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Noninvasive ventilation (NIV) is an increasingly used method of respiratory support. The use of NIV is expanding over the time and if properly applied, it can save patients' lives and improve long-term prognosis. However, both knowledge and skills of its proper use as life support are paramount. This systematic review aimed to assess the importance of NIV education and training. Literature search was conducted (MEDLINE: 1990 to June, 2018) to identify randomized controlled studies and systematic reviews with the results analyzed by a team of experts across the world through e-mail based communications. Clinical trials examining the impact of education and training in NIV as the primary objective was not found. A few studies with indirect evidence, a simulation-based training study, and narrative reviews were identified. Currently organized training in NIV is implemented only in a few developed countries. Due to a lack of high-grade experimental evidence, an international consensus on NIV education and training based on opinions from 64 experts across the twenty-one different countries of the world was formulated. Education and training have the potential to increase knowledge and skills of the clinical staff who deliver medical care using NIV. There is a genuine need to develop structured, organized NIV education and training programs, especially for the developing countries.

Background: Expiratory central airway collapse is an increasingly recognized abnormality of the central airways and may be present in as many as 22% of patients evaluated for chronic obstructive pulmonary disease and/or asthma. Many current treatment options require invasive procedures that have been shown to cause significant morbidity and mortality. To test the hypothesis that Teflon injection will induce sufficient fibroblast proliferation and collagen deposition, we evaluated the time course on the effect of Teflon injection in the posterior membranous trachea on the histopathology of the tracheobronchial tree., Methods: Six Yucatan Pigs were assigned to undergo general anesthesia and injection of 0.3 to 0.5 mL of sterile Teflon paste in 50% glycerin into the posterior membranous tracheal wall. A control pig received an equivalent volume of glycerin. Animals were euthanized in predefined intervals and tracheas were excised and examined under light microscopy for identifying fibroblast proliferation and collagen deposition., Results: Compared with the control pig, the Teflon injection site showed tissue reaction of fibrohistiocytic proliferation and subsequent collagen deposition in all animals. Furthermore, the increased fibroblast proliferation and collagen deposition were time dependent (P<0.01)., Conclusion: This pilot study demonstrates histopathologic changes in the trachea after Teflon injection, comprised of increased fibroblast activity and collagen deposition that could be of potential use in creating greater airway rigidity in patients with sever diffuse excessive dynamic airway collapse.

Objectives: Thiamin deficiency is highly prevalent in patients with sepsis, but the mechanism by which sepsis induces thiamin deficiency is unknown. This study aimed to determine the influence of various severity of sepsis on carrier-mediated intestinal thiamin uptake, level of expressions of thiamin transporters (thiamin transporter-1 and thiamin transporter-2), and mitochondrial thiamin pyrophosphate transporter., Design: Randomized controlled study., Setting: Research laboratory at a Veterans Affairs Medical Center., Subjects: Twenty-four Sprague-Dawley rats were randomized into controls, mild, moderate, and severe sepsis with equal number of animals in each group., Interventions: Sepsis was induced by cecal ligation and puncture with the cecum ligated below the cecal valve at 25%, 50%, and 75% of cecal length, defined as severe, moderate, and mild sepsis, respectively. Control animals underwent laparotomy only., Measurements and Main Results: After 2 days of induced sepsis, carrier-mediated intestinal thiamin uptake was measured using [H]thiamin. Expressions of thiamin transporter-1, thiamin transporter-2, and mitochondrial thiamin pyrophosphate transporter proteins and messenger RNA were measured. Proinflammatory cytokines (interleukin-1β and interleukin-6) and adenosine triphosphate were also measured. Sepsis inhibited [H]thiamin uptake, and the inhibition was a function of sepsis severity. Both cell membrane thiamin transporters and mitochondrial thiamin pyrophosphate transporter expression levels were suppressed; also levels of adenosine triphosphate in the intestine of animals with moderate and severe sepsis were significantly lower than that of sham-operated controls., Conclusions: For the first time, we demonstrated that sepsis inhibited carrier-mediated intestinal thiamin uptake as a function of sepsis severity, suppressed thiamin transporters and mitochondrial thiamin pyrophosphate transporter, leading to adenosine triphosphate depletion.

Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption.

Introduction: Immobilization of hindlimb muscles in a shortened position results in an accelerated rate of inactivity-induced muscle atrophy and contractile dysfunction. Similarly, prolonged controlled mechanical ventilation (CMV) results in diaphragm inactivity and induces diaphragm muscle atrophy and contractile dysfunction. Further, the application of positive end-expiratory airway pressure (PEEP) during mechanical ventilation would result in shortened diaphragm muscle fibers throughout the respiratory cycle. Therefore, we tested the hypothesis that, compared to CMV without PEEP, the combination of PEEP and CMV would accelerate CMV-induced diaphragm muscle atrophy and contractile dysfunction. To test this hypothesis, we combined PEEP with CMV or with assist-control mechanical ventilation (AMV) and determined the effects on diaphragm muscle atrophy and contractile properties., Methods: The PEEP level (8 cmH2O) that did not induce lung overdistension or compromise circulation was determined. In vivo segmental length changes of diaphragm muscle fiber were then measured using sonomicrometry. Sedated rabbits were randomized into seven groups: surgical controls and those receiving CMV, AMV or continuous positive airway pressure (CPAP) with or without PEEP for 2 days. We measured in vitro diaphragmatic force, diaphragm muscle morphometry, myosin heavy-chain (MyHC) protein isoforms, caspase 3, insulin-like growth factor 1 (IGF-1), muscle atrophy F-box (MAFbx) and muscle ring finger protein 1 (MuRF1) mRNA., Results: PEEP shortened end-expiratory diaphragm muscle length by 15%, 14% and 12% with CMV, AMV and CPAP, respectively. Combined PEEP and CMV reduced tidal excursion of segmental diaphragm muscle length; consequently, tidal volume (VT) decreased. VT was maintained with combined PEEP and AMV. CMV alone decreased maximum tetanic force (Po) production by 35% versus control (P < 0.01). Combined PEEP and CMV did not decrease Po further. Po was preserved with AMV, with or without PEEP. Diaphragm muscle atrophy did not occur in any fiber types. Diaphragm MyHC shifted to the fast isoform in the combined PEEP and CMV group. In both the CMV and combined PEEP and CMV groups compared to controls, IGF-1 mRNAs were suppressed, whereas Caspase-3, MAFbx and MuRF1 mRNA expression were elevated., Conclusions: Two days of diaphragm muscle fiber shortening with PEEP did not exacerbate CMV-induced diaphragm muscle dysfunction.

