Postoperative analgesia and respiratory events in patients with symptoms of obstructive sleep apnoea.

Symptoms of obstructive sleep apnoea are common in patients presenting for surgery and are associated with increased morbidity. Analgesia contributes significantly to postoperative respiratory depression and obstruction, so we compared standard morphine patient-controlled analgesia with an opioid-sparing protocol (tramadol patient-controlled analgesia, parecoxib and rescue-only morphine) in these patients. Sixty-two patients presenting for elective surgery with body mass index > or = 28 and signs or symptoms suggesting obstructive sleep apnoea were randomised to receive either the opioid or opioid-sparing postoperative analgesia protocol, with continuous respiratory monitoring for 12 hours on the first postoperative night. The number of respiratory events (apnoeas and hypopnoeas) and oxygen desaturations were compared. There was no difference between treatment groups in the number of obstructive apnoeas, hypopnoeas or central apnoeas. However, central apnoeas and a rate of respiratory events > 15 per hour were related to postoperative morphine dose (P = 0.005 and P = 0.002). In patients at risk of obstructed breathing, intention to treat with an opioid-sparing analgesia protocol did not decrease the rate of respiratory events, although the rate was still related to the total morphine dose.

Preoperative assessment for obstructive sleep apnoea and the prediction of postoperative respiratory obstruction and hypoxaemia.

Patients scheduled for elective surgery requiring general anaesthesia and hospital admission were assessed for risk of obstructive sleep apnoea (OSA) using history, body mass index and upper airway examination to determine any relation between OSA risk and the rate of respiratory events after surgery. Anaesthesia and postoperative analgesia were at the discretion of the treating anaesthetist, who was made aware of any suspicion of OSA. Respiratory monitoring for apnoeas (central or obstructive), hypopnoeas and oxygen desaturations was continuous for a 12-hour period on the first postoperative night. We used automated analysis and visual scanning of respiratory recordings, but sleep stages were not assessed. Patients classified as OSA risk had more respiratory obstructive events per hour than controls (38+/-22 vs. 14+/-10) and an increased proportion of the 12-hour monitored period with oxygen saturation <90% (7+/-12% vs. 2+/-5% of the 12-hour period). Perioperative morphine dose was predictive of central apnoeas for both OSA risk and control patients (P=0.002). This study suggests that preoperative suspicion of OSA should lead to increased postoperative monitoring and efforts to minimise sedation and opioid dose. It also supports the routine use of supplemental oxygen with patient-controlled opioid analgesia.

Alfentanil infusion as a component of intravenous anaesthesia for coronary artery bypass surgery with "fast-track" recovery.

Alfentanil and propofol total intravenous anaesthesia was assessed in 25 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). A manually controlled alfentanil infusion, calculated from estimated lean body mass and published pharmacokinetic data, was effective in achieving target plasma concentrations, while the "Diprifusor" system was used to vary propofol target concentrations according to changes in haemodynamics and anaesthetic requirement. The effects of CPB on alfentanil plasma concentrations were offset by changes in protein binding and free-fraction of the drug. With the use of only two target plasma concentrations for alfentanil (changed after CPB), a pre-determined infusion profile ensured effective plasma concentrations during surgery and concentrations unlikely to inhibit extubation within six hours of sternal closure.

Shape and movement of the interatrial septum predicts change in pulmonary capillary wedge pressure.

We aimed to assess whether movement of the interatrial septum predicts change in pulmonary capillary wedge pressure (PCWP). In 71 patients undergoing cardiac surgery, the interatrial septum was categorised by its shape and movement using transesophageal echocardiography. Fixed curvature (FC) was identified by bowing of the interatrial septum from left to right throughout the cardiac cycle, mid-systolic reversal (MSR) by minimal septal movement and transient reversal (right to left) during mid-systole, and mid-systolic buckling (MSB) by marked movement and buckling of the septum during mid-systole. These were compared with PCWP. Sensitivity and interobserver reliability was studied with continuous PCWP and TEE measurement during a period of acute volume alteration in 10 additional patients. Interatrial septal movement predicted PCWP, with mean PCWP (95% confidence intervals) for FC, 18.1 mmHg (16.7 to 19.6), MSR 13.2 mmHg (12.5 to 13.8) and MSB, 9.9 mmHg (9.0 to 10.7) mmHg. The mean PCWP at which a change in pattern occurred was 8.9 mmHg (8.3 to 9.6) for MSR to MSB, and 10.9 mmHg (10.1 to 11.8) for MSR to FC (p<0.001). There was no significant difference in mean values for all three observers. Movement of the interatrial septum predicts change in PCWP.

