Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity.

Ether link cleavage (ELC) of T4 yielding diiodotyrosine (DIT) has recently been shown in vitro to be the major pathway of T4 metabolism in phagocytosing leukocytes. To evaluate this pathway in vivo and the possible clinical relevance of DIT measurements in diseases with increased leukocyte activity, radioimmunological studies on serum levels of DIT and other thyroid parameters were performed in 125 critically ill patients classified into 3 groups with bacterial infections according to the severity of infection and 1 group without infections. While the pattern of iodothyronine and TSH levels typical for severe nonthyroidal disorders, i.e. decreased total T3 and elevated rT3, normal or decreased total T4 and TSH, and normal free T4, was found in all four groups of intensive care patients studied, elevated serum DIT was observed only in those patients whose clinical course was complicated by severe bacterial infections. Serial measurements revealed a close temporal connection between the infection phase and increased DIT levels. Median values and 16th to 84th percentile ranges (in parentheses) of serum DIT (normal range, 0.02-0.55 nmol/L) were as follows: sepsis, 1.38 (0.32-5.14); severe nonsystemic infections such as peritonitis and abscesses, 3.84 (0.24-17.2); moderate infections such as pneumonia and tracheobronchitis, 0.44 (0.18-1.16); and critical illness without infections, 0.14 (0.08-0.30) nmol/L. These elevations of circulating DIT could neither be correlated with changes in renal function nor attributed to drug effects. The results of the present study do not allow any definitive conclusions to be made about the mechanisms underlying the phenomenon of increased serum DIT levels in infections. Apart from this open question, DIT appears to be a relatively specific serum parameter for the presence and course of severe bacterial inflammations. Its measurement could provide useful clinical information, particularly for monitoring the time course of deep-seated infections.

Acute endocrine failure after brain death?

After brain death, 32 potential organ donors were studied to determine serum and plasma concentrations of hypothalamic-pituitary hormones, thyroid hormones, and cortisol over a period of up to 80 hr. Diagnosis of brain death was established either on the basis of clinical criteria (n = 16) or by angiography (n = 16). While 78% of the organ donors developed diabetes insipidus, none of the circulating hormones of the anterior pituitary gland showed a progressive decline in concentration according to their plasma half-lives. With the exception of arginine vasopressin (AVP), no hormone concentration was found to be subnormal due to the onset of brain death. The subnormal free triiodothyronine (FT3) values in 62% of cases (median FT3 of 2.2 pmol/L within the first 24 hr) and the cortisol concentration of 6.9 micrograms/dl correlate with the frequency of similar findings in patients with severe head injuries. While the adrenocorticotropic hormone (ACTH) concentrations of 10-53 pg/ml remained constant during the study period, thyroid-stimulating hormone (TSH) and human growth hormone (hGH) concentrations showed a 12- and 35-fold increase from baseline values after 30-40 hr. These results suggest that, despite the now generally accepted criteria of brain death, there is still some residual function, and thus also perfusion of the hypothalamic-pituitary neuroendocrine system. This residual function appears to be sufficient to maintain hormonal plasma levels at least in the low reference range in most donors. Hormonal depletion in organ donors subsequent to brain death, as suggested repeatedly in the literature, could not be confirmed. The analysis of serum or plasma concentration patterns of a number of hormonal parameters following brain death does not support the rationale for a routine replacement therapy of total triiodothyronine (TT3) or cortisol to maintain endocrine homeostasis prior to organ harvest. However, dexamethasone therapy may be followed by suppression of the adrenal cortex of the organ donor. In these cases, cortisol substitution may be indicated.

Hemodynamic responses to noxious stimuli in brain-dead organ donors.

The case report presents evidence for the spinal origin of the marked hypertensive responses to noxious stimuli that may occur in organ donors who fulfill the commonly accepted criteria of brain death. Cardiovascular spinal reflex activity does not invalidate these criteria. For the first time, the catecholamine plasma concentrations have been determined during spinal pressor reflex activity. Circulating epinephrine increased more markedly than norepinephrine in both cases, rising to 4.7 and 44 times the baseline concentration respectively. The relation between plasma norepinephrine and epinephrine suggests involvement of the adrenal medulla in the reflex arc. The literature on spinal hemodynamic reflexes is reviewed.

Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 non-neutropenic patients. Paul-Ehrlich Society for Chemotherapy, Divisions of Mycology and Pneumonia Research.

OBJECTIVE: To determine the epidemiological and clinical significance of invasive fungal infections in non-neutropenic patients in intensive care who stay longer than 10 days on the intensive care unit (ICU). DESIGN: Prospective epidemiological multicenter study over a period of 11 months, based on strict clinical, bacteriological, serological and histological criteria. SETTING: Six surgical and two medical ICUs units in five university and two municipal hospitals. PATIENTS: 435 non-neutropenic patients from medical and surgical ICUs with an ICU stay of more than 10 days. MEASUREMENTS AND MAIN RESULTS: A new occurrence of invasive mycosis (3 sepsis/4 peritonitis/1 disseminated candidiasis), corresponding to the protocol conditions with onset after day 10 in the ICU, was detectable in 2.0% (95% confidence interval 0.85 to 3.8%) of the 409 patients who could be assessed. Candida species were identified as an infection-relevant pathogen in all cases. The most important risk factor for the development of an invasive mycosis was the onset of peritonitis by the day 11 in the ICU (odds ratio 11.3; p = 0.003). A fungal colonization was detected in 64% of patients (Candida species 56%, Aspergillus 4%, and other fungi). Six of 8 patients with an invasive mycosis died on the ICU; ICU mortality in patients with fungal colonization was 31% and in noncolonized patients 26%. Serological tests were not helpful clinically. The sensitivity was 88% for the Candida HAT (haemagglutination test) (threshold titer > 1:160), 100% for the Candida IFT (immunofluorescence test) (threshold titer > 1:80), and 50% for the Candida Antigen Test (Candtec Ramco, threshold titer > or = 1:8), and the specificity was 26, 6, and 73%, respectively. The specificity for the Aspergillus HAT (threshold titer > 1:10) was 29%. CONCLUSIONS: Invasive mycoses are rare in non-neutropenic ICU patients, even after a longer stay in the intensive care unit; fungal colonization, on the other hand, is frequently detectable. The mortality of invasive mycosis--even with systemic antimycotic therapy--was high; the mortality in patients with fungal colonization was not significantly increased compared to that in noncolonized patients. The serological test procedures, Candida HAT, Candida IFT, and the Candida Ramco Antigen Test, had a low specificity and were not helpful in diagnosing relevant invasive mycosis.

The necessity of selenium substitution in total parenteral nutrition and artificial alimentation.

For the trace element selenium, in contrast to zinc, iron, copper, chromium, manganese and iodine, there is still no clear official recommendation with regard to routine substitution in artificial nutrition. An overview of the manifestations of selenium deficiency in humans during the period 1979-1995 shows that nutritive deficiencies are exclusively TPN-induced or the result of severe malnutrition. The pathology of TPN-induced selenium deficiency and the analytic assessment of selenium status are described. Patients undergoing long-term parenteral nutrition or suffering from an increased loss of intestinal secretions have to be characterized as being especially at risk for clinical selenium deficiency. The relationship of the serum selenium kinetics in pediatric and adult patients to the depletion of body compartments during the course of short-term and prolonged TPN is discussed. Because of the importance of the selenoproteins, the regularly occurring depletion during selenium-free TPN and the borderline supply of selenium in Germany the routine substitution of selenium in TPN is strongly recommended. The pharmaceutical industry should be encouraged to develop a trace element solution that includes selenium, so that the nutritive requirement of patients on TPN can be satisfied. Adequate intravenous dosage recommendations are based on maintenance of glutathione peroxidase homeostasis. The routine supplementation dosage may not meet the selenium requirements of intensive care patients under conditions of increased metabolic demands on their anti-oxidative system.

