S. Zielmann

Effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure and gram-negative sepsis

Objective: The evaluation of incidences and relating factors of severe persisting critical illness polyneuropathy (CIP) in survivors of multiple organ failure (MOF). Design: Prospective study with an entry period of 24 months. Electrophysiological studies for the diagnosis of CIP were performed 1 or 2 days before the patients were discharged from the intensive care unit (ICU). Factors which might have been related to the development of CIP were identified by a retrospective chart analysis.Setting: The interdisciplinary ICU of a university hospital.Patients: Thirty-three patients who survived MOF. Sixteen of these critically ill patients developed severe sepsis due to nosocomial infections with gram-negative bacteria.Results: In seven survivors of MOF and sepsis typical electrophysiological features of CIP, like spontaneous fibrillations and low compound muscle action potentials, were detectable at the time of discharge from the ICU. Seventeen patients with MOF following multiple trauma who developed no sepsis, and nine survivors of MOF with sepsis showed no signs of persisting CIP at the end of their ICU stay. Chart analysis revealed that eight survivors of MOF with sepsis and without the development of CIP had been treated with intravenous immunoglobulin (IVIG) with a dosage of 0.3 g/kg per day for 3 days immediately (within 24 h) after the diagnosis of sepsis. Four out of seven patients with MOF and sepsis who developed CIP were transferred to our ICU after the onset of sepsis and had not received IVIG treatment. The IVIG treatment in three patients was delayed for more than 24 h after the diagnosis of sepsis and was then omitted. Obviously not related to the development of CIP were aminoglycoside antibiotics, steroids, nutritional disturbances and episodes of hypotension or hypoxia. Neuromuscular blocking agents were not used during intensive care treatment.Conclusions: A high incidence of severe CIP persisting until the day of discharge from the ICU was related to gram-negative sepsis but not to MOF alone. Retrospective chart analysis suggested that early application of IVIG may prevent or mitigate this severe complication. However, these results have to be confirmed in a prospective, placebo-controlled study.

High-dose intravenous magnesium sulfate in the management of life-threatening status asthmaticus

In severe status asthmaticus basic medical treatment often fails to improve the patients condition. Mechanical ventilation in this situation is associated with a high incidence of serious complications. After the bronchodilating effect of moderate-dose magnesium sulfate in asthmatic patients had been demonstrated in previous studies we treated five mechanically ventilated patients with refractory status asthmaticus successfully with high dosages of MgSO4 IV (10–20 g within 1 h depending on the bronchodilating effect). MgSO4 resulted in a significant decrease of peak airway pressure (43.0±6.8 to 32.0±8.0 cmH2O) and inspiratory flow resistance (22.7±7.0 to 11.9±6.0 cmH2O·l−1·s−1) within 1 h. The resulting serum magnesium levels after one hour were up to threefold of the normal serum levels. Although a main-tainance dose of 0.4 g/h had been administered continuously during the following 24 h serum magnesium decreased towards normal values within this time. The only relevant side-effect was a mild to moderate arterial hypotension in two of the five patients during the high dose administration period of MgSO4 which responded readily to dopamine treatment.

Effects of α‐adrenoceptor antagonists on clonidine‐induced inhibition of insulin secretion by isolated pancreatic islets

1 The effects of clonidine, yohimbine, corynanthine and prazosin on glucose‐induced insulin secretion by incubated or perifused mouse pancreatic islets were investigated. 2 Clonidine (0.1 μm) inhibited glucose‐induced insulin secretion alone and in the presence of yohimbine (0.1 μm), corynanthine (10 μm) or prazosin (1 μm). 3 In higher concentrations, yohimbine (1–10 μm) antagonized the inhibitory effect of clonidine (0.1 μm) upon glucose‐induced insulin secretion by incubated islets and by perifused islets. 4 The results support the view that adrenergic inhibition of insulin secretion is mediated by α2‐adrenoceptors on pancreatic β‐cells.

