Patients having complex surgical procedures may require mechanical ventilation during the perioperative period. Because the airway is unstable during the first several days after single-stage laryngotracheal reconstruction (LTR), the rib cartilage graft must be supported by an endotracheal tube. Some pediatric patients can tolerate nasotracheal intubation for this duration with minimum or no sedation [1,2]; however, many infants will not tolerate a nasotracheal tube with sedation alone . In these patients, prolonged sedation and neuromuscular blockade may be necessary to guarantee maintenance of an airway with minimum trauma during healing.
After sustained immobility, recovery of normal muscular function may be slow. Weakness due to disuse atrophy or corticosteroid-induced myopathy, residual effects of sedatives and narcotics on respiratory drive, or residual effects of neuromuscular blockers might all contribute to respiratory failure after tracheal extubation. Although it may be difficult to quantify weakness and to separate the factors contributing to respiratory depression, it is feasible to ensure that blockade of neuromuscular transmission that could impair airway function is absent before extubation of the trachea. This study was undertaken to document the administration of doxacurium based on patient response and to document quantitatively the recovery of neuromuscular transmission so that these variables will not complicate tracheal extubation. A secondary goal was to acquire measurements of doxacurium in the plasma during and after its infusion.
We studied 14 children, between 6 mo and 10 yr of age, undergoing elective LTR consecutively after obtaining informed consent and institutional review board approval. Patients ranged in weight from 4.1 to 37.5 kg, average 11.0 (2.2) kg. Nine patients had been born 3-13 wk prematurely. Three patients had reactive airway disease and/or bronchopulmonary dysplasia. No patient had significant cardiac, hepatic, renal, or neuromuscular disease.
Patients were anesthetized with halothane and nitrous oxide in oxygen and intravenous narcotic. The ulnar nerve was stimulated supramaximally at a frequency of 2 Hz for 2 s (train-of-four [TOF]) every 10 s at the wrist with surface electrodes. The evoked compound electromyogram (EMG) of thumb adduction was recorded using a Datex[R] (Datex, Helsinki, Finland) neuromuscular transmission monitor . Neuromuscular blockade was induced with doxacurium in the operating room and maintained by doxacurium infusion in the intensive care unit (ICU). For patients <15 kg, doxacurium was diluted to 100 micro g/mL in 5% dextrose in water.
When the patient was sedated in the ICU, neuromuscular function was monitored by stimulation of the posterior tibial nerve through electrodes placed on the skin behind the medial malleolus. The electrode current was gradually increased to 80 mA with a frequency of stimulation of 2 Hz. If there was no change in heart rate or movement in response to TOF stimulation, a current of 50 Hz for 5 s followed by 1 Hz for 10 s was delivered. The posttetanic count (PTC; the number of downward movements of the big toe in response to the stimulation at 1 Hz) was recorded.
Doxacurium infusion was stopped each morning until PTC >5 or spontaneous movement of the head, extremities, or trunk was observed. If spontaneous movement or increased PTC was noted within 45-60 min, then the infusion was resumed at the same rate. If no movement was noted within 60 min, the infusion of doxacurium would be restarted at a rate as much as 20% lower than the rate after movement occurred. Any time spontaneous movement of the head or extremities was noted, sedative and narcotic administrations were reviewed and adjusted. A bolus of 100 micro g of doxacurium could be given if spontaneous movement was noted. If repeated boluses of doxacurium were given, the infusion rate was increased accordingly.
In the ICU, diazepam or lorazepam and fentanyl, morphine, or methadone were administered to produce sedation and analgesia. If tachycardia, hypertension, and/or tearing were observed, more of these drugs were administered. Chloral hydrate was given when sedation with benzodiazepines and narcotics was inadequate.
Five to 10 days after surgery, doxacurium and benzodiazepine were stopped and narcotic administration continued. At this time, an infusion of propofol was begun and recovery of neuromuscular function was monitored by EMG as placed intraoperatively, but with intermittent stimulation at TOF every 60 s.
