Section of Anesthesia and Intensive Care Unit, Department of Neuroscience, Psychiatric and Anesthesiological Sciences, University of Messina, Policlinico Universitario G.Martino, I-98125 Messina, Italy
*Corresponding author. E-mail: vfodale@unime.it
Accepted for publication: September 3, 2003
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Abstract |
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Br J Anaesth 2004; 92: 28993
Keywords: anti-inflammatory agent, methylprednisolone; complications, polyneuropathies; complications, weakness; neuromuscular block; neuromuscular block, cisatracurium
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Introduction |
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No case of polyneuropathy related to a continuous infusion of cisatracurium has been described. Only prolonged weakness after discontinuation of a continuous infusion of cisatracurium and concomitant high-dose corticosteroids because of myopathy has been reported in a critically ill patient.8 We present a case of acute motor axonal polyneuropathy with flaccid quadriplegia after discontinuation of a 7-day cisatracurium infusion. The patients who had had chest trauma, also received concomitant corticosteroid therapy.
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Case report |
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The patient required tracheal intubation with mechanical ventilation. Arterial blood gas values were: pH 7.35, PaCO2 6.4 kPa, PaO2 9.1 kPa, SaO2 90.6%. Sedation was achieved with midazolam and morphine, and later with propofol. To minimize barotrauma, the patient was paralysed with a continuous infusion of cisatracurium starting at 1.42 µg kg1 min1, titrated according to clinical evaluation. No other neuromuscular blocking drug was used. The paralysed limbs and trunk were moved passively to maintain a full range of movement three times a day. Correct posture was maintained through orthoses and changing the patient position every 3 h. The aim was to prevent movement of the diaphragm and respiratory muscles. First cisatracurium and then the sedation were stopped every 24 h until the patient was awake and able to move his upper and lower limbs, as suggested by Haenel and colleagues,9 and until the diaphragm and respiratory muscles were contracting. In addition, serum creatine phosphokinase (CPK) concentration was routinely monitored.
Concurrent administration of methylprednisolone 125 mg i.v. every 12 h was also started to reduce lung dysfunction, because of its beneficial effects in severe chest trauma.1013 Other medication included ambroxol, enoxaparin, ranitidine, furosemide, meropenem, and teicoplanin.
One week later, the required infusion rate of cisatracurium had reached 5.75 µg kg1 min1. Respiratory conditions had improved (arterial blood gases: pH 7.40, PaCO2 4.5 kPa, PaO2 11.0 kPa, SaO2 98.6%). First the neuromuscular blocking drug and then the sedative infusions were stopped. After discontinuation, the patient was awake, but manifested flaccid quadriplegia with absence of deep-tendon reflexes, despite the fact that assessment on the day before did not show evidence of any neurological symptoms. No sensory deficits were observed. After developing the tetraplegia, methylprednisolone was discontinued. The patients clinical course after discontinuation of cisatracurium is detailed in Table 1.
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Diagnostic investigations during the period of ICU admission excluded the presence of sepsis, SIRS, multiple organ dysfunction syndrome (MODS), renal and hepatic failure, acidbase and electrolyte disorders, hyperosmolarity, diabetes, alcoholism, porphyria, myoglobinuria, or hyperpyrexia.
Electrophysiological studies
The results of electrophysiological studies performed repeatedly after discontinuation of cisatracurium are detailed in Table 2.
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Discussion |
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Nevertheless, after discontinuation of the cisatracurium infusion, the patient manifested a flaccid quadriplegia and areflexia, without sensory loss. Clinical and electrophysiological findings supported the diagnosis of acute motor axonal polyneuropathy. In addition, there were no risk factors for classic CIP, such as: long stay in ICU; MODS or sepsis;14 16 acidbase and electrolyte disorders or hyperosmolarity;3 hypoxia or hyperpyrexia;17 or diabetes, renal failure, alcoholism, or porphyria.18 In particular, it has been demonstrated recently that lower blood glucose levels reduce the incidence of CIP by 44%.19 It is feasible and safe to maintain blood glucose levels at less than 6.1 mmol litre1 by using a titration algorithm.20 Our patient had hyperglycaemia of 9.9 mmol litre1 on admission, but normoglycaemia was reached after 9 h, within the 24 h safety margin.20 It was maintained during his intensive care by using insulin titration guidelines. Nutritional insufficiency has also been implicated in the genesis of CIP.21 The feeding regimen used in our patient was glutamate-enriched enteral nutrition increasing from 500 to 1600 kcal day1 during the first 7 days of intensive care (the period of severe illness).
