A phylogenetic hypothesis for the origin of hiccough.

The occurrence of hiccoughs (hiccups) is very widespread and yet their neuronal origin and physiological significance are still unresolved. Several hypotheses have been proposed. Here we consider a phylogenetic perspective, starting from the concept that the ventilatory central pattern generator of lower vertebrates provides the base upon which central pattern generators of higher vertebrates develop. Hiccoughs are characterized by glottal closure during inspiration and by early development in relation to lung ventilation. They are inhibited when the concentration of inhaled CO(2) is increased and they can be abolished by the drug baclofen (an agonist of the GABA(B) receptor). These properties are shared by ventilatory motor patterns of lower vertebrates, leading to the hypothesis that hiccough is the expression of archaic motor patterns and particularly the motor pattern of gill ventilation in bimodal breathers such as most frogs. A circuit that can generate hiccoughs may persist in mammals because it has permitted the development of pattern generators for other useful functions of the pharynx and chest wall muscles, such as suckling or eupneic breathing.

Linkage of hiccup with heartbeat.

We explored a possible link between the cardiac cycle and the timing of recurrent hiccups in 10 patients with chronic, intractable hiccups. Recordings made during daytime naps in a sleep laboratory included sleep state; electrocardiogram; and respiration by means of a thermistor to detect airflow, bands around the rib cage and abdomen to assess expansion, and a bipolar surface electrode electromyogram over parasternal intercostal muscles. Hiccups could be detected on the abdominal bands and the parasternal electromyogram. The time of occurrence of each hiccup and each R wave in a continuous tracing of 100 or more hiccups were recorded and analyzed together with semiquantitive estimates of the phase of hiccup respiration. Whereas the hiccup rate ranged from approximately one-third to one-eighth of heart rate and was more variable than heart rate, hiccups showed a tendency, stronger in some subjects than others, to occur in midsystole. Variation in R-wave-R-wave (R-R) interval in association with hiccups was found in five patients. In three of these patients, hiccups were synchronized with respiration so that the cyclic change in R-R interval posthiccup could be explained as sinus arrhythmia, but, in two patients, the hiccups were not synchronized with respiration, so that hiccups are most likely responsible for the variation in heart rate. Also, the variation of R-R interval with hiccups suggests that there is some phasic autonomic efferent activity associated with hiccups.

Automated analysis of digital oximetry in the diagnosis of obstructive sleep apnoea.

BACKGROUND: The gold standard diagnostic test for obstructive sleep apnoea (OSA) is overnight polysomnography (PSG) which is costly in terms of time and money. Consequently, a number of alternatives to PSG have been proposed. Oximetry is appealing because of its widespread availability and ease of application. The diagnostic performance of an automated analysis algorithm based on falls and recovery of digitally recorded oxygen saturation was compared with PSG. METHODS: Two hundred and forty six patients with suspected OSA were randomly selected for PSG and automated off line analysis of the digitally recorded oximeter signal. RESULTS: The PSG derived apnoea hypopnea index (AHI) and oximeter derived respiratory disturbance index (RDI) were highly correlated (R = 0.97). The mean (2SD) of the differences between AHI and RDI was 2.18 (12.34)/h. The sensitivity and specificity of the algorithm depended on the AHI and RDI criteria selected for OSA case designation. Using case designation criteria of 15/h for AHI and RDI, the sensitivity and specificity were 98% and 88%, respectively. If the PSG derived AHI included EEG based arousals as part of the hypopnea definition, the mean (2SD) of the differences between RDI and AHI was -0.12 (15. 62)/h and the sensitivity and specificity profile did not change significantly. CONCLUSIONS: In a population of patients suspected of having OSA, off line automated analysis of the oximetry signal provides a close estimate of AHI as well as excellent diagnostic sensitivity and specificity for OSA.

Sleep of the great.

Both Lewis Carroll and William Shakespeare appear to have made clinical observations of sleep apnea syndromes long before they were discovered by medical science, and to have understood something about their physiological mechanisms. The somnolent dormouse in Alice in Wonderland indicates that his problem is one of sleep and breathing and is subject to modern treatment for obstructive apnea. Shakespeare in Henry IV presents a case of obstructive apnea along with a case of Cheyne-Stokes breathing and uses the plot of these history plays to explain by analogy the theoretical basis for periodic breathing.

A comparison of apnea-hypopnea indices derived from different definitions of hypopnea.

