To block, or not to block is it still the question? Effectiveness of alpha- and beta-blockade in phaeochromocytoma surgery: an institutional analysis.

INTRODUCTION: Phaeochromocytomas/paraganglioma (PPGL) surgery was historically associated with significant risks of perioperative complications. The decreased mortality (<3.0%) had been attributed in part to optimal preoperative alpha-blockade. The value of alpha-blockade in decreasing morbidity is being challenged. The aim of our study is to present an institutional experience of preoperative alpha-blocking of PPGL and its effect on cardiovascular stability and postoperative morbidity. METHODS: A retrospective study using data from our institutional database was conducted. All patients undergoing adrenalectomy for PPGL from October 2011 to September 2020 were included. All patients were routinely alpha-blocked. Intraoperative cardiovascular instability (ICI) was assessed through number of systolic blood pressure (SBP) episodes >160mmHg, SBP <90mmHg, the need for vasoactive drugs and volume of intraoperative crystalloids administered. Morbidity was also evaluated. RESULTS: A total of 100 consecutive patients undergoing surgery were identified of whom 53 patients had complete anaesthetic records available for analysis. Thirty-two patients (60%) had at least one episode with an SBP >160mmHg. Nine (17%) cases had no intraoperative hypotensive episodes, while 3 (6%) patients had >10 intraoperative episodes of an SBP <90mmHg. Twenty-one (40%) patients received vasoactive drugs during surgery. The median volume of intraoperative crystalloids was 2 litres (1-4). Postoperatively, no patient experienced cardiovascular complications, including arrhythmia or myocardial ischaemia. Only two were admitted to an intensive care unit (ICU) and one 30-day readmission occurred. CONCLUSIONS: Cardiac instability remained significant in PPGL surgery despite optimal alpha- and beta-blockade. While omitting blockade would appear empirically questionable, a randomised controlled trial (RCT) of surgery with and without alpha-blockade will provide an answer.

To block, or not to block is it still the question? Effectiveness of alpha- and beta-blockade in phaeochromocytoma surgery: an institutional analysis.

INTRODUCTION: Phaeochromocytomas/paraganglioma (PPGL) surgery was historically associated with significant risks of perioperative complications. The decreased mortality (<3.0%) had been attributed in part to optimal preoperative alpha-blockade. The value of alpha-blockade in decreasing morbidity is being challenged. The aim of our study is to present an institutional experience of preoperative alpha-blocking of PPGL and its effect on cardiovascular stability and postoperative morbidity. METHODS: A retrospective study using data from our institutional database was conducted. All patients undergoing adrenalectomy for PPGL from October 2011 to September 2020 were included. All patients were routinely alpha-blocked. Intraoperative cardiovascular instability (ICI) was assessed through number of systolic blood pressure (SBP) episodes >160mmHg, SBP <90mmHg, the need for vasoactive drugs and volume of intraoperative crystalloids administered. Morbidity was also evaluated. RESULTS: A total of 100 consecutive patients undergoing surgery were identified of whom 53 patients had complete anaesthetic records available for analysis. Thirty-two patients (60%) had at least one episode with an SBP >160mmHg. Nine (17%) cases had no intraoperative hypotensive episodes, while 3 (6%) patients had >10 intraoperative episodes of an SBP <90mmHg. Twenty-one (40%) patients received vasoactive drugs during surgery. The median volume of intraoperative crystalloids was 2 litres (1-4). Postoperatively, no patient experienced cardiovascular complications, including arrhythmia or myocardial ischaemia. Only two were admitted to an intensive care unit (ICU) and one 30-day readmission occurred. CONCLUSIONS: Cardiac instability remained significant in PPGL surgery despite optimal alpha- and beta-blockade. While omitting blockade would appear empirically questionable, a randomised controlled trial (RCT) of surgery with and without alpha-blockade will provide an answer.

The changing face of reoperative parathyroidectomy: a single-centre comparison of 147 parathyroid reoperations.

