Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: a phase I-II study.

Hydroxyurea and fluorouracil (5-FU) are active cytotoxic drugs in head and neck cancer and have shown synergistic activity in vitro. Both drugs also act as radiosensitizers. Therefore, we administered radiotherapy at daily fractions of 180 to 200 cGy with simultaneous continuous infusion 5-FU at 800 mg/m2/d and escalating daily doses of hydroxyurea for five days. Cycles were repeated every other week until completion of radiotherapy. Thirty-nine inoperable patients were treated at six dose levels of hydroxyurea ranging from 500 mg to 3,000 mg orally daily. Little effect of hydroxyurea on the WBC or platelet count was noted in patients receiving less than 2,000 mg daily, whereas both parameters decreased progressively in patients receiving 2,000 mg daily or more. Mucositis occurred at all dose levels, requiring frequent dose reduction of 5-FU; however, in patients receiving a daily hydroxyurea dose of 2,000 mg or less, the median weekly 5-FU dose administered was 1,725 mg/m2 (86% of the intended 5-FU dose), whereas at daily hydroxyurea doses exceeding 2,000 mg, the median weekly 5-FU dose decreased to 1,133 mg/m2 (57%) (P = .001). Of 15 evaluable patients with recurrent disease after prior local therapy only one failed to respond; six had a complete response (CR), and eight a partial response (PR). Of 17 evaluable patients without prior local therapy, 12 had a CR, with no patient developing recurrence in the irradiated field to date; five patients had a PR. We conclude that the recommended dose of hydroxyurea in this regimen is 2,000 mg daily. That dose will cause mild to moderate myelosuppression and will allow for delivery of greater than 80% of the intended 5-FU dose. The activity of this regimen in poor-prognosis head and neck cancer exceeds 90%; its further investigation in previously untreated patients is warranted.

Helium-oxygen breathing in severe chronic obstructive pulmonary disease.

The effect of breathing helium-oxygen (He-O2) mixtures was evaluated in 15 patients with severe chronic obstructive pulmonary disease (COPD). Gas exchange was assessed during quiet breathing at rest before and after 15 minutes of breathing 80 percent He-20 percent O2 mixtures in all patients. Functional residual capacity (FRC) determined during argon (Ar) washing studies fell significantly while breathing He-O2, but we did not find significant changes in minute ventilation, tidal volume, respiratory frequency, or inspiratory or expiratory timing. Eleven patients showed decreases in arterial PCO2 and CO2 excretion during resting breathing on He-O2. Expiratory flows were increased at a given lung volume during He-O2 breathing as expected. Apparently, mechanical work of breathing was decreased in patients with severe COPD while breathing He-O2, leading to a reduction in VCO2 and improvement in overall alveolar ventilation. These findings lend support to the therapeutic use of He-O2 under some conditions in patients with severe COPD.

Acute effects of intravenous cocaine on pulmonary artery pressure and cardiac index in habitual crack smokers.

BACKGROUND: Some habitual crack cocaine smokers who deny IV drug abuse show decreased pulmonary transfer of carbon monoxide (DCO). We speculated that repeated elevations in pulmonary artery pressure (PAP) might cause pulmonary capillary damage and result in a lowered DCO, or that the reduction could be due to anoxic lung injury secondary to repeated episodes of cocaine-induced pulmonary vascular constriction. STUDY OBJECTIVE: Compare the acute effects of i.v. cocaine HCl and placebo on PAP, cardiac stroke volume, and cardiac output estimated indirectly by continuous Doppler echocardiography. DESIGN: A single-blind crossover study in which placebo always preceded the active drug. SUBJECTS: Ten current crack-smoking subjects, 32 to 47 years of age, with a history of limited previous i.v. cocaine use. METHODS: PAP, cardiac stroke volume, heart rate, and BP were measured continuously after injection of placebo followed by cocaine HCl (0.5 mg/kg). RESULTS: i.v. cocaine resulted in no significant change in PAP (-0.14 +/- 3.3[SD] mm Hg, 95% confidence interval [CI] for difference -2.48, +2.21). Stroke volume index showed no significant change after cocaine (-0.1 +/- 2.0 mL; 95% CI, -1.5, +1.3). Heart rate showed a significant increase (10.0 +/- 7.2 min-1; p = 0.0017, 95% CI, +4.9, +15.1). Cardiac index showed a significant increase (0.48 +/- 0.32 L/min; p = 0.0012, 95% CI, +0.25, +0.71). Pulmonary vascular resistance showed no significant change (-44 +/- 101 dyne.s.cm-5/m2, 95% CI, -116, +29). CONCLUSIONS: i.v. cocaine HCl does not cause short-term increases in PAP or stroke volume index, but causes an increase in cardiac index due to its chronotropic effect.

