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  • 1
    ISSN: 1432-055X
    Keywords: Schlüsselwörter SIRS ; Sepsis ; MODS ; Hämodynamik ; Interleukin-2 ; Interferon-α ; Key words SIRS ; Sepsis ; MODS ; Haemodynamics ; Interleukin-2 ; Interferon-alpha
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract Human recombinant interleukin 2 (IL-2), alone or in combination with other cytokines, is currently under investigation for the immunotherapy of metastatic tumours. Objective responses of 20%–35% have been reported in patients with disseminated melanoma and renal cell carcinoma who received high-dose intravenous IL-2 in combination with interferon-α (IFNα). However, treatment with IL-2 is complicated by a syndrome of life-threatening adverse reactions such as disseminated vascular leakage, fluid retention, severe hypotension, and (reversible) multiple organ dysfunction (MODS). A systemic inflammatory reaction (SIRS)/sepsis sepsis-like haemodynamic pattern has been described in patients after IL-2 bolus application alone. Our purpose was to study the haemodynamic changes in patients treated with high-dose IL-2 administered as a constant infusion and in combination with IFNα. Patients and Methods. Haemodynamic variables were obtained during therapy courses of 11 patients (aged 48 to 71 years, median 61) with metastatic renal cell carcinoma receiving immunotherapy with IL-2/IFNα. Therapy consisted in (Fig. 1): IFNα 10·1010 IU/m2 body surface area (BSA) once daily on days 1–5 i.m. on a regular ward, followed by IL-2 as a constant infusion of 18·106 IU/m2 BSA on days 6–11 in an intensive care unit (ICU). Haemodynamics were first measured after 5 days of IFNα application and transfer to the ICU on day 6, a further 24 h after the beginning of IL-2 infusion (day 7), and at the end of the therapy course (days 10 and 11). Mean arterial pressure (MAP) was measured noninvasively using an oscillometric device (Dinamap®, Critikon). Mixed-venous oxygen saturation (sv¯¯ O2) was measured using an CO-oxymeter (OSM 3®, Radiometer) and peripheral arterial oxygen saturation (psaO2) was recorded continuously with a pulse oximeter (Oxyshuttle®, Critikon). In case of haemodynamic instability, stabilisation had priority over invasive haemodynamic measurements, so that nadir values of blood pressure (BP) did not influence mean MAP and are reported separately. Lactate values and criteria for SIRS were obtained before and during IL-2 infusion. Lactate measurements were performed using an enzymatic essay (Abbot FLx®). The mean effect size of the haemodynamic values, SIRS criteria, and lactate concentrations during IL-2 infusion (days 6–11) were calculated, and 95% confidence intervals for the effect sizes are indicated in Table 1. Results. After their daily i.m. injections of IFNα, patients had short episodes of fever and tachycardia without significant drops in BP. A few hours after transfer to the ICU and continuous infusion of IL-2, they developed a syndrome of fever, tachycardia and tachypnoea. The haemodynamic values after 5 days of IFNα therapy remained in the normal range, whereas those during IL-2 infusion strongly resembled SIRS and sepsis, with a decrease in MAP (98 to 82 mm Hg) and systemic vascular resistance (SVR, 1477 to 805 dyn·s·cm−5) and an increase in cardiac output (cardiac index 2.8 to 4.3 l·min−1·m−2) (Fig. 2, Table 1). MAP often had to be stabilised with colloids during the last 48 h of therapy; 5 patients had nadir values below 60 mm Hg, or 30% below