R. J. E. Grouls

Long-lasting Epidural Sensory Blockade by n-Butyl-p-Aminobenzoate in the Terminally Ill Intractable Cancer Pain Patient

An aqueous suspension of n-butyl-p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally in terminally ill cancer patients with intractable pain. The suspension consisted of 10% BAB and 0.025% of the nonionic surfactant polysorbate 80 in 0.9% sodium chloride. Twelve consecutive patients received epidural BAB because pain was uncontrollable either by palliative radiotherapy or oral or epidural administrations of analgesics. The catheter or injecting needle was positioned at the segmental level of the pain. Repeated epidural injections were administered. In all patients, long-lasting sensory blockade (segmental analgesia) occurred, accompanied by a marked reduction or even absence of pain. In all patients, treatment with epidural opioids, alone or combined with local anesthetics, was no longer necessary. Five of the 12 patients did not require further administration of oral opioids. Motor, bowel, and bladder function were well preserved. In 6 patients, extensive necropsy of the spinal cord and spinal nerves did not reveal pathomorphologic changes. The outer aspect of the dura showed signs of focal necrosis on microscopy, yet its collagen structure and thickness were unchanged. Epidurally, focal infiltrative reactions were seen. The epidural use of an extremely lipid-soluble--hence hydrophobic--local anesthetic, with an exceptionally low pKa (2.3), formulated in suspension of the base, is conceptually innovative and needs further investigation. The authors conclude that the epidural administration of a BAB suspension may be an effective alternative to the neurolytic agents alcohol and phenol and may replace procedures such as cordotomy. Further investigation to determine the safety of BAB in this patient group appears warranted.

Using a clinical decision support system to determine the quality of antimicrobial dosing in intensive care patients with renal insufficiency

Background The benefits on clinical practice of a clinical decision support system (CDSS) are predominantly determined by the quality of the clinical rules used in this system. Therefore, it is essential to investigate the performance and potential benefits on quality of care of these rules. Methods A clinical rule assisting physicians in selecting the appropriate dosage according to renal function of frequently prescribed antimicrobials was developed. In 2004, 1788 patients admitted to the intensive care unit (ICU) for more than 12 h were included in this retrospective study. The actual number of dosage adjustments without the support of the CDSS was compared with the theoretical number of dosage adjustments determined by the clinical rule in patients with moderate (creatinine clearance (Clcreat) 10–50 ml/min) and severe (Clcreat <10 ml/min) renal dysfunction. If dosage adjustment was omitted, the duration of excessive anti-infective dosing and extra drug costs involved was determined. Results Dosage adjustment of antimicrobials was omitted in 163 patients (86%) with moderate renal failure and 13 patients (54%) with severe renal failure. Excessive exposure was most frequently detected in patients receiving fluconazole and ciprofloxacin (median duration of 6 days). In our ICU alone, more than €16 000 (

Information processing during cardiac surgery: an event related potential study

19 000) can be saved annually by adjusting the dosage according to renal function of frequently prescribed antimicrobials. Conclusions Despite intensive monitoring of patients in the ICU, dosage adjustment of antimicrobials is often omitted. Implementing this clinical rule has the potential to contribute to a significant improvement in medication safety and is expected to generate substantial savings.

Epidural and intrathecal n-butyl-p-aminobenzoate solution in the rat : Comparison with bupivacaine

The aim of this study was to investigate whether information processing persists during general anesthesia, and if so, to determine the relationship between the degree of cognitive processing measured during anesthesia and the presence or absence of intraoperative memories measured after anesthesia. Subjects were 12 patients, undergoing cardiac surgery with propofol/alfentanil anesthesia. During several periods of the operation, event related potentials (ERPs) to frequent and infrequent tones of different pitch were analyzed. After the operation, a word recognition task with ERP recording was administered to determine whether intraoperatively presented words would elicit a (covert) recognition reaction in the brain. ERP wave forms could be obtained during the intraoperative recording periods but differed substantially from those in the awake state. The presence of ERP components up to 500 msec after stimulus presentation suggests that auditory information processing continued during anesthesia up to a certain level of cognition. Intraoperative ERPs to frequent and infrequent tones were not different from each other implying that differences in pitch could not be detected. The postoperative results demonstrated evidence for intraoperative memories in 3 patients. For 2 of these 3 patients, low propofol levels as well as reliable ERPs with large amplitudes were found close to the moment of information presentation. The results emphasize the importance of combining intra- and postoperative measurements and suggest that late ERP components might be used as indicators of an increased risk of auditory perception.

