sr (pancuronium bromide) during artificial ventilation

Neuromuscular complications in patients given Pavulon@ (pancuronium bromide) during artificial ventilation A.A. W. Op de Coul *, P.C.L.A. Lambregts*, J. Koeman*, H.J. Ter Laak***, and A.A.W.M. Gabreels-Festen***.

M.J.E. van Puyenbroek**,

Introduction Summary In recent years we noticed that some patients subjected to prolonged total muscle relaxation for artificial ventilation, subsequently developed severe peripheral pareses of all extremities in with generalized muscular combination

atrophy. The muscle relaxant used was pancuronium, (Pavulon’” ) usually given over a period of 6 days or longer at a dosage of 4 mg per intravenous injection, repeated every 3-4 hours to ensure a sufftcient effect for artificial ventilation; in all cases another 4 mg dose of Pavulon (PV) was given as soon as the patient became restless or started to tight the ventilator. After termination of artificial ventilation these patients were found to have severe tetraparesis. equally distinct in arms and legs, more frequently at distal than at proximal levels. The pareses were accompanied by complete areflexia and very diffuse atrophy af all extremity muscles. A few patients also showed involvement of the extraocular, facial and deglutitory muscles: in none of the cases were sensory disturbances observed. The pareses as a rule disappeared after very intensive physiotherapy over a period of a few weeks to months, but significant disability persisted in two cases.

This paper reports on 12 patients in a 3-year period (from 1st July 1980 to 1st July 1983) who were treated with artificial ventilation and muscle relaxant pancuronium with the bromide (Pavulona), over a period of 6 days or longer. After discontinuation of this drug these patients developed severe tetraparesis with areflexia, sometimes combined with disturbances of the extraocular and facial muscles and diffuse muscular atrophy, without sensory Seven patients recovered disturbances. completely after 2-5 months, two made an incomplete recovery and three died due to the primary disease. It is suggested that these neuromuscular complications were caused by prolonged high-dosage Pavulon treatment in combination with renal and hepatk disturbances and/or the use of aminogll:cosides. Key words: Pancuronium effects, artificial respiration.

These observations of the 12 PV-treated

bromide.

side

asked for a detailed study patients who developed

pareses between 1st July 1980 and 1st July 1983. In the same period nearly 240 patients were treated in the same Intensive Care with PV: 12 of 60 patients, treated more than 6 days with PV, developed the neuromuscular complications described above.

* Depurrment of Neurology and ** Intensive Care Unir, SI. Elisabeth Hospital, Tilburg, The Netherlands. ***MorpholoRi;,crl Neurolog~~ Research Laborator): Institute of Neurolog): 9. Radboud Hospital. Universqr

of i\liImegen,

The

Nerherlunds. Address for

correspondence

YOl.(l, 5000 LC‘ Tilburg

and reprint

requests: A.A. W. Op de Coul,Department

of Neurologv,

St. Elisaberh Hospiral, P.O. Bo.r

The Netherlands.

hc,cepred I 7X.K4

17

Pharmacokinetics of Pavulon”’ ( PV) PavulonR is a bi-quaternary aminosteroid introduced in the USA in 1972: its two acetylcholine-like fragments are responsible for neuromuscular blockade. PV acts by postsynaptic blockade of acetylcholine receptors, and to a lesser extent by presynaptic inhibition of the release of acetylcholine molecules from the nerve terminal into the synaptic cleft, as demonstrated experimentally”. The drug is degraded quickly (60% plasma half-value time less than 5 minutes) and eliminated by the liver as well as by the kidneys. PV is generally used briefly during operations and also in poorrisk patients with cardiovascular and pulmonary complications. Its effect is live times as strong as that of d-tubocurarine, and the neuromuscular blockade can be abolished with the aid of the cholinesterase pyridostigminei. Patients with inhibitor myasthenia gravis are eight times as sensitive to PV as non-myasthenic patie&“. It has been established that other drugs interact with muscle relaxants* and either increase or decrease their duration of action. Lithium, magnesium sulfate and some antibiotics, especially aminoglycosides (gentamycin, tobramy~in, streptomy~in)*,~ have been reported to prolong the action of PV, These antibiotics themselves exert an influence on neuromuscular transmission, and the same applies to polymyxin derivatives, the tetracyclines and lindomycin derivatives. Prolonged neuromuscular blockade has been reported in a 76-year-old man given a combination of PV and potymyxin B”, in a 4%year-old patient with disturbed liver and kidney functions7, in a 63-year-old woman with acute renal failure and in a 21-year-old woman after a gynaecological operations. In all patients the protracted effect did not last longer than a few hours to three days. We have found no data in the literature on so protracted an effect or influence on neuromuscular transmission as we observed in our patients. Our patients, however, were chronic patients given PV over a period of six days or longer; and in our patients other factors like medication and/or poor liver and kidney functions played a role. 18

