Clifford W. Zwillich

Theophylline-induced seizures in adults. Correlation with serum concentrations.

Eight patients developed grand mal seizures during intravenous theophylline therapy. None had a history of neurologic disorder, and all were acutely ill with severe pulmonary or cardiovascular disease, or both. Serum theophylline concentrations obtained within 1 hour of the seizure ranged from 25 mug/ml to 70mug/ml, with a mean value (53 plus or minus 4.8 mug/ml) more than twice the upper limit of the recommended therapeutic concentration. This serum theophylline concentration was greater than the concentration found in a group of patients with less severe drug-related symptoms (35 plus or minus 1.8 mug/ml, P less than 0.01). A third group of patients without drug-related symptoms had a mean theophylline serum concentration of 19 plus or minus 2.0 mug/ml, which was less than that found in either group with toxicity symptoms (P less than 0.05). Factors predisposing to the high serum concentrations in the patients with seizures were both higher drug dosage, compared with the other groups (P less than 0.01), and hepatic dysfunction, which was more common in both groups with drug-related symptoms.

Complications of assisted ventilation: A prospective study of 354 consecutive episodes

Abstract Three hundred fourteen consecutive patients were studied prospectively during 354 episodes of assisted ventilation in a 5 month period. These patients ranged in age from 15 to 95 years, and ventilatory support was required for from 1 hour to 54 days. Over-all survival was 64 per cent. Eighteen complications were studied prospectively, of which three (intubation of the right mainstem bronchus, endotracheal tube malfunction and alveolar hypoventilation) were associated with decreased survival. Four hundred individual complications or potential complications were observed. Intubation of the right mainstem bronchus was associated with alveolar hyperventilation, atelectasis and/or tension pneumothorax in a significant number of cases (all, P

Respiration during sleep in normal man.

Respiratory volumes and timing have been measured in 19 healthy adults during wakefulness and sleep. Minute ventilation was significantly less (p less than 0.05) in all stages of sleep than when the subject was awake (7.66 +/- 0.34(SEM) 1/min), the level in rapid-eye-movement (REM) sleep (6.46 +/- 0.29 1/min) being significantly lower than in non-REM sleep (7.18 +/- 0.39 1/min). The breathing pattern during all stages of sleep was significantly more rapid and shallow than during wakefulness, tidal volume in REM sleep being reduced to 73% of the level during wakefulness. Mean inspiratory flow rate (VT/Ti), an index of inspiratory drive, was significantly lower in REM sleep than during wakefulness or non-REM sleep. Thus ventilation falls during sleep, the greatest reduction occurring during REM sleep, when there is a parallel reduction in inspiratory drive. Similar changes in ventilation may contribute to the REM-associated hypoxaemia observed in normal subjects and in patients with chronic obstructive pulmonary disease.

Bradycardia during sleep apnea. Characteristics and mechanism.

To determine the characteristics of and mechanisms causing the bradycardia during sleep apnea (SA), both patients with SA and normals were studied. Evaluation of six consecutive SA patients demonstrated that bradycardia occurred during 95% of all apneas (central, obstructive, and mixed) and became marked with increased apnea length (P less than 0.01) and increased oxyhemoglobin desaturation (P less than 0.01). Heart rate slowed 9.5 beats per minute (bpm) during apneas of 10-19 s in duration, 11.4 bpm during 20-39s apneas, and 16.6 bpm during 40-59-s apneas. Sleep stage had no effect unexplained by apnea length or degree of desaturation. Oxygen administration to four SA patients completely prevented the bradycardia although apneas lengthened (P less than 0.05) in three. Sleeping normal subjects did not develop bradycardia during hypoxic hyperpnea but, instead, HR increased with hypoxia in all sleep stages, although the increase in HR was not as great as that which occurred while awake. Breath holding in awake normals did not result in bradycardia during hyperoxia (SaO2 = 99%), but was consistently (P less than 0.01) associated with heart rate slowing during room air breath-holds (-6 bpm) at SaO2 = 93%, with more striking slowing (-20 bpm) during hypoxic breath-holds (P less than 0.01) at SaO2 = 78%. Breath holding during hyperoxic hypercapnia had no significant effect on rate. Breath holding in awake SA subjects demonstrated similar findings. We conclude that the bradycardia of SA is a consistent feature of apnea and results from the combined effect of cessation of breathing plus hypoxemia.

Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome☆

Most patients with extreme obesity do not exhibit alveolar hypoventilation, but an intriguing minority do. The mechanism(s) of this phenomenon remain unknown. A disorder in ventilatory control has been suggested as a major factor in the pathogenesis of the obesity-hypoventilation syndrome. Accordingly, hypoxic and hypercapnic ventilatory drives were measured in 10 patients with the typical symptoms of the syndrome: obesity, hypersomnolence, hypercapnia, hypoxemia, polycythemia and cor pulmonale. Hypoxic ventilatory drive, measured as the shape parameter A, averaged 21.9 +/- 5.35, approximately one-sixth that in normal controls, A = 126 +/- 8.6 (P less than 0.01). The ventilatory response to hypercapnia also was markedly reduced, the slope of the response averaging 0.51 +/- 0.005, or about one-third the normal value of 1.83 +/- 0.13 (P less than 0.01). This decreased responsiveness in hypoxic and hypercapnic ventilatory drive was consistent throughout the group. The depression in ventilatory drive found in the obesity-hypoventilation syndrome may be causally related to the alveolar hypoventilation manifested by these patients.

