The pharmacodynamic effect of a remifentanil bolus on ventilatory control

BACKGROUND: In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously. METHODS: In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PET(CO2)) at approximately 46 or 56 mm Hg (alternate subjects). After 6 min of equilibration, subjects received 0.5 microg/kg remifentanil over 5 s, and minute ventilation (V(E)) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mm Hg). The V(E) data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (k(eo)), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve (gamma). RESULTS: The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l x min(-1) x mm Hg(-1) [-0.12 to 0.66] 2 min after remifentanil (P<0.001); within 5 min, it recovered to approximately 0.6 l x min(-1) x mm Hg(-1), and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mm Hg (VE50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P<0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of VE50 included k(eo) = 0.24 min(-1) (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and gamma = 1.74. CONCLUSIONS: After administration of 0.5 microg/kg remifentanil, there was a decrease in slope and downward shift of the carbon dioxide ventilatory response curve. This reached its nadir approximately 2.5 min after injection, consistent with the computed onset half-time of 2.9 min. The onset of respiratory depression appears to be somewhat slower than previously reported for the onset of remifentanil-induced electroencephalographic slowing. Recovery of ventilatory drive after a small dose essentially was complete within 15 min.     

Mechanisms of improvement of respiratory failure in patients with restrictive thoracic disease treated with non-invasive ventilation

BACKGROUND: Nocturnal non-invasive ventilation (NIV) is an effective treatment for hypercapnic respiratory failure in patients with restrictive thoracic disease. We hypothesised that NIV may reverse respiratory failure by increasing the ventilatory response to carbon dioxide, reducing inspiratory muscle fatigue, or enhancing pulmonary mechanics. METHODS: Twenty patients with restrictive disease were studied at baseline (D0) and at 5-8 days (D5) and 3 months (3M). RESULTS: Mean (SD) daytime arterial carbon dioxide tension (Paco(2)) was reduced from 7.1 (0.9) kPa to 6.6 (0.8) kPa at D5 and 6.3 (0.9) kPa at 3M (p = 0.004), with the mean (SD) hypercapnic ventilatory response increasing from 2.8 (2.3) l/min/kPa to 3.6 (2.4) l/min/kPa at D5 and 4.3 (3.3) l/min/kPa at 3M (p = 0.044). No increase was observed in measures of inspiratory muscle strength including twitch transdiaphragmatic pressure, nor in lung function or respiratory system compliance. CONCLUSIONS: These findings suggest that increased ventilatory response to carbon dioxide is the principal mechanism underlying the long term improvement in gas exchange following NIV in patients with restrictive thoracic disease. Increases in respiratory muscle strength (sniff oesophageal pressure and sniff nasal pressure) correlated with reductions in the Epworth sleepiness score, possibly indicating an increase in the ability of patients to activate inspiratory muscles rather than an improvement in contractility.     

Respiratory effects of epidural sufentanil after cesarean section.

The ventilatory response to CO2 was measured to evaluate the degree of respiratory depression after epidural sufentanil. After cesarean section performed with bupivacaine epidural anesthesia, 14 patients received either 30 micrograms (n = 7) or 50 micrograms (n = 7) of epidural sufentanil. Respiratory measurements were made before and 15, 45, and 120 min after sufentanil injection. The presence and severity of sedation and other nonrespiratory side effects were evaluated throughout the study. Plasma sufentanil assays were performed on blood samples obtained at frequent intervals during the first 2 h. Although changes in resting ventilation did not occur, both sufentanil doses depressed the ventilatory response to CO2. After sufentanil 30 micrograms, the slope of the CO2 response curve decreased significantly at 45 and 120 min (control value, 2.33 +/- 0.3 L.min-1.mm Hg-1 [mean +/- SEM] vs 1.61 +/- 0.24 and 1.72 +/- 0.15, respectively, P less than 0.05). After sufentanil 50 micrograms, significant decreases occurred at 15 and 45 min (control value, 2.84 +/- 0.71 vs 1.81 +/- 0.48 and 1.48 +/- 0.31 L.min-1.mm Hg-1, respectively). The mean maximal decrease in the slope occurred at 45 min and was more pronounced after 50 micrograms (-42.3% +/- 7.4%) than after 30 micrograms (-27.4% +/- 9.9%). Analgesia was similar in both groups. Side effects, particularly sedation, were more severe with the 50-micrograms dose. We conclude that 30 micrograms of epidural sufentanil is preferable to the higher dose with regard to both respiratory and nonrespiratory side effects. Even with the lower dose, monitoring of ventilation is advisable for a minimum of 2 h.     

