Effect of enteral versus parenteral feeding on hepatic blood flow and steady state propofol pharmacokinetics in ICU patients

Objective: The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU). Design and patients: Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D –3, D –2, and D –1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day D0). All patients received a continuous intravenous infusion of propofol (4.5 mg · kg^–1· h^–1) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance. Results: Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 ± 8 ml · min^–1· kg^–1 (mean ± SD) and 33 ± 10 ml · min^–1· kg^–1 on D-3 and D –1, respectively, as compared to 37 ± 11 ml · min^–1· kg^–1 and 34 ± 8 ml · min^–1· kg^–1 on days D + l and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml · min^–1· kg^–1 and was not affected by switching from parenteral to enteral feeding. Conclusions: Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol. Received: 18 July 1997 Accepted: 1 April 1998     

Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects

Objective Nebulized amikacin may be an attractive option for the treatment of lung infections. Low systemic absorption may permit the use of high doses, leading to high lung concentrations without systemic toxicity. We evaluated the pharmacokinetics and safety of an optimized high-dose amikacin nebulization technique. Design in vitro and in vivo pharmacokinetic study. Patients and participants Six healthy volunteers (age 21–30 years, weight 49–68 kg). Interventions The Aeroneb Pro nebulizer with an Idehaler vertical spacer was evaluated in a bench study. Amikacin was administered intravenously (15 mg/kg) and nebulized (40, 50, and 60 mg/kg) during noninvasive pressure-support ventilation through a mouthpiece. Measurements and results Median (interquartile range) in vitro inhaled fraction was 31% (30–32) and inhalable output was 681 mg/h (630–743). Serum concentrations after nebulization were less than or equal to those after infusion. The area under the serum concentration curve was significantly higher after infusion (138 mg h^–1l^–1, 122–143) than after nebulization (49 mg h^–1l^–1, 39–55, at 40 mg/kg; 63, 53–67 at 50; 66, 50–71, at 60). Peak serum concentration was also higher after infusion: 48 mg/l (45–49) after infusion compared to 8.2 (5.6–8.7), 9.2 (7.6–10.2), and 9.2 (5.2–10.3), respectively. Mean absorption times after nebulization were 2 h 24 min (2,07–2,45), 2 h 21 min (2,07–2,35), and 2 h 5 min (2,00–2,25), respectively. No side effect was observed. Conclusions Nebulization of up to 60 mg/kg amikacin appears to be safe in healthy subjects and associated with lower serum concentrations than a 15 mg/kg infusion. Electronic supplementary material The online version of this article(doi:) contains supplementary material, which is available to authorized users.     

Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison

Objective: To compare the efficacy, safety, and cost of midazolam and propofol in prolonged sedation of critically ill patients. Design: Randomized, prospective study. Setting: General intensive care unit (ICU) in a 1100-bed teaching hospital. Patients: 67 critically ill, mechanically ventilated patients. Interventions: Patients were invasively monitored and mechanically ventilated. A loading dose [midazolam 0.11 ± 0.02 (SEM) mg · kg⁻¹, propofol 1.3 ± 0.2 mg · kg⁻¹] was administered, followed by continuous infusion, titrated to achieve a predetermined sedation score. Sedation was continued as long as clinically indicated. Measurements and results: Mean duration of sedation was 141 and 99 h (NS) for midazolam and propofol, respectively, at mean hourly doses of 0.070 ± 0.003 mg · kg⁻¹ midazolam and 1.80 ± 0.08 mg · kg⁻¹ propofol. Overall, 68 % of propofol patients versus 31 % of midazolam (p<0.001) patients had a > 20 % decrease in systolic blood pressure after the loading dose, and 26 versus 45 % (p<0.01) showed a 25 % decrease in spontaneous minute volume. Propofol required more daily dose adjustments (2.1 ± 0.1 vs 1.4 ± 0.1, p<0.001). Nurserated quality of sedation with midazolam was higher (8.2 ± 0.1 vs 7.3 ± 0.1 on a 10-cm visual analog scale, p<0.001). Resumption of spontaneous respiration was equally rapid. Recovery was faster after propofol (p<0.02), albeit with a higher degree of agitation. Amnesia was evident in all midazolam patients but in only a third of propofol patients. The cost of propofol was 4–5 times higher. Conclusions: Both drugs afforded reliable, safe, and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation. Midazolam depressed respiration, allowed better maintenance of sedation, and yielded complete amnesia at a lower cost, while propofol caused more cardiovascular depression during induction. This study was partially supported by a research grant from F. Hoffmann La Roche, Basle, Switzerland Surgical Intensive Care Unit, Palo Alto Veterans Administration Medical Center and Stanford University School of Medicine, Palo Alto, CA, USA     

Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial

Objective To compare the effects of arginine-vasopressin (AVP) and norepinephrine (NE) on hemodynamic variables, organ dysfunction, and adverse events in early hyperdynamic septic shock.Design and setting Randomized, controlled, open-label trial.Patients and participants Twenty-three patients with early (12 h) hyperdynamic septic shock in two teaching hospitals.Interventions AVP (0.04–0.20 U min^–1, n = 13) as a single agent or NE (0.1–2.8 μg kg^–1 min^–1, n = 10) infusion for 48 h to achieve mean arterial pressure at or above 70 mmHg.Measurements and results Hemodynamic parameters and Sequential Organ Failure Assessment (SOFA) score were measured. AVP and NE equally increased mean arterial pressure over 48 h, but NE was required in 36% of AVP patients at 48 h. Compared to baseline, AVP increased systemic vascular resistance, decreased exposure to NE, decreased cardiac output by decreasing heart rate, increased creatinine clearance, and improved SOFA score. The PrCO₂ – PaCO₂ difference remained stable throughout the study. One AVP patient developed acute coronary syndrome with dose-dependent ECG changes. Three patients in both groups died during their ICU stay.Conclusion In early hyperdynamic septic shock, the administration of high-dose AVP as a single agent fails to increase mean arterial pressure in the first hour but maintains it above 70 mmHg in two-thirds of patients at 48 h. AVP decreases NE exposure, has no effect on the PrCO₂ – PaCO₂ difference, and improves renal function and SOFA score.This work was supported by the Cardiovascular Critical Care research Network FRSQ and departmental funding.     

The effect of dobutamine infusion on splanchnic blood flow and oxygen transport in patients with acute pancreatitis

Objectives: To measure the blood flow distribution and oxygen transport in pancreatitis and to evaluate the regional effects of increased systemic blood flow. Design: Nonrandomized controlled trial. Setting: A general intensive care unit in a tertiary care center. Patients: 10 patients with pancreatitis requiring mechanical ventilation were studied after fluid resuscitation, and for the response to dobutamine, the patients served as their own controls. For the baseline, 11 patients scheduled for elective abdominal surgery served as a control group. Interventions: Systemic and regional hemodynamics were measured after fluid resuscitation to predefined hemodynamic endpoints. In patients with pancreatitis, the measurement was repeated after cardiac output had been increased by at least 25 % by dobutamine. Measurements and results: Hepatosplanchnic blood flow was estimated using regional catheterization and the dye dilution method. In patients with pancreatitis, the cardiac index did not differ from that of the control group (3.9 ± 0.8 vs 4.1 ± 0.7 l · min^–1· m^–2;NS). Accordingly, there was no difference in the splanchnic blood flow (1.1 ± 0.4 vs 1.2 ± 0.5 l · min^–1· m^–2;NS). Systemic and splanchnic oxygen consumption was increased in patients with pancreatitis (179 ± 25 vs 147 ± 27 ml · min^–1· m^–2, p < 0.05 and 68 ± 15 vs 49 ± 19 ml · min^–1· m^–2, p < 0.05), and systemic and splanchnic oxygen extraction was higher (0.34 ± 0.08 vs23 ± 0.05, p < 0.01 and 0.46 ± 0.18 vs 0.28 ± 0.08, p < 0.05, respectively). Dobutamine had inconsistent effects on splanchnic blood flow: in individual patients, splanchnic blood flow even decreased substantially. Conclusions: In severe pancreatitis, oxygen consumption is increased in the splanchnic region; increased splanchnic oxygen demand is not always met by adequately increased blood flow. Increasing the systemic blood flow with dobutamine does not improve perfusion in the splanchnic bed. Received: 24 September 1996 Accepted: 5 May 1997     

