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Anesthesia Pharmacology Chapter 13: Opioid Pharmacology Advanced Topics
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17Sensory Evoked Potentials: A more detailed look with emphasis on Clinical Application
17SSEP of course can be induced by physiological stimulation such as muscle stretch; however, as noted earlier the potential is usually elicited by an electrical stimulation.
The electrical stimulation is delivered usually by surface electrodes which provide a depolarizing electrical square waveform with the duration ranging from 0.2-2 ms.
Intraoperative monitoring may utilize "needle" electrodes which permit use a smaller currents less likely to induce significant stimulus artifacts.
As noted earlier, typical stimulation sites include the median nerve at the rest, the common peroneal nerve at the knee and the posterior tibial nerve.
17for mixed peripheral nerves, sensory perception threshold is lower than the stimulus threshold required to cause muscle movement.
Therefore, in this case the stimulating current would be adjusted to minimize joint movement; the amount of current is generally well-tolerated by patients.
Usually recording electrodes be localized on the scalp and over the cervical spine.
For upper extremity recording of SSEPs, the electrodes are localized over the Erb point which is the point on the side of the neck 2-3 centimeters above the clavicle and in front of the transverse process of the sixth cervical vertebra. (This point was named after Wilhelm Erb and pressure over this point causes Duchenne-Erb paralysis whereas electrical stimulation in this region causes various arm muscles to contract). For lower extremity SSEP recording, electrodes would be placed over the lumbosacral spine.
17SSEP waveforms:
These waveforms are analyzed in terms of three major elements: morphology, amplitude and dispersion.
Reference values are defined for each laboratory in terms of electrical latencies and interpeak latency andare normalized for patient height and age.
Conduction velocity is temperature dependent therefore minimum skin temperature values would have to be established also for each laboratory.
Latency values are used to classify responses.
For example, short latency SSEPs describes the initial portion of the SSEP waveform which follows within 25 ms of stimulation for the case of the upper extremity nerves, 40 ms following peroneal nerve stimulation and 50 ms following tibial nerve stimulation.
Long latency references waveforms recorded at a time > 100 ms: stimulation.
Similarly, middle latency SSEPs describes the waveforms occurring between these two other time points.
Nerve stimulation is the current clinical standard; however, other methods exists that include cutaneous or stimulation, dermatomal stimulation (thought to be more specific than cutaneous stimulation), motor point stimulation (direct muscle) and paraspinal stimulation.
17SSEP stimulus: the stimulus preferentially will activate only the largest myelinated fibers within the peripheral nerve.
This activation within include cutaneous and subcutaneous fibers, somesthetic (dealing with sense perception; i.e. somatosensory) and proprioceptive fibers as well as motor axons of comparable diameter.
Predominantly large diameter, fast-conducting muscle group and group II cutaneous fibers are activated.
As described earlier, stimulation would produce action potentials that are transmitted towards the spinal cord and past cell bodies of the sensory axons of the large-fiber sensory system in the dorsal root ganglia then proceeding to the ipsilateral posterior columns of the spinal cord.
Only at this point does the action potential propagate across a synapse in the dorsal column nuclei at the cervicomedullary junction.
The information then travels in second-order neurons to the ventroposterolateral nucleus of the thalamus (VPL) by way of the medial lemniscus.
In the VPL, another synapse occurs, now with a third-order neuron with the information now traveling to area 3b of the parietal sensory cortex.
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17Principal SSEP clinical uses:
"Evaluation of the perform nervous system in a large-fiber sensory tracks in the CNS.
Localization of the anatomic site of somatosensory pathway lesions.
Identification of impaired conduction caused by axonal loss or demyelination
Confirmation of a nonorganic cause of sensory loss."
17Specific applications for SSEP in evaluation of the peripheral nervous system
SSEP analysis is infrequently used to assess peripheral neuropathy since nerve conduction studies represent a better clinical diagnostic choice.
When SSEP approaches are used, then the stimulation would be applied at multiple sites and responses recorded over the scalp.
With polyneuropathies and mononeuropathies, SSEP waveforms may evidence delayed latency is within normal center conduction velocity or may be absent.
SSEPs may be used to measure afferent fiber conduction velocities in proximal segments. Due to the peripheral neuropathy itself, higher stimulation currents are typically needed.
In terms a specific disorders, SSEP analysis has been applied in the following settings:
Hereditary neuropathies such as Charcot-Marie-Tooth disease, which is an inherited, degenerative peripheral nerve disorder in which produces muscle weakness with atrophy and hands, feet, legs, and forearms.
A progressive loss of use in sensation in the limbs occurs.