Interaction of arousal states and low dose halothane on the acute hypercapnic ventilatory response in humans

The purpose of this study was to examine the effect of low dose halothane on the acute ventilatory response to hypercapnia, and to assess whether arousal (due to audiovisual (AV) stimulation or pain) modulates the response to halothane. Single step increases in end-tidal Pco(2) using dynamic end-tidal forcing were performed from eucapnia (end-tidal Pco(2) held 1 mmHg (0.13 kPa) above ambient) to hypercapnia (end-tidal Pco(2) 6 mmHg (0.79 kPa) above ambient) in eight healthy volunteers, with end-tidal PO(2) held at 100 mmHg (13.2 kPa), in six protocols: 1) control conditions (darkened, quiet room, eyes closed) without halothane; 2) control conditions with 0.1 MAC halothane; 3) AV stimulation (bright room, loud television) without halothane; 4) AV stimulation with 0.1 MAC halothane; 5) pain (electrical stimulation of skin over tibia to produce visual analogue pain score 5-6/10) without halothane; 6) pain with 0.1 MAC halothane. Both AV stimulation (p = 0.014) and pain (p = 0.0003) significantly increased the baseline eucapnic minute ventilation modestly (by approximately 1.5-4 l.min(-1)). Halothane did not influence the baseline minute ventilation in any arousal state (p = 0.572), nor did it affect the hypercapnic ventilatory response in any arousal state (p = 0.208). Arousal (either AV stimulation or pain) did not affect the ventilatory response to CO(2), regardless of the presence or absence of halothane (p = 0.585). We conclude that halothane affects neither baseline minute ventilation nor the response to CO(2). Arousal can increase baseline ventilation but has no influence on the ventilatory response to CO(2).     

Comparison of the ventilatory effects of etomidate and methohexital

Using a dual-isohypercapnic technique, the authors determined the effect of equipotent doses of methohexital (1.5 mg/kg) and etomidate (0.3 mg/kg) on the ventilatory response to CO2 (VERCO2) in six healthy volunteers. Speed of induction and duration of hypnosis did not differ significantly between the two drugs. Within 2 min after injection, the slope of VERCO2 decreased significantly after both methohexital (from 2.52 to a minimum of 0.15 l . min-1 . mmHg-1, P less than 0.05) and etomidate (from 2.56 to a minimum of 0.62 l . min-1 . mmHg-1, P less than 0.05); the magnitude of this depression did not differ significantly between the drugs. Methohexital also caused a significant decrease in minute ventilation at end-tidal PCO2 of 46 mmHg (VE 46) from 14.6 to 4.3 l . min-1 within 60 s after injection (P less than 0.05). In contrast, after etomidate VE 46 gradually increased from 17.9 1 . min-1 to a maximum of 31.6 l . min-1 at 3.5 min after injection (P less than 0.05); respiratory rate increased significantly, while changes in tidal volume were not significant. Effects of etomidate and methohexital on VE 46 differed significantly (P less than 0.001). These data indicate that, while etomidate and methohexital similarly depress the medullary centers that modify ventilatory drive in response to changing CO2 tensions, ventilation at any given CO2 tension is greater after etomidate than after methohexital. This indicates that etomidate may cause a CO2-independent stimulation of ventilation, suggesting its use for induction of anesthesia in cases where maintenance of spontaneous ventilation is desirable.     

Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

Background: Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.

Methods: Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.

Results: Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 (x +/- SE, P < 0.05), and decreased the minute ventilation at PET CO2 = 50 mmHg (V with dotE 50) from 19.7 +/- 1.2 to 14.8 +/- 0.9 l [dot] min sup -1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 11.7 +/- 0.8 l [dot] min sup -1 (P <0.05), respectively. With addition of flumazenil, slope and V with dot sub E 50 increased to 1.47 +/- 0.37 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 16.4 +/- 2.0 l [dot] min sup -1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 and 12.5 +/- 1.2 l [dot] min sup -1 did not differ significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at PET CO2 = 46 +/- 1 mmHg, were affected similarly, with flumazenil showing a significant improvement compared to placebo.     