The patients also received treatment for reflux esophagitis and antibiotics. Thirteen of the 14 patients received 1-5 mg [center dot] kg-1 [center dot] day-1 of ranitidine; five received 2.4-3.6 mg [center dot] kg-1 [centered dot] day-1 of metoclopramide; five received cisapride 0.6-0.8 mg [center dot] kg-1 [center dot] day-1; nine received 25-39 mg [center dot] kg-1 [center dot] day-1 of clindamycin; six received 166-306 mg [center dot] kg-1 [center dot] day-1 of ticarcillin with clavulanate; four received 131-183 mg [center dot] kg-1 [center dot] day-1 of ceftazidime; one received 82 mg [center dot] kg-1 [center dot] day-1 of cefazolin; and one received 44 mg [center dot] kg-1 [center dot] day-1 of vancomycin.
Although fluid administration was adjusted to expected needs, patients often experienced increased body weight and increased skin turgor in extremities. Furosemide, 0.3-2.8 mg [center dot] kg-1 [center dot] day-1, was administered to 12 patients. Passive flexion and extension of the extremities of immobile patients, including fingers and toes, was performed for 30 min at least twice a day.
In four patients, doxacurium concentrations were measured in plasma obtained during a period of constant infusion. In another four patients, doxacurium was measured in plasma obtained after termination of the infusion. Venous blood was withdrawn through a catheter in the femoral vein, and the plasma of the heparinized sample was separated by high speed centrifuge and frozen at -70 degrees C until assay by high-performance liquid chromatography . The sensitivity of this assay was 10 ng/mL with a coefficient of variation <10%. Plasma concentrations of doxacurium were fit to compartmental models with the Scientist[R], an interactive computer program (Version 2.0, Micro-Math Scientific Software, Salt Lake City, UT). Systemic clearance was calculated from plasma concentration of doxacurium during stable infusion .
Dexamethasone was administered to all patients on the day before and the day of extubation. The average dose of dexamethasone was 0.71 (0.08) and 1.3 (0.17) mg/kg on the day before and the day of extubation, respectively.
Although this study was not originally designed to observe the patients after discharge from the ICU, chart review supplemented the observations of the investigators regarding recovery of motor function. A nursing assessment which ranked strength in upper and lower extremities as normal, mild weakness, or severe weakness was performed for each patient on discharge from the ICU. Physical therapists and physicians noted the strength and function of these patients in a nonsystematic, prospective manner during hospitalization. Direct patient observation by the investigators during hospitalization and parent interviews months after the surgery and ICU stay also provided information on the quality of muscle strength and coordination postoperatively. One of the 14 families could not be contacted for an interview.
Data are presented as the mean +/- SEM. The infusion rates of doxacurium from 24 to 48 h after admission to the ICU were compared with those on the fifth day after surgery by paired t-test. Mann-Whitney and Fisher's exact tests were used to evaluate differences in outcomes between patients with varied characteristics. P < 0.05 was considered statistically significant.
During the first 24 h in the ICU, bolus doses of 100 micro g of doxacurium were frequently administered. The mean infusion rate of doxacurium was 60.9 +/- 4.8 micro g [center dot] kg-1 [center dot] h-1 during the 24-48 h after ICU admission and 72.1 +/- 6.0 mg [center dot] kg-1 [center dot] h-1 (6.0) on the fifth ICU day, a significant difference (P = 0.019, paired t-test) (Table 1). Doxacurium infusion was continued for over 9 days in three patients.
In eight patients, the adductor pollicis EMG during spontaneous recovery was adequate to measure recovery of the TOF ratio from 0.4 to 0.7. After termination of the doxacurium infusion, this interval ranged between 0.6 and 3.3 h, with a mean of 2.2 (0.31) h. In nine patients it could be determined that between 4.7 and 23 h, mean 11.0 (2.1) h, passed between termination of the doxacurium infusion and the TOF ratio reaching 1.0 (i.e., there was no decrement in neuromuscular function observable when the ulnar nerve was stimulated at 2 Hz) (Table 2). Reasons for failure to observe these intervals included the need to administer neostigmine, administration of other neuromuscular blockers to prevent movement, complete failure of the monitor in one case, erratic signal in two cases, and failure to leave the monitor on in one case.