Effect of amlodipine on cardiopulmonary performance in volunteers.

1. In order to exclude a significant effect of the calcium channel antagonist amlodipine on cardiopulmonary performance in normal subjects, we performed a double-blind cross-over study of amlodipine (10 mg daily for 2 weeks) on oxygen uptake and catecholamine responses during exercise in eight volunteers. 2. Despite a therapeutic plasma concentration of amlodipine (22.8+/-9 ng/mL), there was no change in resting heart rate or blood pressure. Amlodipine did not cause significant change in oxygen uptake at the anaerobic threshold or at maximum exercise and there was also no change in heart rate or catecholamine responses. 3. Although there was an awareness of peripheral vasodilation and reports of lethargy during the active treatment period, the volunteers had no objective evidence of a decrease in cardiopulmonary performance. We suggest that use of amlodipine as a vasodilator in the perioperative period would not add to the myocardial depressant effects of general anaesthesia in patients with normal cardiac function.

Dexmedetomidine and hemodynamic responses to simulated hemorrhage in experimental heart failure.

UNLABELLED: alpha(2)-Adrenoreceptor agonists may counteract the increased basal sympathetic nervous activity in patients with congestive heart failure (CHF), but they may also compromise reflex responses to hypovolemia. We have tested responses to simulated hemorrhage (central hypovolemia) after IV dexmedetomidine in normal animals and in experimental chronic CHF. Rabbits (n = 14) were treated with IV doxorubicin (or control saline) for 8 weeks inducing biventricular dilatation and myocardial damage. Cardiac output (CO) was measured continuously with a transit-time Doppler implanted on the ascending aorta. Progressive inflation of a cuff around the inferior vena cava (simulated hemorrhage) was used to reduce cardiac index at a constant rate. Arterial baroreceptor-mediated vasoconstrictor and heart rate responses were tested with repeated cuff inflations. Although resting CO was reduced in CHF, the blood pressure and heart rate changes with dexmedetomidine were not exaggerated. The slope of the vasoconstrictor response to graded hypovolemia was attenuated by dexmedetomidine with an earlier onset of decompensation. There was no added effect of CHF on the response until the dose of dexmedetomidine was sufficient to reduce resting CO in addition to arterial blood pressure and heart rate. IMPLICATIONS: As an adjunct to anesthesia, dexmedetomidine may be useful in reducing basal sympathetic nervous activity. This study in experimental animals suggests this may be achieved without compromising protective responses to decreased blood volume.

Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits.

1. Effects of the alpha2-adrenoceptor agonist dexmedetomidine on vasoconstrictor and heart rate (HR) responses to acute central hypovolaemia were studied in eight chronically instrumented rabbits. We compared intravenous (i.v.) and fourth ventricular (V4) dexmedetomidine (0.1-10 microg/kg) and the reversal of effects by the alpha2-adrenoceptor antagonist idazoxan and the opioid agonist alfentanil. 2. Gradual inflation of an inferior vena cava (IVC) cuff reduced cardiac index (CI) by 8%/min, with progressive vasoconstriction and increased HR. In control rabbits, at approximately 40% baseline CI, there was sudden decompensation with failure of vasoconstriction and a fall in mean arterial pressure (MAP). 3. Dexmedetomidine (i.v. and V4) reduced resting MAP and HR and caused an earlier decompensation during central hypovolaemia. Intravenous dexmedetomidine (3 and 10 microg/kg) also reduced the slope of the initial vasoconstrictor response and the maximum HR. 4. The effects of dexmedetomidine were reversed by the antagonist idazoxan, which prevented the decompensation phase. Intravenous alfentanil was also effective in restoring the vasoconstrictor response and delaying decompensation with hypovolaemia after dexmedetomidine. Combining dexmedetomidine with an opioid, such as alfentanil, may provide the benefit of reduced sympathetic tone without increased risk of cardiovascular collapse.

Instantaneous end diastolic stiffness (IEDS): a simple, load independent measurement of left ventricular diastolic function in patients undergoing cardiac surgery.