We examined the effects of arousal- and desaturation-based scoring criteria on the apnea-hypopnea index (AHI) and on the measured prevalence of obstructive sleep apnea (OSA). Ninety-four randomly selected patients underwent overnight polysomnography. Studies were scored according to three different criteria for hypopnea, as defined by a >= 10 s discernible reduction in thoracoabdominal movement associated with: (1) >= 4% decrease in oxygen saturation (SaO2) (Type A); (2) either a >= 4% decrease in SaO2 or an arousal (Type B); or (3) electroencephalographically based arousal alone (Type C). Excellent correlation existed between AHI-A, AHI-B, and the oxygen desaturation index (ODI) (r > 0.98). AHI-A and AHI-B differed by only 2.04 +/- 1.72/h (2 SD). AHI-A and AHI-B differed from the ODI by 1.04 +/- 4.07/h and 3.07 +/- 4.30/h, respectively. Despite these small differences, use of the Type B rather than Type A definition resulted in an extra case of OSA being diagnosed for every 14 to 31 patients tested, depending on the definition of OSA (AHI: >= 5, 10, 15, or 20/h). The addition of arousal-based scoring criteria for hypopnea causes only small changes in the AHI, but if OSA is defined solely by an AHI value, the measured prevalence of OSA will increase.

Interaction of cross-sectional area, driving pressure, and airflow of passive velopharynx.

Previous studies have shown that, when the pharyngeal muscles are relaxed, the velopharynx is a highly compliant segment of the pharynx. Thus, under these circumstances, cross-sectional area of the velopharynx (AVP), driving pressure across the velopharynx (DeltaP), and inspiratory airflow (VI) will be mutually interdependent variables. The purpose of the present investigation was to describe the interrelation among these three variables during inspiration. We studied 15 sleeping patients with obstructive sleep apnea/hypopnea when the pharyngeal muscles were rendered hypotonic by applying continuous positive airway pressure to the nasal airway. AVP, determined by endoscopic imaging, was significantly greater at onset of VI limitation than at minimum oropharyngeal pressure (P < 0. 01). Snoring was never observed during VI limitation. In a subgroup of six patients, values for DeltaP, VI, and AVP were obtained at 0. 1-s intervals at various levels of mask pressure. For these six patients, the mathematical expression VI = 0.657(AVP/Amax) . DeltaP0. 332, where Amax is maximal AVP, described the relationship among the three variables (R2 = 0.962) for flow-limited and non-flow-limited inspirations. The impedance of the passive velopharynx, defined as DeltaP0.33/V, was inversely related to AVP and increased dramatically when AVP was <0.3 cm2. In summary, we observed a progressive decrease in AVP during flow-limited inspiration in patients with obstructive sleep apnea. This constriction of the velopharynx contributes to an increase in velopharyngeal impedance that, in turn, counterbalances the increase in DeltaP during flow limitation.

Management of acute respiratory failure in chronic obstructive pulmonary disease.

Acute respiratory failure in the setting of preexisting chronic obstructive pulmonary disease (COPD) is a common reason for hospitalization and results in the consumption of a substantial amount of health care resources. In recent years, new therapies have been proposed, and new information about older therapies has become available. Noninvasive ventilation is finding an important place as a means of avoiding tracheal intubation. The role of bacterial infection as a frequent precipitant to acute respiratory failure in COPD remains poorly defined and presumptive antibiotic therapy remains controversial. Vasodilators of the pulmonary circulation have received much attention but so far have been disappointing in this situation. The role of several other traditional therapies, such as mucolytics and methods of secretion removal, have also been challenged in recent years. In this review we focus or recent advances in the assessment and management of acute respiratory failure in the setting of pre-existing COPD.

Modafinil in obstructive sleep apnea-hypopnea syndrome: a pilot study in 6 patients.

We studied the effects of modafinil, a vigilance-enhancing drug, on excessive daytime sleepiness, memory, night sleep and respiration in 6 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) using a double-blind random cross-over design with 24-hour polysomnography, verbal memory test and a 5-week sleep-wake diary kept by the patients. There were two 2-week treatment periods in which either modafinil or placebo was used; they were separated by a 1-week wash-out period. Our results show that modafinil reduces daytime sleep duration, lengthens the duration of subjective daytime vigilance and improves long-term memory in patients with OSAHS without modifying night sleep and respiration events.