Effect of Ventilatory Settings on Accuracy of Cardiac Output Measurement Using Partial CO2 Rebreathing

Background: Recently, a new device has been developed to measure cardiac output noninvasively using partial carbon dioxide (CO2) rebreathing. Because this technique uses CO2 rebreathing, the authors suspected that ventilatory settings, such as tidal volume and ventilatory mode, would affect its accuracy: they conducted this study to investigate which parameters affect the accuracy of the measurement.

Methods: The authors enrolled 25 pharmacologically paralyzed adult post-cardiac surgery patients. They applied six ventilatory settings in random order: (1) volume-controlled ventilation with inspired tidal volume (VT) of 12 ml/kg; (2) volume-controlled ventilation with VT of 6 ml/kg; (3) pressure-controlled ventilation with VT of 12 ml/kg; (4) pressure-controlled ventilation with VT of 6 ml/kg; (5) inspired oxygen fraction of 1.0; and (6) high positive end-expiratory pressure. Then, they changed the maximum or minimum length of rebreathing loop with VT set at 12 ml/kg. After establishing steady-state conditions (15 min), they measured cardiac output using CO2 rebreathing and thermodilution via a pulmonary artery catheter. Finally, they repeated the measurements during pressure support ventilation, when the patients had restored spontaneous breathing. The correlation between two methods was evaluated with linear regression and Bland-Altman analysis.

Results: When VT was set at 12 ml/kg, cardiac output with the CO2 rebreathing technique correlated moderately with that measured by thermodilution (y = 1.02x, R = 0.63; bias, 0.28 l/min; limits of agreement, -1.78 to +2.34 l/min), regardless of ventilatory mode, oxygen concentration, or positive end-expiratory pressure. However, at a lower VT of 6 ml/kg, the CO2 rebreathing technique underestimated cardiac out-put compared with thermodilution (y = 0.70x; R = 0.70; bias, -1.66 l/min; limits of agreement, -3.90 to +0.58 l/min). When the loop was fully retracted, the CO2 rebreathing technique overestimated cardiac output.     

Biologically variable ventilation prevents deterioration of gas exchange during prolonged anaesthesia

We have studied the time course of changes in gas exchange and respiratory mechanics using two different modes of ventilation during 7 h of isoflurane anaesthesia in pigs. One group received conventional control mode ventilation (CV). The other group received biologically variable ventilation (BVV) which simulates the breath-to-breath variation in ventilatory frequency (f) that characterizes normal spontaneous ventilation. After baseline measurements with CV, animals were allocated randomly to either CV or BVV (FIO2 1.0 with 1.5% end- tidal isoflurane). With BVV, there were 376 changes in f and tidal volume (VT) over 25.1 min. Ventilation was continued over the next 7 h and blood gases and respiratory mechanics were measured every 60 min. The modulation file used to control the ventilator for BVV used an inverse power law frequency distribution (I/fa with a = 2.3 +/- 0.3). After 7 h, at a similar delivered minute ventilation, significantly greater PaO2 (mean 72.3 (SD 4.0) vs 63.5 (6.5) kPa) and respiratory system compliance (1.08 (0.08) vs 0.92 (0.16) ml cm H2O-1 kg-1) and lower PaCO2 (6.5 (0.7) vs 8.7 (1.5) kPa) and shunt fraction (7.2 (2.7)% vs 12.3 (6.2)%) were seen with BVV, with no significant difference in peak airway pressure (16.3 (1.2) vs 15.3 (3.7) cm H2O). A deterioration in gas exchange and respiratory mechanics was seen with conventional control mode ventilation but not with BVV in this experimental model of prolonged anaesthesia.      

Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop.

BACKGROUND: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the mu-opioid receptor agonist morphine. METHODS: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 microg/kg, followed by 30 microg x kg(-1) x h(-1)). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD. RESULTS: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l x min(-1) x mmHg(-1) (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l x min(-1) x mmHg(-1), not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l x min(-1) x mmHg(-1) (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l x min(-1) x mmHg(-1) (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l x min(-1) x %(-1), respectively; P < 0.05). The ventilatory response to sustained hypoxia (i/e., 15 min) did not differ between men and women. CONCLUSIONS: The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.     

