Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study.

PURPOSES: Habitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response. METHODS: In a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations. RESULTS: A total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from - 2.2 ± 0.1 to - 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004). CONCLUSION: The hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

Higher Tissue Concentrations of Vancomycin Achieved With Low-Dose Intraosseous Injection Versus Intravenous Despite Limited Tourniquet Duration in Primary Total Knee Arthroplasty: A Randomized Trial.

BACKGROUND: Vancomycin use has been suggested in high risk patients undergoing total knee arthroplasty (TKA). Previous literature has shown that a lower dose (500 mg) of vancomycin given by intraosseous regional administration (IORA) achieves tissue concentrations 4-10 times higher than intravenous (IV) administration. There is increasing interest in performing TKA with limited tourniquet inflation time. The purpose of this study is to evaluate whether IORA of vancomycin can achieve effective tissue concentrations with limited tourniquet inflation time. METHODS: Based on prior power calculations, 24 patients undergoing primary TKA were randomized into 2 groups. Group IV-Systemic received weight-based (15 mg/kg) vancomycin with the tourniquet inflated for cementation only. Group IORA received 500 mg vancomycin via IORA after tourniquet inflation which remained inflated for 10 minutes, then reinflated for cementation only. Vancomycin concentrations from tissue, serum, and drain fluid were compared between the 2 groups. RESULTS: Median vancomycin concentrations in tissue were significantly higher (5-15 times) at all time points in the IORA group. Concentrations in fat at the time of wound closure, after the tourniquet had been deflated for most of the procedure, were 5.2 µg/g in Group IV-Systemic and 33.1 µg/g in Group IORA (P < .001). Median bone concentrations taken just prior to cementation were 7.9 µg/g in Group IV-Systemic and 21.8 µg/g in Group IORA (P = .006). There were no complications related to IORA. CONCLUSION: For surgeons who wish to limit tourniquet time and when indicated to use vancomycin, low-dose vancomycin IORA achieves tissue concentrations 5-15 times higher than those achieved by IV administration. LEVEL OF EVIDENCE: Level 1 therapeutic randomized trial.

Simultaneous Determination of Dabigatran, Rivaroxaban, and Apixaban in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of anticoagulants require a simple, rapid, and reliable analytical method for monitoring plasma concentrations. The aims of the current work were to develop and validate a liquid chromatography/tandem mass spectrometry method for the simultaneous determination of 3 direct oral anticoagulants (dabigatran, rivaroxaban, and apixaban) in human plasma that is suitable for pharmacokinetic studies and routine therapeutic drug monitoring in busy hospital laboratories. METHODS: This method included a hydrolysis step to account for the active acylglucuronide metabolites of dabigatran that demonstrate an equivalent anticoagulant effect as dabigatran. After hydrolysis, a simple one-step protein precipitation was used for sample preparation. Total dabigatran (the sum of free dabigatran and the contribution from dabigatran acylglucuronides), rivaroxaban, and apixaban, and their corresponding isotopically labeled internal standards were resolved on a C18(2) column. All compounds were detected using electrospray ionization liquid chromatography/tandem mass spectrometry in the positive mode. RESULTS: For all 3 anticoagulants, standard curves were linear over the concentration range of 1.0-1000 mcg/L (r > 0.99), bias was < ±10%, and intraday and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 1.0 mcg/L. For all 3 anticoagulants and corresponding isotopically labeled internal standards, the absolute recoveries were similar and consistent, with mean values of 93%-102%. No significant matrix effects were observed. CONCLUSIONS: This method is simple, rapid, robust, and reliable and can be used to analyze the plasma concentrations of the drugs in patients on dabigatran or rivaroxaban therapy.

Simultaneous Determination of Cefalexin, Cefazolin, Flucloxacillin, and Probenecid by Liquid Chromatography-Tandem Mass Spectrometry for Total and Unbound Concentrations in Human Plasma.