basic values in hypertensive patients. Catecholamine therapy became mandatory in 1 patient and therapy had to be discontinued. Surprisingly, some patients already had elevated plasma lactate concentrations after IFNα therapy. During IL-2 infusion mean plasma lactate levels increased from 2.3 to 3.2 mmol·l−1 and all patients had lactate concentrations above 2.0 mmol·l−1 at the end of therapy (Fig. 3, Table 1). During the last 48 to 72 h of IL-2 infusion, patients suffered from MODS with altered mental state (7 patients), oligoanuria (all patients), cardiac dysrhythmias (4 patients), congestive heart failure (1 patient, which led to a second case of therapy interruption), elevated bilirubin (4 patients), and pulmonary dysfunction. In 9 patients supplementary oxygen was necessary when psaO2 fell below 92%. Chest X-rays showed signs of pulmonary interstitial oedema. All patients developed significant generalised oedema due to a vascular leak syndrome, with fluid retention and weight gains of 6.3% during IL-2 infusion (Tables 1 and 2). Leukocyte counts dropped to 3670 μl−1 after 5 days of IFNα injection and rose to 9970 μl−1 at the and of IL-2 infusion. After discontinuation of IL-2 (day 11) the body temperature, heart rate, BP, and criteria of impaired organ function rapidly returned to the normal range, but leukocyte counts rose to 15360-μl−1 on day 12 (Table 1). Conclusion. High-dose IL-2 administered as a constant infusion and in combination with IFNα results in similar haemodynamic changes to those seen during high-dose IL-2 bolus application alone. The observed haemodynamic pattern strongly resembles SIRS and sepsis. MODS, fluid retention, and increases in plasma lactate indicate microcircular disorders. Elevated levels of sepsis mediators such as tumor necrosis factor and interleukin-1, activation of the complement cascade, activated neutrophil granulocytes and endothelial cells have been reported in patients receiving high-dose IL-2 bolus treatment. Our results and data of other investigators lead us to conclude that not only the (macro)haemodynamic pattern of IL-2/IFNα therapy, but also its pathogenetic pathways parallel SIRS and sepsis. IL-2/IFNα immunotherapy may therefore be used as a clinical “model” for sepsis research.
    Notes: Zusammenfassung Die Zytokine Interleukin-2 (IL-2) und Interferon-α (IFNα) werden zur Immuntherapie metastasierender Malignome eingesetzt. In der vorliegenden Studie wurde bei 11 Patienten mit Nierenzellkarzinom die Hämodynamik während einer fünftägigen, hochdosierten, kontinuierlichen IL-2 Infusion in Kombination mit der i.m.-Applikation von IFNα mit einem Pulmonalarterienkatheter invasiv überwacht. Die Patienten entwickelten wenige Stunden nach Beginn der kontinuierlichen IL-2 Infusion ein Syndrom aus Fieber, Tachykardie, Tachypnoe und im weiteren Verlauf Leukozytose (SIRS). Die Hämodynamik ähnelte den hyperdynamen Kreislaufverhältnissen bei SIRS und Sepsis. Hinweise auf eine Mikrozirkulationsstörung ergaben sich aus einem Anstieg der Plasma-Laktatkonzentrationen, muliplen Organfunktionsstörungen und einer erheblichen interstitiellen Flüssigkeitsretention aufgrund eines „vascular leak“-Syndroms. Hieraus und aus der von anderen Autoren beschriebenen Aktivierung von Sepsis-typischen Mediatoren unter IL-2-Applikation schließen wir auf eine weitgehende Parallelität in der Pathogenese von hochdosierter IL-2-/IFNα Therapie und SIRS bzw. Sepsis. Die IL-2-/IFNα Therapie bietet sich daher als klinisches Modell der Sepsis an.
