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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.54 no.4 Campinas July/Aug. 2004
Evaluation of residual neuromuscular block and late recurarization in the post-anesthetic care unit*
Evaluación del bloqueo neuromuscular residual y de la recurarización tardia en la sala de recuperación pós-anestésica
Maria Cristina Simões de Almeida, TSA, M.D.I; Dalto Rodrigues de Camargo, M.D.II; Saul Fernando Linhares, TSA, M.D.III; Sérgio Galluf Pederneiras, TSA, M.D.IV
IDoutor em Medicina pela Universidade
Johannes Gutenberg-Alemanha, Professora Adjunta da Universidade Federal de Santa
Catarina (UFSC), Florianópolis, SC
IIEx ME do CET Integrado da SES-SC
IIIInstrutor do CET Integrado da SES-SC
IVResponsável pelo CET Integrado da SES-SC
BACKGROUND AND OBJECTIVES:
Residual postoperative paralysis impairs airway patency increasing the risk
for postoperative complications. Anti-cholinesterase agents improve neuromuscular
transmission by acetylcholine build up in the endplate. However, when there
is no longer neostigmine effect, "recurarization" is theoretically
possible since the antagonist agent does not displace neuromuscular blocker
from its action site. This study aimed at determining the degree of residual
neuromuscular block in the Post Anesthetic Care Unit (PACU) and at observing
whether patients receiving neostigmine presented the late "recurarization"
METHODS: Participated in this study 119 adult patients who received neuromuscular blockers for different procedures. At PACU arrival, neuromuscular transmission has been quantified by acceleromyography, with stimulating electrodes placed over the ulnar nerve at the wrist, the train of four (TOF) was used with electrical current of 30mA at 15-minute intervals for a period of 120 minutes. Residual neuromuscular block was considered T4/T1 ratio below 0.9. Clinical symptoms suggesting residual neuromuscular block and vital signs were also recorded in the PACU. Descriptive measures, such as mean and absolute frequency were used for statistical analysis.
RESULTS: Patients receiving pancuronium had a higher incidence of residual block, especially the elderly. Patients receiving neostigmine also presented an expressive percentage of residual curarization. There has been no late recurarization in both groups.
CONCLUSIONS: The incidence of residual block was significantly higher in the pancuronium group. There has been no case of recurarization with neostigmine suggesting that this phenomenon has no clinical significance when patients have no signs of organ failure or co-morbidity impairing neuromuscular transmission.
Key Words: MONITORING: neuromuscular function, acceleromyography; NEUROMUSCULAR BLOCKERS, Nondepolarizing; POSTANESTHETIC RECOVERY: residual neuromuscular block
JUSTIFICATIVA Y OBJETIVOS:
El bloqueo neuromuscular residual altera la patencia de las vías aéreas
aumentando el riesgo de graves complicaciones en el pós-operatorio. En
los pacientes que reciben el anticolinesterásico, la transmisión neuromuscular
es incrementada por el acumulo de acetilcolina en la placa motora, más
que, una vez concluido el efecto de la neostigmina, teoricamente es posible
una "recurarización", visto que el agente antagonista no desloca
el bloqueador neuromuscular de su local de acción. Fue objetivo de este
trabajo cuantificar el grado de parálisis residual en la Sala de Recuperación
Pós-Anestésica (SRPA) y averiguar si los pacientes que recibieron
neostigmina presentan fenómeno de "recurarización" tardia.
MÉTODO: Fueron estudiados en la SRPA 119 pacientes adultos que recibieron bloqueadores neuromusculares para diferentes tipos de procedimientos. Al llegar a la SRPA, la transmisión neuromuscular fue cuantificada a través de un monitor por método acelerográfico. Los electrodos estimuladores fueron instalados en el trayecto del nervio ulnar en el puño, y se utilizó la secuencia de 4 estímulos, con corrientes de 30 mA, en la periodicidad de 15 hasta 120 minutos. En esta pesquisa se consideró como residuo de bloqueo neuromuscular una relación T4/T1 abajo de 0,9. En el tiempo de permanencia de la SRPA fueron igualmente registrados los síntomas clínicos sugestivos de bloqueo neuromuscular residual y aferidos los señales vitales. Para análisis estadística fueron utilizadas medidas descriptivas tales como media y frecuencia absoluta.