BACKGROUND: Pharmacokinetic studies and therapeutic drug monitoring of antibiotics require a simple, rapid, and reliable analytical method for monitoring the concentrations in plasma, including unbound concentrations for highly protein-bound drugs. The aim of the current work was to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound concentrations of 3 widely used ß-lactam antibiotics (cefalexin, cefazolin, and flucloxacillin) and the often coadministered drug probenecid in human plasma, suitable for pharmacokinetic studies and for routine use in ordinary, busy hospital laboratories. METHODS: Unbound drug was separated from bound drug by ultrafiltration. A simple 1-step protein precipitation was used for sample preparation. Cefalexin, cefazolin, flucloxacillin, probenecid, and their corresponding isotopically labeled internal standards were then resolved on a C18 (2) column. All the compounds were detected using electrospray ionization in the positive mode. RESULTS: Standard curves were linear for all compounds over the concentration range of 0.2-100 mg/L (r > 0.99) for total drug in plasma and 0.01-10 mg/L (r > 0.99) for unbound drug in plasma ultrafiltrate. For both total and unbound drugs, bias was <±10%, and intra- and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 0.2 mg/L for total plasma concentrations and 0.01 mg/L for plasma ultrafiltrate concentrations of all drugs. CONCLUSIONS: The method has proven to be simple, rapid, robust, and reliable and is currently being used in clinical pharmacokinetic studies and in the routine clinical service to enhance the effective use of the ß-lactam antibiotics.

The AAHKS Clinical Research Award: Intraosseous Regional Prophylaxis Provides Higher Tissue Concentrations in High BMI Patients in Total Knee Arthroplasty: A Randomized Trial.

BACKGROUND: Obesity is an established risk factor for periprosthetic joint infections after total knee arthroplasty (TKA). In obese patients, a larger dose of prophylactic vancomycin based on actual body weight is required to reach therapeutic concentrations. It is unclear how tissue concentrations are affected when intraosseous regional administration (IORA) is used in this population. This study compared tissue concentrations of low-dose vancomycin via IORA vs actual body weight-adjusted systemic intravenous (IV) dose in primary TKA. METHODS: Twenty-two patients with a body mass index (BMI) >35 undergoing TKA were randomized into 2 groups. The IV group received 15 mg/kg (maximum of 2 g) of systemic IV vancomycin and the IORA group received 500 mg vancomycin into the tibia. Subcutaneous fat and bone samples were taken at regular intervals. Tissue antibiotic concentrations were measured using liquid chromatography coupled with tandem mass spectrometry. A blood sample was taken 1 to 2 hours after tourniquet deflation to measure systemic concentration. RESULTS: The mean BMI was 41.1 in the IORA group and 40.1 in the IV systemic group. The overall mean tissue concentration in subcutaneous fat was 39.3 µg/g in the IORA group and 4.4 µg/g in the IV systemic group (P < .01). Mean tissue concentrations in bones were 34.4 µg/g in the IORA group and 6.1 µg/g in the IV systemic group (P < .01). CONCLUSION: Low-dose IORA was effective in the high-BMI population group, providing tissue concentrations of vancomycin 5-9 times higher than systemic administration. IORA optimizes timing of vancomycin administration and provides high tissue antibiotic concentrations during TKA in this high-risk patient group.

The John N. Insall Award: Higher Tissue Concentrations of Vancomycin Achieved With Intraosseous Regional Prophylaxis in Revision TKA: A Randomized Controlled Trial.