Ventilatory response to CO2 following axillary blockade with bupivacaine

The systemic effect of bupivacaine on the control of ventilation was studied in eight ASA I (six male, two female) unpremedicated healthy subjects aged 30-55 yr (mean 43.5 yr) and weighing 59-82 kg (mean 69 kg) after axillary blockade with bupivacaine 0.5% without epinephrine, 3 mg/kg. The slope of the ventilatory response to CO2 was significantly increased (P less than 0.05) from its control value (1.77 +/- 1.03 l X min-1 X mmHg-1 [mean +/- SD]) 30 min (+19 +/- 32%) and 60 min (+32 +/- 37%) after axillary blockade, while plasma bupivacaine levels were 1.65 +/- 0.82 and 1.40 +/- 0.60 micrograms/ml, respectively. The correlation between individual plasma bupivacaine levels and the changes in the slope of the ventilatory response to CO2 was significant (r = 0.57, n = 16, P less than 0.05). Resting minute ventilation and end-tidal CO2 values did not change significantly. These results suggest that bupivacaine has a systemic stimulating effect on the ventilatory control mechanisms.     

Effect of ventilatory settings on accuracy of cardiac output measurement using partial CO(2) rebreathing.

BACKGROUND: Recently, a new device has been developed to measure cardiac output noninvasively using partial carbon dioxide (CO(2)) rebreathing. Because this technique uses CO(2) rebreathing, the authors suspected that ventilatory settings, such as tidal volume and ventilatory mode, would affect its accuracy: they conducted this study to investigate which parameters affect the accuracy of the measurement. METHODS: The authors enrolled 25 pharmacologically paralyzed adult post-cardiac surgery patients. They applied six ventilatory settings in random order: (1) volume-controlled ventilation with inspired tidal volume (V(T)) of 12 ml/kg; (2) volume-controlled ventilation with V(T) of 6 ml/kg; (3) pressure-controlled ventilation with V(T) of 12 ml/kg; (4) pressure-controlled ventilation with V(T) of 6 ml/kg; (5) inspired oxygen fraction of 1.0; and (6) high positive end-expiratory pressure. Then, they changed the maximum or minimum length of rebreathing loop with V(T) set at 12 ml/kg. After establishing steady-state conditions (15 min), they measured cardiac output using CO(2) rebreathing and thermodilution via a pulmonary artery catheter. Finally, they repeated the measurements during pressure support ventilation, when the patients had restored spontaneous breathing. The correlation between two methods was evaluated with linear regression and Bland-Altman analysis. RESULTS: When VT was set at 12 ml/kg, cardiac output with the CO(2) rebreathing technique correlated moderately with that measured by thermodilution (y = 1.02x, R = 0.63; bias, 0.28 l/min; limits of agreement, -1.78 to +2.34 l/min), regardless of ventilatory mode, oxygen concentration, or positive end-expiratory pressure. However, at a lower VT of 6 ml/kg, the CO(2) rebreathing technique underestimated cardiac out-put compared with thermodilution (y = 0.70x; R = 0.70; bias, -1.66 l/min; limits of agreement, -3.90 to +0.58 l/min). When the loop was fully retracted, the CO(2) rebreathing technique overestimated cardiac output. CONCLUSIONS: Although cardiac output was underreported at small VT values, cardiac output measured by the CO(2) rebreathing technique correlates fairly with that measured by the thermodilution method.     

Ventilatory effects of laparoscopy under epidural anesthesia

This study evaluates the respiratory effects of laparoscopy under epidural anesthesia in seven female patients (ASA physical status I) scheduled for a gamete intrafallopian transfer procedure. Epidural anesthesia was performed with 15-18 mL of 1.5% plain lidocaine using a catheter inserted at the L3-4 level. The upper level of analgesia to pinprick was measured 20 min after lidocaine injection. Ventilatory measurements and arterial blood gas analyses were performed (a) preoperatively, in the horizontal supine position with a T7-9 level of analgesia; (b) in the 20 degrees Trendelenburg position with a T2-5 level of analgesia; (c) during intraabdominal insufflation of CO2 through the laparoscope; and (d) after CO2 exsufflation by manual compression of the abdomen before removal of the laparoscope while in the horizontal position. On-line measurements of VO2, VCO2, VE, VT, F, and PETCO2 were made using a Beckman metabolic cart, while the patients breathed room air through an anesthetic face mask. No significant changes in the ventilatory variables were observed in the Trendelenburg position. In contrast, CO2 insufflation significantly increased VE (from 9.1 +/- 1.0 L/min to 11.8 +/- 2.6 L/min, mean +/- SD), and F (from 16.9 +/- 1.9 breaths/min to 23.1 +/- 3.3 breaths/min, mean +/- SD), whereas VCO2 remained unchanged. PaCO2 remained constant throughout the study. These results suggest that epidural anesthesia may be a safe alternative to general anesthesia for outpatient laparoscopy, as it is not associated with ventilatory depression.     

