Induction of immunosuppression by microemulsion cyclosporine in liver transplantation.

Twenty-five liver transplant patients were administered liquid microemulsion cyclosporine (Neoral, 5 mg/kg b.i.d.) via a nasogastric tube until they could take oral medication. The first dose was given within 6 hr after surgery. Adequate trough levels of cyclosporine were obtained from the first postoperative day. The total exposure to the drug was low on the first postoperative day, but a significantly improved pharmacokinetic profile with a high maximal concentration and a low time to maximal concentration was found from the second postoperative day. The absorption from Neoral increased during the first week. After 1 week, a low within-patient variation coefficient for dose-adjusted cyclosporine trough levels was found (17%). The between-patient variation coefficient was low during the whole postoperative period (31%). We conclude that in liver transplant patients adequate immunosuppressant blood levels of cyclosporine can be obtained in the immediate postoperative period using Neoral without the need to go to the intravenous form of the drug.

Hemodynamic effects of alcohol at rest and during upright exercise in coronary artery disease.

The hemodynamic effects of acute alcohol intoxication were studied at rest and during upright exercise in 28 patients with coronary artery disease by right-sided heart catheterization and radionuclide cardiography. The mean arterial blood pressure at rest was reduced by 5% and the left ventricular ejection fraction at rest decreased 2% because of end-systolic dilation during intoxication (serum ethanol 21 mmol/liter). No changes were observed in heart rate, stroke volume, pulmonary artery pressure, pulmonary artery wedge pressure or total peripheral resistance. No significant changes occurred in plasma catecholamines, and no changes occurred in any variable during mild exercise corresponding to a 30 to 40% heart rate increase. Thus, alcohol ingested in moderate doses causes slight impairment of left ventricular emptying and a reduction in the arterial blood pressure at rest in patients with coronary artery disease. A mild exercise load can be tolerated during alcohol intoxication without hemodynamic changes.

Reversal of 'refractory septic shock' by infusion of amrinone and angiotensin II in an anthracycline-treated patient.

A 53-year-old granulocytopenic woman with malignant lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, including doxorubicin (Adriamycin) and autologues bone marrow transplantation, presented in the clinical state of "refractory septic shock" caused by Escherichia coli. Despite inotropic treatment with dopamine, dobutamine, and norepinephrine infusion, the patient's condition did not improve, but during treatment with amrinone and angiotensin II infusion, the septic shock was reversed. The patient was monitored with a pulmonary artery catheter and underwent repeated echocardiographic examinations. Antibiotic treatment with thienamycin and floxacillin was given. The initial reduction in cardiac performance in this patient may be explained by a state of true down-regulation of the myocardial beta-receptors. Apparently these beta-receptors were bypassed via the enzymatic action of amrinone upon cyclic monoadenosine phosphate. This is, to our knowledge, the first doxorubicin-treated patient with septic shock refractory to conventional vasopressor therapy whose condition reversed by inotropic treatment with amrinone and angiotensin II. This treatment may prove to be an alternative choice for patients developing "refractory septic shock" unresponsive to treatment with norepinephrine, dobutamine, and dopamine.

Ventilation-perfusion distributions and central hemodynamics in chronic obstructive pulmonary disease. Effects of terbutaline administration.

We studied the effects of intravenous terbutaline on VA/Q distributions and central hemodynamics in 11 patients with mixed-type COPD. Terbutaline caused an increase in VA/Q inequality in patients having PaO2 values greater than 60 mm Hg which resulted in a moderate fall in the PaO2. Patients with PaO2 values less than 60 mm Hg, the highest mean PAPs and the poorest spirometric performances demonstrated no significant changes in VA/Q distributions or PaO2 after terbutaline. Cardiac output increased 40 to 60 percent in all patients after terbutaline with an increase in tissue oxygen delivery. Mean PAP did not change in any patient after terbutaline and pulmonary vasodilatation was indicated by a decrease of calculated static PVR. The decrease of PaO2 after terbutaline in COPD is related to a further deterioration of existing VA/Q relationships. The cause of these effects and lack of such responses in patients with more advanced disease are discussed.