The end-diastolic pressure-volume relation is a load-independent measurement of diastolic function. However, its clinical utility is limited because of its complexity. Instantaneous end-diastolic stiffness (IEDS) is a simple to perform, single-point, measurement of ventricular stiffness. We have validated it against the end-diastolic pressure-area relation (EDPAR) in patients undergoing cardiac surgery. EDPARs were analyzed before and after cardiopulmonary bypass in 29 patients and compared with IEDS. Data was collected in an additional 69 patients in order to estimate the range of values of IEDS. End-diastolic area (EDA) measured by transesophageal echocardiography (TEE) was substituted for end-diastolic volume, and pulmonary capillary wedge pressure (PWCP) was substituted for end-diastolic pressure. IEDS = 100 x (log10 PWCP)/EDA. Comparison of the methods was done by ordinary least products regression analysis. Agreement between EDPAR and IEDS was identified by the absence of fixed and proportional bias. The maximal range of corresponding values identified by 95% confidence intervals was within +/- 16% of the mean indicating satisfactory agreement. The geometric mean and 95% confidence intervals (CI) for IEDS were 8. 7 mmHg/dm2 (8.1 to 9.4) and for IEDS indexed to body surface area were 17.2 mmHg/dm(2)/m2 (16.0 to 18.6). IEDS is a load independent index of left ventricular stiffness.

Measurement of cardiac output by transoesophageal echocardiography: a comparison of two Doppler methods with thermodilution.

This study assessed the agreement between three methods of cardiac output (CO) measurement, thermodilution, the current clinical standard, and two transoesophageal echocardiographic techniques. Measurements were performed in 37 patients using thermodilution, continuous wave Doppler across the aortic valve and pulsed wave Doppler positioned in the left ventricular outflow tract. The aortic valve area was measured by direct planimetry, and the left ventricular outflow tract area was calculated from its diameter. Weighted least products regression analysis was employed to detect bias, and standard deviation of the difference (SDdiff) was calculated. There was no fixed bias but there was proportional bias between continuous wave Doppler and thermodilution methods (SDdiff 0.92 l/min). There was fixed bias but not proportional bias between pulsed wave and thermodilution methods (SDdiff 1.1 l/min). There was neither fixed nor proportional bias between pulsed wave and continuous wave Doppler methods (SDdiff 1.1 l/min). The transoesophageal Doppler methods described can be clinical alternatives to thermodilution cardiac output measurement.

Induction of anaesthesia with sevoflurane, preprogrammed propofol infusion or combined sevoflurane/propofol for laryngeal mask insertion: cardiovascular, movement and EEG bispectral index responses.

Inhalation induction with sevoflurane was compared with propofol or sevoflurane/propofol in 60 unpremedicated adults. Target concentrations for the three groups (with 60% nitrous oxide) were 3% end-tidal sevoflurane, 12 mg/l propofol and 1.5% sevoflurane/6 mg/l propofol respectively, prior to insertion of a laryngeal mask airway (LMA) at 10 minutes. Induction of anaesthesia was satisfactory in each group, but movement response to LMA insertion was observed in 20 patients (least in the sevoflurane group). Cardiovascular responses were similar except for a lower heart rate in the sevoflurane group. EEG bispectral index suggested a greater depth of anaesthesia in the inhalation induction group. A bispectral index of 60 separated patients responding to LMA insertion from nonresponders (P = 0.006), and had a sensitivity of 68% and specificity 70%. Movement response was not predicted by cardiovascular changes.

Correction of hypovolemic hypotension by centrally administered naloxone in conscious rabbits.

Our goal was to test directly whether the vasoconstrictor action of naloxone during hypovolemic hypotension is centrally mediated. In eight chronically instrumented rabbits, progressive central hypovolemia and fall in cardiac output (CO) were produced by gradually inflating a cuff on the thoracic vena cava. Central hypovolemia was then sustained for 8 min by holding CO constant. In the main experiment (n = 4), each rabbit was studied eight times over 4 experimental days. Saline or naloxone treatment commenced 10 min before progressive hypovolemia (early treatment) or 2 min after the onset of sustained hypovolemia (late treatment), given by intravenous infusion or into the fourth ventricle (V4). With saline treatment, there was spontaneous recovery of systemic vasoconstriction and arterial pressure during sustained hypovolemia. Late treatment with naloxone (4 mg/kg i.v.; 4-37 micrograms/kg V4) accelerated and exaggerated these changes. Thus, under conditions of constant CO and central blood volume, the vasodilatation of the decompensatory phase of acute hypovolemia is not sustained, and intravenous nalox one's vasoconstrictor action is via a brain stem mechanism.

Patient-controlled epidural versus intravenous pethidine to supplement epidural bupivacaine after abdominal aortic surgery.