[Importance and physiologic nutritional requirement of the selenium trace element within the scope of parenteral nutrition (TPN)]. / Bedeutung und ernährungsphysiologischer Bedarf des Spurenelementes Selen im Rahmen der parenteralen Ernährung (TPN).

BASIS: Selenium-responsive clinical manifestations of selenium deficiency and elucidation of the biochemical and molecular biological basis of the essentiality of selenium give evidence for the biological importance of the trace element in human nutrition. CONCLUSION: The dietary parenteral selenium requirement can be calculated on the basis of the maximal gene expression of the selenoprotein plasma glutathione peroxidase (plGPx). In total parenteral nutrition a daily requirement of 0.01 mumol/kg body weight for adults and 0.025 mumol/kg body weight for children can be seen as adequate and safe.

Multimodal protocol for awake craniotomy in language cortex tumour surgery.

BACKGROUND: Intra-operative neurophysiological language mapping has become an established procedure in patients operated on for tumours in the area of the language cortex. Awake cranial surgery has specific risks and patients are exposed to an increased physical and mental stress. The aim of the study was to establish an algorithm that enables tailoring the neurosurgical and anaesthetic techniques to the individual patient. METHOD: A total of 25 patients underwent awake craniotomy for intra-operative language mapping between 1999 and 2004. Following craniotomy under analgesia and sedation without rigid pin fixation of the head, cortical language mapping was performed in the fully co-operative patient. The results of functional magnetic resonance imaging and of cortical language mapping were incorporated into the 3D dataset for neuronavigation. Depending on the functional data and the individual operative risk tumour resection then proceeded either under conscious sedation with the option of subcortical language monitoring or under general anaesthesia. FINDINGS: After cortical language mapping patients are assigned to one of four groups: BACC (Berlin awake craniotomy criteria) I-IV. BACC I (9 patients): adequate functional data+operative risk not increased-->tumour resection in the awake patient; BACC II (4 patients): limited functional data+operative risk not increased-->tumour resection in the awake patient with the option of language monitoring as needed; BACC III (9 patients): adequate functional data+increased operative risk-->tumour resection under general anaesthesia using functional navigation; BACC IV (3 patients): limited functional data+increased operative risk-->tumour resection in the awake patient with the option of language monitoring as needed. We observed less adverse events in group BACC III. No permanent deterioration of language function occurred in this series. CONCLUSIONS: The multimodal protocol for awake craniotomy provides for tumour resection under general anaesthesia in selected patients using functional neuronavigation. Our experience with the algorithm suggests that it is a useful tool for preserving function in patients undergoing surgery of the language cortex while reducing the operative risk on an individual basis.

Measurement of plasma catecholamines by high-performance liquid chromatography with electrochemical detection in intensive care patients after dobutamine infusion.

A procedure for the determination of plasma catecholamine concentrations in critical care patients after dobutamine infusion is presented. A modified chromatographic system is required with an additional washing procedure to achieve maximum sensitivity and stable chromatographic conditions. The influence of storage time on the catecholamine concentrations of plasma samples is reported in detail. A time-dependent decrease in catecholamine concentrations of up to 12 and 39% was found within two and ten months, respectively.

Changes in intracranial pressure associated with extradural anaesthesia.

The intracranial pressure (ICP) response to the lumbar extradural injection of bupivacaine hydrochloride was measured in two patients on a total of 29 occasions. In the first patient, mean ICP increased from an average figure of 18.8 mm Hg to 39.5 mm Hg after the injection of 10 ml of solution. This increase was maintained for an average of 4.5 min. Both the magnitude and the duration of the increase were less when 5 ml was injected. The second patient had a normal baseline ICP, but the injection of bupivacaine 10 ml produced an increase from a mean of 9.3 mm Hg to 15.6 mm Hg. Injection of the same volumes of physiological saline in the second patient induced increases in ICP similar to those obtained with bupivacaine. There was a good correlation between baseline ICP and the increase produced by the extradural injection. It is concluded that extradural anaesthesia must be used with extreme caution in patients with reduced intracranial compliance, and should not be used at all in a patient with intracranial hypertension or a space-occupying lesion.