RESULTADOS: Los pacientes que recibieron pancuronio presentaron mayor incidencia de residuo de bloqueo neuromuscular, principalmente los edosos. En los pacientes que recibieron neostigmina hubo expresivo porcentual de bloqueo neuromuscular residual. En ningún grupo se observó el fenómeno de "recurarización" tardía.
CONCLUSIONES: Fue constatado expresivo número de pacientes con residuo de bloqueo neuromuscular, cuando utilizado el pancuronio. La etapa de recuperación, cuando fue usada la neostigmina no fue seguida de "recurarización", sugiriendo que ese fenómeno no tenga significado clínico cuando el paciente no presenta señales de falencia de órganos o comorbidades que alteran la transmisión neuromuscular.
Residual postoperative neuromuscular block (NMB) adverse effects are widely known. Authors1 have established in the 70s that when there is fatigue, certified by T4/T1 ratio of approximately 0.6, patient has clear signs of residual NMB, such as palpebral ptosis and tracheal pulling. However, they consider that if this value is approximately 0.7, good ventilation and airway patency would be assured. This concept is being reviewed2 and as from 1997, studies have shown expressive percentage of clinically important postoperative complications with T4/T1 ratio below 0.93-5.
For most cases, residual neuromuscular blocker effects are reversed by neostigmine, which is the substrate for acetylcholinesterase, resulting in increased acetylcholine molecules close to endplate nicotinic receptor. There is a competition for binding sites not occupied by the neuromuscular blocker making neuromuscular transmission effective6. However, electrophysiological studies have shown that anti-cholinesterase drugs do not promote the elimination of neuromuscular blockers from their binding site. The exit of such drugs from the endplate depends exclusively on their physicochemical properties. So it is possible that, in theory, after the end of anti-cholinesterase drugs effect, patients present with residual neuromuscular block7.
This study aimed at evaluating the degree of residual NMB and at observing the incidence of late "recurarization" in the Post-Anesthetic Care Unit (PACU).
After the Ethics Committee approval and their informed and written consent, participated in this study 119 adult PACU patients submitted to anesthesia with neuromuscular blocker. Exclusion criteria were pregnancy, patients with upper limbs immobilization, or those who, for different reasons, had communications difficulties.
After surgery, patients were referred to the PACU were the study was started by checking fatigue.
Fatigue was checked with a neuromuscular transmission monitor by accelerometry, with acceleration transducer fixed on the thumb and stimulating electrodes installed over the ulnar nerve on the wrist. Train of four (TOF) was used with 30 mA current. This measurement was obtained at PACU admission and at 15-minute intervals until a total of 120 minutes.
For analysis purposes, patients were divided in 3 groups according to the neuromuscular blocker: atracurium, vecuronium or pancuronium.
Residual NMB was defined as T4/T1 ratio below 0.9. NMB reversion time was established as the interval in minutes between beginning of neostigmine injection and PACU arrival.
In the same fatigue evaluation period, pulse rate and noninvasive blood pressure were also recorded, in addition to residual NMB clinical signs, such as ability to swallow freely, ability to remove the tongue after manual grasping, and ability to maintain head up for 5 seconds.
Chi-square test was used to analyze gender, age, physical status (ASA) and clinical tests. Non-parametric Kruskal-Wallis test was used for T4/T1 values in different analyses. p < 0.05 was considered statistically significant.
Demographics data, physical status and body mass index are shown in table I. Groups were homogeneous in these variables. There has been a higher concentration of ASA II patients in the atracurium group.
Surgery and NMB reversion times, the use of monitors, and the percentage of patients receiving neostigmine are shown in table II. In spite of no statistical difference in NMB recovery time among neuromuscular blockers, patients receiving pancuronium have taken longer to leave the operating room (10 to 40 minutes). This same group has also shown a higher number of neuromuscular function monitor use and in 100% of cases pharmacological recovery was needed.