Aminoglycosides interfere with neunrmuscular transmission both presynaptically (1~1 inhibiting a~etyl~holin~ release) and posts\naptically (by reducing sensitivity t(r acetylcholine): and the polyneuropathy results from axon damage with secondary segmental demyelination. In addition to amin~)gly~~)side toxicity there are other predisposing factors like renal function disorders. or possibly prc-exiatent neuromuscular disease. A combination of PV administration, aminogly~oside administrati~~n, renal and/or liver function disorders with a poor general condition explains the toxic effect of PV on neuromuscular transmission. Analysis of patient data Between 1st July 1980 and 1st July 1983 prolonged muscular weakness was observed in 12 patients after a period of artificial ventilation with PV administration which ranged from 6 to 21 days (Table I). The total PV dosage varied from 54 mg to I340 mg (daily doses from 6 x 4 mg to 16 x 4 mg). The drug was administered intravenously in doses of 4 mg per injection, repeated every 3-4 hours; in all cases 4-6 intravenous injections of 10 mg diazepam and 1-4 of 10 mg of nicomorphine hydrochloride were given as well. In all cases hypoxia, hypercapnia and dehydration were corrected, as were potassium calcium and magnesium serum levels. Eight of the 12 patients had multiple traumata with severe thoracic injuries (costal fractures and flapping thorax); two had peritonitis and one an abdominal trauma (Table 2). Seven patients recovered after 2-5 months, three died due to the primary disease (nrs. 1,4,6 Table 2) and two made so far a partial recovery (nrs. 10 and 11). Seven patients showed severe renal function disorders which had been pre-existent in two and required hemodialysis in two; two patients had liver function disorders (combined with renal function disorders. Table 1). Eight of the 12 patients were given aminoglycosides (gentamycin or tobramycin), and eleven patients in addition received a few days a large (50-75 mg prednisol~~ne acetaat) dose of coricosteroids (Table 1).

Table

I Data on Pabulon”’ treatment Treatment PV days

8 9 IO II 12

Administration total dose in mg

14 11 17 6 21 14 18 I IO 14 9 10

Table 2. Data on 12 patients

Corticosteroids

+ + + + + + + + + + + +

drugs Aminoglucosides

Disturbed functions*

kidney

+ (hemodialysis) + (pre-existent) + + (hemodialysis)

gentamycin gentamycin gentamycin tobramycin tobramycin tobramycin tobramycin tobramycin

Disturbed tions* *

liver func-

+ (liver rupture) +

+ -

+ (cystic kidneys)

+

1

with neuromuscular

complications

after treatment

with Pavulon” complications

Duration of neurologic: 11 dysfunction t after 5 weeks

Diagnosis

Neuromuscular

I

43

brain concussion, flapping thorax. liver rupture, pelvic fracture

tetraperesis.

areflexia

2

74

brain concussion, costal fractures. kidney functions disturbed (pre-accident)

tetraparesis,

atrophy

3

65

brain concussion, costal fractures, leg fractures

tetraparesis, areflexia

4

50

peritcnitis, syndiome,

tetraperesis,

atrophy,

areflexia

t after 2 weeks

5

52

multitraumatized,

tetraparesis,

atrophy,

areflexia

recovery:

6

50

costal fractures, lung contusion. transverse lesion LI/L12

paresis arms, atrophy,

35

brain concussion, costal fractures, pneumothorax

tetraparesis,

atrophy,

73

brain concussion. costal fracturess. fractured extremities

tetraparesis,

atrophy.

