Emergent case in patient Post Polio Syndrome

A 67 year old male presented urgently to the OR on Christmas Day for evacuation of blood clots from the bladder and ongoing renal dysfunction secondary to hydronephrosis.

The patient appeared debilitated with near complete atrophy of the lower extremities.  There also appeared to be bone deformities with flexion contractures of the upper and lower extremities.

The patient had a reported PMH of diabetes, past CVA, HTN, and polio with post polio syndrome.

The patient had eaten breakfast about 8:30 in the morning and now (at 14:00) required emergent evacuation of blood clots from the bladder.  It was decided to proceed to the OR under GETA.

The patient had come to the ER a few days previous for treatment of cellulitis of his groin area and was on antibiotics.  During the hospitalization, he had received a foley catheter that was removed. This lead to acute urethral obstruction and significant bladder distention.

Since this patient was considered a full stomach by myself, I elected to perform a general anesthetic using RSI.  Given his reported history of post polio syndrome, there was concern that he might have a hyperkalemic response to succinylcholine.    I administered 100 mcg fentanyl, 2 mg of versed, 130 mg of propofol and 80 mg of succinylcholine for intubation.  Intubation was uneventful, and the patient was maintained with sevoflurane.  The surgeon performed a cystoscopy with evacuation of a large amount of clot. The patient was extubated in the OR and went to the PACU with no problems noted.

Post polio syndrome was only first recognized in the 1970's and 1980's as patients from the 1950's who had contracted polio, improved and then suffered a recrudescence and sought medical care.

Polio is a single stranded picornavirus  infection that has been described as one that attacks and destroys the motor neurons lying in the anterior horn of the spinal cord.  The severity is variable, from complete respiratory failure and paralysis to a mild fever that lasts a few days.  However, it has also been noted that histopathologically, there is evidence of damage to the neurons located in the brain, predominantly in the brain stem and cerebellum.  These sites include the reticular formation, vestibular nuclei, and the roof nuclei of the cerebellum.

Post polio syndrome(PPS) symptoms include weakness, fatigue (generalized and muscular), atrophy, and pain.  Unfortunately, the symptoms are vague and non specific and therefore, it is a diagnosis of exclusion in patients who have a history of paralytic polio with residual motor neuron loss followed by a period of recovery and then stability of 15 years or more prior to a subsequent new onset of weakness or abnormal muscle fatigue.

Unfortunately, there are very few case reports of anesthesia in patients with PPS. Two cases reported complications. The first was a 79 year old patient who suffered post operative ventilatory failure.  The second, was a 51 year old patient having foot surgery.  The patient suffered a cardiopulmonary arrest 1 hour post op in her hospital room.  She did not recover.  It was presumed to be related to respiratory obstruction due to oversedation from opioid medication.

There are a number of considerations when anesthetizing a patient with PPS.  Respiratory function can be compromised in these patients. One study demonstrated that 42% of these patients develop new breathing problems requiring intervention.  A history  suggestive of a decreased respiratory reserve should prompt further evaluation with chest x ray and spirometry.  If VC is less than 50% of predicted or less than 1500 ml, then complete pulmonary function testing should be considered.  These patients also need to be screened carefully for symptoms of OSA, and a sleep study considered if there is concern in this regard.  Furthermore, these patients often develop laryngeal dysfunction, ranging from laryngeal muscle weakness to unilateral or bilateral vocal cord paralysis. This makes these patient at high risk for post anesthetic apnea, aspiration, and vocal cord paralysis.

Regional anesthesia may be a good choice despite the possibility that patients have existing neuromuscular deficits.  There are reports of adverse effects due to regional anesthesia.  A series of  PPS patients in Brazil were followed for 22 months after neuraxial anesthesia [1]. There was no evidence of worsening of symptoms in this retrospective review. There are no large scale studies of regional anesthesia in this patient population, but it is likely to be safe.  Using epidural anesthesia may be preferable to spinal anesthesia if a neuraxial technique is chosen.  Animal studies have determined specific intrathecal concentrations of local anesthetics that are lethal for neurons.  Undoubtedly, there are a large number of unhealthy, or marginal motor neurons in the PPS patient and it is very clear that PPS patients have fewer motor neurons than normal.  These fewer motor neurons are likely less healthy, or are impacted by a larger metabolic demand because they must supply a larger motor unit endplate as part of the natural pathogenesis of PPS. In theory, these motor neurons could be more sensitive to drug effects and its very likely that the threshold for local anesthetic neurotoxicity is lower.