Ventilatory Control in Myxedema and Hypothyroidism

Alveolar hypoventilation is known to occur in myxedema. To clarify the role of hypoxic ventilatory drive and hypercapnic ventilatory drive in thyroid hormone insufficiency states, 10 patients with myxedema and seven with hypothyroidism (thyroid ablation) were studied before and after thyroid replacement. An index developed for hypoxic ventilatory drive was markedly reduced in myxedema: 17 plus or minus 4.7 (S.E.M.) (normal, 126 plus or minus 8.7) (P smaller than 0.01) and increased to 78 plus or minus 12.6 (p = 0.02) with thyroid hormone replacement. In the hypothyroid group this index was also depressed as compared to normal at 67 plus or minus 20 (p smaller than 0.01) and increased to 114 plus or minus 19 (p smaller than 0.02) with replacement. An index for hypercapnic ventilatory drive was depressed in myxedema, 0.69 plus or minus 0.01), but was not significantly depressed in hypothyroidism. With thyroid hormone replacement this index did not significantly increase in either group. We conclude that both myxedema and hypothyroid states produce depression of hypoxic ventilatory drive that is responsive to replacement therapy. This alteration in ventilatory control may contribute to the hypoventilation seen in myxedema.

Clinical semi-starvation: depression of hypoxic ventilatory response.

A decreased metabolic rate has been associated with decreased ventilatory response to hypoxia and hypercapnia, and also with starvation. We fed a 500-calorie carbohydrate diet with supplemental electrolytes, designed to simulate alimentation by usual intravenous fluids, to seven normal subjects for 10 days to determine the effect of semi-starvation on metabolic rate and ventilatory responses. By the 10th day metabolic rate was significantly decreased, and hypoxic ventilatory response decreased to 42% of control (P less than 0.05). In two subjects, hypoxic ventilatory response was virtually abolished at day 10. These changes reversed toward normal with refeeding. The decrease in hypoxic ventilatory response response was significantly (P less than 0.01) related to the decrease in metabolic rate. Hypercapnic ventilatory response, measured as the slope of the ventilatory response to hypercapnia, decreased slightly but not significantly. The decrease in hypoxic ventilatory response seen during semi-starvation may contribute to the hypoxemia and respiratory failure subsequent to caloric restriction.

Progesterone for Outpatient Treatment of Pickwickian Syndrome

Ten patients with the Pickwickian syndrome, characterized by obesity, hypoxemia, hypercapnia, polycythemia, and cor pulmonale, underwent long-term treatment as outpatients with medroxyprogesterone acetate. Although there was no significant weight change in the group, PaO2 rose 12.6 +/- 2.7 mm Hg (SEM) from 49 +/- 2.6 mm Hg to 62 +/- 2.3 mm Hg (P less than 0.001), while PaCO2 fell 13 +/- 2.6 mm Hg from 51 +/- 1.9 mm Hg to 38 +/- 1.2 mm Hg (P less than 0.001). Hematocrit fell from 56 +/- 2.5% to 50 +/- 1.2%, a mean fall of 6% (P less than 0.01), during medroxyprogesterone acetate therapy. In the 2 patients who had cardiac catheterization before and during medroxyprogesterone acetate therapy, mean pulmonary arterial pressure fell 13 and 19 mm Hg. There were no recurrences of cor pulmonale during treatment. These effects on arterial blood gas values and clinical state were sustained during therapy. On withdrawal of medroxyprogesterone acetate during 1-month period, arterial oxygen and carbon dioxide tensions deteriorated to their previous pretreatment values. Reinstitution of medroxyprogesterone acetate caused improvement in both the oxygen and carbon dioxide tensions. We conclude that sublingual medroxyprogesterone acetate therapy is useful in the management of the Pickwickian syndrome.

Obstructive Sleep Apnea in Hypothyroidism

To determine the incidence and frequency of sleep apnea in persons with hypothyroidism, 11 consecutive patients with newly diagnosed disease were studied before and during thyroid hormone replacement therapy. Nine patients had episodes of apnea, with the number of episodes per hour of sleep ranging from 17 to 176 (mean, 71.8). Six of the nine patients were obese and had 99.5 episodes per hour compared with 16.3 episodes per hour in the 3 nonobese patients (p less than 0.02). After 3 to 12 months of thyroxine replacement therapy, mean apnea frequency decreased from 71.8 +/- 18.0 (SE) to 12.7 +/- 6.1 episodes per hour, without reduction in body weight. There were fewer changes in sleep stage per hour during treatment (22.1 +/- 4.9) than pretreatment (57.6 +/- 14.5). Carbon dioxide response tests done under non-loaded and flow-resistive loaded conditions before and during thyroxine replacement therapy showed increases in the loaded respiratory effort and ventilation during thyroxine treatment. Sleep apnea episodes are common in persons with untreated hypothyroidism, even with normal lung function. Thyroxine replacement therapy decreases apnea frequency, even without change in body weight.

Hereditary aspects of decreased hypoxic response.

Decreased ventilatory responses to hypoxia and hypercapnia have been demonstrated in a variety of disorders; however, the etiology of these decreased drives remains virtually unknown. Recent observations have suggested a familial influence on hypoxic and hypercapnic ventilatory response, but it is unclear whether this influence is the result of hereditary or environmental influences. Therefore we measured the ventilatory response to isocapnic hypoxia (HVR) and hyperoxic hypercapnia in 12 pairs of identical and 12 pairs of nonidentical twins. Significant correlation (P less than 0.01) was found for HVR within identical twin pairs but not within nonidentical twin pairs. Identical twins resembled each other more closely with respect to HVR than was the case for nonidentical twins (P less than 0.0125). This was independent of body size, blood PCO2, or pH. No such correlation could be found for ventilatory response to hyperoxic hypercapnia. It is concluded that hereditary influences affect HVR and it is speculated that such influences may play a role in clinical conditions characterized by decreased hypoxic ventilatory responses.