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  • 2
    ISSN: 1432-055X
    Keywords: Schlüsselwörter Pulsoxymetrie ; Methämoglobin ; Prilocain ; Plexusanästhesie ; Key words Pulsoximetry ; Methaemoglobinaemia ; Prilocaine ; Plexus block
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract During the last 15 years pulse oximetry has become a widely accepted method of monitoring during general and local anaesthesia. Pulse oximeters measuring with two wavelengths are considerably affected by dyshaemoglobin. At concentrations up to 30%, CO-Hb cannot be distinguished from O2-Hb. Met-Hb, even in low concentrations, leads to a constant error of measurement; some authors recommended exploiting this for estimation of the Met-Hb concentration. To prove the aim of the present study was to test whether this error in measurement can be defined with one formula for different pulse oximeters. Patients and methods. In a prospective, randomized, double-blind study, 171 non-smoking patients with healthy lungs (ASA 1–3) who had received a plexus block for hand surgery were investigated. After premedication with 3.75–15 mg medazolam p.o. each patient received a total of 6 lO2 via a Hudson mask during the investigation. After 10 min the following pulse oximeters were put on the index finger: (1) Ohmeda BIOX 3700e, (2) Critikon Oxyshuttle, (3) Nellcor N 180. Simultaneously a venous blood sample was taken and analysed immediately with a Radiometer OSM3. The procedure was repeated 15, 30, 60 and 120 min after the plexus block. In 41 patients the plexus block was carried out with lidocaine (6 mg/kg body weight) and in 130 patients, with prilocaine (7 mg/kg body weight). Results. There were no significant differences in age, sex and risk groups between the lidocaine and the prilocaine group. In the lidocaine group we were able to show that hyperoxic conditions can be maintained for 2 h with the method described. In the lidocaine group none of the pulse oximeters showed a psO2 less than 99%. Our results show significant differences between the three pulse oximeters. Therefore, in contrast to the convention followed in the literatur, the relation between Met-Hb and psO2 under hyperoxic conditions must be described with different formulas for each pulse oximeter as follows: (1) Ohmeda BIOX 3700e: Met-Hb=(101-psO2)·0.6 (r=0.94); (2) Critikon Oxyshuttle: Met-Hb=(101-psO2)·0.7 (r=0.83); (3) Nellcor N 180: Met-Hb=(101-psO2) ·0.9 (r=0.92). Discussion. Our results show that it is not possible to describe the connection between Met-Hb and psO2 for all pulse oximeters with only one formula, but it is possible to set up different formulas with good correlations for each of the three pulse oximeters. The reasons for the different sensitivity are probably the different algorithms used by the manufacturers. In spite of the good correlations we can not recommend Met-Hb estimation by pulse oximetry measurement with two wavelengths, because the distinction of hypoxia and Met-Hb its not possible when hyperoxic conditions are not stable as they were in our controlled study. A low psO2 measured in patients with normal arterial blood gases can be an indication of Met-Hb, but the exact measurement of dyshaemoglobin is only possibly by using a co-oximeter.
    Notes: Zusammenfassung In einer prospektiven, randomisierten Doppelblindstudie wurde die Beeinflussung der Meßgenauigkeit dreier verschiedener Pulsoxymeter durch Methämoglobin untersucht. 171 Patienten, die sich einem handchirurgischen Eingriff in Plexusanästhesie unterzogen, erhielten während des gesamten Untersuchungszeitraums 6 l O 2 über eine Hudson-Maske. Bei 41 Patienten wurde die Plexusblockade mit Lidocain und bei 130 Patienten mit Prilocain durchgeführt. Vor Anlage der Plexusanästhesie sowie 15, 30, 60 und 120 min danach wurden folgende Pulsoxymeter angelegt: 1. Ohmeda BIOX 3700e, 2. Critikon Oxyshuttle, 3. Nellcor Pulsoxymeter N180. Gleichzeitig wurde eine periphervenöse Blutprobe auf Dyshämoglobine untersucht. Mit der Lidocaingruppe konnte gezeigt werden, daß es mit der beschriebenen Methodik möglich ist hyperoxische Bedingungen aufrechtzuerhalten. In der Prilocaingruppe ergaben sich erhebliche psO 2 -Abfälle, die sich zwischen den drei Pulsoxymetern signifikant unterschieden. Ein Zusammenhang zwischen Met-Hb und psO 2 -Abfall für alle Pulsoxymeter gleich konnte nicht gefunden werden, sondern müßte individuell wie folgt definiert werden: 1. Ohmeda BIOX 3700e: Met-Hb= (101-psO 2 )·0,6 (r=0,94), 2. Critikon Oxyshuttle: Met-Hb= (101-psO 2 )·0,7 (r=0,83), 3. Nellcor Pulsoxymeter N180: Met-Hb=(101-psO 2 )· 0,9 (r=0,92). Obwohl dieser Meßfehler für jeden Gerätetyp gut reproduzierbar ist, halten wir es dennoch nicht für zulässig, aus dem Abfall der psO 2 auf das Ausmaß der Methämoglobinämie zu schließen. Die Bestimmung von Dyshämoglobinen muß daher immer in vitro, d.h. mit einem Co-Oxymeter erfolgen.
