Viva B(vii)

This viva is relevant to the objectives of Section B(vii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the pharmacokinetics of drugs in the epidural and subarachnoid space"

What are the anatomical characteristics of the epidural space?

According to Anatomy for Anaesthetists by Ellis et al (8th ed, 2004 - p.121) its extent is as follows:

• Superiorly, the epidural space extends to the foramen magnum, where it terminates at the fusion of  spinal and periosteal layers of dura mater. This has some relevance for awful accidents (i.e. the intracranial extension of epidurally infused drugs is made impossible by this fixed anatomical limit).
• Inferiorly, the epidural space extends to the sacrococcygeal membrane.
• Posteriorly, it is bounded by the vertebral laminae, capules of the facet joints and the ligamentum flavum
• Laterally, it is bounded by the pedicles of the vertebral arches and the intervertebral foraminae
• Anteriorly, it is bounded by the vertebral bodies, intervertebral discs and posterior longitudinal ligament.
• Its contents are fat, nerve roots, blood vessels,  lymphatics and various haphazard fibrous connections to the ligamentum flavum (which can have an unpredicatble effect on the course of an epidural catheter
• It communicates freely with the paravertebral space via intervertebral foraminae.
• Its arterial supply arises from anterior and posterior spinal arterial arcades, arising from spinal arteries entering the space through every intervertebral foramen. These anastomose freely with the anterior spinal artery.
• Its venous drainage is via a plexus of valveless veins (Bateson's plexus) which is in the anterior epidural space. There are also posterior veins, which are most prominent in the cervical epidural space. The venous plexus receives blood shunted from thoracic and pelvic veins, which means that straining and coughing can transiently engorge them.
• The space is irregular and segmental

What is the capacity of the epidural space?

• Approximately 40ml in the adult

What are the routes of disposition for an epidurally injected drug?

From the epidural space, drugs may go four ways:

• Exit the intervertebral foramina to reach the paraspinous muscle space
• Distribute into epidural fat
• Diffuse into ligaments
• Diffuse across the spinal meninges and into the CSF

What is the main mechanisms and determining factors for epidural drug penetration to the site of action?

Diffusion:

• Concentration
• Surface area, which is largely determined by the volume of the infused drug
• Lipid solubility, and therefore pKa of the drug and pH of the solution 
• Protein binding, which determines the free fraction of the drug

Fat distribution (into epidural fat)

• This is responsible for the 5-10-fold dose difference between subarachnoid and epidural drug administration. The drug then forms a reservoir and redistributes gradually, creating a longer effect

CSF flow and volume:

• The availability of fresh CSF to the administration site results in an increased movement of the drug from its epidural fat reservoir

What are the anatomical characteristics of the subarachnoid space?

• The subarachnoid space is the space between arachoid mater and pia mater. It contains the CSF, and the spinal subarachnoid space communicates with the CSF spaces in the head.
• At the level of the smalls vascular structures in the pia mater, the arachoid space extends along the vessel walls as they penetrate into the spinal cord. There, the arachnoid space interfaces with a series of miniscule pia-lined fluid pockets associated with at least all the arteriole and venules in the CNS (Lam et al, 2017), if not individual groups of neurons. These little fluid pockets are called perivascular spaces or Virchow–Robin spaces in the literature.
• The diffusion distance is not very great - the high CSF concentration achieved by injecting directly into the CSF easily penetrates to the target site (substantia  gelatonosa, lamina II - only 2mm deep). In fact, nowhere in the spinal cord are you ever further than 5mm from some CSF.

What are the features of drug penetration to the target site in intrathecal administration?

• High CSF concentration  is achieved rapidly. Absorption into spinal tissue is therefore very rapid. With no meninges in the way of diffusion, the dose required is much smaller.
• Bypassing the blood-brain barrier is made easier with administration directly into the CSF, and drugs which conventionally are to hydrophilic to cross (eg. methotrexate) can be administered in this fashion. The high concentration which they achieve in this manner improves the penetration of even the least lipid-soluble drugs.
• Systemic absorption is slower than with epidural, and there is no rapid distribution phase. This is because the epidural space is rich with vascular structures which permits rapid uptake. The perfusion of the subarachnoid space is less extensive, and systemic distribution of the drug will be slower. This has implicaions for drug effect. Drugs which would otherwise be rapidly metablised or distributed (eg.  fentanyl or morphine) have persisting effects because their absorption from the CSF wil be slow, and there is nothing there to metabolise them.
• Increased half-life particularly for hydrophlic drugs can be expected, largely because of the above. "A few hours" is mentioned by Kroin (1992). The more lipophilic the drug is, the more rapidly absorbed into the spinal capillaries and therefore the more rapidly cleared from the CSF. 

What is "baricity", and how does it influence drug distribution in the CSF?

• Baricity is defined as the density of the solution divided by the density of the CSF, which is usually 1.003 g/ml. 
• Baricity of solutions is by convention compared at  37°C, as temperature affects the density of solutions (density is inversely related to temperature; the hotter it gets the less dense the solution).
•  Isobaric solutions have the same density as the CSF; and therefore presumably they stay put wherever they've been injected.
• Hyperbaric solutions are heavier than CSF and therefore sink, which means if the patient is sitting upright the local anaesthetic will really only affect their sacral nerve roots.
• Hypobaric solutions are lighter than CSF, and will float to the surface.