Clinical Implications and Hospital Outcome of Immune-Mediated Myositis in Horses.

BACKGROUND: Immune-mediated myositis (IMM) is a cause of rhabdomyolysis, stiffness, and muscle atrophy predominantly affecting Quarter horses. Limited information is available with regard to outcome, prognostic indicators, and associations with concurrent diseases. HYPOTHESIS/OBJECTIVES: To report outcomes and associations between outcome and clinical and laboratory parameters, and presence of concurrent illness. ANIMALS: Sixty-eight horses; 52 Quarter horses and related breeds and 16 other breeds. METHODS: Retrospective cohort study (1991-2014). Medical records of horses with histological diagnosis of IMM were reviewed. Data recovery included signalment, laboratory variables, therapy, and outcome. Logistic regression was used to quantify the association between potential prognostic factors and survival to discharge. RESULTS: Quarter horses were younger (mean < 4 years, range 3 months-21 years) than other breeds (mean < 10 years, range 1-23 years). Pathogens causing concurrent or recent infection included S. equi equi, S. equi zooepidemicus, C. pseudotuberculosis, Anaplasma phagocytophilum, herpes virus-1, and influenza. The most common clinical signs consisted of rapidly progressive diffuse symmetrical muscle atrophy (80%), stiff gait (74%), and fever (44%). All horses that received medical therapy immediately upon admission survived to discharge (survival proportion = 87%). Leucocytosis was a common finding (60%). Horses with concurrent fever and other illness had a poor prognosis for hospital discharge. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses with IMM can have a favorable outcome. Horses with concurrent fever and another illness had decreased probability of survival to discharge.

Prolonged attenuation of acetylcholine-induced phosphorylation of extracellular signal-regulated kinase 1/2 following sevoflurane exposure.

BACKGROUND: Volatile anaesthetics are known to affect cholinergic receptors. Perturbation of cholinergic signalling can cause cognitive deficits. In this study, we wanted to evaluate acetylcholine-induced intracellular signalling following sevoflurane exposure. METHODS: Pheochromocytoma12 PC12 cells were exposed to 4.6% sevoflurane for 2 h. Subsequently, Western blotting was used to measure acetylcholine-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) 1/2 and basal Protein kinase B (AKT) phosphorylation. RESULTS: After exposure, acetylcholine-induced ERK 1/2 phosphorylation was reduced to 58 ± 8% [95% confidence interval (CI): 38-77%, P = 0.003] compared with non-exposed controls. At 30 min after the end of sevoflurane administration [at 0.7% sevoflurane (0.102 mM)], ERK 1/2 phosphorylation remained reduced to 57 ± 7% (95% CI: 39-74%, P = 0.001) and was at 120 min [0.02% (0.003 mM] still reduced to 63 ± 10% (95% CI: 37-88%, P = 0.01), compared with control. At 360 min after exposure, acetylcholine-induced ERK 1/2 phosphorylation had recovered to 98 ± 16% (95% CI: 45-152%, P = 0.98) compared with control. In contrast, immediately after sevoflurane exposure, basal AKT phosphorylation was increased by 228 ± 37% (95% CI: 133-324%, P = 0.02) but had returned to control levels at 30 min after exposure, 172 ± 67% (95% CI: 0-356%, P = 0.34). CONCLUSION: Sevoflurane exposure has differential effects on different intracellular signalling pathways. On one hand, we observed a prolonged attenuation of acetylcholine-induced ERK 1/2 phosphorylation that persisted even when sevoflurane concentrations close to detection level. On the other hand, basal AKT phosphorylation was increased twofold during sevoflurane exposure, with a rapid return to baseline levels after exposure. We speculate that the effects on acetylcholine-induced intracellular signalling observed in our in vitro model could be of relevance also for cholinergic signalling in vivo following sevoflurane exposure.

Breathing and swallowing in normal man--effects of changes in body position, bolus types, and respiratory drive.

