Intensive Care Med (1993) 19: S 36-S 39 Springer-Verlag 1993

Neuromuscular blocking agents in intensive care

B.J. Pollard

University Department of Anaesthesia, Manchester Royal Infirmary, Manchester, UK

Patients undergoing treatment on an intensive care unit may The most straightforward technique is to rely upon the require as one component of their management a period of subjective opinion of a trained nurse aided by autonomic re- controlled ventilation. Such an artificial situation usually dictates sponses to various stimuli (e.g. tracheal suction), and this is the that the patient must be sedated. In addition, patients may also course taken in many intensive care units. It is possible, however, need temporary pharmacological in order to optimise to adopt a more objective approach. The use of the EEG, or treatment. derivatives of the EEG (e.g. the cerebral function monitor, or It is the use of pharmacological agents for this latter purpose, cerebral function analysing monitor) have been used with a to produce temporary paralysis, which forms the subject of this varying degree of success [1]. Cortical responses to auditory symposium. Before detailed examinations are made of the vari- evoked stimuli may also be of value [3]. ous facets, actions, side effects, etc., of the , it is necessary to stand back and take a broad view of the whole Historical aspects situation concerning the use of neuromuscular blocking agents in intensive care. That broad view is the remit of this first article. Sir is credited with the introduction of into the western world and it is quite likely that he was also the first with a muscle relaxant [4]. Among his expeditions he visited Sedation in intensive care Guiana in and described an unusual arrow A precondition for the use of neuromuscular blocking agents in used by the natives. It seems likely that this was a preparation of critically ill patients is that they must already be adequately , although the details are not well reported. sedated. Sedation is, by definition, a calm or restful state and in the absence of pharmacological paralysis it is not usually neces- Table 1. Sedation scoring system~ sary to obtain complete unconsciousness. The ideal regimen should relieve , allay , control agitation, Response Level of response Sedation score enable the patient to tolerate invasive procedures (including Eyes open Spontaneously 4 controlled ventilation) and perhaps help to maintain a sleep To speech 3 pattern and circadian rhythm. Paralysed patients should not be To pain 2 None 1 consciously aware of their surroundings. The precise balance of these components should be tailored to the needs of the individual Cough Spontaneous strong 4 patient. Spontaneous weak 3 Sedative agents generally fall into three broad families - On suction 2 , , and anaesthetic agents. The exact None l choice of agent is less important than ensuring adequate sedation Motor response Obeys commands 4 before a neuromuscular blocking agent is administered. In order Purposeful movements 3 to achieve adequate sedation, a means of measuring and monitor- Non-purposeful movements 2 ing sedation is needed [ 1]. Techniques most commonly rely upon None 1 graded patient responses to a range of stimuli, and that in use at Respirations Spontaneous extubated 5 our institution is based on the scale developed by Cook (Table 1) Spontaneous intubated 4 [2]. The exact level depends upon individual circumstances, but Triggering ventilator 3 in the unparalysed patient, we generally aim for between 2 and 3 Breathing against ventilator 2 on each parameter. This system is, however, not appropriate for No respiratory efforts 1 the paralysed patient. ~Scoring system based on Cook S, Palma O, (1989). $37