T4/T1 values measured at 15-minute intervals are shown in figure 1. Patients receiving pancuronium had lower means as compared to those receiving atracurium and vecuronium. T4/T1 below 0.9 was only reached by the pancuronium group 45 minutes after PACU admission. Sufficiency by sample test has shown that the number of pancuronium group patients was lower than needed to test statistical differences. However, in a frequency distribution it has been recorded that 33% of patients in this group have presented T4/T1 values below 0.7; even those submitted to NMB reversion.
Figure 2 shows pancuronium group divided by age bracket. Although there are lower values for the elderly, there has been no statistical difference between groups.
Figure 3, 4 and 5 show T4/T1 values for patients receiving atracurium, vecuronium and pancuronium as a function of surgery duration. It is observed that, regardless of surgery duration, patients receiving pancuronium had lower values for this variable.
T4/T1 values in different times for patients receiving neostigmine are shown in figure 6. It is observed that, even receiving anti-cholinesterase drugs, an expressive number of patients receiving pancuronium have not shown T4/T1 values above 0.9 at PACU admission.
Figure 7, 8 and 9 show clinical evaluation criteria of residual block at PACU admission at 60 and 120 minutes. It has been observed that 36% and 38% of patients receiving vecuronium were unable to swallow freely and remove the tongue after manual grasping, respectively, and that 52% of those receiving pancuronium and vecuronium were unable to maintain head up for 5 seconds.
Most important results of this study were the expressive percentage of patients admitted to the PACU with residual NMB after receiving pancuronium, and the absence of "recurarization" until 120 minutes of PACU observation.
By concept, there is residual NMB in the presence of muscle fatigue.
Fatigue is the clinical representation of pre-synaptic occupation of nicotinic receptors by neuromuscular blockers8-11 in the presence of highly intense electric stimulation. Pre-synaptic receptors are different from post-synaptic receptors, also known as muscle nicotinic receptors. The former are part of a super-family of receptors needing neurotransmitters for their activation, such as GABAA receptors, glycine and type 3 serotonin (5HT3)12,13. In addition to being present in nervous terminals close to muscles, they are also extensively found in the central nervous system and spinal cord, with functions not yet well established14. Recently, through the cloning of sub-units of these receptors, it has been established that, although similar to muscle nicotinic receptors, they are different in many ways, especially in the presence of just a and b sub-units. This factor establishes affinity differences by agonists and antagonists, in addition to other biophysical profile differences15. So, they not only modulate acetylcholine release but also norepinephrine, dopamine, serotonin, gama-aminobutyric acid and glutamate release16. Studies have shown relationships between central nervous system nicotinic receptors dysfunction and Alzheimer's disease, whose treatment with acetylcholine is still experimental17.
Pre-synaptic occupation varies with the neuromuscular blocker. So, galamine and d-tubocurarine show higher fatigue as compared to pancuronium, reflecting higher affinity of the formers to neuronal nicotinic receptor10. As to atracurium, vecuronium and mivacurium occupation affinity, one may say that pre-synaptic effect is similar among them11,18.
Fatigue may be detected by clinical methods or with the help of neuromuscular transmission monitors. Clinical methods can only be applied with the help of the patient, thus when he/she is already awaken. Among them there are "bedside" tests such as eye opening, maintenance of hand muscle contraction measured with a dynamometer, protrusion or ability to remove the tongue when manually grasped and maintenance of head up for 5 seconds. Among them, the two latter are present when patients have vital capacity above 83% and acceptable values of maximum voluntary ventilation19. If correlated to instrumental methods, head up maintenance needs T4/T1 not below 0.620. It has to be highlighted that clinical tests do not assure normal muscle strength21, especially if a prolonged action neuromuscular blocker has been administered22. They do not quantify fatigue degree or rule out blocker residue and are being abandoned and replaced by instrumental methods2,5,23.
Approximately 30 years ago, it was accepted that patients had satisfactorily recovered from motor block when T4/T1 ratio was around 0.724,25. Today, 0.8 T4/T1 20 is considered acceptable although it is known that even when this ratio is 0.9, there are still symptoms of residual muscle weakness26.
