[Diagnostic image (386). A woman with pneumonia]. / Diagnose in beeld (386). Een vrouw met pneumonie.

A 54-year-old woman developed peritonitis and sepsis following cholecystectomy. She died of refractory septic shock with progressive multiple organ failure. Autopsy revealed invasive pulmonary aspergillosis.

Induction of insulin resistance by androgens and estrogens.

Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.

Increased plasma homocysteine after menopause.

Besides genetic defects in the enzymes involved in homocysteine metabolism and nutritional deficiencies in vitamin cofactors, sex steroid hormones may modulate plasma homocysteine levels. The post-menopausal state has been found to be associated with higher plasma homocysteine levels, but data are inconsistent and studies published so far did not adjust for age, which is an important confounding factor in studying the effect of menopause. In the present study total plasma homocysteine levels were measured in a meticulously selected population in which the contrast in estrogen status between pre- and postmenopausal women of the same age was maximized. The study comprised 93 premenopausal and 93 postmenopausal women of similar age (range 43-55 years). Women were selected from respondents to a mailed questionnaire on menopause, which was sent to all women aged 40-60 years in the Dutch town of Zoetermeer (n = 12675). Postmenopausal women who were at least three years after menopause or whose menses had stopped naturally before age 48 were age-matched with premenopausal women with regular menses and without menopausal complaints. Plasma homocysteine levels in the fasting state were related to menopausal status; the age-adjusted geometric mean was 10.7 micromol/l in premenopausal and 11.5 micromol/l in postmenopausal women (difference of 7%, 95% confidence interval 0.3-14%, P = 0.04). Additional adjustment for plasma creatinine, body mass index, smoking habit (yes, no) and alcohol intake did not influence this difference. The results of this population-based study indicate that plasma homocysteine is affected by menopause.

Central venous catheter use. Part 2: infectious complications.

Central venous catheters (CVCs) are used with increasing frequency in the intensive care unit and in general medical wards. Catheter infection, the most frequent complication of CVC use, is associated with increased morbidity, mortality, and duration of hospital stay. Risk factors in the development of catheter colonisation and bloodstream infection include patient factors (increased risk associated with malignancy, neutropenia, and shock) and treatment-related factors (increased risk associated with total parenteral nutrition, ICU admission for any reason, and endotracheal intubation). Other risk factors are prolonged catheter indwelling time, lack of asepsis during CVC insertion, and frequent manipulation of the catheter. The most important factor is catheter care after placement. Effects of CVC tunnelling on infection rates depend to a large extent on indwelling time and the quality of catheter care. Use of polyurethane dressings can increase the risk of colonisation compared to regular gauze dressing. Thrombus formation around the CVC tip increases the risk of infection; low-dose anticoagulants may decrease this risk. New developments such as CVC impregnation with antibiotics may reduce the risk of infection. Reducing catheter infection rates requires a multiple-strategy approach. Therefore, ICUs and other locations where CVCs are used should implement strict guidelines and protocols for catheter insertion, care, and maintenance.

Inter-observer variability in APACHE II scoring: effect of strict guidelines and training.

OBJECTIVE: To assess the effect of strict guidelines and a rigorous training program on variability in scoring the revised Acute Physiology and Chronic Health Evaluation (APACHE II). DESIGN AND SETTING: Prospective survey and intervention in the surgical ICU of a university teaching hospital. MEASUREMENTS: Seven experienced intensivists and nine residents determined APACHE II scores in one set of patients before and in another set 4 months after a rigorous training program, following strict guidelines for using the APACHE II. RESULTS: APACHE II scores were 14.3+/-4.4 before the training program (n=12) and 18.9+/-2.4 after (n=11). Interobserver agreement rates increased significantly from 59.7% to 76.5% and the interobserver reliability coefficient (weighted kappa) from 0.72 to 0.85 after our training program was implemented. The changes were significantly greater in experienced intensivists than in less experienced residents, indicating that more experienced physicians profited to a greater degree from our training program. CONCLUSION: Interobserver variability in APACHE II scoring decreases markedly when strict guidelines and a regular training program are implemented, particularly among more experienced physicians. However, in our study a degree of variability (10-15%) persisted even in experienced intensivists with similar training, experience, and background, suggesting that a degree of variability is inherent in APACHE II scoring.