Long-lasting Epidural Sensory Blockade by n-Butyl p-Aminobenzoate in the Dog: Neurotoxic or Local Anesthetic Effect?

Background Epidural administration of an aqueous suspension of n‐butyl‐p‐aminobenzoate (BAB) to humans results in long‐lasting sensory blockade without motor block. The dose‐response of BAB administered epidurally and intrathecally as a solution was studied in rats to define the local anesthetic properties in an established animal model. Methods The time course of changes in tail withdrawal latency and motor function were determined in rats after epidural or intrathecal administration of solutions of BAB or bupivacaine. The dose‐response relation was determined and median effective dose values were calculated. Results After epidural and intrathecal administration of BAB solutions, the onset and duration of the antinociceptive action were comparable to bupivacaine. Median effective dose values for tail‐withdrawal latency of 6 s or more were significantly greater for BAB. After both routes of administration, BAB clearly affected motor function. Conclusions When administered epidurally and intrathecally as a solution, BAB is a local anesthetic of relative low potency with onset and duration of action comparable to those of bupivacaine. These findings suggest that the long‐lasting action obtained after applying BAB suspension results from the slow dissolution (continuous release) of the solid BAB deposited in the epidural space.

Physicians' responses to clinical decision support on an intensive care unit-Comparison of four different alerting methods

An aqueous suspension of n-butyl p-aminobenzoate (BAB), a highly lipid-soluble congener of benzocaine, was applied epidurally and around ulnar nerves in dogs. The suspension consisted of 10% BAB and 0.025% polysorbate in 0.9% NaCl. Sensory effects were tested by electrical stimulation. Three epidural injections were given, and the dogs were killed after 21 days. The increase in stimulation threshold was comparable to the effect of lidocaine in a concentration between 0.5% and 1%. Increased sensory threshold lasted for days, whereas no long-lasting motor effects were observed. Pathomorphologic changes were found primarily in the dorsal spinal nerve roots, although slight changes were also found in the ventral spinal roots. White matter degeneration was found only in the lumbar dorsal columns. This result suggested Wallerian degeneration in the dorsal spinal nerves and was at variance with recently published data on epidural BAB. No changes were observed in the ulnar nerves. The authors demonstrated that the pathomorphologic changes were induced by the BAB suspension and not by the suspending additive polysorbate 80. It was postulated that the suspension of BAB, which contains particles of a median size of 15 microns, was mainly confined to the dorsal epidural space where neurolytic changes in axons of the dorsal spinal nerve roots and dorsal columns are induced. This may explain the long-lasting sensory effects seen in intractable cancer pain patients after epidural BAB administration. More research is necessary to define the distribution of BAB in nervous tissue after its epidural administration and to better characterize toxicity, neurolytic effects, and regeneration of nervous tissue after BAB administrations.

The local anesthetic, n-butyl-p-aminobenzoate, reduces rat sensory neuron excitability by differential actions on fast and slow Na+ current components

BACKGROUND In intensive care environments, technology is omnipresent whereby ensuring constant monitoring and the administration of critical drugs to unstable patients. A clinical decision support system (CDSS), with its widespread possibilities, can be a valuable tool in supporting adequate patient care. However, it is still unclear how decision support alerts should be presented to physicians and other medical staff to ensure that they are used most effectively. OBJECTIVE To determine the effect of four different alert presentation methods on alert compliance after the implementation of an advanced CDSS on the intensive care unit (ICU) in our hospital. METHODS A randomized clinical trial was executed from August 2010 till December 2011, which included all patients admitted to the ICU of our hospital. The CDSS applied contained a set of thirteen locally developed clinical rules. The percentage of alert compliance was compared for four alert presentation methods: pharmacy intervention, physician alert list, electronic health record (EHR) section and pop-up alerts. Additionally, surveys were held to determine the method most preferred by users of the CDSS. RESULTS In the study period, the CDSS generated 902 unique alerts, primarily due to drug dosing during decreased renal function and potassium disturbances. Alert compliance was highest for recommendations offered in pop-up alerts (41%, n=68/166), followed by pharmacy intervention (33%, n=80/244), the physician alert list (20%, n=40/199) and the EHR section (19%, n=55/293). The method most preferred by clinicians was pharmacy intervention, and pop-up alerts were found suitable as well if applied correctly. The physician alert list and EHR section were not considered suitable for CDSSs in the process of this study. CONCLUSION The alert presentation method used for CDSSs is crucial for the compliance with alerts for the clinical rules and, consequently, for the efficacy of these systems. Active alerts such as pop-ups and pharmacy intervention were more effective than passive alerts, which do not automatically appear within the clinical workflow. In this pilot study, ICU clinicians also preferred pharmacy intervention and pop-up alerts. More research is required to expand these results to other departments and other hospitals, as well as to other types of CDSSs and different alert presentation methods.

