Mario A. Inchiosa

Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients derivation of dosing weight: (pharmacokinetic mass)

Background: The currently available pharmacokinetic models for fentanyl were derived from normal weight patients and were not scaled to body weight. Their application to obese patients may cause overprediction of the plasma concentration of fentanyl. This study examined the influence of body weight on the predictive accuracy of two models (Anesthesiology 1990; 73:1091–102 and J Pharmacol Exp Ther 1987; 240:159–66). Further, we attempted to derive suggested dosing mass weights for fentanyl that improved predicted accuracy. Method: Seventy patients undergoing major elective surgery with total body weight (TBW) <85 kg and body mass index <30 (Group L) and 39 patients with TBW ≥85 kg and body mass index >30 (Group O) were studied. In Group L and Group O, the mean TBW was 69 kg, and 125 kg, respectively and the mean body mass index in Group L and Group O was 24 and 44, respectively. Fentanyl infusion was used during surgery and postoperatively for analgesia. Plasma fentanyl concentrations were measured and predicted concentrations were obtained by computer simulation; 465 pairs of measured and predicted values were obtained. Results: The influence of TBW on the performance errors of the original two models was examined with nonlinear regression analysis. Shafer error versus TBW showed a highly significant negative relationship (R squared = 0.689, P < 0.001); i.e., the Shafer model systematically overestimated fentanyl concentration as weight increased. The Scott and Stanski model showed greater variation (R squared = 0.303). We used the exponential equation for Shafer performance error versus TBW to derive suggested dosing weights (“pharmacokinetic mass”) for obese patients. The pharmacokinetic mass versus TBW curve was essentially linear below 100 kg (with slope of 0.65) and approached a plateau above 140 kg. For patients weighing 140 to 200 kg, dosing weights of 100–108 kg are projected. Total body clearance (ml/min) showed a strong linear correlation with pharmacokinetic mass (r = 0.793; P < 0.001), whereas the relationship with TBW was nonlinear. Conclusion: Actual body weight overestimates fentanyl dose requirements in obese patients. Dosing weight (pharmacokinetic mass) derived from the nonlinear relationship between prediction error and TBW proved to have a linear relationship with clearance.

Single‐Dose Pharmacokinetics of Oral Ciprofloxacin in Patients With Cystic Fibrosis

The singie‐dose pharmacokinetics of oral ciprofloxacin were studied in ten patients with cystic fibrosis aged 18 to 34 years. Each patient received three different drug doses (500 mg, 750 mg, and 1,000 mg) at successive one‐week intervals. Dosing and drug assays were double blinded. Blood and urine were assayed over the 48 hours following each dose. Ciprofloxacin was absorbed from the gastrointestinal tract. Peak serum concentrations averaged 2.8, 4.5, and 4.6 μg/mL respectively at the three doses, well above the mean inhibitory concentrations of most isolates of Pseudomonas aeruginosa. Time to peak concentration was approximately two hours. The range of sputum levels in three patients was 1.1–2.1 μg/mL at four hours after the three doses. The serum elimination half‐life was 3.7 hours and was independent of dose. Urinary recovery was 26%; greater than 90% of urinary excretion occurred within the first 12 hours. The results of this study indicate that ciprofloxacin has potential for use in the treatment of P aeruginosa infections in patients with cystic fibrosis.

Minimizing Tolerance and Withdrawal to Prolonged Pediatric Sedation: Case Report and Review of the Literature:

Midazolam and fentanyl infusions are commonly used for prolonged sedation and analgesia in the pediatric intensive care setting. Tolerance and withdrawal are major concerns when these infusions are used for days or weeks. Here, we review the current approaches to prolonged pediatric sedation using midazolam and fentanyl and discuss newer strategies to avoid tolerance and withdrawal syndromes. We report the case of a pediatric burn patient who developed tolerance syndrome and a movement disorder in our institution. We also review the relevant literature and methods of minimizing tolerance and withdrawal. Prolonged sedation is often necessary in treating critically ill children, and tolerance and abstinence syndrome can complicate a successful recovery. Scoring systems can be used to minimize oversedation and to titrate effectively. “Drug cycling,” “wake-up protocols,” and weaning regimens, possibly combined with adjuvant drugs, are being implemented successfully. Such novel approaches may decrease the incidence of tolerance and withdrawal associated with prolonged sedative and analgesic use.

