Liposomal Bupivacaine for Peripheral Nerve Blockade: A Randomized, Controlled, Crossover, Triple-blinded Pharmacodynamic Study in Volunteers.

BACKGROUND: Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers. METHODS: Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model. RESULTS: Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade. CONCLUSIONS: The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy.

A prospective observational study on the feasibility of subumbilical laparoscopic procedures under epidural anesthesia in sedated spontaneously breathing infants with a natural airway.

BACKGROUND: Laparoscopic procedures are usually performed under general anesthesia with a secured airway including endotracheal intubation or supraglottic airways. AIMS: This is a prospective study of the feasibility of subumbilical laparoscopic procedures under epidural anesthesia in sedated, spontaneous breathing infants with a natural airway. METHODS: We consecutively enrolled 20 children <3 years old with nonpalpable testes scheduled for diagnostic laparoscopy with or without an ensuing orchidopexy, inguinal revision, or Fowler-Stephens maneuver. Inhalational induction for venous access was followed by sedation with propofol and ultrasound-guided single-shot epidural anesthesia via the caudal or thoracolumbar approach using 1.0 or 0.5 ml kg-1 ropivacaine 0.38%, respectively. The primary outcome measure was block success, defined as no increase in heart rate by >15% or other indicators of pain upon skin incision. RESULTS: Of the 20 children (median age: 10 months; IQR: 8.3-12), 17 (85%) were anesthetized through a caudal and 3 (15%) through a direct thoracolumbar epidural, 18 (90%) underwent a surgical procedure and 2 (10%) diagnostic laparoscopy only. Five patients (25%) received block augmentation using an intravenous bolus of fentanyl (median dose: 0.9 µg kg-1 ; IQR: 0.8-0.95) after the initial prick test and before skin incision. There was no additional need for systemic pain therapy in the operating theater or recovery room. No events of respiratory failure or aspiration were observed. CONCLUSIONS: In experienced hands, given our success rate of 100%, epidural anesthesia performed in sedated spontaneously breathing infants with a natural airway can be an alternative strategy for subumbilical laparoscopic procedures.

Epidural versus general anesthesia for open pyloromyotomy in infants: A retrospective observational study.

BACKGROUND: Thoracic epidural anesthesia for open infantile hypertrophic pyloric stenosis surgery is a controversial issue in the presence of little comparative data. AIMS: To compare this approach to general anesthesia for desaturation events (≤90% oxygen saturation) and absolute values of minimal oxygen saturation, minimal heart frequency, operating-room occupancy time, and durations of surgery in a retrospective study design. METHODS: Data were retrieved for patients with infantile hypertrophic pyloric stenosis managed by thoracic epidurals under sedation or general anesthesia with rapid sequence induction between 01/2007 and 12/2017. Oxygen saturation and heart rate were analyzed over eight 5-minutes intervals relative to the start of anesthesia / sedation (four-time intervals) and before discharge of the patient from the operating room (four-time intervals). Fisher's exact tests and mixed model two-way analysis of variance for repeated measures were employed for intergroup comparisons. RESULTS: The epidural and general anesthesia groups included 69 and 32 evaluable infants, respectively. Patients managed under epidural anesthesia had cumulatively higher minimimal mean (SD) oxygen saturation values (98.2 [2.6] % versus 96.6 [5.2] %, p < 0.001) and lower minimal mean (SD) heart rate values (127.9 [15.0] beats per minute versus 140.7 [17.2] beats per minute, p < 0.001) over time. Similarly, the frequency of desaturation events (defined as ≤90% oxygen saturation) was significantly lower for these patients during the period of 5 minutes after induction of sedation or general anesthesia (odds ratio 7.4 [2.1-25.9]; p = 0.001) and during the subsequent period of five minutes (odds ratio 6.2 [1.1-33.9]; p = 0.031). One case of prolonged respiratory weaning was observed in the general anesthesia group. The mean (SD) operating-room occupancy was 61.9 (16.6) minutes for the epidural anesthesia group versus 73.3 (22.2) minutes for the general anesthesia group (p = 0.005) as a result of shorter emergence from sedation. CONCLUSIONS: In our series, maintaining spontaneous breathing with minimal airway manipulation in patients undergoing open repair of hypertrophic pyloric stenosis under single-shot epidural anesthesia resulted in fewer desaturation events ≤90% than general anesthesia. In addition, this approach seems to result in shorter turnover times in the operating room.

