Management of Restless Legs Syndrome in the Hospital and During Surgery
Restless legs syndrome (RLS) is a quiescegenic disorder; its symptoms emerge at rest. Therefore, a critical worsening of RLS during hospital stays, which include bedrest, is common.
Intraoperative blood loss, type of anesthesia, concomitant medication, and illness- or pain-induced sleep deprivation may further contribute to aggravation of RLS. This must be taken into account when patients with RLS undergo elective or emergency surgery or are subject to hospital stays for other reasons. Apart from a worsening of preexistent RLS, symptoms may also emerge for the first time in these conditions and need to be identified by professionals involved in the postoperative phase.
Special emphasis on the management of RLS during hospital stays and in the perioperative phase will greatly contribute to alleviate the discomfort and tension brought on by often associated with these situations.
Pathophysiologic Aspects of Perioperative Restless Legs Syndrome
The emergence of symptoms at rest is one of the essential symptoms of RLS,1 and immobilization is used to provoke RLS symptoms and derived periodic limb movements (PLM) in the suggested immobilization test.2 From this context, it becomes clear that bedrest during hospital stays and, even more so, immobilization of the legs (possibly also other parts of the body) can trigger RLS symptoms in mild cases or contribute to a critical worsening in more severely affected patients. Intraoperative and postoperative blood loss reduces body iron stores and represents an additional contributing factor.
Both RLS and PLM have been observed during epidural and spinal anesthesia, with symptoms occurring either during anesthesia or as the effect is wearing off. Shin3 pointed out that severe restlessness may occur during epidural anesthesia in patients with RLS. He describes a 30-year old woman with RLS since childhood, which worsened during pregnancy, who had a cesarean section with epidural anesthesia. The patient experienced an urge to move the legs but was unable to do so due to the motor block and violently thrashed her head and arms. Symptoms improved with diazepam.3 Ward4 describes his own experience of an RLS-like syndrome during epidural anesthesia. While the motor block was active and the effect of anesthetic was wearing off, he suffered from a severe urge to move the legs; symptoms were later alleviated by walk-ing around. Although Ward used the term “akathisiâ’ in this case report, the similarity with RLS is evident. Because a previous surgery in spinal anesthesia with carbocaine and epinephrine was uneventful, the author, who is a psychiatrist, attributed his symptoms to the effect of droperidol, which was administered together with metoclopramide in the preoperative phase.4
Periodic limb movements during wakeful-ness (PLMW) were observed in a patient without any history of RLS or PLM during epidural and spinal anesthesia, during the phase of motor paralysis.5 The same authors had reported PLM during wakefulness in another patient during spinal anesthesia, in whom PLM during sleep had also been documented. It was not stated whether this patient also had RLS.6 Watanabe and colleagues5 used the term “anesthesia-related PLM”(AR-PLM) to characterize these phenomena. They suggested that AR-PLM and PLM during sleep may share a common etiology with spinal anesthesia or sleep-related suppression of descending inhibitory spinal pathways or corticospinal tract dysfunction.5
Several other case reports deal with myoclonus-like and other involuntary movements in patients undergoing surgery during spinal or epidural anesthesia, or in the immediate postoperative phase.7-12 In some of them, it is controversial whether the movements resembled PLM or spinal or propriospinal myoclonus. A prospective studyfound that transient RLS occurred in 8.7% of 202 patients undergoing spinal anesthesia for orthopedic and other surgery.13
An imbalance in sensorimotor integration13 may underlie the occurrence of RLS and PLM during spinal anesthesia, specifically during its wearing off. Another suggested mechanism is reduced blood flow in the lower extremities or spinal cord.14 The use of epinephrine in spinal anesthesia prolongs duration of effect15 but may reduce blood flow to spinal cord.16
New onset of RLS independent of type of anesthesia has also been reported in patients undergoing surgery for other reasons. For example, familial RLS first manifested itself after heart surgery in a 9-year-old boy17—in this case, the interaction compromised brain iron regulation and blood loss was discussed. A recent survey focused on patients undergoing lung transplant and reported an extremely high frequency of 47.2%. The authors discuss that the increased incidence of steroid-induced diabetes, drug-induced anemia, renal dysfunction, and neuropathy might all contribute to an increased risk for RLS in this specific surgical population.18
Four general principles apply for the management of RLS in the context of surgery and hospital stays: (1) monitor iron status, (2) ensure continuous treatment of RLS in the perioperative phase, (3) increase dosages during the hospital stay if needed, and (4) avoid drugs with the potential to worsen RLS.