Theophylline and ethylenediamine pharmacokinetics following administration of aminophylline to septic patients with multiorgan failure.

The pharmacokinetics of theophylline and ethylenediamine were examined in 6 patients with septicaemia and multiorgan failure (MOF). The patients received a bolus injection of 4 mg/kg aminophylline. Aminophylline is the ethylenediamine salt of theophylline. The clearance of theophylline was reduced in all our patients ranging from 10-66% of the value obtained in healthy volunteers. The median t 1/2 beta was 18.8 h (range 5.8-25.5) compared to a normal value of 6 h. The median clearance of ethylenediamine was 54% of the normal value, while the peripheral volume of distribution was increased to 650%. Due to this t 1/2 beta was 2.3 (2.0-2.7) h, which is 5 times the normal value of 0.55 h. There was no correlation between clearance of theophylline and ethylenediamine. As theophylline has a narrow therapeutic range, routine monitoring with measurements of serum theophylline is mandatory in patients with MOF.

Trauma stimulates the synthesis of Gc-globulin.

OBJECTIVE: Actin is the dominating intracellular protein and is released to the circulation after tissue injury. Gc-globulin is one of the plasma proteins responsible for removal of actin from the circulation. Recent studies have shown that the level of Gc-globulin is reduced shortly after trauma. Serial changes in Gc-globulin after severe injury have not been studied so far and could provide additional information about the role of Gc-globulin in the pathophysiological response to trauma. DESIGN: Prospective, observational. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Thirty-eight patients were included in the study: 12 women and 26 men with a median age of 38 years (range 19-86) and a median Injury Severity Score (ISS) of 18 (range 6-45). Seven patients died, on day 5, 8, 8, 10, 10, 13 and 21, respectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The serum concentration of Gc-globulin (Gctotal) and the percentage of Gc-globulin bound to actin (Gc%complexed) were measured daily for 1 week using rocket immunoelectrophoresis. Concentrations of free Gc-globulin (Gcfree) and Gc-globulin bound to actin (Gcbound) were calculated from these analytical results. The concentration of Gctotal and Gccomplexed correlated significantly (r = -0.99, p < 0.001) throughout the time period. After day 3 levels of Gc%complexed normalised, whereas levels of Gctotal continued to increase above control values. The concentrations of Gctotal and Gcfree were significantly lower in non-survivors compared to survivors; p = 0.005 and p = 0.03, respectively. This was combined with an inverse correlation of Gcbound between these two groups (r = -0.73; p = 0.04). CONCLUSIONS: Severe injury results in a prolonged load on the extracellular actin scavenger system; more pronounced in patients who do not survive. Gc-globulin displays characteristics of an acute phase reactant, with supra-normal serum levels 1 week after severe injury. Serial measurements of Gc-globulin after trauma could prove to be a method of early identification of patients with increased risk of mortality.

First passage radionuclide cardiography for determination of cardiac output: evaluation of an improved method.

A noninvasive method for determination of cardiac output by aid of first passage radionuclide cardiography is presented. As opposed to most other scintigraphic methods, a forward blood flow is measured, even in patients with valvar incompetence. In addition, the technique allows measurement of cardiac output in the presence of cardiac arrhythmias. No geometrical assumptions, corrections for radiation attenuation, loss of tracer, or empirical correction factors due to extracardiac radioactivity are required. We have evaluated the method in 19 patients with various heart diseases by comparison of the radionuclide cardiac outputs with those derived from the thermodilution technique performed simultaneously. Eight patients had valvar incompetence and 2 had cardiac arrhythmias. The mean radionuclide and thermodilution cardiac output values were 5.03 l/min (SD 1.21) and 5.18 l/min (SD 1.09), respectively. The 95% confidence interval for the bias was -0.40 to 0.10 l/min, and correlation analysis demonstrated an excellent correlation between results obtained with the two methods, r = 0.91 (P less than 0.001). This study shows that the improved gamma camera method represents a valid noninvasive technique for determination of cardiac output.

[Mortality of severe asthma in Danish intensive care units in 1988. A questionnaire study]. / Forekomst af død i forbindelse med akut svaer asthma på danske intensivafdelinger i 1988.

