VENTILATORY RESPONSE TO CARBON DIOXIDE DURING EXTRADURAL ANAESTHESIA WITH LIGNOCAINE AND FENTANYL

Twenty-seven patients undergoing extracorporeal shock-wave lithotripsyor knee arthroscopy received extradural anaesthesia with 2%lignocaine plus adrenaline 1 in 200000. They were allocatedrandomly to three groups, one receiving no fentanyl (n = 6),the two others receiving fentanyl 50 µg either extradurally(n = 15) or i.v. (n = 6). Three tests of sensitivity to carbondioxide (Read's method) were performed successively on eachpatient: before operation and at 1 and 2 h after the extraduralinjection. Whereas lignocaine and adrenaline alone had no significanteffects on basal ventilation and the ventilatory response tocarbon dioxide, extradural fentanyl caused a slight reductionin resting ventilatory rate and ventilation at 1 and 2 h withno change in resting end-tidal carbon dioxide concentration.In addition, the slope of the ventilatory response to carbondioxide was reduced slightly at 1 h and ventilation at end-tidalnCO₂ of 7.3 kPa was reduced also at 1 and 2 h. Conversely, thesame dose of fentanyl i.v. had lesser and shorter effects onventilation at rest and during carbon dioxide rebreathing. Ourresults show that fentanyl 50 µg given extradurally causedslight ventilatory depression which is probably clinically unimportant.     

VENTILATORY RESPONSE TO CARBON DIOXIDE IN PATIENTS WITH HOMOZYGOUS SICKLE-CELL DISEASE

The ventilatory response to carbon dioxide was measured by arebreathing technique in 21 Nigerians who had homozygous sickle-celldisease. The slope of the carbon dioxide response curve wasobtained by plotting the ventilation at successive half-minuteintervals against the corresponding mean end-tidal Pco2. Ourresults showed that sickle-cell patients are as sensitive tocarbon dioxide as are normal subjects.     

LOW VENTILATORY RESPONSE TO CARBON DIOXIDE NOT ASSOCIATED WITH INCREASED DEPRESSION BY MORPHINE

Ventilation (E), end-tidal (P')_co2 mixed venous Pco₂ (P_co2andthe ventilatory response to carbon dioxide (E/Pco₂) were measured before and within 90 min asgtermorphine 0.15 mg kg^–1 i.m. given to 17 adult patientsundergoing elective surgery under general anaesthesia. The hypothesisthat pastients with a low ventilastory response to carbon dioxideare more susceptible to the ventilatory depressant effecstsof morphine was tested. Morephine induced increases in PE'_co2andP_co2 were not correlasted witheither the slope or the position of the preinjection responseto carbon dioxide. Mean E/Pco₂was depressed after morphine (P <0.05), but individual responsesvaried widely. Seven pastients whose control E/Pco₂ was 9.9 litre min^–1kPa^–1 or lessdecreased E/Pco₂ after morphine.In four patients, E/Pco₂ increasedafter morphine; however, in each case, PE'co₂ and Pco₂ increased also. Morphine disphine displaced thecarbon dioxide response to the right (P < 0.001) but no correlationwas found between either the magnitude of the displacement orchange in slope and control E/Pco₂.The results suggest that patients with a low value for E/Pco₂ are not more susceptible tothe ventilatory depressant action of morphine.     

THE EFFECT OF TUBOCURARINE ON THE NORMAL AND DEPRESSED RESPIRATORY RESPONSE TO CARBON DIOXIDE

In young healthy volunteers curarization with (+)tubocurarine was carried to the point at which the ability to lift the head was abolished. In these circumstances, C0₂ administration revealed a considerable respiratory reserve, also after previous administration of pethidine 50 mg/70 kg.

ZUSAMMENFASSUNG

Junge gesunde freiwillige Versuchspersonen wurden mit Tubocurarin so weit curarisiert, dass sie den Kopf nicht mehr heben konnten. Unter diesen Umständen ergab die Verabreichung von Kohlensäure eine beträchtliche respiratorische Reserve, auch nach vorheriger Gabe von 50 mg Pethidin auf 70 kg Körpergewicht.     

ANALYSES OF THE VENTILATORY RESPONSE TO CARBON DIOXIDE: Implications for Clinical Research

Baseline control estimations of the ventilatory response tocarbon dioxide by the rebreathing method were attempted in 92patients. When analysed retrospectively, only 53 were both technicallyand statistically satisfactory, although even these gave riseto some doubts. As the breath-bybreath correlation between ventilation(Vi) and end-tidal carbon dioxide (PE'_CO2 decreased there wasa tendency for the gradients to become suspiciously low andfor the estimates in an individual gradient to become sensitiveto the method of analysis. Even so, when responses were groupedaccording to correlation, the method of analysis did not alterthe mean gradient within a group. Single estimates of the carbondioxide response at each stage of a study may not be a verypowerful technique in clinical research; multiple estimates,if they can be arranged, would be more satisfactory.     