Charles Waterton, 300 years later, during his wanderings in population of intensive care units sampled and differences in the South America, made an observation similar to that of Raleigh, way that questions were asked. There is, however, rather a large with respect to the natives' . He commented that the difference to explain by simple methodological factors alone. preparation was surrounded by ritual and included a large number Was there any specific factor that might have made this a genuine of ingredients, although Waterton suspected that the principal finding? active ingredient was the bark from the wourali plant. When The answer to that question is yes. An editorial appeared in Waterton returned in 1825, he brought samples of the plant and the Lancet in 1981 under the title "Paralysed with Fear" [ 12]. This of the crude extract, and was credited with the first scientific article drew attention to some subjective experiences of patients experiments on the substance. He showed that the substance was who had been paratysed but inadequately sedated during a period inactive by mouth, but rapidly fatal when injected parenterally. of intensive care. This report was followed by a number of The classic experiment was that in which a she-ass was poisoned published recollections from medical colleagues who had re- with the extract and subsequently kept alive by inflation of the ceived intensive care, which further underscored the undesirabil- lungs using a bellows through a tracheostomy until spontaneous ity of paralysis without sedation. It steadily became clear that respiration returned. Waterton postulated that the substance pharmacological paralysis was not the pleasant, calm, pain-free affected the muscles of respiration, a view which was supported state which had hitherto been believed. In any case, such a by Claude Bernard, who showed that the actual site of action was concept can now be seen as pharmacological nonsense. Drugs the junction between nerve and muscle [5]. have side effects, but it is difficult to conceive of any mechanism For nearly 100 years curare was used empirically in medi- whereby an agent which blocks receptors at the neuromuscular cine for the treatment of many conditions, for example hydropho- junction also possesses , sedative, or proper- bia and [6]. In 1939, Bennett introduced the into ties. as an adjuvant to lessen the side effects of pentylene- It is worth re-examining the sedation regimens of the late tetrazol shock therapy [6]. It is likely that the first use in 1970s and early 1980s. A common sedation regimen at that time anaesthesia was by Lawen in 1912 [7], although it is Harold was and pancuronium by intermittent bolus injec- Griffiths of Montreal who is credited with the introduction of tions. It was commonplace to administer both drugs together curare into clinical practice [8]. such that the patient received either both, or neither. It is simple Under the umbrella terms of 'curare' (synonyms include to see, therefore, that confusion might develop over the exact wourali, ourari, urari), come several varieties of plant extract [9]. function of each component. A paralysed patient will lie still and These are all prepared by the Indians of the Amazonian and allow almost any procedure, invasive or non-invasive, to be Orinoco basins from the bark of certain plants, in particular undertaken without any apparent problem. A patient who is not toxifera, S. castenoei, S. gubleri and S. crevauxii. For paralysed but only lightly sedated, however, may be more a time the extract was imported into England in three different 'difficult' to manage. In addition, it is likely that pressure types of containers- gourds, bamboo tubes, or earthenware pots, would be better maintained if the patient were inadequately depending upon the source. This gave rise to the eponymous sedated and paralysed by virtue of the patient's own catecho- names 'calabash curare', 'tube curare' and 'pot curare', respec- lamine drive. All of these things we would now deprecate. Most tively. The different types contain varying ratios of , intensivists would, in addition, question whether phenoperidine which include curarine, calabashcurarine I, calabashcurarine II, is a good sedative. It is nevertheless not difficult to see how protocurine, protocurarine, protocuridine and neoprotocuridine. pancuronium might have developed greater importance than Being an extract of naturally occurring alkaloids, standardisation phenoperidine. The confusion which existed between sedation was initially performed by biological assay, and an extract of and immobility was the problem. the crude drug was used clinically until the active ingredient, Having brought to everybody's attention the fundamental d-tubocurarine, was isolated and purified. differences between neuromuscular blocking agents and seda- tives, surely all would now be satisfactory. The problem contin- ued, however. In 1989, there was a study by Loper and colleagues Changing patterns of use of neuromuscular blocking agents entitled "Paralysed with Pain: The need for education" [13]. The introduction of neuromuscular blocking drugs into clinical Those authors surveyed the pharmacological knowledge of a practice precedes the development of intensive care as a special- number of physicians and intensive care nurses with respect to ity. There has been a considerable change in the pattern of use of the properties of narcotics, benzodiazepines and neuromuscular this family of drugs in intensive care over just the past 10-12 blocking agents. Their surprising findings were that 5-10% years, at least in the UK. In 1979, a survey was undertaken of 34 thought that pancuronium possessed analgesic properties, and intensive care units in the UK [ 10], which showed that over 90% between 50% and 70% thought that pancuronium possessed of those intensive care units used a muscle relaxant on a regular anxiolytic properties. basis. This was usually pancuronium. It would certainly be the The response of many intensivists was to try to cope without recollection of many anaesthetists who were involved in inten- the routine use of neuromuscular blocking agents in intensive sive care around that time that it was a routine part of 'sedation' care patients and to rely solely on sedative agents, anaesthetic to administer pancuronium. A common regimen was agents, and opioids. Although this may on occasions be satisfac- phenoperidine 1-2 mg with pancuronium 2-4 mg as required. tory, a proportion of patients still require a neuromuscular Five years later, in 1986, a larger survey was published blocking agent at some time during their stay on the intensive care which produced very different results [11], in that in 1986 only unit. These drugs must therefore be used properly. 16% of intensive care units were using a neuromuscular blocking Another explanation for the reduction in the use of relaxants agent. What was responsible for this change in practice? Clearly, during the 1980s is improvements in ventilator technology. The one could postulate, among other factors, differences in the early ventilators were inflexible devices which did not allow the $38

