Analysis of Oxygenation in Chronic Thromboembolic Pulmonary Hypertension Using Dead Space Ratio and Intrapulmonary Shunt Ratio.

Current therapeutic methods for chronic thromboembolic pulmonary hypertension (CTEPH) can improve hemodynamic status and are expected to improve prognoses. However, some patients experience dyspnea during effort and continue supplemental oxygenation despite their hemodynamic status being fully improved. Considering the pathogenesis of CTEPH, the dead space and intrapulmonary shunt are assumed to be responsible for hypoxia in CTEPH, but their contributions are unclear. It is also unclear whether they are improved after treatment. The aim of this study was to investigate the implications of the dead space ratio (DSR) and the intrapulmonary shunt ratio (ISR) for hypoxia in CTEPH and treatment for CTEPH.We retrospectively measured the DSR and ISR of 23 consecutive patients with CTEPH. For 11 of these 23 (10 were treated by balloon pulmonary angioplasty, one with riociguat), we also measured these parameters before and after CTEPH treatments. Overall, the DSR and ISR were abnormally elevated (DSR: 0.63 ± 0.06; ISR: 0.20 ± 0.05). After treatment, mean pulmonary artery pressure was improved (from 40.3 ± 8.1 to 25.5 ± 2.7 mmHg). Although atrial oxygen saturation (SaO2), DSR and ISR were improved (SaO2: from 90.2 ± 3.2 to 93.7 ± 1.8%; DSR: from 0.64 ± 0.06 to 0.58 ± 0.05; ISR: from 0.20 ± 0.04 to 0.18 ± 0.02), these improvements were slight compared with that of mean pulmonary artery pressure.The DSR and ISR were abnormally elevated in patients with CTEPH and their improvement by treatment was limited. Only DSR can be a useful marker for normalization of hypoxia in CTEPH.

A simple method for isocapnic hyperventilation evaluated in a lung model.

BACKGROUND: Isocapnic hyperventilation (IHV) has the potential to increase the elimination rate of anaesthetic gases and has been shown to shorten time to wake-up and post-operative recovery time after inhalation anaesthesia. In this bench test, we describe a technique to achieve isocapnia during hyperventilation (HV) by adding carbon dioxide (CO2) directly to the breathing circuit of a standard anaesthesia apparatus with standard monitoring equipment. METHODS: Into a mechanical lung model, carbon dioxide was added to simulate a CO2 production (V(CO2)) of 175, 200 and 225 ml/min. Dead space (V(D)) volume could be set at 44, 92 and 134 ml. From baseline ventilation (BLV), HV was achieved by doubling the minute ventilation and fresh gas flow for each level of V(CO2), and dead space. During HV, CO2 was delivered (D(CO2)) by a precision flow meter via a mixing box to the inspiratory limb of the anaesthesia circuit to achieve isocapnia. RESULTS: During HV, the alveolar ventilation increased by 113 ± 6%. Tidal volume increased by 20 ± 0.1% during IHV irrespective of V(D) and V(CO2) level. D(CO2) varied between 147 ± 8 and 325 ± 13 ml/min. Low V(CO2) and large V(D) demanded a greater D(CO2) administration to achieve isocapnia. The FICO2 level during IHV varied between 2.3% and 3.3%. CONCLUSION: It is possible to maintain isocapnia during HV by delivering carbon dioxide through a standard anaesthesia circuit equipped with modern monitoring capacities. From alveolar ventilation, CO2 production and dead space, the amount of carbon dioxide that is needed to achieve IHV can be estimated.

Anaesthetic conserving device AnaConDa: dead space effect and significance for lung protective ventilation.