Respiratory depression after morphine in the elderly

The effects of intravenous morphine (10 mg/70 kg) on the ventilatory response to CO2 were studied in two groups of subjects, young (18-29 years) and old (66-85 years), prior to elective surgery. In both groups morphine caused a significant depression of respiration as judged by a reduction in the slope of the CO2 response curve, a reduction in the calculated ventilation at an end tidal CO2 tension of 7.3 kPa, a rise in resting end tidal CO2 and a rise in the CO2 threshold. There were no significant differences between the two groups in the changes produced by the drug, suggesting that acute respiratory depression after a single intravenous injection of morphine is similar in old and young people.     

Lung function, hypoxic and hypercapnic ventilatory responses, and respiratory muscle strength in normal subjects taking oral theophylline.

Methylxanthines are known to be respiratory stimulants and are thought by some to augment hypercapnic and hypoxic ventilatory drive and improve respiratory muscle strength. Hypoxic and hypercapnic ventilatory responses were measured in 10 normal subjects before, during, and after administration of theophylline for three and a half days. Pulmonary function, carbon dioxide production, and mouth pressures during maximal static inspiratory and expiratory efforts were also measured. The mean (SD) serum theophylline concentration was 13.8 (3.2) mg/l. Lung volumes and flow rates did not change significantly with theophylline. The mean (SD) values for maximum static inspiratory pressure were 152 (27), 161 (25), and 160 (24) cm H2O, respectively before, during, and after theophylline. Neither these values nor peak expiratory pressure measurements were significantly changed. The slopes of the hypercapnic ventilatory responses were 2.9 (0.9), 3.3 (1.2), and 3.3 (1.4) l/min/mm Hg carbon dioxide tension (PCO2) respectively before, during, and after theophylline administration. The respective values for the slopes of the hypoxic response were -1.4 (0.9), -1.3 (0.8), and -1.1 (0.9) l/min/1% oxyhaemoglobin saturation. None of these values changed significantly with theophylline. Theophylline, however, increased carbon dioxide production (200 to 236 ml/min) and alveolar ventilation (4.7 to 5.7 l/min) significantly, with a concomitant fall of end tidal PCO2 (35.5 to 32.9 mm Hg). It is concluded that in man oral theophylline at therapeutic blood concentrations increases carbon dioxide production and ventilation without changing pulmonary function, respiratory muscle strength, or the hypoxic or hypercapnic ventilatory response significantly.     

Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Background: Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined.

Methods: The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] [almost equal to] 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels [almost equal to] 10 ng/ml) before and after diphenhydramine 0.7 mg/kg.

Results: The slope of the ventilatory response to carbon dioxide decreased from 1.08 +/- 0.38 to 0.79 +/- 0.36 l [middle dot] min-1 [middle dot] mmHg-1 (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17 +/- 0.28 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). The minute ventilation (VE) at PETCO2 [almost equal to] 46 mmHg (VE 46) decreased from 12.1 +/- 3.7 to 9.7 +/- 3.6 l/min (P < 0.05) and the VE at 54 mmHg (V (E) 54) decreased from 21.3 +/- 4.8 to 16.6 +/- 4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, VE 46 did not change significantly, remaining lower than baseline at 9.9 +/- 2.9 l/min (P < 0.05), whereas VE 54 increased significantly to 20.5 +/- 3.0 l/min. During hypoxia, VE at Sp O2 = 90% (VE 90) decreased from 30.5 +/- 9.7 to 23.1 +/- 6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE 90 to 27.2 +/- 9.2 l/min was not significant (P = 0.06).     