patient to breathe spontaneously. The introduction of intermit- Critical gas exchange tent mandatory ventilation in the 1970s made simultaneous In the more critically ill patient who has greatly reduced lung spontaneous breathing and controlled ventilation possible, lead- compliance and in whom there are difficulties in achieving ing to synchronised forms of respiratory support which have adequate gas exchange with the use of sedative agents alone, the helped to reduce dependence on relaxants. addition of a neuromuscular blocking agent is useful. The aboli- The pattern of use of neuromuscular blocking agents in tion of tone in the thoracic musculature may theoretically result intensive care units varies considerably. Some intensive care in a small increase in compliance which may improve ventila- units try never to use one; some use one in most patients. If we are tion. The energy consumption of striated muscle will also fall, intending to foster a more rational approach to the use of these thus decreasing the patient's oxygen requirements and carbon drags in intensive care, some common agreed standards are dioxide production, albeit by a small amount. needed. Muscular and neuromuscular diseases Indications for the use of a neuromuscular blocking agent In certain neuromuscular diseases such as myasthenia gravis, it is often unnecessary to use a neuromuscular blocking agent There are a number of situations where the use of a neuromuscu- because the patient is already weak. On the rare occasions when lar blocking agent is useful or even essential. a neuromuscular blocking agent is judged to be required as part of intensive care management, the agent of choice would seem to Tracheal intubation be atracurium. It must be remembered that maintenance require- It is possible to intubate the trachea without the use of a neuro- ments for a constant neuromuscular block in a myasthenic patient muscular blocking agent if the patient is already weak or under are of the order of 20% of those for a normal adult [16]. the influence of anaesthesia or sedation. suppresses In tetanus, the use of a neuromuscular blocking agent laryngeal responses and may be helpful, but a bolus dose will is essential to reduce muscle and allow controlled produce quite marked in critically ill patients. Local ventilation. Tetanus is accompanied by periods of gross cardio- analgesia of the pharynx or larynx may also be employed and in vascular instability and so the choice of a relaxant with minimal some intensive care units, many patients are routinely intubated cardiovascular action, e.g. atracurium or vecuronium, is bene- awake using local analgesia. The administration of a neuromus- ficial. cular blocking agent, however, does usually allow easier and less traumatic intubation. The use of a neuromuscular blocking agent Disadvantages of using relaxants is also of value when the airway has to be secured without delay or when there is a risk of regurgitation of gastric contents. In the There are no absolute contraindications to the use of a neuromus- latter situations suxanethonium is the agent of choice (with cular blocking drug, except for a known or suspected to cricoid pressure) unless there is a specific contraindication to its that family of drugs. There are, however, a number of interactions use [14]. where the use of a neuromuscular blocking agent might create problems.

