Alan R. Tait

Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation A New Drug–Drug Interaction

Background—We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results—Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34±23, 58±15 (P =0.027), 74±10 (P =0.002), and 89±7 (P =0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55±12 versus 42±12% platelet aggregation;P =0.002), as did troleandomycin (78±18 versus 45±18% platelet aggregation;P <0.0003), whereas rifampin enhanced platelet aggregation inhibition (33±18 versus 56±20% platelet aggregation, P =0.001). Conclusions—CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.

Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance

Background—Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. Methods and Results—Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 &mgr;mol/L)–induced platelet aggregation of <10%, 10% to 29%, and ≥30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r =−0.6, P =0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. Conclusions—Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.

Incidence and predictors of difficult and impossible mask ventilation.

Background:Mask ventilation is an essential element of airway management that has rarely been studied as the primary outcome. The authors sought to determine the incidence and predictors of difficult and impossible mask ventilation. Methods:A four-point scale to grade difficulty in performing mask ventilation (MV) is used at the authors’ institution. They used a prospective, observational study to identify cases of grade 3 MV (inadequate, unstable, or requiring two providers), grade 4 MV (impossible to ventilate), and difficult intubation. Univariate and multivariate analyses of a variety of patient history and physical examination characteristics were used to establish risk factors for grade 3 and 4 MV. Results:During a 24-month period, 22,660 attempts at MV were recorded. 313 cases (1.4%) of grade 3 MV, 37 cases (0.16%) of grade 4 MV, and 84 cases (0.37%) of grade 3 or 4 MV and difficult intubation were observed. Body mass index of 30 kg/m2 or greater, a beard, Mallampati classification III or IV, age of 57 yr or older, severely limited jaw protrusion, and snoring were identified as independent predictors for grade 3 MV. Snoring and thyromental distance of less than 6 cm were independent predictors for grade 4 MV. Limited or severely limited mandibular protrusion, abnormal neck anatomy, sleep apnea, snoring, and body mass index of 30 kg/m2 or greater were independent predictors of grade 3 or 4 MV and difficult intubation. Conclusions:The authors observed the incidence of grade 3 MV to be 1.4%, similar to studies with the same definition of difficult MV. Presence of a beard is the only easily modifiable independent risk factor for difficult MV. The mandibular protrusion test may be an essential element of the airway examination.

Adverse Events and Risk Factors Associated with the Sedation of Children by Nonanesthesiologists

After implementation of hospital-wide monitoring standards, a quality assurance (QA) tool was prospectively completed for 1140 children (aged 2.96 +/- 3.7 yr) sedated for procedures by nonanesthesiologists. The tool captured data regarding demographics, medications used, adequacy of sedation, monitoring, adverse events, and requirement for escalated care. The medical records of children who experienced adverse events were reviewed. Most (99%) children were monitored with pulse oximetry. Chloral hydrate was the most frequently used sedative (74.9% of cases). Of the children, 239 (20.1%) experienced adverse events related to sedation, including inadequate sedation in 150 (13.2%) and decrease in oxygen saturation in 63 (5.5%). Five of these children experienced airway obstruction and two became apneic. No adverse event resulted in long-term sequelae. Of the 854 children who received chloral hydrate, 46 (5.4%) experienced decreased oxygen saturation (>or=to90% of baseline). Children experienced desaturation after the use of chloral hydrate had received the recommended doses of chloral hydrate (38-83 mg/kg). ASA physical status III or IV and age <1 yr were predictors of increased risk of sedation-related adverse events. These data underscore the importance of appropriate monitoring that includes pulse oximetry to permit early detection of adverse events. Implications: This quality assurance study highlights the risks associated with the sedation of children and emphasizes the importance of appropriate monitoring by trained personnel. Children with underlying medical conditions and those who are very young are at increased risk of adverse events, which indicates that a greater degree of vigilance may be required in these patients. (Anesth Analg 1997;85:1207-13)

A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit.

Emergence agitation (EA) is a postanesthetic problem that interferes with a child’s recovery and presents a challenge in terms of assessment and management. In this prospective cohort study, we sought to determine the incidence of EA, evaluate factors associated with and predictive of EA, and describe associated outcomes in healthy children. Children aged 3–7 yr who were undergoing general anesthesia for elective outpatient procedures were included. All perioperative care was documented, and postoperative behaviors in the postanesthesia care unit were recorded. Parents completed the Behavioral Style Questionnaire for 3- to 7-yr-olds. Five-hundred-twenty-one children were studied, of whom 96 (18%) had EA. Agitation lasted up to 45 min in some cases (range, 3–45 min; mean, 14 ± 11 min), required pharmacologic intervention in 52% of children, and was associated with a prolonged postanesthesia care unit stay (117 ± 66 min versus 101 ± 61 min for nonagitated children; P = 0.02). Ten factors were found to be associated with EA, including age, previous surgery, adaptability, ophthalmology and otorhinolaryngology procedures, sevoflurane, isoflurane, sevoflurane/isoflurane, analgesics, and time to awakening. Of these, otorhinolaryngology procedures, time to awakening, and isoflurane were shown to be independent risk factors. IMPLICATIONS: Children may become agitated after general anesthesia. This study describes several factors that may increase the risk for agitation. These data are important in planning anesthesia care for young children.