Generic versus reference listed ropivacaine for peripheral nerve blockade: A randomised, triple-blinded, crossover, equivalence study in volunteers.

BACKGROUND: Generic drug preparations do not require the same degree of scrutiny as the originally licensed preparation before they can be approved for clinical use. The permitted tolerance limits for bioequivalent preparations might be associated with clinically relevant differences for drugs with a narrow therapeutic index, such as local anaesthetics. OBJECTIVE: We compared pharmacokinetic and pharmacodynamic characteristics of generic and reference listed or original preparations of ropivacaine. DESIGN: The current healthy volunteer study used a randomised, triple-blinded, cross-over equivalence design. SETTING: Tertiary university hospital, Medical University of Vienna. SUBJECTS: Healthy male volunteers (N=18) aged 18 to 60 years. INTERVENTIONS: A series of three ultrasound-guided ulnar nerve blocks separated by at least 6 days were carried out on each volunteer. Reference listed ropivacaine (NaropinTM) was used for two blocks and a generic preparation of ropivacaine was used for the other block. Sensory block onset and duration were evaluated using loss of pinprick sensation. MAIN OUTCOME MEASURES: Duration of sensory block was the primary outcome. Secondary outcomes included time-to-onset of sensory block, ropivacaine pharmacokinetics from venous blood samples and pH of the preparations. Equivalence was evaluated using the ratios of means and 90% confidence intervals (CIs) of log transformed data. RESULTS: Equivalence was demonstrated for the primary outcome measure, the duration of sensory block [original : generic ratio 1.01 (90% CI 0.87 to 1.16); P < 0.007] and all pharmacokinetic variables. Equivalence could not be concluded for time-to-onset of sensory block [reference : generic ratio 0.80 (90% CI 0.63 to 1.03); P = 0.27], although reproducibility of this variable using our experimental model was lower than for other variables. The generic preparation was significantly more alkaline [difference 0.06 pH units (95% CI 0.04 to 0.07); P < 0.0001]. CONCLUSION: Our finding of equivalence for sensory block duration and key pharmacokinetic variables between a generic and original preparation of ropivacaine is reassuring. The significant, but small, difference in pH is not clinically important. TRIAL REGISTRATION: EudraCT 2019-003148-61, German Clinical Trials Register (DRKS 00017750).

Brachial plexus block with ultrasound guidance for upper-limb trauma surgery in children: a retrospective cohort study of 565 cases.

BACKGROUND: Upper-limb trauma is a common indication for surgery in children, and general anaesthesia remains the method of choice for these procedures, even though suitable techniques of brachial plexus block are available and fast provision of regional anaesthesia offers a number of distinct advantages. METHODS: A retrospective analysis was performed of the data of a large cohort of children undergoing ultrasound-guided brachial plexus blocks during a 4-yr period at a major trauma centre with a catchment area of 3.5 million. A total of 565 cases were sourced from two independently operating patient documentation systems. Patient data were stratified into age groups with block success as the primary outcome parameter. The influence of age on the incidence of block failure was assessed with logistic regression. RESULTS: The block failure rate was 5.1%, starting at 1.2% in the youngest (0-3 yr), then continuously increasing up to 12.5% in the oldest (15-18 yr) but also smallest group. Age emerged as an independent predictor of block failure with an odds ratio of 1.115 and a 95% confidence interval of 1.014-1.226 (P=0.025). No complications were observed. CONCLUSIONS: In a cohort of children receiving real-world care, with regional blocks performed by a range of anaesthetists with different skill levels, a success rate of 94.9% for upper-limb blocks in children under various levels of sedation was observed. Upper-limb blocks can be performed with high probability of success and an excellent margin of safety; this particularly applies to small children. CLINICAL TRIAL REGISTRATION: NCT03842423.