Facilitation of procedures Difficulties with neurological assessment There are a number of procedures where complete immobility of In a patient who has complete neuromuscular block, it is clearly the patient is either highly desirable or even essential. In order to not possible to assess a number of neurological parameters. obtain the best high quality radiological images, the use of a Spontaneous movement or movement to command is not pos- neuromuscular blocking agent has been recommended [15]. sible. Conscious level will be affected by the sedative agent Other procedures, including magnetic resonance imaging, will which must be present and adequate if the patient is paralysed. also benefit and a neuromuscular blocking agent should usually Some gross changes might be apparent, but they will be difficult be used in these circumstances. Surgical or endoscopic proce- to assess in the presence of a neuromuscular blocking agent. dures will also require the use of a relaxant, e.g. bronchoscopy What is particularly important is that focal or localising neuro- (especially rigid bronchoscopy) and tracheostomy. logical signs may be missed in the paralysed patient, leading to delay in treatment. This could be serious in some circumstances, To assist ventilation e.g. expansion of a subdural haematoma. If a neuromuscular blocking agent is needed, it should be short-acting and discontin- Even though adequately sedated, there are a number of patients ued at suitable intervals to allow the assessment of the patient. who still cannot tolerate positive pressure ventilation. This may The degree of block must be monitored. lead to coughing or making respiratory efforts out of phase with the ventilatory cycle, resulting in potentially dangerous peaks in Disconnection intrathoracic pressure. This will also be reflected in large swings in the intracranial pressure, a situation which is particularly In the event of a patient becoming disconnected from the venti- undesirable in the neurosurgical or head-injured patient. The use lator, neuromuscular blockade would certainly prevent sponta- of a neuromuscular blocking agent in neurological patients is neous breathing and maintenance of gas exchange. It is, therefore considered by some clinicians to be mandatory. In however, unlikely that critically ill patients would be able to addition, coughing during positive pressure ventilation may sustain useful gas exchange even for short periods. Ventilatory contribute to cardiovascular instability, and excess strain on drive is likely to be depressed by sedative drags, and gas abdominal wall sutures may lead to wound dehiscence. exchange by the disease process. Furthermore, the use of $39 ventilators without disconnection alarms is extremely inad- available, whilst in the USA, alcuronium is not available. visable. This, therefore, remains principally a theoretical dis- Pipecuronium and rocuronium will probably appear soon. But advantage of muscle relaxants in this setting. which of these drugs do we use? It is probably true to say that all of them have been used to provide relaxation in intensive care Awareness patients at some time. But is there one drug which is better than the others? What about the cardiovascular side effects of the This has already been discussed above. The injudicious use of a drugs? What if the patient has liver disease or renal disease? muscle relaxant may mask inadequate sedation. Which one(s) have the least potential for accumulation? What, if any, are the long-term effects on the patient's muscles, nerves, Incidence of thromboembolism or the neuromuscular apparatus? Is any one drug better or Critically ill patients who receive a neuromuscular blocking worse than any other? Should we monitor the effects of the agent may be at greater risk of pulmonary emboli. neuromuscular blocking agents, and if so how and when? If there are still deficiencies, can we improve on what we already Disuse atrophy possess? The answers to some of these questions will be exam- ined in this symposium. Critically ill patients suffer muscle wasting, some of which is attributable to disuse atrophy. This may occur within a few days. It has been suggested that in patients who receive long-term use References of neuromuscular blocking agents, such disuse atrophy is likely 1. Shelly MP, Wang DY (1992) The assessment of sedation. BrJ Intensive to be more marked [17]. Care 195-203 2. Cook S, Palma O (I 989) Diprivan as the sole sedative agent for prolonged Pancuronium belly infusion in intensive care. J Drug Dev 2:65-67 3. Sneyd JR, Wang DY, Edwards D et al (1992) Effect of physiotherapy on This unusual situation can be seen in new born infants. If such a the auditory evoked response of paralysed, sedated patients in the inten- new born infant is paralysed from birth, very little, if any, air is sive care unit. Br J Anaesth 68:349-351 swallowed. No air in the gut leads to an unusual picture on the 4. Sykes WS (1982) Curare, or the Squire of Walton. In: Essays on the first 100 years of anaesthesia (Vol 1). Churchill Livingstone, Edinburgh, abdominal x-ray of a ground glass appearance. This has been pp 86-98 termed 'pancuronium belly' [ 18]. 5. Bernard C (1856) Analyse physiologique des propri~t6s des syst6mes musculaire et nerveux au moyen du curare. C R Acad Sci 43:825-829 6. Bennett AE (I968) The history of the introduction of curare into medicine. A relaxant for intensive care Anesth Analg 47:484-492 7. Lawen A (1912) Ueber die verbindung der lokalanasthesie mit der Once a decision has been made to use a neuromuscular blocking narkose, uber hohe extraduralanasthesie und epidurale injektionen agent in an intensive care patient, the next consideration concerns anasthesie-render losungen bei tabischen magenkrisen. Beitr Klin Chir the choice of drug. What properties represent the ideal? 80:168-189 8. Griffiths HR, Johnson GE (1942) The use of curare in general . Cardiovascular stability 3:418-420 No release 9. Wallis TE (1967) Textbook of pharmacognosy (5th Edn) J & A Churchill Non-cumulative Ltd, London, pp 463-464 10. Merriman HM (1981) The techniques used to sedate ventilated patients: Elimination independent of renal or hepatic function A survey of methods used in 34 ICUs in Great Britain. Intensive Care Med Inactive metabolites 7:217-224 No interaction with other drugs 11. Bion JF, Ledingham McAI (1987) Sedation in intensive care - a postal Capable of being administered by infusion survey. Intensive Care Med 13:215-216 12. Editorial (1981) Paralysed with fear. Lancet i:427 13. Loper KA, Butler S, Nessly M, Wild L (1989) Paralyzed with pain: the Choice of drug need for education. Pain 37:315-316 14 Natanson C, Shelhamer JH, Parrillo JE (1985) Intubation of the trachea in A list of all the drugs available at present is as follows: the intensive care setting, JAMA 253:1160-1165 Suxamethonium 15. RavaI B, Steinberg R, Rauschkolb E (1985) Artifact free computed tomography of the chest and abdomen in the severely ill patient. J Comput Tubocurarine Tomogr 9:9-1 i 16. Pollard BJ, Harper NJN, Doran BRH (I 989) Use of continuous prolonged Alcuronium administration of atracurium in the ITU to a patient with myasthenia Pancuronium gravis. Br J Anaesth 61:95-97 Gallamine 17. Wokke JHJ, Jennekens FGI, van den Oord CJM, Veldman H, van Gijn J (1988) Histological investigations of muscle atrophy and end plates in two Atracurium critically ill patients with generalized weakness. J Neurol Sci 88:95-106 Vecuronium 18 Thomas S, Sainsbury C, Murphy JF (1984) Pancuronium Belly. Lancet Pipecuronium 2:870 Doxacurium Dr. B.J. Pollard Mivacurium University Department of Anaesthesia Rocuronium Manchester Royal Infirmary Oxford Road Not every drug listed above is available in every country. In the Manchester M 13 9WL UK for example, neither metocurine or doxacurium are currently UK