Polysomnography: addressing the need for standards.

The field of sleep disorders medicine is facing enormous challenges as it strives to gain recognition from the medical profession, the public and government. One of these challenges is to ensure that limited resources for diagnosis are used wisely. The authors argue that the standards for polysomnography developed by the Canadian Sleep Society and the Canadian Thoracic Society (see pages 1673 to 1678 of this issue) will go a long way toward ensuring that this expensive resource is used prudently. In the mean-time, more research is needed to determine valid measures of the impact of sleep disorders and to establish the reliability of different diagnostic methods.

Chronic hiccups and sleep.

To explore the effect of sleep on hiccups, we studied eight patients aged 20-81 years, all males with chronic hiccups lasting 7 days to 7 years, by means of overnight polysomnography. The incidence of new bouts of hiccups and the likelihood of hiccups being present were both highest in wakefulness and became progressively lower through stages I-IV of slow wave sleep (SWS) to rapid eye movement sleep (REMS). There was a significant tendency for hiccups to disappear at sleep onset and REMS onset. Of all 21 bouts of hiccups that were observed to stop, 10/21 did so during an apnea or hypopnea. Frequency of hiccups within a bout slowed progressively from wakefulness through the stages of SWS to REMS. For the whole group, mean frequency decreased significantly from wakefulness [(25.6 +/- 12.1), (mean +/- SD)] to sleep onset or stage I (22.3 +/- 12.2). Sleep latency was increased from 8 +/- 16.3 minutes when hiccups were absent to 16.35 +/- 19.9 minutes when it was present. Sleep efficiency was poor because of long waking periods, and there were deficiencies of both SWS and REMS. Hiccups themselves were not responsible for any arousals or awakenings. We conclude that neural mechanisms responsible for hiccups are strongly influenced by sleep state and that hiccups disrupt sleep onset but not established sleep.

Interaction between postural and respiratory control of human intercostal muscles.

To study the interaction between postural and respiratory control of intercostal muscles, we used electromyography of intercostal muscles of the lateral chest wall in conscious humans. Bipolar fine-wire electrodes were placed in external and internal intercostal muscles in the midaxillary line of four subjects who sat on a bench and breathed through a pneumotachograph. They were instructed to hold their breath at end expiration, rotate their thorax to the right or left, and then hold the rotation while resuming breathing. Holding a rotation induces steady tonic activity in either internal or external intercostal muscles, depending on the direction of the rotation. The degree of rotation was varied from one run to the next, resulting in varied levels of tonic postural activity. When breathing resumes, internal intercostal muscles have their activity almost completely suppressed with each inspiration independently of whether the tonic postural tone is small or large. External intercostal muscles show inspiratory increases in activity superimposed on the postural tone, which apparently amplifies the effect of respiratory input to their motoneurons.

Inferences about respiratory muscle use after cardiac surgery from compartmental volume and pressure measurements.

BACKGROUND: After upper abdominal surgery, patients have been observed to have alterations in respiratory movements of the rib cage and abdomen and respiratory shifts in pleural and abdominal pressure that suggest dysfunction of the diaphragm. The validity of making such deductions about diaphragm function from these observations is open to discussion. METHODS: In eight adult patients, American Society of Anesthesiologists physical status 2, scheduled for elective cardiac surgery, we measured respiratory rate, tidal volume, rib cage and abdominal cross-section changes, and esophageal (Pes) and gastric (Pga) pressures preoperatively, 1 day postoperatively, and 5 days postoperatively. These data were analyzed in detail by following the variables through each respiratory cycle. RESULTS: Mean delta Pga/delta Pes decreased from 0.73 preoperatively to -0.56 1 day postoperatively and recovered to 0.47 5 days postoperatively. Plots of Pes against Pga and rib cage against abdominal expansion (Konno-Mead diagrams) were constructed. Six patients showed a postoperative pattern of breathing similar to that seen in patients who have undergone abdominal surgery: a decrease in the ratio of delta Pga/delta Pes and a shift toward rib cage expansion, with an increase in breathing rate and a decrease in tidal volume. This change was accomplished in most cases by the use of abdominal muscles in expiration with an increase in inspiratory intercostal muscle action without an increase in diaphragm activation, that is, a shift in the normal balance of respiratory muscle use in favor of muscles other than the diaphragm. A different ventilatory pattern was observed in the other two patients, consisting of minimal rib cage excursion and a large abdominal excursion. In these cases tidal volume was generated largely by contraction and relaxation of abdominal muscles with probable reduction in diaphragm activity. In addition, five patients exhibited positive changes in Pes at the end of inspiration that corresponded to closure of the upper airway, relaxation of inspiratory muscles, and subsequent opening of the airway with sudden exhalation, producing a grunt. CONCLUSIONS: Indirect measurements of respiratory muscle action based on pressure and chest wall motion are easier than are assessments based on implanted electromyogram electrodes and sonomicrometers that measure electric activity and muscle length, respectively, directly. Interpretation requires numerous assumptions and detailed analysis of phase relations among the variables. In patients after thoracic surgery, however, these measurements strongly point to a shift in the distribution of motor output toward muscles other than the diaphragm.