Acute effects of inhaled and i.v. cocaine on airway dynamics.

BACKGROUND: Wheezing has been reported by 32% of habitual smokers of crack cocaine, and several cases of crack-related acute exacerbations of asthma have been reported. STUDY OBJECTIVE: To compare the acute effects of physiologically active doses of smoked cocaine base and, i.v. cocaine hydrochloride (HCl), a subphysiologic dose of cocaine base (smoked "placebo"), and i.v. saline solution placebo on bronchomotor tone, subjective level of intoxication, and cardiovascular responses in healthy habitual crack users. DESIGN: A single-blind crossover study in which the order of route of administration (inhaled vs i.v.) was random but placebo always preceded the active drug. SUBJECTS: Fourteen healthy, nonasthmatic current crack-smoking subjects, 34 to 48 years of age, with a history of previous i.v. cocaine use (1 to 12 times per lifetime). METHODS: Heart rate, BP, self-rated level of intoxication (scale of 0 to 10), and measurements of airway resistance (Raw) and specific airway conductance (SGaw) were recorded during separate sessions before and 3 to 5, 10, 15, and 30 min after administration of smoked cocaine base (38.5 +/- 2.3 [SEM] mg), smoked placebo (2.3 +/- 0.9 mg cocaine base), i.v. cocaine HCl (30.0 +/- 2.0 mg), and i.v placebo (saline solution). RESULTS: Both smoked active cocaine and i.v. cocaine HCl caused comparable, significant (p < 0.05) peak levels of acute intoxication (6.7 +/- 0.7 and 7.3 +/- 0.8, respectively) and increases in heart rate from baseline (29.6 +/- 2.9% and 21.4 +/- 3.7%, respectively, at 5 min). However, only smoked active cocaine caused significant decreases from baseline in SGaw (25.4 +/- 6.3% at 5 min), in contrast to nonsignificant changes after i.v. cocaine HCl (5.6 +/- 7.0% increase) and smoked placebo (10.2 +/- 6.0% decrease). CONCLUSIONS: Smoked cocaine base, but not systemically administered cocaine HCl, causes acute bronchoconstriction that is probably mediated by local airway irritation and could account for reports of crack-induced wheezing and asthma attacks in nonasthmatic and asthmatic individuals, respectively.

Efficacy of salmeterol xinafoate in the treatment of COPD.

STUDY OBJECTIVES: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. DESIGN: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. SETTING: Multiple sites at clinics and university medical centers throughout the United States. PATIENTS: Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. INTERVENTIONS: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. RESULTS: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. CONCLUSIONS: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.

Repetitive nocturnal arterial oxygen desaturation and silent myocardial ischemia in patients presenting for vascular surgery.