Brainwave entrainment to minimise sedative drug doses in paediatric surgery: a randomised controlled trial.

BACKGROUND: Anaesthetic drugs may cause neuroapoptosis in children and are routinely used off-label in specific age groups. Techniques that reduce anaesthetic drug dose requirements in children may thus enhance the safety of paediatric sedation or anaesthesia. Brainwave entrainment, notably in the form of auditory binaural beats, has been shown to have sedative effects in adults. We evaluated the influence of brainwave entrainment on propofol dose requirements for sedation in children. METHODS: We randomised 49 boys scheduled for sub-umbilical surgery under caudal blockade to an entrainment or a control group. Small differences in pitch were applied to each ear to create binaural beats, supplemented by synchronous visual stimuli, within the electroencephalographic frequency bands seen during relaxation and (rapid eye movement/non-rapid eye movement) sleep. After establishment of caudal block, propofol infusion was started at 5 mg kg-1 h-1. Intraoperatively, the infusion rate was adjusted every 5 min depending on the sedation state judged by the bispectral index (BIS). The infusion rate was decreased by 1 mg kg-1 h-1 if BIS was <70, and was increased if BIS was >70, heart rate increased by 20%, or if there were other signs of inadequate sedation. RESULTS: Mean propofol infusion rates were 3.0 (95% confidence interval [CI]: 2.4-3.6) mg kg-1 h-1vs 4.2 (95% CI: 3.6-4.8) mg kg-1 h-1 in the entrainment and control groups, respectively (P<0.01). BIS values were similar in the two groups. CONCLUSIONS: Brainwave entrainment effectively reduced the propofol infusion rates required for sedation in children undergoing surgery with regional anaesthesia. Further studies are needed to investigate the possibility of phasing out propofol infusions completely during longer surgical procedures and optimising the settings of brainwave stimulation. CLINICAL TRIAL REGISTRATION: DRKS00005064.

Intravenous nonopioid analgesic drugs in chronic low back pain patients on chronic opioid treatment: a crossover, randomised, double-blinded, placebo-controlled study.

BACKGROUND: Addition of nonopioid analgesic drugs reduces pain and opioid requirements in acute low back pain. In noncancer chronic low back pain (CLBP), the efficacy of a combined regimen to reduce breakthrough pain has not been proven so far. OBJECTIVE: Evaluation of the effects of intravenous (i.v.) nonopioid analgesic drugs on pain intensity and lumbar mobility in CLBP patients on chronic opioid therapy. DESIGN: Randomised, placebo-controlled, double blinded, crossover study. SETTING: Vienna General Hospital, Austria, from December 2002 to May 2004. PATIENTS: Thirty-six adults with CLBP on chronic opioid therapy. Inclusion criteria are as follows: American Society of Anesthesiologists' physical status less than 3, visual analogue scale (VAS) more than 4 and no known allergy to any of the used drugs. INTERVENTION: After written informed consent and VAS assessment, any oral nonopioid analgesic drug (NSAIDs, metamizol, paracetamol) was replaced by placebo 10 days before the first test infusion as a washout period. Coanalgesics (anticonvulsants, antidepressants) were maintained. Each patient received randomly four i.v. test infusions of diclofenac 75 mg (and orphenadrine 30 mg), parecoxib 40 mg, paracetamol 1 g and isotonic saline. A washout time of 72 h was allowed between each infusion. MAIN OUTCOME MEASURES: Primary outcome was as follows: VAS pain intensity (0 to 100 mm) at inclusion, before and within 30 min after infusion. Secondary outcomes were as follows: Roland-Morris questionnaire, McGill pain questionnaire and a test panel of physical functioning for spinal mobility, muscular endurance, balance and coordination. The differences in means of the above assessments among the groups were analysed. RESULTS: We found an improvement in VAS from the day of inclusion to the day of each appointment. We observed no improvement in pain intensity (VAS) or in any of the physical functioning tests immediately before versus after administration of the four i.v. drugs. Reductions in sensory, affective and cognitive dimensions of the McGill pain questionnaire were statistically significant in the diclofenac group. A trend of McGill pain questionnaire improvement existed in the other groups. CONCLUSION: The present data show that the anticipation of an i.v. infusion of nonopioid analgesic drug improves VAS significantly, probably through expectation-related mechanisms. However, single dose i.v. infusions of nonopioid analgesic drugs fail to improve pain intensity and spinal mobility in CLBP patients on chronic opioid treatment, even immediately after the infusion.