BACKGROUND: Coordination of breathing and swallowing is essential for airway protection and dyscoordination may cause morbidity and mortality. METHODS: Using a recently developed technique for high accuracy respiratory measurements of airflow during swallowing, we investigated the effects of body position (upright vs left lateral), bolus type (spontaneously swallowed saliva vs water), and respiratory drive (normo- vs hypercapnia) on coordination of breathing and swallowing in 32 healthy volunteers. KEY RESULTS: Swallows were in all cases (100%) proceded by expiration and 98% were also followed by expiration, regardless of body position, bolus type, or respiratory drive. While the endpoint of postswallow apnea correlated well to the endpoint of pharyngeal swallowing, duration of preswallow apnea was highly variable. In a small fraction of swallows followed by inspiration (3%), the expiratory phase before swallowing and duration of postswallow apnea was significantly longer. Body position and respiratory drive affected the increase in upper esophageal sphincter tone during inspiration. Increased respiratory drive also reduced swallowing frequency and shortened duration of preswallow apnea. Water swallows had longer duration of preswallow apnea. CONCLUSIONS & INFERENCES: Swallowing occurs during the expiratory phase of respiration, and the fraction of swallows preceded and followed by expiration approach 100% in healthy humans. This integration between breathing and swallowing remains unchanged regardless of body position, bolus characteristics, or respiratory drive. Our results provide a platform for future studies aiming at understanding how this integration is changed by aging, diseases, and drugs.

Swallowing and respiratory pattern in young healthy individuals recorded with high temporal resolution.

The coordination of swallowing and respiration is essential for a safe swallow. Swallowing consists of several subsecond events. To study this, it is important to use modalities with high temporal resolution. In this study, we have examined young healthy individuals with simultaneous videofluoroscopy, videomanometry and respiratory recording, all with high temporal resolution. The onset of 13 predetermined swallowing and respiratory events and the surrounding respiratory phase pattern were studied in different body positions and during different respiratory drives. An increased respiratory drive was induced by breathing 5% CO(2). The results demonstrated a highly repeatable and fixed temporal coordination of the swallowing pattern despite body position and respiratory drive. Previous studies have demonstrated a period of centrally controlled apnoea during swallowing. This apnoea period has a variable length, varying from 1 to 5 s. During increased respiratory drive, we could demonstrate a significantly shorter period of apnoea during swallowing, mainly due to an earlier resumption of respiration. The high temporal recordings in this study have revealed that swallowing during expiration is present basically in all healthy individuals. This swallowing respiratory pattern seems to be appropriate for a safe swallow. This knowledge will be used as a reference for future studies on how swallowing and respiratory coordination might be altered due to ageing and diseases.

An in vitro model for studying neuromuscular transmission in the mouse pharynx.

The muscles of the pharynx are controlled by networks of neurons under the control of specific regions in the brain stem, which have been fairly well studied. However, the transmission between these neurons and the pharyngeal muscles, at the motor end plates, is less well understood. Therefore, an in vitro model for the study of neuromuscular transmission in the pharyngeal muscle of the mouse was developed. Ring preparations from the inferior constrictor and the cricopharyngeus muscles were isolated and mounted for isometric force recording at physiologic temperature. Preparations from the diaphragm and the soleus muscles were examined in parallel. The muscles were stimulated at supramaximal voltage with short tetani at 100 Hz. Following direct stimulation of the muscle fibers, using a longer pulse duration, the rate of force development of the pharyngeal muscles was similar to that of the diaphragm and faster than that of the soleus muscle. By varying the duration of the stimulation pulses, conditions where the nerve-mediated activation contributed to a major extent of the contractile responses were identified. Gallamine completely inhibited the nerve-mediated responses. In separate experiments the dose dependence of gallamine inhibition was examined, showing similar sensitivity in the inferior pharyngeal constrictor compared to the diaphragm and soleus muscles. We conclude that reproducible contractile responses with an identifiable nerve-induced component can be obtained from the mouse inferior pharyngeal constrictor. The pharyngeal muscles have contractile characteristics similar to those of the faster diaphragm. The sensitivity to the neuromuscular blocking agent gallamine of the inferior pharyngeal constrictor was in the same concentration range as that of the diaphragm and soleus muscles.

Fiber-type composition and fiber size of the human cricopharyngeal muscle and the pharyngeal constrictor muscle.