If general anesthesia is chosen there are number of considerations.  The room should be warmed and a warming blanket used due to the high degree of cold intolerance by these patients.  If using NDMB, pre blockade twitch strength should be evaluated as it is often depressed at baseline.  There is evidence to suggest that patients with a remote history of polio have significantly increased sensitivity to NDMB [2,4].  Complete avoidance would be preferable if possible.
Although there is concern about the potential for hyperkalemic reponse to succinylcholine in patients with chronic neuromuscular disorders we don't have any specific evidence that this is true for PPS. Mantz et al reported the safe use of succinylcholine in a woman with PPS for cesarian delivery [3]. In addition, a series of six patients was reported who received succinylcholine with PPS and significant muscular atrophy leading to severe scoliosis requiring harrington rod placement.  All six patients were females with longstanding PPS and paralytic atrophy of the limbs.    There was no reported ill effects in this series.  The authors suggested that since all of these patients had received a defasciculating dose of 20 mcg/kg  of pancuronium, that this may have prevented activation of upregulated ACHrs and thus prevented hyperkalemia.  This suggestion is based on an article from 1976 looking at the prevention of the normal potassium increase that occurs when a prefasciculating dose of pancuronium is administered to normal healthy patients.  This may not be relevant to the current discussion. However, it is clear that in patients with a hyperkalemic reponse to succinylcholine, there is resistance to NDMB due to the upregulation of nicotinic acetylcholine recpetors (nACHr).  In patients with PPS, it is typical that we observe the opposite (increased sensitivity to NDMB).  This could lead one to speculate that upregulation of nACHr is not part of the normal pathophysiology of PPS.

After lower or upper motor neuron denervation and in certain pathologic states (eg burns, sepsis, immobilization, chronic muscle relaxant therapy or botulism, loss of muscle electrical activity), the immature or alpha 7 type may proliferate in a way that they spread across the entire muscle belly. A hyperkalemic response to succinylcholine may result from this very large increase in nACHr.  These so called extrajunctional receptors are not composed of the typical proteins that make up junctional nACHr. Typical nACHr in adults are composed of five subunits arranged to form a pore as seen below. These are referred to as the mature type of nACHr.  There are two subtypes of anomalous nACHr's:  immature and alpha 7.  Each have different characteristics and may account for some of the clinical findings in patients with a proliferation of extrajunctional receptors such as resistance to NDMB and the large hyperkalemic response to succinylcholine. Furthermore, these characteristics, i.e. depolarization at 1/100th the dose for the normal adult receptors and 10 fold increased mean channel open time, indicates that attempting to use a smaller dose of succinylcholine to avoid hyperkalemia, will not be successful.


Above, I referred to an article where it was suggested that perhaps the use of a small dose of a NDMB might prevent a hyperkalemic response to succinylcholine.  There is evidence to suggest that in normal patients, the normal 0.5 to 1.0 mEq rise in K+ seen when given succinylcholine may be prevented with a defasciculating dose of a NDMB. However, we know that in states where extrajunctional nACHr have prolifereated, the fetal and alpha 7 type predominate.  The alpha 7 or neuronal nACHr, in particular, has unique characteristics that make it particularly capable of inducing significant hyperkalemia with succinylcholine.  First, the alpha 7 subtype (neuronal) is fully agonized by choline which is a precursor and metabolite of acetylcholine AND more importantly, a metabolite of succinylcholine.  Choline is only a very weak agonist of the conventional synaptic nACHr.  In addition, the alpha 7 nACHr is not desensitized by the continued presence of choline allowing greater time for potassium efflux from the intracellular space.  Importantly, the neuronal or alpha 7 nACHr which form in extra synaptic muscle tissue have a lower affinity for non depolarizing neuromuscular blockers such as pancuronium.  Furthermore, antagonists only need to bind ONE of the alpha units in a conventional nACHr since it these receptors will not fire unless both alpha units are bound by acetylcholine in the conventional  receptor.  Since the neuronal type nACHr has FIVE alpha subunits, even if an three alpha 1 subunits are bound by a NDMB, two alpha subunits remain free to bind to acetylcholine and thus remain capable of depolarization.