1. Monitoring Iron Status
Continuous monitoring of iron status is critical in all patients with RLS undergoing surgery or hospital stays for other reasons. Replenishing body iron stores improves baseline conditions for RLS treatment. In patients with severe RLS and anemia, blood transfusions may be indicated to treat the RLS. Dramatic improvement after blood transfusions of severe iron-deficient RLS apparently refractory to treatment have been reported.19 Parenteral iron substitution is indicated for rapid correction of iron deficiency. Iron status should be checked in RLS patients even before minor surgery and iron replacement initiated if body iron stores are found to be low.
2. Ensure Continuous Drug Delivery
In the immediate perioperative phase, oral medications often have to be discontinued. Because continuous and efficient RLS treatment is critical in this phase, nonoral drug delivery has to be established when oral medication is withheld for a prolonged period of time. Baseline RLS treatment should be continued as long as possible before surgery. One should remember that re-emergence of RLS symptoms after temporarily stopping oral medication greatly varies due to variable plasma half-life of the medication, from 2 to 4 hours with levodopa20 to 65 hours with cabergoline.21
During suspension of oral medication, parental drug delivery can be achieved by intravenous, subcutaneous, transdermal, and epidural routes for various dopaminergic, opioid and antiepileptic agents.
Systemic Dopaminergic Treatment
Recent studies have shown that transdermal delivery of dopaminergic drugs like rotigotine patch22 or lisuride patch23 is efficacious in RLS. Patch applications may provide a useful treatment mode for patients in the fasting state. Although stable plasma levels can be reached, and patch treatment is expected to provide a good baseline treatment, it remains to be established if the onset of action is fast enough to realize shorthand adaptations to increasing dose needs in inpatients. Rotigotine has already been approved for Parkinson’s disease.
Intravenous levodopa infusions have been used in Parkinson’s disease patients with motor fluctuations.24 Although long-term treatment with intravenous levodopa is classified as undesirable, short-term application has proved to be feasible.24 Phlebitis at the application site and tolerance after infusions lasting only 21 hours have been observed.25 In RLS patients, data on intravenous application of levodopa are not available. Several caveats and inter-actions relevant to this post are mentioned in the drug information for levodopa. The inhalant agent halothane may precipitate cardiac arrhythmia in patients treated with madopar. It should be noted that opioid administration may reduce the efficacy of levodopa. Administration of iron II sulfate reduces the maximal plasma concentration of L- dopa and the area under the curve by 30% to 50%, respectively (see drug informa-tion for L-dopa).
Apomorphine can be delivered via both intravenous and subcutaneous routes. The use-fulness of nocturnal subcutanous apomorphine infusion was first demonstrated in two patients with RLS who received apomorphine delivered over a 12-hour nighttime period.26 In another study, a single dose of 0.5 mg apomorphine subcutaneously was used at bedtime in nine patients with RLS.Asignificant reductionofthePLMSwas found but lasted only 4 hours after injection.27 Subjective symptoms are not reported.27 Tribl and coworkers28 treated nine patients with very severe RLS with intravenous apomorphine. Both subjective (RLS severity visual analogue scale) and objective (PLM in suggested immobilization test) outcome variables were significantly improved. The rapid onset of action was also emphasized. Despite 3 days of pretreatment with domperidone, side effects were frequent and consisted of drowsiness, yawning, and falling asleep.28
Intravenous and subcutaneous use is also described for the dopamine agonist lisuride in patients with Parkinson’s disease.29,30 How-ever, lisuride is not available in all countries. Amantadine has been shown to improve RLS,31,32 and it is available for an endovenous application. Its usefulness in peripoperative patients has not been investigated.
For RLS patients in the perioperative and immediate postoperative phase, subcutaneous application of apomorphine should be a feasible way, but its short plasma half-life (around 30 minutes) will require reinjections in short time intervals along with domperidone. Intravenous administration of dopaminergic drugs will probably remain a more theoretical option.