Comparison of the haemodynamic effects of nitric oxide synthase inhibition and nitric oxide scavenging in endotoxaemic sheep

Objective: The present study compared the effects of nitric oxide (NO) synthase inhibition and NO scavenging with haemoglobin in endotoxaemic sheep. Design: 12 sheep were instrumented for chronic study. Six sheep received l ^G-nitro-arginine-methylester (l-NAME, 2.5 mg/kg bolus followed by a continuous infusion of 0.5 mg/kg per h), the other 6 sheep received pyridoxalated haemoglobin polyoxyethylene conjugate (PHP, 100 mg/kg bolus followed by a continuous infusion of 20 mg/kg per h). Measurements and results: Haemodynamic and oxygenation parameters were measured in healthy sheep, after infusion of Salmonella typhosa endotoxin (10 ng/kg per min) for 24 h and after infusion of l-NAME or PHP. The infusion of endotoxin resulted in a hypotensive, hyperdynamic circulation. Infusion of l-NAME increased mean arterial pressure (MAP) from 76.1 ± 4.2 mmHg to normal values of 95.8 ± 5.7 mmHg (p < 0.05). PHP increased MAP from 73.0 ± 3.0 to 88.6 ± 4.7 mmHg (p < 0.05). This increase in MAP was associated in the l-NAME group with a more prominent drop in cardiac index (from 10.2 ± 0.4 to 7.0 ± 0.5 l · min^–1· m^–2; p < 0.05) than in the PHP group (from 10.7 ± 0.2 to 9.3 ± 0.6 l · min^–1· m^–2). During the first 90 min of infusion, cardiac index remained lower in the l-NAME group than in the PHP group. The increase in pulmonary vascular resistance was also higher in the l-NAME group. Conclusion: These results suggest, that at the doses used in the experiment, NO scavenging with PHP has smaller effects on cardiac index and pulmonary vascular resistance than NO synthase inhibition with l-NAME. Therefore, the concept of NO scavenging in hyperdynamic sepsis should be further evaluated. Received: 29 January 1997 Accepted: 23 October 1997     

Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration

Objective: To evaluate the pharmocokinetics of intravenous milrinone in patients with severe congestive heart failure during continuous venovenous hemofiltration (CVVH). Design: Prospective study of patients with congestive heart failure admitted to the intensive care unit (ICU). Setting: ICU between September 1997 and August 1999. Patients and methods: Six patients with severe congestive heart failure during CVVH: all patients received a continuous infusion of milrinone of 0.25 μg · kg^{− 1}· min^{− 1}. The hemodynamics and plasma concentration of milrinone were measured before and after the infusion. Pharmacokinetics were analyzed with one-compartment model featuring constant rate infusion. Results: The steady-state concentration (Css) was 845 ± 135 (mean ± SD) ng/ml, and the half-life time (t_1/2) was 20.1 ± 3.3 h. Cardiac index and stroke volume index after the infusion of milrinone increased significantly compared with pre-infusion levels. Other hemodynamic parameters did not change significantly. All patients died within 1 month after the injection of milrinone because of severe forms of arrhythmia, such as ventricular tachycardia and ventricular fibrillation. Conclusions: We found that the mean Css and the mean t_1/2 of milrinone in subjects during CVVH were much higher and longer than those previously reported for subjects with normal renal function. It is therefore essential to adjust the dose or modify the dosing interval of milrinone during renal replacement therapy for patients with severe congestive heart failure. However, further studies are needed to determine the details of pharmacokinetics of milrinone and therapeutic procedures for patients with severe heart failure during CVVH. Received: 1 December 1999 Final revision received: 9 March 2000 Accepted: 11 April 2000     

Patient controlled analgesia for extracorporeal shock wave lithotripsy of gallstones.

