Where does spinal cord stimulation fit into the international guidelines for refractory painful diabetic neuropathy? a consensus statement.

BACKGROUND: Although pharmacotherapy with anticonvulsants and/or antidepressants can be effective for many people with painful diabetic neuropathy (PDN), albeit with frequent side-effects, a critical juncture occurs when neuropathic pain no longer responds to standard first- and second-step mono- and dual therapy and becomes refractory. Subsequent to these pharmacotherapeutic approaches, third-line treatment options for PDN may include opioids (short-term), capsaicin 8% patches, and spinal cord stimulation (SCS). AIM: This document summarizes consensus recommendations regarding appropriate treatment for refractory peripheral diabetic neuropathy (PDN), based on outcomes from an expert panel convened on December 10, 2022, as part of the Worldwide Initiative for Diabetes Education Virtual Global Summit, "Advances in the Management of Painful Diabetic Neuropathy." PARTICIPANTS: Nine attendees, eminent physicians and academics, comprising six diabetes specialists, two pain specialists, and one health services expert. EVIDENCE: For individuals with refractory PDN, opioids are a high-risk option that do not provide a long-term solution and should not be used. For appropriately selected individuals, SCS is an effective, safe, and durable treatment option. In particular, high-frequency (HF) SCS (10 kHz) shows strong efficacy and improves quality of life. To ensure treatment success, strict screening criteria should be used to prioritize candidates for SCS. CONSENSUS PROCESS: Each participant voiced their opinion after reviewing available data, and a verbal consensus was reached during the meeting. CONCLUSION: Globally, the use of opioids should rarely be recommended for refractory, severe PDN. Based on increasing clinical evidence, SCS, especially HF-SCS, should be considered as a treatment for PDN that is not responsive to first- or second-line monotherapy/dual therapy.

Randomized clinical trial of perianal surgery performed under spinal saddle block versus total intravenous anaesthesia.

BACKGROUND: The aim of this randomized clinical trial was to determine whether spinal saddle block (SSB) is superior to total intravenous anaesthesia (TIVA) in perianal surgery. METHODS: Suitable patients aged 18-75 years (American Society of Anesthesiologists grade I or II) scheduled to undergo perianal surgery were randomized to SSB (1.0 ml 0.5 per cent hyperbaric bupivacaine) or TIVA with propofol and fentanyl by means of a laryngeal mask. Cumulative consumption of analgesics within 24 h after surgery was recorded, and postoperative recovery and patient satisfaction were evaluated. RESULTS: A total of 201 patients were randomized. Supplemental analgesia within 24 h after surgery was required by 31 of 101 patients having SSB and 58 of 100 who had TIVA (P < 0.001). Median monitoring time in the recovery room was 5 (range 1-45) min for SSB versus 44 (4-148) min for TIVA (P < 0.001). Patients in the SSB group were able to eat and drink more quickly, although times to mobilization and micturition were not significantly different. Patients having SSB were more likely to describe the anaesthesia as 'better than expected'. CONCLUSION: SSB is superior to TIVA in patients undergoing perianal surgery in terms of analgesic consumption within 24 h after surgery and aspects of postoperative recovery. REGISTRATION NUMBER: ISRCTN41981381 (http://www.controlled-trials.com).

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler).

Hurler syndrome (MPS1H) is a progressive inborn error of mucopolysaccharide metabolism leading to premature death. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and improve long-term survival. However, large studies have shown that preparative regimen-related toxicity (RRT) and graft failure rates have been relatively high. We transplanted five Hurler children with a fludarabine-based conditioning regimen, consisting of fludarabine/busulphan/ATG for matched family donor (MFD), with the addition of melphalan for mismatched family donor and matched unrelated donor (MUD) transplantations. Median age at HCT was 27 months (range 10-36). The source of stem cells was bone marrow in one MFD and CD34-selected PBSC in four patients. Median CD34+ cell dose was 25 x 10(6)/kg (range 11.5-54). No RRT > grade II was observed. All patients are surviving at a median of 32 months (range 14-41) and show sustained donor engraftment with 3/5 having full donor chimerism, and 2/5 mixed chimerism (> 85%). We conclude that this regimen is feasible and has low toxicity in Hurler children. In combination with high doses of CD34+ selected cells (> 10 x 10(6)/kg) and donor lymphocyte infusions, stable engraftment could be achieved in unrelated and mismatched related transplantations.