Efficacy of Short-Course Ceftriaxone Therapy for Borrelia burgdorferi Infection in C3H Mice

ABSTRACT Ceftriaxone is highly effective clinically in patients with Lyme disease. We studied a representative invasive human isolate of Borrelia burgdorferi for which the MBC of ceftriaxone was 0.050 μg/ml. A once-per-day dosage regimen of ceftriaxone (50 mg/kg/dose) administered intramuscularly for 5 days was 100% effective in sterilizing tissue samples of C3H mice infected with this strain of B. burgdorferi, regardless of whether the mice were being treated concomitantly with a corticosteroid. Administration of the same five doses of ceftriaxone at 6-h intervals over just 24 h was also 100% effective. These experiments suggest that shorter courses of antibiotics than those currently recommended should be considered for study in patients with early uncomplicated Lyme disease.

Treatment of Complex Regional Pain Syndrome Type I With Oral Phenoxybenzamine: Rationale and Case Reports

▪ Abstract:  The nonselective α‐adrenergic antagonist, phenoxybenzamine, has been used in the treatment of neuropathic pain syndromes, specifically, complex regional pain syndrome (CRPS) types I and II. This agent has also previously been used in intravenous regional peripheral blocks for treatment of CRPS I; however, an intravenous preparation of phenoxybenzamine is not currently available in the U.S.A. In this case series, systemic administration was more appropriate for three of the four patients, as their syndromes had spread beyond the initial area of surgery or trauma. We report an apparent clinical benefit in three of the four patients following oral administration. We postulate that this may be due to the noncompetitive (irreversible) blockade of α1‐ and α2‐adrenergic receptors. We further hypothesize that this blockade could reduce stimulation of an increased population of adrenergic receptors in hyperalgesic skin, blunt the stimulation by norepinephrine of α2‐adrenergic receptors on macrophages, and ultimately reduce the release of proinflammatory cytokines from cellular elements. ▪

Enhancement of bupivacaine sensory blockade of rat sciatic nerve by combination with phenol.

We sought to determine whether the addition of phenol would enhance a bupivacaine nerve block. The effects on nerve conduction of bupivacaine (0.125%) and phenol (0.5%), singly and combined, were evaluated in vivo on the rat sciatic nerve. Three groups of 10 animals each were used. The left sciatic nerve was infiltrated with 0.125% bupivacaine, 0.5% phenol, or a solution that contained 0.125% bupivacaine and 0.5% phenol. The right limb served as control (saline injected). Motor deficits (visual assessment) and sensory blockade (hot-plate assay) were evaluated at 30-min intervals after injection. Phenol injected alone produced no motor blockade. The incidence of motor blockade at 30 min for 0.125% bupivacaine was 70% (P = 0.003), and for the combination treatment, 80% (P = 0.001). The analgesia score derived from the hot-plate test was more and persisted longer for the combination treatment than for either 0.125% bupivacaine or 0.5% phenol given singly; e.g., the average sensory block score after 150 min for the combination treatment was 1.0 compared with 0.1 for either bupivacaine or phenol given alone (P = 0.003). Analysis of the areas under the sensory score-time curves also demonstrated enhanced blockade from the combination treatment, which would be consistent with a synergism of the separate Na(+)-channel blocking effects of charged and uncharged local anesthetics. These findings may suggest other candidates for clinically useful combinations of amine and neutral local anesthetics.