Sixty patients undergoing shock wave lithotripsy of gallbladder stones (ESWL) were randomly assigned to receive alfentanil either by infusion controlled by the attending anesthesiologist (standard treatment group, n = 31) or by analgesia controlled by the patient (PCA group, n = 29). Patients using PCA were allowed to self-administer 0.25 mg of alfentanil i.v. every minute as required. Data collected during treatment included the total dose of drug required, transcutaneous pCO2 values, verbal pain and sedation scores, visual analogue scale (VAS) patient satisfaction scores, and the incidence of nausea or vomiting. PCA patients used less alfentanil than the standard treatment group (PCA group: 12.8 micrograms/kg; standard treatment group: 44.3 micrograms/kg; mean values, P = 0.0001), tolerated significantly higher pain intensities and self-administered the narcotic only to moderate levels of pain but not to pronounced analgesia. Standard treatment patients reported lower levels of pain, were more sedated (P less than 0.05) and showed significantly higher transcutaneous pCO2 values. There was a trend towards a lower incidence of nausea or vomiting in PCA patients without reaching statistical significance. No significant difference with regard to patient satisfaction with pain relief could be demonstrated. Self-administered alfentanil during ESWL of gallbladder stones provided adequate analgesia with minimal side effects and high patient satisfaction. ESWL may represent a new and useful indication for PCA.     

Patient-ventilator asynchrony during noninvasive ventilation: the role of expiratory trigger

Objective: Air leaks around the mask are very likely to occur during noninvasive ventilation, in particular when prolonged ventilatory treatment is required. It has been suggested that leaks from the mask may impair the expiratory trigger cycling mechanism when inspiratory pressure support ventilation (PSV) is used. The aim of this study was to compare the short-term effect of two different expiratory cycling mechanisms (time-cycled vs flow-cycled) during noninvasive inspiratory pressure support ventilation (NIPSV) on patient-ventilator synchronisation in severe hypoxemic respiratory failure. Study population: Six patients with acute lung injury (ALI) due to acquired immunodeficiency syndrome (AIDS)-related opportunistic pneumonia were enrolled in the protocol. Intervention: Each subject was first studied during spontaneous breathing with a Venturi oxygen mask (SB) and successively submitted to a randomly assigned 20 ′ conventional flow-cycling (NIPSVfc) or time-cycling inspiratory pressure support ventilation (NIPSVtc). The pre-set parameters were: inspiratory pressure of 10 cm H₂O, PEEP of 5 cm H₂O for the same inspired oxygen fraction as during SB. A tight fit of the mask was avoided in order to facilitate air leaks around the mask. The esophageal pressure time product (PTPes) and tidal swings (ΔPes) were measured to evaluate the patient's respiratory effort. A subjective “comfort score” and the difference between patient and machine respiratory rate [ΔRR(p-v)], calculated on esophageal and airway pressure curves, were used as indices of patient-machine interaction. Results: Air leaks through the mask occurred in five out of six patients. The values of PEEPi (< 1.9 cm H₂0) excluded significant expiratory muscle activity. NIPSVtc significantly reduced PTPes, ΔPes, and ΔRR(p-v) when compared to NIPSVfc [230 ± 41 (SE) vs 376 ± 72 cm H₂O · s · min^–1 ; 8 ± 2 vs 13 ± 2 cm H₂O; 1 ± 1 vs 9 ± 2 br · min^–1; respectively] with a concomitant significant improvement of the “comfort score”. Conclusions: In the presence of air leaks a time-cycled expiratory trigger provides a better patient-machine interaction than a flow-cycled expiratory trigger during NIPSV. Received: 5 June 1998 Accepted: 24 February 1999     

Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients

Objective: To determine the pharmacokinetics and absolute bioavailability of ciprofloxacin in 12 critically ill patients receiving continuous enteral feeding. Design: a prospective, cross-over study. Setting: 12-bed surgical intensive care unit in a University Hospital. Patients: 12 stable critically ill patients on mechanical ventilation and receiving continuous enteral feeding (Normoréal fibres) without diarrhea or excessive residual gastric contents ( < 200 ml/4 h). None had gastro-intestinal disease, renal insufficiency (estimated creatinine clearance ≥ 50 ml/min) or was receiving medications that could interfere with ciprofloxacin absorption or metabolism. Measurements and main results: The study was carried out after the fourth (steady state) b. i. d. intravenous (i. v.) 1-h infusion of 400 mg and the second b. i. d. nasogastric (NG) dose of 750 mg (crushed tablet in suspension). Plasma concentrations were measured by high-performance liquid chromatography. The median (range) peak concentration after i. v. infusion was 4.1 (1.5–7.4) mg/l, and that after NG administration was 2.3 (0.7–5.8) mg/l, occurring 1.25 (0.75–3.33) h after dosing. The median [range] areas under plasma concentration-time curves were similar for the two administration routes (10.3 [3.3–34.6] and 8.4 [3.6–53.4] for i. v. infusion and NG administration, respectively). Ciprofloxacin bioavailability ranges from 31 to 82 % (median, 44 %). Conclusions: In tube-fed critically ill patients, a switch to the NG ciprofloxacin after initial i. v. therapy to simplify the treatment of severe infections is restricted to those for whom serial assessments of ciprofloxacin levels are routinely available. Received: 7 November 1997 Accepted: 8 July 1998     

Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors

Objective To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients.Design and setting Prospective, randomized, crossover study in the surgical ICU of a university hospital.Patients Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m², and estimated creatinine clearance higher than 70 ml/min.Interventions Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies.Measurements and results Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5–18) and was lower (16 µg/ml, 9–31; vs. 73, 53–106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 µg/ml, 6–24; vs. 9, 5–30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC_0–24h; 309 µg/ml per minute, 180–640; vs. 369, 171–955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 µg/ml (96%, 0–100%; vs. 79%, 13–100%), and the ratio of AUC_0–24h to 10 (77, 45–160; vs. 92, 43–239).Conclusions In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success.     

Accuracy and reproducibility of long-term implanted transit-time ultrasound flow probes in dogs

Objective: To assess the accuracy and reproducibility of long-term implanted ultrasound transit-time flow probes for measuring cardiac output. Design: Prospective animal study. Settings: Animal research laboratory in a university department. Animals: Eleven anaesthetised dogs, 24–34 kg. Measurements and results: Flow probes (16–24 mm S-series, Transonic) were implanted around the pulmonary artery for a mean duration of 22 months (range 6–47 months). Comparisons (n = 147) were made between cardiac output thus obtained and that measured by the direct Fick principle using oxygen uptake (Deltatrac II Metabolic Monitor) and the arterial to mixed venous oxygen content difference measured by a galvanic cell (Lex-O₂-Con-TL). Measurements were made either during baseline conditions or during pharmacologically altered cardiac output (range 22–180 ml · kg^–1· min^–1). Regardless of the intervention, the two methods yielded the same results in half of the dogs. In the others, however, cardiac output was underestimated by the flow probes by up to 38 % (probably because of non-perpendicular position of the probe towards the vessel). This difference was constant for the whole range of cardiac output studied and remained constant over the entire observation period for each individual dog, so that a correction factor was used. Thereafter, the mean difference between the two methods was –1.1 ml · kg^–1· min^–1 with a precision (SD) of 14.2 ml · kg^–1· min^–1 for all experiments. Conclusions: After in vivo calibration, ultrasound transit-time flow probes measure cardiac output precisely for several years, regardless of the intervention. Received: 1 October 1999 Final revision received: 6 January 2000 Accepted: 4 February 2000     

Intrathecal baclofen in tetanus: four cases and a review of reported cases

Objective: Spasms in patients with generalized tetanus can be suppressed by a spinal intrathecal infusion of baclofen. We report on four patients and review reported cases treated by this method elsewhere. Design: Intrathecal baclofen infusion was started with a bolus dose (300–500 μg) and continued at a steady rate of 500–1000 μg/day. The dose was increased in daily steps as needed. Results: Doses of baclofen of 500, 1000, or 2000 μg/day were effective in three patients, while 1500 μg/day was insufficient in the fourth. Bradycardia and hypotonia occurred in one patient at a dose of 2000 μg/day but resolved after the dose was reduced to 1500 μg/day. Another patient developed hypotonia when a bolus of 500 μg was given after a steady infusion of 1500 μg/day. Voluntary movements were preserved in one and returned in two patients when sedation, induced by initial diazepam infusions, receded. The fourth patient needed diazepam during most of the treatment with intrathecal baclofen and required mechanical ventilation while being treated with baclofen. Conclusions: A catheter position higher than T11 would possibly have yielded better results. It may be necessary to adapt the dose during the course of the illness. The preservation of respiratory drive and voluntary movements is the main advantage of treating tetanus with intrathecal baclofen. Additionally it helps to reduce sympathetic hyperactivity. Mortality may thereby be reduced. Received: 4 January 1996 Accepted: 5 June 1997     

