Background. We previously proposed dosing weights for fentanyl, termed ‘pharmacokinetic mass’, that span the total body weight (TBW) range from 40 to 210 kg. In this study, we examined the relationships among fentanyl doses needed to achieve postoperative analgesia, corresponding plasma fentanyl concentrations, and pharmacokinetic mass in lean and obese patients undergoing abdominal surgery. Methods. A total of 69 patients were studied, with TBW ranging from 48 to181 kg. Fentanyl infusion was used during surgery. After surgery, fentanyl infusion rates were titrated to achieve analgesia without significant respiratory depression. Plasma fentanyl concentrations were measured when an apparent steady analgesic state was obtained. Comparisons were made for dosing requirements and effective plasma concentrations for 37 lean patients (body mass index <30, TBW 30, TBW ≥85 kg). Results. The average fentanyl dose (µg h⁻¹) required to achieve and maintain analgesia over the 4 h postoperative period had a non-linear relationship to TBW; in comparison, fentanyl dose had a strong linear relationship to pharmacokinetic mass: dose (µg h⁻¹)=1.22×pharmacokinetic mass−7.5; r = 0.741, P<0.001. Based on results from our earlier study, the corresponding values of TBW and pharmacokinetic mass are: 52 kg – 52 kg; 70 kg – 65 kg; 100 kg – 83 kg; 120 kg – 93 kg; 140 kg – 99 kg; 160 kg – 104 kg; 180 kg – 107 kg; 200 kg – 109 kg. In the group comparisons, there was no statistically significant difference in the postoperative fentanyl dose per unit of pharmacokinetic mass between lean and obese patients. The plasma concentration of fentanyl required for analgesia was approximately 1.5 ng ml⁻¹, and was similar in the two groups. Conclusion. The relationship between dose and pharmacokinetic mass, compared with that of dose vs TBW, may provide confidence for the use of pharmacokinetic mass as a dosing approximation for fentanyl. Fentanyl dose based on TBW may cause overdosing in obese patients.

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. 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. 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). 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.

Sympathomimetic agents have a poor history of long-term success in the treatment of obesity. From earlier experiences with amphetamine and its analogs, to more recent drugs with direct effects on adrenergic receptors or indirect effects from release of catecholamines or inhibition of reuptake, cardiovascular toxicity (strokes and cardiac arrhythmias) has been the major concern. These concerns also extended to food supplements containing ephedra alkaloids and may require consideration for current supplements containing the sympathomimetic drug, synephrine.

The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several “off label” indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.

Objective. To determine whether there is a difference in intraoperative bleeding with inhalational versus noninhalational anesthetic agents for patients undergoing suction dilatation and curettage for first-trimester induced abortion.Methods. This is an IRB-approved retrospective chart review of the electronic medical records of patients undergoing induced abortion at gestational ages between 5 0/7 and 14 0/7 weeks of pregnancy at the New York City Health + Hospitals/Metropolitan. The records of 138 patients who underwent suction dilatation and curettage for induced abortion between June 2012 and June 2014 were reviewed for an association between anesthetic technique and intraoperative hemorrhage. Twenty patients received inhalational anesthetic agents, while 118 received intravenous anesthetics. Blood loss was estimated by the operating gynecologists.Results. The mean intraoperative blood loss for inhalational anesthetics (113.6 ml) was significantly higher than with noninhalational agents (40.2 ml) (p=0.007). Age, body mass index, and gestational age were not statistically different between the groups; the number of methylergonovine doses at induced abortion trended higher with inhalation anesthetics.Conclusions. The difference in blood loss between the two types of anesthetic techniques was statistically significant. These findings may be important for patients with significant anemia or at an increased risk of bleeding, such as those with unrecognized coagulopathies.