Intra-observer variability in APACHE II scoring.

Although the APACHE II score is the most widely used scoring system in intensive care units worldwide, its reliability and variability have not been extensively studied. Differences in case-mix may complicate comparison and interpretation of results. We hypothesised that a degree of variability might be inherent to use of the APACHE II scoring system, and decided to assess intra-observer variability in APACHE II scoring as a potential indicator of inherent score variability. APACHE II scores were assessed twice from the charts of 11 patients by 14 physicians, with a time interval of 4 (range 3.5-4.5) months between the two assessments. Intra-observer was found to be approximately 15%. These findings are in agreement with previous observations regarding inter-observer variability in APACHE II scoring, and strongly suggest that there is an inherent score variability of about 15%.

Modulation of plasma endothelin levels by the menstrual cycle.

Blood pressure varies during the menstrual cycle, but the reason for this is unclear. Administration of (synthetic) sex hormones can influence the level of vasoactive substances such as endothelin (ET). However, it is not known whether short-term variations in sex hormone levels in physiological situations affect ET levels. We assessed the effects of the menstrual cycle on plasma ET-1 in 8 healthy premenopausal women not using oral contraceptives (OCs) and 8 premenopausal women using OCs. ET-1 levels were measured in all subjects on days 1 to 3 (menstrual phase), 9 to 12 (follicular phase), and 20 to 23 (luteal phase) of the menstrual cycle. ET-1 levels remained constant in OC users (2.4 +/- 0.4, 2.6 +/- 0.4, and 2.4 +/- 0.4 pg/mL on days 1 to 3, 9 to 12, and 20 to 23 of the pill cycle). In contrast, ET-1 levels in non-OC users decreased in all women during the follicular and luteal phase of the menstrual cycle compared with the menstrual (low-estrogenic) phase (3.6 +/- 0.5, 2.8 +/- 0.5, and 2.9 +/- 0.3 pg/mL for the menstrual, follicular, and luteal phase, respectively, P < .01 for menstrual vfollicular and P < .01 for menstrual v luteal). The differences between OC users and nonusers were significant in the menstrual phase of the cycle (P < .01). We conclude that ET levels fluctuate during the menstrual cycle. Previously reported effects of the menstrual cycle on blood pressure may be partly explained by the effects of sex hormones on the level of vasoactive mediators. This fluctuation is not present in OC users. Studies on hemodynamic parameters in premenopausal women should account for hormonal variations in the various phases of the menstrual cycle.

Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury.

OBJECT: Induced hypothermia in patients with severe head injury may prevent additional brain injury and improve outcome. However, this treatment is associated with severe side effects, including life-threatening cardiac tachyarrhythmias. The authors hypothesized that these arrhythmias might be caused by electrolyte disorders and therefore studied the effects of induced hypothermia on urine production and electrolyte levels in patients with severe head injury. METHODS: Urine production, urine electrolyte excretion, and plasma levels of Mg, phosphate, K, Ca, and Na were measured in 41 patients with severe head injury. Twenty-one patients (Group I, study group) were treated using induced hypothermia and pentobarbital administration, and 20 patients (Group 2, controls) were treated with pentobarbital administration alone. In Group 1, Mg levels decreased from 0.98+/-0.15 to 0.58+/-0.13 mmol/L (mean +/- standard deviation; p < 0.01), phosphate levels from 1.09+/-0.19 to 0.51+/-0.18 mmol/L (p < 0.01), Ca levels from 2.13+/-0.25 to 1.94+/-0.14 mmol/L (p < 0.01), and K levels from 4.2+/-0.59 to 3.6+/-0.7 mmol/L (p < 0.01) during the first 6 hours of cooling. Electrolyte levels in the control Group 2 remained unchanged. Electrolyte depletion in Group I occurred despite the fact that moderate and, in some cases, substantial doses of electrolyte supplementation were given to many patients, and supplementation doses were often increased during the cooling period. Average urine production increased during the cooling period, from 219+/-70 to 485+/-209 ml/hour. When the targeted core temperature of 32 micro C was reached, urine production returned to levels that approximated precooling levels (241+/-102 ml/hour). Electrolyte levels rose in response to high-dose supplementation. In the control group, urine production and electrolyte excretion remained unchanged throughout the study period. CONCLUSIONS: Induced hypothermia is associated with severe electrolyte depletion, which is at least partly due to increased urinary excretion through hypothermia-induced polyuria. This may be the mechanism through which induced hypothermia can lead to arrhythmias. When using this promising new treatment in patients with severe head injury, stroke, or postanoxic coma following cardiopulmonary resuscitation, prophylactic electrolyte supplementation should be considered and electrolyte levels should be monitored frequently.