OBJECTIVE: To determine whether nocturnal respiratory abnormality (cyclic oxygen desaturation and tachycardia) is associated with nocturnal myocardial ischemia in older individuals with ischemic heart disease. DESIGN: Non-invasive monitoring on a single occasion. SETTING: Tertiary care referral hospital. PATIENTS: Thirty four consecutive older (68.5 +/- 6 yrs) patients referred for elective abdominal or carotid reconstructive vascular surgery. RESULTS: Seven patients (21%) had moderately severe nocturnal respiratory abnormality, defined by more than 50 dips in arterial oxygen saturation and increases in heart rate during the night. Two of these seven had clinical risk factors for ischemic heart disease and had nocturnal myocardial ischemia. Ten patients (29%) developed ischemia at some time during the study, of whom seven hand known ischemic heart disease, hypertension, and/or angina. Those with increased nocturnal ischemia showed very low frequency (1-2 cycles per minute) cyclic heart rate oscillations and repetitive nocturnal episodes of arterial oxygen desaturation, similar to patients with sleep apnea. CONCLUSION: Repetitive nocturnal cyclic arterial desaturation and cyclic increases in heart rate are associated with nocturnal myocardial ischemia in individuals with clinical risk factors for ischemic heart disease. Further investigation in a large patient sample utilizing non-invasive monitoring of saturation, heart rate, and blood pressure may provide definitive evidence regarding causation of some of the nocturnal myocardial ischemia occurring in older individuals with vascular disease.

Ventilation and thoracoabdominal asynchrony during halothane anesthesia in infants.

To evaluate the ventilatory consequences of high chest wall compliance during anesthesia in infants, we assessed the effects of halothane at different fractions of minimal alveolar concentration (0.75, 1.0, and 1.5 MAC) on ventilation and movements of the rib cage and abdomen in infants < or = 12 mo of age (group I) and children (group II) > or = 12 mo of age. Minute ventilation decreased in group I, (20.6%, 0.75 to 1.5 MAC), but the change in group II did not reach the level of statistical significance. Tidal volume decreased with halothane level between 0.75 and 1.5 MAC, and its fall was greater in group I (32.7 +/- 11.2 vs. 22.6 +/- 9.3% in group II, P < 0.05). Duty cycle, or ratio of inspiratory to total time (TI/TT), increased in group II with halothane level but did not change in group I, resulting in a decreased TI in group I at higher halothane levels. Thoracic paradox increased with halothane level in group I but not group II. The increase in thoracic paradox in association with the fall in tidal volume between 0.75 and 1.5 MAC was greater in group I than group II (P < 0.05). We conclude that smaller infants depend more on inspiratory intercostal muscle activity to stabilize the thorax, leading to a greater degree of depression of ventilation during halothane depression of inspiratory intercostal activity.

Differential costal and crural diaphragm compensation for posture changes.

The electromyographic (EMG) activities of the costal and crural diaphragm were recorded from bipolar fine-wire electrodes placed in the costal fibers adjacent to the central tendon and in the anterior portions of the crural fibers in 12 anesthetized cats. The EMG activities of costal and crural recordings were compared during posture changes from supine to head up and during progressive hyperoxic hypercapnia in both positions. The activity of both portions of the diaphragm was greater in the head up compared with supine posture at all levels of CO2; and increases in crural activity were greater than those in costal activity both as a result of changes in posture and with increasing CO2 stimuli. These results are consistent with the concept that diaphragm activation is modulated in response to changes in resting muscle length, and further, that neural control mechanisms allow separate regulation of costal and crural diaphragm activation.

Comparison of thoracoabdominal calibration methods in normal human subjects.

In 19 normal subjects in the supine posture, we compared accuracy and precision of calibration methods that utilized different ranges of tidal volumes and thoracoabdominal partitioning: spontaneous quiet breathing (QB), isovolume maneuvers, and voluntary efforts to breathe with variable tidal volume and thoracoabdominal partitioning. Thoracic and abdominal movements were measured with the respiratory area fluxometer. Calibration methods utilizing one or more types of respiratory efforts were applied to three measurement situations: QB, variable breathing (volume and thoracoabdominal partitioning), and simulated obstructive apnea (isovolume efforts). Qualitative diagnostic calibration (QDC) included QB data only. The isovolume method (ISOCAL) included isovolumetric efforts at end expiration (functional residual capacity) and QB. Multilinear regression analyses were performed on data sets that included 1) voluntary efforts to breathe with variable volume and thoracoabdominal partitioning (CAL 1), 2) QB in addition to variable volume and partitioning (CAL 2), and 3) isovolume maneuvers in addition to QB and variable volume and partitioning efforts (CAL 3). When calibration data included a wide range of tidal volume, variable thoracoabdominal partitioning, and isovolume efforts (CAL 3), a stable calibration with small bias and scatter during all respiratory patterns was obtained. Excluding isovolume maneuvers (CAL 2) and QB (CAL 1) did not diminish accuracy. Limiting data to isovolume efforts at functional residual capacity plus QB (ISO-CAL) caused a significant increase in scatter during variable breathing patterns. Limiting calibration data to that portion of QB with small variation in the uncalibrated sum of thoracic and abdominal movements (QDC) caused significant increases in scatter in both isovolume efforts and variable breathing.

