Rapid elimination of CO through the lungs: coming full circle 100 years on.

At the start of the 20th century, CO poisoning was treated by administering a combination of CO(2) and O(2) (carbogen) to stimulate ventilation. This treatment was reported to be highly effective, even reversing the deep coma of severe CO poisoning before patients arrived at the hospital. The efficacy of carbogen in treating CO poisoning was initially attributed to the absorption of CO(2); however, it was eventually realized that the increase in pulmonary ventilation was the predominant factor accelerating clearance of CO from the blood. The inhaled CO(2) in the carbogen stimulated ventilation but prevented hypocapnia and the resulting reductions in cerebral blood flow. By then, however, carbogen treatment for CO poisoning had been abandoned in favour of hyperbaric O(2). Now, a half-century later, there is accumulating evidence that hyperbaric O(2) is not efficacious, most probably because of delays in initiating treatment. We now also know that increases in pulmonary ventilation with O(2)-enriched gas can clear CO from the blood as fast, or very nearly as fast, as hyperbaric O(2). Compared with hyperbaric O(2), the technology for accelerating pulmonary clearance of CO with hyperoxic gas is not only portable and inexpensive, but also may be far more effective because treatment can be initiated sooner. In addition, the technology can be distributed more widely, especially in developing countries where the prevalence of CO poisoning is highest. Finally, early pulmonary CO clearance does not delay or preclude any other treatment, including subsequent treatment with hyperbaric O(2).

Supplementary oxygen for nonhypoxemic patients: O2 much of a good thing?

Supplementary oxygen is routinely administered to patients, even those with adequate oxygen saturations, in the belief that it increases oxygen delivery. But oxygen delivery depends not just on arterial oxygen content but also on perfusion. It is not widely recognized that hyperoxia causes vasoconstriction, either directly or through hyperoxia-induced hypocapnia. If perfusion decreases more than arterial oxygen content increases during hyperoxia, then regional oxygen delivery decreases. This mechanism, and not (just) that attributed to reactive oxygen species, is likely to contribute to the worse outcomes in patients given high-concentration oxygen in the treatment of myocardial infarction, in postcardiac arrest, in stroke, in neonatal resuscitation and in the critically ill. The mechanism may also contribute to the increased risk of mortality in acute exacerbations of chronic obstructive pulmonary disease, in which worsening respiratory failure plays a predominant role. To avoid these effects, hyperoxia and hypocapnia should be avoided, with oxygen administered only to patients with evidence of hypoxemia and at a dose that relieves hypoxemia without causing hyperoxia.

Hyperinflation-induced cardiorespiratory failure in rats.

We previously showed that severe inspiratory resistive loads cause acute (<1 h) cardiorespiratory failure characterized by arterial hypotension, multifocal myocardial infarcts, and diaphragmatic fatigue. The mechanisms responsible for cardiovascular failure are unknown, but one factor may be the increased ventricular afterload caused by the large negative intrathoracic pressures generated when breathing against an inspiratory load. Because expiratory threshold loads increase intrathoracic pressure and decrease left ventricular afterload, we hypothesized that anesthetized rats forced to breathe against such a load would experience only diaphragmatic failure. Loading approximately doubled end-expiratory lung volume, halved respiratory frequency, and caused arterial hypoxemia and hypercapnia, respiratory acidosis, and increased inspiratory drive. Although hyperinflation immediately reduced the diaphragm's mechanical advantage, fatigue did not occur until near load termination. Mean arterial pressure progressively fell, becoming significant (cardiovascular failure) midway through loading despite tachycardia. Loading was terminated (endurance 125 +/- 43 min; range 82-206 min) when mean arterial pressure dropped below 50 mmHg. Blood samples taken immediately after load termination revealed hypoglycemia, hyperkalemia, and cardiac troponin T, the last indicating myocardial injury that was, according to histology, mainly in the right ventricle. This damage probably reflects a combination of decreased O(2) delivery (decreased venous return and arterial hypoxemia) and greater afterload due to hyperinflation-induced increase in pulmonary vascular resistance. Thus, in rats breathing at an increased end-expiratory lung volume, cardiorespiratory, not just respiratory, failure still occurred. Right heart injury and dysfunction may contribute to the increased morbidity and mortality associated with acute exacerbations of obstructive airway disease.

Repeated inspiratory occlusions acutely impair myocardial function in rats.