Baclofen therapy for chronic hiccup.

Chronic hiccup is a rare but potentially severe condition, that can be symptomatic of a variety of diseases, or idiopathic. Many therapeutic interventions have been reported, most often as case reports. Among other drugs, baclofen has been suggested as a therapy for chronic hiccup. In a large series of patients, we have evaluated its therapeutic position. In patients with chronic hiccup, defined as hiccup spell or recurring hiccup attacks lasting more than 7 days, investigation of the upper gastro-oesophageal tract (fibroscopy, manometry, and pH monitoring) was systematically performed. Most patients had tried numerous drugs in the past, without success. Baclofen was used as a first treatment in patients without evidence of any gastro-oesophageal disease (n = 17), and was undertaken only after full treatment of such disease (n = 55) had failed to solve the hiccup problem (n = 20). Baclofen has, therefore, been administered to 37 patients with chronic hiccup (average duration 4.6 yrs). Baclofen produced a long-term complete resolution (18 cases) or a considerable decrease (10 cases) of hiccups in 28 of the 37 patients. There was no significant difference between patients with or without gastro-oesophageal disease. We conclude that so-called idiopathic chronic hiccup often results from gastro-oesophageal abnormalities. Also, if controlled studies confirm our encouraging results, baclofen can be a major element in the treatment of chronic hiccup that is idiopathic, or that cannot be helped by treatment of gastro-oesophageal diseases.

History of diaphragm physiology: the achievements of Galen.

Galen (129-200 AD) produced a large written output which was to remain one of the major basis of clinical medicine for centuries. His contribution to respiration, reported in his own books and in those of Oribasius, was that of a chest physician and of an experimental physiologist. He described in minute details how to perform a remarkable series of experiments by which he demonstrated the anatomy and function of the respiratory muscles. He described the actions of the diaphragm and how it moves the rib cage, in a series of spinal chord sections and muscle denervations. He investigated the passive or active nature of expiration and made fine observations of lung movements through the exposed pleural space. He described the interaction between the lungs and chest wall and developed the concept of interaction between ribcage and abdominal muscles in maintaining the position of the diaphragm, showing a clear understanding of the principle that the diaphragm can move upward during an isovolume manoeuvre as long as the ribcage is allowed to expand. A skillful clinician, Galen applied his theories of the analysis of problems at the bedside, particularly in patients affected with dyspnoea which he attributed to respiratory muscle dysfunction.

The earliest history of diaphragm physiology.

The diaphragm was recognized as a distinct anatomical structure in the earliest Greek writings. However, the precise description of wounds suffered by warriors during the Trojan war by Homer was not tied to any particular function. The diaphragm was assimilated to the region that harbours thought. The first physiologic explanations of respiration by Empedocles in the 5th century BC and the concepts introduced by Plato and Hippocrates did not include a significant participation of the diaphragm. Aristole was the first to link respiration to a particular organ and a specific movement of the thorax. However, he considered that it was the heart which caused the lungs to expand by heating them, and the lungs in turn forced the thorax to dilate, a concept which was to survive until the 17th century. As in Aristole's theory the diaphragm played no role in respiration and was just a fence separating the thorax from the abdomen. A major break through occurred in Alexandria in the 4th and 3rd century BC: Herophilus was the first to recognize that muscles were the agents of movement and Erasistratus performed animal experiments which showed that the respiratory muscles were the agents of respiratory movements, thus opening the way to the later discoveries of Galen.

Likelihood ratios for a sleep apnea clinical prediction rule.