[Continuous arteriovenous hemofiltration in the newborn]. / Die kontinuierliche arteriovenöse Hämofiltration (CAVH) beim Neugeborenen.

Acute renal failure (ARF) in newborns and infants is a serious postoperative complication. Peritoneal dialysis is considered the treatment of choice, but is often impossible postoperatively. In adult patients or older children, continuous arteriovenous hemofiltration (CAVH) has been established for 10 years. In 1985, Ronco published case reports on four newborn infants treated with CAVH using a specially designed hemofilter. In between, a few more case reports have been published. We report a case of postoperative septic ARF in an 8-week-old girl with a body weight of 4000 g. We used the Minifilter (Amicon Corp.) connected to a femoral arterial Shaldon catheter and initially a central venous line, later a subclavian Shaldon catheter. Intermittent hemodialysis without ultrafiltration was performed as well. With ultrafiltration rates of 2 to 24 ml/h, mean 12.8 ml/h, we achieved an impressive loss of weight and the pulmonary function improved. The baby died on the 5th day of CAVH treatment of septic multiorgan failure. Even though the small patient did not survive, we demonstrated the feasibility of the method in newborns. CAVH is recommended for overhydrated babies with oligoanuric ARF, but it is not sufficient as a substitute for dialysis in these patients.

[Irreversible valproate-associated liver failure]. / Irreversibles valproatassoziiertes Leberversagen.

A very severely retarded infant with a Dandy-Walker malformation was treated with valproate since the age of 6 months on account of infantile spasms. Three weeks after start of therapy dexamethasone was applied additionally because valproate was ineffective. Seventy-six days after initiation of valproate therapy the infant died with the clinical signs of fulminant valproate-associated hepatotoxicity despite the discontinuation of valproate. In combination with a febrile otitis media the child had been periodically restless and lethargic during the last week prior to liver coma. Activity of liver enzymes remained within normal limits up to two days before coma occurred. Analysis of valproate metabolites by gas chromatography/mass spectrometry yielded unusually high concentrations of the di-unsaturated metabolite E,E-2,3'-dien-valproate before and during liver failure. The concentrations of the main metabolites E-2-en-valproate und 3-keto-valproate remained within the usual range found during valproate therapy at steady state. The oxydation products 4-en-valproate and E-2,4-dien-valproate which are formed by alternative pathways and are considered to be hepatotoxic were detected in very low concentrations only. The application of carnitine, of antioxidants thought to improve the capacity of the free radical scavenger system (selen, vitamin E), and of N-acetylcysteine which can detoxify reactive drug metabolites could not prevent the fatal outcome.

Patterns of endocrine secretion during sepsis.

In septic patients the clinical course of the disease is characterized by high DIT and rT3 serum concentrations as well as a low T3-syndrome. While rT3 is elevated in almost all critically ill patients, the increase in DIT is indicative of severe infection. Prolactin levels are regularly elevated in sepsis although to variable degrees. Catecholamines and vasopressin should be regarded as acute responders. The pattern of cortisol secretion is uncertain. In most situations the secretion appears to be elevated; the circadian rhythm is disturbed.

[Preservation of homeostasis following the onset of brain death]. / Zur Aufrechterhaltung der Homöostase nach Eintritt des Hirntodes.

