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.     

RELATIONSHIP OF VENTILATORY DEPRESSION TO STEADY-STATE BLOOD PETHIDINE CONCENTRATIONS

An i.v. infusion regimen was developed to permit rapid attainmentof steady-state blood pethidine concentrations (C_p26). In 10adult volunteers (12 studies) the relationship of pethidineC_p26 to the ventilatory effects of the drug were examined. Meanpethidine C_p26 ranged from 170 to 1320 ng ml_–1, with amedian C_p26 of 480 ng ml^–1. Increased end-tidal (PE' _co2)and mixed venous and decreased slope (I/Pco₂) and position(ISO-I) of the carbon dioxide response wereall significant (P<0.001) for C_P26. (1) 480 and (2) >480ng ml^-1. The averaged changes in PE'_co2, ,I/Pco₂, and ISO-I expressed as a per cent of respectivecontrol variables, were shown to be linear functions of C_P26.It is concluded that, under conditions of C_P26, significantventilarory depression occurs at blood pethidine concentrationsless than those required for analgesia. The possible significanceof these findings in volunteers is discussed in terms of thisapplication to the clinical setting of postoperative pain andits management after general anaesthesia.     

HIGH FREQUENCY JET VENTILATION: THE INFLUENCE OF DIFFFERENT METHODS OF INJECTION ON RESPIRATORY PARAMETERS

Fourteen critically ill patients with ventilatory failure wereventilated with HFJV using a constant driving pressure of 3atm and a constant I: E ratio of 0.43. In six (group I) HFJV,using a frequency of 100 b.p.m., was delivered via a proximalinjector cannula. Four injector cannulae (i.d. 1.8, 1.6, 1.4and 1.2 mm, respectively) were used at random. In eight patients(group II), HFJV using three frequencies (100, 300 and 600 b.p.m.)was administered either via a 1.8-mm i.d. proximal injectorcannula (proximal injection), or via a Hi-Lo jet tracheal tube(distal injection). The following indices were measured in vivo:mean airway pressure (P_sw), mean pulmonary volume above apnoeicFRC (), mean alveolar pressure (clamps method) and arterial blood-gas tensions. Injected volume(Vinj), entrainment (E) and tidal volume (VT) were measuredin vitro using a water-sealed spirometer. Operating pressure(the pressure in the connecting tube) was measured directlyusing a high pressure calibrated transducer. In group I, Psw, Pao2 Vinj and VT significantly decreased whereas operating pressure and E significantly increasedwhen the internal diameter of the injector cannula was reduced.In group II, Psw, , E, VT and operating pressure significantly decreased, whereas Vinj increasedand Pao2 and Paco2 remained unchanged, when proximal injectionwas switched to distal injection. In both groups, a significantrelationship was found between operating pressure and E. Ata constant driving pressure, operating pressure increased withnarrow injector cannulae and increased frequency, and decreasedwhen proximal injection was switched for distal injection. Presented in part at the Annual Meeting of the American Societyof Anesthesiologists, New Orleans, October 1984.     

AN EVALUATION OF REBREATHING WITH THE BAIN SYSTEM DURING ANAESTHESIA WITH SPONTANEOUS VENTILATION

Data from 12 anaesthetized patients breathing spontaneouslyfrom the Bain system were used to calculate the degree of rebreathingoccurring when the fresh gas flowrate(F) was equal to 2,1 and 0.7 times the estimated normalminute ventilation (_tot)- Measurementsof the expired minute volume (E) and end-tidal carbon dioxide tension (PE'_CO2) were made to determinethe effects of this rebreathing. No rebreathing occurred whenF was equal to twice tot. When F was equal to tot rebreathing was usually small in amount and produced no changes in E or PE'_CO2. Changes attributable torebreathing occurred in only two patients when F was reduced to 0.7 _tot.These results are explained by the presence of anaesthesia-inducedventilatory depression and favourable changes occurring in therespiratory wave forms in the majority of patients studied.In some patients, greater values of E and rebreathing occurred in response to strong surgical stimulation.The net result of increased ventilation in these patients wasa decrease in PE'_CO2-,. It is concluded that during anaesthesia,when the Bain system is used with F equal to _tot, any increasein PE'_CO2 which may result from rebreathing is likely to besmall and seldom of clinical importance.     