Effects of patient-triggered automatic switching between mandatory and supported ventilation in the postoperative weaning period.

OBJECTIVE: To compare two ventilator settings in the postoperative weaning period. Patient-triggered automatic switching between controlled ventilation and supported spontaneous breathing (Automode, AM) was compared to synchronised intermittent mandatory ventilation (SIMV) with stepwise manual adjustment of mandatory frequency according to the breathing activity. DESIGN: Prospective clinical investigation. SETTING: Eighteen-bed intensive care unit in a university hospital. PATIENTS: Forty postoperative patients with healthy lungs who had undergone brain tumour surgery. INTERVENTIONS: Randomisation either to the AM or SIMV weaning procedure after entering the ICU. MEASUREMENTS AND RESULTS: Total weaning time and number of manipulations on the ventilator were observed. Cardiocirculatory and respiratory parameters were measured consecutively at five points during the weaning period. No significant differences were seen for cardiocirculatory parameters, airway pressures and oxygenation between the two groups. There was a trend to shorter weaning times with AM (136 +/- 46 min vs 169 +/- 68 min, n.s.), the average number of manipulations on the ventilator was lower (0.55 +/- 0.69 vs 5.05 +/- 1.19,p < 0.001) and arterial partial pressure of carbon dioxide (PaCO2) levels showed fewer variations in the late phase of the weaning period (39.5 +/- 3.1 vs 38.3 +/- 7.2, p < 0.001 for differences in variance). CONCLUSIONS: Automatic, patient-triggered switching between controlled and supported mode of ventilation can be used for postoperative weaning of neurosurgical patients with healthy lungs. Compared to a SIMV weaning procedure, fewer manipulations on the ventilator are necessary and individual adaptation of ventilation seems to be more accurate.

Semifluorinated alkanes--a new class of excipients suitable for pulmonary drug delivery.

INTRODUCTION: Semifluorinated alkanes (SFAs) are considered as diblock molecules with fluorocarbon and hydrocarbon segments. Unlike Perfluorocarbons (PFCs), SFAs have the potential to dissolve several lipophilic or water-insoluble substances. This makes them possibly suitable as new excipients for inhalative liquid drug carrier systems. PURPOSE: The aim of the study was to compare physico-chemical properties of different SFAs and then to test their respective effects in healthy rabbit lungs after nebulisation. METHODS: Physico-chemical properties of four different SFAs, i.e. Perfluorobutylpentane (F4H5), Perfluorohexylhexane (F6H6), Perfluorohexyloctane (F6H8) and Perfluorohexyldodecane (F6H12) were measured. Based on these results, aerosol characteristics of two potential candidates suitable as excipients for pulmonary drug delivery, i.e. F6H8 and F4H5, were determined by laser light diffraction. Tracheotomised and ventilated New Zealand White rabbits were nebulised with either a high- or a low dose of SFAs (F6H8(low/high) and F4H5(low/high)) or saline (NaCl). Ventilated healthy animals served as controls (Sham). Arterial blood gases, lung mechanics, heart rate and blood pressure were recorded prior to nebulisation and in 30 min intervals during the 6-h study period. RESULTS: Out of the four SFAs studied initially, no satisfactory behaviour as a solvent has to be expected because of low lipophilicity for F6H6. Output rate during aerosolisation was very low for F6H12. F6H8 and F4H5 presented comparable aerosolisation characteristics and lipophilicity and were therefore tested in the in vivo model. Aerosol therapy, either SFAs or saline, impaired paO2/FiO2 ratio, dynamic lung compliance and respiratory mechanics in all groups, except for F4H5(low) group which behaved like the control group (Sham). F4H5(low) had no adverse effects on gas exchange or pulmonary mechanics. CONCLUSIONS: Perfluorobutylpentane (F4H5) in a low-dose application may be suitable as a new inhalable excipient in SFA-based pulmonary drug delivery systems for lipophilic or water-insoluble substances.

