Anesthesia and Peri-Operative Care in the primary Periodic Paralysis Disorders. Part 1: A Review of the Literature
Annabelle SJ Baughan [1] MB FRCP FRCPath,
Deborah Cavel-Greant [1],
Janice Megalo [1] AAS-MAA, and
Frank Weber [2] MD PhD.
[1] Periodic Paralysis International (www.hkpp.org)
[2] Colonel, Medical Service (Neurology), German Air Force. Military Hospital (Bundeswehrkrankenhaus), 89081 Ulm, & German Air Force Center of Aerospace Medicine, D-82256 Fürstenfelbruck. Medical Adviser, Periodic Paralysis Association;
Corresponding author: ASJ [email protected]
With grateful acknowledgement to members of the private Listserv at Periodic Paralysis International (www.hkpp.org) and members of the Periodic Paralysis Association (www.periodicparalysis.org) who have contributed much of the anecdotal evidence
Part 2: ‘Practical guidelines’ – separate document at www.hkpp.org
Parts 1 and 2 share the same Introduction. and Reference List
CONTENTS
Introduction
Literature review of peri-operative management in the Periodic Paralysis Disorders:
- A general approach to anaesthesia in neuromuscular disorders
- Hypokalaemic Periodic Paralysis
- Hyperkalaemic Periodic paralysis
- Normokalaemic Periodic Paralysis
- Andersen-Tawil syndrome
- Thyrotoxic periodic paralysis
- The Potassium Aggravated Myotonias including Paramyotonia Congenita (von Eulenburg)
- Alternatives to General Anaesthesia in the PP Disorders
- Periodic Paralysis Disorders and Sleep Apnoea syndromes
Introduction
The primary Periodic Paralysis Disorders (PPDs) comprise a group of related rare genetic ion channelopathies affecting muscle fibre membranes in voluntary muscle [1, 2, 3]. Affected patients have symptoms which vary in severity – both between patients (even within the same kindred) and in the same patient at different times – but are defined by intermittent acute attacks of flaccid paralysis of voluntary muscles, sometimes milder acute muscle paresis, and with or without myotonia. The currently defined forms of genetic Periodic Paralysis (derived from Jurkat-Rott and Lehmann-Horn [4] are shown in table 1.
Table 1: Nomenclature of Periodic Paralysis Disorders
Abbreviation Mutated Gene * Name
Hypo1PP CACNA1S Hypokalaemic Periodic Paralysis Type 1
Hypo2PP SCN4A Hypokalaemic Periodic Paralysis Type 2
Hypo3PP KCNJ18 Hypokalaemic Periodic Paralysis Type 3
HyperPP SCN4A Hyperkalaemic Periodic Paralysis
NormoPP SCN4A Normokalaemic Periodic Paralysis
ATS KCNJ2 Andersen-Tawil Syndrome
TPP KCNJ18 Thyrotoxic Periodic Paralysis
PMC SCN4A Paramyotonia Congenita
PAM SCN4A Potassium Aggravated Myotonia
* Many diagnosed individuals have a documented gene mutation (the incidence varies with the particular disorder). Other patients have been clinically diagnosed with a phenotypically identical disorder but a genetic mutation has not been identified to date. With the current state of knowledge, patients with so-called <gene-negative> PP Disorders should be treated the same as those with a known mutation, and that will include approaches to safe general anaesthesia.
Significant paralysis in patients with PP Disorders can last for minutes, hours, sometimes days. Prolonged attacks (days to many weeks) with reduced muscle stamina, variable muscle weakness and fatigue, are also a feature and may be frequent. These types of chronic attacks are currently designated as <abortive attacks>.
Patients may be diagnosed in childhood or adolescence but much evidence shows that diagnosis may be delayed by many decades. Permanent muscle weakness commonly develops over years and may lead in some patients to very significant disability [5].
The triggers for attacks vary according to the form of Periodic Paralysis, and also between individuals with the same PP Disorder, but typical provocations include changes in plasma potassium or glucose levels, exercise, rest after exercise, alcohol, a wide variety of drugs, physiological or psychological stress, inter-current illness, and exposure to cold temperatures.
Adverse reactions to anaesthesia have been reported anecdotally by many patients with a Periodic Paralysis Disorder. It is obviously unknown how many more events may not have been reported or even thought at the time to have been related to the patient’s PPD. Reactions have included difficulty breathing (even clinical respiratory distress), extreme myotonia, spasms of the jaw and other muscles, and prolonged postoperative paralysis. In some cases reported by patients’ families [6], death due to respiratory failure following anaesthesia has occurred. Patients with Andersen-Tawil Syndrome are at peri-operative risk also of cardiac events, classically catastrophic ventricular dysrythmias including torsades de pointes.
Adverse reactions to anaesthesia, including life-threatening events, thus remain a serious concern for patients with Periodic Paralysis Disorders. Recent research has been helpful in defining these reactions, their mechanisms, and how to avoid them.
Because of the rarity of the periodic paralyses, particularly HyperPP and Andersen-Tawil Syndrome, it is not surprising that the published body of good practice in anaesthesia in patients with PPDs is sparse. The practical guidelines in this review (Part 2 – separate document) are therefore necessarily largely based on sensible practice more than on published experience. No evidence has been found of controlled trials of anaesthetic techniques in patients with PP Disorders (as might be expected given their rarity).
Simple strategies such as good communication and co-operation (between doctors and between doctor and patient), a written Individual Care Plan [7] prepared with the patient and distributed to all relevant staff, close monitoring of muscle function and of glucose and potassium levels, and also cardiac surveillance (especially in ATS), are recommended as the principal measures required to minimize adverse reactions to anaesthesia. Experience of peri-operative management in the PP Disorders, including specific anaesthetic regimes, is outlined as part of a selected literature review, and practical management guidelines are described. (see Part 2 – separate document).