BACKGROUND: In primary TKA, prophylaxis with low-dose vancomycin through intraosseous regional administration (IORA) achieves tissue concentrations six to 10 times higher than systemic administration and was shown to provide more effective prophylaxis in an animal model. However, in revision TKA, the presence of a tibial implant may compromise IORA injection, and tourniquet deflation during a prolonged procedure may lower tissue concentrations. QUESTIONS/PURPOSES: (1) Does low-dose IORA reliably provide equal or higher tissue concentrations of vancomycin compared with systemic IV administration in revision TKA? (2) Are tissue concentrations of vancomycin after IORA maintained for the duration of the revision TKA despite a period of tourniquet deflation? (3) Is there any difference in early postoperative (< 6 weeks) complications between IORA and systemic IV administration in revision TKA? METHODS: Twenty patients undergoing aseptic revision TKA were randomized to two groups. The IV group received 1 g systemic IV prophylactic vancomycin. The IORA group received 500 mg vancomycin as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet before skin incision. In all patients receiving IORA, intraosseous tibial injection was technically possible despite the presence of a tibial implant. Mean procedure length was 3.5 hours in both groups. Mean initial tourniquet inflation was 1.5 hours with a second inflation for a mean of 35 minutes during cementation. During the procedure, subcutaneous fat and bone samples were taken at regular intervals. Tissue vancomycin concentrations were measured using high-performance liquid chromatography. RESULTS: Overall geometric mean tissue concentration of vancomycin in fat samples was 3.7 µg/g (95% confidence interval [CI], 2.6-5.2) in the IV group versus 49.3 µg/g in the IORA group (95% CI, 33.2-73.4; ratio between means 13.5; 95% CI, 8.2-22.0; p < 0.001); mean tissue concentrations in femoral bone were 6.4 µg/g (95% CI, 4.5-9.2) in the IV group versus 77.1 µg/g (95% CI, 42.4-140) in the IORA group (ratio between means 12.0; 95% CI, 6.2-23.2; p < 0.001). Vancomycin concentrations in the final subcutaneous fat sample taken before closure were 5.3 times higher in the IORA group versus the IV group (mean ± SD, 18.2 ± 11.6 µg/g IORA versus 3.6 ± 2.5 µg/g; p < 0.001). The intraarticular concentration of vancomycin on postoperative Day 1 drain samples was not different between the two groups with the numbers available (mean 4.6 µg/L in the IV group versus 6.6 µg/g in the IORA group; mean difference 2.0 µg/g; 95% CI, 6.2-23.2; p = 0.08). CONCLUSIONS: IORA administration of vancomycin in patients undergoing revision TKA resulted in tissue concentrations of vancomycin five to 20 times higher than systemic IV administration despite the lower dose. High tissue concentrations were maintained throughout the procedure despite a period of tourniquet deflation. These preliminary results justify prospective cohort studies, which might focus on broader safety endpoints in more diverse patient populations. We believe that these studies should evaluate patients undergoing revision TKA in particular, because the risk of infection is greater than in patients undergoing primary TKA. LEVEL OF EVIDENCE: Level I, therapeutic study.

Work Related Ocular Injury: Nepal.

INTRODUCTION: Occupational eye injuries comprise a major source of ocular trauma. Knowledge of the epidemiology of occupational eye injuries is essential to formulate viable safety strategies. OBJECTIVES: To evaluate the demographics, patterns of protective eye wear use, and patterns of occupational eye injury among workers in Hetauda, Nepal. MATERIALS AND METHODS: Community based cross-sectional prospective survey was carried out from September 2010 to July 2011. Survey included all workers irrespective of their age and those who are willing to participate in survey by filling details on structured questioners and comprehensive eye examination at community level. RESULTS: 1236 surveys were collected. 38.3% (473) of workers surveyed reported experiencing a work-related eye injury. Over two-thirds [68.3% (844)] of workers surveyed reported never wearing safety eyewear while at work. There was a positive correlation between male sex (P<0.001), reported previous work-related injury (P<0.001), and attending school (P=0.016) and use of personal protective equipment (PPE). CONCLUSIONS: The population studied demonstrates a significant level of work related injury. There are potentially modifiable factors that could lead to increased use of eye protection.

Long-Term Evaluation of Eyebrow Soft Tissue Expansion in Thyroid Eye Disease.

PURPOSE: To evaluate the long-term transformation of lateral eyebrow soft tissue in a group of patients with known thyroid eye disease. METHODS: A retrospective review of all patients with a known diagnosis of thyroid eye disease with clinical photos available from both their initial diagnosis visit and at least 7 years following their initial visit was performed. Age at diagnosis, sex, disease activity, previous orbital, and eyelid surgery were noted, as was history of treatment with radioactive iodine, steroids, and external beam radiation. The area between the upper eyebrow and upper eyelid crease was evaluated in standardized photographs by a panel of 4 expert, independent, masked observers utilizing a previously published visual grading key. RESULTS: One hundred and four patients met inclusion criteria. Fifteen participants were male and 89 were female. The mean patient age was 50.6 years (±1.21 years), and the mean follow up duration was 10.0 years (±0.23 years). The mean initial photo grade (1.24) was significantly higher than the mean follow up photo grade (1.00; p < 0.01). In logistic regression analyses, only the initial photograph grade was significantly associated with improvement in eyebrow soft tissue appearance (p < 0.01). Medical and surgical treatments were not significantly associated with changes in eyebrow soft tissue appearance (all p > 0.05). CONCLUSIONS: Expansion of eyebrow soft tissue may improve over time in patients with thyroid eye disease. This change was not affected by age, sex, disease activity, surgery, or medical therapy.

Case series: toxicity from 25B-NBOMe--a cluster of N-bomb cases.