Agenesis of the corpus callosum associated with paroxysmal hypothermia: Shapiro's syndrome.

Spontaneous recurrent hypothermia and hyperhidrosis associated with agenesis of the corpus callosum was first described by Shapiro and Plum in 1967. Since then, several cases with similar symptoms (now known as Shapiro's syndrome or spontaneous periodic hypothermia) have been described. We report another case of this syndrome in a 21-year-old-man, and discuss possible pathogenetic mechanisms and therapeutic approaches.

Acute renal failure and rhabdomyolysis.

The clinical syndrome of rhabdomyolysis is caused by injury of skeletal muscles, leading to the release of various intracellular muscle constituents. Rhabdomyolysis occurs frequently but is usually asymptomatic (i.e., lab abnormalities only). However, in more serious cases, severe electrolyte disorders and acute renal failure may occur, leading to life-threatening situations. Rhabdomyolysis can develop in any circumstances where energy demands in muscles exceed the available energy supplies; it accounts for between 2 and 5% of all cases of acute renal failure in the ICU. Frequent causes of severe rhabdomyolysis include crush injuries, prolonged immobilization, seizures, severe infections and drug toxicity. Factors contributing to the development of more severe clinical symptoms include hypovolemia, hyperthermia, electrolyte disorders and the presence of pre-existing (congenital) muscle disorders. The diagnosis is established by elevation of serum muscle enzymes and muscle constituents such as creatinine phosphokinase and myoglobin. Preventive measures include maintenance of normal or high intravascular volume and administration of diuretics (loop diuretics rather than mannitol) once hypervolemia/euvolemia have been achieved. Some evidence suggests that early initiation of renal replacement therapy can help improve outcome. Administration of bicarbonate to induce urinary alkalosis can be considered, but it has not been proven to be effective.

Hypothermia and neurological outcome after cardiac arrest: state of the art.

Multi-centred studies in patients who remain comatose after cardiac arrest and also in newborn babies with perinatal asphyxia have clearly demonstrated that mild hypothermia (32-34 degrees C) can improve neurological outcome after post-anoxic injury. This represents a highly promising development in the field of neurocritical care. This review discusses the place of mild therapeutic hypothermia in the overall therapeutic strategy for cardiac arrest patients. Cooling should not be viewed in isolation but in the context of a 'treatment bundle,' which together can significantly improve outcome after cardiac arrest. Favourable outcomes of 50-60% are now routinely achieved in many centres in patients with witnessed arrest and an initial rhythm of ventricular fibrillation or ventricular tachycardia. These results have been achieved by combining a number of therapeutic strategies, including early and effective resuscitation with greater emphasis on continuing chest compressions throughout various procedures (including resumption of compressions immediately after defibrillation even if rhythm has been restored) as well as prevention of hypoxia and hypotension in all stages following restoration of spontaneous circulation. Regarding the use of hypothermia, early induction and proper management of side-effects are the key elements of successful implementation. Treatment should include the rapid infusion of 1500-3000 mL of cold fluids to induce hypothermia and prevent hypovolaemia and hypotension. Educational activities to increase awareness and acceptance of new therapeutic options and European Resuscitation Council guidelines are urgently required.

Continuous vs. intermittent cefotaxime administration in patients with chronic obstructive pulmonary disease and respiratory tract infections: pharmacokinetics/pharmacodynamics, bacterial susceptibility and clinical efficacy.