Dissociation between diaphragmatic and rib cage muscle fatigue.

To assess rib cage muscle fatigue and its relationship to diaphragmatic fatigue, we recorded the electromyogram (EMG) of the parasternal intercostals (PS), sternocleidomastoid (SM), and platysma with fine wire electrodes and the EMG of the diaphragm (DI) with an esophageal electrode. Six normal subjects were studied during inspiratory resistive breathing. Two different breathing patterns were imposed: mainly diaphragmatic or mainly rib cage breathing. The development of fatigue was assessed by analysis of the high-to-low (H/L) ratio of the EMG. To determine the appropriate frequency bands for the PS and SM, we established their EMG power spectrum by Fourier analysis. The mean and SD for the centroid frequency was 312 +/- 16 Hz for PS and 244 +/- 48 Hz for SM. When breathing with the diaphragmatic patterns, all subjects showed a fall in H/L of the DI and none had a fall in H/L of the PS or SM. During rib cage emphasis, four out of five subjects showed a fall in H/L of the PS and five out of six showed a fall in H/L of the SM. Four subjects showed no fall in H/L of the DI; the other two subjects were unable to inhibit diaphragm activity to a substantial degree and did show a fall in H/L of the DI. Activity of the platysma was minimal or absent during diaphragmatic emphasis but was usually strong during rib cage breathing. We conclude that fatigue of either the diaphragm or the parasternal and sternocleidomastoid can occur independently according to the recruitment pattern of inspiratory muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

High-frequency oscillations in human respiratory electromyograms during voluntary breathing.

Electromyograms (EMGs) from respiratory muscles were obtained from human subjects during voluntarily controlled breathing. In 10 studies on 6 subjects EMGs were recorded from the right and left lower ventrolateral surface of the rib cage while the subject emphasized the use of his diaphragm for breathing. Simultaneous samples of the 2 EMG signals of 256-ms duration were obtained once per inspiration (in either the first of second half of inspiration) from each of 30 consecutive breaths using a laboratory minicomputer. Individual power spectra for the 2 EMG signals, and the squared coherence spectrum between them, were calculated. From the coherence spectrum common high-frequency oscillations could be identified within two frequency ranges: 70-100 Hz and 20-50 Hz. Peaks at similar frequencies were identified in both early-inspiratory and late-inspiratory EMG signals. Similar experiments were done on 3 subjects from whom an esophageal diaphragm EMG was obtained as well. The coherence spectrum between the esophageal EMG and the right rib cage surface EMG again demonstrated the presence of common high-frequency oscillations in the same frequency ranges as above. Evidence of these oscillations was not usually apparent in the power spectra. When ECG signal components were allowed to contaminate some of the EMG data samples, the coherence spectrum could be altered considerably, leading to inappropriate conclusions regarding the presence or absence of high-frequency oscillations. It is hypothesized that these high-frequency oscillations are similar to those described in nerve recordings from previous studies on anesthetized and decerebrate cats and dogs and a mechanism for their expression in EMG signals is proposed. The coherence spectrum is a very sensitive method for detecting related signal components in two signals. That high-frequency oscillations can be detected using the less sensitive techniques of autocorrelation and power spectral analysis in some animal preparations may reflect an enhancement of these oscillations in those preparations.

Costal and crural diaphragm and intercostal muscle activity during augmented breaths in cats.