The mortality due to asthma is gradually increasing in Denmark. In 1988, 209 patients died from asthma. Of these patients, 108 were under 70 years. Information about patients who died from asthma in Danish intensive care units (ICU) in 1988 was obtained retrospectively by questionnaires. 99% of all the ICU's replied. Eleven of the abovementioned patients died in an ICU because of inadequate oxygenation or ventilation. In cases where an anaesthesiologist was called to a patient with acute severe asthma, who subsequently died from the disease, the majority had developed cardiac arrest, when the anaesthesiologist arrived. The use of objective monitoring of the degree of pulmonary obstruction by use of peak flow measurements and series of arterial blood gas values is recommended. Hypoxemia, the main risk factor, might be revealed in time by measurements of pulseoximetry. If the arterial PCO2 is increasing, the patient should be monitored in an ICU in view of oxygenation and ventilation, and possibly mechanical ventilation.

[Rational hemotherapy. Indications, complications and practical performance]. / Rationel haemoterapi. Indikationer, komplikationer og praktisk udførelse.

Employment of allogenic blood products involves the risk of a series of complications in the recipient: transfusion-transmitted disease, immune suppression, immunological transfusion reactions and coagulopathy. Hepatitis C is the most common transfusion-transmitted infection with a post-transfusion incidence of 2-4%. Transfusion-transmitted AIDS plays a quantitatively lesser role but the course of the condition is frequently fatal. The duration of the period during which a HIV-sero-negative individual is potentially infectious is uncertain. After blood transfusion, the immune apparatus is suppressed, probably on account of the leukocyte content of the blood transfusion. These disturbances in immune function increase the risk of infection and possibly the frequency of recurrence of cancer after operative treatment of a series of neoplastic diseases. Coagulopathy after blood transfusion may be related primarily to the number of transfusions and can be counteracted by administration of the relevant coagulation factors. Rational hemotherapy aims at minimizing these transfusion-related complications by restricting the indications for blood transfusion, blood component therapy, peroperative normovolaemic haemodilution, preoperative deposition of autologous blood and/or peroperative collection of blood and re-infusion. Employing rational hemotherapy, it becomes possible to reduce the need for transfusion by 20-90% and hence the morbidity and the mortality connected with blood transfusion.

[Translocation and multiple organ failure]. / Translokation og multiorgansvigt.

A review of bacterial translocation and multiple organ failure (MOF) is presented. Splanchnic ischaemia plays a central role in the development of MOF, but the exact mechanism of translocation is unclear. The concentration of endotoxins and bacteria in the gut is high. The critically ill patient is often treated with antibiotics with a broad antibacterial spectrum and overgrowth of Gram negative bacteria will take place in the gut favouring the translocation phenomenon. The regime of selective gut decontamination is discussed. Regional and systemic oxygen kinetics together with metabolic markers are important in detecting splanchnic ischaemia. Hepatic vein catheterisation and gastric mucosa pHi are discussed. The regional inflammation in the gut is often initiated by endotoxins, which stimulate the cytokines IL-1, IL-6 and TNF. Another important factor that can accentuate inflammation of the gut is reperfusion injury. A proposal for treatment of splanchnic ischaemia and translocation is discussed i.e.: optimizing central haemodynamic parameters, optimizing the regional microcirculation, treatment with antibodies to endotoxins, gut decontamination and early enteral nutrition. When splanchnic hypoperfusion is detected it cannot be ignored. It may be possible to correct the hypoperfusion with early gastrointestinal resuscitation and to thereby reduce the duration and mortality of MOF. The above mentioned suggestions are all very demanding of resources, but have to be considered in gut directed therapy.

[Mortality after administration of human albumin to critically ill patients with hypovolemia. An analysis of a systematic Cochrane review]. / Mortalitet efter humant albumin hos kritisk syge patienter med hypovolaemi. En analyse af et systematisk Cochrane-review.