Literature review of peri-operative management in the Periodic Paralysis Disorders:
1. The general approach to anaesthesia in all neuromuscular disorders
Klingler et al [8] make the following important points in their review:
1. (Concerning the risk-benefit review of all interventions): Since patients with neuromuscular diseases are very challenging and may appear deceptively healthy, it is important to document all choices and their rationale on the medical record for subsequent care-givers, future research in rare disorders, and for medico-legal protection of care-givers and institutions.
2. The patient’s outcome correlates with the quality of consultation between anaesthetists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced use of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants.
3. Often the anesthetist is not left with a single absolute risk, but in many cases must balance conflicting management strategies, fully bearing in mind the possible deleterious outcomes even with the chosen course of action.
4. It is also important to identify and treat potential anaesthetic complications promptly. Adverse drug effects or specific risks associated with certain neuromuscular diseases should be taken into account.
Marsh et al also provide a useful overview [9]. They conclude: < Patients with neuromuscular disorders are a concern for anaesthetists….. Although it is impossible to negate risk altogether in these patients, an understanding of the pathophysiology underlying each condition facilitates preoperative, peri-operative, and post-operative planning>.
Marsh and Klingler’s reviews make the following recommendations for peri-operative management in all patients with any neuromuscular disorder:
1. Patients with neuromuscular disorders are not suitable for day case surgery.
2. Thorough pre-operative assessment should include cardiac and respiratory function
3. Temperature measurement and control is extremely important even in regional anaesthesia. In some neuromuscular disorders, hypothermia can exacerbate myotonia and increase sensitivity to non-depolarizing neuromuscular blocking agents. Hyperthermia may occur due to increased muscle activity seen in the myotonia disorders, or malignant hyperthermia. A high index of suspicion should exist for patients with myotonias for concomitant malignant hyperthermia.
4. The use of volatile agents is considered controversial. Volatile agents have been contraindicated in the past due to the association of malignant hyperthermia with some neuromuscular disorders. Cardiovascular decompensation may be caused by the use of volatile agents due to their cardio-depressive and arrhythmogenic properties
5. Intravenous anaesthesia may offer many benefits to patients with neuromuscular disorders as the agents used are short acting and relatively easy to control. Caution must however be exercised due to the potential for autonomic dysfunction and cardiovascular collapse.
6. Depolarizing neuromuscular blocking agents are not recommended for use in patients with neuromuscular disease. The use of succinylcholine will lead to membrane depolarization, and potentially massive potassium efflux. This can cause fatal hyperkalaemia, muscle fibre swelling, and rhabdomyolysis.
7. Neuromuscular block should be checked before the first use of relaxants and then regularly throughout the procedure
8. Many patients with neuromuscular disorders show sensitivity to non-depolarizing neuromuscular blocking agents, which can result in respiratory weakness and inability to wean, sputum retention, and dysphagia. The use of such agents can often be avoided by judicious use of IV induction agents. However, if absolutely required, non-depolarizing neuromuscular blockers should be given in reduced doses (10–20% of the recommended dose) and the degree of neuromuscular block monitored. Agents such as mivacurium and atracurium are preferred due to their degradation process.
9. Anticholinesterases are not recommended.
10. Postoperative admission to high dependency or intensive care is mandatory, with access to physiotherapy, positive pressure circuits, appropriate analgesia and close monitoring of respiratory function.
Their recommendations specifically for the PP Disorders accord with other authors and are included in Part 2 of this review, <Practical Guidelines>, published at
2. Hypokalaemic Periodic Paralysis
Potential peri-operative triggers for hypokalaemic paralysis will include general anaesthesia, post-operative stress including pain, intravenous glucose or saline solutions, long-acting neuromuscular blocking drugs, the typically cold environment in operating theatres, and inappropriate drug prescribing (e.g. drugs affecting potassium levels).
Vicart et al [10] describe: <Individuals with HypoPP are often reported to have pre- or post-anaesthetic weakness, the risk for which requires preventive measures and careful anaesthetic follow up>. They note that PPHypo patients are usefully managed during anaesthesia by controlling plasma potassium levels and avoiding intravenous glucose and saline loads. It is also helpful to maintain body temperature, and stabilise acid-base balance. The use of pre-medication to reduce anxiety, which is a trigger for some hypokalaemic PP patients, is also helpful. They state that any fluctuations in electrolytes, infections or pain could bring on a paralysis attack post surgery and those should be managed appropriately and promptly. Vicart also highlights that: <Individuals with HypoPP are at increased risk (of unknown magnitude) for malignant hyperthermia, though not as great a risk as in those individuals with true autosomal dominant malignant hyperthermia susceptibility. Three individuals with HypoPP who developed malignant hyperthermia have been reported to date; however, in one individual, the cause was clearly a coincidental mutation in RYR1>.
Chitra and Korula’s case study [11] states that giving the patient a light meal the night before and using a light pre-medication sedative (midazolam) to reduce anxiety and stress, were helpful. Their patient also had neuromuscular monitoring during the epidural infusion. They stated <Depolarizing muscle relaxants should not be used because of alterations in membrane potential and alterations in electrolyte levels with the possibility of prolonged weakness>. To further reduce risk of paralysis attack, saline and Ringer’s lactate solution with potassium was used instead of glucose solution or too much saline solution. They emphasize the importance of monitoring the plasma potassium during surgery and paying close attention to acid-base balance <Ventilation was adjusted to a controlled hypercapnia (pCO2 above 40 mmHg) to avoid alkalosis>. The study concluded: <Adequate preoperative preparation, vigilant intraoperative monitoring of potassium and aggressive correction of hypokalaemia, avoiding factors that can trigger hypokalaemia and good postoperative pain relief measures go a long way in the successful management of these groups of patients>.
Rooney et al [13] report a case of a 48 year old scheduled for left inguinal herniorrhaphy. He had a ten-year history of HypoPP well controlled with spironolactone and potassium supplements. He also had a history of angina pectoris with angiography suggestive of a congestive type cardiomyopathy. A resting ECG showed bigeminal rhythm and, on exercise, inferolateral ischaemia. They comment: <The presence of angina, coupled beats and a known cardiomyopathy led us to opt for general anaesthesia and the avoidance of spinal anaesthesia with its potential variable effects on the cardiovascular system. A field block, though possible, would involve the use of a relatively large amount of local anaesthetic with the potential for myocardial depression>. He was premedicated with oral diazepam, anaesthesia was induced with IV thiopental and he was intubated after IV atracurium. Anaesthesia was maintained with nitrous oxide, isoflurane and IV morphine. They do not comment on potassium supplementation but mention that <the plasma potassium was normal at all times>. Postoperative recovery was described as uneventful.