BACKGROUND: The anaesthetic conserving device AnaConDa (ACD) reflects exhaled anaesthetic agents thereby facilitating the use of inhaled anaesthetic agents outside operating theatres. Expired CO2 is, however, also reflected causing a dead space effect in excess of the ACD internal volume. CO2 reflection from the ACD is attenuated by humidity. This study tests the hypothesis that sevoflurane further attenuates reflection of CO2. An analysis of clinical implications of our findings was performed. METHODS: Twelve postoperative patients received mechanical ventilation using a conventional heat and moisture exchanger (HME, internal volume 50 ml) and an ACD (100 ml), the latter with or without administration of sevoflurane. The ACD was also studied with a test lung at high sevoflurane concentrations. Reflection of CO2 and dead space effects were evaluated with the single-breath test for CO2. RESULTS: Sevoflurane reduced but did not abolish CO2 reflection. In patients, the mean dead space effect with 0.8% sevoflurane was 88 ml larger using the ACD compared with the HME (P<0.001), of which 38 ml was due to CO2 reflection. Our calculations show that with the use of the ACD, normocapnia cannot be achieved with tidal volume <6 ml kg(-1) even when respiratory rate is increased. CONCLUSIONS: An ACD causes a dead space effect larger than its internal volume due to reflection of CO2, which is attenuated but not abolished by sevoflurane administration. CO2 reflection from the ACD limits its use with low tidal volume ventilation, such as with lung protection ventilation strategies. CLINICAL TRIAL REGISTRATION: Clinical Trials NCT01699802.

The effect of a peptide-containing synthetic lung surfactant on gas exchange and lung mechanics in a rabbit model of surfactant depletion.

BACKGROUND: Currently, a new generation of synthetic pulmonary surfactants is being developed that may eventually replace animal-derived surfactants used in the treatment of respiratory distress syndrome. Enlightened by this, we prepared a synthetic peptide-containing surfactant (Synsurf) consisting of phospholipids and poly-l-lysine electrostatically bonded to poly-l-glutamic acid. Our objective in this study was to investigate if bronchoalveolar lavage (BAL)-induced acute lung injury and surfactant deficiency with accompanying hypoxemia and increased alveolar and physiological dead space is restored to its prelavage condition by surfactant replacement with Synsurf, a generic prepared Exosurf, and a generic Exosurf containing Ca(2+). METHODS: Twelve adult New Zealand white rabbits receiving conventional mechanical ventilation underwent repeated BAL to create acute lung injury and surfactant-deficient lung disease. Synthetic surfactants were then administered and their effects assessed at specified time points over 5 hours. The variables assessed before and after lavage and surfactant treatment included alveolar and physiological dead space, dead space/tidal volume ratio, arterial end-tidal carbon dioxide tension (PCO2) difference (mainstream capnography), arterial blood gas analysis, calculated shunt, and oxygen ratios. RESULTS: BAL led to acute lung injury characterized by an increasing arterial PCO2 and a simultaneous increase of alveolar and physiological dead space/tidal volume ratio with no intergroup differences. Arterial end-tidal PCO2 and dead space/tidal volume ratio correlated in the Synsurf, generic Exosurf and generic Exosurf containing Ca(2+) groups. A significant and sustained improvement in systemic oxygenation occurred from time point 180 minutes onward in animals treated with Synsurf compared to the other two groups (P < 0.001). A statistically significant decrease in pulmonary shunt (P < 0.001) was found for the Synsurf-treated group of animals, as well as radiographic improvement in three out of four animals in that group. CONCLUSION: In general, surfactant-replacement therapy in the animals did not fully restore the lung to its prelavage condition. However, our data show that the formulated surfactant Synsurf improves oxygenation by lowering pulmonary shunt.

Potential effects of corticosteroids on physiological dead-space fraction in acute respiratory distress syndrome.

BACKGROUND: Increased dead-space fraction is common in patients with persistent acute respiratory distress syndrome (ARDS). We evaluated the changes in the oxygenation and dead-space fraction in patients with persistent ARDS after corticosteroid therapy. METHODS: This was a non-randomized non-placebo, controlled observational study including 19 patients with persistent ARDS treated with corticosteroids. We measured P(aO(2))/F(IO(2)) and dead-space fraction at days 0, 4, and 7 after corticosteroids treatment (methylprednisolone) initiation. Patients were classified in intermediate group when corticosteroids were initiated between days 8-14 after ARDS onset, and in late group when initiated after 14 days. RESULTS: Mean time from the diagnosis of the ARDS to methylprednisolone treatment was 11 ± 2 days in the intermediate group (10 patients) and 21 ± 8 days in the late group (9 patients). When comparing days 0, 4, and 7 after methylprednisolone treatment, we found an increase in the P(aO(2))/F(IO(2)) (145 ± 64 mm Hg, 190 ± 68 mm Hg, and 226 ± 84 mm Hg, respectively, P < .001) and a decrease in the physiological dead-space fraction (0.66 ± 0.10, 0.58 ± 0.12, and 0.53 ± 0.11, respectively, P < .001). No differences were found between the intermediate and late groups. CONCLUSIONS: In patients with persistent ARDS, the increase in oxygenation was accompanied by a decrease in the dead-space fraction after a few days of corticosteroid treatment. To confirm potential benefit of corticosteroids on physiological parameters and mortality will require a powered randomized placebo controlled trial.