To summarize, in normal muscle tissue, nACHr's are clustered in the synaptic cleft of the motor end plate. When acetylcholine is released into the synaptic cleft, it binds to the alpha subunit (must occupy two of two subunits of the conventional nACHr) to cause depolarization of the muscle cell resulting in desired movement.  Succinylcholine, may also bind to the alpha subunit and result in depolarization, resulting in paralysis due to prolonged duration at the receptor site.  This normal pharmacologic activity can relieve potassium into the extracellular space leading to a 0.5 to 1 mEq/L increase in serum potassium.  Loss of muscle excitation for whatever reason (denervation, immobilization, muscle relaxant therapy, toxins), leads to a loss of clustering and spread of the nACHr throughout the whole muscle membrane. The extent of the upregulation is determined by the severity and duration of the pathologic state. The upregulation occurs beyond the synaptic cleft onto the normal muscle membrane and consists of two aberrant subtypes (immature -[2alpha1,beta1,delta, gamma] and neuronal -[5 alpha7]. The proportion of each of these subtypes is unknown.  However, these aberrant nACHr located extrajunctionally, are very sensitive to choline and succinylcholine, remain open longer, have low affinity for NDMBs, and in the case of the neuronal (alpha7) subtype of nACHr, may depolarize even if three of the alpha subunits are bound by NDMBs. Therefore, usual doses of NDMB would not ablate the hyperkalemic response to succinylcholine.

It should be noted that the hyperkalemic response to succinylcholine is dose dependent; i.e. extremely small doses of succinylcholine  (0.1 mg/kg) in denervation states can cause paralysis with no hyperkalemia [5].  However, this one case report does not inform us on care of the general population as the responses can be quite variable.

It has been demonstrated that in PPS, there is residual lesions involving the reticular activating system.  Because the reticular activating system is a theoretical site of action for most anesthetic agents, it would be prudent to cautiously titrate anesthetics to the patients response.  In the current case, the patient did not show an increased sensitivity to sevoflurane, and emergence was uneventful.  The idea that these patients are more sensitive to anesthetics is still theoretical.

Complications reported in this patient population have been reported in the post operative period.  Indeed, this may really be the time period where careful patient monitoring must occur as these patients are likely to have problems with obstruction due to weakness in the pharyngeal dilator muscles and increased sensitivity to opioid pain medications.

In conclusion, this is a report of use of succinylcholine for RSI in a patient with post polio syndrome and a full stomach coming for emergent surgery with no apparent adverse affect.  This case adds to a limited number of cases where succinylcholine has been safely administered.  The use of succinylcholine remains controversial in this setting, however, there is some evidence to suggest that resultant hyperkalemia is unlikely.  This evidence includes several case reports along with the clinical appearance of higher sensitivity to NDMB as opposed to the expected resistance to NDMB seen in denervation conditions where hyperkalemia has been reported after succinylcholine.




1. Rezende DP, Rodrigues MR, Costa VV, Arci EC, and Saraiva RA. Patients with sequelae of poliomyelitis. does the anesthetic technique pose risk. Revista Brasileira de Anestesiologia. 2008. 58(3).

2. Gyermek L. Increased potency of nondepolarizing muscle relaxants after poliomyelitis.  J Clin Pharmacol 1990; 30:170-3.
3.  Wernet A, Bougeois B, Merckx P, Paugam-Burtz C, Mantz J.  Successful use of succinylcholine for cesarean delivery in a patient with postpolio syndrome.  Anesthesiology. 2007;107:680-1.
4. Suneel PR, Sinha PK, Unnikrishnan KP, Abraham M.  Anesthesia for Craniotomy in a patient with previous paralytic polio. J Clin Anesth. 2008. May; 20(3):210-3.

5. Brown TCK, Bell B: Electromyographic responses to small doses of suxamethonium in children after burns. Br J Anaesth 1987; 59:1017–21






Post

Prolonged weakness after succinylcholine

A 55M presented to surgery for repair of the radial head by plate and screws. The patient was induced with 290 mg of propofol (pt weight ~115 kg), and 120 mg of succinylcholine with 250 mcg of fentanyl. The patient was maintained with desflurane in oxygen with 40 mg of rocuronium up front for relaxation. The case lasted for 2 hours. At the end of the case, anesthesia was discontinued and allowed to emerge. An ultrasound guided supraclavicular local anesthetic injection was done. A catheter was left in place for post op pain control. During this time, the patient continued to be minimally responsive. After evaluating the patient after the block for another 15 minutes and supporting his respiratory effort it was clear that the patient was not improving. Hypercarbia devleoped, the patient demonstrated significant upper airway obstruction and was non responsive now even to significant sternal rub. As there was concern for CO2 induced delayed emergence it was decided that reintubation was likely. However, mild residual neuromuscular blockade could not be ruled out as the patient had not received any reversal. Since the patient had not received additional rocuronium during the case and exhibited otherwise relatively good strength, it was considered necessary to only give a small dose. 1 mg of Neostigmine was given to no avail. The patients condition continued to worsen and his breathing became less forceful. At this point, 1 attempt at DL was made without muscle relaxation. This proved futile due to the patient's gag reflex. 100 mg of succinylcholine was administered, fasciculations were observed and intubation was completed. The patient was taken to the PACU intubated. The patients BP was also significantly elevated during this time. This was treated with labetalol. In the PACU, after 15 minutes had passed, a TOF was tested. The patient had 0 twitches. His was placed on mechanical ventilation and a propofol gtt. 2 hours later his train of four demonstrated a clear fade and was slowly returning. After 4 hours the patient woke up but by this time he had already been transferred to the ICU secondary to significant respiratory acidosis.