EFFECTS OF INCREASED CARDIAC OUTPUT ON PULMONARY BLOOD FLOW DISTRIBUTION DURING LOBAR VENTILATION HYPOXIA AND COLLAPSE

Electromagnetic flow probes were placed around the pulmonaryartery and left lower lobe artery in anaesthetized open-chestdogs in order to measure possible changes in the ratio of lobar-to-totalpulmonary blood flow (l/t) in response to changes in cardiacoutput produced by the opening of arterio-venous fistulae orfluid loading. Ventilation of the lobe with 7% oxygen or lobarcollapse reduced l/t by 35% and 42%, respectively, butthere were no significant changes in l/t in response to increases in t of 29–133%. It is concludedthat the changes in t, pulmonary vascular pressures and mixed venous PO₂ within the range studieddid not influence l/t.     

EFFECT OF AGE, GENDER AND ANAESTHETIC TECHNIQUE ON THE PHARMACODYNAMICS OF ATRACURIUM

We have measured in 38 patients the plasma concentration profileof atracurium and its effect on the electromyographic firstresponse of the train-offour. One of three techniques was usedto supplement anaesthesia with 66% nitrous oxide in oxygen,0.9% isoflurane (end-tidal), 0.5% halothane (end-tidal) or midazolam3–10mg. A fourparameter threshold pharmacodynamic modelwasfitted to the data in each patient. Compared with a groupof patients anaesthetized with an i.v. technique, the steady-stateplasma concentration producing 50% block was reduced by halothane, and to a greater extentby isoflurane. The rate constant for exit from the effect compartment(k_o correlated negatively with age and was greater in femalepatients, but unaffected by anaesthetic technique. The valuesof , the slope of the concentration-response curve, and of thethreshold were not affected significantly by age, sex or anaesthetic technique. (Br. J.Anaesth. 1993; 70: 38–41)     

Characterization and comparison of recombinant human and rat TRPV1 receptors: effects of exo- and endocannabinoids

Background. TRPV1 is a ligand-gated ion channel whose activationby capsaicin increases intracellular Ca²⁺ ([Ca²⁺]_i). TRPV1 andcannabinoid CB₁ receptor activation are capable of elicitinganalgesia. In this study, using recombinant human (h) and rat(r) TRPV1 receptors expressed in HEK293 cells, we have performeda comparison of both TRPV1 species at 22 and 37°C and comparedendo- and exocannabinoid activity at both receptors. Methods. [Ca²⁺]_i was measured in Fura-2-loaded HEK293_hTRPV1and HEK293_rTRPV1 cells. To assess native CB₁ receptor activity,[³⁵S]GTPS binding to membranes prepared from rat cerebellumwas measured. Results. Both capsaicin (pEC₅₀ rat 6.9 and pEC₅₀ human 6.8 at37°C) and anandamide (pEC₅₀ rat 5.3 and pEC₅₀ human 5.8at 37°C) produced a concentration-dependent increase in[Ca²⁺]_i in rat and human systems and at 22 and 37°C. InHEK293_rTRPV1 cells, anandamide appeared to be a partial agonist.Capsazepine demonstrated competitive antagonism at both humanand rat TRPV1 receptors and at both temperatures studied. Capsazepineeffects were not temperature dependent: pK_B at rTRPV1 was 5.98at 22°C and 6.02 at 37°C, and pK_B at hTRPV1 was 6.76at 22°C and 6.75 at 37°C. However, there was a consistent6-fold increase in capsazepine potency for hTRPV1 relative torTRPV1. The exocannabinoid ⁹-tetrahydrocannabinol failed toincrease [Ca²⁺]_i, although its solvent ethanol was an effectiveTRPV1 activator. In the [³⁵S]GTPS binding assay using rat cerebellarmembranes, anandamide (pEC₅₀ 5.8) and ⁹-tetrahydrocannabinol(pEC₅₀ 7.1), but not capsaicin, stimulated binding. ⁹-tetrahydrocannabinolwas a partial agonist. pEC₅₀ values for anandamide at rTRPV1and rCB₁ were similar. Conclusions. There were small differences in the pharmacologyof rat and human TRPV1 receptors. Whilst capsaicin activatedTRPV1 and ⁹-tetrahydrocannabinol activated CB₁, anandamide isan endogenous agonist for both receptor systems. Presented in abstract form in the following publications: LamPMW, Smart D, Lambert DG. Anandamide but not ⁹-tetrahydrocannabinolactivates recombinant human vanilloid receptors. Br J Anaesth2003; 90: 418P; Lam PMW, Smart D, Lambert DG. Differences inthe affinity of capsazepine at recombinant rat and human VR1receptors. Br J Pharmacol 2003; 138: 220P.     