The impact of biological sex in peripheral nerve blockade: A prospective pharmacodynamic, pharmacokinetic and morphometric study in volunteers.

STUDY OBJECTIVE: The impact of biological sex in peripheral regional anaesthesia is largely unknown. We therefore designed a prospective study in volunteers to investigate the impact of biological sex on pharmacodynamic, pharmacokinetic and morphometric characteristics for peripheral nerve blockade. METHODS: The initial study plan was powered to include 90 volunteers to find a difference of 35 min in duration of sensory block (primary outcome variable) with 80% power and alpha error at 5%. After discussions in ethical review, a pilot study of 2 x 12 volunteers from each sex were studied. Female and male volunteers received ultrasound guided nerve blockade with 3.0 mL ropivacaine 7.5 mg mL-1. Sensory duration of blockade, as the primary outcome, was evaluated by pinprick testing. Secondary outcomes were sensory onset time of blockade, pharmacokinetic characteristics and the visibility of ulnar nerves using ultrasound. Analyses included Mann-Whitney U-statistics with P<0.05 (two-sided) as significant. RESULTS: After 24 participants, the median (IQR) duration of sensory blockade was 450 (420; 503) min in women and 480 (450; 510) min in men (P = 0.49). Sensory onset time of blockade, and ultrasound visibility of nerves were also similar between the study groups. The total drug exposure across time (AUC0-infinity) was significantly higher in women (P = 0.017). After a the planned power re-analysis after these 24 study paticipants, which suggested that > 400 subjects would be required with 80% power and alpha error of 5% to find significance for the primary outcome parameter for marginal differences, we terminated the study at this point. CONCLUSIONS: We did not detect significant differences between female and male study participants in terms of pharmacodynamic and morphometric characteristics after ultrasound guided ulnar nerve blocks. Women did show significantly greater pharmacokinetic ropivacaine exposures. The results of this study indicate that peripheral regional block pharmacodynamic characteristics are independent of the biological sex, whereas pharmacokinetic parameters are sex-dependent.

Ultrasound-Guided Dorsal Penile Nerve Block in Children: An Anatomical-Based Observational Study of a New Anesthesia Technique.

Dorsal penile nerve block stands out as one of the commonly employed regional anesthetic techniques in children. Despite the large body of experience, failure rates are still significant. We included 20 children (median (SD) age of 73 (31) months) scheduled for circumcision without general anesthesia and secondary airway manipulation in a consecutive case series. Under ultrasound guidance and utilizing an in-plane needle guidance technique, the dorsal penile nerve block was administered with slight sedation, and spontaneous respiration was maintained in all cases. To investigate the underlying anatomy for dorsal penile nerve blockade, we dissected three cadavers. The primary study endpoint was the success rate of surgical blockade, meaning that the surgical procedure could be performed without additional general anesthesia and invasive airway management. The secondary endpoint was the requirement of analgesics until discharge from the post-anesthesia care unit. The primary endpoint was successfully met in all patients according to our strict definition without additional general anesthesia or airway manipulation. In addition, no child received analgesics until discharge from the recovery room. The anatomical investigation clarified the specific anatomy as baseline knowledge for an ultrasound-guided dorsal penile nerve blockade and enabled successful performance in 20 consecutive children where penile surgery was possible in light sedation without additional airway manipulation.

Sex differences in pediatric caudal epidural anesthesia under sedation without primary airway instrumentation.