Bronchopleural fistula (BPF) is a communication between the pleural space and the bronchial tree, and is associated with significant morbidity and mortality. Treatment options for BPF include surgical closure and medical therapy. In an unstable patient, invasive surgical intervention is not an option. In this article, we report the case of a 61-year-old man who developed pneumothorax with a large BPF after a bronchoscopic resection of a malignant endobronchial lesion. We inserted a piece of 1.5×1.5-cm Xeroform dressing to seal the massive air leak with successful closure of the BPF. To our knowledge, this is the first report of successful closure of a massive BPF with Xeroform dressing in an acutely decompensating patient.

Information on the interactive effects of methylprednisolone, controlled mechanical ventilation (CMV), and assisted mechanical ventilation (AMV) on diaphragm function is sparse. Sedated rabbits received 2 days of CMV, AMV, and spontaneous breathing (SB), with either methylprednisolone (MP; 60 mg/kg/day intravenously) or saline. There was also a control group. In vitro diaphragm force, myofibril ultrastructure, αII-spectrin proteins, insulin-like growth factor-1 (IGF-1), and muscle atrophy F-box (MAF-box) mRNA were measured. Maximal tetanic tension (P(o)) decreased significantly with CMV. Combined MP plus CMV did not decrease P(o) further. With AMV, P(o) was similar to SB and controls. Combined MP plus AMV or MP plus SB decreased P(o) substantially. Combined MP plus CMV, MP plus AMV, or MP plus SB induced myofibrillar disruption that correlated with the reduced P(o). αII-spectrin increased, IGF-1 decreased, and MAF-box mRNA increased in both the CMV group and MP plus CMV group. Short-term, high-dose MP had no additive effects on CMV-induced diaphragm dysfunction. Combined MP plus AMV impaired diaphragm function, but AMV alone did not. We found that acute, high-dose MP produces diaphragm dysfunction depending on the mode of mechanical ventilation., (Copyright © 2010 Wiley Periodicals, Inc.)

The time- and dose-dependent effects of acute high-dose corticosteroids on the diaphragm muscle are poorly defined. This study aimed to examine in rabbits the temporal relationships and dose-response effects of acute high-dose methylprednisolone succinate on diaphragmatic contractile and structural properties. Animals were assigned to groups receiving: (1) 80 mg/kg/day methylprednisolone (MP80) intramuscularly for 1, 2, and 3 days; (2) 10 mg/kg/day methylprednisolone (MP10, pulse-dose) for 3 days; or (3) saline (placebo) for 3 days; and (4) a control group. Diaphragmatic in vitro force-frequency and force-velocity relationships, myosin heavy chain (MyHC) isoform protein and mRNA, insulin-like growth factor-1 (IGF-1), muscle atrophy F-box (MAF-box) mRNA, and volume density of abnormal myofibrils were measured at each time-point. MP80 did not affect animal nutritional state or fiber cross-sectional area as assessed in separate pair-fed groups receiving methylprednisolone or saline for 3 days. Compared with control values, MP80 decreased diaphragmatic maximum tetanic tension (Po) by 19%, 24%, and 34% after 1, 2, and 3 days (P < 0.05), respectively, whereas MP10 decreased Po modestly (12%; P > 0.05). Vmax and MyHC protein proportions were unchanged in both the MP80 and MP10 groups. Maximum power output decreased after 2 and 3 days of MP80. Suppression of IGF-1 and overexpression of MAF-box mRNA occurred in both MP groups. Significant myofibrillar disarray was also observed in both MP groups. The decline in Po was significantly associated with the increased volume density of abnormal myofibrils. Thus, very high-dose methylprednisolone (MP80) can produce rapid reductions in diaphragmatic function, whereas pulse-dose methylprednisolone (MP10) produces only modest functional loss.

This study aimed to determine the time-dependent effects of diaphragmatic inactivity on its maximum shortening velocity (V(max)) and the muscle atrophy F-box (MAF-box, atrogin-1) gene expression during controlled mechanical ventilation (CMV). Twenty-four New Zealand White rabbits were grouped into 1 day, 2 days, and 3 days of CMV and controls in equal numbers. The in vitro isotonic contractile properties of the diaphragm were determined. In addition, myosin heavy chain protein and mRNA, myosin light chain, MAF-box mRNA, and volume density of abnormal myofibrils were measured. Tetanic force decreased, and V(max) increased from control of 6.4 to 6.6, 7.7, and 8.1 muscle lengths per second after 1, 2, and 3 days of CMV, respectively (P < 0.02). The increased V(max) compensated for the decreased tetanic force; consequently, compared with the controls, maximum power output was unchanged after 3 days of CMV. V(max) correlated with the volume density of abnormal myofibrils [y = 0.1x + 5.7 (r = 0.87, P < 0.01)]. In the diaphragm, MAF-box was overexpressed (355% of control) after 1 day of CMV, before the evidence of structural myofibril disarray. In conclusion, CMV produced a time-dependent increase in V(max) that was associated with the degree of myofibrillar disarray and independent of changes in myosin isoform expression. Furthermore, CMV produced an increase in MAF-box mRNA levels that may be partially or completely responsible for the degree of myofibrillar disarray resulting from CMV.