REBREATHING CHARACTERISTICS OF THE BAIN CIRCUIT An Experimental and Theoretical Study

The Bain circuit was studied in a model lung on the assumptionthat, in addition to the ratio of fresh gas flow to total ventilation(FG/E), different time fractions of the respiratory cycle might influencerebreathing. We found that the time fraction for active expiration(FE_t) governed rebreathing for each FG/E value. With FE_t, as an independentvariable, a theoretical formula was derived for rebreathing.Rearranging this formula made it possible to calculate the necessaryincrease in ventilation to keep end-tidal carbon dioxide constantfor each FG/E. Thus, at a fresh gas flow of 70 ml kg^-1 min^-1,I has to be increased 2.6 times. For spontaneously breathing patients inhalation anaestheticsthat do not depress carbon dioxide sensitivity seem to be bettersuited to use in the Bain circuit. The FE_CO2 can then kept constantthrough increased ventilation in spite of the concomitant increasein rebreathing     

Blood/gas partition coefficients of halothane,isoflurane and sevoflurane in horse blood

Background. Blood/gas partition coefficients (_b/g) for volatileagents in horse blood are reported for halothane but not forisoflurane and sevoflurane. We measured the _b/g of halothane,isoflurane and sevoflurane in the blood of fasted horses. Thecorrelation with age, weight and some haematological and biochemicalvariables was studied. The temperature correction factor forisoflurane solubility was calculated. Methods. Twenty-four horses were randomly allocated to halothane(n=8), isoflurane (n=8) or sevoflurane (n=8). Blood sampleswere taken after 10 h’ fasting. Calculation of _b/g wasbased on the measurement of anaesthetic partial pressures inblood at 37 °C, which was achieved with tonometer equilibrationand headspace gas chromatography. Results. Mean _b/g was 1.66 (SD 0.06) for halothane, 0.92 (0.04)for isoflurane, and 0.47 (0.03) for sevoflurane. The _b/g valueswere all significantly lower than in humans (P<0.001). Nocorrelation was found between _b/g and weight, age, haematocrit,plasma triglycerides, cholesterol or total bilirubin. The changein isoflurane solubility per 1 °C temperature increase was–2.63 (0.13)%. Conclusion. The _b/g values of halothane, isoflurane and sevofluranein fasted horses are significantly lower than those reportedin humans. The _b/g for halothane in this study agrees with valuesreported in the literature but a positive correlation with plasmatriglycerides could not be confirmed. Knowledge of _b/g can refinemodels of anaesthetic uptake. Br J Anaesth 2003; 91: 276–8     

EFFECTS OF UPPER OR LOWER ABDOMINAL SURGERY ON DIAPHRAGMATIC FUNCTION

Changes in abdominal (AB) and rib cage (RC) movements, and invital capacity, were compared between 23 patients undergoingupper or lower abdominal surgery at 1, 3 and 7 days after surgery.Diaphragmatic index was obtained by measuring the relative abdominalmotion (AB/ AB+RC) using magnetometers. Electrical activityof abdominal muscles was assessed using needle electrodes afterupper abdominal surgery in four additional patients. After upperabdominal surgery, the vital capacity and the diaphragmaticindex were markedly reduced for 1 week. No abdominal muscleactivity was observed at day 1. After lower abdominal surgery,the vital capacity returned to the normal range within 3 daysof operation, without any diaphragmatic impairment. These findingssubstantiate the role of diaphragmatic dysfunction in postoperativereduction in vital capacity observed after upper abdominal surgery.     

PULMONARY BLOOD FLOW DURING CLOSED HEART SURGERY: Use of a Modified Formula Ratio to Assess Adequacy of Palliation of Systemic-Pulmonary Artery Shunts

The ability to assess changes in pulmonary blood flow, usinga modified ratio (), was evaluated in 12 infants withcongenital heart disease and complete intracardiac mixing whounderwent modified Blalock-Taussig shunt procedures. At thevarious measuring stages there were no major changes in meanarterial pressure or heart rate. Arterial oxygen tensions andsaturation increased (P < 0.01) and the arterial to end-tidalcarbon dioxide difference (Pa_CO2–PE'_CO2) was significantlyreduced (P < 0.001) after completion of the shunt procedure.There was a significant increase in mean after chest closure (P < 0.001), which was seento correlate well with early clinical outcome. Two patientswho did not demonstrate any increase in over the course of the procedure had failed shunts.The limitations of use of the are discussed. A modified ratio of less than unity after surgery is strongly indicativeof inadequate palliation. Present address: Department of Anaesthesiology, University ofTexas Health Science Center at Dallas, 5323 Harry Hines Blvd,Dallas, Texas 75235, U.S.A.     