VENTILATORY RESPONSES TO CARBON DIOXIDE IN CHILDREN DURING NITROUS OXIDE-HALOTHANE ANAESTHESIA

The ventilatory response to carbon dioxide was studied in 12unpremedicated children, aged 20–68 months, weighing between10 and 20 kg, under nitrous oxide-halothane anaesthesia. Tidalvolume (VT) and end-tidal carbon dioxide tension (PE'_CO2) werecontinuously measured by pneumotachograph and capnograph. Minuteventilation (), respiratory rate (f), mean in-spiratory flow (VT) and effective inspiratorycycle (T1/T^tot) were calculated during anaesthesia at threedifferent inspired halothane concentrations (0.5, 7 and 1.5%).The ventilatory response to carbon dioxide was determined byrelating the increase in ventilation during exposure to 2% carbondioxide to the change in end-tidal carbon dioxide concentration.When the inspired concentration of halothane increased, therewere significant decreases in , VT, , and a significant increase in PE'_CO2 The slope of the carbon dioxide response under lightnitrous oxide-halothane anaesthesia (0.5% halothane) was relativelyflat (18.64 ml min^–1 kg^– mm Hg^-1) when comparedwith the mean values published for anaesthetized adults, childrenor neonates. When the inspired concentration of halothane wasincreased, the slope decreased significantly (39% of initialvalue at 1 % inspired halothane, 26% at 1.5%). The additionof carbon dioxide produced significant increases in , VT and but no change in respiratory rate. No statistical differencewas observed in the slope of carbon dioxide response betweenthe initial and "control" periods which were measured at thesame inspired halothane concentration (0.5%).     

EFFECT OF ORAL DOXAPRAM ON MORPHINE-INDUCED CHANGES IN THE VENTILATORY RESPONSE TO CARBON DIOXIDE

A double-blind crossover volunteer trial has been carried outto determine if oral doxapram reduces the respiratory depressioncaused by morphine 0.12 mg kg^–1 i.m. Doxapram was givento the subjects 90 min before the morphine and significantlyreduced the displacement of the ventilatory response to carbondioxide caused by the morphine. This occurred despite the factthat the plasma concentrations of doxapram were significantlylower when the subject had been given morphine than when a placeboinjection had been administered. Doxapram alone in doses of300 mg and 600 mg did not alter significantly the respiratoryvariables measured in this study.     

VENTILATORY RESPONSES TO REBREATHING AND CARBON DIOXIDE INHALATION DURING ANAESTHESIA IN CHILDREN

In 12 spontaneously breathing intubated children (9.3–25kg), ventilatory responses to rebreathing and to the inhalationof carbon dioxide (CO₂) were investigated during halothane anaesthesiafor minor surgical procedures. A T-piece (Mapleson F system)was used, modified by the insertion of a pneumotachograph anda paediatric airway adaptor of an in-line capnograph in thepatient limb. Exhaled gas was collected for determination ofexpired CO₂ content. Measurements were made when the fresh gasflow (FGF) was at the borderline for rebreathing (FGF^r) andduring 10 min with a mean FGF 44% lower, producing a maximalinspired CO₂ (I_{CO2 max}) (%) of 1.45±0.38% (mean±1 SD). Measurements were repeated 5 min after returning to aflow exceeding FGF^r and then during CO₂ inhalation for 10 minafter the addition of 1.24±0.32 % CO₂ (mean±1SD) to this flow. During both rebreathing and CO₂ inhalationend-tidal CO₂ (E_CO2) was unchanged and did not increase significantly (18%), but duringCO₂ inhalation alveolar ventilation increased (P < 0.05),indicating an adequate and intact response to this level ofCO₂ inhalation. Estimations of I_{CO2 max} could be made from theexpression: l_CO2 max(%) = –0.7 x FGF/ +2.5 and FGF to minute ventilation () ratios lower than 1 were found to produce l_CO2max of 1.8% or higher. Such low FGF are likely to result inrebreathing within the alveolar ventilation and are thus ofclinical importance. We believe that to increase the marginof safety in anaesthetized spontaneously breathing children,FGF of at least 1.5 to 2 times should be used. Present addresses:^*Department of Anaesthesia, University HospitalS–22185 Lund, Sweden Department of Anaesthesia, Manchester Royal Infirmary, OxfordRoad, Manchester M13 9WL.     