Allogeneic blood SCT for children with Hurler's syndrome: results from the German multicenter approach MPS-HCT 2005.

Hurler's syndrome is an inborn error of mucopolysaccharide metabolism leading to premature death in childhood. Allogeneic hematopoietic SCT can achieve long-term survival by correcting the enzymatic deficiency. In an attempt to improve long-term engraftment and to reduce regimen-related toxicity (RRT), a prospective multicenter approach was initiated in Germany using a fludarabine-based radiation-free preparative regimen. Between 2001 and 2008, 12 children were enrolled. Median age at SCT was 14 months (range, 4-31 months). The conditioning regimen contained fludarabine, BU, melphalan and antithymocyte globulin. CD34 positively selected PBSC were used in 10 children with a matched unrelated donor. Median cell dose was 24.6 x 10(6) CD34+ cells per kg (range 10.0-54.8). Two children with a matched sibling donor received non-manipulated BM. Donor lymphocyte infusions were given in 6/12 children for mixed hematopoietic chimerism. At a median follow-up of 29 months (range 2-85 months), all children engrafted and have either stabilized or improved neurological function. In total, 12/12 patients showed donor-derived engraftment with 9/12 having full and 3/12 having mixed hematopoiesis. One developed acute GVHD >or=grade II. RRT >or=grade II was observed in two patients.

[Haemodynamic effects of mechanical ventilation]. / Hämodynamische Effekte der mechanischen Beatmung.

Mechanical ventilation and positive end-expiratory pressure (PEEP) are considered to be the cornerstones of therapy for acute lung failure and acute respiratory distress syndrome (ARDS), when high levels of PEEP are applied in order to maintain or restore oxygenation, despite the fact that aggressive mechanical ventilation can markedly affect cardiac function in a complex and often unpredictable fashion. As heart rate usually does not change with PEEP, the entire fall in cardiac output is a consequence of a reduction in left ventricular stroke volume (LVSV). Therefore, changes in cardiac output caused by mechanical ventilation and PEEP are analyzed in terms of changes in SV and its determinants, i.e. preload, afterload, contractility and ventricular compliance. Mechanical ventilation with PEEP, like any other active or passive ventilatory maneuver, primarily affects cardiac function by changing lung volume and intrathoracic pressure (ITP). In order to describe the direct cardiocirculatory consequences of respiratory failure necessitating mechanical ventilation and PEEP, this review will focus on the effects of changes in lung volume, factors controlling venous return, the diastolic interactions between the ventricles and the effects of intrathoracic pressures on right and left ventricular function.

[High frequency oscillatory ventilation as therapy for acute lung injury and ARDS] . / Hochfrequenzoszillationsventilation (HFOV) bei akuter Lungenschädigung und ARDS.