Neuman and Kopman [14] describe a case study, in 1993, of a patient undergoing elective caesarean section. She had a history of <hypokalaemic or normokalaemic familial periodic paralysis> with episodes every few months of weakness in the arms and legs lasting up to 48 hours, with a lowest recorded plasma potassium of 3.5 mmol/l. The patient also had <antibody-induced thrombocytopenia>, diagnosed as a child, with a maintained low platelet count of 50 x109/l. Because of this risk of bleeding with regional anaesthetic it was decided to use general anaesthesia. An awake endotracheal intubation was attempted using topical lidocaine and IV thiamylal but the patient’s mouth could not be opened fully nor could the tongue be displaced (she had been able to open her mouth fully preoperatively). Additional thiamylal was given but after induction of anaesthesia she developed pronounced trismus (spasm of the jaw muscles) so IV succinylcholine 40 mg was given which was followed by generalised muscular rigidity and contracture, demonstrated by neuromuscular monitoring of the thenar muscles of the hand. Intubation was then achieved and a healthy baby delivered 5 minutes later. They describe <The serum potassium drawn just before induction of anaesthesia, but reported after surgery, was 2.5 mmol/l>. (The report does not mention the frequency of potassium assays nor any potassium supplementation regime). The patient was extubated uneventfully but developed severe generalised muscular weakness lasting 36 hours, which gradually recovered over the next 2 days.
The authors comment: <The generalized rigidity following the administration of succinylcholine was unexpected, as was the prolonged recovery from the succinylcholine. The diagnosis of myotonia was suggested on the basis of increased muscle tone and the contracture-like response to succinylcholine. It was confirmed by documenting the delay in relaxation following tetanic stimulation>. The authors assumed that the reaction was more marked because of the lower cholinesterase levels normally found during pregnancy, a reduction of up to 30%, but the patient was later found to have a low cholinesterase level when not pregnant. Their summary stated: <Had we been aware of the myotonia and cholinesterase deficiency, our approach to her anaesthetic would have been different. An induction sequence incorporating inhalation of oxygen, cricoid pressure, thiamylal, and two times the ED95 dose of an intermediate- or short- action non-depolarizing muscle relaxant. It would be prudent to question any patient with a history of PP regarding symptoms of myotonia>.
Hofer et al [15] report on a case of a woman with genetically-confirmed HypoPP admitted for surgical reduction of bilateral breast hyperplasia. Her first attack of muscle weakness was at the age of 14. On the day before surgery the plasma potassium was 3.9 mmol/l and IV supplementation at 20 mmol/hour was commenced. Drugs administered included diazepam, mivacurium, propofol and remifentanil, with paracetamol and nicomorphine post-operatively. Lactated Ringers was infused during the operation and blood loss of approximately 1.5 litres was replaced with colloid solution. The plasma potassium level was measured every 20 minutes during surgery and was kept within the normal range by continuous infusion of potassium of up to 45 mmol/hour. Neuromuscular function was monitored with two TOF-Guard monitors. Post-op she was routinely transferred to the intensive care unit where she had an uneventful 2-day stay. She was discharged on day 4 in a stable condition. The authors considered that this total IV anaesthetic technique allowed for rapid and complete recovery of consciousness and muscle strength, and excluded possible triggers of malignant hyperthermia.
Viscomi et al [16] describe the management of childbirth with epidural anaesthesia in a patient with HypoPP. <Avoidance of IV glucose, (giving) potassium supplementation, early epidural analgesia, and a passive second stage of labour may have aided in the prevention of paralytic episodes>. A forceps intervention was used to prevent paralytic episodes provoked by the physical exertion that occurs with delivery. This patient avoided a paralysis attack using these strategies. This report adds to examples of effective and safe use of epidural anaesthesia (sufentanil, bupivacaine and fentanyl in this case) in a patient with HypoPP, providing means of monitoring potassium levels and prevention of hypokalaemia are used.
Robinson et al [17] describe the management of a patient during pregnancy and during labour. The patient had HypoPP, diagnosed at the age of six and with an affected father, and also Wolff-Parkinson-White syndrome. A plan was prepared to avoid the known triggers of HypoPP attacks such as carbohydrate loading, cold, mental stress and muscular exertion. An epidural catheter was sited early in labour and epidural anaesthesia was then prolonged to cover a rotational forceps delivery. ECG monitoring was continuous. The peripartum blood potassium was <maintained in the normal range> with intravenous and oral supplementation. She made an uncomplicated recovery, with no cardiac problems, and was discharged home the next day. Drugs administered included vaginal prostaglandin, oxytocin IV, and epidural lidocaine, bupivacaine, fentanyl and carbonated lidocaine. Close attention was paid to the intravenous potassium supplementation regime.
Zhou et al [18] summarise the anaesthetic considerations for a patient with hypokalaemic periodic paralysis: < Patients with HypoPP undergoing general anaesthesia have been reported to exhibit weakness and respiratory distress in the postoperative period. Important triggers to avoid include peri-operative stress, glucose loading, hypothermia, and depolarizing neuromuscular blocking drugs (NMBDs). Although the safe use of intermediate- and short-acting non-depolarizing NMBDs such as atracurium and mivacurium has been documented, avoiding long-acting muscle relaxants is probably prudent. The use of epidural (including for labour analgesia) and spinal techniques appears to be safe, although hypokalaemia has been documented with the use of epidural techniques, both with and without epinephrine. Unlike HyperPP, an association between HypoPP and MH cannot be categorically ruled out, although the use of isoflurane in HypoPP has been reported. A number of MH-like metabolic crises in patients with HypoPP have been reported. Contracture-like responses to succinylcholine have also been described. In one of the prior descriptions, two unrelated mutations conferring both HypoPP and sensitivity to MH in the same patient seemed likely. Consequently, although the probability of MH in a given patient with HypoPP is likely to be remote, it cannot be ruled out, and the safest course might be the use of a non-triggering anaesthetic. If volatile agents are used, then they should be used with extra vigilance>.