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  • 3
    ISSN: 1432-055X
    Keywords: Schlüsselwörter Prilocain ; Thiopental ; Methämoglobin ; Plexusblockade ; o-Toluidin ; Key words Prilocaine ; Thiopental ; Methaemoglobin ; Plexus block ; o-Toluidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract Although the local anaesthetic prilocaine is less cardio- and neurotoxic than lidocaine, it bears the disadvantage of the formation of methaemoglobin by the metabolite o-toluidine. Prilocaine is often successfully used, especially for the blockade of the brachial plexus, but one problem of this technique is the failure rate of 3–10%, with the consequence that general anaesthesia after administration of prilocaine is frequently necessary. Methaemoglobin formation after prilocaine administration has been thoroughly investigated. Nothing is known, however, about the interactions of prilocaine and the induction of general anaesthesia relative to methaemoglobinaemia. Case report. Two patients (47 and 52 years old) each received 500 mg prilocaine for the axillary blockade of the brachial plexus. After 100 and 120 min respectively, it was necessary to induce general anaesthesia, for which 350 mg thiopental, 1 mg alfentanil and 45 mg atracurium were used. At 15 min after induction, methaemoglobin levels had increased by 70% and 25%, respectively, from baseline before general anaesthesia. Conclusion. It is not possible to explain these findings conclusively with the present method. To check whether displacement of o-toluidine from the plasma protein binding might have been responsible, we provoked methaemoglobinaemia in vitro by adding o-toluidine to heparinised blood.Thiopeontal was then added to half the specimens. Subsequently, methaemoglobin levels were lower in the samples with thiopental. Three explanations seem plausible: (1) Thiopental blocks the hydroxylase of the endoplasmic reticulum, with the result that o-toluidine cannot be further metabolised, leading to higher o-toluidine and methaemoglobin levels. (2) Isoflurane improves the blood supply of the liver. This results in increased metabolism of prilocaine to o-toluidine. (3) The results were accidental. To clarify which of these explanations is correct, further investigation is necessary.
    Notes: Zusammenfassung Es wird über zwei Patienten berichtet, bei denen es nach Anlage einer axillären Plexusblockade mit Prilocain zunächst zu dem bekannten leichten Anstieg des Dyshämoglobins Met-Hb kam. Nach 100 bzw. 120 min mußte bei beiden Patienten eine Allgemeinanästhesie mit Thiopental, Alfentanil und Atracurium eingeleitet werden. Die weitere Narkose wurde mit 70 Vol.-% Lachgas, Isofluran und Alfentanil nach klinischem Bedarf aufrechterhalten. 15 min nach Einleitung der Narkose war der Methämoglobinanteil plötzlich deutlich von 2,0% auf 3,4% bzw. von 4,1% auf 5,1% angestiegen. Um nachzuprüfen, ob die Ursache der offenbar durch die Narkose induzierten Zunahme der Methämoglobinämie eine Verdrängung des o-Toluidins aus der Eiweißbindung durch Thiopental ist, versetzten wir heparinisiertes Blut mit o-Toluidin und Thiopental. Dabei stellte sich heraus, daß Thiopental in vitro einen protektiven Effekt auf die o-Toluidin-induzierte Methämoglobinämie hat. Als Erklärungen für den Met-Hb-Anstieg kommen eine Blockade der mikrosomalen Hydroxylase durch Thiopental und ein dadurch verminderter Abbau von o-Toluidin und/oder eine durch Isofluran relativ vermehrte Leberdurchblutung und damit vermehrter Metabolismus des Prilocains in Frage. Um die Möglichkeit einer Zufallsbeobachtung auszuschließen, sind weitere Untersuchungen notwendig.
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