Hypothyroidism after treatment for nonthyroid head and neck cancer.

OBJECTIVES: To determine the incidence of posttreatment hypothyroidism in patients treated with surgery with or without radiotherapy for advanced-stage nonthyroid head and neck cancer and to make recommendations for its detection. DESIGN: A prospective study to assess the incidence and time frame of occurrence of hypothyroidism in patients by primary tumor site and treatment modality. Thyroid function tests were performed preoperatively, at the first postoperative visit, and then approximately every 6 months. Patients were followed up for up to 3 years. SETTING: Arthur G. James Cancer Hospital and Research Institute, Columbus, Ohio. PATIENTS: A total of 251 patients with nonthyroid head and neck cancer were originally enrolled; 198 patients with evaluable data were studied to determine the incidence of posttreatment hypothyroidism. Approximately 80% of the patients had advanced stage (III or IV) or recurrent cancer. RESULTS: The overall incidence of posttreatment hypothyroidism was 15% in 198 patients followed up for a mean of approximately 12 months. Hypothyroidism developed in 12% of patients treated with nonlaryngeal surgery and radiotherapy. The group undergoing total laryngectomy (with thyroid lobectomy) and radiotherapy had a 61% incidence of hypothyroidism. The average time to detection of hypothyroidism was 8.2 months. CONCLUSIONS: Approximately 15% of patients treated for advanced head and neck cancer with surgery and radiotherapy will develop hypothyroidism. Those treated with total laryngectomy and radiotherapy are at greatest risk.

Response of roosters to resistive loads at constant chemical drive to breathe.

This study investigated the role of mechanoreceptors in the respiratory responses to resistive loading in roosters. Adult roosters were unidirectionally ventilated (maintaining a constant chemical drive to breathe). Electrical circuits assessed the respiratory muscle pressure (Pmus) and controlled the relationship between Pmus and the respiratory volume changes. Respiratory volume changes similar to those achieved by flow-resistive unloading or loading were produced by the circuits, imposing a 'virtual' resistance (Rv). When Rv was doubled (decreased rate of volume change, n = 6), tidal volume (VT, measured by whole body plethysmography) decreased significantly (28%), while thoracic volume (VRIP, measured by respiratory inductance plethysmography) did not change. When RV was quadrupled (n = 4) VT and VRIP decreased significantly (53% and 24%, respectively). Changing RV to one half the normal value (n = 5) did not affect these parameters. Inspiratory time and Pmus were not significantly altered at any RV. It is concluded that, at constant chemical drive, mechanoreceptors play a minimal role in maintaining tidal volume during impeded breathing in roosters. Comparative differences which may explain these results are discussed.

Carbon dioxide storage capacity of endurance and sprint-trained athletes in exercise.

The purpose of this study was to compare CO2 storage capacity of endurance and sprint-trained athletes during steady state exercise. Ten subjects, five sprinters and five distance runners, performed a submaximal treadmill exercise at two different work rates, 45% and 65% of VO2max. CO2 storage capacity was determined by measuring the excess CO2 washout associated with hyperventilation, normalized for body weight and expressed per unit change in mixed venous PCO2 (ml kg-1 Torr-1). Mixed venous PCO2 (PvCO2) was measured by rebreathing equilibration. It was found that CO2 storage capacities of the runners were significantly (P less than 0.05) greater than the sprinters at the two work rates. The sprinters CO2 storage capacities were 2.69 and 2.14 ml kg-1 Torr-1 at low and high work rates, respectively. The corresponding mean values for the runners were 4.56 and 3.92 ml kg-1 Torr-1, respectively. These results may be explained by the metabolic differences between the sprinters and runners. The sprinters' musculature depends more heavily on the glycolytic metabolic pathway, which is associated with an increased lactate production and hence a reduction in the combining power of the blood for CO2 during exercise. At the low work rate, the body's storage capacity for CO2 was significantly (P less than 0.05) greater than the higher work rate for both groups. Obviously, at the higher work level more blood would be presented to the lungs per unit time allowing an increase in CO2 clearance from the body stores.

Effect of sinusoidal forcing of ventilatory volume on avian breathing frequency.