EFFECTS OF ALAPROCLATE AND MORPHINE ON THE VENTILATORY RESPONSE TO CARBON DIOXIDE IN NORMAL MAN

The ventilatory response to carbon dioxide was determined insix healthy volunteers given alaprodate alone and combined withmorphine. A rebreathing technique was used and the slope ofthe ventilatory response to carbon dioxide was plotted. A comparisonof these responses after alaprodate or a placebo showed no significantdifference. Following the administration of morphine i.v., respirationwas depressed, but there was no enhancement of the depressionof the ventilatory response to carbon dioxide in subjects pretreatedwith alaprodate.     

THE RESPIRATORY RESPONSE TO CARBON DIOXIDE DURING INNOVAR-NITROUS OXIDE ANAESTHESIA IN MAN

In seven patients anaesthesia was induced by injection of asingle dose of Innovar and maintained with nitrous oxide andoxygen. Marked respiratory depression persisted for longer thanone hour. Tidal volume, respiratory rate and minute volume measurementswere inadequate indicators of this effect which is well shownby measurement of end-tidal carbon dioxide tension. The bestquantitation is the slope of the ventilatory response to elevatedcarbon dioxide tension, determined in l./min/mm Hg. Displacementof the response curve was very variable after loss of consciousness.The data indicate that spontaneous respiration with this anaesthetictechnique, as with the majority of other general anaesthetics,is accompanied by respiratory acidosis.     

THE VENTILATORY RESPONSE TO CARBON DIOXIDE: An Analysis of Data Obtained by the Rebreathing Method

The ventilatory response to carbon dioxide using the rebreathingmethod was studied repeatedly in four healthy volunteers. Thedata were collected and processed in different ways using amicrocomputer. Least squares linear regression analysis describedthe responses almost as accurately as a non-linear second-orderpolynomial regression. Linear regression analysis was undertakenon Vi/PE'_CO2 points, first breath-by-breath and then on threedifferent groupings of breaths. The gradients and interceptsobtained by grouping agreed with those from breath-by-breath-analysisboth for a single response and for the mean result of a numberof responses. Grouping tended to increase the correlation coefficientof a response, but widened the statistical confidence limitsof the calculated gradient. The performance variability betweenrepeated responses, the same no matter which data points wereused, produced a range of gradients for each subject which waslarger than the confidence limits on the gradient of a singleresponse. ^* Present address: Department of Medical Physics and BiomedicalEngineering, Plymouth General Hospital, Freedom Fields, Plymouth.     

PATTERN OF REDUCTION OF VENTILATORY AND OCCLUSION PRESSURE RESPONSE TO CARBON DIOXIDE BY PENTAZOCINE IN MAN

Mean inspiratory flow, occlusion pressure and end-tidal Pco₂were measured in six healthy, sitting subjects, during breathingair and rebreathing carbon dioxide, before and after pentazocine0.5 mgkg^–1 1.v. and again after naloxone 20 µg kg^–1.Pentazocine reduced the occlusion pressure and inspiratory flowresponses at a given Pco₂ during carbon dioxide rebreathingand these effects were antagonized by naloxone. The relationshipof inspiratory flow and end-tidal carbon dioxide during rebreathingwas used to measure the Pco₂ value at which mean inspiratoryflow was 1 litre s ^–1. Occlusion pressure at this Pco₂was reduced in all the subjects by pentazocine, suggesting thatthe generation of inspiratory flow required less muscle activityThis effect was antagonized by naloxone. ^*Present address: Department of Anaesthetics, Royal Infirmary,Edinburgh EH3 9YW.     

VENTILATION, VENTILATORY CARBON DIOXIDE AND HORMONAL RESPONSE DURING HALOTHANE ANAESTHESIA AND SURGERY IN CHILDREN AFTER MIDAZOLAM PREMEDICATION