Alveolar dead-space response to activated protein C in acute respiratory distress syndrome.

We report a complicated case of acute respiratory distress syndrome (ARDS) from severe sepsis, in which we measured the ratio of physiologic dead space to tidal volume (V(D)/V(T)) with volumetric capnography prior to, during, and after therapy with human recombinant activated protein C. Previous studies hypothesized that early in ARDS, elevated V(D)/V(T) primarily reflects increased alveolar V(D), probably caused by pronounced thrombi formation in the pulmonary microvasculature. This may be particularly true when severe sepsis is the cause of ARDS. We repeatedly measured V(D)/V(T) in a 29-year-old man with sepsis-induced ARDS over the course of activated protein C therapy. Treatment with activated protein C resulted in a pronounced reduction in V(D)/V(T), from 0.55 to 0.27. Alveolar V(D) decreased from 165 mL to 11 mL (93% reduction). Activated protein C was terminated at 41 h because of gastrointestinal bleeding. When the measurement was repeated 29 h after therapy was discontinued, V(D)/V(T) had increased modestly, to 0.34, whereas alveolar V(D) had increased to 71 mL, or 43% of the pre-activated-protein-C baseline measurement. Alveolar V(T) rose from 260 mL to 369 mL and decreased slightly after termination of activated protein C (336 mL). Over the course of activated protein C therapy there was a persistent decrease in alveolar V(D) and increase in alveolar V(T), even while positive end-expiratory pressure was reduced and respiratory-system compliance decreased. Thus, improved alveolar perfusion persisted despite signs of alveolar de-recruitment. This suggests that activated protein C may have reduced microvascular obstruction. This report provides indirect evidence that microvascular obstruction may play an important role in elevated V(D)/V(T) in early ARDS caused by severe sepsis.

Alveolar dead space and capnographic variables before and after thrombolysis in patients with acute pulmonary embolism.

Pulmonary embolism (PE) is a common condition. The central aim of this study was to describe the use of volumetric capnography (VCap) before and after fibrinolytic treatment of major PE. Lung scintigraphy was used as a base of comparison for the results of this treatment. We describe the cases of two conscious and spontaneously breathing patients (20- and by 24-year-old women) with major PE undergoing thrombolysis. Curves of CO(2) were obtained VCap and associated with arterial blood gas analysis and D-dimer. The pattern of VCap was compared with the VCap of health volunteers. Parameters also calculated were: P(a-et)CO(2) gradient, alveolar dead space fraction (AVDSf ), late dead space fraction (fDlate), and slope phase III (Slp III). The VCap results before and after thrombolysis for patients 1 and 2 were, respectively, P(a-et)CO(2): 12.6 to 5.8 and 7.9 to 1.6 (mmHg); AVDSf: 0.46 to 0.18 and 0.25 to 0.05; fDlate: 0.46 to 0.21 and 0.24 to 0.04; Slp III: 1.75 to 5.10 and 1.21 to 5.61 (mmHg/L). Lung scintigraphy was used to compare VCap results from the two subjects with VCap results from healthy volunteers and pigs before and after treatment associated with arterial blood gas, D-dimer, and showed satisfactory agreement.

Spinal serotonin receptor activation modulates the exercise ventilatory response with increased dead space in goats.