Mechanical ventilation is the mainstay of therapy for acute lung injury, a disease with remainingly high morbidity and mortality. As a result of an improved understanding that mechanical ventilation itself can contribute to and aggravate the disease process, the term ventilator-associated lung injury (VALI) has been introduced. Main risk factor for VALI are (1) alveolar overdistention caused by excessivly high tidal volumes and/or inspiratory pressures (volu-/barotrauma), as well as (2) cyclic alveolar collapse promoted by insufficient endexpiratory pressure. So called "lung-protective ventilatory strategies" aim at minimizing these risk factors by the use of small tidal volumes and high PEEP levels. High frequency oscillatory ventilation (HFOV) can be regarded as an ultimate form of this approach, combining minimal pressure changes with a high continuous distending pressure (CDP). That CDP is generated using high fresh gas flows ("Super-CPAP"), while a piston pump incorporated into the system creates an oscillatory flow at frequencies ranging from 3-7 Hz. An initial lung volume recruitment manoeuvre is mandatory for the optimal use of HFOV. Whereas for many years HFOV is a well established therapy for the infant respiratory distress syndrome, experience in adults is still rare. First results, however, look promising, and HFOV might as well turn out as a valuable treatment modalitiy for ARDS.

Pulmonary gas distribution during ventilation with different inspiratory flow patterns in experimental lung injury -- a computed tomography study.

BACKGROUND: There is still controversy about the optimal inspiratory flow pattern for ventilation of patients with acute lung injury. The aim of this study was to compare the effects of pressure-controlled ventilation (PCV) with a decelerating inspiratory flow with volume-controlled ventilation (VCV) with constant inspiratory flow on pulmonary gas distribution (PGD) in experimentally induced ARDS. METHODS: Sixteen adult sheep were randomized to be ventilated with PCV or VCV after surfactant depletion by repeated bronchoalveolar lavage. Positive end-expiratory pressure (PEEP) was increased in a stepwise manner from zero end-expiratory pressure (ZEEP) to 7, 14 and 21 cm H(2)O in hourly intervals. Respiratory rate, inspiration-to-expiration ratio and tidal volume were kept constant. Central hemodynamics, gas exchange and airway pressures were measured. Electron beam computed tomographic (EBCT) scans of the entire lungs were performed at baseline (preinjury) and each level of end-expiratory pressure during an inspiratory and expiratory hold maneuver. The lungs were three-dimensionally reconstructed and volumetric assessments were made separating the lungs into four subvolumes classified as overinflated, normally aerated, poorly aerated and nonaerated. RESULTS: Pressure-controlled ventilation led to a decrease in peak airway pressure and an increase in mean airway pressure. No differences between groups were found regarding plateau pressures, hemodynamics and gas exchange. Recruitment, defined as a decrease in expiratory lung volume classified as nonaerated, was similar in both groups and predominantly associated with PEEP. Overinflated lung volumes were increased with PCV. CONCLUSIONS: In this model of acute lung injury, ventilation with decelerating inspiratory flow had no beneficial effects on PGD when compared with ventilation with constant inspiratory flow, while the increase in overinflated lung volumes may raise concerns regarding potential ventilator-associated lung injury.

Epidermal naevus and segmental hypermelanosis associated with an intraspinal mass: overlap between different mosaic neuroectodermal syndromes.

UNLABELLED: The epidermal naevus syndrome is a neurocutaneous syndrome characterised by the association of epidermal naevi with central nervous system, skeletal, ocular or cardiovascular abnormalities. We report on a 1.75-year-old boy who presented with spastic diparesis, a partial paresis of the left forearm and macrocephaly. He had a large epidermal naevus along the cervical spine and a segmental hypermelanosis. MRI studies revealed a large intraspinal mass extending from the lower cervical to the upper thoracic spine. The condition of our patient demonstrates the overlap of the epidermal naevus syndrome with well-defined mosaic neuroectodermal phenotypes such as encephalocraniocutaneous lipomatosis, Feuerstein-Mims syndrome and Proteus syndrome. CONCLUSION: we recommend evaluation of all patients with large epidermal naevi, especially in the head and neck region, for the presence of central nervous system abnormalities or neoplasms.

Effects of end-inspiratory and end-expiratory pressures on alveolar recruitment and derecruitment in saline-washout-induced lung injury -- a computed tomography study.