In 14 intubated, spontaneously breathing children with bodyweight (bw) ranging from 8.3 to 25.6 kg, the influence of midazolam0.1 mg kg^–1 i.m. (group M_0.1', n = 7) and 0.2 mg kg^–1i.m. (group M_0.2' n = 7) as pre-medication, on sedation, ventilation,ventilatory response to carbon dioxide and hormonal stress responsewas studied in connection with minor surgical procedures duringhalothane anaesthesia. The concentrations of catecholamines,ACTH and cortisol were measured immediately after induction,during undisturbed anaesthesia, during surgery and 15 min afterthe end of the surgical procedure. Sedation was better and plasmacatecholamine concentrations during undisturbed anaesthesiawere less in children receiving the larger dose of midazolam.During surgery and in recovery there were no differences inhormone concentrations. In recovery, the concentrations of allhormones were significantly greater compared with during undisturbedanaesthesia. During surgery, VE and respiratory rate were somewhatlower in group M_0.2 while E'_CO2, was similar. A dose dependentdepression of the response to carbon dioxide was found. However,clinically, the response to carbon dioxide after surgery wasconsidered to be adequate in both groups. ^*Department of Anaesthesia, Manchester Royal Infirmary, OxfordRoad, Manchester Ml3 9WL. Department of Anaesthesia, University Hospital, S-221 85 Lund,Sweden Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden Department of Anesthesiology, Vanderbilt University, Nashville,Tennessee 37232, U.S.A.     

EFFECT OF NALBUPHINE HYDROCHLORIDE ON THE VENTILATORY AND OCCLUSION PRESSURE RESPONSES TO CARBON DIOXIDE IN VOLUNTEERS

We studied the effect of nalbuphine on the ventilatory and occlusionpressure reponses to carbon dioxide rebreathing in six healthymale volunteers (mean age 25.5 yr) in a single-blind laboratorystudy. On four separate days volunteers were assigned randomlyto receive either placebo (0.9% sodium chloride) or three i.v.doses of nalbuphine (15, 30 and 60 mg 70 kg^–1), followed90 min later by naloxone 0.4 mg 70 kg^–1. Duplicate rebreathingtests were performed and the mean intercept at PE'_co2 7 kPaand the slopes of the linear relationship between inspiratoryminute ventilation (Vl) or occlusion pressure (P_0.1) with PE'_co2were measured. Nalbuphine significantly decreased the mean interceptof the Vl (P < 0.01) and P_0.1 (P < 0.05) responses, butcaused no changes in the slopes. No significant difference betweenthe doses was noted, suggesting that an Effect maximum (E'max)for respiratory depression was reached with a dose of approximately15 mg 70 kg^–1. Naloxone was less effective in antagonizingthe depression in Vl at the higher dose of nalbuphine. SimilarP_0.1 values were associated with the same inspiratory flow rate(1 litre s^–1) before and after drug treatment, suggestingthat nalbuphine acts centrally to depress ventilation. Sedationincreased significantly following each dose of nalbuphine (P< 0.001). No demonstrable difference between the doses wasshown, suggesting an Effect maximum (E'max) for sedation wasreached at about 15 mg 70 kg^–1. Administration of nalbuphinewas associated with pain at the injection site, dizziness, dreaming,nausea and vomiting. Cardiovascular stability was maintainedin all subjects.     

MONITORING OF END-TIDAL CARBON DIOXIDE PARTIAL PRESSURE DURING HIGH FREQUENCY JET VENTILATION

A new method has been developed to measure end-tidal carbondioxide partial pressure (PtC0) during high frequency jet ventilation(HFJV). A digital flow controller incorporated in a computerizedhigh frequency jet ventilator was used to deliver either a singledeep breath or a series of three deep breaths. On user request,HFJV was interrupted and the deep breaths delivered, after whichHFJV was resumed. Using a mathematical model, we were able topredict accurately the pressures to which the lungs would beinflated during deep breaths. The effect of varying the deepbreath pressure (Pdb) on the ratio of end-tidal ?C02 to arterialPC02 (Pco2:Paco2 was studied in three dogs. In all the dogs,within an optimum Pdb range of 5–10 cm H20, PCo2 duringthe first deep breath was found to be similar (±0.2kPa)to the PaCO2 immediately before the onset of deep breaths. Deepbreaths delivered above or below the optimum Pdb range resultedin a decrease in the ratio PE'co2 Paco2 The frequency of jetventilation (1–200 b.p.m.) before the onset of the deepbreaths did not affect PE'CO3:PaCOl.     

ALVEOLAR GAS RELATIONSHIPS DURING USE OF THE CIRCLE SYSTEM WITH CARBON DIOXIDE ABSORPTION

Expressions have been derived to show the dependence of alveolaroxygen and anaesthetic concentrations on fresh gas flow to acircle system, the composition of fresh gas, ventilation andgas uptake. The form of these expressions is influenced by thedegree of mixing of fresh and expired gases within the circlesystem. These expressions assume an equilibrium state withinthe circle system and the rate at which equilibrium will beapproached has been quantified in terms of the time-constantsof change of composition of gas within the system. Time-constantsapproach infinity as fresh gas flow approaches values whichjust satisfy gas uptake. Whilst simplifying assumptions madein the derivation of the various alveolar gas equations limitstheir accuracy, the expression can serve as a guide to the likelybehaviour of circle systems under any given conditions of use.     