Diabetic neuropathy
Inflammatory polyradiculopathy is, such as Guillain-Barre syndrome, a peripheral nerve inflammatory disorder associated with weakness, numbness, or tingling in the arms and legs and possibly associated movement loss and loss of feeling in the legs, arms, upper body, and face.
Infectious etiologies such as HIV
Toxic neuropathy
17Specific applications for SSEP in evaluation of the spinal cord
Trauma settings: with complete cervical spinal cord lesions, scalp-recorded SSEPs will be absent. However, less complete lesions result in SSEP abnormalities analysis of which can facilitate localization of the sensory level involved in the trauma and may also have prognostic value.
Surgical monitoring:
SSEP analysis and is often used to assess the condition of spinal cord during those surgeries in which the spinal cord is being manipulated. The type of surgery is that are most likely to utilize SSEP monitoring would be scoliosis correction. During the surgical procedure, should ischemia occur in the ascending somatosensory pathways, the SSEP would exhibit a reduction in amplitude or loss of waveforms. Should such a change occur, the operative procedure may be modified hopefully preventing any permanent deficit. Such ischemic abnormalities are noted to be relatively widespread; furthermore, it appears unlikely that motor function would be lost in the absence of somatosensory pathways being also affected. Other surgical procedures that are likely to utilize SSEP monitoring include vertebral fracture reduction, other vertebral injuries and spinal cord tumor resection.
Other SSEP uses include application for the following conditions:
Transverse myelitis
Subacute combined degeneration
Cervical spondylosis and myelopathy
Syringomyelia
Multiple sclerosis
Vascular lesionsT
Tumors,
Myelomeningocele
Tethered cord syndrome
Infectious disorders including human T-lymphocytic virus 1 and HIV.
17Specific applications for SSEP in evaluation of the brainstem and brain
Multiple sclerosis: SSEPs of upper extremities are abnormal in about 60% of patients with MS.
This percentage is associated with those patients who exhibit MS symptoms.
In asymptomatic patients, SSEPs are abnormal about 40% of the time.
SSEP abnormality is more likely to be detected in lower extremities since associated longer axons are more likely to exhibit areas of demyelination.
The most likely change in the SSEP and MS would be a prolongation of central latency.
SSEP testing in MS has generally been superseded by magnetic resonance imaging (MRI).
Other demyelinating disorders: SSEP abnormalities would also be seen in the following demyelinating pathologies:
Adrenoleukodystrophy
Metachromatic leukodystrophy
Adrenomyeloneuropathy.
Coma: SSEPs analysis is also useful in assessing a comatose patient both from a diagnostic and prognostic point of view.
About 75% of those comatose patients who retain bilateral cortical SSEP responses ultimately exhibit favorable outcomes.
An unfavorable prognosis however is associated with absence of cortical responses bilaterallycome e.g. persistent vegetative state, whereas the presence of a unilateral cortical SSEP response may suggest possible favorable outcome.
In "brain death" SSEP analysis reveals preservation of peripheral components with loss of responses typically generated by neural structures above the lower medullary levels.
17Surgical monitoring SSEP methods:
A shown in the image on the preceding page, electrode strip or grid electrodes may be applied to the exposed cortex during or surgical procedures that require activity in the vicinity of the somatosensory cortex.
The N20 responses used to identify the primary somatosensory cortex in the postcentral gyrus (the N20 responses represent the mean sensory conduction time from wrist to cortex).
With this approach, the motor cortex in the precentral gyrus can be localized also in this localization can facilitate development of the surgical plan.
During vascular surgery (e.g. carotid endarterectomy) scalp-recorded SSEPs can be used to judge possible development of cerebral ischemia although EEG monitoring is more likely used in this application.
A relatively new technology, magnetoencephalography, can be used to measure SSEP.
Magnetoencephalographic information which allows noninvasive cortical mapping can be correlated with imaging information obtained from magnetic resonance.
The combination of magnetoencephalography and MRI can facilitate the development of the surgical plan which might minimize risk of neurological deficit on one hand or provide a better estimation of the risk of the development of such deficits associated with surgery on the other.
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1Intravenous Opioid Anesthetics: Cerebral Blood Flow
1Administration of other drugs/anesthetics influence the effect of opioids on cerebral blood flow.
However, opioids themselves slightly decrease cerebral metabolic rate by about 17% and decrease intracranial pressure (ICP).
In the context of vasodilation produced by inhalational agents, opioids they will produce cerebral vasoconstriction.
In the presence of nitrous oxide, opioids will diminish cerebral blood flow (CBF). Cerebral blood flow is not affected substantially by opioids alone.