A systematic Cochrane review strongly suggested that the administration of human albumin to critically ill patients with hypovolaemia increases mortality. This review has been widely criticised and the aim of the present paper was to analyse the original studies with regard to 1) the randomisation procedure, 2) the blinding procedure, 3) the indication of treatment, 4) whether treatment was clearly defined and consistent, 5) how normovolaemia was defined, and 6) the length of the follow-up period. None of the twelve studies analysed fulfilled common criteria in relation to evidence-based medicine. Consequently, there is no scientific evidence to support the conclusion that human albumin administered to critically ill patients with hypovolaemia increases the mortality. Thus, the validity and quality control of systematic Cochrane reviews may be questioned.

[Paracetamol poisoning]. / Paracetamolforgiftning.

Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that paracetamol in therapeutic doses had fewer and more acceptable side-effects than other analgetic drugs such as acetylsalicylic acid and NSAID-drugs. However, in toxic concentrations, paracetamol is more life-threatening. The toxic effects of paracetamol most often occur in the liver and kidneys. Phosphate and lactate turn-over can also be impaired. Paracetamol poisoning can induce temporary liver dysfunction or even irreversible liver failure with liver transplantation as the only therapeutic possibility. Chronic alcoholics are especially at risk, as liver damage may occur following paracetamol even in recommended doses. When intoxication with paracetamol is presumed, administration of N-acetylcysteine is vital. N-acetylcysteine therapy should be initiated not later than 15 hours after paracetamol intake. Moreover, the antitoxic effect has been observed even when N-acetylcysteine therapy is initiated 24-36 hours after presumed paracetamol intake. Measures of preventing further absorbtion of paracetamol from the gastrointestinal tract should be taken. Activated charcoal should be given if less than two hours have passed since paracetamol intake. Between two and four hours following paracetamol intake gastric lavage should be performed. During the last 10 years the incidence of paracetamol self-poisoning has increased, but death following paracetamol poisoning is relatively constant at around nine per year in Denmark. It is suggested that the incidence of serious cases of paracetamol poisoning could be reduced by simple measures. Special attention should be paid to the risk-group of chronic alcoholics.

[Prostacyclin inhalation in pulmonary failure following smoke inhalation]. / Prostacyklininhalation ved lungesvigt efter røgforgiftning.

A 42 year-old man was admitted to hospital due to smoke inhalation. Thirty-three hours after admission arterial oxygen saturation was 80-90% with FiO2 = 1.0. Inhalation with prostacyclin was commenced with a dose rate of 7 ng/kg/min with an immediate effect, i.e. SATaO2 increased to 100%. Prostacyclin was terminated after 24 hours, when FiO2 was reduced to 0.5. It is concluded that prostacyclin inhalation therapy may have effect in patients following pulmonary smoke injury.

[Nitrogen oxide inhalation in acute pulmonary failure]. / Nitrogenoxidinhalation ved akut lungesvigt.

Two cases of adult respiratory distress syndrome (ARDS) treated successfully with nitric oxide (NO) inhalation are described. One patient had severe sepsis and the other had trauma induced ARDS. The slow entry criteria for extracorporeal membrane oxygenation (ECMO) was fulfilled in both cases. NO inhalation substantially improved oxygenation, reduced pulmonary arterial pressure and peak inspiratory pressure. Treatment with NO inhalation was without side effects and easy to administer through the ventilator. Both patients survived without sequelae. We suggest that inhalation with NO should be tried before ECMO treatment is considered in severe ARDS.

[Liver transplantation in Denmark. First-year experiences]. / Levertransplantation i Danmark. Det første års erfaringer.

During the first 12 months of the Danish Liver Transplantation program, which began in October 1990, 21 transplantations were performed in 11 women, six men and three children. One patient required a retransplant. Fourteen operations were performed electively and six patients were transplanted for acute and subacute fulminant liver failure and coma, two patients had reduced size livers because of large donor liver. There were no peroperative deaths. One of the elective patients died after three weeks from multiorgan failure and sepsis. Two of the emergency patients died after 20 and 22 days. One from graft dysfunction due to stenosis of the celiac trunk and the other of exudative pericarditis. One patient died from chronic rejection and CMV-infection after seven months. Complications were relatively few and acute rejection occurred in 40% of the patients. Fifteen patients are discharged with normal liver function and 11 of these were back at work, school or previous functions in the home. It is concluded that these results are comparable to the best results from other centres but that 21 transplants in 12 months must be a minimum activity.