Background A new class of hallucinogens called NBOMes has emerged. This class includes analogues 25I-NBOMe, 25C-NBOMe and 25B-NBOMe. Case reports and judicial seizures indicate that 25I-NBOMe and 25C-NBOMe are more prevalently abused. There have been a few confirmed reports of 25B-NBOMe use or toxicity. Report Observational case series. This report describes a series of 10 patients who suffered adverse effects from 25B-NBOMe. Hallucinations and violent agitation predominate along with serotonergic/stimulant signs such as mydriasis, tachycardia, hypertension and hyperthermia. The majority (7/10) required sedation with benzodiazepines. Analytical method 25B-NBOMe concentrations in plasma and urine were quantified in all patients using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Peak plasma levels were measured between 0.7-10.1 ng/ml. Discussion The NBOMes are desired by users because of their hallucinogenic and stimulant effects. They are often sold as LSD or synthetic LSD. Reported cases of 25B- NBOMe toxicity are reviewed and compared to our series. Seizures and one pharmacological death have been described but neither were observed in our series. Based on our experience with cases of mild to moderate toxicity, we suggest that management should be supportive and focused on preventing further (self) harm. High doses of benzodiazepines may be required to control agitation. Patients who develop significant hyperthermia need to be actively managed. Conclusions Effects from 25B-NBOMe in our series were similar to previous individual case reports. The clinical features were also similar to effects from other analogues in the class (25I-NBOMe, 25C-NBOMe). Violent agitation frequently present along with signs of serotonergic stimulation. Hyperthermia, rhabdomyolysis and kidney injury were also observed.

Orbital Relapsing Polychondritis: A Unique Presentation, Complication, and Treatment.

An 87-year-old man with a history of relapsing polychondritis presented to the emergency department after 4 days of worsening left periorbital swelling and erythema. On examination, he demonstrated clinical features consistent with orbital cellulitis and was treated with a trial of intravenous antibiotics. His condition did not improve over the next 36 hours and intravenous methylprednisolone was initiated. This led to rapid improvement in orbital symptoms and signs, and a diagnosis of specific orbital inflammation secondary to relapsing polychondritis was made. The patient was discharged on a tapering dose of prednisone. As a steroid-sparing measure, adalimumab was initiated; however, the patient developed Sweet Syndrome. Adalimumab was subsequently discontinued, steroid dose was increased, and anakinra treatment was initiated. This therapeutic course led to significant clinical improvement. Since initiating anakinra, the patient has had no recurrences of Sweet Syndrome. Anakinra may be a useful adjunct therapy for ophthalmic manifestations of relapsing polychondritis.

The Effect of Ptosis Surgery on Brow Position and the Utility of Preoperative Phenylephrine Testing.

INTRODUCTION: Many reports have suggested that upper eyelid position and brow height can be interdependent; however, the relation is not universally observed. This study aims to understand the prevalence of this phenomenon and examine the utility of phenylephrine testing in predicting brow height change after surgery. METHODS: Ptotic eyelids undergoing Muller's muscle conjunctiva resection surgery in which phenylephrine testing was performed were included. The distance from both the center of the pupil to the upper eyelid and the lower brow margin were measured in the midpupillary line. Measurements were performed based on photographs taken on presentation, after phenylephrine testing and at postsurgical follow-up. Change in eyelid margin and brow position between each of these conditions was assessed. Associations between changes in eyelid margin and brow position were analyzed, and a receiver operating characteristic curve for brow change after phenylephrine instillation as a predictor of postoperative brow change was fit. RESULTS: In the sample of 125 eyes, there was a significant change in mean marginal reflex distance one both with application of phenylephrine and after surgery (p < 0.05). There was no significant change in brow height with instillation of phenylephrine (p > 0.05). There was a significant change in brow height with surgery (1 mm; p < 0.05). Change in marginal reflex distance one with surgery or with phenylephrine was not significantly correlated with change in brow height after surgery (Pearson's r = 0.06; p > 0.05). Brow height change with phenylephrine was significantly correlated with brow height change after surgery (p < 0.05). Clinically relevant brow height change was defined as mean change minus one standard deviation, for a total decrease of 3.8 mm. By this criterion, 13.6% patients (n = 17) demonstrated clinically relevant brow height change. These patients had a greater preoperative brow height (p < 0.05) and a greater response to phenylephrine (p < 0.05). Based on receiver operating characteristic analysis, a threshold change of 3.5 mm in brow height with phenylephrine had a sensitivity of 0.94, and specificity of 0.10 for postoperative brow height change. CONCLUSIONS: Approximately 15% of the population studied tends to have a significant change in brow position with ptosis surgery. Patients who do not demonstrate a reduction in brow height of at least 3.5 mm after phenylephrine instillation preoperatively are unlikely to have clinically relevant brow height reduction after surgery.