Awake chickens were unidirectionally ventilated at 3.6 l . min-1 with 3.2-4.8% CO2 in air. The air sacs on each side were made confluent and implanted with exit tubes connected to the following three devices: 1) a system of constant-flow generators which remove air at exactly the same rate that it entered the trachea, allowing no port for spontaneous volume changes; 2) a sinusoidal pump to force volume changes in the chicken; and 3) a pressure transducer to record air sac pressure, which reflected the sum of two pressure components, the passive pressure changes created by the pump and the active pressure changes due to breathing efforts. Over a range of pump frequencies, the amplitude of measured air sac pressure changes varied inversely with frequency. Above and below this range, pressure showed a beat pattern, indicating a difference in the frequencies of the two pressure components. Within the range lacking a beat pattern, breathing movements and the pump stroke had the same frequency. This range was greater at increased stroke volume. Breathing efforts worked with the pump at the high end of the range and against the pump at the low end. These findings show further evidence of the presence of a response to volume forcing and fit a previously described volume threshold model.

Ventilatory pressure loading at constant pulmonary FCO2 in Gallus domesticus.

Seven White Leghorn roosters were unidirectionally ventilated at constant flows and CO2 concentrations. The birds were awake and stood or crouched in a plethysmograph. A servo system clamped the pressure in the air sacs at constant values from -10 to +10 cm H2O in 2 cm H2O increments. Therefore, the animals could inflate or deflate the air sacs with breathing movements without affecting intrapulmonary pressures. Decreasing air sac pressure less than atmospheric caused inspiratory duration (TI), expiratory duration (TE), total period (TTOT) and tidal volume (VR) to decrease, and the ratio, TI/TE to increase. Increasing air sac pressures to 6 cm H2O above atmospheric caused, TE to increase, TI and TI/TE to decrease and VT and TTOT to change very little. After bilateral vagotomy air sac pressure changes caused little or no changes in TI, TE, TTOT or TI/TE, but produced percentage changes in VT similar to before vagotomy. Comparison of end expiratory volumes with apneic volumes (produced by lowering CO2 in the insulfating gas) over the range of air sac pressures clamped shows: (1) chickens actively exhale at pressures as low as -10 cm H2O, and (2) the change of mean air sac volume due to imposed pressure is less during breathing than during apnea. These findings, we believe, are due to a reflex initiated by mechanoreceptors with projections in the vagus nerves.

Rapid ventilatory responses to changes in insufflated CO2 in awake roosters.

The ventilatory responses to pulses or steps in the fraction of CO2 in the insufflated gas stream (FICO2) in awake, unidirectionally ventilated White Leghorn roosters (Gallus domesticus) were studied. Within 0.2-0.5 s of the change in FICO2 at the syrinx, a change in inspiratory or expiratory flow occurred. Increases in FICO2 increased flow and tidal volume (VT), whereas decreases in FICO2 decreased flow and VT. Expiratory duration (TE) was markedly prolonged by decreases in FICO2 and shortened by increases. Inspiratory duration was affected little by FICO2 changes. The TE response to pulses of FICO2 (0.2-0.4 s duration) revealed a time dependency such that a maximum effect occurred when the pulses arrived at the syrinx at approximately midexpiration. The magnitudes of the responses were approximately proportional to the amplitude and duration of the FICO2 changes, but decreases in FICO2 had greater effects than increases. A likely receptor site for these responses is the intrapulmonary chemoreceptors, which appear to function in a reflex controlling airflow and timing of the ongoing breath.

Ventilatory phase duration in the chicken: role of mechanical and CO2 feedback.

Awake upright White Leghorn roosters (Gallus domesticus) were unidirectionally ventilated. Electromyographic activity from inspiratory and expiratory muscles was recorded to demarcate inspiration and expiration. During inspiration, the rate of inflation of the air sac system was varied while the CO2 concentration of the gas passing through the lungs was maintained constant. Inspiratory duration was inversely related to the rate of inflation, producing an inspiratory volume-time threshold (VT) curve with a negative slope. When the CO2 concentration was increased in the lungs, the inspiratory VT curve shifted to the right with a concurrent increase in slope. If the rate of deflation was varied during expiration, it was found that expiratory duration was inversely related to the rate of deflation, producing an expiratory VT curve with a positive slope. Increasing the CO2 concentration shifted the curve to the left with an increased slope. These results indicate that inspiratory and expiratory phase durations are a function of both mechanical and chemical feedback.