While it was clear in the PACU that this patient had a phase II block from the dose of succinylcholine, it was not initially clear what caused the original delayed emergence. Also curious was the prolonged duration of the phase II blockade.

The neuromuscular junction is important in anesthesia practice since we are often required to completely ablate all neuromuscular function. The acetylcholine (nAChr) receptor plays the dominant role in the neuromuscular juntion and is composed of 5 subunits. Two of this are alpha subunits, both of which must be occupied by acetylcholine in order for Na+ ions to be allowed to pass through the protein pore causing depolarization of the sarcolemma. Non depolarizing neuromuscular blockers can bind to the alpha subunit and thus compete with acetylcholine for the receptor effectively shutting down the ability for the muscle cell to depolarize. Succinylcholine on the other hand mimics acetylcholine because it is essentially two acetylcholine molecules hooked together. Succinylcholine, thus, binds to the alpha subunits of the receptor, causes an initial depolarization, but then due to the fact that it is not rapidly cleaved like acetylcholine is, it remains in place causing the cell to remain depolarized and thus paralyzed. This is what we refer to as a Phase I block. A phase II block may occur after the succinylcholine overwhelms the neurmomuscular junction by sheer numbers. After a time, the receptor itself undergoes changes which make it less susceptible to stimulation by acetylcholine. Clinically this will present with a fade on train of four with a twitch monitor which resembles the non depolarizaing muscle relaxants. At least two studies have found that a prolonged duration of succinylcholine resulting in a phase II block can be reversed by neostigmine. In both studies a phase II block was induced by a large dose (infusion) of succinylcholine. The dosages that will put the patient at risk for development of phase II block are in the area of 5 mg/kg. This suggests that the receptor and end plate are capable of being depolarized (and thus the cell had repolarized), but that a larger number of acetylcholine receptors were necessary. In my patient, he had received a single dose of succinylcholine followed by rocuroium from which he had recovered. Therefore, plasma cholinesterase deficiency (the enzyme responsible for degrading succinylcholine) was unlikely. He appeared to have some residual weakness from the rocuronium. This was apparent from pharyngeal muscle weakness. The pharyngeal muscles are more susceptible to neuromuscular blockers than many other muscles, and therefore, although your patient may appear to be strong, they may still obstruct if extubated with a mild even subclinical neuromuscular block. Therefore neostigmine 1 mg was administered. This did not help. Now, the neuromuscular junction was exposed to excessive acetylcholine. Furthermore, neostigmine has the secondary effect of inhibiting plasma cholinesterase. Thus, any succinylcholine administered will be degraded at a lower rate. There is one case report [3] published where a dose of neostigmine 2 hours prior to a dose of succinylcholine resulted in prolonged neuromuscular blockade. The published case report was similar to our situation in every way except three points. 1) The published case had renal insufficiency, 2) The dose of neostigmine was larger but given 2 hours prior not 5 minutes prior, and 3) The patient in the case report received two doses of neostigmine (total 5 mg) in an attempt to reverse the phase II block which caused the patient to develop severe (complete) neuromuscular blockade and go apneic. Fortunately, authors published the dibucaine number and plasma cholinesterase levels during the period of weakness and after recovery. During the period of weakness they found the dibucaine number to be 76% acutely (normal is > 80%) and 86% 24 hours later. No explanation is given for the improvement in the dibucaine number except that perhaps it was affected to a small degree by the neostigmine. However, the plasma cholinesterase level was 1.36 U/mL acutely (normal is 7 to 19 U/mL), but 10.48 U/mL after 24 hours. The authors conclude that the patient did not have a phase II block, (since it couldn't be reversed with neostigmine), but suffered from severe inhibition of plasma cholinesterase activity by neostigmine. The duration of weakness of their patient was about 3 hours from the dose of succinylcholine (this mirrors our time frame). However, in controlled clinical trials, neostigmine given prior to succinylcholine induces a weakness that is only about 35 min in duration [1]. It should be noted that careful measurements of plamsa (pseudo) cholinesterase activity in this study did show a 80% decrement in enzyme in plasma 5 min after neostigmine or pyridostigmine was administered. However, at full muscle recovery, plasma cholinesterase levels are still decreased by about 60% [1]. Therefore, giving neostigmine to a patient who has apparent clinical recovery from succinylcholine, may result in a prolonged block. These authors and others have found that while pyridostigmine reduces plasma cholinesterase levels to the same degree as neostigmine, the clinical prolongation of muscular relaxation is not as much as with neostigimie (23 min vs. 35 min). Thus, the prolonged neuromuscular block seen with anticholinesterase medications is not solely resulting from their inhibition of plasma cholinesterase enzymatic activity. This was made more apparent by Fleming et al. [2], when they compared edrophonium, pyridostigmine and neostigmine. They showed that while edrophonium did not decrease plasma cholinesterase, both pyridostigmine and neostigmine did decrease plasma cholinesterase activity. This group also showed that giving succinylcholine after edrophonium did not result in a prolonged block. However, if pyridostigmine or neostigmine were followed by succinylcholine, the block duration lasted about 18 min with pyridostigmine and 23 min after neostigmine. These data to not fit with the clinical scenario I encountered however. Furthermore, the authors in the studies cited do not indicate whether a phase II block developed or not. In the published case report cited [3], the authors ruled out a phase II block in their patient by virtue of the fact that it was not reversible with neostigmine. However, it is not clear to me that this fact is sufficient evidence to rule out a phase II block. The sine qua non of a phase two block is a TOF fade and evidence of posttetanic potentiation. It has been noted by some authors [4] that indeed patients with atypical plasma cholinesterase enzymes (or inhibited enzymes) will be more susceptible to a phase II block. It is speculated that the reason for this is excessive amounts of succinylcholine reaching the nAChR. Indeed, the vast majority of succinylcholine molecules are enzymatically cleared by plasma cholinesterase activity in normal patients. Therefore, if you give a standard dose of succinylcholine to a patient who has minimal functioning enzyme, then you might expect to develop a phase II block. However, the phase II block characteristics in this scenario may be different from that which develops when succinylcholine is given in a large dose over an long period of time (1 to 2 hours). The mechanism of a phase II block is not certain and there are 2 basic hypotheses. 1) channel blockade by succinylcholine molecules and 2) desensitization of the receptor in the presence of excessive agonists. A third hypothesis is distortion of the junctional membrane from excessive ion fluxes. In patients who receive a large dose of succinylcholine over a prolonged period, the mechanism might involve ion fluxes more than channel blockade. While, if a large influx of succinylcholine all at once occurs, as would be the case in someone who has severely inhibited plasma cholinesterase activity, then a phase II block may result, but the underlying mechanism may differ and thus, reversal with neostigmine (or other anticholinesterase may not be possible).