Clinico-Pathological Patterns of Patients Who Underwent Orbital Exenteration in a Tertiary Eye Hospital of Nepal.

BACKGROUND: Orbital exenteration is a destructive procedure performed by removing all or part of the orbital contents along with entire eyeball. It is a procedure reserved for life threatening malignancies and some nonmalignant disorders which are not controlled by conservative management. METHODS: This is a retrospective study done on patients who underwent orbital exenteration at Tilganga Institute of Ophthalmology from1 January 2006- 30 in December 2014. RESULTS: The mean age of patients was 30 years (range 1-78), with male preponderance of 15(55.6%. Overall presenting duration of eye morbidity was 18 months (2 months-8.5 years). The most common presenting complaint was protrusion of eyeball1, 4(50%), primary site of tumor being intraocular in 10 patients (35.7%,) and total orbital exenteration was the most commonly performed type of surgery in 16(57.1%) out of 27 patients. The most common etiology responsible for orbital exenteration, in pediatric age group of 9/27 patients (64.2%), was retinoblastoma whereas conjunctival squamous cell carcinoma (SCC)accounts for 5 patients (38.4%) in adults. Overall, the most common cause of orbital exenteration was retinoblastoma 9(32.1%). CONCLUSION: The most common etiologies requiring orbital exenteration were retinoblastoma (in children and overall) and conjunctival squamous cell carcinoma (in adults), both diseases that could be addressed with less invasive treatment modality if detected earlier in the disease process. Designing strategy is important for early detection and treatment of these conditions, which would decrease disease morbidity and prognosis, potentially sparing sight and life.

Retinal vein-to-vein anastomoses in Sturge-Weber syndrome documented by ultra-widefield fluorescein angiography.

We report the case of a 6-year-old boy with Sturge-Weber syndrome and unilateral glaucoma in his left eye. He was born with a port wine mark involving his upper left eyelid. On ultra-widefield fluorescein angiography, he was found to have several vein-to-vein anastomoses in his left retina. To our knowledge, this is the first documentation of retinal vein-to-vein anastomoses in Sturge-Weber syndrome.

The role of tissue resection length in the determination of post-operative eyelid position for Muller's muscle-conjunctival resection surgery.

PURPOSE: To investigate the relationships between pre-operative marginal reflex distance (MRD), tissue resection length, phenylephrine response, and change in MRD with surgery for a cohort of individuals undergoing Muller's muscle conjunctival resection (MMCR) surgery. METHODS: All cases of MMCR surgery performed over a 13-year period at a single institution were screened for entry. Individuals with adequate photographic documentation and follow up were included. Patients with previous or concurrent upper eyelid, orbital or eyebrow disease of surgery were excluded. Marginal reflex distance (MRD) was calculated based on photographs utilizing public domain software. Data was plotted for inspection and appropriate statistical tests were performed. RESULTS: During the study period 198 eyes fit criteria for analysis. A loose association between tissue resection length and change in MRD with surgery was found (r = 0.176, p < 0.05); this relationship was not significant in ANOVA analysis (p = 0.367). There was a strong association between MRD change with surgery and pre-operative MRD (r = 0.498, p < 0.01). Approximately 28% of the sample responded to 2.5% phenylephrine drop instillation with a greater than 2 mm increase in MRD. The response to phenylephrine was strongly associated with pre-operative MRD (r = -0.441, p < 0.01). A regression on change in MRD with surgery with tissue resection, phenylephrine response >2 mm and pre-operative MRD as variables revealed a model with pre-operative MRD as the only significant predictor (p < 0.01). CONCLUSION: Tissue resection length and phenylephrine response play small roles relative to pre-operative MRD in the determination of change in MRD with MMCR surgery.

Mueller's Muscle Conjunctival Resection With Skin-Only Blepharoplasty: Effects on Eyelid and Eyebrow Position.