Prothrombin Time and Activated Partial Thromboplastin Time Testing: A Comparative Effectiveness Study in a Million-Patient Sample

Background A substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful. Methods and Findings We evaluated prospectively-collected patient data from 19 major teaching hospitals and 8 hospital-affiliated surgical centers in 7 states (Delaware, Florida, Maryland, Massachusetts, New Jersey, New York, Pennsylvania) and the District of Columbia. A total of 1,053,472 consecutive patients represented every patient admitted for elective surgery from 2009 to 2012 at all 27 settings. A subset of 682,049 patients (64.7%) had one or both tests done and history and physical (H&P) records available for analysis. Unnecessary tests for bleeding risk were defined as: PT tests done on patients with no history of abnormal bleeding, warfarin therapy, vitamin K-dependent clotting factor deficiency, or liver disease; or aPTT tests done on patients with no history of heparin treatment, hemophilia, lupus anticoagulant antibodies, or von Willebrand disease. We assessed the proportion of patients who received PT or aPTT tests who lacked evidence-based reasons for testing. Conclusions This study sought to bring the availability of big data together with applied comparative effectiveness research. Among preoperative patients, 26.2% received PT tests, and 94.3% of tests were unnecessary, given the absence of findings on H&P. Similarly, 23.3% of preoperative patients received aPTT tests, of which 99.9% were unnecessary. Among patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were either a false positive or a true positive (i.e. indicative of a previously-undiagnosed potential bleeding risk). Both PT and aPTT, designed as diagnostic tests, are apparently used as screening tests. Use of unnecessary screening tests raises concerns for the costs of such testing and the consequences of false positive results.

Phenoxybenzamine in complex regional pain syndrome: potential role and novel mechanisms.

There is a relatively long history of the use of the α-adrenergic antagonist, phenoxybenzamine, for the treatment of complex regional pain syndrome (CRPS). One form of this syndrome, CRPS I, was originally termed reflex sympathetic dystrophy (RSD) because of an apparent dysregulation of the sympathetic nervous system in the region of an extremity that had been subjected to an injury or surgical procedure. The syndrome develops in the absence of any apparent continuation of the inciting trauma. Hallmarks of the condition are allodynia (pain perceived from a nonpainful stimulus) and hyperalgesia (exaggerated pain response to a painful stimulus). In addition to severe, unremitting burning pain, the affected limb is typically warm and edematous in the early weeks after trauma but then progresses to a primarily cold, dry limb in later weeks and months. The later stages are frequently characterized by changes to skin texture and nail deformities, hypertrichosis, muscle atrophy, and bone demineralization. Earlier treatments of CRPS syndromes were primarily focused on blocking sympathetic outflow to an affected extremity. The use of an α-adrenergic antagonist such as phenoxybenzamine followed from this perspective. However, the current consensus on the etiology of CRPS favors an interpretation of the symptomatology as an evidence of decreased sympathetic activity to the injured limb and a resulting upregulation of adrenergic sensitivity. The clinical use of phenoxybenzamine for the treatment of CRPS is reviewed, and mechanisms of action that include potential immunomodulatory/anti-inflammatory effects are presented. Also, a recent study identified phenoxybenzamine as a potential intervention for pain mediation from its effects on gene expression in human cell lines; on this basis, it was tested and found to be capable of reducing pain behavior in a classical animal model of chronic pain.

Neural Network Prediction of ICU Length of Stay Following Cardiac Surgery Based on Pre-Incision Variables

