Peter N. Johnson

α2-Receptor Agonists for Treatment and Prevention of Iatrogenic Opioid Abstinence Syndrome in Critically Ill Patients:

Objective: To review the literature regarding the use of α2-agonists in the treatment and prevention of iatrogenic opioid abstinence syndrome (IOAS) in critically ill patients. Data Sources: Primary literature was identified through a search of MEDLINE (1950–June 2009), EMBASE (1988–June 2009), International Pharmaceutical Abstracts (1970–June 2009), and the Cochrane Library (1996–June 2009), using the names of individual α2-agonists and the following key words: children, opioid withdrawal, opioid, and adult. Relevant abstracts from the Society of Critical Care Medicine, reference citations from selected articles, and manufacturers’ product information were also reviewed. Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Three retrospective studies and 6 case reports/series representing 44 patients were included for analysis. Data Synthesis: Central α2-agonists are thought to minimize symptoms of IOAS by decreasing presynaptic outflow of catecholamines. Successful use of clonidine and dexmedetomidine for management of IOAS has been reported. Lofexidine, an α2-agonist not yet approved in the US, may offer similar withdrawal symptom relief but has yet to be studied in the intensive care setting. Although the quality of studies identified was limited, preliminary evidence does provide some support for the use of transdermal clonidine and injectable dexmedetomidine in the treatment and prevention of IOAS. These agents were shown to facilitate discontinuation of opioids and to minimize withdrawal symptoms with few reported adverse events. Conclusions: Central α2-agonists appear to be effective and safe second-line agents for treatment and prevention of IOAS. Further studies should be conducted to determine their role in the therapy of patients with IOAS.

Vancomycin dosage in overweight and obese children

PURPOSE Vancomycin dosages in overweight and obese children were evaluated. METHODS This retrospective study evaluated data for children who were age 2-17 years, received i.v. vancomycin, and were admitted to a childrens hospital from September 1, 2007, through October 31, 2009. Patients were then stratified into two groups: normal-weight patients and overweight or obese patients. The primary objective was to compare the number of vancomycin regimens between groups with a trough concentration of 5-15 μg/mL. Secondary objectives included a comparison of dosage changes and toxicities. Multivariate, conditional logistic regression was performed to assess the relationship between attaining optimal vancomycin concentrations (5-15 μg/mL) and independent variables. RESULTS Data were collected for 232 courses of vancomycin, representing 187 patients. The mean ± S.D. initial dose for the normal-weight and overweight or obese groups differed significantly (461.3 ± 303.1 mg and 658.4 ± 389.6 mg, respectively; p < 0.01); the milligram-per-kilogram initial vancomycin dose did not. The multivariate analysis revealed that every-eight-hour regimens had increased odds of achieving therapeutic concentrations (p < 0.001), while obese children had decreased odds of achieving therapeutic concentrations (p = 0.037). CONCLUSION A study of prescribing behavior in one hospital revealed no significant difference in the size of vancomycin doses (in milligrams per kilogram) given to normal-weight children compared with overweight or obese children. Regimens using every-eight-hour dosing were significantly more likely than other regimens to result in a vancomycin trough concentration of 5-15 μg/mL, and regimens for obese children, compared with regimens for nonobese children, were less likely to produce trough concentrations in the same range of 5-15 μg/mL.

Increased enoxaparin dosing is required for obese children.

Weight-based dosing for enoxaparin is recommended in the 2008 American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) prophylaxis. Enoxaparin 0.5 mg/kg per dose administered subcutaneously every 12 hours is recommended for this indication in children. There is no established upper dosing limit of enoxaparin for prophylaxis in children, and the US Food and Drug Administration–approved enoxaparin dose for adults for VTE prophylaxis is 30 mg subcutaneously every 12 hours or 40 mg subcutaneously daily. Therefore, we assumed that the upper limit for children is 40 mg subcutaneously daily. We reviewed 3 cases of obese adolescent boys who required large doses of enoxaparin to achieve the ACCP-recommended anti-factor Xa range of 0.1 to 0.3 IU/mL for the prevention of VTE. All 3 patients required doses of enoxaparin that are higher than that recommended for adults for VTE prophylaxis: patient A (BMI: 105.9) required >0.28 mg/kg per dose, patient B (BMI: 95.7) required 0.15 mg/kg per dose, and patient C (BMI: 29.9) required 0.49 mg/kg per dose. The desired anti-factor Xa range was achieved when enoxaparin was administered every 12 hours in each patient with no reported episodes of VTE. One patient had minor bruising, but no other adverse events were noted. Because of the variability in dose requirements and unpredictability in patient responses demonstrated in our 3 adolescents, prospective studies are needed to provide definitive recommendations on dosing of enoxaparin for VTE prophylaxis in this subset of obese pediatric patients.