3. Hyperkalaemic Periodic paralysis
Egan and Klein [19] describe three families with Hyperkalaemic Periodic Paralysis, in which at least one member of each family reported waking paralyzed after anaesthesia. In this report several considerations were given for prevention of paralysis, including depletion of potassium levels before anaesthesia, avoiding medications that raise plasma potassium levels, and maintaining normal body temperatures. They did not feel that patients with HyperPP had an abnormal sensitivity to non-depolarizing muscle relaxants, however many more recent studies have since shown that depolarizing muscle relaxants are problematic and should be avoided.
Weller et al [20] report successful epidural anaesthesia in a patient with known HyperPP. A 53-yr-old patient was scheduled for radical retropubic prostatectomy and right inguinal hernia repair. Years earlier the patient experienced his most severe and prolonged episode of weakness following a general anaesthetic, which included administration of succinylcholine. This episode had lasted for four days and was complicated by a deep venous thrombosis, requiring six months of warfarin therapy.
On this later admission the patient was fasted for eight hours prior to surgery. Admission ECG and plasma potassium and glucose were normal. Preoperatively an infusion of 5% dextrose in normal saline was started. Sedation with IV midazolam was given. A subarachnoid block was performed using hyperbaric bupivacaine 0.75%, and he received additional IV midazolam during the case. He breathed spontaneously through a face mask. To prevent hypothermia, ambient temperature was maintained at 72 deg F, an upper body forced-air warming blanket was applied, and all fluids were run through a blood-warming device; minimum rectal temperature was 35.8 deg C. Plasma potassium concentrations were measured hourly during the case and ranged from 3.3 to 3.6 MEq/l. Postoperative pain management was provided by intravenous hydromorphone patient-controlled analgesia. He was discharged from the hospital on day 3, at which time he continued to show no evidence of muscle weakness.
Patangi [21] et al describe the first case report in the literature concerning anesthesia for cardiac surgery with cardiopulmonary bypass in HyperPP. The patient was a 75 year old man, HyperPP was diagnosed in his thirties. Drugs given included temazepam, midazolam, etomidate and fentanyl. Their aim was to keep the plasma potassium at 4.0-4.5 mmol/l <to minimize the risk of postoperative arrhythmia although we were aware that this (plasma potassium level) might trigger the periodic paralysis>. On initiation of bypass the plasma potassium unexpectedly rose to 6.9 mmol/l necessitating the administration of insulin and glucose. 14 hours post-op the patient experienced a mild paralytic episode, arms and legs, lasting 1 hour. The plasma potassium was 3.8 mmol/l at the time but rose to 5.2 mmol/l 150 minutes after the episode started. He had been receiving potassium supplementation in the intravenous infusion. This was stopped and the plasma potassium then gradually fell without further intervention. The patient then made an uneventful recovery.
Weber et al [22] state: < During surgery, avoid use of depolarizing anaesthetic agents (including potassium, suxamethonium, and anticholinesterases) that aggravate myotonia and can result in masseter spasm and stiffness of respiratory and other skeletal muscles, interfering with intubation and mechanical ventilation>. In other words medications that would aggravate myotonia enough to interfere with tracheal intubation. Further complications are described: <The patient may develop respiratory distress in the recovery room resulting from weakness of respiratory muscles in addition to generalized weakness lasting for hours. The weakness is aggravated by drugs that depress respiration and by the hypothermia induced by anesthesia>. It is recommended: <To prevent such attacks, glucose should be infused, a normal body temperature maintained, and plasma potassium kept at low level>. This would reduce or reverse the myotonia or paralysis attack which seems imperative considering the study finding that: <Because the generalized muscle spasms associated with such attacks may lead to an increase in body temperature, individuals with HyperPP have been considered to be susceptible to hyperthermia>. This confirms earlier reports of the risk of malignant hyperthermia in Hyperkalaemic Periodic Paralysis.
Zhou et al [18] summarise the anaesthetic management for patients with HyperPP: <All patients with HyperPP should be preoperatively admitted to allow preoperative fasting to be accompanied by the administration of a dextrose-containing, potassium-free intravenous fluid. Depolarizing agents such as potassium, succinylcholine, and anticholinesterases aggravate the myotonia in HyperPP and are contraindicated. Non-depolarizing NMBDs may be safely used. Although succinylcholine can cause masseter spasm and rigidity in HyperPP, these are related to severe myotonic reactions and are not due to Malignant Hyperthermia. No evidence suggests that patients with HyperPP are susceptible to Malignant hyperthermia. The safe use of both volatile anaesthetics and propofol has been documented. Myotonic contractions during anaesthesia may be improved with the administration of lidocaine, as chronic myotonic symptoms are improved by mexiletine> (in many countries outside the US, mexiletine is difficult to obtain nowadays). <Intra-operatively, maintaining normothermia, preventing hyperkalaemia, and avoiding hypoglycaemia are important. Both spinal and epidural techniques have been successfully used in these patients, including the use of epidural labour analgesia. Non-neuraxial regional techniques have not been extensively investigated; however, a recent report documents the use of a femoral nerve block in a single patient with HyperPP>.
4. Normokalaemic Periodic Paralysis
Weber et al [22] describe NormoPP as <A type of periodic paralysis with normokalaemic episodes of weakness reminiscent of both HyperPP and HypoPP. Potassium sensitivity resembles HyperPP whereas all other features resemble HypoPP. The associated phenotype differs slightly in the ictal plasma potassium levels which can be low or normal. Also, the reaction to oral potassium administration may be different than for HypoPP, anything from amelioration to worsening of the weakness>.