A RATIONAL BASIS FOR THE MEASUREMENT OF FREE PHENYTOIN CONCENTRATION IN CRITICALLY ILL TRAUMA PATIENTS

Phenytoin binding to serum proteins and factors influencing protein binding were investigated in 38 critically ill trauma patients. In 24% of these patients, the free fraction of phenytoin was ≤10%, whereas in 76%, the free phenytoin fraction was increased >10%—up to 24%. Nonantiepileptic co-medication, sex, or age had no influence on phenytoin binding in any of the 38 patients. Elevated free phenytoin fraction was found in those with hypoalbuminemia and hepatic and renal impairments. In these patients, the free phenytoin fraction should be measured routinely.

S-(+)-Ketamin und Kreislauf

ZusammenfassungDas Razemat des Ketamin kommt derzeit sowohl bei der Durchführung von Narkosen, im Rahmen einer Langzeitanalgosedierung auf der Intensivstation wie auch in der Notfallmedizin zum Einsatz. Neuere Untersuchungen zeigten eine etwa doppelt so große analgetische Potenz des rechtsdrehenden Isomers im Vergleich zum Ketamin-Razemat. Des weiteren ist aus tierexperimentellen Studien eine vergleichbare dosisabhängige Toxizität beider Substanzen bekannt. Demzufolge bestand berechtigte Hoffnung, daß durch Halbierung der erforderlichen Substanzmenge bei Verwendung von S-(+)-Ketamin eine entsprechende Reduzierung der bekannten unerwünschten Wirkungen möglich ist. In randomisierten, doppelblinden Studien an gesunden Probanden zeigten sich vergleichbare Anstiege von Herzfrequenz und arteriellem Blutdruck nach 2 mg/kg KG Ketamin-Razemat bzw. 1 mg/kg KG S-(+)-Ketamin. Auch die Zunahme der Katecholaminkonzentrationen im Plasma war vergleichbar. Diese Effekte wurden durch eine Prämedikation mit Midazolam stark reduziert. Auch bei niedriger Dosierung von 0,5 mg/kg KG S-(+)-Ketamin bzw. 1 mg/kg KG Ketamin-Razemat intramuskulär kam es bei gesunden Probanden zu vergleichbaren Anstiegen von Herzfrequenz und arteriellem Blutdruck. Gleichermaßen zeigten Untersuchungen an älteren Patienten, die sich einem größeren orthopädischem Eingriff unterziehen mußten, gleiche sympathomimetische Kreislaufeffekte nach 1 mg/kg KG S-(+)- Ketamin oder 2 mg/kg KG Ketamin-Razemat. Die initialen Blutdruckanstiege führten bei drei Patienten der Razematgruppe zum Abbruch der Untersuchung. In beiden Gruppen kam es zu einem signifikanten und vergleichbaren Anstieg der Plasma-Katecholamine. Ähnliche Untersuchungen an älteren Patienten, die sich einem größeren orthopädischen Eingriff unterziehen mußten, zeigten im Vergleich einer TIVA mit Alfentanil bzw. S-(+)-Ketamin positive Effekte des Ketamin durch stabile intraoperative Kreislaufverhältnisse. Dagegen waren die Ergebnisse einer eigenen Untersuchung zu den Kreislaufwirkungen von S-(+)-Ketamin bzw. Ketamin-Razemat bei Patienten, die sich einer aortokoronaren Bypass-Operation unterzogen, von den Folgen der sympathikotonen Stimulation geprägt. Auch nach starker Sedierung mit Midazolam traten bei jeweils drei von sieben Patienten beider Gruppen erhebliche Anstiege des arteriellen Blutdrucks und der Herzfrequenz auf. In einem Fall der S-(+)-Ketamin-Gruppe mußte die Untersuchung abgebrochen werden. Insgesamt sprechen alle vorliegenden Untersuchungsergebnisse dafür, daß die sympathikotonen Kreislaufeffekte des S-(+)-Ketamin auch bei halber Dosierung im Vergleich zum Ketamin-Razemat nicht signifikant reduziert werden.AbstractThe S-(+) isomer of ketamine has about twice the analgesic potency of the clinically used racemic mixture. Therefore, the known side effects may be reduced when one-half of the usual dose is administered. Several prospective, randomised, and double-blinded studies have been performed to assess whether the S-(+) isomer of ketamine is superior to the racemic mixture with respect to circulatory side effects.Studies in young, healthy volunteers showed that heart rate (HR) and arterial blood pressure (ABP) rise significantly after injection of 2 mg/kg ketamine racemate and 1 mg/kg S-(+) isomer without any significant difference between groups. In the study of Doenicke et al. plasma levels of adrenaline (A) were higher in the racemate group, whereas no difference was found in elevated plasma levels of noradrenaline (NA). Premedication with midazolam blunted major haemodynamic changes. The investigation of Adams et al. confirmed that HR and ABP rise significantly after injection of 2 mg/kg ketamine racemate and 1 mg/kg S-(+) isomer without any significant difference between groups. In this study, no differences were found between groups concerning elevated plasma levels of A and NA. A further study in healthy volunteers also showed comparable haemodynamic changes following i.m. injection of 1.0 mg/kg ketamine racemate or 0.5 mg/kg S-(+) isomer without any significant difference between groups.In a previous clinical study including 40 elderly patients undergoing elective orthopaedic surgery, total intravenous anaesthesia (TIVA) was performed with S-(+)-ketamine or ketamine racemate as an analgesic compound. For induction of TIVA, patients received 0.1 mg/kg midazolam and 1 mg/kg S-(+)-ketamine or 2 mg/kg racemic ketamine, respectively. Throughout surgery, a continuous infusion of 2 mg/kg per hour S-(+)-ketamine or 4 mg/kg racemic ketamine was administered. Three patients in the racemate group showed severe arterial hypertension after induction of anaesthesia and were withdrawn from the study. In both groups plasma A and NA levels as well as HR and ABP increased significantly. In our own randomised, double-blinded study, haemodynamic effects of 2 mg/kg S-(+)-ketamine and 4 mg/kg ketamine racemate, respectively, were investigated in 14 patients undergoing elective aorto-coronary bypass surgery. In both groups HR and ABP significantly increased in 3 patients, each although all patients were deeply sedated with midazolam. One patient in the S-(+)-ketamine group showed severe arterial hypertension and tachycardia after induction of anaesthesia and was withdrawn from the study.With respect to haemodynamic changes, the pharmacodynamic effects of ketamine racemate and S-(+)-ketamine are comparable. Therefore, it can be concluded that neither ketamine nor S-(+)-ketamine should be used in patients who suffer, e.g., from arterial hypertension and coronary artery disease.