Beware the airway filter: deadspace effect in children under 2 years

BACKGROUND: Filters are increasingly used in breathing circuits as they protect the circuit from contamination and facilitate humidification of inspired gas. The use of filters, however, can augment the anatomical deadspace. This can be significant in children because they have much smaller tidal volumes. METHODS: Following institutional ethical approval, 20 healthy children <2 years of age who required tracheal intubation were recruited. Ventilation was adjusted to achieve an endtidal carbon dioxide (P(E)CO(2)) of 4.6 kPa (35 mmHg) when sampled at the tracheal tube (TT) adapter. Following a 10-min period of stabilization, an airway filter (22 ml) was introduced into the circuit. The respiratory rate (RR) was then adjusted to return P(E)CO(2) to 4.6 kPa (35 mmHg). RESULTS: A mean increase in ventilation of 1.42 (0.38) l x min(-1) was required to maintain a normal P(E)CO(2) level. Airway pressure and respiratory rate increased by 7.9 mmHg (4.6) and 19.8 breath x min(-1) (8.7) respectively. The P(E)CO(2) and partial pressure of inspired carbon-di-oxide (PiCO(2)) measured from the TT adapter were higher than measured from the filter port. The mean increase was 3.6 (1.6) mmHg for P(E)CO(2) and 5.9 (3.9) mmHg for PiCO(2). CONCLUSION: Amplified deadspace from airway filters results in a significant increase in ventilation needed to maintain a normal P((E)CO(2) in children <2 years of age with normal lungs. Sampling of P((E)CO(2) and PiCO(2) from the filter significantly underestimates the effect of increased deadspace. The effect of increased deadspace may be predicted using a proposed mathematical model.     

Effect of breathing circuit resistance on the measurement of ventilatory function

BACKGROUND: The American Thoracic Society (ATS) has set the acceptable resistance for spirometers at less than 1.5 cm H2O/l/s over the flow range 0-14 l/s and for monitoring devices at less than 2.5 cm H2O/l/s (0-14 l/s). The aims of this study were to determine the resistance characteristics of commonly used spirometers and monitoring devices and the effect of resistance on ventilatory function. METHODS: The resistance of five spirometers (Vitalograph wedge bellows, Morgan rolling seal, Stead Wells water sealed, Fleisch pneumotachograph, Lilly pneumotachograph) and three monitoring devices (Spiro 1, Ferraris, mini-Wright) was measured from the back pressure developed over a range of known flows (1.6-13.1 l/s). Peak expiratory flow (PEF), forced expiratory flow in one second (FEV1), forced vital capacity (FVC), and mid forced expiratory flow (FEF25-75%) were measured on six subjects with normal lung function and 13 subjects with respiratory disorders using a pneumotachograph. Ventilatory function was then repeated with four different sized resistors (approximately 1-11 cmH2O/l/s) inserted between the mouthpiece and pneumotachograph. RESULTS: All five diagnostic spirometers and two of the three monitoring devices passed the ATS upper limit for resistance. PEF, FEV1 and FVC showed significant (p < 0.05) inverse correlations with added resistance with no significant difference between the normal and patient groups. At a resistance of 1.5 cm H2O/l/s the mean percentage falls (95% confidence interval) were: PEF 6.9% (5.4 to 8.3); FEV1 1.9% (1.0 to 2.8), and FVC 1.5% (0.8 to 2.3). CONCLUSIONS: The ATS resistance specification for diagnostic spirometers appears to be appropriate. However, the specification for monitoring devices may be too conservative. PEF was found to be the most sensitive index to added resistance.     

The Pharmacodynamic Effect of a Remifentanil Bolus on Ventilatory Control

Background: In doses typically administered during conscious sedation, remifentanil may be associated with ventilatory depression. However, the time course of ventilatory depression after an initial dose of remifentanil has not been determined previously.

Methods: In eight healthy volunteers, the authors determined the time course of the ventilatory response to carbon dioxide using the dual isohypercapnic technique. Subjects breathed via mask from a to-and-fro circuit with variable carbon dioxide absorption, allowing the authors to maintain end-tidal pressure of carbon dioxide (PETCO2) at approximately 46 or 56 mmHg (alternate subjects). After 6 min of equilibration, subjects received 0.5 [mu]g/kg remifentanil over 5 s, and minute ventilation ([latin capital V with dot above]E) was recorded during the next 20 min. Two hours later, the study was repeated using the other carbon dioxide tension (56 or 46 mmHg). The [latin capital V with dot above]E data were used to construct two-point carbon dioxide response curves at 30-s intervals after remifentanil administration. Using published pharmacokinetic values for remifentanil and the method of collapsing hysteresis loops, the authors estimated the effect-site equilibration rate constant (keo), the effect-site concentration producing 50% respiratory depression (EC50), and the shape parameter of the concentration-response curve ([gamma]).