Small increases in respiratory dead space (VD) augment the exercise ventilatory response by a serotonin-dependent mechanism known as short-term modulation (STM). We tested the hypotheses that the relevant serotonin receptors for STM are in the spinal cord, and are of the 5-HT2-receptor subtype. After preparing adult female goats with a mid-thoracic (T6-T8) subarachnoid catheter, ventilation and arterial blood gases were measured at rest and during treadmill exercise (4.8 km/h; 5% grade) with and without an increased VD (0.2-0.3 L). Measurements were made before and after spinal or intravenous administration of a broad-spectrum serotonin receptor antagonist (methysergide, 1-2mg total) and a selective 5-HT2-receptor antagonist (ketanserin, 5-12 mg total). Although spinal methysergide had no effect on the exercise ventilatory response in control conditions, the augmented response with increased VD was impaired, allowing Pa(CO)(2) to increase from rest to exercise. Spinal methysergide diminished both mean inspiratory flow and frequency responses to exercise with increased VD. Spinal ketanserin impaired Pa(CO)(2) regulation with increased VD, although its ventilatory effects were less clear. Intrathecal dye injections indicated CSF drug distribution was caudal to the upper cervical spinal cord and intravenous drugs at the same total dose did not affect STM. We conclude that spinal 5-HT2 receptors modulate the exercise ventilatory response with increased VD in goats.

Isoflurane inhalation enhances increased physiologic deadspace volume associated with positive pressure ventilation and compromises arterial oxygenation.

Abnormally increased physiologic deadspace volume (Vd(phys)), consisting of alveolar deadspace volume and airway deadspace volume, is one of several causative factors predisposing to compromised arterial blood gas exchange. We compared the effects of two methods of general anesthesia on Vd(phys) when combined with positive pressure ventilation (PPV): total IV anesthesia (TIVA) and inhaled anesthesia with isoflurane. Forty patients with no history of pulmonary pathology undergoing elective surgery in the supine position were studied. A crossover design was used, and all patients received both anesthetic methods sequentially in randomized order. PPV and TIVA significantly increased Vd(phys) compared with baseline (preoperative and breathing spontaneously) from 164 +/- 60 mL to 264 +/- 79 mL (P < 0.05). Isoflurane inhalation combined with PPV significantly enhanced this increase, resulting in a twofold increase in Vd(phys) to 315 +/- 80 mL (P < 0.05). Also, alveolar deadspace volume increased by more than 200% with isoflurane. Furthermore, isoflurane inhalation (1.15% end-tidal concentration) resulted in impaired arterial oxygenation, as evidenced by a significant decrease in the Pao(2)/fractional inspired oxygen concentration ratio compared with baseline values from 387 +/- 35 to 310 +/- 70 (P < 0.05). Although significant increases in Vd(phys) resulted with PPV combined with TIVA, these adverse changes were much less compared with isoflurane inhalation and PPV. These findings may apply to subjects with compromised pulmonary function (i.e., acute respiratory distress syndrome or severe inhalational burn injury).

Changes in airway dead space in response to methacholine provocation in normal subjects.

Measurements of bronchial hyper-responsiveness rely on sensitive techniques for measurement of bronchoconstriction, ideally based on tidal breathing. A potentially useful technique is measurement of airway dead space (VDaw), which reflects the volume of the conducting airways. The aim of this study was to evaluate measurements of VDaw with the single breath test for CO2 (SBT-CO2), compared to spirometric measurements, as a method of measuring bronchial response to methacholine challenge. Nineteen healthy adults were studied. Dosimetric methacholine challenge tests were performed on two study days. Forced expirations or the SBT-CO2 were used to assess the response. There were dose-dependent reductions in the spirometric measurements, with a 10 +/- 10% reduction from the baseline value of forced expiratory volume at the highest dose of methacholine. There was a dose-dependent reduction from the baseline value of VDaw by 19 +/- 9% at the highest dose. There was also a dose-dependent increase in the slope of the alveolar plateau of the SBT-CO2. This study provides support for measurement of VDaw as a means of evaluating bronchial responsiveness after methacholine challenge. In a group of healthy adults, this method shows a greater response but with similar dispersion as measurement of forced expiratory volume after methacholine challenge.

Effect of dead volume on the efficiency and the cost to deliver medications in cystic fibrosis with four disposable nebulizers.