ERRATUM

Equation (7) should read: dt = d/2f In the equation after equation (8) the right hand side shouldbegin, not (kv/2f), but (kv/2f)     

FRESH GAS REQUIREMENTS OF AN ENCLOSED AFFERENT RESERVOIR BREATHING SYSTEM IN ANAESTHETIZED, SPONTANEOUSLY VENTILATING CHILDREN

We have determined the minimum fresh gas flow rate (F) for use with the Ohmeda enclosedafferent reservoir breathing system (EAR) in 10 anaesthetizedchildren breathing spontaneously. First, we determined the F required to prevent rebreathing asdetected by increased total ventilation (E) and end-tidal carbon dioxide partial pressure.Second, we used a mathematical model to calculate the degreeof rebreathing occurring at each F.A F equal to the predictedalveolar ventilation was sufficient to prevent clinically detectablerebreathing in all pateints. From the model, no rebreathingoccurred when F//E was 0.78 or more. We have shown previously thatthe EAR functions efficiently during controlled ventilationwith a F = 0.6x weight^0.5.As this F is slightly greaterthan the predicted alveolar ventilation, we suggest that theEAR may be used with a F =0.6 x weight ^0.5 regardless of the mode of ventilation.     

A NEW METHOD FOR MEASURING PCO2 DURING ANAESTHESIA

We have evaluated a new method for measuring the oxygenatedmixed venous () in patients undergoing general anaesthesia. Thelungs were inflated with a gas mixture containing 0% carbondioxide and then 12% carbon dioxide and the expired gas wasanalysed both before and after a brief period of breath-holding. was estimated from the differences in carbon dioxide concentration before and after the apnoeicperiod. Simultaneous measurements of were made in blood obtained from radial artery puncture. Therange of , studied was 3·2–6·13 kPa. The relationship between mixed venous and arterial was found to be = 0.87 –0.44 (r= 0·91). We conclude that this method for measuring can be used during anaesthesia allowing to be estimated with considerable accuracy.     

REVERSAL OF NITROUS OXIDE-INDUCED DEPRESSION OF HYPOXIC PULMONARY VASOCONSTRICTION BY LIGNOCAINE HYDROCHLORIDE DURING COLLAPSE AND VENTILATION HYPOXIA OF THE LEFT LOWER LOBE

The blood flow to the left lower lobe (L), and total (T) pulmonary blood flow, were measured in 10 open-chest dogs usingelectromagnetic flowmeters. Ventilation of the left lower lobewith 7% oxygen in nitrogen produced a greater reduction in L/T (41%) than lobar ventilation with 7% oxygen in nitrous oxide(33%). Lobar collapse reduced QL/QT by 65%, but there was nochange in L/T when 50% nitrous oxide was administered to theright lung. The i.v. infusion of lignocaine hydrochloride duringventilation of the lobe with 7% oxygen in nitrogen producedno change in L/T. However, lignocaine infusion during lobar ventilationwith 7% oxygen in nitrous oxide produced a further reductionin L/T to a value which was not significantly differentfrom that observed during ventilation with 7% oxygen in nitrogen.Lignocaine had no effect on L/T during lobar collapse whether theright lung was ventilated with 50% oxygen in nitrogen or 50%oxygen in nitrous oxide. It is concluded that lignocaine reversesthe depression of hypoxic pulmonary vasoconstriction producedby lobar ventilation with nitrous oxide.     

DERIVATION OF VA/Q DISTRIBUTION FROM BLOOD-GAS TENSIONS

Gas exchange was modelled by a Fortran program. Arterial blood-gastensions have higher resolution than inert gas retentions interms of distinguishing a single A/ compartment from a progressively broadeninglognormal distribution. The maximum number of compartments determinableby arterial blood-gas tensions is three; A/ distributions containing more compartments are non-unique. Without utilizing100% inspired oxygen, arterial blood-gas tensions cannot resolvethe relative perfusion in shunt and low-A/ compartments, but the total perfusion in these compartments is determinable.The way in which the arterial blood-gas tensions vary with thevariables of two and three-compartment distributions is described.Two-and three-compartments A/ distributions are derivable from eitherarterial blood-gas tensions or inert gas retentions.     