1,1tPositron emission tomography analysis
following fentanyl administration (1.5
g/kg,
IV) to human volunteers indicated that fentanyl effects on blood flow were
heterogeneous.
For example, pain increased regional cerebral blood flow in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, in contralateral supplementary motor area.
Fentanyl increased regional blood flow in the anterior cingulate in contralateral motor cortices but decreased the regional blood flow in the thalamus (bilateral effect) and posterior cingulate during both stimuli.
With pain stimulation as well as fentanyl administration, fentanyl appeared to augment pain-related regional blood flow increases in the supplementary motor area and prefrontal cortex.
This PET-based activation patternaccompanied decreased pain perception using the visual analogue scale.
This analysis indicated that fentanyl analgesia appeared to augment pain-evoked cerebral responses in some areas but activated and inhibited other brain regions that were not responding to pain stimulation by itself.
1For patients undergoing carotid artery surgery, CBF during fentanyl-nitrous oxide or isoflurane (0.75%)-nitrous oxide anesthesia was reduced relative to halothane (0.5%)-nitrous oxide anesthesia.
Furthermore, balanced anesthesia with fentanyl-nitrous oxide appeared to better maintain the cerebrovascular response to CO2 in those patients with an edematous brain relative to isoflurane-nitrous oxide anesthesia protocols.
1Sufentanil and fentanyl have been noted to
increase middle cerebral artery blood flow velocity by about 25%; other
clinical research indicated that in healthy human volunteers, sufentanil
(0.5 g/kg IV)
did not result in effect on CBF.
In a patient group consisting of
those undergoing carotid endarterectomy, sufentanil 1.5-2.0-g/kg
bolus + 0.2-0.3-g/kg/h
infusion of-nitrous oxide anesthesia caused CBF effects comparable to that
observed with isoflurane (0.75%)-nitrous oxide anesthesia with maintenance
of CO2 cerebrovascular reactivity.
Alfentanil (25 or 50 g/kg
IV) given to patients who were receiving isoflurane (0.4-0.6%)-nitrous oxide
anesthesia resulted in very small reductions in middle cerebral artery flow
velocity.
CBF values during remifentanil-nitrous oxide anesthesia were reported similar to CBF values measured during fentanyl-nitrous oxide and isoflurane-nitrous oxide anesthesia, at the same time cerebrovascular reactivity to CO2 remained.
1Intravenous Opioid Anesthetics: Intracranial Pressure
Generally, opioids do not have significant effects on intracranial pressure (ICP).
For patients undergoing craniotomyfor supratentorial space-occupying tumors, opioids do not cause significant increases in ICP or CSF pressure (anesthesia was provided utilizing isoflurane-nitrous oxide).
ICP does not appear to be altered in head-injury patients who are receiving opioids sedation.
However, other research indicates that harmful opioid-induced ICP effects could be produced, even in the context of patients undergoing craniotomy for supratentorial tumors with mass effect, opioids could increase ICP, perhaps particularly if intracranial compliance has been compromised by tumor dimensions.
Accordingly, the precise effect of opioid administration on intracranial pressure may vary depending on the precise clinical circumstance as well as on potentially the nature of the background anesthetic.
For certain brain tumor patients
anesthetized with thiopental-nitrous oxide-vecuronium, following
sufentanil (1
g/kg)
CSF pressure increased nearly twofold and increased by about 1.2X
following alfentanil (50g/kg).
Comparable patients exhibit a reduction in CSF (5%) following fentanyl
(5g/kg).
This last result has been verified by an additional worker with respect to fentanyl and alfentanil.
Again, on the other hand, other
studies reported no effect of alfentanil (70g/kg
infused over 6 minutes) on ICP in hydrocephalic patients (age
range: 1.3-20
years) who were operated on for shunt revision under isoflurane
(0.5%)-nitrous oxide anesthesia.
Yet, in a different study results
indicated that sufentanil (0.6g/kg)
and fentanyl (3
g/kg)
administration caused significant increases in ICP in fully
resuscitated individuals who had severe head trauma.
In reviewing all these studies, it appears difficult to predict the exact effect on opioids in any specific circumstance.
It is possible that inconsistent results could be due to differences in ICP or CSF pressure assessment methodologies, due to influences of other drugs present, or for reasons undetermined.
Consult the details in reference 1, if desired, for references to the primary literature, the results from some of which have been noted above).
The possible effects of opioids on ICP-focusing on increases in ICP may be due to direct cerebrovascular influences and/or more indirect effects secondary to changes in mean blood pressure or cerebral perfusion pressure with compensatory cerebral vasodilatation.
Which one of these possibilities is more likely true remains for future research to decide.