BACKGROUND: Despite a similar density of nicotinic acetylcholine receptors, the upper esophageal sphincter is sensitive to partial neuromuscular block, whereas the pharyngeal constrictor muscle is more resistant. In order to postulate possible mechanisms behind this difference in pharmacological response, basic knowledge of morphological and physiological features of these muscles is needed. The aim of this study was to compare the muscle fiber-type composition, the size and the morphology of the muscle fibers of the cricopharyngeal muscle, the main component of the upper esophageal sphincter, with that of the pharyngeal constrictor muscle. METHODS: Muscle specimens were obtained from five patients undergoing surgery with laryngectomy. Muscle fiber type was determined by myosin heavy chain immunohistochemistry and the muscle fiber cross-sectional area was measured for each fiber type by planimetry. Morphology of muscle fibers was evaluated by histochemistry. RESULTS: The muscle fiber cross-sectional area was generally smaller in the cricopharyngeal muscle compared with the pharyngeal constrictor muscle (P < 0.001). The composition of fiber types showed a large interindividual variability with no distinct difference between the studied muscles. Aberrant histological features were common in both the cricopharyngeal muscle and the pharyngeal constrictor muscle. CONCLUSION: The main morphological difference between the neuromuscular blocking agents sensitive cricopharyngeal muscle and the more resistant pharyngeal constrictor muscle is a uniformly smaller size of contributing fiber types in the cricopharyngeal muscle than in the pharyngeal constrictor muscle. The muscle fiber-type composition does not differ between the two studied muscles.

Acetylcholine receptor density in human cricopharyngeal muscle and pharyngeal constrictor muscle.

BACKGROUND: Upper esophageal sphincter resting tone is reduced during partial neuromuscular block, whereas contraction of the pharyngeal constrictor muscle is only slightly affected. We hypothesized that this difference may arise from differential nicotinic acetylcholine receptor (nAChR) density, the density supposedly being lower in the more sensitive cricopharyngeal muscle than in the resistant pharyngeal constrictor muscle. The aim of this study was to determine the density of nAChR in the main component of the upper esophageal sphincter, the cricopharyngeal muscle, and in the pharyngeal constrictor muscle. METHOD: After approval by the institutional ethics committee and informed consent, muscle specimens were obtained from five patients undergoing surgery with laryngectomy for malignancies of the larynx or thyroid gland. None had received radiation therapy to the affected area. The nAChR from these tissue specimens were solubilized and incubated with 125I-alpha-bungarotoxin. The quantity of radioligand-receptor complex was measured by radioactive decay in a liquid scintillation counter. The receptor density was expressed as femtomoles per milligram of protein (fmol/mg protein). RESULTS: The nAChR density was determined to 6.8 (3.5) fmol/mg protein (mean (SD)) in the cricopharyngeal muscle and 5.6 (2.1) fmol/mg protein in the pharyngeal constrictor muscle (P = 0.22). Although we could not find any difference in mean nAChR density, contrary to our hypothesis, the density in four of the five patients was higher in the cricopharyngeal muscle than in the pharyngeal constrictor muscle. CONCLUSION: Our results indicate that the density of nicotinic acetylcholine receptors is similar in the cricopharyngeal muscle and in the pharyngeal constrictor muscle. Nicotinic acetylcholine receptor density, as determined by 125I-alpha-bungarotoxin assay, cannot explain the difference in response to neuromuscular blocking drugs between the investigated muscles.

Pharyngeal function and airway protection during subhypnotic concentrations of propofol, isoflurane, and sevoflurane: volunteers examined by pharyngeal videoradiography and simultaneous manometry.

BACKGROUND: Anesthetic agents alter pharyngeal function with risk of impaired airway protection and aspiration. This study was performed to evaluate pharyngeal function during subhypnotic concentrations of propofol, isoflurane, and sevoflurane and to compare the drugs for possible differences in this respect. METHODS: Forty-five healthy volunteers were randomized to receive propofol, isoflurane, or sevoflurane. During series of liquid contrast bolus swallowing, fluoroscopy and simultaneous solid state videomanometry was used to study the incidence of pharyngeal dysfunction, the initiation of swallowing, and the bolus transit time. Pressure changes were recorded at the back of the tongue, the pharyngeal constrictor muscles, and the upper esophageal sphincter. After control recordings, the anesthetic was delivered, and measurements were made at 0.50 and 0.25 predicted blood propotol concentration (Cp50(asleep)) for propofol and 0.50 and 0.25 minimum alveolar concentration (MAC)(awake) for the inhalational agents. Final recordings were made 20 min after the end of anesthetic delivery. RESULTS: All anesthetics caused an increased incidence of pharyngeal dysfunction with laryngeal bolus penetration. Propofol increased the incidence from 8 to 58%, isoflurane from 4 to 36%, and sevoflurane from 6 to 35%. Propofol in 0.50 and 0.25 Cp50(asleep) had the most extensive effect on the pharyngeal contraction patterns (P < 0.05). The upper esophageal sphincter resting tone was markedly reduced from 83 +/- 36 to 39 +/- 19 mmHg by propofol (P < 0.001), which differed from isoflurane (P = 0.03). Sevoflurane also reduced the upper esophageal sphincter resting tone from 65 +/- 16 to 45 +/- 18 mmHg at 0.50 MAC(awake)(P = 0.008). All agents caused a reduced upper esophageal sphincter peak contraction amplitude (P < 0.05), and the reduction was greatest in the propofol group (P = 0.002). CONCLUSION: Subhypnotic concentrations of propofol, isoflurane, and sevoflurane cause an increased incidence of pharyngeal dysfunction with penetration of bolus to the larynx. The effect on the pharyngeal contraction pattern was most pronounced in the propofol group, with markedly reduced contraction forces.