The dihydropyridine derivative, Bay K 8644, enhances insulin secretion by isolated pancreatic islets

SummaryThe effects of the dihydropyridine derivative Bay K 8644 upon insulin secretion by perifused isolated mouse pancreatic islets were examined. At a non-stimulatory glucose concentration (5 mmol/l) Bay K 8644 (1 μmol/l) did not stimulate insulin release. However, the same drug concentration enhanced the insulin secretory responses to an intermediate (15 mmol/l) or high (30 mmol/l) glucose concentration by 80 or 90%, respectively. Bay K 8644 was half maximally effective at 0.1 μmol/l and maximally effective at 1 μmol/l. The results are compatible with the view that voltage-dependent calcium channels are essential for stimulus-secretion coupling in pancreatic B-cells.

Effects of isoprenaline and glucagon on insulin secretion from pancreatic islets.

SummaryThe effects of isoprenaline and glucagon on insulin secretion from pancreatic islets were investigated. In the presence of high concentrations of isoprenaline (10–50 μmol/l), glucose-induced (20 mmol/l) insulin secretion from isolated perifused mouse islets was inhibited. This inhibition was apparently mediated by α2-adrenoceptors, as it was antagonized by rauwolscine. At low concentrations isoprenaline (0.1 or 1 μmol/l) did not affect glucose-induced (2.5; 10 or 20 mmol/l) insulin secretion from perifused mouse or rat islets, even if α2-adrenoceptors were blocked by rauwolscine. A stimulatory effect of isoprenaline on insulin secretion was also not observed in the perfused rat pancreas. However, when incubated mouse islets were exposed to glucose (10 mmol/l), insulin secretion was further enhanced by isoprenaline (0.5 μmol/l). To elucidate the underlying mechanism, the effects of glucagon on insulin secretion were investigated, because glucagon is released from the pancreatic A-cells during stimulation with isoprenaline and is accumulated in the islets and the surrounding medium during incubations of pancreatic islets. Indeed, glucagon stimulated insulin secretion from perifused mouse islets in the presence of high glucose (10 or 15 mmol/l) concentrations but not of low glucose (5 mmol/l) concentrations. Thus it is concluded that direct β-adrenergic stimulation of pancreatic B-cells does not occur in mouse or rat pancreatic islets. Augmentation of glucose-induced insulin secretion by isoprenaline observed in incubation systems can be explained as a result of stimulation by glucagon, which is released from pancreatic A-cells by isoprenaline.