An analysis of the therapeutic efficacy of protracted infusion of low-dose 5-fluorouracil and cisplatin in advanced gastric cancer

To analyze the clinical efficacy of a protracted infusion of low-dose 5-fluorouracil (5-FU) and cisplatin (CDDP), a phase II study was performed in 36 patients with advanced gastric cancer. The treatment schedule of the low-dose administration of 5-FU and CDDP (FP) was a continuous infusion of 5-FU (250 mg/m²) for 28 consecu-tive days and a drip infusion of CDDP (3.5 mg/m²) for 5 consecutive days, followed by a 2-day interval each week in one cycle. The overall response rate was 47.2%. Of importance, the improvement in quality of life assessed by performance status (PS) and oral intake was 13.9% and 33.3%, respectively. The toxicity in low-dose FP treatment was less than grade 2, including gastrointestinal toxicities and bone marrow suppression, and this was tolerable during the treatment. The median survival time (MST) and 1-year survival rate were 8 months and 36.2%, respectively. In a pharmacokinetic analysis following the protracted infusion of low-dose FP, the plasma concentrations of 5-FU and CDDP were increased to about 120–130 ng/ml and 0.3–0.5 μg/ml on day 21 after the treatment, respectively. The plasma concentrations of 5-FU and CDDP were not significantly different between responders and non-responders. The tumor response to low-dose FP treatment was associated with the induction of apoptotic cell death and with the overexpression of apoptosis-related genes, such as Bax and Bcl-Xs, in cancer cells. These results indicate that the protracted infusion of low-dose FP could be a useful regimen for patients with advanced gastric cancer, in terms of the high response rate and low toxi-city, possibly leading to the prolongation of survival and improvement in the quality of life. Received: June 5, 2000 / Accepted: August 7, 2000     

Postoperative analgesia using a computerised infusion of alfentanil following aortic bifurcation graft surgery

Summary A Psion microcomputer controlled infusion system for alfentanil was assessed for the provision of post-operative analgesia in 14 patients who had undergone aortic bifurcation graft surgery. The system employed a pharmacokinetic model working in real time to deliver any selected target plasma concentration of alfentanil. The alfentanil infusion system was used for a mean time of 39 hours and for 96% of this time, patients were scored as having no pain or only mild pain. Severe pain was recorded for only 0.05% of the study time. The use of a pharmacokinetic delivery system may offer a convenient and simple method of providing postoperative analgesia with alfentanil.Abstract presented at the 6th International Symposium on Computing in Anaesthesia and Intensive Care; Hammamatsu, Japan.     

Effects of fenoldopam on systemic and splanchnic haemodynamics and oxygen delivery/consumption relationship during hyperdynamic ovine endotoxaemia

Objective: To evaluate the use of a selective dopamine-1 agonist (fenoldopam) to provide selective splanchnic vasodilatation during sustained hypotensive endotoxaemia in sheep. Design: Randomised, controlled, experimental study. Setting: Animal research laboratory. Subjects: 12 adult instrumented, midazolam-sedated sheep. Interventions: The animals were randomised to receive a 20-min continuous infusion of dopamine (10 μg · kg^{− 1}· min^{− 1}), fenoldopam (10 μg · kg⁻¹· min^{− 1}) and noradrenaline (1 μg · kg^{− 1}· min^{− 1}) under control conditions and 12 h after endotoxaemia was induced by a continuous infusion of Escherichia coli endotoxin producing a stable hyperdynamic state simulating human septic shock. This drug dosage was selected to produce a 25–30 % increase in cardiac output by all three drugs during control conditions. Measurements and results: Systemic and splanchnic haemodynamic data were continuously obtained and systemic and splanchnic oxygen delivery (DO₂) and consumption (VO₂) were calculated. Hyperdynamic hypotensive endotoxaemia did not modify the splanchnic and renal reduction in DO₂ and the vasoconstrictive reactivity to noradrenaline observed during control conditions. In contrast, endotoxaemia abolished the fenoldopam and dopamine-induced increase in splanchnic DO₂ (especially in the coeliac trunk) observed during control conditions. Conclusions: During sustained hyperdynamic endotoxaemia, the dopaminergic-induced selective increase in coeliac trunk blood flow is abolished, most probably because of an already maximally vasodilated splanchnic circulation which prevented dopamine or fenoldopam to vasodilate this area further. Contrary to common belief, selective dopamine-1 agonist administration under these conditions may therefore not be beneficial to the splanchnic organs, though it improves whole body DO₂ and VO₂. Received: 22 May 1997 Accepted: 13 January 1998     