Lofexidine, an α2-Receptor Agonist for Opioid Detoxification

Objective: To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an α2-agonist, for opioid detoxification. Data Sources: Primary literature was identified through a MEDLINE search (1950–September 2009), EMBASE (1988–Juty 2009), International Pharmaceutical Abstracts (1970–September 2009), and the Cochrane Library (1996–September 2009) using the key words lofexidine and opioid withdrawal. Abstracts were included in the absence of published results of studies. Study Selection and Data Extraction: Studies published in English-language literature reporting on animal and human pharmacology, toxicology, and pharmacokinetics were included in addition to clinical trials using lofexidine for opioid detoxification in comparison to placebo or active controls. Data Synthesis: Lofexidine is an α2-agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6–3.2 mg/day in divided doses for a total of 5–18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by α2-agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine. Conclusions: Lofexidine appears to be a promising agent for opioid detoxification. If approved, it would be the first nonopioid agent approved for this indication. Further large-scale controlled studies are needed to identify the safest, most effective dosage regimen required to achieve opioid detoxification.

Evaluation of Inpatient Admissions and Potential Antimicrobial and Analgesic Dosing Errors in Overweight Children

BACKGROUND The prevalence of overweight/obesity in US children has increased over the past several decades. Routine use of weight-based dosing of medications could potentially result in over- or underdosing in these children. OBJECTIVE To determine the percentage of admissions of children with a body mass index (BMI) greater than or equal to the 85th percentile for age and sex and the mean error rate per admission in the overweight versus control group. METHODS We performed a retrospective, preliminary study of children aged 5–12 years who were admitted to a childrens hospital over a period of 6 months. The overweight group included children with a BMI greater than or equal to the 85th percentile; the control group included children with a BMI less than the 85th percentile. Dose appropriateness was assessed, using 2 references. An overdose was defined as: (1) total mg/kg/day or mg/kg/dose greater than or equal to 110% of the maximum recommended pediatric dose, (2) total mg/day greater than the adult maximum recommended dose, or (3) greater than the recommended number of doses per day. An underdose was defined as: (1) total mg/kg/day or mg/kg/dose less than or equal to 90% of the minimum recommended pediatric dose, or (2) fewer than the recommended number of doses per day. Baseline comparisons between groups were done via Students t-tests and χ2 analysis, when appropriate, with an a priori α of p less than or equal to 0.05. RESULTS A total of 839 admissions representing 699 patients were included. The overweight group included 278 (33.1%) admissions. Comparison of overall mean error rate per admission revealed a statistically significant increase in dosing errors for overweight patients (0.4 ± 0.6 vs 0.3 ± 0.6; p = 0.030), with underdose errors occurring more frequently than overdose errors (0.3 ± 0.6 vs 0.2 ± 0.5; p = 0.010). CONCLUSIONS Overweight children accounted for one-third of admissions, and the results of this study suggest that these patients are at greater risk for errors in dosing than are children of age- and sex-appropriate weight. This study did not assess clinical outcomes; however, overweight children could be at increased risk for therapeutic failures or adverse effects.

Selection of the Initial Methadone Regimen for the Management of Iatrogenic Opioid Abstinence Syndrome in Critically Ill Children

Iatrogenic opioid abstinence syndrome (IOAS) is a common complication in critically ill infants and children receiving prolonged exposure to continuous infusions of opioids. Although no guidelines are available regarding management of IOAS in children, several treatment options are available, including clonidine, morphine, and methadone. Methadone is commonly prescribed due to its long half‐life and antagonism of the N‐methyl‐d‐aspartate receptor. Different approaches, such as weight‐based and formula‐based methods, have been used to determine the initial methadone dosing regimen. Because of the vast differences in the recommended dosing regimen from these sources, we conducted a literature search to identify articles evaluating the initial methadone dosing regimen for prevention and/or treatment of IOAS in children. Specifically, we evaluated the reported frequency of withdrawal and oversedation after initiation of methadone treatment. Our literature search was limited to English‐language articles in the MEDLINE (1950–March 2011), EMBASE (1988–March 2011), International Pharmaceutical Abstracts (1970–March 2011), and Cochrane Library (1996–March 2011) databases. Relevant abstracts and reference citations were also reviewed. A total of eight reports representing 183 patients were included in the analysis. There was wide discrepancy in the initial methadone dosing regimen. Approximately one‐third of all patients experienced withdrawal after starting methadone, and there did not appear to be a difference between weight‐based and formula‐based regimens. Seven patients experienced oversedation; however, not all articles reported this complication. It appears that a standard approach to initial methadone dosing does not exist because withdrawal occurred despite the regimen started. Therefore, it seems best to begin with the lowest dose possible and titrate to the childs response to avoid complications such as oversedation. Routine monitoring should be performed in all patients to guide clinicians in the management of IOAS.