Even though muscle biopsy was refused by the patient, an intrinsic muscle disease is unlikely on the basis of the clinical and electrophysiological data. CPK levels were normal (with the exception of the first 2 days because of the acute trauma) whereas they should be elevated in thick filament myopathy and in acute necrotizing myopathy, when myoglobinuria may also occur.2
Lack of an increased protein concentration with a normal cell count on repeated CSF examination did not support the diagnosis of an immune-mediated neuropathy. Moreover, several case reports of acute motor axonal neuropathy have described rapid neurological recovery within a month.22 Other neuropathic causes of rapidly progressive generalized weakness or paralysis, such as GuillanBarrè syndrome or Acute Motor Axonal Neuropathy, were incompatible with the clinical features of this case. Thus, in our patient, co-administration of cisatracurium and corticosteroids was the sole risk factor for acute motor axonal polyneuropathy.
In critically ill patients, neuromuscular blocking drugs and concomitant corticosteroid therapy favour the development of a polyneuropathy.27 The mechanisms by which they may contribute to this iatrogenic complication are still not completely understood; nevertheless sepsis and SIRS are important underlying factors.18
The critical illness per se is unrelated to the development of a neuropathy and sepsis does not induce a neuromuscular transmission defect.23 24 Sepsis does induce early changes in the microvasculature associated with impaired perfusion of peripheral nerves and increased permeability of capillaries.24 25 This process may be accentuated by the administration of corticosteroids or neuromuscular blocking drugs.26 What is more, neuromuscular blocking drugs and corticosteroids could gain entry to nerves and have toxic effects on peripheral nerve axons.18 25 27 Thus, neuromuscular blocking drugs can favour the development of or increase the severity of a neuropathy.3 24
Cases of acute axonal neuropathy or polyneuropathy associated with the use of neuromuscular blocking drugs and corticosteroids have been reported. Gorson and Ropper28 described four critically ill patients with paralysis, acute respiratory failure and continued ventilator dependency following relaxant administration. Electrophysio logical studies supported a severe acute axonal motor neuropathy, considered to be a variant of CIP. Isner-Horobeti and colleagues6 described three cases of polyneuropathy associated with corticosteroids and/or muscle relaxants, and some studies reported vecuronium-associated axonal motor neuropathy in paediatric patients.4 21 As with myopathy in critically ill patients, early reports of neuropathy or polyneuropathy associated with the use of muscle relaxants and corticosteroids implicated steroid-based agents (e.g. pancuronium and vecuronium) rather than benzylisoquinolinium-based drugs (e.g. atracurium, cisatracurium, doxacurium). Nevertheless, in the same way that subsequent reports also associated myopathy with benzylisoquinolinium agents, it is likely that these agents will be implicated in critical illness neuropathy. Neuromuscular blocking drugs are now often avoided in the critically ill, having been replaced by new i.v. sedatives such as propofol. This has reduced the incidence of NMB-related critical illness neuropathy.29
There are no reports of polyneuropathy after discontinuation of cisatracurium. Davis and colleagues described a woman with respiratory distress syndrome who underwent mechanical ventilation and was paralysed with a continuous infusion of cisatracurium for 2 weeks, and developed prolonged weakness.8 The authors ascribe the weakness to a myopathy. This report and our own share several clinical features. Both patients presented were paralysed without sensory loss and with normal CPK levels, and both patients were able to move their fingertips 10 days after cisatracurium discontinuation. Both patients received the same daily dose of methylprednisolone during the 2 days preceding the onset of paralysis. Nevertheless, in the case reported by Davis and colleagues,8 the cisatracurium infusion was stopped after 13 days, approximately 1 week longer than in our patient, and the infusion rates were higher, ranging from 6.3 to 10.5 µg kg1 min1. EMG was not performed. In fact, in the case report of Davis and colleagues,8 the diagnosis of myopathy was based only on clinical findings and no electrophysiological data were provided which could help to distinguish a myopathy from a polyneuropathy.30 31 Moreover, we were not able to ascertain if the patient described by Davis and colleagues8 had as rapid a neurological recovery as our patient.
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