The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium.

BACKGROUND: Residual neuromuscular block caused by vecuronium alters pharyngeal function and impairs airway protection. The primary objectives of this investigation were to radiographically evaluate the swallowing act and to record the incidence of and the mechanism behind pharyngeal dysfunction during partial neuromuscular block. The secondary objective was to evaluate the effect of atracurium on pharyngeal function. METHODS: Twenty healthy volunteers were studied while awake during liquid-contrast bolus swallowing. The incidence of pharyngeal dysfunction was studied by fluoroscopy. The initiation of the swallowing process, the pharyngeal coordination, and the bolus transit time were evaluated. Simultaneous manometry was used to document pressure changes at the tongue base, the pharyngeal constrictor muscles, and the upper esophageal sphincter. After control recordings, an intravenous infusion of atracurium was administered to obtain train-of-four ratios (T4/T1) of 0.60, 0.70, and 0.80, followed by recovery to a train-of-four ratio of more than 0.90. RESULTS: The incidence of pharyngeal dysfunction was 6% during the control recordings and increased (P < 0.05) to 28%, 17%, and 20% at train-of-four ratios 0.60, 0.70, and 0.80, respectively. After recovery to a train-of-four ratio of more than 0.90, the incidence was 13%. Pharyngeal dysfunction occurred in 74 of 444 swallows, the majority (80%) resulting in laryngeal penetration. The initiation of the swallowing reflex was impaired during partial paralysis (P = 0.0081). The pharyngeal coordination was impaired at train-of-four ratios of 0.60 and 0.70 (P < 0.01). A marked reduction in the upper esophageal sphincter resting tone was found, as well as a reduced contraction force in the pharyngeal constrictor muscles. The bolus transit time did not change significantly. CONCLUSION: Partial neuromuscular paralysis caused by atracurium is associated with a four- to fivefold increase in the incidence of misdirected swallowing. The mechanism behind the pharyngeal dysfunction is a delayed initiation of the swallowing reflex, impaired pharyngeal muscle function, and impaired coordination. The majority of misdirected swallows resulted in penetration of bolus to the larynx.

Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers.

BACKGROUND: Functional characteristics of the pharynx and upper esophagus, including aspiration episodes, were investigated in 14 awake volunteers during various levels of partial neuromuscular block. Pharyngeal function was evaluated using videoradiography and computerized pharyngeal manometry during contrast bolus swallowing. METHODS: Measurements of pharyngeal constrictor muscle function (contraction amplitude, duration, and slope), upper esophageal sphincter muscle resting tone, muscle coordination, bolus transit time, and aspiration under fluoroscopic control (laryngeal or tracheal penetration) were made before (control measurements) and during a vecuronium-induced partial neuromuscular paralysis, at fixed intervals of mechanical adductor pollicis muscle train-of-four (TOF) fade; that is, at TOF ratios of 0.60, 0.70, 0.80, and after recovery to a TOF ratio > 0.90. RESULTS: Six volunteers aspirated (laryngeal penetration) at a TOF ratio < 0.90. None of them aspirated at a TOF ratio > 0.90 or during control recording. Pharyngeal constrictor muscle function was not affected at any level of paralysis. The upper esophageal sphincter resting tone was significantly reduced at TOF ratios of 0.60, 0.70, and 0.80 (P < 0.05). This was associated with reduced muscle coordination and shortened bolus transit time at a TOF ratio of 0.60. CONCLUSIONS: Vecuronium-induced partial paralysis cause pharyngeal dysfunction and increased risk for aspiration at mechanical adductor pollicis TOF ratios < 0.90. Pharyngeal function is not normalized until an adductor pollicis TOF ratio of > 0.90 is reached. The upper esophageal sphincter muscle is more sensitive to vecuronium than is the pharyngeal constrictor muscle.