If ICP effects to the opioids were principally secondary to opioid-induced cardiovascular effects, then rapid management of such cardiovascular effects could reduce or prevent adverse ICP effects.
ICP increases could also be secondary to opioid-induced rigidity.
At least for fentanyl, CSF production rates and CSF reabsorption rates do not appear to be affected.
1Intravenous Opioid Anesthetics: Muscle Rigidity
1Increases in muscle tone and muscle rigidity may be associated with opioid administration.
Patients
receiving dehydrobenzperiol (0.44 mg/kg) along with fentanyl (8.8
g/kg)
have a four out of five chance of exhibiting some rigidity.
A single IV fentanyl dose of 0.5-0.8 mg will reliably induce chest wall rigidity within about 60-90 seconds.
Variations in dosage and administration speed are probably responsible for differing incidence of rigidity.
Other factors that contribute to variability include whether or not nitrous oxide is used, the presence or absence of muscle relaxants in patients age.
2Relatively large doses of IV morphine ( 2 mg/kg infused at a rate of 10 mg/minute) induces abdominal muscle rigidity with reduced thoracic compliance.
The maximal effect under these circumstances is reached at about 10 minutes following administration.
Individuals receiving smaller morphine doses in the rate of 10-15 mg have recounted feelings of muscle tension usually in the neck or legs with occasional presentations around the chest.
Elaborating on the nitrous oxide effect noted above, muscle rigidity is significantly increased by 70% nitrous oxide.
Following high-dose opioids, myoclonus in the absence of the EEG evidence of seizure activity has also been noted.
2Muscle rigidity secondary to opioid
administration appears to be a
-receptor
mediated activity at supraspinal sites such as the nucleus raphe pontis
in addition to lateral proximal sites.
2Opioid-induced rigidity can be managed or eliminated by drugs such as naloxone as well as those agents which increased GABA agonist action including thiopental and diazepam and other muscle relaxants.
1Rigidity secondary to opioids may be described by increasing muscle tone which can progress to severe stiffness.
The clinically significant opioid-induced rigidity is usually first detectable just as or immediately after the patient loses consciousness. In conscious patients relatively mild presentations of rigidity manifest as hoarseness. The most frequent initial identifier of opioid rigidity is wrist flexion.
Time course of rigidity: occasionally rigidity can occur upon anesthesia emergence and less commonly hours following the last opioid dose administration.
These delayed or postoperative events are most likely explained by pharmacokinetic manifestations i.e. second peaks in plasma opioid concentrations.
1Pulmonary consequences:
Rigidity can cause a reduction in pulmonary compliance as well as reduced functional residual capacity.
Sometimes more importantly, opioid-induced rigidity may diminish or even prevent adequate ventilation resulting in hypercarbia, hypoxia with elevations in ICP.
1Cardiovascular consequences:
Opioid-induced rigidity changes in number of hemodynamic parameters-including causing an increase in pulmonary artery and central venous pressures as well as an increase in pulmonary vascular resistance.
Arterial blood pressure and cardiac output remained relatively constant.
1Abdominal and/or thoracic muscle rigidity (wooden chest syndrome) was thought to be the reason for opioid-induced impairment of spontaneous or controlled ventilation in the nonparalyzed individual.
Apparently, the difficulty in bag ventilation and masking following opioid administration is mostly due to vocal cord closure.
1More about the opioid induced rigidity mechanisms:
Opioid-induced rigidity is not to due to a direct action on muscle fibers; however the precise mechanism remains to be elucidated.
This conclusion follows from the observation that opioid-induced fiber rigidity can be prevented by pretreatment with muscle relaxants.
Furthermore opioid-induced muscle rigidity is not accompanied by increases in creatinine kinase, a result indicating that limited or no muscle damage occurs with rigidity.
From the electrophysiological point of view, opioids have limited effects on neuromuscular conduction depressing only minimally monosynaptic reflexes associated with muscle stretch receptors.
-receptor
agonists as opposed to 
-or 
-
agonists are effective in inducing rigidity (in the rat model).
Stimulation of GABA interneurons can result in a rigidity which can be blocked by stray lesions.
Striatonigral GABA pathways thought to be rigidity-related are influenced by GABA agonists and antagonists.
There has been some suggestion of relationships between basic neurochemical mechanisms that are involved in Parkinson's disease and opioid-induced catetonia and rigidity.
This consideration follows from the increase opioid-induced rigidity with age as well as muscle movement abnormalities similar to extrapyramidal side effects.
1More about management of opioid-induced rigidity:
Rapid termination of opioid-induced rigidity follows from succinylcholine administration.