INTRODUCTION: Reoperative parathyroidectomy for persistent and recurrent primary hyperparathyroidism is dependent on radiology. This study aimed to compare outcomes in reoperative parathyroidectomy at a single centre using a combination of traditional and newer imaging studies. MATERIALS AND METHODS: Retrospective case note review of all reoperative parathyroidectomies for persistent and recurrent primary hyperparathyroidism over five years (June 2014 to June 2019; group A). Imaging modalities used and their positive predictive value, complications and cure rates were compared with a published dataset spanning the preceding nine years (group B). RESULTS: From over 2000 parathyroidectomies, 147 were reoperations (101 in group A and 46 in group B). Age and sex ratios were similar (56 vs 62 years; 77% vs 72% female). Ultrasound use remains high and shows better positive predictive value (76% vs 57 %). 99mTc-sestamibi use has declined (79% vs 91%) but the positive predictive value has improved (74% vs 53%). 4DCT use has almost doubled (61% vs 37%) with better positive predictive value (88% vs 75%). 18F-fluorocholine positron emission tomography-computed tomography and ultrasound-guided fine-needle aspiration for parathyroid hormone are novel modalities only available for group A. Both carried a positive predictive value of 100%. Venous sampling with or without angiography use has decreased (35% vs 39%) but maintains a high positive predictive value (86% vs 91%). Cure rates were similar (96% vs 100%). Group A had 5% permanent hypoparathyroidism, 1% permanent vocal cord palsy and 1% haematoma requiring reoperation. No complications for group B. CONCLUSION: Optimal imaging is key to good cure rates in reoperative parathyroidectomy. High-quality, non-interventional imaging techniques have produced a shift in the preoperative algorithm without compromising outcomes.

Does fluoroscopy prevent inadvertent parathyroidectomy in thyroid surgery?

INTRODUCTION: Near-infrared imaging may facilitate intraoperative identification of parathyroid glands by causing autofluorescence but its clinical value has not been established. Inadvertent parathyroidectomy occurs in 5-22% of thyroidectomies and is associated with temporary and permanent hypoparathyroidism. The aim of this study was to determine whether near-infrared imaging prevents inadvertent parathyroidectomy and early hypocalcaemia as a surrogate for permanent hypoparathyroidism. MATERIALS AND METHODS: Near-infrared imaging was used in a prospective cohort of consecutive thyroidectomies. Thyroidectomies performed prior to the introduction of near-infrared imaging formed a control group. The thyroid bed and specimen were scanned with near-infrared imaging. Areas of autofluorescence on the specimen were examined and any parathyroid tissue found was autotransplanted. Inadvertent parathyroidectomy was therefore recorded as established intraoperatively by near-infrared imaging (allowing autotransplantation) or on subsequent histology (missed). Serum calcium and parathyroid hormone were measured on day one and at two weeks and six months postoperatively. RESULTS: A total of 269 patients were included: 106 near-infrared imaging and 163 controls. Inadvertent parathyroidectomy was detected by near-infrared imaging in two (and autotransplantation performed) and histologically (i.e. missed by near-infrared imaging in 13, 12.3% vs 17, 10.4% controls). Neither result was statistically significant (P = 0.08, 0.89). There was no significant difference in serum calcium or parathyroid hormone between near-infrared imaging and control groups at one day, two weeks or thereafter. DISCUSSION: Near-infrared imaging may detect inadvertent parathyroidectomy and may allow autotransplantation. It did not, however, reduce the incidence of missed inadvertent parathyroidectomy and no difference was seen in early hypocalcaemia or late hypoparathyroidism. Current near-infrared imaging technology does not appear to confer a clinical benefit sufficient to justify its use.

Risk of needing completion thyroidectomy for low-risk papillary thyroid cancers treated by lobectomy.