During conventional mechanical ventilation, fixed set pressure, flow, and tidal volume result in a mismatch between patient and ventilator inspiratory time and in a patient's inability to adapt to changing ventilatory demand. Synchrony between the patient and ventilator improves neuromuscular coupling and the ability to adapt to increased ventilatory demand or loading. The sensation of dyspnea prevents ineffective inspiratory efforts and attenuates periodic breathing during sleep.

Controlled mechanical ventilation induced a profound diaphragm muscle dysfunction and atrophy. The effects of diaphragmatic contractions with assisted mechanical ventilation on diaphragmatic isometric, isotonic contractile properties, or the expression of muscle atrophy factor-box (MAF-box), the gene responsible for muscle atrophy, are unknown. We hypothesize that assisted mechanical ventilation will preserve diaphragmatic force and prevent overexpression of MAF-box. Studying sedated rabbits randomized equally into control animals, those with 3 days of assisted ventilation, and those with controlled ventilation, we assessed in vitro diaphragmatic isometric and isotonic contractile function. The concentrations of contractile proteins, myosin heavy chain isoform, and MAF-box mRNA were measured. Tetanic force decreased by 14% with assisted ventilation and 48% with controlled ventilation. Maximum shortening velocity tended to increase with controlled compared with assisted ventilation and control. Peak power output decreased 20% with assisted ventilation and 41% with controlled ventilation. Contractile proteins were unchanged with either modes of ventilation; myosin heavy chain 2X mRNA tended to increase and that of 2A to decrease with controlled ventilation. MAF-box gene was overexpressed with controlled ventilation. We conclude that preserving diaphragmatic contractions during mechanical ventilation attenuates the force loss induced by complete inactivity and maintains MAF-box gene expression in control.

This study shows that, over time, diaphragm inactivity with controlled mechanical ventilation (CMV) decreases diaphragm force and produces myofibril damage contributing to the reduced force. We measured in vivo and in vitro diaphragm contractile and morphological properties in 30 sedated rabbits grouped (n = 6) as follows: 1 or 3 days of CMV, 1 or 3 days of 0 cmH(2)O continuous positive airway pressure, and control. The CMV rate was set sufficient to suppress diaphragm electrical activity. Compared with the control group, phrenic-stimulated maximum transdiaphragmatic pressure did not decrease with continuous positive airway pressure but decreased to 63% after 1 day of CMV and to 49% after 3 days of CMV. The in vitro tetanic force decreased to 86% after 1 day of CMV and to 44% after 3 days of CMV. After 3 days of CMV, significant myofibril damage occurred in the diaphragm but not in the soleus. The decrease in tetanic force correlated with the volume density of abnormal myofibrils. We conclude that CMV had a detrimental effect on diaphragm contractile properties.

To determine the long-term effects of continuous positive airway pressure (CPAP) therapy on cardiovascular variability, we measured R-R interval (RR), systolic blood pressure (SBP) and respiration (DeltaV) in 13 awake, supine patients with moderate-to-severe obstructive sleep apnea (OSA), before and after ~6 mo of treatment. Using these data, we estimated the dynamics of the following components of a closed-loop circulatory control model: 1) the baroreflex component, 2) the neural coupling of DeltaV to RR or respiratory sinus arrhythmia (RSA), 3) the mechanical effects of respiration (MER) on SBP, and 4) the circulatory dynamics (CID) component, which is responsible for the feedforward effect of RR fluctuations on SBP. Baroreflex and RSA gains increased whereas MER and CID gains decreased in compliant subjects whose average CPAP use was >3 h/night. In contrast, baroreflex, RSA, and MER gains remained unchanged and CID gain increased in noncompliant subjects. Other summary measures were unchanged in both groups, except for mean RR, which increased in compliant patients. Closed-loop analysis provides a simple but sensitive means for quantitatively assessing cardiovascular control in OSA by using data collected from a single, nonintrusive test procedure.

To determine how long-term treatment with continuous positive airway pressure (CPAP) affects cardiac autonomic function, we measured R-R interval (RRI), respiration, and blood pressure in 13 awake patients with moderate-to-severe obstructive sleep apnea (OSA) in both supine and standing postures, before and after 3 to 9 mo of home therapy. Using visual feedback, the subjects controlled their respiration to track a randomized breathing pattern. From the RRI spectrum, we computed high-frequency power and the ratio of low-frequency to high-frequency power (LHR). To correct for differences in breathing, the average transfer gain relating respiration to RRI changes (G(RSA)) and the modified low-frequency to high-frequency ratio (MLHR) were also derived. CPAP therapy did not change the conventional spectral indices of heart rate variability (HRV). However, G(RSA) increased with average nightly CPAP use in supine (p < 0.01) and standing (p < 0.03) postures, whereas MLHR decreased with CPAP compliance during standing (p < 0.03). Supine mean heart rate decreased with compliance (p < 0.03). None of the estimated parameters was correlated with duration of therapy when actual CPAP use was not taken into account. These results suggest that CPAP treatment improves vagal heart rate control in patients with OSA and that the degree of improvement varies directly with compliance level.

Respiratory alkalosis is an extremely common and complicated problem affecting virtually every organ system in the body. This article reviews the various facets of this interesting problem. Respiratory alkalosis produces multiple metabolic abnormalities, from changes in potassium, phosphate, and calcium, to the development of a mild lactic acidosis. Renal handling of the above ions is also affected. The etiologies may be related to pulmonary or extrapulmonary disorders. Hyperventilation syndrome is a common etiology of respiratory alkalosis in the emergency department setting and is a diagnosis by exclusion. There are many cardiac effects of respiratory alkalosis, such as tachycardia, ventricular and atrial arrhythmias, and ischemic and nonischemic chest pain. In the lungs, vasodilation occurs, and in the gastrointestinal system there are changes in perfusion, motility, and electrolyte handling. Therapeutically, respiratory alkalosis is used for treatment of elevated intracranial pressure. Correction of a respiratory alkalosis is best performed by correcting the underlying etiology.