Succinylcholine also obviates associated cardiovascular changes and typically allows controlled ventilation.
Preventative measures are however considered more definitive in dealing with this problem.
Administration of nondepolarizing muscle relaxants reduces severity and incidence of rigidity.
Beyond this observation some inconsistency exists in the literature concerning other approaches.
For example thiopental induction doses with reduced relative to anesthetic doses of diazepam and midazolam may prevent, reduced, or effectively manage rigidity.
On the other
hand, the reliability of benzodiazepines in this application has
been questioned. Opioid-induced rigidity may also be attenuated by
administration of ketanserin, amantadine, and
2-agonists.
The best method to avoid rigidity in clinical practice appears to involve concomitant administration of a "priming" size dose of a nondepolarizing agent along with avoiding rapid large dose administration of any opioid.
The use of an "priming" dose of nondepolarizing agent is to avoid the possibility of muscle relaxation prior to unconsciousness.
Opioid-induced rigidity in the presence of apnea has been taken to indicate unconsciousness.
Anesthetists may choose to demonstratethe ability to mask ventilate the patient following anesthesia induction but prior to the administration of a muscle relaxant.
This approach will be of only questionable value should opioid-induced rigidity occur during induction, resulting in increased difficulty or even impossibility of patient ventilation.
In view of this observation, should a patient presents with a difficult airway, or the possibility of a difficult airway, or other circumstances exist requiring assurance of the patient must be/can be manually ventilated prior to neuromuscular blockade, as a consequence that only small opioid doses should be given during induction.
Efforts to mask ventilate a patient with opioid-induced muscle rigidity can result in gastric insufflation with inadequate ventilation and oxygenation pending administration and activity of muscle relaxant.
With large doses of opioids used, anticipation of the need for rapid neuromuscular blockade should be part of preoperative planning.
2Intravenous Opioid Anesthetics: Nausea and Vomiting
Nausea and vomiting are significant side effects of morphine and related compounds.
Interoperative opioids as well as morphine premedication may be associated with increased incidence of postoperative vomiting.
This issue is particularly important in view of increasing prominence of same day surgical procedures and and the observation that nausea and vomiting may predispose to an overnight stay.
Independent of the route of administration (oral, intravenous, intramuscular, transmucosal, subcutaneous, transdermal, intrathecal, epidural, or intramuscular) the likelihood of opioid-induced nausea turns out to be similar.
At least concerning morphine, meperidine, fentanyl, sufentanil, and alfentanil, the severity and incidence of nausea and vomiting appear similar through the series.
Neuropharmacology of opioid-induced nausea and vomiting is complex and is represented in the figure below:
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2"The chemotactic trigger zone (CTZ) located in the area postrema the brainstem, contains dopamine, serotonin, histamine, and muscarinic acetylcholine is well as opioid receptors. The vomiting center receives input from the CTZ as well as peripheral sites via the vagus nerve. As illustrated, the role of opioids as complex, and they appear to have both emetic and antiemetic effects."
The vomiting center receives neuronal input from the chemotactic triggers on (CTZ) in the area postrema of the medulla, as well as from the pharynx, GI tract, mediastinum, and visual center.
The CTZ is associated with a number of receptor systems including opioid, dopamine (D2), serotonin (5-HT3), histamine, and acetylcholine (muscarinic).
The CTZ receives input from the vestibular portion of these cranial nerve. Increased vestibular sensitivity is associated with morphine administration and morphine as well as related opioids can cause nausea by direct CTZ stimulation.
Morphins nausea antiemetic effects are increased by vestibular stimulation which can accompany walking, for example.
At the vomiting center, higher morphine (and other opioid) doses exhibits an antiemetic effect which is naloxone-reversible.
The antiemetic effect does not appear to last as long as antiemetic action of morphine.
The results of an experiment which demonstrated this relationship indicated that morphine-induced nausea and vomiting tended to increase when a morphine infusion was discontinued. (Another possibility was noted -- accumulation of the active morphine metabolite, morphine-6-glucuronide continue to accumulate throughout this period which resulted in a worsening of nausea.)
Treatment of opioid induced nausea and vomiting (and prophylaxis) has involved administration of other medications which are antagonists at a number of the receptor sites in the CTZ.
Some antiemetic agents have not had their mechanisms elucidated; some of these agents include benzodiazepines and propofol.
(The Digital Slice of Life is a cooperative project with the Slice
of Life office, KUED Media
Solutions, and the Knowledge
Weavers Project.) http://medlib.med.utah.edu/kw/
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SOCIETY FOR NEUROANESTHESIA AND CRITICAL CARE - 1998 ANNUAL MEETING