Background Advanced predictive analytical techniques are being increasingly applied to clinical risk assessment. This study compared a neural network model to several other models in predicting the length of stay (LOS) in the cardiac surgical intensive care unit (ICU) based on pre-incision patient characteristics. Methods Thirty six variables collected from 185 cardiac surgical patients were analyzed for contribution to ICU LOS. The Automatic Linear Modeling (ALM) module of IBM-SPSS software identified 8 factors with statistically significant associations with ICU LOS; these factors were also analyzed with the Artificial Neural Network (ANN) module of the same software. The weighted contributions of each factor (“trained” data) were then applied to data for a “new” patient to predict ICU LOS for that individual. Results Factors identified in the ALM model were: use of an intra-aortic balloon pump; O2 delivery index; age; use of positive cardiac inotropic agents; hematocrit; serum creatinine ≥ 1.3 mg/deciliter; gender; arterial pCO2. The r2 value for ALM prediction of ICU LOS in the initial (training) model was 0.356, p <0.0001. Cross validation in prediction of a “new” patient yielded r2 = 0.200, p <0.0001. The same 8 factors analyzed with ANN yielded a training prediction r2 of 0.535 (p <0.0001) and a cross validation prediction r2 of 0.410, p <0.0001. Two additional predictive algorithms were studied, but they had lower prediction accuracies. Our validated neural network model identified the upper quartile of ICU LOS with an odds ratio of 9.8(p <0.0001). Conclusions ANN demonstrated a 2-fold greater accuracy than ALM in prediction of observed ICU LOS. This greater accuracy would be presumed to result from the capacity of ANN to capture nonlinear effects and higher order interactions. Predictive modeling may be of value in early anticipation of risks of post-operative morbidity and utilization of ICU facilities.

Concerning ephedra alkaloids for weight loss

The paper, ‘Multinutrient supplement containing ephedra and caffeine causes weight loss and improves metabolic risk factors in obese women: a randomized controlled trial’, by Hackman et al., is difficult to interpret for a number of reasons. The title of the paper, introductory statements and conclusions all suggest that the study is controlled for the inclusion of ephedra and caffeine. However, examination of the many differences between the control and treatment supplements (Table 2) shows that this is not the case. In particular, only the treatment supplement provided 2000 mg per day of Garcinia cambogia extract. The authors note that G. cambogia extract contains ( )-hydroxycitric acid (HCA), and cite reference to a human study in which HCA caused a 15–30% decrease in energy intake. A study by Mattes and Bormann, using a product that provided 1200 mg/day of HCA in a randomized, double-blind design (approximating the dose in the Hackman study), demonstrated increased weight loss in overweight female human subjects. Weight loss over the 12-week study was 3.773.1 kg in the treatment group and 2.472.9 kg for placebo subjects; the difference of 1.3 kg was statistically significant (P1⁄40.026). The difference in weight loss between treated and control patients in the Hackman study for the first 12 weeks averaged 2.1 kg; thus, HCA could have accounted for approximately 60% of that weight loss. Another potential weakness in the paper is that the treatment group had a significantly greater average baseline body weight than the placebo group (by 4.3 kg; Po0.05), and a greater average baseline caloric intake (1930 kcal for treated and 1580 kcal for controls; P1⁄40.005). The importance of baseline weight and intake in relation to body weight loss is obvious. A final concern relates to the assessment of untoward events by the authors. Palpitations are described as a ‘minor symptom’. Palpitations may represent a prelude to a serious ischemic event. The American College of Physicians and family practice perspectives provide similar diagnostic algorithms for ‘palpitations’, which require a patient history, physical examination and a 12-lead electrocardiogram. It is noteworthy that the Hackman study demonstrated a highly significant increased incidence of palpitations in the treated group (Table 6). Thirteen subjects (of 29 that started and 19 that finished) reported palpitations, whereas, only one control subject reported palpitations. The authors noted that a US District Court in 2005 ruled that a supplement providing 10 mg/day of ephedra alkaloids was not restricted by the general FDA ban on ephedra supplements. However, on 17 August 2006, the Tenth Circuit of the United States Court of Appeals reinstated the full FDA ban on all ephedra-containing supplements, regardless of dose, and affirmed the FDA’s judgment of an unreasonable risk associated with such supplements. In view of the small weight loss in this study that may be attributable to ephedra alkaloids and caffeine, and the potential for attending cardiovascular risks, it would appear difficult to conclude that this prescription represents a useful option for the treatment of obesity. Mario A Inchiosa Jr Department of Pharmacology, New York Medical College, Valhalla, NY, USA E-mail: mario_inchiosa@nymc.com