STUDY OBJECTIVE: To identify sex differences associated with caudal epidurals, the most commonly used technique of pediatric regional anesthesia, based on individually validated data of ultrasound-guided blocks performed between 04/2014 and 12/2020. METHODS: Prospectively collected and individually validated data of a cohort of children aged between 0-15 years was analyzed in a retrospective observational study. We included pediatric surgeries involving a primary plan of caudal epidural anesthesia under sedation (without airway instrumentation) and a contingency plan of general anesthesia. Sex-specific rates were analyzed for overall failure of the primary anesthesia plan, for residual pain, for block-related technical complications and for critical respiratory events. We used Fisher´s exact tests and multivariable logistic regressions were used to evaluate sex-specific associations. RESULTS: Data from 487 girls and 2060 boys ≤15 years old (ASA status 1 to 4) were analyzed. The primary-anesthesia-plan failure rate was 5.5% (95%CI 3.8%-7.8%) (N = 27/487) among girls and 4.7% (95%CI 3.9%-5.7%) (N = 97/2060) among boys (p = 0.41). Residual pain was the main cause of failure, with rates of 4.5% (95%CI 2.9-6.6%) (N = 22/487) among girls and 3.0% (95%CI 2.3-3.8%) (N = 61/2060) among boys (p = 0.089). Block-related technical complications were seen at rates of 0.8% (95%CI 0.3%-1.9%) (N = 4/487) among girls vs 2.5% (95%CI 0.5-2.7%) (N = 51/2060) among boys and, hence, significantly more often among male patients (p = 0.023). Male sex was significantly associated with higher odds (adjusted OR: 3.18; 95% CI: 1.12-9; p = 0.029) for such technical complications regardless of age, ASA status, gestational week at birth or puncture attempts. Critical respiratory events occurred at a 1.7% (95%CI 1.2%-2.3%) rate (N = 35/2060) twice as high among boys as 0.8% (95%CI 0.3%-1.9%) (N = 4/487) among girls (p = 0.21). CONCLUSIONS: While the the primary-anesthesia-plan failure rate was equal for girls and boys, technical complications and respiratory events are more likely to occur in boys.

Accuracy of a Dual-Sensor Heat-Flux (DHF) Non-Invasive Core Temperature Sensor in Pediatric Patients Undergoing Surgery.

Accurate temperature measurement is crucial for the perioperative management of pediatric patients, and non-invasive thermometry is necessary when invasive methods are infeasible. A prospective observational study was conducted on 57 patients undergoing elective surgery. Temperatures were measured using a dual-sensor heat-flux (DHF) thermometer (Tcore™) and a rectal temperature probe (TRec), and the agreement between the two measurements was assessed. The DHF measurements showed a bias of +0.413 °C compared with those of the TRec. The limits of agreement were broader than the pre-defined ±0.5 °C range (-0.741 °C and +1.567 °C). Although the DHF sensors tended to overestimate the core temperature compared to the rectal measurements, an error grid analysis demonstrated that 95.81% of the DHF measurements would not have led to a wrong clinical decision, e.g., warming or cooling when not necessary. In conclusion, the low number of measurements that would have led to incorrect decisions suggests that the DHF sensor can be considered an option for continuous temperature measurement when more invasive methods are infeasible.

Ad-hoc preoperative management and respiratory events in pediatric anesthesia during the first COVID-19 lockdown-an observational cohort study.