Changes in breathing pattern mediated by intrapulmonary CO2 receptors in chickens.

The ventilation of unanesthetized tracheostomized chickens was measured using a whole-body plethysmograph. The inspired CO2 fraction was quickly manipulated between 0.05 and 0.0 in such a way as to limit the fresh air inspired to a fixed duration pulse preceded and followed by 5% CO2. As was previously shown with this experimental protocol [Tallman et al., Am. J. Physiol. 237 (Regulatory Integrative Comp. Physiol. 6): R260-R265, 1979], the duration of inspiration and expiration (TI and TE, respectively) was dependent on the timing, relative to inspiration, that the pulse of air arrived at the lung. To study the possible involvement of arterial chemoreceptors in this reflex, a method of denervating the carotid chemoreceptors in this reflex, a method of denervating the carotid bodies was developed. After denervation, the hyperpneic response to intravenous NaCN and 2-3 breaths of N2 was eliminated, indicating the complete removal of arterial chemoreflexes. When tested with the same protocol of CO2 inhalation following carotid body denervation, TI and TE were still dependent on the delay of the fresh air pulse. These experiments support the conclusion that intrapulmonary CO2 receptors (IPC) mediate the reflexes studied and provide evidence that IPC affect the phase-switching mechanisms on a breath-to-breath basis.

Discharge of intrapulmonary chemoreceptors and its modulation by rapid F1CO2 changes in decerebrate ducks.

Single-unit activity was recorded from intrapulmonary chemoreceptors (IPC) in decerebrate ducks inspiring room air (fresh air or control breath), or a short pulse of room air preceded and followed by 5% CO2 (fresh air pulse or experimental breath). Of 36 IPC studied, 28 fired a burst of impulses of similar duration to the fresh air pulse; delaying the fresh air pulse until later and later in inspiration progressively delayed the IPC burst. The remaining 8 IPC did not respond discretely to the fresh air pulse, rather their discharge was reduced diffusely in one or both of the ventilatory phases. The average discharge of the IPC population had a cyclic character during control breathing, with peak discharge mid-way through inspiration and essentially a constant discharge during expiration. An experimental breath had a similar IPC discharge pattern but peak inspiratory discharge was reduced; delaying the fresh air pulse delayed the population IPC burst. The results indicate that IPC could mediate the previously reported changes in T1 and TE that occur when the timing of a fresh air pulse is manipulated in conscious chickens [(Tallman et al. (1979). Am. J. Physiol. 237: R260-R265)].

Effect of timing of FICO2 changes on ventilatory period in domestic fowl.

These experiments were conducted to see if the pacing phenomenon found by Kunz and Miller (Respir. Physiol., 22: 167--177, 1974) in the open-loop, unidirectionally ventilated chicken is important in normally breathing birds. In this study, chickens breathed spontaneously through a tracheostomy from a gas source in which the fraction of CO2 (FICO2) could be rapidly changed. A feedback algorithm kept the FICO2 at 0.05 except for a constant duration pulse (approx 0.6 s) of low FICO2 given tau seconds after the beginning of each inspiration. In all birds tested an increase in tau resulted in a proportional increase of both inspiratory period (TI), expiratory period (TE), and the total period (Ttot). Increases in TI were from 0.5 to 1.0 times the increase in tau. Dynamic expeiments showed TI usually changed on the next breath after a step change in tau, and sinusoidal modulation of tau caused concurrent sinusoidal changes in TI, TE, and Ttot. These findings indicate that the phenomenon that produced pacing in the unidirectionally ventilated birds is important to the ventilatory pattern of normal breathing.

Urinary iodine excretion rates following intrathecal injections of iodinated organic carbonates.

Oily iodinated organic carbonates were investigated for use as myelographic media. The urinary excretion of total iodine was used to monitor the apparent elimination rate of these compounds from the subarachnoid space. Within the chain length series of C2-C6, the decrease of elimination rates and disposition rate constants with increasing chain length was demonstrated. This observation is consistent with a dissolution rate-limited elimination model. Such a model was derived and successfully NONLIN computer fitted to the observed elimination data. The model-derived parameter of clearance from the cerebrospinal fluid through the lipid "blood-brain barrier" correlated well with the compound's water solubilities and projected octanol-water partition coefficients. Additional compounds need to be tested to evaluate the postulated model system.

