Anesth Analg 2008; 107:113-116
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318176be1f
ANESTHETIC PHARMACOLOGY
The Onset Time of Atracurium Is Prolonged in Patients with Sickle Cell Disease
Philippe Dulvadestin, MD, PhD*,
Alain Gilton, MD*,
Philippe Hernigou, MD, PhD , and
Jean Marty, MD, PhD*
From the *Department of Anesthesia and Intensive Care, and Department of Orthopedic Surgery, Hopital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris, Créteil, France.
Address correspondence and reprint requests to Pr Philippe Duvaldestin, Service d’Anesthésie Réanimation Chirurgicale, Hopital Henri Mondor, 94010, France. Address e-mail to philippe. duvaldestin{at}hmn.aphp.fr.
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Abstract
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BACKGROUND: Patients with sickle cell disease (SCD) frequently undergo surgery during their lifetime. Patients with SCD are considered at greater risk of perioperative complications than otherwise healthy patients and require meticulous anesthetic management. The pharmacodynamics of anesthetics may be altered in patients with SCD due to microcirculatory abnormalities or anemia.
METHODS: In this study, we assessed the pharmacodynamics of a single dose of atracurium (0.5 mg/kg) by mechanomyography in 13 patients with SCD and in 17 control patients.
RESULTS: The time between atracurium administration and 90% twitch height depression (onset time) was longer in SCD patients (mean ± sd) 323 ± 124 s than in controls 165 ± 36 s (P < 0.01). Unsatisfactory intubation conditions at 3 min after atracurium administration were observed in 5/13 patients with SCD and 1/17 control patients (P < 0.05). The duration of action of atracurium in patients with SCD was similar to that of control patients. The time to spontaneous return of the train-of-four ratio to 0.9 was 101 ± 24 min in control patients and did not differ 93 ± 24 min in patients with SCD.
CONCLUSION: Delayed onset time, together with unchanged duration of the neuromuscular blocking effect of atracurium, may be explained by an increased distribution volume of atracurium in patients with SCD. Our results suggest that monitoring of neuromuscular block may guide the time of tracheal intubation in patients with SCD.
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Introduction
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Patients with sickle cell disease (SCD) are more likely to undergo surgery during their lifetime than the general population because of the nature of the complications of SCD.1 Since surgery places the patient with SCD at increased risk of SCD-related complications,2 they require meticulous clinical care, including adjusted anesthesia management. Patients with SCD may exhibit different pharmacologic responses to anesthetics due to several pathological alterations, including microcirculatory abnormalities, chronic anemia,3or progressive renal insufficiency.4 We therefore speculated that the pharmacodynamics of neuromuscular blocking drugs may be altered in patients with SCD. In the current study, the pharmacodynamics of an intubating dose of atracurium were compared, in adult patients with SCD, to those of healthy patients.
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METHODS
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Patient Population
After local ethical committee approval and informed consent, 13 patients with SCD and 17 control ASA I or 2 class including 4 blacks and 13 Caucasians were studied. Exclusion criteria included: (1) body mass index (BMI)>30, (2) age over 55 yr, (3) anticipated difficult ventilation or endotracheal intubation, and (4) receiving drugs known to interfere with neuromuscular transmission. Among patients with SCD, 11 had homozygous sickle cell anemia and two had sickle cell-hemoglobin C disease. All SCD and control patients had femoral head aseptic bone necrosis and were undergoing core decompression combined with bone marrow grafting.5 Patients with SCD were considered as undergoing intermediate risk surgery6 and in accordance with to our local transfusional program, they had no preoperative blood transfusions. All patients had preoperative blood hemoglobin assessment.
Anesthesia Management
Anesthesia was induced with propofol 2–3 mg/kg sufentanil 1.5 mcg/kg and maintained with sevoflurane 0.5% to 2% end-tidal and nitrous oxide 50% in oxygen. Tracheal intubation was performed 3 min after the administration of a single dose of 0.5 mg/kg atracurium, ventilation was controlled and end-tidal CO2 maintained at 35 mm Hg. Central body temperature was maintained by surface air warming. Tracheal intubation conditions were scored by an independent observer blinded to neuromuscular monitoring data according to the Copenhagen score7 and defined as clinically acceptable when the score was excellent or good and clinically not acceptable when the score was poor.
Neuromuscular Monitoring
Neuromuscular function was monitored with a force displacement transducer (PCB Piezotronics Orsay, France) fixed to the thumb with a 200 g preload. Train-of-four (TOF) stimulations (TOF Watch SX®) were delivered every 15 s at the wrist. The evoked response was recorded on a stripchart recorder. After a stable response was obtained for at least 3 min, atracurium was administered. Onset of neuromuscular blockade was the time elapsed between atracurium administration and the decrease of the height of the first evoked response to TOF stimulation to 90% of control value (OT90). The maximum depression of the first evoked response to TOF stimulation (Emax) was measured. The times between atracurium administration and the spontaneous return of the height of the first response to TOF stimulation to 25%, 50%, 75%, and 90% of control value (TH25, TH50, TH75, and TH90, respectively) ratio to 0.7 and 0.9 (TOF0.7 and TOF0.9, respectively) were measured.