Postoperative patient-controlled analgesia with alfentanil: analgesic efficacy and minimum effective concentrations

Forty ASA I-III patients recovering from major abdominal or orthopedic operations were investigated in an open clinical study to evaluate analgesic efficacy and threshold plasma concentrations of alfentanil during the early postoperative period using patient-controlled analgesia (PCA) by means of the On-Demand Analgesia Computer. Alfentanil demand dose was 212 micrograms, continuous infusion rate 25 micrograms/hr, hourly maximum dose 1.5 mg/hr; the lockout time was set to 1 min. The duration of PCA was 18.1 +/- 5.2 hr (mean, SD) during which time 23.8 +/- 14.2 demands per patient were recorded, resulting in an average alfentanil consumption of 4.99 +/- 3.03 micrograms/kg/hr. Patient acceptance of PCA was high. Side effects were only of minor intensity and never gave rise to concern. Based on our own earlier PCA experience with other opiate analgesics, alfentanil proved to be about 1/15th as potent an analgesic as fentanyl and about 6-7 times more potent than morphine if both intensity and duration of effect were considered. Minimum effective alfentanil plasma concentration (MEC) varied greatly and could be best described by a lognormal distribution (range 0.6-99.2 ng/mL, median 14.9 ng/mL). Intraindividual MEC variability was consistently lower than intersubject variability (37.0% vs 65.2%).     

Cardiovascular and metabolic response to adrenaline infusion in weight-losing patients with and without cancer

Summary. Fasting is generally accompanied by a decrease in energy metabolism and hormones. On the other hand, indirect evidence has suggested that the response to adrenergic agonists may be maintained or even increased in malnutrition. The present study evaluated whether weight-losing patients with and without cancer have increased plasma concentrations of catecholamines and different responses to intravenously infused adrenaline compared to weight-stable individuals. Eight malnourished cancer and 10 non-cancer patients (11% weight loss) were compared to seven well-nourished and weight-stable patients. Adrenaline was infused i.v. at a rate of 0·005 μg min^-1 kg^-1 body weight during 40 min followed by a 40 min rest period (without infusion) and then a final 40 min period with i.v. adrenaline infusion (0·02 μg min^-1 kg^-1 body weight). Plasma glycerol concentration at fast was higher in weight-losing patients compared to weight-stable individuals. Whole body oxygen uptake, carbon dioxide production, heart rate and plasma concentrations of free fatty acids (FFA) increased while the mean arterial pressure decreased significantly in response to adrenaline infusion at 0·02 μg kg^-1 min^-1 in both weight-losing and weight-stable patients. Adrenaline at 0·005 μg kg^-1 min^-1 increased plasma FFA levels by 19% (P<0·05) in weight-losing patients while no significant alteration was observed in well-nourished patients. Adrenaline infusion at 0·02 μg kg^-1 min^-1 decreased the mean arterial blood pressure and stimulated respiratory gas exchange and heart rate significantly more in weight-losing than in weight-stable patients. The slopes for oxygen uptake, carbon dioxide production, heart rate, plasma FFA and plasma glycerol vs. plasma adrenaline and noradrenaline were all significantly steeper (P<0·05–0·01) in malnourished patients than in well-nourished controls. The present study suggests an increased sensitivity to adrenaline in weight-losing patients compared to matched controls with normal nutritional state and stable weight.     