Of the drugs that might interact with a nondepolarizing blocker and the recovery indices variably measured in this study, clindamycin was the drug most clearly associated with delayed recovery. The median value of the interval from end of infusion of doxacurium to T4/1 = 1.0 was 5.6 h in patients who did not receive clindamycin versus 12.9 h in those who did. But in this small sample this association was not statistically significant (P = 0.09; Mann-Whitney test).
Sedation with propofol and narcotic was continued until direct laryngoscopy and bronchoscopy could be performed in the operating room during general anesthesia to determine the adequacy of the airway. Between 5.6 and 31.5 h, mean 23.1 (2.6) h passed between termination of the doxacurium infusion and extubation of the trachea in the 10 patients who received propofol sedation and no muscle relaxants other than doxacurium before the first postoperative extubation of the trachea (Table 2). One child dislodged his tracheal tube when the TOF ratio was 0.5 at his adductor pollicis and could not maintain adequate upper airway function until neostigmine was given. This occurred more than 11 h after termination of the doxacurium infusion. The trachea of an older child, in whom EMG could not be applied, was extubated when his hand grasp was strong; however, after extubation upper airway obstruction occurred. There was significant retraction of the intercostal muscles on inspiration. Copious secretions were suctioned from the child's airway, his trachea was reintubated, and mechanical ventilation was resumed. Four days later tracheal extubation was successful. However, he was noted to be very weak after this extubation.
The concentration of doxacurium in the plasma after 18-69 h constant infusion when PTC was <5 was between 321 and 808 ng/mL. The clearance of doxacurium estimated from these data was 1.1 to 4.2 mL [center dot] kg-1 [center dot] min-1 (Table 3). Seven blood samples were obtained in two patients and nine samples in one patient after termination of the infusion of doxacurium. These data were best fit to one compartment model that produced estimates of terminal half-life between 60 and 70 min; however, the confidence intervals of these estimates were broad. No model fitting was attempted for the fourth patient from whom only three specimens could be obtained (Figure 1). Fade in TOF was observed when 25-50 ng/mL of doxacurium was measured in the plasma. Twelve hours after termination of infusion, doxacurium concentrations were <10 ng/mL. In one patient doxacurium was not detected in the plasma 8.5 h after the end of the infusion.
Nurses' assessments at the time of discharge from the ICU documented mild weakness of the arms and legs in five patients. After discharge from the ICU while in the hospital, six patients had weakness or lack of coordination noted by their parents, nurses, physical therapists, and the investigators. Three of these had been noted to have normal strength on discharge from the ICU. A 7-mo-old patient would move his eyes but not his head for several days after discharge from the ICU. An 8-mo-old boy was noted to have poor control of his head and weak extremities in the first 24 h after extubation and weak sucking for 3 days after extubation. A 10-mo-old boy lost his balance easily in the hospital and for several weeks at home. His legs were noted to be weaker than his arms. A 15-mo-old boy required assistance to sit up in his crib and had mild weakness of his extremities in the first 24 h after extubation. A 16-mo-old patient who walked independently preoperatively would not walk without support in the hospital or for several weeks postoperatively. The oldest child, aged 9 yr; failed extubation due to inability to clear secretions from his upper airway. After a successful second extubation, he was noted to be very weak. Three of the five patients who were noted to be weak at the time of transfer from the ICU and five of the six who were noted to be weak thereafter, received clindamycin. There was no statistically significant relationship between the administration of clindamycin (P = 0.3, Fisher's exact test), the duration of infusion, or percent change in infusion from the beginning to the end of the infusion and the presence or absence of weakness after extubation (P = 0.6, Mann-Whitney test).
Eleven of the 14 families whose children underwent LTR were contacted by phone from 6 to 21 mo after the surgery. One patient was lost to follow-up and two died of causes not directly related to the LTR. In six cases, the families did not recall any weakness or lack of coordination after surgery. In one of these patients, however, the mother had noted regression in independent walking during the first week after surgery. Two infants, 7 and 8 mo old, had delay of motor milestones in the months after surgery, in part because of prolonged hospitalization and foster care. The 10-mo-old boy who lost his balance easily for several weeks walked normally by 12 mo of age. The 9-yr-old patient was able to walk with normal strength 3 wk after discharge from the hospital.