45

peritonitis, ficiency

tetraparesis,

atrophy.

47

cystic kidneys, myocardial infarction. respiratory insufficiency. flapping thorax

tetraparesis, atrophy, areflexia paresis extra-ocular and facial muscles

partial recovery: 4 months

38

abdominal

tetraparesis, atrophy, areflexia paresis facial muscles

partial recovery: 4 months

38

status asthmaticus

tetraparesis.

recovery:

Patient number

19x0

19x3

+ + + + + + + + + + + +

- additional

Age

Year

1982

Diazepam/ Nicomorphine HCL

384 212 1340 54 380 784 860 26X 216 352 544 558

* creatinine > 120 micromol/ ** SGPT > 100 U/L SGPT > 5OU/L

1981

in 12 patients

respiratory distress poor kidney functions lung contusion

respiratory

trauma

insuf-

atrophy

atrophy,

atrophy,

areflexia

areflexia

hyporeflexia

areflexia

recovery:

4 months

recovery:

5 months

6 weeks

t after 3 months

recovery:

3 months

recovery:

6 weeks

recovery:

2 months

5 months

19

‘l-able 3. EAectromyographlc and neuropathologtc Patient Days since number Pavulon _ treatment denerv. activity ended

2 6

150

7 8 Y 10

210

11

23

12

12

findings rn X patrcnts gtven Pavulon”

Electromyography ~~_____.. reinnerv. mot. cv.* WlVX.* Peroneal-Ulnar N acttvity

+

38

4R

Neurupath~~log!“** disturbed** neuromusc. transnl

myopathy

muscles biop\,v

/-:‘-\ c hrr1P\v

+

neurogenic denervation (intercostal m.)

~~mal degeneratrrln trad~al nerve)

neurogenic denervation reinnervation (soleus) myopathy necrosis (soleus)

,tnonJ degeneratton t~~ral nerve)

-

34 55 15

t t +

+

40

56

t + +

n.r. 45

n.r. 57

62(u)

-

+

48

50

55(U)

t

t

+

38

54

36(s)

+

+

myopath, necrosis (soleus)

dubious dxonal degeneration (sural nerve) dubtoua axonal degeneration (sural nerve)

* m/set (s = sural -, n = ulnar nerve, n.r. = no response) ** significant decrement after supramaximal ulnar nerve stimulation (3 Hz) *** nr. II and 12 two weeks and nr. 6 and IO two months after Pavulon treatment ended

The four patients not given aminoglycosides did have severe renal function disorders (exept patient nr. 12). Eight patients received PV on the day of admission, the other four patients on the second or third hospital day. An extensive electromyographic study was performed in seven patients and neuropathologic examinations (muscle and nerve biopsy specimens) were made in four (Table 3). Exept in one case (patient no. 7, Table 2) electromyography indicated neurogenic abnormalities (denervation or reinnervation symptoms), and in addition disclosed disturbed neuromuscular transmission in two and myopathic abnormalities in three patients. Given the fact that the conduction velocities were only slightly diminished, the EMG tindings indicated mainly axonal degeneration. In one patient (no.10) intravenous injection of 10 mg edrophonium bromide (Tensilon”) was followed by marked improvement of the severe tetraparesis; this lasted about 30 minutes. This patient was subsequently prescribed a regimen of 30 mg pyridostigmine (Mestinonm) orally six times a day, our impression is that his complete recovery was 20

thus sped up significantly (antibodies against motor end-plate acetylcholine receptors: negative). Neuropathologic examination in two patients (nr. 6 and nr. 10) revealed neurogenic abnormalities in intercostalis and soleus muscles respectively, two months after PV treatment. Isolated or some grouped atrophic muscle fibres were observed; (Fig. 1). In the radial and sural nerves, some loss of myelinated fibres was observed (Fig. 2). In two other patients (nr. 11 and 12)the biopsies of soleus showed myopathic changes two weeks after PV treatment (fibres with internal nuclei, basophilic fibres with or without vacuoles probably filled with glycogen (Fig. 3 and 4), some increase of connective tissue) which may be the result of a disturbed neuronal input; however in the sural nerves only minimal indications for axonal pathology were found. Discussion