Sedation and analgesia in critically ill children.

The interplay of pain, discomfort, and fear can cause agitation in critically ill children. Therefore, sedation and analgesia are essential components in the intensive care unit setting and are best managed with a multidisciplinary team approach. No one standard approach exists to assess and manage pain and anxiety. Many tools are available for the assessment of pain and sedation, but each tool has its advantages and disadvantages. Clinicians should consider adopting a validated tool for routine continuous assessment. Multiple pharmacological therapies are available to manage pain, anxiety, fear, and agitation. Dosing of these agents can be influenced by age-related pharmacokinetic and pharmacodynamic changes. Agents should be selected on the basis of the childs disease state, desired level of sedation, and cardiac and respiratory status.

Association of Fentanyl With Neurodevelopmental Outcomes in Very-Low-Birth-Weight Infants

Background: Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited. Objective: The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure. Methods: A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose (“high-dose” versus “low/no-dose”). Results: The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification. Conclusions: When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed.

Use of Continuous-Infusion Loop Diuretics in Critically Ill Children

Loop diuretics are commonly used in critically ill children to achieve appropriate fluid balance. They are often administered as a continuous intravenous infusion (CI) in hemodynamically unstable children because of fewer alterations in central venous pressure, oxygen saturation, and heart rate compared with scheduled intermittent dosing. During the past few years, however, drug shortages have been reported for bumetanide, torsemide, and furosemide. Therefore, to explore the use of alternative agents for CI, we performed a literature search to identify articles evaluating the use of furosemide, bumetanide, ethacrynic acid, and torsemide CI in critically ill children. The search was limited to English‐language articles in the MEDLINE (1946–December 2013), EMBASE (1980–December 2013), and International Pharmaceutical Abstracts (1970–December 2013) databases and the Cochrane Database of Systematic Reviews (2005–December 2013). Reference citations from relevant articles were also reviewed. A total of 10 reports representing 173 pediatric patients were included in the analysis. Most of the reports provided evidence for furosemide, and no reports with torsemide were identified. Wide variability in CI dosing was reported in these studies. When selecting the loop diuretic CI for critically ill patients, clinicians should consider their adverse‐event profiles, compatibility with other concomitant intravenous infusions, and pharmacoeconomics. Fluid balance and urine output should be monitored routinely to ensure appropriate response. The lowest initial dose should be used to achieve an appropriate fluid balance and target urine output of 1–3 ml/kg/hour while limiting the likelihood of toxicity.

Acetazolamide in Critically Ill Neonates and Children With Metabolic Alkalosis

Background: Acetazolamide is an option for hypochloremic metabolic alkalosis, but there are limited reports in children. Objective: To describe the acetazolamide regimen and outcomes in critically ill children with metabolic alkalosis. Methods: This was a descriptive, retrospective study of patients <18 years of age who received ≥3 doses of acetazolamide for metabolic alkalosis (ie, pH > 7.45 and bicarbonate [HCO3] > 26 mEq/L). Patients receiving other treatments for metabolic alkalosis within 24 hours of acetazolamide were excluded. The primary objective was to identify the mean dose and duration of acetazolamide. Secondary objectives were to determine the number of patients with treatment success (ie, serum HCO3 22-26 mEq/L) and occurrence of adverse events. Results: Thirty-four patients were included for analysis, the median age was 0.25 years (range = 0.05-12 years). The acetazolamide regimen included a mean dose of 4.98 ± 1.14 mg/kg for a mean number of 6.1 ± 5.3 (range = 3-24) doses. The majority (70.6%) received acetazolamide every 8 hours. Treatment success was achieved in 10 (29.4%) patients. Statistically significant differences were noted between the pre-acetazolamide and post-acetazolamide pH and HCO3, 7.51 ± 0.05 versus 7.37 ± 0.05 (P < .001) and 39.4 ± 6.1 mEq/L versus 31.4 ± 7.5 mEq/L (P < .001), respectively. Conclusions: This is the first study to evaluate acetazolamide dosing for metabolic alkalosis in children with and without cardiac disease. Acetazolamide treatment resulted in improved HCO3, but the majority of patients did not achieve our definition of treatment success. Future studies should elucidate the optimal acetazolamide regimen.