OBJECTIVES: To evaluate the factors that affect nebulizer efficiency and to compare the relative cost effectiveness of nebulized medications used in the treatment of cystic fibrosis (CF), delivered by four types of disposable jet nebulizers that are widely used in hospitals. DESIGN: The Hudson 1730 Updraft II, Baxter Misty-Neb, Marquest Whisper Jet (WJ), and Marquest Acorn II were evaluated in terms of respirable aerosol output (particles 5 microm or less), nebulizer dead (residual) volume (VD), and time for complete nebulization using saline, salbutamol and tobramycin at flows of 6 and 8 L/min. The respirable fraction (RF) was determined by laser diffraction, and drug output was calculated from the initial volume and concentration of the drug in the nebulizer minus the product of final drug concentration and the VD following nebulization. COST ANALYSIS: The expected pulmonary deposition (DE) was estimated, and incorporated with the material and labour costs to determine the cost effectiveness of each type of nebulizer. RESULTS: With a DE greater than two times that of the WJ at a cost of 2.4 times less, the Updraft II proved most efficient and cost effective of all the nebulizers evaluated in this study. CONCLUSIONS: The cost effectiveness of each nebulizer was determined by its efficiency, which in turn was predominantly related to its VD and RF at each flow. The efficiencies of these four devices were different and could not have been predicted from specifications provided by the respective manufacturers.

Effects of sodium bicarbonate administration on the exercise tolerance of normal subjects breathing through dead space.

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.

Positive end-expiratory pressure improves gas exchange and pulmonary mechanics during partial liquid ventilation.

Partial liquid ventilation (PLV) with perflubron (PFB) has been proposed as an adjunct to the current therapies for the acute respiratory distress syndrome (ARDS). Because PFB has been also referred to as "liquid PEEP," distributing to the most gravity-dependent regions of the lung, less attention has been paid to the amount of applied positive end-expiratory pressure (PEEP). We hypothesized that higher PEEP levels than currently applied are needed to optimize gas exchange, and that the lower inflection point (LIP) of the pressure-volume curve could be used to estimate the amount of PEEP needed when the lung is filled with PFB. Lung injury was induced in 23 sheep by repeated lung lavage with warmed saline until the PaO2/FIO2 ratio fell below 150. Five sheep were used to investigate the change of the LIP when the lung was filled with PFB in increments of 5 ml/kg/body weight to a total of 30 ml/kg/body weight. To evaluate the impact of PEEP set at LIP +1 cm H2O we randomized an additional 15 sheep to three groups with different doses (7.5 ml, 15 ml, 30 ml/kg/body weight) of PFB. In random order a PEEP of 5 cm H2O or PEEP at LIP +1 cm H2O was applied. The LIP decreased with incremental filling of PFB to a minimum at 10 ml (p < 0.05). Increasing PEEP from below LIP to LIP +1 cm H2O at 15 and 30 ml/kg resulted in an improvement in PaO2 from 152 +/- 36 to 203 +/- 68 (NS) and 193 +/- 57 to 298 +/- 80 (p < 0.05), respectively. Pulmonary shunt, and ratio of dead space volume to tidal volume (VD/VT) decreased, and static lung compliance increased with PEEP at LIP +1 cm H2O (p < 0.05). No changes were observed in hemodynamics. We conclude that increasing the dose of PFB shifts the LIP to the left, and that setting PEEP at LIP +1 cm H2O improves gas exchange at moderate to high doses of PFB.

The effects of nitric oxide inhalation on respiratory mechanics and gas exchange during endotoxaemia in the pig.

BACKGROUND: In the adult respiratory distress syndrome, nitric oxide (NO) inhalation improves oxygenation through reducing ventilation-perfusion mismatching, but detailed information on the pulmonary effects of NO inhalation in septic shock is scarce. The present study investigated the effects of inhaled NO on alveolar dead space (Vdalv) and venous admixture as well as on respiratory system compliance (Crs) and respiratory system resistance (Rrs) in a porcine model of septic shock. Protective effects of NO are discussed. METHODS: Thirteen anaesthetised and ventilated pigs were given an infusion of endotoxin for an observation time of 220 min to induce acute lung injury (ALI). In the NO-early group (n=6), an inhalation of 60 ppm NO was started simultaneously with the endotoxin infusion and continued for 190 min. In 7 control/NO-late animals, 60 ppm NO was administered for 30 min following 190 min of endotoxin infusion. Haemodynamics, single-breath CO2-, pressure-, and flow signals were recorded. RESULTS: Endotoxin induced haemoconcentration, pulmonary vasoconstriction, and a decrease in Crs, while venous admixture, Vdalv, and Rrs increased. In the NO-early group, the pulmonary vasoconstriction was attenuated, no increase in pulmonary venous admixture or in Vdalv was seen before cessation of NO, and the improvements in oxygenation outlasted the NO inhalation. In the control/NO-late group, the NO inhalation reversed the changes in dead space and venous admixture. NO had no effect on the changes in respiratory mechanics. CONCLUSION: In porcine ALI, 60 ppm NO diminishes pulmonary vasoconstriction and improves gas exchange by reducing pulmonary venous admixture and alveolar dead space, but does not prevent a fall in Crs. NO inhalation may help prevent long-lasting pulmonary failure.