Patient-ventilator asynchrony during assisted mechanical ventilation

Objective The incidence, pathophysiology, and consequences of patient-ventilator asynchrony are poorly known. We assessed the incidence of patient-ventilator asynchrony during assisted mechanical ventilation and we identified associated factors.Methods Sixty-two consecutive patients requiring mechanical ventilation for more than 24 h were included prospectively as soon as they triggered all ventilator breaths: assist-control ventilation (ACV) in 11 and pressure-support ventilation (PSV) in 51.Measurements Gross asynchrony detected visually on 30-min recordings of flow and airway pressure was quantified using an asynchrony index.Results Fifteen patients (24%) had an asynchrony index greater than 10% of respiratory efforts. Ineffective triggering and double-triggering were the two main asynchrony patterns. Asynchrony existed during both ACV and PSV, with a median number of episodes per patient of 72 (range 13–215) vs. 16 (4–47) in 30 min, respectively (p = 0.04). Double-triggering was more common during ACV than during PSV, but no difference was found for ineffective triggering. Ineffective triggering was associated with a less sensitive inspiratory trigger, higher level of pressure support (15 cmH₂O, IQR 12–16, vs. 17.5, IQR 16–20), higher tidal volume, and higher pH. A high incidence of asynchrony was also associated with a longer duration of mechanical ventilation (7.5 days, IQR 3–20, vs. 25.5, IQR 9.5–42.5).Conclusions One-fourth of patients exhibit a high incidence of asynchrony during assisted ventilation. Such a high incidence is associated with a prolonged duration of mechanical ventilation. Patients with frequent ineffective triggering may receive excessive levels of ventilatory support.B.C. is supported by the Instituto de Salud Carlos III (expedient CM04/00096, Ministerio de Sanidad) and the Instituto de Recerca Hospital de la Santa Creu i Sant Pau     

A Study of the Caeruloplasmin Concentrations found in 75 Patients with Wilson's disease, their Kinships and Various Control Groups

We have studied the concentration of the blue copper proteincaeruloplasmin in the serum of 195 young, normal adults, 147patients with neurological diseases and 78 patients with subacuteor chronic liver disease. These have served as controls for75 patients with Wilson's disease before treatment was startedand during follow up for periods extending up to 20 years. Wehave also studied 444 members of the kinships. Caeruloplasmin has been estimated by an enzyme assay using dimethylpphenylenediamine as substrate and, when necessary, we havechecked the values so obtained by a new immunoenzymatic methodand also by determining serum copper. The mean caeruloplasmin concentration in 83 normal males was333.3 mg/l (S.D. 60·7). In 112 females it was 410·1mg/l (S.D. 130·2). These 112 females were shown to comprisetwo populations, the larger (n 82) had a mean of 365·6mg/l (S.D. 92·8) and the smaller a mean of 606·6mg/l (S.D. 157·5). The former figure is taken as thenormal. The mean value for 75 patients with Wilson's disease was 63·3mg/l (S.D. 87·6) before treatment; after treatment itfell to 45·0 mg/l (S.D. 79·8). However in 11 ofthese patients the mean caeruloplasmin concentration rose, aftertreatment, from 108·5 mg/l (S.D. 27·7) to 168·7mg/l (S.D. 33·6). The mean values for the hepatic and neurological control casesclosely approximated to the mean values for the sex matchednormals. However both these groups showed a wide range of variationwith many patients falling outside the normal 95 per cent confidencelimits. Low caeruloplasmin values in patients with either hepaticor neurological disease may lead to considerable diagnosticconfusion. The mean caeruloplasmin concentration for the obligate heterozygoteswas significantly depressed in bath males and females but only36 out of 160 fell below the normal 95 per cent confidence limit.The percentage of detectable heterozygotes fell, as did thecalculated gene frequency, in more distant relatives. When there was a marked and unexpected discrepancy between theserum caeruloplasmin concentration as estimated by the enzymaticassay and the serum copper concentration the caeruloplasminvalue was checked by the immunoenzymatic method. In patientswith liver disease and in those with treated Wilson's diseasethe immunoenzymatic method was found to be in good agreementwith the serum copper concentration. This suggests that thereis, in some patients, an inhibitor present which interfereswith the enzymatic assay. The finding of a low caeruloplasminlevel in the serum of a patient with undiagnosed hepatic orneurological disease by an enzymatic method cannot be takenas evidence of absence of this protein unless it is confirmedby an immunological technique.