A SYSTEM FOR THE CONTINUOUS MEASUREMENT OF OXYGEN UPTAKE AND CARBON DIOXIDE OUTPUT IN ARTIFICIALLY VENTILATED PATIENTS

A continuous, non-invasive system is described for measuringoxygen uptake () and carbon dioxide output () in mechanically ventilated patients. Inspiratory and mixed expiratory gas sampleswere pumped through fine-bore tubing to a remote mass spectrometerfor analysis. The expiratory flow transducer of a Siemens Servo900B ventilator was used for expiratory flow measurement andinspiratory flow was calculated from this using the Haldanetransformation. A desk-top computer calculated , and respiratory quotient. The system has been validated against standard methodsof gas analysis and flow measurement ( mean difference –lOml min^–1: SD9.13; mean difference 8.12ml min^–1:SD4.66). Comparison with Douglas bag measurements in patientshas been made ( mean difference 10.7ml min^–1: SD9.8; mean difference –1.07ml min^–1: SD4.7).     

EFFECTS OF TEMPERATURE ON THE INTERACTION OF MORPHINE WITH OPIOID RECEPTORS

The electrically stimulated guineapig ileum preparation wasused to determine the effects of temperature on the affinityof morphine for opioid receptors. The potency of morphine (expressedas the concentration which produces 50% inhibition—IC₅₀)was significantly decreased at 30C (IC₅₀ 41.0x10^–8 mollitre^–1) and increased at 40C (IC₅₀ 5.1x10^–1 mollitre^–1) when compared with its potency at 37C (IC₅₀,8.8x10^–8 mol litre^–1). Experiments carried out inthe presence of naloxone (a competitive opioid antagonist) indicatedthat the affinity of opioid receptors for this antagonist wasnot affected by temperature. Further studies using B-funaltrexamine(a mu-specific, non-reversible opioid antagonist) revealed anincrease in morphine receptor affinity when temperature wasincreased from 30 to 37C. The data demonstrated that the potencyof morphine increased with temperature; the affinity of naloxonefor opioid receptors was unaltered by temperature; and the affinityof morphine for mu-receptors reached an optimal value withinthe range 30–37C. Presented in part to the American Society of AnesthesiologistsAnnual Meeting, Las Vegas, Nevada, U.S.A., 1986.     

Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-kappaB

Background. Treatment of neuropathic pain remains a challenge.The current study investigated the therapeutic effect of intrathecaladministration of NF-B antisense oligodeoxynucleotides (ODNs)on mechanical allodynia and thermal hyperalgesia in a chronicconstriction injury (CCI) model of rats. Methods. Lumbar intrathecal catheters were implanted in maleSprague–Dawley rats and a CCI model was established. Thermaland mechanical nociceptive thresholds were assessed with pawwithdrawal latency (PWL) to radiant heat and von Frey filaments.The phosphorothioate-modified antisense ODNs to p65 subunitof NF-B were administered intrathecally on each of five consecutivedays post-CCI. Nuclear NF-B p65 expression was assessed by westernblot. Results. CCI induced mechanical allodynia and thermal hyperalgesiaand significantly increased NF-B p65 protein expression. Intrathecalinjection of antisense ODN markedly suppressed the expressionof NF-B p65 protein and significantly attenuated CCI-inducedmechanical allodynia and thermal hyperalgesia. Conclusion. The activation of NF-B pathway may contribute toneuropathic pain in CCI rats. Suppression of NF-B could be apotential new strategy for the treatment of neuropathic pain.     

Actions of morphine on noradrenaline efflux in the rat locus coeruleus are mediated via both opioid and {alpha}2 adrenoceptor mechanisms

A recent report showed that morphine inhibited [³H]clonidinebinding to human platelet ₂ receptors. As the analgesic effectsof morphine and clonidine are clinically additive, we investigatedthe possibility that morphine might stimulate ₂ receptors or₂ mechanisms in rat locus coeruleus (LC) slices. StimulatedLC noradrenaline efflux was measured by fast cyclic voltammetry.Cumulatively applied morphine 10^–8–10^–4mollitre^–1 had no effect on noradrenaline efflux evoked bypseudo-single-pulse stimulations (20 pulses at 100 Hz) whilethe ₂ agonist dexmedetomidine 2 x 10^–10–10^–7mol litre^–1 decreased efflux of noradrenaline in a concentration-dependentmanner. Administration of single concentrations of morphine10^–6–10^–4 mol litre^–1 significantlydecreased efflux of noradrenaline (by 22% and 17%, respectively)and attenuated the effect of dexmedetomidine in a concentration-dependentfashion. Morphine 10^–6–10^–4mol litre^–1also decreased efflux of noradrenaline on long stimulus trains(50 pulses at 50 Hz). These data suggest that the analgesicpotentiation of ₂ and opioid agonists is not mediated via LC₂ receptors.