BACKGROUND: Lung protective ventilation using low end-inspiratory pressures and tidal volumes (VT) has been shown to impair alveolar recruitment and to promote derecruitment in acute lung injury. The aim of the present study was to compare the effects of two different end-inspiratory pressure levels on alveolar recruitment, alveolar derecruitment and potential overdistention at incremental levels of positive end-expiratory pressure. METHODS: Sixteen adult sheep were randomized to be ventilated with a peak inspiratory pressure of either 35 cm H2O (P35, low VT) or 45 cm H2O (P45, high VT) after saline washout-induced lung injury. Positive end-expiratory pressure (PEEP) was increased in a stepwise manner from zero (ZEEP) to 7, 14 and 21 cm of H2O in hourly intervals. Tidal volume, initially set to 12 ml kg(-1), was reduced according to the pressure limits. Computed tomographic scans during end-expiratory and end-inspiratory hold were performed along with hemodynamic and respiratory measurements at each level of PEEP. RESULTS: Tidal volumes for the two groups (P35/P45) were: 7.7 +/- 0.9/11.2 +/- 1.3 ml kg(-1) (ZEEP), 7.9 +/- 2.1/11.3 +/- 1.3 ml kg(-1) (PEEP 7 cm H2O), 8.3 +/- 2.5/11.6 +/- 1.4 ml kg(-1) (PEEP 14 cm H2O) and 6.5 +/- 1.7/11.0 +/- 1.6 ml kg(-1) (PEEP 21 cm H2O); P < 0.001 for differences between the two groups. Absolute nonaerated lung volumes during end-expiration and end-inspiration showed no difference between the two groups for given levels of PEEP, while tidal-induced changes in nonaerated lung volume (termed cyclic alveolar instability, CAI) were larger in the P45 group at low levels of PEEP. The decrease in nonaerated lung volume was significant for PEEP 14 and 21 cm H2O in both groups compared with ZEEP (P < 0.005). Over-inflated lung volumes, although small, were significantly higher in the P45 group. Significant respiratory acidosis was noted in the P35 group despite increases in the respiratory rate. CONCLUSION: Limiting peak inspiratory pressure and VT does not impair alveolar recruitment or promote derecruitment when using sufficient levels of PEEP.

Accidental intoxication with methylene dianiline p,p'-diaminodiphenylmethane: acute liver damage after presumed ecstasy consumption.

BACKGROUND: MDA is the abbreviation for methylene dianiline (p,p' diaminodiphenylmethane; 4,4'-methylenedianiline; CAS 101-77-9); and for methylendioxyamphetamine (MDMA, N, alpha-dimethyl-1,3-benzodioxole-5-ethanamine; CAS 42542-10-9). While the former is used for the production of polyurethane foams, the latter is a psychometric drug, which is becoming increasingly popular in the techno scene. METHODS: We report six participants of a technoparty (1 female, 5 males, ages 17-25) who were admitted to the hospital with severe colicky abdominal pain and subsequently developed symptoms of hepatotoxicity. They had ingested an alcoholic beverage that had been spiked with a powdery substance they dubbed MDA. RESULTS: All patients showed similar clinical symptoms, with an identical time course. Acute jaundice developed within 2 days after ingestion. Enzymes indicating cholestasis increased steadily over 7 days and reached peak values of 800 U/L (AP) and 380 U/L (GGT), whereas transaminases remained moderately elevated. Between days 5 and 7, all patients became febrile for one day, their body temperatures rising up to 40 degrees C. There was no evidence for hemolysis or an infectious hepatitis. Toxicological analysis revealed the presence of p,p'-diaminodiphenylmethane (4,4'-methylenedianiline) at a concentration of 130 mg/L in one of two urine extracts examined. CONCLUSIONS: The analytical data indicate that the participants of the technoparty assumed the aniline-derivative, the cause of Epping Jaundice, was methylendioxyamphetamine because the same abbreviation, MDA, is used for both compounds. An overview of the acute liver toxicity of aniline derivatives is given and the possibility of amphetamine-induced liver damage is discussed.