Nocturnal polysomnography, the standard diagnostic test for sleep apnea, is an expensive and limited resource. In order to help identify the urgency of need for treatment, we determined which clinical features were most useful for establishing an accurate estimate of the probability that a patient had sleep apnea. Of 263 physician-referred patients, 200 were eligible for the study and 180 (90%) completed it. All patients had their histories recorded with a standard questionnaire, and underwent anthropomorphic measurements and nocturnal polysomnography. Sleep apnea was defined as more than 10 episodes of apnea or hypopnea per hour of sleep. Multiple linear and logistic regression models predictive of sleep apnea were compared with physicians' subjective impressions and previously reported models. Likelihood ratios were calculated for several levels of a sleep apnea clinical score produced by one of the linear models. Predictors of sleep apnea in the final model (R2 = 0.34) included neck circumference, hypertension, habitual snoring, and bed partner reports of nocturnal gasping/choking respirations. This model was superior to physician impression, slightly inferior to more detailed linear and logistic models, and comparable to previously reported models. A sleep apnea clinical score of less than 5 had a likelihood ratio of 0.25 (95% CI: 0.15 to 0.42) and a corresponding posttest probability of 17%, while a score of greater than 15 had a likelihood ratio of 5.17 (95% CI: 2.54 to 10.51) and posttest probability of 81%. These likelihood ratios can simply and accurately determined the probability of whether a patient has sleep apnea.

Arterial blood gases in elderly persons with chronic obstructive pulmonary disease (COPD).

With the increasing number of elderly people in developed countries, physicians are often confronted with patients whose arterial oxygen tension, PaO2, is lower than that of normal young adults. The normal values predicted in the literature for very old individuals are generally extrapolated from younger subjects. The purpose of the present study was to obtain PaO2 values from a large population of elderly subjects with normal and obstructive ventilatory function. We measured arterial blood gases in 274 subjects, aged 65-100 yrs (mean 82 yrs), with chronic bronchitis and moderate airways obstruction (mean forced expiratory volume in one second (FEV1), 53% pred). Mean PaO2 was 10.0 +/- 1.4 kPa (75.2 +/- 10.8 mmHg) and mean arterial carbon dioxide tension (PaCO2) was 5.4 +/- 0.8 kPa (40.5 +/- 6.1 mmHg). Both PaO2 and PaCO2 were independent of age. Blood gas abnormalities were associated with airways obstruction: PaO2 was positively correlated to FEV1 and PaCo2 was negatively correlated to FEV1. PaO2 was 10.8 +/- 1.4 kPa (81.5 +/- 10.7 mmHg) in the patients with FEV1 > or = 90% predicted versus 9.5 +/- 1.3 kPa (71.5 +/- 10.1 mmHg) in those with FEV1 < or = 35% pred. These findings suggest that the predicted PaO2 extrapolated from younger normal values are often erroneously underestimated. It is probably more accurate to accept as normal a PaO2 of 10.6-11.3 kPa (80-85 mmHg) for all subjects over 65 yrs, irrespective of their age.

Impaired ventilatory response to carbon dioxide in patients with chronic renal failure: implications for the intensive care unit.

OBJECTIVES: To compare aspects of ventilatory control and the susceptibility to depressant drugs between patients with chronic renal failure and normal volunteers. DESIGN: Prospective, controlled study. SETTING: Pulmonary function laboratory of a university hospital. PATIENTS: Six patients with chronic renal failure requiring hemodialysis and ten normal, control subjects. INTERVENTIONS: Ventilatory responses to breathing CO2 were studied using a rebreathing method. The effects of triazolam (0.5 mg orally) and meperidine (1 mg/kg, subcutaneously) on these measurements were also studied. MEASUREMENTS AND MAIN RESULTS: Dialysis patients showed definite impairment in the ventilatory response to CO2, which could not be accounted for by differences in respiratory mechanics, muscle strength, or acid-base status. Meperidine impaired ventilatory responses in control subjects and in renal patients, while triazolam had little effect on either group. The effect of the drugs was not proportionately greater in dialysis patients than in control subjects. CONCLUSIONS: Chronic renal failure results in a poorly responsive ventilatory control system, which may make renal failure patients more difficult to wean from mechanical ventilation. Theoretically, these patients may be more vulnerable to disturbances in blood gas homeostasis and subsequent respiratory arrest than other patients in an unmonitored environment.