Because dopamine agonists tend to disrupt sleep,27,33,34 an additional nighttime hypnotic may be warranted in some patients.
The efficacy and role of opioids in the treatment of RLS are discussed earlier.35 Opiate analgesics are part of many postoperative pain treatment regimens. Systemic delivery is well established and includes intravenous, intramuscular, subcutaneous, and transdermal applications. In the immediate perioperative and postoperative phases, as well as in chronic pain conditions, continuous regional or epidural applications are also performed. Substances that have been used in RLS36 include propoxyphene (130 to 520 mg/day), codeine (15 to 120 mg/day), oxycodone (2.5 to 20 mg/day), hydrocodone (5 to 15 mg/day), pentazocine (50 to 200 mg/ day), and tramadol (50 to 150 mg/day) (short half-life agents) and methadone (5 to 30 mg/day), levorphanol, and SR morphine (as long half-life agents).36
In the immediate postoperative phase, opiates can also be administered epidurally, if the catheter remains in situ after surgery.37 Transdermal opiates are also available, such as fentanyl or buprenorphine. However, in pain treatment, transdermal delivery is mainly used to maintain baseline treatment, and intravenous application is preferred, if rapid onset of action is required. RLS patients who have received opioids for more than a few days should be carefully tapered off the medication, because both restlessness and symptoms of RLS can emerge or worsen during abrupt withdrawal from long-term opiates38 or during rapid detoxification in opiate-dependent patients.39 Transient RLS symptoms during opiate withdrawal emerged in 15 of 120 opiate addicts in a retrospective study.40 Development of sleep apnea needs to be monitored in RLS patients receiving opiates.41
Valproic acid (VPA) is available in an intravenous preparation, facilitating both nonoral delivery and rapid saturation. A recent study has shown that VPA is a good treatment alternative for RLS and PLM when dopaminergic drugs cannot be used or are ineffective.42 For treatment of RLS, doses around 600 mg/ day are used. Clonazepam is also used as a co-treatment for RLS.
Treatment of Complications
In patients with the most severe form of RLS, a combination treatment with opiates, dopamin-ergic agent and benzodiazepine, or VPA may be required. One possible specific complication of surgery in RLS patients is persistent PLMS during epidural anesthesia (see earlier case reports). If this occurs, opiates (e.g., epidural morphine) should be applied.37
3. Increase Dosage if Needed
Even if blood loss is insignificant, and disruption of oral medication intake irrelevant, bedrest, immobilization, pain, and sleep deprivation may contribute to the temporary aggravation of RLS. If this occurs, treatment has to be increased above the usual dose during the perioperative phase during hospital stay. In case of acute exacerbation of symptoms, an additional dose of a systemic opiate may rapidly provide relief. Ancillary measures may also be tried, but it has not been investigated whether physical therapy (e.g., exercises, massages, cold/hot application), automatic dynamic/active splints, or pulsatile air bed systems can contribute to alleviation of RLS symptoms in perioperative patients.
4. Avoid Potentially Harmful Drugs
Typical neuroleptics have the potential to induce or worsen RLS and should be avoided in the anesthesia or as antiemetics in RLS patients. This is true both for neuroleptics used in combined anesthesia (e.g., droperidol) and for antiemetics (e.g., metoclopramide, promethazine, prochlorperazine). Ondansetron, a selective serotonin3 receptor antagonist, is effective in the treatment of postoperative nausea and vomiting.43 Scarce studies from the early 1980s report a benefit for intravenous domperidone,44,45 but domperidone is currently used only as an oral preparation in many countries and is not available in others. Beyond the context of surgery, many other medications have been reported to induce or worsen RLS. It might be wise not to initiate these medications in the immediate postoperative phase, but there is no need to dis-continue long-term treatment if there is no temporal relation with worsening of RLS.
Specific, skillful, and sufficient management of RLS is critical in patients during hospital stays and surgery. Specifically designed information brochures, such as the brochure “Surgery and RLS”from the Restless Legs Syndrome Foundation (www.rls.org) provide valuable help.
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