Study Objective: The purpose of this study was to determine whether the administration of sodium bicarbonate to normal individuals would increase their PaCO2 and thereby decrease the ventilatory requirements at a given workload., Design: In this double-blind crossover study, six normal men ingested either 3 mEq/kg NaHCO3 or 1 mEq/kg NaCl once a day for 5 days, in addition to 40 mg of furosemide and 40 mEq KCl. After each 5-day treatment, the subjects underwent a symptom-limited maximal bicycle ergometer exercise test while breathing through external dead space (with a volume of approximately 50% of their FEV1), a second exercise test without any external dead space, and an assessment of their respiratory response to hypercapnia., Results: The administration of the NaHCO3 resulted in a significant increase in the arterial HCO3- from 20.8 to 24.0 mEq/L and a significant increase in the PaCO2 from 31.7 to 36.9 mm Hg at rest that persisted during exercise. During exercise periods with the added dead space, the Borg scores were significantly lower at each workload after the subjects received bicarbonate, but the maximal exercise level did not increase. The mean (+/-SD) slope of the mouth occlusion pressure response to hypercapnia was significantly lower after the administration of NaHCO3 than after NaCl, respectively: 0.73+/-0.41 vs 1.27+/-0.97 cm H2O/mm Hg., Conclusion: From this study we conclude that the administration of NaHCO3 results in a significant increase in the PaCO2, decreases the ventilation and the Borg score at equivalent workloads, and decreases the hypercapnic response in normal individuals.

We examined the role of respiratory control during O2-induced hypercarbia in patients with chronic obstructive pulmonary disease (COPD), by comparing the observed change in ventilation (delta VEobs) with the delta VE predicted (delta VEpred) from the patients' ventilatory drive and the O2-induced delta PaCO2 and delta SaO2. Eleven stable hypoxemic COPD patients (mean +/- SD: FEV1 = 1.00 +/- 0.25 L, FVC = 2.33 +/- 0.38 L; room air PaCO2 = 52.7 +/- 7.9 mm Hg, SaO2 87.7 +/- 5.1%) were studied. Using standard rebreathing methods, we measured the ventilatory responses to hypercapnia (delta VE/PCO2 = 0.76 +/- 0.55 L/min/mm Hg) and to hypoxia (delta VE/delta SaO2 = -0.74 +/- 0.31 L/min/%). After breathing 100% O2 for 15 min, the mean delta VEobs was -0.08 +/- 0.62 (SEM) L/min (p = NS), the delta SaO2 was 7.6 +/- 3.6% (p < 0.001), and the delta PaCO2 was 6.6 +/- 3.3 mm Hg (p < 0.001). The delta VEpred was expressed as the sum of a decrease in ventilation due to suppression of hypoxic drive [calculated as the product (delta VE/SaO2) x delta SaO2] and an increase in ventilation due to the O2-induced hypercarbia [calculated as the production (delta VE/delta PCO2) x delta PaCO2]. The mean delta VEpred [-0.96 +/- 0.68 (SEM)] did not differ significantly from mean delta VEobs. We conclude that the O2-induced delta VEobs is equal to that expected from the ventilatory drives and the changes in PaCO2 and SaO2; and that O2-induced hypercarbia does not indicate a failure of respiratory control mechanisms in the maintenance of PaCO2 homeostasis.

Patient-ventilator synchrony is important in the management of the ventilator-dependent patient. Factors inherent to the patient and the ventilator influence patient-ventilator synchrony. Detection of patient-ventilator synchrony may require monitoring of airway pressure and flow waveforms.

The time course of ventilatory failure, pump failure, and diaphragm peripheral fatigue was determined during the application of external inspiratory resistive loads (IRL) in anesthetized rabbits. Pump failure is defined as the inability of the diaphragm to sustain the expected force under IRL. To assess contractile fatigue, transdiaphragmatic pressures (Pdi) generated by bilateral phrenic nerve stimulation at 75 Hz (Pdi-75) and 20 Hz (Pdi-20) were measured. The amplitude of evoked diaphragm electromyographic (EMG) signals was measured to assess neurotransmission failure. The rate of rise of spontaneous diaphragm EMG was used as an index of respiratory drive. Ventilation was evaluated together with arterial blood gases. During IRL the rate of rise of spontaneous diaphragm EMG increased, and there was a progressive hypercapnic acidosis and hypoxemia, indicating ventilatory failure. In contrast, Pdi-75 and Pdi-20 were stable until the time of respiratory arrest (apnea), when they decreased by 34 and 45%, respectively. The amplitude of evoked diaphragm EMG signals remained unchanged throughout the IRL and decreased only slightly at the time of apnea. We conclude that IRL induces progressive ventilatory failure long before any contractile fatigue of the diaphragm or pump failure occurs. This suggests that ventilatory failure is due to central fatigue, whereas pump failure (apnea) is attributable to multiple factors.

Lung elastance and resistance increase in the supine posture. To evaluate the effects of change in posture on regional lung mechanics at different lung volumes, lung elastance and resistance were measured at graded volume subdivisions and three esophageal levels at seated and supine body positions, using the esophageal balloon technique. Volumes were adjusted to be the same in both postures. In general, lung elastance (both static and dynamic) tended to be higher in supine posture and uniform at all lung volumes, except at 80% vital capacity, where it increased sharply. The ratio of dynamic to static lung elastance was slightly higher at the cephalad esophageal level, where regional flow rates and relative volume expansion are lower. Lung resistance varied inversely with lung volume but was higher at corresponding volume subdivisions in the supine posture. It decreased at more cephalad esophageal levels, where volume expansion and flow are less. Thus, the increase in regional flow at low volume subdivisions (most marked in the supine position) also contributed to higher lung resistance at these volumes. These findings are explained on the basis of a combination of Newtonian physics as well as nonlinear viscoelastic properties of the lung as applied to regional flow and volume expansion.