PURPOSE: To determine the effect of concurrent blepharoplasty and Mueller's muscle conjunctival resection (MMCR) surgery on eyelid position and eyebrow height. METHODS: Clinical data from 274 eyes that met inclusion criteria for this study were reviewed. Mueller's muscle conjunctival resection surgery was performed alone in 198 eyes and was performed with concurrent blepharoplasty in 76 cases. In this study blepharoplasty consisted of only skin removal, leaving the muscle, fat, and tarsus intact. Preoperative and postoperative pupil to eyebrow, and eyelid margin to eyebrow distances were calculated and compared. RESULTS: Preoperative margin reflex distance 1 (MRD1) was similar for both groups of patients (p > 0.05) as was the postoperative MRD1 (p > 0.05). The change in MRD1 was similar between patients undergoing MMCR alone versus those undergoing MMCR with blepharoplasty (1.5 mm vs. 1.3 mm, respectively, p = 0.36). For similar amounts of tissue resection, the postoperative change in MRD1 was similar for patients undergoing MMCR-only surgery and MMCR with blepharoplasty (p > 0.05). Eyebrow height significantly decreased following both MMCR with blepharoplasty (0.73 mm, p < 0.05) and MMCR-only surgery (0.87 mm, p < 0.05), and this change in eyebrow height was not significantly different between the 2 groups. CONCLUSION: Combining MMCR surgery with skin-only blepharoplasty does not significantly alter eyelid height when compared with MMCR surgery alone for the correction of upper eyelid ptosis. This may assist in preoperative planning for combined MMCR with skin-only blepharoplasty.

The Mark Coventry Award: Higher tissue concentrations of vancomycin with low-dose intraosseous regional versus systemic prophylaxis in TKA: a randomized trial.

BACKGROUND: In response to increasing antibiotic resistance, vancomycin has been proposed as an alternative prophylactic agent in TKA. However, vancomycin requires a prolonged administration time, risks promoting further antibiotic resistance, and can cause systemic toxicity. Intraosseous regional administration (IORA) is known to achieve markedly higher antibiotic concentrations than systemic administration and may allow the use of a lower vancomycin dose. QUESTIONS/PURPOSES: We assessed whether low-dose IORA vancomycin can achieve tissue concentrations equal or superior to those of systemic administration in TKA and compared complications between patients treated with IORA and intravenous vancomycin. METHODS: We randomized 30 patients undergoing primary TKA to receive 250 or 500 mg vancomycin via IORA or 1 g via systemic administration. IORA was performed as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet immediately before skin incision. Subcutaneous fat and bone samples were taken during the procedure and antibiotic concentrations measured. RESULTS: The overall mean tissue concentration of vancomycin in subcutaneous fat was 14 µg/g in the 250-mg IORA group, 44 µg/g in the 500-mg IORA group, and 3.2 µg/g in the systemic group. Mean concentrations in bone were 16 µg/g in the 250-mg IORA group, 38 µg/g in the 500-mg IORA group, and 4.0 µg/g in the systemic group. One patient in the systemic group developed red man syndrome during infusion. CONCLUSIONS: Low-dose IORA vancomycin results in tissue concentrations equal or superior to those of systemic administration. IORA optimizes timing of vancomycin administration, and the lower dose may reduce the risk of systemic side effects while providing equal or enhanced prophylaxis in TKA.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

BACKGROUND: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. METHODS: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized. RESULTS: Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC0₋24. CONCLUSIONS: Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.

A simple high-performance liquid chromatography method for simultaneous determination of three triazole antifungals in human plasma.

A rapid and simple high-performance liquid chromatography (HPLC) assay was developed for the simultaneous determination of three triazole antifungals (voriconazole, posaconazole, and itraconazole and the metabolite of itraconazole, hydroxyitraconazole) in human plasma. Sample preparation involved a simple one-step protein precipitation with 1.0 M perchloric acid and methanol. After centrifugation, the supernatant was injected directly into the HPLC system. Voriconazole, posaconazole, itraconazole, its metabolite hydroxyitraconazole, and the internal standard naproxen were resolved on a C(6)-phenyl column using gradient elution of 0.01 M phosphate buffer, pH 3.5, and acetonitrile and detected with UV detection at 262 nm. Standard curves were linear over the concentration range of 0.05 to 10 mg/liter (r(2) > 0.99). Bias was <8.0% from 0.05 to 10 mg/liter, intra- and interday coefficients of variation (imprecision) were <10%, and the limit of quantification was 0.05 mg/liter.