Repeated episodes of hypoxia and sympathetic activation during obstructive sleep apnoea are implicated in the initiation and progression of cardiovascular diseases, but the acute effects are unknown. We hypothesized that repeated inspiratory occlusions cause acute myocardial dysfunction and injury. In 22 spontaneously breathing pentobarbital-anaesthetized rats, inspiration was occluded for 30 s every 2 min for 3 h. After approximately 1.5 h, mean arterial pressure started to fall; heart rate between occlusions was stable throughout, consistent with only transient increases in sympathetic activity during each occlusion. Three hours of occlusions resulted in ventricular diastolic dysfunction (reduced peak rate of change of ventricular pressure and slower relaxation). Post-occlusions, the left ventricular contractile response to dobutamine was blunted. After 1 h of recovery, left ventricular pressure generation had returned to values no different from those in sham animals in 5 of 9 of the animals. Cardiac myofibrils from rats subjected to occlusions had depressed calcium-activated myosin ATPase activity, indicating myofilament contractile dysfunction that was not due to breakdown of contractile proteins. Haematoxylin and eosin-stained cross-sections revealed multifocal areas of necrosis within the septum and both ventricles. Repeated inspiratory occlusions, analogous to moderately severe obstructive sleep apnoea, acutely cause global cardiac dysfunction with multifocal myocardial infarcts.

Cardiorespiratory failure in rat induced by severe inspiratory resistive loading.

The mechanisms underlying acute respiratory failure induced by respiratory loads are unclear. We hypothesized that, in contrast to a moderate inspiratory resistive load, a severe one would elicit central respiratory failure (decreased respiratory drive) before diaphragmatic injury and fatigue. We also wished to elucidate the factors that predict endurance time and peak tracheal pressure generation. Anesthetized rats breathed air against a severe load ( approximately 75% of the peak tracheal pressure generated during a 30-s occlusion) until pump failure (fall in tracheal pressure to half; mean 38 min). Hypercapnia and hypoxemia developed rapidly ( approximately 4 min), coincident with diaphragmatic fatigue (decreased ratio of transdiaphragmatic pressure to peak integrated phrenic activity) and the detection in blood of the fast isoform of skeletal troponin I (muscle injury). At approximately 23 min, respiratory frequency and then blood pressure fell, followed immediately by secondary diaphragmatic fatigue. Blood taken after termination of loading contained cardiac troponin T (myocardial injury). Contrary to our hypothesis, diaphragmatic fatigue and injury occurred early in loading before central failure, evident only as a change in the timing but not the drive component of the central respiratory pattern generator. Stepwise multiple regression analysis selected changes in mean arterial pressure and arterial Pco(2) during loading as the principal contributing factors in load endurance time, and changes in mean arterial pressure as the principal contributing factor in peak tracheal pressure generation. In conclusion, the temporal development of respiratory failure is not stereotyped but depends on load magnitude; moreover respiratory loads induce cardiorespiratory, not just respiratory, failure.

Sequential gas delivery provides precise control of alveolar gas exchange.

Of the factors determining blood gases, only alveolar ventilation (VA) is amenable to manipulation. However, current physiology text books neither describe how breath-by-breath VA can be measured, nor how it can be precisely controlled in spontaneously breathing subjects. And such control must be effected independent of minute ventilation (VE) and the pattern of breathing. Control of VA requires the deliberate partition of inhaled gas between the alveoli and the anatomical deadspace. This distribution is accomplished by sequential gas delivery (SGD): each breath consists of a chosen volume of 'fresh' gas followed by previously exhaled gas. Control of VA through SGD is a simple, inexpensive, yet powerful tool with many applications. Here we describe how to implement SGD, how it precisely controls VA, and consequently how it controls arterial blood gases.

CPAP reduces hypercoagulability, as assessed by thromboelastography, in severe obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with increased cardiovascular morbidity and mortality and hypercoagulability may be an underlying factor. We tested the hypotheses that patients with severe OSA are hypercoagulable and that two weeks of continuous positive airway pressure (CPAP) treatment reduces this hypercoagulability. In a prospective crossover study, twelve patients were randomized to either CPAP or no-CPAP for two weeks, a one week washout period, and then the other testing period for two weeks. Thromboelastography was used to assess coagulability at the start and end of each period and the apnoea-hypopnea indices (AHI) were measured at the end of each period. At baseline, ten patients had, compared to reference values, shorter clotting times, six increased rate of clot formation, twelve increased clot strength, and ten increased clotting indices. CPAP significantly reduced AHI (p=0.0003), clot strength (p=0.019) and clotting index (p=0.014). Hypercoagulability in patients with OSA can be detected by thromboelastography, and is reduced by CPAP.

A simple and portable breathing circuit designed for ventilatory muscle endurance training (VMET).