In the past year, studies on spontaneous pneumothorax have focused on etiology and treatment. Chronic obstructive pulmonary disease remains the most common cause of secondary spontaneous pneumothorax. However, Pneumocystis carinii infections in patients who have AIDS have become the leading cause of spontaneous pneumothorax in a population where its prevalence is high. One of the treatment modalities of spontaneous pneumothorax is tube thoracostomy with the instillation of tetracycline as the sclerosing agent. Tetracycline is no longer available. Fortunately, its derivatives doxycycline and minocycline are equally effective. Talc in slurry or insufflated appears to be more effective than tetracycline derivatives. Experience with talc in slurry for the treatment of spontaneous pneumothorax is still limited. Another treatment modality for spontaneous pneumothorax is thoracoscopy, more recently termed video-assisted thoracic surgery, and it has warranted renewed interest due to the advent of improved endoscopic technology. In the treatment of spontaneous pneumothorax, video-assisted thoracic surgery is nearly as effective as thoracotomy.

Insufflated talc is probably the most effective agent for creating a pleurodesis both in the clinical situation and in animals. However, the insufflation of talc requires an invasive procedure such as thoracoscopy or thoracotomy. Recently, there have been reports that talc in a slurry was effective in the clinical situation. The objective of this project was to determine whether talc in a slurry at varying doses is an effective sclerosant in an experimental model in rabbits. Talc, 50, 100, 200, and 400 mg/kg, in a 2-mL slurry was injected intrapleurally through a small catheter in male rabbits. Eleven rabbits received each dose. Twenty-eight days after the instillation, the animals were killed. The pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The degree of pleurodesis (on a scale of 0 to 4) after the injection of 50, 100, 200, and 400 mg/kg of talc was 1.1 +/- 0.9, 1.5 +/- 1.1, 2.7 +/- 0.6, and 3.4 +/- 0.5, respectively. The degree of microscopic fibrosis similarly increased with increasing doses of talc. These scores were similar to those we have reported with the tetracycline derivatives. In contrast to the results with tetracycline derivatives, none of the rabbits developed fibrothorax or hemothorax. From this study, we conclude that talc in a slurry is a very effective pleural sclerosant in rabbits and does not produce hemothoraces as do the tetracycline derivatives.

Minocycline is as effective as tetracycline in inducing pleural fibrosis, but the long-term pleural changes induced by minocycline are unknown. The objective of this study was to evaluate in rabbits the evolution of the pleural changes induced by the intrapleural instillation of minocycline. Under light anesthesia, minocycline at 10 mg/kg in a total volume of 2 ml of bacteriostatic saline solution was injected into the right pleural space of 25 male rabbits. The animals were sacrificed in groups of five at 15 d and 1, 2, 4, and 6 mo. Macroscopic and microscopic examinations of the pleura were performed for evidence of pleural fibrosis and inflammation. Similarly, the underlying lung was also examined for microscopic alveolar fibrosis and inflammation. During the 6-mo observation period there was no significant change in the degree of pleural fibrosis. In contrast, microscopic pleural inflammation, alveolar fibrosis, and alveolar inflammation all decreased significantly over the observation period. In conclusion, intrapleural minocycline injection results in persistent pleural fibrosis at 6 mo. It remains to be determined whether the pleural fibrosis will persist beyond this period.

Pressure- and flow-triggering are available in the Puritan Bennett 7200ae and Siemens SV 300. Using a mechanical lung model, we described the characteristics of the pressure- and flow-triggered continuous positive airway pressure (CPAP) of both ventilators. In the Puritan Bennett 7200ae, the pressure-triggered CPAP is characterized by the relatively insufficient flow delivery after the triggering, resulting in a greater lung pressure-time product (total PTP) than the flow-triggered CPAP. Pressure support of 5 cmH2O results in total PTP less than that with flow-triggered CPAP. In the Siemens SV 300, total PTP with pressure- or flow-triggered CPAP is comparable. Total PTP is less with pressure- or flow-triggered CPAP of the Siemens SV 300 than that of the Puritan Bennett 7200ae, respectively. The application of small pressure- or flow-triggered pressure support in the Puritan Bennett 7200ae eliminates the difference. The impact of these differences on patient inspiratory muscle work remains to be determined.

Objective: To determine the effect of pressure- and flow-triggered synchronous intermittent mandatory ventilation on inspiratory muscle work., Design: Consecutive clinical, prospective, randomized trial., Setting: Medical intensive care unit (ICU) of a U.S. Veterans Affairs Medical Center., Patients: Eight patients recovering from acute respiratory failure of various etiologies., Interventions: Assist control, followed by randomized application of pressure- and flow-triggered synchronous intermittent mandatory ventilation at 60%, 40%, 20% of the assist-control rate, and flow-triggered continuous positive airway pressure. A total of eight settings were maintained for 10 mins each., Measurements and Main Results: Total work rate (joules/min), inspiratory muscle work (joules/L), and pressure time-product per breath (cm H2O-sec) were measured. During pressure- or flow-triggered synchronous intermittent mandatory ventilation, total work rate increased as the mandatory rate was decreased. The method of ventilator triggering had a significant effect on the total work rate. With pressure-triggered synchronous intermittent mandatory ventilation, the total work rate at 60% of the assist-control rate was similar to that with assist-control; whereas with flow-triggered synchronous intermittent mandatory ventilation, this result was achieved at 40% of the assist-control rate. At a machine support level of 20%, total work rate with pressure-triggered synchronous intermittent mandatory ventilation was significantly greater than with flow-triggered synchronous intermittent mandatory ventilation. The method of ventilator triggering had no significant effect on the inspiratory muscle work of the mandatory breaths. This finding was in contrast to the effect on inspiratory muscle work of spontaneous breaths. With pressure-triggered synchronous intermittent mandatory ventilation, inspiratory muscle work of the spontaneous breaths was greater than with the flow-triggered at machine support of 40% and 20%. With either pressure- or flow-triggered synchronous intermittent mandatory ventilation, inspiratory muscle work of the mandatory breaths was not significantly different from that of the corresponding spontaneous breaths, except at the lower machine support levels with the pressure-triggered synchronous intermittent mandatory ventilation. Pressure-time product followed a trend similar to that of inspiratory muscle work., Conclusions: During synchronous intermittent mandatory ventilation, the method of ventilator triggering has a significant effect on the total work rate and inspiratory muscle work of the spontaneous breaths, particularly at lower machine support levels. Conversely, the method of ventilator triggering has no significant effect on inspiratory muscle work of the mandatory breaths.