In a double-blind, randomized, crossover study of 25 patients after abdominal aortic surgery, we compared patient-controlled analgesia (PCA) with epidural versus intravenous pethidine. All patients received continuous epidural infusions of 0.125% bupivacaine adjusted to maintain appropriate sensory levels. The 48 hour study period commenced 36 to 48 hours after surgery and covered postoperative days 2 and 3. There was a crossover in PCA mode (epidural or intravenous) after 24 hours. Plasma pethidine concentration at the end of each 24 hour period and the total 24 hour pethidine dose did not change significantly between postoperative days 2 and 3. Pethidine plasma concentration was lower after 24 hours epidural than after intravenous PCA [125 (SD 108) ng/ml versus 171 (SD 107) ng/ml, P = 0.03], although pethidine dose did not differ significantly [mean 147 (SD 124) mg/24 h]. Visual analog pain scores (VAS) did not differ significantly between postoperative days 2 and 3, or at rest between epidural and i.v. groups. However, VAS with coughing and with abdominal palpation were lower in the epidural PCA group (P = 0.05, 0.008). With a background epidural infusion of 0.125% bupivacaine, PCA with epidural pethidine provided better pain control than PCA intravenous pethidine and this was achieved at lower plasma pethidine concentrations.

The effects of cardiopulmonary bypass on total and unbound plasma concentrations of propofol and midazolam.

OBJECTIVE: To examine the effects of cardiopulmonary bypass (CPB) on total and unbound plasma concentrations of propofol and midazolam when administered by continuous infusion during cardiac surgery. DESIGN: Prospective clinical study. SETTING: University hospital. PARTICIPANTS: Twenty-four adult patients undergoing cardiac surgery. INTERVENTIONS: Patients received either propofol or midazolam to supplement fentanyl anesthesia. Twelve patients received a propofol bolus (1 mg/kg) followed by an infusion of 3 mg/kg/hr. A second group received midazolam, 0.2 mg/kg bolus, followed by an infusion of 0.07 mg/kg/hr. MEASUREMENTS AND MAIN RESULTS: Blood sample were collected from the radial artery cannula at 0, 2, 4, 8, 8, 10, 15, 20 minutes and then every 10 minutes before CPB, at 1, 2, 3, 4, 6, 10, 15, 20 minutes and then each 10 minutes during CPB. On weaning from CPB samples were collected at 0, 5, 10 and 20 minutes. Plasma binding, total and unbound propofol and midazolam concentrations were determined by ultrafiltration and high-pressure liquid chromatography (HPLC). CPB resulted in a fall in total propofol and midazolam plasma concentrations, but the unbound concentrations remained stable. The propofol unbound fraction increased from 0.22 +/- 0.06% to 0.41 +/- 0.17%. The midazolam unbound fraction increased from 5.6 +/- 1.0% to 11.2 +/- 2.1%. CONCLUSIONS: Unbound concentrations of propofol and midazolam are not affected by cardiopulmonary bypass. Total intravenous anesthesia algorithms do not need to be changed to achieve stable unbound plasma concentrations when initiating CPB.

Oral tenoxicam for peripheral orthopaedic surgery: a pharmacokinetic study.

Non-steroidal anti-inflammatory drugs (NSAIDs) provide effective analgesia after orthopaedic surgery and reduce opioid requirements. The need for parenteral NSAIDs with peripheral surgery is controversial. In this study 10 patients were treated with oral tenoxicam 20 mg preoperatively, and at 4 hours and 28 hours after knee ligament reconstruction surgery. Plasma concentrations of tenoxicam, an NSAID with a long elimination half-life, were measured for 10 days. All patients received patient-controlled intravenous morphine postoperatively, which delayed absorption of the second and third tenoxicam doses. However, plasma concentrations of tenoxicam were achieved and maintained for the five-day surgical admission above the level considered to produce effective analgesia. Oral analgesic administration is a simple and feasible option in the perioperative period.

Haemodynamic response to simulated haemorrhage in the rabbit: interaction of i.v. anaesthesia and hypoxia.

We have studied in eight rabbits the cardiovascular effects of midazolam, propofol and alfentanil with graded hypoxia. Central blood volume was reduced progressively by gradual inflation of a thoracic vena cava cuff so that cardiac index (CI) decreased at a constant rate. Under control conditions the haemodynamic response was biphasic. During phase I, mean arterial pressure (MAP) was maintained by a progressive decrease in systemic vascular conductance (SVCI). When CI had declined to a critical level, phase II occurred with an abrupt increase in SVCI and decrease in MAP. Phase I was prolonged by hypoxia, alfentanil and midazolam, but the effects were not additive. Phase I was shortened by propofol and this effect increased with hypoxia. The gradient of the SVCI response in phase I was also reduced by propofol > midazolam, but not by alfentanil. The occurrence of phase II was less frequent during alfentanil infusion than midazolam and propofol with all of the inspired gas mixtures. Thus the opioid was protective against circulatory collapse with hypoxia and simulated hypovalaemia.