Unexpectedly prolonged duration of weakness after administration of neuromuscular blocking drugs to ICU patients with a variety of underlying diseases is now well recognized. Organ failure, sepsis, administration of corticosteroids, up regulation of acetylcholine receptors (AchRs) and prolonged, intense neuromuscular blockade may increase the risk of prolonged weakness. Delayed clearance of neuromuscular blocker and metabolites [7-9], disuse atrophy, necrotizing myopathy , and critical illness polyneuropathy  are possible causes of prolonged weakness. It has been suggested that reducing the amount of relaxant administered by monitoring neuromuscular transmission may decrease the risk of prolonged paralysis. However, there have also been reports of necrotizing myopathy in patients who received appropriately titrated infusions of neuromuscular blocking drugs and corticosteroids [12-14]. This study demonstrates that in spite of titrated administration of doxacurium to infants and children without organ failure or sepsis, recovery of neuromuscular transmission was prolonged and variable. Furthermore, some of these pediatric patients had clinically evident weakness for days after successful tracheal extubation.
It is likely that upregulation of AchRs and disuse atrophy occurred to some extent in our pediatric patients. Absence of weight bearing , sedation , and administration of nondepolarizing neuromuscular blockers  have been followed by proliferation of AchRs, and resistance to nondepolarizing blockers. An increase in the number of steroid receptors in the cytosol of immobilized muscle  has been demonstrated. It may be that exogenous glucocorticoids exaggerate muscle atrophy, even without the concomitant administration of neuromuscular blocking drugs in immobilized muscle. Indeed, severe atrophy has been observed in a patient who received large-dose steroids and sedation, without neuromuscular blockade .
Our patients did not receive dexamethasone until the doxacurium infusion was stopped, but at that time they had been immobile for five days or longer. It is possible that weakness and lack of coordination days after extubation was due to disuse atrophy exacerbated by the administration of exogenous steroids. Weakness was relatively mild in these pediatric patients. The duration of exposure of our patients to dexamethasone was less than that of adult patients in whom severe myopathy occurred [10,12-14]. In this small group of patients, we were unable to identify predictive factors, such as the duration of exposure to neuromuscular blocker, the relative change in resistance to neuromuscular blockade, the dose of corticosteroid administered and its duration, or the presence of concomitant medications such as clindamycin, which might be associated with an increased risk of prolonged weakness. Differences in the preoperative level of motor development, recall bias, and the absence of a control group that did not receive doxacurium or dexamethasone make it difficult to interpret the significance of residual weakness and lack of coordination noted after discharge from the ICU.
Recovery of neuromuscular transmission was slower and more variable in these pediatric patients after prolonged administration of doxacurium than has been noted after a single bolus. In one study of children, during halothane anesthesia, recovery of TOF ratio to 0.75 occurred about 100 min (range 81-141 min) after one bolus of 50 micro g/kg of doxacurium . The slower rate of recovery in our study of ICU patients might have been due to the presence of higher plasma concentrations at the time of termination of the infusion, slower redistribution after long exposure, younger age of the patients, or potentiating effects of antibiotics or steroids. The plasma concentrations of doxacurium at the end of infusion in four of our pediatric patients, median 500 ng/mL, were greater than those noted immediately after a bolus of 15 micro g/kg of doxacurium in adults , but similar to those noted immediately after a bolus of 25 micro g/kg of doxacurium in adults . The average elimination half-lives noted in these studies of adults were longer than those we observed. The clearance of doxacurium measured after a single bolus in normal adults averaged 2.2 (+/- 1.1 SD), and 2.7 (+/- 1.6 SD) mL [center dot] kg-1 [center dot] min (-1) [20,21], and 1.2 (+/- 0.7 SD) mL [center dot] kg-1 [center dot] min-1 in the presence of renal failure . The clearances we estimated during constant infusion were also in this range. However, data provided by the limited sampling in this study are not adequate to support a strong statement regarding the kinetics of doxacurium after prolonged infusion. It may be that more intensive plasma sampling would have demonstrated a biexponential decline, as has been shown in animals after infusion of pancuronium for two days . An important difference between that animal experiment and this clinical observation is that 24 hours after infusion of a fixed dose of pancuronium was stopped there was significant fade in the TOF ratio, whereas when the infusion of doxacurium was titrated to maintain some PTC, the TOF ratio recovered spontaneously to 1.0 in less than 24 hours in all patients.