Die Bestimmung von Gesamteiweiß eignet sich nicht zur Diagnose der therapiebedürftigen Hypoalbuminämie bei Intensivpatienten

ZusammenfassungIn der klinischen Routine wird die Substitution von Humanalbumin häufig von der Gesamteiweißkonzentration abhängig gemacht, obwohl ein konstantes Verhältnis beider Variablen nicht immer zu erwarten ist. In der vorliegenden Untersuchung wurde die Sensitivität und Spezifität der Gesamteiweißbestimmung im Hinblick auf einen therapiebedürftigen Albuminmangel bei Intensivpatienten untersucht. Als Ergebnis zeigte sich, daß die Bestimmung der Gesamteiweißkonzentration mit erheblichen Fehleinschätzungen der Albuminkonzentration verbunden ist. Bei einer Interventionsschwelle von 5,00 g/dl Gesamteiweiß betrug die Sensitivität 0,64 und die Spezifität 0,86. Dagegen betrug bei einer Gesamteiweißkonzentration von 4,00 g/dl die Sensitivität nur noch 0,25, die Spezifität jedoch annähernd 1. Abhängig von der variablen Interventionsschwelle bezüglich der Gesamteiweißkonzentration wird einerseits ein relevanter Albuminbedarf häufig nicht erkannt. Andererseits kann in einigen Fällen eine unnötige Substitution erfolgen. Daher ist der Gesmteiweißtest zur Indikationsstellung der Albuminsubstitution nicht geeignet. Die direkte Bestimmung der Albuminkonzentration ist kostengünstig und routinemäßig durchführbar und sollte im Sinne einer rationalen Diagnostik und Therapie den Gesamteiweißtest ersetzen.AbstractIn clinical practice, the administration of supplementary albumin often depends on the measured plasma concentration of total protein (TPC). A TPC of less than 5 g/dl is generally accepted as an indication for albumin therapy, assuming an albumin concentration of less than 2.5 g/dl. However, a physiological relation between TPC and albumin cannot be expected in critically ill patients, and thus, measurement of TPC may be misleading as an indicator for the use of albumin. Therefore, we investigated the sensitivity and specificity of TPC testing for diagnosing hypoalbuminaemia requiring treatment. Methods. In this prospective study, 210 consecutive patients were included. Protein electrophoresis was performed three times a week; the second electrophoresis was selected for evaluation. Applied statistical analysis revealed the number of positive total protein tests indicating hypalbuminaemia requiring treatment (sensitivity) and the number of negative with tolerably reduced albumin concentrations (specificity). Results. Of the investigated patients, 27.6% had normal TPCs between 6.2 and 8.0 g/dl. In 81.9% of cases an albumin concentration below 3.5 g/dl was found, while 43 patients had a concentration below 2.5 g/dl. The sensitivity and specificity of TPC measurement for the diagnosis of clinically relevant hypoalbuminaemia (albumin concentration <2.5 g/dl) was calculated at different cutoff points for total protein. With a TPC of 6.0 g/dl, the sensitivity was 0.96 and the specificity 0.44. With a cutoff point of 5.0 g/dl, the sensitivity was reduced to 0.65 and specificity increased to 0.86. Finally, with a TPC of 4.0 g/dl sensitivity was 0.25 and specificity almost 1. Conclusions. Depending on the cutoff point for TPC, a relevant albumin requirement would frequently not be detected. In other cases, a need for albumin would be assumed from a reduced TPC even though the albumin concentration still exceeded 2.5 g/dl. Therefore, determination of TPC is not a suitable indicator of the need for albumin replacement. As a result, we suggest routine determination of albumin concentrations instead of TPC.