AIM: To compare the pharmacokinetics/pharmacodynamics, antibiotic resistance and clinical efficacy of continuous (CA) vs. intermittent administration (IA) of cefotaxime in patients with obstructive pulmonary disease and respiratory infections. METHODS: A randomized controlled prospective nonblinded study was performed in 93 consecutive hospitalized patients requiring antibiotics for acute exacerbations of chronic obstructive pulmonary disease. Forty-seven patients received 2 g of cefotaxime intravenously over 24 h plus a loading dose of 1 g, and 46 patients were given the drug intermittently (1 g three times daily). RESULTS: Similar pathogens were identified in both groups, being mostly Haemophilus influenzae (51%), Streptococcus pneumoniae (21%) and Moraxella catharralis (18%). Mean minimal inhibitory concentration (MIC) values were also similar before and after treatment in both groups. Clinical cure was achieved in 37/40 (93%) (CA) vs. 40/43 (93%) (IA) of patients (P = 0.93). In microbiologically evaluable patients, criteria such as 70% of treatment time with antibiotic concentrations > or = MIC (CA 100%vs. IA 60% of patients) and/or > or = 5 x MIC (CA 100%vs. IA 55% of patients) were significantly better following continuous administration (P < 0.01). Samples with suboptimal antibiotic concentrations were found in 0% of CA vs. 65% of IA patients (P < 0.01). CONCLUSIONS: Although clinical cure rates were comparable, continuous cefotaxime administration led to significantly greater proportions of concentrations > MIC and > 5 x MIC compared with intermittent dosing. Continuous administration of cefotaxime at a lower dose [2 g (CA) vs. 3 g (CI)] is equally effective pharmacodynamically and microbiologically, may be more cost-effective and offers at least the same clinical efficacy. Based on these observations, we recommend continuous administration of cefotaxime as the preferred mode of administration.

[Controlled mild-to-moderate hypothermia in the intensive care unit]. / Kontrollierte milde und moderate Hypothermie.

Controlled hypothermia is used as a therapeutic intervention to provide neuroprotection and (more recently) cardioprotection. The growing insight into the underlying pathophysiology of apoptosis and destructive processes at the cellular level, and the mechanisms underlying the protective effects of hypothermia, have led to improved application and to a widening of the range of potential indications. In many centres hypothermia has now become part of the standard therapy for post-anoxic coma in certain patients, but for other indications its use still remains controversial. The negative findings of some studies may be partly explained by inadequate protocols for the application of hypothermia and insufficient attention to the prevention of potential side effects. This review deals with some of the concepts underlying hypothermia-associated neuroprotection and cardioprotection, and discusses some potential clinical indications as well as reasons why some clinical trials may have produced conflicting results. Practical aspects such as methods to induce hypothermia, as well as the side effects of cooling are also discussed.

Reliability of PRISM and PIM scores in paediatric intensive care.

AIMS: To assess the reliability of mortality risk assessment using the Paediatric Risk of Mortality (PRISM) score and the Paediatric Index of Mortality (PIM) in daily practice. METHODS: Twenty seven physicians from eight tertiary paediatric intensive care units (PICUs) were asked to assess the severity of illness of 10 representative patients using the PRISM and PIM scores. Physicians were divided into three levels of experience: intensivists (>3 years PICU experience, n = 12), PICU fellows (6-30 months of PICU experience, n = 6), and residents (<6 months PICU experience, n = 9). This represents all large PICUs and about half of the paediatric intensivists and PICU fellows working in the Netherlands. RESULTS: Individual scores and predicted mortality risks for each patient varied widely. For PRISM scores the average intraclass correlation (ICC) was 0.51 (range 0.32-0.78), and the average kappa score 0.6 (range 0.28-0.87). For PIM scores the average ICC was 0.18 (range 0.08-0.46) and the average kappa score 0.53 (range 0.32-0.88). This variability occurred in both experienced and inexperienced physicians. The percentage of exact agreement ranged from 30% to 82% for PRISM scores and from 28 to 84% for PIM scores. CONCLUSION: In daily practice severity of illness scoring using the PRISM and PIM risk adjustment systems is associated with wide variability. These differences could not be explained by the physician's level of experience. Reliable assessment of PRISM and PIM scores requires rigorous specific training and strict adherence to guidelines. Consequently, assessment should probably be performed by a limited number of well trained professionals.