The literature describing NormoPP and anaesthesia appears to be extremely limited. But Walsh and Siddiq [23] describe the anaesthetic technique used for a young woman in a large affected kindred, all of whom had normal potassium levels during paralytic attacks, as she underwent two elective operations. They report the successful use of oral diazepam as a pre-medication, then IV propofol, atracurium and morphine. Anaesthesia was maintained with nitrous oxide and isoflurane. Muscle relaxation was reversed with neostigmine and glycopyrronium. She was routinely transferred to Intensive Care for observation and recovery was uneventful.
Walsh and Kelly [24] describe the management of a young boy who underwent emergency scrotal exploration and orchidectomy. He was diagnosed with NormoPP at the age of 4 with a history of previous episodes of weakness – two of which required hospitalisation for respiratory distress – and an extensive family history of periodic paralysis. His pre-op plasma electrolytes were normal. After fentanyl was given a hyperbaric lignocaine sub-arachnoid block was performed. He was given one dose of morphine IM and diclofenac PR and was discharged home on the third day after an uneventful recovery.
5. Andersen-Tawil syndrome
Andersen-Tawil syndrome (ATS) is very rare – a reported incidence of one in a million [25] but anecdotally it is thought it may be significantly underdiagnosed. In 60-70% of cases a mutation in the KCNJ2 gene is found, a gene which encodes the inward rectifier potassium channel, expressed in both skeletal and cardiac muscle, resulting in prolongation of phase 3 of the action potential in both tissues. ATS has a very variable phenotypic expression of a triad of anomalies [26].
1. Periodic paralysis, which is hypokalaemic in most affected people with ATS but may be hyperkalaemic or normokalaemic. Anecdotally, a few people affected by ATS describe paralytic episodes provoked by both hyperkalaemia and hypokalaemia
2. Chronic and/or acute ventricular ectopy and/or atrial ectopy, with or without permanent prolongation of the QTc interval. The ectopy may rarely deteriorate to life-threatening dysrhythmias, including torsade de pointes and ventricular tachycardia.
3. Congenital osteochondral anomalies of variable severity (from very subtle to marked), mainly affecting the mouth, face, toes and fingers.
The principal peri-operative areas of concern, particularly during anaesthesia, are therefore the risk of acute cardiac dysrythmias which may or may not be potassium-sensitive, and the appropriate management of plasma potassium levels with the risk of potassium-sensitive muscular paralysis or paresis. Also, anatomical oro-facial anomalies may cause difficulties with intubation and/or ventilation. These anomalies include 27 malar, maxillary and mandibular hypoplasia, high arched palate, anterior crossbite, narrow dental arches, and missing teeth.
Peri-operative drug choices are complex in patients with Andersen-Tawil Syndrome and include:
1. caution or contra-indication with all drugs that are unsafe with any neuromuscular disorder, and in that patient’s associated periodic paralysis e.g. that may provoke hypo- or hyper- kalaemia
2. caution or contra-indication with pro-arrhythmic drugs
3. an absolute contra-indication to all drugs that prolong the QT interval
Interpretation of peri-operative acute changes in the ECG may be difficult in ATS as some patients have very abnormal steady-state electrocardiograms [28, 29] A normal steady-state ECG is unusual in ATS but is still compatible with the diagnosis [30]. People with ATS can develop complex acute dysrythmias, the management of which may be very challenging. Cardiac manifestations in ATS may include QT and QU prolongation, prominent U waves, premature ventricular contractions, frequent atrial ectopy and supraventricular tachycardias, also bidirectional or polymorphic ventricular tachycardias. Some ATS patients have been shown to have permanent QTc prolongation in steady-state, in some it is intermittent, and in others, routine ECGs while asymptomatic repeatedly demonstrate a normal QTc interval. Until recently Until recently Andersen-Tawil Syndrome was also known as <Long QT Syndrome 7> but there is increasing evidence that this is not an appropriate designation. However, general principles of the management of a patient with Long QT syndrome should be applied to all patients with ATS. Ramakrishna et al provide a detailed expert overview of the appropriate peri-operative approach to patients with Long QT syndromes [31]. Other recommended reviews are Kies et al [32] ,Wisely and Shipton [33] and Nathan et al [34].
Packer and Strätling [35] describe their meticulous preparations for anaesthesia in a woman with Andersen-Tawil Syndrome presenting for elective athroscopic capsular release of the shoulder. She had an intermittent prolongation of the QTc interval and regular palpitations from ventricular extrasystoles but had been free of runs of ventricular tachycardia and had been stabilised on beta-blockade with nadolol. Staff were briefed pre-operatively about ATS and a written management plan was prepared. In addition to standard monitoring, invasive arterial monitoring was sited and defibrillator pads were applied to the chest and attached to an external defibrillator with a transcutaneous pacing facility. The risk of malignant hyperthermia was prepared for e.g. checking stocks of dantrolene. Induction included fentanyl and propofol, and maintenance with propofol and remifentanyl. Placement of two different laryngeal mask airways was unsuccessful so an endotracheal tube was placed. When extubated the patient breathed spontaneously and her muscle power matched her pre-operative strength. Recovery was uneventful and she was discharged home the next day. Other drugs given uneventfully were paracetamol, diclofenac and fentanyl.
Kruger’s case study [36] describes a woman with Andersen-Tawil Syndrome presenting for a repeat Caesarean section. Her history included fluctuating proximal weakness and complex ventricular ectopy. A multi-disciplinary approach was followed (neurology, cardiology, obstetrics and anaesthesia) and initial set-up included all standard monitors plus 5-lead ECG and awake arterial line. A slowly titrated epidural with marcaine and fentanyl was used plus epimorphone after birth. Anaesthetic goals included slowly titrated epidural to the appropriate level to prevent triggers, and meticulous haemodynamic monitoring. The procedure was uneventful and at 6-week follow-up the patient had remained asymptomatic.