Risk factors for perioperative adverse respiratory events in children with upper respiratory tract infections

Background Anesthesia for the child who presents for surgery with an upper respiratory infection (URI) presents a challenge for the anesthesiologist. The current prospective study was designed to determine the incidence of and risk factors for adverse respiratory events in children with URIs undergoing elective surgical procedures. Methods The study population included 1,078 children aged 1 month to 18 yr who presented for an elective surgical procedure. Parents were given a short questionnaire detailing their child’s demographics, medical history, and presence of any symptoms of a URI. Data regarding the incidence and severity of perioperative respiratory events were collected prospectively. Adverse respiratory events (any episode of laryngospasm, bronchospasm, breath holding > 15 s, oxygen saturation < 90%, or severe cough) were recorded. In addition, parents were contacted 1 and 7 days after surgery to determine the child’s postoperative course. Results There were no differences between children with active URIs, recent URIs (within 4 weeks), and asymptomatic children with respect to the incidences of laryngospasm and bronchospasm. However, children with active and recent URIs had significantly more episodes of breath holding, major desaturation (oxygen saturation < 90%) events, and a greater incidence of overall adverse respiratory events than children with no URIs. Independent risk factors for adverse respiratory events in children with active URIs included use of an endotracheal tube (< 5 yr of age), history of prematurity, history of reactive airway disease, paternal smoking, surgery involving the airway, the presence of copious secretions, and nasal congestion. Although children with URIs had a greater incidence of adverse respiratory events, none were associated with any long-term adverse sequelae. Conclusions The current study identified several risk factors for perioperative adverse respiratory events in children with URIs. Although children with acute and recent URIs are at greater risk for respiratory complications, these results suggest that most of these children can undergo elective procedures without significant increase in adverse anesthetic outcomes.

The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment

Background:  Difficulty with pain assessment in individuals who cannot self‐report their pain poses a significant barrier to effective pain management. However, available assessment tools lack consistent reliability as pain measures in children with cognitive impairment (CI). This study evaluated the validity and reliability of the revised and individualized Face Legs Activity Cry and Consolability (FLACC) behavioral pain assessment tool in children with CI.

Prolonged Recovery and Delayed Side Effects of Sedation for Diagnostic Imaging Studies in Children

Objective. Although sedation-related adverse events in children in the hospital setting have been extensively reported, limited data are available regarding adverse events after discharge home. Despite nationally recommended discharge criteria, in busy outpatient settings, children may be sent home into the care of their parents after a brief recovery from sedation, placing them at risk for adverse events in an unmonitored setting. Previous studies have not addressed issues such as requirement for escalation of care after discharge (ie, emergency department visits or hospitalization), or parental satisfaction with their childs sedation experience. This study was undertaken to evaluate the recovery and delayed adverse events after discharge of children who received sedation for magnetic resonance imaging or computed tomography. Methods.  With approval from the institutional review board and written informed consent from a parent, children (<18 years old) sedated for magnetic resonance imaging or computerized tomography were studied. Sedative drugs were ordered at the discretion of the radiologist responsible for the procedure in accordance with institutional sedation guidelines and in consideration of the childs health status. Pediatric nurses in the diagnostic areas administered the sedative agent(s) and monitored children according to preestablished institutional guidelines. Demographics, sedative(s) administered, and adverse events including hypoxemia (decrease in Spo 2 by ≥10% of baseline) and sedation events such as inadequate, failed, or excessive sedation, were documented on the institutional quality assurance tool. Children were discharged from the hospital when they met the following preestablished discharge criteria: return to baseline vital signs, level of consciousness close to baseline, and the ability to maintain a patent airway. The following day, parents were telephoned and questioned regarding the childs alertness, side effects, and whether medical follow-up had been sought. Parents also rated their overall satisfaction with the sedation experience. Results.  Three hundred seventy six children comprised the sample. Eighty nine percent of children received chloral hydrate (CH; 64 ± 13 mg/kg), and 11% midazolam (.15 ± .13 mg/kg) as the primary sedative. There was an 8% incidence of failed sedation, and a 1.6% incidence of hypoxemia during the procedure. Three children required prolonged monitoring in the postanesthesia care unit before discharge; 1 child attributable to an allergic reaction, a second attributable to wheezing and oxygen desaturation, and the third attributable to prolonged sedation from CH and midazolam. These children were discharged home from the postanesthesia care unit without additional sequelae. Side effects after discharge included: motor imbalance (31%), gastrointestinal effects (23%), agitation (19%), and restlessness (14%). Agitation and restlessness lasted greater than 6 hours in more than one third of children who experienced these effects. CH was more commonly associated with imbalance compared with midazolam, and restlessness and prolonged imbalance were associated with younger age. Medical advice was sought after discharge for 15 (4%) children, 3 of whom required a visit to the emergency department for excessive or prolonged sedation. Each of these children had received CH as a sole sedative in recommended doses (61–77 mg/kg). In 1 of these cases, the procedure had been aborted because of inadequate sedation in the hospital, yet the child became difficult to arouse at home. Only 48% of children returned to baseline activity and behavior within 8 hours of the procedure; however, 89% were back to baseline status within 24 hours. Notably, 5% of all children did not return to baseline activity until the second day after the procedure. Although not statistically significant, infants <12 months old experienced delayed recovery (ie, ≥24 hours) more frequently compared with older children. Sixteen percent of parents were dissatisfied with the sedation experience. Inadequate/failed sedation and agitation after discharge contributed to parent dissatisfaction. Conclusions.  Our data demonstrate that children may experience prolonged recovery as well as a significant incidence of delayed side effects after sedation for a diagnostic procedure. Specifically, we found a high incidence of motor imbalance, agitation, gastrointestinal effects, and restlessness after discharge. Factors related to these side effects included younger age (restlessness and prolonged imbalance) and use of CH (agitation and motor imbalance). Failed sedation and agitation contributed significantly to parental dissatisfaction with the childs sedation experience. These findings highlight the importance of careful presedation education and preparation of the patient/family regarding the potential for delayed recovery, anticipated side effects, and how to obtain medical follow-up if necessary. Future studies should focus on sedation methods that reduce sedation-related adverse events and promote the safety of sedated children.