PATTERN OF RESPIRATION AND RESPONSES TO CARBON DIOXIDE DURING TRICHLOROETHYLENE ANAESTHESIA IN THE CAT

Tidal volume (VT), minute ventilation (E), the duration of inspiration and expiration, andPa_co2, were measured via a tracheostomy in adult cats anaesthetizedwith 0.7%, 1% and 1.5% (inspired) trichloroethylene (TCE). Thetracheal cannula was occluded at intervals at the start of inspirationand the tracheal pressure was measured to assess the force ofcontraction of the respiratory muscles. Anaesthesia with TCE0.7% was associated with an increase in E, a reduction in VT, and a marked increase in respiratoryfrequency and mean inspiratory flow rate, but Pa_co2 values didnot differ significantly from those in conscious animals. Ventilationwas also greater than in conscious animals during anaesthesiawith TCE 1%. TCE 1.5% caused a significantly greater Pa_co2,than in conscious animals. All concentrations of TCE causeda reduction in the ventilatory response to carbon dioxide, measuredby the steady-state method. Cervical vagal section did not abolishthe tachypnoea caused by TCE. ^*Present addresses: Ente Ospedaliera Regionale, Ospedale Maggiore,Piazza Ospedale, 34100 Trieste, Italy. Present addresses: Department of Anaesthetics, Royal Infirmaryof Edinburgh, Edinburgh EH3 9YW.     

THE INFLUENCE OF CARBON DIOXIDE ON THE NEUROMUSCULAR BLOCK CAUSED BY TUBOCURARINE CHLORIDE EN THE HUMAN SUBJECT

The influence of carbon dioxide changes on the neuromuscularblocking effect of tubocurarine in the anaesthetized human subjecthas been investigated. To assess neuromuscular transmissiona simple spring myograph attached to a finger was used and themotor nerve stimulated with supramaximal tetanic stimuli. Theplasma levels of tubocurarine were estimated using extractioninto ethyl dichloride and a spectrophotometric method of assay.Respiratory acidaemia in one group of patients was associatedwith high plasma levels of the drug and prolonged neuromuscularblock; respiratory alkalaemia in a further group resulted inlow plasma levels of the drug after the same initial dose andrapid recovery from the block. It is suggested that a likelyexplanation of these findings is related to the fact that thetubocurarine molecule contains, besides its quaternary ammoniumgroups, two phenolic hydroxyl groups which have pK₂ values of8.1 and 9.1 and so vary their degree of ionization within therange of pH changes associated with variations in pulmonaryventilation. Present address: University. Department of Anaesthesia, Cairo     

AGE-DEPENDENT VARIATION IN RESPONSE TO TUBOCURARINE IN THE ISOLATED RAT DIAPHRAGM

The EC₅₀ of tubocurarine was determined in phrenic nerve-hemidiaphragmpreparations obtained from 35 Sprague-Dawley rats aged 0–46days. We measured also the ratio of the fourth to the firsttwitch in the train-of-four (T4: T1) when the first twitch ofthe train was depressed to 50% of control. The preparation wasnot unduly sensitive to tubocurarine at 0 days and there waslittle evidence of T4: T1 fade. However, by age 11 days thepreparation exhibited fade and a three-fold sensitivity to tubocurarinesimilar to that in the human neonate. We conclude that the phrenicnerve-hemidiaphragm preparation from 11 - day-old rats shouldbe a suitable model in which to investigate the biochemicaland electrophysiological basis of the sensitivity seen in humans.     

CARBON DIOXIDE PRODUCTION IN CYANOTIC CHILDREN DURING ANAESTHESIA WITH CONTROLLED VENTILATION

Carbon dioxide production and ventilatory efficiency were measuredduring undisturbed anaesthesia with intermittent positive pressureventilation in 34 children about to undergo closed or open cardiacsurgery. Anaesthesia was provided with fentanyl or halothaneand nitrous oxide. There were 15 cyanotic and 19 acyanotic children.Children with cyanotic heart disease produced approximately20% less carbon dioxide per unit body weight than acyanoticchildren, but ventilation was approximately 20% less efficient.Adequate ventilation should therefore be obtained when "normal"ventilation in relation to body weight is used in cyanotic children. Previously presented at the Anaesthetic Research Society [1].