The pattern of electrical activity of the costal and crural diaphragm and the external intercostal muscles was ascertained in ten anesthetized spontaneously breathing cats during eupnea and during augmented breaths. All muscles studied manifested a biphasic activity pattern during augmented breaths. The increase in activity during the latter portion (phase II) of the augmented breaths was greater for the crural than the costal diaphragm (P less than 0.05), and greater for cranially located intercostal muscles than for the costal diaphragm (P less than 0.02) and more caudally located intercostal muscles (P less than 0.02). These results suggest that during augmented breaths, activity of different thoracic muscles is modulated in a non-uniform manner.

Breathhold cine MRI of left ventricular function in patients with obstructive sleep apnea: work-in-progress.

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that can cause left ventricular (LV) dysfunction. In patients with OSA, the LV dysfunction is usually evaluated by echocardiography. The purpose of this study was to evaluate whether the use of breathhold cine MRI for the study of LV dysfunction would be feasible and well tolerated by patients with OSA. Six volunteers and five patients underwent a breathhold cine MRI study of the LV using a 1.5 Tesla MR imager. Cine MRI was performed using a breathhold k-space segmented TurboFLASH technique during end-expiration. Systolic thickening of the LV septal wall was 49% +/- 16% in normals vs. 25% +/- 10.5% in patients (p < 0.05). Systolic thickening of the LV free wall was 42% +/- 12% in normals vs. 22% +/- 9% in patients (p < 0.05). There was a significant difference in end-diastolic wall thickness between the two groups. All patients tolerated the procedure well. The total duration of each study was relatively short (less than 11 min). Breathhold MRI techniques can be used to study LV dysfunction in patients with respiratory disability such as OSA.

The incidence and value of rectal examination in children with suspected appendicitis.

Rectal examination is considered an important part of the examination of patients presenting with abdominal pain. However, children find anal digitation unpleasant and it was our impression that doctors were becoming less insistent on performing a rectal examination. We performed an audit of rectal examination and assessed whether this made any difference to the management of children with acute abdominal pain. We looked at the records of 48 children from 1989 and 49 children from 1985 presenting with abdominal pain. We found that the rate of rectal examination was halved in this time. Diagnostic accuracy was similar in the two groups, and the morbidity rate was the same. These findings call into question the need for routine rectal examination in children with suspected appendicitis.

Surgical audit without autopsy: tales of the unexpected.

To establish our current practice and the potential value of the autopsy in general surgery, a retrospective review of general surgical autopsies was performed at one district general hospital from January 1989 to August 1991. There was considerable interconsultant variation in autopsy practice with a low 25% overall autopsy rate reflecting a low autopsy request rate. There were discrepancies between the clinical and pathological cause of death in 40 (63%) cases. There were important discrepancies which may have changed management in life in 18 (28%) autopsies, 7 (39%) of which were untreated visceral perforations. Autopsy is an important part of the surgical audit and will disclose considerable unsuspected pathology. Present autopsy rates are low and need to be improved. The unexpected finding of seven untreated visceral perforations requires further study.

Perioperative complications of in-situ vein bypass.

Experience with 146 in-situ vein bypass procedures for obliterative arterial disease are reviewed to determine the specific complication of the technique. Vein wall injury with the Hall valvulotome occurred in 6 patients (4%) and vein patching of a stenosed femoral vein was required in 2 patients. Residual arteriovenous fistulae occurred in 24 patients (16.5%) of whom 9 had an associated graft thrombosis distal to the fistula of which 6 were corrected by thrombectomy and fistula ligation. Perioperative thrombosis occurred in 29 grafts (20%) and was more common in the femoropopliteal group (23/80) than in the femorocrural group (6/66) (P less than 0.01, X2 = 7.55). Fourteen of the femoropopliteal and two of the femorocrural thromboses were corrected resulting in an immediate patency of 89% and 94% respectively with the cumulative patency at one year being 77.5% and 79%. Complications of the in-situ bypass technique remain despite having largely overcome the problems of valve disruption. However, until a standard method emerges careful note must be made of technique and complications when considering reports of in-situ bypass patency.