BACKGROUND: Ventilatory muscle endurance training (VMET) involves increasing minute ventilation (V (E)) against a low flow resistance at rest to simulate the hyperpnea of exercise. Ideally, VMET must maintain normocapnia over a wide range of V (E). This can be achieved by providing a constant fresh gas flow to a sequential rebreathing circuit. The challenge to make VMET suitable for home use is to provide a source of constant fresh gas flow to the circuit without resorting to compressed gas. METHODS: Our VMET circuit was based on a commercial sequential gas delivery breathing circuit (Pulmanex Hi-Ox, Viasys Healthcare, Yorba Linda, CA USA). Airflow was provided either by a small battery-driven aquarium air pump or by the entrainment of air down a pressure gradient created by the recoil of a hanging bellows that was charged during each inhalation. In each case, fresh gas flow was adjusted to be just less than resting V (E). Eight subjects then breathed from the circuit for three 10min periods consisting of relaxed breathing, breathing at 20 and then at 40L/min. We monitored V (E), end-tidal PCO2 (PetCO2) and hemoglobin O2 saturation (SpO2). RESULTS: During hyperpnea at 20 and 40L/min, PetCO2 did not differ significantly from resting levels with either method of supplying fresh gas. SpO2 remained greater than 96% during all tests. CONCLUSION: Isocapnic VMET can be reliably accomplished with a simple self-regulating, sequential rebreathing circuit without the use of compressed gas.

Fast and slow skeletal troponin I in serum from patients with various skeletal muscle disorders: a pilot study.

BACKGROUND: Detection of skeletal muscle injury is hampered by a lack of commercially available assays for serum markers specific for skeletal muscle; serum concentrations of skeletal troponin I (sTnI) could meet this need. Moreover, because sTnI exists in 2 isoforms, slow (ssTnI) and fast (fsTnI), corresponding to slow- and fast-twitch muscles, respectively, it could provide insight into differential injury/recovery of specific fiber types. The purpose of this study was to investigate whether the 2 isoforms of sTnI and their modified forms are present in the blood of patients with various skeletal muscle disorders. METHODS: Serial serum samples were obtained from 25 patients with various skeletal muscle injuries. Serum proteins were separated by a modified sodium dodecyl sulfate-polyacrylamide gel electrophoresis protocol followed by Western blotting for sTnI with monoclonal antibodies specific to ssTnI and fsTnI. RESULTS: We observed (a) intact and, in some cases, degraded sTnI products; (b) evidence of posttranslational modifications in addition to proteolysis; and (c) differential detectability of both skeletal isoforms in the same patient. CONCLUSIONS: It is possible to monitor both sTnI isoforms; this could lead to the development of new diagnostic assays for skeletal muscle damage.

Respiratory muscle injury, fatigue and serum skeletal troponin I in rat.

To evaluate injury to respiratory muscles of rats breathing against an inspiratory resistive load, we measured the release into blood of a myofilament protein, skeletal troponin I (sTnI), and related this release to the time course of changes in arterial blood gases, respiratory drive (phrenic activity), and pressure generation. After approximately 1.5 h of loading, hypercapnic ventilatory failure occurred, coincident with a decrease in the ratio of transdiaphragmatic pressure to integrated phrenic activity (P(di)/ integral Phr) during sighs. This was followed at approximately 1.9 h by a decrease in the P(di)/ integral Phr ratio during normal loaded breaths (diaphragmatic fatigue). Loading was terminated at pump failure (a decline of P(di) to half of steady-state loaded values), approximately 2.4 h after load onset. During 30 s occlusions post loading, rats generated pressure profiles similar to those during occlusions before loading, with comparable blood gases, but at a higher neural drive. In a second series of rats, we tested for sTnI release using Western blot-direct serum analysis of blood samples taken before and during loading to pump failure. We detected only the fast isoform of sTnI, release beginning midway through loading. Differential detection with various monoclonal antibodies indicated the presence of modified forms of fast sTnI. The release of fast sTnI is consistent with load-induced injury of fast glycolytic fibres of inspiratory muscles, probably the diaphragm. Characterization of released fast sTnI may provide insights into the molecular basis of respiratory muscle dysfunction; fast sTnI may also prove useful as a marker of impending respiratory muscle fatigue.

Hypercapnia improves tissue oxygenation.