Parenteral tetracycline, one of the most commonly used agents for producing pleurodesis, is no longer available because of stricter regulations governing the manufacturing process. The objective of this project was to determine whether minocycline, a tetracycline derivative, is an effective sclerosant in an experimental model in rabbits. We also studied the relationship of the dose and the volume injected to the degree of pleurodesis. The following medications were instilled intrapleurally in anesthetized male rabbits: tetracycline, 35 mg/kg; or minocycline, 4, 7, 10, or 20 mg/kg, diluted to a total volume of 1 or 2 ml of bacteriostatic saline solution; or minocycline, 40 mg/kg, diluted to a total volume of 2 ml of the solution. Twenty-eight days after the instillation, the animals were killed. The pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The degree of pleurodesis grossly and microscopically after the injection of 7, 10, 20, or 40 mg/kg of minocycline was comparable to that after the injection of 35 mg/kg of tetracycline, while the dose of 4 mg/kg was less effective. In the animals who received the higher doses of minocycline intrapleurally (ie > or = 20 mg/kg), there was an excess mortality both early (chi 2 = 3.61, 0.05 < p < 0.10) and late (chi 2 = 11.0, p < 0.005) which appeared to be related to the development of hemothorax. The intrapleural injection of the tetracycline derivatives was significantly (p < 0.05) more effective when the total volume of the solution was 2 ml rather than 1 ml. The present study demonstrates that minocycline is an effective agent for producing pleurodesis in the rabbit. Minocycline given intrapleurally at doses of 7 mg/kg or above is comparable to tetracycline, 35 mg/kg. Higher doses of minocycline (> or = 20 mg/kg) produce a high mortality that seems to be related to hemothorax. Since, in humans, a large experience confirms only 20 mg/kg of tetracycline is needed to produce adequate pleurodesis safely, we recommend a dose of 4 mg/kg of minocycline for the production of pleurodesis.

The purpose of this study was to review the cases of iatrogenic pneumothorax that occurred between October 1983 and December 1988 at the Veterans Administration Medical Center, Long Beach, Calif, to determine the treatment and complications. During this time period, 106 patients were identified with iatrogenic pneumothorax, and the charts of 98 were available for review. There were 90 cases of spontaneous pneumothorax at this institution during the same time period. The most common cause of iatrogenic pneumothorax was transthoracic needle aspiration (35), followed by thoracentesis (30), subclavian venipuncture (23), and positive pressure ventilation (7). In 11 cases, the cause was due to miscellaneous triggers. The majority of the patients (65 of 98) were treated with chest tubes. The chest tubes were in place 4.7 +/- 3.9 days. Nine of the patients required a second chest tube. Aspiration of the pneumothorax only was attempted in five patients, and all patients subsequently received a chest tube. Two patients died from iatrogenic pneumothorax. One patient receiving positive pressure ventilation developed an unrecognized tension pneumothorax. The other patient developed a pneumothorax after thoracentesis and was treated with a chest tube, which led to a staphylococcal empyema and death. From this study, we conclude that the incidence of iatrogenic pneumothorax exceeds that of spontaneous pneumothorax and that there is substantial morbidity and some mortality from iatrogenic pneumothorax.

Objectives: To determine the amount of spontaneous variability of cardiac output over time in critically ill patients, and to determine the effect of mechanical ventilation on cardiac output variability over time., Design: Case series., Setting: Medical intensive care unit in a Veterans Affairs Medical Center., Patients: Twenty-two patients with indwelling pulmonary artery flotation catheters were studied. Two patients were studied twice., Interventions: During a 1-hr time period in which no interventions were required or made, thermodilution cardiac output was determined at baseline and then every 15 mins for 1 hr. At each time point, five individual cardiac output measurements were made and a mean was computed. The covariables of heart rate, respiration rate, mean arterial pressure, mean pulmonary arterial pressure, pulmonary artery occlusion pressure, and temperature were also recorded at each time point., Measurements and Main Results: The variability of the five cardiac output measurements made at each time point was expressed by calculating for each patient a coefficient of variation of the measurements. The overall mean coefficient of variation of the measurements was 5.8%. The variability of the cardiac output measurements over time was expressed by calculating for each patient a coefficient of variation over time. The overall mean coefficient of variation over time was 7.7%. A subgroup of 15 "covariable stable" patients (defined as those patients with covariables within +/- 5% of the mean covariable values during the hour) had a mean coefficient of variation over time of 6.4%, whereas "covariable unstable" patients (with > +/- 5% changes in any covariable) had a mean coefficient of variation over time of 9.9% (p < .05). Patients breathing spontaneously had a mean coefficient of variation over time of 10.1%, whereas mechanically ventilated patients had a mean coefficient of variation over time of 6.3% (p < .05)., Conclusions: The spontaneous variability of cardiac output should be considered when interpreting two cardiac output determinations made at separate times. Due to spontaneous variability alone, a patient with a baseline cardiac output of 10.0 L/min would be expected (95% confidence interval) to have a cardiac output range of 9.2 to 10.8 L/min if covariables were stable, and a range of at least 8.8 to 11.2 L/min if covariables were unstable. Patients who were mechanically ventilated displayed less variability than patients who were breathing spontaneously.