Statistical Analysis
The results were expressed as the mean ± sd and range. Statistical analysis of continuous variables were performed using the Student’s t-test with a P value <0.05 representing a statistically significant difference. The  2 test was used for the analysis of discontinuous variables.
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RESULTS
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The characteristics of the patients are listed in Table 1. Age did not differ between the two groups, but the BMI was lower in patients with SCD. Hemoglobin level was lower in patients with SCD [10.1 ± 1.5 g/100 mL (range, 7.6–12.0 g/100 mL)] than in controls [14.1 ± 1.7 g/100 mL (range, 12.1–16.1 g/100 mL)] (P < 0.01). Intubation conditions were clinically not acceptable in 5/13 patients with SCD and in 1/17 controls (P < 0.05). The results of the neuromuscular monitoring data are shown in Table 2. Emax did not differ between the two groups although in three patients with SCD, as opposed to one control patient, Emax remained below 100%. OT90 was longer in patients with SCD [323 ± 124 s (range, 165–490 s)] than in controls [165 ± 36 s (range, 110–230 s)] (P < 0.01). TH25 was shorter in patients with SCD [44 ± 7 min(range, 30–53 min)] than in controls [53 ± 7 min (range, 42–65 min)] (P < 0.05). TH 50, TH75, and TH90 did not differ between the two groups. TOF 0.7 did not differ between patients with SCD [75 ± 13 min (range, 50–90 min)] and controls [82 ± 8 min (range, 70–93 min)]. TOF 0.9 did not differ between patients with SCD [93 ± 24 min (range, 59–146 min)] and controls [101 ± 24 min (range, 82–132 min)].
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DISCUSSION
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This study showed that the onset time of atracurium was longer in patients with SCD than in controls, whereas its duration of action differed only slightly between the two groups. The index of complete recovery from neuromuscular block, such as the TOF 0.9, did not differ between the two groups. Intubating conditions were better in controls than in patients with SCD.
Two factors may influence onset of a fixed intubating dose of neuromuscular relaxant: the muscle blood flow8 and the initial plasma concentration.9 Although microcirculatory abnormalities are common in SCD, no data support a reduction in peripheral muscle blood flow in these patients. On the contrary, chronic anemia is likely to cause an increase in cardiac output in patients with SCD. The initial volume in which atracurium initially distributes corresponds to the plasma volume,10 which is increased in patients with SCD due to chronic anemia.11 Therefore, the initial plasma concentration of atracurium may be lower in patients with SCD than in patients without SCD, and may have been the cause of the increased onset time of atracurium observed in the current study. An increase in onset time of atracurium was reported in patients with cirrhosis or with chronic renal failure.12,13 These two pathological circumstances are likely to be associated to anemia and increased extracellular fluids. These results must be compared with the situation of acute hemodilution, which also induces an increase in the volume of distribution of neuromuscular relaxants.14 However, in contrast to the results of our study, an increase in the potency of vecuronium and atracurium was observed in patients undergoing acute normovolemic hemodilution.15,16 A decrease in the plasma protein binding capacity was thought to explain for the increased potency of neuromuscular blocking drugs during hemodilution15,16 which is arguable, as neuromuscular relaxants are poorly bound to plasma proteins.17–19 A difference in onset time between our two groups could be also explained by the lower BMI of patients with SCD compared with control patients. Although the BMI of patients with SCD remained within normal range. However, there is a large amount of evidence that the onset time of an intubating dose of atracurium is 3 min or less in the general population,20–23 and therefore this difference in BMI cannot explain the prolongation in onset time presently observed in patients with SCD. During the spontaneous recovery from atracurium-induced neuromuscular blockade, only TH25 differed from controls in patients with SCD. TH25 corresponds to the early phase of spontaneous recovery and this finding probably reflects an increase in the volume of distribution of atracurium. Another confounding factor is the difference in racial origin which might modify the response. Our finding that the other pharmacodynamic parameters were unchanged in patients with SCD suggests that the sensitivity of the neuromuscular junction to atracurium is unchanged in patients with SCD.
As onset of the neuromuscular blocking effect is a determinant of the timing of tracheal intubation it is not surprising that intubating conditions 3 min after atracurium administration were less satisfactory in patients with SCD than in controls. We therefore suggest that monitoring of the neuromuscular effect of an intubating dose of atracurium may be advised to guide the time of laryngoscopy in patients with SCD. Another reason for monitoring onset in those patients is the large interindividual variation in OT90 in patients with SCD.
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Footnotes
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Accepted for publication March 17, 2008.
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Abstract
Introduction