Still enigmatic however in the case presented is the fact that the dose of neostigmine (1mg) was very small relative to the patients body size (>100kg). The duration of block was greater than what should be expected given previous studies (about 35 min). If our patient had renal insufficiency this would be a could explanation for the prolonged duration of block as neostigmine is cleared by the kidneys. Some explanation for the somewhat enigmatic reaction seen in the above case described could be explained by other actions of anticholinesterases. Indeed, Flemming et al. [2] demonstrated that inhibition of plasma cholinesterase is only a partial explanation for the increased duration of succinylcholine after anticholinesterases. They showed that while pyridostigmine decreased measurable plasma cholinesterase to a much greater degree than did neostigmine, the duration of muscular blockade was shorter than after neostigmine. It is known for example that neostigmine has a direct depolarizing effect at the neuromuscular end plate (the others do not). Also, neostigmine has a very rapid onset (relative to the other anticholinesterases) and this could change the dynamics of a succinylcholine block.

In any case, given that edrophonium has been shown to not cause a prolonged block of succinylcholine (as well as to not inhibit plasma cholinesterase activity), a trial of reversal in the above scenario would have likely resulted in reduced chances for prolonged weakness.

1. Sunew KY et al. Effects of Neostigmine and Pyridostigmine on duration of Succinylcholine action and pseudocholinesterase activity. Anesthesiology. 1978; 49:188.

2. Fleming NW et al. Neuromuscular blocking action of suxamethonium after atagonism of vecuronium after edrophonium, pyridostigmine, or neostigmine. BJA. 1996; 77: 492.

3. Williams AR, et al. Marked Prolongation of the succinylcholine effect two hours after neostigmine reversal of neuromuscular blockade in a patient with chronic renal insufficiency. Southern Med Journal. 1999; 92(1): 77

4. Abel M. Depolarizing neuromuscular blockade. Clincal Cases in Anesthesiology. Reed A (ed.). Philadelphia, Churchill Livingstone, 3rd ed. 2005. p.117