Objective: To compare cardiac outputs estimated from the classical oxygen Fick and modified CO2 Fick methods with thermodilution cardiac output. The modified CO2 Fick cardiac output was obtained by replacing the oxygen uptake (VO2) in the Fick equation with the CO2 production (VCO2) divided by either an assumed or measured value of the respiratory exchange ratio or with an independently determined constant (Crit Care Med 1991; 19:1270-1277)., Design: Criterion standard study., Setting: The medical and surgical intensive care unit (ICU) in a Veterans Affairs Medical Center., Patients: A total of 17 patients (26 studies) and 11 surgical patients (13 studies), predominantly mechanically ventilated using the intermittent mandatory ventilation mode, were studied over a period of 4.3 hrs., Measurements: A respiratory gas exchange monitor was used to measure VO2, VCO2, and respiratory exchange ratio at 3-min intervals. Calculations were performed with arterial and venous oxygen saturations measured with both a laboratory cooximeter and bedside pulse and venous reflectance oximeters. In the oxygen Fick method, cardiac output was calculated from VO2 together with arterial and venous oxygen saturations. In the modified CO2 Fick methods, cardiac output values were calculated from arterial and venous oxygen saturations with VCO2, divided by either: a) an assumed value of the respiratory exchange ratio equal to 0.8 for all patients (method 1); b) the patient's measured value of the respiratory exchange ratio (method 2); or c) a constant, determined from an initial, simultaneous measurement of thermodilution cardiac output, VCO2, and oximetry saturations. Data were examined by linear regression analysis and bias and precision calculations., Main Results: Thermodilution cardiac output was more related to cardiac outputs calculated with the 3 modified CO2 Fick methods than to the oxygen Fick cardiac output. Thermodilution cardiac output was closely related to the modified CO2 Fick cardiac output calculated via method 3. For this method, with pulse and venous reflectance oximetry saturations, linear regression yielded an r2 = .85, a standard error of the estimate of 0.88 L/min (n = 111) and a bias and precision of 0.11 and 0.97 L/min, respectively. Thermodilution cardiac output was less closely related to oxygen Fick cardiac output, which, when calculated with pulse and venous reflectance oximetry saturations, yielded an r2 = .50, a standard error of the estimate of 1.47 L/min (n = 128), and a bias and precision of 0.01 and 1.85 L/min, respectively., Conclusions: We conclude from this study that thermodilution cardiac output is more closely related to cardiac output calculated from modified CO2 Fick methods than to oxygen Fick cardiac output. Since cardiac output calculated with the modified CO2 Fick method 3 obviates the difficulties associated with measuring VO2 accurately and requires neither an assumption of nor measurement of the respiratory exchange ratio, method 3 may prove to be clinically useful for continuous cardiac output monitoring via oximetry in ICU patients.

The two agents most commonly used for producing a pleurodesis are tetracycline and bleomycin. Tetracycline is no longer available due to more stringent requirements on the manufacturing process. The objective of this project was to determine whether bleomycin is an effective sclerosant in an experimental model in rabbits. The following medications were instilled intrapleurally in anesthetized male rabbits: tetracycline, 35 mg/kg, or bleomycin, 1.5 or 3.0 IU/kg diluted to a total volume of 1 ml with bacteriostatic saline solution. Twenty-eight days after the instillation, the animals were killed, and the pleural spaces were assessed grossly for evidence of pleurodesis and microscopically for evidence of fibrosis and inflammation. The intrapleural injection of bleomycin was ineffective in creating pleural fibrosis, either grossly or microscopically. The mean degree of gross pleurodesis in the six rabbits who received tetracycline was 2.7 +/- 1.5 (scale 0 to 4), while that in the rabbits who received the highest dose of bleomycin was 0.0 +/- 0.0. Based on this study, we recommend that bleomycin not be used as a pleural sclerosant in patients with nonneoplastic pleural disease, eg, those with pneumothorax, congestive heart failure or cirrhosis, and pleural effusion.

To determine the individual contributions of variables in the Fick equation to cardiac output, we simultaneously measured oxygen uptake (VO2), carbon dioxide production (VCO2), venous oxygen saturation (SvO2) and thermodilution cardiac output (Qth) in 28 medical and surgical ICU patients. Patients were intubated and ventilated with the intermittent mandatory ventilation mode. VO2 and VCO2 (averaged over 3 min) were obtained from a metabolic cart. SvO2 was measured with fiberoptic reflectance oximetry (and COoximetry). Thirty-nine studies (average duration, 4.3 h) with 151 Qth measurements were performed. The relationships between Qth and VO2, Qth and VCO2, Qth and SvO2, and 1/Qth and SvO2, as well as between the sequential changes in these variables were analyzed by least squares linear regression. The ability of changes in the variables VO2, VCO2, and SvO2 to predict changes in Qth were analyzed by receiver operating characteristic (ROC) curves. Qth was weakly related to VO2 (r = 0.45), VCO2 (r = 0.45), or SvO2 (r = 0.36). Changes in Qth were weakly related to changes in VCO2 (r = 0.40), and even less to changes in VO2 (r = 0.18) and SvO2 (r = 0.13). The areas under the ROC curves for increases in Qth > 10 percent were as follows: 0.66 for VCO2, 0.50 for VO2, and 0.55 for SvO2. The areas for decreases in Qth < 10 percent were as follows: 0.78 for VCO2, 0.65 for VO2, and 0.49 for SvO2. None of the above oximetry relationships were substantially altered by use of COoximetry venous oxygen saturations. We conclude that Qth cannot be predicted well solely from VO2, VCO2, or SvO2 nor can changes in Qth be predicted well solely from changes in VO2, VCO2, or SvO2. Of the metabolic variables, changes in VCO2 best predicted changes in Qth.