Subbiah et al [37] also report on the management of a patient with ATS during pregnancy and delivery. She had declined prophylactic ATS treatment for many years (including beta-blockers, calcium channel blockers and an implantable defibrillator) except for potassium supplementation. She was closely supervised during pregnancy with regular neurological, cardiological and obstetric reviews. Of interest, during the pregnancy she had noted an increased frequency of periodic paralysis weakness but less frequent palpitations. Labour failed to progress and a caesarean section was performed under spinal anaesthesia. Management included maintenance of the plasma potassium above 4.0 mmol/l, and episodes of prolonged ventricular ectopy were managed with IV metoprolol 2.5mg as required. There were no complications and mother and baby were doing well at review a year later.
Nagashima et al [38] describe the successful surgical repair of an atrial septal defect without using cardioplegia (artificial cardiac arrest for open-heart surgery) in a young patient with KCNJ2-positive ATS and normokalaemic periodic paralysis, They comment: <The deleterious effects of cardioplegia on periodic paralysis and cardiac arrhythmia are unknown, and no studies have reported the performance of cardiac surgery in patients with ATS>. Her resting ECG showed incomplete right bundle branch block, a slightly prolonged QT interval and prominent U waves. A 24-hour Holter ECG showed frequent ventricular ectopics with episodes of bidirectional ventricular tachycardia and polymorphic ventricular tachycardia. The surgery was performed under tepid hypothermic 34 degC cardiopulmonary bypass with direct closure of the ASD under deliberately induced ventricular fibrillation. She was admitted directly to Intensive Care and recovered from the anaesthesia, with successful extubation, four hours later. She complained of muscle weakness on days 2 and 3 but had no further episodes and was discharged well on day 19.
The authors do not mention which drugs were given to the patient, nor any information on potassium surveillance and supplementation. They describe their rationale for not using standard cardioplegia: < Cardioplegia is routinely used in cardiac operations to protect cardiac function during ischemia. To maintain electromechanical arrest of the myocardium, a high concentration of potassium is required in almost all the cardioplegic solutions. However, hyperkalaemia reportedly induced periodic paralysis in approximately 15% of patients with ATS. Tawil and colleagues reported that the oral administration of potassium produced a paralysis attack in 2 of 4 ATS patients. In addition, a cardioplegic solution, which is routinely used at our institution, contains high concentrations of glucose and insulin. These solutions may have a deleterious effect on not only periodic paralysis but also the cardiac condition. Despite euglycaemia, infusion of insulin and glucose evoked muscle weakness in a patient with familial hypokalaemic periodic paralysis [39]. Even in the case of normal young men, insulin infusion reportedly leads to prolongation of the QT interval and increase in the QT dispersion in the ECG [40]. Although the mechanism is unclear, sympatho-adrenal activation induced by hypoglycaemia due to insulin infusion is probably related to abnormal cardiac repolarisation>.
6. Thyrotoxic periodic paralysis
Worldwide, TPP primarily affects people of Asian descent but may be seen in people of all ethnicities. The symptoms of thyrotoxicosis are distinct and usually precede the first paralytic episode. If TPP has not been diagnosed and the patient has a surgical procedure during general or regional anaesthesia, symptoms of the disease may be confused with other adverse peri-operative events such as delayed recovery from neuromuscular paralysis.
The evidence base of anaesthesia in TPP is sparse but Diedrich and Wedel [41] describe a case report of a patient with known TPP undergoing general anaesthesia, with a review of the literature. They also conducted a retrospective case review of of all patients with TPP who underwent anaesthesia at the Mayo Clinic between 1976 and 2002: six patients received five anaesthetics – all general endotracheal anaesthesia with induction drug, paralytic, opioid and volatile, and all but two received a reversal medication. There were no peri-operative complications, specifically no paralytic attacks, peri-operative ventilatory failure, thyroid storm nor abnormal ECG changes from baseline.
The authors concluded: <There is no specific anaesthetic method that is demonstrably superior for patients with TPP. However, several recommendations are supported by the current knowledge about this disease. Preoperative assessment in a patient with TPP should focus on the proper diagnosis and treatment of the thyrotoxicosis. Any elective surgery should be postponed until the patient is euthyroid. The treatment of TPP in patients who are thyrotoxic and undergoing emergent surgical procedures should focus on the cardiovascular management with intravenous beta-blockers. Esmolol, a selective b1-blocker, has been recommended however there are no data to support its use in Thyrotoxic Periodic Paralysis and anaesthesia. Non-selective beta-blockers (e.g. propranolol) are the traditional choice. The day before surgery, the patient should refrain from known triggers of TPP and anxiolytics should be given preoperatively if needed. Should the patient complain of any symptoms of TPP, a serum potassium level should be checked and an ECG obtained. Empiric potassium supplementation in the asymptomatic patient is not recommended. Either regional or general anaesthesia can be performed safely. All patients should have standard ASA monitoring, with additional monitoring dependent on co-morbidities and the surgical procedure. No specific induction method is recommended. Glucose-containing intravenous solutions should be avoided; there is no evidence to support the use of Ringer’s lactate solution (with its 4 MEq/L of potassium) over normal saline. The patient should be kept normothermic. Any medication that could decrease serum potassium (e.g., epinephrine, insulin, and albuterol) could potentially exacerbate a paralytic attack. When using neuromuscular blocking agents, proper titration and monitoring should be used. Neuromuscular monitoring can be done using any peripheral nerve. However, as TPP can affect the muscles in both lower and upper extremities, it may be prudent to use the facial nerve because it is very rare for the bulbar muscles to be affected by the disease. Routine reversal of neuromuscular blockade is recommended>.
7. The Potassium Aggravated Myotonias including Paramyotonia Congenita (von Eulenburg)
Useful brief reviews of PMC and PAM may be found at http://omim.org/entry/168300
and http://omim.org/entry/608390
Potassium Aggravated Myotonia is a term that encompasses all the genetic myotonias in which symptoms are precipitated by a potassium load thus includes PMC, HyperPP where there is myotonia, myotonia fluctuans, myotonia permanens and acetazolamide-responsive myotonia.
Klingler et al’s review [8] describes the challenges during anaesthesia for patients with these disorders:
<Depolarising reagents can induce masseter spasms and stiffness of respiratory and other muscles and can therefore impair intubation and mechanical ventilation. Depolarising muscle relaxants are therefore strictly contraindicated. The incidence of such events seems to be highest in families with myotonia fluctuans, the mildest form of sodium channel myotonia, a potassium-aggravated myotonia>.