Background: Low-risk differentiated thyroid cancers may, according to the American Thyroid Association (ATA) 2015 guidelines, be managed initially with lobectomy. However, definitive risk categorization requires pathological assessment of the specimen, resulting in completion thyroidectomy being recommended when discordance between preoperative and postoperative staging occurs. This study sought to establish the expected rate of completion thyroidectomy in patients with papillary thyroid cancer (PTC) treated by lobectomy. Methods: Patients with PTC treated over 5 years (2013-2017 inclusive) and meeting the ATA criteria for lobectomy were identified from the prospectively developed database of a high-volume, university department of endocrine surgery. Concordance between the ATA initial and final recommendation, and the putative rate of completion thyroidectomy were calculated. Multivariable analysis was used to assess preoperative factors as predictors of the need for total thyroidectomy. Results: Of 275 patients with PTC who met ATA preoperative criteria for lobectomy there was concordance between this and the final recommendation in 158 (57·5 per cent) and discordance in 117 (43·5 per cent). Most common reasons for discordance were: angioinvasion (30·8 per cent), local invasion (23·9 per cent) or both (20·5 per cent). Four patients (1·5 per cent) had permanent hypoparathyroidism. On multivariable analysis, age, sex, tumour size and family history did not independently predict the final treatment required. Conclusion: Although many patients may be treated adequately with lobectomy, just under half would require completion thyroidectomy. Further work is needed on preoperative risk stratification but, before this, total thyroidectomy remains the treatment of choice for low-risk 1-4-cm PTC in the hands of high-volume thyroid surgeons who can demonstrate low complication rates.

Effects of expiratory muscle activation via high-frequency spinal cord stimulation.

In persons with spinal cord injury, lower thoracic low-frequency spinal cord stimulation (LF-SCS; 50 Hz, 15 mA) is a useful method to restore an effective cough. Unfortunately, the high-stimulus-amplitude requirements and potential activation of pain fibers significantly limit this application in persons with intact sensation. In this study, the mechanism of the expiratory muscle activation, via high-frequency SCS (HF-SCS; 500 Hz, 1 mA) was evaluated in dogs. In group 1, the effects of electrode placement on airway pressure generation (P) was evaluated. Maximal P occurred at the T9-T10 level with progressive decrements in P at more rostral and caudal levels for both LF-SCS and HF-SCS. In group 2, electromyographic (EMG) latencies of internal intercostal muscle (II) activation were evaluated before and after spinal root section and during direct motor root stimulation. Onset time of II EMG activity during HF-SCS was significantly longer (3.84 ± 1.16 ms) than obtained during direct motor root activation (1.61 ± 0.10 ms). In group 3, P and external oblique (EO) EMG activity, before and after sequential spinal section at the T11-T12 level, were evaluated. Bilateral dorsal column section significantly reduced EO EMG activity below the section and resulted in a substantial fall in P. Subsequent lateral funiculi section completely abolished those activities and resulted in further reductions in P. We conclude that 1) activation of the expiratory muscles via HF-SCS is dependent entirely on synaptic spinal cord pathways, and 2) HF-SCS at the T9 level produces a comparable level of muscle activation with that achieved with LF-SCS but with much lower stimulus amplitudes. NEW & NOTEWORTHY The findings in the present study suggest that lower thoracic high-frequency spinal cord stimulation with low stimulus currents results in sufficient activation of the expiratory muscles via spinal circuitry to produce large positive airway pressures sufficient to generate an effective cough mechanism. This method, therefore, may be applied in patient populations with intact sensation such as stroke and amyotrophic lateral sclerosis to restore an effective cough.

High frequency spinal cord stimulation-New method to restore cough.