Our paper reports prolonged generalized muscular weakness and muscular atrophy, following administration of PV.

Fig.

I

Biopsy m. soleus (patient nr. 10) type grouping and increased variability of tihre diameters (AIP ase Ph 4,Z). Magnification 27 X

Fig. 2 Nerve biopsy (n. suralis) EM, IF, (patient nr. JO). Diminished density of myeiinated nerve tibers. Magnitication: 130X

Fig. 3 Biopsy m. soleus (patient nr. I I). Muscle fibers with many vacuoles. accumulation PAS-positive material. Magnitkatton: 290 X

Fig. 4 Biopsy m. soleus (patient nr. I I). Muscle fibers with vacuoles and too many internal and vesicular nuclei (heamatoxylineosin). Magnification: 290x.

Although other factors (aminogiucosides, corti~osteroids, disordered liver and kidney functions) will have contributed to the weakness, clinicians should be aware of this severe iatrogenic illness. Isolated cases of less severe weakness have been reported in the literature 6-8, our patients, however, developed complications after more than six days treatment with PV in high dosage. Considering the combination of causes, the protracted muscular blockade and the myopathy may be caused mainly by PV, but the toxic neuropathy could be caused by gentamycin as well; both drugs were administered to patients with poor renal function, which as such can give rise to a neuropathy and corti-

costeroids may produce a toxic myopathy. Compression neuropathies are not the reason of this illness, because the generalized muscular weakness affects symmetrically both arms and legs, including in some cases the facial and extraocular muscles, the weakness is not restricted to a ~ircun~scribed area of nerve supply and there are no sensory disturbances. We never found a trauma of the cervical spinal cord in our patients: spasticity, pyramidal signs and disturbances of long spinal cord tracts were never present. Drachmang described an experimental study in rats, in which neuromuscular transmission was blocked with the aid of alphabungarotoxin (BTX). This substance, which blocks postsynap21

tically, proved to produce morphological effects: muscular atrophy and denervation. Drachman postulated that blockade of leads to neuromuscular transmission denervation of the muscles (to block is to denervate). This experimentally produced effect of BTX bay by comparable with the blockade of neuromuscular transmission by PV, which according to our neuropathologic and EMG findings seems to lead to significant The muscular atrophy in denervation. myasthenia gravis is likewise ascribed to denervation as a result of postsynaptic blockade of the neuromuscular junction’OT1l. Conclusion

The complications described above prompted us, to introduce the following protocol: 1. PV administration is started by intravenous injection of 4 mg, followed by a continous drip at a rate of 1 mg PV per hour (24 mg per day). 2. The PV dosage is kept as low as possible and guided by means of a Neuromuscular Transmission Monitor (Organon) in such a way that not 100% but only 75% neuromuscular blockade occurs, leaving myotatic reflexes intact. All patients are examined neurologically before the first dose of PV is given. 3. PV is no longer combined with aminoglycosides or tetracyclines, and patients with poor liver or kidney functions are monitored with extra alertness. Postscript: With the protocol described above we had no complications with PV (Pavilon@) after the 1st July 1983. On the 1st May 1984we have substituted PV by vercuronium bromide (Norcuron@); this drug has a much shorter plasma half-value time than PV and is eliminated for 60% by the liver, and for 40% by the kidneys.

22

Acknowledgements we are indebted to Dr. E.M.G. Joosten, for his kind support and help concerning the nerve and muscle biopsies.

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