Normal postoperative gastric emptying after orthopaedic surgery with spinal anaesthesia and i.m. ketorolac as the first postoperative analgesic.

We have assessed the effect of i.m. ketorolac or morphine on early postoperative gastric emptying of liquids in patients undergoing orthopaedic surgery with spinal anaesthesia. Liquid gastric emptying was measured by absorption of paracetamol with patients acting as their own controls. There was no delay after ketorolac 30 mg, but morphine 10 mg resulted in marked delay. There was no difference in postoperative visual analogue pain scores between treatments.

The general versus regional anaesthesia debate: time to re-examine the goals.

New justification for the use of regional anaesthesia, either alone or in combination with general anaesthesia, has been provided with reports of some unexpected influences on outcome. A reduction in the incidence of postoperative thrombotic episodes and vascular graft occlusion is strongly suggested in patients with generalized vascular disease. Application of a variety of drugs, including local anaesthetics, opioids and adrenergic agonists, in the region of the spinal cord reduces afferent input during surgery and also the metabolic stress response. Evidence is increasing that this multi-modal approach to anaesthesia has important consequences in the spinal cord which result in modification of the postoperative requirement for analgesia. Premedication with opioid and other analgesics may also enhance this pre-emptive effect. New general anaesthetic and analgesic drugs are available that are more suited to these combined techniques. They have shorter duration of action so that plasma concentration can be rapidly adjusted to match a variable surgical stimulus.

Pharmacokinetics of bupivacaine enantiomers during interpleural infusion.

Interpleural infusions (24 hr) were given to 14 adults (29-81 yr) having surgery via right subcostal incisions. Patient-controlled analgesia with morphine was also available for 72 hours following surgery. An infusion of 0.25% bupivacaine with adrenaline 1/400,000 was commenced at 0.1 ml/kg/hr at the conclusion of surgery after an initial 20 ml bolus. The 24 hr cumulative morphine dose increased by 62% (P < 0.01) on the second postoperative day after the bupivacaine infusion was ceased, but the pain score did not change. There was no clinical evidence of bupivacaine toxicity although the maximum bupivacaine concentration ranged from 0.74-6.52 mg/l, mean 2.90 (SEM 0.44) mg/l and vascular uptake was rapid in two patients. The concentration of S-bupivacaine was consistently greater than R-bupivacaine (P < 0.05) and total body clearance was less. The unbound bupivacaine fraction also changed from 3.6% (SEM 0.6) at the start of the infusion to 2.0% (SEM 0.3) at 24 hr (P < 0.005). The total body clearance of each enantiomer was reduced during the 24 hours (P < 0.001). No relationship between pharmacokinetic parameters and weight, age or sex was found (P > 0.25 for each). Variation between patients was reduced when parameters were estimated for the free (unbound) bupivacaine (P < 0.001).

Regional blood flow effects of dopexamine versus enalaprilat during propofol anaesthesia in rabbits with experimental chronic heart failure.

OBJECTIVE: Chronic congestive heart failure (CHF) was induced in rabbits with doxorubicin in order to evaluate: (1) haemodynamic and regional blood flow responses to propofol anaesthesia; (2) modification of these cardiovascular responses with background intravenous infusions of enalaprilat or dopexamine. METHODS: Rabbits received either doxorubicin, 2 mg.kg-1 weekly intravenously for seven weeks (CHF, n = 6), or saline (controls, n = 6). Doppler flow probes were implanted on the ascending aorta, left renal artery, and lower abdominal aorta. In three separate studies propofol was infused for 40 min periods at 0.6 and then 1.2 mg.kg-1.min-1 after background infusions of either saline, enalaprilat (0.2 mg.kg-1 + 0.003 mg.kg-1.min-1), or dopexamine (0.008 mg.kg-1.min-1). RESULTS: In normal rabbits propofol (1.2 mg.kg-1.min-1) reduced mean arterial pressure from awake control by 33(SEM 3)%, cardiac output by 24(4)%, and hindlimb blood flow (HBF) by 10(2)%, but did not change renal blood flow. In rabbits with CHF, although resting mean blood pressure was lower, propofol did not alter blood pressure or hindlimb blood flow, but renal blood flow was reduced by 37(6)%. CONCLUSIONS: Both enalaprilat and dopexamine increased renal blood flow in the control and CHF groups. Enalaprilat caused marked hypotension during anaesthesia in the CHF group. Dopexamine increased mean arterial pressure, heart rate, and hindlimb blood flow during anaesthesia in controls, but not in CHF.