Spinal cord stimulation (SCS, 50Hz) is a useful method to restore an effective cough in persons with spinal cord injury (SCI). However, high stimulus amplitudes and potential activation of pain fibers, significantly limits this application. It is our hypothesis that high frequency SCS (HF-SCS), with low stimulus amplitudes may provide the same level of expiratory muscle activation. In 6 dogs, the effects of SCS, with varying stimulus parameters on positive pressure (P) generation was evaluated. At any given level of stimulus current, mean P was largest at 500Hz, compared to all other stimulus frequencies. For example, with stimulation at 1mA and frequencies of 200, 500 and 600Hz, P were 25±3, 58±4, 51±6cmH2O, respectively. By comparison, P achieved with conventional SCS parameters was 61±5cmH2O. HF-SCS results in a comparable P compared to that achieved with conventional stimulus parameters but with much lower stimulus amplitudes. This method may be useful to restore cough even in subjects with intact sensation.

Evaluation of an electromagnetic 3D navigation system to facilitate endovascular tasks: a feasibility study.

INTRODUCTION: We describe a novel approach to arterial cannulation using the StealthStation(®) Guidance System (Medtronic, USA). This uses electromagnetic technology to track the guidewire, displaying a 3D image of the vessel and guidewire. METHODS: The study was performed on a 'bench top' simulation model called the Cannulation Suite comprising of a silicone aortic arch model and simulated fluoroscopy. The accuracy of the StealthStation(®) was assessed. 16 participants of varying experience in performing endovascular procedures (novices: 6 participants, ≤5 procedures performed; intermediate: 5 participants, 6-50 procedures performed; experts: 5 participants, >50 procedures performed) underwent a standardised training session in cannulating the left subclavian artery on the model with the conventional method (i.e. with fluoroscopy) and with the StealthStation(®). Each participant was then assessed on cannulating the left subclavian artery using the conventional method and with the StealthStation(®). Performance was video-recorded. The subjects then completed a structured questionnaire assessing the StealthStation(®). RESULTS: The StealthStation(®) was accurate to less than 1 mm [mean (SD) target registration error 0.56 mm (0.91)]. Every participant was able to complete the cannulation task with a significantly lower use of fluoroscopy with the navigation system compared with the conventional method [median 0 s (IQR 0-2) vs median 14 s (IQR 10-19), respectively; p = <0.001]. There was no significant difference between the StealthStation(®) and conventional method for: total procedure time [median 17 s (IQR 9-53) vs median 21 s (IQR 11-32), respectively; p=0.53]; total guidewire hits to the vessel wall [median 0 (IQR 0-1) vs median 0 (IQR 0-1), respectively; p=0.86]; catheter hits to the vessel wall [median 0.5 (IQR 0-2) vs median 0.5 (IQR 0-1), respectively; p=0.13]; and cannulation performance on the global rating scale [median score, 39/40 (IQR 28-39) vs 38/40 (IQR 33-40), respectively; p=0.40]. The intra-class correlation coefficient for agreement between video-assessors for all scores was 0.99. 88% strongly agreed that the StealthStation(®) can potentially decrease exposure of the patient to contrast and radiation. CONCLUSION: Arterial cannulation is feasible with the StealthStation(®).

Minimally-invasive fixation of distal extra-articular femur fractures with locking plates: limitations and failures.

Minimally-invasive fixation using a locking plate and early motion is normal practice. However, technical errors and pitfalls are common. This surgery has a set of rules that encompass both the mechanics of the internal fixation system and the implantation itself. If these rules are not strictly followed, alignment defects and/or early failure of the fixation can occur. We analysed four cases of clinical failure that were encountered after minimally-invasive distal femoral extra-articular fixation with locking plates. The following rules must be followed with this technique: extra-articular fracture, minimally-invasive approach, long plate alternating between locking screw and empty hole (five holes on either side of fracture), bi-cortical screws, placement of locking screws near a complex fracture but away from a simple fracture. Osteoporotic bone, obesity that interferes with the instrumentation, articular fracture, horizontal fracture line and surgeon experience are all limitations of this minimally-invasive technique.

Variations in paranasal sinus anatomy: implications for the pathophysiology of chronic rhinosinusitis and safety of endoscopic sinus surgery.