One of the main problems faced by transplantation medicine is the lack of suitable donor organs. The success of organ transplantation depends on the quality of the organ to be transplanted. The initial function of the transplant depends on the quality of preparation. The aim of efforts after brain death is to maintain the morphological and functional integrity of the donor organ in situ. At our clinic, all potential organ donors undergo direct arterial pressure measurement and many receive a Swan-Ganz catheter. Catecholamine administration--varied on the basis of the hemodynamic parameters--is not associated with an impairment of organ function. Electrolyte determinations at 2-hour intervals and close laboratory controls are obligatory. These intensive-care measures are necessary because of the occurrence of severe metabolic and hemodynamic imbalances. A partly transient diabetes insipidus is the most frequent homeostatic disorder. In addition, severe electrolyte imbalances, disturbed glucose utilization and hypotension may be observed. Our investigations on the plasma concentration course of thyroid hormones, ACTH and cortisol after the onset of brain death suggest that the secretion of pituitary hormones is maintained until total necrosis of the pituitary gland occurs 30 to 40 hours later. The detection of circulating ADH up to 24 hours after the onset of brain death, despite the angiographically confirmed cessation of cerebral circulation, suggests that there may be a residual perfusion of hypothalamus and pituitary. The blood levels of epinephrine, norepinephrine and dopamine measured in brain-dead patients not receiving catecholamines were in part considerably above the reference level. Our data suggest that vigorous intensive care management increases the number and quality of organs suitable for transplantation and reduces to a minimum the incidence of premature organ losses.

[Toxic methemoglobinemia following the postoperative ingestion of 4,4-diaminodiphenylsulfone (DADPS)--on the differential diagnosis of cyanosis]. / Toxische Methämoglobinämie nach postoperativer Einnahme von 4,4-Diaminodiphenylsulfon (DADPS) - Zur Differentialdiagnose der Zyanose.

Blood gas analysis devices routinely used in clinical practice measure pH, pCO2 and pO2 directly, while all other values they specify are calculated on the basis of nomograms. In the presence of higher concentrations of biologically useless forms of haemoglobin, calculation of the haemoglobin saturation (% O2 Hb) leads to a clinically relevant false assessment of oxygen availability. A case is described in which toxic methemoglobinaemia occurred postoperatively after resumption of long-term medication with 150 mg 4,4-diaminodiphenylsulfone (DADPS). Increasing methaemoglobin values up to maximal 17.7% at a total haemoglobin of 11.3 g/dl correlated with the symptoms of cyanosis and respiratory distress. This symptom complex, which is not atypical postoperatively, could not be clarified by differential diagnosis with the aid of cardiac output measurements and arterial blood gas analyses. The cardiac index amounted to 4.1 l/m2 at a pulmonary capillary wedge pressure of 8 mmHg; the arterial partial oxygen pressure was between 16 and 19 kPa. Only the differential determination of oxihaemoglobin, CO-haemoglobin and methaemoglobin with an oximeter yielded evidence of severe arterial hypoxaemia and made therapy possible.

Transcranial Doppler ultrasonography as a screening technique for detection of a patent foramen ovale before surgery in the sitting position.

BACKGROUND: Venous air embolism has been reported to occur in 23-45% of patients undergoing neurosurgical procedures in the sitting position. If venous air embolism occurs, a patent foramen ovale (PFO) is a risk factor for paradoxical air embolism and its sequelae. Preoperative screening for a PFO is therefore recommended by some investigators. The reference standard for identifying a PFO is contrast-enhanced transesophageal echocardiography (c-TEE). Contrast-enhanced transcranial Doppler ultrasonography (c-TCD) and contrast-enhanced transthoracic echocardiography (c-TTE) are noninvasive alternative methods, but so far there are no studies as to their diagnostic validity in neurosurgical patients. METHODS: The sensitivity and specificity of c-TCD and c-TTE in detecting a PFO were determined in a prospective study using c-TEE as the reference standard. Preoperative c-TCD, c-TTE, and c-TEE studies were performed during the Valsalva maneuver after intravenous echo-contrast medium (D-Galactose, Echovist-300, Schering AG, Berlin, Germany) was administered in 92 consecutive candidates (47 men and 45 women; mean age, 51 yr; range, 25-72 yr) before neurosurgical procedures in the sitting position. RESULTS: A PFO was detected in 24 of the 92 patients (26.0%) using c-TEE. c-TCD correctly identified 22 patients, whereas c-TTE only correctly identified 10. This corresponds to a sensitivity of 0.92 for c-TCD and 0.42 for c-TTE. The negative predictive value was 0.97 for c-TCD compared with 0.83 for c-TTE. The prevalence of a PFO in patients with a posterior fossa lesion was 27%, and in the group with cervical disc herniation was 24% as detected by c-TEE. The incidence of intraoperative venous air embolism was 35% in cases of cervical foraminotomy and 75% in posterior fossa surgery as detected by c-TEE. CONCLUSIONS: c-TCD is a highly sensitive and highly specific method for detecting a PFO. Because c-TCD is noninvasive, it may be more suitable than c-TEE for routine preoperative screening for a PFO. C-TTE is not reliable in detecting a PFO.