Residual muscle paralysis represents imminent risk for passive regurgitation and gastric aspiration by pharyngeal and laryngeal muscles dysfunction3, in spite of adequate diaphragm recovery27. More recent studies have shown that neuromuscular blocker residue may also promote decrease in ventilatory response to hypoxia, cooperating with significant percentage of postoperative brain hypoxic injuries28,29. This effect is attributed to a "new" neuromuscular blocker property on carotid chemoreceptors29-31. Equally important are postoperative pulmonary complications, especially atelectasis and pneumonias5.
The incidence of pneumonias is directly related to the type of neuromuscular blocker and varies 20% to 50% for long duration NMBs and approximately 2% to 9% for atracurium and vecuronium21,32-36 and even higher values in more recent publications2. The incidence is significantly lower in children as compared to adults, regardless of the blocker used37.
It is intriguing to observe in our study the expressive percentage of residual NMB in patients receiving neostigmine, calling attention to the fact that pharmacological reversion does not assure total reversion. This fact had already been observed by other authors32, however in lower percentages when they measured T4/T1 in the operating room and PACU at longer intervals4. Some theoretical considerations about factors interfering with relaxation recovery may be done, among them the importance of neuromuscular blocker plasma concentration by the time of the antagonism.
With plasma concentration decrease by metabolic process or simple redistribution, a "reservoir" remains in the biophase, promoting a blocking effect until these sites are emptied from the drug. One may then say that NMB recovery is a function of the affinity constant of the neuromuscular blocker to binding sites during biophase38. The presence of fatigue after neostigmine administration, that is the reversion of the 4th response is slower than that of the 1st response, still remains without a final explanation39, but has the assumption that the recovery of such responses follows different mechanisms. If fatigue was the only consequence of decreased acetylcholine, it should disappear with acetylcholinesterase inhibition and pre-synaptic acetylcholine release, secondary effects to neostigmine administration. So, it is suggested that the concept of fatigue as a result of pre-synaptic occupation of nicotinic receptors by the neuromuscular blocker should not be abandoned, but it should not be considered the single mechanism responsible for the phenomenon39.
The fact that patients receiving pancuronium in our study had a slower recovery as compared to those receiving atracurium or vecuronium is also pharmacokinetically explained by drug concentration. Long duration agents have slower clearance. So, for pancuronium, this value varies 1 to 2 mL.kg-1.min-1, while for atracurium and vecuronium it is 3 to 7 mL.kg-1.min-1. Reversion rate with neostigmine is also directly related to blockers excretion half-life. So, antagonism after 50 to 60 µg.kg-1 neostigmine is faster for mivacurium, followed by atracurium and lastly long duration blockers40.
Some factors also contribute for slow neostigmine reversion. Among them there are anti-cholinesterase drug dose and the presence of inhalational anesthetics41,42.
It is difficult to determine the amount of neostigmine to be administered. This drug by itself, in the absence of neuromuscular blocker, produces fatigue43 and when used in excessive dose for reversion may increase blockade intensity. The mechanism is increased agonist molecules (acetylcholine) leading to an "agonist"-type blockade44. This study did not aim at evaluating how NMB reversion has occurred. It is known, however, that neuromuscular block with neostigmine is more easily observed when administered in fractional doses, for example, 2.5 mg at 2 to 5-minute intervals43.
In our study, all patients have received different inhalational anesthetic concentrations so it was impossible to quantify or analyze the level of anesthetic interference on blockade recovery.
In studies with cloned cells, it has been shown that inhalational agents and propofol occupy pre-synaptic nicotinic receptors promoting acetylcholine release decrease, even in sub-anesthetic concentrations12,13,45,46. As to clinical aspect, d'Honneur et al.47, in a study with volunteers with residual block, have called the attention to the importance of residual anesthetics. They have not found NMB effect on airway patency and suggested that airway obstruction observed at the end of anesthesia would be due more to residual anesthetics or potent analgesics than to residual NMB. However, it cannot be forgotten that upper airway functions need the functioning of two different muscle groups. So, it has been established that swallowing and glottis closing as "protection" against aspiration are impaired by residual blockers, even with T4/T1 of approximately 0.848.