OBJECTIVES: To study the radiologic anatomy of the paranasal sinuses in patients with and without chronic rhinosinusitis to assess whether anatomic variations are associated with disease pathology, and to identify those variants that may impact operative safety. SETTING: Tertiary referral otolaryngology unit. MAIN OUTCOME MEASURES: Incidence and nature of anatomic variants with potential impact on operative safety, and the presence or absence of sinus mucosal disease and its correlation with anatomic variants with a potential impact on mucociliary clearance. METHODS: We reviewed 278 computed tomographic scans from patients with rhinosinusitis symptoms to investigate anatomic variations that may predispose to sinusitis or impact on operative safety. The incidence of variants with potential impact on sinus drainage was compared between patients with and without sinus mucosal disease with logistic regression. RESULTS: A closed osteomeatal complex was identified in 148 patients (53%), followed by concha bullosa in 98 patients (35%). Closed osteomeatal complex and nasal polyposis were independent risk factors for sinus mucosal disease. Anatomic variants with a potential impact on operative safety included anterior clinoid process pneumatization (18%), infraorbital ethmoid cell (12%), sphenomaxillary plate (11%), and supraorbital recess (6%). In 92% of patients, the level difference between the roof of the ethmoid cavity and the cribriform plate was Keros I. CONCLUSIONS: Bony anatomic variants do not increase the risk of sinus mucosal disease. However, anatomic variants with a potential impact on operative safety occur frequently and need to be specifically sought as part of preoperative evaluation.

The range and nature of sleep dysfunction in untreated Parkinson's disease (PD). A comparative controlled clinical study using the Parkinson's disease sleep scale and selective polysomnography.

In this study we have explored the nature and range of sleep dysfunction that occurs in untreated Parkinson's disease (PD) comparing data obtained from the use of the Parkinson's disease sleep scale (PDSS) in an untreated PD patient group compared to advanced PD and healthy controls. 25 untreated (drug-naive, DNPD) PD patients (mean age 66.9 years, range 53-80, 18 males) completed the validated Parkinson's disease sleep scale (PDSS), mean duration of PD was 2.1 years (1-10, up to 4 years in all except one patient with tremulous PD reporting tremor duration of 10 years) and mean Hoehn and Yahr score 1.9 (1-3). Data were compared to 34 advanced PD (mean age 70.2 years, range 51-88, 23 male), mean duration of PD 11 years (range 4-22), mean Hoehn and Yahr score 3.4 (3-5) and PDSS data obtained from 131 healthy controls (mean age 66.6 years, range 50-93, 56 males). Total PDSS scores and PDSS sub-items, except PDSS item 2, were highly significantly different (p<0.001) between DNPD, advanced PD and controls. Controls reported higher mean PDSS scores than both groups of patients, and advanced cases reported lower (mean+/-S.D.) PDSS scores (86.95+/-20.78) than drug-naive (105.72+/-21.5) (p<0.001). Logistic regression analysis showed that items PDSS8 (nocturia), PDSS11 (cramps), PDSS12 (dystonia), PDSS13 (tremor), and PDSS15 (daytime somnolence) were significantly impaired in DNPD compared to controls while PDSS7 (nighttime hallucinations) additionally separated advanced PD from DNPD. In a subgroup of 11 advanced PD cases (mean age 62 years, range=49-84 years, mean Hoehn and Yahr score 2.5, range=1-3) with high Epworth Sleepiness Scale (ESS) scores (mean 14.5), low item 15 PDSS score (mean 4.7) and complaints of severe daytime sleepiness, underwent detailed overnight polysomnography (PSG) studies, all showing abnormal sleep patterns. We conclude that nocturia, nighttime cramps, dystonia, tremor and daytime somnolence seem to be the important nocturnal disabilities in DNPD and some of these symptoms may be reminiscent of "off" period related symptoms even though patients are untreated. Furthermore, polysomnography in "sleepy" PD patients may help diagnose unrecognised conditions such as periodic limb movement of sleep (PLMS), obstructive sleep apnoea (OSA) and REM Sleep Behaviour Disorder.