The infants in this study may have recovered more slowly than have children in other studies because doxacurium is more potent in infants than in children, as was found in the one cumulative dose-response study of doxacurium which included infants . There have been no studies of the pharmacokinetics and pharmacodynamics of doxacurium in normal infants or children.
The presence of other drugs which potentiate block-ade produced by nondepolarizing neuromuscular blockers may have delayed spontaneous recovery in these pediatric ICU patients. Penicillins and cephalo-sporins do not have clinically significant effects on neuromuscular transmission, but clindamycin has been shown to slow the rate of recovery from a bolus of pipecuronium . Potentiation of block produced by pancuronium [24,25] and d-tubocurare [25,26] by clindamycin has also been observed. These studies are consistent with the tendency toward slower spontaneous recovery in the presence of clindamycin that we observed. Acute administration of corticosteroid can also impair neuromuscular transmission .
A previous report on the use of a similar blocker, pancuronium, for days in pediatric ICU patients  differs from this study in several ways. Patients in the pancuronium study were older; although their ages ranged from three months to 17 years, the average age was 4.3 years (SD 4.9 years). Thus most were between two and 6.5 years of age, and their diagnoses varied greatly. Mechanical ventilation was managed with less block than was present in our infants; one to two responses to a TOF were present rather than only PTC. There was no mention of concomitant administration of antibiotics. Seven patients received anticonvulsants. Anticonvulsants can increase the clearance of vecuronium  and may also speed recovery from pancuronium. There was almost a 10-fold range in dose of pancuronium given per hour, whereas the range of dose of doxacurium in our study was only threefold. The higher infusion rates required by some patients and the lesser degree of block produced in pediatric patients given pancuronium is consistent with the relatively faster recovery observed after termination of pancuronium infusion than after termination of doxacurium. A study comparing pancuronium and doxacurium administered in a double-blind fashion for more than 24 hours to adults did not find that recovery from doxacurium was slower than that from pancuronium . Differences in patient population and method of drug administration are more likely to be responsible than the drugs themselves for the difference in speed of recovery between this study and that of Tobias et al. .
Quantitative monitoring benefits patients recovering from long-term administration of blockers, because residual block is difficult to detect and the rate of spontaneous recovery is variable. When the TOF ratio is >0.4, no difference in the four responses can be felt or observed visually . When the TOF ratio reaches 0.7 at the adductor pollicis, a patient in whom no other compromising factors are present will probably maintain adequate respiratory function. However, when vecuronium produces this degree of block, hypoxic drive is inhibited . When this much blockade is present there may also be weakness of head lift  and upper airway dysfunction. Although these observations were made in humans who had received neuromuscular blockers for a period of minutes to hours, they are the result of pharmacologic effect, and the competitive block of AchR, which also exists after prolonged exposure to neuromuscular blockers. Nonquantitative clinical evaluation may falsely suggest that extubation could be successful several hours before the patient is able to sustain airway function or adequate ventilation. This was illustrated by the patient who removed his own endotracheal tube when the TOF ratio was 0.5 at the adductor pollicis and by the patient who "failed extubation" when quantitative monitoring could not be applied. In our patients sedation with a drug of short duration of action allowed documentation of the absence of residual block which is associated with impaired airway function.
Therefore we recommend that sedation be administered during spontaneous recovery from a titrated infusion of neuromuscular blockers of several days duration. If quantitative monitoring is available, the TOF ratio should be 1.0, or an equivalent degree of neuromuscular transmission demonstrated, before awakening begins. Then tracheal extubation is likely to be successful in a patient who also demonstrates the ability to swallow, adequate pulmonary function, and has no upper airway obstruction. Nevertheless, such patients should be closely observed after extubation for signs of weakness or lack of coordination. This is particularly important for patients who have received drugs that potentiate neuromuscular block or produce myopathy when administered during prolonged immobilization.
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