The Reliability and Validity of the Face, Legs, Activity, Cry, Consolability Observational Tool as a Measure of Pain in Children with Cognitive Impairment

Pain assessment remains difficult in children with cognitive impairment (CI). In this study, we evaluated the validity and reliability of the Face, Legs, Activity, Cry, Consolability (FLACC) tool for assessing pain in children with CI. Each child’s developmental level and ability to self-report pain were evaluated. The child’s nurse observed and scored pain with the FLACC tool before and after analgesic administration. Simultaneously, parents scored pain with a visual analog scale, and scores were obtained from children who were able to self-report pain. Observations were videotaped and later viewed by nurses blinded to analgesics and pain scores. One-hundred-forty observations were recorded from 79 children. FLACC scores correlated with parent scores (P < 0.001) and decreased after analgesics (P = 0.001), suggesting good validity. Correlations of total scores (r = 0.5–0.8;P < 0.001) and of each category (r = 0.3–0.8;P < 0.001), as well as measures of exact agreement (&kgr; = 0.2–0.65), suggest good reliability. Test-retest reliability was supported by excellent correlations (r = 0.8–0.883;P < 0.001) and categorical agreement (r = 0.617–0.935; &kgr; = 0.400–0.881;P < 0.001). These data suggest that the FLACC tool may be useful as an objective measure of postoperative pain in children with CI.

Use of the laryngeal mask airway in children with upper respiratory tract infections: a comparison with endotracheal intubation.

Several studies suggest that placement of an endotracheal tube (ETT) in a child with an upper respiratory infection (URI) increases the risk of complications.However, the development of the laryngeal mask airway (LMA) has provided anesthesiologists with an alternative means of airway management. This study was therefore designed to evaluate the use of the LMA in children with URIs and to compare it with the ETT. The study sample consisted of 82 pediatric patients (3 mo to 16 yr of age) who presented for elective surgery with an URI. Patients with URIs were randomly allocated to receive either an ETT (n = 41) or a LMA (n = 41) and were followed for the appearance and severity of any perioperative complications. The two groups were similar with respect to age, gender, anesthesia and surgery times, number of attempts at tube placement, and presenting URI symptoms. There were no differences between groups in the incidence of cough, breath-holding, excessive secretions, or arrhythmias. Although one patient in the ETT group required a muscle relaxant for laryngospasm, the overall incidence of laryngospasm was similar between the two groups. There was, however, a significantly greater incidence of mild bronchospasm in the ETT group compared with the LMA group (12.2% vs 0%, P < 0.05). The incidence of major arterial oxygen desaturation events (Spo2 <90%) during placement of the airway device was also significantly increased in the ETT group (12.5% vs 0%, P < 0.05). Furthermore, the total number of all episodes of respiratory complications, i.e., breath-holding, laryngospasm, bronchospasm, and major oxygen desaturation, was significantly greater in the ETT group (35 vs 19, P < 0.05). Despite this, all respiratory complications were easily managed, and there were no adverse sequelae. Although the risks associated with anesthetizing a child with an URI remain controversial, results from this study suggest that the LMA offers a suitable alternative to the ETT for use in children with URIs. Implications: This study compares the use of the laryngeal mask airway with the endotracheal tube for airway management in children with upper respiratory infections. Results suggest that if the decision is made to proceed with anesthesia for the child with an upper respiratory infection, then the laryngeal mask airway provides a suitable alternative to the endotracheal tube. (Anesth Analg 1998;86:706-11)