It is known that muscle response to neuromuscular blockers is unique and characteristic for each muscle49. Adductor pollicis seems to be the most convenient to evaluate blockade recovery because it is highly sensitive to neuromuscular blockers action50. When this muscle is recovered, one might conclude that there is no residual block in diaphragm or laryngeal muscles51.
Standard method to check motor responses is mechanography. However, these monitors are difficult to handle needing a relatively long time for their installation, in addition to requiring total immobility of the studied muscle, thus being currently restricted to research. Accelerometry has been clinically used to indirectly evaluate muscle strength through an acceleration transducer in general placed on the thumb. Its efficiency in detecting residual muscle block has been shown in children and adults52, reason why this method was used in our study. The classic concept to accurately interpret neuromuscular transmission phenomena implies using current intensity close to the supramaximal, that is, that able to stimulate all axons of a nerve53. However, supramaximal response with stimulations above 30 mA is painful and uncomfortable for awaken patients. This way, 30 mA, usually submaximal for adult patients, has been recommended for PACU measurements53. Fatigue is often successfully detected54,55 and is never lower than that detected with supramaximal currents56. Major advantages of submaximal stimulation have been currently advocated, especially with accelerometry, because it would decrease the percentage of baseline deviations, helping the interpretation of fatigue57.
We have more frequently used neuromuscular transmission monitors for pancuronium. In spite of major advantages offered by these devices, such the possibility of allowing satisfactory and constant intraoperative relaxation53,58 and the choice of the best moment to start reversion13, there has been no decrease in the incidence of residual NMB. In fact, analyses have shown that monitoring does not interfere with residual muscle paralysis, but rather the rational use of neurostimulation allied to adequate interpretation of results43.
"Recurarization" or worsening of residual blockade degree has not been observed in our study. There are some reports on patients who seemed awaken with good ventilatory parameters who became sedated and dyspneic in the PACU. "Recurarization" was attributed to pharmacokinetic problems because the common point of all patients studied was the presence of renal failure59.
"Recurarization" is not a terminology uniformly accepted by investigators of the subject, especially those advocating the existence of the biophase. In fact, there would be no "return" to relaxation because NMB had not yet left it. Residual neuromuscular blocker plasma concentration would constantly tend to replenish biophase reservoir, impairing reversion even in the presence of high acetylcholine levels secondary to the use of anti-cholinesterase drugs38. So, one may speculate that, since there has been no "recurarization" in our patients, pharmacologically induced reversion was superimposed to spontaneous muscle relaxation recovery, as already described by other authors43.
High residual NMB percentage, from its description to date, and the clinical importance of this complication, have already been exhaustively published. Some practical recommendations have been made, such as rational use of long duration neuromuscular blockers and beginning of pharmacological reversion, after some sign of spontaneous clinical reversion60. A promising drug to prevent residual NMB is ORG 25969, still under animal experiments61. It is not an anti-cholinesterase drug, but rather a true steroidal neuromuscular blocker antagonist, cleaving the molecule in its action site. But until its commercial availability, the hazards of residual paralysis will remain.
Results of our study show an expressive percentage of patients admitted to the PACU with residual NMB, and that the absence of worsening in relaxation degree suggests that the concern with PACU "recurarization" has no clinical importance for patients without organ failure or co-morbidities interfering with neuromuscular transmission.
Still with data observed in this study one may suggest that:
1. Neostigmine does not prevent
2. There must be thorough residual NMB investigation in elderly patients;
3. There must be constant surveillance of NMB residue signs and symptoms in patients receiving pancuronium, even during long surgeries.
Results of our study also confirm previous studies showing the importance of PACU neuromuscular transmission monitoring to diagnose residual paralysis, especially in patients receiving neuromuscular blockers of prolonged action, such as pancuronium.
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Submitted for publication July 22,
Accepted for publication October 31, 2003
* Received from Hospital Governador Celso Ramos, CET Integrado da SES-SC, Florianópolis, SC