High-dose intravenous magnesium sulfate in the management of life-threatening status asthmaticus — authors' reply

Sir: The report by Sydow et al. [1] draws attention to the possible use of intravenous magnesium sulfate in the management of status asthmaticus. In 1991, we published our own experience of magnesium in the treatment of the same condition [2]. We used magnesium chloride (MgC12), which is less concentrated than magnesium sulfate (MgSO4) prepared in the usual manner. We observed that MgC12 administered as a rapid infusion in 2 patients resulted in a decrease in peak airway pressure, auto PEEP, and flow resistance. In 1 of the 2 cases, improvement lasted only a short while, and exacerbation of bronchospasm was successfully controlled by halothane anesthesia. After 1 h serum magnesium concentrations reached 1.80-1.87 mmol/1. These concentrations are slightly lower than those published by the authors; however, the concentration infused was considerably smaller (only 4g as opposed to 10-20g) . We have consequently been led to believe that the regulation of serum magnesium concentrations gives rise to rapid urinary loss of magnesium. Furthermore, serum magnesium concentrations over 2.5 mmol/1 may result in temporary non-specific depressions of CNS activity [3], which may prove useful in the management of bronchospasm despite blocking voltage-sensitive calcium channels. As regards myocardial infarction, magnesium infusion is widely used at concentrations much lower than those in this study [4]. These concentrations are specifically chosen so as to avoid respiratory depression and cardiac toxicity. In conclusion, we think the concentration used by the authors might have been too high, and that a similarly satisfactory result could have been obtained with low-dose magnesium.

Escherichia coli sepsis in Fournier's gangrene

Zusammenfassung. Die Fourniersche Gangrän manifestiert sich meist bei Männern mittleren bis höheren Lebensalters als nekrotisierende Fasciitis des äußeren Genitales. Kennzeichnend sind eine typische Anamnese mit progredienter, schmerzhafter Hodenschwellung und Fieber, ein oft explosionsartiger Beginn, der kaum verwechselbare makroskopische Aspekt und die hohe Mortalität infolge septischer Komplikationen. Der unter Umständen dramatische Verlauf der Erkrankung erfordert ein invasives chirurgisches und intensivmedizinisches Vorgehen. Die Entscheidung hierzu setzt die rasche Diagnose des seltenen Krankheitsbilds voraus. Wir berichten über einen jungen Patienten mit Fournierscher Gangrän, der wenige Stunden nach Aufnahme ins Krankenhaus an einem foudroyant verlaufenden septischen Schock verstarb.Abstract. Fourniers gangrene is a necrotising soft-tissue infection of the scrotum and perineal region caused by gram-negative and gram-positive Enterobacteriaceae. The disease is characterised by its unique appearance, its speed of onset, and its high mortality. Case report. A 26-year-old male presented to the emergency room complaining of a painful, tremendously swollen scrotum and penis (Fig. 1) that had developed within the past 24 h. Later, slurred speech, pallor, and hypotension were recognised, leading to the patients admission to the intensive care unit. Suspecting a severe internal haemorrhage, vigorous volume therapy was started using crystalloids and colloids until blood and fresh frozen plasma were available. One hour later, septic shock was presumed and therapy augmented by IV antibiotics, tracheal intubation, and mechanical ventilation. Despite all efforts, the patients condition deteriorated rapidly and he died a few hours later due to multiple organ failure in septic shock. Postmortem, a perforated external hemorrhoidal node was found to be the primary focus of sepsis. Microbiologic cultures revealed Escherichia coli in blood and tissue samples. Discussion. Fourniers gangrene is a rare disease; nevertheless, its clinical picture has to be recognised immediately in order to provide appropriate treatment in time. It occurs predominantly in males after minor trauma, colorectal or urological disease, and perineal or abdominal surgery. Fourniers gangrene usually begins with itching and pain in the scrotal region followed by swelling and dark-blueish discolouration of the scrotum and penis, occasionally including the lower abdominal wall. Fever and chills are usually present. The illness progresses to severe prostration and septic shock with a mortality of 20% – 50%. Tissue cultures mostly reveal E. coli, gram-positive enterococci, Pseudomonas, Proteus, and various anaerobes. The treatment should include immediate radical surgical debridement, IV administration of broad-spectrum antibiotics, and cardiopulmonary support. Conclusion. The dramatic course of Fourniers gangrene requires early recognition, extensive surgical debridement, as well as intensive care treatment in order to prevent irreversible septic shock.