– Skin bacteria (staphylococcus epidermidis, streptococcus and propionibacterium
acnes) were the most commonly found bacteria in cases of infection
–– Most respondents agreed that upon confirmed infection, device usually needs to be
removed, followed by a 10-14 day treatment with IV antibiotics
–– If device is removed, most experts agreed that the waiting period for reimplantation
depends on the length of treatment with antibiotics or until at least 3 CSF cultures are
consecutively sterile. Experts report successful reimplantation
■■ It is highly recommended for a neurosurgeon to be present during drug administration
or have on-call availability within 2-3 hours; however, it is not necessary for a
neurosurgeon to be present at every instance of drug administration
■■ Following appropriate procedures may limit complications. Study by Peryl et al5
utilized protocol-specified aseptic measures, with one case of infection observed over
the 20-year trial period with more than 5000 ICV device accesses in 97 patients
Preparation
ŸŸ Position the patient in a 45-degree “sitting up” or
reclining posture
Materials
ŸŸ Use new pair of sterile gloves, gown, cap and mask for
each instance of ICV access
ŸŸ All personnel/caregivers must wear gloves and masks
Disinfection of skin
ŸŸ Perform rigorous cleaning of puncture site and surrounding
area with iodine-based or alcohol-based solution (betadine,
Isozid) ± chlorhexidine
ŸŸ Use multiple separate swabs 3-5x
Hair removal
ŸŸ If preferred, remove hair carefully around the reservoir
ICV Device Access
Accessing the reservoir
ŸŸ Palpate scalp to identify the reservoir
ŸŸ Use a 24-25G non-coring needle
ŸŸ May use a butterfly or smaller gauge needle for bolus
administrations
ŸŸ Port-a-cath needles (non-coring Huber needles) are
recommended for longer infusions
Aspiration of fluid
ŸŸ Aspirate needed volume of CSF (1-10ml) for:
1. ensuring patency
2. CSF analysis as needed
3. isovolumetric drug delivery as needed (with larger
volumes >5-10ml)
ŸŸ If there is no smooth flow of CSF, stop the procedure and
consult with neurosurgeon
Flush line with flushing solution
Follow-up
Administer medication
ICV Device Access
Post-administration procedure
ŸŸ Remove needle, and cover injection site with sterile gauze
while applying gentle pressure
ŸŸ Cover with sterile patch
ŸŸ Avoid pumping of reservoir
Patient counseling
ŸŸ Leave the dressing in place for 24-48 hours, and wash daily
thereafter with neutral shampoo
ŸŸ Watch for signs of infection (i.e. swelling, pain, discharge,
fever)
ŸŸ Avoid direct trauma to the reservoir
ŸŸ Regularly wash the hair before intrathecal therapy
ŸŸ Avoid touching or scratching the device location
Patient positioning