Airway occlusion pressure (P0.1) and the ratio of breathing frequency (f) to tidal volume (VT) (f/Vt) are good predictors of weaning outcome. However, the specificity of f/VT in predicting weaning success is relatively low. We postulated that the product of P0.1 and f/VT (P0.1*f/VT) would better predict weaning outcome than either variable alone. In 45 male patients, we prospectively evaluated P0.1*f/VT, P0.1, and f/VT in predicting weaning outcome. The threshold values of each variable were determined from published data. The sensitivity, specificity, and positive and negative predictive values in detecting weaning success, and the area under the receiver operating characteristic (ROC) curves were calculated. Ten (22%) of the 45 patients failed weaning. P0.1*f/VT yielded the highest specificity and positive and negative predictive values. P0.1*f/VT, P0.1, and f/VT were all highly sensitive (0.97); but they were less specific, 0.60 for P0.1*f/Vt and 0.40 for P0.1 and f/VT. The areas under the ROC curves for P0.1*f/VT, P0.1, and f/VT were not significantly different. We conclude that P0.1*f/VT has equivalent sensitivity as P0.1 and f/VT. P0.1 slightly improves the specificity of f/VT in predicting weaning success.

Because of the design characteristics, flow-triggering appears to offer measurable advantages over pressure-triggering, particularly during spontaneous breathing. During the trigger phase, flow-triggering provides a relatively shorter time delay than pressure-triggering. A trigger sensitivity that does not cause autocycling can be set while a short time delay is maintained. It remains to be determined whether flow-triggering has less effect on the pressure-time product than pressure-triggering. During the post-trigger phase, the relatively optimal flow delivery with flow-by results in the maintenance of airway pressure at or above the end-expiratory airway pressure level. This accounts for the lower level of inspiratory muscle work observed with flow-by over that observed with demand-flow. Whether inspiratory muscle work on a demand-flow system with optimal flow delivery will be similar to that on flow-by is not known. With a flow-by or demand-flow system, the circuit pressure-sensing site influences the flow-pressure control algorithm in the post-trigger phase only. In microprocessor-based ventilators, the shortcomings seen with pressure-triggering during the post-trigger phase can unquestionably be overcome with a better ventilator algorithm design or the application of a small amount of pressure support. However, during the trigger phase, the impact of this effort is less clear.

Ventilatory responses to hypercapnia in experienced marijuana smokers have previously been shown to decrease, increase, or not change acutely after marijuana. In one study, minute ventilation (VE) and O2 consumption (VO2) increased but hypoxic ventilatory response did not change after smoking marijuana. We further investigated the effects of marijuana of increasing potency (0, 13, and 20 mg THC) on ventilatory and mouth occlusion pressure (P0.1) responses to hypercapnia and hypoxia in 11 young, healthy men who smoked marijuana regularly but refrained from any smoked substance, alcohol, caffeine, or other drugs for greater than or equal to 12 h before study. Ventilatory and P0.1 responses to hypoxia and hypercapnia were measured on 3 separate days before and 5 and 35 min (hypoxia) and 15 and 45 min (hypercapnia) after smoking. In a companion 3-day study, 12 young male habitual marijuana smokers underwent measurements of VE, VO2, and CO2 production (VCO2) before and 5 to 135 min after smoking marijuana containing 0, 15, or 27 mg THC. None of the active marijuana preparations caused significant changes in ventilatory or P0.1 responses to either hypercapnia or hypoxia or in resting VE, VO2 or VCO2. We conclude that smoking marijuana (13 to 27 mg THC) has no acute effect on central or peripheral ventilatory drive or metabolic rate in habitual marijuana smokers. These conclusions cannot be applied to infrequent users of marijuana without further study.

The effect of flow-by continuous positive airway pressure (CPAP) in comparison with continuous-flow (CF) CPAP on inspiratory muscle work of breathing (WI) in intubated patients is not known. We hypothesized that WI during flow-by CPAP would be comparable with that during CF CPAP. In nine intubated male patients recovering from acute respiratory failure related to chronic obstructive pulmonary disease, we compared the effects of flow-by, demand-flow, and CF CPAP on WI. We also evaluated the extent to which the addition of 5 cm H2O of pressure support to demand-flow CPAP (DF-PS5) decreases WI. At CPAP levels of zero and 8 cm H2O, flow-by, demand-flow, DF-PS5 were applied in random order followed by CF CPAP for 15 min each. WI (expressed as Joules per liter and Joules per minute), maximal airway pressure drop during inspiration (delta Paw), total lung resistance (RL), lung compliance (CL), and ventilatory variables were measured. At CPAP of zero cm H2O, WI with flow-by was comparable with CF CPAP, and significantly less than with demand-flow CPAP. At both CPAP of zero and 8 cm H2O, the addition of 5 cm H2O PS to demand-flow CPAP reduced WI significantly to a level comparable with that of flow-by CPAP. At both CPAP levels, delta Paw was the largest, with demand-flow CPAP. RL and CL were not significantly different between the different CPAP systems. We conclude that WI with flow-by CPAP is comparable with that with CF CPAP, and significantly less than with demand-flow CPAP.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to delineate the etiological factors for iatrogenic pneumothorax in the era of increased use of invasive procedures and to determine its impact on morbidity. Between 1983 and 1987 the Department of Veterans Affairs conducted a cooperative study at 13 medical centers to assess the utility of the intrapleural instillation of tetracycline for the prevention of recurrent pneumothorax. Since all patients with any type of pneumothorax were screened at each medical center, it was decided to collect data on all the iatrogenic pneumothoraces during that period. During the study period, the number of reported iatrogenic pneumothoraces were 538. Because of incomplete data, 3 iatrogenic pneumothoraces reported from one center were excluded. The leading causes of iatrogenic pneumothorax were transthoracic needle aspiration (128), subclavicular needle stick (119), thoracentesis (106), transbronchial biopsy (54), pleural biopsy (45) and positive pressure ventilation (38). Most patients required treatment for 4-7 days; however, hospitalization was prolonged due to this treatment in only 8% of patients, presumably because of their underlying disease which required long hospitalization. Patients with underlying chronic obstructive pulmonary disease required significantly longer duration of treatment than those without. We conclude that in our patient population, the three leading causes of iatrogenic pneumothorax are transthoracic needle aspiration, subclavicular needle stick and thoracentesis. Hospitalization is prolonged in only a small percentage of the patients who required treatment for the iatrogenic pneumothorax.