The effect of volume infusion on dead space in mechanically ventilated patients with severe asthma.

Mechanical ventilation of patients with severe asthma is associated with elevated airway pressures that may contribute to increased physiologic dead space. To our knowledge, no previous reports have considered the effect of intravascular volume status on dead space fraction. We herein describe three patients whose dead space decreased by a mean of 4.2% in response to intravascular volume expansion with 250 or 500 mL of normal saline solution administered as part of their routine treatment. No significant changes in CO2 production, minute volume, or airway pressures occurred over the time interval. We conclude with a brief discussion of potential mechanisms to explain these findings and their potential clinical application.

Airway anesthesia and respiratory adaptations to dead space loading and exercise.

In exercising humans, added external dead space (VD) increases minute ventilation (VI) and causes a slower and deeper breathing pattern (J. Appl. Physiol. 1991; 70:55-62). Recent studies suggest that airway receptors sensitive to topical anesthesia influence VI and breathing pattern responses to exercise and to added VD. We tested these hypotheses with a technique of airway anesthesia (Anesthesia) that has been shown to reliably attenuate airway reflexes. Anesthesia was administered by local laryngopharyngeal application and aerosolized lidocaine inhalation, and was confirmed by citric acid aerosol inhalation challenges. Twelve normal males performed maximal incremental cycle ergometer exercise on 4 d (randomized) after Anesthesia with (Anesthesia VD) and without added VD (Anesthesia Control) and after normal saline inhalation (Saline) with (Saline VD) and without added VD (Saline Control). There were no differences in the VI and breathing pattern responses during exercise between the Saline Control and the Anesthesia Control tests. After both Saline and Anesthesia inhalation, added VD resulted in an increase in VI both at rest and during exercise. At matched VI (98 L/min), the differences in tidal volume (VT) between the Saline Control and Saline VD tests (delta = 0.23 +/- 0.24 L, mean +/- SD) and the Anesthesia Control and Anesthesia VD tests (delta = 0.20 +/- 0.28 L) were not significantly different. Our study had a power of greater than 95% to detect significant differences in VI or breathing pattern due to Anesthesia. We conclude that in normal humans, airway receptors do not play a major role in ventilation and breathing pattern control during exercise, and that the respiratory adaptations to added VD during exercise are not mediated by airway afferent reflexes.

Sedative and ventilatory effects of midazolam infusion: effect of flumazenil reversal.

The purpose of this study was to evaluate the effects of flumazenil (1 mg i.v.) on the ventilatory response of premedicated patients receiving a continuous infusion of midazolam for sedation. After assessing baseline ventilatory function using a modified Read rebreathing method for determining hypercapnic ventilatory drive, 16 healthy outpatients were administered fentanyl, 50 micrograms i.v., and midazolam 2 mg i.v., followed by a variable-rate midazolam infusion, 0.3-0.5 mg.min-1. Upon termination of the midazolam infusion, serum midazolam concentrations were measured and ventilatory function was reassessed. Then, 10 ml either saline or flumazenil (1 mg) were administered according to a randomized, double-blind protocol. Ventilatory function was subsequently measured at 5 min, 30 min and 60 min intervals after study drug. Compared with the baseline value, midazolam infusion reduced tidal volume and increased respiratory rate and alveolar dead space. However, midazolam did not decrease the slope of the CO2-response curve. Flumazenil reduced the degree of midazolam-induced sedation and the decrease in tidal volume (P < 0.05), but not the change in resting respiratory rate. In some patients, the ventilatory response to hypercarbia actually decreased after flumazenil administration compared with the immediate prereversal (sedated) values. It is concluded that midazolam infusion, 0.43 mg.min-1, did not impair CO2-responsiveness. Flumazenil's effect on central ventilatory drive was more variable than its reversal of midazolam-induced sedation.