Results: The slope of the carbon dioxide response decreased from 0.99 [95% confidence limits 0.72 to 1.26] to a nadir of 0.27 l [middle dot] min-1 [middle dot] mmHg-1 [-0.12 to 0.66] 2 min after remifentanil (P < 0.001); within 5 min, it recovered to approximately 0.6l [middle dot] min-1 [middle dot] mmHg-1, and within 15 min of injection, slope returned to baseline. The computed ventilation at PET = 50 mmHg ([latin capital V with dot above]E50) decreased from 12.9 [9.8 to 15.9] to 6.1 l/min [4.8 to 7.4] 2.5 min after remifentanil injection (P < 0.001). This was caused primarily by a decrease in tidal volume rather than in respiratory rate. Estimated pharmacodynamic parameters based on computed mean values of [latin capital V with dot above]E50 included keo = 0.24 min-1 (T1/2 = 2.9 min), EC50 = 1.12 ng/ml, and [gamma] = 1.74.     

Using transcutaneous carbon dioxide monitor (TOSCA 500) to detect respiratory failure in patients with amyotrophic lateral sclerosis: A validation study

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, respiratory failure being the commonest cause of death. Quality of life and survival can be improved by supporting respiratory function with non-invasive ventilation. Transcutaneous carbon dioxide monitoring is a non-invasive method of measuring arterial carbon dioxide levels enabling simple and efficient screening for respiratory failure. The aim of this study was to validate the accuracy of carbon dioxide level recorded transcutaneously with a TOSCA 500 monitor. It is a prospective, observational study of 40 consecutive patients with ALS, recruited from a specialist ALS clinic. The partial pressure of carbon dioxide (PCO(2)) in each patient was determined by both transcutaneous monitoring and by an arterialized ear lobe capillary blood sample. The carbon dioxide (CO(2)) levels obtained with these two methods were compared by Bland-Altman analysis. The results showed that the mean difference between arterialized and transcutaneous readings was - 0.083 kPa (SD 0.318). The Bland-Altman limits of agreement ranged from 0.553 to - 0.719 kPa. The difference was ?0.5 kPa, with a maximum recorded difference of 0.95 kPa. In conclusion, non-invasive carbon dioxide monitoring using a TOSCA monitor is a useful clinical tool in neurology practice. Users should be aware of the possibility of occasional inaccurate readings. A clinically unexpected or incompatible reading should be verified with a blood gas analysis, especially when a decision to provide ventilatory support is required.     

Effect of dopamine on hypoxic-hypercapnic interaction in humans

To investigate the effect of intravenous dopamine on the chemical regulation of ventilation, we studied the ventilatory responses to hypercapnic hypoxia during dopamine infusion. Intravenous dopamine (3 micrograms X kg-1 X min-1) was administered to six healthy human subjects. Two hypoxic challenges (PETO2 = 52.5 +/- 2.5 mm Hg, SaO2 = 88.8 +/- 2.2%; mean +/- SD) were administered at three CO2 levels (PETCO2 = 40.8 +/- 0.5, 45.6 +/- 0.2, 49.8 +/- 0.3 mm Hg) to each subject. The ventilatory responses were quantified by calculation of slopes and intercepts of the relationship between minute exhaled ventilation (VE) and arterial hemoglobin saturation (SaO2), and by the relationship between this slope (delta VE/delta SaO2) and carbon dioxide tension. Dopamine caused a 77% reduction in delta VE/delta SaO2 (hypoxic sensitivity) during eucapnia, a 39.5% reduction in hypoxic sensitivity at PETCO2 = 46 mm Hg, and 38% reduction at PETCO2 = 50 mm Hg (P less than 0.05). Dopamine also reduced normoxic ventilation at all carbon dioxide levels. There was a greater depression in VE during hypercapnia (25.7% reduction) than during eucapnia (12% reduction). This indicates that dopamine depresses the normoxic ventilatory response to carbon dioxide. Intravenous dopamine reduces the ventilatory response to both hypoxia and hypercapnia but preserves the augmentation of hypoxic ventilatory drive by hypercapnia.