The learning curve for investigational surgery: lessons learned from laparoscopic diaphragm pacing for chronic ventilator dependence.

BACKGROUND: Electrical stimulation of the phrenic nerve motor point of the diaphragm through laparoscopic implantation of a pacing system is an option for high spinal cord-injured patients with chronic respiratory insufficiency. This study assesses the operative learning curve for the initial series of patients. METHOD: A series of six patients underwent laparoscopic placement of a diaphragm pacing system. The operative procedure was divided into the following four steps for analysis and rapid adjustment after each operation: exposure of the diaphragm, mapping of the phrenic nerve motor point, implantation of the pacing electrodes, and final routing of the wires to the external system. RESULTS: The first case required two operations, and the second case was unsuccessful because of a nonfunctioning phrenic nerve that led to a change in the preoperative screening criteria. The operative time decreased from 469 min for the first operation to 165 min for the sixth operation. The significant time decrease can be attributed to changes in the mapping and routing aspects of the operation. Key changes during this series that helped to reduce the operative time include abandonment of a software-dependent mapping technique, development of a grid algorithm for mapping, software improvement to increase the speed of stimulation and mapping, refinement of the mapping probe to maintain adequate suction on the diaphragm, shortening of the electrode lengths, and experience with the implantation of connections to the external electrodes. Presently, all five of the successfully implanted patients can be maintained on prolonged ventilatory support with the device. CONCLUSION: Analysis of every step of this investigational procedure enabled us to make rapid changes in surgical protocol, leading to decreases in operative times and expectant improvements in patient safety and efficacy. In this series, analysis was the key to developing a low-risk cost-effective outpatient diaphragm pacing system.

Gas exchange during separate diaphragm and intercostal muscle breathing.

In patients with diaphragm paralysis, ventilation to the basal lung zones is reduced, whereas in patients with paralysis of the rib cage muscles, ventilation to the upper lung zones in reduced. Inspiration produced by either rib cage muscle or diaphragm contraction alone, therefore, may result in mismatching of ventilation and perfusion and in gas-exchange impairment. To test this hypothesis, we assessed gas exchange in 11 anesthetized dogs during ventilation produced by either diaphragm or intercostal muscle contraction alone. Diaphragm activation was achieved by phrenic nerve stimulation. Intercostal muscle activation was accomplished by electrical stimulation by using electrodes positioned epidurally at the T(2) spinal cord level. Stimulation parameters were adjusted to provide a constant tidal volume and inspiratory flow rate. During diaphragm (D) and intercostal muscle breathing (IC), mean arterial Po(2) was 97.1 +/- 2.1 and 88.1 +/- 2.7 Torr, respectively (P < 0.01). Arterial Pco(2) was lower during D than during IC (32.6 +/- 1.4 and 36.6 +/- 1.8 Torr, respectively; P < 0.05). During IC, oxygen consumption was also higher than that during D (0.13 +/- 0.01 and 0.09 +/- 0.01 l/min, respectively; P < 0.05). The alveolar-arterial oxygen difference was 11.3 +/- 1.9 and 7.7 +/- 1.0 Torr (P < 0.01) during IC and D, respectively. These results indicate that diaphragm breathing is significantly more efficient than intercostal muscle breathing. However, despite marked differences in the pattern of inspiratory muscle contraction, the distribution of ventilation remains well matched to pulmonary perfusion resulting in preservation of normal gas exchange.

The Parkinson's disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson's disease.