Initiation of each avian inspiration by a CO2 threshold mechanism.

The avian respiratory oscillator has been investigated in a unidirectionally ventilated chicken by changing the dynamic pattern of inflow CO2 concentration (FCO2). Stimulation with periodic FCO2 results in a one-to-one synchronization of the respiratory movements that we have called pacing (Respir. Physiol. 22: 167--177, 1974). A two-parameter CO2 threshold model is proposed to explain this behavior. The model states that when FCO2 reaches a threshold level (L), it initiates the beginning of inspiration a constant time interval (LB) later. According to this model, when a triangular FCO2 concentration is used to synchronize the breathing pattern, the time from the minimum of the wave form to the beginning of inspiration (C-B interval) is dependent on the mean value and the rate of rise of FCO2 as determined by period and amplitude of the triangle. Particularly interesting is the prediction that the direction of the relationship (increasing or decreasing) between FCO2 amplitude and the C-B interval is dependent on whether the mean value of FCO2 is above or below the threshold level. Experimental data obtained during amplitude changes support the above prediction.

A study of the effect of SO2 on pacing and intrapulmonary chemoreceptor discharge in the domestic fowl.

Kunz and Miller )1974) described a phenomenon called pacing in which FCO2 oscillations forced in the lungs of unanesthetized unidirectionally ventilated chickens cause one ventilatory movement per ECO2 oscillation. In the present study SO2 (0.08--0.32 vol%) added to the ventilating gas stream caused a loss of pacing in 11 of 12 birds. In 7 of the 11 birds in which SO2 was effective, pacing returned 3.2--7.0 min after removal of SO2. Intravenous infusion of a similar quantity of SO2 (dissolved in saline) did not block pacing. In a second series of experiments chickens were again unidirectionally ventilated and single nerve fiber recording was used to investigate the effect of SO2 on individual intrapulmonary chemoreceptors (IPC). Of necessity, this work was done on birds which were anesthetized and paralyzed. Discharge was abolished in 10 of 12 IPC by doses of SO2 similar to those which blocked pacing. In 6 of the 10 fibers in which SO2 was effective, discharge resumed after a mean period of quiescence lasting 7 min. It is concluded that pacing is mediated by intrapulmonary rather than systemic chemoreceptors.

Study of CO2 sensitive vagal afferents in the cat lung.

Single unit activity was recorded in the cat vagus in order to detect possible receptors firing in response to changing lung CO2 concentration. The cats were ventilated at a high rate (60-120 breaths per min) and inspired CO2 concentration was altered between 0 and 8% in a step-like fashion, each phase consisting of about 10 breaths. Thus the effects of changing intrapulmonary CO2 concentration could be differentiated from the effects of stretch of lung tissue. Activity was recorded in 7 cats from 120 units firing in phase with ventilation. Many receptors showed some CO2 sensitivity, but no fiber was found discharging in response to CO2 exclusively. The results provide no evidence for the occurence of specific CO2 receptors in the feline lung with vagal afferents functionally similar to those reported for the avian lung.

Avian ventilatory responses to dynamic CO2 signals.

This study uses an awake unidirectionally ventilated avian preparation to examine the effects of dynamic CO2 signals on the respiratory drive. Results show that minute ventilation is affected by both 1) mean CO2 level and 2) amplitude of CO2 oscillations at the frequency of breathing. An increase in mean CO2 level increased minute ventilation. Comparisons of the effects of CO2 oscillations at the same mean CO2 level, however, showed minute ventilation to be less with the larger amplitudes of oscillations than with smaller ones. Graphs of minute ventilation (V) versus mean CO2 for families of oscillation sizes (0.5%, 1% and 2%) showed that the ventilatory sensitivity (slop) was least for the 2% oscillations and greatest for the 0.5% oscillations. Therefore, a static model for the respiratory regulator is not adequate. However, the apneic level of CO2 (V = O intercept) was independent of the size of the CO2 oscillations.