BACKGROUND: Early pre-anesthetic management for surgery is aimed at identifying risk factors, which notably in children are mostly airway related. The first COVID-19 lockdown opened a unique 'window of opportunity' to study what impact an ad-hoc management strategy would bring to bear on intraoperative respiratory events. METHODS: In this observational cohort study we included all patients with an American Society of Anesthesiology (ASA) Physical Status of I or II, aged 0 to ≤18 years, who underwent elective surgery at our center during the first national COVID-19 lockdown (March 15th to May 31st, 2020) and all analogue cases during the same calendar period of 2017-2019. The primary outcome parameter was a drop in peripheral oxygen saturation (SpO2) below 90% during anesthesia management. The study is completed and registered with the German Clinical Trials Register, DRKS00024128. RESULTS: Given 125 of 796 evaluable cases during the early 2020 lockdown, significant differences over the years did not emerge for the primary outcome or event counts (p>0.05). Events were exceedingly rare even under general anesthesia (n = 3) and non-existent under regional anesthesia (apart from block failures: n = 4). Regression analysis for SpO2 events <90% yielded no significant difference for ad-hoc vs standard preoperative management (p = 0.367) but more events based on younger patients (p = 0.007), endotracheal intubation (p = 0.007), and bronchopulmonary procedures (p = 0.001). CONCLUSIONS: Early assessment may not add to the safety of pediatric anesthesia. As a potential caveat for other centers, the high rate of anesthesia without airway manipulation at our center may contribute to our low rate of respiratory events.

ADV6209 for Premedication in Pediatric Anesthesia: A Double-Blinded, Randomized Controlled Trial.

ADV6209, a new formulation of midazolam with the addition of γ-cyclodextrin for oral use, has recently been licensed as the first pediatric sedative in the European Union. We compared the clinical efficacy of ADV6209 to the standard formulation of midazolam in premedication to reduce anxiety in children before anesthesia induction in a randomized, double-blinded controlled trial. Eighty children (ASA I/II; age: 2-8 years) scheduled for elective surgery were randomized to receive 0.25 mg kg-1 of either conventional midazolam or ADV6209. Assessment tools included the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF) as well as scores for oral acceptance of the premedication and facemask acceptance during inhalational anesthesia induction. Mann-Whitney U and Pearson's chi-square tests were used for comparisons of outcome parameters. The primary outcome parameter of the study (mYPAS-SF anxiety score 30 min after the drug administration) did not reveal any significant intergroup difference between the ADV6209 group and the conventional midazolam group. Both drugs revealed their efficacy in reducing anxiety and in providing adequate sedation. The premedication dose was accepted by all children in the ADV6209 but rejected by 15% in the conventional midazolam group (p = 0.037). Acceptance of facemask placement was not found to differ significantly. No adverse events related to the study medications were noted. ADV6209 was better orally accepted than the conventional midazolam preparation and proved its efficacy in reducing preoperative anxiety. This clinically interesting preparation may alleviate the premedication process of 2-8 year-old children and obviates off-label drug use.

Ultrasound-guided epidural anesthesia and sedation for open transvesical Cohen ureteric reimplantation surgery in 20 consecutive children: a prospective case series and proof-of-concept study.

BACKGROUND: Epidural anesthesia is usually combined with general anesthesia (GA) for children undergoing sub-umbilical surgery and GA in children is associated with a potential for respiratory events. Aiming to reduce airway manipulation and the use of GA drugs, we designed a study of transvesical Cohen ureteteric reimplantion under epidural anesthesia in sedated, spontaneously breathing children. METHODS: We enrolled 20 children (3-83 months, 6.3-25.0 kg) scheduled for open transvesical abdominal surgery with Pfannenstiel incision. Sedation was followed by ultrasound-guided epidural anesthesia. Increases in heart rate by >15% and or patient movements upon skin incision were rated as block deficiencies. Intubation equipment for advanced airway management was kept on standby. The primary study endpoint was successful blockade, meaning that no sequential airway management was required for the spontaneous breathing patients during surgery. Secondary endpoints included any use of fentanyl/propofol intraoperatively and of postoperative analgesics in the recovery room. RESULTS: All 20 blocks were successful, with no block deficiencies upon skin incision, no need for sequential airway management, and stable SpO2 levels (97-100%). Surgery took a median of 120.5 minutes (IQR: 89.3-136.5) and included one bolus of fentanyl in one patient 120 minutes into a protracted operation. No more systemic analgesia had to be provided in the recovery room. CONCLUSIONS: Sedation and epidural anesthesia emerged as a useful alternative to GA from our consecutive case series.

Retinal and Corneal Neurodegeneration and Their Association with Systemic Signs of Peripheral Neuropathy in Type 2 Diabetes.