<For these diseases, respiratory distress in the recovery room has often been reported. The weakness is aggravated by drugs that depress respiration and by the hypothermia induced by anaesthesia. Paramyotonia congenita and hyperkalaemic periodic paralysis patients may be paralysed for several hours upon awakening from general anaesthesia. Preventive therapy before surgery, maintaining a normal body temperature and keeping serum potassium at low level and avoiding hypoglycaemia, will help to prevent such attacks>.
<The generalized muscle spasms induced by suxamethonium in myotonic patients may resemble a malignant hyperthermia crisis, particularly when they are associated with an increase in body temperature. Therefore, myotonic patients are often considered to be susceptible to malignant hyperthermia. However, these life-threatening crises may have been rather induced by severe myotonic reactions or mistaken for other diseases, e.g. polymyositis>.
<Other case reports in the literature confirm that severe peri-operative complications may occur in PMC including myotonia and paralysis after the use of succinylcholine, and prolonged quadriplegia after inhalational anaesthesia has also been reported>.
Ashwood et al [42] provide an early (1992) review of PMC and anaesthesia (in the context of hyperkalaemic periodic paralsysis – PMC and HyperPP are frequently both present in the same patient). They describe a family with HyperPP with paramyotonia and the anaesthetic management of four affected members. In three patients, paralytic episodes had been precipitated by previous anaesthesia. The kindred was only definitively diagnosed when the propositus presented after problems with induction of anaesthesia for elective surgery – anaesthesia had to be aborted after the patient had an episode of marked generalised muscle stiffness and a locked jaw, which occurred after being given thiopentone and suxamethonium. Drugs safely given to family members after the diagnosis of their channelopathies included frusemide, thipentone, pancurium, enflurane, morphine, atropine, neostigmine, papaveretum, temazepam, vecuronium and atropine.
The authors concluded with the following recommendations: <On the basis of our experiences we make the following recommendations for anaesthesia in these patients: (a) preoperative potassium depletion with diuretics (b) prevention of carbohydrate depletion during fasting with intravenous dextrose solutions (c) avoidance of potassium-containing fluids and potassium releasing anaesthetic agents (d) temperature monitoring and maintenance of normothermia (e) continuous ECG monitoring and frequent serum electrolyte estimations (f) the availability of calcium gluconate in case of an increase in serum potassium which may be manifested by T wave changes on ECG (g) prophylactic treatment with mexiletine> (in many countries outside the US, mexiletine is difficult to obtain nowadays) <may be considered (h) avoidance of suxamethonium>.
Muralidhar and Anand [43] describe the anaesthetic management of an adult patient with PMC. In this case management was further complicated by the fact that the patient also had myoadenylate deaminase deficiency (a genetic disorder with a wide spectrum of clinical expression, from asymptomatic to significant neuromuscular and joint disorders) and Type 1 diabetes. On admission, the patient’s laboratory values were within normal limits including serum potassium of 4 mmol/l, and the ECG was normal. She was fasted overnight and not given any premedication. The operating room was prewarmed to 30 degC, warming blankets were used and all intravenous fluids and skin sterilising solutions were warmed. All residual traces of inhalational agents were removed by using new disposable breathing circuits and heat and moisture exchanger. The system was then flushed with 100% oxygen for 5 mins to wash out any traces. Anaesthesia was induced with propofol and atracurium and tracheal intubation was accomplished without difficulty. Anaesthesia was maintained with oxygen and nitrous oxide and divided doses of propofol, atracurium and fentanyl. Blood gases, serum Na+, K+ and glucose concentrations were monitored throughout the procedure. Blood pressure and heart rate remained stable throughout and the patient at no time had hypo- or hyper-thermia. The surgical procedure was completed in 4 hours and the patient was allowed to awaken spontaneously – no reversal was used. After demonstration of adequate return of neuromuscular function her trachea was extubated. In the immediate post operative period, she complained of weakness and numbness of the left arm but her recovery was otherwise uneventful and she was discharged on postoperative day 4. The authors discuss their management choices with reference to a review of the literature.
Kim et al [44] report the successful use of epidural anaesthesia in a patient with PMC with a demonstrated SCN4A mutation. Epidural anaesthesia was induced with a test dose of lidocaine and epinephrine then ropivacaine as two divided doses. Propofol was continuously infused for sedation. An air-warming mattress and warmed fluid was used to support the body temperature. The operating room temperature was also raised to 26 deg C. During the operation, vital signs were maintained satisfactorily including a body temperature of 36.0– 37.0 deg C. The recovery from anesthesia was uneventful. Immediate postoperative electrolytes were checked and were in the normal range (Na+ 141 mmol/L, K+ 4.1 mmol/L). Her symptom of myotonia was not aggravated during the peri-operative period. The patient was discharged on day 4 without complications related to anesthesia or surgery.
They summarise a review of the literature and emphasize that depolarizing muscle relaxants should be avoided in PMC due to the potential risk of hyperkalaemia and myotonic attack and that <the use of muscle relaxants should be carefully considered and, if possible, it is desirable to avoid their use>. They also state: <Volatile anesthetics have been uneventfully used in previous reports. However, Haeseler examined in vitro the effects of propofol on a PC mutant skeletal muscle sodium channel and found that propofol blocked sodium inward current at clinical concentrations (5 μmol/L). They suggested that propofol might be the agent of choice for the anesthesia or therapy for myotonic attacks in patients with sodium channel myopathies>.
Kaneda et al [45] report the safe management of anesthesia in an adult patient: <We performed anesthesia for a subtotal gastrectomy in a 70-year-old patient with paramyotonia congenita. Anesthesia was safely maintained using sevoflurane and nitrous oxide together with concomitant epidural anesthesia using mepivacaine. Specifically, refraining from the use of muscle relaxants, care with regard to the composition of infusion fluids during operations, and the maintenance of body temperature are required for anesthesia. In addition, postoperative pain management using a continuous epidural block proved to be a useful method>.