BACKGROUND: No formal instruments are available for quantifying sleep problems in Parkinson's disease. OBJECTIVE: To develop a new sleep scale to quantify the various aspects of nocturnal sleep problems in Parkinson's disease, which may occur in up to 96% of affected individuals. METHODS: Employing a multidisciplinary team approach, a visual analogue scale was devised addressing 15 commonly reported symptoms associated with sleep disturbance in Parkinson's disease-the Parkinson's disease sleep scale (PDSS). In all, 143 patients with Parkinson's disease completed the PDSS, covering the entire spectrum of disease from newly diagnosed to advanced stage. As controls, 137 age healthy matched subjects also completed the scale. Test-retest reliability was assessed in a subgroup of subjects. The Epworth sleepiness scale was also satisfactorily completed by 103 of the patients with Parkinson's disease. RESULTS: PDSS scores in the Parkinson group were significantly different from the healthy controls. Patients with advanced Parkinson's disease had impaired scores compared with early/moderate disease. Individual items of the scale showed good discriminatory power between Parkinson's disease and healthy controls. Relevant items of the PDSS correlated with excessive daytime sleepiness. The scale showed robust test-retest reliability. CONCLUSIONS: This appears to be the first description of a simple bedside screening instrument for evaluation of sleep disturbances in Parkinson's disease. A combination of subitems may help identify specific aspects of sleep disturbance, which in turn may help target treatment.

Mechanism of expiratory muscle activation during lower thoracic spinal cord stimulation.

Lower thoracic spinal cord stimulation (SCS) may be a useful method to restore an effective cough mechanism. In dogs, two groups of studies were performed to evaluate the mechanism of the expiratory muscle activation during stimulation at the T(9)-T(10) level, which results in the greatest changes in airway pressure. In one group, expiratory muscle activation was monitored by evoked muscle compound action potentials (CAPs) from the internal intercostal muscles in the 10th, 11th, and 12th interspaces and from portions of the external oblique innervated by the L(1) and L(2) motor roots. SCS, applied with single shocks, resulted in short-latency CAPs at T(10) but not at more caudal levels. SCS resulted in long-latency CAPs at each of the more caudal caudal recording sites. Bilateral dorsal column sectioning, just below the T(11) spinal cord level, did not affect the short-latency CAPs but abolished the long-latency CAPs and also resulted in a fall in airway pressure generation. In the second group, sequential spinal root sectioning was performed to assess their individual mechanical contribution to pressure generation. Section of the ventral roots from T(8) through T(10) resulted in negligible changes, whereas section of more caudal roots resulted in a progressive reduction in pressure generation. We conclude that 1) SCS at the T(9)-T(10) level results in direct activation of spinal cord roots within two to three segments of the stimulating electrode and activation of more distal roots via spinal cord pathways, and 2) pathway activation of motor roots makes a substantial contribution to pressure generation.

Dichloroacetate reduces diaphragmatic lactate formation but impairs respiratory performance.

Previous studies have found that administration of dichloroacetate (DCA), an agent that reduces lactic acid generation, increases limb muscle endurance. The purpose of the present study was to determine if this agent also improves respiratory muscle performance. To examine this issue, we determined the effect of DCA administration on the response to application of a large inspiratory resistive load (32,000 cm H(2)O/L/s) in unanesthetized decerebrate rats. Studies were carried out in four groups of animals: saline unloaded, DCA unloaded, saline loaded, and DCA loaded. DCA was administered as 100 mg/kg, given intravenously over 30 min, prior to respiratory loading. We found that diaphragm lactate levels were higher in saline-treated loaded animals than in unloaded controls and that DCA administration prevented loading-induced increases in diaphragm lactate (p < 0.001). DCA-treated animals tolerated loading poorly, however, with a more rapid reduction in diaphragm pressure generation and a shorter time to respiratory arrest (42 +/- 3 min) than for saline-treated animals (57 +/- 3 min, p < 0.01). These data indicate that DCA administration decreases the tolerance to loaded breathing despite reductions in diaphragm lactate concentrations. We speculate that suppression of lactate formation by DCA may impair metabolic regulation within the diaphragm during resistive loaded breathing.

Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis.