PURPOSE: To determine the extent of retinal and corneal neurodegeneration and investigate the association with intraepidermal neuronal loss and diabetic peripheral neuropathy (DPN) in type 2 diabetes. DESIGN: Prospective, cross-sectional study. METHODS: Single-center study of 94 patients with type 2 diabetes patients (157 eyes), divided into groups: the groups without diabetic retinopathy (DR) (n = 68); the nonproliferative DR (NPDR) group (n = 48); and the proliferative DR (PDR) group (n = 41). Patients were imaged with optical coherence tomography and confocal microscopy for macular and peripapillary neuroretinal layer thicknesses and corneal nerve length/density, respectively. Distal leg skin punch biopsies and 2 neurological scores were used to depict intraepidermal nerve fiber density (IENFD) and clinical DPN. RESULTS: Among neuroretinal layers, solely the peripapillary retinal nerve fiber layer was decreased in PDR (96 µm; 95% confidence interval [CI], 92-100 µm) versus no DR (103 µm; 95% CI, 100-106 µm) eyes and only after exclusion of outliers (P = .01). Corneal nerve fiber length and density were statistically significantly reduced in the NPDR group (23.0 mm/mm2; 95% CI, 20.0-26.00 mm/mm2 and 14.3 mm; 95% CI, 14.5-16.63 mm, respectively) and the PDR group (18.6 mm/mm2; 95% CI, 14.9-22.30 mm/mm2 and 11.7 mm; 95% CI, 10.2-13-3 mm, respectively) versus the no DR group (25.5 mm/mm2; 95% CI, 23.3-27.70 mm/mm2 and 15.6 mm; 95% CI, 14.5-16.6 mm, respectively), and in the PDR versus the NPDR group. IENFD was statistically significantly reduced in the NPDR (2.0/mm; 95% CI, 1.4-2.7/mm) and PDR stage (1.4/mm; 95% CI, 0.9-2.1/mm) versus in eyes without DR (3.6/mm; 95% CI, 2.9-4.6/mm). A low correlation between intraepidermal and corneal fiber loss was found with both neurological scores (P < .05). CONCLUSIONS: Retinal neurodegenerative changes may develop independently of the microvascular alterations defining DR. Corneal and intraepidermal neuronal loss is more pronounced in advanced stages of DR, indicating a positive severity correlation between DR and DPN.

Comparison of cooling and EMLA to reduce the burning pain during capsaicin 8% patch application: a randomized, double-blind, placebo-controlled study.

Topical capsaicin 8% was developed for the treatment of peripheral neuropathic pain. The pain reduction is associated with a reversible reduction of epidermal nerve fiber density (ENFD). During its application, topical capsaicin 8% provokes distinct pain. In a randomized, double-blind study analyzed with a block factorial analysis of variance, we tested whether cooling the skin would result in reliable prevention of the application pain without inhibiting reduction of ENFD. A capsaicin 8% patch was cut into 4 quarters and 2 each were applied for 1 hour on the anterior thighs of 12 healthy volunteers. A randomization scheme provided for 1 of the application sites of each thigh to be pretreated with EMLA and the other with placebo, whereas both application sites of 1 thigh, also randomly selected, were cooled by cool packs, resulting in a site temperature of 20°C during the entire treatment period. The maximum pain level given for the cooled sites (visual analogue scale [VAS] 1.3 ± 1.4) proved to be significantly lower than for the non-cooled sites (VAS 7.5 ± 1.9) (P < .0001). In contrast, there was no significant difference in application pain between the sites pretreated with EMLA or with placebo (VAS 4.1 ± 3.6 vs 4.8 ± 3.5, P = .1084). At all application sites, ENFD was significantly reduced by 8.0 ± 2.8 (ENF/mm ± SD, P < .0001), that is, 70%, with no significant differences between the sites with the different experimental conditions. In conclusion, cooling the skin to 20°C reliably prevents the pain from capsaicin 8% patch application, whereas EMLA does not. ENFD reduction is not inhibited by cooling.