Russell and Hirsch [46] emphasise the importance of shivering as a trigger for myotonia: <The incidence of postoperative shivering has been reported as being 5-65%. Although shivering may be associated with hypothermia, there is a poor correlation with body temperature. Nevertheless, the maintenance of normothermia reduces the incidence and duration of postoperative shivering. Shivering is more common if large concentrations of volatile agents are used and these should therefore be avoided in myotonic patients. The incidence of shivering may be reduced by the use of doxapram, methylphenidate and pethidine. Management of the myotonic patient should therefore include careful monitoring of core temperature, the use of warming mattresses and warming of intravenous fluids.>. Other authors confirm that hypothermia should be avoided and non-hypothermic shivering should be treated promptly. Sallansonnet-Froment et al [47] also emphasise the risk of myotonia of the diaphragm during anesthesia in PMC.
8. Alternatives to general anaesthesia in the PP Disorders
The key issue to be discussed before finalising the anaesthetic regime in patients with PP Disorders is;
How does the chosen regime generically affect:
1. muscle strength, also depth of, and rate of recovery from, anaesthetic paralysis
2. blood potassium and glucose levels
3. activation of the sympathetic and parasympathetic nervous systems
4. especially in Andersen-Tawil – cardiac function, heart rate and rhythmogenesis
– and what is the evidence base for the anaesthetic regime’s safety in neuromuscular disorders in general, and Periodic Paralysis Disorders in particular.
Ginz et al [48] studied the effect of three anaesthetic techniques on isometric skeletal muscle strength investigating 33 healthy patients undergoing anaesthesia for elective lower limb surgery using a non-invasive muscle force assessment system, with a Grass S11 nerve stimulator, before and during anaesthesia. All patients received oral midazolam. Two different GA techniques were used – a target controlled infusion of propofol or inhalation-induction and maintenance with sevoflurane. The third group underwent spinal anaesthesia with hyperbaric bupivacaine. They concluded that clinical concentrations of propofol or sevoflurane did not influence isometric skeletal muscle strength in healthy adults but that spinal anaesthesia did have an effect – reducing strength by about 20%.
However epidural anaesthesia has theoretical advantages for several reasons in preventing paralysis attacks compared to other methods of anaesthesia. It has been shown to not only reduce pain but also reduce blood catecholamine levels thus lessening the effect on plasma potassium levels [49]. There is much published evidence confirming this e.g. in a meta-analysis, Iwasaki et al [50] state <Regional and general anaesthesia have often been compared to ascertain whether one provides benefits through dampening the stress response>. <Regional anaesthesia offers considerable advantages, by suppressing cortisol and catecholamine levels and reducing muscle breakdown postoperatively. It also has less immunosuppressive effect and potentially reduces the pro-inflammatory cytokine response> but they add < further research into this area is warranted>
9. Periodic Paralysis Disorders and sleep apnoea syndromes
There are many un-referenced published statements that paralytic episodes in the Periodic Paralysis Disorders <very rarely affect respiratory muscles>. There is however much anecdotal evidence from affected patients to the contrary – a number of people with PP Disorders describe breathing difficulties (hypoventilation; choking; a feeling of suffocation; poorer results with CPAP treatment in those already diagnosed with sleep apnoea, & etc) during paralytic or paretic episodes. This adverse respiratory effect would seem logical as the principal respiratory muscles (inter-costal, rectus abdominis, the diaphragm, some muscles of the upper airway) are voluntary <skeletal> muscles and are therefore highly unlikely to be spared from the paralytic effects of a genetic channelopathy. There would not seem to be a published study specifically addressing the incidence and importance of respiratory problems in PP Disorders.
Buzzi [51] describes his questionnaire study of 42 people with PP Disorders (members of the Periodic Paralysis International Listserv). Most of the patients reported symptoms suggestive of disrupted sleep architecture, and many of the symptoms described are compatible with sleep apnoea. There is considerable continuing anecdotal evidence to suggest that people with PP Disorders may have a higher incidence of diagnosable obstructive sleep apnoea syndrome (OSA) although there are no reports to date of physicians routinely screening their PPD patients for sleep apnoea. There is extensive published evidence, including [52 53] that sleep apnoea is common in neuromuscular disorders in general, although no authors other than Buzzi would seem to have specifically cited Periodic Paralysis Disorders.
For some patients with PPDs, obstructive apnoea events (collapsed upper airway) and hypopnoeas (partially collapsed upper airway) may perhaps only occur during paralytic attacks or abortive attacks, and this intermittent sleep apnoea may remain undiagnosed. Anecdotal evidence however suggests that an unexpectedly high proportion of people with a PPD have a confirmed diagnosis of sleep apnoea and are being treated with one of the types of continuous positive airway pressure – CPAP, APAP, Bi-pressure, or Assisted Servo Ventilation (ASV).
PPDs may also lead to permanent muscle weakness. If this is severe and involves truncal and pharyngeal muscles (to date considered, but not evidence-based, to be rare), such patients, as many others with chronic neuromuscular disorders, would also be susceptible to central, or mixed, sleep apnoea syndromes which should be tested for and treated where necessary.
Patients with obstructive sleep apnoea syndrome are a noticeable challenge during anaesthesia, particularly general anaesthesia. But serious respiratory problems may arise with SA during any form of sedation. Useful reviews include the The American Society of Anaesthetists’ <Practice guidelines for the peri-operative management of patients with obstructive sleep apnoea> [54] and den Herder et al [55] <Risks of general anaesthesia in people with obstructive sleep apnoea>.
(END)
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List of References for Parts 1 and 2 of ‘Anaesthesia and peri-operative care in the primary Periodic Paralysis Disorders’
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Anaesthesia and peri-operative care in the primary Periodic Paralysis Disorders.
PART 1: A REVIEW OF THE LITERATURE.
Baughan ASJ, Cavel-Greant D, Megalo J and Weber F.
Published April 2016 at www.hkpp.org Comments are welcome.
This web edition (first published April 2016) will be updated as necessary.