The kinetics of metamizol and its metabolites in critical-care patients with acute renal dysfunction.

We have studied the clearance of monomethylaminoantipyrine (MMAAP), the pharmacologically active form of metamizol, in 46 patients in surgical intensive care with different degrees of renal dysfunction. In 23 patients without any renal impairment, mean clearance was 2.8 ml.min-1 x kg-1. Twenty-one patients with acute renal impairment had a significantly reduced clearance of MMAAP (0.83 ml.min-1 x kg-1). There was also reduced clearance in four patients with septic shock (1.0 ml.min-1 x kg-1). Kinetics of the metabolites of MMAAP (N-formylaminoantipyrine (FAAP), aminoantipyrine (AAP), and its secondary product N-acetylaminoantipyrine (AcAAP)) were calculated. FAAP and AcAAP showed delayed invasion, which can be explained by reduced hepatic metabolic activity. The product of N-demethylation, AAP, was not significantly altered. The delayed elimination of monomethylaminoantipyrine can be explained by reduced hepatic function in parallel with acute renal failure due to disturbed cardiovascular function caused by septic shock. This may also lead to disturbed hepatic macro- and microperfusion associated with altered oxygen supply and oxygen consumption.

Parenteral aluminum loading in critical care medicine. Part I: Aluminum content of infusion solutions and solutions for parenteral nutrition.

BACKGROUND: For patients with disturbed aluminum (Al) excretion, a high Al intake is not without risk. As main aluminum sources infusion solutions and solutions for parenteral nutrition have been identified. This study will give current survey of aluminum loading of the above-mentioned preparations. MATERIAL AND METHODS: The aluminum loading of 139 different infusion solutions and solutions for parenteral nutrition was determined. The solutions were from the clinical pharmacy of the Klinikum Steglitz of the Free University Berlin or were bought in a public pharmacy. The aluminum content was determined by means of two different, independent analytical methods: a) graphite furnace atomic absorption spectroscopy (GFAAS) and b) inductively coupled plasma atomic emission spectroscopy (ICP-AES). The agreement of the measured values was good except for five samples, where different values were found. Mistakes due to contamination were excluded on the basis of the results of measuring standard reference materials. RESULTS: Small-volume additives of TPN (total parenteral nutrition) formulations were highly contaminated with aluminum, e.g. Ca and phosphate solutions (29-12,000 micrograms/l), vitamin C solutions (700-1,200 micrograms/l) and trace element solutions (67-6,200 micrograms/l). Furthermore about 44% of the crystalline amino acid solutions and lipid emulsions had an aluminum content of 25 to 55 micrograms/l. Low aluminum levels were found in carbohydrate solutions, NaCl and KCl solutions and in distilled water (aqua ad injectabilia). CONCLUSIONS: Many of the solutions for parenteral nutritional support have an aluminum content which exceeds, in part considerably, the suggested threshold concentration of 25 micrograms/l (0.93 mumol/l), recommended by the American Society for Clinical Nutrition (ASCN) and the American Society for Parenteral and Enteral Nutrition (ASPEN). The pharmaceutical industry should be required to check the manufacturing process for avoidable sources of contamination, and threshold values for aluminum loading by intravenously applied pharmaceuticals should be laid down in the German and European pharmacopoeia. In cases where contaminations cannot be eliminated during the manufacturing process after careful checking, the aluminum content of the infusion solution should be declared for the user.