The Local Anesthetic n-butyl-p-aminobenzoate Selectively Affects Inactivation of Fast Sodium Currents in Cultured Rat Sensory Neurons

Effects of the local anesthetic, n-butyl-p-aminobenzoate, at a concentration of 100 microM, were investigated using the whole-cell voltage clamp on dorsal root ganglion neurons cultured from neonatal rat in a serum-enriched medium. During current clamp conditions, the drug either increased the firing threshold or blocked tetrodotoxin-sensitive and tetrodotoxin-resistant Na+ action potentials. These actions were reversible. Under voltage clamp conditions, inactivation of the Na+ current revealed the existence of 3 fast Na+ current components, termed F1, F2 and F3 (tetrodotoxin-sensitive) and 2 slow ones, termed S1 and S2 (tetrodotoxin-resistant). The local anesthetic shifted the midpoint potentials of Na+ inactivation curves for F1, F2 and F3 currents by 7, 21 and 6 mV, respectively, towards hyperpolarizing membrane voltages whereas it did not influence these potentials for the slow currents. The amplitudes of only F3 and S2 currents were reduced by n-butyl-p-aminobenzoate to 24 and 11%, respectively, of their control values. These results show that the local anesthetic has a differential mode of action on the 5 types of Na+ currents, which are apparently present in cultured sensory neurons. This differential action can play an important role in the selective analgesic effect observed after epidural administration of a 10% n-butyl-p-amino-benzoate suspension.

Reasons for Discontinuation of Medication During Hospitalization and Documentation Thereof: A Descriptive Study of 400 Geriatric and Internal Medicine Patients

Background Aqueous suspensions of the local anesthetic n-butyl-p-aminobenzoate (BAB), epidurally applied in terminal cancer patients, resulted in a sensory blockade, lasting up to several months. To investigate the mechanism of action on the cellular level, the effect of 100 micro Meter BAB on Sodium sup + action potentials and on Sodium sup + currents in dorsal root ganglion neurons from neonatal rats was studied. Methods Small neurons grown in cell culture were selected for patch-clamp measurements. Both Sodium sup + action potentials, evoked by current pulses of increasing amplitude (current clamp) and Sodium sup + currents, activated at different membrane potentials (voltage clamp), were investigated in the absence and presence of 100 micro Meter BAB. The local anesthetic was applied by external perfusion for 2 or 10 min. Results In the presence of 100 micro Meter BAB, either the firing threshold was raised or the action potential was abolished. The maximal peak conductances, underlying the fast sodium current INa,F and the slow sodium current INa,S, were not changed. However, the inactivation of INa,F Was increased by BAB. The sigmoid inactivation curve shifted 12 mV toward hyperpolarizing membrane voltages, whereas no changes were found for the inactivation of the slow Sodium sup + current. Only at short exposure times of 2 min, the effects of BAB could be reversed during a 10-min wash-out. Conclusions BAB dramatically increased the firing threshold, and in part of the sensory neurons, it blocked the action potential. The inactivation of the fast Sodium sup + channels, but not of the slow Sodium sup + channels, was increased by BAB. Thus, the block of fast Sodium sup + channels by BAB may contribute to epidural analgesia. At exposure times of 10 min, the effect of BAB was not reversible. This probably originates from its high lipid-solubility, which may be an important factor in determining the duration of the block in vivo.

Systems that prevent unwanted represcription of drugs withdrawn because of adverse drug events: a systematic review

attending physician’s name on a dry erase board, only 5 (10%; 95% CI, 3%-22%) were able to correctly identify the name of their attending physician. There was very strong evidence that this proportion was higher for patients with visual representation of their attending physician’s name (P .001), of whom 94 of 96 patients (98%; 95% CI, 93%-100%) were able to correctly identify their attending physician’s name. This indicates that compared with patients with no visual representation, the proportion of patients who were correctly able to identify the name of their attending physician was 88% higher (95% CI, 76%-94%) for patients with visual representation of their attending physician’s name in their room. Of note, of the 4 excluded patients for whom the attending physician’s name was not written on the dry erase board, none were able to correctly identify the name of that physician.