BACKGROUND: Wound infections are common, serious, surgical complications. Oxidative killing by neutrophils is the primary defense against surgical pathogens and increasing intraoperative tissue oxygen tension markedly reduces the risk of such infections. Since hypercapnia improves cardiac output and peripheral tissue perfusion, we tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial carbon dioxide tension (PaCO(2)) in anesthetized humans. METHODS: General anesthesia was induced with propofol and maintained with sevoflurane in 30% oxygen in 10 healthy volunteers. Subcutaneous tissue oxygen tension (PsqO(2)) was recorded from a subcutaneous tonometer. An oximeter probe on the upper arm measured muscle oxygen saturation. Cardiac output was monitored noninvasively. PaCO(2) was adjusted to 20, 30, 40, 50, or 60 mmHg in random order with each concentration being maintained for 45 min.(2) (2) RESULTS: Increasing PaCO(2) linearly increased cardiac index and PsqO(2) : PsqO(2) = 35.42 + 0.77 (PaCO(2)), < 0.001. CONCLUSIONS: The observed difference in PsqO(2) is clinically important because previous work suggests that comparable increases in tissue oxygenation reduced the risk of surgical infection from -8% to 2 to 3%. We conclude that mild intraoperative hypercapnia increased peripheral tissue oxygenation in healthy human subjects, which may improve resistance to surgical wound infections.

Calculation of O2 consumption during low-flow anesthesia from tidal gas concentrations, flowmeter, and minute ventilation.

We present the principles of a new method to calculate O2 consumption (V*O2) during low-flow anesthesia with a circle circuit when the source gas flows, end-tidal O2 concentrations and patient inspired minute ventilation are known. This method was tested in a model with simulated O2 uptake and CO2 production. The difference between calculated V*O2 and simulated V*O2 was 0.01 +/- 0.02 L/min. A similar approach can be used to calculate uptake of inhaled anesthetics. At present, with this method, the limiting factor in precision of measurement of V*O2 and uptake of anesthetic is the precision of measurement of gas flow and gas concentration (especially O2 concentration in end-tidal gas, FETO2) available in clinical anesthetic units.

Normocapnia improves cerebral oxygen delivery during conventional oxygen therapy in carbon monoxide-exposed research subjects.

STUDY OBJECTIVE: We determine whether maintaining normocapnia during hyperoxic treatment of carbon monoxide-exposed research subjects improves cerebral oxygen delivery. METHODS: This experiment used a randomized, single-blinded, crossover design. We exposed 14 human research subjects to carbon monoxide until their carboxyhemoglobin levels reached 10% to 12%. We then treated each research subject with 60 minutes of hyperoxia with or without normocapnia. Research subjects returned after at least 24 hours, were reexposed to carbon monoxide, and were given the alternate treatment. Relative changes in cerebral oxygen delivery were calculated as the product of blood oxygen content and middle cerebral artery velocity (an index of cerebral blood flow) as measured by transcranial Doppler ultrasonography. RESULTS: Maintaining normocapnia during hyperoxic treatment resulted in significantly higher cerebral oxygen delivery compared with standard oxygen treatment (P <.05; 95% confidence interval at 60 minutes 2.8% to 16.7%) as a result of the prevention of hypocapnia-induced cerebral vasoconstriction and more rapid elimination of carbon monoxide due to increased minute ventilation. CONCLUSION: If severely poisoned patients respond like our research subjects, maintaining normocapnia during initial hyperoxic treatment of carbon monoxide poisoning may lead to increased oxygen delivery to the brain. Determining the effect of such a change in conventional treatment on outcome requires clinical studies.

Direct effect of Pa(CO2) on respiratory sinus arrhythmia in conscious humans.

Respiratory sinus arrhythmia (RSA) may improve the efficiency of pulmonary gas exchange by matching the pulmonary blood flow to lung volume during each respiratory cycle. If so, an increased demand for pulmonary gas exchange may enhance RSA magnitude. We therefore tested the hypothesis that CO2 directly affects RSA in conscious humans even when changes in tidal volume (V(T)) and breathing frequency (F(B)), which indirectly affect RSA, are prevented. In seven healthy subjects, we adjusted end-tidal PCO2 (PET(CO2)) to 30, 40, or 50 mmHg in random order at constant V(T) and F(B). The mean amplitude of the high-frequency component of R-R interval variation was used as a quantitative assessment of RSA magnitude. RSA magnitude increased progressively with PET(CO2) (P < 0.001). Mean R-R interval did not differ at PET(CO2) of 40 and 50 mmHg but was less at 30 mmHg (P < 0.05). Because V(T) and F(B) were constant, these results support our hypothesis that increased CO2 directly increases RSA magnitude, probably via a direct effect on medullary mechanisms generating RSA.