Recent studies have indicated that sepsis is associated with enhanced generation of several free-radical species (nitric oxide [NO], superoxide, hydrogen peroxide) in skeletal muscle. It is also known that this enhanced free-radical generation results in reductions in skeletal muscle force-generating capacity, but the precise mechanism(s) by which free radicals exert this effect in sepsis has not been determined. We postulated that free radicals might react directly with the contractile proteins in this condition, altering contractile protein force-generating capacity. To test this theory, we compared the force generation of single Triton-skinned diaphragmatic fibers (Triton skinning exposes the contractile apparatus, permitting direct assessment of contractile protein function) from the following groups of rats: (1) control animals; (2) endotoxin-treated animal; (3) animals given endotoxin plus polyethylene glycol- superoxide dismutase (PEG-SOD), a superoxide scavenger; (4) animals given endotoxin plus N(omega)-nitro-L-arginine methylester (L-NAME), a NO synthase inhibitor; (5 ) animals given only PEG-SOD or L-NAME; and (6 ) animals given endotoxin plus denatured PEG-SOD. We found that endotoxin administration produced both a reduction in the maximum force-generating capacity (Fmax) (i.e., a decrease in Fmax) of muscle fibers and a reduction in fiber calcium sensitivity (i.e., an increase in the Ca2+ concentration required to produce half-maximal activation [Ca50]). L-NAME and PEG-SOD administration preserved Fmax and Ca50 in endotoxin-treated animals; neither drug affected these parameters in non-endotoxin treated animals. Denatured PEG-SOD failed to inhibit endotoxin-related alterations in contractile protein function. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of skinned fibers from endotoxin-treated animals revealed a selective depletion of several proteins; administration of L-NAME or PEG-SOD to endotoxin-treated animals prevented this protein depletion, paralleling the effect of these two agents to prevent a reduction in contractile protein force-generating capacity. These data indicate that free radicals (superoxide, NO, or daughter species of these radicals) play a central role in altering skeletal muscle contractile protein force-generating capacity in endotoxin-induced sepsis.

Neural prostheses in the respiratory system.

Approximately 5% of spinal cord-injured individuals suffer from respiratory muscle paralysis and require chronic mechanical ventilation. Unfortunately, this form of life support is associated with a number of undesirable side effects and discomforts. The only available alternative to mechanical ventilation is diaphragm pacing via bilateral phrenic nerve stimulation. This technique can provide patients with marked improvements in life quality and offers significant advantages compared to mechanical ventilation. Many patients, however, do not have bilateral phrenic function or are not willing to accept the risks inherent with phrenic nerve pacing and therefore are not candidates for this technique. Two alternative methods to ventilate patients with ventilator-dependent tetraplegia are reviewed in this paper. In patients with only a single functional phrenic nerve who are therefore not candidates for phrenic nerve pacing, combined intercostal muscle and unilateral phrenic nerve stimulation has recently been shown to maintain ventilatory support. In patients with bilateral phrenic nerve function, on-going studies suggest that intramuscular diaphragm pacing may be a useful alternative to direct phrenic nerve pacing. With the electrodes placed into the diaphragm laparoscopically, this method allows for the diaphragm to be activated without manipulation of the phrenic nerve, need for thoracotomy, or hospitalization. Both techniques provide benefits similar to that derived from bilateral phrenic nerve pacing and hold promise as alternative methods of ventilatory support in selected populations groups.

PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species.

Contraction-induced respiratory muscle fatigue and sepsis-related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A(2) (PLA(2))-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA(2) activity. To test these hypotheses, we examined H(2)O(2) generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA(2) inhibitors on H(2)O(2) formation. We found that 1) calcium and ADP stimulated H(2)O(2) formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H(2)O(2) formation than mitochondria from control animals under basal, calcium-stimulated, and ADP-stimulated conditions; and 3) inhibitors of 14-kDa PLA(2) blocked the enhanced H(2)O(2) generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA(2) activation) increased mitochondrial H(2)O(2) formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA(2) activation.